Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:10]=[CH:11][C:12]([NH:15][C:16]([NH:18][C:19]([CH:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)=[O:20])=[O:17])=[N:13][CH:14]=2)[CH:5]=[CH:4][N:3]=1.C([O-])(O)=O.[Na+].[CH3:32][C:33]1[CH:38]=[CH:37][C:36](B2OC(C)(C)C(C)(C)O2)=[CH:35][N:34]=1>O1CCOCC1.O.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>[CH3:32][C:33]1[N:34]=[CH:35][C:36]([C:2]2[CH:7]=[C:6]([O:8][C:9]3[CH:10]=[CH:11][C:12]([NH:15][C:16]([NH:18][C:19]([CH:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)=[O:20])=[O:17])=[N:13][CH:14]=3)[CH:5]=[CH:4][N:3]=2)=[CH:37][CH:38]=1
Reactant: O=C(NC(=O)C1CCOCC1)Nc1ccc(Oc2ccnc(Cl)c2)cn1
Reactant: Cc1ccc(B2OC(C)(C)C(C)(C)O2)cn1
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: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: Cc1ccc(-c2cc(Oc3ccc(NC(=O)NC(=O)C4CCOCC4)nc3)ccn2)cn1
Temperature: 95 °C
Yield: 13 %

Procedure:
A mixture of N-((5-((2-chloropyridin-4-yl)oxy)pyridin-2-yl)carbamoyl)tetrahydro-2H-pyran-4-carboxamide (0.334 g, 0.886 mmol), NaHCO3 (0.149 g, 1.773 mmol) and 2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (0.233 g, 1.064 mmol) in dioxane (4 mL) and water (1 mL) was sparged with Ar under sonication for 5 minutes, treated with Pd(PPh3)4 (0.102 g, 0.089 mmol), sparged again with Ar and heated at 95° C. overnight. The mixture was cooled to RT, diluted with THF and washed with brine. The aqueous layer was back-extracted with THF (3×) and the combined organics were dried over Na2SO4 and concentrated to dryness. The material was treated with MeCN and sonicated. The solids were collected via filtration and purified via silica gel chromatography (MeOH/EtOAc) to afford N-((5-((6′-methyl-[2,3′-bipyridin]-4-yl)oxy)pyridin-2-yl)carbamoyl)tetrahydro-2H-pyran-4-carboxamide (50 mg, 13%) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 11.06 (s, 1H), 10.88 (s, 1H), 9.10 (d, J=2.3 Hz, 1H), 8.55 (d, J=5.7 Hz, 1H), 8.30-8.26 (m, 2H), 8.09 (d, J=9.0 Hz, 1H), 7.76 (dd, J=9.0, 2.9 Hz, 1H), 7.63 (d, J=2.4 Hz, 1H), 7.33 (d, J=8.2 Hz, 1H), 6.89 (dd, J=5.7, 2.4 Hz, 1H), 3.91-3.85 (m, 2H), 3.33-3.26 (m, 2H), 2.73-2.64 (m, 1H), 2.50 (s, 3H), 1.75-1.68 (m, 2H), 1.67-1.56 (m, 2H); MS (ESI) m/z: 432.1 (M−H+).
Reaction SMILES: [CH:1]1([C:6]([CH2:21][CH3:22])=[C:7]([C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl[CH2:24][CH:25]([OH:28])[CH2:26][OH:27].C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[CH:1]1([C:6]([CH2:21][CH3:22])=[C:7]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:24][CH:25]([OH:28])[CH2:26][OH:27])=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCC(=C(c1ccccc1)c1ccc(O)cc1)C1CCCC1
Reactant: OCC(O)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCC(=C(c1ccccc1)c1ccc(OCC(O)CO)cc1)C1CCCC1

