Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:5]2([CH2:10][CH2:9][O:8][CH2:7][CH2:6]2)[CH2:4][CH2:3][CH:2]1[C:11]([O:13][CH2:14][CH3:15])=[O:12].CCN(C(C)C)C(C)C.[C:25](Cl)(=[O:27])[CH3:26]>ClCCl>[C:25]([N:1]1[C:5]2([CH2:6][CH2:7][O:8][CH2:9][CH2:10]2)[CH2:4][CH2:3][CH:2]1[C:11]([O:13][CH2:14][CH3:15])=[O:12])(=[O:27])[CH3:26]
Reactant: CC(=O)Cl
Reactant: CCOC(=O)C1CCC2(CCOCC2)N1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C1CCC2(CCOCC2)N1C(C)=O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 58.4 %

Procedure:
To a solution of ethyl 8-oxa-1-azaspiro[4.5]decane-2-carboxylate (166) (135 mg, 0.63 mmol) in anhydrous dichloromethane (2 mL) was added Hunig's base (0.22 mL, 1.3 mmol) followed by acetyl chloride (0.05 mL, 0.76 mmol) and the reaction stirred at room temperature under nitrogen for 1.5 h. The reaction was diluted with dichloromethane and washed with 0.1 N HCl and the organic layer dried over MgSO4 and concentrated in vacuo. The residue was purified by silica gel chromatography eluting with 60-100% hexanes/EtOAc to afford the title compound as a yellow oil (94 mg, 58% yield).
Reaction SMILES: [CH2:1]([N:3]([CH2:16][CH2:17][CH2:18][CH2:19][CH:20]([CH3:22])[CH3:21])[CH2:4][CH2:5][NH:6][C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][CH:8]=1)[CH3:2].[CH2:23](Br)[CH:24]=[CH2:25]>>[CH2:1]([N:3]([CH2:16][CH2:17][CH2:18][CH2:19][CH:20]([CH3:21])[CH3:22])[CH2:4][CH2:5][N:6]([C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][CH:8]=1)[CH2:25][CH:24]=[CH2:23])[CH3:2]
Reactant: C=CCBr
Reactant: CCN(CCCCC(C)C)CCNc1ccc([N+](=O)[O-])cc1
Product: C=CCN(CCN(CC)CCCCC(C)C)c1ccc([N+](=O)[O-])cc1

Procedure:
In a manner similar to Preparation 12 react N-Ethyl-N-(5-methylhexyl)-N'-(4-nitrophenyl)-1,2-ethanediamine with allyl bromide to provide the title compound.
Reaction SMILES: [CH3:1][N:2]1[CH2:6][C@@H:5]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[N:4]([C:14](=[O:28])[C@H:15](OS(C2C=CC(C)=CC=2)(=O)=O)[CH3:16])[C:3]1=[O:29].[NH2:30][C@@H:31]([CH2:42][CH2:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)[C:32]([O:34][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)=[O:33]>>[CH3:1][N:2]1[CH2:6][C@@H:5]([C:7]([O:9][C:10]([CH3:11])([CH3:12])[CH3:13])=[O:8])[N:4]([C:14](=[O:28])[C@@H:15]([NH:30][C@H:31]([C:32]([O:34][CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=[O:33])[CH2:42][CH2:43][C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[CH3:16])[C:3]1=[O:29]
Reactant: Cc1ccc(S(=O)(=O)O[C@H](C)C(=O)N2C(=O)N(C)C[C@H]2C(=O)OC(C)(C)C)cc1
Reactant: N[C@@H](CCc1ccccc1)C(=O)OCc1ccccc1
Product: C[C@H](N[C@@H](CCc1ccccc1)C(=O)OCc1ccccc1)C(=O)N1C(=O)N(C)C[C@H]1C(=O)OC(C)(C)C
Yield: 82.3 %

