Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[N:6]([C:7]2[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=2)[N:5]=[CH:4][CH:3]=1.[CH3:15][O:16][C:17]1[CH:24]=[CH:23][C:20]([CH2:21]O)=[CH:19][CH:18]=1>>[CH3:15][O:16][C:17]1[CH:24]=[CH:23][C:20]([CH2:21][O:1][C:2]2[N:6]([C:7]3[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=3)[N:5]=[CH:4][CH:3]=2)=[CH:19][CH:18]=1
Reactant: N#Cc1ccnc(-n2nccc2O)c1
Reactant: COc1ccc(CO)cc1
Product: COc1ccc(COc2ccnn2-c2cc(C#N)ccn2)cc1
Yield: 14 %

Procedure:
The title compound was prepared in 14% yield from 2-(5-hydroxy-1H-pyrazol-1-yl)pyridine-4-carbonitrile and 4-methoxybenzyl alcohol according to the procedure for the preparation of Example 39, part C. 1H NMR (400 MHz, CDCl3): δ 3.81 (3H, s), 5.17 (2H, s), 5.75 (1H, d, J=2.0 Hz), 6.91-6.93 (2H, m), 7.34-7.39 (3H, m), 7.57 (1H, d, J=2.0 Hz), 8.01 (1H, s), 8.69 (1H, d, J=4.8 Hz). [M+H] Calc'd for C17H14N4O2, 307; Found, 307.
Reaction SMILES: C([NH:5][S:6]([C:9]1[C:10]([C:15]2[CH:20]=[CH:19][C:18]([CH2:21][N:22]([CH2:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[C:23](=[O:30])[CH2:24][C:25]3[S:26][CH:27]=[CH:28][CH:29]=3)=[C:17]([Cl:38])[CH:16]=2)=[CH:11][CH:12]=[CH:13][CH:14]=1)(=[O:8])=[O:7])(C)(C)C.C1(OC)C=CC=CC=1>FC(F)(F)C(O)=O>[CH2:31]([N:22]([CH2:21][C:18]1[CH:19]=[CH:20][C:15]([C:10]2[C:9]([S:6]([NH2:5])(=[O:8])=[O:7])=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:16][C:17]=1[Cl:38])[C:23](=[O:30])[CH2:24][C:25]1[S:26][CH:27]=[CH:28][CH:29]=1)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: CC(C)(C)NS(=O)(=O)c1ccccc1-c1ccc(CN(Cc2ccccc2)C(=O)Cc2cccs2)c(Cl)c1
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: NS(=O)(=O)c1ccccc1-c1ccc(CN(Cc2ccccc2)C(=O)Cc2cccs2)c(Cl)c1
Yield: 127516.5 %

Procedure:
510 mg of 4′-{[benzyl-(2-thiophen-2-ylacetyl)amino]methyl}-3′-chloro-biphenyl-2-sulfonic acid t-butylamide and 110 μl of anisole are allowed to stand at RT for 18 h in 3 ml of trifluoroacetic acid. The volatile constituents are then removed in vacuo, the residue is taken up in 5 ml of toluene and volatile constituents are again removed in vacuo. 586 g of a colorless oil are obtained, which is used further without purification.
Reaction SMILES: [N:1]1([C:12](=[O:13])[C:11]2[NH:10][CH:9]=[N:8][C:7]=2[N:5]([CH3:6])[C:3]1=[O:4])[CH3:2].[N+:14]([C:17]1[CH:22]=[CH:21][C:20](CCBr)=[CH:19][CH:18]=1)([O-:16])=[O:15].[OH-].[Na+].[CH:28]([OH:31])(C)[CH3:29]>O>[CH3:2][N:1]1[C:12](=[O:13])[C:11]2[N:10]([C:20]3[CH:19]=[CH:18][C:17]([N+:14]([O-:16])=[O:15])([O:31][CH2:28][CH3:29])[CH2:22][CH:21]=3)[CH:9]=[N:8][C:7]=2[N:5]([CH3:6])[C:3]1=[O:4]
Reactant: CC(C)O
Reactant: Cn1c(=O)c2[nH]cnc2n(C)c1=O
Reactant: O=[N+]([O-])c1ccc(CCBr)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCOC1([N+](=O)[O-])C=CC(n2cnc3c2c(=O)n(C)c(=O)n3C)=CC1
Yield: 50 %

