Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OP([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])(OCC)=O)C.[H-].[Na+].[Br:17][C:18]1[O:22][C:21]([CH:23]=O)=[CH:20][CH:19]=1>CN(C)C=O>[Br:17][C:18]1[O:22][C:21](/[CH:23]=[CH:9]/[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:20][CH:19]=1
Reactant: O=Cc1ccc(Br)o1
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)/C=C/c1ccc(Br)o1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 95.8 %

Procedure:
To a solution (200 ml) of ethyl diethylphosphonoacetate (10.5 g) in N,N-dimethylformamide was added sodium hydride (60% in oil, 1.87 g), and the mixture was stirred under a nitrogen atmosphere at room temperature for 15 min. To this solution was added a solution of 5-bromo-2-furaldehyde (7.45 g) in N,N-dimethylformamide (40 ml), and the mixture was stirred under a nitrogen atmosphere at room temperature for 1 hr. The reaction was quenched with saturated ammonium chloride solution (50 ml) and the reaction solution was partitioned between ethyl acetate (900 mL) and water (900 mL). The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure and the obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate 90:10-85:15) to give the title compound (10.0 g, yield 96%) as a pale-yellow solid.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[C:8]([F:10])[C:7]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])=[C:6]([F:16])[CH:5]=1)(=O)[CH3:2].[CH3:17][C:18]([S@:21]([NH2:23])=[O:22])([CH3:20])[CH3:19]>C1COCC1.[Cl-].[Na+].O>[F:10][C:8]1[CH:9]=[C:4]([C:1](=[N:23][S:21]([C:18]([CH3:20])([CH3:19])[CH3:17])=[O:22])[CH3:2])[CH:5]=[C:6]([F:16])[C:7]=1[NH:11][S:12]([CH3:15])(=[O:14])=[O:13]
Reactant: CC(C)(C)[S@](N)=O
Reactant: CC(=O)c1cc(F)c(NS(C)(=O)=O)c(F)c1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(=NS(=O)C(C)(C)C)c1cc(F)c(NS(C)(=O)=O)c(F)c1
Temperature: 90 °C
Reaction time: 8 h
Yield: 84.6 %

Procedure:
To a solution of N-(4-acetyl-2,6-difluoro-phenyl)-methanesulfonamide (1.84 g, 7.38 mmol) and (R)-(+)-2-methyl-2-propanesulfinamide (1.07 g, 8.86 mL) in THF (15 mL) was added dropwise Ti(OEt)4 (2.61 mL, 12.6 mmol) at room temperature. The mixture was stirred overnight at 90° C. The mixture cooled to room temperature and then was added brine. After the mixture was extracted three times with EtOAc, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The crude residue was purified by chromatography to yield N-{2,6-difluoro-4-[1-(2-methyl-propane-2-sulfinylimino)-ethyl]-phenyl}-methanesulfonamide (2.2 g, 85%). To a solution of N-{2,6-difluoro-4-[1-(2-methyl-propane-2-sulfinylimino)-ethyl]-phenyl}-methanesulfonamide (2.2 g, 6.24 mmol) in THF (20 mL) was added portionwise NaBH4 (944 mg, 24.9 mmol) dissolved in THF (2 mL) at −48° C. The mixture was stirred for 10 hours at −48° C. room temperature, and then CH3OH was added dropwise until gas was no longer evolved. The mixture was concentrated under reduced pressure, and then was purified by chromatography to afford N-{2,6-difluoro-4-[1-(2-methyl-propane-2-sulfinylamino)-ethyl]-phenyl}-methanesulfonamide (1.89 g, 50%).
Reaction SMILES: Cl[O-].[Na+].[Cl:4][C:5]1[C:10]([Cl:11])=[C:9](NN)[C:8]([Cl:14])=[C:7]([Cl:15])[N:6]=1>>[Cl:4][C:5]1[C:10]([Cl:11])=[CH:9][C:8]([Cl:14])=[C:7]([Cl:15])[N:6]=1
Reactant: NNc1c(Cl)c(Cl)nc(Cl)c1Cl
Agent: [Na+]
Agent: [O-]Cl
Product: Clc1cc(Cl)c(Cl)nc1Cl

