Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:30])([F:29])[C:3]1[N:8]=[CH:7][C:6]([C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[N:14]([S:18]([C:21]2[CH:28]=[CH:27][C:24]([C:25]#[N:26])=[CH:23][CH:22]=2)(=[O:20])=[O:19])[CH2:13][CH2:12]3)=[CH:5][CH:4]=1.Cl.[NH2:32][OH:33].C(N(CC)CC)C>O1CCCC1.CO>[OH:33][NH:32][C:25](=[NH:26])[C:24]1[CH:27]=[CH:28][C:21]([S:18]([N:14]2[C:15]3[C:11](=[CH:10][C:9]([C:6]4[CH:7]=[N:8][C:3]([C:2]([F:30])([F:29])[F:1])=[CH:4][CH:5]=4)=[CH:17][CH:16]=3)[CH2:12][CH2:13]2)(=[O:20])=[O:19])=[CH:22][CH:23]=1
Reactant: N#Cc1ccc(S(=O)(=O)N2CCc3cc(-c4ccc(C(F)(F)F)nc4)ccc32)cc1
Reactant: NO
Agent: Cl
Solvent: C1CCOC1
Solvent: CO
Solvent: CCN(CC)CC
Product: N=C(NO)c1ccc(S(=O)(=O)N2CCc3cc(-c4ccc(C(F)(F)F)nc4)ccc32)cc1
Temperature: 90 °C
Reaction time: 4 h
Yield: 229 %

Procedure:
223 mg 4-[5-(6-Trifluoromethyl-pyridin-3-yl)-2,3-dihydro-indole-1-sulfonyl]-benzonitrile were dissolved in a mixture of 8 ml tetrahydrofuran and 8 ml methanol. 902 mg hydroxylamine hydrochloride were added followed by the addition of 1.82 ml triethylamine. The reaction mixture was stirred at 90° C. for four hours. The solvents were removed in vacuo and the resulting residue poured into 50 ml water and extracted five times with portions of 50 ml ethylacetate. The combined organic extracts were washed with 100 ml brine, dried over MgSO4 and the solvent was evaporated in vacuo to obtain 550 mg crude N-Hydroxy-4-[5-(6-trifluoromethyl-pyridin-3-yl)-2,3-dihydro-indole-1-sulfonyl]-benzamidine. This material was used without further purification.
Reaction SMILES: [NH2:1][C:2](=[O:41])[CH2:3][O:4][N:5]=[C:6]([C:25]1[CH:30]=[CH:29][C:28]([O:31][CH2:32][CH:33]([CH3:35])[CH3:34])=[CH:27][C:26]=1[O:36][CH2:37][CH:38]([CH3:40])[CH3:39])[C:7]1[CH:8]=[CH:9][C:10]([O:20][CH2:21][CH:22]([CH3:24])[CH3:23])=[C:11]([CH2:13][CH2:14][C:15]([O:17]CC)=[O:16])[CH:12]=1.[OH-].[Na+].C(Cl)(Cl)Cl.Cl>C(O)C.O>[NH2:1][C:2](=[O:41])[CH2:3][O:4][N:5]=[C:6]([C:25]1[CH:30]=[CH:29][C:28]([O:31][CH2:32][CH:33]([CH3:34])[CH3:35])=[CH:27][C:26]=1[O:36][CH2:37][CH:38]([CH3:40])[CH3:39])[C:7]1[CH:8]=[CH:9][C:10]([O:20][CH2:21][CH:22]([CH3:24])[CH3:23])=[C:11]([CH2:13][CH2:14][C:15]([OH:17])=[O:16])[CH:12]=1
Reactant: CCOC(=O)CCc1cc(C(=NOCC(N)=O)c2ccc(OCC(C)C)cc2OCC(C)C)ccc1OCC(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: ClC(Cl)Cl
Solvent: O
Product: CC(C)COc1ccc(C(=NOCC(N)=O)c2ccc(OCC(C)C)c(CCC(=O)O)c2)c(OCC(C)C)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 66.2 %

