Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([NH:7][C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:21]([C:22]4[CH:27]=[CH:26][N:25]=[C:24]5[NH:28][CH:29]=[CH:30][C:23]=45)=[CH:20][N:19]([CH2:31][C:32]([OH:34])=O)[N:18]=3)=[CH:13][CH:12]=2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([N:37](CC)CC)C.C(OC(Cl)=O)C.[OH-].[NH4+]>O1CCCC1>[C:1]1([NH:7][C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:21]([C:22]4[CH:27]=[CH:26][N:25]=[C:24]5[NH:28][CH:29]=[CH:30][C:23]=45)=[CH:20][N:19]([CH2:31][C:32]([NH2:37])=[O:34])[N:18]=3)=[CH:13][CH:12]=2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)Cn1cc(-c2ccnc3[nH]ccc23)c(-c2ccc(NC(=O)Nc3ccccc3)cc2)n1
Reactant: CCN(CC)CC
Agent: CCOC(=O)Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: C1CCOC1
Product: NC(=O)Cn1cc(-c2ccnc3[nH]ccc23)c(-c2ccc(NC(=O)Nc3ccccc3)cc2)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 13 %

Procedure:
To a cooled (0° C.) solution of [3-(4-{[(phenylamino)carbonyl]amino}phenyl)-4-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-1-yl]acetic acid (0.166 mmol) in anhydrous tetrahydrofuran (3.3 mL) was added triethylamine (0.25 mmol) and ethylchloroformate (0.18 mmol). After 30 minutes at 0° C., ammonium hydroxide (50 uL) was added and the reaction stirred at room temperature for 1 h. Concentration in vacuo followed by Gilson reverse phase HPLC furnished the title compound as a white solid (13%). ESMS [M+H]+: 452.4
Reaction SMILES: [CH3:1][Li].[CH3:3][O:4][C:5]1[CH:6]=[CH:7][C:8]2[CH2:9][C@H:10]3[N:21]([CH3:22])[CH2:20][CH2:19][C@@:16]4([C:17]=2[CH:18]=1)[C@@:11]3([O:24][CH3:25])[CH:12]=[CH:13][C:14](=[O:23])[CH2:15]4>C(OCC)C.C(Cl)Cl.[Cu](I)I>[CH3:3][O:4][C:5]1[CH:6]=[CH:7][C:8]2[CH2:9][C@H:10]3[N:21]([CH3:22])[CH2:20][CH2:19][C@@:16]4([C:17]=2[CH:18]=1)[C@@:11]3([O:24][CH3:25])[C@@H:12]([CH3:1])[CH2:13][C:14](=[O:23])[CH2:15]4
Reactant: COc1ccc2c(c1)[C@]13CCN(C)[C@H](C2)[C@]1(OC)C=CC(=O)C3
Reactant: [Li]C
Agent: I[Cu]I
Solvent: ClCCl
Solvent: CCOCC
Product: COc1ccc2c(c1)[C@]13CCN(C)[C@H](C2)[C@]1(OC)[C@@H](C)CC(=O)C3
Temperature: -20 °C
Reaction time: 2 h