Procedure:
To a reaction vessel containing 200 milliliters (0.14 mole) of 5.25 percent sodium hypochlorite was added 10 grams (0.04 mole) of 2,3,5,6-tetrachloro-4-hydrazinopyridine. The mixture was heated at the boiling point for 1 hour, cooled and the solid which precipitated was recovered by filtration and dried. The 2,3,5,6-tetrachloropyridine was recovered in a yield of 7.0 grams (84 percent of theoretical) and the structure of the product was confirmed by infrared analysis and vapor phase chromatography.
Reaction SMILES: F[C:2]1[C:7]([C:8]([OH:10])=[O:9])=[C:6]([I:11])[C:5]([CH3:12])=[CH:4][CH:3]=1.[F:13]C1C(C)=C(C=CC=1)N>>[F:13][C:4]1[CH:3]=[CH:2][C:7]([C:8]([OH:10])=[O:9])=[C:6]([I:11])[C:5]=1[CH3:12]
Reactant: Cc1ccc(F)c(C(=O)O)c1I
Reactant: Cc1c(N)cccc1F
Product: Cc1c(F)ccc(C(=O)O)c1I

Procedure:
The title compound was prepared following the same general protocol as described for 6-fluoro-2-iodo-3-methylbenzoic acid in Example A352 using 3-fluoro-2-methylaniline. MS (ESI) 281 (M+H).
Reaction SMILES: [CH3:1][NH:2][CH3:3].[H-].[Na+].[Cl:6][C:7]1[CH:12]=[C:11]([CH2:13]Cl)[CH:10]=[C:9]([Cl:15])[C:8]=1[C:16]1[NH:17][C:18]2[C:24]3[CH:25]=[CH:26][N:27]=[CH:28][C:23]=3[NH:22][C:21]3[N:29]=[CH:30][CH:31]=[CH:32][C:20]=3[C:19]=2[N:33]=1>CN(C)C=O.CO>[Cl:6][C:7]1[CH:12]=[C:11]([CH2:13][N:2]([CH3:3])[CH3:1])[CH:10]=[C:9]([Cl:15])[C:8]=1[C:16]1[NH:17][C:18]2[C:24]3[CH:25]=[CH:26][N:27]=[CH:28][C:23]=3[NH:22][C:21]3[N:29]=[CH:30][CH:31]=[CH:32][C:20]=3[C:19]=2[N:33]=1
Reactant: ClCc1cc(Cl)c(-c2nc3c([nH]2)-c2ccncc2Nc2ncccc2-3)c(Cl)c1
Reactant: CNC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Product: CN(C)Cc1cc(Cl)c(-c2nc3c([nH]2)-c2ccncc2Nc2ncccc2-3)c(Cl)c1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 31 %

Procedure:
A solution of dimethylamine (23 μL, 2.0 M in tetrahydrofuran) was dissolved in N,N-dimethylformamide (0.5 mL) and cooled to 0° C. Sodium hydride (1.1 mg, 0.05 mmol) was added and the mixture was stirred for 15 minutes. 2-[2,6-dichloro-4-(chloromethyl)phenyl]-3,8-dihydroimidazo[4,5-d]dipyrido[2,3-b:4′,3′-f]azepine (10.0 mg, 0.02 mmol) was added and the mixture was stirred at room temperature for 16 hours. The reaction mixture was diluted with methanol and purified on preparative LCMS at pH 10 to give the desired product (3.2 mg, 31%). LC/MS: 437 (M+H)+.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([O:27][CH:28]4[CH2:32][CH2:31][CH2:30][CH2:29]4)[CH:20]=3)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)=[CH:7][CH:6]=1)([O:3]C)=[O:2].[OH-:33].[Na+]>CO>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([C:11]#[C:12][C:13]2([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([O:27][CH:28]4[CH2:29][CH2:30][CH2:31][CH2:32]4)[CH:20]=3)[CH2:18][CH2:17][C:16](=[O:33])[CH2:15][CH2:14]2)=[CH:9][CH:10]=1)([OH:3])=[O:2]
Reactant: [OH-]
Reactant: COC(=O)c1ccc(C#CC2(c3ccc(OC)c(OC4CCCC4)c3)CCCCC2)cc1
Agent: [Na+]
Solvent: CO
Product: COc1ccc(C2(C#Cc3ccc(C(=O)O)cc3)CCC(=O)CC2)cc1OC1CCCC1
Yield: 54.6 %

