Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N(C(C)C)C(C)C.[Li]CCCC.[Cl:13][C:14]1[N:19]=[C:18]([F:20])[C:17]([O:21][CH2:22][O:23][CH3:24])=[CH:16][CH:15]=1.[Br:25][C:26]1[CH:27]=[CH:28][C:29]([F:34])=[C:30]([CH:33]=1)[CH:31]=[O:32]>C1COCC1>[Br:25][C:26]1[CH:27]=[CH:28][C:29]([F:34])=[C:30]([CH:31]([C:16]2[CH:15]=[C:14]([Cl:13])[N:19]=[C:18]([F:20])[C:17]=2[O:21][CH2:22][O:23][CH3:24])[OH:32])[CH:33]=1
Reactant: COCOc1ccc(Cl)nc1F
Reactant: O=Cc1cc(Br)ccc1F
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: COCOc1c(C(O)c2cc(Br)ccc2F)cc(Cl)nc1F
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 76.8 %

Procedure:
A solution of i-Pr2NH (1100 mL, 7.72 mol) in anhydrous THF (3.5 L) was cooled to −10° C. n-BuLi (2.5 M in hexanes, 3087 mL, 7.72 mol) was added drop wise and the solution was stirred for 10 min at 0° C. The reaction mixture was cooled to −78° C. and a solution of 6-chloro-2-fluoro-3-(methoxymethoxy)pyridine (1344 g, 7.02 mol) in anhydrous THF (2 L) was added slowly, keeping the internal temperature below −60° C. The resulting solution was stirred at 75° C. for 1 hr. A solution of 5-bromo-2-fluorobenzaldehyde (1430 g, 7.02 mol) in THF (1.7 L) was added dropwise. After the addition was complete, the reaction mixture was stirred at 75° C. for 30 min. The reaction mixture was warmed to RT and quenched with saturated aqueous NH4Cl solution (3 L). EtOAc (5 L) was added and the mixture was stirred vigorously. After phase separation, the aqueous layer was extracted with EtOAc (3 L×2). The combined organics were washed with brine and dried over anhydrous Na2SO4. The solvent was removed under reduced pressure and the residue was purified by column chromatography (0-10% EtOAc/hexanes) to provide 2128 g of (5-bromo-2-fluorophenyl)(6-chloro-2-fluoro-3-(methoxymethoxy)pyridin-4-yl)methanol as a light yellow solid.
Reaction SMILES: [CH2:1]=[O:2].S(=O)(=O)(O)O.[CH2:8]([N:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]([CH2:21][C:22]([N:24]([CH3:26])[CH3:25])=[O:23])([OH:20])[C:12]1=[O:27])[CH:9]=[CH2:10].C([O-])(=O)C.[Na+]>CC(OCC1C2C(=CC=CC=2)C(COC(C)=O)=C2C=1C=CC=C2)=O.O.C(O)(=O)C>[CH2:8]([N:11]1[C:19]2[C:14](=[C:15]([CH3:16])[C:1]([OH:2])=[CH:17][CH:18]=2)[C:13]([CH2:21][C:22]([N:24]([CH3:25])[CH3:26])=[O:23])([OH:20])[C:12]1=[O:27])[CH:9]=[CH2:10]
Reactant: C=CCN1C(=O)C(O)(CC(=O)N(C)C)c2ccccc21
Reactant: C=O
Agent: CC(=O)OCc1c2ccccc2c(COC(C)=O)c2ccccc12
Agent: CC(=O)[O-]
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Solvent: O
Product: C=CCN1C(=O)C(O)(CC(=O)N(C)C)c2c1ccc(O)c2C
Temperature: 80 °C
Yield: 113 %

