Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.[CH3:25][S:26]([C:29]1[CH:30]=[C:31]([CH:35]=[CH:36][CH:37]=1)[C:32]([OH:34])=O)(=[O:28])=[O:27].Cl.[NH:39]1[CH2:44][CH2:43][C:42](=[O:45])[CH2:41][CH2:40]1.CCN(C(C)C)C(C)C>ClCCl>[CH3:25][S:26]([C:29]1[CH:30]=[C:31]([CH:35]=[CH:36][CH:37]=1)[C:32]([N:39]1[CH2:44][CH2:43][C:42](=[O:45])[CH2:41][CH2:40]1)=[O:34])(=[O:27])=[O:28]
Reactant: O=C1CCNCC1
Reactant: CS(=O)(=O)c1cccc(C(=O)O)c1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CS(=O)(=O)c1cccc(C(=O)N2CCC(=O)CC2)c1
Temperature: 25 °C
Yield: 93 %

Procedure:
PyBrOP™ (17.3 g) was added to a stirred mixture of 3-methanesulphonyl benzoic acid (7.35 g), 4-piperidone hydrochloride (5 g) and Hunig's base (25 ml) in dichloromethane (250 ml) with stirring at RT. The mixture was stirred overnight then washed with saturated NaHCO3 solution (200 ml) and then with saturated brine (200 ml). The organic layer was evaporated and the resulting residue purified by column chromatography (silica, 1:1 ethyl acetate: dichloromethane) to give the product as a thick oil (9.6 g; MS: APCI+(M+H) 282).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([F:9])[CH:8]=1)[NH2:5].Cl[CH:11]([CH3:15])[C:12]([OH:14])=[O:13]>>[F:1][C:2]1[CH:3]=[C:4]([NH:5][CH:11]([C:12]([OH:14])=[O:13])[CH3:15])[CH:6]=[C:7]([F:9])[CH:8]=1
Reactant: CC(Cl)C(=O)O
Reactant: Nc1cc(F)cc(F)c1
Product: CC(Nc1cc(F)cc(F)c1)C(=O)O

Procedure:
Using the procedure set forth in U.S. Pat. No. 3,598,859 (or Example A above), N-(3,5-difluorophenyl)-D,L-alanine was prepared using 3,5-difluoroaniline (Aldrich) and 2-chloropropionic acid (Aldrich).
Reaction SMILES: [CH3:1][C:2]1[C:3](=[O:18])[C:4]2[CH2:13][S:12][C:11]3[CH:14]=[CH:15][CH:16]=[CH:17][C:10]=3[C:5]=2[O:6][C:7]=1C#N.Cl.[OH-:20].[Na+]>CO>[CH3:1][CH:2]1[C:7](=[O:20])[O:6][C:5]2[C:10]3[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=3[S:12][CH2:13][C:4]=2[C:3]1=[O:18]
Reactant: Cc1c(C#N)oc2c(c1=O)CSc1ccccc1-2
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CC1C(=O)OC2=C(CSc3ccccc32)C1=O

Procedure:
A solution of 3-methyl-4-oxo-4H,5H-[1]benzothiopyrano[4,3-b]pyran-2-carbonitrile (0.255 g, 1 mmole, described in Example 6) in 2.5 N aqueous sodium hydroxide (10 ml) and methanol (5 ml) is refluxed overnight. The solution is acidified with hydrochloric acid. The precipitate is collected and dissolved in 1 N aqueous sodium hydroxide. The solution is washed with chloroform and acidified with hydrochloric acid. The precipitate is collected and crystallized from methanol to give the title compound (0.070 g), mp 275°-277° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:7]([OH:12])=[CH:8][C:9]=1[O:10][CH3:11])[CH:5]=[O:6].[CH3:13][C:14]1[C:15](B(O)O)=[CH:16][C:17]2[C:18]([CH3:27])([CH3:26])[CH2:19][CH2:20][C:21]([CH3:25])([CH3:24])[C:22]=2[CH:23]=1.C(=O)([O-])[O-].[K+].[K+].O>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:13][C:14]1[C:15]([C:2]2[CH:3]=[C:4]([C:7]([OH:12])=[CH:8][C:9]=2[O:10][CH3:11])[CH:5]=[O:6])=[CH:16][C:17]2[C:18]([CH3:27])([CH3:26])[CH2:19][CH2:20][C:21]([CH3:25])([CH3:24])[C:22]=2[CH:23]=1
Reactant: COc1cc(O)c(C=O)cc1Br
Reactant: Cc1cc2c(cc1B(O)O)C(C)(C)CCC2(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Product: COc1cc(O)c(C=O)cc1-c1cc2c(cc1C)C(C)(C)CCC2(C)C
Temperature: 25 °C
Yield: 72.1 %

