Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C@@H:2]1[C@H:8]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)[S:7][C:6]2[C:17]3[C:22]([CH:23]=[CH:24][C:5]=2[NH:4][C:3]1=[O:25])=[CH:21][CH:20]=[CH:19][CH:18]=3.C(=O)([O-])[O-].[K+].[K+].[CH3:32][N:33]([CH3:38])[CH2:34][CH2:35][CH2:36]Cl.O>C(OCC)(=O)C>[OH:1][C@@H:2]1[C@H:8]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)[S:7][C:6]2[C:17]3[C:22]([CH:23]=[CH:24][C:5]=2[N:4]([CH2:36][CH2:35][CH2:34][N:33]([CH3:38])[CH3:32])[C:3]1=[O:25])=[CH:21][CH:20]=[CH:19][CH:18]=3
Reactant: COc1ccc([C@@H]2Sc3c(ccc4ccccc34)NC(=O)[C@@H]2O)cc1
Reactant: CN(C)CCCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Product: COc1ccc([C@@H]2Sc3c(ccc4ccccc34)N(CCCN(C)C)C(=O)[C@@H]2O)cc1
Yield: 99.4 %

Procedure:
A mixture of 1.7 g of (±)-cis-2,3-dihydro-3-hydroxy-2-(4-methoxyphenyl)naphtho[1,2-b]-1,4-thiazepin-4(5H)-one, 0.75 g potassium carbonate and 0.7 g of 3-dimethylaminopropyl chloride in 30 mL of ethyl acetate was stirred and heated at reflux for 2 hours then an additional 0.2 g of 3-dimethylaminopropyl chloride was added four times at 2 hour intervals. The mixture was heated at reflux for a total of 12 hours then to the mixture ethyl acetate and water were added. The organic phase was separated, washed with brine and dried (magnesium sulfate). Removal of the solvent gave 2.1 g (100%) (±)-cis-2,3-dihydro-3-hydroxy-5-[3-(dimethylamino)propyl]-2-(4-methoxyphenyl)naphtho[1,2-b]-1,4-thiazepin-4(5H)-one. A sample was crystallized from ether, mp 123°-124°.
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH:4]1[C:9]2[NH:10][C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:16]=3[C:8]=2[S:7][CH2:6][CH2:5]1.C(N(CC)CC)C.[C:24]([O:28][C:29](ON=C(C1C=CC=CC=1)C#N)=[O:30])([CH3:27])([CH3:26])[CH3:25]>O1CCCC1>[CH3:1][N:2]([CH2:3][CH:4]1[C:9]2[NH:10][C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:16]=3[C:8]=2[S:7][CH2:6][CH2:5]1)[C:29]([O:28][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:30]
Reactant: CC(C)(C)OC(=O)ON=C(C#N)c1ccccc1
Reactant: CNCC1CCSc2c1[nH]c1ccccc21
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CN(CC1CCSc2c1[nH]c1ccccc21)C(=O)OC(C)(C)C
Reaction time: 4 h
Yield: 68.1 %

Procedure:
A solution of 4-methylaminomethyl-2,3,4,5-tetrahydrothiopyrano[3,2-b]indole (5.47 g) in dry tetrahydrofuran (50 ml) is mixed with triethylamine (3.58 g) and 2-t-butoxycarbonyloxyimino-2-phenylacetonitrile (5.93 g), allowed to stand at room temperature for 4 hours and evaporated to dryness. The residue is dissolved in methylene chloride and washed with a dilute sodium hydroxide solution. The solution is washed with water, dried and evaporated to dryness. The residue is applied to column chromatography on silica gel eluted with benzene/ether (20:1) to give 4-(N-methyl-N-t-butoxycarbonylaminomethyl)-2,3,4,5-tetrahydrothiopyrano[ 3,2-b]indole (5.33 g): Yield 68.2%. Recrystallization from benzene/petroleum benzine gives crystals melting at 151°-153° C. (decomp.).
