Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[N:10]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]#[N:19])=[C:14]([N:20]=[C:21]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH:13]=2)[C:9](=[O:34])[CH2:8][N:7](C(OCC=C)=O)[CH2:6]1)=[O:4].N1CCOCC1>C(Cl)Cl.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>[CH3:1][O:2][C:3]([CH:5]1[CH2:6][NH:7][CH2:8][C:9](=[O:34])[N:10]1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]#[N:19])=[C:14]([N:20]=[C:21]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:13]=1)=[O:4]
Reactant: C=CCOC(=O)N1CC(=O)N(Cc2ccc(C#N)c(N=C(c3ccccc3)c3ccccc3)c2)C(C(=O)OC)C1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: C1COCCN1
Product: COC(=O)C1CNCC(=O)N1Cc1ccc(C#N)c(N=C(c2ccccc2)c2ccccc2)c1
Reaction time: 0.08 h
Yield: 97 %

Procedure:
Tetrakis(triphenylphosphine)palladium(0) (237 mg, 0.2 mmol) is added to a solution containing (±)-4-[3-(benzhydrylidene-amino)-4-cyano-benzyl]-5-oxo-piperazine-1,3-dicarboxylic acid 1-allyl ester 3-methyl ester (1.10 g, 2.05 mmol) and morpholine (894 mg, 10.2 mmol) in CH2Cl2 (30 mL). After ˜5 min, the reaction mixture is absorbed onto silica gel and chromatographed (CH2Cl2 to 10% MeOH/CH2Cl2) to provide 900 mg (97%) of the title compound as a viscous yellow oil. 1H NMR (300 MHz, CDCl3) δ1.83 (br s, 1H), 2.95 (dd, J=13.5, 4.3 Hz, 1H), 3.27 (br d, J=13.5 Hz, 1H), 3.46-3.72 (m, 4H), 3.73 (s, 3H), 5.40 (d, J=15.3 Hz, 1H), 6.57 (br s, 1H), 6.83 (dd, J=8.0, 1.2 Hz, 1H), 7.17-7.50 (m, 9H), 7.75-7.77 (m, 2H) ppm; MS (ion spray): m/z 453 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[NH:15]([CH2:19][CH2:20][OH:21])[CH2:16][CH2:17][OH:18].Cl>CC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[OH:18][CH2:17][CH2:16][N:15]([CH2:19][CH2:20][OH:21])[SH:8](=[O:9])=[O:10]
Reactant: OCCNCCO
Reactant: O=[N+]([O-])c1cc(S(=O)(=O)Cl)ccc1Cl
Agent: Cl
Solvent: CC(C)=O
Product: O=[N+]([O-])c1ccccc1Cl
Product: O=[SH](=O)N(CCO)CCO
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a stirred solution of 4-chloro-3-nitrobenzene sulphonyl chloride (157.65 g; 0.616 mol) in acetone A.R. (300 ml), diethanolamine (155.19 g; 1.478 mol) was added dropwise at <20° C. over 1 hour. After stirring for a further 11/2 hours at <20° C. the yellow/brown reaction mixture was poured into ice/water (1500 g) with stirring. The resulting mixture was stirred for 11/2 hours and then the pH adjusted to pH7 by the addition of concentrated hydrochloric acid SG 1.18, filtered and washed copiously with water (3 liter). The residue was dried (40° C. vac oven) to give a pale yellow solid (156.89 g; 78% m.pt.96°)
