Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1](=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].[ClH:13].Cl.[F:15][C:16]1[C:21]([F:22])=[C:20]([F:23])[CH:19]=[CH:18][C:17]=1[NH:24][C:25]([NH:27][C:28]([NH2:30])=[NH:29])=[NH:26]>C(O)C>[ClH:13].[NH2:26][C:25]1[N:24]([C:17]2[CH:18]=[CH:19][C:20]([F:23])=[C:21]([F:22])[C:16]=2[F:15])[CH:1]([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])[N:29]=[C:28]([NH2:30])[N:27]=1
Reactant: CCCCCCCCCCC=O
Reactant: N=C(N)NC(=N)Nc1ccc(F)c(F)c1F
Agent: Cl
Solvent: CCO
Product: CCCCCCCCCCC1N=C(N)N=C(N)N1c1ccc(F)c(F)c1F

Procedure:
100 ml of ethanol, 4.8 g (28.2 mmol) of 1-undecanal and 0.8 ml of concentrated hydrochloric acid were added to 5.0 g (18.7 mmol) of N1-(2,3,4-trifluorophenyl)-biguanide hydrochloride, and the mixture was refluxed for 24 hours. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (elution with a mixture of chloroform and methanol (9:1.5)), and recrystallized from 80% aqueous acetonitrile to obtain 3.2 g of colorless crystals having a melting point of 210 to 213° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:4][CH:3]=1.[CH3:14][C:15]1[C:19](/[CH:20]=[CH:21]/[C:22](O)=[O:23])=[C:18]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[O:17][N:16]=1.O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>O.CN(C)C=O>[CH2:12]([O:11][C:9]([CH2:8][C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:22](=[O:23])/[CH:21]=[CH:20]/[C:19]2[C:15]([CH3:14])=[N:16][O:17][C:18]=2[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)=[CH:7][CH:6]=1)=[O:10])[CH3:13]
Reactant: CCOC(=O)Cc1ccc(N)cc1
Reactant: Cc1noc(-c2ccccc2)c1/C=C/C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)Cc1ccc(NC(=O)/C=C/c2c(C)noc2-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 112.5 %

Procedure:
A mixture of ethyl 4-aminophenylacetate (1.11 g), (E)-3-(3-methyl-5-phenyl-4-isoxazolyl)propenoic acid (0.95 g), 1-hydroxy-1H-1,2,3-benzotriazole hydrate (0.75 g), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.91 g) and N,N-dimethylformamide (20 ml) was stirred at room temperature overnight. The reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with dilute hydrochloric acid, saturated aqueous sodium hydrogencarbonate and then saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and (E)-N-(4-ethoxycarbonylmethylphenyl)-3-(3-methyl-5-phenyl-4-isoxazolyl)propenamide (1.82 g, yield 97%) was obtained as colorless crystals from a fraction eluted with ethyl acetate-hexane (1:1, volume ratio). The crystals were recrystallized from ethyl acetate-hexane. melting point: 164–165° C.
Reaction SMILES: [CH2:1]([C:3]1[C:4]([S:18][CH3:19])=[N:5][C:6]2[N:7]([CH:10]=[C:11]([C:13](=[O:17])[C:14]([CH3:16])=[CH2:15])[N:12]=2)[C:8]=1[CH3:9])[CH3:2].[Br:20]N1C(=O)CCC1=O>C(Cl)(Cl)Cl>[Br:20][C:10]1[N:7]2[C:8]([CH3:9])=[C:3]([CH2:1][CH3:2])[C:4]([S:18][CH3:19])=[N:5][C:6]2=[N:12][C:11]=1[C:13](=[O:17])[C:14]([CH3:16])=[CH2:15]
Reactant: C=C(C)C(=O)c1cn2c(C)c(CC)c(SC)nc2n1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)Cl
Product: C=C(C)C(=O)c1nc2nc(SC)c(CC)c(C)n2c1Br
Reaction time: 0.33 h
Yield: 85.5 %

