Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][CH2:3][NH:4][S:5]([C:8]1[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=1)(=[O:7])=[O:6].[C:15]([O:19][C:20]([N:22]1[CH2:29][CH:28]2[O:30][CH:24]([CH2:25][NH:26][CH2:27]2)[CH2:23]1)=[O:21])([CH3:18])([CH3:17])[CH3:16].C([O-])([O-])=O.[K+].[K+]>C(#N)C>[C:15]([O:19][C:20]([N:22]1[CH2:23][CH:24]2[O:30][CH:28]([CH2:27][N:26]([CH2:2][CH2:3][NH:4][S:5]([C:8]3[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=3)(=[O:7])=[O:6])[CH2:25]2)[CH2:29]1)=[O:21])([CH3:18])([CH3:16])[CH3:17]
Reactant: O=S(=O)(NCCBr)c1ccc(F)cc1
Reactant: CC(C)(C)OC(=O)N1CC2CNCC(C1)O2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CC2CN(CCNS(=O)(=O)c3ccc(F)cc3)CC(C1)O2
Temperature: 60 °C
Reaction time: 8 h

Procedure:
A suspension of N-(2-Bromo-ethyl)-4-fluoro-benzenesulfonamide (7 g, 0.0179 mol; see step (i) above) and 9-oxa-3,7-diaza-bicyclo[3.3.1]nonane-3-carboxylic acid tert-butyl ester (11.2 g, 0.159 mol; see WO 01/28992) and K2CO3 (9.7 g, 0.0798 mol) in dry acetonitrile (70 ml) was stirred at 60° C. overnight under nitrogen atmosphere. The reaction mixture was partitioned between brine and ethyl acetate. Organic layer was washed with brine and dried over sodium sulfate. Solvent evaporation under reduced pressure followed by column chromatography over silica gel using 7% ethyl acetate in petroleum ether as eluent afforded the sub-title compound as a solid. Yield: 4 g
Reaction SMILES: [CH2:1]([C:6]1[S:7][CH:8]=[CH:9][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH3:5].[CH2:11]([C@H:14]1[CH2:19][CH2:18][C@H:17]([C:20]2[CH:25]=[CH:24][C:23]([CH2:26][C:27](Cl)=O)=[CH:22][CH:21]=2)[CH2:16][CH2:15]1)[CH2:12][CH3:13].B([O-])=O.[Na+]>>[CH2:11]([C@H:14]1[CH2:19][CH2:18][C@H:17]([C:20]2[CH:25]=[CH:24][C:23]([CH:26]=[CH:27][C:8]3[S:7][C:6]([CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])=[CH:10][CH:9]=3)=[CH:22][CH:21]=2)[CH2:16][CH2:15]1)[CH2:12][CH3:13]
Reactant: CCC[C@H]1CC[C@H](c2ccc(CC(=O)Cl)cc2)CC1
Reactant: CCCCCc1cccs1
Agent: O=B[O-]
Agent: [Na+]
Product: CCCCCc1ccc(C=Cc2ccc([C@H]3CC[C@H](CCC)CC3)cc2)s1

Procedure:
19 g of 2-[4-(trans-4-n-propylcyclohexyl)-styryl]-5-n-pentylthiophene (obtainable by Friedel Crafts acylation of 2-pentylthiophene with 4-(trans-4-n-propylcyclohexyl)-phenylacetyl chloride and reduction of the resulting ketone with sodium boranate to give the alcohol, followed by dehydration) and 5 g of sulfur are heated to 220° for 3 hours. Subsequent working-up by chromatography gives 8.3 g of 2-[4-trans-4-n-propylcyclohexylphenyl]-5-n-pentylthieno[3,2-b]thiophene.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([C:24]3[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=3)[C:10](=[O:23])[C:11]3[CH:16]=[N:15][N:14]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[C:12]=3[N:13]=2)=[CH:4][CH:3]=1.C([Sn](CCCC)(CCCC)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][N:37]=1)CCC>C1(C)C=CC=CC=1.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>[Cl:30][C:27]1[CH:28]=[CH:29][C:24]([N:9]2[C:10](=[O:23])[C:11]3[CH:16]=[N:15][N:14]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[C:12]=3[N:13]=[C:8]2[C:5]2[CH:4]=[CH:3][C:2]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][N:37]=3)=[CH:7][CH:6]=2)=[CH:25][CH:26]=1
Reactant: O=c1c2cnn(-c3ccccc3)c2nc(-c2ccc(Br)cc2)n1-c1ccc(Cl)cc1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: O=c1c2cnn(-c3ccccc3)c2nc(-c2ccc(-c3ccccn3)cc2)n1-c1ccc(Cl)cc1
Temperature: 100 °C
Yield: 46 %

