Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.BrN1C(=O)CCC1=O.[CH:28]1([CH2:33][CH:34]([C:38]2[CH:43]=[CH:42][C:41]([Cl:44])=[C:40]([Cl:45])[CH:39]=2)[C:35]([OH:37])=O)[CH2:32][CH2:31][CH2:30][CH2:29]1.[NH2:46][C:47]1[CH:54]=[CH:53][C:50]([C:51]#[N:52])=[CH:49][N:48]=1.N1C=CC=CC=1>C(Cl)Cl.O>[C:51]([C:50]1[CH:53]=[CH:54][C:47]([NH:46][C:35](=[O:37])[CH:34]([C:38]2[CH:43]=[CH:42][C:41]([Cl:44])=[C:40]([Cl:45])[CH:39]=2)[CH2:33][CH:28]2[CH2:29][CH2:30][CH2:31][CH2:32]2)=[N:48][CH:49]=1)#[N:52]
Reactant: N#Cc1ccc(N)nc1
Reactant: O=C(O)C(CC1CCCC1)c1ccc(Cl)c(Cl)c1
Agent: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: ClCCl
Solvent: c1ccncc1
Product: N#Cc1ccc(NC(=O)C(CC2CCCC2)c2ccc(Cl)c(Cl)c2)nc1
Temperature: 0 °C
Yield: 72.6 %

Procedure:
A solution of triphenylphosphine (1.23 g, 4.70 mmol) in methylene chloride (26 mL) was cooled to 0° C. and then treated with N-bromosuccinimide (948 mg, 5.33 mmol). The reaction mixture was stirred at 0° C. until it was completely dissolved and became light purple in color. The reaction mixture was then treated with 3-cyclopentyl-2-(3,4-dichloro-phenyl)-propionic acid (prepared as in Example 38A, 900 mg, 3.13 mmol). The reaction mixture was stirred at 0° C. for 20 min and then warmed to 25° C. where it stirred for 30 min. After such time, the reaction mixture was treated with 6-amino-nicotinonitrile (560 mg, 4.70 mmol) and pyridine (0.46 mL, 5.64 mmol), and the reaction mixture was stirred at 25° C. for 16 h. The reaction was then diluted with water (25 mL) and then extracted with methylene chloride (3×25 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230–400 mesh, 85/15 hexanes/ethyl acetate) afforded N-(5-cyano-pyridin-2-yl)-3-cyclopentyl-2-(3,4-dichloro-phenyl)-propionamide (882 mg, 73%) as a pink foam: EI-HRMS m/e calcd for C20H19Cl2N3O (M+) 387.0905, found 387.0905.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.BrC1C=CC(C(O)=O)=CC=1.S(Cl)(Cl)=O.[CH2:25]([C:29]1[O:30][C:31]2[CH:37]=[CH:36][C:35]([NH:38][S:39]([CH3:42])(=[O:41])=[O:40])=[CH:34][C:32]=2[CH:33]=1)[CH2:26][CH2:27][CH3:28]>ClCCl>[CH2:25]([C:29]1[O:30][C:31]2[CH:37]=[CH:36][C:35]([NH:38][S:39]([CH3:42])(=[O:40])=[O:41])=[CH:34][C:32]=2[C:33]=1[C:6](=[O:7])[C:5]1[CH:9]=[CH:10][C:2]([Br:1])=[CH:3][CH:4]=1)[CH2:26][CH2:27][CH3:28]
Reactant: CCCCc1cc2cc(NS(C)(=O)=O)ccc2o1
Reactant: O=C(Cl)c1ccc(Br)cc1
Agent: O=C(O)c1ccc(Br)cc1
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: CCCCc1oc2ccc(NS(C)(=O)=O)cc2c1C(=O)c1ccc(Br)cc1

