Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:8])([F:7])[C:3]([F:6])([F:5])I.C[Li].[Br-].[Li+].[Br:13][C:14]1[CH:19]=[CH:18][N:17]=[C:16]([CH:20]=[CH:21][C:22](N(OC)C)=[O:23])[CH:15]=1>>[Br:13][C:14]1[CH:19]=[CH:18][N:17]=[C:16]([CH:20]=[CH:21][C:22](=[O:23])[C:3]([F:6])([F:5])[C:2]([F:8])([F:7])[F:1])[CH:15]=1
Reactant: CON(C)C(=O)C=Cc1cc(Br)ccn1
Reactant: FC(F)(F)C(F)(F)I
Agent: [Br-]
Agent: [Li+]
Agent: [Li]C
Product: O=C(C=Cc1cc(Br)ccn1)C(F)(F)C(F)(F)F
Reaction time: 0.33 h
Yield: 74.9 %

Procedure:
To a saturated solution of pentafluoroiodoethane (0.84 M, in diethyl ether) (31.6 mL, 26.6 mmol), was slowly added a solution of methyllithium/lithium bromide (1.5 M, in diethyl ether) (17.7 mL, 26.6 mmol) under nitrogen atmosphere at −78° C. The reaction mixture was stirred for 20 minutes and then a solution of 3-(4-bromo-pyridin-2-yl)-N-methoxy-N-methyl-acrylamide (2.4 g, 8.9 mmol, in diethyl ether/tetrahydrofuran 20.0 mL/20.0 mL) prepared in Step 2 solution was slowly added thereto at −78° C. The reaction mixture was stirred at −78° C. for 1 hour, quenched with distilled water at room temperature, acidified by a 10% potassium hydrogen sulfate solution (pH=5), and then extracted with ethyl acetate. The extract was washed with a saturated solution of sodium hydrogen carbonate, dried on anhydrous magnesium sulfate, and then concentrated under reduced pressure to give a yellow liquid residue. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/5) to give 2.2 g of the titled compound as a yellow solid.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=[S:10].Br[C:12]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)([CH3:18])[C:13]([O:15][CH2:16][CH3:17])=[O:14].CN(C=O)C.[OH-].[Na+]>O>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[S:10][C:12]([C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)([CH3:18])[C:13]([O:15][CH2:16][CH3:17])=[O:14]
Reactant: CCOC(=O)C(C)(Br)c1ccccc1
Reactant: S=C1Cc2ccccc2N1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)(Sc1cc2ccccc2[nH]1)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 70.6 %

Procedure:
Into a solution of 1,3-dihydroindol-2-thione (19.7 g) and ethyl 2-bromo-2-phenylpropionate (33.9 g) indimethylformamide (DMF, 200 ml), an aqueous 2 N sodium hydroxide solution (66 ml) was added dropwise under ice cooling, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with water, and was extracted with ethyl acetate. The organic layer was washed with water, and then with saturated aqueous sodium chloride solution, and was dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. n-Hexane was added to the evaporation residue to cause crystallization. The resulting crystalline matter was recrystallized from ethyl acetate/n-hexane to give 30.3 g (yield: 71%) of product compound as a pale yellow crystal form. The melting point was 97°-99° C.
Reaction SMILES: [N:1]([O-:3])=O.[Na+].[CH3:5][O:6][C:7](=[O:12])[CH2:8][C:9](=[O:11])[CH3:10]>O>[CH3:5][O:6][C:7](=[O:12])[C:8](=[N:1][OH:3])[C:9](=[O:11])[CH3:10]
Reactant: O=N[O-]
Reactant: COC(=O)CC(C)=O
Agent: [Na+]
Solvent: O
Product: COC(=O)C(=NO)C(C)=O
Yield: 110.3 %

