Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([Cl:21])[C:6]2[N:7]([C:9]([CH2:19]Cl)=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=3)[N:11]=2)[CH:8]=1.[CH3:22][C:23]1[CH:24]=[CH:25][C:26](=[O:29])[NH:27][N:28]=1>>[Cl:2][C:3]1[CH:4]=[C:5]([Cl:21])[C:6]2[N:7]([C:9]([CH2:19][N:27]3[C:26](=[O:29])[CH:25]=[CH:24][C:23]([CH3:22])=[N:28]3)=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=3)[N:11]=2)[CH:8]=1
Reactant: Cc1ccc(-c2nc3c(Cl)cc(Cl)cn3c2CCl)cc1
Reactant: Cc1ccc(=O)[nH]n1
Agent: Cl
Product: Cc1ccc(-c2nc3c(Cl)cc(Cl)cn3c2Cn2nc(C)ccc2=O)cc1

Procedure:
The title compound was prepared according to Method B and the experimentals described for compound 91 from 6,8-dichloro-3-(chloromethyl)-2-p-tolylimidazo[1,2-a]pyridine hydrochloride and 6-methylpyridazin-3(2H)-one. m/e+ 399 for C20H17Cl2N4O [M+H]+; 1H-NMR (300 MHz, CDCl3) δ 8.72 (d, J=1.8 Hz, 1H), 8.01 (d, J=8.1 Hz, 2H), 7.30 (m, 3H), 7.10 (d, J=9.3 Hz, 1H), 6.96 (d, J=9.3 Hz, 1H), 5.70 (s, 2H), 2.43 (s, 3H), 2.29 (s, 3H) ppm.
Reaction SMILES: [F:1][C:2]1[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][C:8]([S:11]([CH3:14])(=[O:13])=[O:12])=[CH:7][C:6]=1[N+:15]([O-])=O.[H][H]>O1CCCC1.[Pd]>[F:1][C:2]1[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][C:8]([S:11]([CH3:14])(=[O:13])=[O:12])=[CH:7][C:6]=1[NH2:15]
Reactant: CS(=O)(=O)c1ccc(Oc2ccc(F)cc2F)c([N+](=O)[O-])c1
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Product: CS(=O)(=O)c1ccc(Oc2ccc(F)cc2F)c(N)c1
Yield: 94.5 %

