Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([O:29][CH:30]2[CH2:34][CH2:33][CH2:32][CH2:31]2)[C:5]2[C:10]([C:11]3[CH:20]=[CH:19][C:14]4[N:15]=[C:16]([CH3:18])[O:17][C:13]=4[CH:12]=3)=[CH:9][N:8]([CH2:21][O:22][CH2:23][CH2:24][Si:25]([CH3:28])([CH3:27])[CH3:26])[C:6]=2[N:7]=1.[NH2:35][C:36]1[CH:41]=[CH:40][C:39]([C:42]([N:44]2[CH2:46][CH2:45]2)=[O:43])=[CH:38][C:37]=1[O:47][CH3:48].C(=O)([O-])[O-].[Cs+].[Cs+].C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[N:44]1([C:42]([C:39]2[CH:40]=[CH:41][C:36]([NH:35][C:2]3[N:3]=[C:4]([O:29][CH:30]4[CH2:34][CH2:33][CH2:32][CH2:31]4)[C:5]4[C:10]([C:11]5[CH:20]=[CH:19][C:14]6[N:15]=[C:16]([CH3:18])[O:17][C:13]=6[CH:12]=5)=[CH:9][N:8]([CH2:21][O:22][CH2:23][CH2:24][Si:25]([CH3:28])([CH3:26])[CH3:27])[C:6]=4[N:7]=3)=[C:37]([O:47][CH3:48])[CH:38]=2)=[O:43])[CH2:46][CH2:45]1
Reactant: Cc1nc2ccc(-c3cn(COCC[Si](C)(C)C)c4nc(Cl)nc(OC5CCCC5)c34)cc2o1
Reactant: COc1cc(C(=O)N2CC2)ccc1N
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: COc1cc(C(=O)N2CC2)ccc1Nc1nc(OC2CCCC2)c2c(-c3ccc4nc(C)oc4c3)cn(COCC[Si](C)(C)C)c2n1
Temperature: 100 °C
Reaction time: 2 h

Procedure:
To a degassed mixture of 6-(2-chloro-4-(cyclopentyloxy)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-methylbenzo[d]oxazole (1 equiv), (4-amino-3-methoxyphenyl)(aziridin-1-yl)methanone (1.2 equiv) and cesium carbonate (3 equiv) in 1,4-dioxane (0.1 M) was added palladium acetate (0.2 equiv) and 2,2′-bis-diphenylphosphanyl-[1,1′]binaphthalenyl (0.2 equiv). The reaction was stirred at 100° C. for 2 h. The reaction mixture was concentrated and the residue was purified by silica gel chromatography (0-10% DCM in MeOH) to afford the title compound (crude) as a yellow solid. The material was used in next step without further purification. MS (ESI) m/z 655.1 [M+1]+.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[NH:13][C:6]2=[N:7][CH:8]=[C:9]([CH2:11][NH2:12])[CH:10]=[C:5]2[CH:4]=1.Cl[C:17]1[CH:22]=[C:21]([CH:23]([CH3:25])[CH3:24])[N:20]=[CH:19][N:18]=1.CCN(C(C)C)C(C)C>CN1CCCC1=O.C(OCC)(=O)C>[CH3:24][CH:23]([C:21]1[N:20]=[CH:19][N:18]=[C:17]([NH:12][CH2:11][C:9]2[CH:10]=[C:5]3[CH:4]=[C:3]([C:2]([F:1])([F:14])[F:15])[NH:13][C:6]3=[N:7][CH:8]=2)[CH:22]=1)[CH3:25]
Reactant: CC(C)c1cc(Cl)ncn1
Reactant: NCc1cnc2[nH]c(C(F)(F)F)cc2c1
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)c1cc(NCc2cnc3[nH]c(C(F)(F)F)cc3c2)ncn1
Yield: 23.9 %

Procedure:
1-[2-(Trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]methanamine (Intermediate 5, 75 mg, 0.349 mmol), 4-chloro-6-(1-methylethyl)pyrimidine (54.6 mg, 0.349 mmol) and DIPEA (0.122 mL, 0.697 mmol) in N-methyl-2-pyrrolidone (1 mL) were stirred in a microwave reactor at 120° C. for 1 hour. The reaction mixture was diluted with ethyl acetate (20 mL) and washed with water (10 mL), brine (10 mL), water (10 mL) and brine (10 mL). The organic layer was dried (sodium sulfate), filtered and concentrated under reduced pressure. This solid was dissolved in a mixture of acetonitrile and DMSO (1:1) (0.9 mL) and purified by MDAP (2 injections). Fractions containing pure product were combined and concentrated under reduced pressure to give the title compound as a yellow oil (28 mg);
