Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH:2]([CH:6]1[CH2:11][CH2:10][C:9]([F:13])([F:12])[CH2:8][CH2:7]1)[C:3]([OH:5])=[O:4].[Cl:14][C:15]1[S:19][C:18]([S:20](Cl)(=[O:22])=[O:21])=[CH:17][CH:16]=1>[OH-].[Na+].C1COCC1>[Cl:14][C:15]1[S:19][C:18]([S:20]([NH:1][CH:2]([CH:6]2[CH2:11][CH2:10][C:9]([F:12])([F:13])[CH2:8][CH2:7]2)[C:3]([OH:5])=[O:4])(=[O:22])=[O:21])=[CH:17][CH:16]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)s1
Reactant: NC(C(=O)O)C1CCC(F)(F)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)C(NS(=O)(=O)c1ccc(Cl)s1)C1CCC(F)(F)CC1
Temperature: 0 °C
Reaction time: 19 h

Procedure:
The amino(4,4-difluorocyclohexyl)acetic acid (2.68g, 10.973 mmol) was dissolved in 2N NaOH (20 mL). The solution was cooled to 0° C., 5-chlorothiophene-2-sulfonyl chloride (3.25g, 12.42 mmol) was added (5 min) dropwise as a solution in THF (10 mL). The solution was allowed to warm up to 25° C. overnight. After 19 h, THF was removed in vacuo and the mixture was acidified to a pH of about 1 to about 2 with 2N HCl (20 mL). The aqueous layer was washed with EtOAc (4×50 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated to produce {[(5-chlorothien-2-yl)sulfonyl]amino}(4,4-difluorocyclohexyl)acetic acid as a crude oil (3.8 g, 98.2%).
Reaction SMILES: C([Li])CCC.[N:6]1([C:11]2[CH:31]=[CH:30][C:14]([CH2:15][C:16]3[C:17]([O:28][CH3:29])=[N:18][C:19]4[C:24]([C:25]=3[Cl:26])=[CH:23][C:22](Br)=[CH:21][CH:20]=4)=[CH:13][CH:12]=2)[CH:10]=[CH:9][CH:8]=[N:7]1.[CH3:32][C:33]1[C:38]([C:39]([C:41]2[N:45]([CH3:46])[N:44]=[N:43][CH:42]=2)=[O:40])=[CH:37][CH:36]=[C:35]([CH3:47])[N:34]=1.O>O1CCCC1>[N:6]1([C:11]2[CH:31]=[CH:30][C:14]([CH2:15][C:16]3[C:17]([O:28][CH3:29])=[N:18][C:19]4[C:24]([C:25]=3[Cl:26])=[CH:23][C:22]([C:39]([C:38]3[C:33]([CH3:32])=[N:34][C:35]([CH3:47])=[CH:36][CH:37]=3)([C:41]3[N:45]([CH3:46])[N:44]=[N:43][CH:42]=3)[OH:40])=[CH:21][CH:20]=4)=[CH:13][CH:12]=2)[CH:10]=[CH:9][CH:8]=[N:7]1
Reactant: Cc1ccc(C(=O)c2cnnn2C)c(C)n1
Reactant: COc1nc2ccc(Br)cc2c(Cl)c1Cc1ccc(-n2cccn2)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: COc1nc2ccc(C(O)(c3ccc(C)nc3C)c3cnnn3C)cc2c(Cl)c1Cc1ccc(-n2cccn2)cc1
Temperature: 23 °C
Reaction time: 0.08 h

