Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[O:5][C:4](=[O:14])[CH:3]=1.O.OC1C2C(=CC(O)=CC=2)OC(=O)C=1.[N+:29]([O-])([OH:31])=[O:30]>>[OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[O:5][C:4](=[O:14])[C:3]=1[N+:29]([O-:31])=[O:30]
Reactant: COc1ccc2oc(=O)cc(O)c2c1
Reactant: O=[N+]([O-])O
Agent: O=c1cc(O)c2ccc(O)cc2o1
Solvent: O
Product: COc1ccc2oc(=O)c([N+](=O)[O-])c(O)c2c1

Procedure:
Fuming nitric acid (30 ml) was added to a stirred suspension of 4-hydroxy-6-methoxycoumarin (m.p. 271°-2°(d); (C10H7NO5 requires C, 50.64; H, 2.97; N, 5.91. Found: C, 50.78; H, 3.18; N, 5.47).
Reaction SMILES: C(OC(=O)[NH:7][C@@:8]([C:16]1[CH:25]=[CH:24][C:23]2[C:18](=[CH:19][CH:20]=[C:21]([O:30][CH:31]3[CH2:36][CH2:35][CH:34]([C:37]([CH3:41])([CH3:40])[CH2:38][CH3:39])[CH2:33][CH2:32]3)[C:22]=2[C:26]([F:29])([F:28])[F:27])[CH:17]=1)([CH3:15])[CH2:9][O:10][P:11]([OH:14])([OH:13])=[O:12])(C)(C)C.O1CCOCC1>Cl>[NH2:7][C@@:8]([C:16]1[CH:25]=[CH:24][C:23]2[C:18](=[CH:19][CH:20]=[C:21]([O:30][CH:31]3[CH2:32][CH2:33][CH:34]([C:37]([CH3:40])([CH3:41])[CH2:38][CH3:39])[CH2:35][CH2:36]3)[C:22]=2[C:26]([F:27])([F:28])[F:29])[CH:17]=1)([CH3:15])[CH2:9][O:10][P:11](=[O:12])([OH:13])[OH:14]
Reactant: CCC(C)(C)C1CCC(Oc2ccc3cc([C@](C)(COP(=O)(O)O)NC(=O)OC(C)(C)C)ccc3c2C(F)(F)F)CC1
Agent: Cl
Solvent: C1COCCO1
Product: CCC(C)(C)C1CCC(Oc2ccc3cc([C@@](C)(N)COP(=O)(O)O)ccc3c2C(F)(F)F)CC1
Yield: 66.3 %

Procedure:
A solution of ((R)-1-{6-[4-(1,1-dimethyl-propyl)-cyclohexyloxy]-5-trifluoromethyl-naphthalen-2-yl}-1-methyl-2-phosphonooxy-ethyl)-carbamic acid tert-butyl ester (45 mg, 0.07 mmol) in 4 M of HCl in dioxane (3 mL, 10 mmol) was stirred at room temperature for 3 hrs. After the solution was concentrated, the crude product was treated with acetonitrile to form precipitate. The precipitate was purified with a silica gel column eluted with 10% TFA in MeOH and DCM from 0 to 30% to give 24 mg of product, 63%. ESI-MS (M+H)+: 518.30, room temperature 1.70 min. 1H NMR (400 MHz, CD3OD) δ: 8.24 (d, 1H), 8.11 (d, 1H), 7.99 (s, 1H), 7.69 (s, 1H), 7.58 (s, 1H), 4.48 (m, 1H), 4.35 (m, 1H), 4.22 (m, 1H), 2.20 (d, 2H), 1.85 (s, 5H), 1.49 (m, 2H), 1.38-1.16 (m, 6H), 0.85 (m, 9H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:9]([CH3:11])=[O:10])=[C:6]([CH:8]=1)[NH2:7].[C:12]1([S:18](Cl)(=[O:20])=[O:19])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:9]([CH3:11])=[O:10])=[C:6]([NH:7][S:18]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)(=[O:20])=[O:19])[CH:8]=1
Reactant: CS(=O)c1ccc(Cl)cc1N
Reactant: O=S(=O)(Cl)c1ccccc1
Product: CS(=O)c1ccc(Cl)cc1NS(=O)(=O)c1ccccc1

