Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CC)CC)C.[CH2:8]([N:10]1[CH2:15][CH2:14][N:13](C(OC(C)(C)C)=O)[C@@H:12]([C:23]([N:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)=[O:24])[CH2:11]1)[CH3:9].[Cl:31][C:32]1[CH:37]=[CH:36][C:35]([N:38]=[C:39]=[O:40])=[CH:34][CH:33]=1.CO>ClCCl>[Cl:31][C:32]1[CH:37]=[CH:36][C:35]([NH:38][C:39]([N:28]2[CH2:27][CH2:26][N:25]([C:23]([C@H:12]3[CH2:11][N:10]([CH2:8][CH3:9])[CH2:15][CH2:14][NH:13]3)=[O:24])[CH2:30][CH2:29]2)=[O:40])=[CH:34][CH:33]=1
Reactant: CCN1CCN(C(=O)OC(C)(C)C)[C@@H](C(=O)N2CCNCC2)C1
Reactant: O=C=Nc1ccc(Cl)cc1
Solvent: CO
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCN1CCN[C@@H](C(=O)N2CCN(C(=O)Nc3ccc(Cl)cc3)CC2)C1
Reaction time: 18 h
Yield: 115.8 %

Procedure:
Triethylamine (29 uL) was added to a solution of tert-butyl (2R)-4-ethyl-2-(piperazin-1-ylcarbonyl)piperazine-1-carboxylate (67.5 mg) in dry dichloromethane (5 ml) followed by 4-chloro phenylisocyanate (35 mg) and the reaction was stirred for 18 h under argon. Methanol (1 ml) was added, the solvent was evaporated and the product purified by chromatography (3-15% MeOH-DCM) to afford the homologated product (91 mg) as a foam. The foam was then dissolved in TFA/DCM (1:1, 6 ml) and stirred for 1 h. The solvent was removed under reduced pressure then taken up in 1M. aqueous sodium hydroxide (30 ml) and extracted with dichloromethane (2×30 ml). The combined organic layers were dried (MgSO4), filtered and evaporated to form the title compound (70 mg) as a white foam.
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.Cl[C:7]1[S:8][CH:9]=[CH:10][C:11]=1[N+:12]([O-:14])=[O:13].CC(C)([O-])C.[K+]>CN(C=O)C.CCOCC>[N+:12]([C:11]1[CH:10]=[CH:9][S:8][C:7]=1[N:1]1[CH:5]=[N:4][CH:3]=[N:2]1)([O-:14])=[O:13]
Reactant: c1nc[nH]n1
Reactant: O=[N+]([O-])c1ccsc1Cl
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccsc1-n1cncn1
Temperature: 90 °C
Reaction time: 2 h

Procedure:
1H-1,2,4-triazole (582 mg, 8.43 mmol), 2-chloro-3-nitrothiophene (1.15 g, 7.03 mmol) and potassium t-butoxide (944 mg, 8.43 mmol) were dissolved in DMF (30 mL). The resulting solution was stirred at 90° C. for 2 h, after which the reaction mixture was cooled to room temperature and diluted with Et2O. The solution was washed with brine and the organic phase was separated, dried (Na2SO4), filtered, concentrated under vacuum to give 1-(3-nitrothiophen-2-yl)-1H-1,2,4-triazole. Retention time (min)=1.073, method [1], MS (ESI) 197.0 (M+H).
Reaction SMILES: [ClH:1].C(OC([N:9]1[CH2:15][CH2:14][C:13]2[N:16]=[N:17][C:18](C3C=CC=CC=3)=C[C:12]=2[CH2:11][CH2:10]1)=O)(C)(C)C.[O:26]1[CH2:31][CH2:30]OCC1>>[ClH:1].[CH3:18][N:17]1[N:16]=[C:13]2[CH2:14][CH2:15][NH:9][CH2:10][CH2:11][C:12]2=[CH:30][C:31]1=[O:26]
Reactant: CC(C)(C)OC(=O)N1CCc2cc(-c3ccccc3)nnc2CC1
Reactant: C1COCCO1
Agent: Cl
Product: Cn1nc2c(cc1=O)CCNCC2

