Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][Si:2]([CH3:14])([CH3:13])[CH2:3][CH2:4][O:5][CH2:6][N:7]1[CH:11]=[C:10]([OH:12])[CH:9]=[N:8]1.[C:15]([O-])([O-])=O.[Cs+].[Cs+].CI>O1CCCC1>[CH3:15][O:12][C:10]1[CH:9]=[N:8][N:7]([CH2:6][O:5][CH2:4][CH2:3][Si:2]([CH3:14])([CH3:13])[CH3:1])[CH:11]=1
Reactant: O=C([O-])[O-]
Reactant: C[Si](C)(C)CCOCn1cc(O)cn1
Agent: [Cs+]
Solvent: C1CCOC1
Solvent: CI
Product: COc1cnn(COCC[Si](C)(C)C)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 92 %

Procedure:
To a solution of 1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-ol (compound 280.2, 2.14 g, 10.0 mmol) in tetrahydrofuran (50 mL) was added Cs2CO3 (6.5 g, 20.0 mmol) in portions. To this was added CH3I (1.25 mL, 20.0 mmol) dropwise. The reaction mixture was stirred for 3 h at room temperature, then concentrated under reduced pressure. The resulting residue was dissolved in 100 mL of EtOAc. The solids were filtered off and the filtrate was concentrated under reduced pressure. This resulted in 2.1 g (92%) of the title compound as a colorless oil.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.Cl.[Br:14][C:15]1[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=1.CN([CH:24]=[O:25])C>C1COCC1>[Br:14][C:15]1[C:20]([CH:24]=[O:25])=[CH:19][N:18]=[CH:17][CH:16]=1
Reactant: CN(C)C=O
Reactant: Brc1ccncc1
Agent: Cl
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: O=Cc1cnccc1Br
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 63.8 %

Procedure:
To a stirred solution of diisopropylamine (9.02 mL, 63.3 mmol) in THF (75 mL) at −78° C. was added n-butyllithium (1.6 M in hexane) (30 mL, 76 mmol) dropwise under nitrogen atmosphere. After complete addition the solution was stirred for 30 min at −78° C. 4-Bromopyridine HCl (5 g, 31.6 mmol) was added portionwise and the resultant solution stirred at −78° C. for 1 h. DMF (2.94 mL, 38.0 mmol) was then added dropwise at −78° C. to the solution. The reaction mixture was warmed to room temperature slowly and stirred for 12 h. The reaction mixture was quenched with 3 N HCl and stirred for 2 h. The solution was neutralized with saturated sodium bicarbonate solution, extracted with EtOAc (75 mL), dried over sodium sulfate and concentrated under reduced pressure to give 4-bromonicotinaldehyde (3.75 g, 20.16 mmol, 64% yield). The crude product was used without purification in the next step. 1H NMR (400 MHz, CDCl3) δ 10.39 (s, 1H), 9.00 (s, 1H), 8.56 (d, J=5.2 Hz, 1H), 7.62 (d, J=5.2 Hz, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C@@H:9]2[C@@H:13]([OH:14])[CH2:12][N:11]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:10]2)=[C:4]([N+:22]([O-:24])=[O:23])[CH:3]=1.[Cl:25][CH2:26][C:27](O)=[O:28].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>O1CCCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C@@H:9]2[C@H:13]([O:14][C:27](=[O:28])[CH2:26][Cl:25])[CH2:12][N:11]([C:15]([O:17][C:18]([CH3:20])([CH3:21])[CH3:19])=[O:16])[CH2:10]2)=[C:4]([N+:22]([O-:24])=[O:23])[CH:3]=1
Reactant: O=C(O)CCl
Reactant: CC(C)(C)OC(=O)N1C[C@H](Nc2ccc(Br)cc2[N+](=O)[O-])[C@@H](O)C1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1C[C@H](Nc2ccc(Br)cc2[N+](=O)[O-])[C@H](OC(=O)CCl)C1
Temperature: 25 °C
Reaction time: 12 h
Yield: 91.9 %

