Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][C:16]=3[N+:18]([O-:20])=[O:19])[NH:11][C:10]=2[CH3:21])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].O.Br[CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32]>C(#N)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8][C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][C:16]=3[N+:18]([O-:20])=[O:19])[N:11]([CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])[C:10]=2[CH3:21])=[CH:6][CH:7]=1
Reactant: CCOC(=O)CBr
Reactant: Cc1[nH]c2cccc([N+](=O)[O-])c2c1Sc1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CCOC(=O)Cn1c(C)c(Sc2ccc(Cl)cc2)c2c([N+](=O)[O-])cccc21
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
3-(4-Chlorophenylsulfanyl)-2-methyl-4-nitro-1H-indole (3.76 kg, 11.8 mol) and potassium carbonate (1.80 kg, 13.0 mol) were suspended in acetonitrile (32.7 kg). Water (0.53 kg) and a solution of ethyl bromoacetate (2.17 kg, 13.0 mol) in acetonitrile (5.75 kg) were added followed by an acetonitrile line rinse (2.97 kg). The mixture was heated at 50° C. for 6 hours then allowed to cool to 20° C. and held at this temperature overnight. Water (35.4 kg) was added to the reaction mixture and stirring continued for 30 minutes at 15° C. The solid product was collected by filtration, washed with acetonitrile (2.95 kg) then dried in a vacuum oven at 40° C. to afford [3-(4-chlorophenylsulfanyl)-2-methyl-4-nitro-1H-indol-1-yl]acetic acid, ethyl ester as a bright yellow solid, 4.33 kg (91%).
Reaction SMILES: Br[C:2]1([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[CH:15]=2)[C:10]2[C:5](=[CH:6][C:7]([Cl:11])=[CH:8][CH:9]=2)[NH:4][C:3]1=[O:12].[C:21]1([NH:27][CH2:28][C:29]([NH2:31])=[O:30])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[Cl:11][C:7]1[CH:6]=[C:5]2[C:10]([C:2]([N:27]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:28][C:29]([NH2:31])=[O:30])([CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[CH:15]=3)[C:3](=[O:12])[NH:4]2)=[CH:9][CH:8]=1
Reactant: O=C1Nc2cc(Cl)ccc2C1(Br)Cc1cccc(Cl)c1
Reactant: NC(=O)CNc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: NC(=O)CN(c1ccccc1)C1(Cc2cccc(Cl)c2)C(=O)Nc2cc(Cl)ccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 13.6 %

Procedure:
The mixture of rac-3-bromo-6-chloro-3-(3-chloro-benzyl)-1,3-dihydro-indol-2-one (370 mg, 1 mmol), 2-phenylamino-acetamide (200 mg, 1.33 mmol) and K2CO3 (300 mg, 2.2 mmol) in DMF (2 mL) was stirred at room temperature for 1 h. The mixture was poured into water (30 ml), extracted with ethyl acetate (10 mL×3). The organic phase was separated, dried over Na2SO4 and concentrated. The residue was purified with chromatography to give 60 mg of rac-2-{[6-chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-phenyl-amino}-acetamide. MS: [M+H]+=439.8.
Reaction SMILES: [C:1]([CH2:3][CH2:4][CH:5]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[C:19]([F:22])([F:21])[F:20])[C:6]([O:8]C(C)(C)C)=[O:7])#[N:2].FC(F)(F)C(O)=O>C(Cl)Cl.C(OCC)C>[C:1]([CH2:3][CH2:4][CH:5]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[C:19]([F:20])([F:22])[F:21])[C:6]([OH:8])=[O:7])#[N:2]
Reactant: CC(C)(C)OC(=O)C(CCC#N)c1ccccc1C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: CCOCC
Solvent: ClCCl
Product: N#CCCC(C(=O)O)c1ccccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 114.4 %

Procedure:
tert-Butyl 4-cyano-2-(2-trifluoromethylphenyl)butanoate (7.2 g) was dissolved in methylene chloride (40 mL). Trifluoroacetic acid (50 mL) was added at 0° C. and the reaction was initiated. After stirring at room temperature for one hour, concentration under reduced pressure gave an oil. The resulting oil was dissolved in diethyl ether, washed with water (three times) and brine and dried over magnesium sulfate. Concentration under reduced pressure gave a yellow oil. The oil was dissolved again in diethyl ether and partitioned between diethyl ether and 5 N sodium hydroxide (15 mL). The resulting aqueous layer was made acidic with 5 N hydrochloric acid (16 mL) and extracted with methylene chloride twice to obtain the title compound (6.76 g) as a colorless transparent oil.
