Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][NH2:6].[CH:7]1([NH:10][C:11]2[CH:16]=[C:15]([C:17]([F:20])([F:19])[F:18])[N:14]=[C:13](F)[N:12]=2)[CH2:9][CH2:8]1.ClCCl>O1CCCC1>[CH:7]1([NH:10][C:11]2[CH:16]=[C:15]([C:17]([F:19])([F:20])[F:18])[N:14]=[C:13]([NH:6][CH2:5][CH2:4][CH2:3][O:2][CH3:1])[N:12]=2)[CH2:8][CH2:9]1
Reactant: Fc1nc(NC2CC2)cc(C(F)(F)F)n1
Reactant: COCCCN
Solvent: C1CCOC1
Solvent: ClCCl
Product: COCCCNc1nc(NC2CC2)cc(C(F)(F)F)n1
Temperature: 25 °C
Reaction time: 6 h
Yield: 977.9 %

Procedure:
6.1 g (0.068 mol) of 3-methoxypropylamine are added dropwise at room temperature to 7 g (0.0031 mol) of 4-cyclopropylamino-2-fluoro-6-trifluoromethylpyrimidine dissolved in 100 ml of tetrahydrofuran, and the mixture is stirred for 6 hours at room temperature. After addition of 2 l of ice-water, extraction with dichloromethane, drying of the organic phase and concentrating, 8.8 g (95.4% of theory) of the desired pyrimidine are obtained.
Reaction SMILES: [CH3:1][Si](C)(C)[N-][Si](C)(C)C.[Na+].[C:11]([O:15][C:16]([N:18]1[CH2:22][C:21](=O)[CH2:20][C@H:19]1[CH2:24][O:25][C:26](=[O:36])[C:27]1[CH:32]=[CH:31][C:30]([N+:33]([O-:35])=[O:34])=[CH:29][CH:28]=1)=[O:17])([CH3:14])([CH3:13])[CH3:12].O>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1(C)C=CC=CC=1>[C:11]([O:15][C:16]([N:18]1[CH2:22][C:21](=[CH2:1])[CH2:20][C@H:19]1[CH2:24][O:25][C:26](=[O:36])[C:27]1[CH:32]=[CH:31][C:30]([N+:33]([O-:35])=[O:34])=[CH:29][CH:28]=1)=[O:17])([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)OC(=O)N1CC(=O)C[C@H]1COC(=O)c1ccc([N+](=O)[O-])cc1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: C=C1C[C@@H](COC(=O)c2ccc([N+](=O)[O-])cc2)N(C(=O)OC(C)(C)C)C1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Methytriphenylphosphonium bromide (38 g, 106 mmol) dissolved in 300 ml of toluene was cooled to 0° C., then added sodium hexamethyldisilazide (48.3 ml, 93.7 mmol) was added dropwise. After 2 hours at room temperature, The temperature was cooled to 0° C., a solution of (S)-2-(4-nitro-benzoyloxymethyl)-4-oxo-pyrrolidine-1-carboxylic acid tert-butyl ester (intermediate 56, 15.5 g, 42.6 mmol) in 300 ml of toluene was added. After 10 minutes 500 ml of water was slowly added, then reaction was allowed to reach room temperature. The organic solvent was washed with brine (500 ml), dried (Na2SO4) and evaporated to obtain crude that was purified by silica gel chromatography (petroleum ether/ethyl acetate from 15/7 to 7/1). (S)-4-Methylene-2-(4-nitro-benzoyloxymethyl)-pyrrolidine-1-carboxylic acid tert-butyl ester was obtained as yellow solid (6.82 g, yield 46%).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:5]2[N:6]=[C:7](N)[S:8][C:4]=2[CH:3]=1.C([CH2:14][O:15][C:16]1[C:17]([F:26])=[C:18]([C:23]([NH2:25])=[O:24])[C:19]([F:22])=[CH:20][CH:21]=1)#N>>[F:26][C:17]1[C:16]([O:15][CH2:14][C:7]2[S:8][C:4]3[CH:3]=[C:2]([CH3:1])[CH:11]=[CH:10][C:5]=3[N:6]=2)=[CH:21][CH:20]=[C:19]([F:22])[C:18]=1[C:23]([NH2:25])=[O:24]
Reactant: N#CCOc1ccc(F)c(C(N)=O)c1F
Reactant: Cc1ccc2nc(N)sc2c1
Product: Cc1ccc2nc(COc3ccc(F)c(C(N)=O)c3F)sc2c1
Yield: 17 %