Procedure:
A solution of Example 252a (10.0 g, 30.4 mmol) in tetrahydrofuran (150 mL) was added to 10% Pd/C (1.616 g, 15.18 mmol) in a 250 mL bottle and the mixture was stirred for 24 hour under a 30 psi hydrogen atmosphere at 40° C. The mixture was filtered through a nylon membrane and concentrated. The residue was purified flash chromatography (silica gel, 70:30 ethyl acetate/hexanes) to provide the title compound (8.6 g, 55% yield).
Reaction SMILES: [C:1]1([C:7]2[NH:8][C:9]([C:18]3[CH:23]=[CH:22][C:21]([C:24]([OH:26])=O)=[CH:20][CH:19]=3)=[CH:10][C:11]=2[C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CN([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.[F:47][P-](F)(F)(F)(F)F.[NH2:54][CH2:55][C:56]1[CH:61]=[CH:60][CH:59]=[CH:58][N:57]=1.C(N(CC)CC)C>CN(C=O)C>[F:47][C:4]1[CH:5]=[CH:6][C:1]([C:7]2[NH:8][C:9]([C:18]3[CH:23]=[CH:22][C:21]([C:24]([NH:54][CH2:55][C:56]4[CH:61]=[CH:60][CH:59]=[CH:58][N:57]=4)=[O:26])=[CH:20][CH:19]=3)=[CH:10][C:11]=2[C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)=[CH:2][CH:3]=1
Reactant: O=C(O)c1ccc(-c2cc(-c3ccncc3)c(-c3ccccc3)[nH]2)cc1
Reactant: F[P-](F)(F)(F)(F)F
Reactant: NCc1ccccn1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(NCc1ccccn1)c1ccc(-c2cc(-c3ccncc3)c(-c3ccc(F)cc3)[nH]2)cc1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a solution of 42 mg (0.124 mmol) 2-phenyl-3-(4-pyridyl)-5-[(4-carboxy)phenyl]-1H-pyrrole (prepared according to Example 51) in 800 uL DMF was added 1.5 equivalents BOP reagent (benzotriazol-1-yloxy-tris-(dimethylamino)phosphonium hexafluorophosphate), 1.2 equivalents 2-(aminomethyl)pyridine, and 2.5 equivalents triethylamine. The mixture was stirred at room temperature for 15 hours. The reaction was quenched by the addition of 5% NaHCO3 solution and ethyl acetate (EtOAc). After separation of phases, the aqueous phase was re-extracted with EtOAc. The combined organic layers were washed with 5% NaHCO3 solution, water, brine, and dried over Na2SO4. After filtration and concentration of the filtrate in vacuo, the crude product was flash chromatographed (gradient elution with 1.0%-5.0% MeOH/CH2Cl2) to the desired product as a cream-colored solid, homogeneous by TLC. FAB ms: Calc.: 430 for C28 H22N4O; Obs.: 431 (M+ +1).
Reaction SMILES: N[C:2]1[CH:3]=[CH:4][C:5]([C:8]([O:10][CH3:11])=[O:9])=[N:6][CH:7]=1.N(OCCCC)=O.CCOCC.[F:24][B-](F)(F)F.[H+]>C(O)C>[F:24][C:2]1[CH:3]=[CH:4][C:5]([C:8]([O:10][CH3:11])=[O:9])=[N:6][CH:7]=1
Reactant: F[B-](F)(F)F
Reactant: COC(=O)c1ccc(N)cn1
Agent: CCCCON=O
Agent: [H+]
Solvent: CCO
Solvent: CCOCC
Product: COC(=O)c1ccc(F)cn1
Temperature: -3 °C

Procedure:
The methyl 5-aminopicolinate (2.2 g) is dissolved in 5.5 ml 48% fluoroboric acid and 20 ml 95% ethanol. This mixture is cooled, with stirring, to -3° C. and then 1.81 g n-butyl nitrite added dropwise. After a further one-half hour at -3° C., 0.5 ml n-butyl nitrite is added slowly and stirring continued for one-half hour at 0° C. After adding 20 ml ether carefully, the mixture is rapidly filtered, and the solid washed twice with cold hexane. The solid is suspended in 100 ml heptane, and the suspension slowly heated with stirring. At about 60° C., a vigorous exothermic reaction occurs. Heating is then continued to 80° C. A red oil separates on the sides of the flask. The heptane solution is filtered, and the filtrate concentrated to give the desired product. The red oil is dissolved in water, excess sodium bicarbonate solution added, and the solution extracted with ethyl acetate. The ethyl acetate extract is washed with saturated brine, dried and concentrated. The residue is chromatographed on silica gel and the product, methyl 5-fluoropicolinate, eluted with 1:1-ether:hexane. This material is used directly for the preparation of the picolinic acid.
Reaction SMILES: [O:1]=[C:2]1[NH:10][C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[N:3]1[CH:11]1[CH2:16][CH2:15][N:14](C(OCC2C=CC=CC=2)=O)[CH2:13][CH2:12]1.[H][H]>CO.[Pd]>[NH:14]1[CH2:13][CH2:12][CH:11]([N:3]2[C:4]3[C:5](=[N:6][CH:7]=[CH:8][CH:9]=3)[NH:10][C:2]2=[O:1])[CH2:16][CH2:15]1
Reactant: O=C(OCc1ccccc1)N1CCC(n2c(=O)[nH]c3ncccc32)CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: O=c1[nH]c2ncccc2n1C1CCNCC1