Procedure:
t-Butyl (4S)-1-methyl-3-[(2R)-2-(p-toluenesulfonyloxy)propionyl]-2-oxoimidazolidine-4-carboxylate (1 g) obtained in Example 1 - (1) and benzyl (2S)-2-amino-4-phenylbutyrate (1.55 g) were treated similarly as in Example 1 - (2) to give t-butyl (4S)-1-methyl-3-{(2S)-2-[N-((1S)-1-benzyloxycarbonyl-3-phenyl-propyl)amino]propionyl}-2-oxoimidazolidine-4-carboxylate (1.01 g) as colorless syrup. Yield: 82.3%.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[O:9][C:10](=[O:17])[C:11]3[CH2:12][NH:13][CH2:14][CH2:15][C:16]=3[C:7]=2[CH:6]=[CH:5][C:4]=1[O:18][CH3:19].Cl[CH2:21][CH2:22][N:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1>>[CH3:1][O:2][C:3]1[C:8]2[O:9][C:10](=[O:17])[C:11]3[CH2:12][N:13]([CH2:21][CH2:22][N:23]4[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]4)[CH2:14][CH2:15][C:16]=3[C:7]=2[CH:6]=[CH:5][C:4]=1[O:18][CH3:19]
Reactant: COc1ccc2c3c(c(=O)oc2c1OC)CNCC3
Reactant: ClCCN1CCCCC1
Product: COc1ccc2c3c(c(=O)oc2c1OC)CN(CCN1CCCCC1)CC3

Procedure:
In the same way as described in Example 5, 5.7 mmoles of 1,2,3,4-tetrahydro-7,8-dimethoxy-5H-[1]benzopyrano[3,4-c]pyridin-5-one was alkylated with N-(2-chloroethyl)-piperidine to give, after recrystallization from MeOH, 0.5 g of product; mp 236°-239°C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:12]=[C:11]([C:13]2[CH:18]=[CH:17][C:16]([N:19]3[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]3)=[CH:15][CH:14]=2)[C:10]([NH:32][C@H:33]([C:38]([O:40]CC2C=CC(OC)=CC=2)=[O:39])[CH2:34][CH:35]([CH3:37])[CH3:36])=[N:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>CCO.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH:12]=[C:11]([C:13]2[CH:14]=[CH:15][C:16]([N:19]3[CH2:20][CH2:21][N:22]([C:25]([O:27][C:28]([CH3:29])([CH3:30])[CH3:31])=[O:26])[CH2:23][CH2:24]3)=[CH:17][CH:18]=2)[C:10]([NH:32][C@H:33]([C:38]([OH:40])=[O:39])[CH2:34][CH:35]([CH3:36])[CH3:37])=[N:9]1)=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: COc1ccc(COC(=O)[C@H](CC(C)C)Nc2nn(C(=O)OC(C)(C)C)cc2-c2ccc(N3CCN(C(=O)OC(C)(C)C)CC3)cc2)cc1
Agent: [Pd]
Solvent: CCO
Product: CC(C)C[C@H](Nc1nn(C(=O)OC(C)(C)C)cc1-c1ccc(N2CCN(C(=O)OC(C)(C)C)CC2)cc1)C(=O)O
Reaction time: 8 h

Procedure:
To 4-methoxybenzyl N-(1-(tert-butoxycarbonyl)4-{4-[4-(tert-butoxycarbonyl)piperazin-1-yl]phenyl}-1H-pyrazol-3-yl)leucinate (1.14 g, 1.68 mmol) in EtOH (30 mL) was added the catalyst palladium on carbon (10%, 500 mg) and the reaction was stirred under a hydrogen atmosphere overnight. After degassing with nitrogen, CH2Cl2 was added and the reaction mixture was filtered on celite, washed with EtOH, concentrated in vacuo and purified by flash chromatography over silica gel (AcOH/EtOAc/Hex, 1/49/50) to afford N-(1-(tert-butoxycarbonyl)-4-{4-[4-(tert-butoxycarbonyl)piperazin-1-yl]phenyl}-1H-pyrazol-3-yl)leucine.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[N+:9]([O-])=O.O.O.O.O.O.O.O.O.O.[S-2:21].[Na+].[Na+]>O>[NH2:9][C:3]1[CH:4]=[C:5]([F:8])[CH:6]=[CH:7][C:2]=1[SH:21]
Reactant: O=[N+]([O-])c1cc(F)ccc1Cl
Reactant: [S-2]
Agent: [Na+]
Solvent: O
Product: Nc1cc(F)ccc1S
Temperature: 25 °C
Reaction time: 32 h
Yield: 24.4 %