Procedure:
A mixture of 3-bromo-6-hydroxy-4-methoxy-benzaldehyde (2 g, 8.66 mmol), (3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydronaphthalen-2-yl) boronic acid (3.18 g, 12.99 mmol), potassium carbonate (4.79 g, 34.63 mmol) and water (4 mL) in anhydrous 1,2-dimethoxyethane (140 mL) was degassed with argon for 15 minutes prior to the addition of tetrakis(triphenylphosphine)palladium(0) (2.0 g, 1.73 mmol). The reaction mixture was heated under reflux for 15 hours, allowed to cool to room temperature and extracted with ethyl acetate (2×100 mL). The organic extracts were successively washed with water (100 mL), a saturated aqueous solution of NH4Cl (100 mL), a saturated aqueous solution of NaCl (100 mL), dried over MgSO4 and filtered. Removal of the solvent under reduced pressure gave an oil which was purified by column chromatography, using a Biotage 40M cartridge, eluting with 5% ethyl acetate/95% hexane, to give 3-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-4-methoxy-6-hydroxybenzaldehyde as a white solid (2.2 g, 73%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:33])[C@@H:4]([NH:17][C:18]([C@@H:20]1[CH2:32][C:31]2[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[NH:24][C:23]=2[CH2:22][NH:21]1)=[O:19])[CH2:5][CH2:6][CH2:7][CH2:8][NH:9]C(OC(C)(C)C)=O.[C:34]1([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[CH:39]=[CH:38][C:37]([S:40](Cl)(=[O:42])=[O:41])=[CH:36][CH:35]=1.C(O)(C(F)(F)F)=O>>[CH3:1][O:2][C:3](=[O:33])[CH:4]([NH:17][C:18]([CH:20]1[CH2:32][C:31]2[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[NH:24][C:23]=2[CH2:22][N:21]1[S:40]([C:37]1[CH:36]=[CH:35][C:34]([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)=[CH:39][CH:38]=1)(=[O:42])=[O:41])=[O:19])[CH2:5][CH2:6][CH2:7][CH2:8][NH2:9]
Reactant: COC(=O)[C@H](CCCCNC(=O)OC(C)(C)C)NC(=O)[C@@H]1Cc2c([nH]c3ccccc23)CN1
Reactant: O=S(=O)(Cl)c1ccc(-c2ccccc2)cc1
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)C(CCCCN)NC(=O)C1Cc2c([nH]c3ccccc23)CN1S(=O)(=O)c1ccc(-c2ccccc2)cc1

Procedure:
6-Amino-2-{[2-(biphenyl-4-sulfonyl)-2,3,4,9-tetrahydro-1H-β-carboline-3-carbonyl]-amino}-hexanoic acid methyl ester was prepared according to the above procedure from 6-tert-Butoxycarbonylamino2-(S)-[(2,3,4,9-tetrahydro-1H-β-carboline-3-(S)-carbonyl)-amino]-hexanoic acid methyl ester (37 mg, 0.08 mmol) and biphenyl-4-sulphonyl chloride (24 mg, 0.1 mmol) to deliver 6 mg of the TFA salt. MS (APCI) M+575.5
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH3:2].[O:14]=[C:15]([CH2:21][CH3:22])[C:16]([O:18][CH2:19][CH3:20])=[O:17]>O1CCCC1>[CH2:19]([O:18][C:16](=[O:17])[C:15]([CH2:21][CH3:22])([OH:14])[CH:5]([CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:4]([O:3][CH2:1][CH3:2])=[O:13])[CH3:20]
Reactant: CCOC(=O)C(=O)CC
Reactant: CCOC(=O)CCc1ccccc1
Solvent: C1CCOC1
Product: CCOC(=O)C(Cc1ccccc1)C(O)(CC)C(=O)OCC
Temperature: -78 °C
Reaction time: 1 h
Yield: 72.6 %

