Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.[C:11]([C:14]1[CH:15]=[C:16](B(O)O)[CH:17]=[CH:18][CH:19]=1)([OH:13])=[O:12].C([O-])([O-])=O.[K+].[K+]>CC([O-])=O.CC([O-])=O.[Pd+2].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=C(S([O-])(=O)=O)C=2OC)CCCCC1.[Na+].O>[C:10]1([C:17]2[CH:16]=[CH:15][C:14]([C:11]([OH:13])=[O:12])=[CH:19][CH:18]=2)[CH:2]=[CH:3][CH:4]=[C:5]([C:6]([OH:8])=[O:7])[CH:9]=1
Reactant: O=C(O)c1cccc(B(O)O)c1
Reactant: O=C(O)c1ccc(Cl)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1ccc(S(=O)(=O)[O-])c(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: O
Product: O=C(O)c1ccc(-c2cccc(C(=O)O)c2)cc1
Yield: 94.5 %

Procedure:
Using microwave irradiation. The general procedure described in Example 3 was used with 4-chlorobenzoic acid (157 mg, 1.00 mmol), 3-carboxyphenylboronic acid (199 mg, 1.20 mmol), Pd(OAc)2 (2.2 mg, 0.010 mmol, 1 mol %), sodium 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl-3′-sulfonate (10.0 mg, 0.020 mmol, 2 mol %), K2CO3 (414 mg, 3.00 mmol), water (3.0 mL), 10 min at 150° C. (using microwave irradiation with cooling). The product was isolated as a white solid (229 mg, 95%). Mp=>250° C. (lit. mp=295° C.). 1H NMR (400 MHz, d6-DMSO/D2O) δ: 8.22 (s, 1H), 8.42 (d, 2H, J=7.6 Hz), 7.98 (d, 1H, J=7.6 Hz), 7.91 (d, 1H, J=7.6 Hz), 7.79 (d, 2H, J=7.6 Hz), 7.59 (t, 1H, J=7.2 Hz). 13C NMR (125 MHz, d6-DMSO/D2O) δ: 167.5, 143.6, 139.7, 131.9, 131.7, 130.4, 130.3, 129.8, 129.4, 127.8, 127.2.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]2[N:9]([CH2:14][CH:15]=O)[C:10](=[O:13])[CH:11]=[CH:12][C:6]2=[N:5][CH:4]=1.[O:17]1[C:26]2[CH:25]=[C:24]([CH2:27][N:28]([CH:36]3[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]3)[C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])[N:23]=[CH:22][C:21]=2[O:20][CH2:19][CH2:18]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>C(Cl)Cl.C(Cl)(Cl)Cl.C(O)(=O)C>[O:17]1[C:26]2[CH:25]=[C:24]([CH2:27][N:28]([CH:36]3[CH2:41][CH2:40][N:39]([CH2:15][CH2:14][N:9]4[C:7]5=[N:8][C:3]([O:2][CH3:1])=[CH:4][N:5]=[C:6]5[CH:12]=[CH:11][C:10]4=[O:13])[CH2:38][CH2:37]3)[C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])[N:23]=[CH:22][C:21]=2[O:20][CH2:19][CH2:18]1
Reactant: CC(C)(C)OC(=O)N(Cc1cc2c(cn1)OCCO2)C1CCNCC1
Reactant: COc1cnc2ccc(=O)n(CC=O)c2n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: COc1cnc2ccc(=O)n(CCN3CCC(N(Cc4cc5c(cn4)OCCO5)C(=O)OC(C)(C)C)CC3)c2n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 112.4 %

Procedure:
To a solution of 0.12 g of (3-methoxy-6-oxopyrido(2,3-b)pyrazin-5(6H)-yl)acetaldehyde in 5 mL of methylene chloride, 0.18 g of tert-butyl (2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-ylmethyl)(piperidin-4-yl)carbamate, 26 μL of acetic acid and 0.12 g of sodium triacetoxyborohydride were added, and the mixture was stirred at room temperature for 2 hours 30 minutes. To the reaction mixture, a saturated aqueous sodium hydrogen carbonate solution and chloroform were added, the organic layer was separated, and the aqueous layer was