Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:29])[CH2:4][CH2:5][NH:6][C:7](=[O:28])[C:8]1[CH:13]=[CH:12][C:11]([CH:14]([O:20][C:21]2[CH:26]=[CH:25][C:24](Br)=[CH:23][CH:22]=2)[CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])=[CH:10][CH:9]=1.[F:30][C:31]([F:43])([F:42])[O:32][C:33]1[CH:38]=[CH:37][C:36](B(O)O)=[CH:35][CH:34]=1>>[F:30][C:31]([F:43])([F:42])[O:32][C:33]1[CH:38]=[CH:37][C:36]([C:24]2[CH:23]=[CH:22][C:21]([O:20][CH:14]([C:11]3[CH:12]=[CH:13][C:8]([C:7]([NH:6][CH2:5][CH2:4][C:3]([OH:29])=[O:2])=[O:28])=[CH:9][CH:10]=3)[CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])=[CH:26][CH:25]=2)=[CH:35][CH:34]=1
Reactant: CCCCCC(Oc1ccc(Br)cc1)c1ccc(C(=O)NCCC(=O)OC)cc1
Reactant: OB(O)c1ccc(OC(F)(F)F)cc1
Product: CCCCCC(Oc1ccc(-c2ccc(OC(F)(F)F)cc2)cc1)c1ccc(C(=O)NCCC(=O)O)cc1

Procedure:
This compound is made in a substantially similar manner to Example 117 using isomer 1 of 3-{4-[1-(4-bromo-phenoxy)-hexyl]-benzoylamino}-propionic acid methyl ester and 4-trifluoromethoxy-phenylboronic acid as starting materials in step D. MS (ES): 530.2 [M+H]+.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[NH2:20])[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].CCN(CC)CC.[CH3:28][N:29]([CH3:33])[C:30](Cl)=[O:31]>C(Cl)Cl.CN(C1C=CN=CC=1)C.CCOC(C)=O>[C:1]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[NH:20][C:30]([N:29]([CH3:33])[CH3:28])=[O:31])[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccccc2N)CC1
Reactant: CN(C)C(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(C)C(=O)Nc1ccccc1N1CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 1 h
Yield: 5.7 %

Procedure:
To a solution of 1-Boc-4-(2-aminophenyl)-piperazine (270 mg, 1.0 mmol) and Et3N (400 microliter, 2.89 mmol) in 10 mL of CH2Cl2 was added dimethylcarbamyl chloride (135 microliter, 1.48 mmol). After stirring for about 1 hour, DMAP (10 mg) was added. After stirring for about 3 days, another 800 microliter of Et3N and 270 microliter of dimethylcarbamyl chloride were added. After stirring overnight, the solution was diluted with EtOAc, washed with 1 M HCl (2×), saturated sodium bicarbonate, water and brine, and then dried (Na2SO4), filtered and concentrated. Purification by silica gel chromatography (35 g SiO2, 20 to 50% EtOAc/hexanes, over 30 minutes at 35 mL/min) afforded about 20 mg (0.057 mmol, 6%) of the tide compound as a white solid. LRMS: 349.2 (M+1)
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:30]=[CH:31][CH:32]=1)[C:5]([NH:7][C:8]1[CH:9]=[CH:10][C:11]2[N:15]=[CH:14][N:13]([CH:16]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH2:17][C:18]([O:20]CC)=[O:19])[C:12]=2[CH:29]=1)=[O:6]>Cl>[NH2:1][C:2]1[CH:3]=[C:4]([CH:30]=[CH:31][CH:32]=1)[C:5]([NH:7][C:8]1[CH:9]=[CH:10][C:11]2[N:15]=[CH:14][N:13]([CH:16]([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH2:17][C:18]([OH:20])=[O:19])[C:12]=2[CH:29]=1)=[O:6]
Reactant: CCOC(=O)CC(c1ccccc1)n1cnc2ccc(NC(=O)c3cccc(N)c3)cc21
Agent: Cl
Product: Nc1cccc(C(=O)Nc2ccc3ncn(C(CC(=O)O)c4ccccc4)c3c2)c1

