Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[CH:5][CH:4]=1.CC(C)N=C=NC(C)C.[C:19]([O:23][C:24]([N:26]1[CH2:39][CH2:38][C:37]2[C:36]3[C:35]([Cl:40])=[C:34]([Cl:41])[CH:33]=[CH:32][C:31]=3[N:30]([CH2:42][C:43](O)=[O:44])[C:29]=2[CH2:28][CH2:27]1)=[O:25])([CH3:22])([CH3:21])[CH3:20]>CN(C1C=CN=CC=1)C.C1COCC1.CCOC(C)=O>[Cl:41][C:34]1[CH:33]=[CH:32][C:31]2[N:30]([CH2:42][C:43]([NH:9][C:6]3[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)=[O:44])[C:29]3[CH2:28][CH2:27][N:26]([C:24]([O:23][C:19]([CH3:21])([CH3:20])[CH3:22])=[O:25])[CH2:39][CH2:38][C:37]=3[C:36]=2[C:35]=1[Cl:40]
Reactant: COc1ccc(N)cc1
Reactant: CC(C)(C)OC(=O)N1CCc2c(n(CC(=O)O)c3ccc(Cl)c(Cl)c23)CC1
Agent: CC(C)N=C=NC(C)C
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1ccc(NC(=O)Cn2c3c(c4c(Cl)c(Cl)ccc42)CCN(C(=O)OC(C)(C)C)CC3)cc1
Reaction time: 4 h
Yield: 37 %

Procedure:
DMAP (89 mg, 0.73 mmol), p-anisidine (0.10 g, 0.81 mmol) and DIC (0.13 mL, 0.81 mmol) were added to the solution of crude [3-(tert-butoxycarbonyl)-9,10-dichloro-2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl]acetic acid (0.30 g, 0.73 mmol) in dry THF (3.5 mL). After 4 h, additional p-anisidine (45 mg, 0.37 mmol) was added. The reaction was diluted with EtOAc after another 17 h and washed with 10% aqueous citric acid (20 mL), saturated aqueous NaHCO3 (20 mL), and brine (20 mL). The organic layer was then dried over Na2SO4, decanted, and concentrated impure product. It was then crystallized from EtOAc/heptane, triturated with pentane, and recrystallized from EtOAc/heptane to give 0.14 g (36%) of a white solid: mp 143.0-144.0° C.; 1H NMR (300 MHz, DMSO) δ 10.30 (s, 1H), 7.47 (m, 3H), 7.25 (d, J 8.7 Hz, 1H), 6.88 (d, J=9.0 Hz, 2H), 5.04 (br s, 2H), 3.71 (s, 3H), 3.63 (m, 4H), 3.39 (m, 2H), 2.99 (m, 2H), 1.40 (app d, 9H); IR (diffuse reflectance) 2975, 1666, 1545, 1514, 1474, 1451, 1414, 1365, 1253, 1239, 1222, 1173, 1158, 830, 784 cm1; MS (EI) m/z 517 (M+), 377, 375, 227, 224, 212, 134, 124, 121, 55, 53; MS (FAB) m/z 518 (M+H+), 520, 519, 518, 517, 464, 463, 462, 461, 418, 57; HRMS (EI) calcd for C26H29Cl2N3O4 517.1535, found 517.1537; Anal. Calcd for C26H29Cl2N3O4: C, 60.24; H, 5.64; N, 8.10; found: C, 59.86; H, 5.68; N, 7.94.
Reaction SMILES: [CH:1]12[CH2:9][CH:5]3[CH2:6][CH:7]([CH2:8]1)[C:3]([NH:10][C:11]([C:13]1[CH:18]=[CH:17][N:16]=[CH:15][C:14]=1[CH:19]([C:28]1[CH:33]=[CH:32][C:31]([O:34]C)=[CH:30][CH:29]=1)[C:20]1[CH:25]=[CH:24][C:23]([O:26]C)=[CH:22][CH:21]=1)=[O:12])([CH2:4]3)[CH2:2]2.CCCCCC.B(Br)(Br)Br.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[CH:1]12[CH2:9][CH:5]3[CH2:6][CH:7]([CH2:8]1)[C:3]([NH:10][C:11]([C:13]1[CH:18]=[CH:17][N:16]=[CH:15][C:14]=1[CH:19]([C:28]1[CH:33]=[CH:32][C:31]([OH:34])=[CH:30][CH:29]=1)[C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=1)=[O:12])([CH2:4]3)[CH2:2]2
Reactant: COc1ccc(C(c2ccc(OC)cc2)c2cnccc2C(=O)NC23CC4CC(CC2C4)C3)cc1
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCCCCC
Product: O=C(NC12CC3CC(CC1C3)C2)c1ccncc1C(c1ccc(O)cc1)c1ccc(O)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 26.8 %