Procedure:
A solution of 1.0 g (3.63 mmol) of 1-(6-ethyl-5-methyl-7-methylthioimidazo[1,2-a]pyrimidin-2-yl)-2-methyl-2-propen-1-one in 50 ml of chloroform was treated with 0.71 g (4.0 mmol) of N-bromo succinimide. After 20 minutes at room temperature, the solvent was removed under reduced pressure and the residue was purified by flash chromatography (silica, 25 g: dichloromethane) to obtain 1.1 g (87%) of 1-(3-bromo-6-ethyl-5-methyl-7-methylthioimidazo[1,2-a]pyrimidin-2-yl)-2-methyl-2-propen-1-one in the form of pale yellow crystals melting at 87°-9° C.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[F:7][C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[C:10]([CH:15]([CH3:20])[C:16]([F:19])([F:18])[F:17])[CH:9]=1.CS(O[CH2:26][C@@H:27]([NH:29]C(OC(C)(C)C)=O)[CH3:28])(=O)=O>CN(C)C=O.O>[F:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:26][C@@H:27]([NH2:29])[CH3:28])=[C:10]([CH:15]([CH3:20])[C:16]([F:17])([F:18])[F:19])[CH:9]=1
Reactant: CC(c1cc(F)ccc1O)C(F)(F)F
Reactant: C[C@@H](COS(C)(=O)=O)NC(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(c1cc(F)ccc1OC[C@H](C)N)C(F)(F)F
Temperature: 60 °C
Reaction time: 1 h

Procedure:
Cesium carbonate (28.6 g, 87.8 mmol) was added to a solution of crude 4-fluoro-2-(1,1,1-trifluoropropan-2-yl)phenol (C44) (6.00 g, 28.8 mmol) in N,N-dimethylformamide (60 mL). After addition of (2S)-2-[(tert-butoxycarbonyl)amino]propyl methanesulfonate (P12) (7.5 g, 29.6 mmol), the reaction mixture was heated in a 60° C. oil bath for 30 minutes, then treated with additional P12 (7.5 g, 29.6 mmol) and heated for 18 hours. At this point, the reaction mixture was allowed to cool to room temperature, diluted with water (500 mL), and extracted with diethyl ether (3×150 mL). The combined organic layers were dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting material (11.23 g) was dissolved in dichloromethane (200 mL); trifluoroacetic acid (40 mL) was added, and the reaction mixture was stirred for 1 hour. After removal of solvents in vacuo, the residue was dissolved in ethyl acetate and washed with saturated aqueous sodium bicarbonate solution and with saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered, and concentrated in vacuo. Purification using silica gel chromatography (Eluents: 75% ethyl acetate in heptane, then ethyl acetate, then 10% methanol in ethyl acetate) afforded the product as a roughly 1:1 mixture of two diastereomers, as assessed by 1H NMR. Yield: 5.44 g, 20.5 mmol, 71%. LCMS m/z 266.1 (M+1). 1H NMR (400 MHz, CDCl3) δ [1.31 (d, J=6.6 Hz) and 1.32 (d, J=6.6 Hz), total 3H], 1.41 (d, J=7.2 Hz, 3H), 3.50-3.59 (m, 1H), 3.82-4.22 (m, 3H), 6.79-6.84 (m, 1H), 6.92-6.98 (m, 1H), 7.05-7.11 (m, 1H). Also obtained was material enriched in the higher Rf diastereomer (1.10 g, 4.15 mmol, 14%) and material enriched in the lower Rf diastereomer (324 mg, 1.22 mmol, 4%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:16][C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][C:25]=3[O:27][CH2:28][CH2:29][NH:30][CH2:31][CH2:32][O:33][CH3:34])[N:20]=[CH:19][N:18]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1.[C:35](Cl)(=[O:37])[CH3:36]>>[Cl:1][C:2]1[CH:3]=[C:4]([NH:16][C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][C:25]=3[O:27][CH2:28][CH2:29][N:30]([CH2:31][CH2:32][O:33][CH3:34])[C:35](=[O:37])[CH3:36])[N:20]=[CH:19][N:18]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1
Reactant: COCCNCCOc1cccc2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c12
Reactant: CC(=O)Cl
Product: COCCN(CCOc1cccc2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c12)C(C)=O
Yield: 30 %