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]([CH3:29])[O:4][C:5]1[N:10]=[C:9]([S:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[C:14]=2[F:20])[N:8]=[C:7]([NH:21][S:22]([N:25]2[CH2:28][CH2:27][CH2:26]2)(=[O:24])=[O:23])[CH:6]=1.N1C=CC=CC=1.[C:36](OC(=O)C)(=[O:38])[CH3:37]>ClCCl>[N:25]1([S:22]([NH:21][C:7]2[N:8]=[C:9]([S:11][CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[C:14]=3[F:20])[N:10]=[C:5]([O:4][C@H:3]([CH3:29])[CH2:2][NH:1][C:36](=[O:38])[CH3:37])[CH:6]=2)(=[O:23])=[O:24])[CH2:26][CH2:27][CH2:28]1
Reactant: C[C@H](CN)Oc1cc(NS(=O)(=O)N2CCC2)nc(SCc2cccc(F)c2F)n1
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)NC[C@@H](C)Oc1cc(NS(=O)(=O)N2CCC2)nc(SCc2cccc(F)c2F)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of N-[6-((R)-2-amino-1-methylethoxy)-2-[[(2,3-Difluorophenyl)methyl]thio]pyrimidin-4-yl]azetidine-1-sulfonamide (the title product of Example 42) (0.05 g) in dichloromethane (10 mL) was added pyridine (0.02 mL), followed by acetic anhydride (0.02 mL). The mixture was stirred overnight at room temperature. Pyridine (0.02 mL) and acetic anhydride (0.02 mL) were added and the reaction mixture was stirred for a further 2 h Pyridine (1.0 mL) and acetic anhydride (0.50 mL) were added and the reaction mixture was stirred for a further 2 h. The reaction mixture was diluted with dichloromethane, washed with aqueous citric acid, H2O, dried (MgSO4), filtered and the solvent evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel using 40% EtOAc in isohexane as eluent. The isolated product was further purified by reverse phase HPLC eluting with acetonitrile/aq. 0.1% ammonium acetate mixtures to give the title compound as a white solid. Yield: 55 mg.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[Cl:11][C:12]1[CH:13]=[C:14]([CH:19]([CH2:34][CH2:35][OH:36])[CH2:20][C:21]([N:23]([CH3:33])[CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[O:31][CH3:32])=[O:22])[CH:15]=[CH:16][C:17]=1[Cl:18].CCN(CC)CC>C(Cl)Cl>[Cl:11][C:12]1[CH:13]=[C:14]([CH:19]([CH2:34][CH:35]=[O:36])[CH2:20][C:21]([N:23]([CH3:33])[CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[O:31][CH3:32])=[O:22])[CH:15]=[CH:16][C:17]=1[Cl:18]
Reactant: COc1ccccc1CN(C)C(=O)CC(CCO)c1ccc(Cl)c(Cl)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccccc1CN(C)C(=O)CC(CC=O)c1ccc(Cl)c(Cl)c1
Reaction time: 0.25 h
Yield: 73.5 %

Procedure:
A solution of oxalyl chloride (1.43 mL) in CH2Cl2 (30 mL) was cooled to -78° C. whereupon DMSO (2.32 mL) was added dropwise over 15 mins. This mixture was stirred for 15 minutes. Whereupon a CH2Cl2 (20 mL) solution of 3,4-Dichloro-β-(2-hydroxyethyl)-N-methyl-N-[(2-methoxyphenyl)methyl]benzenepropanamide (1.3 g) was added over 20 minutes. The mixture was stirred for 30 minutes and then treated with Et3N (9.2 mL) and stirred for an additional 30 minutes at -78° C., followed by 1.5 hours at room temperature. The reaction mixture was quenched with water and diluted with CH2Cl2 (100 mL). The organic fraction was separated, washed sequentially with 1N HCl (1×50 mL), sat. NaHCO3 (1×50 mL) and brine (1×50 mL), dried over MgSO4, filtered and concentrated under reduced pressure to yield an oil. Silica gel chromatography eluting with 50-100% EtOAc/Hex gave the title compound (950 mg).