Procedure:
2-cyclopentyl-1-[p-(2,3-dihydroxypropoxy)phenyl]-1-phenyl-1-butene was prepared from pure E- or Z-isomer of 2-cyclopentyl-1-(p-hydroxyphenyl)-1-phenyl-1-butene and 3-chloro-1,2-propandiol in 2-butanone using potassium carbonate as a base (see example 16). In the case of the E-isomer the semisolid product was purified by chromatography over silica gel using methylene chloride as eluent.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])[CH2:9][CH2:10][C:4]=2[C:3]=1OS(C(F)(F)F)(=O)=O.[NH2:27][CH2:28][C:29]1[CH:34]=[CH:33][C:32]([CH2:35][S:36][CH:37]2[CH2:41][CH2:40][CH2:39][CH2:38]2)=[CH:31][N:30]=1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])[CH2:9][CH2:10][C:4]=2[C:3]=1[NH:27][CH2:28][C:29]1[CH:34]=[CH:33][C:32]([CH2:35][S:36][CH:37]2[CH2:41][CH2:40][CH2:39][CH2:38]2)=[CH:31][N:30]=1
Reactant: O=C(N1CCc2ccc(Cl)c(OS(=O)(=O)C(F)(F)F)c2CC1)C(F)(F)F
Reactant: NCc1ccc(CSC2CCCC2)cn1
Solvent: Cc1ccccc1
Product: O=C(N1CCc2ccc(Cl)c(NCc3ccc(CSC4CCCC4)cn3)c2CC1)C(F)(F)F
Yield: 58.9 %

Procedure:
Use a method similar to the General Procedure 1-2 to couple 7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine (245 mg, 0.58 mmol) with 2-aminomethyl-5-cyclopentylthiomethyl-pyridine (230 mg, 1 mmol) in toluene (5 mL). Purify the crude mixture by chromatography on silica gel eluting with hexane/THF (49:1 to 7:3 gradient) to obtain 7-chloro-6-[(5-cyclopentylthiomethyl-pyridin-2-ylmethyl)-amino]-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (170 mg, 59%). MS (ES+) m/z: 498.1 (M+H)+.
Reaction SMILES: C(OC([NH:11][CH:12]([C:14]1[C:15]([O:35][CH3:36])=[C:16]([C:22]2[CH2:23][CH2:24][N:25]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:26][CH:27]=2)[C:17]([CH3:21])=[C:18]([Cl:20])[CH:19]=1)[CH3:13])=O)C1C=CC=CC=1.Cl.O.[H][H].N>[Pt].C(O)C>[NH2:11][CH:12]([C:14]1[C:15]([O:35][CH3:36])=[C:16]([CH:22]2[CH2:27][CH2:26][N:25]([C:28]([O:30][C:31]([CH3:33])([CH3:32])[CH3:34])=[O:29])[CH2:24][CH2:23]2)[C:17]([CH3:21])=[C:18]([Cl:20])[CH:19]=1)[CH3:13]
Reactant: COc1c(C(C)NC(=O)OCc2ccccc2)cc(Cl)c(C)c1C1=CCN(C(=O)OC(C)(C)C)CC1
Reactant: [H][H]
Agent: [Pt]
Agent: Cl
Agent: N
Solvent: CCO
Solvent: O
Product: COc1c(C(C)N)cc(Cl)c(C)c1C1CCN(C(=O)OC(C)(C)C)CC1
Yield: 101 %

Procedure:
Platinum on carbon (10 wt. % loading (dry basis), matrix activated carbon, 200 mg) was added to a solution of tert-butyl 4-[3-(1-{[(benzyloxy)carbonyl]amino}ethyl)-5-chloro-2-methoxy-6-methylphenyl]-3,6-dihydropyridine-1(2H)-carboxylate (200 mg, 0.388 mmol) in ethanol (30 mL)/0.25 M HCl in water (3.9 mL, 0.97 mmol) and then the reaction was stirred at room temperature under 30 psi of hydrogen atmosphere for 3 d. The mixture was adjusted to basic pH with ammonia and then the solvent was removed. The residue was diluted with methylene chloride, washed with sat. NaHCO3, water, brine, dried over Na2SO4, filtered and concentrated to give the crude desired product (0.15 g) which was used in the next step without further purification. LCMS calculated for C20H32ClN2O3 (M+H)+: m/z=383.2. found: 383.3.
Reaction SMILES: [CH3:1][NH:2][CH3:3].CO[C:6]([C:8]1[N:12]2[C:13]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:14]=3[C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[N:16][CH2:17][C:11]2=[N:10][N:9]=1)=[O:7]>O1CCOCC1.CO>[CH3:1][N:2]([CH3:3])[C:6]([C:8]1[N:12]2[C:13]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:14]=3[C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[N:16][CH2:17][C:11]2=[N:10][N:9]=1)=[O:7]
Reactant: COC(=O)c1nnc2n1-c1ccc(Cl)cc1C(c1ccccc1)=NC2
Reactant: CNC
Solvent: CO
Solvent: C1COCCO1
Product: CN(C)C(=O)c1nnc2n1-c1ccc(Cl)cc1C(c1ccccc1)=NC2
Reaction time: 24 h

