Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:5]([CH2:13][CH2:14][S:15][CH2:16][C:17]#[C:18][C:19]1[S:20][CH:21]=[CH:22][CH:23]=1)[C:6](=[O:12])[C:7]([O:9]CC)=[O:8])([CH3:4])([CH3:3])[CH3:2].[OH-].[K+].Cl>O1CCOCC1.O>[C:1]([N:5]([CH2:13][CH2:14][S:15][CH2:16][C:17]#[C:18][C:19]1[S:20][CH:21]=[CH:22][CH:23]=1)[C:6](=[O:12])[C:7]([OH:9])=[O:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)C(=O)N(CCSCC#Cc1cccs1)C(C)(C)C
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)N(CCSCC#Cc1cccs1)C(=O)C(=O)O
Temperature: 25 °C
Reaction time: 4 h
Yield: 100.3 %

Procedure:
A solution of 520 mg of 9f in 12 ml of dioxane and a solution of 330 mg of KOH in 2 ml of water were mixed and stirred for 4 h at ambient temperature. The reaction mixture was diluted with 20 ml of water and acidified with cold 0.5 HCl to pH3. The product was extracted into ethyl acetate. The extract was washed once with water, dried and concentrated to provide 480 mg of acid 9g as a colorless oil, which was used without further purification in the next step.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[NH2:8][N:9]=[CH:10][NH:11][C:12]1[CH:13]=[C:14]([C:18]([NH:20][CH2:21][C:22]([NH:24][CH:25]([C:32]2[CH:37]=[C:36]([CH3:38])[CH:35]=[C:34]([CH3:39])[CH:33]=2)[CH2:26][C:27]([O:29]CC)=[O:28])=[O:23])=[O:19])[CH:15]=[CH:16][CH:17]=1.[Li+].[OH-].C(O)(C(F)(F)F)=O>O.CC#N>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[NH2:8][N:9]=[CH:10][NH:11][C:12]1[CH:13]=[C:14]([C:18]([NH:20][CH2:21][C:22]([NH:24][CH:25]([C:32]2[CH:37]=[C:36]([CH3:38])[CH:35]=[C:34]([CH3:39])[CH:33]=2)[CH2:26][C:27]([OH:29])=[O:28])=[O:23])=[O:19])[CH:15]=[CH:16][CH:17]=1
Reactant: CCOC(=O)CC(NC(=O)CNC(=O)c1cccc(NC=NN)c1)c1cc(C)cc(C)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CC#N
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(C)cc(C(CC(=O)O)NC(=O)CNC(=O)c2cccc(NC=NN)c2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 83.4 %

Procedure:
To the product from Example 192 (730 mg, 0.0013 mole) in H2O (10 mL) and CH3CN (10 mL) was added LiOH (221 mg, 0.005 mole). The reaction mixture was stirred at room temperature for 1 hour. The pH was lowered to ~2.5 with TFA and the product was isolated by RPHPLC to yield the title compound (570 mg after lyophilization) as a white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([N+:14]([O-:16])=[O:15])[C:10]=1[N+:11]([O-:13])=[O:12])[C:5](O)=[O:6].B.O1CCCC1>O1CCCC1>[CH3:1][C:2]1[CH:3]=[C:4]([CH2:5][OH:6])[CH:8]=[C:9]([N+:14]([O-:16])=[O:15])[C:10]=1[N+:11]([O-:13])=[O:12]
Reactant: Cc1cc(C(=O)O)cc([N+](=O)[O-])c1[N+](=O)[O-]
Agent: B
Solvent: C1CCOC1
Product: Cc1cc(CO)cc([N+](=O)[O-])c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 16 h
Yield: 85.2 %

