Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:26]#[C:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[CH:8][C:9]=1[N:10]1[CH:15]([CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)[CH2:14][CH2:13][C@@H:12]([CH2:22][CH:23]=C)[C:11]1=[O:25])=[O:4].C[N+]1([O-])CC[O:36]CC1.O>CC(C)=O.O=[Os](=O)(=O)=O>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:26]#[C:27][C:28]([CH3:30])([CH3:29])[CH3:31])=[CH:8][C:9]=1[N:10]1[CH:15]([CH:16]2[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]2)[CH2:14][CH2:13][C@@H:12]([CH2:22][CH2:23][OH:36])[C:11]1=[O:25])=[O:4]
Reactant: C=CC[C@@H]1CCC(C2CCCCC2)N(c2cc(C#CC(C)(C)C)sc2C(=O)OC)C1=O
Reactant: C[N+]1([O-])CCOCC1
Agent: O=[Os](=O)(=O)=O
Solvent: CC(C)=O
Solvent: O
Product: COC(=O)c1sc(C#CC(C)(C)C)cc1N1C(=O)[C@H](CCO)CCC1C1CCCCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 60 %

Procedure:
To a solution of 3-((S)-3-allyl-6-cyclohexyl-2-oxo-piperidin-1-yl)-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylic acid methyl ester (less polar diastereomer from previous step) (200 mg, 0.45 mmol, 1.0 equiv) in acetone (3.0 mL) at 0° C. was added N-methylmorpholine oxide (160 mg, 1.36 mmol, 3 equiv), water (1.0 mL) and OsO4 (230 mg, 0.02 mmol, 0.05 equiv). The reaction mixture was stirred at room temperature for 1 hour. The solution was partitioned between brine and EtOAc. The phases were separated and the organic layer was dried over Na2SO4, and concentrated under vacuum. The residue was dissolved in THF/water (3.0 mL/1.0 mL). To the solution was added NaIO4 (194 mg, 0.9 mmol, 2 equiv), and the resulting mixture was stirred at room temperature for 30 minutes, after which another portion of NaIO4 (0.5 equiv) was added. After stirred at room temperature for 30 minutes, the mixture was partitioned between brine and EtOAc. The organic layer was separated, dried over Na2SO4, and concentrated. The residue was dissolved in EtOH (3.0 ml) and the solution was cooled at 0° C. To the solution was added NaBH4 and the mixture was stirred at 0° C. for 15 minutes. The reaction was quenched by addition of water (2.0 mL) and EtOAc (10.0 mL). The organic layer was separated, dried over Na2SO4, and concentrated. The residue was purified by silica gel column chromatography, Heptane/EtOAc 1/1 to give 123 mg of the product (yield 60%). MS: 446 [M+H+]
Reaction SMILES: CC(C)([O-])C.[K+].[NH:7]1[CH2:11][CH2:10][CH2:9][C:8]1=[O:12].[C:13]1([CH2:19][S:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[CH2:27]Cl)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.O>CN(C)C=O>[C:13]1([CH2:19][S:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[CH2:27][N:7]2[CH2:11][CH2:10][CH2:9][C:8]2=[O:12])[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: O=C1CCCN1
Reactant: ClCc1ccccc1SCc1ccccc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C1CCCN1Cc1ccccc1SCc1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of 1.35 g of potassium-tert-butoxide in 25 mL of dimethylformamide, cooled to 0° C., was added 0.92 mL of 2-pyrrolidinone. As a white precipitate formed, the mixture was stirred for 10 minutes, and 3.0 g of 2-phenylmethylthio chloromethyl benzene was added in one portion. The resulting solution was allowed to warm to room temperature, stirred for 1 hour, poured into water, and extracted with methylene chloride. The organic layer was washed well with water, dried over magnesium sulfate, filtered, and the filtrate evaporated to leave 3.0 g of a yellow oil.
Reaction SMILES: Cl.Cl[C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N+:4]=1[O-:13].[N-:14]=[N+:15]=[N-:16].[Na+].O>CC(C)=O>[N:14]([C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N+:4]=1[O-:13])=[N+:15]=[N-:16]
Reactant: [O-][n+]1c(Cl)ccc2ccccc21
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: [N-]=[N+]=Nc1ccc2ccccc2[n+]1[O-]

