Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([B:10]([OH:12])[OH:11])=[CH:6][CH:5]=1)([OH:3])=O.C(Cl)(=O)C(Cl)=O.Cl.[NH2:20][CH2:21][C:22]#[N:23].CCN(C(C)C)C(C)C>CN(C=O)C.ClCCl>[C:21]([CH2:22][NH:23][C:1]([C:4]1[CH:9]=[CH:8][C:7]([B:10]([OH:12])[OH:11])=[CH:6][CH:5]=1)=[O:3])#[N:20]
Reactant: O=C(O)c1ccc(B(O)O)cc1
Reactant: N#CCN
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: N#CCNC(=O)c1ccc(B(O)O)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 87.3 %

Procedure:
To a suspension of 4-carboxyphenylboronic acid (5.0 g, 30 mmol) in DMF (5 mL) and dichloromethane (200 mL) at 0° C. was added oxalylchloride (5.9 mL, 66 mmol) dropwise. When gas evolution slowed, the ice bath was removed and the reaction allowed to warm to room temperature over 30 min. The reaction was then heated at 40° C. for three hours by which time all solids had dissolved. The dichloromethane was removed by distillation and the DMF solution cooled to 0° C. A solution of aminoacetonitrile hydrochloride (3.05 g, 33 mmol) in DMF (80 mL) and DIPEA (13 mL, 75 mmol) was then added dropwise. After the addition was complete the ice bath was removed and the solution allowed to stir at room temperature for 16 h. Most of the DMF was then removed in vacuo and the reaction was partitioned between ethyl acetate and 2 M aqueous hydrochloric acid. The aqueous layer was extracted twice further with ethyl acetate and the combined organic fractions dried (Na2SO4) filtered and concentrated under reduced pressure to afford 4-(cyanomethylcarbamoyl)phenylboronic acid as a waxy pale yellow solid (5.34 g, 87%). 1H NMR (300 MHz, d6-DMSO): 9.18 (br. t, J=5.1 Hz, 1H), 7.8-7.9 (m, 4H), 4.31 (d, J=5.4 Hz, 2H); LC-ESI-MS (method B): rt 0.9 min.; m/z 203.3 [M−H]−.
Reaction SMILES: [K].O[CH:3]=[C:4]([C:8]#[N:9])[CH2:5][C:6]#[N:7].C1(C)C=CC=CC=1.Cl.[CH3:18][NH:19][CH3:20]>CN(C=O)C>[CH3:18][N:19]([CH:3]=[C:4]([C:8]#[N:9])[CH2:5][C:6]#[N:7])[CH3:20]
Reactant: N#CCC(C#N)=CO
Reactant: CNC
Agent: Cl
Agent: [K]
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: CN(C)C=C(C#N)CC#N
Temperature: 25 °C
Yield: 86 %

Procedure:
A 12 liter three-necked round-bottomed flask, fitted with a mechanical stirrer, water condenser, nitrogen inlet and bubbler, was charged with 877 g (6 moles) of the potassium salt of 1-hydroxy-2,3-dicyanoprop-1-ene in 61 of anhydrous toluene and 300 ml of anhydrous DMF. To this heterogeneous mixture was added 514 g (6.3 moles) of dimethylamine hydrochloride. The mixture was heated to 80° then cooled to room temperature, filtered and the filter cake rinsed with toluene. The filtrate was concentrated under vacuum to yield 933 g containing on 75% weight, 86% yield of an off which partially crystallized at -5° C. An aliquot of the crystalline portion was collected and recrystallized twice from ether to give white crystals, m.p. 49° C. of 1-(N,N-dimethylamino)-2,3-dicyanoprop-1-ene (CIS 1).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[C:7]2[CH:8]=[CH:9][NH:10][C:11]=2[CH:12]=[CH:13][CH:14]=1.[CH2:15]1[CH2:24][O:23][C:22]2[CH:21]=[CH:20][C:19]([CH:25]3[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]3)=[CH:18][C:17]=2[O:16]1.[C:31]([OH:36])(=[O:35])[C:32]([OH:34])=[O:33]>C(OCC)(=O)C>[C:31]([OH:36])(=[O:35])[C:32]([OH:34])=[O:33].[NH:10]1[C:11]2[C:7](=[C:6]([O:5][CH2:4][CH2:3][CH2:2][N:28]3[CH2:27][CH2:26][CH:25]([C:19]4[CH:20]=[CH:21][C:22]5[O:23][CH2:24][CH2:15][O:16][C:17]=5[CH:18]=4)[CH2:30][CH2:29]3)[CH:14]=[CH:13][CH:12]=2)[CH:8]=[CH:9]1
Reactant: ClCCCOc1cccc2[nH]ccc12
Reactant: c1cc2c(cc1C1CCNCC1)OCCO2
Agent: O=C(O)C(=O)O
Solvent: CCOC(C)=O
Product: c1cc(OCCCN2CCC(c3ccc4c(c3)OCCO4)CC2)c2cc[nH]c2c1

