Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:9][CH:10]1[C:16](=[O:17])[N:15]2[CH:18]([C:22]([NH:24][CH:25]([CH:30]=[O:31])[CH2:26][C:27]([OH:29])=[O:28])=[O:23])[CH2:19][CH2:20][CH2:21][N:14]2[C:13](=[O:32])[CH2:12][CH2:11]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:33][C:34](OC(C)=O)=[O:35].OS([O-])(=O)=O.[Na+]>N1C=CC=CC=1>[C:1]([NH:9][CH:10]1[C:16](=[O:17])[N:15]2[CH:18]([C:22]([NH:24][CH:25]3[CH2:26][C:27](=[O:29])[O:28][CH:30]3[O:31][C:34](=[O:35])[CH3:33])=[O:23])[CH2:19][CH2:20][CH2:21][N:14]2[C:13](=[O:32])[CH2:12][CH2:11]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=CC(CC(=O)O)NC(=O)C1CCCN2C(=O)CCC(NC(=O)c3ccccc3)C(=O)N12
Reactant: CC(=O)OC(C)=O
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Product: CC(=O)OC1OC(=O)CC1NC(=O)C1CCCN2C(=O)CCC(NC(=O)c3ccccc3)C(=O)N12
Reaction time: 6 h
Yield: 37.6 %

Procedure:
A solution of 214e (287 mg, 0.65 mmol) in pyridine (5 mL) was treated with Ac2O (0.4 mL, 3.62 mmol). After 6 hours, the reaction mixture was poured into 5% NaHSO4 and extracted 3 times with EtOAc. The combined organics were washed with brine, dried over Na2SO4 and concentrated in vacuo. Chromatography (SiO2, EtOAc) afforded 119 mg of 2100h, 1HNMR (CDCl3, mixture of four diastereoisomers) δ 1.80-2.05(m), 2.12(s), 2.13(s), 2.19(s), 2.22(d), 2.67-2.75(m), 2.80-2.95(m), 3.00-3.20(m), 3.21-3.33(m), 3.50-3.95(four discrete multiplets), 4.19(m), 4.55(m), 4.57-4.65(m), 4.69(m), 4.85-4.95(m), 5.04(m), 5.10(s), 5.10-5.22(m), 6.46(d), 6.03(s), 6.50(d), 6.58(d), 6.75(d), 6.95-7.05(m), 7.22(m), 7.30(m), 7.71(d), 7.75-7.83(m).
Reaction SMILES: [SH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([CH3:12])[N:3]=1.Cl[CH2:14][C:15]1[CH:20]=[C:19]([O:21][CH3:22])[C:18]([CH3:23])=[CH:17][N:16]=1>>[CH3:22][O:21][C:19]1[C:18]([CH3:23])=[CH:17][N:16]=[C:15]([CH2:14][S:1][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]=[C:4]([CH3:12])[N:3]=2)[CH:20]=1
Reactant: COc1cc(CCl)ncc1C
Reactant: Cc1nc(S)c2ccccc2n1
Product: COc1cc(CSc2nc(C)nc3ccccc23)ncc1C
Yield: 1.5 %

Procedure:
The title compound(0.12 g) was prepared from 4-mercapto-2-methylquinazoline(4.48 g) and 2-chloromethyl-4-methoxy-5-methylpyridine(6.3 g).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([CH3:11])[CH:3]=1.[I:12]NC(=O)CCC(N)=O.O>CN(C=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH3:11])[C:5]([C:6]([OH:8])=[O:7])=[C:9]([I:12])[CH:10]=1
Reactant: Cc1cc(Cl)ccc1C(=O)O
Reactant: NC(=O)CCC(=O)NI
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(Cl)cc(I)c1C(=O)O
Temperature: 100 °C

