Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:21]=[CH:20][C:5]2[C:6]([C:9]3[CH:14]=[CH:13][C:12]([O:15][CH2:16][C@H:17]4[CH2:19][O:18]4)=[CH:11][CH:10]=3)=[N:7][O:8][C:4]=2[CH:3]=1.[CH2:22]([NH:24][CH2:25][CH3:26])[CH3:23]>CN(C)C=O.C(O)C>[CH2:22]([N:24]([CH2:25][CH3:26])[CH2:19][C@@H:17]([OH:18])[CH2:16][O:15][C:12]1[CH:13]=[CH:14][C:9]([C:6]2[C:5]3[CH:20]=[CH:21][C:2]([F:1])=[CH:3][C:4]=3[O:8][N:7]=2)=[CH:10][CH:11]=1)[CH3:23]
Reactant: CCNCC
Reactant: Fc1ccc2c(-c3ccc(OC[C@H]4CO4)cc3)noc2c1
Solvent: CN(C)C=O
Solvent: CCO
Product: CCN(CC)C[C@@H](O)COc1ccc(-c2noc3cc(F)ccc23)cc1

Procedure:
The title compound is prepared from a mixture of (R)-6-fluoro-3-(4-oxiranylmethoxy-phenyl)-benzo[d]isoxazole in dimethylformamide and diethylamine in ethanol essentially as described above in Example 21. Purity by LC/MS=100%, [M+H]+=359.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[CH2:10]([O:12][P:13]([CH2:22][CH2:23][CH2:24][NH2:25])([CH:15]([O:19][CH2:20][CH3:21])[O:16][CH2:17][CH3:18])=[O:14])[CH3:11].C(O)(=O)C.C([BH3-])#N.[Na+]>CO>[CH2:10]([O:12][P:13]([CH2:22][CH2:23][CH2:24][NH:25][CH2:6][C:5]1[CH:8]=[CH:9][C:2]([Cl:1])=[CH:3][CH:4]=1)([CH:15]([O:19][CH2:20][CH3:21])[O:16][CH2:17][CH3:18])=[O:14])[CH3:11]
Reactant: O=Cc1ccc(Cl)cc1
Reactant: CCOC(OCC)P(=O)(CCCN)OCC
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CCOC(OCC)P(=O)(CCCNCc1ccc(Cl)cc1)OCC
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
1.41 g of p-chlorobenzaldehyde are added to a solution of 2.53 g of 3-aminopropyl(diethoxymethyl)phosphinic acid ethyl ester in 10 ml of anhydrous methanol, and the resulting clear solution is stirred at room temperature for 30 minutes. There are then added first 0.6 g of glacial acetic acid and then, dropwise, 0.21 g of sodium cyanoborohydride in solution in 5 ml of methanol. An exothermic reaction begins. The mixture is stirred at 20° for 3 hours and adjusted to pH 8, and the solvent is removed. The residue is dissolved in dichloromethane and washed with water. The organic phase is separated off, dried over sodium sulfate and concentrated to dryness by evaporation. The oil that remains is purified by chromatography on silica gel, yielding 3-(p-chlorobenzylamino)propyl(diethoxymethyl)phosphinic acid ethyl ester in the form of a yellowish oil.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[N:6]3[CH:11]=[C:10]([C:12](OCC)=[O:13])[N:9]=[C:7]3[S:8][C:4]=2[CH:3]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>>[Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[N:6]3[CH:11]=[C:10]([CH2:12][OH:13])[N:9]=[C:7]3[S:8][C:4]=2[CH:3]=1
Reactant: CCOC(=O)c1cn2c(n1)sc1cc(Cl)ccc12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: OCc1cn2c(n1)sc1cc(Cl)ccc12
Yield: 71.8 %