Procedure:
In this example, 2.00 grams (0.009 mol) of 2-chloroquinoline N-oxide hydrochloride and 2.00 grams (0.031 mol) of sodium azide were added to and dissolved in 50 ml. of water and 100 ml. of acetone and the resulting solution stirred for 72 hours at 25° C. A solid separated and was collected by filtration. Recrystallization of this solid from benzene gave 2-azidoquinoline N-oxide in a yield of 1.01 grams or 58% of theory having a melting point of 103.5° C. to 104.5° C. with decomposition.
Reaction SMILES: [C:1]1([CH2:11][NH2:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[O:13]=[C:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]([C:24](O)=[O:25])[CH2:16][CH2:15]1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[C:1]1([CH2:11][NH:12][C:24]([CH:17]2[C:18]3[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:14](=[O:13])[CH2:15][CH2:16]2)=[O:25])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: O=C1CCC(C(=O)O)c2ccccc21
Reactant: NCc1cccc2ccccc12
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: O=C1CCC(C(=O)NCc2cccc3ccccc23)c2ccccc21
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A mixture of 1-naphthalenemethylamine (1.37 g, 7.2 mmol), 4-oxo-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid (1.13 g, 7.2 mmol) ECD (2.87 g, 15 mmol), and DMAP (1.83 g, 15 mmol) in CH2Cl2 (20 mL) was stirred at room temperature. After 12 h, the reaction mixture was concentrated and the residue was purified by flash column chromatography (2-5% MeOH in CH3Cl to yield the product (2.29 g, 97% liht yellow solid, m.p. 155-156° C.).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[C:7]([O:11][CH2:12][O:13][CH3:14])[C:6]([CH3:15])=[C:5](Br)[C:4]=1[O:17][CH2:18][O:19][CH3:20].C([Li])CCC.CN(C)[CH:28]=[O:29]>CCOCC.CCCCCC>[CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[C:7]([O:11][CH2:12][O:13][CH3:14])[C:6]([CH3:15])=[C:5]([CH:28]=[O:29])[C:4]=1[O:17][CH2:18][O:19][CH3:20]
Reactant: COCOc1c(C)c(Br)c(OCOC)c(OC)c1OC
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CCCCCC
Product: COCOc1c(C)c(C=O)c(OCOC)c(OC)c1OC
Reaction time: 0.5 h
Yield: 80 %

Procedure:
To a cold solution of 2,3-dimethoxy-5-methyl-1,4-bismethoxymethyloxy-6-bromobenzene [oily substance, δ 2.34 (3H), 3.57 (3H), 3.64 (3H), 3.84 (6H), 5.01 (2H), 5.09 (2H)] (9.00 g, 25.6 mmol) in absolute ether (90 ml) was added a solution of 15% n-butyllithium in hexane (17.6 ml). The mixture was stirred for 30 minutes. Dimethylformamide (9.36 g, 128 mmol) was added and the reaction was continued under the same conditions for 30 minutes. Working up in a conventional manner gave 2,3-dimethoxy-5-methyl-1,4-bismethoxymethyloxy-6-formylbenzene [oily substance, δ 2.48 (3H), 3.55 (3H), 3.58 (3H), 3.85 (3H), 3.95 (3H), 4.99 (2H), 5.13 (2H)]. Yield 80%.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[CH:10][C:11]([NH2:14])=[N:12][CH:13]=2)=[C:4]([F:15])[CH:3]=1.[C:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1B(O)O)#[N:17]>>[NH2:14][C:11]1[N:12]=[CH:13][C:8]([C:5]2[CH:6]=[CH:7][C:2]([C:19]3[C:18]([C:16]#[N:17])=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:3][C:4]=2[F:15])=[N:9][CH:10]=1
Reactant: Nc1cnc(-c2ccc(Br)cc2F)cn1
Reactant: N#Cc1ccccc1B(O)O
Product: N#Cc1ccccc1-c1ccc(-c2cnc(N)cn2)c(F)c1

