Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[C:4]([C:6]1[C:7](=[O:22])[N:8]([CH2:20][CH3:21])[C:9](=[O:19])[N:10]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[CH:11]=1)=[O:5])C.[Li+].[OH-].[CH3:25][O:26][C:27]1[CH:28]=[C:29]2[C:34](=[CH:35][C:36]=1[O:37][CH3:38])[N:33]=[CH:32][CH:31]=[C:30]2[O:39][C:40]1[CH:45]=[CH:44][C:43]([NH2:46])=[CH:42][C:41]=1[F:47]>CO.C1COCC1>[CH3:25][O:26][C:27]1[CH:28]=[C:29]2[C:34](=[CH:35][C:36]=1[O:37][CH3:38])[N:33]=[CH:32][CH:31]=[C:30]2[O:39][C:40]1[CH:45]=[CH:44][C:43]([NH:46][C:4]([C:6]2[C:7](=[O:22])[N:8]([CH2:20][CH3:21])[C:9](=[O:19])[N:10]([C:12]3[CH:13]=[CH:14][C:15]([F:18])=[CH:16][CH:17]=3)[CH:11]=2)=[O:5])=[CH:42][C:41]=1[F:47]
Reactant: CCOC(=O)c1cn(-c2ccc(F)cc2)c(=O)n(CC)c1=O
Reactant: COc1cc2nccc(Oc3ccc(N)cc3F)c2cc1OC
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCn1c(=O)c(C(=O)Nc2ccc(Oc3ccnc4cc(OC)c(OC)cc34)c(F)c2)cn(-c2ccc(F)cc2)c1=O

Procedure:
3-Ethyl-1-(4-fluorophenyl)-2,4-dioxo-1,2,3,4-tetrahydro-pyrimidine-5-carboxylic acid ethyl ester was hydrolyzed with 1N LiOH in MeOH and THF at 65° C. The acid was coupled with 4-(6,7-Dimethoxyquinolin-4-yloxy)-3-fluorophenylamine using the method for example 1 to give 3-ethyl-1-(4-fluoro-phenyl)-2,4-dioxo-1,2,3,4-tetrahydro-pyrimidine-5-carboxylic acid [4-(6,7-dimethoxy-quinolin-4-yloxy)-3-fluoro-phenyl]-amide mp 140-142° C.; LCMS m/z=575 (M+1); 1H NMR (DMSO) δ: 11.18 (s, 1H), 8.49 (d, 1H, J=2.5 Hz), 8.46 (s, 1H), 8.03 (dd, 1H, J=3 Hz, J=13 Hz), 7.65-7.39 (m, 6H), 7.55 (s, 1H), 7.41 (s, 1H), 6.49 (d, 1H, J=5.0 Hz), 4.00 (q, 2H, J=7.4 Hz), 3.95 (s, 6H), 1.23 (t, 3H, J=7.3 Hz).
Reaction SMILES: C(OC([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][C:16]=2[CH3:22])[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:23].C(OCC)(=O)C>C(Cl)(Cl)Cl>[ClH:23].[CH3:22][C:16]1[CH:17]=[C:18]([CH3:21])[CH:19]=[CH:20][C:15]=1[N:11]1[CH2:12][CH2:13][CH2:14][NH:8][CH2:9][CH2:10]1
Reactant: Cc1ccc(N2CCCN(C(=O)OC(C)(C)C)CC2)c(C)c1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: ClC(Cl)Cl
Product: Cc1ccc(N2CCCNCC2)c(C)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 1-bromo-2,4-dimethylbenzene (1.85 g) were added 1-BOC-1,4]diazepane (2 g), palladium (II) acetate (0.115 g), rac-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (0.31 g), sodium tert-butoxide (1.34 g) and toluene (35 mL), and the mixture was refluxed for 9 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and the solvent was evaporated. The residue was purified by column chromatography (chloroform:methanol) to give 4-(2,4-dimethylphenyl)-[1,4]diazepane-1-carboxylic acid tert-butyl ester (2.16 g). To 4-(2,4-dimethylphenyl)-[1,4]diazepane-1-carboxylic acid tert-butyl ester (2.16 g) were added 4N hydrogen chloride/ethyl acetate (6.9 mL) and chloroform (17 mL), and the mixture was stirred at room temperature overnight. The solvent was evaporated to give the title compound (1.74 g).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:12]=[C:13]([NH:17][C:18](=[O:22])[CH:19]([CH3:21])[CH3:20])[CH:14]=[CH:15][CH:16]=2)[CH2:7][CH2:6]1.[Cl:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[C:30]1[C:34]([C:35](Cl)=[O:36])=[C:33]([CH3:38])[O:32][N:31]=1>>[Cl:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[C:30]1[C:34]([C:35]([O:1][CH2:2][CH2:3][CH2:4][N:5]2[CH2:10][CH2:9][CH:8]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([NH:17][C:18](=[O:22])[CH:19]([CH3:20])[CH3:21])[CH:12]=3)[CH2:7][CH2:6]2)=[O:36])=[C:33]([CH3:38])[O:32][N:31]=1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCO)CC2)c1
Reactant: Cc1onc(-c2ccccc2Cl)c1C(=O)Cl
Product: Cc1onc(-c2ccccc2Cl)c1C(=O)OCCCN1CCC(c2cccc(NC(=O)C(C)C)c2)CC1