Reaction SMILES: NC(N)=O.[CH:5]12[O:12][CH:9]([CH2:10][CH2:11]1)[CH2:8][N:7]([C:13]1[N:18]=[C:17]([C:19]3[CH:24]=[CH:23][C:22]([NH:25][C:26]([NH:28][CH2:29][CH3:30])=[O:27])=[CH:21][CH:20]=3)[N:16]=[C:15]3[N:31]([CH:34]4[CH2:39]CN(C(OCC)=O)CC4)[N:32]=[CH:33][C:14]=13)[CH2:6]2.NC1C=[CH:53][C:49]([C:50]([NH2:52])=[O:51])=[CH:48][CH:47]=1.NC1C=CC=CC=1>>[CH:5]12[O:12][CH:9]([CH2:10][CH2:11]1)[CH2:8][N:7]([C:13]1[N:18]=[C:17]([C:19]3[CH:20]=[CH:21][C:22]([NH:25][C:26](=[O:27])[NH:28][C:29]4[CH:30]=[CH:53][C:49]([C:50]([NH2:52])=[O:51])=[CH:48][CH:47]=4)=[CH:23][CH:24]=3)[N:16]=[C:15]3[N:31]([CH2:34][CH3:39])[N:32]=[CH:33][C:14]=13)[CH2:6]2
Reactant: NC(=O)c1ccc(N)cc1
Reactant: CCNC(=O)Nc1ccc(-c2nc(N3CC4CCC(C3)O4)c3cnn(C4CCN(C(=O)OCC)CC4)c3n2)cc1
Agent: NC(N)=O
Solvent: Nc1ccccc1
Product: CCn1ncc2c(N3CC4CCC(C3)O4)nc(-c3ccc(NC(=O)Nc4ccc(C(N)=O)cc4)cc3)nc21

Procedure:
A urea formation procedure similar to that used for the synthesis of ethyl 4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(4-(3-ethylureido)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylate is used, utilizing p-amino benzamide as the aniline component. (9%, MS=513.2 (M+H))
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][CH:11]([CH3:14])[CH2:10][CH2:9]2)[CH:5]=[CH:4][N:3]=1.[NH2:15][C:16]1[NH:17][N:18]=[C:19]([CH3:21])[CH:20]=1.C(=O)([O-])[O-].[K+].[K+]>C(O)CCC>[CH3:14][CH:11]1[CH2:12][CH2:13][N:8]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:15][C:16]3[NH:17][N:18]=[C:19]([CH3:21])[CH:20]=3)[N:7]=2)[CH2:9][CH2:10]1
Reactant: CC1CCN(c2ccnc(Cl)n2)CC1
Reactant: Cc1cc(N)[nH]n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCO
Product: Cc1cc(Nc2nccc(N3CCC(C)CC3)n2)[nH]n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 50 %

Procedure:
To a solution of 2-chloro-4-(4-methylpiperidin-1-yl)-pyrimidine (prepared using a procedure similar to the one reported in Eur. J. Med. Chem., 26(7) 729(1991))(222 mg, 1.05 mmol) in BuOH (5 mL) was added 3-amino-5-methyl-2H-pyrazole (305 mg, 3.15 mmol) and the reaction mixture was then heated under reflux overnight. The solvent was evaporated and the residue dissolved in a mixture ethanol/water (⅓, 4 mL). Potassium carbonate (57 mg, 0.41 mmol) was added and the mixture was stirred at room temperature for 2 hours. The resulting suspension was filtered, washed with water twice and rinsed with ether twice to give the title compound as a white solid (143 mg, 50%): mp 193-195° C.; 1H NMR (DMSO) δ 0.91 (3H, d), 1.04 (2H, m), 1.67 (3H, m), 2.16 (3H, s), 2.83 (2H, t), 4.31 (2H, m), 6.19 (2H, m), 7.87 (1H, d), 8.80 (1H, br s), 11.71 (1H, s); IR (solid) 1627, 1579, 1541, 1498, 1417, 1388, 1322, 1246; MS 273.3 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[NH:7][CH:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([NH2:17])[CH:14]=2)[CH2:9]1)([CH3:4])([CH3:3])[CH3:2].C(N(C(C)C)CC)(C)C.