Procedure:
Synthesised from 6-methyl-1,3-benzothiazol-2-amine and 3-(cyanomethoxy)-2,6-difluorobenzene carboxamide, according to Method K, scheme 26. Yield 17% (second step), HPLC-MS (method 1): m/z 335 [M+H]+, Rt=3.70 min.
Reaction SMILES: [N:1]1([C:7]2[CH:12]=[CH:11][C:10]([S:13]([N:16]3[CH2:20][CH2:19][CH2:18][C:17]3=O)(=[O:15])=[O:14])=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:31])=CC=1>C(COC)OC>[N:1]1([C:7]2[CH:12]=[CH:11][C:10]([S:13]([N:16]3[CH2:20][CH2:19][CH2:18][C:17]3=[S:31])(=[O:15])=[O:14])=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: O=C1CCCN1S(=O)(=O)c1ccc(N2CCCCC2)cc1
Solvent: COCCOC
Product: O=S(=O)(c1ccc(N2CCCCC2)cc1)N1CCCC1=S
Yield: 57 %

Procedure:
A mixture comprising 5 g of 1-[4-(1-piperidyl)benzenesulphonyl]-2-pyrrolidinone, prepared as in Example 10 of the European Patent published under No. 0,033,578, and 3.28 g of Lawesson reagent (or 2,4-bis(4-methoxyphenyl)-1,3,2,4-dithiadiphosphetane 2,4-disulphide) in 100 cm3 of dimethoxyethane is heated to reflux for 1 hour. The mixture is allowed to return to room temperature and is evaporated to dryness, and the residue is chromatographed on silica (eluant: ethyl acetate/n-hexane, 1:1). 3.5 g of product are recovered. M.p. 195°-200° C. After crystallization in ethanol, 1.5 g of expected product are obtained. M.p. 211°-212° C.
Reaction SMILES: [NH2:1][C:2]1([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:20][CH2:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24]>>[CH2:26]([O:25][C:23]([CH2:22][CH2:21][CH2:20][NH:1][C:2]1([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1)=[O:24])[CH3:27]
Reactant: CCOC(=O)C1(N)CCCCC1
Reactant: CCOC(=O)CCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCOC(=O)CCCNC1(C(=O)OCC)CCCCC1
Temperature: 130 °C
Reaction time: 18 h

Procedure:
A mixture of ethyl 1-aminocyclohexanecarboxylate (669 g), potassium carbonate (683.1 g) and ethyl 4-bromobutyrate (558 ml) was stirred at 130° C. for 18 hours, then cooled to ambient temperature and poured onto ice-water (3 l). The product was extracted into dichloromethane and the combined extracts were dried over sodium sulphate and the solvent was removed in vacuo to yield ethyl 1-(3-ethoxycarbonylpropylamino)cyclohexanecarboxylate as a brown/orange oil. Yield 943.2 g.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[OH:9])#[N:2].[N+:10]([O-])([O-:12])=[O:11].[Na+].S(=O)(=O)(O)O.N([O-])=O.[Na+]>C(Cl)Cl>[N+:10]([C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([C:1]#[N:2])[C:4]=1[OH:9])([O-:12])=[O:11]
Reactant: N#Cc1ccccc1O
Reactant: O=[N+]([O-])[O-]
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: ClCCl
Product: N#Cc1cccc([N+](=O)[O-])c1O
Reaction time: 24 h
Yield: 42.7 %