Procedure:
A slurry of copper iodide (8.63 g, 0.045 mol) in 250 ml of anhydrous diethyl ether was cooled at -20° to -25° C. in a dry ice/carbon tetrachloride bath while being held under a nitrogen atmosphere. Methyl lithium (49.3 ml of a 1.84 M solution in ether, 0.091 mol) was cannulated into a calibrated dropping funnel and quickly added to the slurry. This complex was cooled an additional 10 minutes at -25° C. before a solution of 7,8-didehydro-3,14-dimethoxy-17-methylmorphinan-6-one (3) (9.47 g, 0.032 mol) in 60 ml of dry methylene chloride was added dropwise and washed in with an additional 30 ml of dry diethyl ether. After stirring at -20° C. for 21/2 hours, the reaction mixture was quenched with 60 ml of 20% ammonium hydroxide and made basic by the addition of 50% sodium hydroxide. The resultant copper salts were removed by suction filtration and the filter cake was washed several times with diethyl ether and water. The layers were separated and the aqueous phase extracted with two additional portions of ether. The ethereal extracts were combined, washed with saturated sodium chloride solution, dried over Na2SO4 and concentrated under reduced pressure. Purification by chromatography on Flosisil (eluted with graded methanol/chloroform) yielded 4.6 g (46% theory) of the title compound.
Reaction SMILES: C([Li])CCCCC.[CH3:8][O:9][C:10]([NH:12][C@@H:13]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:14]([O:16]C)=O)=[O:11].Br[CH2:26][Cl:27].Cl>CCCCCC.O1CCCC1.O>[CH2:18]([C@H:13]([NH:12][C:10](=[O:11])[O:9][CH3:8])[C:14](=[O:16])[CH2:26][Cl:27])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: ClCBr
Reactant: COC(=O)N[C@@H](Cc1ccccc1)C(=O)OC
Agent: Cl
Agent: [Li]CCCCCC
Solvent: O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COC(=O)N[C@@H](Cc1ccccc1)C(=O)CCl
Yield: 37 %

Procedure:
41.7 ml of a 2.6 molar solution of hexyllithium in hexane were added dropwise at -80° C. to a solution of 9.50 g of methyl (S)-2-methoxycarbonylamino-3-phenyl-propionate and 3.22 ml of bromochloromethane in 60 ml of tetrahydrofuran. Subsequently, a further 2.14 ml of bromochloromethane were added and the mixture was again treated with 23 ml of hexyllithium solution, a further 1.54 ml of bromochloromethane were added and the mixture was again treated with 7.7 ml of hexyllithium solution. The solution was treated at -80° C. with 15 ml of 20% methanolic hydrochloric acid, warmed to 22° and diluted with 100 ml of water and 40 ml of tetrahydrofuran. The phases were separated, the organic phase was washed with saturated sodium chloride solution, dried and concentrated. The residue was recrystallized from 40 ml of ethyl acetate and 160 ml of hexane and the crystallizate was dried, yielding 3.83 g (37%) of pure methyl (S)-(1-benzyl-3-chloro-2-oxo-propyl)-carbamate, m.p. 121°-122° C. IR (KBr): 3336s (NH), 1737s and 1686s (C=O), 1535s (amide II).
Reaction SMILES: Cl.[Cl:2][C:3]1[C:12]([Cl:13])=[CH:11][CH:10]=[CH:9][C:4]=1[C:5](=O)[CH2:6][NH2:7].CN(C)[CH:16]=[CH:17][C:18]([O:20][CH3:21])=[O:19].CC[O-].[Na+]>C(O)C>[C:18]([C:17]1[C:5]([C:4]2[CH:9]=[CH:10][CH:11]=[C:12]([Cl:13])[C:3]=2[Cl:2])=[CH:6][NH:7][CH:16]=1)([O:20][CH3:21])=[O:19]
Reactant: NCC(=O)c1cccc(Cl)c1Cl
Reactant: COC(=O)C=CN(C)C
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: COC(=O)c1c[nH]cc1-c1cccc(Cl)c1Cl