Procedure:
10 ml of a 20% solution of dimethylamine in dioxane is added at 25° to a solution of 0.705 g (0.002 mole) of 6-phenyl-8-chloro-4H-s-triazolo[4,3-a][1,4]benzodiazepine-1-carboxylic acid methyl ester in 10 ml of methanol. After 24 hours, the reaction mixture is concentrated by evaporation, and the residue crystallised from ethyl acetate/petroleum ether to obtain N,N-dimethyl-6-phenyl-8-chloro-4H-s-triazolo[4,3-a][1,4]benzodiazepine-1-carboxamide, M.P. 180°-181°.
Reaction SMILES: I[C:2]1[CH:3]=[CH:4][C:5]([N+:13]([O-:15])=[O:14])=[C:6]([CH:12]=1)[C:7]([N:9]([CH3:11])[CH3:10])=[O:8].[Br-].[CH2:17]([O:19][C:20](=[O:24])[CH2:21][CH2:22][Zn+])[CH3:18]>O1CCCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:17]([O:19][C:20](=[O:24])[CH2:21][CH2:22][C:2]1[CH:3]=[CH:4][C:5]([N+:13]([O-:15])=[O:14])=[C:6]([C:7](=[O:8])[N:9]([CH3:11])[CH3:10])[CH:12]=1)[CH3:18]
Reactant: CN(C)C(=O)c1cc(I)ccc1[N+](=O)[O-]
Reactant: CCOC(=O)CC[Zn+]
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: C1CCOC1
Product: CCOC(=O)CCc1ccc([N+](=O)[O-])c(C(=O)N(C)C)c1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
5-Iodo-N,N-dimethyl-2-nitrobenzamide (2.00 g) was dissolved in tetrahydrofuran (20 mL) and bis(triphenylphosphine)palladium(II) dichloride (0.128 g) was added thereto. After cooling down to 0° C., 0.5M 3-ethoxy-3-oxopropylzinc bromide solution (22.5 mL) was added dropwise thereto, the mixture was stirred at room temperature overnight. The reaction solution was concentrated, dissolved in ethyl acetate (100 mL), washed successively with 1N hydrochloric acid (30 mL) and saturated brine (30 mL), and dried over sodium sulfate. Further, the mixture was purified by column chromatography on silica gel (ethyl acetate:hexane=3:2, v/v) to give the title compound (1.52 g) as a brown oil.
Reaction SMILES: C[N:2]([CH3:15])[CH:3]=[CH:4][C:5]([C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=1)=O.Cl.NC1[N:19]=[CH:20][NH:21][C:22]=1[C:23]([NH2:25])=[O:24].C(=O)(O)[O-].[Na+].C(#N)C>C(O)(=O)C>[CH3:14][O:13][C:10]1[CH:9]=[CH:8][C:7]([C:5]2[N:19]3[CH:20]=[N:21][C:22]([C:23]([NH2:25])=[O:24])=[C:15]3[N:2]=[CH:3][CH:4]=2)=[CH:12][CH:11]=1
Reactant: COc1ccc(C(=O)C=CN(C)C)cc1
Reactant: NC(=O)c1[nH]cnc1N
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC#N
Product: COc1ccc(-c2ccnc3c(C(N)=O)ncn23)cc1
Yield: 40.2 %