extracted with chloroform. The organic layer and the extract were combined, the resultant solution was washed with a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The resultant residue was purified by silica gel column chromatography using an eluent of chloroform:methanol=20:1 to obtain 0.32 g of tert-butyl (2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-ylmethyl)(1-(2-(3-methoxy-6-oxopyrido(2,3-b)pyrazin-5(6H)-yl)ethyl)piperidin-4-yl)carbamate as a colorless oily substance.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([N+]([O-])=O)=[C:8]([S:10]([C:13]2[CH:14]=[N:15][C:16]([Cl:20])=[C:17]([Br:19])[CH:18]=2)(=[O:12])=[O:11])[CH:9]=1)=[O:4].[CH3:24][S-:25].[Na+]>>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([S:25][CH3:24])=[C:8]([S:10]([C:13]2[CH:14]=[N:15][C:16]([Cl:20])=[C:17]([Br:19])[CH:18]=2)(=[O:12])=[O:11])[CH:9]=1)=[O:4]
Reactant: COC(=O)c1cc(S(=O)(=O)c2cnc(Cl)c(Br)c2)c([N+](=O)[O-])s1
Reactant: C[S-]
Agent: [Na+]
Product: COC(=O)c1cc(S(=O)(=O)c2cnc(Cl)c(Br)c2)c(SC)s1
Reaction time: 2.5 h
Yield: 20.9 %

Procedure:
The procedure as in Example 27, a was followed using 4-(5-bromo-6-chloro-pyridine-3-sulfonyl)-5-nitro-thiophene-2-carboxylic acid methyl ester (3.5 g, 8.10 mmol, Example 118, step b) and sodium thiomethoxide (560 mg, 8.10 mmol as 1M solution in EtOH). The reaction was allowed to stir for 2.5 hours and was quenched with acetic acid. The resulting mixture was dissolved into EtOAc, and aqueous work up with brine and saturated NaHCO3 resulted in isolation of a mixture. This mixture was purified by SiO2 flash column chromatography (Biotage—40 M, 100% hexanes to 25% EtOAc in hexanes). The product was isolated as a yellow solid (750 mg, 21%). ESI-MS (m/z): Calcd. for C12H10BrClNO4S3: 441.8 (M+H); found: 442.1. 1H-NMR (CD3OD+CDCl3): δ 8.93 (m, 1H), 8.50 (m, 1H), 8.06 (s, 1H), 3.91 (m, 3H), 2.67 (m, 3H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([C:12]2[CH:17]=[C:16]([C:18]([OH:20])=O)[CH:15]=[CH:14][C:13]=2[CH3:21])[C:10]=1[NH2:11])=[O:5])[CH3:2].CCN=C=N[CH2:27][CH2:28][CH2:29][N:30](C)C.C1C=CC2N(O)N=NC=2C=1.C(N(C(C)C)CC)(C)C.C1(N)CC1>CN(C=O)C.CCOC(C)=O.O>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([C:12]2[CH:17]=[C:16]([C:18](=[O:20])[NH:30][CH:29]3[CH2:27][CH2:28]3)[CH:15]=[CH:14][C:13]=2[CH3:21])[C:10]=1[NH2:11])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cnn(-c2cc(C(=O)O)ccc2C)c1N
Reactant: CCN=C=NCCCN(C)C
Agent: NC1CC1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cnn(-c2cc(C(=O)NC3CC3)ccc2C)c1N
Reaction time: 8 h
Yield: 78.7 %

Procedure:
To a solution of 5-amino-1-(5-carboxy-2-methyl-phenyl)-1H-pyrazole-4-carboxylic acid ethyl ester (47 mg, 0.16 mind, 1.0 eq), EDCI (62 mg, 0.32 mmol, 2.0 eq), HOBt (44 mg, 0.32 mmol, 2.0 eq), and diisopropylethyl amine (119 μL, 0.32 mmol, 2.0 eq) in DMF (5 mL) which had been stirred at RT for 15 min was added cyclopropylamine (23 μL, 0.32 mmol, 2.0 eq). After stirring overnight, the solution was diluted with EtOAc and water and the organic layer was