Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:16]=[C:17]([CH3:19])[CH:18]=1)[O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([F:15])([F:14])[F:13])=[CH:8][N:7]=1.C([O:23][B:24](OC(C)C)[O:25]C(C)C)(C)C.C1COCC1.[Li]CCCC>C1(C)C=CC=CC=1>[CH3:19][C:17]1[CH:18]=[C:2]([B:24]([OH:25])[OH:23])[CH:3]=[C:4]([O:5][C:6]2[CH:11]=[CH:10][C:9]([C:12]([F:15])([F:14])[F:13])=[CH:8][N:7]=2)[CH:16]=1
Reactant: Cc1cc(Br)cc(Oc2ccc(C(F)(F)F)cn2)c1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: [Li]CCCC
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: Cc1cc(Oc2ccc(C(F)(F)F)cn2)cc(B(O)O)c1
Temperature: -40 °C
Reaction time: 1 h
Yield: 121.2 %

Procedure:
2-(3-Bromo-5-methylphenoxy)-5-(trifluoromethyl)pyridine (2 g, 0.006 mol) and triisopropylborate (1.66 mL, 0.0072 mol) were dissolved in toluene (40 mL) and THF (20 mL) and cooled to −78° C. n-BuLi (5.38 mL, 0.006 mol) was added while maintaining the reaction at −70° C. The reaction was stirred for 1 h at −40° C. Gradually the temperature was increased to −20-0° C. and the reaction was quenched with 2NHCl. The reaction mixture was warmed to RT, concentrated and extracted with EtOAc. The organic extract was dried over Na2SO4 and concentrated under reduced pressure to give the title compound (2.16 g).
Reaction SMILES: [C:1]1([N:7]2[C:11]([B:12]([OH:14])[OH:13])=[CH:10][CH:9]=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O[C:16]([C:19](O)([CH3:21])[CH3:20])([CH3:18])[CH3:17]>C1(C)C=CC=CC=1>[C:1]1([N:7]2[C:11]([B:12]3[O:13][C:19]([CH3:21])([CH3:20])[C:16]([CH3:18])([CH3:17])[O:14]3)=[CH:10][CH:9]=[N:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)(O)C(C)(C)O
Reactant: OB(O)c1ccnn1-c1ccccc1
Solvent: Cc1ccccc1
Product: CC1(C)OB(c2ccnn2-c2ccccc2)OC1(C)C
Temperature: 40 °C
Yield: 64.4 %

Procedure:
To a mixture of (1-phenyl-1H-pyrazol-5-yl)boronic acid (8.57 g, 45.6 mmol) in toluene (86 mL) was added pinacol (5.39 g, 45.6 mmol) at room temperature. The mixture was heated to 40° C. for 2 days. The mixture was concentrated in vacuo and triturated with hexane to yield the title compound (7.93 g, 64% yield) as a pale yellow solid: 1H NMR (DMSO-d6, 300 MHz): δ ppm 1.23 (12H, s), 6.84 (1H, s), 7.34-7.59 (5H, m), 7.75 (1H, d, J=1.9 Hz)
Reaction SMILES: [F:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:6][C:5]([C:14]([OH:16])=O)=[C:4]([O:17][CH3:18])[CH:3]=1.C(Cl)(=O)C(Cl)=O.Cl.[N+:26]([C:29]1[CH:30]=[C:31]([CH:34]=[CH:35][CH:36]=1)[CH2:32][NH2:33])([O-:28])=[O:27]>ClCCl.CN(C=O)C>[N+:26]([C:29]1[CH:30]=[C:31]([CH:34]=[CH:35][CH:36]=1)[CH2:32][NH:33][C:14]([C:5]1[CH:6]=[C:7]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:2]([F:1])=[CH:3][C:4]=1[O:17][CH3:18])=[O:16])([O-:28])=[O:27]
Reactant: COc1cc(F)c(-c2ccccc2)cc1C(=O)O
Reactant: NCc1cccc([N+](=O)[O-])c1
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1cc(F)c(-c2ccccc2)cc1C(=O)NCc1cccc([N+](=O)[O-])c1
Temperature: 40 °C
Yield: 64.8 %