Procedure:
A stirred solution of 4-(4-carbomethoxyphenylethynyl)-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexane (0.146 g, 0.326 mmol) in dry methanol (5 mL) was treated with 10% aqueous sodium hydroxide solution (0.46 mL, 1.15 mmol) under an argon atmosphere as described in Example 13. The crude acid was purified by chromatography (silica, ethyl acetate/methylene chloride/formic acid; 10:90:1), the product fractions washed with water three times, was stripped in vacuo, was crystalized with ether and was dried in vacuo to afford the titled compound as a white solid (0.077 g, 55%), mp 170°-171° C. Anal. (C27H28O5) calcd: C 74.98, H 6.53 found: C 74.78, H 6.54.
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.[C:6]1([C:12]2[C:21]3[N:20]=[CH:19][CH:18]=[CH:17][C:16]=3[C:15](=O)[NH:14][CH:13]=2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[OH-].[Na+]>C1(C)C=CC=CC=1.CN(C)C1C=CC=CC=1>[C:6]1([C:12]2[CH:13]=[N:14][C:15]([Cl:3])=[C:16]3[C:21]=2[N:20]=[CH:19][CH:18]=[CH:17]3)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1[nH]cc(-c2ccccc2)c2ncccc12
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: CN(C)c1ccccc1
Product: Clc1ncc(-c2ccccc2)c2ncccc12
Temperature: 0 °C

Procedure:
12.1 ml (130 mmol) of phosphoryl chloride are added dropwise at room temperature to a suspension of 22.2 g (100 mmol) of 8-phenyl-1,6-naphthyridin-5(6H)-one [173773-04-1] in 100 ml of toluene. After addition of 5 drops of N,N-dimethylaniline, the reaction mixture is heated under reflux for 5 h. After cooling, the reaction mixture is diluted with 300 ml of toluene, poured onto 1000 g of ice and rendered alkaline (pH about 9) by addition of 5 N NaOH. The organic phase is separated off, washed once with 300 ml of sat. sodium chloride solution, dried over magnesium sulfate, and the toluene is removed in vacuo. Yield: 22.9 g (95 mmol), 95%. Purity: >95% according to 1H-NMR.
Reaction SMILES: [F:1][C:2]1[C:3]([N:9]=[CH:10][N:11]([CH3:13])[CH3:12])=[N:4][C:5]([OH:8])=[N:6][CH:7]=1.[CH2:14]([N:21]=[C:22]=[O:23])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C(Cl)Cl>[CH2:14]([NH:21][C:22]([N:6]1[CH:7]=[C:2]([F:1])[C:3](/[N:9]=[CH:10]/[N:11]([CH3:13])[CH3:12])=[N:4][C:5]1=[O:8])=[O:23])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CN(C)C=Nc1nc(O)ncc1F
Reactant: O=C=NCc1ccccc1
Solvent: ClCCl
Product: CN(C)/C=N/c1nc(=O)n(C(=O)NCc2ccccc2)cc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 62.6 %