Procedure:
690 g (1.96 mol) benzyl 4-(2-oxo-2,3-dihydro-imidazo[4,5-b]pyridin-1-yl)-piperidine-1-carboxylate were dissolved in 5.4 L methanol and hydrogenated with the addition of 46 g Pd/C (10%; 6.6 wt. %) at 60° C. under a hydrogen pressure of 60 psi until all the hydrogen had been taken up. The catalyst was filtered off. 4 L methanol were distilled off from the filtrate. 2 L of methylcyclohexane were added and a further 1.5 L solvent were distilled off. The suspension thus obtained was suction filtered, the residue was washed with methylcyclohexane and dried at 40° C.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[N:19]([CH3:20])[N:18]=[C:17]([O:21][CH2:22][CH2:23][O:24][CH2:25][CH3:26])[C:16]=2[C:27]2[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C[OH:35]>>[CH2:25]([O:24][CH2:23][CH2:22][O:21][C:17]1[C:16]([C:27]2[CH:28]=[CH:29][C:30]([CH3:33])=[CH:31][CH:32]=2)=[C:15]([NH:14][S:11]([C:8]2[CH:7]=[CH:6][C:5]([C:1]([CH3:4])([CH3:2])[CH2:3][OH:35])=[CH:10][CH:9]=2)(=[O:12])=[O:13])[N:19]([CH3:20])[N:18]=1)[CH3:26]
Reactant: CCOCCOc1nn(C)c(NS(=O)(=O)c2ccc(C(C)(C)C)cc2)c1-c1ccc(C)cc1
Reactant: CO
Product: CCOCCOc1nn(C)c(NS(=O)(=O)c2ccc(C(C)(C)CO)cc2)c1-c1ccc(C)cc1
Reaction time: 48 h

Procedure:
Amycolata autotrophica ATCC35203 maintained on a quarter strength ATCC172 agar slope was inoculated as a loopful of spores into five 300 ml Erlenmeyer flasks each containing 50 ml of MY inoculum medium. This was allowed to incubate for 2 days at 28° C., 200 rpm on an Infors Multitron™ Shaker with 1″ throw. Two mls of this inoculum was then transferred to each of sixty 300 ml Erlenmeyer flask containing 50 ml of MY production medium and incubated under the same conditions for a further 24 hours. At this point 20 mg of 4-(tert-butyl)-N-[3-(2-ethoxyethoxy)-1-methyl-4-(4-methylphenyl)-1H-pyrazol-5-yl]benzenesulfonamide (Preparation 8) dissolved in 0.5 ml of methanol was added to each of the flasks and the fermentation allowed to continue under the same conditions for a further 6 hours. Each flask was then extracted with 200 mls of ethyl acetate and the combined ethyl acetate solubles concentrated to dryness to give a gum solid, 2.0 g.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])=[CH:4][C:3]=1[CH3:16].CCN(CC)CC.[C:24]1([N:30]=[C:31]=[O:32])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C1COCC1>[CH3:16][C:3]1[CH:4]=[C:5]([CH2:8][C:9]([O:11][C:12]([CH3:13])([CH3:15])[CH3:14])=[O:10])[CH:6]=[CH:7][C:2]=1[NH:1][C:31]([NH:30][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:32]
Reactant: O=C=Nc1ccccc1
Reactant: Cc1cc(CC(=O)OC(C)(C)C)ccc1N
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1cc(CC(=O)OC(C)(C)C)ccc1NC(=O)Nc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 60.7 %