Procedure:
5.08 g of 4-bromobenzoyl chloride—prepared by reacting 4-bromobenzoic acid with thionyl chloride—and 5.42 g of 2-butyl-5-methanesulfonamido-benzofuran (IV) were dissolved in 30 ml of dichloromethane. The reaction was performed according to Example 10.
Reaction SMILES: [OH:1][C:2]1[CH:13]=[CH:12][C:5]2[S:6][CH:7]=[C:8]([C:9]([OH:11])=[O:10])[C:4]=2[CH:3]=1.O.[C:15](OC(=O)C)(=[O:17])[CH3:16]>N1C=CC=CC=1>[C:15]([O:1][C:2]1[CH:13]=[CH:12][C:5]2[S:6][CH:7]=[C:8]([C:9]([OH:11])=[O:10])[C:4]=2[CH:3]=1)(=[O:17])[CH3:16]
Reactant: O=C(O)c1csc2ccc(O)cc12
Reactant: CC(=O)OC(C)=O
Solvent: O
Solvent: c1ccncc1
Product: CC(=O)Oc1ccc2scc(C(=O)O)c2c1
Reaction time: 3 h
Yield: 97.3 %

Procedure:
A solution of 1,140 mg of the above obtained 5-hydroxybenzo[b]thiophene-3-carboxylic acid (1) in 2 ml of acetic anhydride and 4 ml of pyridine was allowed to stand for 3 hours. After addition of water, the mixture was stirred for 1.5 hours under ice-cooling, and the precipitated crystals were filtered, washed with water, and dried to give 1,349 mg of 5-acetoxybenzo[b]thiophene-3-carboxylic acid (4). Yield 97.3%. mp 239-240° C.
Reaction SMILES: C(OC([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([O:18][CH3:19])[CH:16]=2)[CH2:11][CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O.C(=O)([O-])[O-].[Na+].[Na+]>ClCCl>[CH3:19][O:18][C:15]1[CH:16]=[C:17]2[C:12]([CH2:11][CH2:10][CH2:9][NH:8]2)=[CH:13][CH:14]=1
Reactant: COc1ccc2c(c1)N(C(=O)OC(C)(C)C)CCC2
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc2c(c1)NCCC2
Temperature: 25 °C
Reaction time: 24 h
Yield: 113.3 %

Procedure:
To a solution of 7-methoxy-3,4-dihydro-2H-quinoline-1-carboxylic acid tert-butyl ester (52 mg, 0.20 mmol) in dichloromethane (7 ml) at 0° C. was added dropwise trifluoroacetic acid (0.23 ml, 3.01 mmol) and the reaction mixture was then stirred at room temperature for 24 h. The mixture was then made basic to pH 9 by dropwise addition of saturated aq. sodium carbonate solution. The mixture was extracted three times with a 1:1 mixture of ethyl acetate and tetrahydrofuran, the phases separated, and the organic phase dried over sodium sulphate and concentrated in vacuo to yield the title compound as a light brown oil (37 mg, 92%); MS (ISP): 164.4 ([M+H]+).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][CH:3]=1.[OH-].[Na+].Cl[C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14].C(OCC)(=O)C>C1COCC1.O.[Cl-].[Na+].O>[CH2:16]([O:15][C:13](=[O:14])[NH:7][CH2:6][C:5]1[CH:8]=[CH:9][C:2]([OH:1])=[CH:3][CH:4]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: NCc1ccc(O)cc1
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: O=C(NCc1ccc(O)cc1)OCc1ccccc1
Temperature: 0 °C
Reaction time: 18 h
Yield: 117.6 %