Procedure:
A solution of 3-methyl-4,5-dinitrobenzoic acid (4.0 g, 17.7 mmol) in tetrahydrofuran (200 mL) was cooled to −70° C. with a dry ice/acetone bath. To this solution was added borane-tetrahydrofuran (1M in tetrahydrofuran, 35.4 mL). The reaction mixture was allowed to slowly warm to room temperature and was stirred for 16 h. The reaction was incomplete, was again cooled to −50° C. and additional borane-tetrahydrofuran (1M in tetrahydrofuran, 35.4 mL) was added. Again, the reaction mixture was allowed to slowly warm to room temperature overnight. The reaction was quenched with a mixture of acetic acid and water (1:1, 30 mL) while cooling at 0° C. After stirring for 30 min, all organic solvent was evaporated and the aqueous material was neutralized by pouring into ice cold saturated sodium bicarbonate (350 mL) in small portions. The aqueous layer was extracted with ethyl acetate. The extracts were washed with brine, dried over magnesium sulfate, filtered and evaporated. The residue was subjected to flash column chromatography (1:2 hexanes/ethyl acetate) to give the title compound (3.2 g, 86% yield). 1H-NMR (CDCl3, 300 MHz) δ 8.00 (s, 1H), 7.62 (s, 1H), 4.82 (s, 2H), 2.41 (s, 3H). 13C-NMR (CDCl3, 75 MHz) δ 144.5, 143.3, 140.9, 134.3, 132.9, 120.8, 63.0, 17.4.
Reaction SMILES: [O:1]=[C:2]1[C:8]2=[N:9][C:10]3[CH:15]=[CH:14][C:13]([C:16]([OH:18])=O)=[CH:12][C:11]=3[N:7]2[CH2:6][CH2:5][CH2:4][NH:3]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[CH2:41]([N:43]1[C:47]2[CH:48]=[CH:49][CH:50]=[CH:51][C:46]=2[N:45]=[C:44]1[NH2:52])[CH3:42].C(N(CC)CC)C>CN(C=O)C.O>[CH2:41]([N:43]1[C:47]2[CH:48]=[CH:49][CH:50]=[CH:51][C:46]=2[N:45]=[C:44]1[NH:52][C:16]([C:13]1[CH:14]=[CH:15][C:10]2[N:9]=[C:8]3[C:2](=[O:1])[NH:3][CH2:4][CH2:5][CH2:6][N:7]3[C:11]=2[CH:12]=1)=[O:18])[CH3:42]
Reactant: O=C(O)c1ccc2nc3n(c2c1)CCCNC3=O
Reactant: CCn1c(N)nc2ccccc21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: CCn1c(NC(=O)c2ccc3nc4n(c3c2)CCCNC4=O)nc2ccccc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 52.1 %