Procedure:
40 mL dioxane solution of hydrogen chloride was added to 5.5 g 3-phenyl-5,6,8,9-tetrahydro-1,2,7-triaza-benzocycloheptene-7-carboxylic acid tert-butyl ester in 40 mL dioxane at 5° C. The reaction was stirred over night. The solvent was removed and co-evaporated with ethyl acetate to yield 3.7 g of the desired product. (M+H)+: 180, Rt: 7.84 min (method AE)
Reaction SMILES: C(N(S(F)(F)[F:7])CC)C.[CH2:10]([N:14]1[CH2:31][CH:30]([CH2:32]O)[O:29][C:16]2([CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]2)[CH2:15]1)[C:11]#[C:12][CH3:13].CO.ClCCl>ClCCl>[CH2:10]([N:14]1[CH2:31][CH:30]([CH2:32][F:7])[O:29][C:16]2([CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]2)[CH2:15]1)[C:11]#[C:12][CH3:13]
Reactant: CC#CCN1CC(CO)OC2(CCN(C(=O)OC(C)(C)C)CC2)C1
Reactant: CCN(CC)S(F)(F)F
Solvent: ClCCl
Solvent: CO
Product: CC#CCN1CC(CF)OC2(CCN(C(=O)OC(C)(C)C)CC2)C1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 45.6 %

Procedure:
To a solution of diethylaminosulfur trifluoride (19.5 μL, 0.148 mmol) in dichloromethane (1.0 mL) at −78° C. was added dropwise a solution of tert-butyl 8-but-2-ynyl-10-(hydroxymethyl)-11-oxa-3,8-diazaspiro[5.5]undecane-3-carboxylate (50.0 mg, 0.148 mmol) in dichloromethane (1 mL). The reaction was stirred for 10 min at −78° C. then allowed to warm to room temperature and stirred for 16 h. Silica gel chromatography (4 g silica, 0-15% methanol/dichloromethane) provided tert-butyl 8-but-2-ynyl-10-(fluoromethyl)-11-oxa-3,8-diazaspiro[5.5]undecane-3-carboxylate (23.0 mg, 46%). ESI-MS m/z calc. 340.2. Found 341.3 (M+1)+; Retention time: 1.16 minutes (3 min run). 1H NMR (400 MHz, CDCl3) δ 4.52-4.40 (m, 1H), 4.39-4.28 (m, 1H), 4.06-3.91 (m, 1H), 3.71 (br s, 2H), 3.35-3.14 (m, 3H), 3.08 (t, J=11.4 Hz, 1H), 2.78 (d, J=10.3 Hz, 1H), 2.58 (d, J=11.1 Hz, 1H), 2.31 (d, J=13.5 Hz, 1H), 2.06 (t, J=12.5 Hz, 2H), 1.84 (t, J=2.3 Hz, 3H), 1.57-1.44 (m, 12H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N:8]([CH3:25])[C:9](=[O:24])[C:10]1[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[C:12]([C:20]([F:23])([F:22])[F:21])[CH:11]=1.[Cl:26][C:27]1[CH:28]=[C:29](B(O)O)[C:30]([O:33][CH3:34])=[N:31][CH:32]=1>CN(C=O)C>[Cl:26][C:27]1[CH:28]=[C:29]([C:2]2[CH:7]=[CH:6][N:5]=[CH:4][C:3]=2[N:8]([CH3:25])[C:9](=[O:24])[C:10]2[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[C:12]([C:20]([F:23])([F:22])[F:21])[CH:11]=2)[C:30]([O:33][CH3:34])=[N:31][CH:32]=1
Reactant: COc1ncc(Cl)cc1B(O)O
Reactant: CN(C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cnccc1Br
Solvent: CN(C)C=O
Product: COc1ncc(Cl)cc1-c1ccncc1N(C)C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1