Procedure:
A solution of ethyl 3-{6-[(3-aminobenzoyl)amino]-1H-benzimidazol-1-yl}-3-phenylpropanoate (50 mg, 117 μmol) in hydrochloric acid (20 mL of a 5N solution) was stirred at room temperature for 96 hours. The solution was evaporated in vacuo, and the residue was purified by RP-HPLC to afford the title compound, [LCMS (Method A, Mobile Phase II) RT=3.36 min, MH+ 401].
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([O:13][CH3:14])[C:5]([O:11][CH3:12])=[C:6]([CH:8]([OH:10])[CH3:9])[CH:7]=1.C1C=C[NH+]=CC=1.[O-][Cr](Cl)(=O)=O>C(Cl)Cl.CC(OC)(C)C>[Cl:1][C:2]1[CH:3]=[C:4]([O:13][CH3:14])[C:5]([O:11][CH3:12])=[C:6]([C:8](=[O:10])[CH3:9])[CH:7]=1
Reactant: COc1cc(Cl)cc(C(C)O)c1OC
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: COC(C)(C)C
Solvent: ClCCl
Product: COc1cc(Cl)cc(C(C)=O)c1OC
Reaction time: 0.67 h
Yield: 72 %

Procedure:
1-(5-Chloro-2,3-dimethoxy-phenyl)-ethanol (204 g, 943 mmol) was dissolved in DCM (2.0 L) and PCC (was added to the reaction mixture in portions, over 2 hours. Over the first 1.5 hours the temperature increased from 17.2° C. to 30.7° C. while a total of 315 g PCC was added. Addition of the remaining PCC did not result in a temperature increase. The reaction mixture was tested by TLC 1 hour after the PCC addition was completed; full conversion was observed. After an additional 40 min, 2 L TBME was added and a 4° C. exotherm was observed. The dark slurry was poured into 0.2 kg celite, mixed, then filtered over an additional 0.2 kg celite. The tar-like material remained in the reaction flask. DCM/TBME solution was concentrated under reduced pressure. A coating of tar formed on the flask walls; a solid also formed. The solid was dissolved in 0.2 L DCM (the tar did not dissolve). The solution was mixed with 0.2 kg silica gel and the DCM was allowed to evaporate. The product pre-adsorbed on silica gel was placed on top of a silica gel plug (0.4 kg silica gel) and the organic material was eluted with TBME until no product was observed by TLC. The resulting yellow solution was concentrated to yield a yellow solid. This solid was re-dissolved in TBME and the solution was flushed through a 0.4 kg silica gel plug. The resulting solution was concentrated to yield 145.8 g dry solid (72% yield, 95% pure by HPLC).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:12]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:11]([CH2:20][CH:21]2[CH2:26][CH2:25][C:24](=[O:27])[CH2:23][CH:22]2[C:28](=[O:34])[NH:29][C:30]([CH3:33])([CH3:32])[CH3:31])[O:10][C:9]1([CH3:36])[CH3:35])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl-].[Ce+3].[Cl-].[Cl-].[BH4-].[Na+]>CO>[C:1]([O:5][C:6]([N:8]1[CH:12]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:11]([CH2:20][CH:21]2[CH2:26][CH2:25][CH:24]([OH:27])[CH2:23][CH:22]2[C:28](=[O:34])[NH:29][C:30]([CH3:33])([CH3:32])[CH3:31])[O:10][C:9]1([CH3:36])[CH3:35])=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)(C)NC(=O)C1CC(=O)CCC1CC1OC(C)(C)N(C(=O)OC(C)(C)C)C1Cc1ccccc1
Agent: [BH4-]
Agent: [Ce+3]
Agent: [Cl-]
Solvent: CO
Product: CC(C)(C)NC(=O)C1CC(O)CCC1CC1OC(C)(C)N(C(=O)OC(C)(C)C)C1Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 77.8 %