Procedure:
Following General Procedure B, C, the title compound was prepared from 5-chloro-2-(methylsulfinyl)aniline and benzenesulfonyl chloride.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:29])[CH:5]([CH2:11][C:12]1[C:13]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:14][N:15]2[C:20]=1[C:19](Cl)=[C:18]([C:22]#[N:23])[CH:17]=[N:16]2)[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2].[O:30]([C:37]1[CH:42]=[CH:41][C:40]([NH2:43])=[CH:39][CH:38]=1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>CN(C=O)C>[CH2:1]([O:3][C:4](=[O:29])[CH:5]([CH2:11][C:12]1[C:13]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:14][N:15]2[C:20]=1[C:19]([NH:43][C:40]1[CH:39]=[CH:38][C:37]([O:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)=[CH:42][CH:41]=1)=[C:18]([C:22]#[N:23])[CH:17]=[N:16]2)[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2]
Reactant: Nc1ccc(Oc2ccccc2)cc1
Reactant: CCOC(=O)c1cn2ncc(C#N)c(Cl)c2c1CC(C(=O)OCC)C(=O)OCC
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn2ncc(C#N)c(Nc3ccc(Oc4ccccc4)cc3)c2c1CC(C(=O)OCC)C(=O)OCC

Procedure:
A solution of 2-(4-Chloro-3-cyano-6-ethoxycarbonyl-pyrrolo[1,2-b]pyridazin-5-ylmethyl)-malonic acid diethyl ester 369B (6.5 mg, 0.015 mmol) and 4-phenoxyphenylamine (4.2 mg, 0.023 mmol) in DMF (0.5 ml) was heated at 110° C. for 4 hrs. The reaction mixture was purified by silica gel flash chromatography to isolate 369 as a yellow film (1.7 mg, 20%). [M+H]+32 571.
Reaction SMILES: [CH2:1]([C:5]1[N:10]2[N:11]=[CH:12][N:13]=[C:9]2[N:8]([CH:14]2[CH2:19][CH2:18][CH:17]([OH:20])[CH2:16][CH2:15]2)[C:7](=[O:21])[C:6]=1[CH2:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2[C:30]([C:35]#[N:36])=[CH:31][CH:32]=[CH:33][CH:34]=2)=[CH:25][CH:24]=1)[CH2:2][CH2:3][CH3:4].CI.[CH3:39]N(C)C=O.[H-].[Na+]>C(OCC)(=O)C>[CH2:1]([C:5]1[N:10]2[N:11]=[CH:12][N:13]=[C:9]2[N:8]([CH:14]2[CH2:19][CH2:18][CH:17]([O:20][CH3:39])[CH2:16][CH2:15]2)[C:7](=[O:21])[C:6]=1[CH2:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2[C:30]([C:35]#[N:36])=[CH:31][CH:32]=[CH:33][CH:34]=2)=[CH:25][CH:24]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CN(C)C=O
Reactant: CCCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(C2CCC(O)CC2)c2ncnn12
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CI
Product: CCCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(C2CCC(OC)CC2)c2ncnn12
Temperature: 25 °C
Reaction time: 16 h
Yield: 42 %

Procedure:
To a mixture of 4′-{[7-butyl-4-(4-hydroxycyclohexyl)-5-oxo-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile (0.37 g), methyl iodide (0.053 mL) and N,N-dimethylformamide (10 mL) was added sodium hydride (0.034 g), and the mixture was stirred at room temperature for 16 hr. The reaction mixture was diluted with ethyl acetate, washed with 5% aqueous potassium hydrogensulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.16 g, 42%).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].C1(N=C=NC2CCCCC2)CCCCC1.[C:26]([N:29]1[CH:34]=[C:33]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[N:32]([CH2:41][C:42]([NH:44][C@@H:45]([CH2:49][C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=2)[C:46](O)=[O:47])=[O:43])[C:31](=[O:56])[CH:30]1[CH:57]([CH3:59])[CH3:58])(=[O:28])[CH3:27]>C(OCC)(=O)C>[C:26]([N:29]1[CH:34]=[C:33]([C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)[N:32]([CH2:41][C:42]([NH:44][C@@H:45]([CH2:49][C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=2)[C:46]([O:10][C:7]2[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)=[O:47])=[O:43])[C:31](=[O:56])[CH:30]1[CH:57]([CH3:59])[CH3:58])(=[O:28])[CH3:27]
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: CC(=O)N1C=C(c2ccccc2)N(CC(=O)N[C@@H](Cc2ccccc2)C(=O)O)C(=O)C1C(C)C
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CCOC(C)=O
Product: CC(=O)N1C=C(c2ccccc2)N(CC(=O)N[C@@H](Cc2ccccc2)C(=O)Oc2ccc([N+](=O)[O-])cc2)C(=O)C1C(C)C
Reaction time: 8 h
Yield: 83.3 %

