Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[K+].[Br:3][C:4]1[CH:5]=[CH:6][C:7]2[NH:8][C:9]3[C:14]([C:15]=2[CH:16]=1)=[CH:13][C:12]([Br:17])=[CH:11][CH:10]=3.[Br:18][CH2:19][CH2:20][CH2:21]Br>CN(C=O)C.CCOC(C)=O>[Br:17][C:12]1[CH:11]=[CH:10][C:9]2[N:8]([CH2:21][CH2:20][CH2:19][Br:18])[C:7]3[C:15]([C:14]=2[CH:13]=1)=[CH:16][C:4]([Br:3])=[CH:5][CH:6]=3
Reactant: Brc1ccc2[nH]c3ccc(Br)cc3c2c1
Reactant: BrCCCBr
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: BrCCCn1c2ccc(Br)cc2c2cc(Br)ccc21
Reaction time: 0.5 h
Yield: 28.6 %

Procedure:
Crushed KOH (0.0673 g, 1.20 mmol, 1.2 equiv) was added to 3,6-dibromocarbazole (0.3250 g, 1.00 mmol) in 2 mL DMF solution and the mixture was stirred for 30 min. 1,3-dibromopropane (0.5047 g, 2.50 mmol, 2.5 equiv) in 3 mL DMF solution was added dropwise into the mixture and it was stirred at room temperature overnight. The crude reaction mixture was diluted with 30 mL EtOAc and washed with 1M HCl 2×10 mL and water 3×10 mL. The organic layer was dried over anhydrous Na2SO4 and evaporated to afford the crude product, which was subjected to silica gel chromatography using Hexanes/EtOAc to afford 0.1275 g colorless oil as product, yield 28.6%.
Reaction SMILES: [Cl:1][C:2]1[C:10]([OH:11])=[CH:9][C:8]([C:12]2[N:13]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[C:14]3[C:19]([CH:20]=2)=[CH:18][C:17]([CH2:21][N:22]2[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]2)=[CH:16][CH:15]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:35].C(N(CC)CC)C.[F:43][C:44]([F:50])([F:49])[S:45](Cl)(=[O:47])=[O:46]>ClCCl>[Cl:1][C:2]1[C:10]([O:11][S:45]([C:44]([F:50])([F:49])[F:43])(=[O:47])=[O:46])=[CH:9][C:8]([C:12]2[N:13]([C:28]([O:30][C:31]([CH3:32])([CH3:34])[CH3:33])=[O:29])[C:14]3[C:19]([CH:20]=2)=[CH:18][C:17]([CH2:21][N:22]2[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]2)=[CH:16][CH:15]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:35]
Reactant: O=S(=O)(Cl)C(F)(F)F
Reactant: CC(C)(C)OC(=O)n1c(-c2cc(O)c(Cl)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)n1c(-c2cc(OS(=O)(=O)C(F)(F)F)c(Cl)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Yield: 69.8 %

Procedure:
In a similar manner to Step 1 of Example 299, 4-chloro-5-hydroxy-7-[1-(tert-butoxycarbonyl)-5-(piperidin-1-ylmethyl)indol-2-yl]Isoindolinone (550 mg, 1.12 mmol) was dissolved in dichloromethane (22 mL), and the solution was treated with triethylamine (0.78 ml, 5.56 mmol) and trifluoromethanesulfonyl chloride (0.356 mL, 3.34 mmol), followed by purification by flash chromatography (chloroform, chloroform/methanol=99/1, 95/1) to obtain 4-chloro-5-trifluoromethanesulfonyloxy-7-[1-(tert-butoxycarbonyl)-5-(piperidin-1-ylmethyl)indol-2-yl]isoindolinone (491 mg, yield 71%).
Reaction SMILES: [CH2:1]([NH2:9])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl[C:11]1[C:12]2[C:25]([CH3:26])=[C:24]([CH3:27])[S:23][C:13]=2[N:14]=[C:15]([C:17]2[CH:22]=[N:21][CH:20]=[CH:19][N:18]=2)[N:16]=1>>[N:18]1[CH:19]=[CH:20][N:21]=[CH:22][C:17]=1[C:15]1[N:16]=[C:11]([NH:9][CH2:1][CH2:2][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)[C:12]2[C:25]([CH3:26])=[C:24]([CH3:27])[S:23][C:13]=2[N:14]=1
Reactant: Cc1sc2nc(-c3cnccn3)nc(Cl)c2c1C
Reactant: NCCc1ccccc1
Product: Cc1sc2nc(-c3cnccn3)nc(NCCc3ccccc3)c2c1C