Procedure:
In 40 ml of methylene chloride was dissolved 2.5 g of Compound 1 obtained in Example 1, and the solution was cooled to from -5° to -15° C. Then, 20 ml of a hexane solution containing 1M boron tribromide was added thereto. The mixture was stirred at room temperature for two hours and thirty minutes. The reaction mixture was poured into a saturated aqueous sodium bicarbonate solution, followed by extraction with ethyl acetate. The extract was dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give 0.63 g of the desired compound as a solid.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][Cl:6])=[O:3].[CH3:7][O:8][CH2:9][CH2:10][O:11][CH2:12][CH2:13][O:14][CH2:15][CH2:16][OH:17].N1C=CC=CC=1>C(Cl)Cl>[C:2](=[O:3])([O:17][CH2:16][CH2:15][O:14][CH2:13][CH2:12][O:11][CH2:10][CH2:9][O:8][CH3:7])[O:4][CH2:5][Cl:6]
Reactant: COCCOCCOCCO
Reactant: O=C(Cl)OCCl
Solvent: c1ccncc1
Solvent: ClCCl
Product: COCCOCCOCCOC(=O)OCCl

Procedure:
In a manner similar to the method described in Example 3, chloromethyl chloroformate (Aldrich) was reacted with 2-(2-(2-methoxyethoxy)ethoxy)ethanol (TCI) and pyridine in methylene chloride at −78° C. for 3 h to give chloromethyl 2-(2-(2-methoxyethoxy)ethoxy)ethyl carbonate. This material was then reacted with chiral 4-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoic acid in the presence of cesium carbonate in dimethylformamide overnight to give, after flash chromatography purification (hexane/ethyl acetate, 80/20 to 20/80), chiral 3-oxo-2,4,7,10,13-pentaoxatetradecyl 4-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoate as a white solid. MS (ES+) m/z calcd. for C40H47Cl2F2N3O10: [(M+H)+]: 836, found: 836.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][C:8]2=[O:11])=[CH:4][C:3]=1[O:12][CH3:13].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].C([C:26]([O:28][CH2:29][CH3:30])=[O:27])#N>C1COCC1>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH:7]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[C:8]2=[O:11])=[CH:4][C:3]=1[O:12][CH3:13]
Reactant: COc1cc2c(cc1Cl)C(=O)CC2
Reactant: CCOC(=O)C#N
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)C1Cc2cc(OC)c(Cl)cc2C1=O
Temperature: 25 °C

Procedure:
To a solution of 6-chloro-5-methoxyindan-1-one (27.6 g, 141 mmol) in THF (630 mL) at −78° C. was added a 1.0M solution of lithium bis(trimethylsilyl)amide in THF (309 mL, 309 mmol) and then the solution was slowly warmed to ca −50° C. during 1 hour. After re -cooling to −78° C., ethyl cyanoformate (21.3 mL, 216 mmol) was introduced and the reaction mixture was allowed to warm to room temperature during 2 hours. After quenching with 300 mL of 1N HCl, most of the THF was removed by rotary evaporation under reduced pressure. The residual mixture was extracted with EtOAc and the organic layer was washed with dilute aqueous NaHCO3 and dried over Na2SO4. Filtration through a pad of silica and removal of the solvent under reduced pressure gave ethyl 6-chloro-5-methoxy-1-oxoindane-2-carboxylate as a brown oil.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([CH3:11])[C:3]=1[OH:12].[OH-].[Na+].[C:15](OC(=O)C)(=[O:17])[CH3:16]>O>[C:15]([O:12][C:3]1[C:4]([CH3:11])=[C:5]([CH:9]=[CH:10][C:2]=1[Br:1])[C:6]([OH:8])=[O:7])(=[O:17])[CH3:16]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1c(C(=O)O)ccc(Br)c1O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(=O)Oc1c(Br)ccc(C(=O)O)c1C