Procedure:
The procedure described in Example 5 was repeated using N-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]-5-{2-[(2-methoxyethyl)amino]ethoxy}quinazolin-4-amine and acetyl chloride to give the title compound in 30% yield; NMR spectrum (DMSO-d6) 1.99 (s, 3H), 3.24 (s, 3H), 3.46-3.51 (m, 2H), 3.52-3.57 (m, 2H), 3.88-3.98 (m, 2H), 4.37-4.43 (m, 2H), 5.31 (s, 2H), 7.17 (d, 1H), 7.26 (d, 1H), 7.34 (d, 1H), 7.35-7.40 (m, 1H), 7.55-7.63 (m, 2H), 7.71-7.78 (m, 1H), 7.86-7.92 (m, 1H), 7.94 (d, 1H), 8.46 (s, 1H), 8.61 (d, 1H), 9.86 (s, 1H); Mass spectrum MH+ 522.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6](Cl)=[O:7].C([N:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[NH:20][C:19](=[O:27])[CH2:18]1)(=O)C1C=CC=CC=1.C(N(CC)CC)C.C1COCC1>C(=O)(O)[O-].[Na+]>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([N:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[NH:20][C:19](=[O:27])[CH2:18]1)=[O:7]
Reactant: O=C(Cl)c1ccco1
Reactant: O=C1CN(C(=O)c2ccccc2)c2ccccc2N1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C1CN(C(=O)c2ccco2)c2ccccc2N1
Reaction time: 2 h

Procedure:
2-Furoyl chloride (0.49 ml) is added to a solution of the 1,2,3,4-tetrahydroquinoxalin-2-one (IV, EXAMPLE 1, 710 mg), triethylamine (0.80 ml), and THF (20.0 ml) at 0°. The mixture is stirred for 1.5 hr at 0° and for 2 hr at 20°-25°. The mixture was diluted with aq. sodium bicarbonate and extracted with ethyl acetate and chloroform several times. The organic phases are combined, dried with magnesium sulfate, concentrated, and recrystallized from hot ethyl acetate to give the title compound, mp 229°-230° ; IR (mineral oil) 2954, 2925, 1684, 1648, 1504, 1474, 1391, 1373 and 756 cm-1 ; NMR (CDCl3) 8.53, 7.39, 7.1-7.25, 6.85-7.05, 6.45 and 4.59 δ; MS (m/z) 242 and 95.
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[C:11]([F:13])[C:10]([F:14])=[CH:9][C:3]=1[C:4]([N:6]=[C:7]=[O:8])=[O:5].Cl.[NH2:16][C:17]1[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=1[N:24]1[CH2:29][CH2:28][CH2:27][CH:26]([C:30]([NH2:32])=[O:31])[CH2:25]1>C(#N)C>[Cl:1][C:2]1[CH:12]=[C:11]([F:13])[C:10]([F:14])=[CH:9][C:3]=1[C:4]([NH:6][C:7](=[O:8])[NH:16][C:17]1[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=1[N:24]1[CH2:29][CH2:28][CH2:27][CH:26]([C:30]([NH2:32])=[O:31])[CH2:25]1)=[O:5]
Reactant: O=C=NC(=O)c1cc(F)c(F)cc1Cl
Reactant: NC(=O)C1CCCN(c2ccc(F)cc2N)C1
Agent: Cl
Solvent: CC#N
Product: NC(=O)C1CCCN(c2ccc(F)cc2NC(=O)NC(=O)c2cc(F)c(F)cc2Cl)C1

Procedure:
The equimolar solution of 2-chloro-4,5-difluorobenzoyl isocyanate in acetonitrile was added dropwise to the solution of 109 mg of 1-(2-amino-4-fluorophenyl)piperidine-3-carboxamide hydrochloride in 5 ml of acetonitrile with stirring. The mixture was stirred at RT for 6 h and the precipitate was filtered off with suction and dried at RT under reduced pressure.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[C:5]2[I:11].[CH3:12][O-].[Na+].CI>CO>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH3:12])[N:6]=[C:5]2[I:11]
Reactant: C[O-]
Reactant: Brc1ccc2[nH]nc(I)c2c1
Agent: [Na+]
Solvent: CO
Solvent: CI
Product: Cn1nc(I)c2cc(Br)ccc21
Temperature: 65 °C
Reaction time: 0.5 h

