Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]([O:18][CH3:19])=[O:17])=[CH:11][CH:10]=1.[CH3:20][O:21][CH:22]([O:39][CH3:40])[C:23]1[C:28]([O:29][CH2:30][O:31][CH3:32])=[C:27]([C:33]([F:36])([F:35])[F:34])[CH:26]=[CH:25][C:24]=1[CH2:37]O>>[CH3:40][O:39][CH:22]([O:21][CH3:20])[C:23]1[C:28]([O:29][CH2:30][O:31][CH3:32])=[C:27]([C:33]([F:36])([F:35])[F:34])[CH:26]=[CH:25][C:24]=1[CH2:37][O:8][C:6]1[CH:5]=[CH:4][C:3]([C:9]2[CH:14]=[CH:13][C:12]([CH2:15][C:16]([O:18][CH3:19])=[O:17])=[CH:11][CH:10]=2)=[C:2]([F:1])[CH:7]=1
Reactant: COC(=O)Cc1ccc(-c2ccc(O)cc2F)cc1
Reactant: COCOc1c(C(F)(F)F)ccc(CO)c1C(OC)OC
Product: COCOc1c(C(F)(F)F)ccc(COc2ccc(-c3ccc(CC(=O)OC)cc3)c(F)c2)c1C(OC)OC
Yield: 92 %

Procedure:
According to a method similar to Example (6-7), from methyl (2′-fluoro-4′-hydroxy-1,1′-biphenyl-4-yl)acetate (1.02 g, 3.94 mmol) obtained in Example (14-1) and [2-(dimethoxymethyl)-3-(methoxymethoxy)-4-(trifluoromethyl)phenyl]methanol (1.71 g, 5.52 mmol) obtained in Example (6-6), methyl (4′-{[2-(dimethoxymethyl)-3-(methoxymethoxy)-4-(trifluoromethyl)benzyl]oxy}-2′-fluoro-1,1′-biphenyl-4-yl)acetate was obtained (2.01 g, yield: 92%).
Reaction SMILES: [CH2:1]([Li])[CH2:2][CH2:3][CH3:4].C([Mg]Br)C.[O:10]([C:17]1[CH:18]=[C:19]([CH:26]=[CH:27][CH:28]=1)[CH:20]=[C:21]1[CH2:25][CH2:24][N:23]=[CH:22]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>CCCCCC.C1COCC1>[CH2:1]([CH:22]1[C:21](=[CH:20][C:19]2[CH:26]=[CH:27][CH:28]=[C:17]([O:10][C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH:18]=2)[CH2:25][CH2:24][NH:23]1)[CH2:2][CH2:3][CH3:4]
Reactant: [Li]CCCC
Reactant: C1=NCCC1=Cc1cccc(Oc2ccccc2)c1
Agent: CC[Mg]Br
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCCCC1NCCC1=Cc1cccc(Oc2ccccc2)c1
Yield: 44 %

Procedure:
In a similar manner as Example 62 except for using 18 ml of a solution of 1.6M n-butyllithium in hexane instead of 10 ml of the solution of 3N ethyl magnesiumbromide in THF for reacting with 3-(m-phenoxybenzylidene)-1-pyrroline, 3.2 g (yield 44%) of 2-n-butyl-3-(m-phenoxybenzylidene)-pyrrolidine was obtained.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:11]=[C:10]([C:18]([OH:20])=O)[N:9]=2)=[CH:4][CH:3]=1.F[P-](F)(F)(F)(F)F.[N:28]1(O[P+](N(C)C)(N(C)C)N(C)C)[C:32]2C=CC=CC=2N=N1.Cl.CN.CCN(CC)CC>CN(C=O)C>[I:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:11]=[C:10]([C:18]([NH:28][CH3:32])=[O:20])[N:9]=2)=[CH:4][CH:3]=1
Reactant: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Reactant: O=C(O)c1cc2ccccc2c(-c2ccc(I)cc2)n1
Agent: CN
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CNC(=O)c1cc2ccccc2c(-c2ccc(I)cc2)n1
Temperature: 25 °C
Yield: 81 %