Procedure:
The title compound was prepared using conditions analogous to those used to make Example 6 utilizing 5-(4-bromo-2-fluorophenyl)pyrazin-2-amine and (2-cyanophenyl)boronic acid. MS (ESI): mass calcd. for C17H11FN4, 290.10; m/z found, 291.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.42 (s, 1H), 8.05-7.98 (m, 3H), 7.83 (m, 1H), 7.71 (d, J=7.6, 1H), 7.66-7.47 (m, 3H), 6.77 (s, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.[CH2:12]([N:14]([CH2:37][CH3:38])[CH2:15][CH2:16][CH2:17][NH:18][C:19]([C:21]1[C:25]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[C:24]([CH:32]=O)[NH:23][C:22]=1[CH:34]([CH3:36])[CH3:35])=[O:20])[CH3:13]>>[CH2:37]([N:14]([CH2:12][CH3:13])[CH2:15][CH2:16][CH2:17][NH:18][C:19]([C:21]1[C:25]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[C:24]([CH:32]=[C:5]2[C:4]3[C:8](=[CH:9][CH:10]=[C:2]([Br:1])[CH:3]=3)[NH:7][C:6]2=[O:11])[NH:23][C:22]=1[CH:34]([CH3:36])[CH3:35])=[O:20])[CH3:38]
Reactant: CCN(CC)CCCNC(=O)c1c(C(C)C)[nH]c(C=O)c1-c1ccccc1
Reactant: O=C1Cc2cc(Br)ccc2N1
Product: CCN(CC)CCCNC(=O)c1c(C(C)C)[nH]c(C=C2C(=O)Nc3ccc(Br)cc32)c1-c1ccccc1
Yield: 71 %

Procedure:
5-Bromo-1,3-dihydroindol-2-one (120 mg, 0.31 mmol) was condensed with 5-formyl-2-isopropyl-4-phenyl-1H-pyrrole-3-carboxylic acid (3-diethylaminopropyl)amide (prepared by method C) to give 120 mg (71%) of the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][CH2:10][C@@H:9]1[CH2:12][OH:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N([CH2:19][CH3:20])CC)C.[C:21]1(C)[CH:26]=C[C:24]([S:27](Cl)(=[O:29])=[O:28])=[CH:23][CH:22]=1.[OH-].[Na+]>ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:11][CH2:10][C@@H:9]1[CH2:12][O:13][S:27]([C:24]1[C:19]([CH3:20])=[CH:26][CH:21]=[CH:22][CH:23]=1)(=[O:29])=[O:28])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCN(CC)CC
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H]1CO
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: Cc1ccccc1S(=O)(=O)OC[C@H]1CCN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 94.8 %

Procedure:
A solution of (R)-1-t-butyloxycarbonyl-2-azetidinemethanol (36.5 g, 0.195 mol) in 195 mL of dichloromethane was treated with triethylamine (35.6 ml, 0.255 mol) and then p-toluenesulfonyl chloride (48.5 g, 0.254 mol). The resulting mixture was stirred at room temperature for 16 hours. A 10% solution of sodium hydroxide was added rapidly and the mixture stirred for one hour. After phase separation, the aqueous phase was extracted with additional dichloromethane, combined with the organic phase, washed with NaHCO3 solution and brine, then dried (MgSO4), filtered, and concentrated in vacuo to give 63.1 g of (R)-1-t-butyloxycarbonyl-2-toluensulfonyloxymethylazetidine (94.8%). Next, a solution of 2-chloro-5-hydroxypyridine (from Step 1g below, 24 g, 0.185 mol) in DMF (690 mL) was treated with ground KOH (17.95 g, 0.295 mol) and stirred for 30 minutes at 80° C. To this mixture was rapidly added (2R)-1-t-butyloxycarbonyl)-2-toluensulfonyloxymethylazetidine (63.1 g) dissolved in DMF (395 mL) and the mixture was stirred for 16 hours at 80° C. The mixture was concentrated in vacuo to remove the DMF and the resultant residue was diluted with water and extracted with EtOAc (3×). The organic extracts were combined, dried (MgSO4), filtered and concentrated in vacuo to give 58.5 g of unpurified product. This material was chromatographed (silica gel, 25% EtOAc in hexane) to give 43.2 g of 5-(1-t-butyloxycarbonyl-(2R)-azetidinylmethyloxy)-2-chloropyridine as a clear oil (74%). A solution of 5-(1-t-butyloxycarbonyl-(2R)-azetidinylmethoxy)-2-chloropyridine (30 g, 0.1 mol) in 450 mL of dichloromethane at 0° C. was treated with 225 mL of trifluoroacetic acid dropwise over a 30 minute period. After two hours, the bulk of the solvent was removed in vacuo and the residue was diluted with ethyl acetate, washed with 1.0 M K2CO3 and brine, dried (Na2SO4) and concentrated in vacuo to give 19.1 g of a yellow oil. Flash silica gel chromatography (90:10 CHCl3 :MeOH then 90:10:0.5 CHCl3 :MeOH:NH4OH) gave 16.5 g of the title compound (83% yield): MS (CI/NH3) m/z: 199 (M+H)+ ; 1H NMR (CDCl3, 300 MHz) δ 2.21-2.43 (m, 2H), 3.42-3.50 (m, 1H), 3.69-3.78 (m, 1H), 3.98-4.07 (m, 2H), 4.25-4.34 (m, 1H), 7.22 (d, J=1.7 Hz, 2H), 8.07 (dd, 1.7, 2.0 Hz, 1H).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:4]=[C:5]([CH2:9][C:10]([O:12][CH3:13])=[O:11])[CH:6]=[CH:7][CH:8]=1.[Br:16]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>C(Cl)(Cl)(Cl)Cl.C(N(CC)CC)C>[Br:16][CH:9]([C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:14])([F:15])[F:1])[CH:4]=1)[C:10]([O:12][CH3:13])=[O:11]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)Cc1cccc(C(F)(F)F)c1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: CCN(CC)CC
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)C(Br)c1cccc(C(F)(F)F)c1
Reaction time: 3 h

