Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:22]=[C:23]3[C:27](=[CH:28][C:29]=2[Cl:30])[NH:26][CH:25]=[C:24]3[C:31]([O:33][CH3:34])=[O:32])=[CH:17][C:16]=1[O:35][CH3:36])=O)(C)(C)C.Cl>ClCCl>[Cl:30][C:29]1[CH:28]=[C:27]2[C:23]([C:24]([C:31]([O:33][CH3:34])=[O:32])=[CH:25][NH:26]2)=[CH:22][C:21]=1[C:18]1[CH:19]=[CH:20][C:15]([O:14][CH2:13][C@@H:9]2[CH2:10][CH2:11][CH2:12][NH:8]2)=[C:16]([O:35][CH3:36])[CH:17]=1
Reactant: COC(=O)c1c[nH]c2cc(Cl)c(-c3ccc(OC[C@@H]4CCCN4C(=O)OC(C)(C)C)c(OC)c3)cc12
Agent: Cl
Solvent: ClCCl
Product: COC(=O)c1c[nH]c2cc(Cl)c(-c3ccc(OC[C@@H]4CCCN4)c(OC)c3)cc12
Reaction time: 2 h

Procedure:
To a solution of (S)-methyl 5-(4-((1-(tert-butoxycarbonyl)pyrrolidin-2-yl)methoxy)-3-methoxyphenyl)-6-chloro-1H-indole-3-carboxylate (25.8 mg, 0.050 mmol) in dichloromethane (0.5 mL) was added hydrogen chloride (4 M solution in dioxane, 0.075 mL, 0.30 mmol). After 2 h, the solution was concentrated in vacuo to provide the title compound as the hydrochloride salt contaminated with neopentyl glycol. MS (ES+) 415.2 (M+H)+. 1H NMR (400 MHz, DMSO-d6): δ 8.80 (br. s, 1H), 8.17 (d, 1H), 7.94 (s, 1H), 7.65 (s, 1H), 7.11 (d, 1H), 7.06 (d, 1H), 6.96 (dd, 1H), 4.34-4.26 (m, 2H), 4.15 (dd, 1H), 4.01-3.92 (m, 1H), 3.82 (s, 3H), 3.79 (s, 3H), 3.29-3.19 (m, 2H), 2.21-2.10 (m, 1H), 2.08-1.86 (m, 2H), 1.83-1.72 (m, 1H).
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][C:5]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)=[O:19])=[CH:14][CH:13]=2)=[C:6]([CH:10]=1)[C:7]([NH2:9])=[O:8]>N1CCCCC1.C(Cl)Cl>[Br:1][C:2]1[C:3]([N:4]2[CH2:5][CH2:6][CH2:10][CH2:2][CH2:3]2)=[N:4][C:5]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)=[O:19])=[CH:14][CH:13]=2)=[C:6]([CH:10]=1)[C:7]([NH2:9])=[O:8]
Reactant: NC(=O)c1cc(Br)c(Cl)nc1Nc1ccc(C(=O)N2CCOCC2)cc1
Solvent: C1CCNCC1
Solvent: ClCCl
Product: NC(=O)c1cc(Br)c(N2CCCCC2)nc1Nc1ccc(C(=O)N2CCOCC2)cc1
Temperature: 70 °C
Yield: 189.4 %