Procedure:
A mixture of 1-(4-iodophenyl)-3-isoquinolinecarboxylic acid (0.2073 g, 0.55 mmol), BOP (0.2447 g, 0.55 mmol), Methylamine hydrochloride (0.096 g, 1.42 mmol), and Et3N (0.25 mL, 1.80 mmol) in DMF (8 mL) was stirred under Ar at room temperature. After stirring for 1 h , additional Et3N (0.2 ml,) was added in one portion. The mixture was stirred under Ar for 7 h, then quenched by adding H2O (8 mL). The resulting mixture was extracted with CH2Cl2 (3×20 mL). The combined organic layers were dried (Na2SO4), then filtered. The filtrate was concentrated in vacuo. The residue was purified on column chromatography (SiO2, 35% ethyl acetate in hexane, 0.1% Et3N), thereby affording the title compound as a white solid (0.1724, 81%). mp 163-164 ° C. 1H NMR (CDCl3) d 3.07, 3.09 (two s, total 3 H, N-methyl), 7.46 (d, J=8.4 Hz, 2 H, aromatic), 7.64 (t, J=7.2 Hz, 1 H, aromatic), 7.77 (t, J=6.9 Hz, 1 H, aromatic), 7.92 (d, J=8.4 Hz, 2 H, aromatic), 8.07 (t, J=7.8 Hz, 2 H, aromatic), 8.24 (br s, 1 H, NH), 8.02 (s, 1 H, aromatic). 13C NMR (CDC13) d 26.05 (q,N-methyl), 95.14 (s, C--I), 119.54 (d, aromatic), 127.02 (d, aromatic), 128.58 (d, aromatic), 128.75 (di aromatic), 130.60 (d, aromatic), 131.43 (d, aromatic), 131.56 (aromatic), 137.02 (s, aromatic), 137.40 (d, aromatic), 138.28 (s, aromatic), 142.58 (s, aromatic), 158.09 (s, aromatic), 165.12 (s, CO). HRMS calcd. for C17H13IN2O: 388.0073. Found: 388.0077.
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:62][CH3:63])=[C:10]([CH2:19][NH:20][C:21]([C:23]3[CH:24]=[C:25]([C:29]([NH:31][CH2:32][C:33]4[CH:34]=[C:35]([C:41]5[CH:46]=[CH:45][CH:44]=[C:43]([CH2:47][N:48]6[CH2:53][CH2:52][N:51](C(OC(C)(C)C)=O)[C@@H:50]([CH3:61])[CH2:49]6)[CH:42]=5)[CH:36]=[C:37]([O:39][CH3:40])[CH:38]=4)=[O:30])[CH:26]=[CH:27][CH:28]=3)=[O:22])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2]>C(O)(C(F)(F)F)=O.C(Cl)Cl>[CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:62][CH3:63])=[C:10]([CH2:19][NH:20][C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([NH:31][CH2:32][C:33]4[CH:34]=[C:35]([C:41]5[CH:46]=[CH:45][CH:44]=[C:43]([CH2:47][N:48]6[CH2:53][CH2:52][NH:51][C@@H:50]([CH3:61])[CH2:49]6)[CH:42]=5)[CH:36]=[C:37]([O:39][CH3:40])[CH:38]=4)=[O:30])[CH:24]=3)=[O:22])[C:11]([NH:12][CH:13]3[CH2:14][CH2:15][O:16][CH2:17][CH2:18]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2]
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)NCc2cc(OC)cc(-c3cccc(CN4CCN(C(=O)OC(C)(C)C)[C@@H](C)C4)c3)c2)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)NCc2cc(OC)cc(-c3cccc(CN4CCN[C@@H](C)C4)c3)c2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 40.2 %