Procedure:
A solution of 1-oxo-2,3,4,5-tetrahydro-1H-[1,4]diazepino[1,2-a]benzimidazole-8-carboxylic acid (Intermediate B, 103 mg, 0.42 mmol) and TBTU (149 mg, 0.46 mmol) in DMF (2 mL) is stirred for 10 min. 1-Ethyl-1H-benzimidazol-2-amine (68 mg, 0.42 mmol) and triethylamine (43 mg, 0.42 mmol) are added and the reaction is stirred at room temperature for 16 h. The reaction mixture is diluted with H2O. A yellow solid is formed that is filtered and washed with EtOAc and a small amount of methanol to afford the title compound (85 mg, 51%).
Reaction SMILES: [OH-].[K+].[CH3:3][N:4]1[C:11](=[O:12])[CH:10]([C:13](=[O:22])[NH:14][C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=2)[C:8](=[O:9])[N:7]([CH3:23])[C:5]1=[O:6].Cl[C:25]1[N:26]=[N:27][C:28]([O:31][CH3:32])=[CH:29][CH:30]=1.Cl>C1(C)C=CC=CC=1.CS(C)=O.O>[CH3:23][N:7]1[C:8](=[O:9])[CH:10]([C:13](=[O:22])[NH:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][C:25]3[N:26]=[N:27][C:28]([O:31][CH3:32])=[CH:29][CH:30]=3)=[CH:17][CH:16]=2)[C:11](=[O:12])[N:4]([CH3:3])[C:5]1=[O:6]
Reactant: CN1C(=O)C(C(=O)Nc2ccc(O)cc2)C(=O)N(C)C1=O
Reactant: COc1ccc(Cl)nn1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Solvent: Cc1ccccc1
Product: COc1ccc(Oc2ccc(NC(=O)C3C(=O)N(C)C(=O)N(C)C3=O)cc2)nn1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
4.0 g (0.06 mole) of 85% KOH are added to 8.7 g (0.03 mole) of 1,3-dimethyl-5-(4-hydroxyphenylcarbamoyl)barbituric acid in 70 ml of toluene and 50 ml of dimethyl sulfoxide. The mixture is dewatered with a water separator at reflux temperature. After the toluene has been distilled off, 4.3 g (0.03 mole) of 3-chloro-6-methoxypyridazine are added. The bath temperature is increased gradually until a temperature in the range from 120° to 140° C. is reached, and the mixture is kept at this temperature for 2 hours. The mixture is then cooled to 80° C., neutralised with dilute hydrochloric acid, cooled to room temperature and diluted with water. The precipitate is isolated by filtration, washed with water and dried.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[N:3]=1.[NH:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1>CS(C)=O.O>[CH3:8][C:6]1[CH:5]=[C:4]([CH3:9])[N:3]=[C:2]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[CH:7]=1
Reactant: Cc1cc(C)nc(Cl)c1
Reactant: C1CNCCN1
Solvent: CS(C)=O
Solvent: O
Product: Cc1cc(C)nc(N2CCNCC2)c1
Yield: 51.6 %

Procedure:
A solution of 2-chloro-4,6-dimethyl-pyridine (1 g, 7.09 mmol) and piperazine (2 g, 23.2 mmol) in DMSO was heated at 140° C. for 24 h. The mixture was allowed to cool, diluted with water and extracted with ethyl acetate. The combined extracts were washed with water and brine, dried over anhydrous sodium sulfate and concentrated in vacuo to give a residue which was purified by column chromatography on silica gel (60-120 mesh), eluting with 5% methanol/chloroform to afford 1-(4,6-dimethyl-pyridin-2-yl)-piperazine (0.7 g, 52%).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=1.[Cl:13][C:14]1[C:15]([C:31]#[N:32])=[C:16]([CH:28]=[CH:29][CH:30]=1)[O:17][C:18]1[CH:23]=[CH:22][C:21]([S:24](Cl)(=[O:26])=[O:25])=[CH:20][CH:19]=1>>[Cl:13][C:14]1[C:15]([C:31]#[N:32])=[C:16]([CH:28]=[CH:29][CH:30]=1)[O:17][C:18]1[CH:19]=[CH:20][C:21]([S:24]([NH:1][C:2]2[S:3][CH:4]=[C:5]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=2)(=[O:25])=[O:26])=[CH:22][CH:23]=1
Reactant: N#Cc1c(Cl)cccc1Oc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCOC(=O)Cc1csc(N)n1
Product: CCOC(=O)Cc1csc(NS(=O)(=O)c2ccc(Oc3cccc(Cl)c3C#N)cc2)n1

Procedure:
The title compound was prepared from ethyl 2-amino-4-thiazolylacetate and 4-(3-chloro-2-cyanophenoxy)benzenesulfonyl chloride as described in the synthetic METHOD B to give a white solid (41.4 mg) with purity >90%. LCMS (pos) m/z 478.0.
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[CH:5][N:6]=1.F[C:8]1[CH:18]=[CH:17][C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:10][CH:9]=1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[CH3:1][C:2]1[N:3]([C:8]2[CH:18]=[CH:17][C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:10][CH:9]=2)[CH:4]=[CH:5][N:6]=1
Reactant: CCOC(=O)c1ccc(F)cc1
Reactant: Cc1ncc[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CCOC(=O)c1ccc(-n2ccnc2C)cc1
Temperature: 120 °C
Yield: 34 %