Procedure:
To a mixture of (3S,4S)-tert-butyl 3-(4-bromo-2-nitrophenylamino)-4-hydroxypyrrolidine-1-carboxylate (2.50 mmol, 1.0 g), chloroacetic acid (3.0 mmol, 300 mg) and triphenylphosphine (3.0 mmol, 850 mg) in tetrahydrofuran (40 mL) add diethylazodicarboxylate (3.0 mmol, 600 mg) and stir at room temperature for 12 h. Remove the solvent, add ethyl acetate (50 mL) to the residue and wash with water and brine. Dry over anhydrous sodium sulfate and evaporate. Purify the residue by column chromatography, eluting with 20% ethyl acetate in methylene chloride to obtain the title compound as a yellow solid (1.10 g, 98%). 1H NMR (500 MHz, CDCl3) δ 8.35 (s, 1H), 8.20 (m, 1H), 7.60 (m, 1H), 6.82 (m, 1H), 5.55 (d, J=6.8 Hz, 1H), 4.32 (m, 1H), 4.13 (bd, J=8.2 Hz, 2H), 3.90 (m, 1H), 3.79 (m, 1H), 3.74 (dd, J=4.2, 10.4 Hz, 1H), 3.25 (t, J=7.20 Hz, 1H), 1.41 (s, 9H).
Reaction SMILES: [C:1]([C:4]1([C:7]2[CH:38]=[CH:37][CH:36]=[CH:35][C:8]=2[CH2:9][CH2:10][C:11]2[C:16]([Cl:17])=[CH:15][N:14]=[C:13]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([CH:25]([NH:27]C(=O)OC(C)(C)C)[CH3:26])=[CH:21][CH:20]=3)[N:12]=2)[CH2:6][CH2:5]1)(=[O:3])[NH2:2].FC(F)(F)C(O)=O>C(Cl)Cl>[NH2:27][CH:25]([C:22]1[CH:21]=[CH:20][C:19]([NH:18][C:13]2[N:12]=[C:11]([CH2:10][CH2:9][C:8]3[CH:35]=[CH:36][CH:37]=[CH:38][C:7]=3[C:4]3([C:1]([NH2:2])=[O:3])[CH2:5][CH2:6]3)[C:16]([Cl:17])=[CH:15][N:14]=2)=[CH:24][CH:23]=1)[CH3:26]
Reactant: CC(NC(=O)OC(C)(C)C)c1ccc(Nc2ncc(Cl)c(CCc3ccccc3C3(C(N)=O)CC3)n2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(N)c1ccc(Nc2ncc(Cl)c(CCc3ccccc3C3(C(N)=O)CC3)n2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 93.8 %

Procedure:
To a solution of tert-butyl (1-(4-((4-(2-(1-carbamoylcyclopropyl)phenethyl)-5-chloropyrimidin-2-yl)amino)phenyl)ethyl)carbamate 24 (0.012 g, 0.022 mmol) in DCM (1 mL) was added trifluoroacetic acid (0.5 mL). The mixture was stirred at ambient temperature for 2 hours before the volatiles were removed in vacuo. The crude residue was loaded onto an SCX cartridge conditioned with methanol. The cartridge was washed with methanol and then 2 N ammonia in ethanol. The basic fractions were combined and the solvent removed in vacuo to give the title compound 24A as a colourless oil (0.009 g, 92%). LCMS-C: rt 4.41 min; m/z 436 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8](F)=[CH:9][CH:10]=2)[C:5]([O:13][CH3:14])=[CH:4][N:3]=1.[CH3:15][CH2:16][O-:17].[Na+]>CS(C)=O.CCOC(C)=O>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:17][CH2:16][CH3:15])=[CH:9][CH:10]=2)[C:5]([O:13][CH3:14])=[CH:4][N:3]=1
Reactant: COc1cnc(Cl)c2ccc(F)cc12
Reactant: CC[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CCOc1ccc2c(Cl)ncc(OC)c2c1
Reaction time: 16 h
Yield: 53.4 %