Procedure:
A solution of 4-benzyl-5-(2-tert-butylcarbamoyl-4-oxo-cyclohexylmethyl)-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester (1.1 g, 2.2 mmol) in dry methanol (20 ml) was stirred at room temperature under nitrogen during the addition of cerium chloride (1.8 g, 4.84 mmol). The resulting mixture was stirred at room temperature for 30 minutes, then cooled to −78° C. and treated with sodium borohydride (183 mg, 4.84 mmol). The resulting suspension was allowed to warm to 0° C. over 90 min, then partitioned between ethyl acetate and a mixture of saturated aqueous ammonium chloride solution and brine. The two layers were separated and the aqueous phase was extracted twice with ethyl acetate. The combined organic layers were dried (anhydrous magnesium sulfate) and concentrated in vacuo. Purification by flash chromatography on silica gel (ethyl acetate/hexane: 1/1 to 2/1) provided 4-benzyl-5-(2-tert-butylcarbamoyl-4-hydroxy-cyclohexylmethyl)-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester (860 mg).
Reaction SMILES: II.[Br:3][C:4]1[CH:5]=[C:6]([C:10]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([Cl:20])[CH:13]=2)=[CH2:11])[CH:7]=[CH:8][CH:9]=1.N.[NH2:22][C:23]([NH2:25])=[O:24]>C(OCC)(=O)C.C(#N)C.[Ag]OC#N.ClCCl>[Br:3][C:4]1[CH:5]=[C:6]([C:10]2([C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([Cl:20])[CH:13]=3)[CH2:11][O:24][C:23]([NH2:25])=[N:22]2)[CH:7]=[CH:8][CH:9]=1
Reactant: C=C(c1cccc(Br)c1)c1ccc(OC)c(Cl)c1
Reactant: NC(N)=O
Agent: N#CO[Ag]
Agent: II
Agent: N
Solvent: ClCCl
Solvent: CC#N
Solvent: CCOC(C)=O
Product: COc1ccc(C2(c3cccc(Br)c3)COC(N)=N2)cc1Cl
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 56 %

Procedure:
A solution of iodine (3.76 g, 14.83 mmol) in ethyl acetate (40 mL) was added dropwise over 25 min to a mixture of 4-[1-(3-bromo-phenyl)-vinyl]-2-chloro-1-methoxy-benzene (4.36 g, 13.49 mmol) and silver cyanate (2.42 g, 16.18 mmol) in acetonitrile (38 mL) and ethyl acetate (18 mL), cooled in an ice bath. After complete addition, the reaction suspension was stirred for another 15 min at room temperature when TLC indicated the complete conversion of starting material. The reaction mixture was filtered, and the filtrate concentrated to give a dark grey oil. 80 mL of aqueous ammonia (25%) was added to the oil, and the mixture was stirred and warmed to 60° C. for 4 hours. LC-MS at this point indicated complete conversion of the intermediate urea to the desired aminoxazoline. Dichloromethane (40 mL) was added to the crude and the two phases were separated; organic layer was collected, dried over magnesium sulfate anhydrous, filtered and evaporated under reduced pressure. The solid obtained was washed with cyclohexane to give 2.89 g of desired product as a pale-yellow solid (56%)
Reaction SMILES: [CH2:1]([C:3]1[S:4][C:5]2[C:14]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[N:8]=[C:7]([NH:15]C(=O)C(Cl)(Cl)Cl)[C:6]=2[N:22]=1)[CH3:2].N>CO>[CH2:1]([C:3]1[S:4][C:5]2[C:14]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[N:8]=[C:7]([NH2:15])[C:6]=2[N:22]=1)[CH3:2]
Reactant: CCc1nc2c(NC(=O)C(Cl)(Cl)Cl)nc3ccccc3c2s1
Agent: N
Solvent: CO
Product: CCc1nc2c(N)nc3ccccc3c2s1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
N-(2-ethylthiazolo[4,5-c]quinolin-4-yl)trichloroacetamide (0.40 g) was suspended in a solution of ammonia in methanol (20 mL of 2M) and then stirred at ambient temperature for 30 minutes. The reaction mixture was concentrated under vacuum. The residue was washed with water and then dried to provide 0.19 g of crude product which was recrystallized from ethyl acetate/hexane to provide 2-ethylthiazolo[4,5-c]quinolin-4-amine as tan needles, m.p. 170-172° C. Analysis: Calculated for C12H11N3S: % C, 62.85; % H, 4.83; % N, 18.32; Found: % C, 62.58; % H, 4.78; % N, 18.08.
Reaction SMILES: [CH3:1][CH:2]1[CH2:8][N:7](C(=O)C(F)(F)F)[CH2:6][CH2:5][C:4]2[N:15]=[CH:16][C:17]([NH2:19])=[CH:18][C:3]1=2.C([O-])([O-])=O.[K+].[K+].CO.C([O-])(O)=O.[Na+]>C(Cl)Cl.O>[CH3:1][CH:2]1[CH2:8][NH:7][CH2:6][CH2:5][C:4]2[N:15]=[CH:16][C:17]([NH2:19])=[CH:18][C:3]1=2
Reactant: CC1CN(C(=O)C(F)(F)F)CCc2ncc(N)cc21
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Solvent: ClCCl
Product: CC1CNCCc2ncc(N)cc21
Reaction time: 16 h
Yield: 23.7 %