Procedure:
A solution of 184.30 g of 5-bromo-3-iodo-1H-indazole [459133-66-5] n 2500 ml of methanol is admixed at 40° C. with 212 ml of a sodium methoxide solution (5.4M in methanol). 90 ml of methyl iodide are then added and the reaction mixture is heated to 65° C. After 30 minutes, the reaction mixture is cooled to room temperature, concentrated to approx. 1000 ml by evaporation, diluted with water and extracted with ethyl acetate (2×). The combined organic phases are dried over sodium sulphate and concentrated by evaporation. The title compound is obtained as a dark brown solid from the residue by means of flash chromatography (SiO2 60F). Rf=0.68 (dichloromethane). Rt=4.94 (gradient I). As a by-product, the 5-bromo-3-iodo-2-methyl-2H-indazole regioisomer is also isolated as a red-orange solid. Rf=0.52 (dichloromethane). Rt=4.58 (gradient I).
Reaction SMILES: [OH:1][CH:2]([C:28]1[CH:33]=[CH:32][C:31]([O:34][C:35]2[CH:36]=[N:37][CH:38]=[CH:39][CH:40]=2)=[CH:30][CH:29]=1)[CH:3]([CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([O:21][C:22]([F:27])([F:26])[CH:23]([F:25])[F:24])[CH:16]=1)[C:4]([O:6]CC1C=CC=CC=1)=[O:5].[H][H]>C(O)C.[Pd]>[OH:1][CH:2]([C:28]1[CH:33]=[CH:32][C:31]([O:34][C:35]2[CH:36]=[N:37][CH:38]=[CH:39][CH:40]=2)=[CH:30][CH:29]=1)[CH:3]([CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([O:21][C:22]([F:27])([F:26])[CH:23]([F:25])[F:24])[CH:16]=1)[C:4]([OH:6])=[O:5]
Reactant: [H][H]
Reactant: O=C(OCc1ccccc1)C(Cc1cccc(OC(F)(F)C(F)F)c1)C(O)c1ccc(Oc2cccnc2)cc1
Agent: [Pd]
Solvent: CCO
Product: O=C(O)C(Cc1cccc(OC(F)(F)C(F)F)c1)C(O)c1ccc(Oc2cccnc2)cc1
Reaction time: 1 h

Procedure:
To a solution of benzyl (2RS,3RS)-3-hydroxy-3-[4-(pyridin-3-yloxy)phenyl]-2-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]propanoate (3.00 g, 5.38 mmol) in ethanol (200 ml) was added 10% palladium/carbon (containing water by 50%, 300 mg), and the mixture was stirred under a 1 atm hydrogen stream for 1 hr. The reaction solution was filtered with celite and the filtrate was concentrated to give the objective substance (2.8 g, 100%, crude). The present compound was used for, the next reaction as a crude compound.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=2)[N:5]=[C:4]([CH3:14])[CH:3]=1.[C:15]([N:18]1[CH2:22][C:21](=O)[N:20]=[CH:19]1)(=[O:17])[CH3:16]>>[C:15]([N:18]1[CH2:22][CH2:21][N:20]=[C:19]1[NH:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=2)[N:5]=[C:4]([CH3:14])[CH:3]=1)(=[O:17])[CH3:16]
Reactant: CC(=O)N1C=NC(=O)C1
Reactant: Cc1cc(N)n(-c2ccc(F)cc2)n1
Product: CC(=O)N1CCN=C1Nc1cc(C)nn1-c1ccc(F)cc1

Procedure:
5-Amino-1-(4-fluorophenyl)-3-methylpyrazole (25 g.) and 1-acetyl-2-imidazolinone (20.2 g.) were reacted as described in Example I to give 21.97 g. product, mp 189°-191°
Reaction SMILES: Br[C:2]12[CH2:11][C:6]3([CH3:12])[CH2:7][CH:8]([CH2:10][C:4]([CH3:13])([CH2:5]3)[CH2:3]1)[CH2:9]2.[NH2:14]C(N)=O.Cl.[OH-].[Na+]>C(O)=O>[NH2:14][C:2]12[CH2:11][C:6]3([CH3:12])[CH2:7][CH:8]([CH2:10][C:4]([CH3:13])([CH2:5]3)[CH2:3]1)[CH2:9]2
Reactant: CC12CC3CC(C)(C1)CC(Br)(C3)C2
Reactant: NC(N)=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O=CO
Product: CC12CC3CC(C)(C1)CC(N)(C3)C2
Temperature: 150 °C
Reaction time: 1 h