Procedure:
Water (12 mL) was added to 4-bromo-3-hydroxy-2-methylbenzoic acid (5 g, 21.6 mmol) in an Erlenmeyer flask and cooled in an ice bath. 50% Aqueous NaOH solution (8.06 g mixed with 12 mL water, 108 mmol) was added and the mixture stirred for few minutes until the solution was clear. Acetic anhydride (2.04 mL, 21.6 mmol) was added drop wise until pH 5 was reached; by that time the reaction mixture became a thick slurry having an off white color. The mixture was stirred overnight at room temperature. LCMS showed a major peak with the expected product mass and a minor polar peak of the starting material. The pH was adjusted to 2 and the precipitate was filtered. LCMS of the precipitate showed it as a 3:1 mixture of the expected acetate and the starting phenol. The filtrate also contained some product, so combined everything, dried and adsorbed on silica and subjected to silica gel column chromatography using ISCO. The main peak was collected, the solvent was removed and the product dried under vacuum. 1H NMR (400 MHz, DMSO) δ 13.27 (s, 1H), 7.81-7.33 (m, 2H), 2.37 (s, 6H), 2.34 (s, 3H).
Reaction SMILES: [C:1]([OH:6])(=[O:5])[CH:2]([CH3:4])[OH:3].[C:7]([OH:11])(=[O:10])[CH2:8][OH:9].[N+](=CC)=[N-]>ClCCl>[CH3:7][CH2:8][O:5][C:1]([CH:2]([OH:3])[CH3:4])=[O:6].[C:7]([OH:11])(=[O:10])[CH2:8][OH:9]
Reactant: CC(O)C(=O)O
Agent: CC=[N+]=[N-]
Agent: O=C(O)CO
Solvent: ClCCl
Product: CCOC(=O)C(C)O
Reaction time: 8 h
Yield: 172.4 %

Procedure:
130 g of lactic acid/glycolic acid copolymer having a weight-average molecular weight of about 5,000, (lactic acid/glycolic acid=50/50 (mol %)) was dissolved in 1,900 ml of dichloromethane; this solution was stirred and cooled. While the solution was ice cooled, the above-described diazoethane solution was added dropwise, followed by stirring at room temperature for 2 hours. After the solution was kept standing overnight, the solvent was distilled off under reduced pressure; the residue was vacuum dried at room temperature to yield 131 g of the ethyl ester of lactic acid/glycolic acid.
Reaction SMILES: [O:1]=[C:2]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]([F:18])([F:17])[F:16])=[CH:10][CH:9]=1)[CH2:3][C:4]([OH:6])=O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.ClC(Cl)(Cl)C#N.[NH2:44][C:45]([C:57]1[CH:62]=[CH:61][C:60]([O:63][CH2:64][CH2:65][CH2:66][C:67]([F:70])([F:69])[F:68])=[CH:59][CH:58]=1)([CH3:56])[CH2:46][C:47]([C:49]1[CH:54]=[CH:53][C:52]([CH3:55])=[CH:51][CH:50]=1)=[O:48].N1C=CC=CC=1>C(Cl)Cl>[O:48]=[C:47]([C:49]1[CH:54]=[CH:53][C:52]([CH3:55])=[CH:51][CH:50]=1)[CH2:46][C:45]([NH:44][C:4](=[O:6])[CH2:3][C:2]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]([F:18])([F:17])[F:16])=[CH:10][CH:9]=1)=[O:1])([C:57]1[CH:58]=[CH:59][C:60]([O:63][CH2:64][CH2:65][CH2:66][C:67]([F:68])([F:69])[F:70])=[CH:61][CH:62]=1)[CH3:56]
Reactant: Cc1ccc(C(=O)CC(C)(N)c2ccc(OCCCC(F)(F)F)cc2)cc1
Reactant: O=C(O)CC(=O)Nc1ccc(OC(F)(F)F)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: N#CC(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1ccc(C(=O)CC(C)(NC(=O)CC(=O)Nc2ccc(OC(F)(F)F)cc2)c2ccc(OCCCC(F)(F)F)cc2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 33.2 %