washed with water and brine, dried (Na2SO4) and concentrated. The crude residue was purified by flash chromatography on silica gel eluted with 8/2 EtOAc/hexanes to provide the product as a colorless oil (42 mg, 79%). HPLC (4 minute 10-95 gradient) tR 1.84 min; MS m/z 329.09 [M+H]+; 1H NMR (CD3OD), δ 7.96 (s, 1 H, NH), 7.88 (d, J=7.9 Hz, 1 H), 7.78 (s, 1 H), 7.75 (s, 1 H), 7.50 (d, J=8.0 Hz, 1 H), 4.28 (q, J=7.1 Hz, 2 H), 2.83 (m, 1 H), 2.16 (s, 3 H), 1.35 (d, J=7.0 Hz, 3 H), 0.78 (dd, J=12.3, 7.0 Hz, 2 H), 0.63 (dd, J=7.0, 4.5 Hz, 2 H) ppm; 13C NMR (CD3OD), δ 170.1, 165.8, 152.3, 142.1, 141.8, 137.2, 134.6, 132.8, 130.0, 128.2, 128.1, 95.8, 60.8, 24.1, 17.6, 14.9, 6.6 ppm.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[O:9][CH2:10][CH:11]([C:13]([O:15][CH3:16])=[O:14])[N:12]=2)=[C:4]([NH:17][CH:18]([CH3:20])[CH3:19])[CH:3]=1.[CH2:21]1CCN2C(=NCCC2)CC1.BrC(Cl)(Cl)Cl>C(Cl)Cl>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[O:9][CH:10]=[C:11]([C:13]([O:15][CH2:16][CH3:21])=[O:14])[N:12]=2)=[C:4]([NH:17][CH:18]([CH3:20])[CH3:19])[CH:3]=1
Reactant: COC(=O)C1COC(c2cnc(Cl)cc2NC(C)C)=N1
Reactant: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Solvent: ClC(Cl)(Cl)Br
Product: CCOC(=O)c1coc(-c2cnc(Cl)cc2NC(C)C)n1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a stirred solution of methyl 2-(6-chloro-4-(isopropylamino)pyridin-3-yl)-4,5-dihydrooxazole-4-carboxylate (37) (100 mg, 0.336 mmol) in DCM (20 mL), DBU (1.008 mmol) and bromotrichloromethane (0.403 mmol) were added at 0° C. and stirred the reaction mixture for 2 h at 0° C. Reaction temperature was raised to room temperature and stirred the reaction for 10 min. The reaction mixture was diluted with DCM and washed with water, 10% NaHCO3 solution and brine solution. The organic layer was collected, dried over Na2SO4, filtered and concentrated. The crude material obtained was purified by flash chromatography using silica gel and EtOAC: pet ether as eluent to afford the title compound, ethyl 2-(6-chloro-4-(isopropylamino)pyridin-3-yl)oxazole-4-carboxylate (38). 1H NMR: 400 MHz, DMSO-d6: δ 1.24-1.27 (m, 6H), 3.87 (s, 3H), 3.92-3.97 (m, 1H), 6.92 (s, 1H), 8.36 (d, J=7.60 Hz, 1H), 8.60 (s, 1H), 9.00 (s, 1H).
Reaction SMILES: [CH2:1]([N:8]1[CH:12]=[CH:11][N:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li+].CC([N-]C(C)C)C.[P:21](Cl)([O:26][CH2:27][CH3:28])([O:23][CH2:24][CH3:25])=[O:22]>C1COCC1>[CH2:1]([N:8]1[CH:12]=[CH:11][N:10]=[C:9]1[P:21]([O:26][CH2:27][CH3:28])([O:23][CH2:24][CH3:25])=[O:22])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOP(=O)(Cl)OCC
Reactant: c1ccc(Cn2ccnc2)cc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOP(=O)(OCC)c1nccn1Cc1ccccc1
Reaction time: 2 h

Procedure:
A solution of 1-benzylimidazole (1.1 mmol) in THF was treated with LDA (1.1 mmol) at −78° C. for 1 h, and followed by addition of diethyl chlorophosphate (2 mmol), and stirred for 2 h. Extraction and chromatography gave 1-benzyl-2-diethylphosphonoimidazole as a yellow oil. TLC: Rf=0.35, 80% EtOAc-hexane.