Procedure:
To 100 g of 1-bromo-3,5-dimethyl adamantane and 10 g of urea, adding 60 ml of anhydrous formic acid, heating to 150° C. and hold for 1 hour. Cooling to the room temperature and adding 95 ml of concentrated hydrochloric acid to hydrolyze at 100° C. for 1 hour. Adjusting with 30% sodium hydroxide solution until the solution becomes basic. Extracting with toluene twice, combining the organic layers and washing with water. Concentrating under reduced pressure to yield a limpid yellow solution as 1-amino-3,5-dimethyl adamantane crude. To the crude, adding 150 ml of ethanol and concentrated hydrochloric acid, heating to dissolve and crystallizing to yield white solid. Drying the solid and re-crystallizing with acetone to yield 61.7 g of pure Memantine Hydrochloride. The yield is 69.5% (GC 99.9%).
Reaction SMILES: ClN1C(=O)CCC1=O.[CH2:9]([S:11][CH2:12][CH3:13])[CH3:10].[CH2:14]([C@H:21]([NH:46][C:47](=[O:59])[C@@H:48]([N:52]1[CH2:57][CH2:56][CH2:55][NH:54][C:53]1=[O:58])[CH:49]([CH3:51])[CH3:50])[CH2:22][C@H:23]([OH:45])[C@@H:24]([NH:32][C:33](=[O:44])[CH2:34][O:35][C:36]1[C:41]([CH3:42])=[CH:40][CH:39]=[CH:38][C:37]=1[CH3:43])[CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(N(CC)CC)C>O1CCCC1>[CH2:14]([C@H:21]([NH:46][C:47](=[O:59])[C@@H:48]([N:52]1[CH2:57][CH2:56][CH2:55][NH:54][C:53]1=[O:58])[CH:49]([CH3:51])[CH3:50])[CH2:22][C@H:23]([O:45][CH:9]([S:11][CH2:12][CH3:13])[CH3:10])[C@@H:24]([NH:32][C:33](=[O:44])[CH2:34][O:35][C:36]1[C:37]([CH3:43])=[CH:38][CH:39]=[CH:40][C:41]=1[CH3:42])[CH2:25][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: Cc1cccc(C)c1OCC(=O)N[C@@H](Cc1ccccc1)[C@@H](O)C[C@H](Cc1ccccc1)NC(=O)[C@H](C(C)C)N1CCCNC1=O
Reactant: CCSCC
Agent: O=C1CCC(=O)N1Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCSC(C)O[C@@H](C[C@H](Cc1ccccc1)NC(=O)[C@H](C(C)C)N1CCCNC1=O)[C@H](Cc1ccccc1)NC(=O)COc1c(C)cccc1C
Temperature: -10 °C
Reaction time: 1.5 h

Procedure:
A slurry of N-chlorosuccinimide (6.5 g, 48.7 mmol) in tetrahydrofuran (50 mL) was cooled to −10° C., followed by addition of diethyl sulfide (7.0 mL) and then by addition of a solution of Example 3 (5.0 g) in tetrahydrofuran (20 mL). A solution of triethylamine (9.0 mL) in tetrahydrofuran (15 mL) was then added dropwise and the mixture was stirred at −10° C. for 1.5 h. The reaction was quenched with 10% Na2CO3 and extracted twice with ethyl acetate. The combined organic was washed with water and brine and dried over MgSO4, filtered and evaporated to give the crude product (7.5 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH:12]=[N:13]O)[CH:6]=[CH:5]2.[H][H]>CO.O1CCCC1.[Ni]>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH2:12][NH2:13])[CH:6]=[CH:5]2
Reactant: ON=Cc1ccc2cc(Cl)ccc2n1
Reactant: [H][H]
Agent: [Ni]
Solvent: CO
Solvent: C1CCOC1
Product: NCc1ccc2cc(Cl)ccc2n1

