Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[N:9]=[CH:8][CH:7]=[C:6]([I:10])[C:3]=1[CH:4]=[O:5].[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([Mg]Br)=[CH:14][CH:13]=1>C1COCC1>[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([CH:4]([C:3]2[C:2]([F:1])=[N:9][CH:8]=[CH:7][C:6]=2[I:10])[OH:5])=[CH:14][CH:13]=1
Reactant: Clc1ccc([Mg]Br)cc1
Reactant: O=Cc1c(I)ccnc1F
Solvent: C1CCOC1
Product: OC(c1ccc(Cl)cc1)c1c(I)ccnc1F
Reaction time: 0.25 h

Procedure:
To a solution of 2-fluoro-4-iodonicotinaldehyde (1.50 g, 5.98 mmol) in anhydrous THF (20 mL) at −78° C. was slowly added a solution of (4-chlorophenyl)magnesium bromide (1 M in Et2O) (6.57 mL, 6.57 mmol). After 15 minutes at −78° C., the reaction was quenched with MeOH followed by saturated aqueous ammonium chloride, and the product was extracted with CH2Cl2 (4×). The organic layers were combined, dried over a cotton plug and concentrated to dryness under vacuum. The residue was used without any purification in the next step. LC/MS m/z 364 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:7]([NH:8][C:9](=O)C(C)(C)C)=[CH:6][CH:5]=[C:4]([C:15]([F:18])([F:17])[F:16])[N:3]=1.C1COCC1.[H-].[Na+].CI>O>[Cl:1][C:2]1[C:7]([NH:8][CH3:9])=[CH:6][CH:5]=[C:4]([C:15]([F:16])([F:17])[F:18])[N:3]=1
Reactant: CC(C)(C)C(=O)Nc1ccc(C(F)(F)F)nc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CI
Solvent: O
Product: CNc1ccc(C(F)(F)F)nc1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 52.6 %

Procedure:
To a mixture of N-(2-chloro-6-trifluoromethylpyridin-3-yl)-2,2-dimethylpropionamide (6.59 g) and THF (30 ml), sodium hydride (60% in oily, 1 g) was added under ice-cooling, and stirred at room temperature for 30 minutes. The reaction mixture was ice-cooled, and then methyl iodide (10 g) was added, and stirred at room temperature for 4 hours. Into the reaction mixture, water was poured, and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, and concentrated under reduced pressure. To the resulting residue, acetonitrile (40 ml), concentrated hydrochloric acid (40 ml), and isopropanol (40 ml) were added, and stirred at room temperature for 2 hours, at 60° C. for 2 hours, then at 80° C. for 2 hours. Into the reaction mixture cooled to room temperature, saturated aqueous sodium hydrogen carbonate solution was poured, and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, and concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography to give 2.60 g of (2-chloro-6-trifluoromethylpyridin-3-yl)-methylamine.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:15][CH2:14][CH2:13][C@H:9]1[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN1CCOCC1.ClC(OCC(C)C)=O.Cl.[CH3:32][O:33][C:34](=[O:39])[C@H:35]([CH2:37][OH:38])[NH2:36]>C(Cl)Cl>[CH3:32][O:33][C:34](=[O:39])[C@H:35]([CH2:37][OH:38])[NH:36][C:10](=[O:12])[C@@H:9]1[CH2:13][CH2:14][CH2:15][N:8]1[C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7]
Reactant: COC(=O)[C@@H](N)CO
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Agent: CC(C)COC(=O)Cl
Agent: Cl
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: COC(=O)[C@H](CO)NC(=O)[C@@H]1CCCN1C(=O)OC(C)(C)C
Temperature: -70 °C
Reaction time: 0.08 h