Procedure:
A mixture of 0.59 g (3.26 mmole) of theophylline, 1.5 g (6,52 mmole) of 2-(4-nitrophenyl)ethyl bromide, 0.13 g (3.26 mmole) of NaOH pellets in 4 ml of water and 8 ml of isopropanol is heated to reflux for 24 hours. After returning to 23° C., the insoluble portion is filtered and the filtrate is extracted with 25 ml of CH2Cl2. The organic phase is washed with 10 ml of water followed by 10 ml of brine. After drying over sodium sulphate, filtration and concentration to dryness, the residue is purified on a silica column (eluent: CH2Cl2/MeOH: 95/5). A white solid is obtained with a yield of 50%.
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH:5]([C:8]2[CH:35]=[CH:34][C:11]([C:12]([N:14]3[CH2:19][CH2:18][N:17]([S:20]([C:23]4[CH:32]=[CH:31][C:30]5[C:25](=[CH:26][CH:27]=[C:28]([Cl:33])[CH:29]=5)[CH:24]=4)(=[O:22])=[O:21])[CH2:16][CH2:15]3)=[O:13])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.[CH2:36]([N:38](CC)CC)[CH3:37].Cl.C(=N)(OCC)C>CO>[ClH:33].[C:36]([N:2]1[CH2:7][CH2:6][CH:5]([C:8]2[CH:35]=[CH:34][C:11]([C:12]([N:14]3[CH2:19][CH2:18][N:17]([S:20]([C:23]4[CH:32]=[CH:31][C:30]5[C:25](=[CH:26][CH:27]=[C:28]([Cl:33])[CH:29]=5)[CH:24]=4)(=[O:22])=[O:21])[CH2:16][CH2:15]3)=[O:13])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1)(=[NH:38])[CH3:37]
Reactant: O=C(c1ccc(C2CCNCC2)cc1)N1CCN(S(=O)(=O)c2ccc3cc(Cl)ccc3c2)CC1
Reactant: CCN(CC)CC
Agent: CCOC(C)=N
Agent: Cl
Solvent: CO
Product: CC(=N)N1CCC(c2ccc(C(=O)N3CCN(S(=O)(=O)c4ccc5cc(Cl)ccc5c4)CC3)cc2)CC1
Temperature: 25 °C
Reaction time: 15 h
Yield: 195 %

Procedure:
To a solution of 1-[4-(piperidin-4-yl)benzoyl]-4-(6-chloronaphthalene-2-sulfonyl)piperazine hydrochloride (40 mg) and triethylamine (156 mg) in methanol (15 ml) was added ethyl acetimidate hydrochloride (46 mg), and the solution was stirred at room temperature for 15 hours. The reaction solution was concentrated. To the residue was added 1 N sodium hydroxide solution, and the solution was extracted with dichloromethane. The extract was dried and concentrated. The residue was dissolved in ethyl acetate, to which was added 4 N hydrochloric acid in ethyl acetate. The precipitate was filtered, washed with ether and dried to give a colorless solid of the title compound (42 mg).
Reaction SMILES: [NH2:1][C@@H:2]([CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:3]([NH:5][C:6]1[N:10]([CH3:11])[N:9]=[C:8]([C:12]2[CH:17]=[CH:16][N:15]=[C:14]([Cl:18])[CH:13]=2)[CH:7]=1)=[O:4].CCN(C(C)C)C(C)C.Br[CH2:36][C:37]([O:39][CH2:40][CH3:41])=[O:38]>CN(C=O)C>[Cl:18][C:14]1[CH:13]=[C:12]([C:8]2[CH:7]=[C:6]([NH:5][C:3](=[O:4])[C@@H:2]([NH:1][CH2:36][C:37]([O:39][CH2:40][CH3:41])=[O:38])[CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[N:10]([CH3:11])[N:9]=2)[CH:17]=[CH:16][N:15]=1
Reactant: CCOC(=O)CBr
Reactant: Cn1nc(-c2ccnc(Cl)c2)cc1NC(=O)[C@@H](N)Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)CN[C@@H](Cc1ccccc1)C(=O)Nc1cc(-c2ccnc(Cl)c2)nn1C
Temperature: 0 °C
Reaction time: 16 h