Procedure:
The title compound was prepared in analogy to example 25, from N-(4-bromo-pyridin-3-yl)-N-methyl-3,5-bis-trifluoromethyl-benzamide (example 25, intermediate a) and 5-chloro-2-methoxypyridine-3-boronic acid (CAS RN 943153-22-8) and using DMF as reaction solvent. Off-white solid (28%). MS (ESI): m/z=490.0 [M+H]+.
Reaction SMILES: [CH3:1][C:2]([CH3:26])([CH2:19][C:20]1([CH3:25])OCC[O:21]1)[CH2:3][N:4]1[C:16]2[C:15]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[N:9]=[C:8]([NH2:17])[C:7]=2[N:6]=[C:5]1[CH3:18].Cl>>[NH2:17][C:8]1[C:7]2[N:6]=[C:5]([CH3:18])[N:4]([CH2:3][C:2]([CH3:26])([CH3:1])[CH2:19][C:20](=[O:21])[CH3:25])[C:16]=2[C:15]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[N:9]=1
Reactant: Cc1nc2c(N)nc3ccccc3c2n1CC(C)(C)CC1(C)OCCO1
Agent: Cl
Product: CC(=O)CC(C)(C)Cn1c(C)nc2c(N)nc3ccccc3c21

Procedure:
By the general method of Part E of Example 30, 1-[2,2-dimethyl-3-(2-methyl-[1,3]dioxolan-2-yl)propyl]-2-methyl-1H-imidazo[4,5-c]quinolin-4-amine was hydrolyzed with aqueous hydrochloric acid to provide 5-(4-amino-2-methyl-1H-imidazo[4,5-c]quinolin-1-yl)-4,4-dimethylpentan-2-one as a light brown solid after recrystallization from aqueous acetonitrile, mp 223-225° C.
Reaction SMILES: C[O:2][C:3](=[O:26])[CH2:4][CH:5]([C:18]1[CH:23]=[CH:22][N:21]=[C:20]([S:24][CH3:25])[N:19]=1)[C:6](=[O:17])[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:16])([F:15])[F:14])[CH:8]=1.O1CCOCC1.Cl.CCCCCC>CCOCC>[CH3:25][S:24][C:20]1[N:19]=[C:18]([CH:5]([C:6](=[O:17])[C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:15])([F:14])[F:16])[CH:8]=2)[CH2:4][C:3]([OH:26])=[O:2])[CH:23]=[CH:22][N:21]=1
Reactant: COC(=O)CC(C(=O)c1cccc(C(F)(F)F)c1)c1ccnc(SC)n1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOCC
Solvent: CCCCCC
Product: CSc1nccc(C(CC(=O)O)C(=O)c2cccc(C(F)(F)F)c2)n1

Procedure:
A solution of Compound 4 (27.1 g, 64 mmol) and dioxane (500 mL) were stirred under argon. Hydrochloric acid (6N, 250 mL) was added dropwise using an addition funnel. After 3d dioxane was removed in vacuo. The remaining aqueous mixture was extracted exhaustively with methylene chloride. The combined organic extracts were dried over anhydrous sodium sulfate then the solvent was removed in vacuo to give a yellow oil. Hexane followed by ether was added to afford a solid (5) which was isolated by vacuum filtration: 18.6 g (50.4 mmol, 79%)
Reaction SMILES: [C:1]1([N:7]2[C:11](=[O:12])[C:10]3[CH:13]=[CH:14][CH:15]=[CH:16][C:9]=3[Se:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:17][C@@H:18]([C:23]([OH:25])=[O:24])[C:19]([SH:22])([CH3:21])[CH3:20]>CO.CN(C)C=O.O>[C:1]1([NH:7][C:11]([C:10]2[CH:13]=[CH:14][CH:15]=[CH:16][C:9]=2[Se:8][S:22][C:19]([CH3:21])([CH3:20])[C@H:18]([C:23]([OH:25])=[O:24])[NH2:17])=[O:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)(S)[C@@H](N)C(=O)O
Reactant: O=c1c2ccccc2[se]n1-c1ccccc1
Solvent: CO
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(S[Se]c1ccccc1C(=O)Nc1ccccc1)[C@@H](N)C(=O)O