Reaction SMILES: [F:1][C:2]1[CH:27]=[CH:26][C:5]([C:6](=[O:25])[CH2:7][NH:8][C:9]2[C:17]3[C:12](=[CH:13][C:14]([Cl:19])=[CH:15][C:16]=3[Cl:18])[NH:11][C:10]=2[C:20]([O:22]CC)=[O:21])=[CH:4][CH:3]=1.[OH-].[Li+].O1CCCC1.Cl>O.C(OCC)(=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:6](=[O:25])[CH2:7][NH:8][C:9]2[C:17]3[C:12](=[CH:13][C:14]([Cl:19])=[CH:15][C:16]=3[Cl:18])[NH:11][C:10]=2[C:20]([OH:22])=[O:21])=[CH:26][CH:27]=1
Reactant: CCOC(=O)c1[nH]c2cc(Cl)cc(Cl)c2c1NCC(=O)c1ccc(F)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C(CNc1c(C(=O)O)[nH]c2cc(Cl)cc(Cl)c12)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 75.9 %

Procedure:
Mix 3-[(p-fluorophenacyl)amino]-2-carbethoxy-4,6-dichloroindole (600 mg, 1.52 mmol), lithium hydroxide (191 mg, 4.55 mmol), tetrahydrofuran (20 mL)and water (20 mL). Stir overnight at room temperature. Dilute with water (20 mL) and ethyl acetate (40 mL). Acidify with 1N HCl while stirring and separate the layers. Dry the organic phase over magnesium sulfate, filter and concentrate in vacuo. Recrystallize the residue (ethyl acetate/hexane)to yield the title compound as a white powder (440 mg, 79%); mp 259°-261° C.
Reaction SMILES: [C:1]1([CH2:7][N:8]2[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:15][CH2:16][CH2:17][CH2:18][N:19]=[C:20]=[O:21].O>O1CCOCC1>[CH2:18]([NH:19][C:20](=[O:21])[O:14][CH:11]1[CH2:12][CH2:13][N:8]([CH2:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:9][CH2:10]1)[CH2:17][CH2:16][CH3:15]
Reactant: OC1CCN(Cc2ccccc2)CC1
Reactant: CCCCN=C=O
Solvent: O
Solvent: C1COCCO1
Product: CCCCNC(=O)OC1CCN(Cc2ccccc2)CC1
Yield: 92.4 %

Procedure:
1-(Phenylmethyl)piperidin-4-ol (10 g, 52.2 mmol) was stirred in dioxane (90 ml) at room temperature. N-butyl isocyanate (5.0 g, 52.2 mmol) in dioxane (10 ml) was added and the reaction mixture was heated under reflux for 24 h. Water (20 ml) was added and the reaction mixture was concentrated in vacuo to give a brown oil. The crude product was partitioned between diethyl ether and water and the organic extracts were dried (MgSO4) to give the title compound as an oil (14 g, 92%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:28]=[CH:29][CH:30]=1)/[CH:5]=[C:6]1\[CH2:7][CH2:8][C:9]2[N:10]([S:18]([C:21]3[CH:27]=[CH:26][C:24]([CH3:25])=[CH:23][CH:22]=3)(=[O:20])=[O:19])[C:11]([C:14]([O:16][CH3:17])=[O:15])=[CH:12][C:13]\1=2.