Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH2:2]N(CC)CC.[C:8]([CH2:11][CH2:12][NH:13][C:14]([C:16]1[N:21]=[CH:20][C:19]([C:22]2[CH:30]=[C:29]([Cl:31])[CH:28]=[CH:27][C:23]=2[C:24]([OH:26])=O)=[CH:18][CH:17]=1)=[O:15])([OH:10])=[O:9].[Cl:32][C:33]1[CH:38]=[CH:37][C:36]([C:39]2[CH:44]=[CH:43][C:42]([NH2:45])=[CH:41][CH:40]=2)=[C:35]([CH3:46])[CH:34]=1.CCN=C=NCCCN(C)C>C(Cl)Cl>[Cl:31][C:29]1[CH:28]=[CH:27][C:23]([C:24](=[O:26])[NH:45][C:42]2[CH:43]=[CH:44][C:39]([C:36]3[CH:37]=[CH:38][C:33]([Cl:32])=[CH:34][C:35]=3[CH3:46])=[CH:40][CH:41]=2)=[C:22]([C:19]2[CH:18]=[CH:17][C:16]([C:14]([NH:13][CH2:12][CH2:11][C:8]([O:10][CH2:1][CH3:2])=[O:9])=[O:15])=[N:21][CH:20]=2)[CH:30]=1
Reactant: CCN(CC)CC
Reactant: Cc1cc(Cl)ccc1-c1ccc(N)cc1
Reactant: O=C(O)CCNC(=O)c1ccc(-c2cc(Cl)ccc2C(=O)O)cn1
Agent: CCN=C=NCCCN(C)C
Solvent: ClCCl
Product: CCOC(=O)CCNC(=O)c1ccc(-c2cc(Cl)ccc2C(=O)Nc2ccc(-c3ccc(Cl)cc3C)cc2)cn1
Temperature: 25 °C

Procedure:
Neat Et3N (0.14 mL, 1.0 mmol) was added to a DCM mixture (5 mL) of 2-(6-((2-carboxyethyl)carbamoyl)pyridin-3-yl)-4-chlorobenzoic acid (226 mg, 0.6 mmol), 4′-chloro-2′-methyl-[1,1′-biphenyl]-4-amine (109 mg, 0.5 mmol), and EDCI (192 mg, 1.0 mmol) and the resulting mixture was stirred at room temperature. After 3 h the resulting mixture was directly purified via column chromatography to yield the title compound.
Reaction SMILES: Br[C:2]1[C:3]2[C:4]3[CH:17]=[CH:16][S:15][C:5]=3[C:6](=[O:14])[NH:7][C:8]=2[CH:9]=[CH:10][C:11]=1[O:12][CH3:13].CC1(C)C(C)(C)OB([C:26]2[CH:31]=[CH:30][C:29]([C@H:32]([NH:34][C:35](=[O:41])[O:36][C:37]([CH3:40])([CH3:39])[CH3:38])[CH3:33])=[CH:28][CH:27]=2)O1>>[CH3:13][O:12][C:11]1[CH:10]=[CH:9][C:8]2[NH:7][C:6](=[O:14])[C:5]3[S:15][CH:16]=[CH:17][C:4]=3[C:3]=2[C:2]=1[C:26]1[CH:27]=[CH:28][C:29]([C@H:32]([NH:34][C:35](=[O:41])[O:36][C:37]([CH3:40])([CH3:39])[CH3:38])[CH3:33])=[CH:30][CH:31]=1
Reactant: COc1ccc2[nH]c(=O)c3sccc3c2c1Br
Reactant: C[C@@H](NC(=O)OC(C)(C)C)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Product: COc1ccc2[nH]c(=O)c3sccc3c2c1-c1ccc([C@@H](C)NC(=O)OC(C)(C)C)cc1
Yield: 45.8 %