Procedure:
To a solution of Intermediate 11F (41.6 mg, 0.158 mmol) in anhydrous CH2Cl2 (0.6 mL) was added PPh3 (124 mg, 0.474 mmol) followed by dropwise addition of trichloroacetonitrile (27.4 mg, 0.19 mmol). The reaction was stirred at rt for 3 h. To the freshly prepared acid chloride was added a solution of Intermediate 11E (20 mg, 0.053 mmol) in anhydrous CH2Cl2 (0.3 mL) followed by pyridine (19 mL, 0.237 mmol). The mixture was stirred at rt overnight. The solvent was removed in vacuo. The product was purified by preparative HPLC (MeOH/H2O/TFA) to yield Intermediate 11G (11 mg, 33%) as a brown solid. LCMS Anal. Calc'd for C31H30F6N2O5 624.57, found [M+H] 625.4.
Reaction SMILES: [CH2:1]([O:3][CH2:4][CH2:5][NH:6][CH2:7][CH:8]([OH:11])[CH2:9][OH:10])[CH3:2].[CH:12](=O)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C(O)(=O)C1C=CC=CC=1.C1(C)C=CC=CC=1>[C:13]1([CH:12]2[N:6]([CH2:5][CH2:4][O:3][CH2:1][CH3:2])[CH2:7][CH:8]([CH2:9][OH:10])[O:11]2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CCOCCNCC(O)CO
Reactant: O=Cc1ccccc1
Agent: O=C(O)c1ccccc1
Solvent: Cc1ccccc1
Product: CCOCCN1CC(CO)OC1c1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 73.9 %

Procedure:
A solution of 1 (22.6 g, 0.14 mol), toluene (120 ml), benzaldehyde (48 g, 0.45 mol) and benzoic acid (0.5 g) was heated at reflux with a Dean-Stark trap. After 1.5 hours, the theoretical amount of H2O was collected, the reaction mixture was cooled to room temperature and added to saturated Na2CO3. The aqueous layer was separated and washed with CHCl3 (3X). The combined extracts were dried, filtered, and concentrated to dryness. The residue was distilled at 145°-50° C. at 0.4 mm to yield 26 g (75%) of 2.
Reaction SMILES: [CH3:1][C:2]1([C:7]2[CH:14]=[CH:13][C:10]([CH2:11][OH:12])=[CH:9][CH:8]=2)[O:6][CH2:5][CH2:4][O:3]1.Br[C:16]1[S:17][C:18]([Br:21])=[CH:19][N:20]=1>>[CH2:4]1[O:3][C:2]([C:7]2[CH:14]=[CH:13][C:10]([CH2:11][O:12][C:16]3[S:17][C:18]([Br:21])=[CH:19][N:20]=3)=[CH:9][CH:8]=2)([CH3:1])[O:6][CH2:5]1
Reactant: CC1(c2ccc(CO)cc2)OCCO1
Reactant: Brc1cnc(Br)s1
Product: CC1(c2ccc(COc3ncc(Br)s3)cc2)OCCO1
Yield: 60 %