Procedure:
7-chloro imidazo[2,1-b]-benzthiazole-2-methanol was prepared according to the procedure outlined in Example 1, (Step 2). Starting from ethyl 7-chloroimidazo[2,1-b]-benzthiazole-2-carboxylate (9.0 g, 32.1 mmol) and LiAlH4 (4.0 g, excess), 5.5 g (72% yield) of the alcohol derivative was isolated as brown solid. mp 166° C. (M+H) 239.
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:47])[NH:6][C:7]2[CH:45]=[CH:44][C:10]([O:11][C:12]3[CH:17]=[CH:16][N:15]=[C:14]4[CH:18]=[C:19]([C:21]5[N:26]=[CH:25][C:24]([CH2:27][N:28]6[CH2:33][CH2:32][CH:31]([NH:34][C:35](=O)[O:36]C7C=CC=CC=7)[CH2:30][CH2:29]6)=[CH:23][CH:22]=5)[S:20][C:13]=34)=[C:9]([F:46])[CH:8]=2)[CH2:3][CH2:2]1.[CH3:48][N:49]1[CH2:54][CH2:53][NH:52][CH2:51][CH2:50]1.C([O-])(O)=O.[Na+]>CN(C=O)C.[Cl-].[Na+].O>[CH:1]1([NH:4][C:5](=[O:47])[NH:6][C:7]2[CH:45]=[CH:44][C:10]([O:11][C:12]3[CH:17]=[CH:16][N:15]=[C:14]4[CH:18]=[C:19]([C:21]5[N:26]=[CH:25][C:24]([CH2:27][N:28]6[CH2:29][CH2:30][CH:31]([NH:34][C:35]([N:52]7[CH2:53][CH2:54][N:49]([CH3:48])[CH2:50][CH2:51]7)=[O:36])[CH2:32][CH2:33]6)=[CH:23][CH:22]=5)[S:20][C:13]=34)=[C:9]([F:46])[CH:8]=2)[CH2:3][CH2:2]1
Reactant: CN1CCNCC1
Reactant: O=C(Nc1ccc(Oc2ccnc3cc(-c4ccc(CN5CCC(NC(=O)Oc6ccccc6)CC5)cn4)sc23)c(F)c1)NC1CC1
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CN1CCN(C(=O)NC2CCN(Cc3ccc(-c4cc5nccc(Oc6ccc(NC(=O)NC7CC7)cc6F)c5s4)nc3)CC2)CC1
Temperature: 92.5 °C
Yield: 79 %

Procedure:
To a solution of the phenylcarbamate 356 (0.11 g, 0.169 mmol) in DMF at RT was added the N-methylpiperazine (0.057 mL, 0.51 mmol). The reaction mixture was heated at 90-95° C. for 2 hours, cooled to RT then treated with brine and saturated NaHCO3 solution. A precipitate was formed which was collected by filtration and dried. The crude material was purified by flash column chromatography, eluent 12 to 30% MeOH (containing 2% ammonia) in DCM, to afford the title compound 357 (0.088 g, 79% yield). 1H NMR (400 MHz, CD3OD-d6) δ (ppm): 8.65 (d, J=1.4 Hz, 1H); 8.47 (d, J=5.5 Hz, 1H); 8.15-8.11 (m, 2H); 7.98 (dd, J=8.2, 2.0 Hz, 1H); 7.67 (dd, J=13.1, 2.3 Hz, 1H); 7.30 (t, J=9.0 Hz, 1H); 7.20 (br. d, J=9.0 Hz, 1H); 6.64 (d, J=5.5 Hz 1H); 3.94 (s, 2H); 3.68-3.65 (m, 1H); 3.57 (br. s, 4H); 3.18 (br. d, J=10.4 Hz, 2H); 2.89 (br. s, 4H); 2.65 (s, 3H); 2.63-2.58 (m, 3H); 1.98 (br. d, J=11.7 Hz, 2H); 1.69 (br. d, J=11.0 Hz, 2H); 0.79-0.74 (m, 2H); 0.55-0.52 (m, 2H). [Signals of NH-protons are not seen]. MS (m/z): 659.5 (M+1)+
Reaction SMILES: [CH3:1][C@:2]12[CH2:21][CH2:20][C@H:19]3[C@@H:8]([CH2:9][CH2:10][C:11]4[C@:17]3([CH3:18])[CH2:16][CH2:15][C:13](=[O:14])[CH:12]=4)[C@@H:7]1[CH2:6][CH2:5][C:3]2=[O:4].C(OCC)(OCC)OCC.[C:32]1([CH3:42])[CH:37]=[CH:36][C:35](S(O)(=O)=O)=[CH:34][CH:33]=1.C(O)C1C=CC=CC=1>C1C=CC=CC=1>[CH2:42]([O:14][C:13]1[CH2:15][CH2:16][C@@:17]2([CH3:18])[C:11](=[CH:10][CH2:9][C@@H:8]3[C@@H:19]2[CH2:20][CH2:21][C@@:2]2([CH3:1])[C@H:7]3[CH2:6][CH2:5][C:3]2=[O:4])[CH:12]=1)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: C[C@]12CCC(=O)C=C1CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOC(OCC)OCC
Solvent: c1ccccc1
Solvent: OCc1ccccc1
Product: C[C@]12CCC(OCc3ccccc3)=CC1=CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Yield: 12348.1 %