Procedure:
A mixture of 2-methoxy-5-methyl-3-nitro-7-(trifluoroacetyl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepine (2.00 g, 6.00 mmol), HBr/AcOH (33 wt %, 20 ml) and H20 (5 ml) was stirred for 10 min at room temperature. The reaction was parted between sat. aq. NaHCO3 and EtOAc. The organic phased was dried and concentrated in vacuo to give 1.68 g (88%) of pure 5-methyl-3-nitro-7-(trifluoroacetyl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepin-2-ol. 1H-NMR (CDCl3) δ 8.42 (s, 1H), 4.20-3.20 (m, 8H), 1.45 (d, 1.2H), 1.39 (d, 1.8H) ppm. A mixture of 5-methyl-3-nitro-7-(trifluoroacetyl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepin-2-ol (1.63 g, 5.10 mmol), Bu4NBr (4.94 g, 15.3 mmol), P2O5 (3.62 g, 12.8 mmol) and toluene (100 ml) was heated to 110° C. for 5 h. The reaction was cooled to room temperature and the liquid part was decanted and concentrated in vacuo to give 1.25 g (64%) of pure 2-bromo-5-methyl-3-nitro-7-(trifluoroacetyl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepine. 1H-NMR (CDCl3) δ 8.05 (s, 1H), 3.80 (m, 3H), 3.60-3.25 (m, 4H), 1.41 (d, 1.2H), 1.35 (d, 1.8H) ppm. Concurent reduction of the nitro group and halogene on was carried out with 5% Pd/C in MeOH under H2 (1 atm) to give 1.20 g (97%) of pure 5-methyl-7-(trifluoroacetyl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepin-3-amine. 1H-NMR of rotamers (MeOH-d4) δ 7.77 (2× d, 1H), 7.62 (d, 0.4H), 7.58 (d, 0.6H), 4.10-3.35 (m, 7H), 1.42 (d, 1.3H), 1.35 (d, 1.7H) ppm. A mixture of 5-methyl-7-(trifluoroacetyl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepin-3-amine (130 mg, 476 μmol), K2CO3 (100 mg), MeOH (6 ml) and H2O (1 ml) was stirred for 16 h at room temprature. The reaction mixture was parted between aq. NaHCO3 and DCM, the organic layer was dried and then concentrated in vacuo. The resulting residue was purified by column chromatography to yield 20.0 mg (24%) of 5-methyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepin-3-amine. 1H-NNMR (MeOH-d4) δ 7.68 (s, 1H), 7.24 (s, 1H), 3.45-2.95 (m, 7H), 1.37 (d, 3H) ppm.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:11]2[CH2:15][C@H:14]([CH2:16][OH:17])[CH:13]=[CH:12]2)=[C:4](Cl)[N:3]=1.[CH3:19][NH2:20].[OH-].[Na+]>>[NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:11]2[CH2:15][C@H:14]([CH2:16][OH:17])[CH:13]=[CH:12]2)=[C:4]([NH:20][CH3:19])[N:3]=1
Reactant: CN
Reactant: Nc1nc(Cl)c2ncn([C@H]3C=C[C@@H](CO)C3)c2n1
Agent: [Na+]
Agent: [OH-]
Product: CNc1nc(N)nc2c1ncn2[C@H]1C=C[C@@H](CO)C1
Yield: 70 %