Procedure:
237(b) A mixture of 1,1-dimethylethyl (2S)-4-{[3′-{[({3-[({[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}amino)carbonyl]phenyl}-carbonyl)amino]-methyl}-5′-(methyloxy)-3-biphenylyl]methyl}-2-methyl-1-piperazinecarboxylate (130 mg, 0.19 mmol) in 25% TFA in DCM (3 mL) was stirred at RT for 2 h. It was purified by preparative hplc (NH2OH condition), eluting with 10 to 90% CH3CN in water. The fractions were dried under GeneVac to give a solid. It was purified further using a Gilson HPLC (with 0.1% TFA condition) and eluting with 10 to 90% CH3CN in water. Fractions containing compound were combined and then converted to its free base with saturated NaHCO3. The organic layer was dried over sodium sulfate, filtered and then concentrated to give N-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-N′-[(5-(methyloxy)-3′-{[(3S)-3-methyl-1-piperazinyl]methyl}-3-biphenylyl)methyl]-1,3-benzenedicarboxamide as a white solid (58 mg, 50%). LC-MS m/z 759 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:9]([O:11]C)=O)=[C:4]([CH3:8])[S:5][C:6]=1[CH3:7].Cl[C:14]1[N:19]=[CH:18][C:17]([C:20]([O:22][CH3:23])=[O:21])=[CH:16][CH:15]=1>CO>[CH3:8][C:4]1[S:5][C:6]([CH3:7])=[C:2]2[C:3]=1[C:9](=[O:11])[N:19]1[CH:18]=[C:17]([C:20]([O:22][CH3:23])=[O:21])[CH:16]=[CH:15][C:14]1=[N:1]2
Reactant: COC(=O)c1ccc(Cl)nc1
Reactant: COC(=O)c1c(C)sc(C)c1N
Solvent: CO
Product: COC(=O)c1ccc2nc3c(C)sc(C)c3c(=O)n2c1
Temperature: 180 °C

Procedure:
A mixture of 2.5 g (0.0113 mol) of 4-amino-2,5-dimethyl-3-thiophenecarboxylic acid, methyl ester and 2.5 g (0.0113 mol) of 6-chloro-3-pyridinecarboxylic acid, methyl ester (Alfred Bader Chemical Company) is heated in an oil bath at 180° C. for thirty minutes. The mixture is cooled, dissolved in hot methanol, cooled and 0.3 g of 1,3-dimethyl-10-oxo-10H-pyrido[1,2-a]thieno[3,4-d]pyrimidine-7-carboxylic acid, methyl ester is collected; mp 209°-210° C. after recrystallization from methanol.
Reaction SMILES: [CH2:1]([N:8]([C:28](=[O:33])[C:29]([F:32])([F:31])[F:30])[CH2:9][CH2:10][N:11]([C:18]1[CH:26]=[CH:25][CH:24]=[C:23]2[C:19]=1[C:20](Cl)=[CH:21][NH:22]2)[C:12](=[O:17])[C:13]([F:16])([F:15])[F:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P(=O)(O)(O)[OH:35].O>C(O)(=O)C>[CH2:1]([N:8]([C:28](=[O:33])[C:29]([F:32])([F:31])[F:30])[CH2:9][CH2:10][N:11]([C:18]1[CH:26]=[CH:25][CH:24]=[C:23]2[C:19]=1[CH2:20][C:21](=[O:35])[NH:22]2)[C:12](=[O:17])[C:13]([F:16])([F:15])[F:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=P(O)(O)O
Reactant: O=C(N(CCN(C(=O)C(F)(F)F)c1cccc2[nH]cc(Cl)c12)Cc1ccccc1)C(F)(F)F
Solvent: CC(=O)O
Solvent: O
Product: O=C1Cc2c(cccc2N(CCN(Cc2ccccc2)C(=O)C(F)(F)F)C(=O)C(F)(F)F)N1
Temperature: 77.5 °C
Yield: 23 %

