Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:34])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[C:11]([NH2:33])=[CH:12][C:13]2[N:17]=[C:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[N:15]([C:24]3[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=3)[C:14]=2[CH:32]=1.[F:35][C:36]([F:48])([F:47])[C:37]1[CH:42]=[CH:41][C:40]([S:43](Cl)(=[O:45])=[O:44])=[CH:39][CH:38]=1>>[CH3:1][O:2][C:3](=[O:34])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[C:11]([NH:33][S:43]([C:40]2[CH:39]=[CH:38][C:37]([C:36]([F:35])([F:47])[F:48])=[CH:42][CH:41]=2)(=[O:45])=[O:44])=[CH:12][C:13]2[N:17]=[C:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[N:15]([C:24]3[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=3)[C:14]=2[CH:32]=1
Reactant: O=S(=O)(Cl)c1ccc(C(F)(F)F)cc1
Reactant: COC(=O)CCCCCOc1cc2c(cc1N)nc(-c1ccccc1)n2-c1ccc(OC)cc1
Product: COC(=O)CCCCCOc1cc2c(cc1NS(=O)(=O)c1ccc(C(F)(F)F)cc1)nc(-c1ccccc1)n2-c1ccc(OC)cc1

Procedure:
6-[(5-Amino-1-(4-methoxyphenyl)-2-phenyl-1H-benzimidazol-6-yl)oxy]hexanoic acid methyl ester was reacted with 4-(trifluoromethyl)benzenesulfonic acid chloride according to general operating instructions 13.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@H:9]([CH2:20][CH:21]=O)[CH2:10][N:11]([CH3:19])[C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH:5]=[CH:6][C:7]=1[Cl:8].Cl.[NH:24]1[CH2:27][CH:26]([N:28]2[CH2:33][CH2:32][S:31][CH2:30][CH2:29]2)[CH2:25]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(N(CC)CC)C>ClCCCl>[Cl:1][C:2]1[CH:3]=[C:4]([C@H:9]([CH2:20][CH2:21][N:24]2[CH2:27][CH:26]([N:28]3[CH2:33][CH2:32][S:31][CH2:30][CH2:29]3)[CH2:25]2)[CH2:10][N:11]([CH3:19])[C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CN(C[C@@H](CC=O)c1ccc(Cl)c(Cl)c1)C(=O)OC(C)(C)C
Reactant: C1CN(C2CNC2)CCS1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: CN(C[C@@H](CCN1CC(N2CCSCC2)C1)c1ccc(Cl)c(Cl)c1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 5 h
Yield: 30.3 %

Procedure:
tert-Butyl [(2S)-2-(3,4-dichlorophenyl)-4-oxobutyl]methylcarbamate (see WO 95/05377; 610 mg, 1.8 mmol) was dissolved in 1,2-dichloroethane (20 mL) and to the resultant solution was added 4-azetidin-3-ylthiomorpholine hydrochloride (430 mg, 1.9 mmol) followed by the addition of sodium triacetoxyborohydride (480 mg, 2.2 mmol). The mixture was stirred at room temperature for 5 h and then triethylamine (0.73 mL, 5.2 mmol) was added. The reaction mixture was stirred for 2 h and then partitioned between CH2Cl2 and NaHCO3 aq. The organic layer was washed with water and the combined organic solutions were dried over MgSO4. The solvent was removed by evaporation to yield an oil, which was chromatographed on a reversed phase column using a mixture of acetonitrile and 0.1 M ammonium acetate aq. The appropriate fractions were extracted with ether. The organic solution was dried over MgSO4 and then the solvent was removed by evaporation. There was obtained 266 mg (31%) of tert-butyl [(2S)-2-(3,4-dichlorophenyl)-4-(3-thiomorpholin-4-ylazetidin-1-yl)butyl]methylcarbamate as an oil. 1H NMR (400 MHz, CDCl3): 1.4 (s, 9H), 1.5-3.5 (c m, 23H), 7.0 (dd, 1H), 7.3 (d, 1H), 7.4 (d, 1H); LCMS: m/z 488 (M+1)+.
Reaction SMILES: [N:1]1([CH:10]([NH:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:11]2[C:16](=[O:17])[CH:15]=[CH:14][N:13]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=3)[N:12]=2)C2C=CC=CC=2[N:3]=[N:2]1.[N-]=[N+]=[N-].[Na+].FC(F)(F)C(O)=O>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C(Cl)Cl.O>[C:29]1([N:28]2[C:10]([C:11]3[C:16](=[O:17])[CH:15]=[CH:14][N:13]([C:18]4[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=4)[N:12]=3)=[N:1][N:2]=[N:3]2)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: O=c1ccn(-c2cccc(C(F)(F)F)c2)nc1C(Nc1ccccc1)n1nnc2ccccc21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [N-]=[N+]=[N-]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: O
Product: O=c1ccn(-c2cccc(C(F)(F)F)c2)nc1-c1nnnn1-c1ccccc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 44.2 %

