Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: BrCCBr.Cl[Si](C)(C)C.I[CH:11]1[CH2:14][N:13]([C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:16])[CH2:12]1.[Cl:25][C:26]1[C:27]([CH3:39])=[C:28](I)[C:29]([O:35][CH2:36][CH3:37])=[C:30]([C:32](=[O:34])[CH3:33])[CH:31]=1>CN(C)C=O.[Zn].C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1C=CC=C1P(C1OC=CC=1)C1OC=CC=1>[C:32]([C:30]1[C:29]([O:35][CH2:36][CH3:37])=[C:28]([CH:11]2[CH2:14][N:13]([C:15]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[O:16])[CH2:12]2)[C:27]([CH3:39])=[C:26]([Cl:25])[CH:31]=1)(=[O:34])[CH3:33]
Reactant: CCOc1c(C(C)=O)cc(Cl)c(C)c1I
Reactant: O=C(OCc1ccccc1)N1CC(I)C1
Agent: [Pd]
Agent: C[Si](C)(C)Cl
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: BrCCBr
Solvent: CN(C)C=O
Product: CCOc1c(C(C)=O)cc(Cl)c(C)c1C1CN(C(=O)OCc2ccccc2)C1
Temperature: 70 °C
Reaction time: 1 h
Yield: 80.2 %

Procedure:
Zinc (0.967 g, 14.8 mmol) was suspended with 1,2-dibromoethane (0.085 mL, 0.98 mmol) in N,N-dimethylformamide (17 mL). The mixture was heated at 70° C. for 10 minutes and then cooled to room temperature. Chlorotrimethylsilane (0.125 mL, 0.984 mmol) was added dropwise and stirring was continued for 1 hour. A solution of benzyl 3-iodoazetidine-1-carboxylate (from PharmaBlock) (3.9 g, 12 mmol) in N,N-dimethylformamide (10 mL) was then added and the mixture was heated at 40° C. for 1 hour before a mixture of 1-(5-chloro-2-ethoxy-3-iodo-4-methylphenyl)ethanone (4.4 g, 13 mmol), tris(dibenzylideneacetone)dipalladium(0) (0.22 g, 0.24 mmol) and tri-(2-furyl)phosphine (0.12 g, 0.50 mmol) in N,N-dimethylformamide (30 mL) was added. The reaction mixture was warmed to 70° C. and stirred overnight. The mixture was then cooled to room temperature and partitioned between ether and sat. NH4Cl solutions. The organic layers were washed with water, dried over MgSO4, concentrated and purified on silica gel (eluting with 0 to 20% EtOAc in hexanes) to give the desired product (3.87 g, 78%). LCMS calculated for C22H25ClNO4 (M+H)+: m/z=402.1; Found: 402.1,
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:24](=[O:36])[NH:25][CH2:26][C:27]2[C:28](=[O:35])[NH:29][C:30]([CH3:34])=[CH:31][C:32]=2[CH3:33])[C:5]([CH3:23])=[C:6]([N:8]([CH3:22])[CH: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)[CH:7]=1.[CH:37]([C:39]1[N:44]=[CH:43][C:42](B(O)O)=[CH:41][CH:40]=1)=[O:38].C([O-])([O-])=O.[Na+].[Na+].CO>O1CCOCC1.C(Cl)Cl.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>[CH3:33][C:32]1[CH:31]=[C:30]([CH3:34])[NH:29][C:28](=[O:35])[C:27]=1[CH2:26][NH:25][C:24]([C:4]1[C:5]([CH3:23])=[C:6]([N:8]([CH3:22])[CH:9]2[CH2:10][CH2:11][N:12]([C:15]([O:17][C:18]([CH3:19])([CH3:21])[CH3:20])=[O:16])[CH2:13][CH2:14]2)[CH:7]=[C:2]([C:42]2[CH:43]=[N:44][C:39]([CH:37]=[O:38])=[CH:40][CH:41]=2)[CH:3]=1)=[O:36]
Reactant: O=Cc1ccc(B(O)O)cn1
Reactant: Cc1cc(C)c(CNC(=O)c2cc(Br)cc(N(C)C3CCN(C(=O)OC(C)(C)C)CC3)c2C)c(=O)[nH]1
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: [Na+]
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: CO
Product: Cc1cc(C)c(CNC(=O)c2cc(-c3ccc(C=O)nc3)cc(N(C)C3CCN(C(=O)OC(C)(C)C)CC3)c2C)c(=O)[nH]1
Temperature: 100 °C
Reaction time: 2 h
Yield: 76.3 %