Procedure:
Using an analogous procedure to that described in the first paragraph of the portion of Example 43 which is concerned with the preparation of starting materials, 4-(2-methyl-1,3-dioxolan-2-yl)benzyl alcohol was reacted with 2,5-dibromothiazole to give 4'-(5-bromothiazol-2-yloxymethyl)acetophenone ethylene acetal in 60% yield as an oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:11][C:12]2[C:13]3[N:41]=[CH:40][S:39][C:14]=3[N:15]=[C:16]([N:18]3[CH2:23][CH2:22][CH2:21][CH:20]([C:24]([NH:26][C:27]4[CH:36]=[CH:35][C:30]([C:31]([O:33]C)=[O:32])=[C:29]([O:37][CH3:38])[CH:28]=4)=[O:25])[CH2:19]3)[N:17]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[OH-].[Na+]>O1CCOCC1.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:11][C:12]2[C:13]3[N:41]=[CH:40][S:39][C:14]=3[N:15]=[C:16]([N:18]3[CH2:23][CH2:22][CH2:21][CH:20]([C:24]([NH:26][C:27]4[CH:36]=[CH:35][C:30]([C:31]([OH:33])=[O:32])=[C:29]([O:37][CH3:38])[CH:28]=4)=[O:25])[CH2:19]3)[N:17]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COC(=O)c1ccc(NC(=O)C2CCCN(c3nc(Nc4ccc(OC)c(OC)c4)c4ncsc4n3)C2)cc1OC
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: COc1ccc(Nc2nc(N3CCCC(C(=O)Nc4ccc(C(=O)O)c(OC)c4)C3)nc3scnc23)cc1OC
Temperature: 35 °C
Reaction time: 1 h
Yield: 54.7 %

Procedure:
To a solution of methyl 4-(1-(7-(3,4-dimethoxyphenylamino)thiazolo[5,4-d]pyrimidin-5-yl)piperidine-3-carboxamido)-2-methoxybenzoate (126 mg, 0.22 mmol) in dioxane/H2O (8 mL/8 mL) was added NaOH (75 mg, 1.9 mmol), the reaction mixture was heated to 35° C. with stirring for 1 hour, the dioxane was removed in vacuo, and the aqueous layer was adjusted to pH=4-5 with conc. HCl, the precipitate was collected by filtration and washed with methanol (5 mL) to afford 4-(1-(7-(3,4-dimethoxyphenylamino)thiazolo[5,4-d]pyrimidin-5-yl)piperidine-3-carboxamido)-2-methoxybenzoic acid (68 mg, 54.8%) as a off-white solid. 1H NMR (300 MHz, DMSO): δ 10.23 (s, 1H), 9.63 (s, 1H), 8.83 (s, 1H), 7.63 (d, 1H, J=2.1 Hz), 7.58 (d, 1H, J=8.4 Hz), 7.46 (s, 1H), 7.33 (dd, 1H, J1=8.7 Hz, J2=2.4 Hz), 7.14 (dd, 1H, J1=8.4 Hz, J2=1.5 Hz), 6.80-6.78 (m, 1H), 4.79 (d, 1H, J=11.7 Hz), 4.65 (d, 1H, J=12.6 Hz), 3.68-3.61 (m, 9H), 3.10-2.89 (m, 2H), 2.58-2.54 (m, 1H), 2.03-1.99 (m, 1H), 1.78-1.71 (m, 2H), 1.48-1.44 (m, 1H). LC-MS: 585 [M+H]+, tR=1.48 min. HPLC: 96.06% at 214 nm, 97.26% at 254 nm, tR=5.66 min.
Reaction SMILES: [CH2:1]([N:8]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[N+:22]([O-])=O)[C:9](=[O:15])[CH2:10][C:11]([O:13][CH3:14])=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CCO.[NH4+].[Cl-].[Fe]>[NH2:22][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[N:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:9](=[O:15])[CH2:10][C:11]([O:13][CH3:14])=[O:12]
Reactant: COC(=O)CC(=O)N(Cc1ccccc1)c1ccccc1[N+](=O)[O-]
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Product: COC(=O)CC(=O)N(Cc1ccccc1)c1ccccc1N
Temperature: 70 °C
Yield: 54.9 %