Procedure:
A mixture of 2-methylimidazole (50 g, 0.6 mol), ethyl 4-fluorobenzoate (100 g, 0.6 mol) and potassium carbonate (415 g, 3 mol) in dry DMSO (1.5 l ) was heated at 120° C. for 66 hours under a nitrogen atmosphere. After cooling to room temperature, the reaction mixture was poured into ice-cold water (1 l), and extracted with Et2O (750 ml×2). The organic phase was washed with water (500 ml) and brine (500 ml), dried over MgSO4 and evaporated. The residual solid was recrystallized from ethyl acetate-hexane to give the tided compound (47 g, 33%) as yellow needles.
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([NH:8][CH3:9])=[C:4]([C:10]([OH:12])=[O:11])[CH:3]=1.[CH3:13][O-:14].[Na+]>CO>[CH3:13][O:14][C:2]1[N:7]=[N:6][C:5]([NH:8][CH3:9])=[C:4]([C:10]([OH:12])=[O:11])[CH:3]=1
Reactant: C[O-]
Reactant: CNc1nnc(Cl)cc1C(=O)O
Agent: [Na+]
Solvent: CO
Product: CNc1nnc(OC)cc1C(=O)O
Yield: 21.6 %

Procedure:
A solution of 6-chloro-3-methylamino-pyridazine-4-carboxylic acid (80 mg, 0.43 mmol), sodium methoxide solution (5.4 M in methanol, 1.0 mL, 5.4 mmol) in methanol (1 mL) was heated at 170° C. for 20 min. After cooling, the solution was evaporated, the residue dissolved in water (2 mL) and acidified to pH 3 by addition of 37% aq. hydrochloric acid solution. The precipitate was collected by filtration to afford the title compound (17 mg, 22%). White solid, MS (ISP): 182.1 (M−H)−.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C@H:11]([NH:14][C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:16])[C@H:10]([C:25]([N:27]2[CH2:31][CH2:30][S:29][CH2:28]2)=[O:26])[CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:18]([O:17][C:15](=[O:16])[NH:14][C@H:11]1[CH2:12][CH2:13][NH:8][CH2:9][C@H:10]1[C:25]([N:27]1[CH2:31][CH2:30][S:29][CH2:28]1)=[O:26])[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](NC(=O)OCc2ccccc2)[C@H](C(=O)N2CCSC2)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(N[C@H]1CCNC[C@H]1C(=O)N1CCSC1)OCc1ccccc1
Temperature: 25 °C
Yield: 102.9 %

Procedure:
(3R, 4S)-4-Benzyloxycarbonylamino-3-(thiazolidine-3-carbonyl)-piperidine-1-carboxylic acid tert-butyl ester (325 mg) was dissolved in abs. DCM (12 ml) and TFA (0.44 ml) was added dropwise. The resulting mixture was then allowed to stir at RT over night and was then evaporated. The residue was transferred into ice/brine, basified to pH 10 with 2N NaOH and extracted with ethyl acetate. The organic layer was washed with brine, dried (Na2SO4) and evaporated to give a residue that was purified by flash chromatography to give the desired product as a white foam (260 mg). MS (ESI): 350.1 MH+).
Reaction SMILES: CC1C(C)=C(C)C(C)=[N+]([O-])C=1.Cl[O-].[Na+].[CH3:15][C:16]1[C:21]([CH:22]([OH:27])[C:23]([O:25][CH3:26])=[O:24])=[CH:20][CH:19]=[CH:18][N:17]=1.[K+].[Br-]>C(Cl)Cl.O>[CH3:15][C:16]1[C:21]([C:22](=[O:27])[C:23]([O:25][CH3:26])=[O:24])=[CH:20][CH:19]=[CH:18][N:17]=1
Reactant: COC(=O)C(O)c1cccnc1C
Agent: Cc1c[n+]([O-])c(C)c(C)c1C
Agent: [Br-]
Agent: [K+]
Solvent: O
Solvent: ClCCl
Product: COC(=O)C(=O)c1cccnc1C
Reaction time: 1 h
Yield: 76.7 %