Procedure:
Part A: NaNO2 (13.8 gram) was dissolved in water (48 ml) at 4° C. The resulting solution was slowly added to a magnetically stirred solution of 3-oxo-butyric acid methyl ester (17.4 gram, 0.15 mol) while keeping the temperature <5° C. After stirring the mixture for two hours water (120 ml) was added and the resulting mixture was extracted twice with diethyl ether. The combined organic layers were successively washed with water and a 5% aqueous NaHCO3 solution. The organic layer was dried over MgSO4, filtered and thoroughly concentrated to give crude 2-hydroxyimino-3-oxo-butyric acid methyl ester (24 gram) as a colorless oil which was not further purified. 1H-NMR (400 MHz, CDCl3): 2.42 (s, 3H), 3.91 (s, 3H), 9.90 (br s, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:29]=[CH:28][C:5]([C:6]([NH:8][C:9]2[S:13][C:12]([NH:14][C:15]3[CH:24]=[CH:23][C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[CH:16]=3)=[N:11][C:10]=2[C:25]([NH2:27])=[O:26])=[O:7])=[CH:4][CH:3]=1.CCN(CC)CC.[C:37]([O:40][CH2:41][C:42](Cl)=[O:43])(=[O:39])[CH3:38]>C1COCC1>[C:37]([O:40][CH2:41][C:42]([NH:1][C:2]1[CH:29]=[CH:28][C:5]([C:6]([NH:8][C:9]2[S:13][C:12]([NH:14][C:15]3[CH:24]=[CH:23][C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[CH:16]=3)=[N:11][C:10]=2[C:25]([NH2:27])=[O:26])=[O:7])=[CH:4][CH:3]=1)=[O:43])(=[O:39])[CH3:38]
Reactant: NC(=O)c1nc(Nc2ccc3ccccc3c2)sc1NC(=O)c1ccc(N)cc1
Reactant: CC(=O)OCC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=O)OCC(=O)Nc1ccc(C(=O)Nc2sc(Nc3ccc4ccccc4c3)nc2C(N)=O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.5 %

Procedure:
To a mixture of 5-(4-aminobenzamido)-2-(naphthalen-2-ylamino)thiazole-4-carboxamide (0.15 g, 0.37 mmol) and Et3N (0.3 mL, 2.33 mmol) in THF (20 mL) was added acetoxyacetyl chloride (0.12 mL, 1.11 mmol) at 0° C. The mixture was stirred overnight at rt. The solvent was evaporated, and the residue was purified by silica gel column chromatography eluted with 50% EtOAc in hexane to give 0.15 g (80% yield) of the titled compound.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]2[C:5]([C:6](=[O:18])[C:7]([C:15]([OH:17])=[O:16])=[CH:8][N:9]2[CH:12]2[CH2:14][CH2:13]2)=[CH:4][C:3]=1[F:19].[NH:20]1[CH2:24][CH2:23][CH:22]([C:25]2[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=2)[CH2:21]1>>[CH:12]1([N:9]2[C:10]3[C:5](=[CH:4][C:3]([F:19])=[C:2]([N:20]4[CH2:24][CH2:23][CH:22]([C:25]5[CH:26]=[CH:27][N:28]=[CH:29][CH:30]=5)[CH2:21]4)[N:11]=3)[C:6](=[O:18])[C:7]([C:15]([OH:17])=[O:16])=[CH:8]2)[CH2:14][CH2:13]1
Reactant: c1cc(C2CCNC2)ccn1
Reactant: O=C(O)c1cn(C2CC2)c2nc(Cl)c(F)cc2c1=O
Product: O=C(O)c1cn(C2CC2)c2nc(N3CCC(c4ccncc4)C3)c(F)cc2c1=O
Yield: 67 %

Procedure:
Starting from 7-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid (0.85 g, 3.0 mmol) and 4-(3-pyrrolidinyl)pyridine, a procedure analogous to that given in Example 1 provided the title compound (0.79 g, 67%), mp 223°-225° C.
Reaction SMILES: [C:1]([C:3]1[C:4]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([Cl:25])[CH:19]=2)=[C:5]([C:14](O)=[O:15])[S:6][C:7]=1[N:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1)#[N:2].[CH3:26][S:27]([NH2:30])(=[O:29])=[O:28].Cl.CN(C)CCCN=C=NCC>C(Cl)Cl.Cl.O>[C:1]([C:3]1[C:4]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([Cl:25])[CH:19]=2)=[C:5]([C:14]([NH:30][S:27]([CH3:26])(=[O:29])=[O:28])=[O:15])[S:6][C:7]=1[N:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1)#[N:2]
Reactant: N#Cc1c(N2CCOCC2)sc(C(=O)O)c1Cc1ccc(Cl)c(Cl)c1
Reactant: CS(N)(=O)=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: O
Solvent: ClCCl
Product: CS(=O)(=O)NC(=O)c1sc(N2CCOCC2)c(C#N)c1Cc1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 20.2 %