Procedure:
To the solution of 21.8 g of methyl m-trifluoromethylphenylacetate in 450 ml of carbon tetrachloride a portion of 18.7 g of N-bromosuccinimide is added along with several drops of triethylamine and a pinch of azobisisobutyronitrile. The mixture is warmed to reflux with a 250 watt incandescent bulb and a precipitate is formed. Thereupon the remainder of N-bromosuccinimide is added, the light removed and the solution stirred for 3 hours. It is cooled in an ice bath and the solid formed removed by filtration. The filtrate is evaporated the residue dissolved in diethyl ether-water and the organic phase washed with aqueous sodium bicarbonate and water. It is dried, evaporated, the residue distilled and the fraction boiling at 85°-88°/0.4 mmHg collected, to yield the methyl α-bromo-m-trifluoromethylphenylacetate.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][CH2:10][C:11](Cl)=[O:12])[CH:6]=[CH:7][CH:8]=1.[F:14][C:15]1[CH:21]=[CH:20][C:18]([NH2:19])=[CH:17][CH:16]=1>>[F:14][C:15]1[CH:21]=[CH:20][C:18]([NH:19][C:11](=[O:12])[CH2:10][CH2:9][C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=2)=[CH:17][CH:16]=1
Reactant: COc1cccc(CCC(=O)Cl)c1
Reactant: Nc1ccc(F)cc1
Product: COc1cccc(CCC(=O)Nc2ccc(F)cc2)c1
Yield: 97.2 %

Procedure:
The title compound was prepared as described in Example 1.A, using 3-methoxyphenylpropionylchloride (6.62 g, 33.3 mmol) and 4-fluoroaniline (3.70 g, 33.3 mmol) to afford N-(4-fluorophenyl)-3-(3-methoxyphenyl)propanamide (8.85 g, 97% yield): ES-MS (m/z) 273.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][CH3:9])[N:5]=[C:4]([NH:10][NH:11][C:12](=[O:32])[C@H:13]([CH2:26][CH:27]2[CH2:31][CH2:30][CH2:29][CH2:28]2)[CH2:14][N:15]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:16]=[O:17])[C:3]=1[F:33].Cl.[NH2:35][C@@H:36]([CH2:42][CH3:43])[C:37]([N:39]([CH3:41])[CH3:40])=[O:38].C(N(C(C)C)CC)(C)C>CS(C)=O>[CH:27]1([CH2:26][C@H:13]([CH2:14][N:15]([CH:16]=[O:17])[O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:12]([NH:11][NH:10][C:4]2[N:5]=[C:6]([O:8][CH3:9])[N:7]=[C:2]([NH:35][C@@H:36]([CH2:42][CH3:43])[C:37]([N:39]([CH3:41])[CH3:40])=[O:38])[C:3]=2[F:33])=[O:32])[CH2:31][CH2:30][CH2:29][CH2:28]1
Reactant: COc1nc(Cl)c(F)c(NNC(=O)[C@H](CC2CCCC2)CN(C=O)OCc2ccccc2)n1
Reactant: CC[C@H](N)C(=O)N(C)C
Agent: Cl
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC[C@H](Nc1nc(OC)nc(NNC(=O)[C@H](CC2CCCC2)CN(C=O)OCc2ccccc2)c1F)C(=O)N(C)C
Temperature: 80 °C
Reaction time: 168 h
Yield: 22.4 %