Procedure:
With the procedure of Example 1, the reaction of phenethylamine with 4-chloro-2-(pyrazin-2-yl)-5,6-dimethyl-thieno-[2,3-d]-pyrimidine yields 2-(pyrazin-2-yl)-4-phenethylamino-5,6-dimethyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [C:1]([O:5][C:6](=[O:12])[NH:7][CH:8]1[CH2:11][NH:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.Cl[C:21]([O:23][CH2:24][CH2:25][CH2:26][CH3:27])=[O:22]>C(Cl)Cl>[CH2:24]([O:23][C:21]([N:10]1[CH2:11][CH:8]([NH:7][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:12])[CH2:9]1)=[O:22])[CH2:25][CH2:26][CH3:27]
Reactant: CC(C)(C)OC(=O)NC1CNC1
Reactant: CCCCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCOC(=O)N1CC(NC(=O)OC(C)(C)C)C1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of 686 mg of Azetidin-3-yl-carbamic acid tert-butyl ester in 10 ml of DCM, 403 mg of triethylamine was added and the mixture was cooled to 0° C. Then, 598 mg of butyl chloroformate was slowly added. After the addition was completed the reaction mixture was allowed to warm to RT and to stir for 2 h. Then, 200 ml of DCM was added and the organic phase was washed two times with 0.1M aqueous hydrochloric acid and the with saturated aqueous sodium hydrogen carbonate solution. 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 a gradient of n-heptane/ethyl acetate. The fractions containing the product were combined and the solvent evaporated under reduced pressure. Yield: 910 mg.
Reaction SMILES: O=[C:2]1[C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=[CH:4][O:3]1.[F:12][C:13]1[CH:19]=[CH:18][C:16]([NH2:17])=[CH:15][CH:14]=1>C1COCC1.CN(C=O)C>[F:12][C:13]1[CH:19]=[CH:18][C:16]([N:17]2[CH:4]=[CH:5][CH:6]=[C:7]([C:8]([O:10][CH3:11])=[O:9])[C:2]2=[O:3])=[CH:15][CH:14]=1
Reactant: Nc1ccc(F)cc1
Reactant: COC(=O)c1cccoc1=O
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COC(=O)c1cccn(-c2ccc(F)cc2)c1=O
Reaction time: 2.5 h

Procedure:
To a solution of methyl 2-oxo-2H-pyran-3-carboxylate (Aldrich, 2.31 g, 15 mmol) in THF (40 mL) and DMF (10 mL) at rt was added 4-fluoroaniline (1.67 g, 15 mmol), and the reaction mixture was stirred for 2.5 h. Solid precipitation was observed. To the 4-fluoroaniline adduct intermediate formed via Michael addition obtained in situ was added EDCI.HCl (3.85 g, 20 mmol) and DMAP (120 mg) at rt. The reaction mixture was stirred at rt overnight. To the reaction mixture were added 1N aq HCl (50 mL) and EtOAc (150 mL), the EtOAc layer was separated, and the aqueous layer was washed with EtOAc (150 mL), the combined EtOAc layer was dried over MgSO4 and concentrated in vacuo to obtain a semi-solid material (˜4.4 g). To this crude product were added ether (100 mL) and methanol (15 mL), stirred, and the solid was filtered to obtain the undesired solid product (870 mg). The filtrate solution was concentrated to obtain a semi-solid crude desired product (2.95 g, crude 80%) which was pure enough to use in the next step without further purification. 1H NMR (DMSO-d6) δ 8.23 (dd, 1H, J=7.2, 2.2 Hz), 7.57 (dd, 1H, J=6.6, 1.7 Hz), 7.32-7.34 (m, 2H), 7.17 (t, 2H, J=8.8 Hz), 6.32 (t, 1H, J=7.1 Hz), 3.89 (s, 3H); MS (ESI+) m/z 248.2 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6](=[O:13])[NH:5][N:4]=1.CC([O-])(C)C.[K+].C1(P(O[NH2:37])(C2C=CC=CC=2)=O)C=CC=CC=1>C1COCC1.CCOC(C)=O>[NH2:37][N:5]1[N:4]=[C:3]([C:2]([F:1])([F:14])[F:15])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]1=[O:13]
Reactant: O=c1[nH]nc(C(F)(F)F)c2ccccc12
Reactant: NOP(=O)(c1ccccc1)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Nn1nc(C(F)(F)F)c2ccccc2c1=O
Reaction time: 1 h