Procedure:
To a mixture of 4-cyano-3-(3,4-dichlorobenzyl)-5-morpholinothiophene-2-carboxylic acid (291 mg, 0.732 mmol), in DCM (5.0 mL) was added methanesulfonamide (87.1 mg, 0.916 mmol), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (176 mg, 0.916 mmol), and N,N-dimethylaminopyridine (103 mg, 0.842 mmol) and the resulting solution was stirred at room temperature overnight. The reaction was diluted with DCM (10 mL), 1N HCl (3 mL) and with water (3 mL). The organic layer was dried, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (MeOH/DCM=0/100→20/80) to give 250 mg of crude product. This material was purified by preparative reverse phase chromatography to give 70 mg (20% yield) of the title compound as a white solid. LC/MS (FA) ES+ 474, 476. 1H NMR (400 MHz, MeOH-d4) δ: 7.45 (d, 1H, J=2.0 Hz)), 7.38 (d, 1H, J=8.4 Hz), 7.25 (dd, 1H, J=8.0, 2.0 Hz), 4.38 (s, 2H), 3.82-3.80 (m, 4H), 3.57-3.55 (m, 4H), 3.18 (s, 3H).
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([NH:8][S:9]([CH3:12])(=[O:11])=[O:10])[CH:5]=[CH:6][CH:7]=1.[OH:13][C:14]1[C:26]([C:27]([F:30])([F:29])[F:28])=[CH:25][CH:24]=[C:23]([CH2:31][O:32][C:33]2[CH:38]=[CH:37][C:36](B3OC(C)(C)C(C)(C)O3)=[CH:35][CH:34]=2)[C:15]=1[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17]>>[OH:13][C:14]1[C:26]([C:27]([F:29])([F:30])[F:28])=[CH:25][CH:24]=[C:23]([CH2:31][O:32][C:33]2[CH:38]=[CH:37][C:36]([C:2]3[CH:7]=[CH:6][CH:5]=[C:4]([NH:8][S:9]([CH3:12])(=[O:11])=[O:10])[CH:3]=3)=[CH:35][CH:34]=2)[C:15]=1[C:16]([O:18][C:19]([CH3:22])([CH3:20])[CH3:21])=[O:17]
Reactant: CS(=O)(=O)Nc1cccc(I)c1
Reactant: CC(C)(C)OC(=O)c1c(COc2ccc(B3OC(C)(C)C(C)(C)O3)cc2)ccc(C(F)(F)F)c1O
Product: CC(C)(C)OC(=O)c1c(COc2ccc(-c3cccc(NS(C)(=O)=O)c3)cc2)ccc(C(F)(F)F)c1O

Procedure:
According to a method similar to Example (31), from N-(3-iodophenyl)methanesulfonamide (134 mg, 0.45 mmol) obtained in Example (35-1) and tert-butyl 2-hydroxy-6-{[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]methyl}-3-(trifluoromethyl)benzoate (250 mg, 0.51 mmol) obtained in Example (22-4), the title compound was obtained as a pale violet powder (20 mg, yield: 8%).
Reaction SMILES: [Si:1](Cl)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:19]([C@@H:22]1[C@@H:29]([O:30][CH2:31][C:32]2[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][CH:33]=2)[C@H:28]([OH:40])[C@@H:27]([CH2:41][OH:42])[O:26][C@H:23]1[S:24][CH3:25])=[N+:20]=[N-:21]>CN(C)C1C=CN=CC=1.ClCCCl.C(Cl)(Cl)Cl>[N:19]([C@@H:22]1[C@@H:29]([O:30][CH2:31][C:32]2[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][CH:33]=2)[C@H:28]([OH:40])[C@@H:27]([CH2:41][O:42][Si:1]([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[O:26][C@H:23]1[S:24][CH3:25])=[N+:20]=[N-:21]
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: COc1ccc(CO[C@H]2[C@H](O)[C@@H](CO)O[C@@H](SC)[C@@H]2N=[N+]=[N-])cc1
Agent: CN(C)c1ccncc1
Solvent: ClC(Cl)Cl
Solvent: ClCCCl
Product: COc1ccc(CO[C@H]2[C@H](O)[C@@H](CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)O[C@@H](SC)[C@@H]2N=[N+]=[N-])cc1
Temperature: 80 °C
Reaction time: 2 h
Yield: 78 %