Procedure:
A pinch of tetramethylpyridine N-oxide and 10 ml of 12.5% strength sodium hypochlorite solution are added to a stirred mixture of 3 g (16 mmol) of methyl (2-methylpyrid-3-yl)-α-hydroxyacetate (Example 1b) in 20 ml of methylene chloride and 0.5 g (3.5 mmol) of Na2HPO4, 0.6 g (5 mmol) of NaH2PO4 and 0.2 g (1.6 mmol) of KBr in 20 ml of water. Stirring is carried out for 1 hour at room temperature, after which the organic phase is separated off and evaporated down. 2.2 g (77%) of the title compound are obtained as residual yellow oil.
Reaction SMILES: [CH3:1][CH:2]1[CH2:6][S:5][CH:4]([C:7]([O:9][CH3:10])=[O:8])[C:3]1=O.[CH3:12][CH:13]([CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[CH:14]([C:16]1[CH:17]=C(O)[CH:19]=[C:20]([CH:22]=1)[OH:21])[CH3:15].P(Cl)(Cl)(Cl)=O.C1(C=CC=C(O)C=1)O>C1C=CC=CC=1>[OH:21][C:20]1[C:19]2[C:3]3[CH:2]([CH3:1])[CH2:6][S:5][C:4]=3[C:7](=[O:8])[O:9][C:10]=2[CH:17]=[C:16]([CH:14]([CH:13]([CH3:12])[CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[CH3:15])[CH:22]=1
Reactant: CCCCCC(C)C(C)c1cc(O)cc(O)c1
Reactant: COC(=O)C1SCC(C)C1=O
Agent: Oc1cccc(O)c1
Solvent: O=P(Cl)(Cl)Cl
Solvent: c1ccccc1
Product: CCCCCC(C)C(C)c1cc(O)c2c3c(c(=O)oc2c1)SCC3C

Procedure:
A solution in dry benzene of equimolar amounts of methyl 4-methyl-3-oxo-tetrahydrothiophene-2-carboxylate and 5-(3-methyl-2-octyl) resorcinol plus phosphorous oxychloride (5 ml. of benzene/g. of the resorcinol) was warmed for 13 days at 35°-37°C. in an oil bath. Most of the benzene and HCl were removed at reduced pressure, and the dark tarry residue was stirred with ether and water until solution was complete. The ether layer was washed successively with dilute solutions of sodium bicarbonate, sodium hydroxide and sodium carbonate, then with water and saturated sodium chloride. Drying and concentrating the final organic solution left a friable brick-red foamy solid.
Reaction SMILES: [F:1][C:2]1[C:9]([CH3:10])=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4]Br.[C-]#N.[Na+].[I-].[Na+].CS(C)=O.[C:20]([O:23][CH2:24][CH3:25])(=[O:22])C>O>[F:1][C:2]1[C:9]([CH3:10])=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][C:20]([O:23][CH2:24][CH3:25])=[O:22]
Reactant: CCOC(C)=O
Reactant: Cc1cccc(CBr)c1F
Agent: [C-]#N
Agent: [I-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CCOC(=O)Cc1cccc(C)c1F
Temperature: 60 °C
Reaction time: 2 h