Procedure:
4-Nitrophenol (1.39 g) and dicyclohexylcarbodiimide (2.01 g) are added to a solution of (2S)-2-{(3RS)-4-acetyl-3-isopropyl-2-oxo-6-phenyl-1,2,3,4-tetrahydropyrazin-1-yl}methylcarbonylamino-3-phenylpropionic acid (4.30 g, Compound No. 13-1) in ethyl acetate (100 ml), and the mixture is stirred overnight. The resulting impurity is filtered out, then the filtrate is concentrated under reduced pressure, and the resulting residue is purified by silica gel column chromatography to give the titled compound (4.52 g).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:12]/[OH:13])/[C:8]([O:10][CH3:11])=[O:9])[N:6]=1.C(N(CC)CC)C.[C:21](Cl)([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.O>CN(C)C=O>[C:21]([NH:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:12]/[OH:13])/[C:8]([O:10][CH3:11])=[O:9])[N:6]=1)([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)([C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COC(=O)/C(=N\O)c1csc(N)n1
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)/C(=N\O)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Temperature: -30 °C
Reaction time: 2 h

Procedure:
In 10 ml of N,N-dimethylformamide is dissolved 4.62 g of methyl 2-(2-amino-4-thiazolyl)-(Z)-2-hydroxyiminoacetate, followed by addition of 3 ml of triethylamine. Then, under stirring at -30° C., 6.42 g of trityl chloride is added over one hour. The mixture is further stirred at that temperature for one hour and, then at 15° C. for an additional 2 hours. To this reaction mixture is added 200 ml of water, followed by extraction with 200 ml of ethyl acetate. The ethyl acetate extract is washed twice with 200 ml portions of water and dried over anhydrous sodium sulfate. The solvent is then distilled off. The residue is purified by column chromatography [silica gel: 100 g; eluent:hexane-ethyl acetate (1:1)] and the resultant crystals are recrystallized from ethyl acetate to give methyl 2-(2-tritylamino-4-thiazolyl)-(Z)-2-hydroxyiminoacetate as colorless granules, m.p. 294°-205° C.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[N:10]=[N:9][N:8]([C:11]3[CH:12]=[C:13]4[C:17](=[CH:18][CH:19]=3)[CH2:16][CH2:15][CH2:14]4)[C:6]=2[N:7]=1.[CH2:20]([N:22]([CH2:35][CH3:36])[CH2:23][CH2:24][O:25][C:26](=[O:34])[C:27]1[CH:32]=[CH:31][C:30]([NH2:33])=[CH:29][CH:28]=1)[CH3:21].FC(F)(F)C([O-])=O>CS(C)=O>[CH2:35]([N:22]([CH2:20][CH3:21])[CH2:23][CH2:24][O:25][C:26](=[O:34])[C:27]1[CH:28]=[CH:29][C:30]([NH:33][C:2]2[N:3]=[CH:4][C:5]3[N:10]=[N:9][N:8]([C:11]4[CH:12]=[C:13]5[C:17](=[CH:18][CH:19]=4)[CH2:16][CH2:15][CH2:14]5)[C:6]=3[N:7]=2)=[CH:31][CH:32]=1)[CH3:36]
Reactant: CCN(CC)CCOC(=O)c1ccc(N)cc1
Reactant: Clc1ncc2nnn(-c3ccc4c(c3)CCC4)c2n1
Agent: O=C([O-])C(F)(F)F
Solvent: CS(C)=O
Product: CCN(CC)CCOC(=O)c1ccc(Nc2ncc3nnn(-c4ccc5c(c4)CCC5)c3n2)cc1
Temperature: 25 °C
Yield: 30.7 %