[F:28][C:29]([F:46])([F:45])[C:30]1[CH:35]=[CH:34][C:33]([C:36]2[C:37]([C:42](Cl)=[O:43])=[CH:38][CH:39]=[CH:40][CH:41]=2)=[CH:32][CH:31]=1.C(OCC)(=O)C>C(Cl)Cl>[C:1]([O:5][C:6](=[O:18])[NH:7][CH:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([NH:17][C:42]([C:37]3[C:36]([C:33]4[CH:34]=[CH:35][C:30]([C:29]([F:28])([F:45])[F:46])=[CH:31][CH:32]=4)=[CH:41][CH:40]=[CH:39][CH:38]=3)=[O:43])[CH:14]=2)[CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(Cl)c1ccccc1-c1ccc(C(F)(F)F)cc1
Reactant: CC(C)(C)OC(=O)NC1Cc2ccc(N)cc2C1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NC1Cc2ccc(NC(=O)c3ccccc3-c3ccc(C(F)(F)F)cc3)cc2C1
Reaction time: 16 h

Procedure:
To a solution of the title C compound ((5-amino-indan-2-yl)-carbamic acid tert-butyl ester; 12.5 mmol) in methylene chloride (75 mL) is added diisopropylethyl amine (3.3 g, 25 mmol) followed by a 0.5 M solution of the title D compound (4′-trifluoromethyl-2-biphenyl carboxylic acid chloride, 12.6 mmol) in methylene chloride (25.3 mL). After stirring 16 h, the reaction mixture is poured into ethyl acetate and washed with 1N HCl, 8% NaHCO3 solution, and brine. The organic layer is dried (MgSO4) and concentrated under reduced pressure to give a solid. Recrystallization from toluene gives {5-[(4′-trifluoromethylbiphenyl-2-carbonyl)amino]-indan-2-yl}-carbamic acid tert-butyl ester in two crops; mp 198-201° C. MS (ES+), m/z 514 (M+NH+4).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].O1CCCC1.[F:12][C:13]1[CH:40]=[CH:39][C:16]([C:17]([CH2:19][CH2:20][C:21]([N:23]2[CH2:28][CH2:27][CH:26]([N:29]3[C:33]4[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=4[NH:31][C:30]3=[O:38])[CH2:25][CH2:24]2)=O)=[O:18])=[CH:15][CH:14]=1>O>[F:12][C:13]1[CH:40]=[CH:39][C:16]([CH:17]([OH:18])[CH2:19][CH2:20][CH2:21][N:23]2[CH2:28][CH2:27][CH:26]([N:29]3[C:33]4[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=4[NH:31][C:30]3=[O:38])[CH2:25][CH2:24]2)=[CH:15][CH:14]=1
Reactant: O=C(CCC(=O)N1CCC(n2c(=O)[nH]c3ccccc32)CC1)c1ccc(F)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: O=c1[nH]c2ccccc2n1C1CCN(CCCC(O)c2ccc(F)cc2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred mixture of 2.0 g of lithium aluminum hydride and 180 ml of tetrahydrofuran at room temperature, was added 4.6 g of 1-[1-(β-p-fluorobenzoylpropionyl)-4-piperidyl]-2-oxobenzimidazoline portionwise over a period of about 10 minutes. The mixture was further stirred at room temperature for one hour, then gradually heated to 60°C over a period of one hour, stirred for additional 4 hours at 60° - 65°C, and then cooled in ice. To the reaction mixture was carefully added 20 milliliters of cold water, and the precipitate formed was filtered off. The filtrate was added with 6 ml of acetic acid, and the tetrahydrofuran was removed by distillation under reduced pressure. The residue was made slightly alkaline by adding a 14% aqueous ammonia, and the solid precipitated was collected by filtration, dried, and recrystallized from toluene to obtain a white crystalline powder of 1-(p-fluorophenyl)-4-[4-(2-oxo-1-benzimidazolinyl)-piperidino]-1-butanol, melting at 160° - 161° C.