[OH:31][CH2:32][C:33]1[CH:38]=[CH:37][C:36](B(O)O)=[CH:35][CH:34]=1>>[OH:31][CH2:32][C:33]1[CH:38]=[CH:37][C:36]([C:2]2[CH:30]=[CH:29][CH:28]=[C:4]([CH2:5][CH:6]3[C:13]4[CH:12]=[C:11]([C:14]([O:16][CH3:17])=[O:15])[NH:10][C:9]=4[CH2:8][CH2:7]3)[CH:3]=2)=[CH:35][CH:34]=1.[OH:31][CH2:32][C:33]1[CH:38]=[CH:37][C:36]([C:29]2[CH:30]=[CH:2][CH:3]=[C:4](/[CH:5]=[C:6]3\[CH2:7][CH2:8][C:9]4[N:10]([S:18]([C:21]5[CH:27]=[CH:26][C:24]([CH3:25])=[CH:23][CH:22]=5)(=[O:19])=[O:20])[C:11]([C:14]([O:16][CH3:17])=[O:15])=[CH:12][C:13]\3=4)[CH:28]=2)=[CH:35][CH:34]=1
Reactant: OCc1ccc(B(O)O)cc1
Reactant: COC(=O)c1cc2c(n1S(=O)(=O)c1ccc(C)cc1)CC/C2=C\c1cccc(Br)c1
Product: COC(=O)c1cc2c([nH]1)CCC2Cc1cccc(-c2ccc(CO)cc2)c1
Product: COC(=O)c1cc2c(n1S(=O)(=O)c1ccc(C)cc1)CC/C2=C\c1cccc(-c2ccc(CO)cc2)c1

Procedure:
The title compound was synthesized in three steps. First, (E)-methyl 4-(3-bromobenzylidene)-1-tosyl-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-2-carboxylate (0.301 g, 0.62 mmol) was coupled with 4-(hydroxymethyl)phenylboronic acid (0.141 g, 0.93 mmol) according to General Procedure 9.1 to give (E)-methyl 4-((4′-(hydroxymethyl)biphenyl-3-yl)methylene)-1-tosyl-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-2-carboxylate, then tosyl deprotection according to General Procedure 10.1 to give (E)-methyl 4-((4′-(hydroxymethyl)biphenyl-3-yl)methylene)-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-2-carboxylate. Hydrogenation of (E)-methyl 4-((4′-(hydroxymethyl)biphenyl-3-yl)methylene)-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-2-carboxylate according to General Procedure 6 (with 5% Pd/C), provided the title compound, which was used without purification in the next step. 1H NMR (400 MHz, ACETONE-d6) δ ppm 2.10-2.20 (m, 1H), 2.51-2.60 (m, 1H), 2.61-2.68 (m, 2H), 2.87 (dd, J=7.25, 2.03 Hz, 2H), 3.35 (quin, J=6.88 Hz, 1H), 3.71 (s, 3H), 4.20 (br. s, 1H), 4.67 (s, 2H), 6.35-6.37 (m, 1H), 7.23 (d, J=7.76 Hz, 1H), 7.35-7.40 (m, 1H), 7.42-7.46 (m, 2H), 7.47-7.51 (m, 2H) 7.59-7.63 (m, 2H), 10.48 (br. s, 1H); LCMS-MS (ESI+) 384.0 (M+Na).