Procedure:
A stirring slurry of 6-fluoro-4-methoxy-biphenyl-3-carboxylic acid (1.0 g, 4.06 mmol) in dichloromethane (8.2 mL, 0.5 M) was treated with oxalyl chloride (1.1 mL, 12.2 mmol) and DMF (1 drop). The mixture was heated to 40° C. until the solution was clear (1-2 h). Next, the mixture was allowed to cool to room temperature, concentrated under reduced pressure, and then diluted with dichloromethane (8.2 mL, 0.5 M). To the stirring mixture at 0° C. was added diisdpropylethyl amine (1.8 mL, 10.2 mmol) followed by 3-nitrobenzylamine hydrochloride salt (1.2 g, 6.1 mmol). Stirring under nitrogen, the solution was gradually warmed to room temperature and stirred overnight. The mixture was then diluted with dichloromethane and washed with 2N HCl (2×50 mL) and saturated aq NaCl (1×100 mL) The organic layer was dried over Na2SO4, filtered, and concentrated to afford a yellow oil. Purification by MPLC (10-100% ethyl acetate in heptane, 23 mL/min, 75 min) provided 6-fluoro-4-methoxy-biphenyl-3-carboxylic acid 3-nitro-benzylamide (1.0 g, 65%) as a yellow solid: Rf 0.33 (50% ethyl acetate in heptane); 1H NMR (DMSO-d6, 300 MHz) δ 8.90 (bd t, J=6.2 Hz, 1H), 8.10 (dd, J1=7.2 Hz, J2=2.4 Hz, 1H), 7.84 (d, J=9.3 Hz, 1H), 7.79 (d, J=7.5 Hz, 1H), 7.63 (t, J=8.0 Hz, 1H), 7.52-7.43 (m, 5H), 7.40-7.34 (m, 1H), 7.20 (d, J=12.9 Hz, 1H), 4.61 (d, J=6.0 Hz, 2H), 3.96 (s, 3H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:17]=[CH:16][C:12]([C:13](Cl)=[O:14])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:18][C:19]([F:29])([F:28])[C@H:20]([OH:27])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26].C(N(CC)CC)C>C(Cl)Cl>[F:18][C:19]([F:28])([F:29])[C@H:20]([O:27][C:13](=[O:14])[C:12]1[CH:11]=[CH:10][C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:17][CH:16]=1)[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: O=C(Cl)c1ccc(OCc2ccccc2)cc1
Reactant: CCCCCC[C@@H](O)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCC[C@@H](OC(=O)c1ccc(OCc2ccccc2)cc1)C(F)(F)F
Temperature: 25 °C
Reaction time: 12 h
Yield: 65.1 %

Procedure:
To 5 ml of a methylene chloride solution containing 0.56 g of 4-benzyloxybenzoic acid chloride was slowly added a solution of 0.38 g of (R)-(+)-1-trifluoromethylheptanol and 0.23 g of triethylamine in 5 ml of methylene chloride under ice-cooling. The mixture was allowed to warm to room temperature and stirred at that temperature for 12 hours. The reaction mixture was poured into ice-water and extracted with methylene chloride. The methylene chloride phase was washed successively with diluted hydrochloric acid, water, an aqueous 1N sodium carbonate solution, and water and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure, and the residual crude product was purified by silica gel column chromatography to obtain 0.53 g of (R)-(+)-4-benzyloxybenzoic acid 1-trifluoromethylheptyl ester.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]=[CH:10][C:11]2[N:16]=[CH:15][C:14]([N:17]3[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]3)=[CH:13][CH:12]=2)=[CH:5][CH:4]=1>C(OCC)(=O)C.[C].[Pd]>[OH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11]2[N:16]=[CH:15][C:14]([N:17]3[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]3)=[CH:13][CH:12]=2)=[CH:5][CH:4]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(C=Cc3ccc(CO)cc3)nc2)CC1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(CCc3ccc(CO)cc3)nc2)CC1
Reaction time: 11 h
Yield: 84.1 %