Procedure:
A mixture of 4-chloro-2-methyl-benzoic acid (3.40 g, 20 mmol,), N-iodosuccinamide (4.4 g, 22 mmol) and palladium (II) acetate (0.448 g, 2 mmol) in dry DMF (35 mL) was heated at 100° C. for 36 h under nitrogen atmosphere. After this time, the reaction mixture was cooled to ambient temperature and poured into water. The aqueous solution was extracted with ethyl acetate (2×100 mL) and the combined organic extracts were washed with aqueous sodium thiosulphate (30 mL) and brine (30 mL). The organic solution was dried over anhydrous MgSO4, filtered and concentrated to afford 4-chloro-2-iodo-6-methyl-benzoic acid. The product was used without further purification.
Reaction SMILES: [Br:1][C:2]1[S:3][C:4]([C:7]([OH:9])=O)=[CH:5][N:6]=1.[N:10]1([CH2:15][CH2:16][CH2:17][NH2:18])[CH:14]=[CH:13][N:12]=[CH:11]1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CCN(C(C)C)C(C)C>ClCCl>[N:10]1([CH2:15][CH2:16][CH2:17][NH:18][C:7]([C:4]2[S:3][C:2]([Br:1])=[N:6][CH:5]=2)=[O:9])[CH:14]=[CH:13][N:12]=[CH:11]1
Reactant: NCCCn1ccnc1
Reactant: O=C(O)c1cnc(Br)s1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCCCn1ccnc1)c1cnc(Br)s1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2-Bromothiazole-5-carboxylic acid (0.4 g, 1.923 mmol), 3-(1H-imidazole-1-yl)propan-1-amine (0.265 g, 2.115 mmol), and benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (BOP) (0.935 g, 2.115 mmol) were mixed in dichloromethane (7 ml), treated with Hunig's base (0.705 ml, 4.04 mmol) and stirred at 25° C. for 2 hours. The reaction mixture was diluted with dichloromethane and washed with water and brine. The organic layer was dried (MgSO4), filtered and concentrated. Purification by flash chromatography (silica gel, 2-20% methanol/dichloromethane) afforded the title compound.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[CH:17]=[C:18]5[C:22](=[CH:23][CH:24]=4)[NH:21][C:20]([C:25](O)=[O:26])=[CH:19]5)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1.[CH3:28][C:29]([NH2:32])([CH3:31])[CH3:30].C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C)C=O>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[CH:17]=[C:18]5[C:22](=[CH:23][CH:24]=4)[NH:21][C:20]([C:25]([NH:32][C:29]([CH3:31])([CH3:30])[CH3:28])=[O:26])=[CH:19]5)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: O=C(O)c1cc2cc(NC(=O)C3(c4ccc5c(c4)OCO5)CC3)ccc2[nH]1
Reactant: CC(C)(C)N
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)NC(=O)c1cc2cc(NC(=O)C3(c4ccc5c(c4)OCO5)CC3)ccc2[nH]1
Reaction time: 3 h

Procedure:
5-(1-(Benzo[d][1,3]dioxol-5-yl)cyclopropane-carboxamido)-1H-indole-2-carboxylic acid (36 mg, 0.10 mmol) and 2-methylpropan-2-amine (8.8 mg, 0.12 mmol) were dissolved in N,N-dimethylformamide (1.0 mL) containing triethylamine (28 μL, 0.20 mmol). O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (46 mg, 0.12 mmol) was added to the mixture and the resulting solution was allowed to stir for 3 hours. The mixture was filtered and purified by reverse phase HPLC to yield 5-(1-(benzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-N-tert-butyl-1H-indole-2-carboxamide. ESI-MS m/z calc. 419.2. found 420.3 (M+1)+; retention time 3.12 minutes.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[C:4](F)[CH:3]=1.[CH3:11][O-:12].[Na+]>CO>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[C:4]([O:12][CH3:11])[CH:3]=1
Reactant: C[O-]
Reactant: O=Cc1ccc(Br)cc1F
Agent: [Na+]
Solvent: CO
Product: COc1cc(Br)ccc1C=O
Yield: 61.9 %

Procedure:
To a stirred solution of 4-bromo-2-fluorobenzaldehyde (3.38 g; 16 mmol) in 35 mL methanol at ambient temperature was added sodium methoxide solution (4.0 mL of 25% solution; 17.6 mmol), and the resulting solution was stirred and heated to reflux. After refluxing for 2 hours the solvent was evaporated. The residue was partitioned between 100 mL dichloromethane and 50 mL water. The organic layer was dried over sodium sulfate and evaporated. The residue was purified by silica gel chromatography to give 2.13 g of 4-bromo-2-methoxybenzaldehyde as a white solid. MS (apci, neg) m/z=199.
Reaction SMILES: [CH2:1]([P+:3]([CH2:8]O)([CH2:6]O)[CH2:4]O)O.[Cl-:10].[CH3:11][NH:12][C:13]([NH:15][CH3:16])=[O:14].C1(C)C=CC=CC=1>O>[Cl-:10].[O:14]=[C:13]1[N:15]([CH3:16])[CH2:6][P+:3]2([CH2:1][N:15]([CH3:16])[C:13](=[O:14])[N:12]([CH3:11])[CH2:4]2)[CH2:8][N:12]1[CH3:11]
Reactant: OC[P+](CO)(CO)CO
Reactant: CNC(=O)NC
Agent: [Cl-]
Solvent: Cc1ccccc1
Solvent: O
Product: CN1C[P+]2(CN(C)C1=O)CN(C)C(=O)N(C)C2
Yield: 88.9 %