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:14])[C@H:10]([CH2:12][OH:13])[NH2:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:15]([O:25][C@H:26]([CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])[CH2:27][C:28](O)=[O:29])(=[O:24])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23].C(Cl)CCl.CI>C(Cl)Cl>[CH2:1]([O:8][C:9](=[O:14])[C@H:10]([CH2:12][OH:13])[NH:11][C:28](=[O:29])[CH2:27][C@H:26]([O:25][C:15](=[O:24])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCCCCCCCCC[C@H](CC(=O)O)OC(=O)CCCCCCCC
Reactant: N[C@@H](CO)C(=O)OCc1ccccc1
Solvent: ClCCl
Solvent: ClCCCl
Solvent: CI
Product: CCCCCCCCCCC[C@H](CC(=O)N[C@@H](CO)C(=O)OCc1ccccc1)OC(=O)CCCCCCCC
Yield: 89 %

Procedure:
((1) In the same manner as described in Example 2-(5), L-serine benzyl ester (390 mg, 2.0 mmol) was acylated with (R)-3-nonanoyloxytetradecanoic acid (780 mg, 2.2 mmol) in the presence of EDC MeI (845 mg, 2.5 mmol) in CH2Cl2 to afford 1.0 g (89%) of N-[(R)-3-nonanoyloxytetradecanoyl]-L-serine benzyl ester: mp 52-53° C.; 1H NMR (CDCl3) δ 0.88 (t, 6 H, J=6.6 Hz), 1.1-1.7 (m, 32 H), 2.30 (t, 2 H, J=7.7 Hz), 2.51 (d, 2 H, J=5.8 Hz), 2.62 (t, 1 H, J=6.0 Hz), 3.98 (m, 2 H), 4.65 (m, 1 H), 5.19 (m, 3 H), 6.58 (d, 1 H, J=6.8 Hz), 7.35 (br s, 5 H).
Reaction SMILES: COC1C=C(OC)C=CC=1C[N:6]([C:32]1[CH:37]=[CH:36][N:35]=[CH:34][N:33]=1)[S:7]([C:10]1[CH:15]=[CH:14][C:13]([O:16][C@H:17]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][C@@H:18]2[C:24]2[N:28]([CH3:29])[N:27]=[CH:26][CH:25]=2)=[C:12]([F:30])[C:11]=1[F:31])(=[O:9])=[O:8].C([SiH](CC)CC)C.FC(F)(F)C(O)=O>ClCCl>[F:31][C:11]1[C:12]([F:30])=[C:13]([O:16][C@H:17]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][C@@H:18]2[C:24]2[N:28]([CH3:29])[N:27]=[CH:26][CH:25]=2)[CH:14]=[CH:15][C:10]=1[S:7]([NH:6][C:32]1[CH:37]=[CH:36][N:35]=[CH:34][N:33]=1)(=[O:8])=[O:9]
Reactant: COc1ccc(CN(c2ccncn2)S(=O)(=O)c2ccc(O[C@H]3CCCCC[C@@H]3c3ccnn3C)c(F)c2F)c(OC)c1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cn1nccc1[C@H]1CCCCC[C@@H]1Oc1ccc(S(=O)(=O)Nc2ccncn2)c(F)c1F
Yield: 71 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 1b by using the N-(2,4-dimethoxybenzyl)-2,3-difluoro-4-{[(1S*,2R*)-2-(1-methyl-1H-pyrazol-5-yl)cycloheptyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide (190 mg, 0.310 mmol) prepared in Example 51a, triethylsilane (0.20 mL), trifluoroacetic acid (2.0 mL) and dichloromethane (2.0 mL), to yield the title compound (102 mg, 71%) as a colorless solid.