Reaction SMILES: [C:1]1([NH:7][C:8]2[CH:9]=[C:10]([CH:16]=[CH:17][CH:18]=2)[C:11]([O:13]CC)=[O:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+]>O.O1CCOCC1>[C:1]1([NH:7][C:8]2[CH:9]=[C:10]([CH:16]=[CH:17][CH:18]=2)[C:11]([OH:13])=[O:12])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)c1cccc(Nc2ccccc2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: O=C(O)c1cccc(Nc2ccccc2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Ethyl 3-(phenylamino)benzoate (0.175 g; 0.725 mmol) was added to a mixture of NaOH in water (1 mL; 2M) and dioxane (1 mL) and stirred vigorously at room temperature overnight. The resulting mixture was concentrated in vacuo and extracted with dichloromethane. The aqueous layer was acidified with a 6N solution of hydrochloric acid in water. The precipitated product was collected by filtration to yield 0.155 g (quantitative) of the title compound as a grey solid which was used without further purification.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[CH:11]=[C:10]([O:12]CC2C=CC=CC=2)[C:9]([S:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[CH:8][N:7]=1)(=[O:3])[CH3:2]>O1CCOCC1.O.[Pd]>[C:1]([O:4][CH2:5][C:6]1[NH:7][CH:8]=[C:9]([S:20][C:21]([CH3:24])([CH3:23])[CH3:22])[C:10](=[O:12])[CH:11]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OCc1cc(OCc2ccccc2)c(SC(C)(C)C)cn1
Agent: [Pd]
Solvent: O
Solvent: C1COCCO1
Product: CC(=O)OCc1cc(=O)c(SC(C)(C)C)c[nH]1
Yield: 100.6 %

Procedure:
A solution of (5-[(1,1-dimethylethyl)thio]-4-[(phenylmethyl)oxy]-2-pyridinyl}methyl acetate (6 g) in 1,4-dioxane/water (100 ml/50 ml) was hydrogenated at atmospheric pressure with 10% palladium on charcol (7 g) overnight. Filtration and evaporation afforded a white solid (4.46 g, 95%).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:15]=[C:14]3[N:16]([CH2:19][C:20]([F:23])([F:22])[F:21])[N:17]=[CH:18][C:13]3=[C:12]([N:24]3[CH2:31][CH:30]4[O:32][CH:26]([CH2:27][N:28]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:29]4)[CH2:25]3)[N:11]=2)=[CH:6][CH:5]=1)([O-])=O>O1CCCC1.C(O)C>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[N:15]=[C:14]3[N:16]([CH2:19][C:20]([F:22])([F:23])[F:21])[N:17]=[CH:18][C:13]3=[C:12]([N:24]3[CH2:31][CH:30]4[O:32][CH:26]([CH2:27][N:28]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:29]4)[CH2:25]3)[N:11]=2)=[CH:8][CH:9]=1
Reactant: CC(C)(C)OC(=O)N1CC2CN(c3nc(-c4ccc([N+](=O)[O-])cc4)nc4c3cnn4CC(F)(F)F)CC(C1)O2
Solvent: C1CCOC1
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CC2CN(c3nc(-c4ccc(N)cc4)nc4c3cnn4CC(F)(F)F)CC(C1)O2
Reaction time: 8 h
Yield: 94.3 %

Procedure:
A suspension of tert-butyl 7-(6-(4-nitrophenyl)-1-(2,2,2-trifluoroethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-9-oxa-3,7-diazabicyclo[3.3.1]nonane-3-carboxylate (0.54 g, 0.98 mmol) in tetrahydrofuran (10 mL) and ethanol (10 mL) was degassed by the addition of crushed dry ice and then treated with 10% palladium on carbon (30 mg). The resulting suspension was evacuated under weak vacuum and then filled with hydrogen gas (balloon). This evacuation/fill cycle was performed three more times and on the final iteration, the mixture was left to stir overnight under a hydrogen-filled balloon. The mixture was filtered through a pad of diatomaceous earth, eluting with ethanol. The filtrate was concentrated under reduced pressure to afford tert-butyl 7-(6-(4-aminophenyl)-1-(2,2,2-trifluoroethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-9-oxa-3,7-diazabicyclo[3.3.1]nonane-3-carboxylate as a white solid (0.48 g, 94%). MS (ES+): 520.2 (M+H)+
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[CH2:7][N:8]1[C:14](=[O:15])[C:13]2[CH:16]=[C:17](B3OC(C)(C)C(C)(C)O3)[CH:18]=[CH:19][C:12]=2[O:11][CH2:10][CH2:9]1.Br[C:30]1[S:31][C:32]([CH3:35])=[CH:33][CH:34]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CCOC(C)=O>CN(C=O)C.O.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].Cl[Pd]Cl>[CH3:35][C:32]1[S:31][C:30]([C:17]2[CH:18]=[CH:19][C:12]3[O:11][CH2:10][CH2:9][N:8]([CH2:7][C:2]4[N:1]=[CH:6][CH:5]=[CH:4][N:3]=4)[C:14](=[O:15])[C:13]=3[CH:16]=2)=[CH:34][CH:33]=1
Reactant: CC1(C)OB(c2ccc3c(c2)C(=O)N(Cc2ncccn2)CCO3)OC1(C)C
Reactant: Cc1ccc(Br)s1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1ccc(-c2ccc3c(c2)C(=O)N(Cc2ncccn2)CCO3)s1
Temperature: 85 °C

Procedure:
A mixture of 4-(pyrimidin-2-ylmethyl)-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one (50 mg, 0.13 mmol), 2-bromo-5-methylthiophene (28 mg, 0.156 mmol), cesium carbonate (128 mg, 0.39 mmol), 1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium (9 mg, 0.013 mmol) was dissolved in a degassed mixture of DMF and water 3/1.5 (4.5 ml). The mixture was heated in microwave at 85° C. for 40 min. The mixture was poured into EtOAc and washed with water and brine. The organic layer was collected, dried over sodium sulfate and loaded onto silica gel. A flash column (5% MeOH in EtOAc) and reverse phase chromatography gave 7-(5-methylthiophen-2-yl)-4-(pyrimidin-2-ylmethyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([S:21][CH3:22])=[C:8]([S:10]([C:13]2[CH:14]=[N:15][C:16](Cl)=[C:17]([Br:19])[CH:18]=2)(=[O:12])=[O:11])[CH:9]=1)=[O:4].[N:23]1([CH2:28][CH2:29][CH2:30][NH2:31])[CH:27]=[CH:26][N:25]=[CH:24]1.C(N(C(C)C)CC)(C)C.C1COCC1>CN(C=O)C>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([S:21][CH3:22])=[C:8]([S:10]([C:13]2[CH:14]=[N:15][C:16]([NH:31][CH2:30][CH2:29][CH2:28][N:23]3[CH:27]=[CH:26][N:25]=[CH:24]3)=[C:17]([Br:19])[CH:18]=2)(=[O:12])=[O:11])[CH:9]=1)=[O:4]
Reactant: NCCCn1ccnc1
Reactant: COC(=O)c1cc(S(=O)(=O)c2cnc(Cl)c(Br)c2)c(SC)s1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COC(=O)c1cc(S(=O)(=O)c2cnc(NCCCn3ccnc3)c(Br)c2)c(SC)s1