Procedure:
To a solution of (3) (40 mg, 0.15 mmol) in DMSO (1.6 mL) was added 2-(diethylamino)ethyl-4-aminobenzoate (38 mg, 0.16 mmol). The mixture was irradiated at 140° C. for 10 min. After cooling to room temperature, the mixture was purified by reverse-phase chromatography to furnish the desired product (4) (32.2 mg, 0.046 mmol) as a trifluoroacetate salt. MS calcd. for C26H30N7O2 m/z calcd 472.24 (M+H),+ found 472.24.
Reaction SMILES: [C:1]([OH:4])(=[S:3])[CH3:2].P([O-])([O-])([O-])=O.Br[CH2:11][C:12]1([CH3:38])[CH:16]([C:17]([O:19][CH2:20][C:21]([Cl:24])([Cl:23])[Cl:22])=[O:18])[N:15]2[C:25](=[O:37])[CH:26]([NH:27][C:28](=[O:36])[CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C@H:14]2[S:13]1>CC(C)=O>[C:1]([S:3][CH2:11][C:12]1([CH3:38])[CH:16]([C:17]([O:19][CH2:20][C:21]([Cl:22])([Cl:23])[Cl:24])=[O:18])[N:15]2[C:25](=[O:37])[CH:26]([NH:27][C:28](=[O:36])[CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C@H:14]2[S:13]1)(=[O:4])[CH3:2]
Reactant: CC(O)=S
Reactant: CC1(CBr)S[C@@H]2C(NC(=O)Cc3ccccc3)C(=O)N2C1C(=O)OCC(Cl)(Cl)Cl
Agent: O=P([O-])([O-])[O-]
Solvent: CC(C)=O
Product: CC(=O)SCC1(C)S[C@@H]2C(NC(=O)Cc3ccccc3)C(=O)N2C1C(=O)OCC(Cl)(Cl)Cl
Yield: 32.3 %

Procedure:
Acetone (20 ml) and thioacetic acid (0.12 g) were added to pH 6.7 phosphate buffer (20 ml). To a mixture was added 2,2,2-trichloroethyl 2-bromomethyl-2-methyl-6-(2-phenylacetamido)penam-3-carboxylate (0.54 g) under stirring. After stirring for 5 hours at room temperature, the reaction mixture was post-treated in the similar manner as described in Example 6 to give oily 2,2,2-trichloroethyl 2-acetylthiomethyl-2-methyl-6-(2-phenylacetamido)penam-3-carboxylate (0.173 g).
Reaction SMILES: [Cl:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]1[N:8]=[C:9]([NH2:12])[S:10][CH:11]=1.[CH2:13]([C:16]1[CH:21]=[CH:20][C:19]([S:22](Cl)(=[O:24])=[O:23])=[CH:18][CH:17]=1)[CH2:14][CH3:15]>>[Cl:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]1[N:8]=[C:9]([NH:12][S:22]([C:19]2[CH:20]=[CH:21][C:16]([CH2:13][CH2:14][CH3:15])=[CH:17][CH:18]=2)(=[O:24])=[O:23])[S:10][CH:11]=1
Reactant: CCCc1ccc(S(=O)(=O)Cl)cc1
Reactant: Nc1nc(-c2sccc2Cl)cs1
Product: CCCc1ccc(S(=O)(=O)Nc2nc(-c3sccc3Cl)cs2)cc1

Procedure:
The title compound was prepared from 4-(3-chloro-2-thienyl)-1,3-thiazol-2-amine and 4-n-propylbenzenesulfonyl chloride as described in the synthetic METHOD B to give a brown-red solid (5.3 mg) with purity >90%. MS (pos) m/z 399.2, 401.2.
Reaction SMILES: [NH2:1][C:2]([NH:4][C:5]1[NH:6][C:7]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=2)=[CH:8][C:9]=1[C:10]([NH2:12])=[O:11])=[O:3].[CH3:20][O:21]C(Cl)Cl.Cl.O>ClCCl.[Ti](Cl)(Cl)(Cl)Cl>[NH2:1][C:2]([NH:4][C:5]1[NH:6][C:7]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=2)=[C:8]([CH:20]=[O:21])[C:9]=1[C:10]([NH2:12])=[O:11])=[O:3]
Reactant: COC(Cl)Cl
Reactant: NC(=O)Nc1[nH]c(-c2cccc(Cl)c2)cc1C(N)=O
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: Cl
Solvent: ClCCl
Solvent: O
Product: NC(=O)Nc1[nH]c(-c2cccc(Cl)c2)c(C=O)c1C(N)=O
Temperature: 4 °C
Reaction time: 8 h
Yield: 77 %