Procedure:
A mixture of THPC (19.06 g, 0.1 mol), 1,3-dimethylurea (17.62 g, 0.2 mol), and toluene (150 ml) was heated to reflux in an apparatus fitted with a mechanical stirrer and a Dean-Stark trap for azeotropic removal of the water. The mixture was held at reflux until the evolution of water ceased (4 hr); this condensation, as might be expected, required a longer reflux period and more efficient stirring to displace the last of the water than that of Example 1. Half of the 7.2 ml (100.0%) of water was collected during the first 15 min. The product, which separated during the reaction as a mass of white solids, was broken up, triturated under acetonitrile to remove a resinous by-product (4.09 g), filtered, rinsed with acetonitrile and dried, giving 26.21 g (86.3%) of 3,9-dioxo-2,4,8,10-tetramethyl-2,4,8,10-tetraaza-6-phosphoniaspiro[5.5]undecane chloride (II, R=R'=CH3, X=Cl) as a white, crystalline solid. Two recrystallizations from 2-propanol (12 ml/g) gave pure product, mp 161°-162° C. and resolidifying, then mp 217° C. dec.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)=[C:4]([C:22](=[O:26])[N:23]([CH3:25])[CH3:24])[CH:3]=1.[C:27]1(B(O)O)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C(=O)([O-])[O-].[K+].[K+].O1CCOCC1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[CH3:24][N:23]([CH3:25])[C:22]([C:4]1[CH:3]=[C:2]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:7]=[CH:6][C:5]=1[CH2:8][N:9]1[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]1)=[O:26]
Reactant: OB(O)c1ccccc1
Reactant: CN(C)C(=O)c1cc(Br)ccc1CN1CCN(C(=O)OC(C)(C)C)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: CN(C)C(=O)c1cc(-c2ccccc2)ccc1CN1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 80 °C
Reaction time: 8 h
Yield: 78.7 %

Procedure:
A 100 mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was charged with tert-butyl 4-[[4-bromo-2-(dimethylcarbamoyl)phenyl]methyl]piperazine-1-carboxylate (130 mg, 0.300 mmol, 1.00 equiv), phenylboronic acid (113 mg, 0.930 mmol, 3.00 equiv), potassium carbonate (128 mg, 0.930 mmol, 3.00 equiv), tetrakis(triphenylphosphine)palladium (36.0 mg, 0.030 mmol, 0.10 equiv), dioxane (4 mL), H2O (0.4 mL). The resulting solution was stirred overnight at 80° C. and concentrated under reduced pressure. The residue was chromatographed on a silica gel column with ethyl acetate/petroleum ether (25/75) to provide 100 mg (79% yield) of tert-butyl 4-[[2-(dimethylcarbamoyl)-4-phenylphenyl]methyl]piperazine-1-carboxylate as light yellow oil. LCMS (ESI, m/z): 424 [M+H]+.
Reaction SMILES: O[C:2]1[C:3]2[N:11]=[CH:10][CH:9]=[C:8]([C:12]([NH2:14])=[O:13])[C:4]=2[N:5]=[CH:6][N:7]=1.Cl.[NH2:16][C@@H:17]([C:33]1[CH:38]=[C:37]([F:39])[C:36]([F:40])=[CH:35][C:34]=1[F:41])[CH2:18][N:19]([CH3:32])S(C1C=CC([N+]([O-])=O)=CC=1)(=O)=O>>[CH3:32][NH:19][CH2:18][C@@H:17]([NH:16][C:2]1[C:3]2[N:11]=[CH:10][CH:9]=[C:8]([C:12]([NH2:14])=[O:13])[C:4]=2[N:5]=[CH:6][N:7]=1)[C:33]1[CH:38]=[C:37]([F:39])[C:36]([F:40])=[CH:35][C:34]=1[F:41]
Reactant: NC(=O)c1ccnc2c(O)ncnc12
Reactant: CN(C[C@@H](N)c1cc(F)c(F)cc1F)S(=O)(=O)c1ccc([N+](=O)[O-])cc1
Agent: Cl
Product: CNC[C@@H](Nc1ncnc2c(C(N)=O)ccnc12)c1cc(F)c(F)cc1F