Procedure:
Following General Procedure B, 9-bromo-8-methoxythieno[2,3-c]quinolin-4(5H)-one (3.0 g, 9.7 mmol) was reacted with (R)-tert-butyl 1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethylcarbamate (5.0 g, 14 mmol) to afford the desired product (2.0 g, 47%) as a brown solid: ESI MS m/z 451 [C25H26N2O4S+H]+.
Reaction SMILES: CO[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]1[CH2:15][C:14]2[CH:16]=[C:17]([C:20]([F:23])([F:22])[F:21])[CH:18]=[CH:19][C:13]=2[NH:12][C:11](=[O:24])[CH:10]1[CH3:25].[H-].[Na+].[CH3:28][N:29]([CH2:31][CH2:32][Cl:33])[CH3:30].CN(C)[CH:36]=[O:37]>>[ClH:33].[CH3:28][N:29]([CH3:30])[CH2:31][CH2:32][N:12]1[C:13]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:21])[F:22])=[CH:16][C:14]=2[CH2:15][C@H:9]([C:4]2[CH:5]=[CH:6][C:7]([O:37][CH3:36])=[CH:8][CH:3]=2)[C@H:10]([CH3:25])[C:11]1=[O:24]
Reactant: CN(C)CCCl
Reactant: CN(C)C=O
Reactant: COc1ccccc1C1Cc2cc(C(F)(F)F)ccc2NC(=O)C1C
Agent: [H-]
Agent: [Na+]
Product: COc1ccc([C@H]2Cc3cc(C(F)(F)F)ccc3N(CCN(C)C)C(=O)[C@H]2C)cc1
Product: Cl
Temperature: 85 °C

Procedure:
To a solution of 1,3,4,5-tetrahydro-4-(methoxyphenyl)-3-methyl-7-(trifluoromethyl)-2H-1-benzazepin-2-one (3.37 g; 9.65 mmole) in dry dimethylformamide 75 ml) was added prewashed (hexane) 50% sodium hydride (5.56 g; 11.58 mmole; 1.2 eq.) with stirring. After ~20 minutes, 1.7N (in toluene) N,N-dimethyl-2-chloroethylamine (24.0 ml; 40.8 mmole) was added, and the mixture was heated at 85° C. for four hours. The mixture was made basic with 50% sodium hydride, and extracted with ethyl acetate (three times). The combined organics were dried (magnesium sulfate) and concentrated, and the dark oily residue was placed under vacuum. The crude material was flash chromatographed (silica gel/1% methanol:dichloromethane, followed by 3% methanol:dichloromethane). The acidified (hydrogen chloride saturated ether) product weighed 1.06 g.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]1[CH2:13][N:12]([C:14](OC(C)(C)C)=[O:15])[C@H:11]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:10]=1.FC(F)(F)C(O)=O.C(N(CC)CC)C.[OH:41][C@@H:42]([C:46]([CH3:49])([CH3:48])[CH3:47])C(O)=O.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>ClCCl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]1[CH2:13][N:12]([C:14](=[O:15])[C@@H:42]([OH:41])[C:46]([CH3:49])([CH3:48])[CH3:47])[C@H:11]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:10]=1
Reactant: CC(C)(C)[C@H](O)C(=O)O
Reactant: CC(C)(C)OC(=O)N1CC(c2cc(F)ccc2F)=C[C@H]1c1ccccc1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)[C@H](O)C(=O)N1CC(c2cc(F)ccc2F)=C[C@H]1c1ccccc1
Reaction time: 0.5 h