Procedure:
A mixture of 2-fluoro-3-methylbenzyl bromide (2.0 g), sodium cyanide (2.41 g), sodium iodide (148 mg) and DMSO (10 ml) was stirred at 60° C. for two hours. Water and ethyl acetate were added to the reaction solution, and the organic layer was separated. The organic layer was washed with brine. The resulting organic layer was dried over anhydrous magnesium sulfate. The organic layer was concentrated under reduced pressure. 5 N hydrochloric acid (15 ml) was added to the residue, and the reaction solution was heated at 110° C. for 22 hours. The reaction solution was brought to room temperature. Chloroform was added and the organic layer was separated. The organic layer was concentrated under reduced pressure. Saturated hydrogen chloride-ethanol (15 ml) was added to the residue, and the reaction solution was stirred at 85° C. for four hours. The reaction solution was concentrated under reduced pressure, and then diluted with ethyl acetate and washed with saturated sodium bicarbonate water and then with brine. The resulting organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain the title compound (1.1 g). The property values of the compound are as follows.
Reaction SMILES: [N+](=[CH:3][C:4]([O:6][CH2:7]/[CH:8]=[CH:9]/[C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:18])=[CH:12][C:11]=1[F:27])=[O:5])=[N-]>C1(C)C=CC=CC=1>[F:27][C:11]1[CH:12]=[C:13]([NH:16][C:17](=[O:18])[O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:14]=[CH:15][C:10]=1[C@H:9]1[C@H:3]2[C@@H:8]1[CH2:7][O:6][C:4]2=[O:5]
Reactant: [N-]=[N+]=CC(=O)OC/C=C/c1ccc(NC(=O)OCc2ccccc2)cc1F
Solvent: Cc1ccccc1
Product: O=C(Nc1ccc([C@@H]2[C@H]3COC(=O)[C@H]32)c(F)c1)OCc1ccccc1

Procedure:
A solution of (2E)-3-(4-{[(benzyloxy)carbonyl]amino}-2-fluorophenyl)prop-2-enyl diazoacetate (2.26 g, 6.12 mmol) in toluene (125 mL) was added dropwise over 14 h to a refluxing solution of bis-(N-t-butylsalicylaldiminato)copper(II) (0.254 g, 0.61 mmol, prepared as described by R. G. Charles, J. Org. Chem. 1957, 22, 677) in 125 mL of toluene. After the addition was complete, the reaction mixture was heated another hour at reflux, then cooled, filtered and concentrated. The crude oil was purified by column chromatography (0-0.5% MeOH-DCM) to provide the title compound as a yellow solid.
Reaction SMILES: [BH4-].[Li+].[C:3]([O:7][C:8]([NH:10][C@H:11]1[CH2:16][CH2:15][C@H:14]([C:17](OC)=[O:18])[CH2:13][CH2:12]1)=[O:9])([CH3:6])([CH3:5])[CH3:4].C(O)(=O)CC(CC(O)=O)(C(O)=O)O.[OH-].[Na+]>C(OC)(C)(C)C.O1CCCC1>[OH:18][CH2:17][C@H:14]1[CH2:13][CH2:12][C@H:11]([NH:10][C:8](=[O:9])[O:7][C:3]([CH3:5])([CH3:4])[CH3:6])[CH2:16][CH2:15]1
Reactant: COC(=O)[C@H]1CC[C@H](NC(=O)OC(C)(C)C)CC1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [BH4-]
Agent: [Li+]
Solvent: COC(C)(C)C
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@H](CO)CC1

Procedure:
1.56 g lithium borohydride are placed in 25 ml abs. tetrahydrofuran. A solution of 15.9 g (61 mmol) methyl trans-4-tert-butoxycarbonylamino-cyclohexanecarboxylate in 25 ml abs. tetrahydrofuran is added dropwise to this suspension. This suspension is refluxed for 50 min. After the reaction mixture has cooled it is carefully added dropwise to 25 ml of 0.6 N citric acid solution. Then 30 ml tert-butylmethylether are added, the solution is made alkaline with sodium hydroxide solution and the organic phase is separated off, washed and evaporated down.
Reaction SMILES: C(OC([NH:8][C:9]([NH:18][CH2:19][CH2:20][CH2:21][N:22]1[C:26]([C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=2)=[CH:25][S:24][C:23]1=[N:34][C:35]1[CH:40]=[CH:39][C:38]([F:41])=[CH:37][CH:36]=1)=[N:10]C(OC(C)(C)C)=O)=O)(C)(C)C.Cl>>[F:33][C:30]1[CH:31]=[CH:32][C:27]([C:26]2[N:22]([CH2:21][CH2:20][CH2:19][NH:18][C:9]([NH2:10])=[NH:8])[C:23](=[N:34][C:35]3[CH:40]=[CH:39][C:38]([F:41])=[CH:37][CH:36]=3)[S:24][CH:25]=2)=[CH:28][CH:29]=1
Reactant: CC(C)(C)OC(=O)N=C(NCCCn1c(-c2ccc(F)cc2)csc1=Nc1ccc(F)cc1)NC(=O)OC(C)(C)C
Agent: Cl
Product: N=C(N)NCCCn1c(-c2ccc(F)cc2)csc1=Nc1ccc(F)cc1