Procedure:
Compound 60 was prepared following general synthesis scheme 7 wherein 4-hydroxypyrido[3,2-d]pyrimidine-8-carboxamide (G) was reacted with N—[(S)-2-Amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-N-methyl-4-nitro-benzenesulfonamide hydrochloride to give the title compound as a white solid. LC/MS [377 (M+H)].
Reaction SMILES: C(NC1C=CC(S([N:14]=[N+:15]=[N-])(=O)=O)=CC=1)(=O)C.[O:17]=[C:18]([CH3:27])[CH2:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21]>CC#N>[N+:14](=[C:19]([C:18](=[O:17])[CH3:27])[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])=[N-:15]
Reactant: CC(=O)Nc1ccc(S(=O)(=O)N=[N+]=[N-])cc1
Reactant: CC(=O)CC(=O)OC(C)(C)C
Solvent: CC#N
Product: CC(=O)C(=[N+]=[N-])C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 77 %

Procedure:
4-acetamidobenzenesulfonyl azide (1.5 ml) was added to a solution of tert-butyl 3-oxobutanoate (1.86 g, 10.12 mmol) and TEA (3.85 ml) in CH3CN (60 ml). The mixture was stirred at room temperature overnight, concentrated and purified by flash chromatography to give tert-butyl 2-diazo-3-oxobutanoate as a yellow liquid (1.3 g, 77% yield).
Reaction SMILES: [H-].[Na+].[CH2:3]([C:6]1[CH:11]=[CH:10][C:9]([SH:12])=[CH:8][CH:7]=1)[CH2:4][CH3:5].Br[CH:14]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[C:15]([O:17][CH2:18][CH3:19])=[O:16]>CN(C)C=O.C(OCC)(=O)C>[CH2:3]([C:6]1[CH:11]=[CH:10][C:9]([S:12][CH:14]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:8][CH:7]=1)[CH2:4][CH3:5]
Reactant: CCCc1ccc(S)cc1
Reactant: CCCCCCCC(Br)C(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCCCCCC(Sc1ccc(CCC)cc1)C(=O)OCC
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 81 %

Procedure:
1.6 g (0.033 mole) sodium hydride (50% dispersion in mineral oil) was added to a solution of 5.0 g (0.033 mole) 4-propylthiophenol in 25 ml anhydrous dimethylformamide. After 15 minutes, 8.8 g (0.033 mole) ethyl 2-bromononanoate (prepared according to J. Labelled Compounds Radiopharm. 14, 713 (1978)) was added and the resulting mixture was stirred at room temperature overnight. The reaction mixture was then diluted with 150 ml ethyl acetate and the resulting mixture was washed with 5×60 ml water and then with 60 ml saturated aqueous sodium chloride solution. The ethyl acetate solution was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The resulting oil was chromatographed on 600 g silica gel, eluting with 7:3 hexane/methylene chloride to yield 9.0 g (81% yield) of the desired product as an oil.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6](=[O:17])[S:7][C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10](Br)[CH:9]=2)=[O:4].[CH3:18][N:19]1[C:23]([Sn](CCCC)(CCCC)CCCC)=[CH:22][C:21]([C:37]([F:40])([F:39])[F:38])=[N:20]1>>[CH3:1][O:2][C:3]([C:5]1[C:6](=[O:17])[S:7][C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10]([C:23]1[N:19]([CH3:18])[N:20]=[C:21]([C:37]([F:40])([F:39])[F:38])[CH:22]=1)[CH:9]=2)=[O:4]
Reactant: COC(=O)c1c(O)c2ccc(Br)cc2sc1=O
Reactant: CCCC[Sn](CCCC)(CCCC)c1cc(C(F)(F)F)nn1C
Product: COC(=O)c1c(O)c2ccc(-c3cc(C(F)(F)F)nn3C)cc2sc1=O