Procedure:
Tert-butyl 4-((5-bromo-3-(((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)carbamoyl)-2-methylphenyl)(methyl)amino)piperidin-1-carboxylate (0.5 g, 0.892 mmol), (6-formylpyridin-3-yl)boronic acid (0.31 g, 1.33 mmol) and Pd(PPh3)4 (0.103 g, 0.082 mmol) in 1,4-dioxane (10 mL) was purged with argon for 10 min. Then, 2 M Na2CO3 solution (0.34 g, 3.21 mmol) was added to it and again argon was purged through it for 10 min. The reaction mixture was stirred at 100° C. for 2 h. After completion of the reaction, water was added to it and extraction was carried out using 5% MeOH in DCM. The combined organic layers were washed with water, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to afford crude material which was purified by column chromatography over silica gel (60-120 mesh size) to afford tert-butyl 4-((3-(((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)carbamoyl)-5-(6-formylpyridin-3-yl)-2-methylphenyl)(methyl)amino)piperidine-1-carboxylate (0.40 g, 87.9%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:22]3[O:21][C:20]([C:23]#[N:24])=[C:19]([CH2:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[C:18]=3[CH:17]=[C:16]([CH3:32])[CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].B1([O-])O[O:34]1.O.O.O.O.[Na+].C(O)C>[Cl-].[Na+].O.O>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([C:14]2[C:22]3[O:21][C:20]([C:23](=[O:34])[NH2:24])=[C:19]([CH2:25][C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=4)[C:18]=3[CH:17]=[C:16]([CH3:32])[CH:15]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: [O-]B1OO1
Reactant: Cc1cc(N2CCN(C(=O)OC(C)(C)C)CC2)c2oc(C#N)c(Cc3ccccc3)c2c1
Agent: [Cl-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Cc1cc(N2CCN(C(=O)OC(C)(C)C)CC2)c2oc(C(N)=O)c(Cc3ccccc3)c2c1
Temperature: 130 °C
Yield: 79.4 %

Procedure:
4-(3-Benzyl-2-cyano-5-methyl-benzofuran-7-yl)-piperazine-1-carboxylic acid tert-butyl ester (0.302 gm, 0.7 mmol), sodium perborate tetrahydrate (0.43 gm, 2.8 mmol), ethanol (8 ml) and water (8 ml) were combined in a vial and heated in a microwave reactor to 130° C. for 10 minutes. The reaction mixture was cooled to room temperature, diluted with brine and water and extracted three times with ethyl acetate. The solution was dried over magnesium sulfate and purified by column chromatography (methanol/dichloromethane gradient) to give 4-(3-benzyl-2-carbamoyl-5-methyl-benzofuran-7-yl)-piperazine-1-carboxylic acid tert-butyl ester (0.25 gm, 80% yield).
Reaction SMILES: O[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[CH3:12])[N:5]=[N:4][C:3]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.P(Cl)(Cl)(Cl)(Cl)[Cl:20]>O=P(Cl)(Cl)Cl>[Cl:20][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[CH3:12])[N:5]=[N:4][C:3]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: Cc1cccc2nnc(-c3ccccc3)c(O)c12
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1cccc2nnc(-c3ccccc3)c(Cl)c12