Reaction SMILES: [Cl:1][C:2]1[C:10]([S:11]([CH3:14])(=[O:13])=[O:12])=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([O:15][CH2:16][CH3:17])[CH:3]=1.[N+](=[CH2:20])=[N-]>O1CCCC1.CCOCC>[CH3:20][O:7][C:6](=[O:8])[C:5]1[CH:9]=[C:10]([S:11]([CH3:14])(=[O:12])=[O:13])[C:2]([Cl:1])=[CH:3][C:4]=1[O:15][CH2:16][CH3:17]
Reactant: C=[N+]=[N-]
Reactant: CCOc1cc(Cl)c(S(C)(=O)=O)cc1C(=O)O
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCOc1cc(Cl)c(S(C)(=O)=O)cc1C(=O)OC
Reaction time: 0.17 h

Procedure:
A solution of 4-chloro-2-ethoxy-5-methanesulfonylbenzoic acid (2.5 g, 9.0 mmol) in tetrahydrofuran was cooled to 5° C. and treated with excess diazomethane in ether solution (prepared from N-methyl-N-nitroso-p-toluenesulfonamide, Aldrich) and stirred for 10 min. Solvent and excess diazomethane was removed by rotary evaporation. The resulting residue was dissolved in dichloromethane and filtered through a plug of silica gel and evaporated. The solids were triturated with ether/hexane to give 4-chloro-2-ethoxy-5-methanesulfonyl-benzoic acid methyl ester (2.1 g, colorless solids).
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.S(C1C=CC(C)=CC=1)(O[CH2:13][CH2:14][F:15])(=O)=O>CN(C=O)C.C(OCC)(=O)C>[F:15][CH2:14][CH2:13][NH:6][C:5]1[CH:7]=[CH:8][C:2]([F:1])=[CH:3][CH:4]=1
Reactant: Cc1ccc(S(=O)(=O)OCCF)cc1
Reactant: Nc1ccc(F)cc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: FCCNc1ccc(F)cc1
Temperature: 100 °C
Reaction time: 8 h
Yield: 21 %

Procedure:
In a round bottom flask 4-fluoroaniline (1.3 g, 11.6 mmol, 1.6 mL) 2,6-lutidine (1.24 g, 11.6 mmol) and 2-fluoroethyl tosylate (12; prepared according to Example 2(a)) (2.5 g, 11.6 mmol) were combined in DMF (5 mL) and stirred at 100° C. overnight. The reaction was allowed to cool and then diluted with ethyl acetate (100 mL). This was washed with water (3×40 mL) and the organics were dried and concentrated in vacuo. The crude material was purified by silica gel chromatography eluting with petrol (A) and ethyl acetate (B) (10% B, 100 g, 12 CV, 60 mL/min) to afford 383 mg (20%) of (2-fluoro-ethyl)-(4-fluoro-phenyl)-amine (38) as a yellow oil. The structure was confirmed by 1H NMR (300 MHz, CDCl3) δH 3.30-3.35 (1H, m, NCH2CH2F), 3.40-3.45 (1H, m, NCH2CH2F), 3.90 (1H, s, br, NH), 4.53 (1H, t, J=3 Hz, NCH2CH2F), 4.69 (1H, t, J=3 Hz, NCH2CH2F), 6.51-6.72 (2H, m, 2×NCCH), 6.85-7.05 (2H, m, 2×NCCHCH).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:9]2[CH:17]=[CH:16][C:12]([C:13]([OH:15])=O)=[CH:11][N:10]=2)[CH:6]=[CH:7][CH:8]=1)#[N:2].[F:18][C:19]([F:29])([F:28])[CH2:20][N:21]1[CH2:26][CH2:25][CH:24]([NH2:27])[CH2:23][CH2:22]1>CN(C)C=O>[C:1]([C:3]1[CH:4]=[C:5]([C:9]2[CH:17]=[CH:16][C:12]([C:13]([NH:27][CH:24]3[CH2:25][CH2:26][N:21]([CH2:20][C:19]([F:29])([F:18])[F:28])[CH2:22][CH2:23]3)=[O:15])=[CH:11][N:10]=2)[CH:6]=[CH:7][CH:8]=1)#[N:2]
Reactant: NC1CCN(CC(F)(F)F)CC1
