Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:16]2[N:20]([CH2:21][CH2:22][CH2:23][N:24]([CH3:37])[CH2:25][CH2:26][O:27][C:28]3[CH:33]=[CH:32][C:31]4[O:34][CH2:35][O:36][C:30]=4[CH:29]=3)[C:19](=[O:38])[CH:18]([CH2:39][C:40](OCC)=[O:41])[S:17]2)[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:4])([CH3:3])[CH3:2].[H-].[Al+3].[Li+].[H-].[H-].[H-].O.Cl>O1CCCC1>[C:12]([C:9]1[CH:8]=[C:7]([CH:16]2[N:20]([CH2:21][CH2:22][CH2:23][N:24]([CH3:37])[CH2:25][CH2:26][O:27][C:28]3[CH:33]=[CH:32][C:31]4[O:34][CH2:35][O:36][C:30]=4[CH:29]=3)[C:19](=[O:38])[CH:18]([CH2:39][CH2:40][OH:41])[S:17]2)[CH:6]=[C:5]([C:1]([CH3:3])([CH3:2])[CH3:4])[C:10]=1[OH:11])([CH3:13])([CH3:14])[CH3:15]
Reactant: CCOC(=O)CC1SC(c2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)N(CCCN(C)CCOc2ccc3c(c2)OCO3)C1=O
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: O
Solvent: C1CCOC1
Product: CN(CCCN1C(=O)C(CCO)SC1c1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1)CCOc1ccc2c(c1)OCO2
Temperature: 0 °C
Reaction time: 3 h
Yield: 91.1 %

Procedure:
To a solution of 2-(3,5-di-tert-butyl-4-hydroxyphenyl)-3-[3-[N-methyl-N-[2-(3,4-methylenedioxy-phenoxy)ethyl]amino]propyl]-5-ethoxycarbonylmethyl-1,3-thiazolidin-4-one (80 mg) prepared in Example 46 in dry tetrahydrofuran (5 ml) was added lithium aluminum hydride (20 mg) at -78° C., and the mixture was stirred at 0° C. for 3 hours. To the mixture was added water-containing tetrahydrofuran (5 ml), followed by stirring at that temperature for 1 hour. The mixture was neutralized with 1N hydrochloric acid, concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent; chloroform-methanol, 95:5) to afford 68 mg (86%) of the title compound as a colorless oil. NMR (CDCl3) (200 MHz) δ: 1.41 (18H, s), 1.3-1.8 (4H, m), 2.19 (3H, s), 2.2-2.5 (3H, m), 2.67 (2H, t, J=5.7 Hz), 2.7-2.9 (1H, m), 3.4-3.6 (1H, m), 3.8-4.0 (2H, m), 3.91 (2H, t, J=5.7 Hz), 4.04 (1H, t, J=5.7 Hz), 5.33 (1H, s), 5.60 (1H, s), 5.90 (2H, s), 6.2-6.7 (3H, m), 7.12 (2H, s)
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][CH2:16][OH:17])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:25][S:26](Cl)(=[O:28])=[O:27]>O1CCCC1>[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][CH2:16][O:17][S:26]([CH3:25])(=[O:28])=[O:27])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)Cl
Reactant: OCCCC1CCN(Cc2ccccc2)CC1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CS(=O)(=O)OCCCC1CCN(Cc2ccccc2)CC1
Yield: 83.9 %

Procedure:
2.58 g (11.1 mmol) of 1-benzyl-4-hydroxypropylpiperidine and 3.26 ml (23.4 mmol) of triethylamine were dissolved in 50 ml of tetrahydrofuran, and 1.67 ml (21.6 mmol) of methanesulfonyl chloride wasaddeddropwise. After completion of the reaction, the mixture was partitioned between ethyl acetate and brine. The organic layer was dried over magnesium sulfate, and then evaporated, to give a crude product. The crude product was subjected to 50 g of Cromatorex NH silica gel (ethyl acetate:hexane=1:1), to give 2.90 g (9.31 mmol, 83.9%) the title compound as a yellow oil. The physico-chemical data of the target compound was as indicated below.
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH2:10][CH:9]([S:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[C:20]([F:23])([F:22])[F:21])(=[O:13])=[O:12])[CH2:8][N:7]1[C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([O:30][C:31]([F:34])([F:33])[F:32])[CH:25]=1)=[O:5])C.[OH-].[Li+]>>[F:34][C:31]([F:32])([F:33])[O:30][C:26]1[CH:25]=[C:24]([N:7]2[CH2:8][CH:9]([S:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[C:20]([F:21])([F:22])[F:23])(=[O:13])=[O:12])[CH2:10][CH:6]2[C:4]([OH:5])=[O:3])[CH:29]=[CH:28][CH:27]=1
Reactant: CCOC(=O)C1CC(S(=O)(=O)c2ccccc2C(F)(F)F)CN1c1cccc(OC(F)(F)F)c1
Agent: [Li+]
Agent: [OH-]
Product: O=C(O)C1CC(S(=O)(=O)c2ccccc2C(F)(F)F)CN1c1cccc(OC(F)(F)F)c1