Procedure:
Androstenedione (5 g) was dissolved in dry benzene (100 ml). Triethyl orthoformate (3.25 ml) was added, followed by p-toluenesulphonic acid (20 mg) and the solution heated at 50° for 45 minutes. Benzyl alcohol (7.5 ml) and benzene (150 ml) were then added and the solution distilled until 150 ml of distillate had been collected. A few drops of pyridine were added and the solution evaporated under reduced pressure to give a yellow solid. This solid was recrystallised from ethanol to give 3-benzyloxy-androsta-3,5-dien-17-one (5.4 g) as white needles, M.p. 172°-178°.
Reaction SMILES: C(NCC)C.[C:6]1([C:12]([CH:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)O)=[O:13])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[C:22](#[N:26])[CH2:23][C:24]#[N:25].O>CN(C=O)C>[NH2:26][C:22]1[O:13][C:12]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)=[C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:23]=1[C:24]#[N:25]
Reactant: O=C(c1ccccc1)C(O)c1ccccc1
Reactant: N#CCC#N
Solvent: CCNCC
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1c(N)oc(-c2ccccc2)c1-c1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 48.9 %

Procedure:
Diethylamine (13.8 g) was added dropwise over a period of 30 min to a mixture of benzoin (10 g) and malononitrile (3.8 g) in DMF (30 ml) at 0° C. (the internal temperature should not exceed 40° C.). After the resulting mixture was stirred at room temperature for 16 h, water (100 mL) was added. The resulting precipitate was filtered, washed with sufficient amount of water, then with hexanes, and dried. The solid was recrystallized from ethanol to provide yellowish-brown solid product of the title compound (6 g, 49%). 1H NMR (300 MHz, CDCl3): δ 7.47-7.34 (m, 8H), 7.28-7.18 (m, 2H), 4.94 (br, 2H). LC-MS (ESI) m/z 261.1 (M+H).
Reaction SMILES: C(O[C:4]1[C:5](=[O:16])[C:6](=[O:15])[C:7]=1[NH:8][C:9]1[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=1)C.[CH2:17]([N:24]1[CH2:29][CH2:28][CH:27]([CH2:30][CH2:31][NH2:32])[CH2:26][CH2:25]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[CH2:17]([N:24]1[CH2:29][CH2:28][CH:27]([CH2:30][CH2:31][NH:32][C:4]2[C:5](=[O:16])[C:6](=[O:15])[C:7]=2[NH:8][C:9]2[CH:10]=[CH:11][N:12]=[CH:13][CH:14]=2)[CH2:26][CH2:25]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: NCCC1CCN(Cc2ccccc2)CC1
Reactant: CCOc1c(Nc2ccncc2)c(=O)c1=O
Product: O=c1c(NCCC2CCN(Cc3ccccc3)CC2)c(Nc2ccncc2)c1=O
Yield: 71 %

Procedure:
The title compound was prepared according to the procedure described in example 37 starting from 3-ethoxy-4-(pyridine-4-yl-amino)-3-cyclobutene-1,2-dione prepared according to example 7A and 2-(1-benzylpiperidin-4-yl)-ethylamine.
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[N:6]([CH3:32])[C:7]([CH2:20][NH:21][S:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[Cl:31])(=[O:24])=[O:23])=[CH:8][C:9](=[O:19])[C:10]=1[O:11]CC1C=CC=CC=1)=[O:4].C1(S(C(N)C2N(C)C(C(O)=O)=C(O)C(=O)C=2)(=O)=O)C=CC=CC=1>>[CH3:1][NH:2][C:3]([C:5]1[N:6]([CH3:32])[C:7]([CH2:20][NH:21][S:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[Cl:31])(=[O:23])=[O:24])=[CH:8][C:9](=[O:19])[C:10]=1[OH:11])=[O:4]
Reactant: CNC(=O)c1c(OCc2ccccc2)c(=O)cc(CNS(=O)(=O)c2ccccc2Cl)n1C
Agent: Cn1c(C(N)S(=O)(=O)c2ccccc2)cc(=O)c(O)c1C(=O)O
Product: CNC(=O)c1c(O)c(=O)cc(CNS(=O)(=O)c2ccccc2Cl)n1C
Yield: 52.1 %