Procedure:
The title compound was prepared in similar fashion from 1-chloro-3-(1H-indole-4-oxy)propane and 4-(3,4-ethylenedioxyphenyl)piperidine. The resulting free base was dissolved in ethyl acetate, and precipitated with one equivalent of oxalic acid in ethyl acetate in 59% overall 20 yield as a foam. FDMS m/e=392 (M+ of free base).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([C:9]([OH:11])=O)[C:6]([NH:12][C:13]2[CH:14]=[N:15][CH:16]=[N:17][CH:18]=2)=[N:5][CH:4]=1.[CH3:19][NH:20][C:21]([C:23]1[N:24]([CH3:29])[N:25]=[CH:26][C:27]=1[NH2:28])=[O:22]>>[CH3:29][N:24]1[C:23]([C:21](=[O:22])[NH:20][CH3:19])=[C:27]([NH:28][C:9]([C:7]2[C:6]([NH:12][C:13]3[CH:14]=[N:15][CH:16]=[N:17][CH:18]=3)=[N:5][CH:4]=[C:3]([O:2][CH3:1])[N:8]=2)=[O:11])[CH:26]=[N:25]1
Reactant: COc1cnc(Nc2cncnc2)c(C(=O)O)n1
Reactant: CNC(=O)c1c(N)cnn1C
Product: CNC(=O)c1c(NC(=O)c2nc(OC)cnc2Nc2cncnc2)cnn1C

Procedure:
The product was obtained starting from 6-methoxy-3-(pyrimidin-5-ylamino)-pyrazine-2-carboxylic acid (50 mg, 0.18 mmol) and 4-amino-2-methyl-2H-pyrazole-3-carboxylic acid methylamide (36 mg, 0.23 mmol) according to the method described in example 64, step 6 after purification by preparative HPLC using an acetonitrile/water gradient as yellow solid (16 mg, 22%).
Reaction SMILES: Cl[C:2]1C=CC=CC=1B(O)O.BrC1C=NC=CC=1.C(=O)([O-])[O-].[Na+].[Na+].[Cl:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[C:31]1[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=1.IC.[BH4-].[Na+]>C1(C)C=CC=CC=1.ClCCl.CO.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.C(O)C>[Cl:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[C:31]1[CH2:32][N:33]([CH3:2])[CH2:34][CH2:35][CH:36]=1
Reactant: Clc1ccccc1-c1cccnc1
Reactant: OB(O)c1ccccc1Cl
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: [BH4-]
Solvent: Cc1ccccc1
Solvent: CI
Solvent: Brc1cccnc1
Product: CN1CCC=C(c2ccccc2Cl)C1
Reaction time: 15 h
Yield: 88.8 %