Procedure:
To a stirred solution of tert-butyl 4-amino-3-methylphenylacetate (1.20 g, 5.42 mmol) and Et3N (830 ml, 5.95 mmol) in THF (10 ml) was added phenyl isocyanate (650 ml, 5.98 mmol) and the reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated to a small volume and diluted with n-hexane. Resulting precipitate was collected under a reduced pressure and the filtrate was washed with n-hexane to give tert-butyl 3-methyl4-(N′-phenylureido)phenylacetate (1.12 g, 61%) as a white crystalline powder. mp 143–145° C.; 1H-NMR (CDCl3) δ 1.47 (s, 9 H), 2.09 (s, 3 H), 3.47 (s, 2 H), 6.44 (s, 1 H), 7.01–7.07 (m, 4 H), 7.16–7.27 (m, 2 H), 7.30–7.33 (m, 2 H), 7.45–7.47 (m, 1 H).
Reaction SMILES: Cl.[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][C:8]=2[C:14]2[CH:19]=[CH:18][N:17]=[C:16]3[C:20]([C:24]([NH:26][CH:27]4[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]4)=[O:25])=[C:21]([CH3:23])[NH:22][C:15]=23)[CH2:4][CH2:3]1.C([O:36][CH2:37][C:38](Cl)=[O:39])(=O)C>>[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][C:8]=2[C:14]2[CH:19]=[CH:18][N:17]=[C:16]3[C:20]([C:24]([NH:26][CH:27]4[CH2:28][CH2:29][N:30]([C:37](=[O:36])[CH2:38][OH:39])[CH2:31][CH2:32]4)=[O:25])=[C:21]([CH3:23])[NH:22][C:15]=23)[CH2:4][CH2:3]1
Reactant: Cc1ccc(OCC2CC2)c(-c2ccnc3c(C(=O)NC4CCNCC4)c(C)[nH]c23)c1
Reactant: CC(=O)OCC(=O)Cl
Agent: Cl
Product: Cc1ccc(OCC2CC2)c(-c2ccnc3c(C(=O)NC4CCN(C(=O)CO)CC4)c(C)[nH]c23)c1

Procedure:
Starting from 7-[2-(cyclopropylmethoxy)-5-methylphenyl]-2-methyl-N-(piperidin-4-yl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide hydrochloride (example D.f18) and commercially available 2-chloro-2-oxoethyl acetate the title compound is obtained as colorless solid.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[F:7][B-:8]([F:11])([F:10])[F:9].[CH:12](=[N:19][N+:20]1[CH:24]=[CH:23][N:22]([N:25]=[CH:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:21]=1SC)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.CS.C(OCC)C>CN(C)C=O>[F:7][B-:8]([F:11])([F:10])[F:9].[CH:12](=[N:19][N+:20]1[CH:24]=[CH:23][N:22]([N:25]=[CH:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:21]=1[N:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: CSc1n(N=Cc2ccccc2)cc[n+]1N=Cc1ccccc1
Reactant: C1COCCN1
Agent: CS
Agent: F[B-](F)(F)F
Solvent: CCOCC
Solvent: CN(C)C=O
Product: C(=Nn1cc[n+](N=Cc2ccccc2)c1N1CCOCC1)c1ccccc1

Procedure:
1.45 g of absolute morpholine are added under an argon atmosphere to 4.1 g of 1,3-bis-(benzylideneamino)-2-(methylthio)imidazolium tetrafluoroborate in 15 ml of absolute dimethylformamide, whereby the evolution of methyl mercaptan occurs immediately and a yellow-orange solution results. The solution is stirred at room temperature until the cleavage of methyl mercaptan is complete (about 12 hours). Then the solution is treated with 120 ml of diethyl ether and the resulting, slightly yellowish precipitate is removed by filtration under suction. The precipitate is washed five times with diethyl ether, and twice with a small amount of cold ethanol and re-precipitated from acetonitrile/diethyl ether. There is obtained colorless 1,3-bis(benzylideneamino)-2-morpholinoimidazolium tetrafluoroborate of melting point 242°-245° (decomposition).
Reaction SMILES: [CH:1]([C:4]1[C:5](=[O:21])[NH:6][C:7](=[O:20])[NH:8][C:9]=1[C:10](=[O:19])[C:11]1[CH:16]=[C:15]([CH3:17])[CH:14]=[C:13]([CH3:18])[CH:12]=1)([CH3:3])[CH3:2].[CH3:22][C:23]1[CH:24]=[C:25]([CH:28]=[C:29]([CH3:31])[CH:30]=1)[CH2:26]Br>>[CH3:22][C:23]1[CH:30]=[C:29]([CH:28]=[C:25]([CH3:26])[CH:24]=1)[CH2:31][N:8]1[C:9]([C:10](=[O:19])[C:11]2[CH:12]=[C:13]([CH3:18])[CH:14]=[C:15]([CH3:17])[CH:16]=2)=[C:4]([CH:1]([CH3:3])[CH3:2])[C:5](=[O:21])[NH:6][C:7]1=[O:20]
Reactant: Cc1cc(C)cc(CBr)c1
Reactant: Cc1cc(C)cc(C(=O)c2[nH]c(=O)[nH]c(=O)c2C(C)C)c1
Product: Cc1cc(C)cc(Cn2c(C(=O)c3cc(C)cc(C)c3)c(C(C)C)c(=O)[nH]c2=O)c1
Yield: 79.5 %

