Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[C:18]([CH3:23])[C:17]=1[CH3:24].C1(C)C=CC=CC=1.C(N(CC)CC)C.ClC(Cl)(O[C:43](=[O:49])[O:44][C:45](Cl)(Cl)Cl)Cl.[CH3:51][O:52][C:53]1[CH:63]=[CH:62][C:56]([O:57][CH2:58][CH2:59]CO)=[CH:55][CH:54]=1>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:43](=[O:49])[O:44][CH2:45][CH2:59][CH2:58][O:57][C:56]2[CH:62]=[CH:63][C:53]([O:52][CH3:51])=[CH:54][CH:55]=2)=[C:18]([CH3:23])[C:17]=1[CH3:24]
Reactant: COc1ccc(OCCCO)cc1
Reactant: COc1cc2nccc(Oc3ccc(N)c(C)c3C)c2cc1OC
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: COc1ccc(OCCCOC(=O)Nc2ccc(Oc3ccnc4cc(OC)c(OC)cc34)c(C)c2C)cc1
Temperature: 25 °C
Yield: 88.6 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2,3-dimethylaniline (88 mg) was added to toluene/triethylamine=10/1 (9 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (122 mg) in methylene chloride was then added to the solution, and the mixture was heated under reflux for 15 min. Subsequently, 3-(4-methoxyphenoxy)-1-propanol (74 mg) was added thereto, and the mixture was further stirred with heating under reflux for 2 hr. After the completion of the reaction, the reaction solution was allowed to cool to room temperature before distilled water was added thereto. The mixture was subjected to separatory extraction with chloroform, followed by washing with a 1 N aqueous hydrochloric acid solution and saturated brine. The washed solution was dried over sodium sulfate and was concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (128 mg, yield 83%).
Reaction SMILES: Br[CH2:2][CH2:3][N:4]1[C:29](=[O:30])[N:7]2[CH:8]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([OH:28])[CH:23]=3)[C:9]3[NH:10][C:11]4[C:16]([C:17]=3[CH2:18][C:6]2([CH3:31])[C:5]1=[O:32])=[CH:15][C:14]([O:19][CH2:20][CH3:21])=[CH:13][CH:12]=4.[CH3:33][NH:34][CH3:35].O>C(#N)C.O1CCCC1.C(=O)([O-])[O-].[Na+].[Na+]>[CH3:33][N:34]([CH3:35])[CH2:2][CH2:3][N:4]1[C:29](=[O:30])[N:7]2[CH:8]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([OH:28])[CH:23]=3)[C:9]3[NH:10][C:11]4[C:16]([C:17]=3[CH2:18][C:6]2([CH3:31])[C:5]1=[O:32])=[CH:15][C:14]([O:19][CH2:20][CH3:21])=[CH:13][CH:12]=4
Reactant: CNC
Reactant: CCOc1ccc2[nH]c3c(c2c1)CC1(C)C(=O)N(CCBr)C(=O)N1C3c1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: C1CCOC1
Solvent: O
Product: CCOc1ccc2[nH]c3c(c2c1)CC1(C)C(=O)N(CCN(C)C)C(=O)N1C3c1cccc(O)c1
Yield: 44 %

Procedure:
To a suspension of 200 mg (3aSR,10RS)-2-(2-Bromo-ethyl)-6-ethoxy-10-(3-hydroxy-phenyl)-3a-methyl-3a,4,9,10-tetrahydro-2,9,10a-triaza-cyclopenta[b]fluorene-1,3-dione (example 22) in 10 ml acetonitrile are added 200 μl of a 2 M solution of dimethyl amine in tetrahydrofurane and 85 mg sodium carbonate. The mixture is heated to reflux and additional 1 ml of the 2 m solution of dimethyl amine in THF are added. After additional 2 h heating to reflux, another 600 μl of the solution of dimethyl amine in THF are added. The mixture is heated to reflux for 15 h. Water is added and the mixture is extracted with ethyl acetate. The combined organic layers are washed with brine and dried with magnesium sulfate. After removal of the solvent under reduced pressure, the residue is triturated with diisopropyl ether. 82 mg (44%) of title compound are obtained as a colorless solid. MS: m/z (MH+)=463.2
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[C:10]([N+:12]([O-:14])=[O:13])[CH:11]=1)[CH2:7]Cl)([O-:3])=[O:2].[C:15]1([S:21][C:22]2[NH:26][N:25]=[N:24][N:23]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(N(CC)CC)C>O1CCCC1.O>[N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[C:10]([N+:12]([O-:14])=[O:13])[CH:11]=1)[CH2:7][N:26]1[C:22]([S:21][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[N:23][N:24]=[N:25]1)([O-:3])=[O:2]
Reactant: c1ccc(Sc2nnn[nH]2)cc1