Procedure:
In analogy to the procedure described in example 253e, 1-(3-trifluoromethoxy-phenyl)-4-(2-trifluoromethyl-benzenesulfonyl)-pyrrolidine-2-carboxylic acid ethyl ester was saponified in the presence of lithium hydroxide to give the title compound as yellow oil which was used in the next step without further purification. MS (ESI): m/z=484.2 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1([CH3:11])[O:6][C@:5]([CH2:8][CH2:9][OH:10])([CH3:7])[CH2:4][O:3]1.CCN(CC)CC.[S:19](Cl)([C:22]1[CH:28]=[CH:27][C:25]([CH3:26])=[CH:24][CH:23]=1)(=[O:21])=[O:20]>C(Cl)Cl>[CH3:26][C:25]1[CH:27]=[CH:28][C:22]([S:19]([O:10][CH2:9][CH2:8][C@@:5]2([CH3:7])[CH2:4][O:3][C:2]([CH3:11])([CH3:1])[O:6]2)(=[O:21])=[O:20])=[CH:23][CH:24]=1
Reactant: CC1(C)OC[C@](C)(CCO)O1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCC[C@@]2(C)COC(C)(C)O2)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of compound 4 and Et3N in DCM was added TsCl dropwise. The resulting mixture was stirred at 0° C. for 30 min. The solid was filtered and the solvent was removed. The residue was purified by column chromatography to give compound 5.
Reaction SMILES: [C:1]([NH:4][CH:5]1[CH2:14][CH2:13][C:12]2[C:7](=[C:8]([NH2:17])[CH:9]=[C:10]([F:16])[C:11]=2[CH3:15])[C:6]1=O)(=[O:3])[CH3:2].[CH2:19]([C@:21]1([OH:37])[C:33]2[CH:32]=[C:31]3[N:27]([CH2:28][CH2:29][C:30]3=O)[C:26](=[O:35])[C:25]=2[CH2:24][O:23][C:22]1=[O:36])[CH3:20].C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>C1(C)C=CC=CC=1>[C:1]([NH:4][CH:5]1[C:6]2=[C:29]3[CH2:28][N:27]4[C:31](=[CH:32][C:33]5[C@:21]([CH2:19][CH3:20])([OH:37])[C:22](=[O:36])[O:23][CH2:24][C:25]=5[C:26]4=[O:35])[C:30]3=[N:17][C:8]3[CH:9]=[C:10]([F:16])[C:11]([CH3:15])=[C:12]([C:7]=32)[CH2:13][CH2:14]1)(=[O:3])[CH3:2]
Reactant: CC[C@@]1(O)C(=O)OCc2c1cc1n(c2=O)CCC1=O
Reactant: CC(=O)NC1CCc2c(C)c(F)cc(N)c2C1=O
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: Cc1ccccc1
Product: CC[C@@]1(O)C(=O)OCc2c1cc1n(c2=O)Cc2c-1nc1cc(F)c(C)c3c1c2C(NC(C)=O)CC3
Temperature: 120 °C
Yield: 59.1 %