Reaction SMILES: [CH2:1]([O:11][C:12]1[CH:13]=[C:14]([C:29](=[O:33])[C:30]([OH:32])=O)[CH:15]=[C:16]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[CH:17]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].C(Cl)(=O)C(Cl)=O.[NH:40]([CH2:47][C:48]([O:50][CH2:51][CH3:52])=[O:49])[CH2:41][C:42]([O:44][CH2:45][CH3:46])=[O:43].C(N(CC)CC)C>C(Cl)Cl.CN(C=O)C>[CH2:45]([O:44][C:42](=[O:43])[CH2:41][N:40]([C:30](=[O:32])[C:29]([C:14]1[CH:15]=[C:16]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[CH:17]=[C:12]([O:11][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])[CH:13]=1)=[O:33])[CH2:47][C:48]([O:50][CH2:51][CH3:52])=[O:49])[CH3:46]
Reactant: CCOC(=O)CNCC(=O)OCC
Reactant: CCCCCCCCCCOc1cc(OCCCCCCCCCC)cc(C(=O)C(=O)O)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCCCCCCOc1cc(OCCCCCCCCCC)cc(C(=O)C(=O)N(CC(=O)OCC)CC(=O)OCC)c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 87.6 %

Procedure:
To a solution of 1.0 g (2.16 mmol) of 3,5-bis(decyloxy)-alpha-oxobenzeneacetic acid in 50 ml of anhydrous methylene chloride and 2 drops of DMF stirred in an ice bath was added 0.94 ml (10.8 mmol) of oxalyl chloride. The cooling bath was removed and stirring was continued at room temperature for 2 hours. The solvent was removed at reduced pressure and the residual acid chloride was dissolved in 40 ml of anhydrous methylene chloride and added dropwise to an ice bath cooled solution of 0.6 ml (3.2 mmol) of diethyl iminodiacetate and 0.6 ml (4.3 mmol) of triethylamine in 10 ml of methylene chloride. After stirring in the ice bath for 30 minutes and at room temperature for 18 hours, the reaction mixture was washed with NaHCO3, dried and concentrated at reduced pressure to an oil which was purified by chromatography on 25 g of 230-400 mesh silica gel using 20% ethyl acetate-hexane to give 1.2 g (91% yield) of N-[[3,5-bis(decyloxy)phenyl]-1,2-dioxoethyl]-N-(2-ethoxy-2-oxoethyl)glycine ethyl ester as an oil. The nmr and mass spectra served to confirm the structure.
