Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][OH:2].C([O:5][C:6](=O)[CH:7]=[CH:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][NH:16][C:17](=[O:37])[C:18]2[CH:23]=[CH:22][C:21]([N:24]3[CH2:29][CH2:28][N:27]([CH2:30][C:31]4[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=4)[CH2:26][CH2:25]3)=[CH:20][CH:19]=2)=[CH:11][CH:10]=1)C>CO>[OH:2][NH:1][C:6]([CH:7]=[CH:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:15][NH:16][C:17](=[O:37])[C:18]2[CH:23]=[CH:22][C:21]([N:24]3[CH2:29][CH2:28][N:27]([CH2:30][C:31]4[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=4)[CH2:26][CH2:25]3)=[CH:20][CH:19]=2)=[CH:13][CH:14]=1)=[O:5]
Reactant: CCOC(=O)C=Cc1ccc(CNC(=O)c2ccc(N3CCN(Cc4cccnc4)CC3)cc2)cc1
Reactant: NO
Solvent: CO
Product: O=C(C=Cc1ccc(CNC(=O)c2ccc(N3CCN(Cc4cccnc4)CC3)cc2)cc1)NO
Temperature: 25 °C
Reaction time: 24 h
Yield: 46 %

Procedure:
To a solution of 1.76 M NH2OH in MeOH (1.23 mL) was added the compound (150 mg, 0.31 mmol) from the process (1-2), and the mixture was stirred at room temperature for 24 hours. The reaction mixture was concentrated, and the residue was dissolved in 1 N HCl aqueous solution (pH 5). The solid precipitated was collected by filtration, dried under vacuum, and crystallized from MeOH/CH2Cl2/ether to afford the titled compound (67 mg, 46%) as a pale brown solid.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][CH2:6][CH2:7][NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH3:4].[CH3:16]I.O>O1CCCC1>[CH2:3]([O:5][CH2:6][CH2:7][N:8]([CH3:16])[C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH3:4]
Reactant: CCOCCNC(=O)OC(C)(C)C
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCOCCN(C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2-ethoxyethylamine (502 mg) in water (4 ml) was added 1,4-dioxane (10 ml), and an aqueous solution of 1N sodium hydroxide (6 ml) and di-tert-butyl dicarbonate (1.4 g) were sequentially added thereto on an ice bath. The solution was stirred overnight while warming to room temperature. Water was added thereto, the solution was extracted with diethyl ether, then washed with brine, dried over anhydrous magnesium sulfate, then the solvent was evaporated in vacuo to provide tert-butyl (2-ethoxyethyl)carbamate (1.1 g). To a suspension of 60% sodium hydride (253 mg) in tetrahydrofuran (2 ml) was added dropwise a solution of tert-butyl (2-ethoxyethyl)carbamate (1.1 g) in tetrahydrofuran (8 ml) on an ice bath. The solution was stirred for 30 minutes while warming to room temperature, then methyl iodide (0.7 ml) was added thereto on an ice bath, and the solution was stirred overnight while warming to room temperature. Water was added thereto, the solution was extracted with ethyl acetate, then washed with brine, dried over anhydrous magnesium sulfate, and then the solvent was evaporated in vacuo to provide the title compound (1.2 g).
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8]C)=[CH:6][C:5]([N:10]2[C:14](=[O:15])[N:13]([CH:16]([F:18])[F:17])[C:12]([CH3:19])=[N:11]2)=[C:4]([F:20])[CH:3]=1.B(Br)(Br)Br.O>C(Cl)Cl>[Cl:1][C:2]1[C:7]([OH:8])=[CH:6][C:5]([N:10]2[C:14](=[O:15])[N:13]([CH:16]([F:17])[F:18])[C:12]([CH3:19])=[N:11]2)=[C:4]([F:20])[CH:3]=1
Reactant: COc1cc(-n2nc(C)n(C(F)F)c2=O)c(F)cc1Cl
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: O
Product: Cc1nn(-c2cc(O)c(Cl)cc2F)c(=O)n1C(F)F
Temperature: 10 °C
Reaction time: 4 h
Yield: 99.9 %