Temperature: 80 °C

Procedure:
To a vial containing a stirbar was added 4-(5-bromo-6-chloro-pyridine-3-sulfonyl)-5-methylsulfanyl-thiophene-2-carboxylic acid methyl ester (0.050 g, 0.113 mmol), (Example 2: step c), 3-imidazol-1-yl-propylamine (0.018 g, 0.146 mmol), diisopropylethylamine (0.073 g, 0.565 mmol), THF [0.50 mL], DMF [0.50 mL]. The reaction vessel was sealed and the solution was heated to 80° C. for 18 hours. Removal of the solvents in vacuo followed by chromatography (5% MeOH/DCM) yielded the title compound. 1H-NMR (CDCl3): δ 8.69 (d, 1H, J=2.1 Hz), 8.10 (d, 1H J=2.1 Hz), 8.03 (s, 1H), 8.02 (s, 1H), 7.57 (s, 1H), 7.10 (s, 1H), 6.97 (s 1H), 5.70 (t, 1H, J=5.8 Hz), 4.06 (t, 2H, J=6.8 Hz), 3.89 (s, 3H), 3.57 (m, 2H), 2.97 (s, 2H), 2.90 (s, 2H), 2.64 (s, 3H), 2.17 (m, 2H). ESI-MS (m/z): Calcd. For C18H19BrN4O4S3: 532.5 (M+H); found 530.9, 532.9.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[CH:8]=[CH:7][C:6]([C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[C:11]([N+:17]([O-:19])=[O:18])[CH:10]=2)=[N:5]1.[CH3:20][C:21]1[O:25][N:24]=[C:23]([C:26](O)=[O:27])[CH:22]=1>>[C:13]([C:12]1[CH:15]=[CH:16][C:9]([C:6]2[CH:7]=[CH:8][N:4]([CH2:3][CH2:2][NH:1][C:26]([C:23]3[CH:22]=[C:21]([CH3:20])[O:25][N:24]=3)=[O:27])[N:5]=2)=[CH:10][C:11]=1[N+:17]([O-:19])=[O:18])#[N:14]
Reactant: N#Cc1ccc(-c2ccn(CCN)n2)cc1[N+](=O)[O-]
Reactant: Cc1cc(C(=O)O)no1
Product: Cc1cc(C(=O)NCCn2ccc(-c3ccc(C#N)c([N+](=O)[O-])c3)n2)no1

Procedure:
The title compound was prepared from 4-(1-(2-aminoethyl)-1H-pyrazol-3-yl)-2-nitrobenzonitrile (150 mg) and 5-methylisoxazole-3-carboxylic acid (89 mg) using the method of Example 34(d). Yield 9 mg. 1H-NMR (400 MHz; d6-DMSO): δ 2.44 (s, 3H), 3.70 (q, 2H), 4.40 (t, 2H), 6.48 (d, 1H), 7.05 (d, 1H), 7.88 (d, 1H), 8.18 (d, 1H), 8.32 (dd, 1H), 8.67 (d, 1H), 8.79 (m, 1H).
Reaction SMILES: Cl[S:2]([CH:5]1[CH2:10][CH2:9][N:8]([C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:12])[CH2:7][CH2:6]1)(=[O:4])=[O:3].[NH3:21]>>[NH2:21][S:2]([CH:5]1[CH2:10][CH2:9][N:8]([C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:12])[CH2:7][CH2:6]1)(=[O:4])=[O:3]
Reactant: O=C(OCc1ccccc1)N1CCC(S(=O)(=O)Cl)CC1
Reactant: N
Product: NS(=O)(=O)C1CCN(C(=O)OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of 0.88 NH3 (50 ml) was added benzyl 4-(chlorosulfonyl)piperidine-1-carboxylate (4 g) and the reaction stirred for 72 h at RT. The reaction was then extracted with DCM (3×150 ml). Organics were recovered, dried (MgSO4) and reduced in vacuo to give the subtitle compound as a clear oil. Yield 3.3 g
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][NH:13][CH2:12][CH:11]([C:15]([NH:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[O:16])[CH2:10]2)=[CH:5][CH:4]=1)[CH3:2].Cl[C:25]([O:27][CH2:28][CH2:29][O:30][CH3:31])=[O:26]>>[CH2:1]([C:3]1[CH:4]=[CH:5][C:6]([CH:9]2[CH2:10][CH:11]([C:15](=[O:16])[NH:17][C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH2:12][N:13]([C:25]([O:27][CH2:28][CH2:29][O:30][CH3:31])=[O:26])[CH2:14]2)=[CH:7][CH:8]=1)[CH3:2]