Procedure:
To a suspension of para-formaldehyde (36.2 g, 1.13 mol) in 150 ml of glacial acetic add, sulfuric acid (22.2 g, 0.226 mol) is added and the mixture heated at 80° C., until a clear solution has been formed. To this, during 45 minutes a solution of 2-(1-allyl-3-hydroxy-2-oxo-2,3-dihydro-1H-indol-3-yl)-N,N-dimethyl-acetamide (example 26) (62 g, 226 mmol) in a mixture of glacial acetic acid (350 mL) and water (10 mL) is added. The red reaction mixture is stirred for another hour at 80° C., and by then all of the starting material is consumed (HPLC). Sodium acetate (46.3 g, 564 mmol) is added, and after stirring for 5 minutes an orange suspension forms. The solvent is removed on the rotavapor, and to the residue water (about 250 mL) is added. Extraction with chloroform (2×200 mL), drying the organic layer and removal of the solvent leaves the crude title product (77.7 g, quanta) as a red oil. After chromatographic purification white crystals, mp=125° C. 1H-NMR (CDCl3, 300 MHz) δ 2.71, 2.94 (AB, 2H, 2J=16.1 Hz, CH2CONMe2); 2.83, 2.84 (2 s, 3H each, N(CH3)2); 4.19, 4.25 (ABAllyl, 2H, 2J=16.4 Hz, 3J=5.3 Hz, NCH2); 4.47 (s, 2H, CH2OH); 5.12 (dd, 1H, 2J=1.2 Hz, 3J=10.3 Hz, cis CH═CH2), 5.51 (dd, 1H, 3J=17.3 Hz, trans CH═CH2); 5.75 (ddtr, 1H, CH═CH2); 6.21 (br s, 1H. OH); 6.70 (d, 1H, 3J=7.9 Hz, H-7); 7.15 (dd, 1H, 4J=1.5 Hz, H-6); 7.37 (d, 1H, H-4). 13C-NMR (CDCl3, 75 MHz) δ 35.71, 37.84 (N(CH3)2); 38.87 (CH2CONMe2); 42.67 (NCH2); 64.80 (CH2OH); 74.46 (C-3); 109.36 (C-7); 117.73 (CH═CH2); 123.43 (C-4); 128.63 (C-6); 131.00 (C-9); 131.33 (CH═CH2); 136.35 (C-5); 141.89 (C-8); 170.53 (C-11); 176.36 (C-2).
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:10][CH2:11][CH2:12][OH:13])=[N:4][C:5]([CH3:9])=[N:6][C:7]=1[Cl:8].[Cl:14][C:15]1[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=1[CH:17]=O.ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl>[Fe](Cl)(Cl)Cl.O1CCOCC1>[Cl:8][C:7]1[N:6]=[C:5]([CH3:9])[N:4]=[C:3]2[C:2]=1[N:1]=[C:17]([C:16]1[CH:19]=[CH:20][CH:21]=[CH:22][C:15]=1[Cl:14])[N:10]2[CH2:11][CH2:12][OH:13]
Reactant: O=Cc1ccccc1Cl
Reactant: Cc1nc(Cl)c(N)c(NCCO)n1
Agent: Cl[Fe](Cl)Cl
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: C1COCCO1
Product: Cc1nc(Cl)c2nc(-c3ccccc3Cl)n(CCO)c2n1
Temperature: 102.5 °C
Reaction time: 2 h
Yield: 31.4 %

