Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][NH:11][C@@H:10]([CH3:14])[CH2:9]1)=O)(C)(C)C.N1C=CC=CC=1.[CH3:21][S:22](Cl)(=[O:24])=[O:23]>C(Cl)Cl>[CH3:21][S:22]([N:11]1[CH2:12][CH2:13][NH:8][CH2:9][C@@H:10]1[CH3:14])(=[O:24])=[O:23]
Reactant: CS(=O)(=O)Cl
Reactant: C[C@H]1CN(C(=O)OC(C)(C)C)CCN1
Solvent: ClCCl
Solvent: c1ccncc1
Product: C[C@H]1CNCCN1S(C)(=O)=O
Reaction time: 8 h
Yield: 38.8 %

Procedure:
First step: To a stirred solution of commercially available (S)-3-methyl-piperazine-1-carboxylic acid tert-butyl ester (2.38 g, 12 mmol) in CH2Cl2 (25 mL) at 0° C. were added pyridine (1.91 mL, 24 mmol) and methanesulfonyl chloride (0.92 mL, 12 mmol). Stirring was continued at RT overnight, the reaction was poured onto water and extracted with CH2Cl2. The combined organic phases were dried on Na2SO4 and concentrated under vacuo. The crude product was dissolved in CH2Cl2 (20 mL) and TFA (4 mL) was added. After 2 hours at RT, the volatiles were removed under vacuo, the crude was dissolved in CH2Cl2 and washed with aq. NaHCO3 (until pH=8). The organic phase was dried on Na2SO4 and concentrated under vacuo to yield 0.83 g (39%) of (s)-1-methanesulfonyl-2-methyl-piperazine as a light yellow oil.
Reaction SMILES: COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:10])=CC=1.[N:23]1[CH:28]=[CH:27][C:26]([C:29]2[CH:34]=[CH:33][N:32]3[C:35]([C:38]4[CH:43]=[CH:42][C:41]([CH2:44][C:45]([NH:47][C:48]5[CH:53]=[CH:52][CH:51]=[C:50]([C:54]([F:57])([F:56])[F:55])[CH:49]=5)=O)=[CH:40][CH:39]=4)=[CH:36][N:37]=[C:31]3[CH:30]=2)=[CH:25][CH:24]=1.CO>CN(C)P(N(C)C)(N(C)C)=O>[N:23]1[CH:28]=[CH:27][C:26]([C:29]2[CH:34]=[CH:33][N:32]3[C:35]([C:38]4[CH:43]=[CH:42][C:41]([CH2:44][C:45]([NH:47][C:48]5[CH:53]=[CH:52][CH:51]=[C:50]([C:54]([F:57])([F:56])[F:55])[CH:49]=5)=[S:10])=[CH:40][CH:39]=4)=[CH:36][N:37]=[C:31]3[CH:30]=2)=[CH:25][CH:24]=1
Reactant: O=C(Cc1ccc(-c2cnc3cc(-c4ccncc4)ccn23)cc1)Nc1cccc(C(F)(F)F)c1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: CO
Product: FC(F)(F)c1cccc(NC(=S)Cc2ccc(-c3cnc4cc(-c5ccncc5)ccn34)cc2)c1
Temperature: 80 °C
Reaction time: 8 h
Yield: 31.3 %

Procedure:
Add Lawesson's reagent (0.246 g, 0.61 mmol, 1.2 eq.) to the solution of 2-[4-(7-pyridin-4-yl-imidazo[1,2-a]pyridin-3-yl)-phenyl]-N-(3-trifluoromethyl-phenyl)-acetamide (0.240 g, 0.51 mmol, 1.0 eq.) in hexamethylphosphoramide (2.5 mL). Stir the reaction mixture at 80° C. overnight. Cool the mixture down to room temperature and load onto a Varian MegaElut® SCX cartridge (5 gram cartridge prewashed with methanol). Rinse with methanol to remove impurities then elute crude product with 2 M NH3 in methanol. Concentrate this solution in vacuo then purify HPLC to give a yellow foam (0.078 g, 31%). MS (ES), m/z 489 (M+1).
Reaction SMILES: [CH3:1][NH:2][CH3:3].[I:4][C:5]1[CH:10]=[CH:9][C:8]([S:11](Cl)(=[O:13])=[O:12])=[CH:7][CH:6]=1.O>N1C=CC=CC=1>[I:4][C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:2]([CH3:3])[CH3:1])(=[O:13])=[O:12])=[CH:7][CH:6]=1
Reactant: CNC
Reactant: O=S(=O)(Cl)c1ccc(I)cc1
Solvent: c1ccncc1
Solvent: O
Product: CN(C)S(=O)(=O)c1ccc(I)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 87.8 %