Procedure:
A solution of 5-bromo-6-chloro-2-(4-(morpholine-4-carbonyl)phenylamino)nicotinamide (200 mg, 0.454 mmol) in piperidine (1 ml) was stirred at rt for 2 h and heated to 70° C. for 1 h. The mixture was diluted with CH2Cl2, washed with water three times, and concentrated. The residue was purified by chromatography (ISCO, hexane/ethyl acetate gradient, 40 g silica gel column) to give 210 mg of 5-bromo-2-(4-(morpholine-4-carbonyl)phenylamino)-6-(piperidin-1-yl)nicotinamide as a white solid. LCMS: (M+H)+=488.02, 489.96 (Br pattern). 1H NMR (400 MHz, CDCl3-MIX) δ ppm 11.11 (1H, s), 7.89 (1H, s), 7.76 (2H, d, J=8.79 Hz), 7.38 (2H, d, J=8.79 Hz), 3.72 (8H, br. s.), 3.46-3.52 (4H, m), 1.73 (6 H, m).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[N:20]([CH3:25])[S:21]([CH3:24])(=[O:23])=[O:22])[CH2:10][CH2:9]1)=O)(C)(C)C.[F:26][C:27]([F:32])([F:31])[C:28]([OH:30])=[O:29].ClCCl>>[F:26][C:27]([F:32])([F:31])[C:28]([OH:30])=[O:29].[CH3:25][N:20]([C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[CH:11]1[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1)[S:21]([CH3:24])(=[O:23])=[O:22]
Reactant: CN(c1ccccc1C1CCN(C(=O)OC(C)(C)C)CC1)S(C)(=O)=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN(c1ccccc1C1CCNCC1)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
N-[2-(1-t-Butoxycarbonylpiperidin-4-yl)phenyl]-N-methylmethanesulfonamide (662 mg) was dissolved in trifluoroacetic acid-dichloromethane (10%, 50 mL) and stirred at room temperature 2 h. The solvent was evaporated under reduced pressure to give the title compound as a colourless gum (670 mg), m/e (ES+) 269 (MH+).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH:10]([C:12]3[S:13][C:14](Br)=[CH:15][CH:16]=3)[OH:11])=[CH:9][C:4]=2[CH:3]=[CH:2]1.N.[CH3:19][N:20]1CCCC1=O>[C-]#N.[Zn+2].[C-]#N.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>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH:10]([OH:11])[C:12]3[S:13][C:14]([C:19]#[N:20])=[CH:15][CH:16]=3)=[CH:9][C:4]=2[CH:3]=[CH:2]1
Reactant: OC(c1ccc2occc2c1)c1ccc(Br)s1
Reactant: CN1CCCC1=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: N
Agent: [C-]#N
Product: N#Cc1ccc(C(O)c2ccc3occc3c2)s1
Temperature: 120 °C
Reaction time: 3 h
Yield: 58 %

Procedure:
To a solution of benzofuran-5-yl-(5-bromo-thiophen-2-yl)-methanol described in Preparation Example 176 (755 mg, 2.44 mmol) in 1-methyl-2-pyrrolidinone (15 mL) were added zinc cyanide (344 mg, 2.93 mmol) and tetrakis(triphenylphosphine)palladium (282 mg, 0.244 mmol), and the mixture was stirred at 120° C. for 3 hours. The reaction mixture was cooled to room temperature, then, aqueous ammonia was added, and the solution was filtered through Celite pad. The mother liquor was extracted with ethyl acetate, and the organic layer was washed with brine. Anhydrous magnesium sulfate was added to the organic layer for drying, which was then filtered, the filtrate was concentrated in vacuo, the residue was purified by silica gel column chromatography (heptane/ethyl acetate=3/1), and the title compound (364 mg, 58%) was obtained as a pale yellow oil.
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([CH:9]=[CH:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[Cl:17])[O:6][C:7]=1[CH3:8].[C-:18]#[N:19].[Na+]>>[Cl:17][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[CH:10]=[CH:9][C:5]1[O:6][C:7]([CH3:8])=[C:3]([CH2:2][C:18]#[N:19])[N:4]=1
Reactant: Cc1oc(C=Cc2ccccc2Cl)nc1CCl
Reactant: [C-]#N
Agent: [Na+]
Product: Cc1oc(C=Cc2ccccc2Cl)nc1CC#N
Yield: 96.9 %