Procedure:
[(2R)-3-{2-[6-Chloro-5-fluoro-2-(methyloxy)-4-pyrimidinyl]hydrazino}-2-(cyclopentylmethyl)-3-oxopropyl][(phenylmethyl)oxy]formamide (0.133 g, 0.28 mmol), (2S)-2-amino-N,N-dimethylbutanamide, hydrochloride salt (Example 83) (0.075 g, 0.45 mmol) and diisopropylethylamine (0.1 mL, 0.62 mmol) were stirred in DMSO (2 mL) overnight at 65° C. Then additional diisopropylethylamine (0.2 mL) was added, and the reaction was stirred for 7 days at 80° C. Purified by RP-HPLC to provide (2S)-2-{[6-{2-[(2R)-3-cyclopentyl-2-({formyl[(phenylmethyl)oxy]amino}methyl)propanoyl]hydrazino}-5-fluoro-2-(methyloxy)-4-pyrimidinyl]amino}-N,N-dimethylbutanamide (0.036 g, 23%). LCMS: (M+H)+=574.3.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[C:9]=1[OH:10])[CH:5]=O.[CH:14]1([C:17](=[O:24])[CH2:18][C:19]([CH:21]2[CH2:23][CH2:22]2)=[O:20])[CH2:16][CH2:15]1.N1CCCCC1>C(O)(=O)C>[CH:21]1([C:19](=[O:20])[C:18](=[CH:5][C:4]2[CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[C:9]([OH:10])=[C:2]([OH:1])[CH:3]=2)[C:17]([CH:14]2[CH2:15][CH2:16]2)=[O:24])[CH2:22][CH2:23]1
Reactant: O=Cc1cc(O)c(O)c([N+](=O)[O-])c1
Reactant: O=C(CC(=O)C1CC1)C1CC1
Solvent: CC(=O)O
Solvent: C1CCNCC1
Product: O=C(C(=Cc1cc(O)c(O)c([N+](=O)[O-])c1)C(=O)C1CC1)C1CC1

Procedure:
A mixture containing 2.75 g of 3,4-dihydroxy-5-nitrobenzaldehyde, 3.8 g of 1,3-dicyclopropyl-l,3-propanedione, 0.2 ml of piperidine and 0.4 ml of acetic acid was refluxed for 1 h with a Dean-Stark separator. After cooling the product was filtered and recrystallized from acetic acid. Yield 2.85 g, mp 159°-162° C.
Reaction SMILES: C([O:3][C:4](=[O:34])[CH2:5][N:6]1[C:14]2[CH2:13][CH2:12][CH2:11][CH:10]([NH:15][S:16]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([NH:25][C:26](=[O:33])[C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[CH:20]=3)(=[O:18])=[O:17])[C:9]=2[CH:8]=[N:7]1)C.C(NC1C=C(S(NC2C3C=NN(CC(O)=O)C=3CCC=2)(=O)=O)C=CC=1)(=O)C1C=CC=CC=1>>[C:26]([NH:25][C:21]1[CH:20]=[C:19]([S:16]([NH:15][CH:10]2[CH2:11][CH2:12][CH2:13][C:14]3[N:6]([CH2:5][C:4]([OH:34])=[O:3])[N:7]=[CH:8][C:9]2=3)(=[O:17])=[O:18])[CH:24]=[CH:23][CH:22]=1)(=[O:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: CCOC(=O)Cn1ncc2c1CCCC2NS(=O)(=O)c1cccc(NC(=O)c2ccccc2)c1
Agent: O=C(O)Cn1ncc2c1CCC=C2NS(=O)(=O)c1cccc(NC(=O)c2ccccc2)c1
Product: O=C(O)Cn1ncc2c1CCCC2NS(=O)(=O)c1cccc(NC(=O)c2ccccc2)c1