Procedure:
Iron powder (3 g) was added to a solution of methyl 3-(benzyl(2-nitrophenyl)amino)-3-oxopropanoate (400 mg, 1.22 mmol) in EtOH (10 mL) and NH4Cl (10 mL). The reaction mixture was heated at 70° C. for 2 h. The mixture was filtered off and the filtrate was extracted by EA (50 mL), the separated organic layer was dried over Na2SO4. After the solvent was removed in vacuum, the residue was purified by combi-flash to give methyl 3-((2-aminophenyl)(benzyl)amino)-3-oxopropanoate as a yellow solid (200 mg, 55%). LRMS (M+H)+: 298 m/z.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:14](=[O:15])[CH2:13][N:12]([C:16]3[CH:17]=[C:18]([CH:23]=[CH:24][CH:25]=3)[C:19]([O:21]C)=[O:20])[C:11]2=[O:26])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[I-].[Li+]>N1C=CC=CC=1>[CH:1]([C:4]1[CH:5]=[CH:6][C:7]([N:10]2[C:14](=[O:15])[CH2:13][N:12]([C:16]3[CH:17]=[C:18]([CH:23]=[CH:24][CH:25]=3)[C:19]([OH:21])=[O:20])[C:11]2=[O:26])=[CH:8][CH:9]=1)([CH3:3])[CH3:2]
Reactant: COC(=O)c1cccc(N2CC(=O)N(c3ccc(C(C)C)cc3)C2=O)c1
Agent: [I-]
Agent: [Li+]
Solvent: c1ccncc1
Product: CC(C)c1ccc(N2C(=O)CN(c3cccc(C(=O)O)c3)C2=O)cc1
Yield: 72.9 %

Procedure:
A solution of methyl 3-[1-(4-isopropylphenyl)-2,5-dioxo-imidazolidin-3-yl]-benzoate (0.30 g, 0.85 mmol) in pyridine (2 mL) was treated with anhydrous lithium iodide (1.5 g, 11.2 mmol), and the resulting mixture was heated to reflux for 4 h. The solution was cooled, evaporated and partitioned between ethyl acetate and 1N aq. HCl. The aqueous layer was extracted with more ethyl acetate, and the extracts were washed with satd. aq. brine, combined, dried over anhydrous magnesium sulfate, filtered and evaporated to afford the title product as a solid (0.21 g, 0.62 mmol, 73%), m.p. 249-252° C. 1H NMR (d6-DMSO, 300 MHz): d 13.09 (1H, br), 8.29 (1H, t, J=2 Hz), 7.82 (1H, d, J=8 Hz), 7.72 (1H, d, J=8 Hz), 7.56 (1H, t, J=8 Hz), 7.38 (2H, d, J=8 Hz), 7.31 (2H, d, J=8 Hz), 4.62 (2H, s), 2.96 (1H, m, J=7 Hz), 1.22 (6H, d, J=7 Hz). Mass spectrum (ES+): m/z 340 (18), 339 (100). Elemental analysis: calculated for C19H18N2O4 C, 67.45; H, 5.32; N, 8.28; observed C, 67.26; H, 5.10; N, 8.12.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[N:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:11]=[C:10]([C:18]3[CH:19]=[N:20][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:22][CH:23]=3)[N:9]=2)[CH:5]=[CH:4][N:3]=1.[C:28]([NH:32][S:33]([C:36]1[CH:37]=[C:38](B(O)O)[CH:39]=[CH:40][CH:41]=1)(=[O:35])=[O:34])([CH3:31])([CH3:30])[CH3:29]>>[C:28]([NH:32][S:33]([C:36]1[CH:37]=[CH:38][CH:39]=[C:40]([C:2]2[CH:7]=[C:6]([C:8]3[N:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:11]=[C:10]([C:18]4[CH:19]=[N:20][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:22][CH:23]=4)[N:9]=3)[CH:5]=[CH:4][N:3]=2)[CH:41]=1)(=[O:35])=[O:34])([CH3:31])([CH3:29])[CH3:30]
Reactant: CC(C)(C)NS(=O)(=O)c1cccc(B(O)O)c1
Reactant: FC(F)(F)c1ccc(-c2cc(C(F)(F)F)nc(-c3ccnc(Cl)c3)n2)cn1
Product: CC(C)(C)NS(=O)(=O)c1cccc(-c2cc(-c3nc(-c4ccc(C(F)(F)F)nc4)cc(C(F)(F)F)n3)ccn2)c1