Procedure:
To a 1000 ml flask was added 8.6 g of (2S)-2-amino-N-(3-(2-chloropyridin-4-yl)-1-methyl-1H-pyrazol-5-yl)-3-phenylpropanamide 1.E, 100 ml of DMF, 6.0 ml of DIEA and the reaction was cooled to 0° C. To the reaction was then added 2.8 ml of ethyl bromoacetate and the reaction was stirred at 22° C. for 16 hours at which time the crude was partitioned between 1500 ml EtAc, 2×400 ml of saturated brine, and 2×400 ml of water (Note: no product observed in aqueous layer). The organic solvent was removed by rotary evaporation and the crude purified with a silica gel column (eluting with 30% EtAc in Hexane) to give 6.3 g of ethyl 2-((S)-1-(3-(2-chloropyridin-4-yl)-1-methyl-1H-pyrazol-5-ylamino)-1-oxo-3-phenylpropan-2-ylamino)acetate 17.7.F as a white solid.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][C:2]1=[O:6].[H-].[Na+].[CH2:9]([O:11][C:12]([C:14]1[C:15](Cl)=[N:16][C:17]2[C:22]([C:23]=1[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[CH:21][C:20]([Cl:30])=[CH:19][CH:18]=2)=[O:13])[CH3:10]>C1COCC1>[CH2:9]([O:11][C:12]([C:14]1[C:15]([N:1]2[CH2:5][CH2:4][CH2:3][C:2]2=[O:6])=[N:16][C:17]2[C:22]([C:23]=1[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[CH:21][C:20]([Cl:30])=[CH:19][CH:18]=2)=[O:13])[CH3:10]
Reactant: CCOC(=O)c1c(Cl)nc2ccc(Cl)cc2c1-c1ccccc1
Reactant: O=C1CCCN1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)c1c(N2CCCC2=O)nc2ccc(Cl)cc2c1-c1ccccc1
Reaction time: 0.5 h
Yield: 6.5 %

Procedure:
To a solution of pyrrolidin-2-one (0.054 ml, 0.69 mmol) in THF in a microwave vessel under nitrogen, was added NaH (28 mg, 0.69 mmol) portion wise at 25° C. The reaction mixture was stirred for 30 min followed by the addition of a solution of 2,6-dichloro-4-phenyl-quinoline-3-carboxylic acid ethyl ester (prepared as described in example 11 step B, 200 mg, 0.58 mmol) in 2 ml THF at 25° C. Then the resulting reaction mixture was stirred for 1 h at 60° C. in a microwave. After cooling, reaction mixture was quenched with saturated aqueous NH4Cl solution and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo to afford a crude residue which was purified by flash column chromatography (eluting with 20% ethyl acetate in hexane) to obtain 6-chloro-2-(2-oxo-pyrrolidin-1-yl)-4-phenyl-quinoline-3-carboxylic acid ethyl ester (15 mg, 7%) as an off white solid. LC-MS: 395 (M+H)+.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.C(N(CC)C(C)C)(C)C.Cl[C:25]([O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:26].C(=O)(O)[O-].[Na+]>ClCCl>[CH2:28]([O:27][C:25]([NH:1][CH:2]1[CH2:3][CH2:4][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:6][CH2:7]1)=[O:26])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(NC(=O)OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 78.5 %