Reactant: O=[N+]([O-])c1cc(CCl)cc([N+](=O)[O-])c1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O
Product: O=[N+]([O-])c1cc(Cn2nnnc2Sc2ccccc2)cc([N+](=O)[O-])c1
Temperature: 10 °C
Reaction time: 8 h
Yield: 94.2 %

Procedure:
To a solution of 50 g (0.231 mol) of 3,5-dinitrobenzylchloride and 41 g (0.231 mol) of phenylmercaptotetrazole in one liter of dry tetrahydrofuran under nitrogen was added all at once with stirring 23.4 g (0.231 mol) of triethylamine. The temperature rose slowly from 23° to 29°. After stirring overnight the reaction mixture was diluted with one liter of water, cooled to 10° C., filtered and the filter cake was washed well with water. Oven drying at 110° C. for 24 hours gave 78 g (83%) of product mp. 156°-158° C. Recrystallization from tetrahydrofuran gives analytically pure 5, mp. 161.5°-162.5° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9]C(O)=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.C(N=C=NCCCN(C)C)C.O.[OH:26]N1C2C=CC=CC=2N=N1.[CH:36]([C:39]1[C:47]2[C:42](=[N:43][CH:44]=[CH:45][C:46]=2[C:48]2[CH:49]=[N:50][C:51]3[C:56]([CH:57]=2)=[CH:55][CH:54]=[CH:53][CH:52]=3)[N:41]([C:58]2[CH:65]=[CH:64][C:61]([C:62]#[N:63])=[C:60]([NH:66][CH:67]3[CH2:72][CH2:71][NH:70][CH2:69][CH2:68]3)[CH:59]=2)[N:40]=1)([CH3:38])[CH3:37]>CN(C=O)C.O.C(OCC)(=O)C>[C:62]([C:61]1[CH:64]=[CH:65][C:58]([N:41]2[C:42]3=[N:43][CH:44]=[CH:45][C:46]([C:48]4[CH:49]=[N:50][C:51]5[C:56]([CH:57]=4)=[CH:55][CH:54]=[CH:53][CH:52]=5)=[C:47]3[C:39]([CH:36]([CH3:38])[CH3:37])=[N:40]2)=[CH:59][C:60]=1[NH:66][CH:67]1[CH2:68][CH2:69][N:70]([O:26][CH2:9][NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[CH2:71][CH2:72]1)#[N:63]
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Reactant: CC(C)c1nn(-c2ccc(C#N)c(NC3CCNCC3)c2)c2nccc(-c3cnc4ccccc4c3)c12
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)c1nn(-c2ccc(C#N)c(NC3CCN(OCNC(=O)OC(C)(C)C)CC3)c2)c2nccc(-c3cnc4ccccc4c3)c12
Temperature: 25 °C
Reaction time: 15 h

Procedure:
N-(Tert-butoxycarbonyl)glycine (0.021 g), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.029 g), and 1-hydroxybenzotriazole monohydrate (0.016 g) were added to a solution of compound (77a) (0.050 g) in DMF (1.0 mL), followed by stirring under argon flow at room temperature for 15 hr. The reaction solution was distributed between ethyl acetate and water, and the organic layer was washed with saturated saline. The organic layer after the washing was dried over anhydrous sodium sulfate, and then the solvent was distilled away to obtain tert-butyl 2-{4-(2-cyano-5-(3-isopropyl-4-(quinolin-3-yl)-1H-pyrazolo[3,4-b]pyridin-1-yl)phenylamino)piperidin-1-yl}-2-oxaethylcarbamate, which was used in the subsequent reaction without being purified. According to Example 1(7), tert-butyl 2-{4-(2-carbamoyl-5-(3-isopropyl-4-(quinolin-3-yl)-1H-pyrazolo[3,4-b]pyridin-1-yl)phenylamino)piperidin-1-yl}-2-oxaethylcarbamate was prepared using tert-butyl 2-{4-(2-cyano-5-(3-isopropyl-4-(quinolin-3-yl)-1H-pyrazolo[3,4-b]pyridin-1-yl)phenylamino)piperidin-1-yl}-2-oxaethylcarbamate instead of (1f) and was used in the subsequent reaction without being purified. Tert-butyl 2-{4-(2-carbamoyl-5-(3-isopropyl-4-(quinolin-3-yl)-1H-pyrazolo[3,4-b]pyridin-1-yl)phenylamino)piperidin-1-yl}-2-oxaethylcarbamate was dissolved in trifluoroacetic acid, followed by stirring at room temperature for 1 hr. The reaction solution was distributed between chloroform and saturated sodium bicarbonate water. The organic layer was washed with saturated saline and then dried over anhydrous sodium sulfate. After distillation of the solvent, the residue was purified by neutral silica gel column chromatography (chloroform/methanol) to obtain compound (79) (0.035 g, the third stage yield: 55%) as a white solid.