Procedure:
To a suspension of N′-(5-fluoro-2-hydroxy-pyrimidin-4-yl)-N,N-dimethylformamidine (0.25 g, 1.35 mmol) in CH2Cl2 (5 mL) was added benzyl isocyanate (0.187 mL, 1.49 mmol) forming a solution that was stirred at room temperature overnight. The mixture was diluted with CH2Cl2 (100 mL) and was washed with brine (2×50 mL). The combined aqueous layers were extracted with CH2Cl2 (2×25 mL). The organic extracts were dried over sodium sulfate (Na2SO4), filtered and concentrated. The residue was purified by normal phase chromatography (gradient, methanol/CH2Cl2) and then by reverse phase chromatography (gradient, acetonitrile (CH3CN) in water (H2O)). The resulting solution was concentrated under reduced pressure forming a precipitate. The mixture was extracted with CH2Cl2 (4×100 mL), dried (Na2SO4), filtered and concentrated to yield (E)-N-benzyl-4-((dimethylamino)methyleneamino)-5-fluoro-2-oxopyrimidine-1(2H)-carboxamide (0.268 g, 62%) as a white solid: mp 147-150° C.; 1H NMR (300 MHz, CDCl3) δ 10.83 (t, J=4.94 Hz, 1H), 8.81 (s, 1H), 8.44 (d, J=6.59 Hz, 1H), 7.32-7.22 (m, 5H), 4.56 (d, J=5.93 Hz, 2H), 3.21 (s, 3H), 3.20 (s, 3H); ESIMS m/z 318.2 ([M+H]+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[N:12]([CH2:15][C:16]([OH:18])=O)[C:11](=[O:19])[CH:10]=[N:9]2)=[CH:4][C:3]=1[C:20](=[O:31])[NH:21][CH2:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[Cl:30].Cl.CN.C[CH2:36][N:37]=C=NCCCN(C)C>CN(C1C=CN=CC=1)C.CN(C=O)C.Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[N:12]([CH2:15][C:16](=[O:18])[NH:37][CH3:36])[C:11](=[O:19])[CH:10]=[N:9]2)=[CH:4][C:3]=1[C:20]([NH:21][CH2:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[Cl:30])=[O:31]
Reactant: CCN=C=NCCCN(C)C
Reactant: O=C(O)Cn1c(=O)cnn(-c2ccc(Cl)c(C(=O)NCCc3ccccc3Cl)c2)c1=O
Agent: CN
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Product: CNC(=O)Cn1c(=O)cnn(-c2ccc(Cl)c(C(=O)NCCc3ccccc3Cl)c2)c1=O
Reaction time: 5 h
Yield: 27.3 %

Procedure:
A slurry of (2-{4-Chloro-3-[2-(2-chloro-phenyl)-ethylcarbamoyl]-phenyl}-3,5-dioxo-2,5-dihydro-3H-[1,2,4]triazin-4-yl)-acetic acid (71.4 mg, 0.154 mmol), methylamine HCl (15.6 mg, 0.231 mmol), EDCI (44.4 mg, 0.231 mmol), and DMAP (75.5 mg, 0.616 mmol) in DMF (1.0 mL) were stirred at ambient temperature for 20 hours. The reaction was diluted with 1N HCl, and let stir for 5 hours. The crude was filtered and triturated from hexane to give the title compound (20 mg). LCMS (m/z) 476.1 M+1.
Reaction SMILES: [Na].C[O-].[Na+].[CH:5](OCC)=[O:6].[S:10]1[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[C:13](=[O:20])[CH2:12][CH2:11]1>C1C=CC=CC=1.CO>[OH:6][CH:5]=[C:12]1[C:13](=[O:20])[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[S:10][CH2:11]1
Reactant: CCOC=O
Reactant: O=C1CCSc2ccccc21
Agent: C[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CO
Solvent: c1ccccc1
Product: O=C1C(=CO)CSc2ccccc21
Reaction time: 8 h