Procedure:
A solution of 0.78 g (3.79 mmol) of 6-chloroquinoline-2-carbaldehydeoxime in 30 mL of saturated ammoniacal methanol and 10 mL of tetrahydrofuran is hydrogenated with Raney nickel for 48 hours at 3 bar hydrogen pressure. The catalyst is filtered off and the solution is concentrated. The residue is chromatographed on silica gel, eluting with a gradient of dichloromethane/methanol (90:10) to dichloromethane/methanol/25% aqueous ammonia (90:10:1). The corresponding fractions are combined and concentrated by evaporation. Yield: 0.33 g (45% of theory); Rf value: 0.43 (silica gel; dichloromethane/methanol=9:1); C10H9ClN2 (192.65); mass spectrum: (M+H)+=193/195 (chlorine isotope).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:17]([O:19]CC3C=CC=CC=3)=[O:18])[CH:15]=2)[CH:10]=[CH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>C(O)=O.CO.[Pd]>[C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:17]([OH:19])=[O:18])[CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)n1ccc2ccc(C(=O)OCc3ccccc3)cc21
Agent: [Pd]
Solvent: O=CO
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCc2ccc(C(=O)O)cc21
Temperature: 25 °C
Reaction time: 4 h
Yield: 80 %

Procedure:
To a solution of benzyl 1-tert-butoxycarbonylindole-6-carboxylate (1.27 g) in 5.0% formic acid-methanol (20.0 ml) was added 10% palladium on carbon (1.27 g) and the mixture was stirred under nitrogen atmosphere at ambient temperature for 4 hours and stand overnight. The resulting solution was filtered through a bed of celite and the filtrate was concentrated in vacuo. The residue was diluted with chloroform and the solution was washed successively with water and brine. The organic layer was dried over magnesium sulfate and concentrated in vacuo. The residue was triturated with ether:n-hexane (1:5) to give 1-tert-butoxycarbonylindoline-6-carboxylic acid (761 mg).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH:19](O)[C:18]3[CH:17]=[CH:16][N:15]=[C:14]([F:21])[C:13]=3[C:12]2=[O:22])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C([SiH](CC)CC)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([N:11]2[CH2:19][C:18]3[CH:17]=[CH:16][N:15]=[C:14]([F:21])[C:13]=3[C:12]2=[O:22])=[CH:9][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc(N2C(=O)c3c(ccnc3F)C2O)cc1
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)c1ccc(N2Cc3ccnc(F)c3C2=O)cc1

Procedure:
To a mixture of 2-(4-tert-butyl-phenyl)-4-fluoro-1-hydroxy-1,2-dihydro-pyrrolo[3,4-c]pyridin-3-one (0.085 g, 0.28 mmol, Step C) and triethylsilane (0.029 mL, 1.80 mmol) in 6 mL of CH2Cl2 was added TFA (0.62 mL, 7.80 mmol) at RT. The mixture was heated at reflux for 2 h, and the volatiles were removed under reduced pressure. The residue was purified by flash column chromatography (5 to 10% of EtOAc in CH2Cl2), to yield the titled compound as a white solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[C:5](=[N:20]OCC)[C:6]1[N:7]=[C:8]([NH:11][C:12]([O:14][CH2:15][C:16]([Cl:19])([Cl:18])[Cl:17])=[O:13])[S:9][CH:10]=1)[CH3:2].[H][H]>Cl.C(O)C.[Pd]>[ClH:17].[CH2:1]([O:3][C:4](=[O:24])[CH:5]([NH2:20])[C:6]1[N:7]=[C:8]([NH:11][C:12]([O:14][CH2:15][C:16]([Cl:17])([Cl:19])[Cl:18])=[O:13])[S:9][CH:10]=1)[CH3:2]
Reactant: CCON=C(C(=O)OCC)c1csc(NC(=O)OCC(Cl)(Cl)Cl)n1
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: CCOC(=O)C(N)c1csc(NC(=O)OCC(Cl)(Cl)Cl)n1
Yield: 144.1 %