Procedure:
A mixture of 2-chlorophenylboronic acid (5.0 g), 3-bromopyridine (4.8 g) and tetrakis(triphenylphosphine)palladium(0) (1.0 g) in toluene (47 ml), aqueous 2 M sodium carbonate solution (35 ml) and ethanol (2.4 ml) was heated under reflux for 5.5 h. The reaction mixture was cooled, and the toluene layer was separated. The aqueous layer was extracted with ethyl acetate and the combined organic extracts were dried (MgSO4), filtered, and the filtrate evaporated under reduced pressure to give crude 3-(2-chlorophenyl)pyridine (7.9 g). To a solution of the 3-(2-chlorophenyl)pyridine (7.9 g) in dichloromethane (50 ml) was added iodomethane (3.8 ml) and the mixture was stirred for 15 h. The solvent was evaporated under reduced pressure and the obtained residue was crystallized from ethyl acetate to give a pale-yellow crystal. To a solution of the obtained crystals in methanol (60 ml) was added sodium borohydride (1.7 g) under ice-cooling, and the mixture was stirred at room temperature for 3 h. The mixture was quenched with a saturated aqueous sodium chloride solution. The mixture was extracted with ethyl acetate. The extract was washed with a saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give a crude 5-(2-chlorophenyl)-1,2,3,6-tetrahydro-1-methylpyridine (5.9 g).
Reaction SMILES: [Br:1][C:2]1[C:8](F)=[CH:7][C:5]([NH2:6])=[C:4]([N+:10]([O-:12])=[O:11])[CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[F:19][C:20]1[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:21]=1[OH:27]>CS(C)=O.C(OCC)(=O)C.O>[Br:1][C:2]1[C:8]([O:27][C:21]2[CH:22]=[CH:23][C:24]([F:26])=[CH:25][C:20]=2[F:19])=[CH:7][C:5]([NH2:6])=[C:4]([N+:10]([O-:12])=[O:11])[CH:3]=1
Reactant: Nc1cc(F)c(Br)cc1[N+](=O)[O-]
Reactant: Oc1ccc(F)cc1F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CS(C)=O
Product: Nc1cc(Oc2ccc(F)cc2F)c(Br)cc1[N+](=O)[O-]
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 94.5 %

Procedure:
A solution of 4-bromo-5-fluoro-2-nitroaniline (1.08 g, 4.60 mmol) [Combi-Blocks, AN-1501] and cesium carbonate (1.80 g, 5.52 mmol) in dimethyl sulfoxide (5.0 mL) was treated with 2,4-difluorophenol (0.90 mL, 5.53 mmol) [Acros Organics, 24320] and stirred at 80° C. for 30 min. The reaction mixture was diluted with ethyl acetate and water. The organic layer was separated and washed with water and brine, dried with magnesium sulfate, filtered, and concentrated to give the desired product (1.50 g, 95%) as a yellow solid that was used without further purification. LCMS calculated for C12H8BrF2N2O3 (M+H)+: m/z=345.0, 347.0. found: 345.0, 346.9.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[F:9])[NH2:5].[C:10]([CH2:12][C:13](OCC)=[O:14])#[N:11]>C(OCC)(=O)C.O1CCCC1>[C:10]([CH2:12][C:13]([NH:5][C:4]1[CH:6]=[CH:7][C:8]([F:9])=[C:2]([F:1])[CH:3]=1)=[O:14])#[N:11]
Reactant: Nc1ccc(F)c(F)c1
Reactant: CCOC(=O)CC#N
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: N#CCC(=O)Nc1ccc(F)c(F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 50 %

Procedure:
A mixed solution of 3,4-difluoroaniline (10 g, 77.5 mmol) and ethyl cyanoacetate (10.5 g, 92.9 mmol) was heated to 180° C. and stirred for 8 hr. After cooling to room temperature, the mixture was dissolved in ethyl acetate/tetrahydrofuran and washed with water and saturated brine in this order. The mixture was dried over anhydrous magnesium sulfate and filtered. The solvent was evaporated under reduced pressure, and the obtained residue was washed with ethyl acetate and collected by filtration to give the title compound (7.6 g, 56%) as a yellow solid.
Reaction SMILES: [CH3:1][N:2]([CH3:18])[CH2:3][CH2:4][CH:5]([CH:15]1[CH2:17][CH2:16]1)[O:6][C:7]1[CH:12]=[CH:11][C:10]([O:13]C)=[CH:9][CH:8]=1.Cl.N1C=CC=CC=1>>[CH3:18][N:2]([CH3:1])[CH2:3][CH2:4][CH:5]([CH:15]1[CH2:16][CH2:17]1)[O:6][C:7]1[CH:8]=[CH:9][C:10]([OH:13])=[CH:11][CH:12]=1
Reactant: COc1ccc(OC(CCN(C)C)C2CC2)cc1
Agent: Cl
Solvent: c1ccncc1
Product: CN(C)CCC(Oc1ccc(O)cc1)C1CC1
Reaction time: 3 h