Procedure:
To anhydrous tetrahydrofuran (5 mL) was added diisopropylamine (759 mg, 7.5 mmol) under nitrogen stream, and the solution was cooled to −78° C. To this solution was added a 1.58 M n-butyl lithium-hexane solution (4.3 mL, 6.8 mmol), and the mixture was stirred at −78° C. for 5 min and at 0° C. for 15 min. A solution of lithium diisopropylamide tetrahydrofuran thus obtained above was cooled to −78° C. To the solution, a solution of 3-phenylpropionic acid ethyl ester (891 mg, 5.0 mmol) in anhydrous tetrahydrofuran (10 mL) was added dropwise over 1 h, and the reaction mixture was further stirred at −78° C. for 1 h. The cold solution of the enolate thus prepared above was added dropwise via a cannula to a solution of ethyl 2-ketobutyrate (781 mg, 6.0 mmol) in anhydrous tetrahydrofuran (5 mL) having been cooled to −78° C. After stirring at −78° C. for 2 h, the reaction mixture was quenched with a 10% aqueous citric acid solution, and extracted with ethyl acetate. The organic layer was washed with 1 M hydrochloric acid, a saturated aqueous sodium hydrogen carbonate solution and brine, dried over anhydrous magnesium sulfate, and filtered. The residue obtained by concentrating the filtrate under reduced pressure was subjected to silica gel column chromatography (hexane-ethyl acetate 9:1) to give 1.12 g of 3-benzyl-2-ethyl-2-hydroxysuccinic acid diethyl ester as oil in the form of a diastereomer mixture (yield: 73%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:22])[CH2:13][CH2:12][N:11]([C:14]3[N:19]=[C:18](Cl)[N:17]=[C:16]([Cl:21])[N:15]=3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[OH-:23].[Na+]>>[Cl:21][C:16]1[NH:17][C:18](=[O:23])[N:19]=[C:14]([N:11]2[CH2:12][CH2:13][C:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)([OH:22])[CH2:9][CH2:10]2)[N:15]=1
Reactant: [OH-]
Reactant: OC1(c2ccc(Cl)cc2)CCN(c2nc(Cl)nc(Cl)n2)CC1
Agent: [Na+]
Product: O=c1nc(N2CCC(O)(c3ccc(Cl)cc3)CC2)nc(Cl)[nH]1
Yield: 93.5 %

Procedure:
The crude product of 4-(4-chlorophenyl)-1-(4,6-dichloro-1,3,5-triazin-2-yl)piperidin-4-ol (10.0 mmol) synthesized in Reference Synthesis Example 20 and 1 M sodium hydroxide aqueous solution (120.0 mL, 120 mmol) were used to obtain the title compound (3.19 g, yield 93%) by synthesis in a similar manner to Reference Synthesis Example 2.
Reaction SMILES: [O:1]=[S:2]1(=[O:25])[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[N:20]4[N:21]=[C:22]([NH2:24])[N:23]=[C:19]4[CH:18]=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:4][CH2:3]1.Br[C:27]1[CH:32]=[CH:31][C:30]([N:33]2[CH2:38][CH2:37][N:36]([CH3:39])[CH2:35][CH2:34]2)=[CH:29][CH:28]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)CCCCC1>>[O:25]=[S:2]1(=[O:1])[CH2:3][CH2:4][N:5]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[N:20]4[N:21]=[C:22]([NH:24][C:27]5[CH:28]=[CH:29][C:30]([N:33]6[CH2:38][CH2:37][N:36]([CH3:39])[CH2:35][CH2:34]6)=[CH:31][CH:32]=5)[N:23]=[C:19]4[CH:18]=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:6][CH2:7]1
Reactant: Nc1nc2cccc(-c3ccc(CN4CCS(=O)(=O)CC4)cc3)n2n1
Reactant: CN1CCN(c2ccc(Br)cc2)CC1
Agent: c1ccc(P(C2CCCCC2)C2CCCCC2)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c1
Product: CN1CCN(c2ccc(Nc3nc4cccc(-c5ccc(CN6CCS(=O)(=O)CC6)cc5)n4n3)cc2)CC1