Procedure:
A reaction tube charged with 6-(4-bromophenyl)-5-(4-chloro-phenyl)-1-phenyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one (40.0 mg, 0.084 mmol) and Pd(PPh3)4 (9.7 mg, 0.0084 mmol) is purged with nitrogen. A solution of 2-tributylstannanyl-pyridine (61.6 mg, 0.168 mmol) in anhydrous toluene (1.0 mL) is added via syringe. The reaction mixture is heated at 100° C. overnight, and is partitioned between water and ethyl acetate. The organic phase is washed with brine, concentrated, and purified by preparative LCMS followed by silica gel chromatography to provide the title compound (18.4 mg, 46% yield) as a white solid product; HPLC-MS calculated for C28H18ClN5O (M+H+) 476.1. Found: 476.1.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[N:4][NH:5][CH:6]=1.[OH-].[Na+].[Cl:9][CH2:10][C:11]([N:13]([CH2:22]Cl)[C:14]1[C:19]([CH3:20])=[CH:18][CH:17]=[CH:16][C:15]=1[CH3:21])=[O:12].[Br-].C([P+](CCCC)(CCCC)C)CCC>ClC1C=CC=CC=1Cl.O>[Cl:9][CH2:10][C:11]([N:13]([CH2:22][N:4]1[CH:3]=[C:2]([CH3:1])[CH:6]=[N:5]1)[C:14]1[C:19]([CH3:20])=[CH:18][CH:17]=[CH:16][C:15]=1[CH3:21])=[O:12]
Reactant: Cc1cn[nH]c1
Reactant: Cc1cccc(C)c1N(CCl)C(=O)CCl
Agent: CCCC[P+](C)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: Clc1ccccc1Cl
Solvent: O
Product: Cc1cnn(CN(C(=O)CCl)c2c(C)cccc2C)c1
Reaction time: 5 h

Procedure:
A solution of 9.0 parts by weight of 4-methylpyrazole and 4.0 parts by weight of sodium hydroxide in 20 parts by volume of water was added dropwise at 0° C., with vigorous stirring, to a solution of 24.6 parts by weight of 2-chloro-N-chloromethyl-2',6'-dimethylacetanilide and 0.15 part by weight of tri-n-butylmethylphosphonium bromide in 80 parts by volume of o-dichlorobenzene, and the stirring was continued for 5 hours at 10° C. The organic phase was washed with three times 50 parts by volume of water, dried over sodium sulfate and evaporated under reduced pressure at 70° C. to give 25.6 parts by weight of 2-chloro-2',6'-dimethyl-N-(4-methylpyrazol-1-yl-methyl)-acetanilide of melting point 100° C.; the product was pure according to the 1H-NMR spectrum and according to thin layer chromatography carried out using a 3:7 ethyl acetate:toluene mixture.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[N:8]=[CH:7][C:6]([CH2:9]O)=[CH:5][CH:4]=1.P([N:29]=[N+:30]=[N-:31])(=O)(OC1C=CC=CC=1)OC1C=CC=CC=1.C1CCN2C(=NCCC2)CC1>C1(C)C=CC=CC=1>[N:29]([CH2:9][C:6]1[CH:5]=[CH:4][C:3]([C:2]([F:12])([F:11])[F:1])=[N:8][CH:7]=1)=[N+:30]=[N-:31]
Reactant: OCc1ccc(C(F)(F)F)nc1
Reactant: [N-]=[N+]=NP(=O)(Oc1ccccc1)Oc1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: Cc1ccccc1
Product: [N-]=[N+]=NCc1ccc(C(F)(F)F)nc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 100.7 %