Procedure:
A solution of n-butyllithium in hexanes (1.6 M, 0.73 mL, 1.2 mmol) was added dropwise to a stirring solution of 3-(4-(1H-pyrazol-1-yl)benzyl)-6-bromo-4-chloro-2-methoxyquinoline (500 mg, 1.2 mmol, Intermediate 10) in tetrahydrofuran (10 mL) at −78° C. After 5 minutes, a solution of (2,6-dimethylpyridin-3-yl)(1-methyl-1H-1,2,3-triazol-5-yl)methanone (250 mg, 1.2 mmol, Intermediate 19: step b) in tetrahydrofuran (1.6 mL) was added dropwise. After 5 minutes, the flask was placed into an ice-water bath. After 30 minutes, water (5 mL) was added and the mixture was allowed to warm to 23° C. The biphasic mixture was partitioned between half-saturated aqueous sodium chloride solution (100 mL) and ethyl acetate (100 mL). The layers were separated. The organic layer was dried with sodium sulfate and the dried solution was filtered. The filtrate was concentrated and the residue was purified by RP-HPLC eluting initially with 5% acetonitrile-water (containing 0.05% trifluoroacetic acid), grading to 95% acetonitrile-water (containing 0.05% trifluoroacetic acid) to provide the title compound as a white solid after partitioning the purified material between dichloromethane-saturated aqueous sodium bicarbonate solution, separating the layers, drying the organic layer with sodium sulfate, filtering the dried solution, and concentrating the filtrate to dryness. 1H NMR (600 MHz, CDCl3) δ ppm 8.08 (d, J=2.2 Hz, 1H), 7.85 (d, J=2.5 Hz, 1H), 7.83 (d, J=8.7 Hz, 1H), 7.67 (d, J=1.7 Hz, 1H), 7.59-7.54 (m, 2H), 7.40-7.34 (m, 3H), 6.98-6.91 (m, 3H), 6.45-6.41 (m, 1H), 4.32 (s, 2H), 4.10 (s, 3H), 3.93 (s, 3H), 3.61 (s, 1H), 2.55 (s, 3H), 2.38 (s, 3H); MS (ESI): mass calcd. for C31H28ClN7O2, 565.2. m/z found, 566.1 [M+H]+.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH:9]2[CH2:17][CH2:16][CH:15]3[CH:11]([CH2:12][N:13]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14]3)[CH2:10]2)[C:5]([Cl:25])=[CH:4][N:3]=1.Cl.[CH3:27][N:28]1[CH:32]=[C:31]([NH2:33])[CH:30]=[N:29]1.C(N(C(C)C)C(C)C)C>CCCCO>[Cl:25][C:5]1[C:6]([NH:8][CH:9]2[CH2:17][CH2:16][CH:15]3[CH:11]([CH2:12][N:13]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14]3)[CH2:10]2)=[N:7][C:2]([NH:33][C:31]2[CH:30]=[N:29][N:28]([CH3:27])[CH:32]=2)=[N:3][CH:4]=1
Reactant: Cn1cc(N)cn1
Reactant: CC(C)(C)OC(=O)N1CC2CCC(Nc3nc(Cl)ncc3Cl)CC2C1
Agent: Cl
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: Cn1cc(Nc2ncc(Cl)c(NC3CCC4CN(C(=O)OC(C)(C)C)CC4C3)n2)cn1
Temperature: 150 °C
Reaction time: 8 h
Yield: 55.6 %

Procedure:
To a suspension of tert-butyl 5-((2,5-dichloropyrimidin-4-yl)amino)hexahydro-1H-isoindole-2(3H)-carboxylate (767.3 mg, 1.98 mmol) and 1-methyl-1H-pyrazol-4-amine hydrochloride (411.5 mg, 3.08 mmol) in n-BuOH (5 mL) was added N-ethyldiisopropylamine (792.9 g, 6.14 mmol). The reaction mixture was stirred at 150° C. in a sealed tube overnight and concentrated in vacuo. The residue was purified by silica gel column chromatography ((EtOAc/PE (v/v)=1/1) to give the title compound as a pale yellow solid (493 mg, 55.6%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[F:11])[C:5]([OH:7])=[O:6].[Si](C=[N+]=[N-])(C)(C)[CH3:13].CCOCC>C1COCC1.CO>[CH3:13][O:6][C:5](=[O:7])[C:4]1[CH:8]=[CH:9][C:10]([F:11])=[C:2]([Br:1])[CH:3]=1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: O=C(O)c1ccc(F)c(Br)c1
Solvent: CCOCC
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)c1ccc(F)c(Br)c1
Yield: 100 %