Procedure:
A stirred mixture of 15.0 g of 3-dimethylamino-4'-methoxyacrylophenone (prepared as described in Example 8) and 9.2 g of 4-amino-5-imidazolecarboxamide hydrochloride in 450 ml of glacial acetic acid was heated at reflux for 24 hours. Evaporation of the solvent in vacuo gave a solid which was treated with saturated sodium bicarbonate solution, then washed with water and filtered to give colorless crystals. This material was treated with hot acetonitrile and collected by filtration. Recrystallization from ethanol gave 6.1 g of the desired product as yellow crystals, mp 246°-249° C.
Reaction SMILES: [CH:1]1[C:13]2[N:12]([C:14]3[CH:19]=[CH:18][C:17]([C:20]4[CH:25]=[CH:24][C:23]([N:26]5[C:38]6[CH:37]=[CH:36][C:35]([CH:39]=[O:40])=[CH:34][C:33]=6[C:32]6[C:27]5=[CH:28][CH:29]=[CH:30][CH:31]=6)=[CH:22][CH:21]=4)=[CH:16][CH:15]=3)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.O1CCCC1.[BH4-].[Na+]>CO>[CH:1]1[C:13]2[N:12]([C:14]3[CH:15]=[CH:16][C:17]([C:20]4[CH:21]=[CH:22][C:23]([N:26]5[C:38]6[CH:37]=[CH:36][C:35]([CH2:39][OH:40])=[CH:34][C:33]=6[C:32]6[C:27]5=[CH:28][CH:29]=[CH:30][CH:31]=6)=[CH:24][CH:25]=4)=[CH:18][CH:19]=3)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: O=Cc1ccc2c(c1)c1ccccc1n2-c1ccc(-c2ccc(-n3c4ccccc4c4ccccc43)cc2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: OCc1ccc2c(c1)c1ccccc1n2-c1ccc(-c2ccc(-n3c4ccccc4c4ccccc43)cc2)cc1
Reaction time: 1 h
Yield: 98.4 %

Procedure:
A 100-ml Kolben equipped with a stirrer and a condenser was charged under a nitrogen stream with 18 g (15.6 mmol) of 4-(carbazol-9-yl)-4′-(3-formylcarbazol-9-yl)-biphenyl prepared above and 800 ml of tetrahydrofuran. Sodium tetrahydroborate (0.65 g, 17.2 mmol) was introduced at room temperature into the above mixture, and the mixture was stirred for one hr. Thereafter, 160 ml of methanol was introduced into the reaction solution, and the mixture was stirred for 3 hr. The solvent was distilled off, and the residue was dissolved in 500 ml of toluene. The solution was washed with water, and the solvent was then distilled off to give 4-(carbazol-9-yl)-4′-(3-hydroxymethylcarbazol-9-yl)-biphenyl (7.9 g, yield 98.4%).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]([CH2:15][OH:16])[CH2:10][C:11](=[O:14])[NH:12][N:13]=2)=[CH:4][C:3]=1[N+:17]([O-:19])=[O:18].[NH:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1>>[N+:17]([C:3]1[CH:4]=[C:5]([C:8]2[CH:9]([CH2:15][OH:16])[CH2:10][C:11](=[O:14])[NH:12][N:13]=2)[CH:6]=[CH:7][C:2]=1[N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1)([O-:19])=[O:18]
Reactant: O=C1CC(CO)C(c2ccc(Cl)c([N+](=O)[O-])c2)=NN1
Reactant: C1CNCCN1
Product: O=C1CC(CO)C(c2ccc(N3CCNCC3)c([N+](=O)[O-])c2)=NN1