Procedure:
From 9.2 g of sodium (0.4 mol) and 160 ml of absolute methanol there is prepared sodium methanolate. Then the surplus of methanol is evaporated in vacuo and 200 ml of dry benzene and 32.6 g of ethyl formate (0.44 mol) are added to the dry residue. While stirring and passing nitrogen through the mixture, there are added 32.8 g of 2,3-dihydro-4H-1-benzothiopyran-4-one, dissolved in 160 ml of dry benzene dropwise to it to keep the reaction temperature in the range from 0° to 50° C. All components become dissolved and after that, the sodium salt of the 2,3-dihydro-3-(hydroxymethylene)-4H-1-benzothiopyran-4-one precipitates. After allowing the reaction mixture to stand overnight at room temperature, 400 ml of water are added for dissolving the sodium salt. The aqueous layer is separated from the organic solvent and, after agitating twice with ether and treatment with charcoal, it is acidified with half-concentrated aqueous hydrochloric acid. The oily title compound is extracted with chloroform, dried with sodium sulphate and after evaporation of the solvent, distilled in vacuo. b.p. 0.3 mm, 134°-138°; yield: 32.9 g (85.6%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:18]3=[N:19][CH:20]=[N:21][C:22](Cl)=[C:17]3[CH:16]=[N:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:24][C:25]1[C:30]([NH2:31])=[CH:29][CH:28]=[C:27]([N:32]2[CH:36]=[N:35][CH:34]=[N:33]2)[N:26]=1.CC(C)([O-])C.[Na+]>CN(C)C=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CC(CN1P2N(CC(C)C)CCN(CCN2CC(C)C)CC1)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:18]3=[N:19][CH:20]=[N:21][C:22]([NH:31][C:30]4[C:25]([CH3:24])=[N:26][C:27]([N:32]5[CH:36]=[N:35][CH:34]=[N:33]5)=[CH:28][CH:29]=4)=[C:17]3[CH:16]=[N:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1nc(-n2cncn2)ccc1N
Reactant: CC(C)(C)OC(=O)N1CCC(n2ncc3c(Cl)ncnc32)CC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: CN(C)C=O
Product: Cc1nc(-n2cncn2)ccc1Nc1ncnc2c1cnn2C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 160 °C
Yield: 25.2 %

Procedure:
A mixture of 4-(4-chloro-pyrazolo[3,4-d]pyrimidin-1-yl)-piperidine-1-carboxylic acid tert-butyl ester (Intermediate 19; 50 mg, 0.15 mmol), 2-methyl-6-[1,2,4]triazol-1-yl-pyridin-3-ylamine (Intermediate 7, Step 2; 26 mg, 0.15 mmol), palladium(II) acetate (0.3 mg, 0.01 eq), triisobutylphosphatrane (1 mg, 0.02 eq) and sodium tert-butoxide (34 mg, 0.36 mmol) in dimethylformamide (2 mL) was heated in the microwave oven at 160° C. for 10 min. The mixture was filtered through a PTFE filter with a 0.45 μM pore size to remove the catalyst, and the solid was rinsed with ethyl acetate. Ethyl acetate and water were added to the combined filtrate and washings, and the aqueous layer was extracted twice with ethyl acetate. The ethyl acetate layers were combined, evaporated, and purified by preparative C18 HPLC, eluting with 10-100% acetonitrile/water. Samples containing the product were extracted twice with dichloromethane and the solvent was evaporated to give 4-[4-(2-methyl-6-[1,2,4]triazol-1-yl-pyridin-3-ylamino)-pyrazolo[3,4-d]pyrimidin-1-yl]-piperidine-1-carboxylic acid tert-butyl ester (18 mg, 26%) as a light yellow powder. 1H NMR (300 MHz, DMSO-d6) δ 1.43 (s, 9H), 1.75-2.07 (m, 4H), 2.99 (br s, 2H), 3.98-4.15 (m, 2H), 4.77-5.00 (m, 1H), 7.77 (d, 1H, J=8.5 Hz), 8.04-8.15 (m, 2H), 8.30 (s, 2H), 9.33 (s, 1H), 10.00 (br s, 1H). Mass spectrum (ES) MH+=477. HRMS Calcd. for C23H29N10O2 (MH+): 477.2470. Found: 477.2468.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:16]=[C:15]([NH:17][C@H:18]4[CH2:22][CH2:21][N:20](S(C)(=O)=O)[CH2:19]4)[C:14]([F:27])=[CH:13][N:12]=3)=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[C:28](=O)([O:37][CH2:38][CH:39]1[CH2:43][CH2:42][O:41][CH2:40]1)[O:29]N1C(=O)CCC1=O>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:16]=[C:15]([NH:17][CH:18]4[CH2:22][CH2:21][N:20]([C:28]([O:37][CH2:38][C@H:39]5[CH2:43][CH2:42][O:41][CH2:40]5)=[O:29])[CH2:19]4)[C:14]([F:27])=[CH:13][N:12]=3)=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: CS(=O)(=O)N1CC[C@H](Nc2nc(-c3c[nH]c4ncc(Cl)cc34)ncc2F)C1
Reactant: O=C(OCC1CCOC1)ON1C(=O)CCC1=O
Product: O=C(OC[C@H]1CCOC1)N1CCC(Nc2nc(-c3c[nH]c4ncc(Cl)cc34)ncc2F)C1
Yield: 10 %