Procedure:
A solution of 3-[1H-benzotriazol-1-yl(phenylamino)methyl]-1-[3-(trifluoromethyl)phenyl]pyridazin-4(1H)-one (0.094 g, 0.20 mmol), sodium azide (0.030 g, 0.46 mmol), and tetrabutylammonium bromide (0.015 g, 0.047 mmol) in methylene chloride (5 mL) and water (5 mL) was treated with trifluoroacetic acid (0.040 mL, 0.52 mmol) and stirred 24 h at room temperature. After that time, the organic layer was separated and the aqueous layer was extracted with methylene chloride (3×25 mL). The combined organic extracts were washed with saturated NaCl aqueous solution (50 mL), dried (MgSO4), and concentrated. The crude product purified by flash column chromatography (silica gel, 80:20 hexanes/ethyl acetate to ethyl acetate) to give an off-white solid that was recrystallized from ethyl acetate/hexanes to give 0.034 g (56%) of 3-(1-phenyl-1H-tetrazol-5-yl)-1-[3-(trifluoromethyl)phenyl]pyridazin-4(1H)-one as colorless crystals.
Reaction SMILES: [O-2].[Zn+2:2].N.C(=O)=[O:5].[C:7]([OH:26])(=[O:25])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]>O>[O-2:5].[Zn+2:2].[C:7]([OH:26])(=[O:25])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24].[C:7]([O-:26])(=[O:25])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24].[Zn+2:2].[C:7]([O-:26])(=[O:25])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: O=C=O
Agent: CCCCCCCCCCCCCCCCCC(=O)O
Agent: N
Agent: [O-2]
Solvent: O
Product: CCCCCCCCCCCCCCCCCC(=O)[O-]
Temperature: 80 °C

Procedure:
130 kg of zinc oxide is dispersed in a rotor-stator shear machine with 16 liters of 25% aqueous ammonia in 480 liters of cold water with simultaneous introduction of gaseous carbon dioxide. Simultaneously, 900 kg of molten stearic acid is emulsified at 80° C. in 180 liters of water and to the emulsion there is added 36 liters of 25% aqueous ammonia. Both dispersions are fed at 80° C. through correspondingly adjusted dosing pumps to a rotor-stator shear machine likewise heated to 80° C., so that stoichiometric amounts are reacted per unit of time. From the 130 kg of zinc oxide and 900 kg of stearic acid (saponification number=204) there is formed 1000 kg of zinc stearate. The pasty zinc stearate drawn off from the rotor-stator shear machine has a water content of about 45%. It is fed directly to a flowing air dryer in which it is dried to a water content of 0.2%. The end product is a finely granular, extremely pure, electrolyte-free zinc stearate.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH:13]=[C:12]2I.C([Sn](CCCC)(CCCC)[C:31]1[N:36]=[C:35]([N:37]2[CH2:42][CH2:41][CH2:40][CH:39]([NH:43][C:44](=[O:50])[O:45][C:46]([CH3:49])([CH3:48])[CH3:47])[CH2:38]2)[CH:34]=[N:33][CH:32]=1)CCC>CN(C=O)C.C(Cl)Cl.O.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.[Cu]I>[C:46]([O:45][C:44]([NH:43][CH:39]1[CH2:40][CH2:41][CH2:42][N:37]([C:35]2[N:36]=[C:31]([C:12]3[C:11]4[C:15](=[CH:16][CH:17]=[C:9]([C:3]5[C:2]([F:1])=[CH:7][CH:6]=[CH:5][C:4]=5[F:8])[CH:10]=4)[N:14]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH:13]=3)[CH:32]=[N:33][CH:34]=2)[CH2:38]1)=[O:50])([CH3:49])([CH3:47])[CH3:48]
Reactant: CCCC[Sn](CCCC)(CCCC)c1cncc(N2CCCC(NC(=O)OC(C)(C)C)C2)n1
Reactant: CC(C)(C)OC(=O)n1cc(I)c2cc(-c3c(F)cccc3F)ccc21
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NC1CCCN(c2cncc(-c3cn(C(=O)OC(C)(C)C)c4ccc(-c5c(F)cccc5F)cc34)n2)C1
Temperature: 100 °C