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:9][C:10]1[CH:27]=[CH:26][C:25]2[C@@H:24]3[C@H:15]([C@H:16]4[C@@:20]([CH2:22][CH2:23]3)([CH3:21])[C:19](=[O:28])[CH2:18][CH2:17]4)[C@@H:14]([OH:29])[CH2:13][C:12]=2[CH:11]=1.[OH-].[Li+]>CN(C)C=O>[CH2:1]([O:9][C:10]1[CH:27]=[CH:26][C:25]2[C@@H:24]3[C@H:15]([C@H:16]4[C@@:20]([CH2:22][CH2:23]3)([CH3:21])[C:19](=[O:28])[CH2:18][CH2:17]4)[C@@H:14]([OH:29])[CH2:13][C:12]=2[CH:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: BrCc1ccccc1
Reactant: C[C@]12CC[C@@H]3c4ccc(O)cc4C[C@H](O)[C@H]3[C@@H]1CCC2=O
Agent: [Li+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: C[C@]12CC[C@@H]3c4ccc(OCc5ccccc5)cc4C[C@H](O)[C@H]3[C@@H]1CCC2=O
Temperature: 100 °C
Reaction time: 0.5 h

Procedure:
12.83 g (75 mmol) of benzylbromide is added to a suspension of 20 g (67.74 mmol) of 3,7β-dihydroxy-estra-1,3,5(10)-trien-17-one, 3.55 g (148.23 mmol) of lithium hydroxide in 700 ml of dry dimethylformamide, and it is stirred under an argon atmosphere for 30 minutes at 100° C. For working-up, the reaction solution is poured into tartaric-acid ice water, the precipitated product is suctioned off and dried in air. The crude product is taken up in dichloromethane, the organic phase is washed with water and dried on sodium sulfate. After the solvent is drawn off in a vacuum, it is chromatographed on silica gel (dichloromethane-ethyl acetate, gradient of up to 3:2), yield 22.81 g (87%).
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.[C:17]([O:21][C:22](=[O:33])[NH:23][C@H:24]1[CH2:29][CH2:28][C@H:27]([CH2:30][CH:31]=O)[CH2:26][CH2:25]1)([CH3:20])([CH3:19])[CH3:18].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[C:17]([O:21][C:22](=[O:33])[NH:23][C@H:24]1[CH2:25][CH2:26][C@H:27]([CH2:30][CH2:31][N:12]2[CH2:11][CH2:10][CH:9]([C:6]3[C:5]4[CH:15]=[CH:16][C:2]([F:1])=[CH:3][C:4]=4[O:8][N:7]=3)[CH2:14][CH2:13]2)[CH2:28][CH2:29]1)([CH3:20])([CH3:19])[CH3:18]
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](CC=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@H](CCN2CCC(c3noc4cc(F)ccc34)CC2)CC1
Reaction time: 12 h

Procedure:
A mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (4 g, 18.1 mmol), trans-[4-(2-oxo-ethyl)-cyclohexyl]-carbamic acid tert-butyl ester (5.4 g, 22.7 mmol), in 1,2 dichloroethane (55 mL) was stirred for 4 h at room temperature and sodium triacetoxyborohydride (6.9 g, 32.7 mmol) was added slowly and the resulting solution was stirred for 12 hours until the TLC indicated completion of the reaction. The mixture was filtrated and concentrated to dryness and purified with column chromatography on silica gel using CH2Cl2—CH2Cl2/MeOH (1-9:1). The product fractions were concentrated to give 9.4 g (21 mmol, 100% yield) of a light brown solid. MS (m/e): 446.3 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[N:7][N:8]([C:11]([CH3:14])([CH3:13])[CH3:12])[C:9]=1[CH3:10])=[O:4].[Br:15]N1C(=O)CCC1=O.[Al]>C(Cl)(Cl)(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[N:7][N:8]([C:11]([CH3:14])([CH3:13])[CH3:12])[C:9]=1[CH2:10][Br:15])=[O:4]