Procedure:
1-chloro-6-fluoro-4-methoxyisoquinoline (533 mg, 2.52 mmol) was dissolved in DMSO (5 mL) then NaOEt (171 mg, 2.52 mmol) was added to the solution. The reaction was stirred for 16 h. The reaction was diluted with EtOAc and washed with 1N HCl, then brine. The organic layer was collected, dried over sodium sulfate and concentrated under vacuum. The crude material was purified by silica gel chromatography using DCM as eluent. The product fractions were collected and solvent was removed under vacuum to give 1-chloro-6-ethoxy-4-methoxyisoquinoline (320 mg, 54% yield). MS m/z 238.0 (M++1).
Reaction SMILES: C1(C)C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+].Br[C:15]1[CH:32]=[CH:31][C:18]([O:19][CH2:20][C@H:21]([OH:30])[CH2:22][CH2:23][C:24]2[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=2)=[CH:17][CH:16]=1.[F:33][C:34]1[CH:35]=[C:36](B(O)O)[CH:37]=[CH:38][CH:39]=1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(O)C>[F:33][C:34]1[CH:39]=[C:38]([C:15]2[CH:32]=[CH:31][C:18]([O:19][CH2:20][C@H:21]([OH:30])[CH2:22][CH2:23][C:24]3[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=3)=[CH:17][CH:16]=2)[CH:37]=[CH:36][CH:35]=1
Reactant: O[C@H](CCc1cccnc1)COc1ccc(Br)cc1
Reactant: OB(O)c1cccc(F)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: O[C@H](CCc1cccnc1)COc1ccc(-c2cccc(F)c2)cc1
Temperature: 110 °C

Procedure:
Prepared according to the method described in Example 33a) from toluene (5 ml), ethanol (3 ml), aqueous sodium carbonate (2 M, 1 ml), (2R)-1-(4-bromophenoxy)-4-(3-pyridyl)-2-butanol (0.25 g), ethanol (1 ml), 3-fluorobenzeneboronic acid (0.16 g) and tetrakis(triphenylphosphine)palladium(0) (60 mg) with heating at 110° C. for 4 hours. The residue obtained after work up was purified by column chromatography over silica eluting with ethyl acetate to give the title compound after trituration with diethyl ether:hexane (1:1) as a white solid (0.13 g).
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[F:13][C:14]1[CH:15]=[C:16]([NH2:24])[C:17](=[CH:21][C:22]=1[F:23])[C:18]([OH:20])=O.Cl.[CH2:26]([O:29][NH2:30])[CH:27]=[CH2:28].C(N(CC)CC)C>C1COCC1>[NH2:24][C:16]1[CH:15]=[C:14]([F:13])[C:22]([F:23])=[CH:21][C:17]=1[C:18]([NH:30][O:29][CH2:26][CH:27]=[CH2:28])=[O:20]
Reactant: C=CCON
Reactant: Nc1cc(F)c(F)cc1C(=O)O
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C=CCONC(=O)c1cc(F)c(F)cc1N
Yield: 53.6 %

Procedure:
Carbonyldiimidazole (3.37 g, 20 mmol) was added to a suspension of 4,5-difluoroanthranilic acid (3.0 g, 17 mmol) in 80 mL of THF, and the mixture was heated to reflux for 2 hours. The solution was cooled and O-allylhydroxylamine hydrochloride (1.89 g, 17 mmol) and triethylamine (2.8 mL, 20 mmol) were added, and the mixture was heated to reflux for 17 hours. The reaction mixture was concentrated and washed with 1N HCl, saturated NaHCO3, and brine and dried over magnesium sulfate. The solution was concentrated and purified by column chromatography (silica gel, CHCl3/MeOH, 98:2) to give 2.08 g of the title compound as a solid.
Reaction SMILES: [Br:1][C:2]1[CH:16]=[CH:15][C:14](I)=[CH:13][C:3]=1[CH2:4][O:5][Si:6]([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:8])[CH3:7].C([Mg]Cl)(C)C.[Cl-].[Li+].[Cl:25][CH2:26][C:27](N(OC)C)=[O:28]>O1CCCC1.C(OCC)(=O)C>[Br:1][C:2]1[CH:16]=[CH:15][C:14]([C:27](=[O:28])[CH2:26][Cl:25])=[CH:13][C:3]=1[CH2:4][O:5][Si:6]([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:8])[CH3:7]
Reactant: CON(C)C(=O)CCl
Reactant: CC(C)(C)[Si](C)(C)OCc1cc(I)ccc1Br
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)[Si](C)(C)OCc1cc(C(=O)CCl)ccc1Br
Temperature: 25 °C
Yield: 66.5 %