Procedure:
Dimethylamine (100 mL of 2.0 M solution in tetrahydrofuran; 200 mmol) was added to a solution of 4-iodobenzenesulfonyl chloride (54.76 g; 181 mmol) in pyridine (300 mL) at 0° C. under N2, followed by the addition of 4-N,N-dimethylaminopyridine (15 mg). The reaction was allowed to warm to room temperature and was stirred under N2 for 48 hrs. The reaction solution was poured into 1.2 liter of water, and the precipitated product was collected by filtration and rinsed with water (300 mL×2). The solid was dissolved in ethyl acetate (500 mL) and washed with 5% aqueous hydrochloric acid (300 mL×3), water (300 mL×2) and brine (300 mL). The organic solution was dried over anhydrous sodium sulfate and concentrated to give 4-iodo-N,N-dimethyl-benzenesulfonamide (49.46 g; 88%) as a white solid, which was used in the next reaction without further purification. 1H NMR (300 MHz, CDCl3) δ 7.88 (d, 2H, J=8.5 Hz), 7.46 (d, 2H, J=8.5 Hz), 2.69 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].[Cl:11][C:12]1[N:17]=[C:16]([CH3:18])[N:15]=[C:14]([NH:19][C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=2)[C:13]=1[NH2:27]>N1C=CC=CC=1>[Cl:11][C:12]1[C:13]([NH:27][C:4](=[O:5])[C:3]2[CH:7]=[CH:8][CH:9]=[CH:10][C:2]=2[F:1])=[C:14]([NH:19][C:20]2[CH:21]=[CH:22][C:23]([Cl:26])=[CH:24][CH:25]=2)[N:15]=[C:16]([CH3:18])[N:17]=1
Reactant: Cc1nc(Cl)c(N)c(Nc2ccc(Cl)cc2)n1
Reactant: O=C(Cl)c1ccccc1F
Solvent: c1ccncc1
Product: Cc1nc(Cl)c(NC(=O)c2ccccc2F)c(Nc2ccc(Cl)cc2)n1
Temperature: 25 °C
Reaction time: 7 h

Procedure:
2-Fluorobenzoyl chloride (93 μl, 0.78 mmol) was added to 6-chloro-N4-(4-chlorophenyl)-2-methylpyrimidine-4,5-diamine I-(7A-80)a (173 mg) and pyridine (1 ml) and stirred at room temperature for 7 h. The reaction was incomplete at this time so an additional 1.5 equivalents of 2-fluorobenzoyl chloride was added to the reaction mixture and continued stirring overnight at room temperature. The reaction was extracted from saturated NaHCO3 solution into ethyl acetate. The organic layers were combined, dried (Na2SO4), filtered, and concentrated to dryness to afford the desired crude product I-(7A-80)b (0.25 g): +ESI MS (M+1) 391.2.
Reaction SMILES: [CH:1]1([CH:6]=[C:7]2[CH2:16][CH2:15][C:14]3[CH:13]=[C:12]([NH:17][C:18](=[O:20])[CH3:19])[CH:11]=[CH:10][C:9]=3[C:8]2=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[Cl:23][C:24]1[CH:31]=[C:30]([NH:32][NH2:33])[CH:29]=[CH:28][C:25]=1[C:26]#[N:27]>>[Cl:23][C:24]1[CH:31]=[C:30]([N:32]2[CH:6]([CH:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)[CH:7]3[C:8]([C:9]4[CH:10]=[CH:11][C:12]([NH:17][C:18](=[O:20])[CH3:19])=[CH:13][C:14]=4[CH2:15][CH2:16]3)=[N:33]2)[CH:29]=[CH:28][C:25]=1[C:26]#[N:27]
Reactant: N#Cc1ccc(NN)cc1Cl
Reactant: CC(=O)Nc1ccc2c(c1)CCC(=CC1CCCC1)C2=O
Agent: Cl
Product: CC(=O)Nc1ccc2c(c1)CCC1C2=NN(c2ccc(C#N)c(Cl)c2)C1C1CCCC1
Yield: 59 %