Reactant: N#Cc1cccc(-c2ccc(C(=O)O)cn2)c1
Solvent: CN(C)C=O
Product: N#Cc1cccc(-c2ccc(C(=O)NC3CCN(CC(F)(F)F)CC3)cn2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 61.5 %

Procedure:
To a solution of 6-(3-cyanophenyl)nicotinic acid (50 mg, 0.222 mmol) in dimethylformamide (1 mL) was added 1,11-carbonylbis(1H-imidazole) (36.3 mg, 0.224 mmol) and the reaction mixture stirred at room temperature for 1 hour. A solution of 1-(2,2,2-trifluoroethyl)piperidin-4-amine (49 mg, 0.269 mmol) in dimethylformamide (0.5 mL) was then added and the reaction stirred overnight at room temperature. Further 1,11-carbonylbis(1H-imidazole) (18 mg, 0.132 mmol) was added and the reaction stirred for 30 minutes and then further 1-(2,2,2-trifluoroethyl)piperidin-4-amine (25 mg, 0.134 mmol) in dimethylformamide (0.5 mL) was added and the solution stirred for one hour. The dimethylformamide was evaporated off and the residue partitioned between ethyl acetate (10 mL) and water (3 mL). The organic layer was separated, dried over anhydrous MgSO4, filtered and evaporated to a white solid. This was triturated with t-butyl methyl ether and the white solid was filtered off and dried to give 6-(3-cyanophenyl)-N-[1-(2,2,2-trifluoroethyl)piperidin-4-yl]nicotinamide 53 mg 1H NMR (400 MHz, DMSO-d6) ppm 1.57-1.67 (m, 2H) 1.80-1.87 (m, 2H) 2.43-2.54 (m, 2H) 2.93-2.99 (m, 2H) 3.20 (q, J=10.1 Hz, 2H) 3.83 (m , 1H) 7.76 (t, J=8.2 Hz, 1H) 7.97 (m, 1H) 8.24 (m, 1H) 8.34 (dd, J=6.2, 2.4 Hz, 1H) 8.52 (m, 2H) 8.61*m, 1H) 9.12 (m, 1H) LCMS 389 (M+1) ELSD 1.27 minutes.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]([OH:10])[CH:7]=[CH:8][CH:9]=1.Cl[C:12]1[C:21]2[C:16](=[CH:17][C:18]([O:24][CH3:25])=[C:19]([O:22][CH3:23])[CH:20]=2)[N:15]=[CH:14][N:13]=1.CCOC(C)=O>C1COCC1>[Cl:3][C:4]1[CH:5]=[C:6]([CH:7]=[CH:8][CH:9]=1)[O:10][C:12]1[C:21]2[C:16](=[CH:17][C:18]([O:24][CH3:25])=[C:19]([O:22][CH3:23])[CH:20]=2)[N:15]=[CH:14][N:13]=1
Reactant: COc1cc2ncnc(Cl)c2cc1OC
Reactant: Oc1cccc(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1cc2ncnc(Oc3cccc(Cl)c3)c2cc1OC
Temperature: 25 °C

Procedure:
THF (5 ml) and NaH (60% disp in oil, approx. 28 mg) is added to a dry flask maintained under inert atmosphere at room temperature. 3-Chlorophenol (0.09 g) is added as a soln. in THF (1 mL) and stirring is continued until the solution became clear. 4-Chloro-6,7-dimethoxyquinazoline is added all at once (as the solid) and stirring was maintained overnight at RT. The solution is partitioned between CH2Cl2 and 5% NaOH. The organic layer is washed with brine, dried (Na2SO4) and concentrated. Flash column chromatography (40% EtOAc/Hex) provided the pure compound. An analytical sample is obtained by recrystallization from EtOAc/Hex to provide 4-(3-chlorophenoxy)-6,7-dimethoxyquinazoline (0.05 g), white needles, m.p. 152°-153° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:13]3=[N:14][NH:15][C:16](=[O:21])[C:17]4[CH:18]=[CH:19][CH:20]=[C:11]([C:12]=43)[NH:10][CH:9]2[C:22]2[CH:29]=[CH:28][C:25]([CH:26]=O)=[CH:24][CH:23]=2)=[CH:4][CH:3]=1.