Procedure:
3-Bromo-4-fluoro-benzoic acid (2.5 g, 11.42 mmol) was placed in a 100 ml round bottom flask charged with a stir bar, sealed with a septum and placed under a nitrogen atmosphere and dissolved in 9 ml dry THF and 3 ml dry MeOH. A 2.0M solution of TMS diazomethane in ether (6.28 ml, 12.56 mmol) was added dropwise to the stirring solution of the acid. Conversion of the acid to the ester was complete after twenty minutes according to LC/MS analysis. The solvent was removed under reduced pressure and product was used without further purification. Recovered a light oil (2.66 g, 100% yield) LC/MS (10-99%) M/Z 234, retention time 3.09 minutes.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1.Cl[C:24](Cl)([O:26][C:27](=[O:33])OC(Cl)(Cl)Cl)Cl.[CH2:35](O)[CH:36]=C.C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(N(CC)CC)C.C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:27](=[O:33])[O:26][CH2:24][CH:35]=[CH2:36])=[CH:18][CH:17]=1
Reactant: C=CCO
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COc1cc2ncnc(Oc3ccc(N)cc3)c2cc1OC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=CCOC(=O)Nc1ccc(Oc2ncnc3cc(OC)c(OC)cc23)cc1
Yield: 65.5 %

Procedure:
4-[(6,7-Dimethoxy-4-quinazolinyl)oxy]aniline (50 mg) was added to toluene (5 ml), and triethylamine (0.5 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (77 mg) in methylene chloride was then added thereto, and the mixture was heated under reflux for 10 min. Next, 2-propen-1-ol (15 mg) was added thereto, and the mixture was further stirred with heating under reflux for 3 hr. A saturated aqueous sodium bicarbonate solution was added to stop the reaction, and the reaction solution was then extracted with chloroform, followed by washing with a 1 N aqueous hydrochloric acid solution, water, and saturated brine in that order. The extract was dried over sodium sulfate and was then concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (42 mg, yield 54%).
Reaction SMILES: I[C:2]1[N:9]2[C:5]([S:6][C:7]([C:10]3[CH:11]=[C:12]([CH:16]=[CH:17][CH:18]=3)[C:13]([NH2:15])=[O:14])=[N:8]2)=[N:4][CH:3]=1.CC1(C)C(C)(C)OB([C:27]2[CH:28]=[C:29]([C:34]([F:37])([F:36])[F:35])[C:30]([NH2:33])=[N:31][CH:32]=2)O1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.C(Cl)Cl.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[NH2:33][C:30]1[N:31]=[CH:32][C:27]([C:2]2[N:9]3[C:5]([S:6][C:7]([C:10]4[CH:11]=[C:12]([CH:16]=[CH:17][CH:18]=4)[C:13]([NH2:15])=[O:14])=[N:8]3)=[N:4][CH:3]=2)=[CH:28][C:29]=1[C:34]([F:37])([F:35])[F:36]
Reactant: NC(=O)c1cccc(-c2nn3c(I)cnc3s2)c1
Reactant: CC1(C)OB(c2cnc(N)c(C(F)(F)F)c2)OC1(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Solvent: ClCCl
Product: NC(=O)c1cccc(-c2nn3c(-c4cnc(N)c(C(F)(F)F)c4)cnc3s2)c1
Temperature: 100 °C
Yield: 2.7 %

Procedure:
A mixture of 3-(5-Iodo-imidazo[2,1-b][1,3,4]thiadiazol-2-yl)-benzamide (70 mg, 0.18 mmol), 5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3-trifluoromethyl-pyridin-2-ylamine (75 mg, 0.24 mmol), PdCl2(PPh3)2 (20 mg) and Na2CO3 (60 mg, 0.567 mmol) in dioxane (2 mL) and water (0.5 mL) was heated at 100° C. in a sealed tube for 2 h. The mixture was diluted with DCM (20 mL), washed with sat aq NaHCO3 (2×20 mL) and brine (30 mL), dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography and by HPLC to give the desired product (2 mg, 3%). HPLC-MS (5-100% B in 8 min at 0.8 mL): tR=4.26 min, [M+H]+ m/z 405.2; 1H NMR (300 MHz, DMSO) δ 8.84 (s, 1H), 8.34 (s, 1H), 8.30 (s, 1H), 8.22 (s, 1H), 8.06 (t, J=8.6 Hz, 2H), 7.75 (s, 1H), 7.66 (t, J=7.8 Hz, 1H), 7.55 (s, 1H), 6.67 (s, 2H).
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[OH:11][CH:12]([C:25]1[CH:26]=[C:27]([Si:30]([CH3:33])([CH3:32])[CH3:31])[O:28][CH:29]=1)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24].C(N(CC)CC)C>ClCCl>[O:11]=[C:12]([C:25]1[CH:26]=[C:27]([Si:30]([CH3:33])([CH3:32])[CH3:31])[O:28][CH:29]=1)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: CCCCCCCCCCCCC(O)c1coc([Si](C)(C)C)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CS(C)=O
Product: CCCCCCCCCCCCC(=O)c1coc([Si](C)(C)C)c1
Reaction time: 0.08 h