Reaction SMILES: [CH3:1][N:2]([CH3:21])[NH:3][C:4]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][C:7]([C:13]([F:16])([F:15])[F:14])=[C:6](Cl)[C:5]=1[N+:18]([O-:20])=[O:19].[NH3:22].C(O)C>O>[CH3:1][N:2]([NH:3][C:4]1[C:5]([N+:18]([O-:20])=[O:19])=[C:6]([NH2:22])[C:7]([C:13]([F:16])([F:15])[F:14])=[CH:8][C:9]=1[N+:10]([O-:12])=[O:11])[CH3:21]
Reactant: N
Reactant: CN(C)Nc1c([N+](=O)[O-])cc(C(F)(F)F)c(Cl)c1[N+](=O)[O-]
Solvent: O
Solvent: CCO
Product: CN(C)Nc1c([N+](=O)[O-])cc(C(F)(F)F)c(N)c1[N+](=O)[O-]
Temperature: 65 °C
Reaction time: 8 h

Procedure:
A 50 ml. Pyrex ampule was charged with N-dimethylamino-3-chloro-2,6-dinitro-4-trifluoromethylaniline (5.0 g.; 0.015 mole), ethanolic ammonia (8.54 g. of 6.06% w/w solution; 0.03 mole) and enough absolute ethanol to bring the liquid level to within one inch of the neck. The ampule was chilled in a bath of dry iceacetone, sealed, heated with hot water (65° - 75° C.) until the starting material was in solution, and then placed in an oven at 65° C. After heating at 65° C. for 72 hours, the ampule was opened and the reaction mixture was transferred to a flask and evaporated to dryness under vacuum. Cyclohexane (200 ml.) was added to the residue. The resultant mixture was heated under reflux for one hour, then filtered hot and allowed to cool to 40° C., at which temperature the product began to crystallize. The solution was decanted away from a small amount of solids and the product was allowed to crystallize slowly from the decantate by standing at room temperature overnight. The crystalline product was collected by filtration to obtain 2.7 g., m.p. 150° - 153.5° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([NH:12][CH2:13][CH:14](OC)OC)=[S:11])=[CH:5][CH:4]=1.OS(O)(=O)=O>O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH:14]=[CH:13][N:12]=[C:10]2[SH:11])=[CH:5][CH:4]=1
Reactant: COc1ccc(NC(=S)NCC(OC)OC)cc1
Agent: O=S(=O)(O)O
Solvent: O
Product: COc1ccc(-n2ccnc2S)cc1

Procedure:
A solution of 10 g (.06 mole) of p-methoxyphenyl isothiocyanate in 100 ml of CHCl3 was treated with 6.3 g (.06 mole) of aminoacetaldehyde dimethyl acetal. The solvent was evaporated and the residue was recrystallized from ethanol to yield N-(p-methoxyphenyl)-N'-(β,β-dimethoxyethyl)thiourea, 9.2 g (57%). A suspension of this thiourea in a solution of 5 ml of concentrated H2SO4 and 20 ml of H2O was refluxed for 3 hours. The mixture was cooled and a solid was filtered, washed with H2O and dried. Recrystallization from ethanol gave 1-(4-methoxyphenyl)-2-mercaptomidazole, 4.9 g (70%), mp 215-7° . The compound can be deprotected, for example, as illustrated in Example 5 and 6, below, to prepare the phenol, Y is --OH.