Procedure:
A solution of tert-butyl(2S)-4-(2,5-difluorophenyl)-2-phenyl-2,5-dihydro-1H-pyrrole-1-carboxylate (5-5, 113 mg, 0.316 mmol, 1 equiv) in a 1:1 mixture of dichloromethane and trifluoroacetic acid (20 mL) was stirred for 30 minutes, then concentrated. The residue was dried via toluene azeotrope (1×10 mL), then dissolved in DMF (4 mL). Triethylamine (0.176 mL, 1.27 mmol, 4.00 equiv), (2S)-2-hydroxy-3,3-dimethylbutanoic acid (84 mg, 0.632 mmol, 2.00 equiv), and PYBOP (329 mg, 0.632 mmol, 2.00 equiv) were added, and the resulting mixture was stirred at 23° C. for 24 hours. Additional triethylamine (0.176 mL, 1.27 mmol, 4.00 equiv), (2S)-2-hydroxy-3,3-dimethylbutanoic acid (84 mg, 0.632 mmol, 2.00 equiv), and PYBOP (329 mg, 0.632 mmol, 2.00 equiv) were added, and the resulting mixture was stirred at 23° C. for 20 hours. The reaction mixture was partitioned between water (70 mL) and ethyl acetate (2×55 mL). The combined organic layers were dried over sodium sulfate and concentrated. The residue was purified by reverse-phase LC (H2O/CH3CN gradient w/0.1% TFA present) to provide (2S)-1-[(2S)-4-(2,5-difluorophenyl)-2-phenyl-2,5-dihydro-1H-pyrrol-1-yl]-3,3-dimethyl-1-oxobutan-2-ol (22-1) as a white solid. 1H NMR (500 MHz, CDCl3) rotamers: δ 7.43-7.02 (m, 8H), 6.42 (m, 1H), 5.93 (m, 1H), 5.01-4.82 (m, 2H), 4.16 (major rotamer, s, 1H), 3.85 (minor rotamer, s, 1H), 1.00 (minor, s, 9H), 0.92 (major, s, 9H). LRMS m/z (M+H) 372.0 found, 372.2 required.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]([CH3:12])=[C:10]2[C:6]([C:7](=[O:13])[O:8][CH2:9]2)=[C:5]([O:14][CH2:15][O:16][CH2:17][CH2:18][O:19][CH3:20])[C:4]=1[CH2:21][CH:22]=O.C1(P(C2C=CC=CC=2)(C2C=CC=CC=2)=[C:31]([CH3:34])[CH:32]=[O:33])C=CC=CC=1>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[C:11]([CH3:12])=[C:10]2[C:6]([C:7](=[O:13])[O:8][CH2:9]2)=[C:5]([O:14][CH2:15][O:16][CH2:17][CH2:18][O:19][CH3:20])[C:4]=1[CH2:21]/[CH:22]=[C:31](\[CH3:34])/[CH:32]=[O:33]
Reactant: COCCOCOc1c(CC=O)c(OC)c(C)c2c1C(=O)OC2
Reactant: CC(C=O)=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Product: COCCOCOc1c(C/C=C(\C)C=O)c(OC)c(C)c2c1C(=O)OC2

Procedure:
A solution of 2-(1,3-dihydro-6-methoxy-4-methoxyethoxymethoxy -7-methyl-3-oxoisobenzofuran-5-yl)acetaldehyde (10.3 g) and 2-(triphenyl-phosphoranylidene)-propionaldehyde (11.6 g) in toluene (250 ml) was refluxed for 7 hours. The solvent was removed under vacuum and the residue was chromatographed on silica gel, eluting with 9:1 hexane:ethyl acetate, to afford (E)-4-(1,3-dihydro-6-methoxy-4-methoxyethoxymethoxy-7-methyl -3-oxoisobenzofuran-5-yl)-2-methylbut-2-enaldehyde, mp 67°-68° C., (methylene chloride/hexane).
Reaction SMILES: CC1[N:7]=[CH:6][C:5]2C=NNC=2C=1.[C:11]([C:14]1[C:22]2[C:17](=[CH:18]N=C(C)[CH:21]=2)[N:16]([CH2:24][C:25]([OH:27])=[O:26])[N:15]=1)(=[O:13])[NH2:12]>>[C:11]([C:14]1[C:22]2[CH:21]=[N:7][C:6]([CH3:5])=[CH:18][C:17]=2[N:16]([CH2:24][C:25]([OH:27])=[O:26])[N:15]=1)(=[O:13])[NH2:12]
Reactant: Cc1cc2[nH]ncc2cn1
Reactant: Cc1cc2c(C(N)=O)nn(CC(=O)O)c2cn1
Product: Cc1cc2c(cn1)c(C(N)=O)nn2CC(=O)O