Procedure:
21.5 g of t-butoxycarbonylproline is dissolved in 200 ml of methylene chloride. 22.2 ml of N-methylmorpholine is added to the solution. The solution is cooled to -70° C. 13.1 ml of isobutyl chloroformate is then added. The reaction mixture is warmed up to -15° C. and stirred for 5 minutes. The reaction mixture is again cooled to -70° C. 15.6 g of serine methyl ester hydrochloride is added to the reaction mixture. The reaction mixture is allowed to warm to room temperature, and then stirred for 16 hours. The reaction mixture is extracted three times with 0.5 M potassium bisulfate and once with brine. The methylene chloride solution is dried over anhydrous sodium sulfate, filtered and stripped of solvent. The residue is dissolved in 200 ml of ethyl ether. The ether solution is added to cold rapidly stirring Skellysolve B. The white precipitate is filtered and dried to afford the product t-butoxycarbonylprolylserine methyl ester.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]3[O:15][CH2:16][CH2:17][O:18][C:11]=3[CH:10]=2)[C:5]([F:19])=[CH:4][N:3]=1.[F:20][C:21]1[CH:22]=[C:23]([CH:25]=[C:26]([F:28])[CH:27]=1)[NH2:24]>>[CH2:17]1[CH2:16][O:15][C:12]2[CH:13]=[CH:14][C:9]([NH:8][C:6]3[C:5]([F:19])=[CH:4][N:3]=[C:2]([NH:24][C:23]4[CH:22]=[C:21]([F:20])[CH:27]=[C:26]([F:28])[CH:25]=4)[N:7]=3)=[CH:10][C:11]=2[O:18]1
Reactant: Nc1cc(F)cc(F)c1
Reactant: Fc1cnc(Cl)nc1Nc1ccc2c(c1)OCCO2
Product: Fc1cc(F)cc(Nc2ncc(F)c(Nc3ccc4c(c3)OCCO4)n2)c1

Procedure:
In like manner to the preparation of 5-fluoro-N4-(3-hydroxyphenyl)-N2-[4-(3-phenyl-1,2,4-oxadiazol-5-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine, 2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine and 3,5-difluoroaniline were reacted to provide N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3,5-difluorophenyl)-2,4-pyrimidinediamine. 1H NMR (CDCl3): δ 7.94 (d, 1H, J=3.3 Hz), 7.20-7.11 (m, 3H), 7.02 (s, 1H), 6.92-6.90 (m, 2H), 6.65 (s, 1H), 6.39 (tt, 1H, J=2.4 and 9.0 Hz), 4.31 (s, 4H); 19F NMR (282 MHz, CDCl3): −31142, −47002; LCMS: purity: 97%; MS (m/e): 375(MH+).
Reaction SMILES: C(OC([N:8]1[CH2:14][CH2:13][C:12]2[C:15]([S:20][C:21](=O)N(C)C)=[C:16]([Cl:19])[CH:17]=[CH:18][C:11]=2[CH2:10][CH2:9]1)=O)(C)(C)C.ClC[C:28]1[CH:41]=[CH:40][C:31]([C:32]([NH:34][CH2:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:33])=[CH:30][CH:29]=1>>[ClH:19].[Cl:19][C:16]1[CH:17]=[CH:18][C:11]2[CH2:10][CH2:9][NH:8][CH2:14][CH2:13][C:12]=2[C:15]=1[S:20][CH2:21][C:28]1[CH:41]=[CH:40][C:31]([C:32](=[O:33])[NH:34][CH2:35][C:36]([CH3:38])([CH3:37])[CH3:39])=[CH:30][CH:29]=1
Reactant: CC(C)(C)CNC(=O)c1ccc(CCl)cc1
Reactant: CN(C)C(=O)Sc1c(Cl)ccc2c1CCN(C(=O)OC(C)(C)C)CC2
Product: CC(C)(C)CNC(=O)c1ccc(CSc2c(Cl)ccc3c2CCNCC3)cc1
Product: Cl

Procedure:
Use a method similar to the Example 456, using 3-tert-butoxycarbonyl-7-chloro-6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-1H-benzo[d]azepine and 4-chloromethyl-N-(2,2-dimethyl-propyl)-benzamide to give, after deprotection by a method similar to the General Procedure 14, the title compound as a white solid. MS (ES+) m/z: 417 (M+H)+.
Reaction SMILES: C1(C)C(C)=CC=CC=1.[CH2:9]([NH2:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[C:17](O)(=[O:25])[C@@H:18]([C@H:20]([C:22](O)=[O:23])[OH:21])[OH:19].CO>CCOC(C)=O>[CH2:9]([N:16]1[C:22](=[O:23])[C@H:20]([OH:21])[C@@H:18]([OH:19])[C:17]1=[O:25])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=C(O)[C@H](O)[C@@H](O)C(=O)O
Reactant: NCc1ccccc1
Solvent: CO
Solvent: Cc1ccccc1C
Solvent: CCOC(C)=O
Product: O=C1[C@H](O)[C@@H](O)C(=O)N1Cc1ccccc1
Temperature: 135 °C
Reaction time: 1 h
Yield: 78.5 %