Procedure:
Prepared by Procedure Q1 and Scheme C2 (TEA) using N-{3-[1-(3-hydroxypropyl)-4-piperidinyl]phenyl}-2-methylpropanamide and 3-(2-chlorophenyl)-5-methyl-4-isoxazolecarbonyl chloride: ESMS m/e: 524.2 (M+H)+.
Reaction SMILES: CCN(C(C)C)C(C)C.[C:10]1([N:16]2[CH:20]=[C:19]([C:21]([NH:23][CH2:24][C:25]([OH:27])=O)=[O:22])[N:18]=[CH:17]2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[Cl:50][C:51]1[CH:63]=[CH:62][CH:61]=[CH:60][C:52]=1[O:53][CH:54]1[CH2:59][CH2:58][NH:57][CH2:56][CH2:55]1>CN(C=O)C.O>[Cl:50][C:51]1[CH:63]=[CH:62][CH:61]=[CH:60][C:52]=1[O:53][CH:54]1[CH2:59][CH2:58][N:57]([C:25](=[O:27])[CH2:24][NH:23][C:21]([C:19]2[N:18]=[CH:17][N:16]([C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:20]=2)=[O:22])[CH2:56][CH2:55]1
Reactant: Clc1ccccc1OC1CCNCC1
Reactant: O=C(O)CNC(=O)c1cn(-c2ccccc2)cn1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCC(=O)N1CCC(Oc2ccccc2Cl)CC1)c1cn(-c2ccccc2)cn1
Reaction time: 0.03 h
Yield: 62.5 %