Procedure:
19.86 g (0.07 mol) of 6-(4-chloro-3-nitro-phenyl)-4,5-dihydro-5-hydroxymethyl-3(2H)-pyridazinone are reacted with 18.1 g (0.21 mol) of piperazine in a manner analogous to Example 1.
Reaction SMILES: CO[C:3]([C:5]1[C:10](=[O:11])[N:9]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[N:8]2[CH:20]=[C:21]([Cl:23])[CH:22]=[C:7]2[C:6]=1[OH:24])=[O:4].[NH2:25][C@H:26]([C:28]([OH:30])=[O:29])[CH3:27].C[O-].[Na+]>>[Cl:23][C:21]1[CH:22]=[C:7]2[C:6]([OH:24])=[C:5]([C:3]([NH:25][C@@H:26]([CH3:27])[C:28]([OH:30])=[O:29])=[O:4])[C:10](=[O:11])[N:9]([CH2:12][C:13]3[CH:14]=[CH:15][C:16]([F:19])=[CH:17][CH:18]=3)[N:8]2[CH:20]=1
Reactant: COC(=O)c1c(O)c2cc(Cl)cn2n(Cc2ccc(F)cc2)c1=O
Reactant: C[C@H](N)C(=O)O
Agent: C[O-]
Agent: [Na+]
Product: C[C@H](NC(=O)c1c(O)c2cc(Cl)cn2n(Cc2ccc(F)cc2)c1=O)C(=O)O

Procedure:
Prepared according to the reaction condition used in Example 19 step a) from 6-chloro-4-hydroxy-2-oxo-1-(4-fluoro-benzyl)-1,2-dihydro-pyrrolo[1,2-b]pyridazine-3-carboxylic acid methyl ester, L-alanine and NaOMe. ESI (m/z): 408 (M+H)+.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]3[N:38]=[C:19]4[CH:20]=[CH:21][CH:22]=[C:23]([C:24]5[CH:25]=[C:26](OS(C(F)(F)F)(=O)=O)[CH:27]=[CH:28][CH:29]=5)[N:18]4[N:17]=3)=[CH:11][CH:10]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:39]1(B(O)O)[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>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>[C:26]1([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[CH:27]=[CH:28][CH:29]=[C:24]([C:23]2[N:18]3[N:17]=[C:16]([NH:15][C:12]4[CH:13]=[CH:14][C:9]([O:8][CH2:7][CH2:6][N:1]5[CH2:2][CH2:3][CH2:4][CH2:5]5)=[CH:10][CH:11]=4)[N:38]=[C:19]3[CH:20]=[CH:21][CH:22]=2)[CH:25]=1
Reactant: OB(O)c1ccccc1
Reactant: O=S(=O)(Oc1cccc(-c2cccc3nc(Nc4ccc(OCCN5CCCC5)cc4)nn23)c1)C(F)(F)F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Product: c1ccc(-c2cccc(-c3cccc4nc(Nc5ccc(OCCN6CCCC6)cc5)nn34)c2)cc1
Temperature: 150 °C

Procedure:
A microwave vial was charged with trifluoro-methanesulfonic acid 3-{2-[4-(2-pyrrolidin-1-yl-ethoxy)-phenylamino]-[1,2,4]triazolo[1,5-a]pyridin-5-yl}-phenyl ester (50 mg, 0.09 mmol), benzeneboronic acid (15 mg, 0.12 mmol), tetrakis(triphenylphosphine)palladium (10 mg, 0.009 mmol), potassium phosphate (0.5M in water, 0.36 ml, 0.18 mmol) and N,N′-dimethylacetamide (1 ml). The reaction was heated to 150° C. for 10 minutes under microwave irradiation. The mixture was then filtered through a plug of silica, washed with methanol and concentrated in vacuo. The product was purified by preparatory LCMS to yield the desired product. RT: 2.96 min, MI: 476.22, Method: 2
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8]CC(C)=C)=[CH:4][CH:3]=1.[C:13](OC)([CH3:16])([CH3:15])[CH3:14]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:8])=[C:6]([CH2:15][C:13]([CH3:16])=[CH2:14])[CH:7]=1
Reactant: COC(C)(C)C
Reactant: C=C(C)COc1ccc(Br)cc1
Solvent: CN(C)C=O
Product: C=C(C)Cc1cc(Br)ccc1O
Temperature: 25 °C
Yield: 65 %