Procedure:
According to the procedure for compound 398 using 2,5-dioxopyrrolidin-1-yl (tetrahydrofuran-3-yl)methyl carbonate (0.023 g, 0.096 mmol) afforded 5.7 mg (10% yield) of 484, as a trifluoroacetic acid salt after preparatory HPLC purification.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:4]=1N.N([O-])=O.[Na+].C([O-])(=O)C.[Na+].C(OC([S-])=[S:25])C.[K+].[OH-].[K+]>O.C(O)C.C(Cl)Cl>[Cl:2][C:3]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:4]=1[SH:25]
Reactant: COc1ccc(Cl)c(N)c1
Reactant: CCOC(=S)[S-]
Agent: CC(=O)[O-]
Agent: Cl
Agent: O=N[O-]
Solvent: CCO
Solvent: O
Solvent: ClCCl
Product: COc1ccc(Cl)c(S)c1

Procedure:
A mixture of 450 ml of concentrated hydrochloric acid and 1,200 ml of water is added to 157.6 g of 2-chloro-5-methoxy-aniline, while stirring, and the mixture is diazotised with a solution of 69 g of NaNO2 in 130 ml of water at 0°-5°. The mixture is then buffered with sodium acetate and the diazonium salt solution is added dropwise, while stirring, to a solution, at 70°, of 256 g of potassium ethylxanthate in 360 ml of water. After cooling, the mixture is worked up with CH2Cl2 and the resulting crude xanthic acid ester is saponified with KOH in ethanol and the mixture is evaporated, acidified and distilled with steam to give 2-chloro-5-methoxy-thiophenol; b.p. 110°/0.5 mm.
Reaction SMILES: C([Li])CCC.[C:6]([O:10][CH2:11][CH3:12])(=[O:9])[C:7]#[CH:8].[CH3:13][O:14][C:15]1[CH:16]=[C:17]([CH:20]=[C:21]([O:25][CH3:26])[C:22]=1[O:23][CH3:24])[CH:18]=[O:19].[Cl-].[NH4+]>O1CCCC1.CCOCC.CCCCCC.O1CCCC1.C(OCC)(=O)C>[OH:19][CH:18]([C:17]1[CH:20]=[C:21]([O:25][CH3:26])[C:22]([O:23][CH3:24])=[C:15]([O:14][CH3:13])[CH:16]=1)[C:8]#[C:7][C:6]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: COc1cc(C=O)cc(OC)c1OC
Reactant: C#CC(=O)OCC
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOC(=O)C#CC(O)c1cc(OC)c(OC)c(OC)c1
Reaction time: 0.33 h