Procedure:
To a solution of 2-chloro-5-fluoronitrobenzene (1.81 g, 10.31 mmol) dissolved in 30 mL of deionized water at room temperature was added sodium sulfide nonahydrate (9.90 g, 41.24 mmol) in a single portion. The resulting solution was heated to reflux and stirred under nitrogen for 32 hours. The resulting light yellow solution was then cooled to room temperature and was washed with 5×50 mL of ethyl acetate. The organic phase was dried over anhydrous magnesium sulfate, filtered, and evaporated to yield a yellow oil. The crude material was purified by flash chromatography eluting with CH2Cl2:MeOH=10:1 to yield 0.36 g (25%) of the title compound. MS (m/z, ES+): 144.0 (M+1, 100%); IR (KBr): 3430, 3340, 1615, 1573, 1482, 1281, 1248, 1172, 1124, 1044, 975, 840, 792 cm−1; 1H NMR (300 MHz, ppm, DMSO-d6) δ: 6.89 (dt, 1H), 6.50 (dd, 1H), 6.21 (dt, 1H), 5.80 (br s, 2H).
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3([CH2:22][NH2:23])[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)=[CH:12][CH:11]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.CCN(C(C)C)C(C)C.Cl.C(O[C:37]1[CH:42]=[CH:41][N:40]=[CH:39][C:38]=1[N+:43]([O-:45])=[O:44])C>C(#N)C>[N+:43]([C:38]1[CH:39]=[N:40][CH:41]=[CH:42][C:37]=1[NH:23][CH2:22][C:16]1([C:13]2[CH:14]=[CH:15][C:10]([O:9][CH2:8][CH2:7][CH2:6][N:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)=[CH:11][CH:12]=2)[CH2:17][CH2:18][O:19][CH2:20][CH2:21]1)([O-:45])=[O:44]
Reactant: CCOc1ccncc1[N+](=O)[O-]
Reactant: NCC1(c2ccc(OCCCN3CCCC3)cc2)CCOCC1
Agent: Cl
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: O=[N+]([O-])c1cnccc1NCC1(c2ccc(OCCCN3CCCC3)cc2)CCOCC1
Yield: 38.8 %

Procedure:
To a stirred solution of {4-[4-(3-Pyrrolidin-1-ylpropoxy)phenyl]tetrahydropyran-4-yl}methylamine (390 mg, 1.2 mmol) in acetonitrile (˜5 mL), was added Hunig's base (230 μL, 1.35 mmol, 1.1 eq.) and 4-ethoxy-3-nitropyridine hydrogen chloride (250 mg, 1.2 mmol, 1 eq.) and the mixture stirred at reflux for 72 hours. To this a further portion of 4-ethoxy-3-nitropyridine hydrogen chloride (50 mg, 0.24 mmol, 0.2 eq.) was added and the mixture stirred at reflux for a further 24 hours. The reaction mixture was then concentrated in vacuo to give a dark yellow oily residue. This was partitioned between 2M NaOH (30 mL) and DCM (2×30 mL). The organics were combined, dried over sodium sulphate, filtered and concentrated in vacuo to give a dark yellow oil. The crude product was purified by flash chromatography on silica gel eluting with dichloromethane:methanol:ammonia (98:2:0.2 to 90:10:1, by volume) to provide the title compound (205 mg, 38%). HRMS ESI+ m/z 441.2486 [MH]+.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:18]=[CH:17][C:6]([CH2:7][O:8][C:9]2[CH:14]=[CH:13][N:12]=[C:11]([CH2:15]O)[CH:10]=2)=[CH:5][CH:4]=1.S(Cl)([Cl:23])=O>ClCCl>[F:1][C:2]([F:20])([F:19])[C:3]1[CH:18]=[CH:17][C:6]([CH2:7][O:8][C:9]2[CH:14]=[CH:13][N:12]=[C:11]([CH2:15][Cl:23])[CH:10]=2)=[CH:5][CH:4]=1
Reactant: OCc1cc(OCc2ccc(C(F)(F)F)cc2)ccn1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: FC(F)(F)c1ccc(COc2ccnc(CCl)c2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
2.2 g (7.8 mmol) of the title compound from Example 3 are dissolved in 50 ml of anhydrous dichloromethane and a solution of 2 ml of thionyl chloride in 6 ml of dichloromethane is added dropwise at -10° C. The mixture is warmed to room temperature, stirred for 30 minutes more, and concentrated. The crystalline residue is brought to crystallization using diisopropyl ether and dried using an oilpump, m.p. 133°-135° C.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([F:9])=[C:5]([CH3:10])[CH:4]=1)#[CH:2].C(N(CC)CC)C.[Cl:18][C:19]1[CH:20]=[C:21](OS(C(F)(F)F)(=O)=O)[CH:22]=[N:23][CH:24]=1>C(OCC)(=O)C.[Cu]I.C1(C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)[Pd][P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:18][C:19]1[CH:24]=[N:23][CH:22]=[C:21]([C:2]#[C:1][C:3]2[CH:8]=[CH:7][C:6]([F:9])=[C:5]([CH3:10])[CH:4]=2)[CH:20]=1
Reactant: O=S(=O)(Oc1cncc(Cl)c1)C(F)(F)F
Reactant: C#Cc1ccc(F)c(C)c1
Agent: [Cu]I
Agent: c1ccc([P]([Pd][P](c2ccccc2)(c2ccccc2)c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: Cc1cc(C#Cc2cncc(Cl)c2)ccc1F
Temperature: 70 °C
Yield: 43.9 %