Procedure:
A solution of 4-hydroxybenzylamine (1 g, 8.1 mmol) in THF (20 ml) and water (20 ml) was cooled down to 0° C. with sodium hydroxide (357 mg, 8.9 mmol). Benzyl chloroformate (1.27 ml, 8.9 mmol) was added slowly and the reaction mixture was stirred at 0° C. for 1 h and at r.t. for 18 hours. Brine (20 ml) and ethyl acetate (20 mL) were added and the phases were separated. The aqueous phase was extracted with EtOAc (20 mL). The organic phase was dried over magnesium sulfate, filtered and concentrated to dryness to yield a light pink solid (2.45 g, 100%). 1H NMR (300 MHz, CDCl3), δ: 4.30 (2 H, d, J=5.8 Hz, CH2NH), 5.15 (2 H, s, OCH2), 6.67 (1 H, br. s, NH), 6.78 (2 H, d, J=8.5 Hz, Ar), 7.12 (2 H, d, J=8.1 Hz, Ar), 7.29-7.44 (5 H, m, Ar)
Reaction SMILES: Br.[C:2]1([C:8]2[N:9]=[C:10]3[C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:14][CH:13]=[CH:12][N:11]3[CH:21]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P(Cl)(Cl)(Cl)=O.[OH-].[Na+].CN([CH:32]=[O:33])C>>[CH:32]([C:21]1[N:11]2[CH:12]=[CH:13][CH:14]=[C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:10]2=[N:9][C:8]=1[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:33]
Reactant: CCOC(=O)c1cccn2cc(-c3ccccc3)nc12
Reactant: CN(C)C=O
Agent: Br
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Product: CCOC(=O)c1cccn2c(C=O)c(-c3ccccc3)nc12
Temperature: 0 °C
Yield: 85.5 %

Procedure:
To a solution of ethyl 2-phenyl-imidazo[1,2-a]-pyridine-8-carboxylate hydrogen bromide (14.7 g, 4 m mol) in DMF (8 ml) was dropwise added phosphorus oxychloride (2 ml) keeping the inner temperature to below 15° C. Then, the mixture was allowed to react at room temperature for 30 minutes and at 70° C. for 2 hours. After completion of the reaction, the reaction mixture was cooled, poured into ice water and adjusted to pH 7 by adding 20% sodium hydroxide. The precipitated crystals were collected by filtration and recrystallized from ethanol to obtain the object compound (1.0 g, yield 85.5%) as colorless crystals. m.p. 139° C.
Reaction SMILES: [C:1](=[O:4])(O)[O-:2].[Na+].ClC(OCC)=O.[CH2:12]([O:19][C:20]1[CH:26]=[CH:25][C:23]([NH2:24])=[CH:22][CH:21]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[CH2:27]1[CH2:31][O:30][CH2:29][CH2:28]1>O>[CH2:12]([O:19][C:20]1[CH:21]=[CH:22][C:23]([N:24]2[CH2:27][C@H:28]([CH2:29][O:30][CH3:31])[O:2][C:1]2=[O:4])=[CH:25][CH:26]=1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: Nc1ccc(OCc2ccccc2)cc1
Reactant: C1CCOC1
Reactant: O=C([O-])O
Agent: CCOC(=O)Cl
Agent: [Na+]
Solvent: O
Product: COC[C@H]1CN(c2ccc(OCc3ccccc3)cc2)C(=O)O1
Reaction time: 18 h
Yield: 91 %

Procedure:
6.3 g sodium bicarbonate followed by 5.28 ml (55.10-3 mol) of ethyl chloroformate was added to a solution of 10 g (10-3 mol) of 4-benzyloxy aniline in 90 ml THF and 10 ml water. After agitation for 18 hours, the reaction medium was filtered and concentrated. The residue was dissolved in ethyl acetate. The organic solution was washed with water, dried on Na2SO4 and concentrated. The product was obtained with a 91% yield.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH2:12][O:13][CH2:14][CH:15]=2)=[CH:7][N:6]=1)=[O:4].[CH3:16][O:17][C:18]([C:20]1[CH:25]=[CH:24][C:23]([C:26]2[O:27][CH2:28][CH2:29][CH:30]=2)=[CH:22][N:21]=1)=[O:19]>CO.[Pd]>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[CH2:15][CH2:14][O:13][CH2:12]2)=[CH:7][N:6]=1)=[O:4].[CH3:16][O:17][C:18]([C:20]1[CH:25]=[CH:24][C:23]([CH:26]2[CH2:30][CH2:29][CH2:28][O:27]2)=[CH:22][N:21]=1)=[O:19]
Reactant: COC(=O)c1ccc(C2=CCOC2)cn1
Reactant: COC(=O)c1ccc(C2=CCCO2)cn1
Agent: [Pd]
Solvent: CO
Product: COC(=O)c1ccc(C2CCCO2)cn1
Product: COC(=O)c1ccc(C2CCOC2)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 97 %