Procedure:
A mixture of dimethyl sulfoxide (0.5 ml) and dichloromethane (5 ml) was added dropwise to a solution of oxalyl chloride (0.36 ml, 4.18 mmol) in dichloromethane (5 ml) at -78° under argon. After 5 minutes, a solution of 4-(1-hydroxytridecyl)-2-trimethylsilylfuran (Compound 25, 1.01 g, 2.98 mmol) in dichloromethane (5 ml), followed by triethylamine (1.66 ml, 11.9 mmol) after 20 minutes, was added. Stirring was continued for 3 hours while the cooling bath attained room temperature. The mixture was quenched with water and extracted with dichloromethane. The dried (magnesium sulfate) extracts on evaporation gave a residue which was purified by a silica column using 2.5% ethyl ether/hexane. Fractions with Rf of about 0.27 (5% ethyl ether/hexane) on evaporation gave the titled ketone as an off-white solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][C:17]=1[O:18][CH3:19])[O:5][C:6]1[C:11]([CH3:12])=[CH:10][C:9]([NH2:13])=[CH:8][C:7]=1[CH3:14].N([O-])=O.[Na+].C([N:26]([C:32](=[O:36])[CH2:33][C:34]#[N:35])[C:27]([O:29][CH2:30][CH3:31])=[O:28])C.[N:37]1C=CC=CC=1>Cl.O>[CH2:30]([O:29][C:27](=[O:28])[NH:26][C:32](=[O:36])[C:33](=[N:37][NH:13][C:9]1[CH:10]=[C:11]([CH3:12])[C:6]([O:5][C:4]2[CH:15]=[CH:16][C:17]([O:18][CH3:19])=[C:2]([Br:1])[CH:3]=2)=[C:7]([CH3:14])[CH:8]=1)[C:34]#[N:35])[CH3:31]
Reactant: c1ccncc1
Reactant: CCOC(=O)N(CC)C(=O)CC#N
Reactant: COc1ccc(Oc2c(C)cc(N)cc2C)cc1Br
Agent: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: CCOC(=O)NC(=O)C(C#N)=NNc1cc(C)c(Oc2ccc(OC)c(Br)c2)c(C)c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a suspension of 4-(3-bromo-4-methoxy-phenoxy)-3,5-dimethyl-phenylamine (2.0 g) of PREPARATION 2 in 6N hydrochloric acid (45 ml) at 0° C. was added dropwise a solution of sodium nitrite (560 mg) in water (1.25 ml). After stirring 30 min at 0° C., this solution was added in portions to a mixture of ethylcyanoacetylurethane (2.4 g) and pyridine (12 ml) in water (150 ml) at room temperature. The resulting solids were collected, washed with water, and dried to afford the title compound as an orange solid (1.5 g) which was used directly.
Reaction SMILES: [Si:1]([O:8][CH2:9][C@@H:10]([NH:14][C:15]([C:17]1[N:18]=[C:19]([N:22]2[CH2:25][CH:24]([OH:26])[CH2:23]2)[S:20][CH:21]=1)=[O:16])[CH:11]([CH3:13])[CH3:12])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH3:27][S:28](Cl)(=[O:30])=[O:29].C(N(CC)CC)C>C(Cl)Cl>[Si:1]([O:8][CH2:9][C@@H:10]([NH:14][C:15]([C:17]1[N:18]=[C:19]([N:22]2[CH2:23][CH:24]([O:26][S:28]([CH3:27])(=[O:30])=[O:29])[CH2:25]2)[S:20][CH:21]=1)=[O:16])[CH:11]([CH3:13])[CH3:12])([C:4]([CH3:6])([CH3:7])[CH3:5])([CH3:2])[CH3:3]
Reactant: CC(C)[C@@H](CO[Si](C)(C)C(C)(C)C)NC(=O)c1csc(N2CC(O)C2)n1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)[C@@H](CO[Si](C)(C)C(C)(C)C)NC(=O)c1csc(N2CC(OS(C)(=O)=O)C2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 107.1 %