Procedure:
Add 4-ethynyl-1-fluoro-2-methylbenzene (0.56 g, 4.21 mmol), triethylamine (2.2 mL, 15 mmol), copper (I) iodide (36 mg, 0.19 mmol), and bis(triphenylphosphine)palladium (II) dichloride (110 mg, 0.15 mmol) to a solution of trifluoromethanesulfonic acid 5-chloropyridin-3-yl ester, (prepared as described in PREPARATION 25), (1.0 g, 3.8 mmol) in ethyl acetate (5 mL) under nitrogen. Heat the at 70° C. for 16 h and concentrate. Purify by silica gel chromatography, eluting with 100% dichloromethane, followed by a second silica gel chromatography eluting with 50:50 to 60:40 dichloromethane:hexanes, to give the title compound as a light yellow solid (410 mg, 44%).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[CH:16]=[C:17]([CH:21]=[C:22]([O:33][CH2:34][CH2:35][OH:36])[C:23]=2[O:24][C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([O:31][CH3:32])[CH:26]=2)[C:18](O)=[O:19])(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:37]1[O:46][C:45]2[CH:44]=[CH:43][C:41]([NH2:42])=[CH:40][C:39]=2[O:38]1>>[O:46]1[C:45]2[CH:44]=[CH:43][C:41]([NH:42][C:18](=[O:19])[C:17]3[CH:21]=[C:22]([O:33][CH2:34][CH2:35][OH:36])[C:23]([O:24][C:25]4[CH:30]=[CH:29][CH:28]=[C:27]([O:31][CH3:32])[CH:26]=4)=[C:15]([NH:14][S:11]([C:8]4[CH:9]=[CH:10][C:5]([C:1]([CH3:3])([CH3:2])[CH3:4])=[CH:6][CH:7]=4)(=[O:12])=[O:13])[CH:16]=3)=[CH:40][C:39]=2[O:38][CH2:37]1
Reactant: Nc1ccc2c(c1)OCO2
Reactant: COc1cccc(Oc2c(NS(=O)(=O)c3ccc(C(C)(C)C)cc3)cc(C(=O)O)cc2OCCO)c1
Product: COc1cccc(Oc2c(NS(=O)(=O)c3ccc(C(C)(C)C)cc3)cc(C(=O)Nc3ccc4c(c3)OCO4)cc2OCCO)c1