Procedure:
5 g (18,2 mmol) 2-phenyl-1,2-benzoisoselenazole-3-(2H)-one are dissolved in 250 ml methanol and 30 ml dimethylformamide. A solution of 2,71 g (18,2 mmol) D-penicillamine in 100 ml water is added while stirring. To this clear solution, so much water is added until a slight haze is to be seen. After stirring for 18 hours, the precipitate is filtered and recristallized from ethanol/water (3:2).
Reaction SMILES: C(NC1CCCCC1)(C)C.[CH3:11][C:12]([CH3:26])=[C:13]([N:18]1[C@H:21]([CH2:22][CH:23]=[CH2:24])[CH2:20][C:19]1=[O:25])[C:14]([O:16][CH3:17])=[O:15].[CH3:27][C:28]([CH3:30])=[O:29].Cl>O1CCCC1.C(OCC)(=O)C>[CH3:11][C:12]([CH3:26])=[C:13]([N:18]1[C@H:21]([CH2:22][CH:23]=[CH2:24])[C@@H:20]([C:28]([OH:29])([CH3:30])[CH3:27])[C:19]1=[O:25])[C:14]([O:16][CH3:17])=[O:15]
Reactant: CC(C)=O
Reactant: C=CC[C@@H]1CC(=O)N1C(C(=O)OC)=C(C)C
Agent: CC(C)NC1CCCCC1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C=CC[C@@H]1[C@@H](C(C)(C)O)C(=O)N1C(C(=O)OC)=C(C)C
Temperature: -70 °C
Reaction time: 0.33 h

Procedure:
1.55M Butyl lithium-hexane solution (2.82 ml) was added to a solution of N-isopropylcyclohexylamine (0.72 ml) in tetrahydrofuran (6 ml) at -70° C., and the mixture was stirred for 20 minutes at -70° C. This mixture was added to a solution of methyl 3-methyl-2-[(4R)-2-oxo-4-allylazetidin-1-yl]but-2-enoate (247 mg) in tetrahydrofuran (6 ml) at -70° C. and the mixture was stirred for 1 hour at -70° C., and for 30 minutes at -30° C. Acetone (0.12 ml) was added to the reaction mixture at -70° C., and the mixture was stirred for 1 hour at -70° C. and for 30 minutes at -30° C.-15° C. 3N Hydrochloric acid was added to the reaction mixture at -70° C. and the mixture was diluted with ethyl acetate (200 ml). The solution was washed with water, brine, aqueous sodium bicarbonate and brine, dried over magnesium sulfate, and evaporated in vacuo. Triethylamine (0.15 ml) was added to a solution of the residue in dichloromethane (3 ml) at 0° C. and the mixture was stirred overnight at ambient temperature. The reaction mixture was diluted with ethyl acetate (20 ml) and the solution was washed with 0.1N hydrochloric acid (15 ml) brine, aqueous sodium bicarbonate and brine, dried over magnesium sulfate, and evaporated in vacuo. The residue was chromatographed on silica gel (10 g) eluting with a mixture of benzene and acetone (10:1-2:1) to give methyl 3-methyl-2-[(3S, 4R)-3-(1-hydroxy-1-methylethyl)-2-oxo-4-allylazetidin-1-yl]but-2-enoate (100 mg); IR (CH2Cl2): 1740, 1715 cm-1. NMR (CDCl3) δ: 1.31 (s, 3H), 1.38 (s, 3H), 1.96 (s, 3H), 2.18 (s, 3H), 2.2-2.5 (m, 3H), 2.90 (d, 1H, J=3 Hz), 3.76 (s, 3H), 3.81 (dt, 1H, J=3, 7 Hz), 4.9-5.2 (m, 2H), 5.5-6.0 (m, 1H) and methyl 3-methyl-2-[(3R,4R)-3-(1-hydroxy-1-methylethyl)-2-oxo-4-allylazetidin-1-yl]but-2-enoate (50 mg).
Reaction SMILES: C(OC([C@@:8]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)([OH:29])[C@H:9]([NH:16][C@@H:17]1[CH2:23][C:22]2[CH:24]=[CH:25][CH:26]=[CH:27][C:21]=2[CH2:20][NH:19][C:18]1=[O:28])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[C:10]1([C@@H:9]([NH:16][C@@H:17]2[CH2:23][C:22]3[CH:24]=[CH:25][CH:26]=[CH:27][C:21]=3[CH2:20][NH:19][C:18]2=[O:28])[C@H:8]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[OH:29])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CC(C)(C)OC(=O)[C@](O)(c1ccccc1)[C@H](N[C@@H]1Cc2ccccc2CNC1=O)c1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C1NCc2ccccc2C[C@H]1N[C@H](c1ccccc1)[C@@H](O)c1ccccc1
Reaction time: 3 h
Yield: 99 %