Procedure:
To a solution of 1-{4-[(1S)-1-(t-butyldimethylsilyloxymethyl)-2-methylpropylcarbamoyl]-1,3-thiazol-2-yl}-3-hydroxyazetidine (700 mg, 1.75 mmol) (obtained as described in Reference Example 36(4)) in methylene chloride (35 ml) were added methanesulfonyl chloride (406 μl, 5.25 mmol) and triethylamine (736 μl, 5.25 mmol) in an ice bath. After stirring the mixture in the ice bath for 10 minutes, the mixture was stirred at room temperature for 1 hour. After checking the completion of the reaction, the reaction mixture was partitioned between ethyl acetate and saturated aqueous sodium hydrogencarbonate solution. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using n-hexane:ethyl acetate (2:1→1:2) as the eluant to afford 1-{4-[(1S)-1-(t-butyldimethylsilyloxymethyl)-2-methylpropylcarbamoyl]-1,3-thiazol-2-yl}-3-methanesulfonyloxyazetidine (895 mg, yield 100%) as a pale yellow oil.
Reaction SMILES: CN1CCOCC1.ClC(OCC)=O.[NH:14]([C:43]([O:45][CH2:46][C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)=[O:44])[C@H:15]([C:40](O)=[O:41])[CH2:16][CH2:17][C:18](=[O:39])[NH:19][C:20]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[BH4-].[Na+]>C1COCC1.O>[CH2:46]([O:45][C:43](=[O:44])[NH:14][C@H:15]([CH2:40][OH:41])[CH2:16][CH2:17][C:18](=[O:39])[NH:19][C:20]([C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1)[C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1
Reactant: O=C(CC[C@H](NC(=O)OCc1ccccc1)C(=O)O)NC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCOC(=O)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CN1CCOCC1
Product: O=C(CC[C@@H](CO)NC(=O)OCc1ccccc1)NC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 23 °C
Reaction time: 0.33 h

Procedure:
4-Methylmorpholine (1.89 mL, 17.2 mmol, 1 equiv) and ethyl chloroformate (1.65 mL, 17.3 mmol, 1 equiv) were added to a mixture of commercially available Cbz-Gln(Trt)-OH (9.00 g, 17.2 mmol, 1 equiv) in THF (23 mL) at −10° C. After stirring 20 min, the reaction mixture was filtered and the filtrate was added dropwise to a suspension of NaBH4 (1.47 g, 38.9 mmol, 2.25 equiv) in H2O (10 mL) at 0° C. The resulting mixture was allowed to warm to 23° C. and stirred for 5 h. It was then cooled again to 0° C., quenched by the careful addition of 1 N HCl (30 mL) and then partitioned between MTBE (500 mL) and brine (2×100 mL). The organic phase was dried over Na2SO4 and evaporated to provide the title intermediate which was used without further purification.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:9][CH2:10][N:11]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH2:12][CH:13]=2)=[CH:4][CH:3]=1.C([Li])CCC.[C:26](=O)([O:30]CC)[O:27][CH2:28][CH3:29].O>O1CCCC1.CCCCCC>[CH2:14]([N:11]1[CH2:12][CH:13]=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([C:26]([O:27][CH2:28][CH3:29])=[O:30])=[CH:3][CH:4]=2)[CH2:9][CH2:10]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CCOC(=O)OCC
Reactant: Brc1ccc(C2=CCN(Cc3ccccc3)CC2)cc1
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCOC(=O)c1ccc(C2=CCN(Cc3ccccc3)CC2)cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 11 g of 4-(4-bromophenyl)-1-benzyl-1,2,3,6-tetrahydropyridine in 200 ml of tetrahydrofuran was added 27 ml of a 2.5 M solution of n-butyllithium in hexane at −78° C. and the resulting mixture was stirred at the same temperature for 15 minutes. Into the reaction mixture was dropped 42 ml of diethyl carbonate and the mixture was heated to room temperature over 15 minutes. After adding water, the reaction mixture was extracted with ethyl acetate, washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. After distilling off the solvent under reduced pressure, the residue was purified by silica gel column chromatography (eluted with n-hexane/ethyl acetate) to thereby give 2.8 g of the title compound as a yellow oily substance.
Reaction SMILES: [N:1](OCCC(C)C)=O.[NH2:9][C:10]1[C:15]([F:16])=[CH:14][CH:13]=[CH:12][C:11]=1[C:17](=[O:38])[CH:18]=[P:19]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>Cl>[F:16][C:15]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:10]=1[N:9]=[N:1][C:18](=[P:19]([C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1)([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)[C:17]2=[O:38]
Reactant: Nc1c(F)cccc1C(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(C)CCON=O
Agent: Cl
Product: O=C1C(=P(c2ccccc2)(c2ccccc2)c2ccccc2)N=Nc2c(F)cccc21
Temperature: 25 °C