Procedure:
A mixture of xylene, (1.2 L), benzylamine (120 g, 1.10 mol, 1.0 eq) and L-(+)-tartaric acid (173 g, 1.15 mol, 1.05 eq) were heated at 135° C. for 12 hr (flask jacket temperature). Upon reaction completion, the mixture was cooled to 65° C. and MeOH (120 mL, 1 vol) was added. The resulting mixture was stirred for 1 hr and the resulting suspension was cooled to 20° C. followed by the addition of EtOAc (480 mL). Stirring was continued at 10° C. for 2 hr. The crude product was isolated by filtration and washed with EtOAc (120 mL) and dried on the filter. The crude product was then taken up in MeOH (480 mL) and heated at a gentle reflux for 1 hr, then cooled to 20° C. and granulated for 1 hr. The suspension was filtered and the precipitate washed with MeOH (240 mL) and dried to give the title compound (191 g, 864 mmol, 79%) as a white granular solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.38-7.30 (m, 2H) 7.30-7.22 (m, 3 H) 6.32 (br. s., 1 H) 4.59 (d, J=14.8 Hz, 1 H) 4.53 (d, J=14.8 Hz, 1 H) 4.40 (br. D., J=4.3 Hz, 2 H). m/z (EI+) for C11H11NO4 221.0 (M)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]([O:12][CH3:13])[C:9]([O:14][CH3:15])=[CH:8][C:4]=1[C:5](O)=[O:6].S(Cl)([Cl:18])=O.CN(C)C=O>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:11]=[C:10]([O:12][CH3:13])[C:9]([O:14][CH3:15])=[CH:8][C:4]=1[C:5]([Cl:18])=[O:6]
Reactant: O=S(Cl)Cl
Reactant: COc1cc(OC)c(C(=O)O)cc1OC
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: COc1cc(OC)c(C(=O)Cl)cc1OC
Temperature: 80 °C
Reaction time: 1 h

Procedure:
2,4,5-Trimethoxybenzoic acid (500 g) was suspended in dried toluene (2 l) and to the suspension, thionyl chloride (206 ml) and N,N-dimethylformamide (1.0 ml) were added at room temperature, and the mixture was stirred at 80° C. for 1 hour. The reaction mixture was concentrated under reduced pressure. To the resultant residue, n-hexane was added and through co-boiling the mixture, 2,4,5-trimethoxybenzoyl chloride was obtained. To the resultant compound, 2-amino-4-methoxycarbonyl-1,3-thiazole (372.7 g) and 1,2-dichloroethane (4.5 l) were added and the mixture was refluxed for 6 hours. After completion of reaction, the reaction mixture was allowed to cool. Crystals so precipitated were collected by filtration, washed with 1,2-dichloroethane, and air-dried. The crystals were suspended in water (8 l) and to the suspension, ice (2 kg) was added. While cooling, a solution of sodium hydroxide (94 g) in water (850 ml) was added thereto to thereby adjust the pH of the suspension at about 7.5. Subsequently, the mixture was stirred for 3 hours at room temperature. Crystals so precipitated were collected by filtration, washed with water, and air-dried to thereby obtain the title compound (702.7 g).
Reaction SMILES: [CH:1]1([C:7]2[C:8]3[CH:9]=[CH:10][C:11]([C:38]([O:40]C(C)(C)C)=[O:39])=[CH:12][C:13]=3[N:14]3[CH2:20][C:19]([C:21]([N:23]4[CH:28]5[CH2:29][CH2:30][CH:24]4[CH2:25][N:26]([CH3:31])[CH2:27]5)=[O:22])=[CH:18][C:17]4[CH:32]=[C:33]([O:36][CH3:37])[CH:34]=[CH:35][C:16]=4[C:15]=23)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:45]([OH:51])([C:47]([F:50])([F:49])[F:48])=[O:46]>ClCCCl>[F:48][C:47]([F:50])([F:49])[C:45]([OH:51])=[O:46].[CH:1]1([C:7]2[C:8]3[CH:9]=[CH:10][C:11]([C:38]([OH:40])=[O:39])=[CH:12][C:13]=3[N:14]3[CH2:20][C:19]([C:21]([N:23]4[CH:28]5[CH2:29][CH2:30][CH:24]4[CH2:25][N:26]([CH3:31])[CH2:27]5)=[O:22])=[CH:18][C:17]4[CH:32]=[C:33]([O:36][CH3:37])[CH:34]=[CH:35][C:16]=4[C:15]=23)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1ccc2c(c1)C=C(C(=O)N1C3CCC1CN(C)C3)Cn1c-2c(C2CCCCC2)c2ccc(C(=O)OC(C)(C)C)cc21
Solvent: ClCCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc2c(c1)C=C(C(=O)N1C3CCC1CN(C)C3)Cn1c-2c(C2CCCCC2)c2ccc(C(=O)O)cc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 109.1 %