Procedure:
tert-Butyl 4-aminopiperidine-1-carboxylate (10 g, 49.9 mmol), N,N-diisopropylethylamine (26 ml, 149 mmol), benzyl chloroformate (8.5 ml, 59.5 mmol) and dichloromethane (dehydrated) (300 ml) were mixed under ice-cooling. The resulting mixture was stirred at room temperature for one hour. An aqueous saturated sodium bicarbonate solution was added to the reaction mixture, which was extracted with dichloromethane three times. The organic layer was washed with brine and dried over anhydrous sodium sulfate, and the solvent was distilled off. The residue was purified by silica gel column chromatography (silica gel, elution solvent: ethyl acetate/heptane) to give the title compound (13.1 g, yield 78.5%).
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([NH:9][C:10]2[CH:18]=[CH:17][CH:16]=[C:15]3[C:11]=2[C:12](=[O:32])[N:13]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([CH2:27][C:28](SC)=[NH:29])=[CH:23][CH:22]=2)[C:14]3=[O:19])=[O:8])=[CH:4][CH:3]=1.C([O-])(=O)C.[NH4+:37].[Cl-].[NH4+]>CO.C(Cl)Cl>[NH2:29][C:28](=[NH:37])[CH2:27][C:24]1[CH:25]=[CH:26][C:21]([CH2:20][N:13]2[C:12](=[O:32])[C:11]3[C:15](=[CH:16][CH:17]=[CH:18][C:10]=3[NH:9][C:7]([C:5]3[S:6][C:2]([Cl:1])=[CH:3][CH:4]=3)=[O:8])[C:14]2=[O:19])=[CH:22][CH:23]=1
Reactant: CSC(=N)Cc1ccc(CN2C(=O)c3cccc(NC(=O)c4ccc(Cl)s4)c3C2=O)cc1
Reactant: [NH4+]
Agent: CC(=O)[O-]
Agent: [Cl-]
Solvent: ClCCl
Solvent: CO
Product: N=C(N)Cc1ccc(CN2C(=O)c3cccc(NC(=O)c4ccc(Cl)s4)c3C2=O)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
320 mg (0.661 mmol) of methyl 2-{4-[(4-{[(5-chloro-2-thienyl)carbonyl]amino}-1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]phenyl}ethaneimidothioate are suspended in 40 ml of methanol, and 153 mg (1.98 mmol) of ammonium acetate and 106 mg (1.98 mmol) of ammonium chloride are added. The mixture is stirred at room temperature overnight, diluted with methanol and methylene chloride until a clear solution is formed and adsorbed on silica gel. Chromatography on silica gel (CH2Cl2/EtOH=10/1 to 3/1) gives the desired compound. The product is dissolved in methanol and methylene chloride, and trifluoroacetic acid is added. Removal of the solvent under reduced pressure gives 298 mg (80% of theory) of the desired product as trifluoroacetic acid salt.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]2[N:13](CC3C=C(F)C=CC=3Br)[C:12](=[O:23])[N:11]([CH3:24])[C:10](=[O:25])[CH:9]=2)[CH2:3]1.[Cl:26][C:27]1[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][C:28]=1[CH2:29]Br>>[NH2:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]2[N:13]([CH2:29][C:28]3[CH:31]=[C:32]([Cl:35])[CH:33]=[CH:34][C:27]=3[Cl:26])[C:12](=[O:23])[N:11]([CH3:24])[C:10](=[O:25])[CH:9]=2)[CH2:3]1
Reactant: Clc1ccc(Cl)c(CBr)c1
Reactant: Cn1c(=O)cc(N2CCC[C@@H](N)C2)n(Cc2cc(F)ccc2Br)c1=O
Product: Cn1c(=O)cc(N2CCC[C@@H](N)C2)n(Cc2cc(Cl)ccc2Cl)c1=O