Reaction SMILES: C[Al](C)C.[C:5]([C:9]1[CH:13]=[C:12]([NH2:14])[N:11]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:10]=1)([CH3:8])([CH3:7])[CH3:6].[O:21]=[C:22]1[NH:41][C:25]2=[N:26][CH:27]=[CH:28][C:29]([O:30][C:31]3[CH:32]=[C:33]([CH:38]=[CH:39][CH:40]=3)[C:34](OC)=[O:35])=[C:24]2[NH:23]1>C1COCC1>[C:5]([C:9]1[CH:13]=[C:12]([NH:14][C:34](=[O:35])[C:33]2[CH:38]=[CH:39][CH:40]=[C:31]([O:30][C:29]3[CH:28]=[CH:27][N:26]=[C:25]4[NH:41][C:22](=[O:21])[NH:23][C:24]=34)[CH:32]=2)[N:11]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:10]=1)([CH3:8])([CH3:6])[CH3:7]
Reactant: COC(=O)c1cccc(Oc2ccnc3[nH]c(=O)[nH]c23)c1
Reactant: CC(C)(C)c1cc(N)n(-c2ccccc2)n1
Agent: C[Al](C)C
Solvent: C1CCOC1
Product: CC(C)(C)c1cc(NC(=O)c2cccc(Oc3ccnc4[nH]c(=O)[nH]c34)c2)n(-c2ccccc2)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Method L2: A solution of AlMe3 (solution in toluene 2M, 260 μL, 0.527 mmol,) was added dropwise to a cooled (0° C.) solution of 3-tert-butyl-1-phenyl-1H-pyrazol-5-amine (113 mg, 0.527 mmol) in THF (2.5 mL). When the addition was complete, the mixture was allowed to warm to room temperature and stirring was continued for 30 minutes. Then methyl 3-(2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-7-yloxy)benzoate (100 mg, 0.351 mmol) was added and the mixture was heated under reflux for 19 hours. The mixture was cooled to room temperature and carefully quenched with 5% aq HCl (1 mL). After evaporation of solvent, the residue was retaken in CH2Cl2, washed with saturated solution of NaHCO3 then with brine, dried over MgSO4 and evaporated under vacuum. The obtained residue was chromatographied (eluent: EtOAc) and the title compound was obtained as a light yellow solid (54 mg, 33%). 1H-NMR (δ, ppm, DMSO-d6): 1.30 (s, 9H, tBu), 6.39 (s, 1H, Hpyrrazole) 6.51 (d, 1H, HPy,5, J=5.9 Hz), 7.31 (t, 1H, Harom, J=7.4 Hz), 7.37 (dd, 1H, Harom, J=8.0 Hz, J=2.3 Hz), 7.41-7.44 (m, 2H, Harom), 7.49-7.51 (m, 2H, Harom), 7.55-7.62 (m, 2H, Harom), 7.71 (d, 1H, Harom, J=8.1 Hz), 7.82 (d, 1H, HPy,6, J=5.9 Hz), 10.34 (s, 1H, NHamide), 11.18 (s, 1H, NHurea), 11.42 (s, 1H, NHurea). LC-MS (m/z): 469 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([O:8][CH2:9][C:10]2[CH:17]=[CH:16][C:13]([CH:14]=O)=[CH:12][CH:11]=2)[CH:3]=1.[N+:18]([CH3:21])([O-:20])=[O:19].C([O-])(=O)C.[NH4+]>C(O)(=O)C>[F:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([O:8][CH2:9][C:10]2[CH:17]=[CH:16][C:13](/[CH:14]=[CH:21]/[N+:18]([O-:20])=[O:19])=[CH:12][CH:11]=2)[CH:3]=1
Reactant: C[N+](=O)[O-]
Reactant: O=Cc1ccc(COc2cc(F)ccn2)cc1
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CC(=O)O
Product: O=[N+]([O-])/C=C/c1ccc(COc2cc(F)ccn2)cc1
Temperature: 100 °C
Reaction time: 6 h
Yield: 96.6 %

Procedure:
A mixture of the 4-(4-fluoro-pyridine-2-yloxymethyl)-benzaldehyde (1.5 g, 6.49 mmol) described in Manufacturing Example 59-1-2, nitromethane (698 μL, 13 mmol), ammonium acetate (750 mg, 9.74 mmol) and acetic acid (15 mL) was stirred for 6 hours at 100° C. This mixture was cooled to room temperature, concentrated under a reduced pressure, and diluted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure to obtain the title compound (1.72 g).