Procedure:
A solution of 478 mg (1.01 mmol) of 4(R)-[[t-butoxycarbonyl][(1R,2S)-1,2-diphenyl-2-hydroxyethyl]]amino-2,3,4,5-tetrahydro-1H-2-benzazepin-3-one (Example 1, Step B) in 5 mL of methylene chloride at room temperature was treated with 0.5 mL of trifluoroacetic acid. The mixture was stired at room temperature for 3 hours then all volatiles removed under vacuum. The residue was dissolved in 5 mL of water and the solution made basic (pH 10-11) by the addition of solid sodium carbonate. The mixture was extracted with chloroform (5×) and the combined extracts dried over anhydrous potassium carbonate, filtered and solvents removed under vacuum to give 372 mg (1.00 mmol, 99%) of 4(R)-[[(1R,2S)-1,2-diphenyl-2-hydroxyethyl]]amino-2,3,4,5-tetrahydro-1H-2-benzazepin-3-one which was used in the next step without purification.
Reaction SMILES: [CH:1]1[C:6]([C:7]2[C:16](=[O:17])[C:15]3[CH:14]=[CH:13][C:12]([OH:18])=[CH:11][C:10]=3[O:9][CH:8]=2)=[CH:5][CH:4]=[C:3]([OH:19])[CH:2]=1.[C:20]([O-])([O-])=O.[K+].[K+].IC>CS(C)=O>[CH3:20][O:18][C:12]1[CH:11]=[C:10]2[C:15]([C:16](=[O:17])[C:7]([C:6]3[CH:5]=[CH:4][C:3]([OH:19])=[CH:2][CH:1]=3)=[CH:8][O:9]2)=[CH:14][CH:13]=1
Reactant: O=C([O-])[O-]
Reactant: O=c1c(-c2ccc(O)cc2)coc2cc(O)ccc12
Agent: [K+]
Solvent: CS(C)=O
Solvent: CI
Product: COc1ccc2c(=O)c(-c3ccc(O)cc3)coc2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 45.1 %

Procedure:
To a solution of 5.1 g of daidzein (20.06 mmol) in 40 ml of DMSO was added 3.5 g of anhydrous K2CO3 (25.4 mmol) and 6 ml of iodomethane (96.4 mmol). The mixture was stirred at room temperature for 2 hours and then poured into ice water to precipitate product. Precipitates were extracted with ethyl acetate, dried by flash evaporation and purified on a Sephadex LH-20 column (chloroform:methanol/7:3). Final product was recrystallized from acetone to give 2.3 g of crystalline analog 2, a yield of 45.1% (w/w): mp 210-211° C.; 1H NMR (DMSO-d6) δ 3.89 (—OCH3), 6.81 (d, 2H, J=8.43 Hz, 3′, 5′-H), 7.05 (dd, 1H, J=8.89, 2.39 Hz, 6-H), 7.11 (d, 1H, J=2.07 Hz, 8-H), 7.39 (d, 2H, J=8.62 Hz, 2′, 6′-H), 8.01 (d, 1H, J=8.87 Hz; 5-H), 8.35 (s, 1H, 2-H), 9.54 (s, 1H, 4′-OH). Anal. (C16H12O4) for C, H. Cacld: 71.64, 4.51; found: 71.24, 4.47.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:11]2[CH:12]=[C:13]([Cl:16])[CH:14]=[CH:15][C:10]=2[O:9][C:8]2[CH:17]=[CH:18][CH:19]=[CH:20][C:7]=2[CH:6]=1)=[O:4].C(N=C(N(C)C)N(C)C)(C)(C)C.[N+:33]([CH3:36])([O-:35])=[O:34].Cl>C1COCC1.O.C(OC)(C)(C)C>[CH3:1][O:2][C:3]([C@@H:5]1[C:11]2[CH:12]=[C:13]([Cl:16])[CH:14]=[CH:15][C:10]=2[O:9][C:8]2[CH:17]=[CH:18][CH:19]=[CH:20][C:7]=2[C@H:6]1[CH2:36][N+:33]([O-:35])=[O:34])=[O:4]
Reactant: COC(=O)C1=Cc2ccccc2Oc2ccc(Cl)cc21
Reactant: C[N+](=O)[O-]
Agent: CN(C)C(=NC(C)(C)C)N(C)C
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Solvent: COC(C)(C)C
Product: COC(=O)[C@@H]1c2cc(Cl)ccc2Oc2ccccc2[C@H]1C[N+](=O)[O-]