Reactant: COCCOC(=O)Cl
Reactant: CCc1ccc(C2CNCC(C(=O)Nc3ccccc3)C2)cc1
Product: CCc1ccc(C2CC(C(=O)Nc3ccccc3)CN(C(=O)OCCOC)C2)cc1

Procedure:
68 mg (0.20 mmol) of 5-(4-ethylphenyl)-N-phenylpiperidine-3-carboxamide (Example 17A) and 38 mg (0.22 mmol, 1.1 eq.) of 2-methoxyethyl chloroformate were reacted according to General Method 5. Yield: 73 mg (89% of theory)
Reaction SMILES: [Si:1]([O:8][CH:9]([CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])[CH2:10][CH2:11][C@H:12]1[C@H:16]([O:17][CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][O:19]2)[CH2:15][C@H:14](O)[C@@H:13]1[CH2:25]/[CH:26]=[CH:27]\[CH2:28][CH2:29][CH2:30][C:31]([OH:33])=[O:32])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C1C=C(SSC2N=CC=CC=2)N=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1(C)C(C)=CC=CC=1>[Si:1]([O:8][CH:9]([CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])[CH2:10][CH2:11][C@@H:12]1[C@@H:13]2[C@@H:14]([O:32][C:31](=[O:33])[CH2:30][CH2:29][CH2:28][CH:27]=[CH:26][CH2:25]2)[CH2:15][C@H:16]1[O:17][CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][O:19]1)([C:4]([CH3:5])([CH3:7])[CH3:6])([CH3:2])[CH3:3]
Reactant: CCCCCCCC(CC[C@@H]1[C@@H](C/C=C\CCCC(=O)O)[C@@H](O)C[C@H]1OC1CCCCO1)O[Si](C)(C)C(C)(C)C
Agent: CCCCCCCC(CC[C@@H]1[C@H]2C/C=C\CCCC(=O)O[C@H]2C[C@H]1OC1CCCCO1)O[Si](C)(C)C(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Agent: c1ccc(SSc2ccccn2)nc1
Solvent: Cc1ccccc1C
Product: CCCCCCCC(CC[C@@H]1[C@H]2CC=CCCCC(=O)O[C@H]2C[C@H]1OC1CCCCO1)O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of (Z)-7-[(1R,2R,3R,5S)-2-(3-(tert-butyldimethyl-silyloxy)decyl)-5-hydroxy-3-(tetrahydro-2H-pyran-2-yloxy)cyclopentyl)hept-5-enoic acid (61 g from Example 39) in 250 mL xylene was treated with 2,2′-dipyridyl disulfide (36 g, 0.17 mol) and triphenylphosphine (38 g, 0.43 mol). This mixture was then stirred for 1 hour at room temperature under an atmosphere of nitrogen and the resulting mixture was heated to 80° C. for 18 hours. Then, the xylene was removed under reduced pressure, and the residue was diluted with 200 ml saturated sodium bicarbonate aqueous solution and extracted with 200 ml ethyl acetate twice. The organic layer was dried over anhydrous MgSO4. The solid was filtered off and organic solvent was evaporated off under vacuum. The crude product was purified by chromatography on silica gel using a mixture of hexane and ethyl acetate as a gradient eluent. Yield of the title compound was 25 g (75% in 3 steps).
Reaction SMILES: [S:1]1[C:5]2=[CH:6][CH:7]=[CH:8][C:9]([S:10]([NH:13][C:14]3[CH:22]=[CH:21][C:17]([C:18]([OH:20])=[O:19])=[CH:16][CH:15]=3)(=[O:12])=[O:11])=[C:4]2[N:3]=C1.O.NN>CCO>[NH2:3][C:4]1[C:5]([SH:1])=[CH:6][CH:7]=[CH:8][C:9]=1[S:10]([NH:13][C:14]1[CH:22]=[CH:21][C:17]([C:18]([OH:20])=[O:19])=[CH:16][CH:15]=1)(=[O:11])=[O:12]