Procedure:
The title compound was prepared from N-(6-(cyclopentylmethylene)-5-oxo-5,6,7,8-tetrahydronaphthalen-2-yl)acetamide; Preparation 36 and 2-chloro-4-hydrazinylbenzonitrile hydrochloride (Preparation 1) according to Method B (tan solid, 159 mg, 0.37 mmol, 59% yield). The title compound was largely present as (O)—N-((3RS,3aSR)-2-(3-chloro-4-cyanophenyl)-3-cyclopentyl-3,3a,4,5-tetrahydro-2H-benzo[g]indazol-7-yl)acetamide. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.08-1.59 (m, 7H), 1.65-1.87 (m, 2H), 1.98-2.05 (m, 1H), 2.06 (s, 3H), 2.13-2.24 (m, 1H), 2.78-2.97 (m, 2H), 3.51 (ddd, J=13.56, 9.26, 4.83 Hz, 1H), 4.86 (dd, J=9.26, 5.50 Hz, 1H), 7.11 (dd, J=9.26, 1.48 Hz, 1H), 7.32 (d, J=1.88 Hz, 1H), 7.46 (dd, J=8.59, 1.88 Hz, 1H), 7.60 (s, 1H), 7.64 (d, J=8.86 Hz, 1H), 7.93 (d, J=8.59 Hz, 1H), 10.11 (s, 1H). ES-MS m/z 433 (M+H).
Reaction SMILES: C(OC([NH:8][C:9]1([C:13]2[CH:18]=[CH:17][C:16]([C:19]3[C:24]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)=[CH:23][N:22]4[N:31]=[C:32]([C:34]([OH:36])=[O:35])[N:33]=[C:21]4[N:20]=3)=[CH:15][CH:14]=2)[CH2:12][CH2:11][CH2:10]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:8][C:9]1([C:13]2[CH:14]=[CH:15][C:16]([C:19]3[C:24]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)=[CH:23][N:22]4[N:31]=[C:32]([C:34]([OH:36])=[O:35])[N:33]=[C:21]4[N:20]=3)=[CH:17][CH:18]=2)[CH2:12][CH2:11][CH2:10]1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4nc(C(=O)O)nn4cc3-c3ccccc3)cc2)CCC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NC1(c2ccc(-c3nc4nc(C(=O)O)nn4cc3-c3ccccc3)cc2)CCC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To the solution of 8-3 (49 mg, 0.1 mmol) in 1 mL of DCM was added TFA (1 mL) and the mixture was stirred at room temperature for 3 h. The mixture was concentrated by evaporation and the residue was purified by prep.HPLC to give the product 8-4.
Reaction SMILES: [C:1]([OH:10])(=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[OH-].[Na+:12].C(O)C>O>[CH3:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][C:1]([O-:10])=[O:9].[Na+:12]
Reactant: CCCCCCCC(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCCCCCCC(=O)[O-]

Procedure:
The sodium octoate was prepared by stirring 3.60 g of octanoic acid in 3 g of water and neutralizing with 2.00 g of aqueous sodium hydroxide (50%). 5 g of water was used for dilution and rinse. A waxy solid formed which was dissolved by adding about 10 ml of ethanol. pH paper indicated a pH of about 8. The total solution was evaporated on a watch glass on a steam bath under a flow of nitrogen to give 4.04 g white solid. The solid was titrated in ethanol with aqueous HCl: the titer was 5.88 mmol/g. Estimated purity was 97.6%
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:8])=[N:4][CH:5]=[CH:6][CH:7]=1.ClC1C=CC=C(C(OO)=[O:17])C=1>C(Cl)Cl>[Br:1][C:2]1[C:3]([CH3:8])=[N+:4]([O-:17])[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ncccc1Br
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: Cc1c(Br)ccc[n+]1[O-]
Temperature: 0 °C
Reaction time: 3 h
Yield: 81 %