Procedure:
To a solution of N-[2-(benzyl-trifluoroacetyl-amino)-ethyl]-2,2,2-trifluoro-N-(3-chloro-1H-indol-4-yl)acetamide (1.4 g, 2.85 mmol) in acetic acid (18 mL) was added a mixture of 85% phosphoric acid (10 mL) and water (3 mL). The reaction was heated at 75-80° C. for 16 hours. The mixture was poured into water (100 mL) and the crude product crystallized as a solid. After filtration, the solids were dissolved in ethyl acetate (100 mL), washed with water (50 mL), saturated sodium bicarbonate solution (50 mL) and brine (20 mL), dried over anhydrous magnesium sulfate and filtered. Purification of the residue by chromatography (silica gel, 40% hexane-ethyl acetate) and crystallization from ether-petroleum ether afforded the title compound as a white solid, (0.31 g, 23.0%), mp 108-111° C.; MS EI m/e 473 (M+).
Reaction SMILES: [NH2:1][C:2]1[C:7]([F:8])=[C:6]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[C:11]([O:16][CH3:17])[C:10]=2[F:18])[N:5]=[C:4]([C:19]([O:21]C)=[O:20])[C:3]=1[O:23][CH3:24].[OH-].[Na+].Cl>CO>[NH2:1][C:2]1[C:7]([F:8])=[C:6]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[C:11]([O:16][CH3:17])[C:10]=2[F:18])[N:5]=[C:4]([C:19]([OH:21])=[O:20])[C:3]=1[O:23][CH3:24]
Reactant: COC(=O)c1nc(-c2ccc(Cl)c(OC)c2F)c(F)c(N)c1OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1c(C(=O)O)nc(-c2ccc(Cl)c(OC)c2F)c(F)c1N
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.1 %

Procedure:
Methyl 4-amino-6-(4-chloro-2-fluoro-3-methoxyphenyl)-5-fluoro-3-methoxypicolinate (0.77 g, 2.15 mmol) was dissolved in CH3OH (14 mL) and 2 N sodium hydroxide (NaOH; 4.3 mL) was added. The solution was stirred at room temperature overnight, acidified with 2 N HCl and concentrated to remove the majority of CH3OH. The precipitate that formed was filtered, washed with H2O and dried under vacuum to provide the title compound as a white solid (668 mg, 90%): mp 143-146° C.; 1H NMR (400 MHz, CDCl3) δ 7.30 (dd, J=8.5, 1.6 Hz, 1H), 7.19 (dd, J=8.4, 6.8 Hz, 1H), 4.83 (s, 2H), 4.07 (s, 3H), 4.02 (d, J=1.1 Hz, 3H); 19F NMR (376 MHz, CDCl3) δ −128.66, −128.74, −134.93, −135.01; ESIMS m/z 345 ([M+H]+), 343 ([M−H]−).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][C:9]2[CH:10]=[C:11]([CH:21]=[CH:22][CH:23]=2)[CH2:12]P(=O)(OCC)OCC)=[N:6][CH:7]=1.[H-].[Na+].[C:26]([O:30][C:31]([N:33]1[CH2:38][CH2:37][C:36](=O)[CH2:35][CH2:34]1)=[O:32])([CH3:29])([CH3:28])[CH3:27].O>C1COCC1.O1CCOCCOCCOCCOCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][C:9]2[CH:10]=[C:11]([CH:21]=[CH:22][CH:23]=2)[CH:12]=[C:36]2[CH2:37][CH2:38][N:33]([C:31]([O:30][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:32])[CH2:34][CH2:35]2)=[N:6][CH:7]=1
Reactant: CCOP(=O)(Cc1cccc(Oc2ccc(Br)cn2)c1)OCC
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: C1COCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(=Cc2cccc(Oc3ccc(Br)cn3)c2)CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 61.5 %