Reactant: O=C(O)c1ccc(NS(=O)(=O)c2cccc3scnc23)cc1
Agent: NN
Solvent: O
Solvent: CCO
Product: Nc1c(S)cccc1S(=O)(=O)Nc1ccc(C(=O)O)cc1
Temperature: 130 °C
Reaction time: 1.5 h
Yield: 92.3 %

Procedure:
To a solution of 4-(benzo[d]thiazole-4-sulfonamido)benzoic acid (500 mg, 1.5 mmol) in 6 mL of EtOH was added hydrazine hydrate (479 mg, 15 mmol) at r.t. The reaction mixture was then stirred at 130° C. in microwave for 1.5 h. The resulting mixture was then cooled, and partitioned between water and EtOAc. The organic phase was washed with brine, dried over anhy. Na2SO4 and concentrated in vacuo to afford the title compound (449.0 mg). LC-MS: m/z 323.4 (M+H)+
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[C:6]([CH3:7])=[CH:5][CH2:4][CH:3]1[CH:8]([CH2:11][C:12]([CH3:14])=[CH2:13])[CH2:9][OH:10].CC1C=CC(S(O)(=O)=O)=CC=1>CCCCCC>[CH3:13][C:12]1([CH3:14])[CH2:11][CH:8]([CH:3]2[CH2:4][CH:5]=[C:6]([CH3:7])[C:2]2([CH3:15])[CH3:1])[CH2:9][O:10]1
Reactant: C=C(C)CC(CO)C1CC=C(C)C1(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCCCCC
Product: CC1=CCC(C2COC(C)(C)C2)C1(C)C
Yield: 91.6 %

Procedure:
A 500 ml 3 neck round bottomed flask was charged with 56.1 g of 2-(2,2,3-trimethylcyclopent-3-en-1-yl)-4-methyl-4-pentenol, (0.26 mole), 260 ml of hexane, and 0.75 g of p-TSA. The mixture was then refluxed for 7 hours. After cooling the batch was washed with 250 ml of 10% sodium carbonate, and once with 250 ml of brine. The batch was dried with magnesium sulfate, filtered, and concentrated in vacuo. The crude product was distilled through a 10 cm micro Vigreaux column to afford 49.6 g of puffted product (90% yield). BP 51°-52° C./0.2 mmHg; 1H-NMR (300 MHz), δ0.85 (3H, s), 0.95 (3H, s), 1.22 (3H, s), 1.27 (3H, s), 1.45 (1H, m), 1.58 (3H, s), 1.73 (1H, m), 1.83-2.0 (2H, m), 2.15 (1H, m), 2.40 (1H, m), 3.46 (1H, m, B part of ABX, JAB =6.63 Hz, JBX =6.63 Hz), 4.07 (1H, t, A part of ABX, JAB =6.63 Hz, JAX =6.63 Hz), 5.21 (1H, s), 13C-NMR (75 MHz), δ12.59, 19.93, 26.57, 28.87, 29.09, 35.42, 42.06, 45.82, 47.09, 54.39, 72.08, 79.67, 121.98, 149.07; IR (Neat), 2980, 1055 cm-1 ; MS (m/e), 208 (M+), 193, 177, 43 (Base);
Reaction SMILES: [CH:1]1([NH:4][C:5]([C:7]2[CH:8]=[CH:9][C:10]([CH3:25])=[C:11]([NH:13][C:14]([C:16]3[CH:24]=[C:23]4[C:19]([CH:20]=[CH:21][NH:22]4)=[CH:18][CH:17]=3)=[O:15])[CH:12]=2)=[O:6])[CH2:3][CH2:2]1.[H-].[Na+].[CH:28](Br)([CH3:30])[CH3:29]>CN(C=O)C>[CH:1]1([NH:4][C:5]([C:7]2[CH:8]=[CH:9][C:10]([CH3:25])=[C:11]([NH:13][C:14]([C:16]3[CH:24]=[C:23]4[C:19]([CH:20]=[CH:21][N:22]4[CH:28]([CH3:30])[CH3:29])=[CH:18][CH:17]=3)=[O:15])[CH:12]=2)=[O:6])[CH2:2][CH2:3]1
Reactant: CC(C)Br