Procedure:
was prepared from 6-methyl-1H-pyrazolo[4,3-c]pyridine by using the same procedures as for the preparation of (3-carbamoyl-5-methyl-pyrazolo[3,4-c]pyridin-1-yl)-acetic acid (Scheme A27). MS (LC-MS): 235 [M+H]+, tR (HPLC conditions k): 0.29 min.
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.C1(C)C=CC=CC=1.[C:18]([O:22][C:23]([N:25]1[CH2:30][CH2:29][N:28]([C:31]2[CH:36]=[CH:35][C:34]([C:37](OC)=[O:38])=[CH:33][CH:32]=2)[CH2:27][CH2:26]1)=[O:24])([CH3:21])([CH3:20])[CH3:19]>C1COCC1>[C:18]([O:22][C:23]([N:25]1[CH2:26][CH2:27][N:28]([C:31]2[CH:32]=[CH:33][C:34]([CH2:37][OH:38])=[CH:35][CH:36]=2)[CH2:29][CH2:30]1)=[O:24])([CH3:21])([CH3:19])[CH3:20]
Reactant: COC(=O)c1ccc(N2CCN(C(=O)OC(C)(C)C)CC2)cc1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(CO)cc2)CC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 86.9 %

Procedure:
Diisobutylaluminium hydride in toluene (1.5M, 15 ml, 22.5 mmol) was added dropwise to a solution of 1-(tert-butoxycarbonyl) -4-(4-methoxycarbonylphenyl)piperazine (2.90 g, 9.05 mmol) in THF (116 ml) at 0° C. The mixture was stirred at 0° C. for 2 hours then allowed to warm to room temperature. The solution was recooled to -4° C. and the reaction quenched by the addition of methanol (6 ml), water (3 ml) and finally 2M sodium hydroxide (3 ml). The mixture was allowed to warm to room temperature, the precipitated aluminium salts collected under suction and washed with dichloromethane. The filtrate was concentrated in vacuo and the residue purified by flash chromatography, eluting with dichloromethane/ethyl acetate, to give the title compound (2.30 g, 74%); δH (CDCl3) 1.48 (9H, s, C(CH3)3), 1.60 (1H, v br, CH2OH), 3.13 (4H, m, 2×piperazinyl CH2), 3.58 (4H, m, 2×piperazinyl CH2), 4.61 (2H, s, CH2OH), 6.92 (2H, m, ArH), and 7.29 (2H, m, ArH).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].C[O:6][C:7]1[CH:24]=[CH:23][C:10]2[CH2:11][CH:12]([CH2:18][C:19]([O:21][CH3:22])=[O:20])[C:13](=[O:17])[N:14]([CH3:16])[CH2:15][C:9]=2[CH:8]=1.C(S)C>C(Cl)Cl>[OH:6][C:7]1[CH:24]=[CH:23][C:10]2[CH2:11][CH:12]([CH2:18][C:19]([O:21][CH3:22])=[O:20])[C:13](=[O:17])[N:14]([CH3:16])[CH2:15][C:9]=2[CH:8]=1
Reactant: COC(=O)CC1Cc2ccc(OC)cc2CN(C)C1=O
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCS
Solvent: ClCCl
Product: COC(=O)CC1Cc2ccc(O)cc2CN(C)C1=O
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 87.5 %

Procedure:
Anhydrous aluminum chloride (1.35 g, 10.15 mmole) was added all at once to a solution of methyl (±)-8-methoxy-2-methyl-3-oxo-2,3,4,5-tetrahydro-1H-2-benzazepine-4-acetate (562 mg, 2.03 mmole) and ethanethiol (0.75 mL, 10.15 mmole) in anhydrous CH2Cl2 (20 mL) at 0° C. under argon. The mixture was warmed to RT and stirred for 4.5 hr, then was recooled to 0° C. Ice cold H2O (20 mL) was added, and the mixture was stirred briskly for 5 min, then was extracted with CHCl3 (3×20 mL). The combined CHCl3 layers were dried (MgSO4) and concentrated to leave a residue. The aqueous layer was suction filtered to collect a solid precipitate. This precipitate and the residue from the CHCl3 layer were combined in 1:1 MeOH/CHCl3, and the solution was concentrated to leave an off-white solid. This was triturated with hot MeOH, and the mixture was allowed to cool to RT. The solid was collected by suction filtration and washed sequentially with cold MeOH and Et2O. Drying in high vacuum at 40° C. gave the title compound (467.9 mg, 88%) as a colorless solid: TLC (5% MeOH/CHCl3) Rf 0.17; 1H NMR (250, DMSO-d6) δ 9.29(s, 1 H), 6.89 (d, J=8.1 Hz, 1 H), 6.50-6.70 (m, 2 H), 5.16 (d, J=16.4 Hz, 1 H), 3.84 (d, J=16.4 Hz, 1 H), 3.60-3.85 (m, 1 H), 3.56 (s, 3 H), 2.30-3.00 (m, 4 H), 2.86 (s, 3 H); MS (ES) m/e 286 (M+Na)+, 264 (M+H)+.
Reaction SMILES: [C:1]([CH2:3][CH:4]1[CH2:8][CH2:7][C:6](=[O:9])[CH:5]1[CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])#[N:2].C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH3:26][C:27](CC)=[O:28]>>[C:1]([CH2:3][CH:4]1[CH2:8][CH2:7][C:6]2([O:28][CH2:27][CH2:26][O:9]2)[CH:5]1[CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])#[N:2]
Reactant: CCCCCC1C(=O)CCC1CC#N
Reactant: CCC(C)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: CCCCCC1C(CC#N)CCC12OCCO2
Reaction time: 5 h
Yield: 73.4 %