Procedure:
(±)-cis-4-(2-Amino-6-chloro-9H-purin-9-yl)-2-cyclopentene-1-methanol (0.400 g, 1.5 mmol) from Example 4 and methylamine (40% aqueous solution, 25 mL) were stirred at 60° C. for 0.5 hours. The solution was allowed to cool to room temperature before the addition of 1.5 mL of 1.5 N NaOH. Evaporation left the crude product which was purified by elution from a silica gel column with 5% methanolchloroform. The resulting solid was slurried in acetonitrile to yield a pale yellow powder (0.274 g, 70%); m.p. 221-223° C.
Reaction SMILES: O.[OH-].[Li+].C([O:6][C:7]([C@H:9]([O:28][C:29]([N:31]1[CH2:36][CH2:35][CH:34]([N:37]2[CH2:43][CH2:42][C:41]3[CH:44]=[CH:45][CH:46]=[CH:47][C:40]=3[NH:39][C:38]2=[O:48])[CH2:33][CH2:32]1)=[O:30])[CH2:10][C:11]1[CH:12]=[C:13]2[C:17](=[C:18]([CH3:20])[CH:19]=1)[N:16]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[N:15]=[CH:14]2)=[O:8])C>O.C1COCC1>[C:7]([C@H:9]([O:28][C:29]([N:31]1[CH2:32][CH2:33][CH:34]([N:37]2[CH2:43][CH2:42][C:41]3[CH:44]=[CH:45][CH:46]=[CH:47][C:40]=3[NH:39][C:38]2=[O:48])[CH2:35][CH2:36]1)=[O:30])[CH2:10][C:11]1[CH:12]=[C:13]2[C:17](=[C:18]([CH3:20])[CH:19]=1)[N:16]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[N:15]=[CH:14]2)([OH:8])=[O:6]
Reactant: CCOC(=O)[C@@H](Cc1cc(C)c2c(cnn2C(=O)OC(C)(C)C)c1)OC(=O)N1CCC(N2CCc3ccccc3NC2=O)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(C[C@@H](OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)O)cc2cnn(C(=O)OC(C)(C)C)c12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 19.2 mg (0.8 mmol) lithium hydroxide hydrate in 10 mL water was added at RT to a solution of 330 mg (0.53 mmol) tert.-butyl 5-{(R)-2-ethoxycarbonyl-2-[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carbonyloxy]-ethyl}-7-methyl-indazol-1-carboxylate in 30 mL THF and the reaction mixture was stirred for 30 min at RT. It was evaporated down i.vac., the residue was taken up in 100 mL water, combined with 10% citric acid with stirring, extracted twice with 100 mL DCM and the combined organic phases were dried over Na2SO4. After the desiccant and solvent had been eliminated the residue was reacted further without purification.
Reaction SMILES: [C:1]([O:5][C:6](=[O:28])[NH:7][C:8]1[CH:13]=[CH:12][C:11](/[CH:14]=[CH:15]/[C:16]2[C:17]([O:23][CH3:24])=[N:18][CH:19]=[CH:20][C:21]=2[Cl:22])=[C:10]([N+:25]([O-])=O)[CH:9]=1)([CH3:4])([CH3:3])[CH3:2].O>P(OCC)(OCC)OCC>[C:1]([O:5][C:6](=[O:28])[NH:7][C:8]1[CH:9]=[C:10]2[C:11]([CH:14]=[C:15]([C:16]3[C:17]([O:23][CH3:24])=[N:18][CH:19]=[CH:20][C:21]=3[Cl:22])[NH:25]2)=[CH:12][CH:13]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1nccc(Cl)c1/C=C/c1ccc(NC(=O)OC(C)(C)C)cc1[N+](=O)[O-]
Agent: CCOP(OCC)OCC
Solvent: O
Product: COc1nccc(Cl)c1-c1cc2ccc(NC(=O)OC(C)(C)C)cc2[nH]1
Temperature: 25 °C
Yield: 24.4 %