Procedure:
A mixture of t-butyldiphenylsilyl chloride (8.66 g, 31.53 mmol), 4-dimethylaminopyridine (5.12 g, 42.04 mmol) and methyl 2-azido-2-deoxy-3-O-(4-methoxybenzyl)-1-thio-β-D-glucopyranoside (9) (7.21 g, 21.02 mmol) in dry 1,2-dichloroethane (100 mL) was stirred at 80° C. for 2 hours. The resulting clear solution was cooled to room temperature, diluted with CHCl3 (300 mL), washed with H2O (3×200 mL), brine solution (200 mL), dried over MgSO4 and evaporated. The residue was purified by chromatography using hexane—ether 2:1 as the mobile phase to give methyl 2 -azido-6-O-tert-butyldiphenylsilyl-2-deoxy-3-O-(4-methoxybenzyl-1-thio-β-D glucopyranoside (10) (9.73 g, 80%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([F:25])=[C:6]([C:8]2[N:9]=[C:10](O)[C:11]3[CH:17]=[CH:16][C:15]([NH:18][CH2:19][CH2:20][N:21]([CH3:23])[CH3:22])=[N:14][C:12]=3[N:13]=2)[CH:7]=1.C([O-])(O)=O.[Na+].P(Cl)(Cl)([Cl:33])=O>>[Cl:33][C:10]1[C:11]2[CH:17]=[CH:16][C:15]([NH:18][CH2:19][CH2:20][N:21]([CH3:23])[CH3:22])=[N:14][C:12]=2[N:13]=[C:8]([C:6]2[CH:7]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=2[F:25])[N:9]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CN(C)CCNc1ccc2c(O)nc(-c3cc(Cl)ccc3F)nc2n1
Agent: O=C([O-])O
Agent: [Na+]
Product: CN(C)CCNc1ccc2c(Cl)nc(-c3cc(Cl)ccc3F)nc2n1

Procedure:
The 2-(5-Chloro-2-fluoro-phenyl)-7-(2-di-methylamino-ethylamino)-pyrido[2,3-d]pyrimidin-4-ol (0.18 g) was dissolved in P(O)Cl3 (10 mL) and heated to reflux for 2 hr. The mixture was reduced in volume and NaHCO3 (sat aq) was added. The mixture was extracted with CH2Cl2 (×3). The extracts were combined and dried over MgSO4, filtered and evaporated to dryness to afford N′-[4-Chloro-2-(5-chloro-2-fluoro-phenyl)-pyrido[2,3-d]pyrimidin-7-yl]-N,N-dimethylethane-1,2-diamine.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)=[CH:8][CH:7]=1)=[O:4].C(N(CC)CC)C.[N:28]1([S:34](Cl)(=[O:36])=[O:35])[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1>ClCCl>[F:20][C:2]([F:1])([F:19])[C:3]([NH:5][C:6]1[CH:7]=[CH:8][C:9]([CH2:12][CH:13]2[CH2:14][CH2:15][N:16]([S:34]([N:28]3[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]3)(=[O:36])=[O:35])[CH2:17][CH2:18]2)=[CH:10][CH:11]=1)=[O:4]
Reactant: O=C(Nc1ccc(CC2CCNCC2)cc1)C(F)(F)F
Reactant: O=S(=O)(Cl)N1CCCCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Nc1ccc(CC2CCN(S(=O)(=O)N3CCCCC3)CC2)cc1)C(F)(F)F
Temperature: 2.5 °C
Reaction time: 1.5 h
Yield: 63.3 %