Procedure:
A stirred mixture of 4.6 g (0.015 mole) of 1-(4-chloro-2-fluoro-5-methoxyphenyl)-4-difluoromethyl-4,5-dihydro-3-methyl-1,2,4-triazol-5(1H)-one in 200 mL of methylene chloride was cooled to 10° C. and a solution of 11.2 g (0.045) mole of boron tribromide in 45 mL of methylene chloride was added. Upon complete addition the reaction mixture was stirred for four hours as it warmed to ambient temperature. After this time 100 mL of water was added, and stirring was continued for an additional 18 hours. The organic layer was separated, dried with anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure to yield 4.4 g of 1-(4-chloro-2-fluoro-5-hydroxyphenyl)-4-difluoromethyl-4,5-dihydro-3-methyl-1,2,4-triazol-5(1H)-one; mp 147°-152° C.
Reaction SMILES: C(O)C.[F:4][C:5]1[C:13]([F:14])=[C:12]([F:15])[CH:11]=[C:10]2[C:6]=1[CH:7]=[C:8]([C@H:16]1[CH2:21][CH2:20][C@H:19]([CH2:22][CH2:23][CH3:24])[CH2:18][CH2:17]1)[CH2:9]2.[H][H]>[C].[Pd].C(OCC)(=O)C>[F:4][C:5]1[C:13]([F:14])=[C:12]([F:15])[CH:11]=[C:10]2[C:6]=1[CH2:7][CH:8]([C@H:16]1[CH2:21][CH2:20][C@H:19]([CH2:22][CH2:23][CH3:24])[CH2:18][CH2:17]1)[CH2:9]2
Reactant: CCC[C@H]1CC[C@H](C2=Cc3c(cc(F)c(F)c3F)C2)CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCC[C@H]1CC[C@H](C2Cc3cc(F)c(F)c(F)c3C2)CC1

Procedure:
Ethanol (70 ml), ethyl acetate (30 ml) and 5% palladium-carbon (450 mg) were added to 4,5,6-trifluoro-2-(trans-4-propylcyclohexyl)indene (4.5 g), and stirred for 1 hour in a hydrogen atmosphere. The reaction solution was filtered with celite, the filtrate was concentrated, and the residue was purified with a silica gel short column (hexane) to obtain 4,5,6-trifluoro-2-(trans-4-propylcyclohexyl)indane (4.5 g). Moreover, this was then recrystallized from ethanol to obtain 4,5,6-trifluoro-2-(trans-4-propylcyclohexyl)indane (4.5 g, purity: 99.8%). The melting point of this compound was 52° C.
Reaction SMILES: [CH2:1]([S:3]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[C:20]3[C:15](=[C:16]([C:29]([NH2:31])=[O:30])[CH:17]=[C:18]([C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([CH:27]=O)[CH:22]=4)[CH:19]=3)[NH:14][CH:13]=2)[CH2:8][CH2:7]1)(=[O:5])=[O:4])[CH3:2].[N:32]1([CH2:38][CH2:39][O:40][CH2:41][CH2:42][OH:43])[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[CH2:1]([S:3]([N:6]1[CH2:7][CH2:8][CH:9]([C:12]2[C:20]3[C:15](=[C:16]([C:29]([NH2:31])=[O:30])[CH:17]=[C:18]([C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([CH2:27][N:35]5[CH2:36][CH2:37][N:32]([CH2:38][CH2:39][O:40][CH2:41][CH2:42][OH:43])[CH2:33][CH2:34]5)[CH:22]=4)[CH:19]=3)[NH:14][CH:13]=2)[CH2:10][CH2:11]1)(=[O:5])=[O:4])[CH3:2]
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cccc(C=O)c4)cc23)CC1
Reactant: OCCOCCN1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Product: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cccc(CN5CCN(CCOCCO)CC5)c4)cc23)CC1
Yield: 24.9 %