Procedure:
Diethyl 3-(5-bromopyridin-2-yloxy)benzylphosphonate (2.00 g, 5.00 mmol) from Step 3 and 1,4,7,10,13-pentaoxacyclopentadecane (15-Crown-5, 0.025 mL, 0.13 mmol) were combined in THF (7 mL). The mixture was cooled to 0° C. and sodium hydride (210 mg, 60% dispersion in mineral oil, 5.25 mmol) was added. The reaction was warmed to room temperature, stirred for 30 min and then cooled back to 0° C. A solution of 4-oxo-piperidine-1-carboxylic acid tert-butyl ester (1.05 g, 5.25 mmol) in THF (4 mL) was added and the reaction was warmed to room temperature. After 16 h, an additional amount of sodium hydride (spatula tip) was added and the mixture was stirred an additional 6 h. Water was added and the mixture was extracted twice with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated to a yellow oil. This material was crystallized from hot isopropyl ether/heptane. The supernatant was decanted and the solid was washed with heptane and dried in vacuo to afford the title compound (1.37 g, 62% yield) as an off-white solid. MS (APCI) M−100=345.0; 1H NMR (400 MHz, CDCl3) δ ppm 1.48 (s, 9H) 2.30-2.37 (m, 2H) 2.44-2.50 (m, 2H) 3.38-3.44 (m, 2H) 3.48-3.54 (m, 2H) 6.35 (s, 1H) 6.85 (dd, J=8.77, 0.58 Hz, 1H) 6.94-7.00 (m, 2H) 7.03-7.07 (m, 1H) 7.35 (t, J=7.80 Hz, 1H) 7.78 (dd, J=8.67, 2.63 Hz, 1H) 8.23 (dd, J=2.53, 0.58 Hz, 1H).
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[NH:6][CH:5]([S:9][CH3:10])[N:4]([N:11]=C(C)C)[C:3]1=[O:15].C1(C)C=CC(S(O)(=O)=O)=CC=1>C(O)C>[CH3:1][N:2]1[C:7](=[O:8])[NH:6][CH:5]([S:9][CH3:10])[N:4]([NH2:11])[C:3]1=[O:15]
Reactant: CSC1NC(=O)N(C)C(=O)N1N=C(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Product: CSC1NC(=O)N(C)C(=O)N1N
Yield: 94.6 %

Procedure:
22.8 g (0.1 mol) of 1-methyl-3-isopropylideneamino-4-methylmercapto-tetrahydro-1,3,5-triazine-2,6-dione (prepared according to Example C-1) were dissolved in 250 ml of ethanol and warmed, with addition of a little p-toluene-sulphonic acid, for 5 hours to 50°C, a vacuum of approximately 200 mm Hg being applied. The mixture was evaporated in vacuo and the residue was recrystallized from ethanol. 18 g (96%) of 1-methyl-3-amino-4-methylmercapto-tetrahydro-1,3,5-triazine-2,6-dione were obtained as colorless needles, melting point 174°-175°C.
Reaction SMILES: [C:1]([O:4][CH:5]([CH3:20])[CH2:6][C:7]([CH2:18]Br)=[CH:8][CH:9]([NH:15][CH:16]=[O:17])[C:10]([O:12][CH2:13][CH3:14])=[O:11])(=[O:3])[CH3:2].[P:21]([O:30]C(C)C)([O:26][CH:27]([CH3:29])[CH3:28])[O:22][CH:23]([CH3:25])[CH3:24]>>[C:1]([O:4][CH:5]([CH3:20])[CH2:6][C:7]([CH2:18][P:21]([O:26][CH:27]([CH3:29])[CH3:28])([O:22][CH:23]([CH3:25])[CH3:24])=[O:30])=[CH:8][CH:9]([NH:15][CH:16]=[O:17])[C:10]([O:12][CH2:13][CH3:14])=[O:11])(=[O:3])[CH3:2]
Reactant: CC(C)OP(OC(C)C)OC(C)C
Reactant: CCOC(=O)C(C=C(CBr)CC(C)OC(C)=O)NC=O
Product: CCOC(=O)C(C=C(CC(C)OC(C)=O)CP(=O)(OC(C)C)OC(C)C)NC=O
Reaction time: 18 h