Reaction SMILES: [CH3:1][N:2]([CH3:13])[S:3]([C:6]1[CH:11]=[CH:10][C:9](Br)=[CH:8][CH:7]=1)(=[O:5])=[O:4].C([O-])(=O)C.[K+].[CH3:19][O:20][C:21]1[CH:26]=[CH:25][N:24]=[C:23]([CH2:27][CH2:28][C:29]2[NH:38][C:32]3=[N:33][CH:34]=[C:35](I)[CH:36]=[C:31]3[N:30]=2)[CH:22]=1.C(=O)([O-])[O-].[K+].[K+].[Cl-].[Li+]>O1CCOCC1.O.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[CH3:19][O:20][C:21]1[CH:26]=[CH:25][N:24]=[C:23]([CH2:27][CH2:28][C:29]2[NH:38][C:32]3=[N:33][CH:34]=[C:35]([C:9]4[CH:10]=[CH:11][C:6]([S:3]([N:2]([CH3:13])[CH3:1])(=[O:5])=[O:4])=[CH:7][CH:8]=4)[CH:36]=[C:31]3[N:30]=2)[CH:22]=1
Reactant: COc1ccnc(CCc2nc3cc(I)cnc3[nH]2)c1
Reactant: CN(C)S(=O)(=O)c1ccc(Br)cc1
Agent: [Fe+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: COc1ccnc(CCc2nc3cc(-c4ccc(S(=O)(=O)N(C)C)cc4)cnc3[nH]2)c1
Yield: 81.6 %

Procedure:
A mixture of 1.984 g of N,N-dimethyl4-bromobenzenesulfonamide, 2.1 g of bis-(pinacolato)-diboron, 0.125 g of 1,1′-bis-(diphenylphosphino)-ferrocene, 0.165 g of [1,1′-bis(diphenyl-phosphino)ferrocene]palladium-dichloride (complex with CH2Cl2), 2.21 g of potassium acetate in 50 ml of degassed dioxane are heated to reflux under N2 for 16 hours. To the resulting mixture 40 ml of degassed dioxane, 2.14 g of 2-[2-(4-methoxypyridin-2-yl)ethyl]-6-iodo-3H-imidazo[4,5-b]pyridine (starting material A1), 0.65 g of tetrakis(triphenylphos-phine)-palladium(0) and a solution of 1.56 g of potassium carbonate and 0.48 g of lithium chloride in 40 ml of degassed water are added under N2. The mixture is heated to reflux under N2 for 7 hours and, after cooling, addition of water and adjusting the pH to 7, it is extracted three times with dichloromethane. The combined organic phases are dried over sodium sulfate, concentrated and the residue is chromatographed on a silica gel column (dichloromethane/methanol 30-15:1). Concentration of the chromatographically pure fractions, crystallization from methanol and recrystallization from ethylacetate gives 2.01 g of the title compound as a solid of m.p. 217-218° C. The mass spectrum shows the molecular peak MH+ at 438.3 Da.
Reaction SMILES: Cl.[NH2:2][C:3]1[N:32]=[C:6]2[N:7]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=3)[C:8]([CH3:21])=[C:9]([C:19]#[N:20])[C@@H:10]([C:11]3[CH:16]=[CH:15][C:14]([C:17]#[N:18])=[CH:13][CH:12]=3)[N:5]2[N:4]=1.N1C=CC=CC=1.[F:39][C:40]1([F:47])[CH2:42][C:41]1([CH3:46])[C:43](Cl)=[O:44]>C1COCC1>[C:19]([C:9]1[C@@H:10]([C:11]2[CH:16]=[CH:15][C:14]([C:17]#[N:18])=[CH:13][CH:12]=2)[N:5]2[N:4]=[C:3]([NH:2][C:43]([C:41]3([CH3:46])[CH2:42][C:40]3([F:47])[F:39])=[O:44])[N:32]=[C:6]2[N:7]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:29])([F:31])[F:30])[CH:23]=2)[C:8]=1[CH3:21])#[N:20]
Reactant: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2)n2nc(N)nc2N1c1cccc(C(F)(F)F)c1
Reactant: CC1(C(=O)Cl)CC1(F)F
Agent: Cl
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2)n2nc(NC(=O)C3(C)CC3(F)F)nc2N1c1cccc(C(F)(F)F)c1

Procedure:
Under an atmosphere of argon protective gas, (7R)-2-amino-7-(4-cyanophenyl)-5-methyl-4-[3-(trifluoromethyl)phenyl]-4,7-dihydro[1,2,4]triazolo[1,5-a]pyrimidine-6-carbonitrile hydrochloride (30 mg, 66 μmol) was dissolved in abs. pyridine (1.5 ml). At room temperature, a solution of 2,2-difluoro-1-methylcyclopropanecarbonyl chloride (25 mg, 165 μmol, 2.5 eq.) in abs. THF (1 ml) was added in two portions. Once analysis of the reaction by HPLC showed substantial conversion (3 h), the reaction mixture was concentrated under reduced pressure and directly purified by preparative HPLC (Kromasil C18 column, 5 μm, 50×20 mm; mobile phase: acetonitrile-water-0.1% TFA). After lyophilization, the product was obtained as a solid (26.8 mg, 76% of theory).