Procedure:
tert-Butyl 13-cyclohexyl-3-methoxy-6-((3-methyl-3,8-diazabicyclo[3.2.1]oct-8-yl)carbonyl)-7H-indolo[2,1-a][2]benzazepine-10-carboxylate (300 mg, 0.504 mmol) was dissolved into DCE (5 mL) and then TFA (700 μl, 9.09 mmol) was added (reaction became green) and the reaction was stirred at rt for 1 h (˜70% conversion by LCMS). More TFA (700 μl, 9.09 mmol) was added and the reaction was stirred 1 h (complete by LCMS). The reaction mixture was concentrated on a rotary evaporator, diluted with diethyl ether and reconcentrated twice to yield 13-cyclohexyl-3-methoxy-6-((3-methyl-3,8-diazabicyclo[3.2.1]oct-8-yl)carbonyl)-7H-indolo[2,1-a][2]benzazepine-10-carboxylic acid trifluoroacetate (362 mg, 0.55 mmol, quant.) as a dark yellow solid. Used without further purification. 1HNMR (300 MHz, DMSO-d6) δ ppm 1.06-2.13 (m, 21H), 2.68-2.86 (m, 1H), 3.36-3.50 (m, 2H), 3.90 (s, 3H), 4.11-5.35 (m, 2H), 7.14 (s, 1H), 7.18-7.28 (m, 2H), 7.53 (d, J=8.4 Hz, 1H), 7.61 (dd, J=8.4, 1.1 Hz, 1H), 7.87 (d, J=8.4 Hz, 1H), 8.21 (br s, 1H), 9.55 (br s, 1H). LC-MS retention time: 3.72 min; m/z 596 (MH+). LC-MS retention time: 2.50 min; 538 m/z (MH−). LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Phenomenex-Luna 10u C18 4.6×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 5 mL/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 4 min, a hold time of 1 min, and an analysis time of 5 min where solvent A was 5% acetonitrile/95% H2O/10 mM ammonium acetate and solvent B was 5% H2O/95% acetonitrile/10 mM ammonium acetate. MS data was determined using a Micromass Platform for LC in electrospray mode.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:8]=[CH:7][C:6]([C:9](=[O:12])[CH2:10][CH3:11])=[CH:5][CH:4]=1.[CH2:15]=O.Cl.[NH:18]1[CH2:22][CH2:21][CH2:20][CH2:19]1.Cl>>[F:1][C:2]([F:13])([F:14])[C:3]1[CH:4]=[CH:5][C:6]([C:9](=[O:12])[CH:10]([CH3:15])[CH2:11][N:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)=[CH:7][CH:8]=1
Reactant: C1CCNC1
Reactant: CCC(=O)c1ccc(C(F)(F)F)cc1
Reactant: C=O
Agent: Cl
Product: CC(CN1CCCC1)C(=O)c1ccc(C(F)(F)F)cc1
Yield: 44.8 %

Procedure:
A mixture of 1-(4-trifluoromethylphenyl)-1-propanone (2.50g), paraformaldehyde (1.10g), pyrrolidine hydrochloride (1.60g), and hydrochloric acid (0.1 ml) was refluxed for 16 hours. The mixture was evaporated in vacuo to give the residue. The residue was partitioned into water and ethyl acetate. The aqueous layer was neutralized with ammonia water and then extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and then filtered. The filtrate was evaporated in vaccuo to give 1-(4-trifluoromethylphenyl)-2-methyl-3-pyrrolidino-1propanone (1.58g; yield: 44.8%) as an oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[N:10][C:11]([CH:23]([CH3:25])[CH3:24])=[C:12]([CH2:21][OH:22])[C:13]=2[C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)=[CH:4][CH:3]=1.C1C=C[NH+]=CC=1.[O-][Cr](Cl)(=O)=O.CCOCC>ClCCl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[N:10][C:11]([CH:23]([CH3:25])[CH3:24])=[C:12]([CH:21]=[O:22])[C:13]=2[C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)=[CH:6][CH:7]=1
Reactant: CC(C)c1nnc(-c2ccc(F)cc2)c(-c2ccc(F)cc2)c1CO
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Solvent: CCOCC
Product: CC(C)c1nnc(-c2ccc(F)cc2)c(-c2ccc(F)cc2)c1C=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 80.6 %