Procedure:
In 10 ml of ethanol is dissolved 1.08 g of ethyl 3-{5-[[(2-amino-2-oxoethoxy)imino](2,4-diisobutoxyphenyl)methyl]-2-isobutoxyphenyl}propanoate, to which is added 1.1 ml of 5 mol/L sodium hydroxide solution. The mixture is stirred at ambient temperature for 3 hours. Chloroform and water are added to the reaction mixture, pH is adjusted to 2 with 6 mol/L hydrochloric acid, and the organic layer is separated. The organic layer thus obtained is washed with water and saturated aqueous solution of sodium chloride successively and dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure. The residue thus obtained is purified by silica gel column chromatography (eluent; chloroform:ethanol=10:1) to obtain 0.68 g of 3-{5-[[(2-amino-2-oxoethoxy)imino](2,4-diisobutoxyphenyl)methyl]-2-isobutoxyphenyl}propanoic acid as a white foaming product.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH2:11][C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH:18]1(O)[CH2:22][CH2:21][CH2:20][CH2:19]1.C(C=P(CCCC)(CCCC)CCCC)#N>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([CH:11]([CH:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)[C:12]2[CH:13]=[CH:14][N:15]=[CH:16][CH:17]=2)(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: O=S(=O)(Cc1ccncc1)c1ccc(Cl)cc1
Reactant: OC1CCCC1
Agent: CCCCP(=CC#N)(CCCC)CCCC
Solvent: Cc1ccccc1
Product: O=S(=O)(c1ccc(Cl)cc1)C(c1ccncc1)C1CCCC1
Temperature: 25 °C
Yield: 87.8 %

Procedure:
A toluene (5 ml) solution of the 4-(4-chlorophenylsulfonylmethyl)pyridine (70 mg, 0.261 mmol) obtained in Example 119, cyclopentanol (49 μl, 0.538 mmol) and cyanomethylenetri-n-butylphosphorane (129 mg, 0.538 mol) was heated under reflux for 3 days under an argon atmosphere. After cooling to room temperature, the reaction mixture was added with cyclopentanol (49 μl, 0.538 mmol) and cyanomethylenetri-n-butylphosphorane (129 mg, 0.538 mol). The mixture was heated under reflux for 22 hours under an argon atmosphere. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The residue was subjected to flash chromatography on a silica gel column, and the fraction obtained from the hexane:ethyl acetate (=2:1) eluate was concentrated under reduced pressure to give the title compound (77 mg, 88%) as a white solid. The resulting solid was washed with hexane-ether and collected by filtration, whereby the title compound was obtained as a white powder.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10](Cl)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:3]=1.C(N(CC)CC)C.[N:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[CH2:32][NH2:33]>C1COCC1>[Cl:1][C:2]1[N:11]=[C:10]([NH:33][CH2:32][C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][N:26]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:3]=1
Reactant: NCc1ccccn1
Reactant: Clc1nc(Cl)c2c(-c3ccccc3)cccc2n1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Clc1nc(NCc2ccccn2)c2c(-c3ccccc3)cccc2n1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 75.7 %

Procedure:
2,4-Dichloro-5-phenylquinazoline (1.38 g, 5.03 mmol) was dissolved in THF (80 mL) and triethylamine (1.33 mL, 9.56 mmol) was added dropwise. The mixture was stirred for 5 min at room temperature and then pyridin-2-ylmethanamine (0.57 mL, 5.53 mmol) was added dropwise. The resulting mixture was stirred at ambient temperature for 14 hours. After this time, the mixture was filtered through a medium porosity glass frit, concentrated to dryness under reduced pressure and then purified by ISCO flash column chromatography (80 g silica gel column) eluting with 0-100% ethyl acetate/hexanes over 30 min to provide 2-chloro-5-phenyl-N-(pyridin-2-ylmethyl)quinazolin-4-amine (1.32 g, 75%). LCMS Method A [M+1] observed 347.1. HPLC Method B: Purity 99.1% retention time 6.66 min. 1H NMR (400 MHz, chloroform-d) δ ppm 8.16 (1H, d, J=4.77 Hz), 7.79 (1H, d, J=7.28 Hz), 7.70 (1H, t, J=7.78 Hz), 7.59 (1H, dt, J=7.53, 1.51 Hz), 7.40-7.55 (5H, m), 7.08-7.25 (4H, m), 4.66 (2H, d, J=4.02 Hz).
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[Br:7][C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([Cl:17])[CH:15]=2)[NH:10][CH:9]=1.CI.[CH2:20](OC(=O)C)C>CN(C=O)C.CCCCCC>[Br:7][C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([Cl:17])[CH:15]=2)[N:10]([CH3:20])[CH:9]=1
Reactant: CCOC(C)=O
Reactant: Clc1ccc2[nH]cc(Br)c2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: Cn1cc(Br)c2cc(Cl)ccc21
Reaction time: 0.5 h
Yield: 65 %