[CH3:30][CH:31]1[CH2:36][NH:35][CH2:34][CH:33]([CH3:37])[N:32]1[C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39]>C(Cl)Cl>[C:41]([O:40][C:38]([N:32]1[C@H:33]([CH3:37])[CH2:34][N:35]([CH2:26][C:25]2[CH:28]=[CH:29][C:22]([CH:9]3[NH:10][C:11]4[C:12]5[C:13](=[N:14][NH:15][C:16](=[O:21])[C:17]=5[CH:18]=[CH:19][CH:20]=4)[CH:8]3[C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)=[CH:23][CH:24]=2)[CH2:36][C@H:31]1[CH3:30])=[O:39])([CH3:44])([CH3:42])[CH3:43]
Reactant: O=Cc1ccc(C2Nc3cccc4c(=O)[nH]nc(c34)C2c2ccc(F)cc2)cc1
Reactant: CC1CNCC(C)N1C(=O)OC(C)(C)C
Solvent: ClCCl
Product: C[C@@H]1CN(Cc2ccc(C3Nc4cccc5c(=O)[nH]nc(c45)C3c3ccc(F)cc3)cc2)C[C@@H](C)N1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 7.9 %

Procedure:
A mixture of 4-(9-(4-fluorophenyl)-3-oxo-3,7,8,9-tetrahydro-2H-pyrido[4,3,2-de]phthalazin-8-yl)benzaldehyde (200 mg, 520 mmol), tert-butyl 2,6-dimethylpiperazine-1-carboxylate (335 mg, 1.56 mmol) in methylene chloride (10 mL) was stirred at room temperature overnight, then NaBCNH3 (129 mg, 2.08 mmol) was added and the mixture was stirred for another 5 hours. After removal of solvents, the residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate=3:1 to 1:1) to give the title compound (72 mg, 24%). LC-MS (ESI) m/z: 584 (M+1)+.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:28])[NH:10][C@@H:11]([CH3:27])[CH2:12][N:13]1[C:21]2[C:16](=[CH:17][CH:18]=[C:19]3[O:24][C:23]([CH2:25][NH2:26])=[CH:22][C:20]3=2)[CH:15]=[N:14]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:36]([NH:39][C:40]1[CH:49]=[CH:48][C:43]([S:44](Cl)(=[O:46])=[O:45])=[CH:42][CH:41]=1)(=[O:38])[CH3:37].C(=O)(O)[O-].[Na+]>C1COCC1.O>[CH2:1]([O:8][C:9](=[O:28])[NH:10][C@@H:11]([CH3:27])[CH2:12][N:13]1[C:21]2[C:16](=[CH:17][CH:18]=[C:19]3[O:24][C:23]([CH2:25][NH:26][S:44]([C:43]4[CH:42]=[CH:41][C:40]([NH:39][C:36](=[O:38])[CH3:37])=[CH:49][CH:48]=4)(=[O:46])=[O:45])=[CH:22][C:20]3=2)[CH:15]=[N:14]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[C@@H](Cn1ncc2ccc3oc(CN)cc3c21)NC(=O)OCc1ccccc1
Reactant: CC(=O)Nc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)Nc1ccc(S(=O)(=O)NCc2cc3c(ccc4cnn(C[C@H](C)NC(=O)OCc5ccccc5)c43)o2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 65.4 %

Procedure:
A solution of the product from Example 17, Step B (0.32 g, 0.85 mmol) in THF (10 mL) containing triethylamine (3.39 mmol, 0.47 mL) was cooled (ice bath) and N-acetylsulfanilyl chloride (0.20 g, 0.85 mmol) was added followed by stirring for one hour. The reaction mixture was warmed to room temperature, water (1 mL) was added, and stirring continued until all the solids dissolved. Saturated aqueous sodium bicarbonate (150 mL) was added and the mixture was extracted with ethyl acetate (2×100 mL). The combined extracts were washed with brine (100 mL), dried (MgSO4) and evaporated to a residue which was purified by chromatography (silica gel, hexane/ethyl acetate gradient) to give an amorphous solid (0.32 g, 66%): LC/MS m/z 576 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:10]([C:11](Cl)=[O:12])=[C:9]([CH3:14])[S:8][C:7]=2[CH:15]=1.