Procedure:
27.3 g (0.116 mol) of the compound from Example VI are boiled under reflux with 18.3 g of PCl5 and 200 ml of POCl3 for 18 h. The mixture is added to ice with good stirring and extracted with methylene chloride, and the organic phase is washed with saturated NaHCO3 solution, dried and evaporated in vacuo. 12 g (41% crude yield) of a solid are obtained, which after chromatography has a m.p. of 128° C.
Reaction SMILES: C([O:8][C:9]([C:11]1([C:24]([O:26]CC2C=CC=CC=2)=[O:25])[CH2:16][CH2:15][P:14](=[O:23])([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:13][CH2:12]1)=[O:10])C1C=CC=CC=1.[H][H]>[Pd].C(O)C>[O:23]=[P:14]1([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:15][CH2:16][C:11]([C:9]([OH:10])=[O:8])([C:24]([OH:26])=[O:25])[CH2:12][CH2:13]1
Reactant: [H][H]
Reactant: O=C(OCc1ccccc1)C1(C(=O)OCc2ccccc2)CCP(=O)(c2ccccc2)CC1
Agent: [Pd]
Solvent: CCO
Product: O=C(O)C1(C(=O)O)CCP(=O)(c2ccccc2)CC1
Reaction time: 1 h
Yield: 35.4 %

Procedure:
To a 500 mL Parr flask was added 1-oxo-1-phenyl-1λ5-phosphinane-4,4-dicarboxylic acid dibenzyl ester (8.5 g, 18 mmol), ethanol (250 mL), and palladium on carbon (10%, 1.1 g). The flask was charged with hydrogen (51 psi), and agitated on a mechanical shaker. After 1 hour, the ballast was re-charged to 50 psi (from 40 psi) and shaking continued overnight (14 hours). The reaction mixture was filtered and the solvent removed in vacuo to provide 1-oxo-1-phenyl-1λ5-phosphinane-4,4-dicarboxylic acid (1.8 g, 35%) as a white solid. 1H NMR (400 MHz, d6-DMSO) δ 7.9-7.4 (m, 5H), 2.6 -1.4 (m, 8H); ESMS m/z: found, 283 (M+1)+.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:13]2[N:12]=[C:11]([NH2:14])[NH:10][C:9]=2[CH:8]=[CH:7][CH:6]=1)=[O:4].CO[C:17](=O)[C:18]1C=C(C)C=C([N+]([O-])=O)[C:19]=1N>>[CH3:1][O:2][C:3]([C:5]1[C:13]2[N:12]=[C:11]([NH2:14])[NH:10][C:9]=2[CH:8]=[C:7]([CH2:17][CH2:18][CH3:19])[CH:6]=1)=[O:4]
Reactant: COC(=O)c1cccc2[nH]c(N)nc12
Reactant: COC(=O)c1cc(C)cc([N+](=O)[O-])c1N
Product: CCCc1cc(C(=O)OC)c2nc(N)[nH]c2c1
Yield: 85 %

Procedure:
0.3 g (85% overall yield) 2-amino-6-propyl-1H-benzoimidazole-4-carboxylic acid methyl ester was synthesized according to procedures described for the synthesis of 2-Amino-1H-benzoimidazole-4-carboxylic acid methyl ester (intermediate A) starting from 0.35 g (1.5 mmol) of above synthesized 2-amino-5-methyl-3-nitrobenzoic acid methyl ester. LCMS: 234 (M+1)+.
Reaction SMILES: [CH:1]([O:4][C:5]([N:7]1[C:16]2[C:11](=[CH:12][C:13]([C:17]([F:20])([F:19])[F:18])=[CH:14][CH:15]=2)[C@H:10]([N:21]([CH2:26][C:27]2[CH:32]=[C:31]([C:33]([F:36])([F:35])[F:34])[CH:30]=[C:29]([C:37]([F:40])([F:39])[F:38])[CH:28]=2)[C:22]([O:24][CH3:25])=[O:23])[CH2:9][C@@H:8]1[CH:41]1[CH2:43][CH:42]1[C:44](OCC)=[O:45])=[O:6])([CH3:3])[CH3:2].[BH4-].[Na+]>CO>[CH:1]([O:4][C:5]([N:7]1[C:16]2[C:11](=[CH:12][C:13]([C:17]([F:20])([F:19])[F:18])=[CH:14][CH:15]=2)[C@H:10]([N:21]([CH2:26][C:27]2[CH:28]=[C:29]([C:37]([F:38])([F:39])[F:40])[CH:30]=[C:31]([C:33]([F:36])([F:34])[F:35])[CH:32]=2)[C:22]([O:24][CH3:25])=[O:23])[CH2:9][C@@H:8]1[CH:41]1[CH2:43][CH:42]1[CH2:44][OH:45])=[O:6])([CH3:2])[CH3:3]
Reactant: CCOC(=O)C1CC1[C@H]1C[C@@H](N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)C(=O)OC)c2cc(C(F)(F)F)ccc2N1C(=O)OC(C)C
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)[C@@H]1C[C@H](C2CC2CO)N(C(=O)OC(C)C)c2ccc(C(F)(F)F)cc21
Yield: 59.8 %