Reaction SMILES: [C:1]([C:5]1[N:10]=[C:9]([O:11][CH2:12][CH3:13])[C:8]([C:14]2[N:15]([C:33](Cl)=[O:34])[CH:16]([C:26]3[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=3)[CH:17]([C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=3)[N:18]=2)=[CH:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:36][N:37]([CH3:47])[C:38](=[O:46])[CH2:39][N:40]1[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1>>[ClH:25].[C:1]([C:5]1[N:10]=[C:9]([O:11][CH2:12][CH3:13])[C:8]([C:14]2[N:15]([C:33]([N:43]3[CH2:42][CH2:41][N:40]([CH2:39][C:38]([N:37]([CH3:47])[CH3:36])=[O:46])[CH2:45][CH2:44]3)=[O:34])[C@H:16]([C:26]3[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=3)[C@H:17]([C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=3)[N:18]=2)=[CH:7][N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOc1nc(C(C)(C)C)ncc1C1=NC(c2ccc(Cl)cc2)C(c2ccc(Cl)cc2)N1C(=O)Cl
Reactant: CN(C)C(=O)CN1CCNCC1
Product: CCOc1nc(C(C)(C)C)ncc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)N1CCN(CC(=O)N(C)C)CC1
Product: Cl

Procedure:
cis-4-[2-(2-tert-Butyl-4-ethoxy-pyrimidin-5-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dihydro-imidazole-1-carbonyl chloride (example 20) was reacted with N,N-dimethyl-2-piperazin-1-yl-acetamide (Oakwood Products) to give cis-2-{4-[2-(2-tert-butyl-4-ethoxy-pyrimidin-5-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dihydro-imidazole-1-carbonyl]-piperazin-1-yl}-N,N-dimethyl-acetamide hydrochloride in an analogous manner as described in example 1. HR-MS (ES, m/z) calculated for C34H42N7O3Cl2 [(M+H)+] 666.2721, observed 666.2721.
Reaction SMILES: [C:1]1([NH2:8])[CH:6]=[CH:5][C:4]([NH2:7])=[CH:3][CH:2]=1.[CH3:9][C:10]1[C:16]([OH:17])=[CH:15][CH:14]=[CH:13][C:11]=1[OH:12].[NH3:18]>O>[NH2:7][C:4]1[CH:5]=[CH:6][C:1]([NH:8][C:13]2[C:11](=[O:12])[C:10]([CH3:9])=[C:16]([OH:17])[C:15](=[N:18][C:1]3[CH:6]=[CH:5][C:4]([NH2:7])=[CH:3][CH:2]=3)[CH:14]=2)=[CH:2][CH:3]=1
Reactant: Cc1c(O)cccc1O
Reactant: Nc1ccc(N)cc1
Reactant: N
Solvent: O
Product: CC1=C(O)C(=Nc2ccc(N)cc2)C=C(Nc2ccc(N)cc2)C1=O
Reaction time: 48 h

Procedure:
10 g (0.055 mol) of para-phenylenediamine, 3.43 g of 2-methylresorcinol and 330 ml of water are successively placed in a 1 liter round-bottomed flask with a mechanical stirrer and a sparging-air inlet. The pH is adjusted to 8.5 with 16 ml of 20% aqueous ammonia. The reaction medium is stirred for 48 hours and then filtered through a sinter funnel. The solid obtained is washed with water and then purified by chromatography on a column of silica (eluent: 80/20 dichloro-methane/methanol). 0.52 g of 6-(4-aminophenylamino)-4-(4-aminophenylimino)-3-hydroxy-2-methylcyclohexa-2,5-dienone (1a) is obtained.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([F:19])[CH:18]=[C:13]3[CH:12]=[C:11]2[C:20](OS(C2C=CC(C)=CC=2)(=O)=O)=[CH:21][CH:22]2[CH2:26][CH2:25][CH2:24][CH2:23]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:38][O:39][C:40](=[O:57])[C:41]1[CH:46]=[CH:45][C:44](B2OC(C)(C)C(C)(C)O2)=[CH:43][C:42]=1[F:56].C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.C(OCC)(=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:38][O:39][C:40](=[O:57])[C:41]1[CH:46]=[CH:45][C:44]([C:20]([C:11]2[N:10]([S:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)(=[O:9])=[O:8])[C:14]3=[N:15][CH:16]=[C:17]([F:19])[CH:18]=[C:13]3[CH:12]=2)=[CH:21][CH:22]2[CH2:26][CH2:25][CH2:24][CH2:23]2)=[CH:43][C:42]=1[F:56]