Procedure:
A mixture of (6-(trifluoromethyl)pyridin-3-yl)methanol (2.0 g, 11.3 mmol) and diphenyl phosphorazidate (2.93 mL, 14 mmol) was dissolved in dry toluene (20 mL). The mixture was cooled to 0° C. under Argon, and neat DBU (2.1 mL, 14 mmol) was added. The reaction mixture was stirred for 2 h at 0° C. and then at rt for 16 h. The resulting two-phase mixture was washed with water and extracted with EtOAc. The combined organic layer was concentrated in vacuo and purified by silica gel chromotography afford 5-(azidomethyl)-2-(trifluoromethyl)pyridine (2.3 g, quantitative yield) of a light yellow oil: 1H NMR (300 MHz, CDCl3+CD3OD), d: 8.686 (m, 1H), 7.853 (m, 1H), 7.723 (d, J=8.1 Hz, 1H), 4.518 (s, 2H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]([NH:12][C@H:13]([C:23]([O:25]C)=[O:24])[CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)=[O:11])[CH:5]=[CH:6][CH:7]=1.[OH-].[Na+]>CO>[F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]([NH:12][C@H:13]([C:23]([OH:25])=[O:24])[CH2:14][C:15]2[CH:16]=[CH:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=2)=[O:11])[CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)[C@H](Cc1ccc(OC)cc1)NC(=O)C=Cc1cccc(F)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc(C[C@H](NC(=O)C=Cc2cccc(F)c2)C(=O)O)cc1
Yield: 61 %

Procedure:
The same procedures as in Example 90 were carried out from the compound obtained in Example 39 (2.9 g), 1 mol/L of an aqueous sodium hydroxide solution (12 mL), and methanol (120 mL), to give the captioned compound (1.7 g, 61%) as crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[O:12][CH3:13])[CH2:6][CH2:7][OH:8].C(O[CH:17](OCC)[CH2:18][Cl:19])C.Cl>O>[Cl:19][CH2:18][CH:17]1[C:9]2[C:5](=[CH:4][C:3]([O:2][CH3:1])=[C:11]([O:12][CH3:13])[CH:10]=2)[CH2:6][CH2:7][O:8]1
Reactant: CCOC(CCl)OCC
Reactant: COc1ccc(CCO)cc1OC
Agent: Cl
Solvent: O
Product: COc1cc2c(cc1OC)C(CCl)OCC2
Temperature: 90 °C
Reaction time: 0.17 h

Procedure:
To a mixture of 10 g. of 3,4-dimethoxyphenethylalcohol and 10 g. of chloroacetaldehyde diethyl acetal was added 14 ml of 10% hydrochloric acid. The mixture was stirred at 90° C for 10 minutes. After cooling, 100 ml of water was added to the reaction mixture, followed by extraction with benzene. The extract was rinsed with water, dried and concentrated under reduced pressure. By the above procedure was obtained 12 g of 1-chloromethyl-6,7-dimethoxyisochroman as an oil colored light-tan.
Reaction SMILES: Br(O)(=O)=O.[Br:5][CH2:6][CH2:7][NH2:8].C(N(CC)CC)C.Cl[C:17]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18]>ClCCl>[CH2:20]([O:19][C:17](=[O:18])[NH:8][CH2:7][CH2:6][Br:5])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: NCCBr
Reactant: O=C(Cl)OCc1ccccc1
Agent: [O-][Br+2]([O-])O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(NCCBr)OCc1ccccc1
Temperature: 25 °C