Procedure:
A solution of {4-[(E)-2-(4-chloro-2-methoxy-pyridin-3-yl)-vinyl]-3-nitro-phenyl}-carbamic acid tert-butyl ester (800 mg, 1.97 mmol) in triethyl phosphite (16.0 ml) was refluxed for 3 hours. The reaction mixture was cooled to 25° C., and poured into water. The aqueous phase was extracted three times with ethyl acetate. The combined organic layers were washed with brine and dried over magnesium sulfate. Filtration followed by concentration in vacuo gave a brown solid. Flash chromatography (70/30 hexanes/ethyl acetate) afforded [2-(4-chloro-2-methoxy-pyridin-3-yl)-1H-indol-6-yl]-carbamic acid tert-butyl ester (180 mg, 33%) as a white solid. MH+ 374.0.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[N+:20]([O-:22])=[O:21])=[CH:7][CH:8]=[C:9]([C:11](=[S:13])[NH2:12])[CH:10]=1)=[O:4].Br[CH2:24][C:25]([C:27]1[CH:31]=[CH:30][S:29][CH:28]=1)=O>>[N+:20]([C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[C:6]1[C:5]([C:3]([OH:2])=[O:4])=[CH:10][C:9]([C:11]2[S:13][CH:24]=[C:25]([C:27]3[CH:31]=[CH:30][S:29][CH:28]=3)[N:12]=2)=[CH:8][CH:7]=1)([O-:22])=[O:21]
Reactant: COC(=O)c1cc(C(N)=S)ccc1-c1ccccc1[N+](=O)[O-]
Reactant: O=C(CBr)c1ccsc1
Product: O=C(O)c1cc(-c2nc(-c3ccsc3)cs2)ccc1-c1ccccc1[N+](=O)[O-]
Yield: 19 %

Procedure:
2′-Nitro-4-(4-thiophen-3-yl-thiazol-2-yl)-biphenyl-2-carboxylic acid (50 mg, 19%) was prepared from 2′-nitro-4-thiocarbamoyl-biphenyl-2-carboxylic acid methyl ester (which may be prepared as described for Intermediate 4) and 2-bromo-1-(3-thienyl)-1-ethanone (available from Maybridge) using the procedure described for the preparation of Example 1. 1H NMR (300 MHz, DMSO-d6) δ 13.13 (s, 1H), 8.54 (d, J=1.7 Hz, 1H), 8.23 (dd, J=7.8, 1.8 Hz, 1H), 8.04-8.15 (m, 3H), 7.78 (t, J=6.8 Hz, 1H), 7.62-7.69 (m, 3H), 7.44 (t, J=8.1 Hz, 2H).
Reaction SMILES: [C:1]1(=[O:7])[O:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:8]([NH2:15])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]>C1(C)C=CC=CC=1>[CH2:8]([NH:15][C:1](=[O:7])[CH2:2][CH2:3][CH2:4][CH2:5][OH:6])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: CCCCCCCN
Reactant: O=C1CCCCO1
Solvent: Cc1ccccc1
Product: CCCCCCCNC(=O)CCCCO
Temperature: 110 °C
Reaction time: 1 h
Yield: 95 %