Procedure:
Analogously to Example 74, by condensing 3-(4-tert-butyl-benzenesulphonylamino)-5-(2-hydroxy-ethoxy)-4-(3-methoxy-phenoxy)-benzoic acid with 3,4-methylenedioxyaniline there was obtained N-benzo-[1,3]dioxol-5-yl-3-(4-tert-butylbenzenesulphonylamino)-5-(2-hydroxy-ethoxy)-4-(3-methoxy-phenoxy)-benzamide.
Reaction SMILES: [Cl-].[Cl:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][C:4]=1[NH:13][CH2:14][CH2:15][NH3+:16].[Cl:17][C:18]1[S:22][C:21]([CH:23]=O)=[CH:20][CH:19]=1>>[Cl:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][C:4]=1[NH:13][CH2:14][CH2:15][NH:16][CH2:23][C:21]1[S:22][C:18]([Cl:17])=[CH:19][CH:20]=1
Reactant: O=Cc1ccc(Cl)s1
Reactant: [NH3+]CCNc1ccc2ccccc2c1Cl
Agent: [Cl-]
Product: Clc1ccc(CNCCNc2ccc3ccccc3c2Cl)s1
Yield: 52 %

Procedure:
Prepared from 2-[(1-chloronaphthalen-2-yl)amino]ethanaminium chloride and 5-chlorothiophene-2-carbaldehyde in 52% yield as a white oil.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([N:7]2[CH:16]=[C:15]3[C:9]([CH2:10][CH2:11][N:12]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:14]3)=[N:8]2)[CH2:3][CH2:2]1.Br[C:25]1[CH:26]=[CH:27][C:28]([CH3:31])=[N:29][CH:30]=1.C1C=CC(P(C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(C)([O-])C.[Na+]>CO.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O1CCOCC1>[CH3:31][C:28]1[N:29]=[CH:30][C:25]([N:1]2[CH2:6][CH2:5][CH:4]([N:7]3[CH:16]=[C:15]4[C:9]([CH2:10][CH2:11][N:12]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:14]4)=[N:8]3)[CH2:3][CH2:2]2)=[CH:26][CH:27]=1
Reactant: Cc1ccc(Br)cn1
Reactant: CC(C)(C)OC(=O)N1CCc2cn(C3CCNCC3)nc2CC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: C1COCCO1
Solvent: CO
Product: Cc1ccc(N2CCC(n3cc4c(n3)CCN(C(=O)OC(C)(C)C)CC4)CC2)cn1
Reaction time: 14 h

Procedure:
1,1-Dimethylethyl 2-(4-piperidinyl)-4,5,7,8-tetrahydropyrazolo[3,4-d]azepine-6(2H)-carboxylate (may be prepared as described in Description 49) (65 mg, 0.21 mmol), 5-bromo-2-methylpyridine (52 mg, 0.30 mmol), palladium acetate (5 mg, 0.02 mmol), (+/−) BINAP (25 mg, 0.04 mmol), sodium tert-butoxide (39 mg, 0.041 mmol) and dioxane (2 ml) were mixed and heated to reflux under Argon and kept at this temperature for 14 h. After an additional 1.5 h, more 5-bromo-2-methylpyridine (1.5 eq), palladium acetate (0.1 eq), (+/−) BINAP (0.2 eq) and sodium tert-butoxide (2 eq) were added and the mixture stirred at reflux under Argon for an additional 7 h. the mixture was then allowed to cool over 45 mins and was then diluted with methanol and purified by SCX eluting with methanol, then 2M methanol/NH3. Purified further by SPE(Si) eluting with dichloromethane:methanol 50:1→25:1→10:1. Further purification by Mass Directed Autopreparation afforded the title compound (D50). MS (ES+) m/e 412 [M+H]+.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][NH2:9])[CH:5]=[CH:4][N:3]=[CH:2]1.[F:10][C:11]([F:22])([F:21])[C:12]1[CH:13]=[C:14]([N:18]=[C:19]=[O:20])[CH:15]=[CH:16][CH:17]=1>C1(C)C=CC=CC=1>[N:1]1([CH2:6][CH2:7][CH2:8][NH:9][C:19]([NH:18][C:14]2[CH:15]=[CH:16][CH:17]=[C:12]([C:11]([F:10])([F:21])[F:22])[CH:13]=2)=[O:20])[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: NCCCn1ccnc1
Reactant: O=C=Nc1cccc(C(F)(F)F)c1
Solvent: Cc1ccccc1
Product: O=C(NCCCn1ccnc1)Nc1cccc(C(F)(F)F)c1
Reaction time: 8 h