Reactant: COC(=O)c1cnn(C(C)(C)C)c1C
Reactant: O=C1CCC(=O)N1Br
Agent: [Al]
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1cnn(C(C)(C)C)c1CBr
Yield: 95.2 %

Procedure:
A solution of 1-tert-butyl-5-methyl-1H-pyrazole-4-carboxylic acid methyl ester (3.38 g, 17.22 mmol) (as described in Example 54, Step 2) in carbon tetrachloride (12.2 mL, 1.41M) at 25° C. was treated with N-bromosuccinimide (3.10 g, 17.41 mmol). The reaction flask was fitted with a reflux condenser. The set-up was wrapped with aluminum foil and was then illuminated with a 250 Watt sun lamp for 3 h. At this time, the reaction was filtered and was rinsed with carbon tetrachloride. The filtrate was transferred to a separatory funnel and was washed with water (1×50 mL) and a saturated aqueous sodium chloride solution (1×50 mL). The organics were dried over magnesium sulfate, filtered, rinsed with carbon tetrachloride and concentrated in vacuo to a light yellow oil. ISCO CombiFlash chromatography (120 g, 0-10% ethyl acetate/hexanes) afforded 5-bromomethyl-1-tert-butyl-1H-pyrazole-4-carboxylic acid methyl ester (4.51 g, 95%) as a clear oil. The material was used without further purification.
Reaction SMILES: FC(F)(F)C(O)=O.C(O)(=O)C.Br[CH:13]([C:31](=[O:38])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[CH:14]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:15]([N:17]1[CH2:24][CH2:23][CH2:22][C@H:18]1[C:19]([OH:21])=[O:20])=[O:16].[C:39]([O-:42])(=[S:41])[CH3:40].[Na+]>C(#N)C>[C:39]([S:41][CH:13]([C:31](=[O:38])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[CH:14]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:15]([N:17]1[CH2:24][CH2:23][CH2:22][C@H:18]1[C:19]([OH:21])=[O:20])=[O:16])(=[O:42])[CH3:40]
Reactant: CC([O-])=S
Reactant: O=C(c1ccccc1)C(Br)C(C(=O)N1CCC[C@H]1C(=O)O)c1ccccc1
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)SC(C(=O)c1ccccc1)C(C(=O)N1CCC[C@H]1C(=O)O)c1ccccc1

Procedure:
A 0.01 mole sample of 3-benzoyl-2-(phenyl)propionic acid is dissolved in tetrahydrofuran and 0.01 mole of N,N-carbonyldiimidazole added. After stirring 3 hours at room temperature, 0.01 mole of L-proline t-butyl ester is added. After 24 hours the solvent is removed and 1-[3-benzoyl-2-(phenyl)-propionyl]-L-proline t-butyl ester isolated. The preceding compound is reacted with trifluoroacetic acid to remove the t-butyl group. Separation of isomers A and B is carried out as described for Example 69. Reaction of the isomers with bromine is acetic acid and reaction of the 1-[3-bromo-3-benzoyl-2-(phenyl)propionyl]-L-proline isomers with sodium thioacetate in acetonitrile as for Example 69 gives the products of the example. The product from isomer A is separated by chromatography to give [S-(R*,R*)] and [S-(R*,S*)]-1-[3-acetylthio-3-benzoyl-2-(phenyl)propionyl]-L-proline.