Procedure:
To a 5 L 3-neck round bottom flask was added 8-chloro-dibenz[b,f]-oxepin-10-carboxylic acid methyl ester (305 g, 1.06 mol, 1 eq) followed by THF (1.25 L) and t-butyl-tetramethylguanidine (27 g, 0.15 mol, 0.14 eq). To this solution was added nitromethane (576 g, 9.45 mol, 8.9 eq) in THF (0.5 L) while maintaining a temperature of less than 30° C. The resultant mixture was stirred at room temperature until judged complete by HPLC (overnight, <3% starting material). Once complete, methyl tertiary butyl ether (1.25 L), water (0.6 L) and 1N HCl (0.6 L) were added, the layers were separated, and the aqueous layer was extracted a second time with MTBE (1 L). The combined organic layers were washed with 1N HCl (2×0.6 L) and saturated sodium chloride (0.6 L). After addition of toluene (2 L) the organic fraction was concentrated under vacuum to a volume less than 2 L, toluene (1 L) was added, and the mixture was concentrated to minimum volume. Addition of THF (0.5 L) afforded the titled compound as a light colored solution which was used without further purification (368 g, 1.06 mol, theoretical). HPLC area %: 45% toluene, 48% trans-nitro ester, 6% cis-nitro ester, 1% starting material.
Reaction SMILES: C([N:3](CC)CC)C.[NH2:8][C:9]1[C:17]([CH3:18])=[CH:16][CH:15]=[CH:14][C:10]=1[C:11]([OH:13])=O.[C:19](Cl)(=[O:23])[CH:20]([CH3:22])[CH3:21].C(=O)([O-])[O-].[NH4+].[NH4+]>CN(C=O)C.CN(C1C=CC=CN=1)C>[C:19]([NH:8][C:9]1[C:17]([CH3:18])=[CH:16][CH:15]=[CH:14][C:10]=1[C:11]([NH2:3])=[O:13])(=[O:23])[CH:20]([CH3:22])[CH3:21]
Reactant: CC(C)C(=O)Cl
Reactant: Cc1cccc(C(=O)O)c1N
Reactant: CCN(CC)CC
Agent: CN(C)c1ccccn1
Agent: O=C([O-])[O-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: Cc1cccc(C(N)=O)c1NC(=O)C(C)C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 33.9 %

Procedure:
Dimethylaminopyridine (15 mg) followed by triethylamine (4.14 mL, 0.0279 mol) were added to a stirred solution of 2-amino-3-methylbenzoic acid (1.50 g, 0.0099 mol) in DMF (15 mL) under nitrogen at 0° C. The iso-butyryl chloride (2.07 mL, 0.0198 mol) was added dropwise then the mixture stirred at 0° C. for 30 min. followed by 30 min. at room temperature then at 120° C. for 1 hr. The suspension was then stirred at room temperature for 2 days. Ammonium carbonate (3.5 g) was added in portions and the mixture heated at 120° C. for 3 hr. After cooling to room temperature the mixture was poured into ice/water and extracted with ethyl acetate (3 times). The combined organic phase was washed with water, brine, dried (magnesium sulfate) and the solvent removed in vacuo to leave a cream solid. Recrystallisation (1:1 ethyl acetate/hexane) afforded 2-(iso-butyryl)amino-3-methylbenzamide (739 mg, 34%).
Reaction SMILES: C1CCC(N=C=NC2CCCCC2)CC1.[CH:16](O)=[O:17].[CH2:19]([O:26][C:27](=[O:67])[N:28]([CH2:64][CH:65]=[CH2:66])[C:29]1[C:34](=[O:35])[N:33]2[C@H:36]([C:41](=[O:63])[NH:42][CH2:43][C:44]3[CH:49]=[CH:48][C:47]([C:50]([NH:52][C:53]([O:55][CH2:56][C:57]4[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=4)=[O:54])=[NH:51])=[CH:46][CH:45]=3)[CH2:37][C@:38]([NH2:40])([CH3:39])[C:32]2=[N:31][CH:30]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.N1C=CC=CC=1>C(Cl)Cl>[CH2:19]([O:26][C:27](=[O:67])[N:28]([CH2:64][CH:65]=[CH2:66])[C:29]1[C:34](=[O:35])[N:33]2[C@@H:36]([C:41](=[O:63])[NH:42][CH2:43][C:44]3[CH:49]=[CH:48][C:47]([C:50]([NH:52][C:53]([O:55][CH2:56][C:57]4[CH:58]=[CH:59][CH:60]=[CH:61][CH:62]=4)=[O:54])=[NH:51])=[CH:46][CH:45]=3)[CH2:37][C@@:38]([NH:40][CH:16]=[O:17])([CH3:39])[C:32]2=[N:31][CH:30]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: C=CCN(C(=O)OCc1ccccc1)c1cnc2n(c1=O)[C@H](C(=O)NCc1ccc(C(=N)NC(=O)OCc3ccccc3)cc1)C[C@@]2(C)N
Reactant: O=CO
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Solvent: c1ccncc1
Product: C=CCN(C(=O)OCc1ccccc1)c1cnc2n(c1=O)[C@@H](C(=O)NCc1ccc(C(=N)NC(=O)OCc3ccccc3)cc1)C[C@]2(C)NC=O
Reaction time: 2 h
Yield: 74.5 %