Procedure:
1.8 g (5.5 mmol) of the compound from Example 7a in 30 ml of dichloromethane are poured into a suspension of 1.8 g (0.4 mmol) of PCC in 30 ml of dichloromethane at room temperature. After stirring at room temperature for 3 h, 3 volumes of ether are added, and the mixture is filtered through silica gel. Removal of the solvent in vacuo, and chromatography on silica gel (cyclohexane/ethyl acetate 1) yields 1.5 g of the title compound as a solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([S:13]([CH3:16])(=[O:15])=[O:14])=[N:8][C:7]([CH3:17])=[C:6]2[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(Br)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[CH2:16]([S:13]([C:9]1[C:10]2[C:5](=[CH:4][C:3]([O:2][CH3:1])=[CH:12][CH:11]=2)[C:6]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[C:7]([CH3:17])[N:8]=1)(=[O:14])=[O:15])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: COc1ccc2c(S(C)(=O)=O)nc(C)c(-c3ccccc3)c2c1
Reactant: BrCc1ccccc1
Product: COc1ccc2c(S(=O)(=O)Cc3ccccc3)nc(C)c(-c3ccccc3)c2c1

Procedure:
Following the procedure 6-methoxy-3-methyl-1-(methylsulfonyl)-4-phenylisoquinoline, using (in Step B) benzyl bromide in place of iodomethane, the titled compound was synthesized.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([CH3:12])=[CH:9][CH:10]=2)[CH:5]=[C:4]([C:13]([OH:15])=O)[CH:3]=1.[CH2:16]([O:20][C:21]([N:23]1[CH2:28][CH2:27][N:26]([C:29](=[O:41])[C@@H:30]([NH2:40])[CH2:31][CH2:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:25][CH2:24]1)=[O:22])[CH2:17][CH2:18][CH3:19].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>CN(C=O)C.O>[CH2:16]([O:20][C:21]([N:23]1[CH2:28][CH2:27][N:26]([C:29](=[O:41])[C@@H:30]([NH:40][C:13]([C:4]2[CH:3]=[C:2]([OH:1])[C:11]3[C:6](=[CH:7][C:8]([CH3:12])=[CH:9][CH:10]=3)[CH:5]=2)=[O:15])[CH2:31][CH2:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:25][CH2:24]1)=[O:22])[CH2:17][CH2:18][CH3:19]
Reactant: Cc1ccc2c(O)cc(C(=O)O)cc2c1
Reactant: CCCCOC(=O)N1CCN(C(=O)[C@@H](N)CCC(=O)OC(C)(C)C)CC1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: O
Solvent: CN(C)C=O
Product: CCCCOC(=O)N1CCN(C(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)c2cc(O)c3ccc(C)cc3c2)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 550 mg of 4-Hydroxy-7-methyl-naphthalene-2-carboxylic acid and 1.0 g of 4-((S)-2-Amino-4-tert-butoxycarbonyl-butyryl)-piperazine-1-carboxylic acid butyl ester in 8.3 ml of DMF, 458 mg of HOBT and 573 mg of EDC was added and the reaction mixture was stirred for 16 h at RT. Then, the reaction mixture was diluted with water and extracted with ethyl acetate. The organic phase was dried over MgSO4 and the solvents were removed under reduced pressure. The crude product was purified by chromatography on silica gel eluting with n-heptane/ethyl acetate (1/1). The fractions containing the product were combined and the solvent evaporated under reduced pressure. Yield: 1.0 g.
Reaction SMILES: [OH:1][CH2:2][C:3]1([CH3:12])[C:7]2(OCC[O:8]2)[CH2:6][S:5][CH2:4]1.C1COCC1.O>C(O)(=O)C>[OH:1][CH2:2][C:3]1([CH3:12])[CH2:4][S:5][CH2:6][C:7]1=[O:8]
Reactant: CC1(CO)CSCC12OCCO2
Solvent: CC(=O)O
Solvent: O
Solvent: C1CCOC1
Product: CC1(CO)CSCC1=O
Yield: 108.3 %