Procedure:
A 2.50 g. portion of 1H-imidazole-1-propanamine was added to 20 ml. of toluene. A solution of 3.7 g. of m-trifluoromethylphenyl isocyanate in 20 ml. of toluene was added and the mixture was stirred overnight, then evaporated to a syrup. This syrup was triturated twice with ether giving 4.95 g. of crystals. These crystals were dissolved in methylene chloride, hot ethyl acetate or a mixture of the two and passed through a silica gel column, developing with 200 ml. of ethyl acetate and discarding the 200 ml. fraction. The column was then eluted with 10% methanol in ethyl acetate, collecting three 200 ml. fractions. These fractions were combined and evaporated in vacuo, giving 4.33 g. of the desired product as colorless waxy crystals, mp 105°-108° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][NH:5][CH:6]=1.Cl[CH:8]([CH3:11])[C:9]#[N:10].C(=O)([O-])[O-].[Cs+].[Cs+].O1CCCC1>CCOCC>[Cl:1][C:2]1[CH:3]=[N:4][N:5]([CH:8]([CH3:11])[C:9]#[N:10])[CH:6]=1
Reactant: Clc1cn[nH]c1
Reactant: CC(Cl)C#N
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(C#N)n1cc(Cl)cn1
Temperature: 100 °C
Yield: 116.3 %

Procedure:
4-Chloro-1H-pyrazole (4.05 g, 39.5 mmol), 2-chloropropanenitrile (3.71 g, 41.5 mmol), cesium carbonate (15.6 g, 44.3 mmol) and anhydrous tetrahydrofuran (20 mL) were added into a sealed tube and the reaction mixture was heated to 100° C. for 2 h. The mixture was diluted with ether (100 mL) and filtered. The solids were rinsed with ether (30 mL×3) and the filtrate was diluted with dichloromethane (10 mL). The solution was concentrated under reduced pressure to afford the title compound as oil (7.15 g). The material was taken to the next step without further purification. 1H NMR (500 MHz, CDCl3) δ 1.90 (d, 3H), 5.21-5.30 (m, 1H), 7.51 (s, 1H), 7.58 (s, 1H); MS (EI+) (M+) 155; GCMS retention time: 1.23 minutes (Method O).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:17](=[O:18])[C:16]2[C@@H:15]3[C:19]([CH3:21])([CH3:20])[C@@:12]([CH3:22])([CH2:13][CH2:14]3)[C:11]=2[NH:10]1.[CH2:23](I)[CH3:24]>CN(C)C=O>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:17](=[O:18])[C:16]2[C@@H:15]3[C:19]([CH3:21])([CH3:20])[C@@:12]([CH3:22])([CH2:13][CH2:14]3)[C:11]=2[N:10]1[CH2:23][CH3:24]
Reactant: CC1(C)[C@@H]2CC[C@@]1(C)c1[nH]n(-c3ccc(F)cc3F)c(=O)c12
Reactant: CCI
Solvent: CN(C)C=O
Product: CCn1c2c(c(=O)n1-c1ccc(F)cc1F)[C@H]1CC[C@]2(C)C1(C)C
Temperature: 100 °C
Yield: 67.1 %