Procedure:
Following the general procedure of example 1, 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3-formylphenyl)-1H-indole-7-carboxamide (50.0 mg, 0.112 mmol), 2-{[2-(1-piperazinyl)ethyl]oxy}ethanol (150 mg, 0.87 mmol) and NaBH(OAc)3 (58.0 mg, 0.303 mmol) were reacted to give the title compound (16.7 mg, 25%).
Reaction SMILES: [O:1]=[C:2]1[C@H:8]2[CH2:9][C@H:4]([CH2:5][CH2:6][C@@H:7]2[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[O:3]1.[CH3:17][O-:18].[Na+].Cl>CO>[OH:3][C@H:4]1[CH2:5][CH2:6][C@H:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[C@@H:8]([C:2]([O:18][CH3:17])=[O:1])[CH2:9]1
Reactant: C[O-]
Reactant: CC(C)(C)OC(=O)[C@H]1CC[C@H]2C[C@@H]1C(=O)O2
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: COC(=O)[C@H]1C[C@@H](O)CC[C@@H]1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 88.4 %

Procedure:
tert-butyl(1S,2S,5S)-7-oxo-6-oxabicyclo[3.2.1]octane-2-carboxylate (5.65 g, 25.0 mmol) was suspended in methanol (20 mL). To that suspension was added a 25 wt % solution of sodium methoxide in methanol (52 mL) and the reaction mixture was stirred at rt for 2 h. Then it was cooled into an ice-water bath and neutralized with a 4 M HCl solution to pH 6. After removing the volatiles, brine was added (50 mL) and the solution was extracted with ethyl acetate (3×40 mL). The combined organic layers were dried over MgSO4, filtered and concentrated to provide the desired product (5.70 g, 88.4% yield). LCMS: m/z 281.1 (M+Na)+.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[S:14][N:13]=[C:12]([C:15]3[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][C:23]([O:25]C(C)(C)C)=[O:24])=[CH:17][C:16]=3[CH3:30])[N:11]=2)=[CH:6][C:5]=1[CH:31]=[CH2:32])[CH3:2].[H][H]>CO.C(OCC)(=O)C.[Pd]>[CH2:31]([C:5]1[CH:6]=[C:7]([C:10]2[S:14][N:13]=[C:12]([C:15]3[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][C:23]([OH:25])=[O:24])=[CH:17][C:16]=3[CH3:30])[N:11]=2)[CH:8]=[CH:9][C:4]=1[O:3][CH2:1][CH3:2])[CH3:32]
Reactant: C=Cc1cc(-c2nc(-c3ccc(CCC(=O)OC(C)(C)C)cc3C)ns2)ccc1OCC
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: CCOc1ccc(-c2nc(-c3ccc(CCC(=O)O)cc3C)ns2)cc1CC
Temperature: 25 °C
Reaction time: 2 h
Yield: 45.4 %