Procedure:
To a solution of 3-bromo-2-methylpyridine (5 g, 29.1 mmol) in DCM (50 ml) was added portionwise at 0° C. m-chloroperbenzoic acid (70%, 8.6 g, 34.9 mmol). The solution was stirred at 0° C. for three hours and then at room temperature overnight. The mixture was filtered, the residue was washed with DCM and the combined DCM phases were quenched with a 10% solution of sodium thiosulfate. The phases were separated, the organic phase was washed with a saturated solution of sodium bicarbonate and brine, dried (sodium sulfate) and concentrated under reduced pressure. The residue was purified by column chromatography (silica, diethyl ether, then DCM/methanol 95:5) to yield 4.44 g (23.6 mmol, yield 81%) MS (multi-mode) m/z=190.0 [M+1]+.
Reaction SMILES: [CH2:1]([N:3]([CH2:28][CH3:29])[C:4]([C:6]1[CH:7]=[CH:8][C:9]2[CH:10]([CH:20]3[CH2:26][CH:25]4[NH:27][CH:22]([CH2:23][CH2:24]4)[CH2:21]3)[C:11]3[C:16]([O:17][C:18]=2[CH:19]=1)=[CH:15][CH:14]=[CH:13][CH:12]=3)=[O:5])[CH3:2].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.C[N+](C)(C)C.[O:48]1[CH:52]=[CH:51][C:50]([CH:53]=O)=[CH:49]1>C(Cl)Cl>[CH2:28]([N:3]([CH2:1][CH3:2])[C:4]([C:6]1[CH:7]=[CH:8][C:9]2[C:10](=[C:20]3[CH2:26][CH:25]4[N:27]([CH2:53][C:50]5[CH:51]=[CH:52][O:48][CH:49]=5)[CH:22]([CH2:23][CH2:24]4)[CH2:21]3)[C:11]3[C:16]([O:17][C:18]=2[CH:19]=1)=[CH:15][CH:14]=[CH:13][CH:12]=3)=[O:5])[CH3:29]
Reactant: O=Cc1ccoc1
Reactant: CCN(CC)C(=O)c1ccc2c(c1)Oc1ccccc1C2C1CC2CCC(C1)N2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C[N+](C)(C)C
Solvent: ClCCl
Product: CCN(CC)C(=O)c1ccc2c(c1)Oc1ccccc1C2=C1CC2CCC(C1)N2Cc1ccoc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 9-(8-aza-bicyclo[3.2.1]oct-3-yl)-9H-xanthene-3-carboxylic acid diethylamide, 9a (0.65 g, 1.7 mmol) in CH2Cl2 (20 mL) were added tetramethylammonium triacetoxyborohydride (0.53 g, 2.5 mmol) and 3-furaldehyde (0.17 mL, 2.0 mmol). The mixture was stirred at rt for 24 h, diluted with CH2Cl2 (10 mL), and washed with 1 N NaOH. The organic phase was dried over sodium sulfate, filtered, and concentrated. The crude product was purified by flash chromatography (eluent: 5% 0.5 M NH3 in methanol in CH2Cl2) to yield title compound 9-(8-furan-3-ylmethyl-8-aza-bicyclo[3.2.1]oct-3-ylidene)-9H-xanthene-3-carboxylic acid diethylamide, 10a (0.25 g, 0.53 mmol). MS m/z=471.2 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]([OH:20])([CH2:15][O:16]C(=O)C)[CH2:10][O:11]C(=O)C.[OH-].[K+]>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]([OH:20])([CH2:15][OH:16])[CH2:10][OH:11]
Reactant: CC(=O)OCC(O)(COC(C)=O)c1ccc(F)cc1F
Agent: [K+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: OCC(O)(CO)c1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 24 h
Yield: 91.8 %