Procedure:
To a solution of 5-(2,5-dihydrofuran-3-yl)-pyridine-2-carboxylic acid methyl ester (a1) and 5-(4,5-dihydrofuran-2-yl)-pyridine-2-carboxylic acid methyl ester (a2) (mixture from Example 101 a, 8 g, 39 mmol) in methanol (200 ml) was added palladium on carbon (10% w/w, 0.8 g). The mixture was stirred under hydrogen balloon overnight at room temperature. After concentration, the crude product was purified by column chromatography (silica gel, 100 g, eluting with 30% ethyl acetate in petroleum ether) to give 5-(tetrahydrofuran-3-yl)-pyridine-2-carboxylic acid methyl ester (b1) and 5-(tetrahydrofuran-2-yl)-pyridine-2-carboxylic acid methyl ester (b2) (mixture, b1/b2=1/0.85 at UV 254 nm, 7.8 g, 97%) as colorless oil; MS (EI): m/e=208.1 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[N:10](CC=C)[C:9]2[C:8](=[O:14])[NH:7][C:6](=[O:15])[N:5]([CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[C:4]=2[N:3]=1.Br[CH2:22][CH2:23][CH2:24][CH2:25][CH:26]1[CH2:30][CH2:29][N:28]([CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:27]1=[O:38].C(=O)([O-])[O-].[K+].[K+].N1CCOCC1>C1COCC1.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:1][C:2]1[NH:10][C:9]2[C:8](=[O:14])[N:7]([CH2:22][CH2:23][CH2:24][CH2:25][CH:26]3[CH2:30][CH2:29][N:28]([CH2:31][C:32]4[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=4)[C:27]3=[O:38])[C:6](=[O:15])[N:5]([CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[C:4]=2[N:3]=1
Reactant: C=CCn1c(Cl)nc2c1c(=O)[nH]c(=O)n2CCCCC
Reactant: O=C1C(CCCCBr)CCN1Cc1ccccc1
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: [K+]
Solvent: C1CCOC1
Solvent: C1COCCN1
Product: CCCCCn1c(=O)n(CCCCC2CCN(Cc3ccccc3)C2=O)c(=O)c2[nH]c(Cl)nc21
Temperature: 50 °C
Reaction time: 18 h

Procedure:
To a solution of 8-chloro-3-pentyl-7-(2-propen-1-yl)-3,7-dihydro-1H-purine-2,6-dione (0.086 g, 0.29 mmol) and 3-(4-bromobutyl)-1-(phenylmethyl)-2-pyrrolidinone (0.17 g, 0.55 mmol, 1:1 mixture with 2-(phenylmethyl)-2-azaspiro[4.4]nonan-1-one) in THF (5 ml) was added potassium carbonate (0.08 g, 0.58 mmol) and the mixture heated and stirred at 50° C. for 18 h. The solution was allowed to cool then degassed (sequential evacuation followed by addition of nitrogen×3) and Pd(PPh3)4 (0.09 g, 0.077 mmol) followed by morpholine (0.2 ml, 2.2 mmol) added and the solution stirred at ambient temperature for 18 h. The solution was separated between ethyl acetate and dil HCl and the organics washed with brine, dried and concentrated. Purification of the residues using an aminopropyl SPE (5 g) eluting first with MeOH then 5% AcOH/MeOH yielded the title compound as a yellow oil which crystallised on standing under ether (0.031 g, 22%).
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([C@@H:10]2[C:14]3[C:15]([CH3:28])=[C:16]([NH:20][C:21](=[O:27])[CH2:22][C:23]([CH3:26])([CH3:25])[CH3:24])[C:17]([CH3:19])=[CH:18][C:13]=3[O:12][CH2:11]2)=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[C:29](Cl)(=[O:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>>[C:29]([C:18]1[C:13]2[O:12][CH2:11][C@H:10]([C:7]3[CH:6]=[CH:5][C:4]([CH:1]([CH3:2])[CH3:3])=[CH:9][CH:8]=3)[C:14]=2[C:15]([CH3:28])=[C:16]([NH:20][C:21](=[O:27])[CH2:22][C:23]([CH3:26])([CH3:25])[CH3:24])[C:17]=1[CH3:19])(=[O:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: Cc1cc2c(c(C)c1NC(=O)CC(C)(C)C)[C@@H](c1ccc(C(C)C)cc1)CO2
Product: Cc1c(NC(=O)CC(C)(C)C)c(C)c2c(c1C(=O)c1ccccc1)OC[C@@H]2c1ccc(C(C)C)cc1
Yield: 74 %