[CH3:16][NH2:17]>C1COCC1>[CH3:16][NH:17][C:11]([C:10]1[C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:15][C:7]=2[S:8][C:9]=1[CH3:14])=[O:12]
Reactant: CN
Reactant: COc1ccc2c(C(=O)Cl)c(C)sc2c1
Solvent: C1CCOC1
Product: CNC(=O)c1c(C)sc2cc(OC)ccc12
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of this crude 6-methoxy-2-methylbenzo[b]thiophene-3-carbonyl chloride in THF (50 ml) was combined with a 2.0 M solution of CH3NH2 in THF (20 ml, 40 mmole). The resultant reaction mixture was stirred at ambient temperature for 3 hours. The solvent was removed by concentration, in vacuo, and the residue obtained was partitioned between H2O (50 ml) and CH2Cl2 (50 ml). The layers were separated and the aqueous phase was extracted with CH2Cl2 (2×30 ml). The combined organic extracts were dried over Na2SO4 and concentrated, in vacuo, to give 0.8 g of an amber solid which was purified by silica gel chromatography. Elution with CH2Cl2: EtOAc (80:20) and evaporation of the appropriate fractions gave 693 mg (72%) of an off-white solid. 1H NMR (DMSO-d6) δ 8.15 (1H, q, J=4.6 Hz), 7.62 (1H, d, J=8.9 Hz), 7.47 (1H, d, J=2.4 Hz), 6.97 (1H, dd, J=2.4, 8.9 Hz), 3.79 (3H, s), 2.80 (3H, d, J=4.6 Hz), 2.53 (3H, s). Anal. Calcd. for C12H13NO2S: C, 61.25; H, 5.57; N, 5.95; S, 13.63. Found: C, 60.97; H, 5.56; N, 5.85; S, 13.44.
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]([CH2:9][CH2:10][OH:11])[CH:6]=[CH:7][CH:8]=1.FC(F)(F)C(O)=O.[CH3:19][C:20]1[S:24][C:23]([C:25]([N:27]2[CH2:32][C:31]3([CH2:37][CH2:36][NH:35][CH2:34][CH2:33]3)[O:30][CH2:29][CH2:28]2)=[O:26])=[CH:22][CH:21]=1.C(N(CC)CC)C>CC#N>[OH:11][CH2:10][CH2:9][C:5]1[CH:4]=[C:3]([CH:8]=[CH:7][CH:6]=1)[CH2:2][N:35]1[CH2:36][CH2:37][C:31]2([O:30][CH2:29][CH2:28][N:27]([C:25]([C:23]3[S:24][C:20]([CH3:19])=[CH:21][CH:22]=3)=[O:26])[CH2:32]2)[CH2:33][CH2:34]1
Reactant: OCCc1cccc(CBr)c1
Reactant: Cc1ccc(C(=O)N2CCOC3(CCNCC3)C2)s1
Solvent: CC#N
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(C(=O)N2CCOC3(CCN(Cc4cccc(CCO)c4)CC3)C2)s1
Reaction time: 1 h

Procedure:
2-(3-(Bromomethyl)phenyl)ethanol (example 6, step a) (0.136 g) was added to a stirred solution of (5-methylthiophen-2-yl)(1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)methanone trifluoroacetate (example 9, step b) (0.250 g) and triethylamine (0.278 mL) in MeCN (5 mL). After 1 h, the reaction mixture was concentrated and applied to a silica gel column eluting with ethyl acetate:triethylamine, 95:5 to give the subtitled compound. Yield 0.24 g.