Procedure:
To a solution of (2-bromo-5-iodobenzyloxy)-(tert-butyl)dimethylsilane (8.7 g, 20.3 mmol) in tetrahydrofuran (135 mL) under argon at −20° C. was added i-propylmagnesium chloride-lithium chloride solution (1.3M in THF, 16.4 mL, 21.3 mmol). After stirring at this temperature for thirty minutes, a solution of 2-chloro-N-methoxy-N-methyl acetamide (3.4 g, 24.3 mmol) in tetrahydrofuran (5 mL) was added to the reaction via cannula. The reaction was stirred at −20° C. for one hour and then warmed to room temperature. After one hour at room temperature the reaction was diluted with ethyl acetate and the organics were washed with saturated aqueous NH4Cl solution, water and brine. The organic layer was dried (MgSO4) and concentrated, and the resulting residue was purified by flash chromatography to yield 1-(4-bromo-3-((tert-butyldimethylsilyloxy)methyl)phenyl)-2-chloroethanone (5.1 g, 67%).
Reaction SMILES: [C:1]([CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]([NH2:13])[CH:5]=1)#[N:2].Cl.Cl[C:16]1[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=1.O.C(=O)([O-])[O-].[Na+].[Na+]>C(O)(C)C>[C:1]([CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]([NH:13][C:16]2[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=2)[CH:5]=1)#[N:2]
Reactant: Clc1ccncc1
Reactant: N#CCc1cn(N)c2ccccc12
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)O
Product: N#CCc1cn(Nc2ccncc2)c2ccccc12
Temperature: 90 °C
Yield: 126.4 %

Procedure:
3-Cyanomethyl-1H-indol-1-amine (12 g) and 4-chloropyridine hydrochloride (12 g) were combined in isopropanol (250 ml). After stirring at reflux (90° C.) for six hours, the mixture was poured into water (500 ml) and stirred five minutes. Thereafter the pH of the mixture was adjusted to 10 with sodium carbonate and the mixture was extracted with ethyl acetate (2x). The organic layer was washed with water (2x), brine, dried over anhydrous magnesium sulfate, filtered and evaporated to give an oil (22 g). This oil was eluted on a silica gel column with ethyl acetate. Fractions containing product were combined and concentrated to an oil (16 g) which solidified upon standing. A portion of this solid was recrystallized from ethanol/ether (1:20) to give the title compound as a solid (2 g), m.p. 152°-153° C.
Reaction SMILES: C([C@@H:3]1[C@@H:7]([CH2:8][O:9]C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[O:6][C@@H:5]([N:29]2[CH:37]=[C:35]([CH3:36])[C:33](=[O:34])[NH:32][C:30]2=[O:31])[CH2:4]1)=O.CC(O)=[O:40].Cl.CON>C(Cl)Cl.CO>[C@@H:5]1([N:29]2[CH:37]=[C:35]([CH3:36])[C:33](=[O:34])[NH:32][C:30]2=[O:31])[O:6][C@H:7]([CH2:8][OH:9])[C@@H:3]([OH:40])[CH2:4]1
Reactant: Cc1cn([C@H]2C[C@H](C=O)[C@@H](COC(c3ccccc3)(c3ccccc3)c3ccccc3)O2)c(=O)[nH]c1=O
Reactant: CC(=O)O
Agent: CON
Agent: Cl
Solvent: ClCCl
Solvent: CO
Product: Cc1cn([C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)[nH]c1=O
Reaction time: 0.5 h