Procedure:
Using (+)-N-((3R)-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide obtained in Example 37 and benzoyl chloride, the title compound was obtained in the same manner as in Example 38. Yield: 74%. Melting point: 205-206° C. (ethyl acetate-hexane).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=2)=[C:5]([C:7]([N:9]2[CH2:14][C@H:13]3[C@H:11]([CH2:12]3)[C@H:10]2[CH2:15][NH2:16])=[O:8])[N:6]=1.[CH3:24][O:25][C:26]1[CH:27]=[C:28]([CH:32]=[C:33]([O:35][CH3:36])[CH:34]=1)[C:29](O)=[O:30]>>[NH2:1][C:2]1[S:3][C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=2)=[C:5]([C:7]([N:9]2[CH2:14][C@H:13]3[C@H:11]([CH2:12]3)[C@H:10]2[CH2:15][NH:16][C:29](=[O:30])[C:28]2[CH:32]=[C:33]([O:35][CH3:36])[CH:34]=[C:26]([O:25][CH3:24])[CH:27]=2)=[O:8])[N:6]=1
Reactant: COc1cc(OC)cc(C(=O)O)c1
Reactant: NC[C@@H]1[C@H]2C[C@H]2CN1C(=O)c1nc(N)sc1-c1cccc(F)c1
Product: COc1cc(OC)cc(C(=O)NC[C@@H]2[C@H]3C[C@H]3CN2C(=O)c2nc(N)sc2-c2cccc(F)c2)c1

Procedure:
prepared by reaction of [2-Amino-5-(3-fluoro-phenyl)-thiazol-4-yl]-((1S,2S,5R)-2-aminomethyl-3-aza-bicyclo[3.1.0]hex-3-yl)-methanone with 3,5-dimethoxy-benzoic acid. LC-MS (basic): tR=0.80 min; [M+H]+=497.3.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([S:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:5]([NH:8][C:9]([NH2:11])=[S:10])=[N:6][CH:7]=1.C(N(CC)CC)C.Cl[CH2:27][C:28](=O)[CH3:29].CCO>O>[Br:1][C:2]1[CH:3]=[C:4]([S:12][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:5]([NH:8][C:9]2[S:10][CH:27]=[C:28]([CH3:29])[N:11]=2)=[N:6][CH:7]=1
Reactant: NC(=S)Nc1ncc(Br)cc1Sc1ccccc1
Reactant: CC(=O)CCl
Solvent: CCN(CC)CC
Solvent: CCO
Solvent: O
Product: Cc1csc(Nc2ncc(Br)cc2Sc2ccccc2)n1
Yield: 100.8 %