Procedure:
18.0 g (51.4 mmol) of ethyl 6-acetoxy-4-bromomethyl-2-formylamino-hept-3-enoate and 56.3 ml (205.6 mmol) of 90% triisopropyl phosphite are heated to 80° C. and the mixture is stirred for 18 hours under a pressure of 100-150 mbar. Excess triisopropyl phosphite is removed by distillation and the residue is purified by chromatography on silica gel with ethyl acetate/isopropanol (7:2), giving ethyl 6-acetoxy-2-formylamino-4-diisopropylphosphonomethyl-hept-3-enoate as an orange oil. yield.
Reaction SMILES: [H-].[Na+].[Br-].C1([P+](C2C=CC=CC=2)(C2C=CC=CC=2)[CH:11]2[CH2:13][CH2:12]2)C=CC=CC=1.[CH:26]([C:28]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[N:30]([CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[C:40]([C:44]([F:47])([F:46])[F:45])[CH:39]=2)[C:29]=1[C:48]([O:50][CH2:51][CH3:52])=[O:49])=O>O1CCCC1>[C:11]1(=[CH:26][C:28]2[C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[N:30]([CH2:37][C:38]3[CH:43]=[CH:42][CH:41]=[C:40]([C:44]([F:46])([F:45])[F:47])[CH:39]=3)[C:29]=2[C:48]([O:50][CH2:51][CH3:52])=[O:49])[CH2:13][CH2:12]1
Reactant: CCOC(=O)c1c(C=O)c2ccccc2n1Cc1cccc(C(F)(F)F)c1
Reactant: c1ccc([P+](c2ccccc2)(c2ccccc2)C2CC2)cc1
Agent: [Br-]
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)c1c(C=C2CC2)c2ccccc2n1Cc1cccc(C(F)(F)F)c1
Temperature: 0 °C

Procedure:
Sodium hydride (60% dispersion in mineral oil, 128 mg, 3.20 mmol) was suspended in anhydrous tetrahydrofuran (10 mL) and cooled to 0° C. Triphenyl-cyclopropylphosphonium bromide (1.23 g, 3.20 mmol) was added as a solid all at once, and the mixture was allowed to stir at room temperature. Once gas evolution ceased, a tetrahydrofuran solution of ethyl 3-formyl-1-[3-(trifluoromethyl)benzyl]-1H-indole-2-carboxylate (Example 40, 1.0 g, 2.7 mmol) was added, the mixture was stirred for 15 hours, and the resulting mixture was partitioned between water and ethyl acetate. Layers were separated, and the aqueous layer was extracted with ethyl acetate (2×). The combined organic layers were dried over anhydrous magnesium sulfate and concentrated. The resulting crude oil was purified by flash chromatography on silica gel eluted with 5% ethyl acetate/hexane. The title compound was collected as a bright yellow oil (403 mg, 38%). The product had: 1H NMR (300 MHz, CDCl3) δ 8.04 (d, 1 H), 7.53 (s, 1 H), 7.41-7.38 (m, 2 H), 7.29-7.20 (m, 3 H), 7.15-7.12 (m, 1 H), 7.05 (d, 1 H), 5.72 (s, 2 H), 4.27 (q, 2 H), 1.50-1.45 (m, 2 H), 1.25 (t, 3 H), 0.83-0.76 (m, 2 H); mass spectroscopy gave MH+=400.2 (calc'd exact mass for C23H20F3NO2=399.14).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][NH:9][C:10](=[O:18])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1N.N([O-])=O.[Na+]>C(O)C.Cl.O>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([OH:18])=[N:9]1
Reactant: Nc1ccccc1C(=O)NNc1ccccc1F
Agent: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Oc1nn(-c2ccccc2F)c2ccccc12
Temperature: 55 °C
Reaction time: 3 h
Yield: 94 %