Procedure:
10 g (49 mmol) of 2-bromoethylamine bromate and 15 ml of triethylamine were dissolved in dichloromethane. 7.8 ml (49 mmol) of benzyl chloroformate was added to the solution under cooling with ice, and they were stirred at room temperature. After the treatment with dichloromethane as the extractant in an ordinary manner, the crude product was obtained. The crude product was purified by the silica gel column chromatography to obtain the title compound.
Reaction SMILES: [C:1]1([CH:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8]([OH:10])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CN(C1C=CC=CN=1)C.[CH2:26]([O:33][C:34]1[C:43]2[C:38](=[C:39]([CH2:44][CH2:45][NH2:46])[CH:40]=[CH:41][CH:42]=2)[CH:37]=[CH:36][CH:35]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.CCN=C=NCCCN(C)C.Cl>C(Cl)Cl.O>[CH2:26]([O:33][C:34]1[C:43]2[C:38](=[C:39]([CH2:44][CH2:45][NH:46][C:8]([CH:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[O:10])[CH:40]=[CH:41][CH:42]=2)[CH:37]=[CH:36][CH:35]=1)[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: NCCc1cccc2c(OCc3ccccc3)cccc12
Reactant: O=C(O)C(c1ccccc1)c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccccn1
Agent: Cl
Solvent: O
Solvent: ClCCl
Product: O=C(NCCc1cccc2c(OCc3ccccc3)cccc12)C(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 51.6 %

Procedure:
To a solution of diphenylacetic acid (0.171 g) in methylene chloride (10 ml), dimethylaminopyridine (0.01 g) and 1-benzyloxy-5-(2-aminoethyl)naphthalene (0.196 g) were added at room temperature. After 10 minutes, EDC·HCl (0.154 g) was added to the mixture solution. The mixture was stirred overnight at room temperature for 1 night. After termination of reaction, water and methylene chloride were added to the reaction mixture. The organic layer was washed with a saturated aqueous solution of ammonium chloride, water and a saturated aqueous solution of sodium chloride, dried over and concentrated under reduced pressure. The residue was purified on silica gel chromatography to give the title compound (0.172 g) having the following physical data.
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[C:7]([S:9]([CH3:12])(=[O:11])=[O:10])[CH:6]=[CH:5][C:4]=1[NH:13][C@H:14]1[CH2:19][CH2:18][CH2:17][N:16]([CH:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)[C:15]1=[O:26].[OH-].[K+].Cl[C:30]1[C:35]([CH3:36])=[CH:34][C:33]([CH2:37][CH3:38])=[CH:32][N:31]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(N(C)C)=CC=CC=2)CCCCC1.CC([O-])(C)C.[Na+]>CO.O.CC([O-])=O.CC([O-])=O.[Pd+2].C1(C)C=CC=CC=1>[CH2:37]([C:33]1[CH:34]=[C:35]([CH3:36])[C:30]([N:23]2[CH2:22][CH2:21][CH:20]([N:16]3[CH2:17][CH2:18][CH2:19][CH:14]([NH:13][C:4]4[CH:5]=[CH:6][C:7]([S:9]([CH3:12])(=[O:11])=[O:10])=[CH:8][C:3]=4[F:2])[C:15]3=[O:26])[CH2:25][CH2:24]2)=[N:31][CH:32]=1)[CH3:38]
Reactant: CS(=O)(=O)c1ccc(N[C@H]2CCCN(C3CCNCC3)C2=O)c(F)c1
Reactant: CCc1cnc(Cl)c(C)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: Cc1ccccc1
Solvent: CO
Solvent: O
Product: CCc1cnc(N2CCC(N3CCCC(Nc4ccc(S(C)(=O)=O)cc4F)C3=O)CC2)c(C)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 66.5 %