Procedure:
A mixture of Example 11A and KOtBu (1 M in THF, 2.8 mL, 2.8 mmol) in THF (5 mL) was stirred for 60 min, and O-(diphenylphosphoryl)hydroxylamine (0.680 mg, 0.348 mmol) was added and stirred for 1 hour. The mixture was diluted with EtOAc, washed with 1 N NaOH and water, dried (Na2SO4), and concentrated to give the title compound as a white solid (402 mg) which was used without purification. 1H NMR (300 MHz, DMSO-d6) δ 8.45-8.35 (m, 1H), 8.10-7.92 (m, 3H), 6.58 (s, 2H).
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([N:11]([S:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[S:28]([CH3:31])(=[O:30])=[O:29])(=[O:21])=[O:20])C(OC(C)(C)C)=O)[CH:9]=2)[N:4](C(OC(C)(C)C)=O)[N:3]=1.[O:39]1[CH:43]=[CH:42][CH:41]=[C:40]1B(O)O.C(=O)([O-])O.[Na+]>CN(C)C=O>[O:39]1[CH:43]=[CH:42][CH:41]=[C:40]1[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([NH:11][S:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[S:28]([CH3:31])(=[O:30])=[O:29])(=[O:20])=[O:21])[CH:9]=2)[NH:4][N:3]=1
Reactant: OB(O)c1ccco1
Reactant: CC(C)(C)OC(=O)N(c1ccc2c(c1)c(I)nn2C(=O)OC(C)(C)C)S(=O)(=O)c1ccccc1S(C)(=O)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1ccccc1S(=O)(=O)Nc1ccc2[nH]nc(-c3ccco3)c2c1
Yield: 32.5 %

Procedure:
N-(3-Furan-2-yl-1H-indazol-5-yl)-2-methylsulfonylbenzenesulfonamide can be obtained as described in Example 47 from 1 g of tert-butyl 3-iodo-5-(N-tert-butoxycarbonyl-2-methylsulfonylbenzenesulfonylamino)indazole-1-carboxylate, 330 mg of 2-furanboronic acid, 40 ml of dimethylformamide, 3.2 ml of a saturated aqueous sodium hydrogencarbonate solution and 42.7 mg of tetrakis(triphenylphosphine)palladium[0]. 200 mg of N-(3-furan-2-yl-1 H-indazol-5-yl)-2-methylsulfonylbenzenesulfonamide are thus obtained in the form of a white solid melting at 248° C. (analysis C18H15N3O5S2 % calculated C, 51.79; H, 3.62; N, 10.07; O, 19.16; S, 15.36. % found C, 51.95; H, 3.75; N, 9.68; S, 14.75).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:32]=[C:33]([CH:35]=O)[CH:34]=1)[CH2:5][N:6]1[C:10]2[CH:11]=[CH:12][C:13]3[N:14]([C:15]([CH3:18])=[N:16][N:17]=3)[C:9]=2[CH:8]=[C:7]1[C:19]([O:21]CC1C=C(C=O)C=C(Cl)C=1)=[O:20].[NH:37]1[CH2:41][CH2:40][CH2:39][CH2:38]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>C(Cl)Cl.C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:32]=[C:33]([CH2:35][N:37]2[CH2:41][CH2:40][CH2:39][CH2:38]2)[CH:34]=1)[CH2:5][N:6]1[C:10]2[CH:11]=[CH:12][C:13]3[N:14]([C:15]([CH3:18])=[N:16][N:17]=3)[C:9]=2[CH:8]=[C:7]1[C:19]([OH:21])=[O:20]
Reactant: Cc1nnc2ccc3c(cc(C(=O)OCc4cc(Cl)cc(C=O)c4)n3Cc3cc(Cl)cc(C=O)c3)n12
Reactant: C1CCNC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: C1CCOC1
Product: Cc1nnc2ccc3c(cc(C(=O)O)n3Cc3cc(Cl)cc(CN4CCCC4)c3)n12
Reaction time: 8 h