Procedure:
To a solution of tert-butyl 4-(6-{2-[4-(hydroxymethyl)phenyl]vinyl}pyridin-3-yl)piperazine-1-carboxylate (848.0 mg, 2.144 mmol) in ethyl acetate (45 ml) was added 5% palladium carbon (84.5 mg, 50% containing water), and the mixture was hydrogenated at room temperature, under atmospheric pressure for 11 hrs. The reaction mixture was filtered through Celite. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate:hexane=6:4→7:3) to give tert-butyl 4-(6-{2-[4-(hydroxymethyl)phenyl]ethyl}pyridin-3-yl)piperazine-1-carboxylate (716.9 mg, yield 84.1%) as a white solid.
Reaction SMILES: [CH2:1]([N:4]1[C:12](=[O:13])[C:11]2[N:10]=[C:9]([CH:14]([C:17]3[CH:22]=[CH:21][C:20]([NH:23][CH2:24][C:25]([OH:27])=[O:26])=[CH:19][CH:18]=3)[CH2:15][CH3:16])[NH:8][C:7]=2[N:6]([CH2:28][CH2:29][CH3:30])[C:5]1=[O:31])[CH2:2][CH3:3].S(=O)(=O)(O)O.[CH3:37]O>C(OCC)C>[CH2:1]([N:4]1[C:12](=[O:13])[C:11]2[N:10]=[C:9]([CH:14]([C:17]3[CH:22]=[CH:21][C:20]([NH:23][CH2:24][C:25]([O:27][CH3:37])=[O:26])=[CH:19][CH:18]=3)[CH2:15][CH3:16])[NH:8][C:7]=2[N:6]([CH2:28][CH2:29][CH3:30])[C:5]1=[O:31])[CH2:2][CH3:3]
Reactant: CO
Reactant: CCCn1c(=O)c2nc(C(CC)c3ccc(NCC(=O)O)cc3)[nH]c2n(CCC)c1=O
Agent: O=S(=O)(O)O
Solvent: CCOCC
Product: CCCn1c(=O)c2nc(C(CC)c3ccc(NCC(=O)OC)cc3)[nH]c2n(CCC)c1=O
Temperature: 60 °C

Procedure:
Dissolve 2-[4-[1-(2,3,6,9-tetrahydro-1,3-dipropyl-2,6-dioxo-1H-purin-8-yl)propyl]phenylamino]acetic acid (85.49, 0.2 mol) in methanol (500 mL) and treat with concentrated sulfuric acid (0.5 mL). Heat to 60° C. for 16 hours, cool and reduce the solvent by 50% in vacuo. Dilute with ethyl ether (500 mL), wash with saturated sodium hydrogen carbonate, then brine. Dry (MgSO4) and evaporate the solvent in vacuo to give the title compound.
Reaction SMILES: C([O:5][C:6]([CH:8]1[CH:14]([NH:15][C:16]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:17])[CH2:13][CH:12]=[CH:11][CH2:10][N:9]1[S:26]([C:29]1[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=1)(=[O:28])=[O:27])=[O:7])(C)(C)C>ClCCl.FC(F)(F)C(O)=O>[CH2:19]([O:18][C:16]([NH:15][CH:14]1[CH2:13][CH:12]=[CH:11][CH2:10][N:9]([S:26]([C:29]2[CH:30]=[CH:31][C:32]([O:35][CH3:36])=[CH:33][CH:34]=2)(=[O:27])=[O:28])[CH:8]1[C:6]([OH:7])=[O:5])=[O:17])[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: COc1ccc(S(=O)(=O)N2CC=CCC(NC(=O)OCc3ccccc3)C2C(=O)OC(C)(C)C)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(S(=O)(=O)N2CC=CCC(NC(=O)OCc3ccccc3)C2C(=O)O)cc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
3-Benzyloxycarbonylamino-1-(4-methoxy-benzenesulfonyl)-2,3,4,7-tetrahydro-1H-azepine-2-carboxylic acid tert-butyl ester (28 mg, 0.054 mmol) is dissolved in 4 ml Dichloro-methane/Trifluoroacetic Acid; 3:1 and stirred for 5 h at room temperature. The solvent/reagent are evaporated and the remaining oil is co-evaporated from Toluene twice. Flash-chromatography, Hexane/Ethylacetate; 1:1 afforded the desired product: Cal. 460.51, found (M)+ 460.9.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]1[C:12](=C(C)C)[CH:7]2[CH2:6][CH2:5]1.[O:16]=[O+][O-].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C(Cl)Cl.CO>[Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]1[C:12](=[O:16])[CH:7]2[CH2:6][CH2:5]1
Reactant: CC(C)=C1C2CCC1c1c(Cl)cccc12
Reactant: O=[O+][O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CO
Solvent: ClCCl
Product: O=C1C2CCC1c1c(Cl)cccc12
Temperature: -40 °C