Procedure:
A glass microwave reaction vessel was charged with tert-butyl 5-(2,6-difluorophenyl)-3-iodo-1H-indole-1-carboxylate (350 mg, 0.769 mmol), tert-butyl 1-(6-(tributylstannyl)pyrazin-2-yl)piperidin-3-ylcarbamate (436 mg, 0.769 mmol), Pd(PPh3)4 (89 mg, 0.077 mmol), and CuI (15 mg, 0.077 mmol) in DMF (6 mL). The reaction mixture was stirred and heated in a Initiator microwave reactor (Personal Chemistry, Biotage AB, Inc., Uppsala, Sweden) at 100° C. for 30 min. The mixture was diluted with DCM and water. The organic layer was separated, washed with water and brine, dried over Na2SO4, filtered and concentrated to give the crude product, tert-butyl 3-(6-(3-(tert-butoxycarbonylamino)piperidin-1-yl)pyrazin-2-yl)-5-(2,6-difluorophenyl)-1H-indole-1-carboxylate. MS (ESI, pos. ion) m/z: 606 (M+1). To a solution of tert-butyl 3-(6-(3-(tert-butoxycarbonylamino)piperidin-1-yl)pyrazin-2-yl)-5-(2,6-difluorophenyl)-1H-indole-1-carboxylate (466 mg, 0.769 mmol) in DCM (6 mL) was added TFA (4 mL) and the reaction was stirred at RT for 3 h, then solvent was removed. The residue was diluted with DCM and washed with saturated NaHCO3 aqueous solution twice. The organic layer was dried over Na2SO4, filtered and concentrated. The residue was purified with RP-HPLC to give 1-(6-(5-(2,6-difluorophenyl)-1H-indol-3-yl)pyrazin-2-yl)piperidin-3-amine as a light brown solid. MS (ESI, pos. ion) m/z: 406 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:3]=1[NH:4][C:5]1[S:9][C:8]2[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=2[C:6]=1[C:14]#[N:15].Cl>CO.O>[NH2:15][C:14]1[C:6]2[C:7]3[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=3[S:9][C:5]=2[NH:4][C:3]2[CH:16]=[C:17]([F:20])[CH:18]=[CH:19][C:2]=2[N:1]=1
Reactant: N#Cc1c(Nc2cc(F)ccc2N)sc2ccccc12
Agent: Cl
Solvent: CO
Solvent: O
Product: NC1=Nc2ccc(F)cc2Nc2sc3ccccc3c21

Procedure:
2-(2-Amino-5-fluoroanilino)benzo[b]thiophene-3-carbonitrile (155 g) was suspended in a mixture of methanol (250 ml) and water (200 ml) and 35% aqueous hydrochloric acid (42 ml) was added. The mixture was stirred under reflux with heating for 5.5 hours. The reaction mixture was cooled and stirred at 20° C. for 1 hour. The precipitated crystals were filtered by suction, washed successsively with water (500 ml) and isopropyl alcohol (200 ml) and dried in a drying box overnight to give 12-amino-8-fluoro-6H-[1]benzothieno[2,3-b][1,5]benzodiazepine.1 hydrochloride (104 g) as yellow crystals.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[C:6]([C:11](=[O:13])[CH3:12])[CH:5]=1.S(=O)(=O)(O)O.[N:20]([O-])=O.[Na+]>C(O)(=O)C>[CH3:1][O:2][C:3]([C:4]1[CH:5]=[C:6]2[C:7](=[CH:8][CH:9]=1)[NH:10][N:20]=[CH:12][C:11]2=[O:13])=[O:14]
Reactant: COC(=O)c1ccc(N)c(C(C)=O)c1
Reactant: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CC(=O)O
Product: COC(=O)c1ccc2[nH]ncc(=O)c2c1
Temperature: 0 °C
Reaction time: 48 h
Yield: 16.7 %