Procedure:
A solution of 1-bromo-4-(2-methylallyloxy)benzene (6) (1.0 g, 4.4 mmol) in DMF (8 mL) was heated in a microwave reactor at 190° C. for 2 h. After cooling to room temperature, the reaction mixture was diluted with methyl tert-butyl ether (50 mL), and washed with H2O (25 mL), brine (25 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, eluting with 5% ethyl acetate in hexanes) to give the title compound (7) (0.7 g, 65%) as a liquid. 1H NMR (CDCl3, 400 MHz) δ 7.27-7.25 (m, 2H), 6.72 (d, J=8.4 Hz, 1H), 4.95 (s, 1H), 4.86 (s, 1H), 3.34 (s, 2H), 1.74 (s, 3H); MS (ESI, M+H+) C10H12BrO, calcd. 227.1. found 227.0, 229.0.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8]C)=[O:7])=[CH:4][C:3]=1[O:12][CH3:13].Br[CH2:15][CH2:16][CH2:17][CH3:18]>>[CH2:15]([O:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[O:12][CH3:13])[CH2:16][CH2:17][CH3:18]
Reactant: COC(=O)c1ccc(O)c(OC)c1
Reactant: CCCCBr
Product: CCCCOc1ccc(C(=O)O)cc1OC

Procedure:
Methyl 4-hydroxy-3-methoxybenzoate was alkylated with bromobutane by method H and hydrolyzed by method P-a. This resulted in the product with the molecular weight of 224.26 (C12H16O4); MS (ESI): 225 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4](=[O:28])[C:5]2[N:6]=[CH:7][N:8]([CH:11]3[CH2:15][CH:14]([Si](C)(C)C4C=CC=CC=4)[CH:13]([CH2:25][OH:26])[C:12]3=[CH2:27])[C:9]=2[N:10]=1.C(O)(=[O:31])C>CO>[NH2:1][C:2]1[NH:3][C:4](=[O:28])[C:5]2[N:6]=[CH:7][N:8]([CH:11]3[CH2:15][CH:14]([OH:31])[CH:13]([CH2:25][OH:26])[C:12]3=[CH2:27])[C:9]=2[N:10]=1
Reactant: CC(=O)O
Reactant: C=C1C(CO)C([Si](C)(C)c2ccccc2)CC1n1cnc2c(=O)[nH]c(N)nc21
Solvent: CO
Product: C=C1C(CO)C(O)CC1n1cnc2c(=O)[nH]c(N)nc21
Temperature: 95 °C
Reaction time: 4 h

Procedure:
A 2-L 3-necked round bottomed flask, oven dried and equipped with a mechanical stirrer, an addition funnel, temperature probe, and argon inlet, was charged with compound 71 (34.1 g, 86.2 moles), acetic acid (40.4 mL, 8 eq) and acetic acid-boron trifluoride complex (38 mL). The reaction mixture was heated to 95° C., stirred for 4 hours and then cooled to room temperature. The reaction mixture was diluted with MeOH (200 mL) and quenched with aqueous KOH (10 N, ˜220 mL) to adjust the pH to about 9.5. Potassium bicarbonate (17.9 g) followed by aqueous hydrogen peroxide (30 wt. %, 39 g) was added to the solution. The resulting solution was warmed to 70° C. and stirred for 10 hours. The reaction was cooled to 5–10° C. Sodium bisulfite (16.2 g) was added portion-wise over 30 minutes. The reaction mixture was concentrated in vacuo to remove most of the MeOH. The resulting yellow semi-solid was cooled to −5° C. and concentrated HCl (˜55 mL) added to adjust the pH to 0.15. The resulting solution was extracted with EtOAc (500 mL) and aqueous KOH (10 N, ˜48 mL) added to adjust the pH to ˜11. The solution was stirred for 1 hour and then the pH was adjusted to ˜7 with HCl (4 mL). The reaction mixture was stirred at room temperature for 1 hour and at ˜5° C. for 3 hours. The solid was collected by filtration and dried under high vacuum for 16 hours. The solid was redissolved in water (600 mL) at 90° C. The clear solution was cooled to ˜60–55° C. and seeded with 21. The solution was allowed to cool to room temperature for 5 hours. The resulting white crystalline solid was collected by filtration and dried under vacuum at 50° C. for 16 hours to afford the title compound (12.9 g).
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([N:10]2[CH2:15][CH2:14][CH:13]([S:16]([CH3:19])(=[O:18])=[O:17])[CH2:12][CH2:11]2)[C:3]=1[CH:4]=O.[CH3:20][S:21][C:22]1[N:27]=[C:26]([NH:28][NH2:29])[CH:25]=[CH:24][N:23]=1.C1CCN2C(=NCCC2)CC1>CS(C)=O>[CH3:19][S:16]([CH:13]1[CH2:14][CH2:15][N:10]([C:6]2[CH:7]=[CH:8][CH:9]=[C:2]3[C:3]=2[CH:4]=[N:29][N:28]3[C:26]2[CH:25]=[CH:24][N:23]=[C:22]([S:21][CH3:20])[N:27]=2)[CH2:11][CH2:12]1)(=[O:18])=[O:17]
Reactant: CSc1nccc(NN)n1
Reactant: CS(=O)(=O)C1CCN(c2cccc(F)c2C=O)CC1
Solvent: CS(C)=O
Solvent: C1CCC2=NCCCN2CC1
Product: CSc1nccc(-n2ncc3c(N4CCC(S(C)(=O)=O)CC4)cccc32)n1
Temperature: 180 °C
Reaction time: 1.5 h
Yield: 38.7 %