Procedure:
To a solution of cis-4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-(2-ethoxycarbonyl-cyclopropyl)-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid isopropyl ester (Example 53) (100 mg, 0.14 mmol) in refluxing methanol (40 ml) was added sodium borohydride (1.0 g) in portions, and the resulting mixture was heated to reflux for an additional 30 min. The cooled reaction was concentrated and the residue was partitioned between ethyl acetate and 2N HCl. The aqueous layer was extracted again with ethyl acetate and the combined extracts were dried (MgSO4), filtered and concentrated. The residue was chromatographed with 15-20% ethyl acetate/hexane to afford the title product (55 mg). MS m/z 657.2 (M+); 1H NMR (CDCl3) δ 3.8 (s, 3H), 3.9 (q, 1H), 7.1 (s, 1H), 7.5 (s, 2H), 7.7 (s, 1H).
Reaction SMILES: [C:1]([NH:5][C:6]1[C:11]([C:12]2[N:16]([C:17]3[CH:22]=[CH:21][C:20]([CH:23]=[CH2:24])=[C:19]([F:25])[C:18]=3[F:26])[N:15]=[N:14][N:13]=2)=[CH:10][CH:9]=[CH:8][N:7]=1)([CH3:4])([CH3:3])[CH3:2].[H][H]>C(OCC)(=O)C.[Pd]>[C:1]([NH:5][C:6]1[C:11]([C:12]2[N:16]([C:17]3[CH:22]=[CH:21][C:20]([CH2:23][CH3:24])=[C:19]([F:25])[C:18]=3[F:26])[N:15]=[N:14][N:13]=2)=[CH:10][CH:9]=[CH:8][N:7]=1)([CH3:3])([CH3:2])[CH3:4]
Reactant: C=Cc1ccc(-n2nnnc2-c2cccnc2NC(C)(C)C)c(F)c1F
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCc1ccc(-n2nnnc2-c2cccnc2NC(C)(C)C)c(F)c1F
Temperature: 25 °C
Reaction time: 12 h
Yield: 49.7 %

Procedure:
N-tert-Butyl-3-(1-(2,3-difluoro-4-vinylphenyl)-1H-tetrazol-5-yl)pyridin-2-amine (Compound 1081, 260 mg) was dissolved in 30 ml of ethyl acetate. 10% Palladium on carbon was added to the mixture and the reaction flask was charged with hydrogen (1 atm). After stirring at RT for 12 hours, the reaction was filtered through diatomaceous earth, concentrated in vacuo, and the residue purified by column chromatography (SiO2), eluting with 0-20% EtOAc/Hexane, to afford 130 mg of N-tert-Butyl-3-(1-(4-ethyl-2,3-difluorophenyl)-1H-tetrazol-5-yl)pyridin-2-amine (Compound 1082); MS (M+1)=359.4.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8](=[O:10])[NH:7][C:6]=2[CH:11]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:18](I)[CH:19]=[CH2:20]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8](=[O:10])[N:7]([CH2:20][CH:19]=[CH2:18])[C:6]=2[CH:11]=1
Reactant: C=CCI
Reactant: O=c1[nH]c2cc(Cl)ccc2s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C=CCn1c(=O)sc2ccc(Cl)cc21
Temperature: 100 °C