Procedure:
6-[(2-Chloro-benzenesulfonylamino)-methyl]-3-hydroxy-1-methyl-4-oxo-1,4-dihydro-pyridine-2-carboxylic acid methylamide (16-03) (110.0 mg, 52.09%, purified by Prep-HPLC) was synthesized as a yellow solid from 3-benzyloxy-6-[(2-chloro-benzenesulfonylamino)-methyl]-1-methyl-4-oxo-1,4-dihydro-pyridine-2-carboxylic acid methylamide (15-03) (260.0 mg, 0.547 mmol) following the procedure described for 6-(benzene sulfonyl amino-methyl)-3-hydroxy-1-methyl-4-oxo-1,4-dihydro-pyridine-2-carboxylic acid (14-01).
Reaction SMILES: [N:1]1[N:2]=[N:3][N:4]2[CH:9]=[C:8]([C@@H:10]3[CH2:12][O:11]3)[CH:7]=[CH:6][C:5]=12.[CH3:13][C:14]([NH2:28])([CH3:27])[CH2:15][C:16]1[C:24]2[C:19](=[CH:20][CH:21]=[C:22]([O:25][CH3:26])[CH:23]=2)[NH:18][CH:17]=1>C(O)C>[CH3:27][C:14]([NH:28][CH2:12][C@@H:10]([C:8]1[CH:7]=[CH:6][C:5]2[N:4]([N:3]=[N:2][N:1]=2)[CH:9]=1)[OH:11])([CH3:13])[CH2:15][C:16]1[C:24]2[C:19](=[CH:20][CH:21]=[C:22]([O:25][CH3:26])[CH:23]=2)[NH:18][CH:17]=1
Reactant: c1cc2nnnn2cc1[C@@H]1CO1
Reactant: COc1ccc2[nH]cc(CC(C)(C)N)c2c1
Solvent: CCO
Product: COc1ccc2[nH]cc(CC(C)(C)NC[C@H](O)c3ccc4nnnn4c3)c2c1

Procedure:
A solution of 598 mg of (R)-2-(tetrazolo[1,5-a]pyrid-6-yl)oxirane and 782 mg of (1,1-dimethyl-2-(5-methoxy-1H-indol-3-yl)ethyl amine (B. Heath-Brown and P. G. Philpott, J. Chem. Soc., 7165 (1965)) in 12 ml of absolute ethanol was heated at reflux for 44 hours. The reaction mixture was concentrated and the residue (1.15 g) was chromatographed on silica gel (95:5:0.5 CH2Cl2 :MeOH:NH4OH) to give 0.997 g of (R)-α-[[(1,1-dimethyl-2-(5-methoxy-1H-indol-3-yl)ethyl)amino]methyl]tetrazolo[1,5-a]pyridine-6-methanol.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1[NH:11][C:12](=O)OC(C)(C)C)=O.CO/C=[CH:22]/[C:23]([O:25][CH3:26])=[O:24].Cl.C([O-])([O-])=O.[Na+].[Na+]>CO>[CH3:10][O:9][C:5]1[CH:6]=[CH:7][CH:8]=[C:3]2[C:4]=1[N:11]=[CH:12][C:22]([C:23]([O:25][CH3:26])=[O:24])=[CH:1]2
Reactant: COc1cccc(C=O)c1NC(=O)OC(C)(C)C
Reactant: CO/C=C/C(=O)OC
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1cnc2c(OC)cccc2c1
Temperature: 25 °C
Yield: 86 %