Procedure:
Charge a 500 mL three-necked round bottom flask with 2-[(5-amino-6-chloro-2-methyl-pyrimidin-4-yl)amino]ethanol (13.0 g, 0.064 mol) and 1,4-dioxane (300 mL). Add 2-chlorobenzaldehyde (13.5 g, 0.096 mol) followed by iron (III) chloride, 5 wt % on silica gel (37.5 g) in one portion. Heat the mixture to 100-105° C. for 48 h. Cool to 20-35° C., filter and rinse the cake with 1,4-dioxane (40 mL). Combine the filtrates and concentrate under vacuum. Dissolve the residue with dichloromethane (260 mL, 20 mL/g) and cool to 0-5° C. Add 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (14.5 g, 0.064 mol) at 0° C., warm up the mixture to 10-25° C., and stir for 2 h. Filter and rinse the cake with ethanol (100 mL) and combine the filtrates. Concentrate down the filtrates under vacuum to give a dark residue. Re-dissolve the residue with dichloromethane (300 mL), wash this solution with 1 N aqueous sodium hydroxide to pH 10-11 followed by water (2×60 mL). Concentrate the organic layer to give crude material. Purify the crude over 400 g silica gel, eluting with dichloromethane/methanol (50:1) to afford a yellow solid (6.5 g). 1H NMR (dmso-d6): δ 7.73-7.56 (m, 4H); 4.83 (t, J=6 Hz, 1H); 4.12 (t, J=6 Hz, 2H); 3.61 (q, J=6 Hz, 2H); 2.73 (s, 3H).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[NH2:7][C:8]1[N:12]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[N:11]=[CH:10][C:9]=1[C:20](=[O:31])[C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([C:27](=[O:30])[CH2:28]Br)[CH:22]=1>CN(C)C=O.[Cl-].[Na+].O>[NH2:7][C:8]1[N:12]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[N:11]=[CH:10][C:9]=1[C:20](=[O:31])[C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([CH2:28][N:1]2[CH2:6][CH2:5][O:4][CH2:3][CH2:2]2)=[O:30])[CH:22]=1
Reactant: Nc1c(C(=O)c2cccc(C(=O)CBr)c2)cnn1-c1ccc(F)cc1
Reactant: C1COCCN1
Agent: [Cl-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Nc1c(C(=O)c2cccc(C(=O)CN3CCOCC3)c2)cnn1-c1ccc(F)cc1
Reaction time: 16 h
Yield: 21.9 %

Procedure:
To a solution of morpholine (0.25 ml, 2.79 mmol) in dimethylformamide (5 ml) was added a solution of 5-amino-4-[3-(2-bromoacetyl)benzoyl]-1-(4-fluorophenyl)pyrazole (0.22 g, 0.56 mmol) in dimethylformamide (5 ml). After 16 h, the reaction mixture was poured into brine and the product was extracted into ethyl acetate. The organic layer was separated, washed with brine, dried over sodium sulfate and concentrated in vacuo. The residue was purified by flash chromatography (elution gradient: ethyl acetate-10% methanol/ethyl acetate) to give 5-amino-1-(4-fluorophenyl)-4-[3-(morpholin-4-ylmethylcarbonyl)benzoyl]pyrazole (0.05 g) as a solid.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH:10]=2)[N:5]=[CH:4][C:3]=1[N+:18]([O-:20])=[O:19].[Br:21][C:22]1[CH:28]=[CH:27][CH:26]=[CH:25][C:23]=1[NH2:24]>C(O)(=O)C>[Br:21][C:22]1[CH:28]=[CH:27][CH:26]=[CH:25][C:23]=1[NH:24][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH:10]=2)[N:5]=[CH:4][C:3]=1[N+:18]([O-:20])=[O:19]
Reactant: Nc1ccccc1Br
Reactant: O=[N+]([O-])c1cnc2ccc(-c3ccccc3)cc2c1Cl
Solvent: CC(=O)O
Product: O=[N+]([O-])c1cnc2ccc(-c3ccccc3)cc2c1Nc1ccccc1Br

Procedure:
The title compound is prepared in analogy to Example 19d, starting from 0.5 g (1.756 mmol) 4-chloro-3-nitro-6-phenyl-quinoline (Example 53d) and 0.339 g (1.932 mmol) 2-bromoaniline in 3 ml acetic acid. mp: 198-204° C.; MS: 420 (M++1); HPLC: tret=12.17 min (Grad 1).
Reaction SMILES: [CH2:1](Cl)[CH2:2][OH:3].[F:5][C:6]([F:14])([F:13])[C:7]([C:9]([F:12])([F:11])[F:10])=[O:8].COC(C)(C)C.C(=O)([O-])[O-].[K+].[K+]>O>[F:5][C:6]([F:14])([F:13])[C:7]1([C:9]([F:12])([F:11])[F:10])[O:3][CH2:2][CH2:1][O:8]1
Reactant: O=C(C(F)(F)F)C(F)(F)F
Reactant: OCCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COC(C)(C)C
Solvent: O
Product: FC(F)(F)C1(C(F)(F)F)OCCO1
Reaction time: 0.25 h
Yield: 62.7 %