Reactant: Cc1ccc(C(=O)NC2CC2)cc1NC(=O)c1ccc2cc[nH]c2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc(C(=O)NC2CC2)cc1NC(=O)c1ccc2ccn(C(C)C)c2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 26.6 %

Procedure:
To N-(5-(cyclopropylcarbamoyl)-2-methylphenyl)-1H-indole-6-carboxamide (0.05 g, 0.15 mmol, example 94, table 5) in DMF (0.5 mL) was added sodium hydride (60% dispersion, 0.030 g, 0.75 mmol) over a period of 3 min, at room temperature. After stirring at room temperature for 5 min. isopropyl bromide (21 μL, 0.225 mmol) is added and the contents stirred at room temperature for 1 h. The reaction mixture was quenched with 100 μL of methanol and subjected to reverse phase preparative HPLC (YMC S5 20×100 mm, 10 min. run, solvent A: 10% MeOH: 90% H2O: 0.1% TFA, solvent B: 90% MeOH, 10% H2O, 0.1% TFA). The desired fractions were collected, and concentrated using speedVac® Plus (SC250DDA) to yield the title compound (Example 224, 0.015 g). HPLC retention time (YMC S5 Combiscreen ODS; 4.6×50 mm (4 min. gradient); Solvent A=10% MeOH, 90% H2O, 0.2% H3PO4; solvent B=90% MeOH, 10% H2O, 0.2% H3PO4): 3.1 min. LCMS [M+H]+ 376.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]2[C:20]3[CH:21]=[C:22]([C:25]([NH:27][NH2:28])=[O:26])[CH:23]=[CH:24][C:19]=3[NH:18][C:17]3[N:29]=[C:30]([C:33]([F:36])([F:35])[F:34])[CH:31]=[CH:32][C:16]=3[CH2:15]2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C([O-])(O)=O.[Na+].[N:42]#[C:43]Br>O1CCOCC1>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([S:11]([N:14]2[C:20]3[CH:21]=[C:22]([C:25]4[O:26][C:43]([NH2:42])=[N:28][N:27]=4)[CH:23]=[CH:24][C:19]=3[NH:18][C:17]3[N:29]=[C:30]([C:33]([F:35])([F:36])[F:34])[CH:31]=[CH:32][C:16]=3[CH2:15]2)(=[O:13])=[O:12])=[CH:9][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc(S(=O)(=O)N2Cc3ccc(C(F)(F)F)nc3Nc3ccc(C(=O)NN)cc32)cc1
Reactant: N#CBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: CC(C)(C)c1ccc(S(=O)(=O)N2Cc3ccc(C(F)(F)F)nc3Nc3ccc(-c4nnc(N)o4)cc32)cc1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of 6-[(4-tert-butylphenyl)sulfonyl]-2-(trifluoromethyl)-6,11-dihydro-5H-pyrido[2,3-b][1,5]benzodiazepine-8-carbohydrazide (intermediate 57, 0.040 g, 0.0771 mmol) and NaHCO3 (7 mg in 0.187 mL of water) in dioxane (0.75 mL) was added cyanogen bromide (9 mg in 0.084 mL of dioxane) was in four equal portions over 5 min. After stirring at rt for 2 h, the reaction was quenched with saturated aqueous NaHCO3 and the product was extracted with EtOAc and DCM. The combined extracts were washed with brine, dried (MgSO4) and concentrated. The residue was purified by SiO2 column chromatography to provide the title compound. LC/MS: m/e 545.1 (M+H)+. 1H NMR (500 MHz, CD3OD): δ 7.78 (1H, s), 7,76 (1H, d, J=8.5 Hz), 7.67 (1H, d, J=3.6 Hz), 7.63 (1H, d, J=7.3 Hz), 7.07-7.13 (3H, m), 6.91 (1H, d, J=8.5 Hz), 4.6-4.9 (2H, br), 3.53 (3H, s), 1.22 (9H, s).