Procedure:
A solution of tert-Butyl 3-(4-(5-(4-ethoxy-3-vinylphenyl)-1,2,4-thiadiazol-3-yl)-3-methylphenyl)propanoate (0.01 g, 0.025 mmol) in methanol (1.5 mL) and ethyl acetate (1.5 mL) was degassed with nitrogen. 10% Palladium/Carbon (0.01 g) was added to the reaction mixture which was stirred under a balloon of hydrogen for 30 min. The reaction was filtered through a disposable frit and concentrated in vacuo. The resulting oil was dissolved in 20% solution of trifluoroacetic acid in dichloromethane (4 mL) and stirred at rt for 2 h after which the reaction was concentrated in vacuo. Silica gel chromatography eluting with 2% methanol/methylene chloride afforded 4.5 mg of the title compound: 1H NMR (500 MHZ, CDCl3) δ 7.86 (s, 1H), 7.83 (d, J=8.5 Hz, 1H), 7.69 (d, J=7.8 Hz, 1H), 7.23 (s, 1H), 7.19 (d, J=7.5 Hz, 1H), 6.93 (d, J=8.2 Hz, 1H), 4.20-4.30 (m, 2H), 3.00-3.08 (m, 2H), 2.70-2.79 (m, 4H), 2.65 (s, 3H), 1.48-1.52 (m, 3H), 1.23-1.32 (m, 3H), ESI-MS (m/z) 453.3; HPLC A: 4.68 min.
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([S:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:19]([F:22])([F:21])[F:20])(=[O:12])=[O:11])[CH2:7][NH:6]1)=[O:4].C([O:27][C:28](=O)[CH2:29][C:30](=[O:37])[CH:31]1[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1)(C)(C)C>>[CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([S:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:19]([F:22])([F:20])[F:21])(=[O:11])=[O:12])[CH2:7][N:6]1[C:28](=[O:27])[CH2:29][C:30](=[O:37])[CH:31]1[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1)=[O:4]
Reactant: CC(C)(C)OC(=O)CC(=O)C1CCOCC1
Reactant: COC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccccc2C(F)(F)F)CN1
Product: COC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccccc2C(F)(F)F)CN1C(=O)CC(=O)C1CCOCC1

Procedure:
In analogy to the procedure described in example 192f, (2S,4R)-4-(2-trifluoromethyl-benzenesulfonyl)-pyrrolidine-2-carboxylic acid methyl ester (example 192e) was reacted with 3-oxo-3-(tetrahydro-pyran-4-yl)-propionic acid tert-butyl ester to give the title compound as yellow foam. MS (ESI): m/z=492.2 [M+H]+.
Reaction SMILES: N(C(OC(C)C)=O)=NC(OC(C)C)=O.[OH:15][C@@H:16]1[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17]1.[C:28]1(O)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[O:15]([C@H:16]1[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17]1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: Oc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](O)C1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC[C@H](Oc2ccccc2)C1
Temperature: 25 °C
Reaction time: 20 h
Yield: 63.5 %

Procedure:
Diisopropyl azodicarboxylate (1.19 g, 5.87 mmol) was added to an ice cooled mixture of tert-butyl (3R)-3-hydroxypyrrolidine-1-carboxylate (1 g, 5.34 mmol), phenol (0.5 g, 5.34 mmol) and triphenylphosphine (1.5 g, 5.8 mmol) in THF (14 mL). The mixture was stirred at room temperature for 20 h. The mixture was then concentrated under vacuum and the residue was twice triturated with diethyl ether. The resultant solid was filtered off and discarded. The filtrate was washed with 1M aq. sodium hydroxide, dried over sodium sulfate and concentrated. The residue was purified by FCC, eluting with 10% EtOAc in heptane to afford the title compound (0.893 g, 63%). Method B HPLC-MS: MH+ requires m/z=208 Found: m/z=208, Rt=2.20 min (91%).
Reaction SMILES: C(N(S(F)(F)[F:7])CC)C.[F-].[K+].[CH2:12]([O:19][C:20](=[O:31])[CH2:21][CH:22]1[NH:25][C:24](=[O:26])[CH:23]1[C:27](O)([CH3:29])[CH3:28])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.O>ClCCl>[CH2:12]([O:19][C:20](=[O:31])[CH2:21][CH:22]1[NH:25][C:24](=[O:26])[CH:23]1[C:27]([F:7])([CH3:29])[CH3:28])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CCN(CC)S(F)(F)F
Reactant: CC(C)(O)C1C(=O)NC1CC(=O)OCc1ccccc1
Agent: [F-]
Agent: [K+]
Solvent: ClCCl
Solvent: O
Product: CC(C)(F)C1C(=O)NC1CC(=O)OCc1ccccc1
Reaction time: 0.25 h