Procedure:
5-{4-[(1,1-dioxidothiomorpholin-4-yl)methyl]phenyl}-N-[4-(4-methylpiperazin-1-yl)phenyl][1,2,4]triazolo[1,5-a]pyridin-2-amine was prepared from 5-{4-[(1,1-dioxidothiomorpholin-4-yl)methyl]phenyl}[1,2,4]triazolo[1,5-a]pyridin-2-amine (75.0 mg, 0.210 mmol) and 1-(4-bromo-phenyl)-4-methyl-piperazine (65.0 mg, 0.255 mmol) with 2,2′-bis-dicyclohexylphosphanyl-biphenyl (22.0 mg, 0.0402 mmol) as the ligand in a manner analogous to Step 2d. The title compound was isolated as a yellow foam (0.045 g, 40%). 1H NMR (400 MHz, CDCl3, δ, ppm): 8.00 (d, J=7.0 Hz, 2H), 7.52-7.43 (m, 6H), 6.98-6.91 (m, 3H), 6.67 (s, 1H), 3.76 (s, 2H), 3.18-3.03 (m, 12H), 2.62-2.56 (m, 4H), 2.36 (s, 3H). MS=532 (MH)+.
Reaction SMILES: [C:1]([OH:5])(=O)[C:2]#[CH:3].N1(C(N2C=CN=C2)=O)C=CN=C1.[NH:18]1[C:22]2[CH2:23][CH2:24][CH2:25][CH2:26][C:21]=2[N:20]=[C:19]1[CH2:27][C:28]([C:30]1[S:31][CH:32]=[CH:33][CH:34]=1)=[O:29]>C1COCC1>[S:31]1[CH:32]=[CH:33][CH:34]=[C:30]1[C:28]([C:27]1[CH:3]=[CH:2][C:1](=[O:5])[N:20]2[C:21]3[CH2:26][CH2:25][CH2:24][CH2:23][C:22]=3[NH:18][C:19]=12)=[O:29]
Reactant: O=C(Cc1nc2c([nH]1)CCCC2)c1cccs1
Reactant: C#CC(=O)O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: O=C(c1cccs1)c1ccc(=O)n2c3c([nH]c12)CCCC3
Temperature: 25 °C
Reaction time: 3 h
Yield: 43.7 %

Procedure:
126.2 mg (1.73 mmol) of propiolic acid and 336.6 mg (2.08 mmol) of 1-(1H-imidazol-1-ylcarbonyl)-1H-imidazole are dissolved in 10 ml THF. The mixture is stirred for 3 h at room temperature. To this solution 300 mg (1.15 mmol) of 2-(4,5,6,7-Tetrahydro-1H-benzimidazol-2-yl)-1-(2-thienyl)ethanone (example XII are added and the mixture is refluxed for 24 h. The solvent is evaporated under vacuum and sodium hydrogen carbonate—solution (saturated in water) is added to the crude. The solution is extracted ethyl acetate. The collected organic phases are reextracted with brine—solution an dried over sodium sulfate. The solvent is evaporated under vacuum and the crude is purified over preparative HPLC (RP18-Column, Eluent: acetonitrile-Water Gradient) to yield 150 mg (43.6% of th.) 4-(2-Thienylcarbonyl)-6,7,8,9-tetrahydropyrido[1,2-a]benzimidazol-1(5H)-one.
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[C:30]([O:31][CH3:32])=[CH:29][C:25]([C:26]([OH:28])=O)=[C:24]([F:33])[CH:23]=4)=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[CH3:35][N:36]1[CH2:41][CH2:40][N:39]([CH2:42][C:43]2[CH:49]=[CH:48][C:46]([NH2:47])=[CH:45][CH:44]=2)[CH2:38][CH2:37]1>>[CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[C:30]([O:31][CH3:32])=[CH:29][C:25]([C:26]([NH:47][C:46]5[CH:45]=[CH:44][C:43]([CH2:42][N:39]6[CH2:38][CH2:37][N:36]([CH3:35])[CH2:41][CH2:40]6)=[CH:49][CH:48]=5)=[O:28])=[C:24]([F:33])[CH:23]=4)=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1cc(C(=O)O)c(F)cc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Reactant: CN1CCN(Cc2ccc(N)cc2)CC1
Agent: Cl
Product: COc1cc(C(=O)Nc2ccc(CN3CCN(C)CC3)cc2)c(F)cc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C