Procedure:
A mixture of (4S,7R)-2-(2,4-difluoro-phenyl)-7,8,8-trimethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (Intermediate 14; 200 mg, 0.65 mmol) and ethyl iodide (262 μL, 3.3 mmol) in dimethylformamide (2 mL) was heated at 100° C. over the weekend. The solvent was evaporated and ethyl acetate was added. The solution was washed twice with saturated aqueous sodium thiosulfate, and three times with water. The solution was dried (magnesium sulfate), filtered, evaporated, and purified by column chromatography, eluting with 75% ethyl acetate/petroleum ether, to give (4S,7R)-2-(2,4-difluoro-phenyl)-1-ethyl-7,8,8-trimethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (145 mg, 67%) as a white solid. IR 1667 cm−1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](Cl)[N:5]=[C:4]([NH:9][CH3:10])[N:3]=1.[K+].[F:12][C:13]([F:25])([F:24])[C:14]1[CH:15]=[C:16]([S:20]([NH-:23])(=[O:22])=[O:21])[CH:17]=[CH:18][CH:19]=1>CN1CCCC1=O>[Cl:1][C:2]1[N:3]=[C:4]([NH:9][CH3:10])[N:5]=[C:6]([NH:23][S:20]([C:16]2[CH:17]=[CH:18][CH:19]=[C:14]([C:13]([F:12])([F:25])[F:24])[CH:15]=2)(=[O:21])=[O:22])[CH:7]=1
Reactant: CNc1nc(Cl)cc(Cl)n1
Reactant: [NH-]S(=O)(=O)c1cccc(C(F)(F)F)c1
Agent: [K+]
Solvent: CN1CCCC1=O
Product: CNc1nc(Cl)cc(NS(=O)(=O)c2cccc(C(F)(F)F)c2)n1
Yield: 45.7 %

Procedure:
0.27 g (0.00155 mol) of (4,6-dichloro-pyrimidin-2-yl)-methylamine and 0.82 g (0.0031 mol) of 3-trifluoromethyl-benzenesulfonamide potassium salt were stirred in 10 ml of 1-methyl-2-pyrrolidone at 150° C. for 8 hours. Then, the solvent was distilled off in a high vacuum, the residue was partitioned in ethyl acetate/water and extracted. The aqueous phase was made acid with 4N HCl and extracted with dichloromethane. The residue was chromatographed over silica gel with cyclohexane/ethyl acetate 2:1 as the eluent. There was obtained 0.26 g (69%) of N-(6-chloro-2-methylamino-pyrimidin-4-yl)-3-trifluoromethyl-benzenesulfonamide as white/beige crystals; m.p.: 190-193° C.
Reaction SMILES: [F:1][C:2]([F:21])([CH3:20])[CH2:3][C@H:4]1[C:8](=[O:9])[O:7]C[N:5]1[C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11].[OH-].[Na+].Cl>CC(C)=O>[CH2:13]([O:12][C:10]([NH:5][C@@H:4]([CH2:3][C:2]([F:1])([F:21])[CH3:20])[C:8]([OH:9])=[O:7])=[O:11])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CC(F)(F)C[C@H]1C(=O)OCN1C(=O)OCc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Product: CC(F)(F)C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Temperature: 0 °C
Reaction time: 2.5 h

Procedure:
The compound from example 14 (4.9 g, 16.37 mmol) was dissolved in 30 ml of acetone and cooled to 0° C., and then 1 N sodium hydroxide solution (32.74 ml, 32.74 mmol, 2 eq.) was added. For about 2.5 h, the reaction mixture was stirred at room temperature; reaction monitoring by LC-MS indicated complete conversion. This was followed by addition of 20 ml of 1 N HCl, distilling-off of acetone under reduced pressure and adjustment of the solution to pH 3 to 4. The mixture was extracted twice by shaking with ethyl acetate. The organic phase was washed with saturated NaCl solution, dried over sodium sulfate and concentrated by evaporation to dryness under reduced pressure. The crude product was chromatographed using silica gel with a DCM/methanol gradient (0-6% methanol).
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:20])[C:4]2[C:9]([C:10]=1[C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:12]=1[F:18])=[CH:8][CH:7]=[C:6]([OH:19])[CH:5]=2.BrC1C(=O)C2C(C=1C1C=CC=CC=1)=CC=C(O)C=2.[O:39]=[S:40]1(=[O:49])[CH2:45][CH2:44][N:43]([CH2:46][CH2:47]O)[CH2:42][CH2:41]1>>[Br:1][C:2]1[C:3](=[O:20])[C:4]2[C:9]([C:10]=1[C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:12]=1[F:18])=[CH:8][CH:7]=[C:6]([O:19][CH2:47][CH2:46][N:43]1[CH2:44][CH2:45][S:40](=[O:49])(=[O:39])[CH2:41][CH2:42]1)[CH:5]=2
Reactant: O=C1C(Br)=C(c2ccc(F)cc2F)c2ccc(O)cc21
Reactant: O=S1(=O)CCN(CCO)CC1
Agent: O=C1C(Br)=C(c2ccccc2)c2ccc(O)cc21
Product: O=C1C(Br)=C(c2ccc(F)cc2F)c2ccc(OCCN3CCS(=O)(=O)CC3)cc21
Yield: 65 %