Procedure:
The title compound was prepared from compound 1 using the same procedures as in the preparation of compound 10, except that 2,5-di-chloro-benzyl bromide was used in the place of 2-bromo-5-fluoro-benzyl bromide. 1H-NMR (400 MHz, CDCl3-CD3OD 10:1): δ ppm 7.50 (d, J=8.6 Hz, 1H), 7.39 (dd, J=8.3, 2.526 Hz, 1H), 7.22 (d, J=2.5 Hz, 1H), 5.41 (s, 1H), 5.01-4.93 (ABq, J=41.9, 16.2 Hz, 2H), 3.25 (m, 2H), 3.10 (s, 3H), 2.85 (m, 1H), 2.76 (m, 1H), 2.67 (m, 1H), 1.91 (m, 1H), 1.75 (m, 1H), 1.45 (m, 2H). MS (ES) [m+H] calc'd for C17H21Cl2N4O2, 383.1; found 383.1.
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH:8][CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)=[CH:6][CH:5]=[CH:4][N:3]=1.C1N=CN([C:27](N2C=NC=C2)=[O:28])C=1>CC#N>[O:28]=[C:27]1[NH:1][C:2]2=[N:3][CH:4]=[CH:5][CH:6]=[C:7]2[N:8]1[CH:9]1[CH2:10][CH2:11][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:13][CH2:14]1
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2cccnc2N)CC1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCC(n2c(=O)[nH]c3ncccc32)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 108.3 %

Procedure:
To a solution of tert-Butyl 4-(2-aminopyridin-3-ylamino)piperidine-1-carboxylate (3.0 g, 10.3 mmol) in CH3CN (206 ml) at RT was added CDI (4.2 g, 25.7 mmol) in portions and the reaction mixture was stirred at RT for 16 hours. The reaction mixture was evaporated to dryness and the residue was take up in DCM and water. The layers were separated and the organic layer was washed with brine, dried (Na2SO4) and evaporated to dryness. Purification by column chromatography (1-10% MeOH in DCM) gave the desired solid as a beige solid (3.55 g). LC/MS (10% to 99%): M/Z (M+H)+ (obs)=319; tR=2.31.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10](=[O:24])[CH2:11][CH2:12][CH2:13][N:14]2[CH2:19][CH2:18][CH:17]([NH:20][C:21]([NH2:23])=[O:22])[CH2:16][CH2:15]2)=[CH:2]1.[C:25](Cl)(=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>>[C:25]([NH:23][C:21]([NH:20][CH:17]1[CH2:16][CH2:15][N:14]([CH2:13][CH2:12][CH2:11][C:10]([C:3]2[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[NH:1][CH:2]=2)=[O:24])[CH2:19][CH2:18]1)=[O:22])(=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: NC(=O)NC1CCN(CCCC(=O)c2c[nH]c3ccccc23)CC1
Reactant: O=C(Cl)c1ccccc1
Product: O=C(NC(=O)c1ccccc1)NC1CCN(CCCC(=O)c2c[nH]c3ccccc23)CC1

Procedure:
The product may be prepared by the alternative method of treating 1-[1-(4-[3-indolyl]-4-oxobutyl)piperid-4-yl]urea with benzoyl chloride following the procedure of Example 1.
Reaction SMILES: Br[CH:2]([CH3:24])[C:3]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[N:10]([S:14]([C:17]1[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=1)(=[O:16])=[O:15])[CH:9]=[CH:8]2)=[O:4].[OH:25][C:26]1([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1.C(N(CC)CC)C>C(O)C>[OH:25][C:26]1([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH2:31][CH2:30][N:29]([CH:2]([CH3:24])[C:3]([C:5]2[CH:6]=[C:7]3[C:11](=[CH:12][CH:13]=2)[N:10]([S:14]([C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=2)(=[O:16])=[O:15])[CH:9]=[CH:8]3)=[O:4])[CH2:28][CH2:27]1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3cc(C(=O)C(C)Br)ccc32)cc1
Reactant: OC1(c2ccccc2)CCNCC1
Solvent: CCO
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)n2ccc3cc(C(=O)C(C)N4CCC(O)(c5ccccc5)CC4)ccc32)cc1
Yield: 86.8 %