Procedure:
In a 50 ml, round bottom flask, 2-fluoro-6-(4-methanesulfonylpiperidine-1-yl)benzaldehyde (1.37 g, 4.8 mmol), N-(2-methylsulfanyl-pyrimidin-4-yl)-hydrazine (0.75 g, 4.8 mmol) and DBU (2.19 g, 14.4 mmol) were combined with DMSO (17 mL). The mixture was stirred at 180° C. for 1.5 hr in a microwave. The brown solution was blown to dryness and the residue was purified through ISCO flash column chromatography (30% to 100% ethyl acetate in hexanes) to provide 4-(4-methanesulfonyl-piperidin-1-yl)-1-(2-methylsulfanyl-pyrimidin-4-yl)-1H-indazole as a pale orange solid (750 mg, 38.7% yield). LC-MS calcd for C18H21N5O2S2 (m/e) 403.11, obsd 404.0 (M+H).
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]([N:5]1[CH2:14][CH2:13][C:12]2[C:7](=[CH:8][C:9]([S:15](Cl)(=[O:17])=[O:16])=[CH:10][CH:11]=2)[CH2:6]1)=[O:4].Cl.[CH3:22][NH:23][CH3:24].C(N(CC)CC)C>O1CCOCC1>[CH3:22][N:23]([CH3:24])[S:15]([C:9]1[CH:8]=[C:7]2[C:12]([CH2:13][CH2:14][N:5]([C:3](=[O:4])[C:2]([F:20])([F:19])[F:1])[CH2:6]2)=[CH:11][CH:10]=1)(=[O:17])=[O:16]
Reactant: CNC
Reactant: O=C(N1CCc2ccc(S(=O)(=O)Cl)cc2C1)C(F)(F)F
Agent: Cl
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CN(C)S(=O)(=O)c1ccc2c(c1)CN(C(=O)C(F)(F)F)CC2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 82.1 %