Procedure:
To a solution of (S)-3-(2-fluoro-4-(methylsulfonyl)phenylamino)-1,4′-bipiperidin-2-one hydrochloride (prepared according to the method of Example 45) (0.100 g, 0.246 mmol) in 5 mL MeOH was added KOH (0.014 g, 0.246 mmol). The mixture was stirred for 30 minutes at ambient temperature, cooled in an ice bath and filtered through a syringe filter, and the filtrate was concentrated and used directly. To the obtained residue was added 2-chloro-5-ethyl-3-methylpyridine (0.0460 g, 0.296 mmol), toluene (5 mL), Pd(OAc)2 (0.00830 g, 0.0370 mmol), 2′-(dicyclohexylphosphino)-N,N-dimethylbiphenyl-2-amine (also known as “DavePhos”) (0.0291 g, 0.0739 mmol), and NaOtBu (0.0710 g, 0.739 mmol) and the mixture was heated at 110° C. overnight. The reaction was cooled to ambient temperature, diluted with water and extracted with CH2Cl2. The organic layers were combined, dried over Na2SO4 and purified on silica gel eluting with 100% EtOAc to give 1′-(5-ethyl-3-methylpyridin-2-yl)-3-(2-fluoro-4-(methylsulfonyl)phenylamino)-1,4′-bipiperidin-2-one (0.080 g, 66.5% yield) as a white solid. Mass spectrum (apci) m/z=489.3 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH2:7][CH:6]([CH2:11][NH:12][C@@H:13]1[CH2:18][CH2:17][C@H:16]([N:19]3[C:23]4[CH:24]=[CH:25][C:26]([CH3:28])=[CH:27][C:22]=4[N:21]=[C:20]3[C:29]([OH:32])([CH3:31])[CH3:30])[CH2:15][CH2:14]1)[CH2:5]2>C1CCCCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH2:7][CH:6]([CH2:11][NH:12][C@H:13]1[CH2:18][CH2:17][C@H:16]([N:19]3[C:23]4[CH:24]=[CH:25][C:26]([CH3:28])=[CH:27][C:22]=4[N:21]=[C:20]3[C:29]([OH:32])([CH3:30])[CH3:31])[CH2:15][CH2:14]1)[CH2:5]2
Reactant: Cc1ccc2c(c1)nc(C(C)(C)O)n2[C@H]1CC[C@@H](NCC2Cc3ccc(Cl)cc3C2)CC1
Solvent: C1CCCCC1
Product: Cc1ccc2c(c1)nc(C(C)(C)O)n2[C@H]1CC[C@H](NCC2Cc3ccc(Cl)cc3C2)CC1

Procedure:
This compound was isolated as the second and more polar substance in the preparation of cis-2-(1-{4-[(5-chloro-indan-2-ylmethyl)-amino]-cyclohexyl}-5-methyl-1H-benzoimidazol-2-yl)-propan-2-ol. The analysis of the 1H-NMR confirmed the trans-conformation of the cyclohexane. LC-MS showed a single peak, C27H34ClN3O (m/e) calcd 451.2390, obsd 452.3 (M+H).
Reaction SMILES: [CH3:1][C:2]1([CH3:11])[C:7](=[O:8])[CH2:6][C:5](=[O:9])[CH:4]([CH3:10])[O:3]1.C(Cl)(Cl)Cl.C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.[Br:28][C:29]1[CH:34]=[CH:33][C:32]([Pb+3])=[C:31]([CH2:36][CH3:37])[CH:30]=1.Cl>CN(C)C1C=CN=CC=1.C1(C)C=CC=CC=1>[Br:28][C:29]1[CH:34]=[CH:33][C:32]([CH:6]2[C:5](=[O:9])[CH:4]([CH3:10])[O:3][C:2]([CH3:11])([CH3:1])[C:7]2=[O:8])=[C:31]([CH2:36][CH3:37])[CH:30]=1
Reactant: CCc1cc(Br)ccc1[Pb+3]
Reactant: CC1OC(C)(C)C(=O)CC1=O
Agent: CC(=O)[O-]
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: Cc1ccccc1
Product: CCc1cc(Br)ccc1C1C(=O)C(C)OC(C)(C)C1=O
Temperature: 80 °C
Yield: 23 %