Procedure:
3-Chloro-5-formylbenzyl 6-(3-chloro-5-formylbenzyl)-1-methyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyridine-7-carboxylate (0.035 g, 0.067 mmol, from Example 131, Step 7) was suspended in DCM (4 mL) and pyrrolidine (0.03 g, 0.4 mmol, Aldrich) and sodium triacetoxyborohydride (0.2 g, 0.8 mmol, Aldrich) were added. After stirring overnight, the reaction mixture was made basic by the addition of 1N solution of NaOH, and the product was extracted with EtOAc. The organic extract was dried over sodium sulfate, filtered and concentrated. The crude product was stirred with 1.0 M solution of NaOH (2 mL, 2 mmol) and THF (2 mL) for 1.5 hours. The product was purified by preparative HPLC-MS (Waters XBridge C18, eluting with a gradient of MeCN/H2O containing 0.15% NH4OH). Yield: (5 mg, 18%). LCMS (M+H)+: 424.2.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[C:6](=[CH:8][S:9][CH:10]=2)[N:7]=1.[CH3:12][CH2:13][O-:14].[Na+].O>C(O)C>[Cl:1][C:2]1[N:3]=[C:4]([O:14][CH2:13][CH3:12])[C:5]2[C:6](=[CH:8][S:9][CH:10]=2)[N:7]=1
Reactant: Clc1nc(Cl)c2cscc2n1
Reactant: CC[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCOc1nc(Cl)nc2cscc12
Reaction time: 2 h