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.C[O:13][CH:14](OC)[C:15]1[CH:20]=[CH:19][N:18]=[CH:17][C:16]=1[N:21]1[CH2:30][CH2:29][C:28]2[C:23](=[CH:24][C:25]([C:31]([F:34])([F:33])[F:32])=[CH:26][CH:27]=2)[C:22]1=[O:35].CO>CC(C)=O.O.C(Cl)(Cl)Cl>[O:35]=[C:22]1[C:23]2[C:28](=[CH:27][CH:26]=[C:25]([C:31]([F:32])([F:33])[F:34])[CH:24]=2)[CH2:29][CH2:30][N:21]1[C:16]1[CH:17]=[N:18][CH:19]=[CH:20][C:15]=1[CH:14]=[O:13]
Reactant: COC(OC)c1ccncc1N1CCc2ccc(C(F)(F)F)cc2C1=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: ClC(Cl)Cl
Solvent: O
Product: O=Cc1ccncc1N1CCc2ccc(C(F)(F)F)cc2C1=O
Temperature: 25 °C
Reaction time: 48 h
Yield: 14 %

Procedure:
p-Toluene sulphonic acid (PTSA) (4.3 g, 23.093 mmol) was added to a stirred solution of 2-(4-dimethoxymethyl-pyridin-3-yl)-7-trifluoromethyl-3,4-dihydro-2H-isoquinolin-1-one (I-53b: 900 mg, 2.4568 mmol) in acetone (30 mL) and water (30 mL) and resulting reaction mixture was stirred for 48 hours at room temperature. The reaction mass was distilled under vacuum and the crude residue was dissolved in methanol (20 mL). This was followed by the addition of 2 N HCl (10 mL) and refluxed the resulting reaction mass for 3 hours. The reaction was monitored by TLC (10% methanol in CHCl3). The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The crude residue was diluted with ice, basified using saturated NaHCO3 solution and extracted using CHCl3. The organic layer was washed with water, brine solution, dried over Na2SO4 and concentrated under reduced pressure. Purification by column chromatography on silica gel (2% methanol in CHCl3) afforded 110 mg of the product (14% yield).
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].[CH:5]1([NH2:11])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1>ClC1C=CC=CC=1>[CH:5]1([N:11]=[C:1]=[O:2])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1
Reactant: NC1CCCCC1
Reactant: O=C(Cl)Cl
Solvent: Clc1ccccc1
Product: O=C=NC1CCCCC1
Temperature: 78.5 °C
Yield: 175.6 %

Procedure:
500 g of chlorobenzene were placed in the glass vessel and 40 g of gaseous phosgene was introduced at room temperature. The reaction mixture was subsequently heated to 77° C., with vigorous phosgene reflux being established. While stirring vigorously at 77-80° C., a total of 99.2 g of cyclohexylamine (1 mol) dissolved in 200 g of chlorobenzene and at the same time a further 92 g of phosgene were introduced over a period of 3 hours. After addition was complete, the system was maintained at 77-80° C. for a further one hour without introduction of phosgene to allow further reaction to occur and the residual unreacted phosgene was subsequently stripped out at 50° C. by means of nitrogen. The reaction mixture obtained was a suspension from which the solid obtained was separated by filtration. 15 g of solid which, according to IR-spectroscopic analysis, was mainly amine hydrochloride were able to be isolated in this way. The filtered crude product was worked up by distillation. Removal of the solvent and fractional distillation gave 88.8 g of cyclohexyl isocyanate (0.710 mol). This corresponds to 71.0% of the theoretical yield.