Procedure:
Into a 300 mL three-necked flask equipped with a gas-inlet tube, a reflux condenser, and a thermometer was charged 10.0 g (0.12 mol) of ethylene chlorohydrin beforehand, followed by cooling with ice. Then, 20.0 g (0.12 mol) of hexafluoroacetone was added through the gas-inlet tube. After completion of the addition, the whole was stirred for 15 minutes as it was and then 100 mL of t-butyl methyl ether was added. Then, 16.6 g (0.12 mol) of potassium carbonate was added portionwise over a period of 1 hour and, after completion of the addition, the whole was stirred as it was. The resulting mixture was poured into 100 mL of water and an organic layer was separated by two-layer separation in a separating funnel. The resulting organic layer was subjected to distillation under normal pressure to collect a fraction of 106° C. to 107° C. to obtain 15.8 g (purity 99%, yield 62.0%) of 2,2-bis(trifluoromethyl)-1,3-dioxolane (fluorinated acetal (E)).
Reaction SMILES: [CH2:1]1[O:10][C:9]2[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=2[O:2]1.[N+:11]([C:14]1[CH:22]=[CH:21][C:17]([C:18](Cl)=[O:19])=[CH:16][CH:15]=1)([O-:13])=[O:12]>>[N+:11]([C:14]1[CH:15]=[CH:16][C:17]([C:18]([NH:6][C:5]2[CH:7]=[CH:8][C:9]3[O:10][CH2:1][O:2][C:3]=3[CH:4]=2)=[O:19])=[CH:21][CH:22]=1)([O-:13])=[O:12]
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Reactant: Nc1ccc2c(c1)OCO2
Product: O=C(Nc1ccc2c(c1)OCO2)c1ccc([N+](=O)[O-])cc1
Yield: 87 %

Procedure:
Using 3,4-methylenedioxyaniline (1.44 g, 10.5 mmol) and 4-nitrobenzoyl chloride (1.86 g, 10.0 mmol), the procedure of Reference Example 11 was repeated to obtain 2.49 g (87.2%) of the title compound in the form of yellow crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[S:15][C:14]([CH3:17])([CH3:16])[CH2:13][NH:12][C:11]2[N:18]([CH3:22])[N:19]=[C:20]([CH3:21])[C:10]1=2.C1C=C(Cl)C=C(C(OO)=[O:31])C=1.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[S:15](=[O:31])[C:14]([CH3:17])([CH3:16])[CH2:13][NH:12][C:11]2[N:18]([CH3:22])[N:19]=[C:20]([CH3:21])[C:10]1=2
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1nn(C)c2c1C(c1ccc(Cl)cc1Cl)SC(C)(C)CN2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1nn(C)c2c1C(c1ccc(Cl)cc1Cl)S(=O)C(C)(C)CN2
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 62.5 %