Reactant: Cc1ccc(S(=O)(=O)OC(=CC2CCCC2)c2cc3cc(F)cnc3n2S(=O)(=O)c2ccccc2)cc1
Reactant: COC(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(C(=CC2CCCC2)c2cc3cc(F)cnc3n2S(=O)(=O)c2ccccc2)cc1F
Yield: 83.2 %

Procedure:
To a mixture of toluene-4-sulfonic acid 1-(1-benzenesulfonyl-5-fluoro-1H-pyrrolo[2,3-b]pyridin-2-yl)-2-cyclopentyl-vinyl ester (prepared as in Example 88, 3 g, 5.75 mmol), 2-fluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzoic acid methyl ester (prepared as in Example 95, 3.9 g, 13.9 mmol) and dichlorobis(triphenylphosphine)palladium (II) (390 mg, 0.6 mmol) in dioxane (24 mL) was added an aqueous sodium carbonate solution (2 M, 6.93 mL). The resulting mixture was subjected to microwave irradiation for 2 h at 100° C. The mixture was diluted with ethyl acetate (200 mL), washed with a saturated aqueous sodium bicarbonate solution (3×50 mL), brine, dried over anhydrous sodium sulfate and then concentrated in vacuo. Purification by flash silica gel chromatography (silica gel from QingDao, 200-300 mesh, glass column from Shanghai SD company, 25% ethyl acetate/hexanes) afforded 4-[1-(1-benzenesulfonyl-5-fluoro-1H-pyrrolo[2,3-b]pyridin-2-yl)-2-cyclopentyl-vinyl]-2-fluoro-benzoic acid methyl ester (2.50 g, 86%) as a white solid: LC/MS m/e calcd for C28H24F2N2O4S [M+H]+ 523.58, observed 522.7.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([C:20]([NH:22][C:23]2[CH:24]=[C:25]3[C:30](=[CH:31][CH:32]=2)[CH:29]=[N:28][CH:27]=[CH:26]3)=[O:21])[CH2:10][N:11]([CH3:19])[C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[CH:5][CH:4]=1.C(Cl)CCl.[CH3:37][C:38]1[CH:46]=[C:45]([CH3:47])[CH:44]=[CH:43][C:39]=1[C:40](O)=[O:41]>N1C=CC=CC=1.CN(C1C=CN=CC=1)C>[CH3:37][C:38]1[CH:46]=[C:45]([CH3:47])[CH:44]=[CH:43][C:39]=1[C:40]([O:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([CH:9]([CH2:10][N:11]([C:12]([O:13][C:14]([CH3:15])([CH3:17])[CH3:16])=[O:18])[CH3:19])[C:20]([NH:22][C:23]2[CH:24]=[C:25]3[C:30](=[CH:31][CH:32]=2)[CH:29]=[N:28][CH:27]=[CH:26]3)=[O:21])=[CH:7][CH:8]=1)=[O:41]
Reactant: Cc1ccc(C(=O)O)c(C)c1
Reactant: CN(CC(C(=O)Nc1ccc2cnccc2c1)c1ccc(CO)cc1)C(=O)OC(C)(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Solvent: c1ccncc1
Product: Cc1ccc(C(=O)OCc2ccc(C(CN(C)C(=O)OC(C)(C)C)C(=O)Nc3ccc4cnccc4c3)cc2)c(C)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To tert-butyl 2-(4-(hydroxymethyl)phenyl)-3-(isoquinolin-6-ylamino)-3-oxopropyl(methyl)carbamate (E205-1) in pyridine was added was added EDC, DMAP, and 2,4-dimethylbenzoic acid, and the solution was stirred overnight at room temperature. The mixture was poured into NaHCO3(sat) and extracted with EtOAc. The organics were dried (MgSO4), filtered, and evaporated. Column chromatography (SiO2, 0-5% MeOH/CH2Cl2gradient) gave pure 4-(3-(tert-butoxycarbonyl(methyl)amino)-1-(isoquinolin-6-ylamino)-1-oxopropan-2-yl)benzyl 2,4-dimethylbenzoate (E205-2).