Procedure:
5-Chloro-1,3-benzothiazol-2(3H)-one (1.85 g, 10 mmol) was dissolved in DMF (50 ml) and treated with potassium carbonate (1.66 g, 12 mmol) and allyl iodide (1.1 ml, 12 mmol) then heated at 100° C. for 18 hrs. The solvent was then removed in-vacuo and the residue partitioned between water (100 ml) and ethyl acetate (2×100 ml). The organic layer was washed with saturated brine, separated and dried. Chromatography on silica gel eluting with a gradient of 10-50% ethyl acetate/40-60 petroleum ether gave the title compound as an oil that crystalised on standing (2.14 g, 95%).
Reaction SMILES: [C:1]1([CH:11]=[CH:12][C:13](=O)[CH3:14])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.Cl.[NH2:17][OH:18].[OH-].[Na+]>CO>[C:1]1([CH:11]=[CH:12][C:13](=[N:17][OH:18])[CH3:14])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: NO
Reactant: CC(=O)C=Cc1cccc2ccccc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C=Cc1cccc2ccccc12)=NO
Yield: 60.9 %

Procedure:
In a 250 ml single neck flask was charged 5.88 g (30.3 mmoles, 1.0 eq.) of 4-(1-naphthyl)-3-buten-2-one and 5.2 g (75.4 mmoles, 2.5 eq) of hydroxylamine hydrochloride and 6 g of 50% sodium hydroxide (75 mmoles, 2.5 eq) and 100 ml of methanol. The reaction mixture was stirred at reflux for 2 hours. The reaction mixture was concentrated, diluted with water (50 ml), and then extracted with ethyl acetate (2×50 ml). The organic phase was dried and concentrated, to obtain 3.9 g of 4-(1-naphthyl)-3-buten-2-one 2-oxime (E/Z mixture of isomers) as an oil in 62% yield.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl[CH2:26][CH2:27][C:28]([OH:30])=O.CCN(C(C)C)C(C)C.[Cl:40][C:41]1[C:42]([NH:62][C:63]2[CH:67]=[C:66]([CH3:68])[NH:65][N:64]=2)=[N:43][C:44]([NH:47][C:48]2[CH:53]=[C:52]([CH3:54])[C:51]([CH:55]3[CH2:60][CH2:59][NH:58][CH2:57][CH2:56]3)=[CH:50][C:49]=2[CH3:61])=[N:45][CH:46]=1>CN(C=O)C>[Cl:40][C:41]1[C:42]([NH:62][C:63]2[CH:67]=[C:66]([CH3:68])[NH:65][N:64]=2)=[N:43][C:44]([NH:47][C:48]2[C:49]([CH3:61])=[CH:50][C:51]([CH:55]3[CH2:60][CH2:59][N:58]([C:28](=[O:30])[CH:27]=[CH2:26])[CH2:57][CH2:56]3)=[C:52]([CH3:54])[CH:53]=2)=[N:45][CH:46]=1
Reactant: O=C(O)CCCl
Reactant: Cc1cc(Nc2nc(Nc3cc(C)c(C4CCNCC4)cc3C)ncc2Cl)n[nH]1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C=CC(=O)N1CCC(c2cc(C)c(Nc3ncc(Cl)c(Nc4cc(C)[nH]n4)n3)cc2C)CC1
Temperature: 25 °C
Reaction time: 0.05 h