Reaction SMILES: Br[CH2:2][CH2:3]Br.[Cl-].[NH4+:6].O1[CH2:11][CH2:10][CH2:9][CH2:8]1>>[C:8]1([C:8]2[N:6]=[C:8]([CH2:9][CH2:10][C:11]3[CH:11]=[CH:10][CH:9]=[C:8]([C:3]4[CH:2]=[CH:11][CH:10]=[CH:9][CH:8]=4)[N:6]=3)[CH:11]=[CH:10][CH:9]=2)[CH:2]=[CH:3][CH:11]=[CH:10][CH:9]=1
Reactant: [NH4+]
Reactant: BrCCBr
Reactant: C1CCOC1
Agent: [Cl-]
Product: c1ccc(-c2cccc(CCc3cccc(-c4ccccc4)n3)n2)cc1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 65.1 %

Procedure:
The tetrahydrofuran (12 ml) solution of 2-methyl-6-phenylpyridine (1.0 g, 5.9 mmol) obtained by Reference Example 10 was cooled to −78° C., then lithium diisopropylamide tetrahydrofuran solution obtained as above was dropwise added thereto while 15 minutes. The reaction mixture was additionally stirred at −78° C. for 1 hour, then a tetrahydrofuran (10 ml) solution of 1,2-dibromoethane (510 μL, 5.9 mmol, 1 equivalent) was dropwise added thereto, the reaction temperature was allowed to warm to 0° C. while 40 minutes. Then the reaction mixture was poured into an aqueous saturated ammonium chloride solution, an organic layer was separated, furthermore an aqueous layer was extracted with toluene. The organic layer was combined, and the solvent was distilled off, and the residue was purified by silica gel column chromatography and recrystallization, thereby obtaining 646 mg of 1,2-bis(6-phenylpyridine-2-yl)ethane as white powder. Yield: 65.1%.
Reaction SMILES: [C:1]1([NH:7][CH2:8][C:9]([OH:11])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:12]1([N:18]=[C:19]=[S:20])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1>C(O)C>[C:1]1([N:7]2[CH2:8][C:9](=[O:11])[N:18]([CH:12]3[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]3)[C:19]2=[S:20])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)CNc1ccccc1
Reactant: S=C=NC1CCCCC1
Solvent: CCO
Product: O=C1CN(c2ccccc2)C(=S)N1C1CCCCC1
Temperature: 100 °C
Reaction time: 8 h
Yield: 40.1 %

Procedure:
A mixture of N-phenyl glycine (15.1 g, 0.1M) and cyclohexylisothiocyanate (21.2 g, 0.15M) was heated at 100° C. for 8 hours and then allowed to stand at room temperature overnight. The reaction mixture was placed in about 50 ml of ethanol, collected by filtration and recrystallized from ethanol to produce 11 grams (0.047M) of the above-identified product having a melting point of 156° C.
Reaction SMILES: BrC1C=CC2OCC3(C4SC(C(OCC)=O)=[N:15]C=4C=2C=1)OCCO3.C([C@]1(O)CCN(C)C1=O)#C.[OH:35][C@@:36]1([C:43]#[C:44][C:45]2[CH:67]=[CH:66][C:48]3[O:49][CH2:50][C:51]4([C:56]5[S:60][C:59]([C:61]([O:63]CC)=O)=[N:58][C:57]=5[C:47]=3[CH:46]=2)[O:55][CH2:54][CH2:53][O:52]4)[CH2:40][CH2:39][N:38]([CH3:41])[C:37]1=[O:42]>>[OH:35][C@@:36]1([C:43]#[C:44][C:45]2[CH:67]=[CH:66][C:48]3[O:49][CH2:50][C:51]4([C:56]5[S:60][C:59]([C:61]([NH2:15])=[O:63])=[N:58][C:57]=5[C:47]=3[CH:46]=2)[O:55][CH2:54][CH2:53][O:52]4)[CH2:40][CH2:39][N:38]([CH3:41])[C:37]1=[O:42]
Reactant: CCOC(=O)c1nc2c(s1)C1(COc3ccc(C#C[C@]4(O)CCN(C)C4=O)cc3-2)OCCO1
Reactant: CCOC(=O)c1nc2c(s1)C1(COc3ccc(Br)cc3-2)OCCO1
Agent: C#C[C@]1(O)CCN(C)C1=O