Reaction SMILES: Br[CH:2]1[CH2:7][CH2:6][CH2:5][CH:4]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:3]1=O.[CH3:15][O:16][C:17]1[CH:18]=[C:19]([NH:29][C:30]([NH2:32])=[S:31])[CH:20]=[CH:21][C:22]=1[N:23]1[CH:27]=[N:26][C:25]([CH3:28])=[N:24]1>C(O)C.CCOC(C)=O>[CH3:15][O:16][C:17]1[CH:18]=[C:19]([NH:29][C:30]2[S:31][C:2]3[CH2:7][CH2:6][CH2:5][CH:4]([C:8]4[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=4)[C:3]=3[N:32]=2)[CH:20]=[CH:21][C:22]=1[N:23]1[CH:27]=[N:26][C:25]([CH3:28])=[N:24]1
Reactant: O=C1C(Br)CCCC1c1ccccc1
Reactant: COc1cc(NC(N)=S)ccc1-n1cnc(C)n1
Solvent: CCOC(C)=O
Solvent: CCO
Product: COc1cc(Nc2nc3c(s2)CCCC3c2ccccc2)ccc1-n1cnc(C)n1
Yield: 39 %

Procedure:
A mixture of 2-bromo-6-phenylcyclohexanone (84 mg, 0.332 mmol, from preparation AAA) and 1-(3-methoxy-4-(3-methyl-1H-1,2,4-triazol-1-yl)phenyl)thiourea (87 mg, 0.332 mmol, from step 4 of preparation F) was heated in ethanol (0.55 mL) at 80° C. for 3 h. The crude reaction was diluted with EtOAc and washed with saturated sodium bicarbonate solution. The organic layer was concentrated in vacuo. The crude product was purified using preparatory TLC (60% acetone/hexanes) to give 54 mg (39% yield) of the titled compound as a white solid. LC-MS (M+H)+ 418.0. 1H NMR (400 MHz, chloroform-d) δ ppm 8.44 (s, 1 H) 7.49 (dd, J=5.41, 3.15 Hz, 2 H) 7.23-7.35 (m, 2 H) 7.12-7.21 (m, 3 H) 6.60 (dd, J=8.56, 2.27 Hz, 1H) 3.98-4.08 (m, 1 H) 3.49 (s, 3 H) 2.66-2.85 (m, 2 H) 2.46 (s, 3 H) 2.17-2.26 (m, 1 H) 1.92-2.05 (m, 1 H) 1.78-1.91 (m, 2 H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[S:7][CH:8]=[C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[C:17]([CH:20]=[C:21]([CH3:23])[CH3:22])[CH:18]=3)[N:13]([S:24]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)(=[O:26])=[O:25])[CH:12]=2)[N:10]=1)=[O:5])[CH3:2].C(Cl)Cl>CO.[OH-].[OH-].[Pd+2]>[CH2:1]([O:3][C:4]([C:6]1[S:7][CH:8]=[C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[C:17]([CH2:20][CH:21]([CH3:23])[CH3:22])[CH:18]=3)[N:13]([S:24]([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)(=[O:26])=[O:25])[CH:12]=2)[N:10]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1nc(-c2cn(S(=O)(=O)c3ccccc3)c3ncc(C=C(C)C)cc23)cs1
Agent: [Pd+2]
Agent: [OH-]
Solvent: ClCCl
Solvent: CO
Product: CCOC(=O)c1nc(-c2cn(S(=O)(=O)c3ccccc3)c3ncc(CC(C)C)cc23)cs1
Reaction time: 72 h
Yield: 75 %

Procedure:
To a solution of 80 (548 mg, 1.32 mmol) in MeOH:CH2Cl2=3:1 (v/v; 20 mL) was added 20% Pd(OH)2 on carbon (100 mg, cat.), and the reaction mixture was stirred vigorously under H2 for 72 h. The mixture was then filtered through Celite, which was then washed with MeOH:CH2Cl2=1:1 (v/v; 100 mL). The solutions were combined and concentrated to afford 81 as a foam (412 mg, 0.99 mmol, 75%). 1H NMR (400 MHz, CDCl3) δ 0.84 (d, J=6.6 Hz, 2H), 1.40 (t, J=7.1 Hz, 3H), 1.82 (nonet, J=6.7 Hz, 1H), 2.51 (d, J=7.2 Hz, 2H), 4.45 (q, J=7.1 Hz, 2H), 7.41 (t, J=7.8 Hz, 2H), 7.48 (t, J=7.6 Hz, 1H), 7.66 (s, 1H), 8.03 (d, J=1.8 Hz, 1H), 8.15 (d, J=7.5 Hz, 1H), 8.20 (s, 1H), 8.22 (d, J=1.9 Hz, 1H).