Procedure:
1.0M Titanium tetrachloride in dichloromethane solution (2 mL, 2.0 mmol) was added to a suspension of 2-aminocarbonylamino-5-(3-chlorophenyl)pyrrole-3-carboxamide (Compound No. 1-25, 140 mg, 0.50 mmol) in dichloromethane (3 mL) at −30° C. and the mixture was stirred for 40 minutes. Moreover, dichloromethyl methyl ether (0.27 mL, 3.0 mmol) was added thereto and the whole was stirred overnight at 4° C. Under ice-cooling, 1N hydrochloric acid (4 mL) was added thereto and the mixture was stirred for 1 hour, and then water (10 mL) was add thereto. The precipitated solid was filtered off, washed with chloroform (10 mL) and water (10 mL), and dried under reduced pressure to give the target compound (120 mg) as a brown solid (Yield 77%).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:15](=[O:16])[C:14]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([C:24]4[C:25]([C:30]#[N:31])=[CH:26][CH:27]=[CH:28][CH:29]=4)=[CH:20][CH:19]=3)=[C:13]([CH2:32][CH2:33][CH3:34])[N:12]=[C:11]2[CH2:35][CH3:36])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[CH3:37][Li].[Cl-].[NH4+]>O1CCCC1>[CH2:35]([C:11]1[N:10]([C:7]2[CH:6]=[CH:5][C:4]([C:1]([OH:3])([CH3:37])[CH3:2])=[CH:9][CH:8]=2)[C:15](=[O:16])[C:14]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]3[C:25]([C:30]#[N:31])=[CH:26][CH:27]=[CH:28][CH:29]=3)=[CH:20][CH:19]=2)=[C:13]([CH2:32][CH2:33][CH3:34])[N:12]=1)[CH3:36]
Reactant: CCCc1nc(CC)n(-c2ccc(C(C)=O)cc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: [Li]C
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCCc1nc(CC)n(-c2ccc(C(C)(C)O)cc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reaction time: 1 h
Yield: 37 %

Procedure:
To a solution of 4′-{[1-(4-acetylphenyl)-2-ethyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile (0.78 g) in tetrahydrofuran (20 mL) was added methyllithium (2.4 mL, 1.4 M diethyl ether solution) under ice-cooling, and the mixture was stirred for 1 hr. A saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.30 g, 37%).
Reaction SMILES: [CH3:1][C:2]1(SC)[CH:8]2[CH:6]([CH2:7]2)[C:5](=[O:9])[CH2:4][C:3]1=[O:10]>CO.[Ni]>[CH3:1][C:2]1[C:3](=[O:10])[CH2:4][C:5](=[O:9])[CH2:6][CH2:7][CH:8]=1
Reactant: CSC1(C)C(=O)CC(=O)C2CC21
Agent: [Ni]
Solvent: CO
Product: CC1=CCCC(=O)CC1=O

Procedure:
1.0 g (5.4 mmol) of the 5-methyl-5-methylsulfanylbicyclo[4.1.0]heptane-2,4-dione isomers II is hydrogenated for 90 minutes under atmospheric pressure in 15 ml of methanol in the presence of 5 g Raney nickel. The mixture is concentrated and purified over silica gel (mobile phase ethyl acetatelhexane 1:1), and 4-methylcyclohept-4-ene-1,3-dione, 1H-NMR (CDCl3): 6.84, m, CH, 3.94, s, CH2, 2.77, m, CH2, 2,59, m, CH2, 1.88 ppm, s, CH3, is obtained as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[CH2:4]P(=O)(OCC)OCC.[Br:17][C:18]1[C:26]2[O:25][C:24]([CH:27]=O)=[CH:23][C:22]=2[CH:21]=[C:20]([O:29][CH3:30])[CH:19]=1.[H-].[Na+].O>O1CCCC1>[Br:17][C:18]1[C:26]2[O:25][C:24](/[CH:27]=[CH:4]/[C:3]3[CH:13]=[CH:14][CH:15]=[CH:16][C:2]=3[Cl:1])=[CH:23][C:22]=2[CH:21]=[C:20]([O:29][CH3:30])[CH:19]=1
Reactant: CCOP(=O)(Cc1ccccc1Cl)OCC
Reactant: COc1cc(Br)c2oc(C=O)cc2c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(Br)c2oc(/C=C/c3ccccc3Cl)cc2c1
Temperature: 60 °C
Yield: 84 %