Procedure:
2,2,6-Trimethylpyran-3,5-dione (1 g, 6.4 mmol) and 4-dimethylaminopyridine (3.9 g, 32 mmol) are added to a mixture of chloroform (20 ml) and toluene (5 ml). The reaction mixture is flushed with nitrogen for 15 minutes at ambient temperature. 4-Bromo-2-ethylphenyllead triacetate (4.3 g, 7.57 mmol) is added in one portion and the reaction mixture is stirred and heated to 80° C. (pre-heated oil bath) under an atmosphere of nitrogen for 1 hour. The reaction mixture is cooled to room temperature, acidified to pH 1 with 2N aqueous hydrochloric acid, filtered through a plug of diatomaceous earth and the two phases are separated. The aqueous phase is extracted with chloroform (2×25 ml), the organic phases are combined, washed with water, and dried over anhydrous sodium sulfate. The mixture is filtered, and the filtrate is evaporated under reduced pressure. The residue is purified by column chromatography on silica gel to give 4-(4-bromo-2-ethylphenyl)-2,2,6-trimethylpyran-3,5-dione as a white solid (0.5 g).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5](Br)=[CH:4][N:3]=1.[C:9]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)(=[O:12])[CH:10]=[CH2:11].C(N(C(C)C)CC)(C)C>C(#N)CC.CC([O-])=O.CC([O-])=O.[Pd+2]>[NH2:1][C:2]1[N:3]=[CH:4][C:5](/[CH:11]=[CH:10]/[C:9]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:12])=[CH:6][CH:7]=1
Reactant: Nc1ccc(Br)cn1
Reactant: C=CC(=O)OCc1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CCC#N
Solvent: CCN(C(C)C)C(C)C
Product: Nc1ccc(/C=C/C(=O)OCc2ccccc2)cn1
Yield: 39.3 %

Procedure:
A solution of 2-amino-5-bromopyridine (2.25 g, 13.0 mmole), benzyl acrylate (3.2 g, 19.7 mmole), Pd(OAc)2 (0.31 g, 1.4 mmole), tri-ort/10-tolylphosphine (0.73 g, 2.4 mmole), and diisopropylethylamine (3.5 mL, 20.0 mmole) in propionitrile (50 mL) was heated at reflux overnight. The dark mixture was filtered through Celite®, and the filtrate was concentrated. Flash chromatography on silica gel (3% MeOH/CH2Cl2) gave the title compound (1.3 g, 39%): MS (ES) m/e 255 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C@@H:11](O)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH3:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN(CC)CC.CS(Cl)(=O)=O.[N-:40]=[N+:41]=[N-:42].[Na+]>C(Cl)Cl>[N:40]([C@H:11]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[C@@H:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH3:10])=[N+:41]=[N-:42]
Reactant: [N-]=[N+]=[N-]
Reactant: CCCCCCCCCCCCCCC[C@H](O)[C@H](C)NC(=O)OC(C)(C)C
Agent: CS(=O)(=O)Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCCCCCCCCCCC[C@@H](N=[N+]=[N-])[C@H](C)NC(=O)OC(C)(C)C
Reaction time: 2 h
Yield: 50.7 %

Procedure:
To a cold (0° C.) solution of alcohol 94 (48 mg, 0.12 mmol) in CH2Cl2 (1.25 mL), Et3N (52 μL, 0.37 mmol) and MsCl (24 μL, 0.31 mmol) were added. After stirring for 2 h, the mixture was quenched with H2O (10 mL), extracted with CH2Cl2 (3×10 mL), dried over Na2SO4 and concentrated in vacuo. The crude mesylate was dissolved in DMF (0.65 mL) and NaN3 (40.5 mg, 0.62 mmol) was added. The mixture was stirred at 120 C. for 3 h and then quenched with H2O (10 mL), extracted with Et2O (3×10 mL), dried over Na2SO4 and concentrated in vacuo. The crude was purified by column chromatography on silica (hexane/EtOAc 10:1 to 5:1) to obtain azide 95 as a colorless oil (25 mg, 49% yield).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([Cl:20])=[C:6]([N:8]2[CH2:18][C@@H:17]([CH3:19])[CH2:16][C@H:9]2[C:10]([NH:12][CH2:13][C:14]#[N:15])=[O:11])[CH:7]=1.[C:21]([O:25][C:26]([N:28]1[CH2:33][CH2:32][N:31]([C:34]2[CH:39]=[CH:38][C:37](B(O)O)=[CH:36][CH:35]=2)[CH2:30][CH2:29]1)=[O:27])([CH3:24])([CH3:23])[CH3:22].C(=O)([O-])[O-].[Na+].[Na+].O>CN(C=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[C:21]([O:25][C:26]([N:28]1[CH2:33][CH2:32][N:31]([C:34]2[CH:39]=[CH:38][C:37]([C:2]3[CH:3]=[CH:4][C:5]([Cl:20])=[C:6]([N:8]4[CH2:18][C@@H:17]([CH3:19])[CH2:16][C@H:9]4[C:10]([NH:12][CH2:13][C:14]#[N:15])=[O:11])[CH:7]=3)=[CH:36][CH:35]=2)[CH2:30][CH2:29]1)=[O:27])([CH3:24])([CH3:22])[CH3:23]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(B(O)O)cc2)CC1
Reactant: C[C@H]1C[C@@H](C(=O)NCC#N)N(c2cc(Br)ccc2Cl)C1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CN(C)C=O
Product: C[C@H]1C[C@@H](C(=O)NCC#N)N(c2cc(-c3ccc(N4CCN(C(=O)OC(C)(C)C)CC4)cc3)ccc2Cl)C1
Temperature: 95 °C