Reaction SMILES: Cl.[F:2][C:3]1[C:11]2[NH:10][C:9](=[O:12])[N:8]([CH:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)[C:7]=2[CH:6]=[C:5]([CH3:19])[CH:4]=1.C(N(CC)CC)C.[O:27]1[CH2:32][CH2:31][C:30](=O)[CH2:29][CH2:28]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl.ClCCCl>[F:2][C:3]1[C:11]2[NH:10][C:9](=[O:12])[N:8]([CH:13]3[CH2:18][CH2:17][N:16]([CH:30]4[CH2:31][CH2:32][O:27][CH2:28][CH2:29]4)[CH2:15][CH2:14]3)[C:7]=2[CH:6]=[C:5]([CH3:19])[CH:4]=1
Reactant: Cc1cc(F)c2[nH]c(=O)n(C3CCNCC3)c2c1
Reactant: O=C1CCOCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCCl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cc(F)c2[nH]c(=O)n(C3CCN(C4CCOCC4)CC3)c2c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
4-Fluoro-6-methyl-1-(4-piperidinyl)-1,3-dihydro-2H-benzimidazol-2-one hydrochloride (D5) (0.072 mmol, 21 mg) was dissolved in dichloromethane (2 ml) and triethylamine (3 eq., 0.216 mmol, 30 microliters), tetrahydro-4H-pyran-4-one (7 eq., 0.5 mmol, 47 microliters) were added and the mixture was stirred at room temperature for 10 minutes; sodium triacetoxyborohydride (7 eq., 0.5 mmol, 106 mg) was added at room temperature and the mixture was stirred at room temperature for one overnight. Reaction mixture was quenched with NaHCO3 (saturated solution) and diluted with dichloromethane; the two phases were separated and the organic solvent was evaporated to afford the crude product. The crude obtained was dissolved in 1,2-dichloroethane (3 ml) and triethylamine (3 eq., 0.216 mmol, 30 microliters), tetrahydro-4H-pyran-4-one (7 eq., 0.5 mmol, 47 microliters) were added again and the mixture was stirred at room temperature for 10 minutes; sodium triacetoxyborohydride (7 eq., 0.5 mmol, 106 mg) was subsequently added at room temperature and the mixture was stirred at room temperature for 3 extra hours. Reaction mixture was quenched with NaHCO3 (saturated solution) and diluted with dichloromethane; the two phases were separated and the organic solvent was evaporated to afford the crude product that was purified by chromatography (methanol-NH3-dichloromethane) to afford 4-fluoro-6-methyl-1-[1-(tetrahydro-2H-pyran-4-yl)-4-piperidinyl]-1,3-dihydro-2H-benzimidazol-2-one, 10 mg, 42%, M++H=334, which was converted to the HCl salt using 1M HCl in diethyl ether.
Reaction SMILES: [CH3:1][S:2]([C:4]1[CH:5]=[C:6]([CH2:10][C:11]([OH:13])=[O:12])[CH:7]=[CH:8][CH:9]=1)=[O:3].[C:14](N1C=CN=C1)(N1C=CN=C1)=O.CO>C1COCC1>[CH3:1][S:2]([C:4]1[CH:5]=[C:6]([CH2:10][C:11]([O:13][CH3:14])=[O:12])[CH:7]=[CH:8][CH:9]=1)=[O:3]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CS(=O)c1cccc(CC(=O)O)c1
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)Cc1cccc(S(C)=O)c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 81.4 %

Procedure:
A solution of [3-(methylsulfinyl)phenyl]acetic acid (1.31 g, 6.60 mmol) and carbonyldiimidazole (1.18 g, 7.26 mmol) in 25.0 mL THF was stirred at room temperature for 15 minutes, then methanol (2.1 mL, 52.8 mmol) was added. After 10 minutes the reaction was briefly warmed to near reflux temperature, then allowed to cool to room temperature. After 20 minutes, the reaction was partitioned between EtOAc and NaHCO3/brine mixture. The EtOAc layer was washed with dilute brine, dilute HCl solution, brine, dried with anhydrous Na2SO4 and rotary evaporated to give the title compound as a yellow-orange oil (1.14 g, 82%).