Procedure:
To a solution of 3-acetyl-4-amino-benzoic acid methyl ester (2063 mg, 10.68 mmol) in acetic acid (39 mL) was added sulfuric acid (6.5 mL) on an ice bath, then, an aqueous solution (6.5 mL) of sodium nitrite (922 mg, 13.35 mmol) was added thereto, followed by stirring on the ice for 1 hour, and at room temperature for 2 days. The reaction mixture was concentrated until it reached half of the amount, water was added, then an aqueous solution of 2N sodium hydroxide was added on an ice bath to adjust the pH to 5. The insoluble matter was separated by filtration, then, the filtrate was extracted with ethyl acetate, the organic layer was dried over sodium sulfate and then evaporated. Diethyl ether was added to the resulting residue for solidification, the resulting solid was washed with diethyl ether, and 365 mg of the title compound (1.78 mmol, 16.6%) was obtained.
Reaction SMILES: Cl.Cl.[Cl:3][C:4]1[CH:5]=[C:6](/[CH:17]=[CH:18]/[C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH:7]=[N:8][C:9]=1[NH:10][CH:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1.CCN(CC)CC.[CH3:31][C:32]1[CH:39]=[CH:38][C:35]([CH:36]=O)=[CH:34][CH:33]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl.CCOC(C)=O>[Cl:3][C:4]1[CH:5]=[C:6](/[CH:17]=[CH:18]/[C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH:7]=[N:8][C:9]=1[NH:10][CH:11]1[CH2:16][CH2:15][N:14]([CH2:31][C:32]2[CH:39]=[CH:38][C:35]([CH3:36])=[CH:34][CH:33]=2)[CH2:13][CH2:12]1
Reactant: Cc1ccc(C=O)cc1
Reactant: CCOC(=O)/C=C/c1cnc(NC2CCNCC2)c(Cl)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)/C=C/c1cnc(NC2CCN(Cc3ccc(C)cc3)CC2)c(Cl)c1
Temperature: 23 °C
Reaction time: 0.5 h

Procedure:
To a solution of ethyl (2E)-3-[5-chloro-6-(4-piperidylamino)-3-pyridyl]acrylate dihydrochloride (710 mg) in CH2Cl2 (14 ml) was added Et3N(0.517 ml), the mixture was stirred at 23° C. for 30 minutes. To the mixture was added 4-Methyl-benzaldehyde (0.241 ml) and SODIUM triacetoxyborohydride (590 mg), the mixture was stirred at 23° C. for 24 hours. The reaction mixture was poured into sat.NaHCO3aq. (20 ml)-AcOEt (20 ml). The organic layer was washed with water, dried over magnesium sulfate and concentrated. The residue was purified by silica gel column chromatography eluted with 5% MeOH in dichloromethane to give ethyl (2E)-3-(5-chloro-6-{[1-(4-methylbenzyl)-4-piperidyl]amino}-3-pyridyl)acrylate (671 mg).
Reaction SMILES: [C:1](=[O:8])([O:5][CH2:6][CH3:7])OCC.CN(C)P(=O)(N(C)C)N(C)C.[CH3:20][C:21](=[O:26])[C:22]([CH3:25])([CH3:24])[CH3:23].Cl>O>[CH2:6]([O:5][C:1](=[O:8])[CH2:20][C:21](=[O:26])[C:22]([CH3:25])([CH3:24])[CH3:23])[CH3:7]
Reactant: CC(=O)C(C)(C)C
Reactant: CCOC(=O)OCC
Agent: Cl
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: O
Product: CCOC(=O)CC(=O)C(C)(C)C
Temperature: 45 °C
Reaction time: 1 h
Yield: 67 %