Procedure:
5-Isopropyl-6-(3,5-dimethylbenzoyl)-2,4-pyrimidinedione and 3,5-dimethylbenzyl bromide were reacted by the same way with the example 1 to obtain the titled compound (322 mg, yield: 79.5%).
Reaction SMILES: [C:1]1([C:7]2[O:11][CH:10]=[N:9][C:8]=2[C:12]([OH:14])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[F:16][C:17]1[CH:30]=[CH:29][C:20]([C:21]([CH:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)=[O:22])=[CH:19][CH:18]=1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C>CN(C)C=O>[F:16][C:17]1[CH:30]=[CH:29][C:20]([C:21]([CH:23]2[CH2:28][CH2:27][N:26]([C:12]([C:8]3[N:9]=[CH:10][O:11][C:7]=3[C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[O:14])[CH2:25][CH2:24]2)=[O:22])=[CH:19][CH:18]=1
Reactant: O=C(c1ccc(F)cc1)C1CCNCC1
Reactant: O=C(O)c1ncoc1-c1ccccc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(c1ccc(F)cc1)C1CCN(C(=O)c2ncoc2-c2ccccc2)CC1
Temperature: 25 °C

Procedure:
5-Phenyl-1,3-oxazole-4-carboxylic acid (40 mg, 0.211 mmol), 4-(4-Fluorobenzoyl)piperidine hydrochloride (56.2 mg, 0.215 mmol), O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (86.2 mg, 0.268 mmol) and diisopropylethylamine (25.4 mg, 0.197 mmol) were mixed in dimethylformamide (1.0 mL) and stirred at room temperature. Solvent was evaporated in vacuo, and the residue was taken up in methanol (1 mL), filtered and purified by preparative chromatography. The combined fractions were partitioned between NaHCO3 (sat) and ethylacetate. The organic layer was washed with water and concentrated in vacuo to afford the title compound. HRMS (ESI, pos. ion) m/z calcd for C22H19FN2O3: 378.1380, found 378.1384.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([CH2:10]Br)=[N:7][C:6]=2[CH:12]=1.[F:13][C:14]1[C:22]([OH:23])=[CH:21][CH:20]=[C:19]([F:24])[C:15]=1[C:16]([NH2:18])=[O:17].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([CH2:10][O:23][C:22]3[C:14]([F:13])=[C:15]([C:19]([F:24])=[CH:20][CH:21]=3)[C:16]([NH2:18])=[O:17])=[N:7][C:6]=2[CH:12]=1
Reactant: BrCc1nc2cc(Br)ccc2s1
Reactant: NC(=O)c1c(F)ccc(O)c1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: NC(=O)c1c(F)ccc(OCc2nc3cc(Br)ccc3s2)c1F
Temperature: 25 °C
Reaction time: 24 h
Yield: 769.7 %