Procedure:
6.15 g (0.03 mole) of 2,4-dichloro-thieno[3,4-d]pyrimidine are suspended in 250 ml. of absolute alcohol at 0°C. Whilst agitating constantly a solution of 0.03 mole sodium ethylate in ethyl alcohol is added drop by drop. The speed of addition is regulated in such a manner that the temperature of the reaction medium is maintained at between 0° and 5°C. One obtains a clear solution in which a precipitate is gradually formed. When the addition is completed, the agitation is continued for a further 2 hours at ordinary temperature. The reaction mixture is then poured into 2 liters of iced water and the precipitate formed is filtered off, washed with water and then dried in vacuo. After recrystallization from toluene, 5.2 g of 2-chloro-4-ethoxythieno[3,4-d]pyrimidine are obtained (81% of theory). M.P. 136°-140°C.
Reaction SMILES: [OH:1][C:2]1[C:3]([C:9]2[C:14]([OH:15])=[CH:13][CH:12]=[C:11]([CH3:16])[N:10]=2)=[N:4][C:5]([CH3:8])=[CH:6][CH:7]=1.[C:17](Cl)(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(Cl)(Cl)Cl>N1C=CC=CC=1>[C:17]([O:15][C:14]1[C:9]([C:3]2[C:2]([O:1][C:17](=[O:24])[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:7][CH:6]=[C:5]([CH3:8])[N:4]=2)=[N:10][C:11]([CH3:16])=[CH:12][CH:13]=1)(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: Cc1ccc(O)c(-c2nc(C)ccc2O)n1
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: Cc1ccc(OC(=O)c2ccccc2)c(-c2nc(C)ccc2OC(=O)c2ccccc2)n1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
3,3'-Dihydroxy-6,6'-dimethyl-2,2'-bipyridine (5) (0.22 g, 1.02 mmoles) was dissolved in 12 ml pyridine and benzoylchloride (0.30 g, 2.13 mmoles) was added. After stirring for 1.5 hours at room temperature, 100 ml chloroform was added and the solution was extracted with 100 ml saturated sodium hydrogen carbonate solution. The chloroform phase was dried and evaporated to dryness. The product was crystallized as a grey powder from cyclohexane.
Reaction SMILES: [N:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=O)=[CH:6][CH:5]=1)=[N+:2]=[N-:3].C1C=CC2N(O)N=NC=2C=1.[NH2:23][CH2:24][CH2:25][N:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1.CCN=C=NCCCN(C)C>C(#N)C.CN(C=O)C>[N:1]([C:4]1[CH:5]=[CH:6][C:7]([C:8]([NH:23][CH2:24][CH2:25][N:26]2[CH2:31][CH2:30][O:29][CH2:28][CH2:27]2)=[O:10])=[CH:11][CH:12]=1)=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=Nc1ccc(C(=O)O)cc1
Reactant: NCCN1CCOCC1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CC#N
Solvent: CN(C)C=O
Product: [N-]=[N+]=Nc1ccc(C(=O)NCCN2CCOCC2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
4-Azidobenzoic acid (846 mg, 5.08 mmol), HOBt (416 mg, 3.05 mmol, 0.6 eq.) and N-(2-aminoethyl)morpholine (0.716 ml, 5.34 mmol, 1.05 eq.) were dissolved in acetonitrile (9 ml) and DMF (3 ml), WSC (1.19 g, 6.10 mmol, 1.2 eq.) was added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was concentrated, dissolved in ethyl acetate (40 ml), and washed with 5% aqueous sodium carbonate solution and saturated brine. The aqueous layers were each extracted with ethyl acetate (30 ml). The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated at 30° C. or below to give the title compound as a pale-yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:31])=[C:6]([C:8]2[CH:17]=[C:16]3[C:11]([CH:12]=[C:13]([NH:18][C:19](=O)[O:20]C4C=CC([N+]([O-])=O)=CC=4)[N:14]=[CH:15]3)=[CH:10][CH:9]=2)[CH:7]=1.CN(C)C=O.[CH3:37][N:38]1[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]1>ClCCl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:31])=[C:6]([C:8]2[CH:17]=[C:16]3[C:11]([CH:12]=[C:13]([NH:18][C:19]([N:41]4[CH2:42][CH2:43][N:38]([CH3:37])[CH2:39][CH2:40]4)=[O:20])[N:14]=[CH:15]3)=[CH:10][CH:9]=2)[CH:7]=1
Reactant: CN1CCNCC1
Reactant: Cc1ccc(F)cc1-c1ccc2cc(NC(=O)Oc3ccc([N+](=O)[O-])cc3)ncc2c1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1ccc(F)cc1-c1ccc2cc(NC(=O)N3CCN(C)CC3)ncc2c1
Temperature: 90 °C
Yield: 3.8 %