Procedure:
250 g of potassium-tert.-butylate were suspended in a solution of 480 cc of diethyl carbonate and 100 cc of hexamethyl phosphoric acid triamide, followed by the gradual dropwise addition of 100 g pinacolone at 45° C/normal pressure. On completion of the addition, the mixture was stirred for 1 hour at 45° C and, after cooling, alcohol, water and finally hydrochloric acid carefully added one after the other to the reaction mixture. The reaction mixture was then treated and purified in the same way as described in 1 above. The yield was 67% of pivaloyl acetic acid ethyl ester.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([O:8][Si:9]([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10])[CH:5]=[CH:4][C:3]=1[CH2:16][OH:17].C([Li])CCC.[CH3:23][C:24]([CH3:26])=[O:25]>CCCCCC.C1COCC1>[Si:9]([O:8][C:6]1[CH:5]=[CH:4][C:3]([CH2:16][OH:17])=[C:2]([C:24]([OH:25])([CH3:26])[CH3:23])[CH:7]=1)([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10]
Reactant: CC(C)=O
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(CO)c(Br)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(C)(O)c1cc(O[Si](C)(C)C(C)(C)C)ccc1CO
Reaction time: 2 h
Yield: 51.4 %

Procedure:
To a solution of [2-bromo-4-[tert-butyl(dimethyl)silyl]oxy-phenyl]methanol (Intermediate 9, 500 mg, 1.5758 mmol) in dry hexane (8 mL) and THF (2 mL) at −15° C. butyllithium 1.6M in hexane (2.17 ml, 3.467 mmol) was slowly added (10 min) and the reaction mixture was stirred at the same temperature for 2 hours. Then a solution of acetone (118.98 mg, 2.0486 mmol) in dry hexane (1 ml) was added at −15° C. and the reaction mixture stirred at the same temperature for additional 1 hour. The reaction was quenched with an aqueous saturated solution of ammonium chloride and extracted with ethyl acetate (100 ml). The organic layer was washed with brine, dried over sodium sulphate and concentrated under vacuum. The residue was purified by flash chromatography on silica gel (Biotage system) using a SNAP 50 g as column and cyclohexane/ethyl acetate from 100:0 to 60:40 as eluent in 12 column volumes, to give the title compound (240 mg) as a colourless oil.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]([NH:6][C:7]1[CH:12]=[C:11]([O:13][C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-])=O)=[CH:16][C:15]=2[CH3:23])[CH:10]=[CH:9][N:8]=1)=[O:5].[H][H]>CO.CC(O)=O.[Pt]>[NH2:20][C:17]1[CH:18]=[CH:19][C:14]([O:13][C:11]2[CH:10]=[CH:9][N:8]=[C:7]([NH:6][C:4](=[O:5])[CH2:3][O:2][CH3:1])[CH:12]=2)=[C:15]([CH3:23])[CH:16]=1
Reactant: COCC(=O)Nc1cc(Oc2ccc([N+](=O)[O-])cc2C)ccn1
Reactant: [H][H]
Agent: [Pt]
Solvent: CO
Solvent: CC(=O)O
Product: COCC(=O)Nc1cc(Oc2ccc(N)cc2C)ccn1

Procedure:
A solution of 2-methoxy-N-(4-(2-methyl-4-nitrophenoxy)pyridin-2-yl)acetamide (357 mg, estimated purity 92%, 1.04 mmol) in a mixture of MeOH (20 mL) and AcOH (2.0 mL) was subjected to hydrogenation by passage through a Thales H-cube (1.0 mL min−1, 25° C., 55 mm 10% Pt/C Cat-Cart, full hydrogen mode) and was then evaporated in vacuo. The residue was taken up into a mixture of MeOH (20 mL) and AcOH (2 mL) and re-subjected to hydrogenation under the same flow conditions, at an elevated temperature (1.0 mL min−1, 40° C., 55 mm 10% Pt/C Cat-Cart, full hydrogen mode). The mixture was concentrated by evaporation in vacuo to afford the title compound, Intermediate H2, as a viscous liquid; Rt 1.05 min (Method 1); m/z 288 (M+H)+ (ES+); which was used directly in the next step (below).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:15]=[CH:14][C:6]([CH:7]=[N:8][C@H:9]([C:11]([O-:13])=[O:12])[CH3:10])=[CH:5][CH:4]=1.[Na+].[C:17](Cl)(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[K+].[Br-].N>C(Cl)(Cl)Cl>[C:17]([N:8]1[C@@H:9]([CH3:10])[C:11](=[O:13])[O:12][C@H:7]1[C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:15][CH:14]=1)(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: COc1ccc(C=N[C@@H](C)C(=O)[O-])cc1
Agent: N
Agent: [Br-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Product: COc1ccc([C@@H]2OC(=O)[C@H](C)N2C(=O)c2ccccc2)cc1