Procedure:
72 ml of n-butyllithium solution (1.6M in hexane) were added at -110° to a solution of 11.72 ml (0.115 mol) of ethyl propiolate in 195 ml of tetrahydrofuran/ether/hexane (4:2:1). The mixture was stirred at -110° for 20 minutes and then treated with 15.0 g (76.4 mmol) of 3,4,5-trimethoxybenzaldehyde in 30 ml of tetrahydrofuran. The mixture was thereafter stirred at -78° for 1.5 hours and treated at -30° with 100 ml of saturated ammonium chloride solution and 100 ml of ethyl acetate. The aqueous phase was extracted twice with ethyl acetate. The combined organic phases were dried over magnesium sulphate and evaporated. The residue was chromatographed on 500 g of silica gel with ethyl acetate/hexane (1:1), whereafter there was obtained ethyl 4-hydroxy-4-(3,4,5-trimethoxyphenyl)-2-butynoate.
Reaction SMILES: [CH2:1]([N:8]1[CH2:18][CH2:17][C:11]2[N:12]=[CH:13][N:14]=[C:15](Cl)[C:10]=2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:19][C@H:20]1[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21]1.C(N(CC)CC)C>COC(C)(C)C.O>[C:28]([O:27][C:25]([N:22]1[CH2:23][CH2:24][C@H:20]([NH:19][C:15]2[C:10]3[CH2:9][N:8]([CH2:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)[CH2:18][CH2:17][C:11]=3[N:12]=[CH:13][N:14]=2)[CH2:21]1)=[O:26])([CH3:31])([CH3:29])[CH3:30]
Reactant: Clc1ncnc2c1CN(Cc1ccccc1)CC2
Reactant: CC(C)(C)OC(=O)N1CC[C@H](N)C1
Solvent: CCN(CC)CC
Solvent: O
Solvent: COC(C)(C)C
Product: CC(C)(C)OC(=O)N1CC[C@H](Nc2ncnc3c2CN(Cc2ccccc2)CC3)C1
Reaction time: 0.17 h
Yield: 94.3 %

Procedure:
6-Benzyl-4-chloro-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine (5.0 g, 19.06 mmol), (S)-tert-butyl 3-aminopyrrolidine-1-carboxylate (4.11 g, 20.96 g) and triethylamine (3.98 mL, 28.6 mmol) were heated in a sealed vial at 120° C. for 42 h. The mixture was allowed to cool, diluted with tert-butyl methyl ether (100 mL) and the resulting suspension stirred for 10 min. The mixture was diluted with water (50 mL) and the organic layer separated. The organic layer was washed with brine (20 mL), dried (Na2SO4) and evaporated in vacuo to give a brown gum. The residue was purified by column chromatography on silica gel with EtOAc/MeOH, 98/2 to 82/18 to give (S)-3-(6-benzyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-ylamino)-pyrrolidine-1-carboxylic acid tert-butyl ester as a pale yellow foam (7.36 g, 93% yield). 1H-NMR (400 MHz, CDCl3, 298 K): δ ppm 1.48 (s, 9H) 2.10-2.31 (m, 2H) 2.80-2.96 (m, 4H) 3.15-3.87 (m, 8H) 4.44-4.77 (m, 1H) 5.62-5.73 (m, 1H) 7.29-7.45 (m, 5H) 8.50 (s, 1H). LCMS: [M+H]+=410.0, Rt(6)=1.39 min.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=1)(C)(C)C.[ClH:19]>O1CCOCC1>[ClH:19].[F:17][C:14]1[CH:15]=[CH:16][C:11]([O:10][CH2:9][CH2:8][NH2:7])=[CH:12][CH:13]=1
Reactant: CC(C)(C)OC(=O)NCCOc1ccc(F)cc1
Agent: Cl
Solvent: C1COCCO1
Product: NCCOc1ccc(F)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 80.7 %