Procedure:
A solution of HATU (108 mg, 0.28 mmol), 3-chloropropanoic acid (30 mg, 0.28 mmol) and DIEA (0.1 mL) in DMF (1 mL) was stirred at rt. After 3 min, this solution was transferred to a solution of 5-chloro-N2-(2,5-dimethyl-4-(piperidin-4-yl)phenyl)-N4-(5-methyl-1H-pyrazol-3-yl)pyrimidine-2,4-diamine solution (111 mg, 0.27 mmol) in DMF (10 mL). The resulting mixture was stirred at rt overnight. The reaction was quenched with water (20 mL) and extracted with EtOAc (3×30 mL). The combined EtOAc layers were washed with brine (10 mL), dried over Na2SO4 and concentrated in vacuo. The crude product was purified by silica chromatography (0-10% MeOH in DCM gradient with 1% NH3 additive) to give 1-(4-(4-(5-chloro-4-(5-methyl-1H-pyrazol-3-ylamino)pyrimidin-2-ylamino)-2,5-dimethylphenyl)piperidin-1-yl)prop-2-en-1-one as a light brown oil; ESMS m/z 466.1 (M+H+).
Reaction SMILES: [Br:1][C:2]1[C:10]2[CH2:9][O:8][C:7](=[O:11])[C:6]=2[CH:5]=[CH:4][C:3]=1[CH:12]=[CH2:13].C1C=C(Cl)C=C(C(OO)=[O:22])C=1>C(Cl)Cl>[Br:1][C:2]1[C:10]2[CH2:9][O:8][C:7](=[O:11])[C:6]=2[CH:5]=[CH:4][C:3]=1[CH:12]1[CH2:13][O:22]1
Reactant: C=Cc1ccc2c(c1Br)COC2=O
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: O=C1OCc2c1ccc(C1CO1)c2Br
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution 4-bromo-5-ethenyl-2-benzofuran-1(3H)-one (2.00 g, 8.37 mmol) in DCM (20 mL) was slowly added mCPBA (2.60 g, 8.37 mmol) at 0° C. The flask was warmed to room temperature and the mixture was then stirred for 12 hours. Analysis by TLC as well as LC indicated that reaction had gone to completion. The reaction mixture was washed with aqueous Na2S2O3, NaHCO3, and water. The organic layer was washed with brine and then concentrated to dryness. The residue was purified over silica gel to give 4-bromo-5-oxiran-2-yl-2-benzofuran-1(3H)-one.
Reaction SMILES: [ClH:1].[N:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][C:11]([OH:13])=[O:12])=[CH:4][CH:3]=1>[Pd].O>[ClH:1].[NH:2]1[CH2:7][CH2:6][CH:5]([CH2:8][CH2:9][CH2:10][C:11]([OH:13])=[O:12])[CH2:4][CH2:3]1
Reactant: O=C(O)CCCc1ccncc1
Agent: [Pd]
Agent: Cl
Solvent: O
Product: O=C(O)CCCC1CCNCC1
Reaction time: 4.5 h
Yield: 97 %

Procedure:
The procedure of Example 1 was repeated except the following. The same reactor as used in Example 1 was charged with 13.5 g (0.067 mole) of a γ-(4-pyridyl)butyric acid hydrochloride with a purity of at least 99%, 27.0 g of water and 0.67 g of 5% Pd/C [0.25% by weight in terms of Pd based on the γ-(4-pyridyl)butyric acid hydrochloride]. The reaction was conducted at 80° C. for 4.5 hours. A γ-(4-piperidyl)butyric acid hydrochloride was produced in a yield of 97%.
Reaction SMILES: COC(=O)[CH2:4][NH:5][C:6](=[O:37])[C:7]1[CH:12]=[C:11]([Cl:13])[C:10]([O:14][C:15]2[CH:20]=[CH:19][N:18]=[CH:17][C:16]=2[C:21]([N:23]2[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[N:26]([CH:33]3[CH2:35][CH2:34]3)[CH2:25][CH2:24]2)=[O:22])=[CH:9][C:8]=1[Cl:36].[CH3:39][O:40][C:41]([C:43]1[N:44]([CH3:49])[CH:45]=C(N)[CH:47]=1)=[O:42]>CCCCCCC.C(OCC)(=O)C>[CH3:39][O:40][C:41]([C:43]1[N:44]([CH3:49])[CH:45]=[C:4]([NH:5][C:6](=[O:37])[C:7]2[CH:12]=[C:11]([Cl:13])[C:10]([O:14][C:15]3[CH:20]=[CH:19][N:18]=[CH:17][C:16]=3[C:21]([N:23]3[C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[N:26]([CH:33]4[CH2:35][CH2:34]4)[CH2:25][CH2:24]3)=[O:22])=[CH:9][C:8]=2[Cl:36])[CH:47]=1)=[O:42]
Reactant: COC(=O)CNC(=O)c1cc(Cl)c(Oc2ccncc2C(=O)N2CCN(C3CC3)c3ccccc32)cc1Cl
Reactant: COC(=O)c1cc(N)cn1C
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: COC(=O)c1cc(NC(=O)c2cc(Cl)c(Oc3ccncc3C(=O)N3CCN(C4CC4)c4ccccc43)cc2Cl)cn1C