Procedure:
Delta valerolactone (40 g, 0.4 mole) was added dropwise with stirring to n heptylamine (50.6 g, 0.44 mole) so that the temperature of the mixture was maintained at 85° to 90° C. Heat was applied and the temperature raised to 110° C. over 20 minutes after which the temperature was maintained at 110° to 115° C. for a further 6 hours (after 3 hours N.M.R. indicated that the reaction was 90 to 95% complete). Toluene (200 ml, 173 g) was added and the solution cooled to 0° C. with stirring. After 1 hour at 0° C., the solid was collected and washed successively with ice cold toluene (50 ml, 43 g) and n-heptane (50 ml, 34 g). The material was dried at room temperature overnight to give the product. (81.6 g (95% yield) m.p. 53° to 54° C.).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]2[C:15]3[C:10](=[C:11]([C:21]([NH2:23])=[O:22])[CH:12]=[C:13]([C:16]4[CH:17]=[N:18][NH:19][CH:20]=4)[CH:14]=3)[NH:9][N:8]=2)[CH2:3][CH2:2]1.C(N(C(C)C)CC)(C)C.[CH3:33][N:34]1[CH:38]=[C:37]([S:39](Cl)(=[O:41])=[O:40])[N:36]=[C:35]1[CH3:43]>CN(C1C=CN=CC=1)C>[CH3:33][N:34]1[CH:38]=[C:37]([S:39]([N:1]2[CH2:2][CH2:3][CH:4]([C:7]3[C:15]4[C:10](=[C:11]([C:21]([NH2:23])=[O:22])[CH:12]=[C:13]([C:16]5[CH:17]=[N:18][NH:19][CH:20]=5)[CH:14]=4)[NH:9][N:8]=3)[CH2:5][CH2:6]2)(=[O:41])=[O:40])[N:36]=[C:35]1[CH3:43]
Reactant: Cc1nc(S(=O)(=O)Cl)cn1C
Reactant: NC(=O)c1cc(-c2cn[nH]c2)cc2c(C3CCNCC3)n[nH]c12
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc(S(=O)(=O)N2CCC(c3n[nH]c4c(C(N)=O)cc(-c5cn[nH]c5)cc34)CC2)cn1C
Yield: 27.4 %

Procedure:
Following the general procedure of Example 11, 3-(4-piperidinyl)-5-(1H-pyrazol-4-yl)-1H-indazole-7-carboxamide (Example 75) (0.07 mmol), diisopropyl-ethylamine (100 uL, 0.56 mmol), DMAP (25 mg, 0.014 mmol) and 1,2-dimethyl-1H-imidazole-4-sulfonyl chloride (33 mg, 0.17 mmol) were reacted to give the title compound (9 mg, 27% for 3 steps). LC/MS: 469.4 Rt: 1.33 min.
Reaction SMILES: [Br:1][C:2]1[C:8]([O:9][CH3:10])=[CH:7][C:5]([NH2:6])=[C:4]([F:11])[CH:3]=1.[C:12]1(=O)[O:17][C:15](=[O:16])[C:14]2[CH2:18][CH2:19][CH2:20][CH2:21][C:13]1=2.O>C(O)(=O)C>[Br:1][C:2]1[C:8]([O:9][CH3:10])=[CH:7][C:5]([N:6]2[C:15](=[O:16])[C:14]3[CH2:18][CH2:19][CH2:20][CH2:21][C:13]=3[C:12]2=[O:17])=[C:4]([F:11])[CH:3]=1
Reactant: COc1cc(N)c(F)cc1Br
Reactant: O=C1OC(=O)C2=C1CCCC2
Solvent: CC(=O)O
Solvent: O
Product: COc1cc(N2C(=O)C3=C(CCCC3)C2=O)c(F)cc1Br
Temperature: 25 °C
Yield: 33.9 %