Procedure:
4-Chloromethyl-2-(2-chlorostyryl)-5-methyloxazole was reacted with sodium cyanide in the same manner as Example 1-(5) to give 2-(2-chlorostyryl)-4-cyanomethyl-5-methyloxazole. Yield 96.9%. Light-yellow needles (recrystallized from ethanol). Mp 89°-90° C.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[C:7]([C:9](=[O:12])[CH2:10][CH3:11])[CH:6]=[CH:5][C:4]=1[C:13]1[CH:18]=[C:17]([OH:19])[CH:16]=[CH:15][C:14]=1[CH2:20][CH3:21])[CH3:2].[C:22]([O:30][CH2:31][C:32]1[CH:33]=[C:34]([CH:37]=[CH:38][C:39]=1[CH2:40][O:41][C:42](=[O:49])[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)[CH2:35]Br)(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[C:22]([O:30][CH2:31][C:32]1[CH:33]=[C:34]([CH:37]=[CH:38][C:39]=1[CH2:40][O:41][C:42](=[O:49])[C:43]1[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=1)[CH2:35][O:19][C:17]1[CH:16]=[CH:15][C:14]([CH2:20][CH3:21])=[C:13]([C:4]2[CH:5]=[CH:6][C:7]([C:9](=[O:12])[CH2:10][CH3:11])=[CH:8][C:3]=2[CH2:1][CH3:2])[CH:18]=1)(=[O:29])[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: CCC(=O)c1ccc(-c2cc(O)ccc2CC)c(CC)c1
Reactant: O=C(OCc1ccc(CBr)cc1COC(=O)c1ccccc1)c1ccccc1
Product: CCC(=O)c1ccc(-c2cc(OCc3ccc(COC(=O)c4ccccc4)c(COC(=O)c4ccccc4)c3)ccc2CC)c(CC)c1

Procedure:
In a manner similar to that of Example 1(o), by reacting 1.67 g (5.9 mmol) of 1-(2,2′-diethyl-5′-hydroxybiphenyl-4-yl)-1-propanone with 2.73 g (6.2 mmol) of 3,4-bis(benzoyloxymethyl)benzyl bromide, and after purification by chromatography on a column of silica eluted with a mixture of heptane and ethyl acetate (95/5), 1.88 g (50%) of the expected product are obtained in the form of an oil.
Reaction SMILES: Cl[C:2]1[C:3]([N:39]2[CH2:44][C@@H:43]([NH:45][C:46]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:47])[CH2:42][C@@H:41]([NH:53][C:54]([O:56][C:57]([CH3:60])([CH3:59])[CH3:58])=[O:55])[CH2:40]2)=[N:4][C:5]([N:17]2[CH2:22][C@@H:21]([NH:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][C@@H:19]([NH:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:18]2)=[C:6](Cl)[C:7]=1[NH:8][C:9]1[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][CH:10]=1.C([O-])=O.[NH4+]>CO.[Pd]>[C:57]([O:56][C:54]([NH:53][C@@H:41]1[CH2:42][C@H:43]([NH:45][C:46]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:47])[CH2:44][N:39]([C:3]2[CH:2]=[C:7]([NH:8][C:9]3[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][CH:10]=3)[CH:6]=[C:5]([N:17]3[CH2:22][C@@H:21]([NH:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][C@@H:19]([NH:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:18]3)[N:4]=2)[CH2:40]1)=[O:55])([CH3:58])([CH3:59])[CH3:60]
Reactant: CC(C)(C)OC(=O)N[C@@H]1C[C@H](NC(=O)OC(C)(C)C)CN(c2nc(N3C[C@H](NC(=O)OC(C)(C)C)C[C@H](NC(=O)OC(C)(C)C)C3)c(Cl)c(Nc3ccc(N)cc3)c2Cl)C1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: CC(C)(C)OC(=O)N[C@@H]1C[C@H](NC(=O)OC(C)(C)C)CN(c2cc(Nc3ccc(N)cc3)cc(N3C[C@H](NC(=O)OC(C)(C)C)C[C@H](NC(=O)OC(C)(C)C)C3)n2)C1
Reaction time: 3 h
Yield: 42.1 %