Procedure:
DIPEA (170 mg, 1.3 mmol) was added to a stirred solution of [(1-phenyl-1H-imidazole-4-carbonyl)-amino]-acetic acid (prepared from Intermediate 68 by means of Step 3 of the General Scheme) (55 mg, 0.29 mmol) in DMF (5 mL) followed by HOBt (43 mg, 0.32 mmol) and EDCI (140 mg, 0.7 mmol). After 2 minutes of stirring, 4-(2-chloro-phenoxy)-piperidine hydrochloride (98 mg, 0.32 mmol) was added and the resulting mixture was stirred at ambient temperature overnight. The reaction mixture was diluted with cold water and the precipitate was collected. The precipitate was purified by recrystallisation from a mixture of 20% EtOAc in hexane (15 mL) and MeOH (0.1 mL) to afford the 80 mg (62.5% Yield) of 1-phenyl-1H-imidazole-4-carboxylic acid {2-[4-(2-chloro-phenoxy)-piperidin-1-yl]-2-oxo-ethyl}-amide. LC/MS [M+H]+: 439.15, 98.75%. 1H NMR (300 MHz, DMSO-d6): δ 8.4 (s, 1H), 8.3 (s, 1H), 8.08 (t, 1H), 7.8 (d, 2H), 7.6 (t, 2H), 7.48 (m, 2H), 7.34 (m, 2H), 7.1 (t, 1H), 4.8 (m, 1H), 4.2 (d, 2H), 3.8 (t, 2H), 3.6 (t, 2H), 2.0 (d, 2H), 1.8 (d, 2H).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]([OH:9])=[O:8])[CH2:3][CH2:2]1.[C:10]1([CH:16]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[N:17]2[CH2:20][C:19](=O)[CH2:18]2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C([BH3-])#N.C[NH+](C)C>CO.C(O)(=O)C>[C:10]1([CH:16]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[N:17]2[CH2:20][CH:19]([N:1]3[CH2:6][CH2:5][CH:4]([C:7]([OH:9])=[O:8])[CH2:3][CH2:2]3)[CH2:18]2)[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: O=C1CN(C(c2ccccc2)c2ccccc2)C1
Reactant: O=C(O)C1CCNCC1
Agent: C[NH+](C)C
Agent: [BH3-]C#N
Solvent: CO
Solvent: CC(=O)O
Product: O=C(O)C1CCN(C2CN(C(c3ccccc3)c3ccccc3)C2)CC1
Temperature: 120 °C
Yield: 99.9 %

Procedure:
To a mixture of piperidine-4-carboxylic acid (0.13 g, 1.0 mmol) and 1-(diphenylmethyl)azetidin-3-one (see Bioorg. Med. Chem. Lett.; 13; 2003; 2191-2194, 0.24 g, 1.0 mmol), methanol (3 mL) and acetic acid (0.3 mL) was added (polystyrylmethyl) trimethylammonium cyanoborohydride (4.1 mmol/g, 0.25 g). The reaction mixture was heated for 5 min at 120° C. using microwave single node heating. Methanol was added and then the resin was filtered off. The solvent was removed by evaporation. There was obtained 0.35 g (100%) of 1-[1-(diphenylmethyl)azetidin-3-yl]piperidine-4-carboxylic acid. 1H NMR (500 MHz, CDCl3): 1.6-1.8 (m, 2H), 1.9-2.0 (m, 4H), 2.3-2.4 (m, 1H), 2.7-2.8 (m, 2H), 2.9-3.0 (m, 3H), 3.4 (t, 2H), 4.4 (s, 1H), 7.2 (t, 2H), 7.2-7.3 (t, 4H), 7.4 (d, 4H); LCMS: m/z 351 (M+1)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]=[CH:15][C:14]([C:20](=[O:24])[CH:21]([CH3:23])[CH3:22])=[C:13]3[NH:25][C@H:26]2[CH2:31][CH2:30][C@H:29]([NH:32]C(=O)OC(C)(C)C)[CH2:28][CH2:27]2)[CH:5]=[C:6]([Cl:9])[C:7]=1[OH:8].C(O)(C(F)(F)F)=O>>[NH2:32][C@H:29]1[CH2:30][CH2:31][C@H:26]([NH:25][C:13]2[C:12]3[C:17](=[CH:18][CH:19]=[C:10]([C:4]4[CH:3]=[C:2]([Cl:1])[C:7]([OH:8])=[C:6]([Cl:9])[CH:5]=4)[CH:11]=3)[N:16]=[CH:15][C:14]=2[C:20](=[O:24])[CH:21]([CH3:22])[CH3:23])[CH2:27][CH2:28]1
Reactant: CC(C)C(=O)c1cnc2ccc(-c3cc(Cl)c(O)c(Cl)c3)cc2c1N[C@H]1CC[C@H](NC(=O)OC(C)(C)C)CC1
Solvent: O=C(O)C(F)(F)F
Product: CC(C)C(=O)c1cnc2ccc(-c3cc(Cl)c(O)c(Cl)c3)cc2c1N[C@H]1CC[C@H](N)CC1