Procedure:
In a 20 liter reactor, 600 g of 5-chloro-9-isopropylidene-1,2,3,4-tetrahydro-1,4-methano-naphthalene (27.43 mol) were charged in a mixture of 13 l CH2Cl2 and 0.5 l of MeOH. The reaction mixture was cooled down at −40° C. and an ozone stream (55 kg/h) was feed until change of color. After elimination of the ozone residue, PPh3 (23.83 mol) was added and reaction mixture was heated to ambient temperature. The purification was done via chromatography. 421 g white solid product was isolated with a purity >98%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12](O)=[O:13])[N:8]=[CH:7][N:6]=[C:5]2[NH:15][CH:16]([C:18]1[NH:22][C:21]2[CH:23]=[CH:24][C:25]([Cl:27])=[CH:26][C:20]=2[N:19]=1)[CH3:17].FC1C(OC(N(C)C)=[N+](C)C)=C(F)C(F)=C(F)C=1F.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.[OH:63][CH:64]1[CH2:69][CH2:68][CH2:67][NH:66][CH2:65]1>CS(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]([N:66]1[CH2:67][CH2:68][CH2:69][CH:64]([OH:63])[CH2:65]1)=[O:13])[N:8]=[CH:7][N:6]=[C:5]2[NH:15][CH:16]([C:18]1[NH:22][C:21]2[CH:23]=[CH:24][C:25]([Cl:27])=[CH:26][C:20]=2[N:19]=1)[CH3:17]
Reactant: OC1CCCNC1
Reactant: CC(Nc1ncnc2cc(C(=O)O)c(Cl)cc12)c1nc2cc(Cl)ccc2[nH]1
Agent: CN(C)C(Oc1c(F)c(F)c(F)c(F)c1F)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(Nc1ncnc2cc(C(=O)N3CCCC(O)C3)c(Cl)cc12)c1nc2cc(Cl)ccc2[nH]1

Procedure:
Prepared analogously to Example 37a from 6-chloro-4-[1-(5-chloro-1H-benzimidazol-2-yl)-ethylamino]-7-hydroxycarbonyl-quinazoline, pentafluorophenyl-tetramethyluronium-hexafluorophosphate (PFTU), diisopropylethylamine and 3-hydroxy-piperidine in DMSO at ambient temperature.
Reaction SMILES: CO[C:3](=[O:18])[C:4]([CH3:17])([CH3:16])[C@:5]([NH2:15])([C:7]1[CH:12]=[C:11]([Br:13])[CH:10]=[CH:9][C:8]=1[F:14])[CH3:6].[CH3:19][NH:20][C:21]([NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=S>>[C:26]([O:25][C:24](=[O:30])[NH:23][C:21]1[N:20]([CH3:19])[C:3](=[O:18])[C:4]([CH3:16])([CH3:17])[C@:5]([C:7]2[CH:12]=[C:11]([Br:13])[CH:10]=[CH:9][C:8]=2[F:14])([CH3:6])[N:15]=1)([CH3:29])([CH3:28])[CH3:27]
Reactant: COC(=O)C(C)(C)[C@](C)(N)c1cc(Br)ccc1F
Reactant: CNC(=S)NC(=O)OC(C)(C)C
Product: CN1C(=O)C(C)(C)[C@@](C)(c2cc(Br)ccc2F)N=C1NC(=O)OC(C)(C)C

Procedure:
Starting from (S)-3-amino-3-(5-bromo-2-fluoro-phenyl)-2,2-dimethyl-butyric acid methyl ester and tert-butyl [(methylamino)carbonothioyl]carbamate, the product [(S)-4-(5-bromo-2-fluoro-phenyl)-1,4,5,5-tetramethyl-6-oxo-1,4,5,6-tetrahydro-pyrimidin-2-yl]-carbamic acid tert-butyl ester was obtained as a white solid. MS (ESI): m/z=442.2 and 444.1 [M+H]+.
Reaction SMILES: [CH2:1]([N:5]([C:12]1[C:13](I)=[N:14][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:16][CH:17]=1)C(=O)C(F)(F)F)[CH:2]=[CH:3][CH3:4].O>CN(C=O)C.[N+](CCCC)(CCCC)(CCCC)CCCC.[Cl-].CC([O-])=O.CC([O-])=O.[Pd+2]>[CH2:3]([C:2]1[C:13]2=[N:14][C:15]([C:18]([F:19])([F:20])[F:21])=[CH:16][CH:17]=[C:12]2[NH:5][CH:1]=1)[CH3:4]
Reactant: CC=CCN(C(=O)C(F)(F)F)c1ccc(C(F)(F)F)nc1I
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CN(C)C=O
Solvent: O
Product: CCc1c[nH]c2ccc(C(F)(F)F)nc12
Temperature: 100 °C
Reaction time: 1 h
Yield: 86.3 %