Procedure:
10.7 g of 2,3-dichlorophenacylamine hydrochloride and 6 g of methyl 3-dimethylaminoacrylate are heated for 2 hours under reflux in 120 ml of ethanol. Then a solution of 4 g of sodium ethylate in 40 ml of ethanol is added dropwise and the reaction mixture is heated for another hour under reflux. The reaction mixture is then concentrated by evaporation and the oily residue is purified by column chromatography (silica gel; elution with a 3:1 mixture of toluene/ethyl acetate. Melting point: 205°-206° C.
Reaction SMILES: [NH2:1][C:2]1[C:34]([C:35]#[N:36])=[N:33][C:5]2[CH:6]=[C:7]3[C:16](=[N:17][C:4]=2[CH:3]=1)[C:15]1[N:14]=[C:13]2[C:18](=CC4C=CC=CC=4)[CH2:19][CH2:20][CH2:21][C:12]2=[C:11]([CH2:29][CH2:30][CH2:31][CH3:32])[C:10]=1[CH2:9][CH2:8]3.N#N.[O:39]=[O+][O-].CSC>CO>[NH2:1][C:2]1[C:34]([C:35]#[N:36])=[N:33][C:5]2[CH:6]=[C:7]3[C:16](=[N:17][C:4]=2[CH:3]=1)[C:15]1[N:14]=[C:13]2[C:18](=[O:39])[CH2:19][CH2:20][CH2:21][C:12]2=[C:11]([CH2:29][CH2:30][CH2:31][CH3:32])[C:10]=1[CH2:9][CH2:8]3
Reactant: O=[O+][O-]
Reactant: CCCCc1c2c(nc3c1CCc1cc4nc(C#N)c(N)cc4nc1-3)C(=Cc1ccccc1)CCC2
Agent: N#N
Solvent: CSC
Solvent: CO
Product: CCCCc1c2c(nc3c1CCc1cc4nc(C#N)c(N)cc4nc1-3)C(=O)CCC2
Temperature: -78 °C
Yield: 35 %

Procedure:
To a 250 mL round bottomed flask were added 0.305 g (0.147 mmol) of crude 2-amino-12-benzylidene-8-n-butyl-3-cyano-6,7,9,10,11,12hexahydrobenzo[b]pyrido[2,3-j][1,10]phenanthroline, 40 mL of CH2CL2 and 115 mL of CH3OH. The solution was cooled to approximately -78° C. by means of a dry ice/acetone bath and N2 was passed through the solution for 5 min. A stream of O3 was passed through the solution until the color turned from dark orange-brown to dark green-brown. N2 was passed through the solution for an additional 5 min. then 0.6 mL of dimethyl sulfide was added via syringe. The solution was allowed to warm to room temperature overnight and the solvents removed by rotary evaporation. The crude product was washed with ether (3×50 mL) then recrystallized from CHCL3 /EtOH. Vacuum filtration gave 0.09 g (35%) of product as a yellow solid after drying at 0.5 mm Hg pressure and 61° C. for 48 hr. (mp>300° C.).
Reaction SMILES: C[O:2][C:3]1[C:4]([CH3:33])=[C:5]([CH:30]=[CH:31][CH:32]=1)[CH2:6][CH:7]1[CH2:12][CH2:11][CH2:10][CH:9]=[C:8]1[C:13]1[O:14][C:15]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:17]=1.B(Br)(Br)Br.O>C(Cl)Cl>[C:18]1([C:16]2[N:17]=[C:13]([C:8]3[CH:7]([CH2:6][C:5]4[C:4]([CH3:33])=[C:3]([OH:2])[CH:32]=[CH:31][CH:30]=4)[CH2:12][CH2:11][CH2:10][CH:9]=3)[O:14][C:15]=2[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: COc1cccc(CC2CCCC=C2c2nc(-c3ccccc3)c(-c3ccccc3)o2)c1C
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: O
Product: Cc1c(O)cccc1CC1CCCC=C1c1nc(-c2ccccc2)c(-c2ccccc2)o1
Temperature: 5 °C
Reaction time: 1 h
Yield: 80.5 %