Procedure:
To 4-(2,4-dichlorophenyl)-1,3,6,6-tetramethyl-7,8-dihydro-4H-pyrazolo[3,4-e][1,4]thiazepine (0.1 g, 0.28 mmol), Example D.4) in DCM (5 mL) at 0° C., was added m-CPBA (48.5 mg, 0.28 mmol) dissolved in 3 mL DCM (dropwise in 10 min). The resulting mixture was stirred for about 10 min at rt. Subsequently, 5% aqueous sodium bicarbonate (10 mL) and DCM (20 mL) were added. The layers were separated and the organic layer was washed with water (25 mL), dried (MgSO4), filtered and concentrated in vacuo. The resulting residue was purified by column chromatography (SiO2, ethyl acetate followed by 10% MeOH in ethyl acetate) to afford 4-(2,4-dichlorophenyl)-1,3,6,6-tetramethyl-7,8-dihydro-4H-pyrazolo[3,4-e][1,4]thiazepine 5-oxide (65 mg, 0.175 mmol, 62%), as white solid: LC-MS (Table 1, Method a) Rt=2.72 (major) and 2.97 (minor), diastereomeric ratio (64:36); m/z 372 (M+H)+; Isomer A: 1H NMR (400 MHz, CDCl3) δ ppm 1.08 (3 H, s) 1.35 (3 H, s) 1.74 (3 H, s) 3.05 (1 H, dd, J=14.7, 6.1 Hz) 3.55 (1 H, dd, J=14.7, 3.8 Hz) 3.66 (3H, s) 3.65-3.69 (1 H, m) 5.67 (1 H, s) 7.17-7.23 (2 H, m) 7.18-7.23 (1 H, m); Isomer B: 1H NMR (400 MHz, CDCl3) δ ppm 1.37 (3 H, s) 1.38 (3 H, s) 1.39 (3 H, s) 3.02 (1 H, dd, J=14.6, 7.1 Hz) 3.51 (1 H, dd, J=14.6, 2.8 Hz) 3.61 (1 H, dd, J=2.8 Hz) 3.64 (3 H, s) 5.50 (1 H, s) 7.34 (1 H, dd, J=8.6, 2.2 Hz) 7.47 (1 H, d, J=2.2 Hz) 7.89 (1 H, d, J=8.6 Hz).
Reaction SMILES: B([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10]([N:13]([C:20]1[O:24][N:23]=[C:22]([CH3:25])[C:21]=1[CH3:26])COCCOC)(=[O:12])=[O:11])(O)O.C(=O)([O-])[O-].[Na+].[Na+].Br[C:34]1[CH:41]=[CH:40][C:39]([C:42]2[N:47]=[CH:46][CH:45]=[CH:44][N:43]=2)=[CH:38][C:35]=1[CH:36]=[O:37]>C1(C)C=CC=CC=1.CCO.O.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:25][C:22]1[C:21]([CH3:26])=[C:20]([NH:13][S:10]([C:5]2[C:4]([C:34]3[CH:41]=[CH:40][C:39]([C:42]4[N:47]=[CH:46][CH:45]=[CH:44][N:43]=4)=[CH:38][C:35]=3[CH:36]=[O:37])=[CH:9][CH:8]=[CH:7][CH:6]=2)(=[O:11])=[O:12])[O:24][N:23]=1
Reactant: O=Cc1cc(-c2ncccn2)ccc1Br
Reactant: COCCOCN(c1onc(C)c1C)S(=O)(=O)c1ccccc1B(O)O
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: Cc1ccccc1
Product: Cc1noc(NS(=O)(=O)c2ccccc2-c2ccc(-c3ncccn3)cc2C=O)c1C
Yield: 116.3 %

Procedure:
To a solution of 0.554 g (1.188 mmol) of 2-borono-N-(3,4-dimethyl-5-isoxazolyl)-N-[(2-methoxyethoxy)methyl]benzenesulfonamide (prepared as described in U.S. patent application Ser. No. 08/603,975, filed Feb.20, 1996 by Murugesan et al. (Attorney Docket No. HA662d)) and 0.0578 g (0.05 mmol) of tetrakis(triphenylphosphine)-palladium(0) in 20 mL of toluene under argon, 10 mL of 2M aqueous sodium carbonate was added followed by 0.25 g (0.95 mmol) of the title compound of Step E added in 10 mL of 95% EtOH. The mixture was refluxed for 2 hrs and then diluted with 100 mL of water and extracted with 3×50 mL of EtOAc. The combined organic extracts were washed once with 100 mL of brine and dried and evaporated. The residue was chromatographed on 100 mL of silica gel using Hexanes/EtOAc 1:1 to afford 0.48 g (80%) of the title compound of this step as a colorless gum.
Reaction SMILES: [NH2:1][C:2]([CH2:21][CH2:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])([CH2:12][CH2:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:3][CH2:4][C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6].C(N(CC)CC)C.[C:37](Cl)(=[O:39])[CH3:38]>C(Cl)Cl>[C:26]([O:25][C:23](=[O:24])[CH2:22][CH2:21][C:2]([NH:1][C:37](=[O:39])[CH3:38])([CH2:12][CH2:13][C:14]([O:16][C:17]([CH3:18])([CH3:19])[CH3:20])=[O:15])[CH2:3][CH2:4][C:5]([O:7][C:8]([CH3:11])([CH3:9])[CH3:10])=[O:6])([CH3:29])([CH3:28])[CH3:27]
Reactant: CC(=O)Cl
Reactant: CC(C)(C)OC(=O)CCC(N)(CCC(=O)OC(C)(C)C)CCC(=O)OC(C)(C)C
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)NC(CCC(=O)OC(C)(C)C)(CCC(=O)OC(C)(C)C)CCC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 4 h
Yield: 71.9 %