Procedure:
To a -78° cold solution of 3 ml of diethylaminosulphurtrifluoride and 1.7 g of potassium fluoride in 80 ml of dichloromethane is added a solution of 3.2 g of (3SR,4RS)-3-(1-hydroxy-1-methyethyl)-2-oxoazetidine-4-yl acetic acid benzylester in 170 ml of dichloromethane. This mixture is stirred for 15 minutes at -78° and then mixed with water. After addition of further dichloromethane the phases are separated and the organic phase washed with saturated NaCl, dried over MgSO4 and evaporated to dryness. Chromatography of the residue over silica gel (ethylacetate/cyclohexane=1/1) yields the title compound m.p. 112°-116°.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([N:12](C)[C:13](=O)C)=[C:5]2[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.CO.Cl>O.[OH-].[Na+]>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([NH:12][CH3:13])=[C:5]2[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: CC(=O)N(C)c1cnc2ccc(Cl)cc2c1-c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CNc1cnc2ccc(Cl)cc2c1-c1ccccc1

Procedure:
A mixture of 6-chloro-3-(N-methylacetamido)-4-phenylquinoline (0.9 g), methanol (5 ml) and conc. hydrochloric acid (5 ml) was refluxed for 5 hrs. It was diluted with water and neutralized with aqueous sodium hydroxide solution. The resultant precipitate was collected by filtration and recrystallized from methanol to give 6-chloro-3-methylamino-4-phenylquinoline as pale yellow crystals. Yield 0.65 g (83.5%). m.p. 139°-140° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][C@@H:9]([C@H:11]2[CH2:15][NH:14][C:13](=[O:16])[CH2:12]2)[CH3:10])[C:5]2[N:17]([CH3:20])[CH:18]=[N:19][C:4]=2[CH:3]=1.CC1(C)C(C)(C)OB([C:29]2[CH:30]=[CH:31][C:32]3[S:36][CH:35]=[N:34][C:33]=3[CH:37]=2)O1>>[S:36]1[C:32]2[CH:31]=[CH:30][C:29]([C:2]3[N:7]=[C:6]([O:8][C@@H:9]([C@H:11]4[CH2:15][NH:14][C:13](=[O:16])[CH2:12]4)[CH3:10])[C:5]4[N:17]([CH3:20])[CH:18]=[N:19][C:4]=4[CH:3]=3)=[CH:37][C:33]=2[N:34]=[CH:35]1
Reactant: CC1(C)OB(c2ccc3scnc3c2)OC1(C)C
Reactant: C[C@@H](Oc1nc(Cl)cc2ncn(C)c12)[C@H]1CNC(=O)C1
Product: C[C@@H](Oc1nc(-c2ccc3scnc3c2)cc2ncn(C)c12)[C@H]1CNC(=O)C1

Procedure:
Following General Procedure B, beginning with crude (R)-4-((R)-1-(6-chloro-3-methyl-3H-imidazo[4,5-c]pyridin-4-yloxy)ethyl)pyrrolidin-2-one 2.06 (50 mg, 0.17 mmol) and 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]thiazole (49 mg, 0.19 mmol), (R)-4-((R)-1-(6-(benzo[d]thiazol-5-yl)-3-methyl-3H-imidazo[4,5-c]pyridin-4-yloxy)ethyl)pyrrolidin-2-one 3B.27 was isolated, following column chromatography.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[C:10]([C:13]1[CH:18]=[CH:17][C:16]([S:19]([NH2:22])(=[O:21])=[O:20])=[CH:15][CH:14]=1)([OH:12])=[O:11].CC1C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[N:22][S:19]([C:16]2[CH:17]=[CH:18][C:13]([C:10]([OH:12])=[O:11])=[CH:14][CH:15]=2)(=[O:21])=[O:20])=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(Cl)cc1
Reactant: NS(=O)(=O)c1ccc(C(=O)O)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: O=C(O)c1ccc(S(=O)(=O)N=Cc2ccc(Cl)cc2)cc1