Procedure:
To a solution of 2-[1-(3-methoxy-2-methylbenzyl)-2-cyclohexen-2-yl]-4,5-diphenyloxazole (1.16 g) in CH2Cl2 (25 ml) was added boron tribromide (1M solution in CH2Cl2, 5.32 ml) at −60° C. and the mixture was warmed to 5° C. After stirring for 1 hour at the same temperature, the reaction mixture was stirred for further 1 hour at room temperature. To the mixture was added water under ice-cooling, extracted with EtOAc. The organic layer was washed with water, saturated sodium hydrogen carbonate, water, and brine, dried over magnesium sulfate, evaporated in vacuo. The residue was purified by silica gel column chromatography (hexane-EtOAc 5:1) to give 3-{[2-(4,5-diphenyloxazol-2-yl)-2-cyclohexen-1-yl]methyl}-2-methylphenol (903.8 mg) as an amorphous solid.
Reaction SMILES: [C:1]([O:4][C@H:5]([C@H:9]1[O:14][CH2:13][CH2:12][N:11]([C:15]2[CH:16]=[C:17]3[C:21](=[CH:22][CH:23]=2)[CH2:20][N:19]([CH3:24])[C:18]3=[O:25])[C:10]1=[O:26])[C:6]([OH:8])=O)(=[O:3])[CH3:2].[NH2:27][C:28]1[CH:42]=[CH:41][C:31]([CH2:32][NH:33][C:34](=[O:40])[O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[CH:30][CH:29]=1>>[C:1]([O:4][C@H:5]([C@H:9]1[O:14][CH2:13][CH2:12][N:11]([C:15]2[CH:16]=[C:17]3[C:21](=[CH:22][CH:23]=2)[CH2:20][N:19]([CH3:24])[C:18]3=[O:25])[C:10]1=[O:26])[C:6]([NH:27][C:28]1[CH:29]=[CH:30][C:31]([CH2:32][NH:33][C:34]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:40])=[CH:41][CH:42]=1)=[O:8])(=[O:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NCc1ccc(N)cc1
Reactant: CC(=O)O[C@@H](C(=O)O)[C@H]1OCCN(c2ccc3c(c2)C(=O)N(C)C3)C1=O
Product: CC(=O)O[C@@H](C(=O)Nc1ccc(CNC(=O)OC(C)(C)C)cc1)[C@H]1OCCN(c2ccc3c(c2)C(=O)N(C)C3)C1=O
Yield: 74.2 %

Procedure:
According to the Step 70-5 in the synthetic method for EXAMPLE 70, compound 70-4 (50 mg) was treated with tert-butyl 4-aminobenzylcarbamate (37 mg) to afford compound 71-1 (58 mg) as white solid after preparative LC purification.
Reaction SMILES: Cl[C:2]1[C:10]2[C:9]3[CH:11]=[C:12]([C:15]#[N:16])[N:13]=[CH:14][C:8]=3[N:7](COCC[Si](C)(C)C)[C:6]=2[N:5]=[CH:4][CH:3]=1.[CH3:25][N:26]([CH3:33])[CH2:27][C:28]([CH3:32])([CH3:31])[CH2:29][OH:30]>>[CH3:25][N:26]([CH3:33])[CH2:27][C:28]([CH3:32])([CH3:31])[CH2:29][O:30][C:2]1[C:10]2[C:9]3[CH:11]=[C:12]([C:15]#[N:16])[N:13]=[CH:14][C:8]=3[NH:7][C:6]=2[N:5]=[CH:4][CH:3]=1
Reactant: CN(C)CC(C)(C)CO
Reactant: C[Si](C)(C)CCOCn1c2cnc(C#N)cc2c2c(Cl)ccnc21
Product: CN(C)CC(C)(C)COc1ccnc2[nH]c3cnc(C#N)cc3c12

Procedure:
The title compound was prepared following a similar procedure to the previous example with 4-chloro-9-(2-trimethylsilanyl-ethoxymethyl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile, using 3-(dimethylamino)-2,2-dimethylpropan-1-ol. 1H NMR (400 MHz, d6-DMSO) δ 12.78 (s, 1H), 8.99 (d, J=0.8, 1H), 8.55 (d, J=5.7, 1H), 8.39 (d, J=0.8, 1H), 7.06 (d, J=5.8, 1H), 4.12 (s, 2H), 2.41 (s, 2H), 2.24 (s, 6H), 1.10 (s, 6H). LCMS (Method E): RT=3.58 min, M+H+=324.1.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]=O.C([O-])(=O)C.[NH4+].[N+:18]([CH2:21][CH3:22])([O-:20])=[O:19]>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]=[C:21]([N+:18]([O-:20])=[O:19])[CH3:22]
Reactant: O=Cc1c[nH]c2ccc(Cl)cc12
Reactant: CC[N+](=O)[O-]
Agent: CC(=O)[O-]
Agent: [NH4+]
Product: CC(=Cc1c[nH]c2ccc(Cl)cc12)[N+](=O)[O-]