Procedure:
N-(3,5-dichloro-2,6-bis-((3R,5S)-3,5-bis-(tert-butoxycarbonylamino)-piperidin-1-yl)-pyridin-4-yl)-benzene-1,4-diamine (140) (0.205 g, 0.233 mmol) was dissolved in MeOH (15 mL). Pd/C (1 g, 10%, wet) was added followed by ammonium-formate (2 g). The mixture was shaken in a Teflon septum capped 40 mL I-Chem vial, with occasional venting, for 3 hours. LC-MS indicated complete de-chlorination at this point. The mixture was filtered through a plug of Celite and the filtrate was concentrated and purified by flash chromatography using a gradient of hexane and EtOAc (eluding with 15–100% EtOAc in hexane in 30 minutes followed by 100% EtOAc in 10 minutes) to give the desired product (141) as a yellow/green oil (0.08 g, 0.098 mmol, 42.3% yield). LC-MS (ESI): (exact mass: 811.50) m/e=812.7 [M+1]+ (100%).
Reaction SMILES: C[N:2](C)[CH:3]=[CH:4][C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=2)[N:8]=1)=O.Cl.[F:26][C:27]1[CH:32]=[CH:31][C:30]([NH:33]N)=[CH:29][CH:28]=1.CCN(CC)CC>C(O)C>[F:26][C:27]1[CH:32]=[CH:31][C:30]([N:33]2[C:5]([C:7]3[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]4[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=4)[N:8]=3)=[CH:4][CH:3]=[N:2]2)=[CH:29][CH:28]=1
Reactant: CN(C)C=CC(=O)c1nn(-c2cccc(C(F)(F)F)c2)ccc1=O
Reactant: NNc1ccc(F)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: O=c1ccn(-c2cccc(C(F)(F)F)c2)nc1-c1ccnn1-c1ccc(F)cc1
Temperature: 100 °C
Reaction time: 3 h
Yield: 29.7 %

Procedure:
To a solution of 3-[3-(dimethylamino)prop-2-enoyl]-1-[3-(trifluoromethyl)phenyl]pyridazin-4(1H)-one (337 mg, 1.0 mmol) in ethanol (100 mL) were added 4-fluorophenylhydrazine hydrochloride (244 mg, 1.5 mmol) and Et3N (0.28 mL, 2.0 mmol). The mixture was stirred at 100° C. for 3 h and the solvent was removed under reduced pressure. Preparative HPLC chromatography provided 3-[1-(4-fluorophenyl)-1H-pyrazol-5-yl]-1-[3-(trifluoromethyl)phenyl]pyridazin-4(1H)-one as a pale brown solid (119 mg, 30%).
Reaction SMILES: C1(S(N2C=CNC(=O)[C@H]2CC#C)(=O)=O)C=CC=CC=1.CO[CH:22](OC)[CH2:23][NH:24][C:25](=[O:42])[C@H:26]([NH:30][S:31]([C:34]1[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=1)(=[O:33])=[O:32])[CH2:27][C:28]#[CH:29]>>[O:40]([C:37]1[CH:38]=[CH:39][C:34]([S:31]([N:30]2[CH:22]=[CH:23][NH:24][C:25](=[O:42])[C@H:26]2[CH2:27][C:28]#[CH:29])(=[O:33])=[O:32])=[CH:35][CH:36]=1)[CH3:41]
Reactant: C#CC[C@@H](NS(=O)(=O)c1ccc(OC)cc1)C(=O)NCC(OC)OC
Agent: C#CC[C@@H]1C(=O)NC=CN1S(=O)(=O)c1ccccc1
Product: C#CC[C@@H]1C(=O)NC=CN1S(=O)(=O)c1ccc(OC)cc1