Procedure:
A stirred suspension of 105 g (0.429 mole) of 2-amino-benzoic acid N′-(2-fluoro-phenyl)-hydrazide in 1250 mL of ethanol and 1250 mL of 1N hydrochloric acid was heated to 55° C. A solution of 59 g (0.858 mole) of sodium nitrite in 200 mL of water was added dropwise over a 30 minute period. Approximately 10 minutes into the addition a solid began separating. External heating was continued until the reaction temperature reached 65° C. and then it was turned off. The temperature remained at 65-68° C. during the addition and gas evolution became vigorous approximately halfway through the addition. Toward the end of the addition, gas evolution slowed and the temperature dropped below 65° C. External heating was reapplied and the mixture was stirred at 70° C. for 3 hours. The mixture was cooled to −10° C. and filtered. The solid was rinsed once with 50 mL of ethanol, then once with 100 mL of water, and pressed dry under suction. Further drying in vacuo at 35° C. for 7 hours afforded 92 g (94%) of product.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C@@H:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[N:11]([C:20](Cl)=[O:21])[C:10]([C:23]3[CH:28]=[CH:27][C:26]([C:29]([C:32]#[N:33])([CH3:31])[CH3:30])=[CH:25][C:24]=3[O:34][CH2:35][CH3:36])=[N:9]2)=[CH:4][CH:3]=1.[CH3:37][C:38]1[C:42]([C:43]([N:45]2[CH2:50][CH2:49][NH:48][CH2:47][CH2:46]2)=[O:44])=[C:41]([CH3:51])[O:40][N:39]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C@H:8]2[C@@H:12]([C:13]3[CH:14]=[CH:15][C:16]([Cl:19])=[CH:17][CH:18]=3)[N:11]([C:20]([N:48]3[CH2:49][CH2:50][N:45]([C:43]([C:42]4[C:38]([CH3:37])=[N:39][O:40][C:41]=4[CH3:51])=[O:44])[CH2:46][CH2:47]3)=[O:21])[C:10]([C:23]3[CH:28]=[CH:27][C:26]([C:29]([CH3:31])([CH3:30])[C:32]#[N:33])=[CH:25][C:24]=3[O:34][CH2:35][CH3:36])=[N:9]2)=[CH:6][CH:7]=1
Reactant: CCOc1cc(C(C)(C)C#N)ccc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)Cl
Reactant: Cc1noc(C)c1C(=O)N1CCNCC1
Product: CCOc1cc(C(C)(C)C#N)ccc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)N1CCN(C(=O)c2c(C)noc2C)CC1

Procedure:
2-(4-{(4S,5R)-4,5-Bis-(4-chloro-phenyl)-1-[4-(3,5-dimethyl-isoxazole-4-carbonyl)-piperazine-1-carbonyl]-4,5-dihydro-1H-imidazol-2-yl}-3-ethoxy-phenyl)-2-methyl-propionitrile was prepared from (4S,5R)-4,5-bis-(4-chloro-phenyl)-2-[4-(cyano-dimethyl-methyl)-2-ethoxy-phenyl]-4,5-dihydro-imidazole-1-carbonyl chloride (example 12j) and (3,5-dimethyl-isoxazol-4-yl)-piperazin-1-yl-methanone (example 13) in an analogous manner as described in example 25. LR-MS: 713.3 [(M+H)+]
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([CH:7]2[CH2:10][N:9](C(OC(C)(C)C)=O)[CH2:8]2)[CH2:3][CH2:2]1.Cl.O1CCOCC1>C(Cl)Cl>[NH:9]1[CH2:10][CH:7]([N:4]2[CH2:5][CH2:6][O:1][CH2:2][CH2:3]2)[CH2:8]1
Reactant: CC(C)(C)OC(=O)N1CC(N2CCOCC2)C1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: C1CN(C2CNC2)CCO1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
tert-butyl 3-morpholinoazetidine-1-carboxylate (31 mg) was treated with 4N HCl in dioxane (5 eq) in 1 mL of DCM. The reaction mixture was stirred for 3 hours at room temperature and then concentrated to dryness to yield 4-(azetidin-3-yl)morpholine in quantitative yield. 4-(6-(Bromomethyl)-2-chloropyrido[3,2-d]pyrimidin-4-yl)morpholine 7 (0.413 g) was reacted with 4-(azetidin-3-yl)morpholine via General Procedure B to afford 0.4 g 4-(1-((2-chloro-4-morpholinopyrido[3,2-d]pyrimidin-6-yl)methyl)azetidin-3-yl)morpholine
Reaction SMILES: Cl.[NH2:2][CH:3]1[CH2:15][CH2:14][C:13]2[N:12]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=3)[C:11]3[CH:10]=[CH:9][C:8]([C:24]#[N:25])=[CH:7][C:6]=3[C:5]=2[CH2:4]1.C(N(CC)CC)C.[CH:33]1([S:36](Cl)(=[O:38])=[O:37])[CH2:35][CH2:34]1>ClCCl>[C:24]([C:8]1[CH:7]=[C:6]2[C:11](=[CH:10][CH:9]=1)[N:12]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=1)[C:13]1[CH2:14][CH2:15][CH:3]([NH:2][S:36]([CH:33]3[CH2:35][CH2:34]3)(=[O:38])=[O:37])[CH2:4][C:5]2=1)#[N:25]
Reactant: O=S(=O)(Cl)C1CC1
Reactant: N#Cc1ccc2c(c1)c1c(n2Cc2cccc(F)c2)CCC(N)C1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: N#Cc1ccc2c(c1)c1c(n2Cc2cccc(F)c2)CCC(NS(=O)(=O)C2CC2)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 41.2 %