Procedure:
12.9 g of 5-chloro-3-formylindole and 1.3 g of ammonium acetate are suspended in 26 ml of nitroethane and refluxed for 1 hour. After the whole of the reactants have dissolved a mass of orange crystals are seen to form. The reaction mixture is then cooled and filtered after dilution with di-isopropyl ether. The product is recrystallised from 96% ethyl alcohol.
Reaction SMILES: [CH3:1][S:2][C:3]1[C:11]2[C:6](=[CH:7][C:8]([N:12]3[CH2:17][CH2:16][N:15]([C:18]([CH:20]4[CH2:25][CH2:24][CH2:23][N:22](C(OC(C)(C)C)=O)[CH2:21]4)=[O:19])[CH2:14][CH2:13]3)=[CH:9][CH:10]=2)[N:5]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[N:4]=1.[ClH:39]>ClCCl>[ClH:39].[CH3:1][S:2][C:3]1[C:11]2[C:6](=[CH:7][C:8]([N:12]3[CH2:17][CH2:16][N:15]([C:18]([CH:20]4[CH2:25][CH2:24][CH2:23][NH:22][CH2:21]4)=[O:19])[CH2:14][CH2:13]3)=[CH:9][CH:10]=2)[N:5]([C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[N:4]=1
Reactant: CSc1nn(-c2ccccc2)c2cc(N3CCN(C(=O)C4CCCN(C(=O)OC(C)(C)C)C4)CC3)ccc12
Agent: Cl
Solvent: ClCCl
Product: CSc1nn(-c2ccccc2)c2cc(N3CCN(C(=O)C4CCCNC4)CC3)ccc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Into a 50-mL 3-necked round-bottom flask, was placed a solution of tert-butyl 3-(1-(3-(methylthio)-1-phenyl-1H-indazol-6-yl)piperazine-4-carbonyl)piperidine-1-carboxylate (80 mg, 0.15 mmol, 1.00 equiv) in dichloromethane (10 mL). To the resulting mixture, HCl (g) was introduced at 0-5° C. The resulting solution was stirred for 1 h at room temperature. The solids were collected by filtration, then washed with diethyl ether (3×10 mL) to yield (4-(3-(methylthio)-1-phenyl-1H-indazol-6-yl)piperazin-1-yl)(piperidin-3-yl)methanone hydrochloride as a yellow solid.
Reaction SMILES: O1CCCC1.CS(C)=O.[N:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21](/[CH:24]=[CH:25]/[N+:26]([O-:28])=[O:27])=[CH:20][CH:19]=1.C(O)(=O)C.[BH4-].[Na+]>O>[N:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[CH2:16][CH2:17][C:18]1[CH:19]=[CH:20][C:21]([CH2:24][CH2:25][N+:26]([O-:28])=[O:27])=[CH:22][CH:23]=1
Reactant: O=[N+]([O-])/C=C/c1ccc(CCc2ccccn2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: O=[N+]([O-])CCc1ccc(CCc2ccccn2)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 74.2 %

Procedure:
To a mixed tetrahydrofuran-dimethyl sulfoxide (1:1) solution of 4-(2-pyridin-2-yl-ethyl)-((E)-2-nitro-vinyl)-benzene (2.83 g, 11.1 mmol) described in Manufacturing Example 93-1-6 and acetic acid (3 mL) was added sodium borohydride (630 mg, 16.7 mmol) at room temperature while cooling appropriately under nitrogen atmosphere, which was stirred for 15 minutes at room temperature. Water was added dropwise into this reaction mixture at room temperature while cooling appropriately. The reaction mixture was partitioned into water and ethyl acetate. The organic layer was washed with water and saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate, and the solvent was evaporated under a reduced pressure. The residue was purified by NH silica gel column chromatography (ethyl acetate:heptane=1:9 then 2:8) to obtain the title compound (2.11 g, 74%).
Reaction SMILES: C1(C[N:8]2[CH2:13][CH2:12][CH:11]([N:14]3[CH2:19][C:18]4[CH:20]=[CH:21][CH:22]=[N:23][C:17]=4[NH:16][C:15]3=[O:24])[CH2:10][CH2:9]2)C=CC=CC=1.[H][H]>CO.[Pd]>[NH:8]1[CH2:9][CH2:10][CH:11]([N:14]2[CH2:19][C:18]3[CH:20]=[CH:21][CH:22]=[N:23][C:17]=3[NH:16][C:15]2=[O:24])[CH2:12][CH2:13]1
Reactant: [H][H]
Reactant: O=C1Nc2ncccc2CN1C1CCN(Cc2ccccc2)CC1
Agent: [Pd]
Solvent: CO
Product: O=C1Nc2ncccc2CN1C1CCNCC1