Procedure:
To (4S)-1-(5-bromo-2-chlorophenyl)-N-(cyanomethyl)-4-methyl-L-prolinamide (40 mg, 0.112 mmol),4-[4-(tert-butoxycarbonyl)-1-piperazinyl]phenylboronic acid (42 mg, 0.135 mmol, prepared as described in Example 1) and catalyst PdCl2(dppf) (5 mg, 0.0034 mmol) in DMF (2 mL) under dry nitrogen was added aqueous sodium carbonate (2.0 M, 0.17 mL, 0.336 mmol). The reaction was heated to 95° C. for 1 hour and an additional aliquot of PdCl2(dppf) (365 mg, 0.45 mmol) was added and the reaction mixture was heated for 3 hours. Water was added and the product extracted with ether (3×), dried over Na2SO4, concentrated in vacuo and purified by flash chromatography over silica gel (EtOAc/Hex, 4/6) to afford (4S)-1-{4′-[4-(tert-butoxycarbonyl)piperazin-1-yl]-4-chloro-1,1′-biphenyl-3-yl}-N-(cyanomethyl)-4-methyl-L-prolinamide.
Reaction SMILES: [CH3:1][C:2]1[C:6]2[C:7](=[O:19])[N:8]([CH2:12][CH2:13][N:14]3[CH2:18][CH2:17][CH2:16][CH2:15]3)[CH2:9][CH2:10][CH2:11][C:5]=2[NH:4][C:3]=1[CH:20]=O.[F:22][C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][CH:31]=1)[NH:28][C:27](=[O:32])[CH2:26]2>>[F:22][C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][CH:31]=1)[NH:28][C:27](=[O:32])/[C:26]/2=[CH:20]\[C:3]1[NH:4][C:5]2[CH2:11][CH2:10][CH2:9][N:8]([CH2:12][CH2:13][N:14]3[CH2:15][CH2:16][CH2:17][CH2:18]3)[C:7](=[O:19])[C:6]=2[C:2]=1[CH3:1]
Reactant: O=C1Cc2cc(F)ccc2N1
Reactant: Cc1c(C=O)[nH]c2c1C(=O)N(CCN1CCCC1)CCC2
Product: Cc1c(/C=C2\C(=O)Nc3ccc(F)cc32)[nH]c2c1C(=O)N(CCN1CCCC1)CCC2
Yield: 80.8 %