Procedure:
2-cyanophenol (2.38 g, 20 mmol) was dissolved in methylene chloride (40 mL) followed by the addition of sodium nitrate (1.88 g, 22 mmol). The addition of sulfuric acid (20 mL/3M) was then made, followed by addition of a catalytic amount of sodium nitrite. The mixture was allowed to stir. After 24 hours, the reaction mixture was diluted with methylene chloride and extracted with water. The organic layer was dried over MgSO4 and filtered. The solvent was evaporated and chromatography of the resulting solid on silica gel (4%MeOH/CH2CH2) gave the desired product (1.4 g, 42%). 1H NMR (CD3COCD3): d 8.47 (d, 1H), 8.15 (d, 1H), 7.30 (t, 1H).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[C:10](=[O:21])[NH:11][CH:12]=[C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=2)[CH:14]=1)#[N:2].[CH2:22](O)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>O1CCCC1.C1(C)C=CC=CC=1>[C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[C:10](=[O:21])[N:11]([CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:12]=[C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=2)[CH:14]=1)#[N:2]
Reactant: N#Cc1ccccc1-c1cc(-c2ccccn2)c[nH]c1=O
Reactant: OCc1ccccc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: N#Cc1ccccc1-c1cc(-c2ccccn2)cn(Cc2ccccc2)c1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 19.6 %

Procedure:
3-(2-Cyanophenyl)-5-(2-pyridyl)-2 (1H)-pyridone (46 mg), 36 mg of benzyl alcohol and 88 mg of triphenylphosphine were dissolved in 2 ml of tetrahydrofuran, 147 mg of a 40% solution of diethylazo dicarboxylate in toluene were added with ice cooling and the mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated in vacuo and purified by a silica gel chromatography (hexane-ethyl acetate system) to give 12 mg of the title compound.
Reaction SMILES: [C:1]([O:5][C:6](=[O:12])[NH:7][C@H:8]([CH3:11])[CH2:9][OH:10])([CH3:4])([CH3:3])[CH3:2].C(N(CC)C(C)C)(C)C.[CH3:22][S:23](Cl)(=[O:25])=[O:24].[Cl-].[NH4+]>ClCCl>[C:1]([O:5][C:6]([NH:7][C@H:8]([CH3:11])[CH2:9][O:10][S:23]([CH3:22])(=[O:25])=[O:24])=[O:12])([CH3:4])([CH3:2])[CH3:3]
Reactant: CS(=O)(=O)Cl
Reactant: C[C@H](CO)NC(=O)OC(C)(C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](COS(C)(=O)=O)NC(=O)OC(C)(C)C
Temperature: 25 °C
Yield: 101.1 %

Procedure:
((R)-2-Hydroxy-1-methyl-ethyl)-carbamic acid tert-butyl ester (0.5 g, 2.85 mmol) was dissolved in dichloromethane (14 ml) and stirred in an ice bath. N,N-diisopropylethylamine (0.75 ml, 4.28 mmol) and then methanesulfonyl chloride (0.27 ml, 3.4 mmol) were slowly added and the reaction was warmed to room temperature over 16 h. Ammonium chloride solution was added to the reaction and it was extracted two times with ethyl acetate. The combined organics were washed with sodium chloride solution and dried over sodium sulfate. Evaporation gave 0.73 g of methanesulfonic acid (R)-2-tert-butoxycarbonylamino-propyl ester as a waxy white solid. 1H NMR (CDCl3) δ: 4.51-4.68 (m, 1H), 4.19-4.28 (m, 1H), 4.11-4.18 (m, 1H), 3.90-4.04 (m, 1H), 3.03 (s, 3H), 1.24 (d, J=6.8 Hz, 3H).
Reaction SMILES: [CH3:1][S:2](O[C@@H]1CCC[C@H]1OC1C=CC(Br)=CC=1)(=[O:4])=[O:3].[Br:19][C:20]1[N:25]=[CH:24][C:23]([O:26][C@@H:27]2[CH2:31][O:30][CH2:29][C@H:28]2[OH:32])=[CH:22][CH:21]=1>>[CH3:1][S:2]([O:32][C@H:28]1[C@H:27]([O:26][C:23]2[CH:24]=[N:25][C:20]([Br:19])=[CH:21][CH:22]=2)[CH2:31][O:30][CH2:29]1)(=[O:4])=[O:3]
Reactant: O[C@@H]1COC[C@H]1Oc1ccc(Br)nc1
Reactant: CS(=O)(=O)O[C@@H]1CCC[C@H]1Oc1ccc(Br)cc1
Product: CS(=O)(=O)O[C@@H]1COC[C@H]1Oc1ccc(Br)nc1