Procedure:
A solution of 4.7 g (0.0146 mol) of 3,4-dihydro-3-[1-(phenylmethyl)-4-piperidinyl]-2(1H)-pyrido[2,3-d]-pyrimidinone in 50 ml of methanol was hydrogenated at a temperature of 50° C. and in the presence of 2.0 g of 20% palladium/charcoal until the uptake of hydrogen ceased. After removal of the catalyst and solvent 3.3 g (97.3% of theory) of a colourless oil of Rf=0.35 (FM1) were obtained.
Reaction SMILES: [C:1](P(=O)(OCC)OCC)#[N:2].[CH3:11][S:12][C:13]1[CH:14]=[C:15]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[N+:16]([O-])=[CH:17][CH:18]=1.C(N(CC)CC)C>C(#N)C>[CH3:11][S:12][C:13]1[CH:18]=[C:17]([C:1]#[N:2])[N:16]=[C:15]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[CH:14]=1
Reactant: CSc1cc[n+]([O-])c(-c2ccccn2)c1
Reactant: CCOP(=O)(C#N)OCC
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CSc1cc(C#N)nc(-c2ccccn2)c1
Temperature: 90 °C
Reaction time: 2 h

Procedure:
Diethyl cyanophosphonate 90% (1.3 mL, 8.4 mmol) was slowly added at 25° C. to a mixture of 4-Methylsulfanyl-[2,2′]bipyridinyl 1-oxide (650.0 mg, 2.98 mmol) and triethylamine (0.50 mL, 3.58 mmol) in acetonitrile (14 mL) and stirred for 2 hours at 90° C. The reaction mixture was concentrated under reduced pressure, methanol (5 mL) added and the solid formed filtered and washed with methanol (2×5 mL), the filtrate was concentrated and purified by column chromatography on silica gel (0 to 10% Methanol in dichloromethane) to afford 4-methylsulfanyl-[2,2′]bipyridinyl-6-carbonitrile as a white solid that was combined with the previous white solid obtained (500.0 mg, 74%).
Reaction SMILES: [F:1][CH:2]([F:24])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12]#[CH:13])=[C:7]2[N:6]=[C:5]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[CH:4]=1.Br[C:26]1[CH:27]=[C:28]([S:32]([NH:35][C:36]([CH3:40])([CH3:39])[CH2:37][OH:38])(=[O:34])=[O:33])[CH:29]=[CH:30][CH:31]=1>>[F:24][CH:2]([F:1])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12]#[C:13][C:26]3[CH:27]=[C:28]([S:32]([NH:35][C:36]([CH3:40])([CH3:39])[CH2:37][OH:38])(=[O:33])=[O:34])[CH:29]=[CH:30][CH:31]=3)=[C:7]2[N:6]=[C:5]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[CH:4]=1
Reactant: CC(C)(CO)NS(=O)(=O)c1cccc(Br)c1
Reactant: C#Cc1cnn2c(C(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Product: CC(C)(CO)NS(=O)(=O)c1cccc(C#Cc2cnn3c(C(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)c1