Procedure:
Into a 2 liter flask fitted with a 1 meter adiabatic column provided with a metallic lining, are placed: 400 g of 3-cyanomethyl-2-n-pentyl-1-cyclopentanone, 522 g of the glycoketal of methylethyl ketone and 4.5 g of paratoluenesulphonic acid. The mass is progressively heated in order to slowly distil the methyl ethyl ketone from the head of the column (temperature of the mass 128°-132°C; temperature of the vapour 80°C). The operation lasts about 5 hours. Then the excess glycoketal of methylethyl ketone is removed (temperature of the mass 132°-135°C; temperature of the vapour 110°-112°C). The mass is then cooled, 30 g of dry sodium carbonate added thereto, stirred for a half-hour and the mass washed to neutrality after diluting with 200 ml of ethyl ether. After distillation of the solvent and rectification of the crude product, there is obtained 360 g of 3-cyanomethyl-1,1-ethylenedioxy-2-n-pentyl-cyclopentane, which represents a yield of 73.4%. The product exhibits the following constants: b.p.0.5 = 136°-138°C, nD15 = 1.4724.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:13][C:14]2[CH:19]=[N:18][CH:17]=[C:16](Cl)[N:15]=2)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].[CH:21]1[CH:26]=[C:25]2[CH:27]=[CH:28][CH:29]=[C:30]([SH:31])[C:24]2=[CH:23][CH:22]=1>>[C:30]1([S:31][C:16]2[N:15]=[C:14]([NH:13][C:5]3[CH:4]=[C:3]([O:2][CH3:1])[C:8]([O:9][CH3:10])=[C:7]([O:11][CH3:12])[CH:6]=3)[CH:19]=[N:18][CH:17]=2)[C:24]2[C:25](=[CH:26][CH:21]=[CH:22][CH:23]=2)[CH:27]=[CH:28][CH:29]=1
Reactant: COc1cc(Nc2cncc(Cl)n2)cc(OC)c1OC
Reactant: Sc1cccc2ccccc12
Product: COc1cc(Nc2cncc(Sc3cccc4ccccc34)n2)cc(OC)c1OC
Yield: 32 %