Procedure:
In a similar manner to Example 2, 4.00 g (29 mmol) of 4-chlorobenzaldehyde, 5.72 g (29 mmol) of 4-carboxybenzenesulfonamide and 20 mg of TsOH in 150 mL of toluene were heated for 24 hours to provide 6.60 g (71%) of SULF-3 as a light tan powder: IR (Nujol) 3400-2500 (br), 1685, 1595, 1285, 1215, 1005 cm-1 ; 1H NMR (DMSO-d6, TMS ext std) δ 9.15 (s, 1), 8.2-7.3 (m, 8).
Reaction SMILES: [C:1]([CH2:8][N:9]1[CH2:20][CH2:19][N:18]2[CH2:21][CH:22]([CH2:24][C:25]3[CH:30]=[CH:29][C:28]([N+:31]([O-])=O)=[CH:27][CH:26]=3)[CH2:23][N:12]([CH2:13][CH2:14][N:15]([CH2:34][C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:16][CH2:17]2)[CH2:11][CH2:10]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]>C(O)C.[Pd]>[C:35]([CH2:34][N:15]1[CH2:14][CH2:13][N:12]2[CH2:23][CH:22]([CH2:24][C:25]3[CH:30]=[CH:29][C:28]([NH2:31])=[CH:27][CH:26]=3)[CH2:21][N:18]([CH2:19][CH2:20][N:9]([CH2:8][C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])[CH2:10][CH2:11]2)[CH2:17][CH2:16]1)([O:37][C:38]([CH3:40])([CH3:39])[CH3:41])=[O:36]
Reactant: CC(C)(C)OC(=O)CN1CCN2CCN(CC(=O)OC(C)(C)C)CCN(CC1)CC(Cc1ccc([N+](=O)[O-])cc1)C2
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)CN1CCN2CCN(CC(=O)OC(C)(C)C)CCN(CC1)CC(Cc1ccc(N)cc1)C2
Temperature: 25 °C
Reaction time: 12 h
Yield: 97.9 %

Procedure:
To a solution of compound 31 (4.18 g, 7.26 mmol) in ethanol (100 mL) was added 10% Pd/C (1.25 g). The resulting mixture was stirred under H2 (g) atmosphere at room temperature for 12 hours. The reaction mixture was filtered through a celite pad and washed with ethanol (2×20 mL) The combined filtrate was evaporated in vacuo to give an oily residue which was triturated with Et2O to provide an off-white solid 32 (3.88 g, 98% yield).
Reaction SMILES: [Br:1][C:2]1[C:3]([Cl:31])=[C:4]([C:8]2[O:9][C:10]3[C:15]([C:16](=[O:18])[CH:17]=2)=[C:14]([O:19]C)[CH:13]=[C:12]([O:21]C)[C:11]=3[C@@H:23]2[CH2:27][CH2:26][N:25]([CH3:28])[C@H:24]2[CH2:29][OH:30])[CH:5]=[CH:6][CH:7]=1.Cl.N1C=CC=CC=1.C([O-])([O-])=O.[Na+].[Na+]>CO>[Br:1][C:2]1[C:3]([Cl:31])=[C:4]([C:8]2[O:9][C:10]3[C:15]([C:16](=[O:18])[CH:17]=2)=[C:14]([OH:19])[CH:13]=[C:12]([OH:21])[C:11]=3[C@@H:23]2[CH2:27][CH2:26][N:25]([CH3:28])[C@H:24]2[CH2:29][OH:30])[CH:5]=[CH:6][CH:7]=1
Reactant: COc1cc(OC)c2c(=O)cc(-c3cccc(Br)c3Cl)oc2c1[C@@H]1CCN(C)[C@H]1CO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CO
Product: CN1CC[C@@H](c2c(O)cc(O)c3c(=O)cc(-c4cccc(Br)c4Cl)oc23)[C@@H]1CO
Temperature: 180 °C