Procedure:
(2S,4S)-N-Benzoyl-2-(4'-methoxyphenyl)4-methyl-1,3-oxazolidin-5-one (17) was prepared from sodium N-(para-methoxybenzylidene)-(L)-alaninate (2.29 g, 10.0 mM) and benzoyl chloride (1.16 mL, 10.0 mM) following general procedure D and obtained as a white solid after purification by flash column chromatography, using 20% ethyl acetate/petrol as eluant (2.15 g, 69%, mixture of two diastereomers in a ratio of 3:1 by 1H NMR). After crystallisation from diethyl ether 17 was obtained as very fine white needles and as a single diastereomer by 1H NMR: [α]D20 +78.2 (c 1.0, CHCl3); mp 145-147° C.; IR (KBr): 1795, 1735, 1650 cm-1 ; 1H NMR (500 MHz, d8 -toluene, 90° C.): δ 6.80-7.21 (m, 5H), 6.51-6.53 (m, 4H), 6.43 (s, 1H), 4.44 (q, J=7 Hz, 1H), 3.29 (s, 3H), 1.25 (d, J=7 Hz, 3H); 13C NMR (50.3 MHz, CDCl3): 6172.5, 170.5, 160.6, 135.2, 130.9, 128.0, 127.6, 126.9, 126.8, 114.0, 90.3, 55.3, 52.7, 18.4; LRMS (NH3): 312 (MH+). Anal. Calcd for C18H17NO4 : C, 69.45; H: 5.46; N, 4.50.; found: C, 69.18; H, 5.55; is N, 4.38.
Reaction SMILES: C[O:2][C:3](=[O:26])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH2:11][CH:12]1[C:21]2[C:16](=[CH:17][C:18]([O:24][CH3:25])=[C:19]([O:22][CH3:23])[CH:20]=2)[CH2:15][CH2:14][NH:13]1.[OH-].[Na+]>CO>[CH3:25][O:24][C:18]1[CH:17]=[C:16]2[C:21](=[CH:20][C:19]=1[O:22][CH3:23])[CH:12]([CH2:11][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=1[CH2:4][C:3]([OH:26])=[O:2])[NH:13][CH2:14][CH2:15]2
Reactant: COC(=O)Cc1ccccc1CC1NCCc2cc(OC)c(OC)cc21
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1cc2c(cc1OC)C(Cc1ccccc1CC(=O)O)NCC2
Temperature: 25 °C
Yield: 47.1 %

Procedure:
A mixture of 2-[(1,2,3,4-tetrahydro-6,7-dimethoxy-1-isoquinolinyl)methyl]benzeneacetic acid methyl ester (Xc, Ex. 12) (1.0 g, 2.8 mmole) 1.0N sodium hydroxide solution and methanol (1 ml) was heated under reflux for 1.5 hr, and filtered after being cooled to room temperature. The filtrate was acidified with dilute hydrochloric acid, and chilled in ice with scratching. A white cotton-like precipitate was collected on a filter and washed with cold water to give the titled product (0.45 g, 41%), mp 129°-145° dec.
Reaction SMILES: C([O:4][CH2:5][C:6]1[C:7]([N:39]2[CH2:51][CH2:50][N:42]3[C:43]4[CH2:44][CH2:45][CH2:46][CH2:47][C:48]=4[CH:49]=[C:41]3[C:40]2=[O:52])=[N:8][CH:9]=[CH:10][C:11]=1[C:12]1[CH:17]=[C:16]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([N:25]3[CH2:30][CH2:29][N:28]([CH:31]4[CH2:34][O:33][CH2:32]4)[CH2:27][C:26]3([CH3:36])[CH3:35])=[CH:21][N:20]=2)[C:15](=[O:37])[N:14]([CH3:38])[CH:13]=1)(=O)C.[OH-].[Li+].C(O)(C)C.C1COCC1>O>[CH3:35][C:26]1([CH3:36])[CH2:27][N:28]([CH:31]2[CH2:34][O:33][CH2:32]2)[CH2:29][CH2:30][N:25]1[C:22]1[CH:23]=[CH:24][C:19]([NH:18][C:16]2[C:15](=[O:37])[N:14]([CH3:38])[CH:13]=[C:12]([C:11]3[CH:10]=[CH:9][N:8]=[C:7]([N:39]4[CH2:51][CH2:50][N:42]5[C:43]6[CH2:44][CH2:45][CH2:46][CH2:47][C:48]=6[CH:49]=[C:41]5[C:40]4=[O:52])[C:6]=3[CH2:5][OH:4])[CH:17]=2)=[N:20][CH:21]=1
Reactant: CC(=O)OCc1c(-c2cc(Nc3ccc(N4CCN(C5COC5)CC4(C)C)cn3)c(=O)n(C)c2)ccnc1N1CCn2c(cc3c2CCCC3)C1=O
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CC(C)O
Product: Cn1cc(-c2ccnc(N3CCn4c(cc5c4CCCC5)C3=O)c2CO)cc(Nc2ccc(N3CCN(C4COC4)CC3(C)C)cn2)c1=O
Temperature: 30 °C
Reaction time: 1 h
Yield: 46.2 %