Procedure:
The title compound was prepared in a manner analogous to compound 149 from 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b][1,4]diazepin-2-ylamino)-2-fluoro-5-methoxybenzoic acid and 4-((4-methylpiperazin-1-yl)methyl)aniline hydrochloride with yield 48 mg (37%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.62 (br. s., 4 H) 1.73 (br. s., 2 H) 1.98 (m, 2 H) 2.14 (s, 3 H) 2.17-2.45 (m, 8 H) 3.40 (s, 2 H) 3.94 (s, 3 H) 4.09 (t, J=12 Hz, 2 H) 4.84 (t, J=8.08 Hz, 1 H) 7.16-7.37 (m, 3 H) 7.66 (d, J=8.34 Hz, 2 H) 8.10 (s, 1 H) 8.19-8.39 (m, 2 H) 10.13 (s, 1 H). [M+H] calc'd for C33H39F3N8O3, 653; found 653.
Reaction SMILES: [CH3:1][N:2]([CH3:6])[C:3](Cl)=[O:4].[NH2:7][C:8]1[CH:9]=[C:10]([CH:19]=[CH:20][CH:21]=1)[C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:12].Cl>CN(C)C=O.C(N(CC)CC)C>[C:11]([C:10]1[CH:9]=[C:8]([NH:7][C:3](=[O:4])[N:2]([CH3:6])[CH3:1])[CH:21]=[CH:20][CH:19]=1)(=[O:12])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: Nc1cccc(C(=O)c2ccccc2)c1
Reactant: CN(C)C(=O)Cl
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CN(C)C(=O)Nc1cccc(C(=O)c2ccccc2)c1
Temperature: 60 °C

Procedure:
Dimethylcarbamoyl chloride (7.5 grams, 0.07 mole) was added to a solution of 3-aminobenzophenone (10 grams, 0.05 mole) in dimethylformamide (150 ml.), triethylamine (10 ml.) at 10° C. with stirring and ice cooling. The reaction temperature was next raised to 60° C. for 20 hours, then cooled and poured onto ice water (500 grams) containing dilute hydrochloric acid. A tarry solid was obtained by decanting off the aqueous organic solution. Purification was effected by dissolving the tarry solid in methylene chloride and passing through a silica gel dry column eluant methylene chloride. On elution with dichloromethane, the product, 3-(m-benzoylphenyl)-1,1-dimethyl urea, is obtained. Melting point was 104° -105° C. Crystallization from benzene-hexane (9:1) mixture gave solid 109° - 110° C., which on benzene-hexane crystallizations afforded a melting point of from 121° to 122° C. identified as the desired urea by comparison with the sample prepared from phosgene and dimethylamine.
Reaction SMILES: N[C:2]1[CH:11]=[C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:9]=[C:8]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:3]=1[C:4](OC)=[O:5].C(O)(=O)C.[CH:32]([NH2:34])=[NH:33]>COCCO>[CH2:21]([O:20][C:8]1[CH:9]=[C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:11]=[C:2]2[C:3]=1[C:4](=[O:5])[NH:33][CH:32]=[N:34]2)[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: N=CN
Reactant: COC(=O)c1c(N)cc(OCc2ccccc2)cc1OCc1ccccc1
Solvent: CC(=O)O
Solvent: COCCO
Product: O=c1[nH]cnc2cc(OCc3ccccc3)cc(OCc3ccccc3)c12
Yield: 89.5 %