Procedure:
To 150 mg of 2-acetylamino-8-amino-6-fluoro-5-methyl-1-tetralone and 158 mg of (4S)-4-ethyl-7,8-dihydro-4-hydroxy-1H-pyrano[3,4-f]indolizine-3,6,10(4H)-trione, 30 ml of toluene and then 150 mg of pyridinium p-toluenesulfonate were added, followed by heating at an external temperature of 120° C. under reflux for 28 hours. After completion of the reaction, the solvent was removed under reduced pressure. Acetone was added to the residue and crystals so precipitated were collected by filtration, whereby 169 mg of the title compound were obtained.
Reaction SMILES: [CH3:1][N:2]([CH2:4][C@@H:5]1[CH2:9][CH2:8][N:7]([C:10]([NH:12][C:13]2[CH:18]=[C:17]([O:19][C:20]3[CH:25]=[CH:24][C:23]([N+:26]([O-])=O)=[CH:22][C:21]=3[F:29])[N:16]=[CH:15][N:14]=2)=[O:11])[CH2:6]1)[CH3:3]>O1CCCC1.[OH-].[Pd+2].[OH-].[C]>[NH2:26][C:23]1[CH:24]=[CH:25][C:20]([O:19][C:17]2[CH:18]=[C:13]([NH:12][C:10]([N:7]3[CH2:8][CH2:9][C@@H:5]([CH2:4][N:2]([CH3:3])[CH3:1])[CH2:6]3)=[O:11])[N:14]=[CH:15][N:16]=2)=[C:21]([F:29])[CH:22]=1
Reactant: CN(C)C[C@@H]1CCN(C(=O)Nc2cc(Oc3ccc([N+](=O)[O-])cc3F)ncn2)C1
Agent: [Pd+2]
Agent: [OH-]
Solvent: C1CCOC1
Product: CN(C)C[C@@H]1CCN(C(=O)Nc2cc(Oc3ccc(N)cc3F)ncn2)C1
Reaction time: 8 h
Yield: 91.5 %

Procedure:
4-{[(3S)-3-(Dimethylaminomethyl)pyrrolidin-1-yl]carbonylamino}-6-(2-fluoro-4-nitrophenoxy)pyrimidine (124 mg) was dissolved in tetrahydrofuran (15 ml). After adding 20% palladium hydroxide-carbon (86 mg), the mixture was stirred overnight under a hydrogen atmosphere. The catalyst was filtered and washed with tetrahydrofuran. The filtrate and the washings were combined and concentrated under reduced pressure, and then the resultant residue was dried under reduced pressure to provide the title compound (105 mg, 91%) as a pale yellow oil.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].C(Cl)(=O)C([Cl:14])=O>>[Cl:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([Cl:14])=[O:5]
Reactant: O=C(O)c1cccnc1Cl
Reactant: O=C(Cl)C(=O)Cl
Product: O=C(Cl)c1cccnc1Cl
Yield: 98 %

Procedure:
2-Chloronicotinic acid (317 mmol) was diluted with oxalyl chloride (130 mL) and the resulting solution was heated at reflux for 18 h. The volatiles were removed by evaporation to provide 2-chloronicotinoyl chloride in 98% yield as a white solid.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:4][CH:3]1[C:15]([O:17]CC)=[O:16].[OH-].[Na+].Cl>C1COCC1.O>[OH:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:4][CH:3]1[C:15]([OH:17])=[O:16]
Reactant: CCOC(=O)C1CN(Cc2ccccc2)CCC1O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)C1CN(Cc2ccccc2)CCC1O
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of ethyl 4-hydroxy-1-(phenylmethyl)-3-piperidinecarboxylate (30 g, 114.4 mmol) in THF/water (800 ml/80 mL) was added 2N sodium hydroxide solution (126 mL). The reaction mixture was stirred at room temperature for 5 h and then the pH was adjusted to 7 with 5N hydrochloric acid solution.
Reaction SMILES: C([O:4][C@@H:5]1[C@H:9]([O:10]C(=O)C)[C@@H:8]([C:14]2[N:15]=[N:16][N:17]([CH2:19][CH3:20])[N:18]=2)[O:7][C@H:6]1[N:21]1[CH:29]=[N:28][C:27]2[C:22]1=[N:23][C:24]([CH2:45][NH:46][S:47]([CH2:50][CH:51]([CH3:53])[CH3:52])(=[O:49])=[O:48])=[N:25][C:26]=2[NH:30][CH2:31][CH:32]([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)(=O)C.C(=O)([O-])[O-].[Na+].[Na+]>CO.O>[C:39]1([CH:32]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH2:31][NH:30][C:26]2[N:25]=[C:24]([CH2:45][NH:46][S:47]([CH2:50][CH:51]([CH3:52])[CH3:53])(=[O:48])=[O:49])[N:23]=[C:22]3[C:27]=2[N:28]=[CH:29][N:21]3[C@H:6]2[C@H:5]([OH:4])[C@H:9]([OH:10])[C@@H:8]([C:14]3[N:15]=[N:16][N:17]([CH2:19][CH3:20])[N:18]=3)[O:7]2)[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1
Reactant: CCn1nnc([C@H]2O[C@@H](n3cnc4c(NCC(c5ccccc5)c5ccccc5)nc(CNS(=O)(=O)CC(C)C)nc43)[C@H](OC(C)=O)[C@@H]2OC(C)=O)n1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CCn1nnc([C@H]2O[C@@H](n3cnc4c(NCC(c5ccccc5)c5ccccc5)nc(CNS(=O)(=O)CC(C)C)nc43)[C@H](O)[C@@H]2O)n1
Yield: 92.5 %