Procedure:
A solution of N-but-2-enyl-2,2,2-trifluoro-N-(2-iodo-6-trifluoromethyl-pyridin-3-yl)-acetamide (5.2 g, 11.9 mmol) in DMF (24 mL) is treated with n-Bu4NCl (3.6 g, 13.1 mmol), Pd(OAc)2 (107 mg, 0.48 mmol), and stirred at 100° C. for 1 h. H2O (10 mL) is added, and the mixture is cooled to rt and filtered through a pad of silica gel. The filtrate is extracted with EtOAc/heptane (3×50 mL) (1:1). The combined organic layer is dried (Na2SO4), filtered and concentrated in vacuo. The residue is purified by silica gel chromatography eluting with 5%-50% EtOAc in heptane to afford 3-ethyl-5-trifluoromethyl-1H-pyrrolo[3,2-b]pyridine (2.2 g, 86%). MS: 215 (M+H); 1H NMR (300 MHz, CDCl3): δ 8.24 (s, NH, 1H), 7.73 (d, 1H), 7.50 (d, 1H), 7.34 (d, 1H), 2.93 (q, 2H), 1.36 (t, 3H).
Reaction SMILES: C[N:2](C)[CH:3]=[O:4].[N+:6]([C:9]1[CH:17]=[C:16]2[C:12]([CH2:13][CH2:14][CH:15]2C(O)=O)=[CH:11][CH:10]=1)([O-:8])=[O:7].S(Cl)(Cl)=O.C1(C)C=CC=CC=1>ClCCl>[N+:6]([C:9]1[CH:17]=[C:16]2[C:12]([CH2:13][CH2:14][CH:15]2[C:3]([NH2:2])=[O:4])=[CH:11][CH:10]=1)([O-:8])=[O:7]
Reactant: CN(C)C=O
Reactant: O=C(O)C1CCc2ccc([N+](=O)[O-])cc21
Solvent: O=S(Cl)Cl
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: NC(=O)C1CCc2ccc([N+](=O)[O-])cc21
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
Dimethylformamide (DMF, 1 ml) was added to a solution of 6-nitro-1-indancarboxylic acid, 1a (13 g) and thionylchloride (18 ml) in dichloromethane (125 ml). The mixture was heated to reflux for 4 hours. Toluene was added and volatile material was evaporated in vacuo. The thus obtained carboxylic acid chloride was dissolved in dichloromethane (100 ml) and added dropwise to a solution of 4-(4-fluorophenyl)piperidine (19.5 g) and triethylamine (7 ml) in dichloromethane (100 ml) at 0-5° C. The mixture was stirred at room temperature for another 1.5 hours. Water was added, the organic phase separated, washed with brine, dried (anh. MgSO4), filtered, and dichloromethane evaporated in vacuo leaving the crude 6-nitroindan-1-carboxamide derivative as an oil (35 g). Purification by column chromatography on silica gel (eluted with a 1:1 mixture of ethyl acetate and heptane) yielded 12 g of the pure carboxamide as an oil. All of this oil was dissolved in refluxing 90% ethanol (350 ml). Fe-powder (10 g) and concentrated aqueous HCl (1 ml) were added successively in small portions during 10 minutes. The resulting mixture was refluxed for another 2.5 hours. Inorganic salts were filtered off while still hot and ethanol evaporated in vacua, Diluted aqueous NH4OH was added until pH>9. Extraction with ethyl acetate (2×200 ml) and working-up as above of the organic phase afforded 8 g of the 6-aminoindan-1-carboxamide derivative. Mp: 144-145° C. To a suspension of LiAlH4 (2.7 g) in dry tetrahydrofuran (THF, 125 ml) was added dropwise a solution of all of the carboxamide in THF (125 ml). The mixture was gently refluxed for 2 hours. After cooling to 10° C. water (10 ml ) and a 15% aqueous NaOH solution were cautiously added to destroy excess LiAlH4. Inorganic salts were filtered off and washed extensively with THF. The combined THF solutions were evaporated leaving 6.5 g of the title compound 2a as an oil. The hydrochloride salt crystallized from 2-propanol. Mp: 198-201° C. 1H NMR (DMSO-d 6): δ 1.85-2.40 (m, 6H); 2.60-2.90 (m, 3H); 3.00-3.15 (m, 3H); 3.35 (broad s, 3H); 3.45-3.60 (m, 2H); 3.65-3.75 (m, 1H); 6.45 (d, 1H); 6.50 (s, 1H); 6.95 (d, 1H); 7.15 (t, 2H); 7.25-7.35 (m, 2H).
Reaction SMILES: [OH-].[Li+].[C:3]([N:6]1[CH:11]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:9]([CH2:18][C:19]([O:21]CC)=[O:20])[C:8](=[O:24])[CH:7]1[CH:25]([CH3:27])[CH3:26])(=[O:5])[CH3:4].Cl>C(O)C>[C:3]([N:6]1[CH:11]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:9]([CH2:18][C:19]([OH:21])=[O:20])[C:8](=[O:24])[CH:7]1[CH:25]([CH3:27])[CH3:26])(=[O:5])[CH3:4]
Reactant: CCOC(=O)CN1C(=O)C(C(C)C)N(C(C)=O)C=C1c1ccccc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Product: CC(=O)N1C=C(c2ccccc2)N(CC(=O)O)C(=O)C1C(C)C