Procedure:
In a 200 ml reaction vessel, 10 g of 2-(2,4-difluorophenyl)-1,3-diacetoxy-2-propanol was dissolved in 30 ml of toluene and thereto was added 30 ml of 30% aqueous KOH solution. The resulting liquid was stirred at room temperature for 24 hours and more. Then a toluene-layer and an aqueous layer were separated from each other and the aqueous layer was extracted twice with 50 ml of ethyl acetate. The organic layer was washed with brine and then dried over anhydrous sodium sulfate. The solvent was removed therefrom and the residue was purified in the same manner as in Example 32 to give 6.5 g of 2-(2,4-difluorophenyl)-1,2,3-propanetriol.
Reaction SMILES: O[CH2:2][CH2:3][O:4][C:5]1[CH:6]=[C:7]([C:14]2[C:15](=[O:31])[N:16]([CH3:30])[C:17](=[O:29])[C:18]=2[C:19]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[N:21]([CH3:28])[CH:20]=2)[C:8]2[O:12][CH:11]=[CH:10][C:9]=2[CH:13]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:52]>ClCCl>[Br:52][CH2:2][CH2:3][O:4][C:5]1[CH:6]=[C:7]([C:14]2[C:15](=[O:31])[N:16]([CH3:30])[C:17](=[O:29])[C:18]=2[C:19]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[N:21]([CH3:28])[CH:20]=2)[C:8]2[O:12][CH:11]=[CH:10][C:9]=2[CH:13]=1
Reactant: BrC(Br)(Br)Br
Reactant: CN1C(=O)C(c2cn(C)c3ccccc23)=C(c2cc(OCCO)cc3ccoc23)C1=O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CN1C(=O)C(c2cn(C)c3ccccc23)=C(c2cc(OCCBr)cc3ccoc23)C1=O

Procedure:
Add to a solution of 3-[5-(2-hydroxyethoxy)benzofur-7-yl]-1-methyl-4-(1-methyl-1H-indol-3-yl)pyrrole-2,5-dione (1.87 g, 4.49 mmol) in dichloromethane (30 ml), triphenylphosphine (1.41 g, 5.39 mmol) and carbon tetrabromide (1.79 g, 5.39 mmol). Stir the reaction for 15 minutes under nitrogen atmosphere. Add another 2.2 mmol of triphenylphosphine and 2.2 mmol of carbon tetrabromide and stir for 15 more minutes. Diluted with dichloromethane, wash with water, brine, dry over magnesium sulfate, filter and concentrate. Flash chromatography over silica gel (1% methanol:dichloromethane) affords the title compound as an orange solid. MS(ES+): 479.0, 481.0.
Reaction SMILES: Cl.[NH2:2][OH:3].C(=O)(O)[O-].[Na+].O.[Cl:10][C:11]1[CH:12]=[C:13]([C:17]2[C:22]3[N:23]([CH2:33][C@H:34]4[CH2:39][CH2:38][C@H:37]([CH3:40])[CH2:36][CH2:35]4)[C:24]([N:26]4[CH2:30][CH2:29][CH2:28][C@H:27]4[CH2:31][F:32])=[N:25][C:21]=3[CH:20]=[C:19]([C:41]#[N:42])[N:18]=2)[CH:14]=[N:15][CH:16]=1>C(O)C>[Cl:10][C:11]1[CH:12]=[C:13]([C:17]2[C:22]3[N:23]([CH2:33][C@H:34]4[CH2:39][CH2:38][C@H:37]([CH3:40])[CH2:36][CH2:35]4)[C:24]([N:26]4[CH2:30][CH2:29][CH2:28][C@H:27]4[CH2:31][F:32])=[N:25][C:21]=3[CH:20]=[C:19]([C:41](=[N:2][OH:3])[NH2:42])[N:18]=2)[CH:14]=[N:15][CH:16]=1
Reactant: C[C@H]1CC[C@H](Cn2c(N3CCC[C@H]3CF)nc3cc(C#N)nc(-c4cncc(Cl)c4)c32)CC1
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: C[C@H]1CC[C@H](Cn2c(N3CCC[C@H]3CF)nc3cc(C(N)=NO)nc(-c4cncc(Cl)c4)c32)CC1
Temperature: 100 °C
Reaction time: 0.25 h