Procedure:
A 50-mL single-neck round-bottomed flask equipped with a magnetic stirrer was charged with (4-(5-(5-(2,2-dimethyl-4-(oxetan-3-yl)piperazin-1-yl)pyridin-2-ylamino)-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-2-(1-oxo-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-2(1H)-yl)pyridin-3-yl)methyl acetate 190i (100 mg, 1 eq., 0.14 mmol), lithium hydroxide(54 mg, 10 eq., 1.4 mmol), i-propanol (3 mL), THF (3 mL) and water (2 mL). The mixture was stirred at 30° C. for 1 h. It was then filtered and the filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase prep-HPLC to afford 190 as a white solid (43 mg, 46%). MS-ESI: [M+H]+ 665.3. 1H NMR (500 MHz, DMSO-d6) δ 8.69 (d, J=2.0 Hz, 1H), 8.60 (s, 1H), 8.48 (d, J=5.0 Hz, 1H), 7.93 (d, J=2.0 Hz, 1H), 7.51 (d, J=1.5 Hz, 1H), 7.42-7.40 (m, 1H), 7.35 (d, J=5.0 Hz, 1H), 7.24 (d, J=8.5 Hz, 1H), 6.58 (s, 1H), 4.98 (brs, 1H), 4.54 (t, J=6.0 Hz, 2H), 4.46-4.38 (m, 4H), 4.25-3.85 (m, 4H), 3.60 (s, 3H), 3.38-3.35 (m, 1H), 3.03-2.54 (m, 4H), 2.47 (t, J=6.0 Hz, 2H), 2.32-2.12 (m, 4H), 1.79-1.67 (m, 4H), 0.97 (s, 6H)
Reaction SMILES: C(O)C.[CH2:4]([O:11][C:12]1[CH:13]=[CH:14][C:15]([CH2:18][C:19]#[N:20])=[N:16][CH:17]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[Cl-].[OH:22][NH3+:23].C(=O)([O-])[O-].[K+].[K+]>O>[CH2:4]([O:11][C:12]1[CH:13]=[CH:14][C:15]([CH2:18][C:19]([NH:23][OH:22])=[NH:20])=[N:16][CH:17]=1)[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: N#CCc1ccc(OCc2ccccc2)cn1
Reactant: [NH3+]O
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: N=C(Cc1ccc(OCc2ccccc2)cn1)NO
Temperature: 70 °C
Reaction time: 0.33 h
Yield: 27.1 %

Procedure:
To an ethanol (30 mL) solution of (5-benzyloxy-pyridin-2-yl)-acetonitrile (1.77 g, 7.89 mmol) described in Manufacturing Example 127-1-4 were added hydroxylammonium chloride (848 mg, 11.8 mmol) and potassium carbonate (2.18 g, 15.8 mmol), which was stirred for 11 hours and 20 minutes at 70° C. The mixture was then stirred for another 5 hours and 45 minutes under reflux. Water was added to the reaction mixture at room temperature, which was extracted with ethyl acetate. The organic layer was separated, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate:methanol=10:1) to obtain the title compound (550 mg, 27%).