Procedure:
To a solution of 5-bromo-2-bromomethyl-benzothiazole (1.1 g, 0.358 mmol) in 5 ml of anhydrous DMF was added 2,6-difluoro-3-hydroxybenzamide (0.620 g, 0.22 mol) and potassium carbonate (1.73 g, 1.25 mmol). The reaction mixture was stirred at 25° C. for 24 h under nitrogen atmosphere. Water was added to the reaction mixture the compound was precipitated out, filtered and washed with diethylether to give the title compound as yellow solid (1.1 g, 76%). 1H NMR (DMSO-d6, 400 MHz): δ 5.71 (s, 2H), 7.11 (dt, 1H J=8.8 Hz (o-coupling), 7.38-7.39 (m, 1H), 7.65 (d, 1H, J=8.8 Hz (o-coupling), 7.90 (broad s, 1H), 8.13 (d, 1H, J=8.8 Hz (o-coupling), 8.18 (s, 1H), 8.26 (broad s, 1H). MS ES+ (400.9), HPLC (method 5) Rt=16.57 min.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9][S:10]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])/[C:16]/2=[CH:23]\[C:24]1[NH:28][C:27]([CH3:29])=[C:26]([CH2:30][C:31]([OH:33])=O)[C:25]=1[CH3:34])(=[O:12])=[O:11].[CH:35]1[CH:36]=[CH:37][C:38]2[N:43](O)N=[N:41][C:39]=2C=1.CCN=C=NCCCN(C)C.N1CCCC1C[C@H:62]1C[CH2:65][C@@H:64]([OH:67])[CH2:63]1>CN(C=O)C.C(Cl)Cl>[Cl:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[CH2:9][S:10]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])/[C:16]/2=[CH:23]\[C:24]1[NH:28][C:27]([CH3:29])=[C:26]([CH2:30][C:31]([N:43]2[CH2:35][CH2:36][CH2:37][C@@H:38]2[CH2:39][N:41]2[CH2:62][CH2:63][C@@H:64]([OH:67])[CH2:65]2)=[O:33])[C:25]=1[CH3:34])(=[O:12])=[O:11]
Reactant: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(Cl)cccc4Cl)cc32)c(C)c1CC(=O)O
Reactant: On1nnc2ccccc21
Reactant: O[C@@H]1CC[C@H](CC2CCCN2)C1
Agent: CCN=C=NCCCN(C)C
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(Cl)cccc4Cl)cc32)c(C)c1CC(=O)N1CCC[C@@H]1CN1CC[C@@H](O)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of {5-[5-(2,6-dichloro-phenylmethanesulfonyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrol-3-yl}-acetic acid (200 mg), HOBt (1 eq.), EDAC (2 eq.), TEA (3 eq.) and (R)-3-(R)-1-pyrrolidin-2-ylmethyl-cyclopentanol (3 eq.) in DMF (4 mL) was stirred at rt for overnight. The reaction was diluted with DCM, washed with water (2×) and 10% sodium carbonate (2×). The DCM was dried, concentrated and purified on a silica gel column to give 21 mg of the titled compound. MS m/z 671 [M++1].
Reaction SMILES: Cl.[CH2:2]([N:9]1[CH2:14][CH2:13][C:12](=O)[CH:11]([C:16]([O:18]CC)=O)[CH2:10]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(O)(=O)C.[CH:25]([NH2:27])=[NH:26].C[O-].[Na+]>CO>[CH2:2]([N:9]1[CH2:14][CH2:13][C:12]2[N:26]=[CH:25][NH:27][C:16](=[O:18])[C:11]=2[CH2:10]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CCOC(=O)C1CN(Cc2ccccc2)CCC1=O
Reactant: N=CN
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: O=c1[nH]cnc2c1CN(Cc1ccccc1)CC2
Temperature: 85 °C
Yield: 64.6 %

Procedure:
A mixture of ethyl 1-benzyl-4-oxopiperidine-3-carboxylate hydrochloride (50.0 g, 0.168 mol), formamidine acetate (16.2 g, 0.201 mol), 4.37 M of sodium methoxide in methanol (190 mL) and methanol (200 mL) was heated at 85° C. for 16 hour in a 350 mL sealed reaction vessel. The mixture was allowed to cool and concentrated in vacuo. The residue was dissolved in 1N NaOH (150 mL) and poured over ice. Glacial acetic acid was added to the mixture until the pH of the mixture was 7 and a tan solid precipitated out. The solid was filtered, washed with water and cold ether, and dried on high vacuum to yield the title compound as a tan solid (26.2 g, 61.4%).
Reaction SMILES: [F:1][C:2]([F:7])([CH2:5][OH:6])[CH2:3][OH:4].FC1C=CC(B(O)O)=CC=1.C([O-])([O-])=O.[K+].[K+].[CH2:24](Br)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>CN(C=O)C.C(OCC)(=O)C>[CH2:24]([O:4][CH2:3][C:2]([F:7])([F:1])[CH2:5][OH:6])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: BrCc1ccccc1
Reactant: OCC(F)(F)CO
Agent: O=C([O-])[O-]
Agent: OB(O)c1ccc(F)cc1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: OCC(F)(F)COCc1ccccc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 46.2 %