Reaction SMILES: [CH:1]([NH:4][C:5](=[S:8])[NH:6][NH2:7])([CH3:3])[CH3:2].[Cl:9][C:10]1[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:11]=1[C:12](=O)[CH2:13]Cl>CO>[ClH:9].[Cl:9][C:10]1[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:11]=1[C:12]1[CH2:13][S:8][C:5]([NH:4][CH:1]([CH3:3])[CH3:2])=[N:6][N:7]=1
Reactant: O=C(CCl)c1ccc(Cl)cc1Cl
Reactant: CC(C)NC(=S)NN
Solvent: CO
Product: CC(C)NC1=NN=C(c2ccc(Cl)cc2Cl)CS1
Product: Cl

Procedure:
3.99 g (0.03 mole) of 4-isopropyl-thiosemicarbazide and 6.70 g (0.03 mole) of 2,4-dichlorophenacyl chloride are reacted in 150 ml of methanol under the conditions of Example 2. The concentrated product is crystallized and recrystallized from methanol/ethyl acetate. The product is dried under high vacuum at 65° C. and recrystallized again from methanol/ethyl acetate. It is finally dried again at 65° C. under high vacuum producing 5-(2,4-dichlorophenyl)-N-(1-methylethyl)-6H-1,3,4-thiadiazin-2-amine monohydrochloride. m.p. 207°-208° C.
Reaction SMILES: C([N:8](CC1C=CC=CC=1)[C@H:9]1[CH2:14][CH2:13][C@H:12]([N:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)[CH2:11][CH2:10]1)C1C=CC=CC=1>CO.[Pd]>[N:15]1([C@H:12]2[CH2:11][CH2:10][C@H:9]([NH2:8])[CH2:14][CH2:13]2)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: c1ccc(CN(Cc2ccccc2)[C@H]2CC[C@H](N3CCCCC3)CC2)cc1
Agent: [Pd]
Solvent: CO
Product: N[C@H]1CC[C@H](N2CCCCC2)CC1

Procedure:
1.7 g (4.8 mmol) of trans-dibenzyl-4-piperidino-cyclohexylamine were dissolved in 35 mL MeOH and hydrogenated on 350 mg of Pd/C (10%) at 20° C. The solvent was eliminated in vacuo and the residue crystallised from ethanol and conc. HCl.
Reaction SMILES: [CH:1]([NH:14][C:15](=[O:30])[O:16][CH:17]1[CH2:22][CH2:21][N:20](CC2C=CC=CC=2)[CH2:19][CH2:18]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)=O>CO.[Pd]>[CH:1]([NH:14][C:15](=[O:30])[O:16][CH:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1)([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: O=C(NC(c1ccccc1)c1ccccc1)OC1CCN(Cc2ccccc2)CC1
Agent: [Pd]
Solvent: CO
Solvent: O=CO
Product: O=C(NC(c1ccccc1)c1ccccc1)OC1CCNCC1
Reaction time: 18 h
Yield: 46.5 %

Procedure:
1-benzyl-4-piperidyl benzhydrylcarbamate (1.1 g, 4.5 mmol) was dissolved in anhydrous methanol (15 mL) and formic acid (5 mL, 132 mmol) and the solution was flushed with gaseous nitrogen for 15 min. 10% Palladium on carbon (0.3 g) was added and the reaction mixture was stirred under nitrogen atmosphere . After 18 h, the reaction mixture was filtered through Celite® and the filtrate was concentrated to give a yellow solid. The solid was partitioned