Procedure:
To a solution of diethyl 2-chlorobenzylphosphonate (4.91 g, 0.018 mol) and 7-bromo-5-methoxybenzofuran-2-carbaldehyde (11.27 g, 0.016 mol) in tetrahydrofuran (80 mL) was added sodium hydride (60% dispersion in mineral oil, 0.74 g, 0.0185 mol). After 5 min. the reaction mixture was warmed to 60° C. for 1 h. The reaction mixture was cooled to room temperature, water (10 mL) was carefully added and the tetrahydrofuran was removed. Water (50 mL) was added and the mixture was extracted with ethyl acetate (3×100 mL). The combined ethyl acetate extracts were washed with brine (50 mL), dried over magnesium sulphate, filtered and concentrated to dryness. Trituration with diethyl ether (20 mL) gave solid material which was further washed with diethyl ether (20 ml). The liquors were concentrated and triturated with diethyl ether (10 mL), the solid being collected. The combined solids gave (859) (4.89 g, 84%). 1H NMR δ (CDCl3) 7.70 (d, J=16 Hz, 1H), 7.65 (dd, J=7.7, 1.5 Hz, 1H), 7.4 (dd, J=6.0, 1 Hz, 1H), 7.23 (m, 2H), 7.05 (d, J=2.3 Hz, 1H), 6.94 (d, J=16 Hz, 1H), 6.92 (d, J=2.3 Hz, 1H), 6.72 (s, 1H), 3.82 (s, 3H); MH+:364.9, 362.9 MH−:362.9, 360.9.
Reaction SMILES: [F:1][CH:2]([F:18])[CH2:3][N:4]1[CH2:10][CH2:9][C:8]2[CH:11]=[C:12]([NH2:17])[C:13]([O:15][CH3:16])=[CH:14][C:7]=2[CH2:6][CH2:5]1.[Cl:19][C:20]1[CH:21]=[CH:22][C:23]([O:35][CH3:36])=[C:24]([NH:26][C:27]2[C:32]([Cl:33])=[CH:31][N:30]=[C:29](Cl)[N:28]=2)[CH:25]=1>>[Cl:33][C:32]1[C:27]([NH:26][C:24]2[CH:25]=[C:20]([Cl:19])[CH:21]=[CH:22][C:23]=2[O:35][CH3:36])=[N:28][C:29]([NH:17][C:12]2[C:13]([O:15][CH3:16])=[CH:14][C:7]3[CH2:6][CH2:5][N:4]([CH2:3][CH:2]([F:1])[F:18])[CH2:10][CH2:9][C:8]=3[CH:11]=2)=[N:30][CH:31]=1
Reactant: COc1cc2c(cc1N)CCN(CC(F)F)CC2
Reactant: COc1ccc(Cl)cc1Nc1nc(Cl)ncc1Cl
Product: COc1cc2c(cc1Nc1ncc(Cl)c(Nc3cc(Cl)ccc3OC)n1)CCN(CC(F)F)CC2

Procedure:
The title compound was prepared from 3-(2,2-Difluoro-ethyl)-8-methoxy-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamine and (5-Chloro-2-methoxy-phenyl)-(2,5-dichloro-pyrimidin-4-yl)-amine in an analogous manner to Example 61e. Product isolated as an off-white solid (0.053 g, 70%). MP: 172-178° C. 1H NMR (400 MHz, CDCl3, δ, ppm): 8.47 (s, 1H), 8.11-8.09 (m, 1H), 8.01 (s, 1H), 7.77 (s, 1H), 7.43 (s, 1H), 7.03-6.98 (m, 1H), 6.86-6.82 (m, 1H), 6.65 (s, 1H), 6.07-5.74 (m, 1H), 3.93 (s, 3H), 3.88 (s, 3H), 2.97-2.74 (m, 10H). MS: 524 (MH)+.
Reaction SMILES: [C:1]([C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][C:5]=1[CH3:14])(=[S:3])[NH2:2].Cl[CH2:16][C:17](=O)[CH3:18]>C(O)C>[CH3:14][C:5]1[CH:6]=[C:7]([CH:12]=[CH:13][C:4]=1[C:1]1[S:3][CH:16]=[C:17]([CH3:18])[N:2]=1)[C:8]([O:10][CH3:11])=[O:9]
Reactant: CC(=O)CCl
Reactant: COC(=O)c1ccc(C(N)=S)c(C)c1
Solvent: CCO
Product: COC(=O)c1ccc(-c2nc(C)cs2)c(C)c1
Yield: 69 %