Procedure:
Next, to a solution of [2-(4-fluorophenoxy)ethyl]carbamic acid tert-butyl ester (7.0 g, 27.4 mmol) in dioxane (20 mL) cooled in an ice bath was added 4N—HCl in dioxane (100 mL) dropwise. The mixture was stirred at 0° C. for 2 hours, and at room temperature for 16 hours. The precipitates were filtered, washed with diethylether, and dried under reduced pressure to yield 2-(4-fluorophenoxy)ethylamine HCl salt (4.24 g, 80.7% yield).
Reaction SMILES: [CH:1]1([NH2:4])[CH2:3][CH2:2]1.[NH2:5][C:6]1[C:7]2[C:32]([CH3:38])([C:33](OCC)=[O:34])[C:31](=[O:39])[NH:30][C:8]=2[N:9]=[C:10]([C:12]2[C:20]3[C:15](=[N:16][CH:17]=[CH:18][CH:19]=3)[N:14]([CH2:21][CH2:22][C:23]([F:29])([F:28])[C:24]([F:27])([F:26])[F:25])[N:13]=2)[N:11]=1>>[NH2:5][C:6]1[C:7]2[C:32]([CH3:38])([C:33]([NH:4][CH:1]3[CH2:3][CH2:2]3)=[O:34])[C:31](=[O:39])[NH:30][C:8]=2[N:9]=[C:10]([C:12]2[C:20]3[C:15](=[N:16][CH:17]=[CH:18][CH:19]=3)[N:14]([CH2:21][CH2:22][C:23]([F:29])([F:28])[C:24]([F:25])([F:27])[F:26])[N:13]=2)[N:11]=1
Reactant: CCOC(=O)C1(C)C(=O)Nc2nc(-c3nn(CCC(F)(F)C(F)(F)F)c4ncccc34)nc(N)c21
Reactant: NC1CC1
Product: CC1(C(=O)NC2CC2)C(=O)Nc2nc(-c3nn(CCC(F)(F)C(F)(F)F)c4ncccc34)nc(N)c21

Procedure:
Cyclopropylamine (10.71 mL, 155 mmol) was added to ethyl 4-amino-5-methyl-6-oxo-2-[1-(3,3,4,4,4-pentafluorobutyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidine-5-carboxylate, as prepared by the procedure described in Example 158, (594 mg, 1.189 mmol) and the resultant mixture heated at 50° C. for 16 hours. The mixture was concentrated in vacuo and the residue purified by silica gel column chromatography using a hexanes/EtOAc gradient. Chiral separation using SFC on a Chiralpak AD-H column provided both enantiomers of the title compound, 1H NMR (500 MHz, DMSO-d6): δ 9.02 (1H, d, J=8.09 Hz), 8.63 (1H, d, J=4.45 Hz), 7.63 (1H, d, J=4.01 Hz), 7.38 (1H, dd, J=8.08, 4.48 Hz), 6.75 (2H, s), 4.87 (2H, t, J=6.77 Hz), 3.03-2.90 (2H, m), 2.68-2.62 (1H, m), 1.56 (3H, s), 0.63-0.54 (2H, m), 0.51-0.44 (2H, m). m/z=511.2 (M+H).
Reaction SMILES: [NH3:1].[Br:2][C:3]1[CH:8]=[CH:7][C:6]([S:9](Cl)(=[O:11])=[O:10])=[CH:5][C:4]=1[CH3:13]>C1COCC1>[Br:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([NH2:1])(=[O:11])=[O:10])=[CH:5][C:4]=1[CH3:13]
Reactant: N
Reactant: Cc1cc(S(=O)(=O)Cl)ccc1Br
Solvent: C1CCOC1
Product: Cc1cc(S(N)(=O)=O)ccc1Br
Temperature: 0 °C
Reaction time: 6.5 h
Yield: 54 %

Procedure:
A 28% aqueous NH3 solution (2.0 ml) was added to a solution of 4-bromo-3-methyl-benzenesulfonyl chloride (250 mg, 0.927 mmol) in THF (2.0 ml) at 0° C. The mixture was stirred at 0° C. for 6.5 hours. The reaction mixture was quenched with 1 N HCl and extracted with CH2Cl2. The organic layer was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (CH2Cl2—AcOEt) to give 4-bromo-3-methyl-benzenesulfonamide as a white powder (126 mg, 54%).