Procedure:
To a stirred solution of 3′-deoxy-3′-C-formyl-5′-O-tritylthymidine (0.59, 1 mmol, prepared as per Example 4 in CH2Cl2:MeOH (2:1, 30 vol.) was added AcOH (0.5 ml) and methoxyamine hydrochloride (0.189, 2.2 mml) at room temperature. The mixture was stirred for 30 min., concentrated under vacuum and the residue dissolved in MeOH (20 ml). To this solution, concentrated HCl (0.1 ml) was added and stirred for 1 h. The solution was neutralized with NH4OH (≈2 ml) and concentrated under a vacuum to furnish the 3′-C-[(methoxyimido)methyl] derivative of thymidine. 1H NMR (CDCl3) δ 9.67 (s, 1, NH); 7.67 (s, 1, H-6); 7.33 (d, 0.70, H-3″ E isomer), 6.65 (d, 0.30, H-3′ Z isomer); 6.15 (m, 1, H-1′); 3.60-4.12 (m, 3.3, H-4′, H-5′5″, H-3′ Z isomer); 3.91 (s, 0.9, OCH3 Z isomer); 3.82 (s, 2.1, OCH3 oxime E isomer); 3.26 (m, 0.7, H-3′ E isomer); 2.27-2.60 (m, 2, H-2′,2″); 1.91 (2s, 3, C6CH3).
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]([CH2:13][OH:14])[CH:8]=2)=[CH:4][C:3]=1[F:17].CCN(CC)CC.[Si:25](Cl)([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26]>CN(C=O)C>[Si:25]([O:14][CH2:13][C:9]1[CH:8]=[C:7]([O:6][C:5]2[CH:15]=[CH:16][C:2]([NH2:1])=[C:3]([F:17])[CH:4]=2)[CH:12]=[CH:11][N:10]=1)([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: Nc1ccc(Oc2ccnc(CO)c2)cc1F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)[Si](C)(C)OCc1cc(Oc2ccc(N)c(F)c2)ccn1
Temperature: 25 °C
Reaction time: 4 h
Yield: 33.2 %

Procedure:
A solution of (4-(4-amino-3-fluorophenoxy)pyridin-2-yl)methanol (750 mg, 3.2 mmol) and Et3N (821 mg, 8 mmol) in DMF (10 ml) at 0° C. was treated with tert-butyldimethylsilyl chloride (624 mg, 4.16 mmol). The resulting solution was stirred at RT for 4 hours. The solvent was removed in vacuo and the residue was purified by silica gel column chromatography to provide 4-(2-((tert-butyldimethylsilyloxy)methyl)pyridin-4-yloxy)-2-fluorobenzenamine (370 mg, 33% yield). 1H NMR (400 MHz, DMSO-d6) δ 8.32 (d, J=5.6 Hz, 1H), 7.02 (s, 1H), 6.67-6.82 (m, 4H), 4.76 (s, 2H), 3.71 (s, 2H), 0.89 (s, 9H), 0.07 (s, 6H); MS (ESI) m/z: 349.2 (M+H+).
Reaction SMILES: [OH:1]O.[C:3]1([S:9][CH2:10][CH2:11][CH2:12][CH2:13][O:14][C:15]2[CH:24]=[CH:23][CH:22]=[C:21]3[C:16]=2[CH:17]=[CH:18][C:19](=[O:25])[NH:20]3)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>C(O)(=O)C.O>[C:3]1([S:9]([CH2:10][CH2:11][CH2:12][CH2:13][O:14][C:15]2[CH:24]=[CH:23][CH:22]=[C:21]3[C:16]=2[CH:17]=[CH:18][C:19](=[O:25])[NH:20]3)=[O:1])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: OO
Reactant: O=c1ccc2c(OCCCCSc3ccccc3)cccc2[nH]1
Solvent: CC(=O)O
Solvent: O
Product: O=c1ccc2c(OCCCCS(=O)c3ccccc3)cccc2[nH]1