Procedure:
The title compound was prepared from 7-Difluoromethyl-3-ethynyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (example C.2) (340 mg, 1.0 mmol) and 3-Bromo-N-(2-hydroxy-1,1-dimethyl-ethyl)-benzenesulfonamide (example B.6) (281 mg, 1.0 mmol) according to general procedure II. Obtained as a yellow solid (310 mg, 54%). MS (ISP) 565.4 [(M+H)+]; mp 161–162° C.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([O:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]([NH:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[O:17])=[CH:11][CH:10]=2)[CH:3]=1.[F:25][C:26]1[CH:27]=[C:28]([CH:30]=[CH:31][CH:32]=1)[NH2:29].O>CN1CCCC1=O.C(OCC)(=O)C.CCCCCC>[F:25][C:26]1[CH:27]=[C:28]([NH:29][C:2]2[N:7]=[CH:6][N:5]=[C:4]([O:8][C:9]3[CH:14]=[CH:13][C:12]([NH:15][C:16]([NH:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[O:17])=[CH:11][CH:10]=3)[CH:3]=2)[CH:30]=[CH:31][CH:32]=1
Reactant: O=C(Nc1ccccc1)Nc1ccc(Oc2cc(Cl)ncn2)cc1
Reactant: Nc1cccc(F)c1
Solvent: O
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: O=C(Nc1ccccc1)Nc1ccc(Oc2cc(Nc3cccc(F)c3)ncn2)cc1
Yield: 52 %

Procedure:
N-(4-(6-Chloropyrimidin-4-yloxy)phenyl)-N′-phenylurea (68.0 mg, 0.200 mmol) and 3-fluoroaniline (111 mg, 1.00 mmol) were heated and stirred in 1-methylpyrrolidone (1 ml) at 150° C. for 90 minutes. The reaction solution was distributed between ethyl acetate and water, the organic layer was washed with saturated aqueous sodium bicarbonate, water and saturated brine and dried over anhydrous magnesium sulfate, the drying agent was filtered off and the filtrate was distilled off under reduced pressure. The obtained crude product was suspended in ethyl acetate, the suspension was diluted with hexane, and the crystals were filtered out, washed with hexane and then blow-dried to obtain the title compound (43.0 mg, 0.104 mmol, 52%) as colorless crystals.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[C:16]([N:22]3[CH:26]=[C:25]([N+:27]([O-])=O)[CH:24]=[N:23]3)=[N:17][CH:18]=[C:19]([Cl:21])[CH:20]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]>C(O)C.[Pd]>[NH2:27][C:25]1[CH:24]=[N:23][N:22]([C:16]2[C:15]([NH:14][S:11]([C:8]3[CH:9]=[CH:10][C:5]([C:1]([CH3:3])([CH3:2])[CH3:4])=[CH:6][CH:7]=3)(=[O:12])=[O:13])=[CH:20][C:19]([Cl:21])=[CH:18][N:17]=2)[CH:26]=1
Reactant: CC(C)(C)c1ccc(S(=O)(=O)Nc2cc(Cl)cnc2-n2cc([N+](=O)[O-])cn2)cc1
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)c1ccc(S(=O)(=O)Nc2cc(Cl)cnc2-n2cc(N)cn2)cc1
Reaction time: 2 h