Procedure:
4-nitrophenyl 7-(5-fluoro-2-methylphenyl)isoquinolin-3-ylcarbamate (0.156 g, 0.374 mmol) was dissolved in N,N-dimethylformamide (2.0 mL, 26 mmol) and 1-methyl-piperazine (0.20 mL, 1.8 mmol) was added. The reaction mixture was heated at 90° C. for 1 hour. The reaction mixture was then diluted with dichloromethane, washed with saturated aqueous NaHCO3, dried over MgSO4, and evaporated in vacuo. The crude product was purified via flash chromatography on silica gel (12 g silica, solvent gradient: 0-20% methanol in dichloromethane with 2% triethylamine) followed by reverse phase HPLC and lyophilization to yield 5.4 mg (4%) of N-(7-(5-fluoro-2-methylphenyl)isoquinolin-3-yl)-4-methylpiperazine-1-carboxamide. LCMS (ESI): RT (min)=4.017, M+H=379.1, method=E; 1H NMR (400 MHz, DMSO-d6) δ 9.22 (s, 1H), 9.12 (s, 1H), 8.23 (s, 1H), 7.99 (s, 1H), 7.88 (d, J=8.3 Hz, 1H), 7.67 (d, J=8.7 Hz, 1H), 7.38 (s, 1H), 7.16 (t, J=8.3 Hz, 2H), 3.52 (s, 4H), 2.33 (s, 4H), 2.25 (s, 3H), 2.21 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8](O)[C:9]2[CH:14]=[CH:13][C:12]([C:15]3[NH:19][C:18]4[CH:20]=[CH:21][C:22]([C:24]([NH2:26])=[O:25])=[CH:23][C:17]=4[N:16]=3)=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.S(Cl)(Cl)=O.[NH:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([N:32]2[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)[C:9]2[CH:14]=[CH:13][C:12]([C:15]3[NH:19][C:18]4[CH:20]=[CH:21][C:22]([C:24]([NH2:26])=[O:25])=[CH:23][C:17]=4[N:16]=3)=[CH:11][CH:10]=2)=[CH:4][CH:3]=1
Reactant: C1CNCCN1
Reactant: NC(=O)c1ccc2[nH]c(-c3ccc(C(O)c4ccc(Cl)cc4)cc3)nc2c1
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: NC(=O)c1ccc2[nH]c(-c3ccc(C(c4ccc(Cl)cc4)N4CCNCC4)cc3)nc2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 76.2 %

Procedure:
To a suspension of 2-{4-[(4-chloro-phenyl)-hydroxy-methyl]-phenyl}-1H-benzoimidazole-5-carboxylic acid amide (Example 20, 20.0 mg, 0.05 mmol) in CH2Cl2 (10 mL) was added thionyl chloride (0.04 mL, 0.06 mmol), and the mixture was stirred at RT for 1 h. Solvent was removed under reduced pressure, and the residue was dried under high vacuum. The crude product was dissolved in acetonitrile (10 mL). Piperazine (21 mg, 0.24 mmol) was added, and the mixture was heated to reflux for 12 h. Solvent was removed under reduced pressure, and purification of the residue by chromatography (silica gel, 1% methanol saturated with ammonia/9% methanol/CH2Cl2) afforded 17 mg (77%) of the title compound. HPLC (Method A): Rt=6.44. MS (ESI−): mass calculated for C25H24ClN5O, 445.2; m/z found, 444.6 [M−H]−. 1H NMR (500 MHz, CD3OD): δ 8.17 (br s, 1H), 8.09 (d, J=8.4 Hz, 2H), 7.82–7.80 (dd, J=8.5, 1.5 Hz, 1H), 7.66 (d, J=8.4 Hz, 2H), 7.63 (br s, 1H), 7.50 (d, J=8.5 Hz, 2H), 7.35 (d, J=8.5 Hz, 2H), 4.56 (s, 1H), 3.31–3.27 (m, 8H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:20]2[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=2)[CH2:9][C:10]([C:12]2[CH:13]=[CH:14][C:15](=[O:19])[N:16]([CH3:18])[CH:17]=2)=[O:11])=[C:4]([CH3:27])[CH:3]=1.[CH3:28][O:29][C:30]([C:32]1[CH:33]=[C:34](B(O)O)[CH:35]=[CH:36][CH:37]=1)=[O:31].N1C=CC=CC=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH3:28][O:29][C:30](=[O:31])[C:32]1[CH:33]=[CH:34][CH:35]=[C:36]([O:26][C:23]2[CH:22]=[CH:21][C:20]([CH:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][C:4]=3[CH3:27])[CH2:9][C:10]([C:12]3[CH:13]=[CH:14][C:15](=[O:19])[N:16]([CH3:18])[CH:17]=3)=[O:11])=[CH:25][CH:24]=2)[CH:37]=1
Reactant: Cc1cc(Cl)ccc1C(CC(=O)c1ccc(=O)n(C)c1)c1ccc(O)cc1
Reactant: COC(=O)c1cccc(B(O)O)c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)c1cccc(Oc2ccc(C(CC(=O)c3ccc(=O)n(C)c3)c3ccc(Cl)cc3C)cc2)c1