Procedure:
A mixture of methyl 2-amino-4,6-dibenzyloxybenzoate (7.7 g), formamidine acetate (7.2 g) and 2-methoxyethanol (100 ml) was stirred and heated to reflux until all of the starting material had reacted. The mixture was evaporated and the residue was triturated under water (60 ml). The resultant solid was isolated, washed with water and dried under vacuum to give 5,7-dibenzyloxy-3,4-dihydroquinazolin-4-one (6.8 g); NMR Spectrum: (DMSOd6) 5.24 (s, 4H), 6.75 (s, 1H), 6.8 (s, 1H), 7.3–7.7 (m, 10H), 7.95 (s, 1H), 11.75 (br s, 1H).
Reaction SMILES: [CH:1]1[C:10]2[C:11]3[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][C:12]=3[N:8]3[C:9]=2[C:4]([CH2:5][CH2:6][CH2:7]3)=[CH:3][C:2]=1[NH2:18].[C:19](Cl)(=[O:22])[CH2:20][CH3:21]>ClC(Cl)C>[CH:1]1[C:10]2[C:11]3[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][C:12]=3[N:8]3[C:9]=2[C:4]([CH2:5][CH2:6][CH2:7]3)=[CH:3][C:2]=1[NH:18][C:19](=[O:22])[CH2:20][CH3:21]
Reactant: CCC(=O)Cl
Reactant: Nc1cc2c3c(c1)c1c(n3CCC2)CCCCC1
Solvent: CC(Cl)Cl
Product: CCC(=O)Nc1cc2c3c(c1)c1c(n3CCC2)CCCCC1
Yield: 39.4 %

Procedure:
Following the procedure of Example 1, Step 4, 5,6,9,10,11,12-hexahydro-4H,8H-cyclohepta[4,5]pyrrolo[3,2,1-ij]quinolin-2-amine (0.10 g, 0.42 mmol), propionyl chloride (0.036 mL, 0.42 mmol) and poly-(4-vinylpyridine) (600 mg) in dichloroethane (15 mL) provided 49 mg of N-5,6,9,10,11,12-hexahydro-4H,8H-cyclohepta[4,5]pyrrolo[3,2,1-ij]quinolin-2-ylpropanamide (49 mg). MS (ES) m/z 297.2; HPLC purity 100% at 210-370 nm, 10.0 min.; 99.3% at 250 nm, 10.0 min. (Xterra RP18, 3.5 u, 150×4.6 mm column, 1.2 mL/min, 85/15-5/95 ((Ammon. Form. Buff. pH=3.5/ACN and MeOH) for 10 min, hold 4 min); HRMS: calcd for C19H24N2O+H+, 297.19614; found (ESI, [M+H]+), 297.1973.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[CH:9]([CH3:23])[C:10]([C:16]1[CH:21]=[CH:20][N:19]=[C:18]([Cl:22])[CH:17]=1)([OH:15])[C:11]([F:14])([F:13])[F:12].[CH3:24][O:25][C:26]([C:28]1[CH:29]=[N:30][C:31](Cl)=[N:32][CH:33]=1)=[O:27]>>[CH3:24][O:25][C:26]([C:28]1[CH:29]=[N:30][C:31]([O:8][C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([CH:9]([CH3:23])[C:10]([C:16]3[CH:21]=[CH:20][N:19]=[C:18]([Cl:22])[CH:17]=3)([OH:15])[C:11]([F:14])([F:13])[F:12])[CH:4]=2)=[N:32][CH:33]=1)=[O:27]
Reactant: CC(c1cc(O)ccc1Cl)C(O)(c1ccnc(Cl)c1)C(F)(F)F
Reactant: COC(=O)c1cnc(Cl)nc1
Product: COC(=O)c1cnc(Oc2ccc(Cl)c(C(C)C(O)(c3ccnc(Cl)c3)C(F)(F)F)c2)nc1