Procedure:
The title compound of Step 2 was prepared according to the general procedure for the synthesis of trans-2-(4-bromophenoxy)cyclopentyl methanesulfonate in Example 5, except that trans-4-[(6-bromopyridin-3-yl)oxy]tetrahydrofuran-3-ol was used instead of trans-2-(4-bromophenoxy)cyclopentanol. The product was obtained as a solid. Yield: 5.95 g, 17.6 mmol, 87%. 1H NMR (400 MHz, CDCl3) δ 3.07 (s, 3H), 3.94 (br dd, J=10.5, 1.8 Hz, 1H), 4.00 (m, 1H), 4.11 (dd, J=11.1, 4.1 Hz, 1H), 4.18 (dd, J=10.6, 4.5 Hz, 1H), 4.97 (br d, J=4.4 Hz, 1H), 5.13 (br d, J=3.8 Hz, 1H), 7.19 (dd, J=8.7, 3.2 Hz, 1H), 7.35 (dd, J=8.7, 0.5 Hz, 1H), 8.04 (dd, J=3.2, 0.5 Hz, 1H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]([NH2:11])=[S:10])[N:3]=1.II.[F:14][C:15]([F:34])([F:33])[CH2:16][C:17]([C:19]1[CH:20]=[N:21][N:22]([CH2:24][C:25]2[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=2)[CH:23]=1)=O>N1C=CC=CC=1>[CH3:32][O:31][C:28]1[CH:27]=[CH:26][C:25]([CH2:24][N:22]2[CH:23]=[C:19]([C:17]3[N:11]=[C:9]([NH:8][C:4]4[N:3]=[C:2]([CH3:1])[CH:7]=[CH:6][N:5]=4)[S:10][C:16]=3[C:15]([F:34])([F:14])[F:33])[CH:20]=[N:21]2)=[CH:30][CH:29]=1
Reactant: COc1ccc(Cn2cc(C(=O)CC(F)(F)F)cn2)cc1
Reactant: Cc1ccnc(NC(N)=S)n1
Agent: II
Solvent: c1ccncc1
Product: COc1ccc(Cn2cc(-c3nc(Nc4nccc(C)n4)sc3C(F)(F)F)cn2)cc1
Temperature: 80 °C
Reaction time: 0.25 h
Yield: 50.6 %

Procedure:
According to Scheme 9 Step 3: To a solution of 1-(4-methylpyrimidin-2-yl)thiourea (0.79 mmol, 133 mg) in pyridine (1 mL) was added iodine (0.79 mmol, 200 mg). The solution was stirred at 80° C. for 15 minutes and then 3,3,3-trifluoro-1-(1-(4-methoxybenzyl)-1H-pyrazol-4-yl)propan-1-one (0.79 mmol, 235 mg) was added. The reaction mixture was stirred for 2 hours at 80° C. The solvent was removed under reduced pressure. The crude mixture was partitioned between AcOEt and a saturated aqueous solution of Na2CO3. The aqueous layer was extracted with AcOEt. The combined organic layers were dried over MgSO4, were filtered and were evaporated under reduced pressure. The resulting crude product was purified by flash chromatography over silica gel using DCM/MeOH (99:1) to afford 4-(1-(4-methoxybenzyl)-1H-pyrazol-4-yl)-N-(4-methylpyrimidin-2-yl)-5-(trifluoromethyl)thiazol-2-amine (0.40 mmol, 180 mg, 51%).
Reaction SMILES: [N:1]1([C:6]2[CH:26]=[CH:25][C:9]([O:10][CH2:11][C:12]3[N:13]=[C:14]([CH:17]4[CH2:22][CH2:21][N:20]([C:23]#[N:24])[CH2:19][CH2:18]4)[S:15][CH:16]=3)=[CH:8][CH:7]=2)[CH:5]=[N:4][N:3]=[N:2]1.C([OH:29])C.O>Cl>[N:1]1([C:6]2[CH:7]=[CH:8][C:9]([O:10][CH2:11][C:12]3[N:13]=[C:14]([CH:17]4[CH2:22][CH2:21][N:20]([C:23]([NH2:24])=[O:29])[CH2:19][CH2:18]4)[S:15][CH:16]=3)=[CH:25][CH:26]=2)[CH:5]=[N:4][N:3]=[N:2]1
Reactant: N#CN1CCC(c2nc(COc3ccc(-n4cnnn4)cc3)cs2)CC1
Reactant: CCO
Agent: Cl
Solvent: O
Product: NC(=O)N1CCC(c2nc(COc3ccc(-n4cnnn4)cc3)cs2)CC1