Procedure:
To a solution of tert-butyl N-(2-formyl-6-methoxyphenyl)carbamate (2.85 g, 11.35 mmol) [described in Org. Lett. 2002, 4(1), 39-42] and methyl trans-3-methoxyacrylate (2.70 mL, 24.96 mmol) dissolved in 60 ml of methanol, was added slowly 40 mL of an aqueous solution of hydrochloric acid 3M. The resulting mixture was stirred under reflux for 3 hours. The reaction mixture was then cooled to room temperature and neutralised by adding Na2CO3. The aqueous solution was extracted with CH2Cl2 (4×70 mL). The combined organic layers were dried over MgSO4, filtered and evaporated under vacuum giving 2.12 g of compound of molecular formula C12H11NO3. The crude product was used without further purification in the next stage. Aspect: orange powder.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Mg]Br)=[CH:4][CH:3]=1.CON(C)[C:13]([C:15]1[CH:16]=[N:17][CH:18]=[N:19][CH:20]=1)=[O:14]>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:13]([C:15]2[CH:16]=[N:17][CH:18]=[N:19][CH:20]=2)=[O:14])=[CH:4][CH:3]=1
Reactant: CON(C)C(=O)c1cncnc1
Reactant: Clc1ccc([Mg]Br)cc1
Solvent: C1CCOC1
Product: O=C(c1ccc(Cl)cc1)c1cncnc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4-chlorophenylmagnesium bromide (1 M in Et2O, 4.53 mL, 4.53 mmol) was added to a solution of crude N-methoxy-N-methylpyrimidine-5-carboxamide (505 mg, 3.02 mmol, Intermediate 28, step a) in THF at 0° C. The reaction mixture was allowed to warm to room temperature and was stirred overnight. The reaction was quenched by addition of saturated aqueous NH4Cl, diluted with water, and extracted three times with EtOAc. The organic phase was dried (Na2SO4), filtered, and concentrated. The residue was purified by flash column chromatography (silica gel, gradient 1-5% MeOH-DCM), affording impure title compound which was used without further purification.
Reaction SMILES: [CH3:1][NH:2][C:3]1[N:4]=[CH:5][C:6]2[CH:12]=[CH:11][C:10]([CH3:13])=[N:9][C:7]=2[N:8]=1.[Al].[Br:15]N1C(=O)CCC1=O>C(#N)C>[Br:15][C:11]1[C:10]([CH3:13])=[N:9][C:7]2[N:8]=[C:3]([NH:2][CH3:1])[N:4]=[CH:5][C:6]=2[CH:12]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CNc1ncc2ccc(C)nc2n1
Agent: [Al]
Solvent: CC#N
Product: CNc1ncc2cc(Br)c(C)nc2n1
Yield: 30.7 %

Procedure:
Cool a solution of N,7-dimethylpyrido[2,3-d]pyrimidin-2-amine (6.73 g, 38.6 mmol) in acetonitrile (160 mL) in an ice bath and shield from light with aluminum foil. Add N-bromosuccinimide (6.88 g, 38.6 mmol) and stir at 0° C. for 2 h. Transfer the reaction to a 5° C. refrigerator for 4 days. Collect the solid by filtration. Wash the solid with DCM and concentrate the washings to obtain the title compound (3.0 g, 31% yield). MS (m/z): 253.0/255.0 (M+1).
Reaction SMILES: [NH3:1].[CH3:2][N:3]([CH:16]1[CH2:21][CH2:20][N:19]([C:22](=[O:34])[C:23]2[CH:28]=[CH:27][C:26]([N:29]3[CH:33]=[N:32][CH:31]=[N:30]3)=[CH:25][CH:24]=2)[CH2:18][CH2:17]1)[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12](OC)=[O:13])=[CH:8][CH:7]=1>CO>[CH3:2][N:3]([CH:16]1[CH2:21][CH2:20][N:19]([C:22](=[O:34])[C:23]2[CH:24]=[CH:25][C:26]([N:29]3[CH:33]=[N:32][CH:31]=[N:30]3)=[CH:27][CH:28]=2)[CH2:18][CH2:17]1)[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12](=[O:13])[NH2:1])=[CH:8][CH:7]=1
Reactant: COC(=O)c1ccc(CCN(C)C2CCN(C(=O)c3ccc(-n4cncn4)cc3)CC2)cc1
Reactant: N
Solvent: CO
Product: CN(CCc1ccc(C(N)=O)cc1)C1CCN(C(=O)c2ccc(-n3cncn3)cc2)CC1
Temperature: 110 °C
Reaction time: 69.5 h