Procedure:
A mixture of 1 g of 1-dimethylamino-3-cyclopropyl-3-p-methoxyphenoxy-propane and 1 g of pyridine hydrochloride is stirred for 3 hours at 160°. After the customary working up, 1-dimethylamino-3-cyclopropyl-3-p-hydroxyphenoxy-propane is obtained.
Reaction SMILES: [CH:1]1[C:14]2[CH:13]([C:15]([OH:17])=O)[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[O:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[NH2:18][C@H:19]1[CH2:23][CH2:22][N:21]([CH2:24][CH2:25][C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=2)[CH2:20]1>>[F:32][C:29]1[CH:30]=[CH:31][C:26]([CH2:25][CH2:24][N:21]2[CH2:22][CH2:23][C@H:19]([NH:18][C:15]([CH:13]3[C:14]4[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=4[O:6][C:7]4[C:12]3=[CH:11][CH:10]=[CH:9][CH:8]=4)=[O:17])[CH2:20]2)=[CH:27][CH:28]=1
Reactant: O=C(O)C1c2ccccc2Oc2ccccc21
Reactant: N[C@H]1CCN(CCc2ccc(F)cc2)C1
Product: O=C(N[C@H]1CCN(CCc2ccc(F)cc2)C1)C1c2ccccc2Oc2ccccc21

Procedure:
9-Xanthenylcarboxylic acid and (S)-3-amino-1-(2-(4-fluorophenyl)ethyl)pyrrolidine were reacted under the same conditions as in Example 23 to give (S)-N-(1-(2-(4-fluorophenyl)ethyl)pyrrolidin-3-yl)-9-xanthenylcarboxamide.
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([Cl:9])[C:3]=1[C@H:10]([O:12][C:13]1[C:14]([NH2:30])=[N:15][CH:16]=[C:17]([C:19]2[CH:20]=[N:21][N:22]([CH:24]3[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]3)[CH:23]=2)[N:18]=1)[CH3:11].[CH3:31][N:32]([CH2:34][C:35](O)=[O:36])[CH3:33].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.C(N(CC)CC)C.BrC1N=C(O[C@@H](C2C(Cl)=CC=C(F)C=2Cl)C)C(N)=NC=1>CN(C=O)C>[NH2:30][C:14]1[N:15]=[CH:16][C:17]([C:19]2[CH:20]=[N:21][N:22]([CH:24]3[CH2:29][CH2:28][N:27]([C:35](=[O:36])[CH2:34][N:32]([CH3:33])[CH3:31])[CH2:26][CH2:25]3)[CH:23]=2)=[N:18][C:13]=1[O:12][C@@H:10]([C:3]1[C:4]([Cl:9])=[CH:5][CH:6]=[C:7]([F:8])[C:2]=1[Cl:1])[CH3:11]
Reactant: CN(C)CC(=O)O
Reactant: C[C@@H](Oc1nc(-c2cnn(C3CCNCC3)c2)cnc1N)c1c(Cl)ccc(F)c1Cl
Agent: C[C@@H](Oc1nc(Br)cnc1N)c1c(Cl)ccc(F)c1Cl
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: C[C@@H](Oc1nc(-c2cnn(C3CCN(C(=O)CN(C)C)CC3)c2)cnc1N)c1c(Cl)ccc(F)c1Cl