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])C.C(O)=O.[Br:11][C:12]1[N:17]=[C:16]([CH2:18][NH:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][C:22]=2[O:29][CH3:30])[CH:15]=[CH:14][CH:13]=1>O1CCCC1>[Br:11][C:12]1[N:17]=[C:16]([CH2:18][N:19]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][C:22]=2[O:29][CH3:30])[CH:1]=[O:3])[CH:15]=[CH:14][CH:13]=1
Reactant: COc1ccc(CNCc2cccc(Br)n2)c(OC)c1
Reactant: CC(=O)OC(C)=O
Solvent: C1CCOC1
Solvent: O=CO
Product: COc1ccc(CN(C=O)Cc2cccc(Br)n2)c(OC)c1
Temperature: 55 °C
Reaction time: 0.75 h

Procedure:
To acetic anhydride (0.703 mL) was added dropwise formic acid (0.349 mL) under ice-cooling, and the mixture was stirred at 55° C. for 45 min. The mixture was allowed to be cooled to room temperature, and tetrahydrofuran (10 mL) was added thereto. A solution of 1-(6-bromopyridin-2-yl)-N-(2,4-dimethoxybenzyl)methanamine obtained in Reference Example 19 (930 mg) in tetrahydrofuran (10 mL) was added dropwise thereto over 3 min under ice-cooling, and the reaction mixture was stirred at room temperature for 30 min. The reaction solution was concentrated under reduced pressure, the obtained colorless oil was subjected to azeotropy with toluene, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (932 mg).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[CH:4]([CH2:14][C:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[NH:17][CH:16]=1)[NH:5][CH2:6][O:7][CH:8]([Si:10]([CH3:13])([CH3:12])[CH3:11])[CH3:9].C(N(C(C)C)CC)(C)C.[CH:34]12[CH2:43][CH:38]3[CH2:39][CH:40]([CH2:42][CH:36]([CH2:37]3)[CH:35]1[O:44][C:45](Cl)=[O:46])[CH2:41]2>C1COCC1.O>[CH3:1][O:2][C:3](=[O:24])[CH:4]([CH2:14][C:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[NH:17][CH:16]=1)[N:5]([CH2:6][O:7][CH:8]([Si:10]([CH3:13])([CH3:12])[CH3:11])[CH3:9])[C:45]([O:44][CH:35]1[CH:34]2[CH2:43][CH:38]3[CH2:39][CH:40]([CH2:42][CH:36]1[CH2:37]3)[CH2:41]2)=[O:46]
Reactant: COC(=O)C(Cc1c[nH]c2ccccc12)NCOC(C)[Si](C)(C)C
Reactant: O=C(Cl)OC1C2CC3CC(C2)CC1C3
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)C(Cc1c[nH]c2ccccc12)N(COC(C)[Si](C)(C)C)C(=O)OC1C2CC3CC(C2)CC1C3
Temperature: 25 °C
Reaction time: 4 h
Yield: 67.8 %

Procedure:
A mixture of α-trimethylsilylethoxymethyl-DL-tryptophan methyl ester (1.0 g, 2.8 mmol), diisopropylethylamine (0.4 g, 3 mmol) and 2-adamantylchloroformate (0.65 g, 3 mmol) in 20 mL dry THF was stirred at room temperature for 4 hours. The reaction mixture was diluted with distilled water and extracted with ethyl acetate (4×50 mL). The organic extract was washed with brine and dried over Na2SO4. Evaporation of the organic solvent gave the title compound as a colorless foam (1.0 g, 67.8%). -[(2-Adamantyloxy)carbonyl]-α-trimethylsilylethoxymethylmethyl-DL-tryptophan
Reaction SMILES: [CH:1]([CH:5]1[NH:10][NH:9][C:8](=[S:11])[N:7]([CH3:12])[C:6]1=[O:13])([CH2:3][CH3:4])[CH3:2].[OH-].[Na+].[CH3:16]I>O>[CH:1]([C:5]1[C:6](=[O:13])[N:7]([CH3:12])[C:8]([S:11][CH3:16])=[N:9][N:10]=1)([CH2:3][CH3:4])[CH3:2]
Reactant: CI
Reactant: CCC(C)C1NNC(=S)N(C)C1=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCC(C)c1nnc(SC)n(C)c1=O

Procedure:
1 ml of 3-benzyl-4-hydroxy-biphenyl polyglycol ether, as an emulsifier, and 995 g (5 mol) of 6-sec.-butyl-4-methyl-5-oxo-3-thioxo-tetrahydro-1,2,4(2H,4H)-triazine (IX) were added to a solution of 202 g of NaOH in 5 liters of water. 724 g (5.1 mol) of methyl iodide were added dropwise and the mixture was subsequently stirred until the slightly exothermic reaction had ended and the pH value had reached 7-8. After filtering off the product, washing it with water and drying it at 30° C. in vacuo, 907 g (85% of theory) of the compound (IIb) of melting point 45°-50° C. were obtained. The crude product was sufficiently pure for further reaction. A sample recrystallised from pentane melted at 54°-55° C.