Procedure:
A solution of (2R,3R,4R,5R)-4-(acetyloxy)-2-(6-[(2,2-diphenylethyl)amino]-2-{[(isobutylsulphonyl)amino]methyl}-9H-purin-9-yl)-5-(2-ethyl-2H-tetrazol-5-yl)tetrahydro-3-furanyl acetate (Preparation 26) (230 mg, 0.31 mmol) and sodium carbonate (130 mg, 1.23 mmol) in methanol (15 ml) and water (1.5 ml) was stirred at room temperature overnight. The solvent was evaporated under reduced pressure and the residue was partioned between ethyl acetate (50 ml) and water (10 ml). The organic layer was washed with brine (10 ml), dried (anhydrous sodium sulphate) and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with dichloromethane:methanol (97:3 by volume). Product containing fractions were evaporated to afford the title compound as a white powder (190 mg).
Reaction SMILES: [C:1]([OH:14])(=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[CH3:15][C:16]([CH:20]=O)([CH2:18][OH:19])[CH3:17].C1(C)C=CC=CC=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>O>[C:1]([O:14][CH2:15][C:16]([CH3:20])([CH3:17])[CH:18]=[O:19])(=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCCCCC(=O)O
Reactant: CC(C)(C=O)CO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CCCCCCCCCCCC(=O)OCC(C)(C)C=O

Procedure:
To a hot (80° C.) solution of lauric acid (70 g., 0.35 mole), and hydroxypivaldehyde (30.6 g., 0.3 mole) in 120 g. of toluene was added 1.75 g. of p-toluenesulfonic acid monohydrate (0.009 mole). The mixture was then heated at total reflux for 1.5 hrs. and water generated in the reaction mixture was removed by azeotropic distillation. The reaction mixture was cooled, washed with saturated aqueous sodium bicarbonate and brine, then dried over magnesium sulfate, filtered, and evaporated in vacuo. GLC analysis of the product showed that it contained 90% of the desired laurate ester. Fractional distillation of the crude sample gave a product cut, b.p. 180° C./4.0 mm, of 95% purity (GLC, area %). NMR (CDCL3): 9.73 (s, 1H,--CHO), 4.2 (s, 2H, --CO2CH2 --), 2.3 (t, 2H, --CH2CO2 --), 0.9-1.9 (m, 23H, CH2 (CH2)10CH2CO 2 --), and 1.17 (s, 6H, --C(CH2)2.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]2[C:11](=[N:12][C:13]=1[CH3:14])[N:10]=[CH:9][C:8]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:7]2[OH:20])[CH3:2].O.[C:22]([OH:26])(=[O:25])[CH:23]=O>FC(F)(F)C(O)=O>[CH2:1]([O:3][C:4]1[C:13]([CH:14]=[CH:23][C:22]([OH:26])=[O:25])=[N:12][C:11]2[C:6]([CH:5]=1)=[C:7]([OH:20])[C:8]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:9][N:10]=2)[CH3:2]
Reactant: CCOC(=O)c1cnc2nc(C)c(OCC)cc2c1O
Reactant: O=CC(=O)O
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1cnc2nc(C=CC(=O)O)c(OCC)cc2c1O