Procedure:
The title compound was prepared according to procedure 63 using 3-[(R)-1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-5-(1-piperidin-4-yl-1H-pyrazol-4-yl)-pyrazin-2-ylamine coupled with dimethylamino-acetic acid in the presence of HOBt/EDC/triethylamine in DMF as described in procedure 5 using 5-bromo-3-[(R)-1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyrazin-2-ylamine as the starting material. 1H NMR (400 MHz, DMSO-d6) δ 7.90 (s, 1H), 7.76 (s, 1H), 7.65 (s, 1H), 7.49 (m, 1H), 7.36 (t, 1H), 6.47 (q, 1H), 6.15 (s, 2H), 4.39 (m, 1H), 4.16 (m, 1H), 3.16 (m, 2H), 3.02 (m, 1H), 2.75 (m, 1H), 2.19 (s, 6H), 2.01 (m, 2H), 1.88 (s, 1H), 1.75 (d, 3H); LCMS: 536 [M+1]; c-Met Ki: 0.015 μM.
Reaction SMILES: CO[C:3]([C:5]1[N:6]=[CH:7][C:8]2[C:9](=[O:27])[N:10]([CH2:16][C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][C:18]=3[O:25][CH3:26])[CH:11]=[CH:12][C:13]=2[C:14]=1[OH:15])=[O:4].[NH2:28][CH2:29][C:30]([OH:32])=[O:31].C[O-].[Na+]>>[CH3:26][O:25][C:18]1[CH:19]=[C:20]([O:23][CH3:24])[CH:21]=[CH:22][C:17]=1[CH2:16][N:10]1[C:9](=[O:27])[C:8]2[CH:7]=[N:6][C:5]([C:3]([NH:28][CH2:29][C:30]([OH:32])=[O:31])=[O:4])=[C:14]([OH:15])[C:13]=2[CH:12]=[CH:11]1
Reactant: NCC(=O)O
Reactant: COC(=O)c1ncc2c(=O)n(Cc3ccc(OC)cc3OC)ccc2c1O
Agent: C[O-]
Agent: [Na+]
Product: COc1ccc(Cn2ccc3c(O)c(C(=O)NCC(=O)O)ncc3c2=O)c(OC)c1
Yield: 42.7 %

Procedure:
A mixture of 7-(2,4-dimethoxy-benzyl)-4-hydroxy-8-oxo-7,8-dihydro-[2,7]naphthyridine-3-carboxylic acid methyl ester (25 mg, 0.068 mmol), glycine (675 mg, 8.9 mmol) and NaOMe solution (13.5 mL, 6.8 mmol, 0.5 M in MeOH) was refluxed for 16 h. Solvent was evaporated in vacuo, and the residue was dissolved in saturated NaHCO3 and washed with ether. The aqueous layer was acidified with 4 M HCl to pH about 1, and the resulting precipitate was isolated by filtration. The crude solid was further purified by silica gel chromatography (10-90% EtOAc/hexanes+2% AcOH) to give 12 mg of the title compound as a light yellow solid. MS: (+) m/z 414.31 (M+1).
Reaction SMILES: [CH2:1]([NH2:4])[CH2:2][NH2:3].[O:5](C(OC(C)(C)C)=O)[C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=O>C(Cl)(Cl)Cl>[C:6]([NH:3][CH2:2][CH2:1][NH2:4])([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:5]
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Reactant: NCCN
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)NCCN
Reaction time: 16 h

Procedure:
Ethylenediamine (16-1) (Aldrich) (18.04 g, 0.50 mol) in CHCl3 (200 ml) was treated with a solution of BOC2O (13.1 g, 0.06 moles) in CHCl3 (100 ml) at room temperature over 1 h. This was stirred for 16 h, filtered, and concentrated to give 16-2 as a clear oil.
Reaction SMILES: [CH2:1]1[O:12][C:11]2[CH:10]=[C:9]3[C:5]([CH:6]=[C:7]([S:22](Cl)(=[O:24])=[O:23])[N:8]3[S:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)(=[O:15])=[O:14])=[CH:4][C:3]=2[O:2]1.[OH-].[NH4+:27]>CC(C)=O>[CH2:1]1[O:12][C:11]2[CH:10]=[C:9]3[C:5]([CH:6]=[C:7]([S:22](=[O:24])(=[O:23])[NH2:27])[N:8]3[S:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)(=[O:15])=[O:14])=[CH:4][C:3]=2[O:2]1
Reactant: [NH4+]
Reactant: O=S(=O)(Cl)c1cc2cc3c(cc2n1S(=O)(=O)c1ccccc1)OCO3
Agent: [OH-]
Solvent: CC(C)=O
Product: NS(=O)(=O)c1cc2cc3c(cc2n1S(=O)(=O)c1ccccc1)OCO3
Temperature: 25 °C