Procedure:
Methyl 4-carbamothioyl-3-methylbenzoate (8.9 g, 42.5 mmol) and chloroacetone (3.94 g, 42.5 mmol) were dissolved in ethanol (50 mL), and refluxed for 12 hours. The solvent was evaporated, and the residue was purified on a silica gel column, eluting with 20%-40% ethyl acetate in hexanes, to get methyl 3-methyl-4-(4-methylthiazol-2-yl)benzoate as white waxy solids (contains some ethyl 3-methyl-4-(4-methylthiazol-2-yl)benzoate) (7.4 g, 69% yield). An aliquot amount of the methyl and ethyl ester mixture was separated for identification purpose.
Reaction SMILES: [C:1]([O:20][CH:21]([CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH:40]=[CH:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH3:49])[CH2:22][C:23]([NH:25][C@H:26]([C:30](O)=[O:31])[CH:27]([CH3:29])[CH3:28])=[O:24])(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH:9]=[CH:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[NH2:50][C@H:51]([C:57]([OH:59])=[O:58])[CH2:52][CH2:53][C:54]([OH:56])=[O:55]>>[C:1]([O:20][CH:21]([CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH:40]=[CH:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH3:49])[CH2:22][C:23]([NH:25][C@H:26]([C:30]([NH:50][C@H:51]([C:57]([OH:59])=[O:58])[CH2:52][CH2:53][C:54]([OH:56])=[O:55])=[O:31])[CH:27]([CH3:29])[CH3:28])=[O:24])(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH:9]=[CH:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCCCC=CCCCCCCCC(=O)OC(CCCCCCCC=CCCCCCCCC)CC(=O)N[C@H](C(=O)O)C(C)C
Reactant: N[C@@H](CCC(=O)O)C(=O)O
Product: CCCCCCCCC=CCCCCCCCC(=O)OC(CCCCCCCC=CCCCCCCCC)CC(=O)N[C@H](C(=O)N[C@@H](CCC(=O)O)C(=O)O)C(C)C
Yield: 31.2 %

Procedure:
Starting from N-[3-(9-octadecenoyloxy)-11-eicosenoyl]-L-valine (2.7 g) and L-glutamic acid (2.2 g), N-[N-[3-(9-octadecenoyloxy)-11-eicosenoyl]-L-valyl]-L-glutamic acid (1.0 g) was obtained as powder according to a similar manner to that of Example 2.
Reaction SMILES: [ClH:1].[NH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([C:9]([O:11][CH3:12])=[O:10])[CH2:5][CH2:4]1.[C:13]1([CH2:19][CH2:20][CH:21]=O)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C([BH3-])#N.[Na+]>CO.O>[ClH:1].[CH3:12][O:11][C:9]([C@H:6]1[CH2:5][CH2:4][C@H:3]([NH:2][CH2:21][CH2:20][CH2:19][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:8][CH2:7]1)=[O:10]
Reactant: COC(=O)[C@H]1CC[C@H](N)CC1
Reactant: O=CCCc1ccccc1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COC(=O)[C@H]1CC[C@H](NCCCc2ccccc2)CC1