Procedure:
The compound (1.12 g) obtained in the above (1) was treated in a similar manner to in Example 9 (2) to give the title compound (905 mg) as hydrochloride.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:7]=[C:6]([C:8]2[N:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[O:5][N:4]=1.C(N(CC)CC)C.[CH3:21][S:22](Cl)(=[O:24])=[O:23]>ClCCl>[CH3:21][S:22]([O:1][CH2:2][C:3]1[CH:7]=[C:6]([C:8]2[N:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[O:5][N:4]=1)(=[O:24])=[O:23]
Reactant: CS(=O)(=O)Cl
Reactant: OCc1cc(-c2ncccn2)on1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCc1cc(-c2ncccn2)on1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a mixture of 2-(3-hydroxymethyl-isoxazol-5-yl)-pyrimidine (14 gm) and triethylamine (22 ml) in dichloromethane (400 ml), was added methanesulfonyl chloride (7.2 ml) at 0° C. The reaction mixture was stirred at 0° C. over a period of 0.5 h. The reaction was quenched by addition of water and layers were separated. Organic layer was evaporated under vacuum to provide title compound in 19.7 gm quantity (97.7%) as a yellow solid. This was used as such for the next reaction.
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([I:15])=[CH:11][C:10]=2[F:16])=[C:6]([CH3:17])[C:5](=[O:18])[N:4]2[CH2:19][CH2:20][S:21][C:3]=12.[CH:22]1([S:26](Cl)(=[O:28])=[O:27])[CH2:25][CH2:24][CH2:23]1>N1C=CC=CC=1>[F:16][C:10]1[CH:11]=[C:12]([I:15])[CH:13]=[CH:14][C:9]=1[NH:8][C:7]1[C:2]([NH:1][S:26]([CH:22]2[CH2:25][CH2:24][CH2:23]2)(=[O:28])=[O:27])=[C:3]2[S:21][CH2:20][CH2:19][N:4]2[C:5](=[O:18])[C:6]=1[CH3:17]
Reactant: Cc1c(Nc2ccc(I)cc2F)c(N)c2n(c1=O)CCS2
Reactant: O=S(=O)(Cl)C1CCC1
Solvent: c1ccncc1
Product: Cc1c(Nc2ccc(I)cc2F)c(NS(=O)(=O)C2CCC2)c2n(c1=O)CCS2
Yield: 14 %

Procedure:
Using the same reaction conditions and workup as described for the preparation of Example 19A, 8-amino-7-(2-fluoro-4-iodo-phenylamino)-6-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one (I-19f: 0.1 g, 0.23 mmol) in pyridine (2 mL) was reacted with cyclobutanesulfonyl chloride (0.04 g, 0.20 mmol) to afford the crude product. Purification by preparative HPLC afforded 15 mg of the product (12% yield).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N+:16]([O-])=O)[C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[O:14][CH3:15])=[N:6][CH:7]=1.O.O.[Sn](Cl)Cl>CCOC(C)=O>[Br:1][C:2]1[CH:3]=[C:4]([NH2:16])[C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[O:14][CH3:15])=[N:6][CH:7]=1
Reactant: COc1ccccc1-c1ncc(Br)cc1[N+](=O)[O-]
Agent: Cl[Sn]Cl
Solvent: CCOC(C)=O
Solvent: O
Product: COc1ccccc1-c1ncc(Br)cc1N
Temperature: 70 °C
Reaction time: 19 h