Procedure:
In analogy to example 222, step 1, 5-[3-(4-chloro-2-methyl-phenyl)-3-(4-hydroxy-phenyl)-propionyl]-1-methyl-1H-pyridin-2-one (example 346, step 1) was reacted with 3-methoxycarbonylphenylboronic acid in dichloromethane in the presence of copper(II) acetate, pyridine and air to give the title compound as a colourless solid, MS (ESI+): m/z=516.4 [M+H]+.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]2[C:11](=[O:12])[O:10][C:8](=[O:9])[C:7]2=[CH:13][C:14]=1[Cl:15].[CH3:16][OH:17]>>[Cl:15][C:14]1[C:4]([Cl:3])=[CH:5][C:6]([C:11]([OH:10])=[O:12])=[C:7]([C:8]([O:17][CH3:16])=[O:9])[CH:13]=1
Reactant: O=C1OC(=O)c2cc(Cl)c(Cl)cc21
Reactant: CO
Agent: [H-]
Agent: [Na+]
Product: COC(=O)c1cc(Cl)c(Cl)cc1C(=O)O
Reaction time: 1 h

Procedure:
To methanol (200 mL) was added sodium hydride (2.72 g, 60% dispersion, 68.0 mmol) portionwise under nitrogen at ambient temperature. To the solution was then added a solution of 4,5-dichlorophthalic anhydride (5.90 g, 27.2 mmol) in methanol (50 mL) dropwise under nitrogen at room temperature. The reaction was stirred for one hour and then concentrated to remove the methanol. The residue was taken up in aqueous 10% potassium carbonate solution and extracted with ethyl acetate (2×). The aqueous portion was acidified to pH 2 with 10% hydrochloric acid and extracted with ethyl acetate (3×), dried (Na2SO4) and concentrated to afford the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 3.81 (s, 3H) 7.94-8.01 (m, 2H) 13.60-13.70 (br, 1H); MS (+DCI/NH3) m/z 266.0 [M+NH4]+.
Reaction SMILES: CS([O:5][C@H:6]1[CH2:10][CH2:9][C@@H:8]([N:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)[CH2:7]1)(=O)=O.[CH:17]1([CH2:20][NH:21][C:22](=[O:42])[CH2:23][N:24]2[C:33](=[O:34])[C:32]3[C:27](=[CH:28][CH:29]=[C:30](O)[CH:31]=3)[N:26]=[C:25]2[C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH2:19][CH2:18]1.C([O-])([O-])=O.[Cs+].[Cs+]>CS(C)=O.O>[CH:17]1([CH2:20][NH:21][C:22](=[O:42])[CH2:23][N:24]2[C:33](=[O:34])[C:32]3[C:27](=[CH:28][CH:29]=[C:30]([O:5][C@H:6]4[CH2:10][CH2:9][C@H:8]([N:11]5[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]5)[CH2:7]4)[CH:31]=3)[N:26]=[C:25]2[C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH2:18][CH2:19]1
Reactant: O=C(Cn1c(-c2ccccc2)nc2ccc(O)cc2c1=O)NCC1CC1
Reactant: CS(=O)(=O)O[C@H]1CC[C@@H](N2CCCCC2)C1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: O
Product: O=C(Cn1c(-c2ccccc2)nc2ccc(O[C@H]3CC[C@H](N4CCCCC4)C3)cc2c1=O)NCC1CC1
Temperature: 80 °C
Yield: 14.5 %