Procedure:
A suspension of 2,2-difluoropropane-1,3-diol (Compound 59I, 6.0 g, 53.5 mmol), 4-fluorophenylboronic acid (1.5 g, 10.7 mmol) and K2CO3 (11.0 g, 80.3 mmol) in DMF (50 mL) was treated with benzyl bromide (8.9 mL, 74.9 mmol). The reaction mixture was stirred at RT for 72 h, diluted with ethyl acetate (200 mL) and washed with water (5×100 mL). The organic layer was dried over Na2SO4, filtered and concentrated to give yellow oil which was purified by column chromatography (SiO2, 20% ethyl acetate/hexanes) to give 5 g (50%) of the desired product as an oil. 1H NMR (500 MHz, CDCl3) δ 7.38-7.34 (m, 5H), 4.70 (s, 2H), 3.89-3.88 (m, 2H), 3.77 (t, J=12.6 Hz, 2H).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][C:13](=[O:15])[N:12]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[CH:17]=3)[C:11]([CH3:26])=[C:10]2[C:27]([OH:29])=[O:28])=[CH:5][CH:4]=1)#[N:2].C1N=CN(C(N2C=NC=C2)=O)C=1.O[CH2:43][CH2:44][N:45]1[CH2:49][CH2:48][CH2:47][CH2:46]1.C(N(CC)CC)C>CN(C)C=O.O>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([CH:9]2[CH2:14][C:13](=[O:15])[N:12]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:24])([F:25])[F:23])[CH:17]=3)[C:11]([CH3:26])=[C:10]2[C:27]([O:29][CH2:43][CH2:44][N:45]2[CH2:49][CH2:48][CH2:47][CH2:46]2)=[O:28])=[CH:7][CH:8]=1)#[N:2]
Reactant: CC1=C(C(=O)O)C(c2ccc(C#N)cc2)CC(=O)N1c1cccc(C(F)(F)F)c1
Reactant: OCCN1CCCC1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: CC1=C(C(=O)OCCN2CCCC2)C(c2ccc(C#N)cc2)CC(=O)N1c1cccc(C(F)(F)F)c1
Temperature: 100 °C
Reaction time: 1 h

Procedure:
To a solution of 40 mg (0.1 mmol) of the compound of Example 47 in 0.3 ml dry dimethylformamide are added 48.6 mg (0.3 mmol) N,N-carbonyldiimidazole. After allowing the reaction mixture to stand for one hour, the reaction mixture is diluted with water and extracted with ethyl acetate. After drying with magnesium sulfate, the solvent is evaporated off in vacuo. To the residue are added 0.5 ml (492 mg, 4.28 mmol) 1-(2-hydroxyethyl)pyrrolidin and 10 μl (0.07 mmol) triethylamine. The reaction mixture is stirred at 100° C. for one hour. Then the reaction mixture is filtered and purified by preparative HPLC (column: Nucleosil 100-5 C 18 Nautilus 20 mm×50 mm, 5 μm; solvent A: acetonitrile, solvent B: water+0.1% formic acid; gradient: 0 min 10% A, 2 min 10% A, 6 min 90% A, 7 min 90% A, 7.1 min 10% A, 8 min 10% A; wavelength: 220 nm; injection volume: approx. 550 μl; number of injections: 1). The product containing fractions are combined and concentrated in vacuo.
Reaction SMILES: CO[C:3]1[CH2:4][CH2:5][CH2:6][CH:7]([C:10]([F:13])([F:12])[F:11])[CH2:8][N:9]=1.[Cl-:14].[NH4+:15]>CO>[ClH:14].[F:11][C:10]([F:13])([F:12])[CH:7]1[CH2:8][NH:9][C:3](=[NH:15])[CH2:4][CH2:5][CH2:6]1
Reactant: [NH4+]
Reactant: [Cl-]
Reactant: COC1=NCC(C(F)(F)F)CCC1
Solvent: CO
Product: Cl
Product: N=C1CCCC(C(F)(F)F)CN1
Yield: 98.2 %