Procedure:
Hydroxylamine hydrochloride (108 mg, 1.56 mmol), sodium bicarbonate (196 mg, 2.34 mmol), and water (1.56 mL) were combined in a vial and stirred for 15 minutes. This solution was added to a vial containing 4-(5-chloropyridin-3-yl)-2-[(2S)-2-(fluoromethyl)pyrrolidin-1-yl]-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridine-6-carbonitrile (364 mg, 0.78 mmol) dissolved in ethanol (3.6 mL). The mixture was sealed and heated at 100° C. for 1 hour. The reaction was cooled to room temperature, quenched with water, and extracted with ethyl acetate (2×). The combined organic layers were dried over sodium sulfate, filtered, and concentrated to afford 4-(5-chloropyridin-3-yl)-2-[(2S)-2-(fluoromethyl)pyrrolidin-1-yl]-N′-hydroxy-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridine-6-carboximidamide. MS ESI calc'd. for C25H31ClFN7O [M+H]+ 500. found 500.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[N:10]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[CH:21]=3)[N:11]=[C:12]3[C:17]=2[CH:16]=[C:15]([F:18])[C:14]([F:19])=[CH:13]3)[CH:5]=[CH:6][CH:7]=1.[CH:27]1([N:33]=[C:34]=[O:35])[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1.CCN(CC)CC>ClCCCl>[Cl:1][C:2]1[CH:3]=[C:4]([N:8]([C:9]2[N:10]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[CH:21]=3)[N:11]=[C:12]3[C:17]=2[CH:16]=[C:15]([F:18])[C:14]([F:19])=[CH:13]3)[C:34]([NH:33][CH:27]2[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]2)=[O:35])[CH:5]=[CH:6][CH:7]=1
Reactant: O=C=NC1CCCCC1
Reactant: Fc1cc2nn(-c3cccc(Cl)c3)c(Nc3cccc(Cl)c3)c2cc1F
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: O=C(NC1CCCCC1)N(c1cccc(Cl)c1)c1c2cc(F)c(F)cc2nn1-c1cccc(Cl)c1

Procedure:
In analogy to the procedure described in example 1.2, (3-chloro-phenyl)-[2-(3-chloro-phenyl)-5,6-difluoro-2H-indazol-3-yl]-amine was reacted with cyclohexylisocyanate ([3173-53-3]) in 1,2-dichloroethane in the presence of Et3N (3 eq.) for 3 d under reflux conditions to give the title compound as white solid. MS: m/e=515.4 [M+H+].
Reaction SMILES: [N:1]1[C:6]([P:11]([OH:14])(=[O:13])[OH:12])([P:7]([OH:10])(=[O:9])[OH:8])[CH2:5][CH2:4][N:3]2[CH:15]=[CH:16][CH:17]=[CH:18][C:2]=12.[H][H]>O.O=[Pt]=O>[N:1]1[C:6]([P:7]([OH:10])(=[O:8])[OH:9])([P:11]([OH:14])(=[O:12])[OH:13])[CH2:5][CH2:4][N:3]2[CH2:15][CH2:16][CH2:17][CH2:18][C:2]=12
Reactant: O=P(O)(O)C1(P(=O)(O)O)CCN2C=CC=CC2=N1
Reactant: [H][H]
Agent: O=[Pt]=O
Solvent: O
Product: O=P(O)(O)C1(P(=O)(O)O)CCN2CCCCC2=N1

Procedure:
3 g of the diphosphonic acid obtained in Example 1 were dissolved in 250 ml water and, after addition of 1.5 g PtO2, hydrogenated at atmospheric pressure up to the take-up of the calculated amount of hydrogen. After separation off of the catalyst and evaporation in a vacuum, the residue was brought to crystallisation from water/acetone. Mrel. 0.33, yield 2.61 g (85% of theory), m.p. 279°-285° C. (decomp.).
Reaction SMILES: [NH:1]([C:23]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:24])[C@H:2]([C:7]([NH:9][C@H:10]([C:18](OCC)=[O:19])[CH2:11][CH2:12][CH2:13][NH:14][C:15](=[NH:17])[NH2:16])=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5].[NH2:33][NH2:34].O>CO>[NH:1]([C:23]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:24])[C@H:2]([C:7]([NH:9][C@H:10]([C:18]([NH:33][NH2:34])=[O:19])[CH2:11][CH2:12][CH2:13][NH:14][C:15](=[NH:17])[NH2:16])=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5]
Reactant: NN
Reactant: CCOC(=O)[C@H](CCCNC(=N)N)NC(=O)[C@H](CC(C)C)NC(=O)OCc1ccccc1
Solvent: CO
Solvent: O
Product: CC(C)C[C@H](NC(=O)OCc1ccccc1)C(=O)N[C@@H](CCCNC(=N)N)C(=O)NN
Temperature: 25 °C
Reaction time: 18 h
Yield: 74.1 %