Procedure:
The title compound was prepared under the same conditions as described in step 4 of Example 28 with 3-methyl-4-oxo-5-(2-pyrrolidin-1-yl-ethyl)-1,4,5,6,7,8-hexahydro-pyrrolo[3,2-c]azepine-2-carbaldehyde 28c obtained from step 3 of Example 28 and 5-fluoro-1,3-dihydro-indol-2-one as starting materials to obtain (Z)-2-(5-fluoro-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-3-methyl-5-(2-pyrrolidin-1-yl-ethyl)-5,6,7,8-tetrahydro-1H-pyrrolo[3,2-c]azepin-4-one 45 (61 mg, yield 80.8%) as an orange solid.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[N:9]([CH3:23])[C:10](=[O:22])[CH2:11][C@:12]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([NH2:21])[CH:16]=2)([CH3:14])[N:13]=1)(C)(C)C.[F:25][C:26]([F:34])([F:33])[C:27]1([C:30](O)=[O:31])[CH2:29][CH2:28]1>>[NH2:7][C:8]1[N:9]([CH3:23])[C:10](=[O:22])[CH2:11][C@:12]([C:15]2[CH:16]=[C:17]([NH:21][C:30]([C:27]3([C:26]([F:34])([F:33])[F:25])[CH2:29][CH2:28]3)=[O:31])[CH:18]=[CH:19][CH:20]=2)([CH3:14])[N:13]=1
Reactant: O=C(O)C1(C(F)(F)F)CC1
Reactant: CN1C(=O)C[C@@](C)(c2cccc(N)c2)N=C1NC(=O)OC(C)(C)C
Product: CN1C(=O)C[C@@](C)(c2cccc(NC(=O)C3(C(F)(F)F)CC3)c2)N=C1N

Procedure:
The coupling of [(S)-4-(3-amino-phenyl)-1,4-dimethyl-6-oxo-1,4,5,6-tetrahydro-pyrimidin-2-yl]-carbamic acid tert-butyl ester (intermediate F3) and 1-trifluoromethyl-cyclopropanecarboxylic acid followed by deprotection of the intermediate yielded the title compound as a white solid. MS (ESI): m/z=369.2 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[F:11])[NH:7][N:6]=[C:5]2[C:12]([OH:14])=[O:13].CC1(C)COB([C:22]2[CH:27]=[CH:26][C:25]([CH:28]3[CH2:33][CH2:32][O:31][CH2:30][CH2:29]3)=[CH:24][CH:23]=2)OC1.C(=O)([O-])[O-].[K+].[K+].Cl>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C1(C)C=CC=CC=1.C(O)C>[F:11][C:10]1[CH:9]=[C:8]2[C:4]([C:5]([C:12]([OH:14])=[O:13])=[N:6][NH:7]2)=[CH:3][C:2]=1[C:22]1[CH:23]=[CH:24][C:25]([CH:28]2[CH2:29][CH2:30][O:31][CH2:32][CH2:33]2)=[CH:26][CH:27]=1
Reactant: O=C(O)c1n[nH]c2cc(F)c(Br)cc12
Reactant: CC1(C)COB(c2ccc(C3CCOCC3)cc2)OC1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CCO
Product: O=C(O)c1n[nH]c2cc(F)c(-c3ccc(C4CCOCC4)cc3)cc12
Temperature: 110 °C
Yield: 10.6 %

Procedure:
A mixture of 5-bromo-6-fluoro-1H-indazole-3-carboxylic acid (793 mg, 3.06 mmol), 5,5-dimethyl-2-[4-(tetrahydro-2H-pyran-4-yl)phenyl]-1,3,2-dioxaborinane (839 mg, 3.06 mmol) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (175 mg, 0.214 mmol) were sealed in a vial and purged with nitrogen. Ethanol (4 mL), toluene (2 mL) and aqueous 2M potassium carbonate (3.67 ml, 7.34 mmol) were added and the mixture was heated at 110° C. for 50 minutes. The cooled reaction mixture was poured into dilute HCl and extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo to give crude material, which was purified using reverse-phase chromatography. The product was crystallized from isopropanol/hexane to give the title compound as a crystalline solid (110 mg, 11% yield). MS (ES−) 339.1 (M−H)−. 1H NMR (500 MHz, CD3OD) δ 8.34 (d, J=7.32 Hz, 1H), 7.54 (d, 2H), 7.35 (d, 2H), 7.27 (d, J=10.25 Hz, 1H), 4.08 (d, J=10.25 Hz, 2H), 3.61 (td, J=10.98, 3.42 Hz, 2H), 2.88 (m, 1H), 1.81-1.90 (m, 4H). m.p.=295° C.