Procedure:
45 ml of a saturated solution of ammonia in methanol was added to 600 mg of 4-{N-methyl-N-[2-(4-methoxycarbonylphenyl)ethyl]amino}-1-[4-(1,2,4-triazol-1-yl)benzoyl]piperidine. The mixture was stirred at 110° C. for 69.5 hours in a sealed tube. The reaction mixture was cooled to room temperature and then subjected to distillation to remove the solvent. The residue was purified by a silica gel column chromatography (eluant: dichloromethane/methanol/ammonia water=200/20/1). The product was washed with diethyl ether for crystallization, followed by recrystallization from ethanol to obtain 320 mg of 4-{N-methyl-N-[2-(4-carbamoylphenyl)ethyl]amino}-1-[4-(1,2,4-triazol-1-yl)benzoyl]piperidine as a white powder.
Reaction SMILES: OC1C(=O)NN=C(CCC2C=CC=CC=2)C=1.C([O:24][C:25]1[N:26]=[N:27][C:28]([C:39]#[C:40][C:41]2[CH:46]=[CH:45][CH:44]=[C:43]([O:47][CH:48]([F:50])[F:49])[CH:42]=2)=[CH:29][C:30]=1[O:31]CC1C=CC=CC=1)C1C=CC=CC=1.O1CCCC1>CO>[F:50][CH:48]([F:49])[O:47][C:43]1[CH:42]=[C:41]([CH:46]=[CH:45][CH:44]=1)[CH2:40][CH2:39][C:28]1[CH:29]=[C:30]([OH:31])[C:25](=[O:24])[NH:26][N:27]=1
Reactant: FC(F)Oc1cccc(C#Cc2cc(OCc3ccccc3)c(OCc3ccccc3)nn2)c1
Agent: O=c1[nH]nc(CCc2ccccc2)cc1O
Solvent: C1CCOC1
Solvent: CO
Product: O=c1[nH]nc(CCc2cccc(OC(F)F)c2)cc1O

Procedure:
Prepared by the same method as for 4-hydroxy-6-(2-phenylethyl)pyridazin-3(2H)-one (Example 1) from 3,4-bis(benzyloxy)-6-((3-(difluoromethoxy)phenyl)ethynyl)pyridazine (Intermediate 38) except that the mixture of solvent mixture used for the hydrogenation was made up of tetrahydrofuran and methanol and the final compound was recrystallised from a mixture of ethanol and heptane.
Reaction SMILES: [CH2:1]1[C:13]2[C:4](=[N:5][C:6]3[CH:7]=[CH:8][CH:9]=[CH:10][C:11]=3[CH:12]=2)[CH2:3][CH2:2]1.[H][H]>CO.O=[Pt]=O>[CH2:1]1[C@@H:13]2[C@H:4]([NH:5][C:6]3[CH:7]=[CH:8][CH:9]=[CH:10][C:11]=3[CH2:12]2)[CH2:3][CH2:2]1
Reactant: c1ccc2nc3c(cc2c1)CCC3
Reactant: [H][H]
Agent: O=[Pt]=O
Solvent: CO
Product: c1ccc2c(c1)C[C@@H]1CCC[C@H]1N2

Procedure:
The title compound was prepared by catalytic hydrogenation of 2,3-dihydro-1H-cyclopenta[b]quinoline (0.5 g, 2.43 mmol) in the presence of PtO2 and hydrogen (45 psi) in methanol (50 ml) to give the cis and trans isomers. Separation by flash chromatography (10–30% ethyl acetate/petroleum ether) gave the title compounds as light yellow solids (75%).
Reaction SMILES: [OH-].[Na+].[Br:3][C:4]1[C:12]2[NH:11][C@H:10]3[CH2:13][CH2:14][NH:15][CH2:16][C@H:9]3[C:8]=2[CH:7]=[CH:6][CH:5]=1.C(N(CC)CC)C.Cl[C:25]([O:27][CH2:28][CH3:29])=[O:26]>C1COCC1>[Br:3][C:4]1[C:12]2[NH:11][C@H:10]3[CH2:13][CH2:14][N:15]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH2:16][C@H:9]3[C:8]=2[CH:7]=[CH:6][CH:5]=1
Reactant: CCOC(=O)Cl
Reactant: Brc1cccc2c1N[C@H]1CCNC[C@@H]21
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)N1CC[C@@H]2Nc3c(Br)cccc3[C@@H]2C1
Temperature: 25 °C