between 0.1 N hydrochloric acid (300 mL) and diethyl ether (300 mL). The aqueous layer was washed with diethyl ether and then basified with 1 N sodium hydroxide solution to pH 12. A white solid precipitated out which was extracted into ethyl acetate. The ethyl acetate layer was dried over magnesium sulfate and evaporated to dryness to give 4-piperidyl benzhydrylcarbamate as a colorless solid (0.65 g, 78%). MS=311.3 MH+.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([N:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][N:19]4[C:23](=[O:24])[C:22]5=[CH:25][CH:26]=[CH:27][CH:28]=[C:21]5[C:20]4=[O:29])[CH2:13][CH2:12]3)=[N:7][NH:8]2)=[CH:4][CH:3]=1.Cl[C:31]([O:33][CH2:34][CH3:35])=[O:32].[C:36]([O-:39])([OH:38])=O.[Na+]>O>[C:23]([OH:32])(=[O:24])/[CH:22]=[CH:25]\[C:36]([OH:39])=[O:38].[CH2:34]([O:33][C:31]([N:8]1[C:9]2[C:5](=[CH:4][CH:3]=[C:2]([F:1])[CH:10]=2)[C:6]([N:11]2[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][N:19]3[C:23](=[O:24])[C:22]4=[CH:25][CH:26]=[CH:27][CH:28]=[C:21]4[C:20]3=[O:29])[CH2:13][CH2:12]2)=[N:7]1)=[O:32])[CH3:35]
Reactant: O=C([O-])O
Reactant: O=C1c2ccccc2C(=O)N1CCN1CCN(c2n[nH]c3cc(F)ccc23)CC1
Reactant: CCOC(=O)Cl
Agent: [Na+]
Solvent: O
Product: CCOC(=O)n1nc(N2CCN(CCN3C(=O)c4ccccc4C3=O)CC2)c2ccc(F)cc21
Product: O=C(O)/C=C\C(=O)O
Reaction time: 0.17 h

Procedure:
A mixture of N-[2-[4-(6-fluoro-1H-indazol-3-yl)-1-piperazinyl]ethyl]phthalimide (1.8 g, 4.6 mmol) and ethyl chloroformate (5.7 g, 52.3 mmol) was heated on a stream bath for 10 minutes. The reaction was cooled and an additional 2.3 g (20.9 mmol) ethyl chloroformate was added. The reaction was returned to the steam bath for 10 minutes longer and then cooled. The resultant solid was triturated with anhydrous Et2O and collected to yield 2.0 g. The solid was suspended in H2O (100 ml) and NaHCO3 was added to make the pH=8. The aqueous mixture was extracted with CH2Cl2 and the CH2Cl2 extract was washed with H2O, dried with Na2SO4 and concentrated to afford 2.0 g of a yellow oil that crystallized readily. The product was flashed over 80 g silica gel using 2% Et2NH-EtOAc as eluent to afford 1.10 g (2.36 mmol) of an off-white solid. The compound was dissolved in hot absolute ethanol (55 ml) and maleic add (0.28 g, 2.36 mmol) was added. The solution was refluxed gently for 10 minutes and then cooled. Most of the ethanol was removed in vacuo and the resultant white suspension was diluted with anhydrous Et2O (50 ml). The solid that was produced was collected to yield 1.35 g. Recrystallization from CH3CN gave 1.15 g of the maleate salt as a white powder, m.p. 214-216° C.