Procedure:
Starting with [4-(3-benzoylamino-benzenesulfonylamino)-4,5,6,7-tetrahydro-indazol-1-yl]-acetic acid ethyl ester using the method analogous to the one described for example 1-1a, [4-(3-benzoylamino-benzenesulfonylamino)-6,7-dihydro-indazol-1-yl]-acetic acid (11.0 mg, 50%) as a white solid. 1H NMR (400 MHz, CD3OD) δ ppm 8.48 (s, 1 H), 7.98 (m, 3 H), 7.73-7.52 (m, 5 H), 6.79 (s, 1 H), 4.78 (s, 2 H), 4.42 (s, 1 H), 2.55 (m, 2 H), 2.04-1.77 (m, 4 H). MS cald. for C22H22N4O5S 454, obsd. (ESI+) [(M+H)+] 455.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[C:5]([CH3:10])[CH:4]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20]>C(#N)C.O>[OH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])=[C:5]([CH3:10])[CH:4]=1
Reactant: CCOC(=O)CBr
Reactant: Cc1cc(CO)ccc1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CC#N
Product: CCOC(=O)COc1ccc(CO)cc1C
Yield: 96.2 %

Procedure:
To a solution of 4-(hydroxymethyl)-2-methylphenol (7.95 g, 57 mmol) in dry acetonitrile (300 mL) at 5° C., was added cesium carbonate (20.42 g, 62 mmol) and ethyl bromoacetate (6.38 mL, 57 mmol). The resultant mixture was stirred for 3 h at 5° C. under nitrogen. The reaction mixture was diluted with water (500 mL), extracted with EtOAc (2×750 mL), dried (Na2SO4) and the solvents removed in vacuo to afford the title compound as a yellow oil (12.3 g).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:6][C:7]([CH3:9])=O.[C-:10]#[N:11].[K+]>O>[CH3:6][C:7]([N:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1)([CH3:9])[C:10]#[N:11]
Reactant: CC(C)=O
Reactant: C1CCNC1
Reactant: [C-]#N
Agent: [K+]
Solvent: O
Product: CC(C)(C#N)N1CCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 77.4 %

Procedure:
To a stirred, ice-cooled mixture of pyrrolidine (8.35 ml; 0.1 mol) and acetone (7.34 ml; 0.1 mol) was added a solution of potassium cyanide (6.51 g; 0.1 mol) in water (50 ml) dropwise over 10 min. After stirring at room temperature overnight, the crude reaction mixture was extracted with diethyl ether (2×250 ml) and the combined extracts washed with saturated brine (150 ml), dried (MgSO4), and evaporated under reduced pressure to afford the title product as a pale green liquid (10.7 g; 78%) which was used without further purification. 1H NMR (CDCl3) δ: 1.51 (6H, s), 1.80-1.90 (4H, m), 2.70-2.80 (4H, m).
Reaction SMILES: [CH2:1]([C@:3]12[CH2:11][CH2:10][C@@H:9]3[C:12]4[CH2:13][CH:14]=[C:15]([O:20]C)[CH2:16][C:17]=4[CH2:18][CH2:19][C@H:8]3[C@@H:7]1[CH2:6][CH2:5][C:4]2=[O:22])[CH3:2].CO.Cl.C(=O)(O)[O-].[Na+]>O>[CH2:1]([C@:3]12[CH2:11][CH2:10][C@@H:9]3[C@@H:12]4[C:17]([CH2:18][CH2:19][C@H:8]3[C@@H:7]1[CH2:6][CH2:5][C:4]2=[O:22])=[CH:16][C:15](=[O:20])[CH2:14][CH2:13]4)[CH3:2]
Reactant: CC[C@]12CC[C@@H]3C4=C(CC[C@H]3[C@@H]1CCC2=O)CC(OC)=CC4
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CC[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@H]43)[C@@H]1CCC2=O
Reaction time: 2 h
Yield: 81.3 %