Procedure:
5-(2-Bromopropionyl)-1-(p-toluenesulfonyl)indole (1.67 g, 3.37 mmol, 83% purity) was dissolved in hot ethanol (100 ml) and 4-hydroxy-4-phenylpiperidine (0.6 g, 3.39 mmol) and triethylamine (0.94 ml, 6.74 mmol) were added. The mixture was refluxed overnight. The reaction was cooled and concentrated directly onto silica gel and flash chromatographed. Elution with 1:3 ethyl acetate:hexane removed 0.1 g of non-brominated ketone. Continued elution with 1:1 ethyl acetate hexane gave 1.47 g, 87% of the title product as a glassy orange solid. NMR 8.34 (s, 1H), 8.09 (d, J=9 Hz, 1H), 8.00 (d, J=8.5 Hz, 1H), 7.77 (d, J=8.5 Hz, 2H), 7.61 (d, J=3.5 Hz, 1H), 7.45 (d, J=9 Hz, 2H), 7.33-7.29 (m, 2H), 7.24-7.21 (m, 4H), 6.72 (d, J=3.5 Hz, 1H), 4.18 (q, J=7 Hz, 1H), 2.88-2.84 (m, 2H), 2.73-2.62 (m, 2H), 2.32 (s, 3H), 2.18-2.06 (m, 1H), 2.05-1.97 (m, 1H), 1.77-1.66 (m, 1H), 1.59-1.54 (m, 1H), 1.31 (d, J=7 Hz, 3H). IR 1679, 1605, 1375, 1289, 1260, 1169, 1126, 994. FAB HRMS calcd for C29H31N2O4S (MH+): 503.2006. Observed m/e: 503.2023.
Reaction SMILES: C(N(CC)CC)C.[F:8][C:9]1[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:10]=1[C@:16]([OH:32])([C@H:23]([N:25]1[CH:29]=[C:28]([CH2:30][OH:31])[N:27]=[N:26]1)[CH3:24])[CH2:17][N:18]1[CH:22]=[N:21][CH:20]=[N:19]1.[CH3:33][S:34](Cl)(=[O:36])=[O:35]>ClCCl>[F:8][C:9]1[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:10]=1[C@:16]([OH:32])([C@H:23]([N:25]1[CH:29]=[C:28]([CH2:30][O:31][S:34]([CH3:33])(=[O:36])=[O:35])[N:27]=[N:26]1)[CH3:24])[CH2:17][N:18]1[CH:22]=[N:21][CH:20]=[N:19]1
Reactant: CS(=O)(=O)Cl
Reactant: C[C@@H](n1cc(CO)nn1)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@@H](n1cc(COS(C)(=O)=O)nn1)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Triethylamine (0.26 ml) was added dropwise to a solution of (2R,3R)-2-(2,4-difluorophenyl)-3-(4-hydroxy methyl-1H-1,2,3-triazol-1-yl)-1-(1H-1,2,4-triazol-1-yl)-2-butanol (Compound 56, 0.6 g) and methanesulfonyl chloride (0.14 ml) in dichloromethane (20 ml) under ice-cooling. The mixture was stirred for 30 minutes at room temperature. After addition of dichloromethane (20 ml), the mixture was washed with water (20 ml) and 5% sodium hydrogen carbonate aqueons solution (20 ml). The organic layer was dried over anhydrous magnesium sulfate and distilled under reduced pressure to give (2R,3R)-2-(2,4-difluorophenyl)-3-(4-methanesulfonyloxymethyl-1H-1,2,3-triazol-1-yl)-1(1H-1,2,4-triazol-1-yl)-2-butanol as colorless oil.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[H-].[Na+].I[CH2:13][C:14]([NH2:16])=[O:15]>CN(C=O)C>[N:1]1([CH2:13][C:14]([NH2:16])=[O:15])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: c1ccc2[nH]ccc2c1
Reactant: NC(=O)CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: NC(=O)Cn1ccc2ccccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of indole (10 g; 0.085 mol) in DMF (50 mL) was added dropwise to an ice cooled suspension of NaH (supplied as 60% dispersion in mineral oil) (4.1 g; 0.10 mol) in DMF (100 mL). The reaction was allowed to warm to room temperature and stirred for 4 hours until all NaH was consumed. A solution of iodoacetamide (18.5 g; 0.1 mol) in DMF (50 mL) was added and the reaction left to stir at room temperature overnight. The DMF was removed in vacuo and the residue dissolved in ethyl acetate (1 L). The organic solution was washed with water until the washings were clear (3×500 mL), brine (500 mL), dried over anhydrous magnesium sulfate and the solvent removed in vacuo. Recrystallisation from ethyl acetate provided intermediate C1 as an off white solid (9.20 g, 62%). m.p. 177–179° C. 1H NMR (500 MHz, DMSO-d6) δ 4.79 (2H, s), 6.44 (1H, dd, J 3.1, 0.7), 7.03 (1H, ddd, J 7.8, 7.8, 0.9), 7.13 (1H, ddd, J 8.2, 8.2, 1.0), 7.24 (1H, br), 7.31 (1H, d, J 3.1), 7.35 (1H, dd, J 8.2, 0.6), 7.50 (1H, br), 7.55 (1H, d, J 7.8).
Reaction SMILES: [I:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH:11]=[O:12])[CH:9]=2)[N:4]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[N:3]=1.[CH2:21](O)[CH2:22][OH:23].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[O:12]1[CH2:21][CH2:22][O:23][CH:11]1[C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][CH:7]=1)[N:4]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[N:3]=[C:2]2[I:1]
Reactant: C[Si](C)(C)CCOCn1nc(I)c2cc(C=O)ccc21
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: C[Si](C)(C)CCOCn1nc(I)c2cc(C3OCCO3)ccc21