Procedure:
Following general procedure A-2, tert-butyl trans-4-[6-(3,5-dichloro-4-hydroxyphenyl)-3-isobutyrylquinolin-4-ylamino]cyclohexylcarbamate (60 mg, 0.100 mmol) was reacted with TFA (2 mL) to afford the desired product (20.3 mg, 43%) as a yellow solid: 1H NMR (500 MHz, CD3OD) δ 8.98 (s, 1H), 8.33 (s, 1H), 8.02 (d, J=8.8 Hz, 1H), 7.93 (d, J=8.7 Hz, 1H), 7.67 (s, 2H), 4.18 (s, 1H), 3.80-3.70 (m, 1H), 2.96 (s, 1H), 2.40 (d, J=11.4 Hz, 2H), 2.20 (d, J=12.2 Hz, 2H), 1.73 (q, J=11.1 Hz, 2H), 1.65-1.53 (m, 2H), 1.24 (d, J=6.8 Hz, 6H); ESI MS m/z 472 [C25H27Cl2N3O2+H]+; HPLC 98.7% (AUC), tR=10.95 min.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[CH:5][NH:4][N:3]=1.C(N(CC)CC)C.[C:14](Cl)(=[O:19])[C:15]([CH3:18])([CH3:17])[CH3:16].[OH-].[Na+]>C(Cl)Cl.CO>[CH3:16][C:15]([CH3:18])([CH3:17])[C:14]([NH:1][C:2]1[CH:6]=[CH:5][NH:4][N:3]=1)=[O:19]
Reactant: CC(C)(C)C(=O)Cl
Reactant: Nc1cc[nH]n1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CO
Product: CC(C)(C)C(=O)Nc1cc[nH]n1
Temperature: 25 °C
Reaction time: 6 h
Yield: 74.8 %

Procedure:
3-Aminopyrazole (9 g, 108 mmol) was dissolved in DCM (250 ml). Triethylamine (27 g, 262 mmol) was added in one portion. Pivaloyl chloride (30 g, 248 mmol) was added slowly at room temperature. After stirring at room temperature for 6 hours, the solvent was concentrated under reduced pressure to give a solid. The solid was dissolved in methanol (200 ml). Aqueous NaOH (2.5M, 120 ml) was added slowly and the mixture was stirred at room temperature for 30 minutes. The solvent was evaporated off under reduced pressure. The slurry was transferred into water (300 ml). The solid was filtrated and dried to give the title product (13.5 g) as a yellow solid, yield: 76%. 1H-NMR (400 MHz, d6-DMSO): δ 12.3 (s, 1H), 9.77 (s, 1H), 7.58 (s, 1H), 6.49 (s, 1H), 1.2 (s, 9H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[CH:5]([NH2:21])[CH:6]([C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][C:15]=2[O:17][CH:18]([CH3:20])[CH3:19])[NH:10][CH:9]=1)[CH3:7])[CH3:2].O.[C:24]([OH:28])(=[O:27])[CH:25]=O.C([O-])([O-])=O.[K+].[K+]>C(OC(=O)C)C.O>[CH:18]([O:17][C:15]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:16]=1[C:8]1[CH:6]([CH3:7])[CH:5]([C:4]([O:3][CH2:1][CH3:2])=[O:22])[NH:21][CH:25]([C:24]([OH:28])=[O:27])[C:9]=1[NH:10]2)([CH3:20])[CH3:19]
Reactant: O=CC(=O)O
Reactant: CCOC(=O)C(N)C(C)c1c[nH]c2cccc(OC(C)C)c12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Product: CCOC(=O)C1NC(C(=O)O)c2[nH]c3cccc(OC(C)C)c3c2C1C
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a stirred solution of 27.25 g 2-amino-3(4-isopropoxyindole-3-yl)butanoic acid ethylester in 70 ml ethylacetate was added 9.99 g glyoxylic acid hydrate dissolved in 70 ml water. The mixture was adjusted to pH 4 (10% K2CO3 -solution) and further stirred at room temperature for 6 hours. The yellow precipitate was collected by filtration, washed with ethylacetate and dried.
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16]Br)=[C:12]([Cl:18])[CH:11]=1.C([O-])([O-])=O.[Na+].[Na+]>C1COCC1>[CH2:1]([NH:8][CH2:16][C:13]1[CH:14]=[CH:15][C:10]([Br:9])=[CH:11][C:12]=1[Cl:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCc1ccccc1
Reactant: Clc1cc(Br)ccc1CBr
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Clc1cc(Br)ccc1CNCc1ccccc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
765 μl of benzylamine are dissolved in 10 ml of THF (anhydrous) and treated with 1.0 g of 4-bromo-1-bromomethyl-2-chlorobenzene at 0° C. and stirred at RT for 4 h. 100 ml of a half-saturated aqueous Na2CO3 solution are then added and the mixture is extracted three times with 100 ml of EA each time. It is dried over MgSO4 and chromatographed on silica gel using DIP. 590 mg of a colorless oil are obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][CH:15]=1)[O:5][C:6]1[S:10][C:9]([CH2:11][NH2:12])=[CH:8][CH:7]=1.[N:16]1[CH:17]=[CH:18][N:19]2[CH:24]=[C:23]([C:25](O)=[O:26])[CH:22]=[CH:21][C:20]=12.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)CC)C>CN(C)C=O.O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][CH:15]=1)[O:5][C:6]1[S:10][C:9]([CH2:11][NH:12][C:25]([C:23]2[CH:22]=[CH:21][C:20]3[N:19]([CH:18]=[CH:17][N:16]=3)[CH:24]=2)=[O:26])=[CH:8][CH:7]=1
Reactant: NCc1ccc(Oc2cccc(Cl)c2)s1
Reactant: O=C(O)c1ccc2nccn2c1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: O=C(NCc1ccc(Oc2cccc(Cl)c2)s1)c1ccc2nccn2c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 89 %