Procedure:
A solution of 2,2,2-trifluoro-N-[4-(piperidin-4-ylmethyl)-phenyl]acetamide (0.5 g, 1.75 mmol) (prepared as previously described in Example 19, steps 1 to 3) and triethylamine in dichloromethane (10 mL) was cooled in an ice bath under a nitrogen atmosphere. The mixture was then treated with a solution of 1-piperidinesulfonyl chloride (0.39 g, 2.09 mmol) in dichloromethane (1 mL). The reaction mixture was stirred for 1.5 hours at 0-5° C. and quenched with water. The organic layer was separated, and the aqueous layer extracted with dichloromethane. The combined organic extracts were washed with water and brine, dried, and solvents removed in vacuo. The residue was chromatographed on silica gel, eluting with 30% ethyl acetate/hexanes, to give 2,2,2-trifluoro-N-[4-(1-piperidinesulfonylpiperidin-4-ylmethyl)-phenyl]acetamide (0.48 g) as a white solid, m.p. 156-157° C.; Analysis for C19H26N3O3SF3: Calc.: C, 52.64; H, 6.05; N, 9.69; Found: C, 52.84; H, 6.00; N, 9.79.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[C:22](=[O:23])[N:21]([CH2:24][CH3:25])[C:12]2[N:13]=[C:14](S(C)(=O)=O)[N:15]=[CH:16][C:11]=2[CH:10]=1.[CH2:26]([O:28][C:29]1[CH:35]=[CH:34][C:32]([NH2:33])=[CH:31][CH:30]=1)[CH3:27]>C(O)(=O)C.O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[C:22](=[O:23])[N:21]([CH2:24][CH3:25])[C:12]2[N:13]=[C:14]([NH:33][C:32]3[CH:34]=[CH:35][C:29]([O:28][CH2:26][CH3:27])=[CH:30][CH:31]=3)[N:15]=[CH:16][C:11]=2[CH:10]=1
Reactant: CCn1c(=O)c(-c2c(Cl)cccc2Cl)cc2cnc(S(C)(=O)=O)nc21
Reactant: CCOc1ccc(N)cc1
Solvent: O
Solvent: CC(=O)O
Product: CCOc1ccc(Nc2ncc3cc(-c4c(Cl)cccc4Cl)c(=O)n(CC)c3n2)cc1

Procedure:
A mixture of 0.150 g (0.38 mmol) of 6-(2,6-dichlorophenyl)-8-ethyl-2-methanesulfonyl-8H-pyrido[2,3-d]pyrimidin-7-one of Example 68 and 0.500 g (3.60 mmol) of 4-ethoxyaniline was fused in a 160° C. oil bath for 10 minutes. The dark violet melt was cooled and dissolved in 1 mL of warm glacial acetic acid. This solution was diluted to 10 mL volume with water to precipitate a solid. The solid was filtered, washed well with water, and dried; wt 0.140 g. Purification was effected by filtration of an ethyl acetate solution through a layer of silica gel and washing the silica gel with ethyl acetate. The filtrate was concentrated to 2 mL volume and 2 mL of petroleum ether was added. The crystals that separated on inducement were filtered and washed with ether; wt 0.094 g; mp 192°-194° C.
Reaction SMILES: C([O:5][C:6]([NH:8][C@@H:9]1[CH2:14][CH2:13][C@H:12]([C:15]([O:17][CH3:18])=[O:16])[CH2:11][C@@H:10]1[NH:19][C:20]([C:22]1[NH:23][C:24]2[C:29]([CH:30]=1)=[CH:28][C:27]([Cl:31])=[CH:26][CH:25]=2)=[O:21])=O)(C)(C)C.Cl.[CH3:33][N:34]1[CH2:39][CH2:38][C:37]2[N:40]=[C:41](C([O-])=O)[S:42][C:36]=2[CH2:35]1.[Li+]>C(O)C>[Cl:31][C:27]1[CH:28]=[C:29]2[C:24](=[CH:25][CH:26]=1)[NH:23][C:22]([C:20]([NH:19][C@H:10]1[CH2:11][C@@H:12]([C:15]([O:17][CH3:18])=[O:16])[CH2:13][CH2:14][C@H:9]1[NH:8][C:6]([C:41]1[S:42][C:36]3[CH2:35][N:34]([CH3:33])[CH2:39][CH2:38][C:37]=3[N:40]=1)=[O:5])=[O:21])=[CH:30]2
Reactant: COC(=O)[C@H]1CC[C@@H](NC(=O)OC(C)(C)C)[C@@H](NC(=O)c2cc3cc(Cl)ccc3[nH]2)C1
Reactant: CN1CCc2nc(C(=O)[O-])sc2C1
Agent: Cl
Agent: [Li+]
Solvent: CCO
Product: COC(=O)[C@H]1CC[C@@H](NC(=O)c2nc3c(s2)CN(C)CC3)[C@@H](NC(=O)c2cc3cc(Cl)ccc3[nH]2)C1