Reaction SMILES: [C:1]([C:4]1[C:8]([CH2:9][O:10]C)=[C:7]([C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)[NH:6][C:5]=1[C:18]1[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=1)(=[O:3])[CH3:2].C(=O)(O)[O-].[Na+]>Cl>[C:1]([C:4]1[C:8]([CH2:9][OH:10])=[C:7]([C:12]2[CH:13]=[CH:14][N:15]=[CH:16][CH:17]=2)[NH:6][C:5]=1[C:18]1[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=1)(=[O:3])[CH3:2]
Reactant: COCc1c(-c2ccncc2)[nH]c(-c2ccncc2)c1C(C)=O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: CC(=O)c1c(-c2ccncc2)[nH]c(-c2ccncc2)c1CO
Temperature: 70 °C
Yield: 43.7 %

Procedure:
3-Acetyl-4-methoxymethyl-2,5-di(4-pyridyl)-1H-pyrrole (0.36 g, 1.17 mmol) was dissolved in 10% aqueous HCl solution (14 mL). The mixture was heated at 70° C. for 15 hours. After cooling, the mixture was neutralized with saturated aqueous sodium bicarbonate solution. Insolubles were filtered off, and the filtrate was extracted with ethyl acetate-EtOH (5:1, 200 mL×2). The combined organic layers were washed with brine (50 mL), dried over MgSO4, and concentrated ill vaciio. The crude product was recrystallized from ethyl acetate to provide the title product (150 mg, 44% yield) as a solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([C:18]#[N:19])[C:9]2[C:14]([C:15]=1[OH:16])=[CH:13][CH:12]=[C:11](Br)[CH:10]=2)=[O:5])[CH3:2].[CH2:20]([NH:27][C:28]([NH2:30])=[O:29])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([C:18]#[N:19])[C:9]2[C:14]([C:15]=1[OH:16])=[CH:13][CH:12]=[C:11]([NH:30][C:28]([NH:27][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:29])[CH:10]=2)=[O:5])[CH3:2]
Reactant: NC(=O)NCc1ccccc1
Reactant: CCOC(=O)c1nc(C#N)c2cc(Br)ccc2c1O
Product: CCOC(=O)c1nc(C#N)c2cc(NC(=O)NCc3ccccc3)ccc2c1O

Procedure:
7-(3-Benzyl-ureido)-1-cyano-4-hydroxy-isoquinoline-3-carboxylic acid ethyl ester was prepared from 7-bromo-1-cyano-4-hydroxy-isoquinoline-3-carboxylic acid ethyl ester under conditions analogous to Example 116(a) using benzylurea. MS ESI(+) m/e: 391.0935 (M+1).