Procedure:
6.11 g (15.2 mmol) 3-iodo-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-indazole-5-carbaldehyde (Example 5A), 2.82 g (45.6 mmol) ethylene glycol and a trace amount of p-toluene sulfonic acid in toluene (100 ml) were heated to reflux overnight using a Dean-Stark trap. After cooling, the mixture was extracted twice with saturated aqueous sodium bicarbonate solution and washed with brine. The organic layer was dried with sodium sulfate, filtered and evaporated to dryness. The remaining substance was purified by preparative RP-HPLC (acetonitrile/water gradient) yielding 3.94 g (58% of th.) of the pure title compound.
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]2[CH2:7][CH2:8][CH2:9][CH:10]([CH2:13][C:14]([OH:16])=O)[C:11](=O)[C:4]=2[CH:3]=1.[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([NH:24][NH2:25])=[CH:20][CH:19]=1>C1(C)C=CC=CC=1>[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([N:24]2[C:14](=[O:16])[CH2:13][CH:10]3[CH2:9][CH2:8][CH2:7][C:5]4[S:6][C:2]([CH3:1])=[CH:3][C:4]=4[C:11]3=[N:25]2)=[CH:20][CH:19]=1
Reactant: Cc1cc2c(s1)CCCC(CC(=O)O)C2=O
Reactant: NNc1ccc(Cl)cc1
Solvent: Cc1ccccc1
Product: Cc1cc2c(s1)CCCC1CC(=O)N(c3ccc(Cl)cc3)N=C21
Yield: 74.6 %