Procedure:
To a solution of DCC (18.6 mg, 0.090 mmol) and formic acid (8.28 mg, 0.180 mmol) in CH2Cl2 that had been stirred at 0° C. for 10 min, was added intermediate 26a (30 mg, 0.045) in a solution of pyridine. The reaction was stirred at 0° C. for 15m then at rt for 2 h. The reaction mixture was concentrated in vacuo, then taken up in brine and extracted with chloroform (6×), dried (Na2SO4) and concentrated. It was purified by SiO2 chromatography (gradient elution, 1–12% MeOH/CH2Cl2) to afford 23.3 mg (75%) of intermediate 42a. MS (ESI) 692.2 (M+H+).
Reaction SMILES: [CH3:1][CH:2]([O:4][C:5]1[CH:6]=[C:7]([O:25][C:26]2[CH:31]=[CH:30][C:29]([S:32]([CH3:35])(=[O:34])=[O:33])=[CH:28][CH:27]=2)[CH:8]=[C:9]2[C:13]=1[NH:12][C:11]([C:14]1[S:15][CH:16]([CH2:19]C(OCC)=O)[CH2:17][N:18]=1)=[CH:10]2)[CH3:3].[O:36]1[CH2:40][CH2:39]CC1.[CH3:41][Mg]Br.Cl>O1CCCC1>[CH3:41][C:40]([OH:36])([CH3:39])[CH2:19][CH:16]1[S:15][C:14]([C:11]2[NH:12][C:13]3[C:9]([CH:10]=2)=[CH:8][C:7]([O:25][C:26]2[CH:31]=[CH:30][C:29]([S:32]([CH3:35])(=[O:33])=[O:34])=[CH:28][CH:27]=2)=[CH:6][C:5]=3[O:4][CH:2]([CH3:3])[CH3:1])=[N:18][CH2:17]1
Reactant: C[Mg]Br
Reactant: CCOC(=O)CC1CN=C(c2cc3cc(Oc4ccc(S(C)(=O)=O)cc4)cc(OC(C)C)c3[nH]2)S1
Reactant: C1CCOC1
Agent: Cl
Product: CC(C)Oc1cc(Oc2ccc(S(C)(=O)=O)cc2)cc2cc(C3=NCC(CC(C)(C)O)S3)[nH]c12
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 10 %