Procedure:
(1R*,2S*,4S*)-N1-tert-Butoxycarbonyl-N2-[(5-chloroindol-2-yl)carbonyl]-4-methoxycarbonyl-1,2-cyclohexanediamine was treated with a saturated ethanol solution of hydrochloric acid and then condensed with lithium 5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]-pyridine-2-carboxylate in a similar manner to Example 118 to obtain the title compound.
Reaction SMILES: [CH2:1]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9][C:8]2[C:3](=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:2]1.[Br:16][C:17]1[CH:24]=[C:21]([CH:22]=O)[C:20]([O:25][CH3:26])=[CH:19][CH:18]=1>>[Br:16][C:17]1[CH:18]=[CH:19][C:20]([O:25][CH3:26])=[C:21]([CH:24]=1)[CH:22]=[C:9]1[C:8]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[CH2:2][CH2:1][C:15]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]1=2
Reactant: c1ccc2c(c1)CCc1ccccc1C2
Reactant: COc1ccc(Br)cc1C=O
Product: COc1ccc(Br)cc1C=C1c2ccccc2CCc2ccccc21
Yield: 65.5 %

Procedure:
Following the procedures essentially as described for Preparation 5 and Example 28 above, using dibenzosuberane (15.0 g, 77.2 mmol) and 5-bromo-o-anisaldehyde (16.6 g, 77.2 mmol), recrystallization from boiling toluene/hexanes affords 19.78 g (65%) of the title compound as a tan solid. 1H-NMR (CDCl3) δ 2.76-3.70 (br m, 4H), 3.81 (s, 3H), 6.69 (d, 1H), 6.76 (d, 1H), 6.88-7.29 (m, 9H), 7.53 (m, 1H); HPLC shows 100% purity.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([OH:14])[CH2:13][CH2:12][NH:11][CH2:10]2)[CH:5]=[C:6]([F:8])[CH:7]=1.C(#N)C.C(=O)([O-])[O-].[K+].[K+].I[CH2:25][CH2:26][CH3:27]>O>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([OH:14])[CH2:13][CH2:12][N:11]([CH2:25][CH2:26][CH3:27])[CH2:10]2)[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: OC1(c2cc(F)cc(Cl)c2)CCNC1
Reactant: CCCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CCCN1CCC(O)(c2cc(F)cc(Cl)c2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 44.2 %