Procedure:
3-{4-[4-Trifluoromethyl-6-(6-trifluoromethyl-pyridin-3-yl)-pyrimidin-2-yl]-pyridin-2-yl}-benzenesulfonic acid tert-butylamide was prepared from 2-(2-chloro-pyridin-4-yl)-4-trifluoromethyl-6-(6-trifluoromethyl-pyridin-3-yl)-pyrimidine (example B.4) (0.81 g, 2.0 mmol) and commercially available 3-(tert.-butylsulfamoyl)-phenylboronic acid (0.62 g, 2.4 mmol) according to the general procedure III. Obtained as off-white solid (0.71 g), which was subsequently deprotected.
Reaction SMILES: [CH3:1][S:2]([O:5][C:6]1[CH:7]=[CH:8][C:9]2[O:13][CH:12]([OH:14])[C:11]([CH3:16])([CH3:15])[C:10]=2[CH:17]=1)(=[O:4])=[O:3].[C:18](Cl)(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.Cl>N1C=CC=CC=1>[CH3:1][S:2]([O:5][C:6]1[CH:7]=[CH:8][C:9]2[O:13][CH:12]([O:14][C:18](=[O:25])[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:11]([CH3:15])([CH3:16])[C:10]=2[CH:17]=1)(=[O:3])=[O:4]
Reactant: CC1(C)c2cc(OS(C)(=O)=O)ccc2OC1O
Reactant: O=C(Cl)c1ccccc1
Agent: Cl
Solvent: c1ccncc1
Product: CC1(C)c2cc(OS(C)(=O)=O)ccc2OC1OC(=O)c1ccccc1

Procedure:
To a cooled solution of 2-hydroxy-2,3-dihydro-3,3-dimethylbenzofuran-5-yl methanesulphonate (8.0 parts) in dry pyridine (42 parts) was added benzoyl chloride (4.75 parts) at such a rate that the temperature did not exceed 10° C. After one hour the mixture was poured into a slight excess of dilute hydrochloric acid. The product was extracted with ether and the ethereal solution washed, dried with sodium sulphate and evaporated to give an oil which solidified on scratching. The solid was recrystallised from a mixture of benzene and light petroleum to give 2-benzoyloxy-2,3-dihydro-3,3-dimethylbenzofuran-5-yl methanesulphonate (5.1 parts), melting point 102°-104° C.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[C:6]([O:13][CH2:14][CH2:15][OH:16])[CH:7]=[CH:8][CH:9]=2)[N:4]=1.Cl[C:18]1[C:23]([N:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)=[N:22][CH:21]=[CH:20][N:19]=1>>[CH3:1][NH:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[C:6]([O:13][CH2:14][CH2:15][O:16][C:18]3[C:23]([N:24]4[CH2:25][CH2:26][NH:27][CH2:28][CH2:29]4)=[N:22][CH:21]=[CH:20][N:19]=3)[CH:7]=[CH:8][CH:9]=2)[N:4]=1
Reactant: Clc1nccnc1N1CCNCC1
Reactant: CNc1ccc2cccc(OCCO)c2n1
Product: CNc1ccc2cccc(OCCOc3nccnc3N3CCNCC3)c2n1
Yield: 31 %