Procedure:
A mixture of ethyl 6-ethoxy-4-hydroxy-7-methyl-1,8-naphthyridine-3-carboxylate (2.8 g), glyoxylic acid monohydrate (1.5 g) acetic acid (20 ml) and trifluoroacetic acid (10 ml) was heated at 90°-95° C. for 2 hours, with stirring. The mixture was evaporated down under reduced pressure. The residue was triturated with hot ethanol and filtered to give 3-(3-ethoxy-6-ethoxycarbonyl-5-hydroxy-1,8-naphthyridin-2-yl)acrylic acid, m.p.>280° C.
Reaction SMILES: [CH3:1][N:2]([CH3:7])[CH2:3][C:4](O)=[O:5].C(N1CCOCC1)C.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.O1CCCCC1ONC([C@H]([C@@H:58]([CH2:67][CH:68]([CH3:70])[CH3:69])[C:59]([NH:61][NH:62][CH2:63][CH:64]([CH3:66])[CH3:65])=[O:60])C/C=C/C1C=CC=CC=1)=O>CN(C)C=O.C(OCC)(=O)C>[CH2:63]([N:62]([C:4](=[O:5])[CH2:3][N:2]([CH3:7])[CH3:1])[NH:61][C:59](=[O:60])[CH2:58][CH2:67][CH:68]([CH3:70])[CH3:69])[CH:64]([CH3:66])[CH3:65]
Reactant: CN(C)CC(=O)O
Reactant: CC(C)CNNC(=O)[C@H](CC(C)C)[C@H](C/C=C/c1ccccc1)C(=O)NOC1CCCCO1
Agent: CCN1CCOCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)CCC(=O)NN(CC(C)C)C(=O)CN(C)C
Reaction time: 1 h

Procedure:
A solution of 0.155 g of N,N-dimethylglycine in 10 ml of dimethylformamide was treated in sequence with 0.167 ml of N-ethylmorpholine, 0.216 g of 1-hydroxybenzotriazole and 0.307 g of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride. Stirring was continued for 1 hour at room temperature and then 0.459 g of (E)-2(R)-[1(S)-[(tetrahydro-2(RS)-pyranyloxy)carbamoyl]-4-phenyl-3-butenyl]-2′-isobutyl-4-methylvalerohydrazide was added. Stirring was continued overnight and then the mixture was diluted with ethyl acetate and washed in sequence with 5% aqueous sodium hydrogen carbonate and brine. Drying over magnesium sulphate and evaporation gave 0.591 g of (E)-2(R)-[1(S)-(tetrahydro-2(RS)-pyranyloxy)carbamoyl]-4-phenyl-3-butenyl]-2′-isobutyl-4-methyl-2′-[2-(dimethylamino)acetyl]valerohydrazide in the form of a white solid.
Reaction SMILES: [Br:1][C@@H:2]([CH2:6][O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]([OH:5])=[O:4].[C:15]1([C:21]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[N+]=[N-])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(O)(=O)C>CC(C)=O>[Br:1][C@@H:2]([CH2:6][O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]([O:5][CH:21]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:4]
Reactant: O=C(O)[C@@H](Br)COCc1ccccc1
Reactant: [N-]=[N+]=C(c1ccccc1)c1ccccc1
Solvent: CC(=O)O
Solvent: CC(C)=O
Product: O=C(OC(c1ccccc1)c1ccccc1)[C@@H](Br)COCc1ccccc1
Reaction time: 0.75 h
Yield: 51 %

Procedure:
To a solution of (S)-2-bromo-3-(phenylmethoxy)propanoic acid (7.63 g, 29.4 mmol) in acetone (30 ml) was added solid diphenyldiazomethane (5.81 g, 29.9 mmol) over the course of three minutes. The solution heated and nitrogen evolved vigorously. The purple solution was stirred for an additional 45 minutes, followed by the addition of acetic acid (1 ml) to quench any residual diphenyldiazomethane. The solution was extracted with saturated sodium bicarbonate (50 ml), washed with saturated sodium chloride (50 ml), dried over magnesium sulfate and evaporated at reduced pressure to give the crude product (11.24 g). Purification by chromatography on silica gel (95:5; hexane:ethyl acetate) afforded the title compound (6.38 g).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[N:13]([CH3:17])[C:12](=[O:18])[CH2:11]3)[CH:5]=[N:6][CH:7]=1.[CH:19]1([B-](F)(F)F)[CH2:21][CH2:20]1.[K+].C1COCC1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>ClCCl.O>[CH:19]1([C:2]2[CH:3]=[C:4]([C:8]3[CH:9]=[C:10]4[C:14](=[CH:15][CH:16]=3)[N:13]([CH3:17])[C:12](=[O:18])[CH2:11]4)[CH:5]=[N:6][CH:7]=2)[CH2:21][CH2:20]1
Reactant: CN1C(=O)Cc2cc(-c3cncc(Br)c3)ccc21
Reactant: F[B-](F)(F)C1CC1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: O
Product: CN1C(=O)Cc2cc(-c3cncc(C4CC4)c3)ccc21
Temperature: 125 °C