Procedure:
Using the procedure described for compound 45, (R)-N-(2,2-dimethoxyethyl)-2-(4-methoxybenzenesulfonamido)pent-4-ynamide afforded the title compound as a tan solid. 1H NMR (300 MHz, DMSO-d6): δ 2.45 (m, 2H), 2.96 (s, 1H), 3.89 (s, 3H), 4.38 (t, 7.0 Hz, 1H), 5.98 (m, 2H), 7.09 (d, 8.3 Hz, 2H), 7.76 (d, 8.3 Hz, 2H), 9.65 (d, 5.4 Hz, 1H).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH2:17])[N:8]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)[N:9]=1)([CH3:4])([CH3:3])[CH3:2].N1C=CC=CC=1.[Cl:24][CH2:25][C:26](Cl)=[O:27]>C(Cl)Cl.C(=O)(O)[O-].[Na+]>[C:1]([C:5]1[CH:6]=[C:7]([NH:17][C:26](=[O:27])[CH2:25][Cl:24])[N:8]([C:10]2[CH:11]=[CH:12][C:13]([CH3:16])=[CH:14][CH:15]=2)[N:9]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C(Cl)CCl
Reactant: Cc1ccc(-n2nc(C(C)(C)C)cc2N)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)CCl)cc1
Yield: 99.1 %

Procedure:
A solution of 5-tert-butyl-2-p-tolyl-2H-pyrazol-3-ylamine (886 mg, 3.86 mmol), pyridine (465 μL, 5.80 mmol) and chloroacetyl chloride (462 μL, 5.80 mmol) in DCM (5 mL) was stirred at RT for 2 h. The reaction mixture was diluted with aq. sat. sodium bicarbonate and DCM and the resulting aqueous layer was extracted twice with DCM. The combined organic layers were dried (MgSO4) and concentrated in vacuo to afford the title compound (1.17 g, 100%) as a yellow solid. LCMS (Method 5): Rt 4.41 min, m/z 306 [MH+].
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[CH:7]1([C:15]2[CH:20]=[CH:19][C:18]([C:21]([CH3:28])=[CH:22][C:23](OCC)=[O:24])=[CH:17][CH:16]=2)[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1>CCOCC>[CH:7]1([C:15]2[CH:16]=[CH:17][C:18]([C:21]([CH3:28])=[CH:22][CH2:23][OH:24])=[CH:19][CH:20]=2)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14]1
Reactant: CCOC(=O)C=C(C)c1ccc(C2CCCCCCC2)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: CC(=CCO)c1ccc(C2CCCCCCC2)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 79.3 %

Procedure:
To an ice cooled slurry of LiAlH4 (2.9 g) in dry ether (200 ml) was added a solution of ethyl 3-(4′-cyclooctylphenyl)-but-2-enoate (3d, 10 g) in dry ether (50 ml) dropwise. The reaction mixture was stirred at 0° C. for 2 h. The reaction mixture was quenched with water (11 ml). A solution of 10% NaOH (10 ml) was added and ether layer was decanted. The precipitate was washed with ether and combined extracts were concentrated. The crude product was purified by column chromatography on silica gel to give 6.82 g (79.3% yield) of 3-(4′-cyclooctylphenyl)-2-butenol (4d, formula 4, R=cyclooctyl) m.p. 40-44° C.
Reaction SMILES: COC[N:4]1[CH:8]=[CH:7][N:6]=[C:5]1[C:9]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=1)[OH:10].C(O)(=O)C.Cl>O>[C:21]1([C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=2)([C:5]2[NH:4][CH:8]=[CH:7][N:6]=2)[OH:10])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: COCn1ccnc1C(O)(c1ccccc1)c1cccc(C(F)(F)F)c1
Agent: Cl
Solvent: O
Solvent: CC(=O)O
Product: OC(c1ccccc1)(c1cccc(C(F)(F)F)c1)c1ncc[nH]1