Procedure:
To a solution of C-(5-(3-chloro-phenoxy)-thiophen-2-yl)-methylamine described in Preparation Example 167 (104 mg, 0.434 mmol) and imidazo[1,2-a]pyridine-6-carboxylic acid (77 mg, 0.477 mmol) in N,N-dimethylformamide (3 mL) were added benzotriazol-1-yloxy tris(dimethylamino)phosphonium hexafluorophosphate (250 mg, 0.564 mmol) and triethylamine (181 μL) at room temperature, and the solution was stirred at room temperature for 4 hours. Water was added to the reaction solution, which was then extracted with ethyl acetate, and the organic layer was washed with water and brine. Anhydrous magnesium sulfate was added to the organic layer for drying, filtration was carried out, then, the solvent was evaporated in vacuo, the residue was purified by NH silica gel column chromatography (ethyl acetate/methanol=40/1), and the title compound (149 mg, 89%) was obtained as a white solid.
Reaction SMILES: [CH:1]([C:3]1[C:11]2[C:6](=[C:7]([C:12]([O:14][CH3:15])=[O:13])[CH:8]=[CH:9][CH:10]=2)[NH:5][CH:4]=1)=O.Cl.[OH:17][NH3+:18]>CN(C)C=O>[OH:17][N:18]=[CH:1][C:3]1[C:11]2[C:6](=[C:7]([C:12]([O:14][CH3:15])=[O:13])[CH:8]=[CH:9][CH:10]=2)[NH:5][CH:4]=1
Reactant: COC(=O)c1cccc2c(C=O)c[nH]c12
Reactant: [NH3+]O
Agent: Cl
Solvent: CN(C)C=O
Product: COC(=O)c1cccc2c(C=NO)c[nH]c12
Yield: 97.4 %