Procedure:
The title compound was prepared in analogy to Example 1, from 2,5-dichloro-4-[3-(4-cyclopropyl-3,4-dihydro-2H-quinoxaline-1-carbonyl)-pyridin-4-yloxy]-benzoic acid (Example 29, intermediate) and 4-amino-1-methyl-1H-pyrrole-2-carboxylic acid methyl ester (commercially available, CAS RN 180258-45-1) and using a gradient of n-heptane:ethyl acetate (100:0 to 0:100) for the chromatiographic purification. Light brown foam (70%). MS (ESI): m/z=620.147 [M+H]+.
Reaction SMILES: [CH3:1][CH:2]([CH3:39])[CH2:3][C@@H:4]([NH:31]C(=O)OC(C)(C)C)[C:5](=[O:30])[NH:6][CH:7]1[CH2:16][C:15]2[C:10](=[C:11]([N:17]3[CH2:21][CH2:20][CH2:19][C:18]3=[O:22])[CH:12]=[CH:13][CH:14]=2)[N:9]([CH2:23][C:24]2[CH:28]=[CH:27][S:26][CH:25]=2)[C:8]1=[O:29].Cl.C(=O)(O)[O-].[Na+]>C(O)C>[NH2:31][C@H:4]([CH2:3][CH:2]([CH3:39])[CH3:1])[C:5]([NH:6][CH:7]1[CH2:16][C:15]2[C:10](=[C:11]([N:17]3[CH2:21][CH2:20][CH2:19][C:18]3=[O:22])[CH:12]=[CH:13][CH:14]=2)[N:9]([CH2:23][C:24]2[CH:28]=[CH:27][S:26][CH:25]=2)[C:8]1=[O:29])=[O:30]
Reactant: CC(C)C[C@@H](NC(=O)OC(C)(C)C)C(=O)NC1Cc2cccc(N3CCCC3=O)c2N(Cc2ccsc2)C1=O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CC(C)C[C@@H](N)C(=O)NC1Cc2cccc(N3CCCC3=O)c2N(Cc2ccsc2)C1=O
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
tert-Butyl (2R)-4-methyl-1-oxo-1-[2-oxo-8-(2-oxopyrrolidin-1-yl)-1-(thiophen-3-ylmethyl)-1,2,3,4-tetrahydroquinolin-3-ylamino]pentan-2-ylcarbamate (588 mg) was dissolved in ethanol (2.9 mL), and concentrated hydrochloric acid (1.2 mL) was added thereto. The mixture was heated at 50° C. while being stirred for 30 minutes. The resultant mixture was neutralized with saturated sodium bicarbonate solution under cooling on ice. Subsequently, the mixture was extracted with ethyl acetate, and the aqueous layer was further extracted with ethyl acetate. The organic layers were combined, and the combined organic layer was washed with saturated sodium chloride solution, followed by drying over sodium sulfate. The solvent was evaporated under reduced pressure, whereby the title compound (416 mg) was yielded.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]([C:12]1[N:13]([C:21]2[CH:26]=[CH:25][C:24]([C:27]3[CH:32]=[C:31](S(C)(=O)=O)[C:30]([CH2:37][OH:38])=[C:29]([F:39])[CH:28]=3)=[CH:23][C:22]=2[F:40])[CH:14]=[C:15]([C:17]([OH:20])([CH3:19])[CH3:18])[N:16]=1)([CH3:11])[CH3:10].[C:41]([O:45][P:46]([O:53][CH2:54][C:55]1[CH:56]=[C:57]([CH:61]=[CH:62][CH:63]=1)[C:58](O)=[O:59])([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:47])([CH3:44])([CH3:43])[CH3:42].C1CCC(N=C=NC2CCCCC2)CC1>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:49]([O:48][P:46]([O:53][CH2:54][C:55]1[CH:56]=[C:57]([CH:61]=[CH:62][CH:63]=1)[C:58]([O:38][CH2:37][C:30]1[CH:31]=[CH:32][C:27]([C:24]2[CH:25]=[CH:26][C:21]([N:13]3[CH:14]=[C:15]([C:17]([OH:20])([CH3:19])[CH3:18])[N:16]=[C:12]3[C:9]([C:3]3[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][C:4]=3[Cl:8])([CH3:11])[CH3:10])=[C:22]([F:40])[CH:23]=2)=[CH:28][C:29]=1[F:39])=[O:59])([O:45][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:47])([CH3:50])([CH3:51])[CH3:52]
Reactant: CC(C)(O)c1cn(-c2ccc(-c3cc(F)c(CO)c(S(C)(=O)=O)c3)cc2F)c(C(C)(C)c2c(Cl)cccc2Cl)n1
Reactant: CC(C)(C)OP(=O)(OCc1cccc(C(=O)O)c1)OC(C)(C)C
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)OP(=O)(OCc1cccc(C(=O)OCc2ccc(-c3ccc(-n4cc(C(C)(C)O)nc4C(C)(C)c4c(Cl)cccc4Cl)c(F)c3)cc2F)c1)OC(C)(C)C
Temperature: 25 °C
Reaction time: 15 h
Yield: 62 %