Procedure:
To 5 ml CH2Cl2 was added 1 g of triester 62 (2.4 mmol, 1 equiv) and 0.3 g triethylamine (2.9 mmol, 1.2 equiv.) The solution was cooled to 0° C. with an ice bath and 0.23 g acetyl chloride (2.9 mmol, 1.2 equiv) was added dropwise. The solution was stirred for a further 4 hours and allowed to warm slowly to room temperature. The solution was poured into a separating funnel and washed with 2×15 ml HCl (5% aqueous) and 1×15 ml concentrated NaCl. The solution was dried over Na2SO4 and the solvent was removed in vacuo. The residue was dissolved in minimal EtOAc and loaded onto a silica column, where it was purified by column chromatography with EtOAc and hexane (1:1) to give 0.79 g of a white solid in 72% yield.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([O:11][CH2:12][C:13]2([CH3:30])[CH2:17][CH2:16][N:15]([C:18]([C@H:20]3[CH2:25][CH2:24][C@H:23]([C:26]([F:29])([F:28])[F:27])[CH2:22][CH2:21]3)=[O:19])[CH2:14]2)[C:5]([C:8]([NH2:10])=O)=[N:6][CH:7]=1.FC(F)(F)[C@H]1CC[C@H](C(O)=O)CC1.N1C2C(=CC=CC=2)C=C1C(O)=O>>[Cl:1][C:2]1[CH:3]=[C:4]([O:11][CH2:12][C:13]2([CH3:30])[CH2:17][CH2:16][N:15]([C:18]([C@H:20]3[CH2:25][CH2:24][C@H:23]([C:26]([F:27])([F:28])[F:29])[CH2:22][CH2:21]3)=[O:19])[CH2:14]2)[C:5]([C:8]#[N:10])=[N:6][CH:7]=1
Reactant: CC1(COc2cc(Cl)cnc2C(N)=O)CCN(C(=O)[C@H]2CC[C@H](C(F)(F)F)CC2)C1
Agent: O=C(O)[C@H]1CC[C@H](C(F)(F)F)CC1
Agent: O=C(O)c1cc2ccccc2[nH]1
Product: CC1(COc2cc(Cl)cnc2C#N)CCN(C(=O)[C@H]2CC[C@H](C(F)(F)F)CC2)C1

Procedure:
The title compound was prepared according to the procedure described in Step 3 of EXAMPLE 1 using 5-chloro-3-((3-methylpyrrolidin-3-yl)methoxy)picolinonitrile dihydrochloride (EXAMPLE 84, Step 4) and trans-4-(trifluoromethyl)cyclohexanecarboxylic acid instead of (R)-3-(pyrrolidin-2-ylmethoxy)picolinamide dihydrochloride and indole-2-carboxylic acid.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:10][CH2:11][CH3:12])[C:5](OCC)=[O:6])[CH3:2].[OH-].[NH4+:14]>C(Cl)Cl>[CH2:1]([O:3][CH:4]([O:10][CH2:11][CH3:12])[C:5]([NH2:14])=[O:6])[CH3:2]
Reactant: CCOC(=O)C(OCC)OCC
Reactant: [NH4+]
Agent: [OH-]
Solvent: ClCCl
Product: CCOC(OCC)C(N)=O
Reaction time: 3 h
Yield: 87 %