Procedure:
Using Method X with 150 mg of 2-(3,4,5-trimethoxyphenylamino)-6-chloropyrazine and 1-thionaphthol, the title compound was obtained (68 mg). Yield: 32%. 1H NMR (250 MHz, DMSO-d6) δ 3.60 (s, 3H), 3.61 (s, 6H), 6.94 (s, 2H), 7.25 (s, 1H), 7.57-7.63 (m, 3H), 7.91 (s, 1H), 7.95 (dd, 1H, J1=1.2 Hz, J2=7.1 Hz), 8.03-8.07 (m, 1H), 8.11 (d, 1H, J=8.3 Hz), 8.26-8.30 (m, 1H), 9.54 (s, 1H). 13C NMR (62.9 MHz, DMSO-d6) δ 55.55, 60.09, 96.41, 124.82, 126.23, 126.58, 126.74, 127.65, 128.90, 129.90, 130.63, 131.09, 132.52, 133.33, 133.97, 134.60, 136.13, 151.27, 152.55, 152.74. m/z 420.1 [(M+H)+ calcd for C23H21N3O3S 419.1].
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4]([NH:12][C:13]2[CH:27]=[CH:26][C:16]([CH2:17][P:18](=[O:25])([O:22][CH2:23][CH3:24])[O:19][CH2:20][CH3:21])=[CH:15][C:14]=2[O:28][CH3:29])[N:3]=1.[NH2:30][C:31]1[C:32]([C:44]([NH:46][CH3:47])=[O:45])=[N:33][C:34]([C@H:37]2[CH2:42][CH2:41][C@H:40]([OH:43])[CH2:39][CH2:38]2)=[CH:35][CH:36]=1>O>[OH:43][C@H:40]1[CH2:41][CH2:42][C@H:37]([C:34]2[N:33]=[C:32]([C:44](=[O:45])[NH:46][CH3:47])[C:31]([NH:30][C:2]3[C:7]([C:8]([F:10])([F:9])[F:11])=[CH:6][N:5]=[C:4]([NH:12][C:13]4[CH:27]=[CH:26][C:16]([CH2:17][P:18](=[O:25])([O:19][CH2:20][CH3:21])[O:22][CH2:23][CH3:24])=[CH:15][C:14]=4[O:28][CH3:29])[N:3]=3)=[CH:36][CH:35]=2)[CH2:38][CH2:39]1
Reactant: CNC(=O)c1nc([C@H]2CC[C@H](O)CC2)ccc1N
Reactant: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Cl)n2)c(OC)c1)OCC
Solvent: O
Product: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc([C@H]4CC[C@H](O)CC4)nc3C(=O)NC)n2)c(OC)c1)OCC

Procedure:
The title compound was prepared according to the procedure for Example 231 using diethyl (4-{[4-chloro-5-(trifluoromethyl)pyrimidin-2-yl]amino}-3-methoxybenzyl)phosphonate (44.9 mg, 0.0989 mmol) and 3-amino-6-(trans-4-hydroxycyclohexyl)-N-methylpyridine-2-carboxamide (Example 232A, 37 mg, 0.15 mmol). The reaction mixture was poured into water and extracted twice with EtOAc. The combined organic layers were dried over Na2SO4, filtered, concentrated and purified on an ISCO CombiFlash system (eluting with 0-4% MeOH/DCM) to isolate, after concentrating the relevant fractions and drying in vacuo, the desired product as 44.5 mg of a white solid. 1H NMR (400 MHz, DMSO-d6) δ 1.20 (t, J=7.07 Hz, 6H), 1.23-1.33 (m, 2H), 1.59-1.72 (m, 2H), 1.77-1.86 (m, 2H), 1.94 (dd, J=13.01, 3.66 Hz, 2H), 2.56-2.67 (m, 1H), 2.83 (d, J=4.80 Hz, 3H), 3.28 (d, J=17.94 Hz, 2H), 3.45-3.55 (m, 1H), 3.74 (s, 3H), 3.94-4.04 (m, 4H), 4.57 (d, J=4.29 Hz, 1H), 6.89 (ddd, J=8.02, 2.27, 2.08 Hz, 1H), 7.05 (s, 1H), 7.35 (d, J=8.84 Hz, 1H), 7.41 (br. s., 1H), 8.38 (s, 1H), 8.88-8.95 (m, 1H), 9.01 (br. s., 1H), 12.33 (s, 1H). HRMS (ES+): m/z=667.2100 (100) [M+1]. HPLC: tR=1.50 min (ZQ2, polar—3 min).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:19]=[CH:18][C:6]2[CH:7]=[C:8]3[C:13](=[CH:14][C:5]=2[CH:4]=1)[NH:12][CH:11]=[C:10]([C:15]#[N:16])[C:9]3=O.P(Cl)(Cl)([Cl:22])=O>CN(C)C=O>[Cl:22][C:9]1[C:8]2[C:13](=[CH:14][C:5]3[CH:4]=[C:3]([O:2][CH3:1])[CH:19]=[CH:18][C:6]=3[CH:7]=2)[N:12]=[CH:11][C:10]=1[C:15]#[N:16]
Reactant: COc1ccc2cc3c(=O)c(C#N)c[nH]c3cc2c1
Reactant: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Product: COc1ccc2cc3c(Cl)c(C#N)cnc3cc2c1
Yield: 81.6 %