Procedure:
A mixture of 13 g. (0.037 mol) of 1-methoxymethyl-α-phenyl-α-(m-trifluoromethyl-phenyl)imidazole-2-methanol, 100 ml. of glacial acetic acid, 10 ml. of concentrated hydrochloric acid and 10 ml. of water was refluxed for three hours. After cooling, the liquid was distilled off and the residue was dissolved in a small amount of ethanol. The solution was made alkaline with 2 N sodium hydroxide solution and the alcohol was evaporated. The remaining aqueous phase was then extracted with diethyl ether. The extract was dried over sodium sulphate and the ether was distilled off. The residue was crystallised from toluene, the toluenic solution being decolorised with active charcoal. There was obtained α-phenyl-α-(m-trifluoromethyl-phenyl)imidazole-2-methanol. Melting point 151.5°-152.5° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[N:12]=[C:11]3[N:13]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([O:25]CC)=[O:24])[CH2:14][CH2:15][CH2:16][C:10]3=[N:9][C:8]=2[C:28]2[CH:33]=[CH:32][C:31]([CH3:34])=[CH:30][CH:29]=2)=[CH:3][CH:2]=1.[Li+].[OH-]>C1COCC1.O>[N:1]1[CH:6]=[CH:5][C:4]([C:7]2[N:12]=[C:11]3[N:13]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([OH:25])=[O:24])[CH2:14][CH2:15][CH2:16][C:10]3=[N:9][C:8]=2[C:28]2[CH:29]=[CH:30][C:31]([CH3:34])=[CH:32][CH:33]=2)=[CH:3][CH:2]=1
Reactant: CCOC(=O)CCCCCCN1CCCc2nc(-c3ccc(C)cc3)c(-c3ccncc3)nc21
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(-c2nc3c(nc2-c2ccncc2)N(CCCCCCC(=O)O)CCC3)cc1
Temperature: 70 °C
Reaction time: 4 h

Procedure:
A solution of ethyl 7-(3-(pyridin-4-yl)-2-p-tolyl-7,8-dihydropyrido[2,3-b]pyrazin-5(6H)-yl)heptanoate (step 2) (15 mg, 0.033 mmol) in THF (2 ml) and water (1 ml) was treated with LiOH (7.83 mg, 0.327 mmol) and stirred at 70° C. for 4 hours. The mixture was cooled to room temperature and concentrated under vacuum. The residue was acidified (1N HCl, pH ˜5) and extracted with DCM (×3). The combined extracts were washed with brine, dried (MgSO4) and evaporated under vacuum to a yellow gum which was triturated with ether and dried under vacuum at 40° C. for 2.5 hours to afford the title compound;
Reaction SMILES: [CH2:1]([C@:3]12[CH2:11][CH2:10][C@@H:9]3[C:12]4[CH:13]=[CH:14][C:15]([O:20][CH3:21])=[CH:16][C:17]=4[CH2:18][CH2:19][C@H:8]3[C@@H:7]1[CH2:6][CH2:5][C@@H:4]2[OH:22])[CH3:2].N.[Li].[Cl-].[NH4+]>COCC(O)C.O>[CH2:1]([C@:3]12[CH2:11][CH2:10][C@@H:9]3[C:12]4[CH2:13][CH:14]=[C:15]([O:20][CH3:21])[CH2:16][C:17]=4[CH2:18][CH2:19][C@H:8]3[C@@H:7]1[CH2:6][CH2:5][C@@H:4]2[OH:22])[CH3:2]
Reactant: CC[C@]12CC[C@@H]3c4ccc(OC)cc4CC[C@H]3[C@@H]1CC[C@@H]2O
Agent: N
Agent: [Cl-]
Agent: [Li]
Solvent: O
Solvent: COCC(C)O
Product: CC[C@]12CC[C@@H]3C4=C(CC[C@H]3[C@@H]1CC[C@@H]2O)CC(OC)=CC4