Procedure:
0.165 ml of 30% hydrogen peroxide, dissolved in 8 ml of glacial acetic acid, were added to 0.56 gm of 5-(4-phenylmercapto-butoxy)-carbostyril. The mixture was diluted with water and extracted twice with chloroform. The chloroform extract was washed with dilute sodium carbonate solution and with water, dried over magnesium sulfate and evaporated. The residue was admixed with ethyl acetate, yielding colorless crystals with a melting point of 155°-157° C.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[CH3:7][O:8][CH2:9][C:10]1[N:15]=[C:14](Cl)[CH:13]=[CH:12][N:11]=1.O.Cl>O1CCCC1>[CH3:7][O:8][CH2:9][C:10]1[N:15]=[C:14]([N:1]2[CH2:6][CH2:5][O:4][CH2:3][CH2:2]2)[CH:13]=[CH:12][N:11]=1
Reactant: COCc1nccc(Cl)n1
Reactant: C1COCCN1
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: COCc1nccc(N2CCOCC2)n1
Yield: 53.2 %

Procedure:
A solution of morpholine (12.67 g) and 2-methoxymethyl-4-chloropyrimidine (7.69 g) in tetrahydrofuran (100 ml) was heated under reflux for 1 hour. On cooling, the mixture was treated with water (100 ml), the pH adjusted to 8 (conc HCl) and extracted with chloroform. After drying (K2CO3) the extracts were stripped, and the residue purified by chromatography (silica gel, CHCl3 /methanol) to give 2-methoxymethyl-4-morpholinopyrimidine (5.4 g) as an oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[C:11]([N:13]1[CH2:20][CH:19]2[CH:15]([CH2:16][NH:17][CH2:18]2)[CH2:14]1)=[O:12].Cl[C:22]1[S:23][C:24]2[CH:30]=[CH:29][CH:28]=[CH:27][C:25]=2[N:26]=1>>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[C:11]([N:13]1[CH2:20][CH:19]2[CH2:18][N:17]([C:22]3[S:23][C:24]4[CH:30]=[CH:29][CH:28]=[CH:27][C:25]=4[N:26]=3)[CH2:16][CH:15]2[CH2:14]1)=[O:12]
Reactant: Clc1nc2ccccc2s1
Reactant: COc1ccc(C(=O)N2CC3CNCC3C2)c(OC)c1
Product: COc1ccc(C(=O)N2CC3CN(c4nc5ccccc5s4)CC3C2)c(OC)c1

Procedure:
The title compound was prepared in a manner analogous to Example 15 utilizing Intermediate 38 and 2-chloro-benzothiazole. MS (ESI) mass calcd. for C22H23N3O3S, 409.51; m/z found, 410.2 [M+H]+.
Reaction SMILES: C(OC(=O)[N:7]([C:17]1[CH:22]=[CH:21][C:20]([CH:23]([OH:43])[C:24]2[C:32]3[CH:31]=[N:30][CH:29]=[N:28][C:27]=3[N:26]([Si](C(C)C)(C(C)C)C(C)C)[CH:25]=2)=[C:19]([CH3:44])[N:18]=1)[CH2:8][C:9]1[CH:10]=[N:11][C:12]([O:15][CH3:16])=[CH:13][CH:14]=1)(C)(C)C.C([SiH](CC)CC)C.FC(F)(F)C(O)=O>ClCCCl>[CH3:16][O:15][C:12]1[N:11]=[CH:10][C:9]([CH2:8][NH:7][C:17]2[N:18]=[C:19]([CH3:44])[C:20]([C:23]([C:24]3[C:32]4[CH:31]=[N:30][CH:29]=[N:28][C:27]=4[NH:26][CH:25]=3)=[O:43])=[CH:21][CH:22]=2)=[CH:14][CH:13]=1
Reactant: COc1ccc(CN(C(=O)OC(C)(C)C)c2ccc(C(O)c3cn([Si](C(C)C)(C(C)C)C(C)C)c4ncncc34)c(C)n2)cn1
Agent: CC[SiH](CC)CC
Solvent: ClCCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(CNc2ccc(C(=O)c3c[nH]c4ncncc34)c(C)n2)cn1
Temperature: 70 °C
Reaction time: 8 h
Yield: 30.7 %