Procedure:
A mixture of 3-(3-chloro-5-fluorophenyl)pyrrolidin-3-ol (1.10 g, 5 mmol), acetonitrile (20 mL), potassium carbonate (1.4 g, 10.1 mmol) and iodopropane (1.13 mg, 6.65 mmol) was stirred at ambient temperature for 2 h. The temperature was shortly raised to 40° C. twice during this period. Water was added and the aqueous phase was extracted with ethyl acetate, the combined organic phase was dried (MgSO4), and evaporated. Purification by flash chromatography on silica gel (ethyl acetate/methanol, 1:0 to 1:1) gave the title compound (0.57 g). The amine was converted to the oxalic acid salt and recrystallized from ethanol/diisopropyl ether: M.p. 157.2° C.; MS m/z (relative intensity, 70 eV) 257 (M+, 8), 228 (bp), 198 (46), 129 (36), 84 (59).
Reaction SMILES: F[C:2]1[CH:28]=[CH:27][C:5]2[N:6]=[C:7]([C:9]3[C:10]([NH2:26])=[N:11][CH:12]=[C:13]([C:15]4[CH:16]=[N:17][N:18]([CH:20]5[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]5)[CH:19]=4)[CH:14]=3)[S:8][C:4]=2[CH:3]=1.I[C:30]1SC2C=CC=C(C)C=2N=1>>[CH3:30][C:27]1[C:5]2[N:6]=[C:7]([C:9]3[C:10]([NH2:26])=[N:11][CH:12]=[C:13]([C:15]4[CH:16]=[N:17][N:18]([CH:20]5[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]5)[CH:19]=4)[CH:14]=3)[S:8][C:4]=2[CH:3]=[CH:2][CH:28]=1
Reactant: Nc1ncc(-c2cnn(C3CCNCC3)c2)cc1-c1nc2ccc(F)cc2s1
Reactant: Cc1cccc2sc(I)nc12
Product: Cc1cccc2sc(-c3cc(-c4cnn(C5CCNCC5)c4)cnc3N)nc12

Procedure:
Same procedure as 3-(6-fluorobenzothiazol-2-yl)-5-(1-piperidin-4-yl-1H-pyrazol-4-yl)-pyridin-2-ylamine except using 2-iodo-4-methyl-1,3-benzothiazole in place of 2-chloro-6-fluorobenzothiazole to afford the title compound as a yellow solid. 1H NMR (400 MHz, DMSO-d6): δ=2.10-2.31 (m, 4H), 2.74 (s, 3H), 3.05-3.18 (m, 2H), 3.41 (d, J=13.2 Hz, 2H), 4.49-4.57 (m, 1H), 7.41-7.48 (m, 2H), 8.02 (dd, J=6.4, 2.7 Hz, 1H), 8.09 (s, 1H), 8.45 (s, 1H), 8.49 (br. s., 1H), 8.56 (d, J=1.8 Hz, 1H). MS (ES+): m/z=391.14 [MH+]. HPLC: tR=2.11 min (ZQ2, polar—5 min).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[N:18][OH:19])[CH2:9][O:10][CH:11]([CH:16]=[CH2:17])[C:12]([F:15])([F:14])[F:13].C1(C=CC(O)=CC=1)O.Cl>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]12[CH2:9][O:10][CH:11]([C:12]([F:15])([F:14])[F:13])[CH:16]1[CH2:17][O:19][NH:18]2
Reactant: C=CC(OCC(=NO)c1ccccc1F)C(F)(F)F
Agent: Cl
Agent: Oc1ccc(O)cc1
Product: Fc1ccccc1C12COC(C(F)(F)F)C1CON2
Temperature: 128 °C
Reaction time: 1 h

Procedure:
To a solution of 1-(2-fluorophenyl)-2-(1,1,1-trifluorobut-3-en-2-yloxy)ethanone oxime 4 (1.085 kg, 3.328 mol) in xylenes (6.9 L) was added hydroquinone (86.2 g, 0.8 mol) at rt. The solution was heated to 128° C. (internal temperature) for 18 h. The solution was cooled to rt, and hexanes (7.0 L) was added, followed by 4.0 M aq. HCl (2.4 L). The reaction mixture was stirred for 1 h, and filtered. To the solid was added water (2.0 L), methyl tert-butyl ether (7.0 L) and 25% wt. aq. NaOH (0.4 L). The aq, layer was extracted once with methyl tert-butyl ether (7.0 L), the organics were combined, washed with 27% aq. NaCl (2.0 L) and concentrated under vacuum to a black oil 5 (512.0 g, 56%).
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]2[C:8]([C:11]([NH:13][C:14]([CH3:25])([CH3:24])[CH2:15][O:16][Si:17]([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18])=[O:12])=[CH:9][NH:10][C:5]2=[N:4][CH:3]=1.[C:26]([O:32][CH2:33]Cl)(=[O:31])[C:27]([CH3:30])([CH3:29])[CH3:28].C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[C:26]([O:32][CH2:33][N:10]1[C:5]2[C:6](=[N:7][C:2]([Br:1])=[CH:3][N:4]=2)[C:8]([C:11](=[O:12])[NH:13][C:14]([CH3:25])([CH3:24])[CH2:15][O:16][Si:17]([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:18])[CH3:19])=[CH:9]1)(=[O:31])[C:27]([CH3:30])([CH3:29])[CH3:28]
Reactant: CC(C)(C)C(=O)OCCl
Reactant: CC(C)(CO[Si](C)(C)C(C)(C)C)NC(=O)c1c[nH]c2ncc(Br)nc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(CO[Si](C)(C)C(C)(C)C)NC(=O)c1cn(COC(=O)C(C)(C)C)c2ncc(Br)nc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 44 %