Procedure:
Isoamyl nitrite (1.9 eq) was added to a stirred solution of D2 in HCl (0.5 M solution in MeOH) at 0° C. After the consumption of the starting material (15-30 min), the solution was allowed to warm to RT and was made alkaline (pH=9) by addition of 10% NaOH. The resulting precipitate was collected by filtration affording the title compound as a white solid.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[N:2]1.Cl[C:7]1[N:8]=[C:9]([NH:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]3[O:25][CH2:26][CH2:27][O:28][C:21]=3[CH:20]=2)[C:10]2[C:15]([CH3:16])=[CH:14][S:13][C:11]=2[N:12]=1>>[N:1]1([C:7]2[N:8]=[C:9]([NH:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]4[O:25][CH2:26][CH2:27][O:28][C:21]=4[CH:20]=3)[C:10]3[C:15]([CH3:16])=[CH:14][S:13][C:11]=3[N:12]=2)[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: c1cn[nH]c1
Reactant: Cc1csc2nc(Cl)nc(NCc3ccc4c(c3)OCCO4)c12
Product: Cc1csc2nc(-n3cccn3)nc(NCc3ccc4c(c3)OCCO4)c12

Procedure:
Following the procedure of Example 97, the reaction of pyrazole with 2-chloro-5-methyl-4-(3,4-ethylendioxybenzylamino)-thieno-[2,3-d]-pyrimidine gives 2-(pyrazol-1-yl)-5-methyl-4-(3,4-ethylendioxybenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:6][CH2:7][CH:8]([OH:11])[CH2:9][OH:10])[CH:4]=[CH2:5].Br[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]>C1C=CC=CC=1.[O-][Mo]([O-])(=O)=O>[CH2:3]([O:6][CH2:7][CH:8]([O:11][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH2:9][O:10][CH2:15][CH:14]=[CH2:13])[CH2:4][CH2:5][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH3:16]
Reactant: CCCCCCCCCCCCCCBr
Reactant: C=CCOCC(O)CO
Agent: O=[Mo](=O)([O-])[O-]
Agent: [H-]
Agent: [Na+]
Solvent: c1ccccc1
Product: C=CCOCC(COCCCCCCCCCCCCCC)OCCCCCCCCCCCCCC
Temperature: 25 °C
Yield: 57.2 %