Procedure:
According to the procedure of example 101, 446.7 mg (1.8 mmol) of 8-methoxy-4-oxo-1,4-dihydrobenzo[g]quinoline-3-carbonitrile is refluxed in 102 mL of phosphorus oxychloride and 4 drops of N,N-dimethylformamide (DMF) for 1.5 hours to give 389.0 mg (81.6%) of 4-chloro-8-methoxy-benzo[g]quinoline-3-carbonitrile as a bright yellow solid, mp 258–260° C.
Reaction SMILES: C(O[CH:4]=[C:5]([C:11](=[O:22])[C:12]1[CH:17]=[C:16]([F:18])[C:15]([F:19])=[C:14]([Cl:20])[C:13]=1F)[C:6]([O:8][CH2:9][CH3:10])=[O:7])C.ClC1C(F)=C(C=C(F)C=1F)C(CC(OCC)=O)=O.[NH2:41][C:42]1[C:47]([F:48])=[CH:46][C:45]([F:49])=[C:44]([NH:50][CH3:51])[N:43]=1>C(Cl)(Cl)Cl>[Cl:20][C:14]1[C:15]([F:19])=[C:16]([F:18])[CH:17]=[C:12]2[C:13]=1[N:41]([C:42]1[C:47]([F:48])=[CH:46][C:45]([F:49])=[C:44]([NH:50][CH3:51])[N:43]=1)[CH:4]=[C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])[C:11]2=[O:22]
Reactant: CCOC=C(C(=O)OCC)C(=O)c1cc(F)c(F)c(Cl)c1F
Reactant: CNc1nc(N)c(F)cc1F
Agent: CCOC(=O)CC(=O)c1cc(F)c(F)c(Cl)c1F
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1cn(-c2nc(NC)c(F)cc2F)c2c(Cl)c(F)c(F)cc2c1=O
Temperature: 90 °C
Reaction time: 0.17 h

Procedure:
To 5 ml of chloroform solution of ethyl 3-ethoxy-2-(3-chloro-2,4,5-trifluorobenzoyl)acrylate prepared from 0.70 g of ethyl 3-chloro-2,4,5-trifluorobenzoylacetate by normal process was added 430 mg of 2-amino-3,5-difluoro-6-(methylamino)pyridine. The solution was concentrated under reduced pressure. To the residue were added 0.3 g of anhydrous potassium carbonate and 2 ml of N,N-dimethyl-formamide, and the mixture was stirred at 90° C. for 10 minutes and allowed to cool. The solution was separated by adding 30 ml of chloroform and 300 ml of distilled water, and the chloroform layer was washed twice with 300 ml distilled water, dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and allowed to stand. The precipitate was collected by filtration, washed with ethanol and diisopropylether successively to obtain 784 mg of the title compound as a colorless powder.
Reaction SMILES: [OH:1][C:2]1[C:10]([CH2:11][CH2:12][CH3:13])=[CH:9][C:5]2[O:6][CH2:7][O:8][C:4]=2[CH:3]=1.Br[CH2:15][C:16]#[C:17][CH3:18].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:15]([O:1][C:2]1[C:10]([CH2:11][CH2:12][CH3:13])=[CH:9][C:5]2[O:6][CH2:7][O:8][C:4]=2[CH:3]=1)[C:16]#[C:17][CH3:18]
Reactant: CCCc1cc2c(cc1O)OCO2
Reactant: CC#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC#CCOc1cc2c(cc1CCC)OCO2
Yield: 84 %

Procedure:
Following the same procedure as in Example 2, 3.65 g (0.02 moles) of 5-hydroxy-6-propyl-benzo[1.3]dioxole were reacted with 2.7 g (0.02 moles) of 1-bromo-2-butyne and 2.8 g (0.02 moles) of anhydrous potassium carbonate in 15 ml of acetone. After the work up of the reaction as in Example 2, a residue was obtained that after distillation at 115-117° C./0.2 mbar gave 3.9 g of a liquid product that, after some time, crystallized with m.p. 39° -40 ° C. and whose NMR and MS analyses correspond to those of the aforementioned compound.
Reaction SMILES: [C:1]1([C@@H:7]2[NH:12][CH2:11][CH2:10][N:9]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[CH3:22][O:23][CH2:24][CH2:25]Br.O>CN(C=O)C.C(OCC)(=O)C>[CH3:22][O:23][CH2:24][CH2:25][N:12]1[CH2:11][CH2:10][N:9]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:8][C@@H:7]1[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COCCBr
Reactant: CC(C)(C)OC(=O)N1CCN[C@@H](c2ccccc2)C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: COCCN1CCN(C(=O)OC(C)(C)C)C[C@@H]1c1ccccc1
Reaction time: 0.5 h