Procedure:
mL 1-(5-Bromo-3-(phenylthio)pyridin-2-yl)thiourea (5.0 g, 14.69 mmol), triethylamine (6.0 mL, 44 mmol), 1-chloropropan-2-one (2.3 mL, 29.4 mmol), and EtOH (100 mL) were heated to 70° C. for 6 hours. The ethanol was reduced to ˜½ volume and water (150 mL) added and the precipitate was filtered to afford the title compound (5.6 g, 100% yield) as a tan solid after drying. 1H NMR (CDCl3) δ 9.01 (s, 1H), 8.42 (m, 1H), 7.92 (m, 1H), 7.32-7.15 (m, 5H), 6.44 (m, 1H0, 2.32 (m, 3H). Mass spectrum (apci) m/z=379.8 (M+H).
Reaction SMILES: [CH3:1][C:2]1[N:7]([C:8]2[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:11]=[CH:10][CH:9]=2)[C:6](=[O:18])[C:5]([C:19]([OH:21])=O)=[CH:4][C:3]=1[C:22]1[N:23]([CH3:27])[N:24]=[CH:25][CH:26]=1.CN(C(O[N:36]1N=[N:43][C:38]2C=CC=C[C:37]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CC(N(C)C)=O.Cl.NCC#N>O1CCOCC1>[C:37]([CH2:38][NH:43][C:19]([C:5]1[C:6](=[O:18])[N:7]([C:8]2[CH:9]=[CH:10][CH:11]=[C:12]([C:14]([F:17])([F:15])[F:16])[CH:13]=2)[C:2]([CH3:1])=[C:3]([C:22]2[N:23]([CH3:27])[N:24]=[CH:25][CH:26]=2)[CH:4]=1)=[O:21])#[N:36]
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: Cc1c(-c2ccnn2C)cc(C(=O)O)c(=O)n1-c1cccc(C(F)(F)F)c1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: N#CCN
Solvent: CC(=O)N(C)C
Solvent: C1COCCO1
Product: Cc1c(-c2ccnn2C)cc(C(=O)NCC#N)c(=O)n1-c1cccc(C(F)(F)F)c1
Reaction time: 0.17 h
Yield: 72.2 %

Procedure:
The compound obtained in step (a) (0.2 g, 0.53 mmol) was dissolved in 1,4-dioxane (5 ml), HBTU (0.19 g, 0.5 mmol) and DMA (0.32 g, 2.5 mmol). The mixture was stirred for 10 minutes and aminoacetonitrile hydrochloride (0.55 g, 0.6 mmol) was added. After 1 h the mixture was evaporated and the residue purified by chromatography on silica to give the amide (0.15 g, 72%) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)=[CH:4][C:3]=1[N:16]1[C:20](=[O:21])[C:19]2[CH2:22][CH2:23][CH2:24][CH2:25][C:18]=2[C:17]1=[O:26].[CH2:27]([N:29](CC)CC)[CH3:28].[CH:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>>[F:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)=[CH:4][C:3]=1[NH:16][C:17](=[O:26])[C:18]1[CH2:25][CH2:24][CH2:23][CH2:22][C:19]=1[C:20]([NH:29][CH:27]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[CH3:28])=[O:21]
Reactant: CCN(CC)CC
Reactant: O=C1C2=C(CCCC2)C(=O)N1c1cc(OC2CCCCC2)c(Cl)cc1F
Reactant: c1ccccc1
Product: CC(NC(=O)C1=C(C(=O)Nc2cc(OC3CCCCC3)c(Cl)cc2F)CCCC1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.3 %

Procedure:
N-(2-Fluoro-4-chloro-5-cyclohexyloxyphenyl)-3,4,5,6-tetrahydrophthalimide (1.00 g, 2.65 mmol), R-(+)-1-phenylethylamine (0.65 g, 5.36 mmol), triethylamine (0.268 g, 2.65 mmol) and benzene (25 ml) as a solvent were placed into a round bottom flask (50 cc) and stirred overnight at room temperature. After completion of the reaction, the solvent was distilled off under reduced pressure, and the precipitated crystals were isolated by filtration. The crystals were washed with hexane and dried to obtain N-(2-fluoro-4-chloro-5-cyclohexyloxyphenyl)-N'-(1-phenylethyl)-3,4,5,6-tetrahydrophthalamide as white crystals (1.09 g, 82.3% yield).
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[NH:7][C@H:8]1[CH2:13][CH2:12][C@@H:11]([N:14]=[N+:15]=[N-:16])[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[CH3:18][O:19][C:20](=[O:23])[C:21]#[CH:22].CCN(C(C)C)C(C)C>[Cu]I.C1COCC1>[CH3:18][O:19][C:20]([C:21]1[N:16]=[N:15][N:14]([C@H:11]2[CH2:12][CH2:13][C@@H:8]([NH:7][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:17])[CH2:9][CH2:10]2)[CH:22]=1)=[O:23]
Reactant: C#CC(=O)OC
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](N=[N+]=[N-])CC1
Agent: [Cu]I
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COC(=O)c1cn([C@H]2CC[C@@H](NC(=O)OC(C)(C)C)CC2)nn1
Temperature: 25 °C