Procedure:
To a stirred solution of 2-(2-(2-(2,6-dichlorophenyl)propan-2-yl)-1-(3,3′-difluoro-4′-(hydroxymethyl)-5′-(methylsulfonyl)biphenyl-4-yl)-1H-imidazol-4-yl)propan-2-ol (prepared in the manner described in PCT Publication No. WO 2010/138598, 0.1 g, 0.16 mmol) in CH2Cl2 (2 mL) was added 3-((di-tert-butoxyphosphoryloxy)methyl)benzoic acid (140 mg, 0.40 mmol), DMAP (4 mg, 0.33 mmol) and DCC (86 mg, 0.42 mmol). The reaction mixture was stirred at rt. After 15 h, the reaction mixture was filtered, washed with CH2Cl2 (2×10 mL), and the solvents were removed under reduced pressure to yield the crude material. The crude product was purified by column chromatography (basic alumina, EtOAc:Hexane) to afford (4′-(2-(2-(2,6-dichlorophenyl)propan-2-yl)-4-(2-hydroxypropan-2-yl)-1H-imidazol-1-yl)-3,3′-difluorobiphenyl-4-yl)methyl 3-((di-tert-butoxyphosphoryloxy)methyl)benzoate (95 mg, 0.10 mmol, 62%). LCMS: (Ascentis Express C8 (50×2.1 mm-2.7 μm); Solvent A=10 mM NH4COOH in 98% H2O and 2% acetonitrile; Solvent B=98% acetonitrile and 2% 10 mM NH4COOH in H2O; gradient 0% (1.5 min) then to 100% (1.5-3.2 min), 100% (3.2-4 min) B over 4 min), retention time: 2.22 min; LCMS (MM-ES+APCI), flow 1 mL/min, m/z 937.2.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4](I)[C:3]=1[Cl:9].[NH:10]1[C:18]2[C:13](=[C:14]([CH2:19][N:20]3[CH2:25][CH2:24][CH:23]([C:26]4[CH:27]=[C:28]([NH:32][C:33](=[O:37])[CH:34]([CH3:36])[CH3:35])[CH:29]=[CH:30][CH:31]=4)[CH2:22][CH2:21]3)[CH:15]=[CH:16][CH:17]=2)[CH:12]=[CH:11]1>>[Cl:9][C:3]1[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][C:4]=1[N:10]1[C:18]2[C:13](=[C:14]([CH2:19][N:20]3[CH2:25][CH2:24][CH:23]([C:26]4[CH:27]=[C:28]([NH:32][C:33](=[O:37])[CH:34]([CH3:35])[CH3:36])[CH:29]=[CH:30][CH:31]=4)[CH2:22][CH2:21]3)[CH:15]=[CH:16][CH:17]=2)[CH:12]=[CH:11]1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(Cc3cccc4[nH]ccc34)CC2)c1
Reactant: Clc1cccc(I)c1Cl
Product: CC(C)C(=O)Nc1cccc(C2CCN(Cc3cccc4c3ccn4-c3cccc(Cl)c3Cl)CC2)c1

Procedure:
Prepared by Procedure C and Scheme Q1, with CuBr in place of Cu, using 1,2-dichloro-3-iodobenzene and N-{3-[1-(1H-indol-4-ylmethyl)-4-piperidinyl]phenyl}-2-methylpropanamide: ESMS m/e: 520.2 (M+H)+.