Procedure:
Z-Leu-Arg-OEt was dissolved in 500 mL of methanol. NH2NH2.H2O 150 mL was added with ice cooling to the solution, then the mixture was stirred at room temperature for 18 hours. The reaction mixture was concentrated under reduced pressure, 500 mL of water was added to the obtained residue, then the product was extracted 5 times with 1000 mL of n-butanol. The extract was washed 4 times with 500 mL of water, then concentrated under reduced pressure. The resulting residue was solidified by treatment with ether, then it was dried. Thus, 209.7 g of Z-Leu-Arg-NHNH2 (74.1% yield) was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:5]([C:6]([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([S:16]([N:19]3[CH2:24][CH2:23][C:22](=O)[CH2:21][CH2:20]3)(=[O:18])=[O:17])=[CH:12][CH:11]=2)=[O:7])=[CH:4][CH:3]=1.[CH2:28]([NH2:34])[CH2:29][CH2:30][CH2:31][CH2:32][CH3:33]>C1COCC1.CO>[Cl:1][C:2]1[CH:27]=[CH:26][C:5]([C:6]([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([S:16]([N:19]3[CH2:24][CH2:23][CH:22]([NH:34][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[CH2:21][CH2:20]3)(=[O:18])=[O:17])=[CH:12][CH:11]=2)=[O:7])=[CH:4][CH:3]=1
Reactant: CCCCCCN
Reactant: O=C1CCN(S(=O)(=O)c2ccc(CNC(=O)c3ccc(Cl)cc3)cc2)CC1
Solvent: C1CCOC1
Solvent: CO
Product: CCCCCCNC1CCN(S(=O)(=O)c2ccc(CNC(=O)c3ccc(Cl)cc3)cc2)CC1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
4-chloro-N-{4-[(4-oxo-1-piperidinyl)sulfonyl]benzyl}benzamide 7d (500 mg, 1.23 mmol) was suspended in THF/methanol (10 ml/20 ml), N-hexylamine (149 mg, 1.48 mmol) and Cyanoborohydride-IRA400 (1.0 g, 3.0 mmol) were added and the reaction mixture was stirred at 50° C. overnight. Excess amine was scavenged with Ameba-PS (415 mg, 0.50 mmol) by shaking for 2 h. The resins were filtered off, solvent removed in vacuo and the obtained residue purified by column chromatography on silica gel using a step gradient of 2.5% methanol in DCM and 5% methanol in DCM. Fractions with Rf=0.28 (5% methanol in DCM,) were collected and evaporated to dryness (Note: Up to 1% conc. NH3 (13.5 M) may be added during the chromatography to reduce loss of material). The residue was dissolved in DCM (10 ml) and 1 N HCl in ether (3 ml) added. After aging at room temp for 1 h the precipitate was filtered off and dried in vacuo. The hydrochloric salt of sulfonamide 4-chloro-N-(4-{[4-(hexylamino)-1-piperidinyl]sulfonyl}benzyl)benzamide 7 was isolated as off-white powder (260 mg, 36%) in >95% purity. M/Z APCI 492.0 (M+1), 490.2 (M−1). 1H-NMR (DMSO-d6) (HCl salt) δ 9.39 (t, 1H, H—N5, 3J=5.92 Hz), 8.97 (m, br, 2H, H—N16), 7.99 (d, 2H, 3J=8.65 Hz, H—C2, 3), 7.75 (d, 2H, 3J=8.20 Hz, H—C8, 9), 7.61 (m, 4H, H—C1, 4, 7, 10), 4.61 (d, 2H, 3J=5.92 Hz, H—C6), 3.73* (d, 2H, 2J=11.84 Hz, Heq—C11, 15), 3.07 (m, br, 1H, H—C13), 2.83 (m, br, 2H, H—C17), 2.29* (m, 2H, Hax—C12, 14), 2.10* (d, br, 2H, 2J=11.90 Hz, Hax—C11, 15), 1.71-1.54* (m, 4H, Heq—C12, 14 and H—C18), 1.36-1.23 (m, 6H, H—C19, 20, 21), 0.89 (t, 3H, 3J=6.60 Hz, H—C22)
Reaction SMILES: Cl[C:2]1[S:3][C:4]2[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:5]=2[N:6]=1.[N:14]1([CH2:20][CH2:21][NH2:22])[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1>O>[N:14]1([CH2:20][CH2:21][NH:22][C:2]2[S:3][C:4]3[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:5]=3[N:6]=2)[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1
Reactant: O=[N+]([O-])c1ccc2nc(Cl)sc2c1
Reactant: NCCN1CCOCC1
Solvent: O
Product: O=[N+]([O-])c1ccc2nc(NCCN3CCOCC3)sc2c1
Temperature: 65 °C
Yield: 26.2 %