Procedure:
To a stirred mixture of 5-bromo-2-(2-methoxyphenyl)-3-nitropyridine (0.2618 g, 0.85 mmol) in EtOAc (10.0 mL) was added tin(II) chloride dihydrate (0.9667 g, 4.28 mmol) in portions. Upon complete addition of the reducing agent, the mixture was carefully heated to 70° C. After 19 h, the reaction was cooled to rt and diluted with EtOAc, then washed with 1M NaOH, water, and brine. After drying over anhydrous sodium sulfate, filtration, and concentration, the residue was identified as 5-bromo-2-(2-methoxyphenyl)pyridin-3-amine. 1H NMR (500 MHz, CDCl3) δ ppm 8.19 (1H, d, J=2.0 Hz), 7.46 (2H, m), 7.24 (1H, d, J=1.2 Hz), 7.14 (1H, m), 7.03 (1H, d, J=8.3 Hz), 3.84 (3H, s).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[N:9]([CH:11]1[CH2:15][CH2:14][CH2:13][CH2:12]1)[N:8]=[C:7]2[C:16]1[CH:21]=[CH:20][C:19]([O:22]C)=[CH:18][C:17]=1[CH3:24].B(Br)(Br)Br.C1CCCCC=1>>[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[N:9]([CH:11]1[CH2:15][CH2:14][CH2:13][CH2:12]1)[N:8]=[C:7]2[C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][C:17]=1[CH3:24]
Reactant: COc1ccc(-c2nn(C3CCCC3)c3c(Cl)cccc23)c(C)c1
Agent: BrB(Br)Br
Solvent: C1=CCCCC1
Product: Cc1cc(O)ccc1-c1nn(C2CCCC2)c2c(Cl)cccc12
Yield: 41.2 %

Procedure:
Prepared according to Method D step C from 7-chloro-1-cyclopentyl-3-(4-methoxy-2-methylphenyl)-1H-indazole (0.090 g, 0.26 mmol), boron tribromide (0.100 mL, 1.0 mmol) and 1.0 mL of cyclohexene to give the product (0.035 g) as a white solid.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:13]([CH3:14])[N:12]=[C:11]([C:15](=O)[CH3:16])[C:10]=2[OH:18])=[CH:5][CH:4]=1)[CH3:2].[NH:19]([C:21]([NH:23][C:24]1[CH:32]=[CH:31][C:27]([C:28]([OH:30])=[O:29])=[CH:26][CH:25]=1)=[S:22])[NH2:20].CN(C)C=O>Cl.O>[CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:13]([CH3:14])[N:12]=[C:11]([C:15](=[N:20][NH:19][C:21]([NH:23][C:24]3[CH:32]=[CH:31][C:27]([C:28]([OH:30])=[O:29])=[CH:26][CH:25]=3)=[S:22])[CH3:16])[C:10]=2[OH:18])=[CH:5][CH:4]=1)[CH3:2]
Reactant: NNC(=S)Nc1ccc(C(=O)O)cc1
Reactant: CCc1ccc(-c2c(O)c(C(C)=O)nn2C)cc1
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Product: CCc1ccc(-c2c(O)c(C(C)=NNC(=S)Nc3ccc(C(=O)O)cc3)nn2C)cc1
Yield: 72.7 %

Procedure:
1-[5-(4-Ethylphenyl)-1-methyl-4-hydroxy-1H-pyrazol-3-yl]ethanone (0.159 mmol, 38.8 mg) and 4-hydrazinocarbonothioylaminobenzoic acid (0.159 mmol, 33.6 mg) were stirred with dimethylformamide (2.3 mL) and three drops of concentrated hydrochloric acid at room temperature for 23.5 hours. After addition of water, the precipitated yellow solid was recovered by filtration, washed with water and dried by means of a vacuum pump. The resulting solid was stirred with chloroform/n-hexane for a while, then recovered by filtration and dried by means of a vacuum pump to give the desired product as a pale yellow solid (50.6 mg, yield 73%).