Procedure:
A mixture of 2-trifluoroacetyl-1,2,3,4-tetrahydro-isoquinoline-7-sulfonyl chloride (400 mg, 1.22 mmol, J. Med. Chem. 1980, 23, 837), dimethylamine hydrochloride (150 mg, 1.83 mmol), and triethylamine (0.50 mL, 3.66 mmol) in dioxane (10 mL) was refluxed with stirring for 30 min, cooled to room temperature, concentrated, and purified by flash column chromatography (10→50% ethyl acetate/hexanes) to give 337 mg (82%) of the title compound of Example 247, Step A as a yellow oil. 1H NMR (CDCl3, 300 MHz, 9:5 mixture of rotamers) δ 7.67-7.52 (c, 2H), 7.36 (t, 1H), 4.87 (s, 1.3H), 4.81 (s, 0.7H), 3.96-3.86 (c, 2H), 3.08-3.02 (c, 2H), 2.72 (s, 6H); MS (TS) 337 (MH+).
Reaction SMILES: C1([C@H]([NH:9][C@@H:10]2[CH2:15][CH2:14][CH2:13][CH2:12][C@@H:11]2[C:16]([F:19])([F:18])[F:17])C)C=CC=CC=1.[ClH:20]>C(O)C.[OH-].[OH-].[Pd+2]>[ClH:20].[F:17][C:16]([F:18])([F:19])[C@H:11]1[CH2:12][CH2:13][CH2:14][CH2:15][C@H:10]1[NH2:9]
Reactant: C[C@@H](N[C@@H]1CCCC[C@@H]1C(F)(F)F)c1ccccc1
Agent: [Pd+2]
Agent: Cl
Agent: [OH-]
Solvent: CCO
Product: N[C@@H]1CCCC[C@@H]1C(F)(F)F
Temperature: 60 °C
Reaction time: 48 h

Procedure:
To a solution of (1R,2S)—N-[(1R)-1-phenylethyl]-2-(trifluoromethyl)cyclohexanamine (3.53 g) and 13 mL of HCl (2M ethanol solution) in 35 mL of ethanol was added Pd(OH)2(2.78 g) under N2. H2 gas was purged and stirred for 2 days under 4 atm at 60° C. Pd(OH)2 was filtered off through a pad of Celite. Solvent was removed under reduced pressure. (1R,2S)-2-(Trifluoromethyl)cyclohexanamine hydrochloride (2.37 g) was obtained as a white solid.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([NH2:9])=[C:4]([NH2:10])[CH:3]=1.[C:11](OCC)(=[O:15])[C:12]([CH3:14])=O>O1CCCC1>[CH3:14][C:12]1[C:11](=[O:15])[NH:9][C:5]2[C:4]([N:10]=1)=[CH:3][C:2]([CH3:1])=[C:7]([CH3:8])[CH:6]=2
Reactant: CCOC(=O)C(C)=O
Reactant: Cc1cc(N)c(N)cc1C
Solvent: C1CCOC1
Product: Cc1cc2nc(C)c(=O)[nH]c2cc1C
Temperature: 25 °C

Procedure:
4,5-Dimethyl-o-phenylenediamine (10.0 g., 0.073 mol.) was dissolved in tetrahydrofuran (200 ml.) and ethyl pyruvate (12.75 g., 0.11 mol.) added. The reaction mixture was stirred at room temperature for eighteen hours, during which time a white solid precipitated was collected by filtration (13.35 g.). Recrystallization from methanol-chloroform gave fine white needles. (12.65 g., m.p. 306-308°, 92%).
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][CH:5]=[C:6]([Cl:15])[C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=1.[NH2:16][NH2:17]>O1CCOCC1>[Cl:15][C:6]1[C:7]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=2)=[C:2]([NH:16][NH2:17])[N:3]=[N:4][CH:5]=1
Reactant: Clc1ccc(-c2c(Cl)cnnc2Cl)cc1
Reactant: NN
Solvent: C1COCCO1
Product: NNc1nncc(Cl)c1-c1ccc(Cl)cc1
Temperature: 70 °C
Yield: 22 %

Procedure:
To a solution of 3,5-dichloro-4-(4-chlorophenyl)pyridazine (2.56 g, 10 mmol) in dioxane (36 mL) at RT was added hydrazine (3.2 mL, 100 mL). After addition, the reaction was heated to 70° C. for 2 h. After cooling to RT, the reaction was concentrated under reduced pressure. To the obtained residue was added 2-propanol (80 mL) and the resulting white solid was removed by filtration. The collected liquid was concentrated under reduced pressure to give the title compound 1-(5-chloro-4-(4-chlorophenyl)pyridazin-3-yl)hydrazine as an off-white solid (560 mg, 22%) which contained 15% of by-product (1-(3-chloro-4-(4-chlorophenyl)pyridazin-5-yl)hydrazine). The mixture was used directly in the next step, 273E. LC/MS (method A): RT=1.89 min, (M+H)+=255.