Procedure:
A mixture of 24.85 g of ethyl diethoxyacetate and 140 ml of concentrated ammonium hydroxide was stirred for 3 hours. The ammonia and H2O were evaporated under reduced pressure on a water bath at 50°-60° leaving a wet solid. The wet solid was dried in a vacuum oven at 53° for 18 hours giving a dark pink solid. The solid was dissolved in CH2Cl2. The solution was filtered to remove a small amount of red insoluble material. The filtrate was concentrated and Skellysolve B was added. Cooling gave 18.0 g (87%) of diethoxyacetamide as orange plates, m.p. 76.5-79°.
Reaction SMILES: [O:1]=[C:2]([C:16]1[O:17][C:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=2)=[CH:19][N:20]=1)[CH2:3][CH2:4][CH2:5][CH2:6][C:7]#[C:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([Cl:15])[CH:10]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C1COCC1.[Ni]>[O:1]=[C:2]([C:16]1[O:17][C:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=2)=[CH:19][N:20]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([Cl:15])[CH:10]=1
Reactant: O=C(CCCCC#Cc1cccc(Cl)c1)c1ncc(-c2ccccn2)o1
Agent: [Ni]
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: C1CCOC1
Product: O=C(CCCCCCc1cccc(Cl)c1)c1ncc(-c2ccccn2)o1
Temperature: 25 °C
Reaction time: 8 h
Yield: 67 %

Procedure:
A solution of the oxo-1-[5-(2-pyridyl)oxazol-2-yl]-7-(3-chlorophenyl)hept-6-yne (4hh, 15 mg, 0.041 mmol) in anhydrous THF (1 mL) was treated with a catalytic amount of Raney nickel (washed before use with THF). The reaction mixture was purged with H2 and stirred at 25° C. overnight. The suspension was filtered through Celite and concentrated. The crude product was dissolved in anhydrous CH2Cl2 (2 mL) and treated with Dess-Martin reagent (29 mg, 0.068 mmol). After stirring for 3 h at 25° C., the reaction mixture was quenched with saturated aqueous Na2CO3 and saturated aqueous Na2S2O3. After stirring for 15 min, the mixture was extracted with CH2Cl2. The organic layer was dried over Na2SO4, filtered and concentrated. PTLC (SiO2, 40% EtOAc-hexanes) afforded the title compound (5hh, 10 mg, 0.027 mmol, 67%) as a white solid: mp 91-92° C.; 1H NMR (CDCl3, 600 MHz) 8.68-8.66 (m, 1H), 7.89-7.86 (m, 2H), 7.82 (td, 1H, J=7.8, 1.4 Hz), 7.34-7.31 (m, 1H), 7.21-7.14 (m, 3H), 7.04 (d, 1H, J=7.5 Hz), 3.11 (t, 2H, J=7.4 Hz), 2.59 (t, 2H, J=7.4 Hz), 1.81-1.76 (m, 2H), 1.65-1.60 (m, 2H), 1.46-1.36 (m, 4H); 13C NMR (CDCl3, 125 MHz) 188.4, 157.3, 153.2, 150.1, 146.3, 144.7, 137.1, 133.9, 129.5, 128.5, 126.8, 126.6, 124.1, 120.4, 39.0, 35.5, 31.0, 28.9, 28.8, 23.8; IR (film) νmax 2930, 2856, 1698, 1601, 1575, 1505, 1470, 1426, 1385, 1285, 1081, 1035, 990, 962, 935, 783, 741, 696 cm−1; ESI-TOF m/z 369.1363 (C21H21ClN2O2+H+ requires 369.1364).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)[CH:5]=[CH:4][N:3]=1.C(=O)([O-])[O-:23].[K+].[K+]>O1CCOCC1.O>[O:23]=[C:2]1[N:7]=[C:6]([O:8][CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)[CH:5]=[CH:4][NH:3]1
Reactant: O=C([O-])[O-]
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccnc(Cl)n2)CC1
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(Oc2cc[nH]c(=O)n2)CC1
Temperature: 25 °C
Yield: 103.5 %