Procedure:
To 5-(5-bromo-pyridin-3-yl)-1-methyl-1,3-dihydro-indol-2-one, prepared as described in Example 21, (100 mg, 0.330 mmol) was added potassium cyclopropyltrifluoroborate (50 mg, 0.35 mmol), THF (2 mL), water, (0.66 mL), and tripotassium phosphate (245 mg, 1.155 mmol). The reaction mixture was degassed and placed under an argon atmosphere, and then [1,1′-bis(diphenylphospihino)-ferrocene]-dichloropalladium(II) complexed with dichloromethane (CAS#72287-26-4 13.5 mg, 0.016 mmol) was added. The reaction vessel was sealed and was heated by microwave irradiation at 125° C. for 85 minutes. The reaction mixture was cooled to room temperature, diluted with dichloromethane and filtered through glass wool. The filtrate was further diluted with saturated aqueous sodium bicarbonate and the layers were separated. The aqueous layer was extracted two times with dichloromethane, and the organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated. The resulting residue was purified by silica gel flash chromatography (ethyl acetate-dichloromethane, 0 to 100%) to afford 5-(5-cyclopropyl-pyridin-3-yl)-1-methyl-1,3-dihydro-indol-2-one; HRMS: (ESI) m/z 265.1345 (M+H)+; 1H NMR (400 MHz, CDCl3) δ ppm 0.72-0.89 (m, 2H), 1.03-1.19 (m, 2H), 1.85-2.11 (m, 1H), 3.27 (s, 3H), 3.61 (s, 2H), 6.92 (d, J=8.1 Hz, 1H), 7.39-7.61 (m, 3H), 8.38 (d, J=1.8 Hz, 1H), 8.60 (d, J=2.0 Hz, 1H).
Reaction SMILES: [O:1]=[C:2]([N:15]1[CH2:19][CH2:18][CH2:17][C@H:16]1[C:20]1[NH:21][C:22]([C:25]2[CH:30]=[CH:29][C:28]([C:31]3[S:35][C:34]4[CH:36]=[C:37](B5OC(C)(C)C(C)(C)O5)[CH:38]=[CH:39][C:33]=4[CH:32]=3)=[CH:27][CH:26]=2)=[CH:23][N:24]=1)[C@H:3]([NH:10][C:11](=[O:14])[O:12][CH3:13])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Br[C:50]1[N:51]=[C:52]([C@@H:55]2[CH2:59][CH2:58][CH2:57][N:56]2[C:60]([O:62][C:63]([CH3:66])([CH3:65])[CH3:64])=[O:61])[NH:53][CH:54]=1.C(=O)([O-])[O-].[K+].[K+].C(COC)OC>[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.O>[CH3:13][O:12][C:11]([NH:10][C@H:3]([C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1)[C:2]([N:15]1[CH2:19][CH2:18][CH2:17][C@H:16]1[C:20]1[NH:21][C:22]([C:25]2[CH:30]=[CH:29][C:28]([C:31]3[S:35][C:34]4[CH:36]=[C:37]([C:54]5[N:53]=[C:52]([C@@H:55]6[CH2:59][CH2:58][CH2:57][N:56]6[C:60]([O:62][C:63]([CH3:66])([CH3:65])[CH3:64])=[O:61])[NH:51][CH:50]=5)[CH:38]=[CH:39][C:33]=4[CH:32]=3)=[CH:27][CH:26]=2)=[CH:23][N:24]=1)=[O:1])=[O:14]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1c1nc(Br)c[nH]1
Reactant: COC(=O)N[C@@H](C(=O)N1CCC[C@H]1c1ncc(-c2ccc(-c3cc4ccc(B5OC(C)(C)C(C)(C)O5)cc4s3)cc2)[nH]1)c1ccccc1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: COC(=O)N[C@@H](C(=O)N1CCC[C@H]1c1ncc(-c2ccc(-c3cc4ccc(-c5c[nH]c([C@@H]6CCCN6C(=O)OC(C)(C)C)n5)cc4s3)cc2)[nH]1)c1ccccc1
Temperature: 85 °C
Yield: 2.8 %