Reaction SMILES: Cl.[NH2:2][N:3]1[CH:7]=[CH:6][N:5]=[C:4]1[CH3:8].[OH:9][C:10]1[C:17]([C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:16][C:13]([CH:14]=O)=[CH:12][C:11]=1[C:22]([CH3:25])([CH3:24])[CH3:23]>C(O)C>[OH:9][C:10]1[C:17]([C:18]([CH3:20])([CH3:19])[CH3:21])=[CH:16][C:13]([CH:14]=[N:2][N:3]2[CH:7]=[CH:6][N:5]=[C:4]2[CH3:8])=[CH:12][C:11]=1[C:22]([CH3:25])([CH3:24])[CH3:23]
Reactant: Cc1nccn1N
Reactant: CC(C)(C)c1cc(C=O)cc(C(C)(C)C)c1O
Agent: Cl
Solvent: CCO
Product: Cc1nccn1N=Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
5.35 g of 1-amino-2-methylimidazole hydrochloride are dissolved in 300 ml of ethanol, whereupon 9.3 g of 4-hydroxy-3,5-di-tert.-butylbenzaldehyde are added. The mixture is stirred at room temperature for 1 hour and then evaporated in a vacuum. 150 ml of ice-water and 200 ml of methylene chloride are added to the residue and the mixture is neutralized (pH=7) with saturated sodium bicarbonate solution. The methylene chloride phase is separated and the aqueous phase is extracted with 100 ml of methylene chloride. The combined methylene chloride phases are dried and evaporated. The residue is stirred with ether and filtered. The filter residue is dried at 80° in a vacuum and there is obtained 1-(4-hydroxy-3,5-di-tert.-butylbenzylideneamino)-2-methylimidazole of m.p. 206°-207°.
Reaction SMILES: [C:1]([C:3]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][C:4]=1[C:5](OCC)=[O:6])#[N:2].[Li+].[BH4-]>C1COCC1>[C:1]([C:3]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][C:4]=1[CH2:5][OH:6])#[N:2]
Reactant: CCOC(=O)c1cc(OC)ccc1C#N
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc(C#N)c(CO)c1
Reaction time: 19 h

Procedure:
To a solution of ethyl 2-cyano-5-methoxybenzoate (5 g, 24 mmol) in THF (100 mL) at room temperature was added a solution of LiBH4 in THF (2M, 12 mL, 24 mmol). After 19 h, there was about 60% conversion of starting material. An additional quantity of LiBH4 in THF (2M, 12 mL, 24 mmol) was added and stirring continued for an additional 15 h. The solvent was removed under reduced pressure then water was carefully added to the residue. Excess hydride was destroyed by careful proportionwise addition of a saturated aqueous solution of NH4Cl. Once complete, the resulting mixture was extracted with ether and then with ethyl acetate. The combined extracts were dried over Na2SO4 and the solvents then removed in vacuo. The residue was purified by column chromatography eluting with 2:1:2 hexane/chloroform/ethyl acetate. The title compound was isolated as a white solid: 1H NMR (CDCl3) δ7.58 (d, J=8.5 Hz, 1H), 7.15 (d, J=2.7 Hz, 1H), 6.86 (dd, J=2.7, 8.5 Hz, 1H), 4.89 (d, J=6.0 Hz, 2H), 3.88 (s, 1H), 2.01 (t, J=6.0 Hz, 1H).