Procedure:
To a stirred mixture of 2-bromo-N-(1-(tert-butyldimethylsilyloxy)-2-methylpropan-2-yl)-5H-pyrrolo[3,2-b]pyrazine-7-carboxamide in DMF (5 mL) was added chloromethyl pivalate (288 mg, 1.92 mmol) followed by K2CO3 (353 mg, 2.56 mmol). The mixture was stirred at room temperature for 16 hours, then poured into water and extracted with EtOAc (3×10 mL). The combined organic layers were washed with brine and dried over Na2SO4. After filtration and concentration, the residue was purified by column chromatography on silica gel eluting with petroleum ether/EtOAc (5:1, v/v) to give (2-bromo-7-(1-(tert-butyldimethylsilyloxy)-2-methylpropan-2-ylcarbamoyl)-5H-pyrrolo[3,2-b]pyrazin-5-yl)methyl pivalate (305 mg, 44% over two steps) as a yellow solid. MS: (M+H)+=541; 1H NMR (300 MHz, CDCl3): δ 8.41 (s, 1H), 8.33 (s, 1H), 7.84 (s, 1H), 6.20 (s, 2H), 3.71 (s, 2H), 1.49 (s, 6H), 1.15 (s, 9H), 0.90 (s, 9H), 0.09 (s, 6H).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[CH:11]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:9]=[CH:8]2)#[N:2].Cl>CO.[Pd]>[NH2:2][CH2:1][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[CH:11]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:9]=[CH:8]2
Reactant: COC(=O)c1ccc2cccc(C#N)c2c1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: COC(=O)c1ccc2cccc(CN)c2c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 74.5 %

Procedure:
A mixture of methyl 8-cyano-2-naphthoate (1.0 g, 0.0047 mol) in methanol (35 mL) with concentrated hydrochloric acid (0.69 mL) and palladium on carbon catalyst (0.20 g, 5% Pd/C) was shaken for 6 hours at ambient temperature under an atmosphere of hydrogen (50 psi). The reaction mixture was filtered over Celite@ and washed with-methanol. The filtrate was evaporated to dryness under reduced pressure and the residue was triturated with hexane to give methyl 8-aminomethyl-2-naphthoate (0.76 g, 0.0035 mol, 75%) as an oil. 1H NMR (DMSO) d 8.75 (s, 1H), 8.5 (bs, 2H), 8.2-8.05 (m, 3H), 7.75-7.70 (m, 2H), 4.6 (s, 2H), 3.95 (m, 3H).
Reaction SMILES: [CH2:1]=[CH:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[CH3:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH:19]=[CH:20][CH2:21][CH2:22][CH2:23]CCCCC>>[CH2:1]=[CH:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH3:11]
Reactant: CCCCCCCCC=CCCCCCCCC
Reactant: C=CCCCCCCCC
Product: C=CCCCCCCCCCCCCCCCCCCCCC
Reaction time: 0.08 h

Procedure:
Example 1 was repeated, with the difference that 20 ml. of 1-decene was utilized in place of 9-octadecene. Within 5 minutes, 4.8% by weight of tricosene was formed and within 30 minutes, 5.7% by weight of tricosene was obtained.