Procedure:
4-[4-(4-Tetrazol-1-yl-phenoxymethyl)-thiazol-2-yl]-piperidine-1-carbonitrile (1.07 g, 2.92 mmol) was dissolved in 4 N HCl in ethanol/water (1:1). The solution was refluxed for 1 hour, cooled and the solid precipitate was filtered off. The filtrate was neutralized by the addition of excess sodium carbonate. The excess sodium carbonate was filtered off and the filtrate was diluted with EtOAc. The solution was washed with water, separated, dried (Na2SO4), filtered and concentrated. The residual oil was chromatographed on silica gel (1:1 Hexanes/EtOAc) to afford the desired compound. 1H NMR (CDCl3): δ 8.92 (1H, s), 7.60 (2H, d), 7.23 (1H, s), 7.167 (2H, d), 5.21 (2H, s), 4.25 (2H, m), 4.15 (2H, m), 3.22 (1H, m), 2.90 (2H, m), 2.18 (2H, m).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:12]([OH:14])=O)[CH:6]=[CH:5]2.S(Cl)([Cl:17])=O>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:12]([Cl:17])=[O:14])[CH:6]=[CH:5]2
Reactant: O=C(O)c1ccc2cc(Br)ccc2c1
Reactant: O=S(Cl)Cl
Product: O=C(Cl)c1ccc2cc(Br)ccc2c1
Temperature: 60 °C
Reaction time: 16 h

Procedure:
6-Bromonaphthalene-2-carboxylic acid (25.1 g) was suspended in thionyl chloride (200 mL), stirred at 60° C. for 16 hours and evaporated under vacuum. Solid was dissolved in dichloromethane (50 mL) and evaporated under vacuum, giving 6-bromonaphthalene-2-carbonyl chloride (27.0 g, crude) as a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:17]([OH:19])=O)[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N1C=CN=C1)(N1C=CN=C1)=O.Cl.[CH3:33][NH:34][O:35][CH3:36].C(N(CC)C(C)C)(C)C>ClCCl>[C:1]([O:5][C:6]([NH:8][C@H:9]([C:17]([N:34]([O:35][CH3:36])[CH3:33])=[O:19])[CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CNOC
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CON(C)C(=O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Reaction time: 0.25 h

Procedure:
1000 mg (3.77 mmol) N-(tert-butoxycarbonyl)-L-phenylalanine was placed in 10 mL dichloromethane and mixed with 733 mg (4.52 mmol) 1,1′-carbonyldiimidazole. The batch was stirred for 15 min until the evolution of gas had stopped. Next the mixture was mixed with 441 mg (4.52 mmol) N,O-dimethylhydroxylamine hydrochloride and 657 μL (3.77 mmol) N,N-diisopropylethylamine and stirred for 1 hour at RT. Next the batch was diluted with dichloromethane and washed with distilled water, 0.5N hydrochloric acid and saturated sodium chloride solution in succession. The organic phase was separated and the combined aqueous phases were re-extracted with ethyl acetate. The combined organic phases were dried over magnesium sulfate and concentrated in vacuo, yielding 1090 mg (93% of the theoretical) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:12][CH2:11][CH2:10][NH:9]2)=[CH:4][CH:3]=1.[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[CH:16][CH:15]=1>>[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([S:20]([N:9]2[CH2:10][CH2:11][CH2:12][CH:8]2[C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)(=[O:22])=[O:21])=[CH:16][CH:15]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Reactant: Clc1ccc(C2CCCN2)cc1
Product: O=S(=O)(c1ccc(Cl)cc1)N1CCCC1c1ccc(Cl)cc1