Procedure:
A solution of 5,6-methylenedioxy-1-benzenesulfonylindole-2-sulfonyl chloride (3.66 gm, 9.15 mmol) in acetone (35 ml) was added dropwise to a solution of concentrated ammonium hydorxide (5 ml) in acetone (20 ml) which was cooled in an ice bath. After 1 hour the reaction was warmed to room temperature and the solvent was evaporated. The residue was suspended in cold water and crystalline solid was collected by filtration. This solid was dissolved in ethyl acetate, dried (anhydrous Na2SO4), evaporated, and the residue was triturated with diethyl ether to give crystalline product (1.75 gm), mp 229°-232° C.
Reaction SMILES: [CH3:1][C:2]1([C:7]2[O:11][C:10]([CH2:12][N:13]3[N:17]=[C:16]([NH2:18])[CH:15]=[N:14]3)=[CH:9][CH:8]=2)[O:6]CCO1.[Cl:19][C:20]1[CH:21]=[C:22]([C:26]2[O:30][C:29]([CH3:31])=[N:28][C:27]=2[C:32](O)=[O:33])[CH:23]=[CH:24][CH:25]=1>>[C:2]([C:7]1[O:11][C:10]([CH2:12][N:13]2[N:17]=[C:16]([NH:18][C:32]([C:27]3[N:28]=[C:29]([CH3:31])[O:30][C:26]=3[C:22]3[CH:23]=[CH:24][CH:25]=[C:20]([Cl:19])[CH:21]=3)=[O:33])[CH:15]=[N:14]2)=[CH:9][CH:8]=1)(=[O:6])[CH3:1]
Reactant: Cc1nc(C(=O)O)c(-c2cccc(Cl)c2)o1
Reactant: CC1(c2ccc(Cn3ncc(N)n3)o2)OCCO1
Product: CC(=O)c1ccc(Cn2ncc(NC(=O)c3nc(C)oc3-c3cccc(Cl)c3)n2)o1

Procedure:
Following general procedure A followed by L, starting from 2-[5-(2-methyl-[1,3]dioxolan-2-yl)-furan-2-ylmethyl]-2H-[1,2,3]triazol-4-ylamine and 5-(3-chloro-phenyl)-2-methyl-oxazole-4-carboxylic acid.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[C:16]([O:17][CH3:18])=[CH:15][CH:14]=[C:13]([C:19]3[CH:20]=[C:21]4[C:25](=[CH:26][CH:27]=3)[C:24](=[O:28])[O:23][CH2:22]4)[C:7]=2[O:8][CH2:9][C:10]([OH:12])=O)[CH2:3][CH2:2]1.CCN=C=[N:33][CH2:34][CH2:35][CH2:36]N(C)C.Cl.C(N(CC)CC)C.C1C=CC2N(O)N=NC=2C=1.C(N)CC>ClCCl.O>[CH:1]1([CH2:4][O:5][C:6]2[C:16]([O:17][CH3:18])=[CH:15][CH:14]=[C:13]([C:19]3[CH:20]=[C:21]4[C:25](=[CH:26][CH:27]=3)[C:24](=[O:28])[O:23][CH2:22]4)[C:7]=2[O:8][CH2:9][C:10]([NH:33][CH2:34][CH2:35][CH3:36])=[O:12])[CH2:2][CH2:3]1
Reactant: COc1ccc(-c2ccc3c(c2)COC3=O)c(OCC(=O)O)c1OCC1CC1
Reactant: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCCN
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCNC(=O)COc1c(-c2ccc3c(c2)COC3=O)ccc(OC)c1OCC1CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 13.6 %