Procedure:
Add 13β-ethyl-3-methoxy-gona-2,5(10)-dien-17-one (12.9 g.) with stirring under nitrogen to methanol (300 cc.) containing 11N hydrochloric acid (20 cc) and water (13 cc.). Stir two hours and add sodium bicarbonate (21 g.) portionwise. Filter the mixture and evaporate and filtrate to dryness. Recrystallize the residue from ethyl acetate (75 cc.) to obtain the title compound (10 g.), m.p. 158°-161° C; ultraviolet absorption peak at 240 mμ (ε17,800); infrared absorption peaks at 5.78, 6.00, 6.17 μ.
Reaction SMILES: [H-].[Na+].[N:3]1[NH:4][CH:5]=[C:6]2[CH2:10][N:9]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:8][C:7]=12.[CH:18]1([S:21](Cl)(=[O:23])=[O:22])[CH2:20][CH2:19]1.[C:25](#N)[CH3:26]>>[CH:18]1([S:21]([N:4]2[CH:5]=[C:6]3[CH2:10][N:9]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:8][C:7]3=[N:3]2)(=[O:23])=[O:22])[CH2:26][CH2:25][CH2:19][CH2:20]1.[CH:18]1([S:21]([N:3]2[C:7]3[CH2:8][N:9]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:10][C:6]=3[CH2:5][NH:4]2)(=[O:23])=[O:22])[CH2:26][CH2:25][CH2:19][CH2:20]1
Reactant: O=S(=O)(Cl)C1CC1
Reactant: CC(C)(C)OC(=O)N1Cc2c[nH]nc2C1
Reactant: CC#N
Agent: [H-]
Agent: [Na+]
Product: CC(C)(C)OC(=O)N1CC2=C(C1)N(S(=O)(=O)C1CCCC1)NC2
Product: CC(C)(C)OC(=O)N1Cc2cn(S(=O)(=O)C3CCCC3)nc2C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a suspension of sodium hydride (60% dispersion in oil, 1.55 g, 38.7 mmol) in anhydrous acetonitrile (200 mL) was added to tert-butyl 2,6-dihydropyrrolo[3,4-c]pyrazole-5(4H)-carboxylate (5.3 g, 25.5 mmol) in one portion under nitrogen at room temperature. The reaction mixture was stirred at room temperature for 2 h. To the resulting white suspension was slowly added cyclopropanesulfonyl chloride (6.9 g, 49.1 mmol) and the mixture was stirred at room temperature for 18 h, quenched with water (120 mL) and the layers were separated. The aqueous layer was then extracted with dichloromethane (2×100 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude material was purified on silica chromatography (300 g Biotage™ column) and eluted with 15-80% ethyl acetate in hexanes to yield the title compound and tert-butyl 1-(cyclopentylsulfonyl)-2,6-dihydropyrrolo[3,4-c]pyrazole-5(4H)-carboxylate as a white solid. LC/MS: 314.2 (M+1).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.Br[C:21]1[CH:26]=[C:25]([NH2:27])[CH:24]=[CH:23][N:22]=1.C([Sn](CCCC)(CCCC)[CH:33]=[CH:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)CCC>CN(C=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH:33](/[C:21]1[CH:26]=[C:25]([NH2:27])[CH:24]=[CH:23][N:22]=1)=[CH:34]\[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: CCCC[Sn](C=Cc1ccccc1)(CCCC)CCCC
Reactant: Nc1ccnc(Br)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: Nc1ccnc(/C=C/c2ccccc2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 39.2 %

Procedure:
Under inert atmosphere (Ar) a mixture of palladium-(II)-acetate (0.117 mg, 0.5 mmol) and triphenylphosphine (0.248 g, 0.9 mmol) in DMF (13 ml) was stirred for 30 min at rt. 2-Bromo-pyridin-4-ylamine (0.90 g, 5.2 mmol) (H. J. den Hertog, C. R. Kolder and W. P. Combe, Rec. Trav. Chim., 1951, 70, 591) was added followed by tributyl-styryl-stannane (3.93 g, 10 mmol). After heating at 130° C. for 15 min the solvent was evaporated and the residue partitioned between AcOEt and 3N HCl. The aqueous phase was neutralized with 6N NaOH and extracted with AcOEt. The organic phase was dried with Na2SO4, concentrated and chromatographed (SiO2 with CH2Cl2/CH3OH/NH4OH=140/10/1) to give the title compound (0.40 g, 39%) as a colorless solid. Mp. 164–165° C. (AcOEt), MS: 196 (M+).