Reaction SMILES: [C:1]([O:5]O)([CH3:4])([CH3:3])C.[Cl-].[Na+].[C:9]([O:26][CH:27]1[CH2:32][C:31]([CH3:34])([CH3:33])[NH:30][C:29]([CH3:36])([CH3:35])[CH2:28]1)(=[O:25])[CH2:10][CH2:11][C:12]([O:14][CH:15]1[CH2:20][C:19]([CH3:22])([CH3:21])[NH:18][C:17]([CH3:24])([CH3:23])[CH2:16]1)=[O:13]>[Mo]=O.C1CCCCC1>[C:9]([O:26][CH:27]1[CH2:32][C:31]([CH3:34])([CH3:33])[N:30]([O:5][CH:1]2[CH2:4][CH2:20][CH2:15][CH2:16][CH2:3]2)[C:29]([CH3:36])([CH3:35])[CH2:28]1)(=[O:25])[CH2:10][CH2:11][C:12]([O:14][CH:15]1[CH2:16][C:17]([CH3:24])([CH3:23])[N:18]([O:5][CH:1]2[CH2:4][CH2:11][CH2:10][CH2:9][CH2:3]2)[C:19]([CH3:22])([CH3:21])[CH2:20]1)=[O:13]
Reactant: CC(C)(C)OO
Reactant: CC1(C)CC(OC(=O)CCC(=O)OC2CC(C)(C)NC(C)(C)C2)CC(C)(C)N1
Agent: O=[Mo]
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCCCC1
Product: CC1(C)CC(OC(=O)CCC(=O)OC2CC(C)(C)N(OC3CCCCC3)C(C)(C)C2)CC(C)(C)N1OC1CCCCC1
Temperature: 140 °C
Reaction time: 4 h
Yield: 137.6 %

Procedure:
A two-phase mixture of 70% aqueous t-butyl hydroperoxide (103.9 g, 807 mmol), cyclohexane (200 ml) and sodium chloride (15 g) is shaken in a separatory funnel. The organic phase is dried over magnesium sulfate, filtered, and added to 40.0 g (101 mmol) of di-(2,2,6,6-tetramethylpiperidin-4-yl) succinate. Molybdenum oxide (2.0 g) is added, and the mixture is refluxed for one hour. Water is collected in a Dean-Stark trap. The entire reaction mixture is then transferred to a Fischer-Porter bottle and heated at 140° C. for 6 hours. Additional t-butyl hydroperoxide (90%, 10.1 g, 101 mmol) is added and heating is resumed for another 4 hours. The colorless reaction mixture is filtered, concentrated, and dissolved in heptane (20 0 ml). The heptane solution is passed through a short column of silica gel with heptane. Subsequent evaporation affords an oil which is crystallized from ethanol to yield 41.2 g (69%) of a white powder, m.p. 122°-6° C.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=O.O1C[CH2:17][CH2:16][N:15]([CH2:19][C:20]2[CH:36]=[CH:35][C:23]([O:24][C:25]3[CH:34]=[CH:33][C:28]([C:29]([NH:31][NH2:32])=[O:30])=[CH:27][CH:26]=3)=[CH:22][CH:21]=2)[CH2:14]1.[C:37](O)(=[O:39])C>>[I:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[N:32][NH:31][C:29](=[O:30])[C:28]1[CH:27]=[CH:26][C:25]([O:24][C:23]2[CH:22]=[CH:21][C:20]([CH2:19][N:15]3[CH2:16][CH2:17][O:39][CH2:37][CH2:14]3)=[CH:36][CH:35]=2)=[CH:34][CH:33]=1
Reactant: O=C1Nc2ccc(I)cc2C1=O
Reactant: NNC(=O)c1ccc(Oc2ccc(CN3CCCOC3)cc2)cc1
Reactant: CC(=O)O
Product: O=C1Nc2ccc(I)cc2C1=NNC(=O)c1ccc(Oc2ccc(CN3CCOCC3)cc2)cc1
Temperature: 100 °C
Yield: 67 %

Procedure:
Into a suspension of 5-iodo-1H-indole-2,3-dione in acetic acid was added 4-[4-(1,3-oxazinan-3-ylmethyl)phenoxy]benzohydrazide. After stirring at 100° C., the reaction mixture was cooled to rt and a yellow solid precipitated out. Filtration on a fritté, washing with AcOH, water and drying under vacuo at 60° C. overnight gave 194 mg of the title compound (67%) as a yellow solid in 98.9% purity by HPLC (Rt: 3.27, gradient of 8 min, MaxPlot detection between 230 and 400 nm).