Procedure:
To a THF (30 ml) solution under Ar of (cis-4-azido-cyclohexyl)carbamic acid tert-butyl ester (3.00 g) and propiolic acid methyl ester (1.05 g) were added CuI (2.38 g) and DIPEA (3.18 ml). The resulting slurry was stirred at RT over night. After dilution with EtOAc (200 ml) the mixture was washed with H2O (200 ml), dried over Na2SO4 and the solvent was evaporated. Chromatography (silica, CH2Cl2/MeOH 95:5) yielded 2.63 g (65%) of product. White crystals. MS 325.4 (95, [M+H]+), 269.4 (100, [M−tBu].+).
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][C:10]2([CH2:17][CH2:16][CH2:15][N:14]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C:13]2=[CH2:25])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C12BC(CCC1)CCC2.[OH-:35].[Na+].OO>O1CCCC1>[CH2:1]([N:8]1[CH2:12][CH2:11][C:10]2([CH2:17][CH2:16][CH2:15][N:14]([C:18]([O:20][C:21]([CH3:22])([CH3:24])[CH3:23])=[O:19])[CH:13]2[CH2:25][OH:35])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=C1N(C(=O)OC(C)(C)C)CCCC12CCN(Cc1ccccc1)C2
Reactant: [OH-]
Agent: B1C2CCCC1CCC2
Agent: OO
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCCC2(CCN(Cc3ccccc3)C2)C1CO
Temperature: 60 °C
Reaction time: 15 h

Procedure:
A solution of 5 mmol of tert-butyl 2-benzyl-6-methylene-2,7-diazaspiro[4.5]decane-7-carboxylate in 60 ml of tetrahydrofuran is admixed at 0° C. with 10.6 mmol of 9-borabicyclo[3.3.1]nonane (0.5M in tetrahydrofuran). The reaction solution is stirred at 60° C. for 15 hours and then cooled to room temperature. The solution is admixed with 50 ml each of 3M sodium hydroxide solution and 30% hydrogen peroxide. The reaction mixture is stirred at room temperature for 2 hours. Subsequently the phases are separated and the aqueous phase is saturated with potassium carbonate and extracted with ethyl acetate (3×). The combined organic phases are dried over sodium sulphate and evaporated. From the residue the title compound is identified by means of flash chromatography (SiO2 60 F) on the basis of the Rf value.
Reaction SMILES: S(O[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][O:17][C:18]1[NH:19][C:20]2[CH:26]=[CH:25][CH:24]=[CH:23][C:21]=2[N:22]=1)(C1C=CC(C)=CC=1)(=O)=O.[SH:27][C:28]1[NH:29][C:30]2[CH:36]=[CH:35][CH:34]=[CH:33][C:31]=2[N:32]=1.C(N(CC)CC)C.O>C(#N)C>[N:29]1[C:30]2[CH:36]=[CH:35][CH:34]=[CH:33][C:31]=2[NH:32][C:28]=1[S:27][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][O:17][C:18]1[NH:22][C:21]2[CH:23]=[CH:24][CH:25]=[CH:26][C:20]=2[N:19]=1
Reactant: Cc1ccc(S(=O)(=O)OCCCCCOc2nc3ccccc3[nH]2)cc1
Reactant: Sc1nc2ccccc2[nH]1
Solvent: CCN(CC)CC
Solvent: O
Solvent: CC#N
Product: c1ccc2[nH]c(OCCCCCSc3nc4ccccc4[nH]3)nc2c1
Temperature: 25 °C
Yield: 57 %