Procedure:
A mixture of crude (1S,3R)-3-piperidin-1-ylcyclopentyl methanesulphonate (INTERMEDIATE XII.1) (90 mg, 0.4 mmol), N-cyclopropylmethyl-2-(6-hydroxy-4-oxo-2-phenyl-4H-quinazolin-3-yl)acetamide (INTERMEDIATE IV.6) (71 mg, 0.2 mmol) and Cs2CO3 (326 mg, 1.0 mmol) in DMSO (0.3 mL) was heated at 80° C. for 16 h. The mixture was then cooled and diluted with water. The aqueous layer was extracted with ethyl acetate (3×20 mL). The combined organics were dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by chromatography on silica gel with methanol:dichloromethane (1:9, v/v) as eluent to afford N-cyclopropylmethyl-2-[4-oxo-2-phenyl-6-((1S,3S)-3-piperidin-1-ylcyclopentyloxy)-4H-quinazolin-3-yl]acetamide (EXAMPLE 5a) (14 mg, 0.029 mmol, 14%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:14])[C:10]([F:13])([F:12])[F:11])=[CH:4][C:3]=1[NH:15][C:16](=O)[C:17]([F:20])([F:19])[F:18].C1C(=O)N(Br)C(=O)C1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C(Cl)(Cl)(Cl)Cl.C1(C)C=CC=CC=1>[F:11][C:10]([F:13])([F:12])[C:9]([NH:8][C:5]1[CH:4]=[C:3]2[C:2]([CH:1]=[C:16]([C:17]([F:20])([F:19])[F:18])[NH:15]2)=[CH:7][CH:6]=1)=[O:14]
Reactant: Cc1ccc(NC(=O)C(F)(F)F)cc1NC(=O)C(F)(F)F
Agent: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClC(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: O=C(Nc1ccc2cc(C(F)(F)F)[nH]c2c1)C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 25.2 %

Procedure:
A mixture of N,N′-(4-methyl-1,3-phenylene)bis(2,2,2-trifluoroacetamide) (1.02 g, 3.25 mmol), NBS (0.80 g, 4.5 mmol) in CCl4 (6 mL) was stirred overnight at room temperature under irradiation of a 300 W lamp. The precipitate formed was collected by filtration and washed with CCl4. The crude residue was taken up in dry toluene (9.7 mL) in the presence of PPh3 (1.3 g, 4.96 mmol) and stirred at 60° C. for 16 h. The phosphonium precipitate was collected by filtration, then dissolved in dry DMF (10 mL) and stirred at 165° C. until complete conversion to the product (6.5 h). The solvent was removed in vacuo and the residue obtained was purified by silica gel column chromatography (5-25% AcOEt in hexanes) to obtain 2,2,2-trifluoro-N-(2-(trifluoromethyl)-1H-indol-6-yl)acetamide (243 mg, 25%). LC/MS: m/z 297.3 (M+H)+ at 1.68 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([C:23]([F:26])([F:25])[F:24])=[C:13]2[C:17]=1[NH:16][C:15]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:14]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH3:29]I>CN(C)C=O>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([C:23]([F:26])([F:25])[F:24])=[C:13]2[C:17]=1[N:16]([CH3:29])[C:15]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:14]2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CI
Reactant: CCOC(=O)c1cc2c(C(F)(F)F)ccc(OCc3ccccc3)c2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2c(C(F)(F)F)ccc(OCc3ccccc3)c2n1C

Procedure:
The reaction was carried out in a manner similar to Reference Example 18 a) except for using 8.00 g (22.0 mmol) of ethyl 7-benzyloxy-4-trifluoromethyl-2-indolecarboxylate, 0.88 9 (22.0 mmol) of 60% sodium hydride, 6.25 g (44.0 mmol) of methyl iodide and 150 ml of dimethylformamide. Ethyl 7-benzyloxy-1-methyl-4-trifluoromethyl-2-indolecarboxylate was thus obtained in the yield of 7.40 g (89.1%).