Procedure:
To 13β-ethyl-3-methoxy-gona-1,3,5(10)-trien-17β-ol (1.0 g.) in 1-methoxypropan-2-ol (100 cc.) add liquid ammonia (200 cc.), followed by lithium metal (1.2 g.) in small pieces with stirring. After discharge of the blue color add an excess of ammonium chloride, followed by water; filter off the crude 13β-ethyl-3-methoxy-gona-2,5(10)-dien-17β-ol and dry, m.p. 98°-104°. No selective ultra-violet absorption beyond 220 mμ; infrared absorption peaks at 3.03, 5.92, 6.01 μ.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:10][CH:11]=[C:12]([CH2:14]O)[N:13]=2)=[CH:5][CH:4]=1.P(Br)(Br)[Br:17].O>C1(C)C=CC=CC=1>[Br:17][CH2:14][C:12]1[N:13]=[C:9]([C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[S:10][CH:11]=1
Reactant: BrP(Br)Br
Reactant: COc1ccc(-c2nc(CO)cs2)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: COc1ccc(-c2nc(CBr)cs2)cc1
Temperature: 120 °C
Yield: 91.5 %

Procedure:
To a solution of [2-(4-Methoxy-phenyl)-thiazol-4-yl]-methanol (0.12 g, 0.50 mmol) in 3 ml of toluene was added PBr3 (0.078 ml, 0.813 mmol) and the reaction mixture was heated at 120° C. for 20 min under nitrogen atmosphere. After the completion of the reaction mixture (TLC monitoring), water (25 mL) was added and extracted with ethyl acetate (3×50 mL). The combined organics was washed with water, brine, dried (Na2SO4), filtered and concentrated to get the desired product (0.13 g, 84%).
Reaction SMILES: [Cl:1][C:2]1[S:3][CH:4]=[C:5]([C:7]([OH:9])=O)[N:6]=1.[CH2:10]([O:12][C:13](=[O:22])[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([NH2:21])[CH:16]=1)[CH3:11]>>[CH2:10]([O:12][C:13](=[O:22])[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([NH:21][C:7]([C:5]2[N:6]=[C:2]([Cl:1])[S:3][CH:4]=2)=[O:9])[CH:16]=1)[CH3:11]
Reactant: CCOC(=O)Cc1cccc(N)c1
Reactant: O=C(O)c1csc(Cl)n1
Product: CCOC(=O)Cc1cccc(NC(=O)c2csc(Cl)n2)c1

Procedure:
2-Chloro-thiazole-4-carboxylic acid (79) (70 mg, 0.43 mmol) was coupled with ethyl ester (6) (77 mg, 0.43 mmol) following Method C to give the title compound.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[CH:11]=[C:10]([C:12]#[N:13])[CH:9]=[CH:8][N:7]=2)[N:3]=[CH:2]1.Cl[CH2:15][CH2:16][N:17]1[CH2:21][CH2:20][CH2:19][C:18]1=[O:22]>>[O:22]=[C:18]1[CH2:19][CH2:20][CH2:21][N:17]1[CH2:16][CH2:15][N:1]1[CH:5]=[C:4]([C:6]2[CH:11]=[C:10]([C:12]#[N:13])[CH:9]=[CH:8][N:7]=2)[N:3]=[CH:2]1
Reactant: N#Cc1ccnc(-c2c[nH]cn2)c1
Reactant: O=C1CCCN1CCCl
Product: N#Cc1ccnc(-c2cn(CCN3CCCC3=O)cn2)c1