Procedure:
A mixture of tert-butyl 4-(2-chloropyrimidin-4-yloxy)piperidine-1-carboxylate (341.5 mg, 0.90 mmol), potassium carbonate (225.6 mg, 1.64 mmol, EMD) and 1,4-diazacyclo[2,2,2]octane (48.8 mg, 0.44 mmol, commercially available from Alfa Aesar) in dioxane/H2O (10 mL/10 mL) was heated at 70° C. for 6 h, cooled to room temperature and then evaporated. The residual was purified by flash chromatography (0 to 10% MeOH/CH2Cl2) to yield 275 mg (85%) of the product as an off-white solid.
Reaction SMILES: [C:1]([C:3]1[C:4]([C:24]([F:27])([F:26])[F:25])=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][C:13]1[O:17][C:16]([C:18]([NH2:20])=O)=[CH:15][CH:14]=1)[C:7]([CH2:21][CH2:22][CH3:23])=[CH:6]2)#[N:2].N1C=CC=CC=1.O=P(Cl)(Cl)Cl>C(Cl)Cl>[C:18]([C:16]1[O:17][C:13]([CH2:12][N:8]2[C:9]3[C:5](=[C:4]([C:24]([F:26])([F:27])[F:25])[C:3]([C:1]#[N:2])=[CH:11][CH:10]=3)[CH:6]=[C:7]2[CH2:21][CH2:22][CH3:23])=[CH:14][CH:15]=1)#[N:20]
Reactant: CCCc1cc2c(C(F)(F)F)c(C#N)ccc2n1Cc1ccc(C(N)=O)o1
Solvent: ClCCl
Solvent: O=P(Cl)(Cl)Cl
Solvent: c1ccncc1
Product: CCCc1cc2c(C(F)(F)F)c(C#N)ccc2n1Cc1ccc(C#N)o1
Temperature: 2.5 °C
Reaction time: 2 h
Yield: 55.4 %

Procedure:
A solution containing 5-{[5-cyano-2-propyl-4-(trifluoromethyl)-1H-indol-1-yl]methyl}-2-furancarboxamide (Example 271B) (0.388 g, 1.03 mmol), pyridine (10 mL) and CH2Cl2 (25 mL) was cooled to 0-5° C. This mixture was mixed with POCl3 (0.792 g, 5.17 mmol) and the resulting mixture was stirred at rt for 2 h. The reaction mixture was then partitioned between CH2Cl2 and saturated NaHCO3. The organics were washed with 1.0N HCl, dried (MgSO4) and concentrated to dryness. The residue was purified by flash chromatography (0-10% EtOAc-hexanes gradient) to afford a pure product (0.204 g, 55% yield): MS (ES) m/z 357 (M+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][OH:6].[Cl:10][C:11]1[C:16]([Cl:17])=[CH:15][CH:14]=[CH:13][C:12]=1[S:18]([NH:21][C:22]1[C:27](Cl)=[N:26][C:25]([Cl:29])=[CH:24][N:23]=1)(=[O:20])=[O:19]>>[Br:1][C:2]1[CH:3]=[C:4]([CH2:5][O:6][C:27]2[C:22]([NH:21][S:18]([C:12]3[CH:13]=[CH:14][CH:15]=[C:16]([Cl:17])[C:11]=3[Cl:10])(=[O:20])=[O:19])=[N:23][CH:24]=[C:25]([Cl:29])[N:26]=2)[CH:7]=[CH:8][CH:9]=1
Reactant: OCc1cccc(Br)c1
Reactant: O=S(=O)(Nc1ncc(Cl)nc1Cl)c1cccc(Cl)c1Cl
Product: O=S(=O)(Nc1ncc(Cl)nc1OCc1cccc(Br)c1)c1cccc(Cl)c1Cl

Procedure:
Prepared by the method of Example 31b using 3-bromobenzylalcohol (1.3 g) and 2,3-dichloro-N-(3,5-dichloro-2-pyrazinyl)benzenesulphonamide (Example 74) (1.1 g). Yield is 1.1 g.