Procedure:
Benzene (250 ml) was added to 95% sodium hydride (11.4 g, 450.0 mmol), and the flask was flushed with nitrogen and sealed. A solution of 3-allyloxy-1,2-propanediol (6.6 g, 50.0 mmol) in benzene (75 ml) was added to the flask. Using a syringe, 97% 1-bromotetradecane (36.7 ml, 120.0 mmol) was added to the flask and the reaction was left to reflux overnight under a constant stream of nitrogen. Once cooled to room temperature, the excess sodium hydride was slowly quenched with ethanol until no further effervescence was observed. The solution was transferred to a reparatory funnel with benzene (250 ml) and washed with distilled water (3×200 ml). The organic layer was dried with magnesium sulfate and the solvent removed on the rotary evaporator to yield a colourless oil. TLC (5% ether-hexane, developed in Molybdate) indicated that most of the starting material had reacted to form product. This resulting product was further purified by flash column chromatography (1-5% ether-hexane) to yield 15.0 g (57.3%) of 1,2-dimyristyloxy-3-allyloxypropane 1.
Reaction SMILES: O.[NH2:2][C:3]1[C:8]([Cl:9])=[CH:7][C:6]([C:10]([CH:12]=O)=[O:11])=[CH:5][C:4]=1[Cl:14].[CH3:15][C:16]([NH2:29])([CH3:28])[CH2:17][NH:18][C:19](=[O:27])[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C([BH3-])#N.[Na+]>C(#N)C.C(O)(=O)C>[ClH:9].[ClH:9].[NH2:2][C:3]1[C:4]([Cl:14])=[CH:5][C:6]([CH:10]([OH:11])[CH2:12][NH:29][C:16]([CH3:28])([CH3:15])[CH2:17][NH:18][C:19](=[O:27])[CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:7][C:8]=1[Cl:9]
Reactant: Nc1c(Cl)cc(C(=O)C=O)cc1Cl
Reactant: CC(C)(N)CNC(=O)Cc1ccccc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O
Solvent: CC#N
Solvent: CC(=O)O
Product: CC(C)(CNC(=O)Cc1ccccc1)NCC(O)c1cc(Cl)c(N)c(Cl)c1
Product: Cl
Reaction time: 0.5 h
Yield: 174.6 %

Procedure:
A mixture of 4-amino-3,5-dichlorophenylglyoxal hydrate (2.35 g.) and 1,1-dimethyl-2-(2-phenylacetamido)ethylamine (2.06 g.) in acetonitrile (50 ml.) and acetic acid (3 ml.) was stirred for 30 minutes. Sodium cyanoborohydride (1.26 g.) was then added to the reaction mixture in portions over 5 minutes. After 16 hours of stirring the mixture was evaporated and the residue was partitioned between 10% v/v aqueous acetic acid (100 ml.) and ethyl acetate (100 ml.). The organic phase was separated, dried (MgSO4) and evaporated. The semi-solid residue was dissolved in propan-2-ol (10 ml.) and ethereal hydrogen chloride was added to bring the pH to 2-3. Addition of dry ether then gave a precipitate (2.8 g., 63%) of 1-(4-amino-3,5-dichlorophenyl)-2-[1,1-dimethyl-2-(2-phenylacetamido)ethylamino]ethanol dihydrochloride m.p. 105°-108° C.
Reaction SMILES: Cl.[O:2]=[C:3]1[NH:12][C:11]2[N:10]=[CH:9][C:8](/[CH:13]=[CH:14]/[C:15]([OH:17])=O)=[CH:7][C:6]=2[CH2:5][CH2:4]1.Cl.[CH3:19][C:20](=[CH2:27])[CH2:21][O:22][CH:23]1[CH2:26][NH:25][CH2:24]1.CCN(C(C)C)C(C)C.CCN=C=NCCCN(C)C>CN(C1C=CN=CC=1)C.CN(C=O)C>[CH3:27][C:20](=[CH2:19])[CH2:21][O:22][CH:23]1[CH2:26][N:25]([C:15](=[O:17])/[CH:14]=[CH:13]/[C:8]2[CH:7]=[C:6]3[C:11](=[N:10][CH:9]=2)[NH:12][C:3](=[O:2])[CH2:4][CH2:5]3)[CH2:24]1
Reactant: C=C(C)COC1CNC1
Reactant: O=C(O)/C=C/c1cnc2c(c1)CCC(=O)N2
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C=C(C)COC1CN(C(=O)/C=C/c2cnc3c(c2)CCC(=O)N3)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 16.5 %

Procedure:
A 16 mL vial flask was successively charged with (2E)-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylic acid hydrochloride (60 mg, 0.24 mmol), DMF (5.8 mL), 3-[(2-methylprop-2-en-1-yl)oxy]azetidine hydrochloride (78 mg, 0.48 mmol; which may be prepared as described in Step 2), DIPEA (119 μL, 0.72 mmol), DMAP (2.4 mg, 0.02 mmol) and EDAC (56 mg, 0.29 mmol). The reaction mixture was stirred at room temperature overnight and concentrated to dryness. The residue was precipitated in methanol/water and then filtered. The resulting solid was dissolved in chloroform and washed with water to give a beige solid. This solid was triturated in diethyl ether to give the title compound (13 mg, 16%) as a white solid.