Procedure:
A solution of 10.45 g of α-ethoxyimino-α-[2-(trichloroethoxycarbonylamino)thiazol-4-yl]acetic acid ethyl ester in a mixture of 10% hydrochloric acid and ethanol is catalytic-hydrogenated over 8.0 g of 5% palladium on charcoal at room temperature under atomospheric pressure. After the absorption of two equivalents of hydrogen, the catalyst in the reaction mixture is filtered off and the filtrate is concentrated to dryness under reduced pressure. By the procedure, 7.43 g of α-amino-α-[2-(trichloroethoxycarbonylamino)thiazol-4-yl]acetic acid ethyl ester hydrochloric acid salt is obtained (yield, 72%). This product is suspended in ethyl acetate and the obtained suspension is washed with saturated sodium bicarbonate aq. solution, washed with water and dried over anhydrous magnesium sulfate. The oily product obtained by the distillation of the solvent, is dissolved in 60 ml of N,N-dimethylformamide and, to the solution is added 4.2 g of tetramethylguanidine and then 3.94 g of t-butyloxycarbonylazide, followed by the stirring for 15 hours at room temperature. The reaction mixture is poured into water and extracted with ethyl acetate. The organic layer is washed with 1N hydrochloric acid and then saturated NaCl aq. solution and dried over anhydrous magnesium sulfate. The oily product obtained by the distillation of the solvent is purified by a column chromatography packed with silica gel. The procedure gives 4.06 g of α-t-butyloxycarbonylamino-α-[2-(trichloroethoxycarbonylamino)thiazol-4-yl]acetic acid ethyl ester (yield, 46.5%). Melting point: 94°-95° C.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:19])[NH:10][CH2:11][C@H:12]([NH2:18])[C@@H:13]([OH:17])[C:14]#[C:15][CH3:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.[N:29]1([C:33]([NH:35][C:36]2[CH:48]=[CH:47][C:46]([C:49]([F:52])([F:51])[F:50])=[CH:45][C:37]=2[C:38]([NH:40][CH2:41][C:42](O)=[O:43])=[O:39])=[O:34])[CH2:32][CH2:31][CH2:30]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[CH2:1]([O:8][C:9](=[O:19])[NH:10][CH2:11][C@H:12]([NH:18][C:42](=[O:43])[CH2:41][NH:40][C:38](=[O:39])[C:37]1[CH:45]=[C:46]([C:49]([F:51])([F:52])[F:50])[CH:47]=[CH:48][C:36]=1[NH:35][C:33]([N:29]1[CH2:32][CH2:31][CH2:30]1)=[O:34])[C@@H:13]([OH:17])[C:14]#[C:15][CH3:16])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)CNC(=O)c1cc(C(F)(F)F)ccc1NC(=O)N1CCC1
Reactant: CC#C[C@H](O)[C@@H](N)CNC(=O)OCc1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC#C[C@H](O)[C@H](CNC(=O)OCc1ccccc1)NC(=O)CNC(=O)c1cc(C(F)(F)F)ccc1NC(=O)N1CCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 63.8 %

Procedure:
(2S,3S)-(2-Amino-3-hydroxy-hex-4-ynyl)-carbamic acid benzyl ester (520 mg, prepared as in WO PCT 0250019) was dissolved in CH2Cl2 (20 ml) and DIEA (0.74 ml) and cooled to 0° C. prior to the addition of {2-[(azetidine-1-carbonyl)-amino]-5-trifluoromethyl-benzoylamino}-acetic acid (684 mg, prepared as in WO PCT 0250019) and HATU (756 mg). After the reaction was stirred overnight at room temperature, the CH2Cl2 was removed and EtOAc was added. The organic layer was washed with saturated NH4Cl solution (aq) brine, dried, filtered, and concentrated. Flashed chromatography of the resulting residue gave (2S,3S)-[2-(2-{2-[(azetidine-1-carbonyl)-amino]-5-trifluoromethyl-benzoylamino}-acetylamino)-3-hydroxy-hex-4-ynyl]-carbamic acid benzyl ester (745 mg). MS found: (M+H)+=590.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.[C:9](O)(=[O:13])[CH2:10][CH2:11][CH3:12].C1CCC(N=C=NC2CCCCC2)CC1>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:9]([NH:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1)(=[O:13])[CH2:10][CH2:11][CH3:12]
Reactant: CCCC(=O)O
Reactant: Nc1cccc(O)c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCCC(=O)Nc1cccc(O)c1

Procedure:
3-aminophenol (550 mg; 5 mmol) is added to a solution of butyric acid (1.4 mL; 15 mmol) in DCM (20 mL) at room temperature and stirred vigorously. To this solution DCC (2.48 g; 12 mmol) is added followed by DMAP (24 mg) and the contents stirred overnight at room temperature. The reaction mixture is then filtered and washed with DCM. The filtrate is concentrated and redissolved in methanol, added with 10% aqueous sodium bicarbonate solution and stirred vigorously until diacylated byproduct disappeared (as detected by LC-MS) to yield 3-butyramidophenol as the only product. The product was used for further transformation without further purification.