Reaction SMILES: [K].[C:2]([O:5][C:6]1[CH:18]=[CH:17][C:16]([CH:19]=[CH:20][C:21]2[CH:26]=[CH:25][C:24]([S:27]([OH:30])(=O)=[O:28])=[CH:23][CH:22]=2)=[CH:15][C:7]=1[C:8]([O:10][CH2:11][CH:12]([CH3:14])[CH3:13])=[O:9])(=[O:4])[CH3:3].CN(C)C=O.S(Cl)([Cl:38])=O.[OH-].[Na+]>ClCCl.O>[C:2]([O:5][C:6]1[CH:18]=[CH:17][C:16]([CH:19]=[CH:20][C:21]2[CH:26]=[CH:25][C:24]([S:27]([Cl:38])(=[O:30])=[O:28])=[CH:23][CH:22]=2)=[CH:15][C:7]=1[C:8]([O:10][CH2:11][CH:12]([CH3:14])[CH3:13])=[O:9])(=[O:4])[CH3:3]
Reactant: CC(=O)Oc1ccc(C=Cc2ccc(S(=O)(=O)O)cc2)cc1C(=O)OCC(C)C
Reactant: O=S(Cl)Cl
Agent: [K]
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: O
Product: CC(=O)Oc1ccc(C=Cc2ccc(S(=O)(=O)Cl)cc2)cc1C(=O)OCC(C)C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Isobutyl 2-acetyloxy-5-[2-(4-sulfophenyl)ethenyl]benzoate potassium salt (36.1 g, 0.08 mol) was suspended in dichloromethane. Dimethylformamide (20 ml) and thionyl chloride (20 ml) were added, and the mixture refluxed with stirring for 3 h. After cooling to room temperature, water (15 ml) was added. By careful addition of 5M sodium hydroxide, the pH of the aqueous phase was adjusted to about 7. The phases were separated and the organic phase washed with water. The solution was dried (MgSO4), treated with activated carbon and filtered. After evaporation of the solvent, the solid residue was recrystallized from a toluene and petroleum ether mixture. Yield 19.5 g (57%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[CH:9]([CH3:24])[C:10]([C:16]1[CH:17]=[CH:18][C:19](=[O:23])[N:20]([CH3:22])[CH:21]=1)([OH:15])[C:11]([F:14])([F:13])[F:12].[F:25][C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][C:33]=1F)[C:29]#[N:30].C(=O)([O-])[O-].[Cs+].[Cs+].CCOC(C)=O>CN(C)C(=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([CH:5]=[CH:4][C:3]=1[CH:9]([CH3:24])[C:10]([OH:15])([C:16]1[CH:17]=[CH:18][C:19](=[O:23])[N:20]([CH3:22])[CH:21]=1)[C:11]([F:13])([F:14])[F:12])[O:8][C:33]1[CH:32]=[CH:31][C:28]([C:29]#[N:30])=[CH:27][C:26]=1[F:25]
Reactant: CC(c1ccc(O)cc1Cl)C(O)(c1ccc(=O)n(C)c1)C(F)(F)F
Reactant: N#Cc1ccc(F)c(F)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: CC(c1ccc(Oc2ccc(C#N)cc2F)cc1Cl)C(O)(c1ccc(=O)n(C)c1)C(F)(F)F
Temperature: 25 °C
Reaction time: 18 h
Yield: 100.1 %

Procedure:
To a solution of 5-[2-(2-chloro-4-hydroxy-phenyl)-1-hydroxy-1-trifluoromethyl-propyl]-1-methyl-1H-pyridin-2-one (Example 196, 100 mg) in N,N-dimethylacetamide (2 ml) were added 3,4-difluorobenzonitrile (46 mg) and cesium carbonate (272 mg). The mixture was stirred for 18 h at room temperature. EtOAc and ice water were added and the mixture was extracted with EtOAc. The organic phase was washed with water, dried (MgSO4), filtered and concentrated to dryness. The product was purified by chromatography (SiO2, cyclohexane/EtOAc 95:5=>0:1) to give the title compound (133 mg) as a colorless solid. MS (m/e)=481.1 [M+H+].