Procedure:
To a stirring solution of 2-(2-(cyclopropylmethoxy)-3-methoxy-6-(1-oxo-1,3-dihydroisobenzofuran-5-yl)phenoxy)acetic acid (200 mg, 0.519 mmol) in dichloromethane (20 mL) was added EDCI.HCl (150 mg, 0.779 mmol), triethylamine (156 mg, 1.55 mmol), HOBt (158 mg, 1.038 mmol) and propylamine (91 mg, 1.553 mmol) and the resultant reaction mixture was stirred at RT for 16 h. The reaction mixture was diluted with water and extracted with dichloromethane (3×). The combined dichloromethane layers were washed with brine, dried over sodium sulphate and concentrated under reduced pressure. Purification of the residue by flash column chromatography (silica gel, 5-40% ethyl acetate in pet ether) afforded the title compound as a solid (30 mg, 14%).
Reaction SMILES: IC1C=CC(C(Cl)=O)=CC=1.[CH3:11][O:12][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][C:22]=1[O:23][CH3:24])[N:19]=[CH:18][CH:17]=[C:16]2[O:25][C:26]1[CH:32]=[CH:31][C:29]([NH2:30])=[CH:28][C:27]=1[F:33].[I:34][C:35]1[CH:40]=[CH:39][C:38]([C:41]([N:43]=[C:44]=[S:45])=[O:42])=[CH:37][CH:36]=1>C1(C)C=CC=CC=1.C(O)C>[I:34][C:35]1[CH:36]=[CH:37][C:38]([C:41]([N:43]=[C:44]=[S:45])=[O:42])=[CH:39][CH:40]=1.[CH3:11][O:12][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][C:22]=1[O:23][CH3:24])[N:19]=[CH:18][CH:17]=[C:16]2[O:25][C:26]1[CH:32]=[CH:31][C:29]([NH:30][C:44]([NH:43][C:41](=[O:42])[C:38]2[CH:39]=[CH:40][C:35]([I:34])=[CH:36][CH:37]=2)=[S:45])=[CH:28][C:27]=1[F:33]
Reactant: COc1cc2nccc(Oc3ccc(N)cc3F)c2cc1OC
Agent: O=C(Cl)c1ccc(I)cc1
Agent: O=C(N=C=S)c1ccc(I)cc1
Solvent: Cc1ccccc1
Solvent: CCO
Product: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)c4ccc(I)cc4)cc3F)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 88 %

Procedure:
4-Iodo-1-benzenecarbonyl isothiocyanate was prepared using commercially available 4-iodo-1-benzenecarbonyl chloride (80 mg) as a starting compound according to the description of the literature. 4-[(6,7-Dimethoxy-4-quinolyl)oxy]-3-fluoroaniline (50 mg) was dissolved in toluene (5 ml) and ethanol (1 ml) to prepare a solution. A solution of 4-iodo-1-benzenecarbonyl isothiocyanate in ethanol (1 ml) was then added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (84 mg, yield 88%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:27])[NH:7][C@H:8]([C:10](=O)[NH:11][C:12]1[C:17]([NH:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:16][CH:15]=[CH:14][C:13]=1[Cl:25])[CH3:9])([CH3:4])([CH3:3])[CH3:2]>CC(O)=O>[C:1]([O:5][C:6](=[O:27])[NH:7][C@H:8]([C:10]1[N:18]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:17]2[CH:16]=[CH:15][CH:14]=[C:13]([Cl:25])[C:12]=2[N:11]=1)[CH3:9])([CH3:4])([CH3:3])[CH3:2]
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)Nc1c(Cl)cccc1Nc1ccccc1
Solvent: CC(=O)O
Product: C[C@H](NC(=O)OC(C)(C)C)c1nc2c(Cl)cccc2n1-c1ccccc1
Temperature: 25 °C
Yield: 93.6 %

Procedure:
A solution of [(S)-1-(2-chloro-6-phenylaminophenylcarbamoyl)ethyl]carbamic acid tertbutyl ester (1.58 g, 4.05 mmol) in AcOH (25 mL) was stirred for 18 h at 65° C. After cooling to RT, volatiles were evaporated under reduced pressure and the residue was partitioned between EtOAc and a saturated solution of NaHCO3. The aqueous phase was further extracted with EtOAc and the combined organic layers were washed with brine, then dried (Na2SO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, gradient 0-2% 2M NH3/MeOH in DCM) affording [(S)-1-(4-Chloro-1-phenyl-1H-benzoimidazol-2-yl)ethyl]carbamic acid tertbutyl ester as an off-white solid (1.41 g, 93%). LCMS: RT 3.90 min [M+H]+ 372.2.
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[N:9]([CH2:13][C:14]2[CH:19]=[C:18]([Cl:20])[CH:17]=[C:16]([Cl:21])[CH:15]=2)[CH:10]=[CH:11][N:12]=1)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[F:25][C:26]1[CH:33]=[CH:32][C:29]([CH2:30]Br)=[CH:28][CH:27]=1>CN(C=O)C>[C:1]([O:5][C:6](=[O:22])[N:7]([C:8]1[N:9]([CH2:13][C:14]2[CH:19]=[C:18]([Cl:20])[CH:17]=[C:16]([Cl:21])[CH:15]=2)[CH:10]=[CH:11][N:12]=1)[CH2:30][C:29]1[CH:32]=[CH:33][C:26]([F:25])=[CH:27][CH:28]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1nccn1Cc1cc(Cl)cc(Cl)c1
Reactant: Fc1ccc(CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N(Cc1ccc(F)cc1)c1nccn1Cc1cc(Cl)cc(Cl)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 76 %