Procedure:
To {5-[hydroxy-(7-triisopropylsilanyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-methyl]-6-methyl-pyridin-2-yl}-(6-methoxy-pyridin-3-ylmethyl)-carbamic acid tert-butyl ester (75, 0.317 g, 0.501 mmol) dissolved in 15.0 mL of 1,2-dichloroethane, triethylsilane (1.00 mL, 6.26 mmol) was added, followed by trifluoroacetic acid (0.482 mL, 6.26 mmol). The reaction was stirred at 70° C. overnight, then concentrated under vacuum and combined with 1 N aqueous potassium carbonate and extracted with ethyl acetate. The organic layer was washed with brine, then dried with sodium sulfate, filtered and the filtrate adsorbed onto silica. This was purified by silica gel column chromatography eluting with 50-100% ethyl acetate in hexanes. Appropriate fractions were combined and the solvents removed under vacuum to provide the desired compound (P-0019, 57.5 mg). 1H NMR was consistent with the compound structure.
Reaction SMILES: [CH:1]([CH:9]1[CH2:14][C:13](=[O:15])[O:12][C:10]1=[O:11])=[CH:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[OH-:16].[K+]>>[CH:1]([CH:9]([CH2:14][C:13]([OH:12])=[O:15])[C:10]([OH:16])=[O:11])=[CH:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCC=CC1CC(=O)OC1=O
Reactant: [OH-]
Agent: [K+]
Product: CCCCCCC=CC(CC(=O)O)C(=O)O

Procedure:
Octenyl succinic anhydride was added to an aqueous, 45% potassium hydroxide solution, and heated to form the di-potassium salt of 2-octenyl-1,4-butanedioic acid (the friction modifier). A lubricant, methyl 9EO tallowate, and the friction modifier were mixed together to form a composition having a ratio of 9:1 by weight, respectively.
Reaction SMILES: [C:1]1(=[O:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Br[C:9]([F:16])([F:15])[C:10]([O:12][CH2:13][CH3:14])=[O:11].C1COCC1>CCOCC.[Zn]>[F:15][C:9]([F:16])([C:1]1([OH:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)[C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: O=C1CCCCC1
Reactant: CCOC(=O)C(F)(F)Br
Agent: [Zn]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCOC(=O)C(F)(F)C1(O)CCCCC1
Yield: 69.3 %

Procedure:
A stirred suspension of zinc (0.981 g, 15.01 mmol) in a solution of cyclohexanone (0.491 g, 5.0 mmol) and ethyl 2-bromo-2,2-difluoroacetate (2.031 g, 10.01 mmol) in an. THF (5 mL) was sonicated for 4-5 h and then heated to reflux for 1-2 h. The reaction mixture was cooled and diluted with ether and washed with 1 N HCl, satd. NaHCO3, water, brine and dried (MgSO4). Evaporation of solvents afforded an oil which was purified by silica gel FCC (5-10% EtOAc in DCM) to afford ethyl 2,2-difluoro-2-(1-hydroxycyclohexyl)acetate as a clear oil (770 mg, ˜70%). 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 4.37 (q, J=7.2 Hz, 2H), 2.10-2.01 (m, J=3.4 Hz, 1H), 1.82-1.69 (m, 3H), 1.68-1.54 (m, 6H), 1.38 (t, J=7.2 Hz, 3H), 1.20 (br. s, 1H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH:9]([NH2:15])[CH2:8][CH2:7][CH2:6][C:5]2=1.[C:16]1([N:22]=[C:23]=[O:24])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[CH3:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH:9]([NH:15][C:23]([NH:22][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[O:24])[CH2:8][CH2:7][CH2:6][C:5]2=1
Reactant: O=C=Nc1ccccc1
Reactant: Cc1ccc2[nH]c3c(c2c1)CCCC3N
Product: Cc1ccc2[nH]c3c(c2c1)CCCC3NC(=O)Nc1ccccc1