Procedure:
A mixture of compound of example 28 (0.280 g, 0.550 mmol) and pyridine hydrochloride (0.780 g, 6.74 mmol) was heated at 180° C. for a period of 2.5 hours. The reaction mixture was diluted with methanol (60 mL) and basified with solid Na2CO3 to pH 10. The reaction mixture was filtered, and washed with methanol. The organic layer was concentrated and the residue purified by column chromatography using 0.01% ammonia and 4.5% methanol in chloroform as eluent to afford the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH3:9])=[C:4]([N+:10]([O-])=O)[CH:3]=1.O.O.[C:15]([OH:20])(=O)[C:16](O)=[O:17]>C(O)C.Cl>[Cl:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:6][CH:7]=1)[N:8]([CH3:9])[C:16](=[O:17])[C:15](=[O:20])[NH:10]2
Reactant: CNc1ccc(Cl)cc1[N+](=O)[O-]
Reactant: O=C(O)C(=O)O
Agent: Cl
Solvent: CCO
Solvent: O
Product: Cn1c(=O)c(=O)[nH]c2cc(Cl)ccc21
Yield: 23 %

Procedure:
A suspension of 4-chloro-1-methylamino-2-nitrobenzene (1.73 g, 9.3 mmol) in 50 ml of ethanol was hydrogenated at room temperature and 2 atm. pressure in the presence of 5% palladium-on-carbon (0.5 g) until the theoretical amount of hydrogen was absorbed. The catalyst was filtered off, and 50 ml of IN hydrochloric acid was added to the filtrate. The acidic filtrate was evaporated to dryness and the solid residue was refluxed with oxalic acid dihydrate (1.4 g, 11 mmol) in 100 ml of 4M hydrochloric acid for 90 min. The mixture was cooled and the precipitated product was collected by filtration and washed with water, ethanol and ether to give 0.45 g (23%) of the title compound. M.p. 341.5° C. (N,N-dimethylformamide); IR (KBr): 1700, 1660 cm-1, 1H-NMR (DMSO-d6 : 3.43 (s, 3H, CH3), 6.97-7.40 (m, 3H, ArH), 12.0 (broad s, 1H, NH); MS m/z: 212 (M+ +2, 50%), 210 (M+, 100%).
Reaction SMILES: CN.ClC(Cl)C.[Cl:7][C:8]1[C:13]2[C:14]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[F:27])=[N:15][CH2:16][C:17](=[O:20])[N:18]([CH3:19])[C:12]=2[CH:11]=[CH:10][C:9]=1[N:28]=[C:29]=[O:30].[NH2:31][C:32]1C=CC2N(C)C(=O)CN=C(C3C=CC=CC=3F)C=2C=1Cl>>[Cl:7][C:8]1[C:13]2[C:14]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[F:27])=[N:15][CH2:16][C:17](=[O:20])[N:18]([CH3:19])[C:12]=2[CH:11]=[CH:10][C:9]=1[NH:28][C:29]([NH:31][CH3:32])=[O:30]
Reactant: CN1C(=O)CN=C(c2ccccc2F)c2c1ccc(N)c2Cl
Reactant: CN1C(=O)CN=C(c2ccccc2F)c2c1ccc(N=C=O)c2Cl
Agent: CN
Solvent: CC(Cl)Cl
Product: CNC(=O)Nc1ccc2c(c1Cl)C(c1ccccc1F)=NCC(=O)N2C