Procedure:
To a solution of 4-tert-butyl-N-[5-chloro-2-(4-nitro-pyrazol-1-yl)-pyridin-3-yl]-benzenesulfonamide (100 mg, 0.229 mmol) in 2 mL of ethanol was added 10% Pd/C and the heterogeneous solution was stirred under an atmosphere of hydrogen. After two hours, the reaction was filtered through celite and concentrated in vacuo. The crude reside was subsequently purified by flash column chromatography (0-100% ethyl acetate in hexanes) to afford N-[2-(4-amino-pyrazol-1-yl)-5-chloro-pyridin-3-yl]-4-tert-butyl-benzene sulfonamide as a white solid: MS (ES) M+H expected 406.1, found 406.0.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:23]([O-:25])=[O:24])[CH2:10][C@H:11]([CH2:15][C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=1)[C:12]([O-:14])=[O:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].CC1C=CC(S(O[CH2:37][C@H:38]2[C@H:42]([CH2:43][O:44][S:45]([C:48]3[CH:53]=[CH:52][C:51]([CH3:54])=[CH:50][CH:49]=3)(=[O:47])=[O:46])[O:41][C:40]([CH3:56])([CH3:55])[O:39]2)(=O)=O)=CC=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[C:1]([O:5][C:6]([NH:8][C@H:9]([C:23]([O:25][C:11]([CH3:15])([CH3:12])[CH3:10])=[O:24])[CH2:10][C@H:11]([CH2:15][C:16]1[CH:17]=[CH:18][C:19]([O:22][CH2:37][C@H:38]2[C@H:42]([CH2:43][O:44][S:45]([C:48]3[CH:53]=[CH:52][C:51]([CH3:54])=[CH:50][CH:49]=3)(=[O:47])=[O:46])[O:41][C:40]([CH3:56])([CH3:55])[O:39]2)=[CH:20][CH:21]=1)[C:12]([O:14][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:13])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@@H](C[C@H](Cc1ccc(O)cc1)C(=O)[O-])C(=O)[O-]
Reactant: Cc1ccc(S(=O)(=O)OC[C@@H]2OC(C)(C)O[C@H]2COS(=O)(=O)c2ccc(C)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)OC[C@@H]2OC(C)(C)O[C@H]2COc2ccc(C[C@@H](C[C@H](NC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)cc2)cc1
Temperature: 100 °C
Yield: 65.5 %

Procedure:
To 0.47 g (1 mmol) (4S)—N-(tert-butoxycarbonyl)-4-(4-hydroxybenzyl)-L-glutamate and 0.47 g (1 mmol) [(4S,5S)-2,2-dimethyl-1,3-dioxolane-4,5-diyl]dimethanediyl bis(4-methylbenzenesulfonate) in 15 mL DMF was added potassium carbonate (0.28 g, 2 mmol). The mixture was heated in a microwave for 2 h at 100° C. Water was added and the mixture was extracted with dichloromethane. The organic phase was dried over sodium sulfate, filtered and concentrated. The crude product was purified by flash chromatography (silica, 20% ethyl acetate in hexane) to afford 0.25 g (33%) di-tert-butyl (4S)—N-(tert-butoxycarbonyl)-4-(4-{[(4S,5S)-2,2-dimethyl-5-({[(4-methylphenyl)sulfonyl]oxy}methyl)-1,3-dioxolan-4-yl]methoxy}benzyl)-L-glutamate.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[C:11]([N+:13]([O-])=O)[CH:12]=1)[N:9]=[C:8]([CH:16]=[CH2:17])[CH:7]=[CH:6]2.O.NN>[Ni].C1(C)C=CC=CC=1>[NH2:13][C:11]1[CH:12]=[C:3]([O:2][CH3:1])[CH:4]=[C:5]2[C:10]=1[N:9]=[C:8]([CH2:16][CH3:17])[CH:7]=[CH:6]2
Reactant: C=Cc1ccc2cc(OC)cc([N+](=O)[O-])c2n1
Agent: [Ni]
Agent: NN
Solvent: Cc1ccccc1
Solvent: O
Product: CCc1ccc2cc(OC)cc(N)c2n1

Procedure:
To a mixture of 9.6 g (0.04 mole) of 6-methoxy-8-nitro-2-vinylquinoline, 5 g (wet weight, washed with ethanol) of Raney nickel catalyst and 250 ml of toluene-95% ethanol (1:1) was added 25 ml of 85% hydrazine hydrate in portions, and after the vigorous reaction was over the mixture was heated under reflux for 5 hr. The condensor was removed and the mixture heated (ethanol added) until the vapors were faintly alkaline. The mixture was cooled, filtered over diatomaceous earth, and the filtrate concentrated in vacuo. The oily residue was dissolved in anhydrous ether and treated with HBr gas. The hydrobromide precipitated as a yellow powder and was recrystallized from ethanol-chloroform. The yield was 6.6 g (56%) of the desired 8-amino-2-ethyl-6-methoxyquinoline hydrobromide, mp 239°-241°. Rf : 0.62 (19.2 ethyl acetate-diethylamine), 0.67 (19:1 ethanol-diethylamine), 0.74 (19:1 methanol-diethylamine).