Procedure:
Under a nitrogen atmosphere, to a solution of 330 mg of tert-butyl (3S)-3-phenylpiperazine-1-carboxylate in 3.5 mL of DMF was added 75.4 mg of sodium hydride (including 40% mineral oil) under ice-cooling, followed by stirring for 30 minutes. To the mixture was added 0.27 mL of 2-bromoethyl methyl ether, followed by stirring at room temperature for 16 hours. To the mixture were added 75.4 mg of sodium hydride (including 40% mineral oil) and 0.6 mL of 2-bromoethyl methyl ether, followed by further stirring for 8 hours. The mixture was poured into a mixture of water and ethyl acetate, and the aqueous layer was separated. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (chloroform/methanol) to obtain 330 mg of tert-butyl (3S)-4-(2-methoxyethyl)-3-phenylpiperazine-1-carboxylate.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:8]#[N:9])=[N:4][CH:5]=[CH:6][N:7]=1.[OH:10][CH2:11][CH2:12][O:13][CH2:14][C:15](N)=[NH:16].CC(C)=O>C(O)C>[NH2:9][C:8]1[C:3]2[C:2](=[N:7][CH:6]=[CH:5][N:4]=2)[N:1]=[C:15]([CH2:14][O:13][CH2:12][CH2:11][OH:10])[N:16]=1
Reactant: N=C(N)COCCO
Reactant: N#Cc1nccnc1N
Solvent: CC(C)=O
Solvent: CCO
Product: Nc1nc(COCCO)nc2nccnc12

Procedure:
Obtained using the procedure described in section c of Example 2, starting with 16.0 g (0.133 mole) of 3-amino-2-pyrazinecarbonitrile and the above solution of 2-(2-hydroxyethoxy)acetamidine in absolute ethanol. Refluxing time: 2 hours 30 minutes. Yld: 20.5 g (70%), m.p. 149°-151° C. (ethanol). An analytical sample was obtained by recrystallization from a mixture of acetone and ethanol. M.p. 159°-161° C.
Reaction SMILES: C([O:3][P:4]([O:8]CC)[O:5]CC)C.[CH2:11]=O.[CH2:13]([CH2:15][NH2:16])[OH:14].[OH-].[Na+:18]>>[OH:14][CH2:13][CH2:15][NH:16][CH2:11][P:4](=[O:3])([O-:5])[O-:8].[Na+:18].[Na+:18]
Reactant: NCCO
Reactant: CCOP(OCC)OCC
Reactant: C=O
Agent: [Na+]
Agent: [OH-]
Product: O=P([O-])([O-])CNCCO
Temperature: 100 °C
Yield: 56 %

Procedure:
Triethylphosphite (16.6 g, 0.1 mmol), paraformaldehyde (3.0 g, 0.1 mmol) and ethanolamine (48.8 g, 0.8 mmol) was charged into a round bottom flask equipped with magnetic stir bar and reflux condenser. The reaction was heated to 100° C. for 16 h. Base hydrolysis of the intermediate esters was achieved by adding 2 equiv of NaOH (16 g of a 50% solution) and heating to 120° C. for 16 hours. The reaction was allowed to cool and was concentrated under vacuum. Methanol (100 mL) was added on the solvent was again removed under vacuum. This was repeated several times until a white solid formed the flask. The solid, which is a mixture of inorganic salts and sodium N-(2-hydroxyethyl) aminomethylphosphonate, was filtered and dried under vacuum to give 56% yield of sodium N-hydroxyethylaminomethylphosphonate. 31P-NMR obtained in D2O containing conc. HCl (pH=of sample is 0.7)δ=10.8 ppm. FAB-MS obtained in a glutathione/HCl matrix M+H=156.