Procedure:
A solution of 0.23 g (1.2 mmol) of product from Step C, 4.8 ml THF, 4.8 ml H2O, and 7.2 ml acetic acid was heated at 70° C. for 96 hours. The cooled mixture was concentrated and the residue was dissolved in ethyl acetate (75 ml), washed with saturated sodium bicarbonate solution (15 ml), and brine, dried, filtered, and concentrated to give 0.19 g of an oil. The oil was flash chromatographed on silica gel eluting with chloroform to give 0.09 g (50%) of product as an oil; NMR (deuteriochloroform): δ 3.79 (dd, 1H), 3.58 (dd, 1H), 3.33 (d, 2H), 3.30 (d, 1H), 2.71 (d, 1H), 1.98 (t, 1H, --OH), 1.22 (S, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:18]([NH2:21])(=[O:20])=[O:19])[CH:5]=[C:6]([Cl:17])[C:7]=1[N:8]1[C:13]([CH3:14])=[CH:12][C:11]([OH:15])=[CH:10][C:9]1=[O:16].[Br:22]N1C(=O)CCC1=O.[F:30][C:31]1[CH:38]=[C:37]([F:39])[CH:36]=[CH:35][C:32]=1[CH2:33]Br.C(=O)([O-])[O-].[K+].[K+]>>[Br:22][C:10]1[C:9](=[O:16])[N:8]([C:7]2[C:6]([Cl:17])=[CH:5][C:4]([S:18]([NH2:21])(=[O:19])=[O:20])=[CH:3][C:2]=2[Cl:1])[C:13]([CH3:14])=[CH:12][C:11]=1[O:15][CH2:33][C:32]1[CH:35]=[CH:36][C:37]([F:39])=[CH:38][C:31]=1[F:30]
Reactant: O=C1CCC(=O)N1Br
Reactant: Fc1ccc(CBr)c(F)c1
Reactant: Cc1cc(O)cc(=O)n1-c1c(Cl)cc(S(N)(=O)=O)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1cc(OCc2ccc(F)cc2F)c(Br)c(=O)n1-c1c(Cl)cc(S(N)(=O)=O)cc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 16.2 %

Procedure:
A mixture of 3,5-dichloro-4-(4-hydroxy-6-methyl-2-oxopyridin-1(2H)-yl)benzenesulfonamide (0.18 g, 0.0005 mol), N-bromosuccinimide (0.1 g, 0.00056 mol)in acetici acid (2.0 mL) was stirred at room temperature under argon atmosphere for 1 h. Acetic acid was removed in vacuo, the residue was dissolved in DMF (2.0 mL), and added 2,4-difluorobenzyl bromide (0.128 g, 0.0006 mol), potassium carbonate (0.1 g, 0.0007 mol). The resulting mixture was stirred at room temperature for 1 h. The solvents were distilled in vacuo, and the residue was purified by flash chromatography (EtOAc/hexane 1:3 v/v) to give 0.14 g of partially purified product. This was further purified by reverse-phase HPLC using 10-90% CH3CN/Water (30 min gradient) at a flow rate of 100 mL/min. The appropriate fractions (m/z 553) were combined and freeze dried to afford 0.045 g of pale yellow powder. This was partitioned between EtOAc (25 ml) and 5% sod. bicarbonate. The organic phase was washed with water, dried (Na2SO4) and concentrated under reduced pressure. This material was dried invacuo to afford the title compound (0.033 g) as a white amorphous substance:
Reaction SMILES: [CH:1]#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]C.C1(C#C)C=CC=CC=1.[F:17][C:18]1[CH:25]=[CH:24][C:21]([C:22]#N)=[CH:20][CH:19]=1>C(#N)C1C=CC=CC=1>[F:17][C:18]1[CH:25]=[CH:24][C:21]([C:22]#[C:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7])=[CH:20][CH:19]=1
Reactant: N#Cc1ccc(F)cc1
Reactant: C#CCCCCCC
Solvent: C#Cc1ccccc1
Solvent: N#Cc1ccccc1
Product: CCCCCCC#Cc1ccc(F)cc1
Reaction time: 45 h
Yield: 67 %