Reaction SMILES: [C:1]([C:5]1[S:9][C:8]([C:10]([OH:12])=O)=[C:7]([N+:13]([O-:15])=[O:14])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C1COCC1.[CH3:21][N:22]([CH3:34])[CH2:23][CH2:24][N:25]1[CH2:30][CH2:29][NH:28][C:27]([CH3:32])([CH3:31])[C:26]1=[O:33].CCN(C(C)C)C(C)C>S(Cl)(Cl)=O.C(OCC)(=O)C>[C:1]([C:5]1[S:9][C:8]([C:10]([N:28]2[CH2:29][CH2:30][N:25]([CH2:24][CH2:23][N:22]([CH3:21])[CH3:34])[C:26](=[O:33])[C:27]2([CH3:32])[CH3:31])=[O:12])=[C:7]([N+:13]([O-:15])=[O:14])[CH:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)c1cc([N+](=O)[O-])c(C(=O)O)s1
Reactant: CN(C)CCN1CCNC(C)(C)C1=O
Solvent: O=S(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CN(C)CCN1CCN(C(=O)c2sc(C(C)(C)C)cc2[N+](=O)[O-])C(C)(C)C1=O
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 85 %

Procedure:
A stirred solution of 5-tert-butyl-3-nitrothiophene-2-carboxylic acid (0.214 g, 0.933 mmol) in 2 ml thionyl chloride was warmed at 45° C. for 1 h and then concentrated under vacuum. The residue was dissolved in 2 ml THF and added to a 3 ml THF solution of 1-(2-(dimethylamino)ethyl)-3,3-dimethylpiperazin-2-one (0.242 g, 1.21 mmol) and DIEA (0.362 g, 2.80 mmol). The resulting mixture was stirred at room temperature for 5 minutes, diluted with ethyl acetate, washed with 1N HCl, water, brine, dried and the solvent eliminated under vacuum to yield 0.300 g, (˜85% purity) of 4-(2-tert-butyl-4-nitrothiophene-5-carbonyl)-1-(2-(dimethylamino)ethyl)-3,3-dimethyl-piperazin-2-one that was used as-is for the next step.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1)#[N:2].[CH2:10](Br)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(=O)([O-])[O-].[K+].[K+]>[I-].[K+].C(#N)C>[CH2:10]([O:9][C:6]1[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: BrCc1ccccc1
Reactant: N#Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Product: N#Cc1ccc(OCc2ccccc2)cc1
Yield: 100.3 %

Procedure:
Add 4-cyanophenol (1.191 g, 10 mmol), benzyl bromide (1.881 g, 11 mmol), potassium carbonate (3.455 g, 25 mmol) and potassium iodide (166 mg, 1 mmol) to acetonitrile (80 mL) and heat at reflux for 12 h. Cool, partition between EtOAc and water, separate he organic layer, and extract the aqueous layer with EtOAc. Combine the organic extracts, wash with brine, dry over Na2SO4, filter and concentrate. Purify by chromatography on silica gel eluting with EtOAc/hexane (1:6) to give the desired intermediate as a white solid (2.098 g, 100%). MS (ES+) m/z: 227 (M+NH4)+.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][C:11]1[NH:12][C:13]2[CH:19]=[C:18]([C:20](O)=[O:21])[CH:17]=[CH:16][C:14]=2[N:15]=1)([CH3:3])[CH3:2].[NH2:23][C:24]1[CH:32]=[C:31]2[C:27]([C:28]([NH:33][C:34]([CH:36]3[CH2:41][CH2:40][N:39]([CH3:42])[CH2:38][CH2:37]3)=[O:35])=[N:29][NH:30]2)=[CH:26][CH:25]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>>[CH3:42][N:39]1[CH2:38][CH2:37][CH:36]([C:34]([NH:33][C:28]2[C:27]3[C:31](=[CH:32][C:24]([NH:23][C:20]([C:18]4[CH:17]=[CH:16][C:14]5[N:15]=[C:11]([NH:10][C:5]6[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=6[CH:1]([CH3:2])[CH3:3])[NH:12][C:13]=5[CH:19]=4)=[O:21])=[CH:25][CH:26]=3)[NH:30][N:29]=2)=[O:35])[CH2:41][CH2:40]1
Reactant: CN1CCC(C(=O)Nc2n[nH]c3cc(N)ccc23)CC1
Reactant: CC(C)c1ccccc1Nc1nc2ccc(C(=O)O)cc2[nH]1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: CC(C)c1ccccc1Nc1nc2ccc(C(=O)Nc3ccc4c(NC(=O)C5CCN(C)CC5)n[nH]c4c3)cc2[nH]1

Procedure:
2-(2-Isopropylphenylamino)-3H-benzimidazole-5-carboxylic acid (0.3 mmol; see Example 66) was coupled with aforementioned 1-methylpiperidine-4-carboxylic acid (6-amino-1H-indazol-3-yl)-amide (0.3 mmol) using HBTU as described in general procedure D to afford the desired product, 2-(2-Isopropylphenylamino)-3H-benzimidazole-5-carboxylic acid {3-[(1-methylpiperidine-4-carbonyl)-amino]-1H-indazol-6-yl}-amide. MS: m/z 551 (M+H)+.