Procedure:
To a solution of ethyl (2-{7-(1-methylethoxy)-5-[4-(methylsulfonyl)phenoxy]-1H-indol-2-yl}-4,5-dihydro-1,3-thiazol-5-yl)acetate (490 mg) in tetrahydrofuran (10 mL) was added 1M methylmagnesium bromide tetrahydrofuran solution (7.6 mL) at 0° C. After the mixture was stirred at room temperature for 1.5 h, 1M methylmagnesium bromide tetrahydrofuran solution (3.4 mL) was added to the mixture again at room temperature. The mixture was stirred at room temperature for 2 h. Furthermore, 1M methylmagnesium bromide tetrahydrofuran solution (3.4 mL) was added to the mixture at room temperature and the mixture was stirred at room temperature for 30 min. The mixture was acidified with 1M hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (ethyl acetate/hexane=3/97 to 60/40, volume ratio) to give a yellow oil. The oil was crystallized from ethyl acetate-diethyl ether-hexane to give pale yellow crystals. The crystals were recrystallized from ethyl acetate-diisopropyl ether to give the title compound (50 mg, 10%) as pale yellow crystals. MS 503 (MH+).
Reaction SMILES: CS(C)=O.[H-].[Na+].[Cl:7][C:8]1[CH:22]=[CH:21][C:11]2[CH2:12][CH2:13][C@H:14]([N:18]([CH3:20])[CH3:19])[CH2:15][C@@H:16]([OH:17])[C:10]=2[CH:9]=1.Cl[C:24]1[CH:29]=[CH:28][C:27]([N+:30]([O-:32])=[O:31])=[CH:26][CH:25]=1>O>[ClH:7].[CH3:20][N:18]([CH3:19])[C@H:14]1[CH2:13][CH2:12][C:11]2[CH:21]=[CH:22][C:8]([Cl:7])=[CH:9][C:10]=2[C@H:16]([O:17][C:24]2[CH:29]=[CH:28][C:27]([N+:30]([O-:32])=[O:31])=[CH:26][CH:25]=2)[CH2:15]1
Reactant: CN(C)[C@H]1CCc2ccc(Cl)cc2[C@H](O)C1
Reactant: O=[N+]([O-])c1ccc(Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CN(C)[C@H]1CCc2ccc(Cl)cc2[C@H](Oc2ccc([N+](=O)[O-])cc2)C1
Product: Cl
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 183.5 %

Procedure:
12 ml of anhydrous dimethylsulfoxide were added under nitrogen to 1.2 g of sodium hydride as a 50% oil dispersion and the mixture was stirred at 60° C. for 30 minutes and was then cooled to 25° C. 4.8 g of trans 3-chloro-7-dimethylamino-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-ol were added thereto and the mixture was stirred for 15 minutes at 25° C. after which 6.3 g of p-chloronitrobenzene were added thereto. The mixture was stirred for one hour and 500 ml of water were added thereto. The mixture was extracted with methylene chloride and the organic phase was dried over magnesium sulfate and was evaporated to dryness under reduced pressure. The residue was taken up in 130 ml of N hydrochloric acid and after standing for 20 minutes, the mixture was vacuum filtered. The recovered product was washed with ether, then water and dried under vacuum to obtain 7.3 g of product which was crystallized from methanol and ethyl acetate to obtain 5 g of trans N,N-dimethyl-3-chloro-5-[4-nitrophenoxy]-6,7,8,9-tetrahydro-5H-benzocyclohepten-7-amino hydrochloride in the form of colorless crystals melting at 230° C.
Reaction SMILES: C([O:5][C:6]([N:8]1[CH2:13][CH:12]=[CH:11][CH2:10][CH2:9]1)=[O:7])(C)(C)C.C1C=C(Cl)C=C(C(OO)=[O:22])C=1.CCOC(C)=O.CCCCCC>C(Cl)Cl>[CH:10]12[O:22][CH:11]1[CH2:12][CH2:13][N:8]([C:6]([OH:5])=[O:7])[CH2:9]2
Reactant: CC(C)(C)OC(=O)N1CC=CCC1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: O=C(O)N1CCC2OC2C1
Reaction time: 8 h

Procedure:
To a stirred solution of 3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (Aldrich, 15.99 g, 87.28 mmol) in methylene chloride (600 mL) at 0° C., mCPBA (Aldrich, 29.4 g, 77%, 131 mmol) was added and the mixture was stirred overnight. The reaction was quenched with 10% Na2S2O3 and the organic layer was separated and washed with 5% sodium carbonate, brine and water and dried over sodium sulfate and concentrated to give a light yellow oil, which was chromatographied (10% EtOAc/Hexane) to yield a colorless oil. 14.93 g. The compound was used directly for the next step.