Procedure:
The procedure was identical to Example 2, with the exception that 1-octyne (0.590 ml; 0.441 g; 4.00 mmol) was used as a substrate instead of phenylacetylene and 4-fluorobenzonitrile (0.242 g; 2.00 mmol) was used as a substrate instead of benzonitrile. GC analysis of the organic phase of the hydrolyzed reaction sample after 45 h at 65° C. showed the presence of 1.34 mmol (67% yield) of 1-fluoro-4-(1-octynyl)benzene and no remaining 4-fluorobenzonitrile in the reaction mixture.
Reaction SMILES: [OH:1][C:2]1[C:9]([CH3:10])=[C:8]([OH:11])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[CH2:12](Br)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C([O-])(O)=O.[Na+].O1CCOCC1>O>[CH2:12]([O:11][C:8]1[CH:7]=[CH:6][C:3]([CH:4]=[O:5])=[C:2]([OH:1])[C:9]=1[CH3:10])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: BrCc1ccccc1
Reactant: Cc1c(O)ccc(C=O)c1O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: Cc1c(OCc2ccccc2)ccc(C=O)c1O
Temperature: 60 °C
Reaction time: 8 h

Procedure:
A mixture of 2,4-dihydroxy-3-methyl-benzaldehyde (3.31 g, 21.8 mmol), benzylbromide (4.09 g, 23.9 mmol), NaHCO3 (5.49 g, 65.4 mmol), 1,4-dioxane (30 mL) and water (12 mL) was stirred at 60° C. for overnight. Then the reaction mixture was cooled to RT, water (100 mL) was added, extracted with EtOAc (2×200 mL). The extract was dried over Na2SO4, evaporated. The residue was purified on SiO2 (25 g) column, hexane-EtOAc (0 to 5%). Yield 1.57 g (6.48 mmol, 29%) as off-white solid.
Reaction SMILES: [S:1](=[N:4][C:5]([NH2:7])=[O:6])(=[O:3])=[O:2].C(OC(=O)[N:14]([C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][C:25]=1[F:26])[C:22](=[O:27])[N:21]([C:28]1[CH:33]=[CH:32][C:31](N)=[CH:30][CH:29]=1)[CH:20]=[CH:19]2)C)(C)(C)C.[Cl:36][C:37]1[CH:41]=[CH:40][S:39][C:38]=1S(N)(=O)=O>>[NH2:14][C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][C:25]=1[F:26])[C:22](=[O:27])[N:21]([C:28]1[CH:29]=[CH:30][C:31]([NH:7][C:5]([NH:4][S:1]([C:38]3[S:39][CH:40]=[CH:41][C:37]=3[Cl:36])(=[O:3])=[O:2])=[O:6])=[CH:32][CH:33]=1)[CH:20]=[CH:19]2
Reactant: CN(C(=O)OC(C)(C)C)c1cc2ccn(-c3ccc(N)cc3)c(=O)c2cc1F
Reactant: NS(=O)(=O)c1sccc1Cl
Reactant: NC(=O)N=S(=O)=O
Product: Nc1cc2ccn(-c3ccc(NC(=O)NS(=O)(=O)c4sccc4Cl)cc3)c(=O)c2cc1F

Procedure:
An analogous sulfonylurea coupling and de-protection procedure to that described in Example 29 was performed on [2-(4-Amino-phenyl)-7-fluoro-1-oxo-1,2-dihydro-isoquinolin-6-yl]-methyl-carbamic acid tert-butyl ester (Example 9) using 3-chloro-thiophene-2-sulfonic acid amide as the coupling partner to give N-({[4-(6-amino-7-fluoro-1-oxoisoquinolin-2(1H)-yl)phenyl]amino}carbonyl)-3-chlorothiophene-2-sulfonamide. ES-MS (M+H)+=507.0, 509.0 (Cl); 1H-NMR (DMSO-d6) δ (ppm): 8.98-8.91 (bs, 1H), 8.06-7.98 (m, 1H), 7.66-7.60 (d, J=12.8 Hz, 1H), 7.48-7.40 (d, J=8.8 Hz, 2H), 7.30-7.25 (d, J=8.8 Hz, 2H), 7.24-7.20 (m, 1H), 7.24-7.18 (d, J=7.3 Hz, 1H), 6.72-6.66 (d, J=8.4 Hz, 1H), 6.56-6.48 (bs, 1H), 6.50-6.46 (d, J=7.3 Hz, 1H), 2.82-2.75 (s, 3H).