Procedure:
N-(6-Methyl-2,3,4,9-tetrahydro-1H-carbazol-1-yl)-N′-phenylurea was prepared from 6-methyl-2,3,4,9-tetrahydro-1H-carbazol-1-amine and phenyl isocyanate in a similar manner as described above to give a white solid (82% yield). 1H-NMR (DMSO-d6): δ 10.57 (s, 1H), 8.27 (s, 1H), 7.42-7.34 (m, 2H), 7.20 (m, 2H), 7.17-7.11 (m, 2H), 6.87 (m, 1H), 6.82 (m, 1H), 6.51 (d, 1H), 4.92 (m, 1H), 2.58 (m, 2H), 2.32 (s, 3H), 1.97 (m, 1H), 1.87-1.70 (m, 3H); MS m/z 318 (M−1).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:6][N:5]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[C@H:4]([C:14]([O:16][CH3:17])=[O:15])[CH2:3]1.C(N(CC)CC)C.[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([S:32](Cl)(=[O:34])=[O:33])=[CH:28][CH:27]=1>ClCCl>[C:10]([O:9][C:7]([N:5]1[CH2:6][C@H:2]([NH:1][S:32]([C:29]2[CH:30]=[CH:31][C:26]([Cl:25])=[CH:27][CH:28]=2)(=[O:34])=[O:33])[CH2:3][C@H:4]1[C:14]([O:16][CH3:17])=[O:15])=[O:8])([CH3:11])([CH3:12])[CH3:13]
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Reactant: COC(=O)[C@@H]1C[C@@H](N)CN1C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)[C@@H]1C[C@@H](NS(=O)(=O)c2ccc(Cl)cc2)CN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.2 %

Procedure:
To a solution of (2S,4R)-4-amino-1-t-butoxycarbonyl-2-methoxycarbonylpyrrolidine (6.04 g) in dichloromethane (60 ml) were added triethylamine (3.44 ml) and p-chlorobenzenesulfonyl chloride (6.26 g) in an ice bath. After being stirred at room temperature overnight, the solution was washed successively with diluted hydrochloric acid, saturated aqueous sodium bicarbonate and brine and dried over magnesium sulfate. The solvent was evaporated in vacuo and the residue was crystallized from n-hexane to give (2S,4R)-1-t-butoxycarbonyl-4-(4-chlorophenylsulfonylamino)-2-methoxycarbonylpyrrolidine (9.13 g) as a pale yellow crystal.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH:17]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:18]([OH:20])=O)[CH2:11][CH2:10]1.C(N(CC)CC)C.O=C1N(N(N2CCOC2=O)P(Cl)(Cl)=O)CCO1.[CH3:51][NH:52][CH2:53][C:54]#[CH:55].C1(N)C(F)=C(F)C(F)=C(N)C=1F.Cl.Cl>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:10][CH2:11][N:12]([CH2:15][CH2:16][CH:17]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:18]([N:52]([CH3:51])[CH2:53][C:54]#[CH:55])=[O:20])[CH2:13][CH2:14]1
Reactant: C#CCNC
Reactant: COc1ccccc1N1CCN(CCC(C(=O)O)c2ccccc2)CC1
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Agent: O=C1OCCN1N(N1CCOC1=O)P(=O)(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C#CCN(C)C(=O)C(CCN1CCN(c2ccccc2OC)CC1)c1ccccc1
Yield: 93.7 %

Procedure:
The title compound was prepared from 4-[4-(2-methoxyphenyl)piperazin-1-yl]-2-phenylbutanoic acid (1.77 g, 5 mmole), triethylamine (1.518 g, 15 mmole), N,N-bis(2-oxo-3-oxazolidinyl)phosphoramidic chloride (1.527 g, 6 mmole), N-methylpropargylamine (0.415 g, 6 mmole) and methylene chloride (80 mL) in the manner described in Example 1, to yield 1.9 g of the title compound as the dihydrochloride, m.p. 197°-8° C.