Procedure:
4-Hydroxy-7-(2-methyl-5-trifluoromethyl-2H-pyrazol-3-yl)-2-oxo-2H-thiochromene-3-carboxylic acid methyl ester was prepared from 7-bromo-4-hydroxy-2-oxo-2H-thiochromene-3-carboxylic acid methyl ester under conditions analogous to Example 44(a) using 1-Methyl-5-tributylstannanyl-3-trifluoromethyl-1H-pyrazole. The crude material was used in the next step without purification.
Reaction SMILES: [Br:1][C:2]1[CH:29]=[C:28]([F:30])[C:5]([CH2:6][N:7]2[C:11]3[CH:12]=[C:13]([OH:16])[CH:14]=[CH:15][C:10]=3[N:9]=[C:8]2[C@H:17]2[CH2:22][CH2:21][CH2:20][CH2:19][C@H:18]2[C:23]([O:25][CH2:26][CH3:27])=[O:24])=[C:4]([F:31])[CH:3]=1.Cl[CH2:33][C:34]1[C:39]([F:40])=[CH:38][C:37]([CH3:41])=[CH:36][N:35]=1.C([O-])([O-])=O.[Cs+].[Cs+]>C(#N)C>[Br:1][C:2]1[CH:29]=[C:28]([F:30])[C:5]([CH2:6][N:7]2[C:11]3[CH:12]=[C:13]([O:16][CH2:33][C:34]4[C:39]([F:40])=[CH:38][C:37]([CH3:41])=[CH:36][N:35]=4)[CH:14]=[CH:15][C:10]=3[N:9]=[C:8]2[C@H:17]2[CH2:22][CH2:21][CH2:20][CH2:19][C@H:18]2[C:23]([O:25][CH2:26][CH3:27])=[O:24])=[C:4]([F:31])[CH:3]=1
Reactant: Cc1cnc(CCl)c(F)c1
Reactant: CCOC(=O)[C@@H]1CCCC[C@@H]1c1nc2ccc(O)cc2n1Cc1c(F)cc(Br)cc1F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CCOC(=O)[C@@H]1CCCC[C@@H]1c1nc2ccc(OCc3ncc(C)cc3F)cc2n1Cc1c(F)cc(Br)cc1F
Temperature: 100 °C

Procedure:
To a mixture of racemic cis-ethyl 2-(1-(4-bromo-2,6-difluorobenzyl)-6-hydroxy-1H-benzo[d]imidazol-2-yl)cyclohexanecarboxylate (110 mg, 0.22 mmol), 2-(chloromethyl)-3-fluoro-5-methylpyridine (35 mg, 0.22 mmol) in acetonitrile (5 mL) was added Cs2CO3 (79 mg, 0.24 mmol) and heated at 100° Celsius. After 1 hr the mixture was concentrated to dryness and the residue was purified by FCC to provide racemic cis-ethyl 2-(1-(4-bromo-2,6-difluorobenzyl)-6-((3-fluoro-5-methylpyridin-2-yl)methoxy)-1H-benzo[d]imidazol-2-yl)cyclohexanecarboxylate. To the resulting ethyl ester was added MeOH (2 mL), and NaOH (1 mL, 1 N). The mixture was heated to 110° Celsius. After 1 h the mixture was concentrated to dryness and purified by FCC to provide the title compound and the trans-isomer see Example 124. MS (ESI): mass calcd. for C28H25BrF3N3O3, 587.10; m/z found, 588.2 [M+H]+. 1H NMR (500 MHz, CD3OD) δ 8.22 (s, 1H), 7.52-7.45 (m, 2H), 7.28 (d, J=7.6, 2H), 6.99 (d, J=2.0, 1H), 6.88 (dd, J=8.7, 2.3, 1H), 5.54 (two d, J=16.4, 2H), 5.18 (s, 2H), 3.79 (d, J=4.6, 1H), 2.78-2.63 (m, 1H), 2.40 (s, 3H), 2.36-2.20 (m, 1H), 2.12-1.86 (m, 3H), 1.86-1.67 (m, 2H), 1.51-1.39 (m, 2H).
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]([O:24][CH2:25][CH2:26][C:27](=[O:29])[NH2:28])=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][N:10]=[C:9]2/[CH:15]=[CH:16]/[C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=1)=[O:5])C>S(=O)(=O)(O)O>[C:27]([CH2:26][CH2:25][O:24][C:7]1[C:6]([C:4]([OH:5])=[O:3])=[CH:14][CH:13]=[C:12]2[C:8]=1[C:9](/[CH:15]=[CH:16]/[C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=1)=[N:10][NH:11]2)(=[O:29])[NH2:28]
Reactant: CCOC(=O)c1ccc2[nH]nc(/C=C/c3ccc(F)cc3)c2c1OCCC(N)=O
Agent: O=S(=O)(O)O
Product: NC(=O)CCOc1c(C(=O)O)ccc2[nH]nc(/C=C/c3ccc(F)cc3)c12
Temperature: 35 °C
Reaction time: 16 h
Yield: 55.1 %