Procedure:
188 mg of the compound obtained in Example 15a and 75 mg of 2-mercaptobenzimidazole were refluxed for 4 hours in 10 ml of acetonitrile containing 0.1 g of triethylamine. After cooling to room temperature, the reaction mixture was added with water and extracted with ethyl acetate. The extract was dried over sodium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate:hexane) to obtain 100m g of the title compound (yield: 57%).
Reaction SMILES: [OH-].[NH4+:2].Cl[CH2:4][CH:5]=O.[C:7]([O:13][CH2:14][CH3:15])(=[O:12])[CH2:8][C:9]([CH3:11])=O>>[CH2:14]([O:13][C:7]([C:8]1[CH:5]=[CH:4][NH:2][C:9]=1[CH3:11])=[O:12])[CH3:15]
Reactant: O=CCCl
Reactant: CCOC(=O)CC(C)=O
Reactant: [NH4+]
Agent: [OH-]
Product: CCOC(=O)c1cc[nH]c1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 33.4 %

Procedure:
Ammonium hydroxide (28 to 30% (HCl titration (as NH3)), 290 mL, 4.3 mol) was added dropwise to a mixture of chloroacetaldehyde (50% wt aqueous solution, 182 mL, 1.43 mol) and ethyl acetoacetate (183 mL, 1.43 mol) at 0° C. The ice bath was removed, and the reaction mixture was stirred at ambient temperature overnight. The reaction mixture was extracted twice with ethyl acetate. The combined organic layers were washed with 2N hydrochloric acid and saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by flash chromatography eluting from silica gel with a gradient of 0-50% ethyl acetate in hexanes to afford 73.1 g of the title compound as a yellow solid. 1H NMR (200 MHz, CDCl3) δ 6.55 (2H, d, J=2.4 Hz), 4.26 (2H, q, J=7.4 Hz), 2.52 (3H, s), and 1.34 (3H, t, J=7.4 Hz).
Reaction SMILES: [CH3:1][N:2]([CH3:36])[C:3]([C:5]1[CH:6]=[C:7]([S:11]([C:13]2[CH:22]=[C:21]3[C:16]([C:17]([NH:26][C:27]4[CH:32]=[CH:31][CH:30]=[C:29]([O:33][CH3:34])[CH:28]=4)=[C:18]([C:23]([NH2:25])=[O:24])[CH:19]=[N:20]3)=[CH:15][C:14]=2I)=[O:12])[CH:8]=[CH:9][CH:10]=1)=[O:4].C(N(CC)CC)C>[Pd].C(O)C.CN(C)C=O>[CH3:1][N:2]([CH3:36])[C:3]([C:5]1[CH:6]=[C:7]([S:11]([C:13]2[CH:22]=[C:21]3[C:16]([C:17]([NH:26][C:27]4[CH:32]=[CH:31][CH:30]=[C:29]([O:33][CH3:34])[CH:28]=4)=[C:18]([C:23]([NH2:25])=[O:24])[CH:19]=[N:20]3)=[CH:15][CH:14]=2)=[O:12])[CH:8]=[CH:9][CH:10]=1)=[O:4]
Reactant: COc1cccc(Nc2c(C(N)=O)cnc3cc(S(=O)c4cccc(C(=O)N(C)C)c4)c(I)cc23)c1
Agent: [Pd]
Solvent: CN(C)C=O
Solvent: CCO
Solvent: CCN(CC)CC
Product: COc1cccc(Nc2c(C(N)=O)cnc3cc(S(=O)c4cccc(C(=O)N(C)C)c4)ccc23)c1
Reaction time: 4 h
Yield: 29.3 %

Procedure:
A mixture containing Intermediate 65 (0.15 g), 10% palladium on activated carbon (0.04 g) and triethylamine (5 ml) in ethanol (25 ml) and N,N-dimethylformamide (10 ml) was hydrogenated at room temperature for 4 h. The suspension was filtered through celite, the residue washed with ethanol/N,N-dimethylformamide (3:1, 50 ml), and the filtrate concentrated in vacuo. The residue was purified by mass directed preparative HPLC (Method A) to give the title compound as a yellow solid (0.035 g).