Procedure:
5 g of methyl 3-formylindole-7-carboxylate (0.024 mol) are added to a solution of 0.03 mol of hydroxylammonium hydrochloride in dimethylformamide. The reaction mixture is heated at 125° for one hour and subjected to conventional work-up, giving 5.1 g of methyl 3-(hydroxyiminomethyl)indole-7-carboxylate.
Reaction SMILES: C([O:4][C:5]1[CH:14]=[C:13]([O:15]C(=O)C)[CH:12]=[C:11]2[C:6]=1[C:7](=[O:23])[C:8](C(=O)C)=[C:9]([CH3:19])[O:10]2)(=O)C.Cl>C(=O)([O-])[O-].[Na+].[Na+]>[OH:4][C:5]1[CH:14]=[C:13]([OH:15])[CH:12]=[C:11]2[C:6]=1[C:7](=[O:23])[CH:8]=[C:9]([CH3:19])[O:10]2
Reactant: CC(=O)Oc1cc(OC(C)=O)c2c(=O)c(C(C)=O)c(C)oc2c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: Cc1cc(=O)c2c(O)cc(O)cc2o1

Procedure:
5,7-Diacetoxy-3-acetyl-2-methylchromen-4-one is refluxed for 1 hour with 40 ml of 10% sodium carbonate solution. After cooling, the suspension is adjusted to a pH of about 6 using 2N HCl and cooled. The precipitate is filtered off, giving 0.6 g of very pale brown powder (TM=279.9° C.)
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[NH:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([C:20]([O:22][CH3:23])=[O:21])[CH:18]=2)[CH:13]=[CH:12]1.[Cl-].C([Al+]CC)C>ClCCCl>[F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([C:13]2[C:14]3[C:19](=[CH:18][C:17]([C:20]([O:22][CH3:23])=[O:21])=[CH:16][CH:15]=3)[NH:11][CH:12]=2)=[O:7])=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccc2cc[nH]c2c1
Reactant: O=C(Cl)c1ccc(F)cc1
Agent: CC[Al+]CC
Agent: [Cl-]
Solvent: ClCCCl
Product: COC(=O)c1ccc2c(C(=O)c3ccc(F)cc3)c[nH]c2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 38.1 %

Procedure:
A solution of 4-fluorobenzoyl chloride 43b (2 mmol, 0.24 mL) in 8 mL of DCE was added dropwise to an ice-cold solution of methyl 1H-indole-6-carboxylate 43a (1.43 mmol, 250 mg) and diethylaluminum chloride (1 M in hexanes, 1.86 mmol, 1.86 mL) in 8 mL of DCE. After 2 h at 0° C., the mixture was warmed to room temperature and was stirred overnight. To the mixture was added pH 7 buffer; the resulting solid was filtered and washed with CH2Cl2 to give 162 mg (38%) of methyl 3-(4-fluorobenzoyl)-1H-indole-6-carboxylate 43c. MS m/z (M+H+) 298.0.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([C:10]2[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=2[O:17][CH3:18])=[O:9])=[CH:6][N:5]=[C:4]([NH:19][CH:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)[N:3]=1.[Cl:26][CH2:27][CH2:28][CH2:29][CH2:30][S:31](Cl)(=[O:33])=[O:32]>>[NH2:1][C:2]1[C:7]([C:8]([C:10]2[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=2[O:17][CH3:18])=[O:9])=[CH:6][N:5]=[C:4]([NH:19][CH:20]2[CH2:21][CH2:22][N:23]([S:31]([CH2:30][CH2:29][CH2:28][CH2:27][Cl:26])(=[O:33])=[O:32])[CH2:24][CH2:25]2)[N:3]=1
Reactant: COc1ccc(F)cc1C(=O)c1cnc(NC2CCNCC2)nc1N
Reactant: O=S(=O)(Cl)CCCCCl
Product: COc1ccc(F)cc1C(=O)c1cnc(NC2CCN(S(=O)(=O)CCCCCl)CC2)nc1N