Procedure:
A 4 N aqueous lithium hydroxide solution (0.4 ml) is added to a solution of ethyl {(3RS)-4-acetyl-3-isopropyl-2-oxo-6-phenyl-1,2,3,4-tetrahydropyrazin-1-yl}acetate (185 mg, Reference compound No. 50-1) in ethanol (5 ml), and the mixture is stirred for 35 minutes. To the reaction mixture is added 1 N hydrochloric acid to acidify the system, and the whole is extracted with ethyl acetate. The extract is washed with saturated brine and dried over anhydrous magnesium sulfate. The extract is concentrated under reduced pressure to give the titled reference compound (167 mg).
Reaction SMILES: [OH-].[K+].[Br:3][C:4]1[S:8][C:7]2=[C:9]([C:12]([O:14]CC)=[O:13])[N:10]=[CH:11][N:6]2[CH:5]=1>Cl>[Br:3][C:4]1[S:8][C:7]2=[C:9]([C:12]([OH:14])=[O:13])[N:10]=[CH:11][N:6]2[CH:5]=1
Reactant: CCOC(=O)c1ncn2cc(Br)sc12
Agent: Cl
Agent: [K+]
Agent: [OH-]
Product: O=C(O)c1ncn2cc(Br)sc12
Temperature: 60 °C
Reaction time: 1 h
Yield: 91.1 %

Procedure:
A 2 M aqueous solution (35 ml) of potassium hydroxide was added to ethyl 2-bromoimidazo[5,1-b] thiazole-7-carboxylate (1.32 g, 4.80 mmol), and the mixture was stirred at 60° C. for one hr. After the completion of the reaction, the reaction solution was poured into 4 M hydrochloric acid (20 ml) under ice cooling to precipitate a solid. The resultant solid was washed with water, and a mixed solvent composed of ethanol and toluene was added thereto. The solvent was removed by distillation under the reduced pressure, and the residue was then dried to give 2-bromoimidazo[5,1-b]thiazole-7-carboxylic acid (1.08 g, 91%) as a white solid.
Reaction SMILES: O.P(=O)(O)(O)O.[C:7]([C:9]1[CH:14]=[C:13]([C:15]([NH:17][NH:18][C:19]([C:21]2[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=2)=O)=[NH:16])[CH:12]=[CH:11][N:10]=1)#[N:8]>CC(O)CC>[N:24]1[CH:25]=[CH:26][C:21]([C:19]2[NH:18][N:17]=[C:15]([C:13]3[CH:12]=[CH:11][N:10]=[C:9]([C:7]#[N:8])[CH:14]=3)[N:16]=2)=[CH:22][CH:23]=1
Reactant: N#Cc1cc(C(=N)NNC(=O)c2ccncc2)ccn1
Agent: O=P(O)(O)O
Solvent: CCC(C)O
Solvent: O
Product: N#Cc1cc(-c2n[nH]c(-c3ccncc3)n2)ccn1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
Water (82 mL), 2-butanol (8.2 mL), and phosphoric acid (4.00 g) were added to 4-pyridinecarboxylic acid N′-(2-cyanopyridine-4-carbonimidoyl)hydrazide (4) (9.25 g), and the mixture was stirred at 80° C. for 8 hours. The reaction mixture was cooled to room temperature, and precipitated crystals were recovered through filtration. The crystals were washed with a water-2-butanol (10:1) mixture (92.5 mL). The thus-washed crystal were dried at 80° C. for 13 hours under reduced pressure, to thereby yield 7.89 g of 4-[5-(pyridin-4-yl)-1H-1,2,4-triazol-3-yl]pyridine-2-carbonitrile (1).
Reaction SMILES: [CH2:1]1[C@@H:5]2[CH2:6][NH:7][CH2:8][C@@H:4]2[CH2:3][N:2]1[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10].Br[C:17]1[CH:18]=[N:19][CH:20]=[C:21]([CH:27]=1)[C:22]([O:24][CH2:25][CH3:26])=[O:23].C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1>[CH2:25]([O:24][C:22]([C:21]1[CH:27]=[C:17]([N:7]2[CH2:6][C@@H:5]3[CH2:1][N:2]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:3][C@@H:4]3[CH2:8]2)[CH:18]=[N:19][CH:20]=1)=[O:23])[CH3:26]
Reactant: CCOC(=O)c1cncc(Br)c1
Reactant: CC(C)(C)OC(=O)N1C[C@H]2CNC[C@H]2C1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: CCOC(=O)c1cncc(N2C[C@H]3CN(C(=O)OC(C)(C)C)C[C@H]3C2)c1
Temperature: 90 °C
Yield: 94 %