Reaction SMILES: [CH3:1][O:2][N:3]([CH3:21])[C:4]([C@H:6]1[CH2:11][CH2:10][C@@H:9]([C:12](=[O:20])[C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)[CH2:8][CH2:7]1)=[O:5].[CH2:22]([O:24]C(OCC)OCC)[CH3:23].C(O)CO>C1(C)C=CC=CC=1.O.C1(C)C(S(O)(=O)=O)=CC=CC=1>[CH3:1][O:2][N:3]([CH3:21])[C:4]([C@H:6]1[CH2:7][CH2:8][C@@H:9]([C:12]2([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[O:24][CH2:22][CH2:23][O:20]2)[CH2:10][CH2:11]1)=[O:5]
Reactant: CON(C)C(=O)[C@H]1CC[C@@H](C(=O)c2ccc(Cl)cc2)CC1
Reactant: CCOC(OCC)OCC
Agent: Cc1ccccc1S(=O)(=O)O
Solvent: Cc1ccccc1
Solvent: OCCO
Solvent: O
Product: CON(C)C(=O)[C@H]1CC[C@@H](C2(c3ccc(Cl)cc3)OCCO2)CC1
Temperature: 25 °C
Yield: 74.3 %

Procedure:
A solution of cis-4-(4-chlorobenzoyl)-cyclohexanecarboxylic acid, methoxy-methyl amide (1.6 g, 5.17 mmol), triethylorthoformate (843 mg, 0.95 mL, 5.7 mmol), ethylene glycol (1.6 g, 1.45 mL, 25.9 mmol) and toluenesulfonic acid monohydrate (50 mg) in toluene (50 mL) was stirred overnight at 60° C., and then cooled to room temperature and concentrated to dryness in vacuo. The reaction mixture was redissolved in ethyl acetate, washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. Purification by flash column chromatography (silica gel, 0-30% ethyl acetate in heptane) gave cis-4-[2-(4-chlorophenyl)-[1,3]-dioxolan-2-yl]-cyclohexanecarboxylic acid, methoxy-methyl amide as a colorless oil (1.36 g, 74%); 1H NMR (CDCl3, 300 MHz) δ 7.33 (d, J=8.5 Hz,), 7.27 (d, J=8.5 Hz, 2H), 3.96 (m, 2H), 3.68 (m, 2H), 3.64 (s, 3H), 3.14 (s, 3H), 2.83 (m, 1H), 1.96 (m, 2H), 1.76 (m, 1H), 1.67 (m, 3H) and 1.47 (m, 4H); MS (+CI): m/z for C18H24ClNO4: expected 353.1. found 354.2 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][S:11]([CH:14]2[CH2:16][CH2:15]2)(=[O:13])=[O:12])=[CH:6][CH:5]=1)([O-])=O.[P].[S]>[Pd].C(O)C.CCOC(C)=O>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([O:10][S:11]([CH:14]2[CH2:16][CH2:15]2)(=[O:13])=[O:12])=[CH:6][CH:5]=1
Reactant: O=[N+]([O-])c1ccc(OS(=O)(=O)C2CC2)cc1
Agent: [Pd]
Agent: [P]
Agent: [S]
Solvent: CCO
Solvent: CCOC(C)=O
Product: Nc1ccc(OS(=O)(=O)C2CC2)cc1

Procedure:
This material was prepared from cyclopropanesulfonic acid 4-nitro-phenyl ester (J. F. King et al; Phosphorus, Sulfur and Silicon and the Related Elements; 1-4; 1993; p 445) (1.096 g) by hydrogenation over 10% Pd/C as catalyst, in ethanol/AcOEt as solvent (10 ml/15 ml) for 16 h, and at atmospheric pressure and RT. Yellow oil (0.55 g). MS (m/e): 214.2 [MH+].
Reaction SMILES: [Cl:1][C:2]1[CH:6]=[C:5]([C:7]([O:9]C)=[O:8])[N:4]([C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)[N:3]=1>Cl>[ClH:1].[Cl:1][C:2]1[CH:6]=[C:5]([C:7]([OH:9])=[O:8])[N:4]([C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)[N:3]=1
Reactant: COC(=O)c1cc(Cl)nn1-c1cccnc1
Agent: Cl
Product: O=C(O)c1cc(Cl)nn1-c1cccnc1
Temperature: 25 °C
Yield: 205.1 %

Procedure:
Methyl 3-chloro-1-(pyridin-3-yl)-1H-pyrazole-5-carboxylate (1.5 g, 6.0 mmol) was stirred in concentrated hydrochloric acid (25 mL). The reaction mixture was heated at reflux to afford a yellow solution. After heating overnight a solid had precipitated, and LCMS analysis of the mixture indicated that the reaction was complete. The mixture was allowed to cool to room temperature and dioxane (50 mL) was added. The mixture was concentrated to dryness. acetonitrile (50 mL) was added and the resulting mixture was concentrated. The residue was vacuum dried at 40° C. to afford the desired product as a yellow solid (1.6 g, 97%).