Procedure:
85.3 mg of 4-(2-carbamoylethoxy)-3-[(E)-2-(4-fluorophenyl)-vinyl]-1H-indazole-5-carboxylic acid ethyl ester obtained by Example 763 was dissolved in 3 mL of concentrated sulfuric acid, stirred at 35° C. for 16 hours, and then added with ice under ice cooling. The precipitated crystals were collected by filtration, washed with water, and then dried under reduced pressure, to afford 43.7 mg of the title compound as yellow crude crystals.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][CH:8]2[NH:11][C:12]2[CH:21]=[CH:20][C:19]3[C:14](=[CH:15][CH:16]=[C:17]([NH2:22])[CH:18]=3)[N:13]=2)=[CH:4][CH:3]=1.[CH:23]1([C:26](O)=[O:27])[CH2:25][CH2:24]1>>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][CH:8]2[NH:11][C:12]2[CH:21]=[CH:20][C:19]3[C:14](=[CH:15][CH:16]=[C:17]([NH:22][C:26]([CH:23]4[CH2:25][CH2:24]4)=[O:27])[CH:18]=3)[N:13]=2)=[CH:4][CH:3]=1
Reactant: Nc1ccc2nc(NC3CCc4ccc(F)cc43)ccc2c1
Reactant: O=C(O)C1CC1
Product: O=C(Nc1ccc2nc(NC3CCc4ccc(F)cc43)ccc2c1)C1CC1

Procedure:
The title compound was prepared in accordance with the general method 14 described in example 119 from rac-N2-(6-fluoro-indan-1-yl)-quinoline-2,6-diamine and cyclopropanecarboxylic acid; MS: m/e=362.4 (M+H−).
Reaction SMILES: [ClH:1].[ClH:2].[CH3:3][O:4][C:5]1[CH:6]=[C:7]([N:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)[CH:8]=[CH:9][CH:10]=1.[Cl:17]N1C(=O)CCC1=O>C(O)(=O)C.O>[ClH:17].[Cl:1][C:8]1[CH:9]=[C:10]([Cl:2])[C:5]([O:4][CH3:3])=[CH:6][C:7]=1[N:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1
Reactant: O=C1CCC(=O)N1Cl
Reactant: COc1cccc(N2CCNCC2)c1
Agent: Cl
Solvent: O
Solvent: CC(=O)O
Product: COc1cc(N2CCNCC2)c(Cl)cc1Cl
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To a solution of 530 mg (2.0 mmol) of 1-(3-Methoxyphenyl)piperazine dihydrochloride in 7 mL of acetic acid and 4 mL of water at 0° C. was added 700 mg (4.4 mmol) of N-chlorosuccinimide. The reaction was taken out of the ice/water bath after 2 hours, and allowed to stir overnight. After 12 hours, the reaction was concentrated to an oil in vacuo, and the oil was partitioned between ether and water. The phases were separated, the aqueous was basified with 1M NaOH, and was extracted with ethyl acetate. The ethyl acetate phase was washed once each with water and brine, dried over Na2SO4, filtered, and the filtrate was concentrated to an oil in vacuo. The oil was dissolved in a minimum volume of methanol, the solution was acidified with 5M HCl in isopropanol and was diluted with ethyl acetate to effect crystallization. The product was isolated by filtration. 1H NMR (D2O, 400 MHz) 7.38 (s, 1H), 6.72 (s, 1H), 3.78 (s, 3H), 3.32 (m, 4H), 3.19 (m, 4H) ppm.
Reaction SMILES: [F:1][CH:2]([F:15])[C:3]1([C:9]([O:11]C(C)C)=[O:10])[CH2:6][C:5]([F:8])([F:7])[CH2:4]1.[OH-].[Na+]>C(O)C.O>[F:15][CH:2]([F:1])[C:3]1([C:9]([OH:11])=[O:10])[CH2:6][C:5]([F:7])([F:8])[CH2:4]1
Reactant: CC(C)OC(=O)C1(C(F)F)CC(F)(F)C1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)C1(C(F)F)CC(F)(F)C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 73.6 %