Procedure:
A suspension of the product from Example 1C (2.00 g, 9.42 mmol), ethyl 5-bromonicotinate (2.80 g, 12.0 mmol), tris(dibenzylideneacetone)dipalladium(0) (259 mg, 0.283 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (491 mg, 0.848 mmol) and cesium carbonate (4.91 g, 15.1 mmol) in anhydrous dioxane (50 mL) were heated at 90° C. for 72 hours. The reaction mixture was cooled and filtered through a glass frit. The filtrate was concentrated and the residue was purified by silica gel chromatography (eluted with 50% EtOAc in hexane) to afford the title compound (3.2 g, 94%). MS (APCI) m/z 362 (M+H)+.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:12][C:13]2[CH:17]=[CH:16][NH:15][N:14]=2)[N:3]=1.[F:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[OH:25]>>[F:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[O:25][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:12][C:13]2[CH:17]=[CH:16][NH:15][N:14]=2)[N:3]=1
Reactant: Clc1nc(Nc2cc[nH]n2)cc2ccccc12
Reactant: Oc1ccccc1F
Product: Fc1ccccc1Oc1nc(Nc2cc[nH]n2)cc2ccccc12

Procedure:
Similar procedure as described in example 10 was used, starting from (1-chloro-isoquinolin-3-yl)-(1H-pyrazol-3-yl)-amine and 2-fluoro-phenol to give [1-(2-fluoro-phenoxy)-isoquinolin-3-yl]-(1H-pyrazol-3-yl)-amine. LC-MS m/e 321 (MH+).
Reaction SMILES: CCCCCC.[CH3:7][C:8]1[NH:9][C:10]2[C:15]([CH:16]=1)=[CH:14][C:13]([N+:17]([O-:19])=[O:18])=[CH:12][CH:11]=2.[CH2:20](Br)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>O>[CH3:7][C:8]1[N:9]([CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:10]2[C:15]([CH:16]=1)=[CH:14][C:13]([N+:17]([O-:19])=[O:18])=[CH:12][CH:11]=2
Reactant: Cc1cc2cc([N+](=O)[O-])ccc2[nH]1
Reactant: BrCc1ccccc1
Solvent: CCCCCC
Solvent: O
Product: Cc1cc2cc([N+](=O)[O-])ccc2n1Cc1ccccc1
Reaction time: 0.33 h
Yield: 75.1 %

Procedure:
Hexane was used to wash 80 mg 2.0 mmol) of 60% NaH/mineral oil and 6 mL of DMF was added followed by 352 mg (2.0 mmol) of 2-methyl-5-nitro-1H-indole. After 0.33 hours, 0.24 mL (2.0 mol) of benzyl bromide was added, stirred 0.5 hours and diluted with water. The mixture was extracted with EtOAc, the EtOAc washed with a saturated NaCl solution, dried (MgSO4) and on concentrating at reduced pressure, crystals formed. These were washed with MeOH to give 400 mg (75% yield) of 2-methyl-5-nitro-1-(phenylmethyl)-1H-indole, mp, 150-152° C.