Procedure:
The procedure of Step 6 of Example 1 was repeated except for using 2-bromo-3-(2,4-difluorophenyl)-6-hydroxy-1H-inden-1-one obtained in Step 5 of Example 82 as a starting material instead of 2-bromo-6-hydroxy-3-phenyl-1H-inden-1-one, 2-(1,1-dioxothiomorpholin-4-yl)ethanol instead of 4-(2-hydroxyethyl)morpholine to obtain the title compound (65%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:31])[CH:5]([CH:7]1[C:12](=[O:13])[N:11]([C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=2)[CH2:10][CH2:9][N:8]1C(OCC1C=CC=CC=1)=O)[OH:6])[CH3:2]>CCO>[OH:6][CH:5]([CH:7]1[C:12](=[O:13])[N:11]([C:14]2[CH:15]=[CH:16][C:17]([CH3:20])=[CH:18][CH:19]=2)[CH2:10][CH2:9][NH:8]1)[C:4]([O:3][CH2:1][CH3:2])=[O:31]
Reactant: CCOC(=O)C(O)C1C(=O)N(c2ccc(C)cc2)CCN1C(=O)OCc1ccccc1
Solvent: CCO
Product: CCOC(=O)C(O)C1NCCN(c2ccc(C)cc2)C1=O
Yield: 97.3 %

Procedure:
According to the Step 33-1 in synthetic method for EXAMPLE 33, compound 109-1 (0.3 g) with EtOH was used instead of EXAMPLE 32 to obtain compound 109-2 (0.2 g) as a pale yellow amorphous solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:10]([CH2:11][C:12]3[C:13]([F:23])=[C:14]([CH:19]=[CH:20][C:21]=3[F:22])[O:15][CH2:16][CH2:17][OH:18])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[N:24]1[CH:29]=[CH:28][CH:27]=[C:26](B(O)O)[CH:25]=1.C(=O)([O-])[O-].[K+].[K+].O>C(#N)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:23][C:13]1[C:12]([CH2:11][C:10]2[C:4]3[C:5](=[N:6][CH:7]=[C:2]([C:26]4[CH:25]=[N:24][CH:29]=[CH:28][CH:27]=4)[CH:3]=3)[NH:8][CH:9]=2)=[C:21]([F:22])[CH:20]=[CH:19][C:14]=1[O:15][CH2:16][CH2:17][OH:18]
Reactant: OB(O)c1cccnc1
Reactant: OCCOc1ccc(F)c(Cc2c[nH]c3ncc(Br)cc23)c1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: OCCOc1ccc(F)c(Cc2c[nH]c3ncc(-c4cccnc4)cc23)c1F
Yield: 31.7 %

Procedure:
To 2-[3-(5 Bromo-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-2,4-difluoro-phenoxy]-ethanol (P-1392, 35.0 mg, 0.091 mmol) in acetonitrile (4.0 mL) were added 3-pyridylboronic acid (14.6 mg, 0.12 mmol), tetrakis(triphenylphosphine)palladium(0) (3.0 mg, 0.0026 mmol) and 1 M potassium carbonate solution (1.5 mL). The reaction was microwaved (300 watts) at 160° C. for 7 minutes. The reaction was poured into water and extracted with ethyl acetate. The organic layer was collected and dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting 4% methanol in methylene chloride to give the compound as white solid (P-1394, 11.0 mg, 32%). MS (ESI) [M+H+]+=382.2.