Procedure:
The product of EXAMPLE 52 (77 mg, 0.39 mmol) in 3.0 mL of MeOH was reacted with ammonium chloride (21.0 mg, 0.39 mmol) by the method of EXAMPLE 27 to yield 83 mg (94%) of the title material.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:10]([C:12]1[C:17]([N:18]2[N:22]=[CH:21][CH:20]=[N:19]2)=[CH:16][CH:15]=[C:14]([CH3:23])[N:13]=1)=[O:11].Cl[C:25]1[CH:32]=[CH:31][C:28]([C:29]#[N:30])=[CH:27][N:26]=1>>[CH3:9][C@@H:8]1[CH2:7][CH2:6][CH2:5][N:4]([C:10](=[O:11])[C:12]2[C:17]([N:18]3[N:22]=[CH:21][CH:20]=[N:19]3)=[CH:16][CH:15]=[C:14]([CH3:23])[N:13]=2)[C@@H:3]1[CH2:2][NH:1][C:25]1[CH:32]=[CH:31][C:28]([C:29]#[N:30])=[CH:27][N:26]=1
Reactant: N#Cc1ccc(Cl)nc1
Reactant: Cc1ccc(-n2nccn2)c(C(=O)N2CCC[C@@H](C)[C@H]2CN)n1
Product: Cc1ccc(-n2nccn2)c(C(=O)N2CCC[C@@H](C)[C@H]2CNc2ccc(C#N)cn2)n1

Procedure:
The title compound was prepared following the same general protocol as described for Example A1, using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-1-yl)(6-methyl-3-(2H-1,2,3-triazol-2-yl)pyridin-2-yl)methanone and 6-chloronicotinonitrile. ESI-MS (m/z): 417 [M+1]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11]1[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=1)[N:6]=[C:5]2[CH:21]1[CH2:26][CH2:25][N:24](C)[CH2:23][CH2:22]1.[Cl:28]C(OC(Cl)=O)C>ClCCCl>[ClH:28].[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11]1[CH:12]=[CH:13][C:14]([C:17]([F:18])([F:19])[F:20])=[CH:15][CH:16]=1)[N:6]=[C:5]2[CH:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1
Reactant: CN1CCC(c2nn(-c3ccc(C(F)(F)F)cc3)c3ccc(F)cc23)CC1
Reactant: CC(Cl)OC(=O)Cl
Solvent: ClCCCl
Product: Cl
Product: Fc1ccc2c(c1)c(C1CCNCC1)nn2-c1ccc(C(F)(F)F)cc1
Reaction time: 0.25 h
Yield: 45 %

Procedure:
To a solution of 5-fluoro-1-[4-(trifluoromethyl)phenyl]-3-(1-methyl-4-piperidinyl)-1H-indazole (13.2 g, 0.035 moles) in 1,2-dichloroethane (35 ml) at 0° C. was added 1-chloroethylchloroformate (3.9 ml. 0.035 moles). The reaction was stirred for 15 minutes at 0° and then for 4 hours at ambient temperature. The solvent was removed and then methanol (90 ml) was added. The mixture was refluxed for 1 hour and then the methanol was removed which left 17.8 g of a solid. The product was recrystallized twice from isopropyl alcohol to yield 6.3 g (45%) of 5-fluoro-1-[4-(trifluoromethyl)phenyl]-3-(4-piperidinyl)-1H-indazole hydrochloride, mp 276°-278°.