Procedure:
Combine 6-amino-9-(3-fluoro-benzyl)6,7,8,9-tetrahydro-5H-carbazole-3-carbonitrile, hydrochloride salt (Preparation 54) (125 mg, 0.35 mmol) and triethylamine (0.195 mL, 1.4 mmol) in dichloromethane (3 mL) under nitrogen. Add cyclopropylsulfonylchloride (51 mg, 0.36 mmol) in dichloromethane (1 mL). Stir for 18 h at room temperature. Purify the reaction solution directly by flash chromatography, eluting with 20% ethyl acetate/hexane and then a gradient up to 50% ethyl acetateihexane to obtain 80 mg. Triturate in diethyl ether to obtain 61 mg (41%) of a tan solid. MS (ES): m/z 424 (M+1), 422 (M−1); 1H NMR(DMSO-d6): δ 7.98 (d, 1H, J=1.3 Hz), 7.56 (d, 1H, J=8.4 Hz), 7.41 (dd, 1H, J=8.4, 1.3 Hz), 7.36-7.30 (m, 2H), 7.07 (dt, 1H, J=8.7, 2.5 Hz), 6.88 (d, 1H, J=9.7 Hz), 6.83 (d, 1H, J=7.9 Hz), 5.42 (d, 2H, J=5.3 Hz), 3.68 (m, 1H), 3.10 (dd, 1H, J=15.4, 5.3 Hz), 2.90-2.81 (m, 1H), 2.79-2.61 (m, 3H), 2.13 (m, 1H), 1.86 (m, 1H), 0.98-0.91 (m, 4H).
Reaction SMILES: [C:1]1([CH:7]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[N:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][N:17]3[C:21]4[CH:22]=[C:23]([CH3:26])[CH:24]=[CH:25][C:20]=4[N:19](C(C)=C)[C:18]3=[O:30])[CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(O)C.Cl>O>[C:31]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][N:17]3[C:21]4[CH:22]=[C:23]([CH3:26])[CH:24]=[CH:25][C:20]=4[NH:19][C:18]3=[O:30])[CH2:10][CH2:9]2)[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: C=C(C)n1c(=O)n(CCCN2CCN(C(c3ccccc3)c3ccccc3)CC2)c2cc(C)ccc21
Agent: Cl
Solvent: O
Solvent: CCO
Product: Cc1ccc2[nH]c(=O)n(CCCN3CCN(C(c4ccccc4)c4ccccc4)CC3)c2c1
Reaction time: 0.5 h

Procedure:
To a stirred solution of 9.6 parts of 3-{3-[4-(diphenylmethyl)-1-piperazinyl]propyl}-1,3-dihydro-5-methyl-1-(1-methylethenyl)-2H-benzimidazol-2-one in 80 parts of ethanol are added 24 parts of a concentrated hydrochloric acid solution and 50 parts of water (exothermic reaction: temperature rises to 50° C.). Stirring is continued for 30 minutes at room temperature. The reaction mixture is evaporated and the residue is triturated in 2-propanone. The hydrochloride salt is filtered off and the free base is liberated in the conventional manner with ammonium hydroxide. Methylbenzene is added and the precipitated free base is filtered off. It is crystallized from a mixture of 2-propanol and a small amount of N,N-dimethylformamide, yielding 1-{3-[4-(diphenylmethyl)-1-piperazinyl]propyl}-1,3-dihydro-6-methyl-2H-benzimidazol-2-one; mp. 195.7° C.