Procedure:
To a solution of Intermediate 304D (500 mg, 2.191 mmol) in ethanol (10 mL) and water (2 mL) was added NaOH (2.191 mL, 10.96 mmol, 5 M in water) and the resulting solution was stirred at RT for 4 h. EtOH was removed under reduced pressure, and the aqueous solution was acidified with a 1.5 N aq. solution of HCl which was then extracted with DCM (3×30 mL). The combined organic layer was washed with brine, dried over Na2SO4, filtered and the filtrate was concentrated to afford Intermediate 304E as a pale yellow liquid (300 mg, 74% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 13.87 (br. s., 1H), 6.21-6.63 (m, 1H), 2.77-3.11 (m, 4H).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([N:9]([CH2:20][C:21](O)=[O:22])[S:10]([C:13]2[C:14]([CH3:19])=[CH:15][CH:16]=[CH:17][CH:18]=2)(=[O:12])=[O:11])=[CH:5][CH:4]=1.[CH2:24]([NH:26][CH2:27][C:28]1[CH:35]=[CH:34][C:31]([C:32]#[N:33])=[CH:30][CH:29]=1)[CH3:25]>>[C:32]([C:31]1[CH:34]=[CH:35][C:28]([CH2:27][N:26]([CH2:24][CH3:25])[C:21](=[O:22])[CH2:20][N:9]([C:6]2[CH:7]=[N:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[S:10]([C:13]2[C:14]([CH3:19])=[CH:15][CH:16]=[CH:17][CH:18]=2)(=[O:11])=[O:12])=[CH:29][CH:30]=1)#[N:33]
Reactant: COc1ccc(N(CC(=O)O)S(=O)(=O)c2ccccc2C)cn1
Reactant: CCNCc1ccc(C#N)cc1
Product: CCN(Cc1ccc(C#N)cc1)C(=O)CN(c1ccc(OC)nc1)S(=O)(=O)c1ccccc1C

Procedure:
prepared by reaction of [(6-methoxy-pyridin-3-yl)-(toluene-2-sulfonyl)-amino]-acetic acid with 4-ethylaminomethyl-benzonitrile
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]([CH3:9])([CH3:8])[C:5]([OH:7])=[O:6].C(N(C(C)C)CC)(C)C.[CH:19]1[C:31]2[CH:30]([CH2:32][O:33][C:34](Cl)=[O:35])[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[C:23]=2[CH:22]=[CH:21][CH:20]=1>ClCCl>[CH:19]1[C:31]2[CH:30]([CH2:32][O:33][C:34]([NH:2][CH2:3][C:4]([CH3:9])([CH3:8])[C:5]([OH:7])=[O:6])=[O:35])[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[C:23]=2[CH:22]=[CH:21][CH:20]=1
Reactant: O=C(Cl)OCC1c2ccccc2-c2ccccc21
Reactant: CC(C)(CN)C(=O)O
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(CNC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Reaction time: 18 h
Yield: 45.2 %

Procedure:
To 3-amino-2,2-dimethylpropanoic acid, hydrochloride salt (250 mg, 1.63 mmol, 1 eq.) in dichloromethane (4 mL, 0.4 M) was added diisopropylethylamine (859 μL, 4.88 mmol, 3 eq.) followed by (9H-fluoren-9-ylmethoxy)carbonyl chloride (473 mg, 1.79 mmol, 1.1 eq.) The reaction was stirred for 18 hours and then concentrated in vacuo. The residue was taken up in ethyl acetate (3 mL) and washed with 1 M aqueous hydrochloric acid solution (2×1 mL) and with brine. The organic layer was dried over sodium sulfate, filtered, and purified by silica gel chromatography (Gradient: 0% to 100% ethyl acetate in heptane) to give #93 (250 mg, 45%) as an oil. 1H NMR (400 MHz, DMSO-d6) δ 12.22 (s, 1H), 7.89 (d, J=7.4 Hz, 2H), 7.72 (d, J=7.4 Hz, 2H), 7.38-7.44 (m, 2H), 7.27-7.35 (m, 3H), 4.18-4.30 (m, 3H), 3.16 (d, J=6.2 Hz, 2H), 1.05 (s, 6H).