Procedure:
The title compound was prepared according to the procedure of Example 90, Step 2, starting from the product obtained in Step 2 above and 2-chloro-3-( (1-piperazinyl)piperazine (from Example 90, Step 1). The crude product was purified by column chromatography (gradient: 1% NH4OH in EtOAc/MeOH (90:10) to 1% NH4OH in EtOAc/MeOH (80:20) in first purification step and gradient 0.5% NH4OH in CHCl3/MeOH (95:5) to 1% NH4OH in CHCl3/MeOH (90:10) in second purification). Yield 31%; mp 54.0-56.5° C.; MS m/z 381 (M+H)+. Anal. (C20H24N6O20.5 H2O) C, H, N.
Reaction SMILES: [C:1]([NH:4][CH:5]1[CH2:14][CH2:13][C:12]2[C:7](=[CH:8][C:9]([O:15][CH3:16])=[CH:10][CH:11]=2)[C:6]1=[O:17])(=[O:3])[CH3:2].[BH4-].[Na+].C(O)(=O)C.CCOCC>C(O)C>[C:1]([NH:4][C@@H:5]1[CH2:14][CH2:13][C:12]2[C:7](=[CH:8][C:9]([O:15][CH3:16])=[CH:10][CH:11]=2)[C@H:6]1[OH:17])(=[O:3])[CH3:2]
Reactant: COc1ccc2c(c1)C(=O)C(NC(C)=O)CC2
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CCO
Solvent: CC(=O)O
Product: COc1ccc2c(c1)[C@@H](O)[C@H](NC(C)=O)CC2
Reaction time: 0.5 h
Yield: 35 %

Procedure:
To a stirred solution of 2-acetamido-7-methoxy-3,4-dihydronaphthalen 1(2H)-one in absolute ethanol (100 ml) was added sodium borohydride (1.6 gms, 0.04 m) in portions. After stirring for 1/2 hour, acetic acid was added to decompose any excess sodium borohydride. The reaction mixture was poured onto water (150 ml) and this was extracted with ethyl acetate (3×150). The ethyl acetate was washed with aqueous saturated sodium chloride, and was dried over anhydrous sodium sulfate. After filtration, the ethyl acetate was removed under reduced pressure (20 mm) to give a semisolid. The solid was slurried with ether and filtered to yield 3.3 gms (35%) of product as a white solid, m.p. 135°-140° C.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([O:15][C:16]2[CH:17]=[N:18][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:20][CH:21]=2)[CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12](=[S:14])[NH2:13])=[CH:8]2)[CH3:2].[C:26]([O:31][CH2:32][CH3:33])(=[O:30])[C:27]#[C:28][CH3:29].O1CCCC1.C(P(CCCC)CCCC)CCC>C1(C)C=CC=CC=1>[CH2:32]([O:31][C:26](=[O:30])[CH2:27][CH:28]1[S:14][C:12]([C:9]2[NH:10][C:11]3[C:7]([CH:8]=2)=[CH:6][C:5]([O:15][C:16]2[CH:17]=[N:18][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:20][CH:21]=2)=[CH:4][C:3]=3[CH2:1][CH3:2])=[N:13][CH2:29]1)[CH3:33]
Reactant: CC#CC(=O)OCC
Reactant: CCc1cc(Oc2ccc(S(C)(=O)=O)nc2)cc2cc(C(N)=S)[nH]c12
Agent: CCCCP(CCCC)CCCC
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CCOC(=O)CC1CN=C(c2cc3cc(Oc4ccc(S(C)(=O)=O)nc4)cc(CC)c3[nH]2)S1
Temperature: 40 °C
Reaction time: 3 h
Yield: 84 %

Procedure:
To a mixed solution of 7-ethyl-5-{[6-(methylsulfonyl)pyridin-3-yl]oxy}-1H-indole-2-carbothioamide (2.8 g), ethyl 2-butynoate (1.8 mL), tetrahydrofuran (40 mL), and toluene (60 mL), tri-n-butylphosphine (2.2 mL) was added under an argon atmosphere at room temperature, and the mixture was stirred at 40° C. for 3 hr. The reaction solution was concentrated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (ethyl acetate:hexane=25:75 to 60:40, volume ratio) to give the title compound (3.05 g, yield 84%) as a pale-yellow amorphous solid.