Procedure:
The title compound was prepared in analogy to Example 132 from 4-chloro-3-[2-(2-chloro-pyridin-4-yl)-3,3,3-trifluoro-2-hydroxy-1-methyl-propyl]-phenol (obtained in Example 130, step 7) with methyl-2-chloropyrimidine-5-carboxylate [CAS Reg. No. 287714-35-6]. MS (neg. ion, m/e)=500.0 [(M−H)−].
Reaction SMILES: [OH:1][C@H:2]1[C:18]([CH3:20])([CH3:19])[O:17][C:5]2=[CH:6][C:7]3[C:8]([CH3:16])=[CH:9][C:10]([C:14]#[N:15])=[N:11][C:12]=3[CH:13]=[C:4]2[C@@H:3]1[NH:21][CH2:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C(O)(=O)C.[Pd]>[NH2:15][CH2:14][C:10]1[CH:9]=[C:8]([CH3:16])[C:7]2[CH:6]=[C:5]3[O:17][C:18]([CH3:20])([CH3:19])[C@H:2]([OH:1])[C@@H:3]([NH:21][CH2:22][CH2:23][C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[C:4]3=[CH:13][C:12]=2[N:11]=1
Reactant: Cc1cc(C#N)nc2cc3c(cc12)OC(C)(C)[C@H](O)[C@H]3NCCc1ccccc1
Agent: [Pd]
Solvent: CC(=O)O
Product: Cc1cc(CN)nc2cc3c(cc12)OC(C)(C)[C@H](O)[C@H]3NCCc1ccccc1
Reaction time: 2 h

Procedure:
To a solution of (3R*,4S*)-3-hydroxy-2,2,9-trimethyl-4-[(2-phenylethyl)amino]-3,4-dihydro-2H-pyrano[2,3-g]quinoline-7-carbonitrile described in Synthesis Example 14(110 mg, 0.283 mmol) in acetic acid (5 mL), 10% Pd/C (22 mg) was added at room temperature, and the resulting mixture was stirred for 2 hours under hydrogen atmosphere. Upon the completion of the reaction, the resulting solution was filtered through celite, the solvent was distilled off and then aqueous sodium carbonate solution was added to the residue, and the resulting solution was extracted with chloroform, dried over anhydrous magnesium sulfate, and the solvent was distilled off to obtain crude product of (3R*,4S*)-7-aminomethyl-2,2,9-trimethyl-4-[(2-phenylethyl)amino]-3,4-dihydro-2H-pyrano[2,3-g]quinolin-3-ol (75.1 mg).
Reaction SMILES: S(Cl)([Cl:4])(=O)=O.[F:6][C:7]1[CH:20]=[CH:19][CH:18]=[CH:17][C:8]=1[C:9]([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])=[O:10]>C(Cl)Cl>[Cl:4][CH:11]([C:9](=[O:10])[C:8]1[CH:17]=[CH:18][CH:19]=[CH:20][C:7]=1[F:6])[C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: CCOC(=O)CC(=O)c1ccccc1F
Reactant: O=S(=O)(Cl)Cl
Solvent: ClCCl
Product: CCOC(=O)C(Cl)C(=O)c1ccccc1F
Reaction time: 0.5 h
Yield: 93.3 %