Product: CN1CC[C@@](O)(C#Cc2ccc3c(c2)-c2nc(C(N)=O)sc2C2(CO3)OCCO2)C1=O

Procedure:
Similar to as described in General Procedure G, ethyl 9-bromo-5H-spiro[benzo[2,3]oxepino[4,5-d]thiazole-4,2′-[1,3]dioxolane]-2-carboxylate was reacted with (R)-3-ethynyl-3-hydroxy-1-methylpyrrolidin-2-one to give a diasteromeric mixture of (R)-ethyl 9-((3-hydroxy-1-methyl-2-oxopyrrolidin-3-yl)ethynyl)-5H-spiro[benzo[2,3]oxepino[4,5-d]thiazole-4,2′-[1,3]dioxolane]-2-carboxylate. Following aminolysis of the ethyl ester (similar to as described in General Procedure M) the titled compound was obtained after purification by prep HPLC
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:13]([C:16]([F:19])([F:18])[F:17])=[N:14][N:15]=3)[N:12]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[N:20]1([C:26]2[CH:33]=[CH:32][C:29]([CH:30]=O)=[CH:28][CH:27]=2)[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1>>[N:20]1([C:26]2[CH:33]=[CH:32][C:29]([CH2:30][N:4]3[CH2:3][CH2:2][N:1]([C:7]4[CH:8]=[CH:9][C:10]5[N:11]([C:13]([C:16]([F:17])([F:18])[F:19])=[N:14][N:15]=5)[N:12]=4)[CH2:6][CH2:5]3)=[CH:28][CH:27]=2)[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1
Reactant: O=Cc1ccc(N2CCOCC2)cc1
Reactant: FC(F)(F)c1nnc2ccc(N3CCNCC3)nn12
Product: FC(F)(F)c1nnc2ccc(N3CCN(Cc4ccc(N5CCOCC5)cc4)CC3)nn12

Procedure:
Reductive amination of 6-(piperazin-1-yl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine with 4-morpholin-4-ylbenzaldehyde was carried out according to General Synthetic Method 7. The crude product was purified by hplc using a Waters XBridge Prep C18 OBD column, 5μ silica, 30 mm diameter, 100 mm length eluted with decreasingly polar mixtures of water (containing 0.1% aqueous ammonia) and acetonitrile as eluents to give 6-[4-[(4-morpholin-4-ylphenyl)methyl]piperazin-1-yl]-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:13]=[CH:12][C:6]([CH2:7][CH2:8][C:9](O)=[O:10])=[CH:5][CH:4]=1.B.C1COCC1.CO.O>C1COCC1>[F:1][C:2]([F:14])([F:15])[C:3]1[CH:4]=[CH:5][C:6]([CH2:7][CH2:8][CH2:9][OH:10])=[CH:12][CH:13]=1
Reactant: O=C(O)CCc1ccc(C(F)(F)F)cc1
Agent: B
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: OCCCc1ccc(C(F)(F)F)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To an ice-cooled homogeneous solution of 4-(trifluoromethyl)hydrocinnamic acid (9.800 g; 44.918 mmol) in anhydrous THF (250 ml) was added dropwise a solution of 1M BH3.THF (67.4 ml; 67.4 mmol) over 20 min. The resulting homogeneous solution was further stirred at 0° C., under nitrogen, for 1 h, and then at rt for 14 h. The colorless homogeneous reaction mixture was cooled to 0° C., and MeOH (100 ml) was carefully added followed by water (100 ml). MeOH and THF were then removed under vacuum. After extraction with DCM (3×100 ml), the combined organic extracts were washed with brine (100 ml), dried over anh. MgSO4, filtered, and concentrated to dryness under reduced pressure. The crude was purified by FC (DCM/MeOH=9/1) to give the pure product 3-(4-trifluoromethyl-phenyl)-propan-1-ol as a colorless oil which was further dried under HV (9.180 g; 100%). LC-MS: tR=0.89 min.; [M+H]+: no ionisation.