Procedure:
To a mixture of 2-chloro-6-nitrobenzothiazole (1.00 g, 4.66 mmol) in water (9.0 mL) was added 2-morpholin-4-yl-ethylamine (2.45 mL, 18.6 mmol). The dark reaction mixture was stirred under argon and refluxed for 4.5 hours at which time the reaction became red-brown in colour. The mixture was then cooled to 65° C. and stirred an additional 17.75 hours. The precipitate was then collected by suction filtration after cooling to room temperature giving a yellow solid (377 mg, 26%). 1H NMR (DMSO-d6) δ: 8.69 (d, 1H, J=2.1 Hz), 8.10 (dd, 1H, J=2.1, 8.9 Hz), 7.46 (d, 1H, J=8.9 Hz), 3.59 (m, 6H), 2.55 (t, 2H, J=6.2 Hz), 2.51 (m, 4H), 2.43 (m, 4H).
Reaction SMILES: Br[CH:2]([C:14](=[O:22])[C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=1)[CH2:3][C:4]([N:6]1[CH2:13][CH2:12][CH2:11][C@H:7]1[C:8]([OH:10])=[O:9])=[O:5].[C:23]([O-:26])(=[S:25])[CH3:24].[K+]>C(O)C>[C:23]([S:25][CH:2]([C:14](=[O:22])[C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=1)[CH2:3][C:4]([N:6]1[CH2:13][CH2:12][CH2:11][C@H:7]1[C:8]([OH:10])=[O:9])=[O:5])(=[O:26])[CH3:24]
Reactant: CC([O-])=S
Reactant: O=C(c1ccc(F)cc1)C(Br)CC(=O)N1CCC[C@H]1C(=O)O
Agent: [K+]
Solvent: CCO
Product: CC(=O)SC(CC(=O)N1CCC[C@H]1C(=O)O)C(=O)c1ccc(F)cc1

Procedure:
To a solution of 3.7 g. of 1-[3-bromo-3-(4-fluorobenzoyl)propionyl]-L-proline (Example 19) in 37 ml. of ethanol is added 1.37 g. of potassium thioacetate. The procedure of Example 12 is followed giving the desired product as 1.02 g. of a glass.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[C:7]3[C:11](=[CH:12][C:4]=2[N:3]=[C:2]1[SH:13])[CH2:10][CH2:9][CH2:8]3.[OH-].[Na+].Cl.[CH3:17][C:18]1[CH:19]=[CH:20][C:21]([CH2:24]Cl)=[N:22][CH:23]=1>O>[CH3:17][C:18]1[CH:19]=[CH:20][C:21]([CH2:24][S:13][C:2]2[NH:3][C:4]3[CH:12]=[C:11]4[C:7](=[CH:6][C:5]=3[N:1]=2)[CH2:8][CH2:9][CH2:10]4)=[N:22][CH:23]=1
Reactant: Sc1nc2cc3c(cc2[nH]1)CCC3
Reactant: Cc1ccc(CCl)nc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1ccc(CSc2nc3cc4c(cc3[nH]2)CCC4)nc1
Reaction time: 0.5 h
Yield: 56.8 %

Procedure:
To 13.5 g of 1,5,6,7-tetrahydroindeno(5,6-d)imidazole-2-thiol, suspended in 200 ml of alcohol, were added dropwise while stirring 5.9 g of sodium hydroxide in 100 ml of water and, after 30 minutes, 13.0 g of 5-methyl-2-chloromethyl-pyridine hydrochloride were added. The mixture was left to boil at reflux overnight, then evaporated and the residue was taken up in methylene chloride. This was washed neutral and, after drying over sodium sulfate, evaporated in vacuo. The residue, recrystallized from acetonitrile, gave 11.9 g (56.9% of theory) of 1,5,6,7-tetrahydro-2-[[(5-methyl-2-pyridyl)methyl]thio]indeno(5,6-d)imidazole of melting point 157°-158° C.