Procedure:
The title compound, white solid, m.p. 159° C. and MS: m/e=355 (M+) was prepared in accordance with the general method of example 1e from (RS)-2-(4-chloro-phenyl)-pyrrolidine and 4-chloro-benzenesulfonyl chloride.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][NH:9]C(=O)OC(C)(C)C)=[CH:4][CH:3]=1.[CH3:17][O:18][C:19]1[CH:28]=[C:27]2[C:22]([C:23]([O:29][C:30]3[CH:42]=[CH:41][C:33]4[C:34]([C:38](O)=[O:39])=[C:35]([CH3:37])[O:36][C:32]=4[CH:31]=3)=[CH:24][CH:25]=[N:26]2)=[CH:21][CH:20]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:9][CH2:8][C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:38]([C:34]2[C:33]3[CH:41]=[CH:42][C:30]([O:29][C:23]4[C:22]5[C:27](=[CH:28][C:19]([O:18][CH3:17])=[CH:20][CH:21]=5)[N:26]=[CH:25][CH:24]=4)=[CH:31][C:32]=3[O:36][C:35]=2[CH3:37])=[O:39])=[N:7][CH:6]=1
Reactant: COc1ccc2c(Oc3ccc4c(C(=O)O)c(C)oc4c3)ccnc2c1
Reactant: CC(C)(C)OC(=O)NCc1ccc(N)nc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc2c(Oc3ccc4c(C(=O)Nc5ccc(CN)cn5)c(C)oc4c3)ccnc2c1

Procedure:
117-C was coupled with 6-[(7-methoxyquinolin-4-yl)oxy]-2-methyl-1-benzofuran-3-carboxylic acid 117-D (as prepared in Scheme II discussed previously). After work up the mixture was treated with 50% TFA in CH2Cl2 to give N[5-(aminomethyl)pyridin-2-yl]-6-[(7-methoxyquinolin-4-yl)oxy]-2-methyl-1-benzofuran-3-carboxamide 117-E.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([O:12][C:13]2[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[CH:15][N:14]=2)=[CH:4][N:3]=1.[CH3:21]B1OB(C)OB(C)O1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH3:21][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([O:12][C:13]2[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[CH:15][N:14]=2)=[CH:4][N:3]=1
Reactant: CB1OB(C)OB(C)O1
Reactant: N#Cc1ccc(Oc2cnc(Cl)c3ccccc23)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1ncc(Oc2ccc(C#N)cn2)c2ccccc12
Temperature: 80 °C

Procedure:
To a solution of 6-(1-chloroisoquinolin-4-yloxy)nicotinonitrile (Preparation 17) (300 mg, 1.1 mmol) in DMF (8 mL) under argon was added trimethylboroxine (148 μL, 1.1 mmol) followed by K2CO3 (442 mg, 3.2 mmol) and palladium tetrakistriphenylphosphine (123 mg, 0.1 mmol). The mixture was purged with argon for 5 min and then heated to 80° C. for 16 h. Solvent was removed in vacuo. The residue was partitioned between EtOAc (100 mL) and water (40 mL), the organic phase was washed with water (40 mL), NaHCO3 (40 mL), brine (30 mL) and dried (MgSO4). Solvent was removed in vacuo and the residue purified by column chromatography (2% MeOH: DCM) to give the title compound: RT=2.40 min; m/z (ES+)=262.4 [M+H]+.
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][CH2:5][NH:4][CH2:3]1.C(N(CC)CC)C.Br[CH:15]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C(#N)C>[C:16]1([CH:15]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[N:4]2[CH2:5][CH2:6][C@H:2]([OH:1])[CH2:3]2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O[C@H]1CCNC1
Reactant: BrC(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: O[C@H]1CCN(C(c2ccccc2)c2ccccc2)C1
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 89.4 %