Procedure:
[1-(3,5-Dichloro-benzyl)-1H-imidazol-2-yl]-carbamic acid tert-butyl ester was dissolved in anhydrous DMF and NaH was added. The mixture was stirred at room temperature for 10 min and 4-fluorobenzyl bromide was added. The reaction mixture was stirred at room temperature for another 1 h. The reaction was quenched with water and extracted with EtOAc (×3). The combined organic phase was dried over Na2SO4 and concentrated. The resulting residue was purified by silica gel preparative TLC using CH2Cl2:MeOH 95:5 as an eluent to afford [1-(3,5-dichloro-benzyl)-1H-imidazol-2-yl]-(4-fluoro-benzyl)-carbamic acid tert-butyl ester (50 mg, 76%); LCMS m/z 450 [C22H22Cl2FN3O2+H]+.
Reaction SMILES: [O:1]=[S:2]1(=[O:19])[CH2:6][CH2:5][CH2:4][N:3]1[C:7]([C:10]1[CH:18]=[CH:17][C:13]([C:14]([OH:16])=O)=[CH:12][CH:11]=1)([CH3:9])[CH3:8].[CH3:20][C:21]1[C:22]([N:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)=[N:23][CH:24]=[C:25]([CH:28]=1)[C:26]#[N:27]>>[O:19]=[S:2]1(=[O:1])[CH2:6][CH2:5][CH2:4][N:3]1[C:7]([C:10]1[CH:11]=[CH:12][C:13]([C:14]([N:32]2[CH2:33][CH2:34][N:29]([C:22]3[C:21]([CH3:20])=[CH:28][C:25]([C:26]#[N:27])=[CH:24][N:23]=3)[CH2:30][CH2:31]2)=[O:16])=[CH:17][CH:18]=1)([CH3:8])[CH3:9]
Reactant: CC(C)(c1ccc(C(=O)O)cc1)N1CCCS1(=O)=O
Reactant: Cc1cc(C#N)cnc1N1CCNCC1
Product: Cc1cc(C#N)cnc1N1CCN(C(=O)c2ccc(C(C)(C)N3CCCS3(=O)=O)cc2)CC1
Yield: 86.5 %

Procedure:
Using 4-[1-(1,1-dioxo-1λ6-isothiazolidin-2-yl)-1-methylethyl]benzoic acid (100 mg) described in Preparation Example 39 and 5-methyl-6-(piperazin-1-yl)nicotinonitrile (71 mg) described in Preparation Example 103 and by the reaction and treatment in the same manner as in Example 87, the title compound (142 mg) was obtained.
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([NH2:13])=[C:9]([C:14]#[N:15])[CH:8]=2)[N:6]=1.[OH2:16]>>[CH3:1][C:2]1[NH:3][CH:4]=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([NH2:13])=[C:9]([C:14](=[O:16])[NH2:15])[CH:8]=2)[N:6]=1
Reactant: Cc1nc(-c2ccc(N)c(C#N)c2)c[nH]1
Reactant: O
Product: Cc1nc(-c2ccc(N)c(C(N)=O)c2)c[nH]1

Procedure:
A mixture of 2-methyl-4-(3-cyano-4-amino-phenyl)-1H-imidazole (6.2 g), the ion exchanger Amerlite® IRA 400 (OH) (12 g) and water (150 ml) was refluxed for 5 hours. After cooling and filtration, the resulting solution was evaporated to dryness to give 4.1 g of the title compound.