Procedure:
A mixture of methyl (R)-2-oxo-1-phenyl-2-((S)-2-(5-(4-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[b]thiophen-2-yl)phenyl)-1H-imidazol-2-yl)pyrrolidin-1-yl)ethylcarbamate (261 mg, 0.39 mmol), (S)-tert-butyl 2-(4-bromo-1H-imidazol-2-yl)pyrrolidine-1-carboxylate (125 mg, 0.39 mmol), and tetrakis(triphenylphosphine) palladium (0) (45 mg, 0.039 mmol), 1,1′-Bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (29 mg, 0.039 mmol), potassium carbonate (109 mg, 0.78 mmol), dimethoxyethane (5 mL), and water (1 mL) was heated at 85° C. for 16 hours. The solvent was removed under reduced pressure and the residue was take up in dichloromethane (15 mL) and washed with water (5 mL) and brine (5 mL). The organic phase was dried over sodium sulfate and filtered. The solvent was removed under reduced pressure and the residue was subjected to flash chromatography with eluant of (10% methanol in ethyl acetate) and hexane. The product containing fractions were combined and the solvent was removed under reduced pressure to provide (S)-tert-Butyl 2-(4-(2-(4-(2-((S)-1-((R)-2-(methoxycarbonylamino)-2-phenylacetyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)phenyl)benzo[b]thiophen-6-yl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate (88 mg, 0.011 mmol, 28%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:13](=[CH:14][CH:15]=1)[N:12]([CH:16]([CH3:23])[CH2:17][N:18]1[CH2:22][CH2:21][CH2:20][CH2:19]1)[C:11]1[CH:10]=[C:9]([C:24]#[N:25])[CH:8]=[CH:7][C:6]=1[S:5]2.C(N(CC)CC)C.[SH2:33]>N1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:13](=[CH:14][CH:15]=1)[N:12]([CH:16]([CH3:23])[CH2:17][N:18]1[CH2:19][CH2:20][CH2:21][CH2:22]1)[C:11]1[CH:10]=[C:9]([C:24](=[S:33])[NH2:25])[CH:8]=[CH:7][C:6]=1[S:5]2
Reactant: S
Reactant: CC(CN1CCCC1)N1c2ccc(Cl)cc2Sc2ccc(C#N)cc21
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Product: CC(CN1CCCC1)N1c2ccc(Cl)cc2Sc2ccc(C(N)=S)cc21
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A mixture of 7-chloro-10-[(2RS)-1-(1-pyrrolidinyl)-2-propyl]-2-phenothiazinecarbonitrile (31.07 g) and triethylamine (11.8 cc) in anhydrous pyridine (300 cc) is saturated with hydrogen sulphide for 4 hours at 25° C. The clear solution obtained is kept stirred for 12 hours at 25° C. The mixture is outgassed by bubbling nitrogen through for 2 hours, then diluted with ethyl acetate (250 cc) and washed with distilled water (5×200 cc). The organic phase is dried over magnesium sulphate and filtered, and the filtrate is concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa). The residue is purified by chromatography on a column (height: 38 cm; diameter: 6.5 cm) of silica gel (0.06-0.2 mm), eluting with a mixture of cyclohexane and ethyl acetate in proportions (by volume) of 70:30 (6 liters), 50:50 (4 liters) and 30:70 (4 liters), then with pure ethyl acetate (2 liters) and finally with a 90:10 mixture (6 liters) of ethyl acetate and methanol, collecting 50-cc fractions. The first 13.3 liters are discarded and fractions 6 to 94 are combined and concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 50° C. to give 7-chloro-10-[(2RS)-1-(1-pyrrolidinyl)-2-propyl]-2-phenothiazinethiocarboxamide (21.43 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][CH:9]=[C:10]2[CH2:13][CH2:14][CH2:15][NH:16][C:17](=[O:19])[CH3:18])=[CH:5][CH:4]=1.[C:20](Cl)(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[C:8]([C:20](=[O:27])[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH:9]=[C:10]2[CH2:13][CH2:14][CH2:15][NH:16][C:17](=[O:19])[CH3:18])=[CH:5][CH:4]=1
Reactant: COc1ccc2cccc(CCCNC(C)=O)c2c1
Reactant: O=C(Cl)c1ccccc1
Product: COc1ccc2cc(C(=O)c3ccccc3)cc(CCCNC(C)=O)c2c1

Procedure:
By reacting N-[3-(7-methoxy-1-naphthyl)propyl]acetamide obtained in Example 1 with benzoyl chloride, the compound of the title is obtained.