Procedure:
4-Bromo-2-fluoro-5-methoxyaniline (1.1 g) and 3,4,5,6-tetrahydrophthalic anhydride (0.8 g) were dissolved in acetic acid (5 ml) and refluxed for 3 hours. The resultant mixture was allowed to cool to room temperature and poured into water, followed by extraction with ether. The ether extract was washed with water, dried over anhydrous sodium sulfate and subjected to filtration. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel chromatography to obtain 0.6 g of N-(4-bromo-2-fluoro-5-methoxyphenyl)-3,4,5,6-tetrahydrophthalimide (Compound No. 12).
Reaction SMILES: [Cl:1][C:2]1[C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C@:7]([OH:19])([C:15]([F:18])([F:17])[F:16])[C:6]=2[CH:5]=[C:4]([O:20]CCCC(O)=O)[CH:3]=1.CN1CCCC1=O.Cl.N1C=CC=CC=1>C(OCC)(=O)C>[Cl:1][C:2]1[C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C@@:7]([C:15]([F:17])([F:18])[F:16])([OH:19])[C:6]=2[CH:5]=[C:4]([OH:20])[CH:3]=1
Reactant: O=C(O)CCCOc1cc(Cl)c2c(c1)[C@@](O)(C(F)(F)F)c1ccccc1-2
Agent: Cl
Solvent: c1ccncc1
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: Oc1cc(Cl)c2c(c1)[C@@](O)(C(F)(F)F)c1ccccc1-2
Temperature: 200 °C
Reaction time: 48 h
Yield: 57.6 %

Procedure:
To 4-[(9R)-4-chloro-9-hydroxy-9-(trifluoromethyl)-9H-fluoren-2-yloxy]butyric acid (50 g) were added N-methylpyrrolidone (200 ml) and pyridine hydrochloride (298 g), and the mixture was stirred at an oil bath temperature of 200° C. for 2 days. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (500 ml), and washed twice with water. The obtained aqueous layer was extracted again with ethyl acetate (300 ml). The combined organic layer was washed successively with water, 1N hydrochloric acid and saturated brine. To the obtained organic layer were added anhydrous magnesium sulfate and activated carbon (10 g), and the mixture was stirred at room temperature. The insoluble material was filtered off through celite. The solvent in the obtained organic layer was evaporated, hexane was added to the residue, and the mixture was stirred at room temperature. The precipitated solid was collected by filtration, and dried under reduced pressure at room temperature. The obtained crude product was dissolved in ethyl acetate (500 ml), washed 3 times with water, dried over anhydrous magnesium sulfate. The insoluble material was filtered off, and the solvent in the filtrate was evaporated. To the residue was added hexane, and the mixture was stirred at room temperature. The precipitated solid was collected by filtration, dried under reduced pressure at room temperature to give the title compound (22.4 g).
Reaction SMILES: [CH:1]1([C:4]2[C:9]([CH:10](O)[CH3:11])=[CH:8][N:7]=[C:6]([C:13]3[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=3)[N:5]=2)[CH2:3][CH2:2]1.S(Cl)([Cl:25])=O>ClCCl>[Cl:25][CH:10]([C:9]1[C:4]([CH:1]2[CH2:2][CH2:3]2)=[N:5][C:6]([C:13]2[CH:14]=[CH:15][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:17][CH:18]=2)=[N:7][CH:8]=1)[CH3:11]
Reactant: O=S(Cl)Cl
Reactant: CC(O)c1cnc(-c2ccc(C(F)(F)F)cc2)nc1C1CC1
Solvent: ClCCl
Product: CC(Cl)c1cnc(-c2ccc(C(F)(F)F)cc2)nc1C1CC1
Yield: 102.9 %

Procedure:
A solution of 357 mg (1.16 mmol) [rac]-1-[4-cyclopropyl-2-(4-trifluoromethyl-phenyl)-pyrimidin-5-yl]-ethanol and 0.09 ml (1.22 mmol) thionylchloride in 4 ml dichloromethane were stirred for 1 h at RT. The reaction mixture was concentrated under reduced pressure to provide 390 mg of pure [rac]-5-(1-chloro-ethyl)-4-cyclopropyl-2-(4-trifluoromethyl-phenyl)-pyrimidine.