Procedure:
(4aS,9bR)-ethyl 6-bromo-3,4,4a,5-tetrahydro-1H-pyrido[4,3-b]indole-2(9bH)-carboxylate may be prepared by first obtaining [4aS,9bR]-6-bromo-2,3,4,4a,5,9b-hexahydro-1H-pyrido[4,3-b]indole (36.0 g, 0.142 mol)) as a free base by using 50% aqueous sodium hydroxide solution and extracting the product into MTBE. The conversion to (4aS,9bR)-ethyl 6-bromo-3,4,4a,5-tetrahydro-1H-pyrido[4,3-b]indole-2(9bH)-carboxylate may then be done by cooling a suspension of compounds of [4aS,9bR]-6-bromo-2,3,4,4a,5,9b-hexahydro-1H-pyrido[4,3-b]indole (36.0 g, 0.142 mol)) in THF (300 ml) and triethylamine (24 ml) in an ice-water bath. Ethyl chloroformate is added dropwise (13.5 ml, 0.142 mol) via a syringe pump over 1 hour. The ice-water bath is removed and the reaction mixture is stirred at room temperature for another hour. The reaction mixture is passed through a pad of celite and the solvent is evaporated to give (4aS,9bR)-ethyl 6-bromo-3,4,4a,5-tetrahydro-1H-pyrido[4,3-b]indole-2(9bH)-carboxylate). 1H NMR (CDCl3, 300 MHz): 1.20-1.35 (m, 3H), 1.73-1.85 (m, 1H), 1.85-1.99 (m, 1H), 3.22-3.52 (m, 3H), 3.52-3.66 (m, 1H), 3.66-3.95 (Br, 1H), 3.95-4.21 (m, 4H), 6.60 (t, J=7.7 Hz, 1H), 7.04 (d, J=7.2 Hz, 1H), 7.20 (d, J=8.1 Hz, 1H).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[CH:12]=[C:13]([C:15]4[N:19]([C:20]5[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=5[Cl:26])[N:18]=[C:17]([NH2:27])[N:16]=4)[N:14]=[C:7]3[C:6]=2[CH:28]=1.[C:29]1(B(O)O)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.C([O-])([O-])=O.[Cs+].[Cs+].O>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Cl:26][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[N:19]1[C:15]([C:13]2[N:14]=[C:7]3[C:6]4[CH:28]=[C:2]([C:29]5[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=5)[CH:3]=[CH:4][C:5]=4[O:11][CH2:10][CH2:9][N:8]3[CH:12]=2)=[N:16][C:17]([NH2:27])=[N:18]1
Reactant: OB(O)c1ccccc1
Reactant: Nc1nc(-c2cn3c(n2)-c2cc(Br)ccc2OCC3)n(-c2ccccc2Cl)n1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: Nc1nc(-c2cn3c(n2)-c2cc(-c4ccccc4)ccc2OCC3)n(-c2ccccc2Cl)n1
Temperature: 130 °C
Reaction time: 0.5 h
Yield: 20.7 %

Procedure:
A mixture of 5-(10-bromo-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-2-yl)-1-(2-chlorophenyl)-1H-1,2,4-triazol-3-amine (0.5 mmol), phenylboronic acid (200 mg, 0.75 mmol), Cs2CO3 (490 mg, 1.5 mmol) was stirred in dioxane and water (5:1, 3.0 mL) followed by the addition of Pd(dppf)Cl2 (30 mg). The reaction mixture was bubbled with N2 gas for 10 min, the reaction tube was sealed, and the contents were stirred at 130° C. under microwave irradiation for 30 min. The mixture was filtered through celite and the filtrate was concentrated and purified with prep-HPLC to give 564 (47 mg, 21%). 1H-NMR (DMSO, 400 MHz): δ 7.90 (s, 1H), 8.89 (s, 1H), 7.38-7.70 (m, 10H), 7.03 (d, J=10.8 Hz, 1H), 5.48 (s, 2H), 4.43-4.49 (m, 4H)
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([CH3:11])[CH:10]=[C:6]2[N:5]=[C:4]([NH:12][C:13](=[O:24])[C:14]2[CH:19]=[CH:18][C:17]([C:20]([OH:23])([CH3:22])[CH3:21])=[CH:16][CH:15]=2)[CH:3]=1.[CH:25]([O:28][C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1)([CH3:27])[CH3:26].O1CCOCC1>CO.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].Cl[Pd]Cl>[OH:23][C:20]([C:17]1[CH:18]=[CH:19][C:14]([C:13]([NH:12][C:4]2[CH:3]=[C:2]([C:32]3[CH:33]=[CH:34][C:29]([O:28][CH:25]([CH3:27])[CH3:26])=[CH:30][CH:31]=3)[N:7]3[N:8]=[C:9]([CH3:11])[CH:10]=[C:6]3[N:5]=2)=[O:24])=[CH:15][CH:16]=1)([CH3:22])[CH3:21]
Reactant: Cc1cc2nc(NC(=O)c3ccc(C(C)(C)O)cc3)cc(Cl)n2n1
Reactant: CC(C)Oc1ccc(B(O)O)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: C1COCCO1
Solvent: CO
Product: Cc1cc2nc(NC(=O)c3ccc(C(C)(C)O)cc3)cc(-c3ccc(OC(C)C)cc3)n2n1
Temperature: 110 °C
Yield: 48.6 %