Procedure:
A suspension of 2.5 g of 2-methyl-4-oxo-5,6,7,8-tetrahydro-4H-cyclohepta[b]thiophene-5-acetic acid and 1.95 g of 4-chlorophenyl hydrazine in 50 ml of toluene is refluxed under heating for 4 hours. After cooling, the mixture is concentrated under reduced pressure and the precipitated crystals are recrystallzed from ethanol to give 2.7 g of 2-(4-chlorophenyl)-9-methyl-2,4,4a,5,6,7-hexahydro-3H-thieno[2',3':6,7]cyclohepta[1,2-c]pyridazin-3-one, melting at 119°-121° C.
Reaction SMILES: C(N(S(F)(F)[F:7])CC)C.[CH2:10]([N:17]([CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH2:18][CH2:19][CH2:20][C:21]([CH3:24])(O)[CH3:22])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C(Cl)Cl>[CH2:10]([N:17]([CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH2:18][CH2:19][CH2:20][C:21]([F:7])([CH3:24])[CH3:22])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CC(C)(O)CCCN(Cc1ccccc1)Cc1ccccc1
Reactant: CCN(CC)S(F)(F)F
Solvent: ClCCl
Product: CC(C)(F)CCCN(Cc1ccccc1)Cc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 40.6 %

Procedure:
Add diethylaminosulfur trifluoride (17.9 g, 111 mmol) drop-wise to a −78° C. solution of 5-(dibenzylamino)-2-methylpentan-2-ol (11 g, 37 mmol) in DCM (100 mL), under N2, warm to RT and stir overnight. Pour the mixture into ice-water, neutralize with satd. NaHCO3, extract with EtOAc (3×), wash the combined organics with brine, dry over Na2SO4, concentrate and purify via silica gel chromatography to afford the title compound (4.5 g, 41%). 1H NMR (400 MHz, DMSO-d6): δ 7.30-7.13 (m, 10H), 3.48 (s, 4H), 2.35 (m, 2H), 1.51-1.48 (m, 4H), 1.22 (d, J=21.2 Hz, 6H).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:7]2[CH2:8][NH:9][CH2:10][CH2:11][N:6]2[N:5]=1)([O-:3])=[O:2].[N+](C1C=C2CN(C(=O)C)CCN2N=1)([O-])=O.C([O-])([O-])=O.[K+].[K+].Br[CH2:35][CH2:36][O:37][CH3:38]>C(#N)C>[CH3:38][O:37][CH2:36][CH2:35][N:9]1[CH2:10][CH2:11][N:6]2[N:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:12]=[C:7]2[CH2:8]1
Reactant: O=[N+]([O-])c1cc2n(n1)CCNC2
Reactant: COCCBr
Agent: CC(=O)N1CCn2nc([N+](=O)[O-])cc2C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COCCN1CCn2nc([N+](=O)[O-])cc2C1
Temperature: 80 °C

Procedure:
To a solution of 2-nitro-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine (190 mg, 1.13 mmol) 209a in acetonitrile (10 mL) was added K2CO3 (311.9 mg, 2.26 mmol) and 1-bromo-2-methoxyethane (188.3 mg, 1.36 mmol). The reaction mixture was heated at 80° C. for 17 h under microwave irradiation. Analysis of the reaction mixture by LCMS showed complete conversion to the desired product. The mixture was cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure to afford 327a as a white solid (230 mg, 90%), which was used in the next step without further purification. MS-ESI: [M+H]+ 227.0
Reaction SMILES: CN1CCCC1=O.F[C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[C:14](=[O:18])[CH2:13][CH2:12]2.[NH:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1.O>C(OCC)(=O)C>[N:19]1([C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[C:14](=[O:18])[CH2:13][CH2:12]3)[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1
Reactant: O=C1CCc2cc(F)ccc21
Reactant: C1COCCN1
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN1CCCC1=O
Product: O=C1CCc2cc(N3CCOCC3)ccc21
Yield: 77.2 %

Procedure:
A 1-methyl-2-pyrrolidone (10 mL) solution of 5-fluoroindanone (1.97 g) and morpholine (1.71 g) was agitated at 100° C. for 26 hours and 30 minutes. Water and ethyl acetate were added to the reaction solution, and the organic layer was partitioned. After the obtained organic layer was washed with a saturated saline solution, it was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (elution solvent: heptane-ethyl acetate system), and 2.20 g of the title compound was obtained. The physical properties of the compound are as follows.