Procedure:
A solution of 2 g of methyl trans-4-aminocyclohexane-carboxylate-hydrochloride, 1.5 ml of 3-phenylpropionaldehyde and 1.3 g of sodium cyanoborohydride in 40 ml of dry methanol is stirred for 20 hours at ambient temperature. The mixture is diluted with water and extracted with ethyl acetate. The combined ethyl acetate phases are dried, acidified with ethereal hydrochloric acid and the solvent is removed under reduced pressure. The residue is triturated with acetone, suction filtered and washed with acetone and then with ether. Yield: 1.9 g (59.1% of theory), Melting point: 258°-260° C.
Reaction SMILES: [C@H:1]12[CH2:6][C@H:5]1[CH2:4][C@@H:3]([CH2:7][NH:8][C:9]([C:11]1[CH:12]=[CH:13][CH:14]=[C:15]3[O:19][CH:18]=[CH:17][C:16]=13)=[O:10])[NH:2]2.[NH2:20][C:21]1[S:22][CH:23]=[C:24]([C:26]2[CH:34]=[CH:33][CH:32]=[CH:31][C:27]=2[C:28](O)=[O:29])[N:25]=1>>[NH2:20][C:21]1[S:22][CH:23]=[C:24]([C:26]2[CH:34]=[CH:33][CH:32]=[CH:31][C:27]=2[C:28]([N:2]2[C@H:3]([CH2:7][NH:8][C:9]([C:11]3[CH:12]=[CH:13][CH:14]=[C:15]4[O:19][CH:18]=[CH:17][C:16]=34)=[O:10])[CH2:4][C@H:5]3[C@@H:1]2[CH2:6]3)=[O:29])[N:25]=1
Reactant: Nc1nc(-c2ccccc2C(=O)O)cs1
Reactant: O=C(NC[C@@H]1C[C@@H]2C[C@@H]2N1)c1cccc2occc12
Product: Nc1nc(-c2ccccc2C(=O)N2[C@H](CNC(=O)c3cccc4occc34)C[C@@H]3C[C@@H]32)cs1

Procedure:
prepared by reaction of benzofuran-4-carboxylic acid [(1S,3S,5S)-2-aza-bicyclo[3.1.0]hex-3-ylmethyl]-amide with 2-(2-amino-thiazol-4-yl)-benzoic acid. LC-MS (basic): tR=1.28 min; [M+H]+=458.9.
Reaction SMILES: [CH2:1]([N:9]1[CH:13]=[C:12]([C:14]2[C:22]3[C:17](=[N:18][CH:19]=[C:20]([C:23]4[CH:24]=[C:25]([NH:29][CH:30]5[CH2:35][CH2:34][N:33](C(OC(C)(C)C)=O)[CH2:32][CH2:31]5)[CH:26]=[CH:27][CH:28]=4)[CH:21]=3)[NH:16][CH:15]=2)[CH:11]=[N:10]1)[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>Cl.CO>[CH2:1]([N:9]1[CH:13]=[C:12]([C:14]2[C:22]3[C:17](=[N:18][CH:19]=[C:20]([C:23]4[CH:24]=[C:25]([NH:29][CH:30]5[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]5)[CH:26]=[CH:27][CH:28]=4)[CH:21]=3)[NH:16][CH:15]=2)[CH:11]=[N:10]1)[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2cccc(-c3cnc4[nH]cc(-c5cnn(CCc6ccccc6)c5)c4c3)c2)CC1
Agent: Cl
Solvent: CO
Product: c1ccc(CCn2cc(-c3c[nH]c4ncc(-c5cccc(NC6CCNCC6)c5)cc34)cn2)cc1
Yield: 27.4 %

Procedure:
Using similar reaction conditions as described in step-ii of example-7, tert-butyl 4-((3-(3-(1-phenethyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)amino)piperidine-1-carboxylate (80 mg, 0.142 mmol) was deprotected in HCl in methanol (5 ml). This afforded 18 mg (21.9% yield) of the titled compound. 1H NMR (CD3OD, 400 MHz): δ 8.55 (s, 1H), 8.435-8.431 (d, 1H), 7.91 (s, 1H), 7.81 (s, 1H), 7.71 (s, 1H), 7.39-7.32 (t, 1H), 7.29-7.20 (t, 2H), 7.16-7.13 (m, 2H), 7.04-7.03 (m, 2H), 6.85-6.80 (d, 1H), 4.49-4.46 (t, 2H), 3.85-3.75 (m, 1H), 3.52-3.49 (m, 2H), 3.22-3.19 (m, 4H), 2.35-2.25 (dd, 2H), 1.80-1.65 (m, 2H). MS: m/z=463.3 (M+1), HPLC: 90.63% in method A.