Procedure:
The compound was prepared from [4-amino-2-(piperidin-4-ylamino)-pyrimidin-5-yl]-(5-fluoro-2-methoxy-phenyl)-methanone (Example 59) and 4-chloro-butane-1-sulfonyl chloride (Example 254) in an analogous manner as described in Example 177. HR-MS (ES, m/z) calculated for C21H27N5O4SFCI [(M+H)+]500.1532, observed 500.1529.
Reaction SMILES: [C:1]1(O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([N:19]3[C:27]4[C:22](=[CH:23][C:24]([O:28][CH3:29])=[CH:25][CH:26]=4)[C:21]([CH2:30][C:31]([OH:33])=[O:32])=[C:20]3[CH3:34])=[N:14][CH:15]=[N:16]2)=[CH:11][CH:10]=1.C1(N=C=NC2CCCCC2)CCCCC1>COCCOC>[Cl:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([N:19]3[C:27]4[C:22](=[CH:23][C:24]([O:28][CH3:29])=[CH:25][CH:26]=4)[C:21]([CH2:30][C:31]([O:33][C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)=[O:32])=[C:20]3[CH3:34])=[N:14][CH:15]=[N:16]2)=[CH:11][CH:10]=1
Reactant: Oc1ccccc1
Reactant: COc1ccc2c(c1)c(CC(=O)O)c(C)n2-c1ncnc2cc(Cl)ccc12
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: COCCOC
Product: COc1ccc2c(c1)c(CC(=O)Oc1ccccc1)c(C)n2-c1ncnc2cc(Cl)ccc12
Temperature: 25 °C

Procedure:
A mixture of phenol (0.27g.) and anhydrous 1-(7-chloroquinazolin-4-yl)-5-methoxy-2-methylindol-3-ylacetic acid (1.0g.) in dry 1,2-dimethoxyethane (20ml.; dried over sodium aluminosilicate powder) was stirred at room temperature and treated with dicyclohexylcarbodiimide (0.75g.). The mixture became opaque, and was stirred overnight at room temperature and then filtered. Evaporation of the filtrate gave a dark yellow syrup, which was purified by chromatography on silica gel (175g.), using an increasing gradient of ether in petroleum ether (b.p. 40°-60° C.) (polarity increased by incremental addition of 10% v/v ether). The major product, phenyl 1-(7-chloroquinazolin-4-yl)-5-methoxy-2-methylindol-3-ylacetate, was obtained as a yellow glass (NMR: OCH3 at 6.20τ; pure by TLC: systems A and D), from the petrol rich fractions. A second product, 1-[1-(7-chloroquinazolin-4-yl)-5-methoxy-2-methylindol-3-ylacetyl]-1,3-dicyclohexylurea, was obtained as a pale yellow solid of m.p. 105°-107° C. NMR: OCH3 at 6.23τ; pure by TLC: system C).
Reaction SMILES: Cl.[NH2:2][C@H:3]([C:14]([O:16][CH3:17])=[O:15])[CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][CH:6]=1.C(N(CC)CC)C.[F:25][C:26]1[CH:36]=[CH:35][CH:34]=[CH:33][C:27]=1[CH:28]=[CH:29][C:30](O)=[O:31].CCN=C=NCCCN(C)C.Cl>C(Cl)Cl>[F:25][C:26]1[CH:36]=[CH:35][CH:34]=[CH:33][C:27]=1[CH:28]=[CH:29][C:30]([NH:2][C@H:3]([C:14]([O:16][CH3:17])=[O:15])[CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][CH:6]=1)=[O:31]
Reactant: O=C(O)C=Cc1ccccc1F
Reactant: COC(=O)[C@@H](N)Cc1c[nH]c2ccccc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)C=Cc1ccccc1F
Yield: 98.7 %

Procedure:
The same procedures as in Example 2 were carried out from methyl L-tryptophanate hydrochloride (5.0 g), triethylamine (2.9 mL), 2-fluorocinnamic acid (3.4 g), WSC.HCl (3.9 g), and methylene chloride (130 mL), to give the captioned compound (7.1 g, 99%) as an oily product.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:12]=[C:13]3[CH2:19][CH:18]([CH:20]4[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]4)[O:17][C:14]3=[CH:15][N:16]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].[F:26][C:27]([F:38])([F:37])[C:28]1([CH2:31]OS(C)(=O)=O)[CH2:30][CH2:29]1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CN1CCCC1=O>[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:12]=[C:13]3[CH2:19][CH:18]([CH:20]4[CH2:25][CH2:24][N:23]([CH2:31][C:28]5([C:27]([F:38])([F:37])[F:26])[CH2:30][CH2:29]5)[CH2:22][CH2:21]4)[O:17][C:14]3=[CH:15][N:16]=2)=[CH:7][CH:6]=1)(=[O:3])=[O:4]
Reactant: CS(=O)(=O)OCC1(C(F)(F)F)CC1
Reactant: CS(=O)(=O)c1ccc(-c2cc3c(cn2)OC(C2CCNCC2)C3)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: CS(=O)(=O)c1ccc(-c2cc3c(cn2)OC(C2CCN(CC4(C(F)(F)F)CC4)CC2)C3)cc1
Temperature: 100 °C
Reaction time: 4 h