Procedure:
The title compound was prepared from 2-(1H-imidazol-4-yl)pyridine-4-carbonitrile and 1-(2-chloroethyl)-2-pyrrolidinone according to the procedure for the preparation of Example 43, part A (heating to 120°). [M+H] Calc'd for C15H15N5O, 282. Found, 282.
Reaction SMILES: N1C=CC=CC=1.[Cl:7][C:8]1[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:11]=[C:10]([Cl:18])[C:9]=1[N:19]1[C:23]([N:24]([CH2:26][CH2:27]O)[CH3:25])=[C:22]([S:29]([C:32]([F:35])([F:34])[F:33])(=[O:31])=[O:30])[C:21]([C:36]#[N:37])=[N:20]1>ClCCl.[O-2].[Cr+6].[O-2].[O-2]>[Cl:18][C:10]1[CH:11]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:13]=[C:8]([Cl:7])[C:9]=1[N:19]1[C:23]([N:24]([CH3:25])[CH:26]=[CH2:27])=[C:22]([S:29]([C:32]([F:35])([F:33])[F:34])(=[O:30])=[O:31])[C:21]([C:36]#[N:37])=[N:20]1
Reactant: CN(CCO)c1c(S(=O)(=O)C(F)(F)F)c(C#N)nn1-c1c(Cl)cc(C(F)(F)F)cc1Cl
Agent: [Cr+6]
Agent: [O-2]
Solvent: c1ccncc1
Solvent: ClCCl
Product: C=CN(C)c1c(S(=O)(=O)C(F)(F)F)c(C#N)nn1-c1c(Cl)cc(C(F)(F)F)cc1Cl
Yield: 25 %

Procedure:
To a solution of pyridine (0.186 g, 0.23 mmol) in dichloromethane (10 mL) was slowly added chromium (VI) oxide (0.119 g, 0.12 mmol) at room temperature under nitrogen. The resulting mixture was stirred at room temperature for 15 minutes before 1-[2,6-dichloro-4-(trifluoromethyl)phenyl]-5-[(2-hydroxy-ethyl)(methyl)amino]-4-[(trifluoromethyl)sulfonyl]-1H-pyrazole-3-carbonitrile (0.200 g, 0.4 mmol) was introduced. The reaction mixture was allowed to stirr at room temperature for two additional hours. It was then concentrated to dryness and then diluted with diethyl ether. The mixture was then filtered through silica gel and then concentrated to afford a pale oil (0.04 g, 0.1 mmol). 19F NMR: −64.37, −80.74.
Reaction SMILES: C([O:3][C:4](=[O:30])[CH:5]([O:27][CH2:28][CH3:29])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([NH:22][S:23]([CH3:26])(=[O:25])=[O:24])=[CH:18][CH:17]=2)=[CH:9][CH:8]=1)C.O.[OH-].[Li+]>O1CCCC1.O>[CH2:28]([O:27][CH:5]([CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:13][CH2:14][CH2:15][C:16]2[CH:17]=[CH:18][C:19]([NH:22][S:23]([CH3:26])(=[O:24])=[O:25])=[CH:20][CH:21]=2)=[CH:11][CH:12]=1)[C:4]([OH:30])=[O:3])[CH3:29]
Reactant: CCOC(=O)C(Cc1ccc(OCCc2ccc(NS(C)(=O)=O)cc2)cc1)OCC
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(Cc1ccc(OCCc2ccc(NS(C)(=O)=O)cc2)cc1)C(=O)O
Yield: 104.3 %

Procedure:
2-Ethoxy-3-{4-[2-(4-methanesulfonylaminophenyl)ethoxy]phenyl}propanoic acid ethyl ester (described in Example 62) (0.554 g; 1.27 mmole) was dissolved in tetrahydrofuran (5.7 ml). Lithium hydroxide hydrate (0.137 g; 3,26 mmole) was dissolved in water and added in portions during 30 minutes at room temperature. The reaction mixture was kept in the refrigerator over night. Tetrahydrofuran was evaporated in vacuo. The water residue was washed with ethyl acetate, acidified with hydrochloric acid (1M) to pH 1-2 and the mixture was extracted with ethyl acetate. The organic phase was washed with brine, dried (sodium sulfate), filtered and the solvent was evaporated in vacuo to give 0.54 g (yield 100%) of 2-ethoxy-3-{4-[2-(4-methanesulfonylaminophenyl)ethoxy]phenyl}propanoic acid.