Procedure:
Excess gaseous methylamine is conducted into a dichloroethane solution of [6-chloro-5-(o-fluorophenyl)-2,3-dihydro-1-methyl-2-oxo-1H-1,4-benzodiazepin-7-yl]isocyanate, obtained in analogy to the procedure described in paragraph (a) of Example 1 from 10 g (0.031 M) of 7-amino-6-chloro-5-(o-fluorophenyl)-1,3-dihydro-1-methyl-2H-1,4-benzodiazepin-2-one, and the mixture is concentrated. The residue is dissolved in methylene chloride/water and extracted with methylene chloride. The organic phase is separated, dried with sodium sulphate, filtered and concentrated. After purification on a 500 g silica gel column using ethyl acetate as the eluting agent, the product is crystallised from ethyl acetate/ether. There is obtained 1-[6-chloro-5-(o-fluorophenyl)-2,3-dihydro-1-methyl-2-oxo-1H-1,4-benzodiazepin-7-yl]-3-methylurea which melts at 145°-160° C. with decomposition.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[CH:9][C:8]([Br:11])=[CH:7][C:3]=1[C:4](O)=[O:5].[CH3:12][NH:13][O:14][CH3:15].C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>CN1CCOCC1.ClCCl>[NH2:1][C:2]1[N:10]=[CH:9][C:8]([Br:11])=[CH:7][C:3]=1[C:4]([N:13]([O:14][CH3:15])[CH3:12])=[O:5]
Reactant: Nc1ncc(Br)cc1C(=O)O
Reactant: CNOC
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CON(C)C(=O)c1cc(Br)cnc1N
Temperature: 25 °C
Reaction time: 18 h
Yield: 62.6 %

Procedure:
To a solution of 2-amino-5-bromonicotinic acid (7 g, 32.3 mmol), N,O-dimethylhydroxylamine (5.99 g, 61.37 mmol) in N-methylmorpholine (60 ml) and dichloromethane (500 ml) at 0° C. was added PyBop (25.2 g, 48.45 mmol) portionwise. The solution was allowed to warm to room temperature and the mixture was stirred at room temperature for 18 hours. The reaction mixture was washed with a 2M aqueous solution of NaOH and with a 10 wt % solution of citric acid. The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo. The resulting oil was dissolved in ether and the formed solid was filtered off. The mother liquors were concentrated in vacuo to approximatively half of the original volume. This solution was diluted with dichloromethane and stirred vigorously while adding a 2M HCl solution in diethylether until complete formation of the precipitate. The solid was filtered off and partitioned between a 2M aqueous solution of NaOH and EtOAc. The organic layer was collected, dried over sodium sulfate, filtered and concentrated to dryness to afford the title compound as a cream solid (5.26 g, 63% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]=[C:11]([CH2:13]O)[S:10][N:9]=2)=[C:4]([O:15][CH3:16])[CH:3]=1.P(Br)(Br)[Br:18].O>C1(C)C=CC=CC=1>[Br:18][CH2:13][C:11]1[S:10][N:9]=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][C:4]=2[O:15][CH3:16])[N:12]=1
Reactant: BrP(Br)Br
Reactant: COc1cc(Cl)ccc1-c1nsc(CO)n1
Solvent: O
Solvent: Cc1ccccc1
Product: COc1cc(Cl)ccc1-c1nsc(CBr)n1
Temperature: 60 °C
Yield: 63.6 %

Procedure:
To a solution of (3-(4-chloro-2-methoxyphenyl)-1,2,4-thiadiazol-5-yl)methanol (0.08 g, 0.31 mmol) in toluene (4 ml) was added PBr3 (49 μl, 0.47 mmol) and the resulting reaction mixture was heated at 60° C. for 2 h. After the completion of the reaction (TLC monitoring), the reaction mixture was cooled to 0° C., added water (50 ml) and extracted with ethyl acetate (3×50 ml). The combined organics was washed with saturated NaHCO3 solution, dried over Na2SO4, filtered and concentrated under vacuum. The crude residue was purified over silica gel (100-200 M, 5% EtOAc-Hexane) to get the desired product (0.063 g, 64%). MS: 319 (M+H)+.