Procedure:
A suspension of N-(7-chloro-2-methylpyrazolo[1,5-a]pyrimidin-5-yl)-4-(2-hydroxypropan-2-yl)benzamide (2F, 60 mg, 0.174 mmol), 4-isopropoxyphenylboronic acid (41 mg, 0.226 mmol), and 1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (10 mg, 13.6 μmol) in 2:1 1,4-dioxane/saturated aqueous NaHCO3 (0.58 mL of 1,4-dioxane and 0.29 mL of saturated aqueous NaHCO3) was prepared in a 10 mL microwave reaction vessel and the sealed reaction vessel warmed to 110° C. for 10 minutes in a CEM microwave reactor. The reaction mixture was cooled to rt, diluted with methanol, filtered, and purified via preparative HPLC (70-70% MeCN/H2O gradient+0.01% TFA). Lyophilization of the combined fractions gave the titled compound as a yellow solid (37.6 mg, 49%). 1H NMR (DMSO-d6) δ: 11.07 (s, 1H), 8.03 (d, J=8.8 Hz, 2H), 7.96 (d, J=8.3 Hz, 2H), 7.90 (s, 1H), 7.55 (d, J=8.6 Hz, 2H), 7.08 (d, J=8.8 Hz, 2H), 6.30 (s, 1H), 4.71 (spt, 1H), 2.34 (s, 3H), 1.39 (s, 6H), 1.27 (d, 6H); ESI-MS: m/z 445.3 (M+H)+.
Reaction SMILES: ClC1SC(C(O)[C:8]2[C:9](CC(C)C)=[C:10]([C:21]([O:23]C)=[O:22])[C:11](C(F)F)=[N:12][C:13]=2C(F)(F)F)=CN=1.C(N(CC)CC)C>[Pd].CO>[N:12]1[CH:13]=[CH:8][CH:9]=[C:10]([C:21]([OH:23])=[O:22])[CH:11]=1
Reactant: COC(=O)c1c(C(F)F)nc(C(F)(F)F)c(C(O)c2cnc(Cl)s2)c1CC(C)C
Agent: [Pd]
Solvent: CO
Solvent: CCN(CC)CC
Product: O=C(O)c1cccnc1
Reaction time: 18 h

Procedure:
This example illustrates the preparation of Compounds 62, 106, 107, and 109, an example of reduction of a .varies.-hydroxyhaloheterocyclomethyl derivative to the .varies.-hydroxyheterocyclomethyl derivative, and oxidation of this derivative to compounds of the present invention. A mixture of methyl 5-[(2-chloro-5-thiazolyl)-hydroxymethyl)-2-(difluoromethyl)-4-(2-methylpropyl)-6-(trifluoromethyl)-3-pyridinecarboxylate (7.2 g, 16 mmol), 6 mL triethylamine, and 5% of palladium on activated carbon catalyst (5 g) in 80 mL methanol was placed in a Parr hydrogenation apparatus at 50 psi and RT for 18 h. The reaction mixture was filtered through celite. The celite was thoroughly washed with methanol. The combined filtrates was concentrated in vacuo. The residual solid was purified by flash chromatography on silica gel with 30% ethyl acetate-cyclohexane to afford 3-pyridinecarboxylic acid, 2-(difluoromethyl)-5-(hydroxy-5-thiazolylmethyl)-4-(2-methylpropyl)-6-(trifluoromethyl)-, methyl ester (5 g, 73.5%) as A light yellow solid. m.p. 140°-150° C.