Procedure:
(3S)-3-Hydroxypyrrolidine (2.0 g) was dissolved in acetonitrile (10.0 mL) under cooling with ice. Triethylamine (4.8 mL) was added to the solution, and bromodiphenylmethane (5.7 g) in acetonitrile (10.0 mL) was added dropwise to the mixture, followed by stirring at room temperature for 4.5 hours. After completion of reaction, the insoluble material was removed through filtration, and water and toluene were added to the filtrate, whereby the organic layer was extracted. The formed aqueous layer was again extracted with toluene, and the organic layers were combined together, washed with saturated brine, and dried over sodium sulfate. The drying agent was removed through filtration, and the filtrate was concentrated under reduced pressure, to thereby yield crystalline residue. The residue was subjected to silica gel chromatography, to thereby give the target compound (5.2 g, yield 89.7%). The thus-obtained compound can be crystallized through treatment with hexane-ethyl acetate, alcohol-water, and so on.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5](B(O)O)[CH:6]=[CH:7][C:8]=1[F:9])#[N:2].P([O-])([O-])([O-])=O.[K+].[K+].[K+].C1(C)C=CC=CC=1.[F:28][C:29]1[CH:30]=[C:31]([CH:34]=[C:35]([F:37])[CH:36]=1)[CH2:32]Br>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(OCC)C>[F:28][C:29]1[CH:30]=[C:31]([CH:34]=[C:35]([F:37])[CH:36]=1)[CH2:32][C:5]1[CH:6]=[CH:7][C:8]([F:9])=[C:3]([CH:4]=1)[C:1]#[N:2]
Reactant: Fc1cc(F)cc(CBr)c1
Reactant: N#Cc1cc(B(O)O)ccc1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: N#Cc1cc(Cc2cc(F)cc(F)c2)ccc1F
Temperature: 100 °C
Yield: 129.8 %

Procedure:
3-Cyano-4-fluorophenylboronic acid (1.649 g, 10 mmol), powdered potassium phosphate (4.254 g, 20 mmol) and Pd(PPh3)4 (231 mg, 0.2 mmol) were charged in an oven-dried flask under argon atmosphere. The flask was evacuated and back-filled with argon thrice and then toluene (30 mL) and 3,5-difluorobenzyl bromide (1.295 mL, 10 mmol) were added by means of a syringe through a lattice stopper, under good stirring. The reaction mixture was heated to 100° C. in half an hour and maintained at that temperature for 1.5 hours. The black mixture was taken up with diethylether (200 mL), washed with saturated aqueous ammonium chloride (2×20 mL), brine (3×30 mL), dried over sodium sulphate and evaporated to dryness to afford 3.21 g of yellow oil. The crude was purified by flash chromatography on silica gel eluting with n-hexane/ethyl acetate 95:5 to yield 1.89 g (yield 76.4%) of whitish solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:20]3[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=3)=[C:10]([CH2:13][CH2:14][C:15]([O:17]CC)=[O:16])[S:11][CH:12]=2)=[C:4]([O:27][CH3:28])[CH:3]=1.[OH-].[Na+]>CCO.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:20]3[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=3)=[C:10]([CH2:13][CH2:14][C:15]([OH:17])=[O:16])[S:11][CH:12]=2)=[C:4]([O:27][CH3:28])[CH:3]=1
Reactant: CCOC(=O)CCc1scc(-c2ccc(Cl)cc2OC)c1-c1ccc(O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: COc1cc(Cl)ccc1-c1csc(CCC(=O)O)c1-c1ccc(O)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 61.8 %

Procedure:
To a solution of ethyl 3-(4-(4-chloro-2-methoxyphenyl)-3-(4-hydroxyphenyl)thiophen-2-yl)propanoate (220 mg, 0.53 mmol) in EtOH (5 mL) was added NaOH (42 mg, 1.06 mmol), and the mixture was stirred at room temperature for 2 hours. The mixture was diluted with water, neutralized to pH=4-5, extracted with EtOAc, and concentrated to give 3-(4-(4-chloro-2-methoxyphenyl)-3-(4-hydroxyphenyl)thiophen-2-yl)propanoic acid (Scheme II, 12, X1=4-hydroxyphenyl, X2=4-chloro-2-methoxyphenyl) (127.42 mg, yield 62%). 1H NMR (DMSO-d6 400 MHz): δ 9.36 (br, 1H), 7.25 (s, 1H), 7.01 (d, J 8.0 Hz, 1H), 6.91-6.88 (m, 2H), 6.79 (d, J=8.4 Hz, 2H), 6.64 (d, J=8.4 Hz, 2H), 3.40 (s, 3H), 2.92 (t, J=7.2 Hz, 2H), 2.47 (t, J=7.2 Hz, 2H); MS (ESI): m/z [M+1]+=389.0.