Procedure:
A mixture of 5-(4-methanesulfonyl-phenyl)-2-piperidin-4-yl-2,3-dihydro-furo[2,3-c]pyridine (435 mg), methanesulfonic acid (1-trifluoromethyl-cyclopropyl)methyl ester (700 mg), potassium carbonate (850 mg), and potassium iodide (100 mg) in N-methyl-2-pyrrolidone (8 mL) is stirred at 100° C. for 4 h and then at room temperature overnight. The solvent is evaporated and the residue is triturated with methanol and filtered. The filtrate is concentrated in vacuo and the residue is purified by HPLC to give the title compound. LC (method 1): tR=1.09 min; Mass spectrum (ESI+): m/z=481 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([Br:11])=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].C([N:19]1[CH2:24][CH2:23][C:22](=O)[CH2:21][CH2:20]1)(OC(C)(C)C)=O.S(=O)(=O)(O)O>C(O)(=O)C.C(OCC)C>[Br:11][C:8]1[CH:7]=[C:3]2[C:2](=[CH:10][CH:9]=1)[NH:1][C:22]1([CH2:23][CH2:24][NH:19][CH2:20][CH2:21]1)[NH:6][C:4]2=[O:5]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: NC(=O)c1cc(Br)ccc1N
Agent: O=S(=O)(O)O
Solvent: CCOCC
Solvent: CC(=O)O
Product: O=C1NC2(CCNCC2)Nc2ccc(Br)cc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 33 mg (0.15 mmol) of 2-amino-5-bromobenzamide and 30 mg (0.15 mmol) of 1-Boc-4-piperidone in 400 μL of acetic acid containing 10 μL of sulfuric acid is stirred overnight at room temperature. The reaction mixture is diluted with diethyl ether. The yellow precipitate is collected by filtration, washed with excess ether, and dried under vacuum to give 55 mg (0.15 mmol) of the acetic acid salt of 6′-bromospiro-[piperidine-4,2′(1′H)-quinazolin]-4′-(3′H)-one. MS m/z: 297.0 (M+H)+, 319.0 (M+Na)+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([S:11][C:12]2[C:20]3[C:15](=[CH:16][C:17]([Cl:21])=[CH:18][CH:19]=3)[NH:14][C:13]=2[CH3:22])[CH:6]=1)[CH3:2].Br[C:25]1[C:26]([CH3:31])=[N:27][N:28]([CH3:30])[CH:29]=1>>[CH2:1]([O:3][C:4](=[O:23])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([S:11][C:12]2[C:20]3[C:15](=[CH:16][C:17]([Cl:21])=[CH:18][CH:19]=3)[N:14]([C:25]3[C:26]([CH3:31])=[N:27][N:28]([CH3:30])[CH:29]=3)[C:13]=2[CH3:22])[CH:6]=1)[CH3:2]
Reactant: CCOC(=O)c1cccc(Sc2c(C)[nH]c3cc(Cl)ccc23)c1
Reactant: Cc1nn(C)cc1Br
Product: CCOC(=O)c1cccc(Sc2c(C)n(-c3cn(C)nc3C)c3cc(Cl)ccc23)c1

Procedure:
Prepared according to the procedure described in Example 55, Step 2 using the following starting materials: 3-(6-chloro-2-methyl-1H-indol-3-ylsulfanyl)-benzoic acid ethyl ester and 4-Bromo-1,3-dimethyl-1H-pyrazole.