Procedure:
Sulfuryl chloride (4.25 g, 32 mmol) was added dropwise to a solution ethyl 2-(2-flurobenzoyl)acetate (6.30 g, 30 mmol) in CH2Cl2 (75 mL) at room temperature. No exotherm was observed after 30 minutes, only slight bubbling. After stirring overnight TLC analysis indicated that all of the starting material had been consumed. The reaction mixture was treated with H2O (100 mL). The resultant mixture was stirred for 20 minutes and the phases were separated. The organic phase was washed with H2O (2×100 mL), dried over anhydrous MgSO4, filtered and concentrated in vacuo to give 6.85 g (93% yield) of the desired product as an orange oil: 1H NMR (CDCl3) δ8.0-7.9 (m, 1H), 7.6-7.5 (m, 1H), 7.3-7.1 (m, 2H), 5.6 (s, 1H), 4.25 (q, 2H), 1.25 (t, 3H).
Reaction SMILES: [OH-].[Li+].[F:3][C:4]([F:26])([F:25])[C:5]1[CH:6]=[C:7]([S:11]([N:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH:15]2[CH2:20][C:21]([O:23]C)=[O:22])(=[O:13])=[O:12])[CH:8]=[CH:9][CH:10]=1>O.O1CCCC1>[F:26][C:4]([F:3])([F:25])[C:5]1[CH:6]=[C:7]([S:11]([N:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH:15]2[CH2:20][C:21]([OH:23])=[O:22])(=[O:13])=[O:12])[CH:8]=[CH:9][CH:10]=1
Reactant: COC(=O)CC1CCCCN1S(=O)(=O)c1cccc(C(F)(F)F)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)CC1CCCCN1S(=O)(=O)c1cccc(C(F)(F)F)c1
Temperature: 0 °C
Yield: 90 %

Procedure:
A solution of lithium hydroxide (1 g, 22 mmol) in water (44 ml) was added dropwise to a solution of methyl 2-(1-(3-(trifluoromethyl)phenylsulfonyl)piperidin-2-yl)acetate (4.38 g, 12 mmol) in tetrahydrofuran (176 ml) while stirring at 0° C. The mixture was stirred for 16 h at 25° C. The solvent was removed under vacuum, the residue dissolved in water and washed with diethyl ether. The aqueous phase was carefully acidified with citric acid solution (10%) and extracted with ethyl acetate. This organic phase was washed with water and saturated sodium chloride solution, dried over sodium sulfate, filtered and concentrated to small volume under vacuum. The crude product was used in the next stage with no further purification. Yield: 90%
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([OH:13])=O)=[CH:8][CH:9]=2)[CH2:4][NH:3]1.Cl.[F:15][C:16]([F:36])([F:35])[C:17]1[CH:22]=[CH:21][C:20]([C@@H:23]([C:25]2[C:30]([C:31]([F:34])([F:33])[F:32])=[CH:29][CH:28]=[CH:27][N:26]=2)[NH2:24])=[CH:19][CH:18]=1>>[O:1]=[C:2]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([NH:24][C@@H:23]([C:20]3[CH:21]=[CH:22][C:17]([C:16]([F:36])([F:15])[F:35])=[CH:18][CH:19]=3)[C:25]3[C:30]([C:31]([F:32])([F:33])[F:34])=[CH:29][CH:28]=[CH:27][N:26]=3)=[O:13])=[CH:8][CH:9]=2)[CH2:4][NH:3]1
Reactant: O=C(O)c1ccc2c(c1)CNC2=O
Reactant: N[C@@H](c1ccc(C(F)(F)F)cc1)c1ncccc1C(F)(F)F
Agent: Cl
Product: O=C(N[C@@H](c1ccc(C(F)(F)F)cc1)c1ncccc1C(F)(F)F)c1ccc2c(c1)CNC2=O

Procedure:
1-Oxoisoindoline-5-carboxylic acid was then coupled with Intermediate 1 using the general methods described above for the amide coupling reaction (Table 2) to provide the title compound, (S)-1-oxo-N-((4-(trifluoromethyl)phenyl)(3-(trifluoromethyl)pyridin-2-yl)methyl)isoindoline-5-carboxamide, as a white solid. 1H NMR (400 MHz, CDCl3) δ ppm 8.92 (d, J=4.7 Hz, 1H), 8.36 (d, J=7.4 Hz, 1H), 8.09-7.99 (m, 2H), 7.97-7.88 (m, 2H), 7.65-7.53 (m, 5H), 7.51 (dd, J=4.9, 7.8 Hz, 1H), 6.90 (d, J=7.6 Hz, 1H), 4.54 (s, 2H). MS (ESI pos. ion) m/z: 480.2 (M+H).