Procedure:
K2CO3 (1.39 g, 10.08 mmol) was added to a stirred solution of 3-bromo-5-chloro-1H-indole (775 mg, 3.36 mmol) in DMF (7.5 mL) and the resulting mixture was stirred for 30 minutes. This was followed by the addition of methyl iodide (572.5 mg, 4.03 mmol) at 0-5° C. and the stirring was continued for a further 2 hours at room temperature. The reaction was monitored by TLC (10% ethylacetate in hexane). The reaction mixture was partitioned between ice water and DCM. The organic layer was concentrated to afford the crude product. Purification by column chromatography on silica gel (5% ethylacetate in hexane) afforded 530 mg of 3-Bromo-5-chloro-1-methyl-1H-indole (65% yield).
Reaction SMILES: [CH2:1]([NH:3][C:4]([C:6]1[C:10](I)=[C:9]([C:12]2[CH:17]=[C:16]([Cl:18])[C:15]([O:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:14][C:13]=2[O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[O:8][N:7]=1)=[O:5])[CH3:2].[C:35]([O-:38])(O)=O.[Na+].CN(C=O)C>CCOC(C)=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:1]([NH:3][C:4]([C:6]1[C:10]([C:12]2[CH:17]=[CH:16][C:15]([CH:35]=[O:38])=[CH:14][CH:13]=2)=[C:9]([C:12]2[CH:17]=[C:16]([Cl:18])[C:15]([O:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:14][C:13]=2[O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[O:8][N:7]=1)=[O:5])[CH3:2]
Reactant: O=C([O-])O
Reactant: CCNC(=O)c1noc(-c2cc(Cl)c(OCc3ccccc3)cc2OCc2ccccc2)c1I
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCNC(=O)c1noc(-c2cc(Cl)c(OCc3ccccc3)cc2OCc2ccccc2)c1-c1ccc(C=O)cc1
Temperature: 80 °C
Yield: 163.6 %

Procedure:
5-(2,4-Bis-benzyloxy-5-chloro-phenyl)-4-iodo-isoxazole-3-carboxylic acid ethylamide (prepared as for Example 31) (2 g, 3.4 mmol), 4-formylboronic acid (0.612 g, 4.08 mmol), NaHCO3 (10.2 ml, 1M aq. solution, 10.2 mmol), PdCl2(PPh3)2 (119 mg, 0.17 mmol) and DMF (50 ml) were combined. The mixture was then degassed by bubbling N2 through it for 5 minutes before being heated at 80° C. for 1 hour. The mixture was then evaporated in vacuo and partitioned between EtOAc (3×50 ml) and water (50 ml). The combined, dried (Na2SO4) organics were evaporated in vacuo to give a crude oil. This was dissolved in EtOAc and passed through a plug of SiO2, washing through with EtOAc. The filtrate was evaporated in vacuo and the resulting oil triturated with Et2O to afford 5-(2,4-Bis-benzyloxy-5-chloro-phenyl)-4-(4-formyl-phenyl)-isoxazole-3-carboxylic acid ethylamide (1.577 g, 82%) as a pale coloured solid, LC/MS: RT=2.908 min. 567.3 (MH+).
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]([C:7]1[CH:26]=[CH:25][C:10]([CH2:11][CH:12]([C:19]([O:21][CH2:22][CH:23]=[CH2:24])=[O:20])[C:13]([O:15][CH2:16][CH:17]=[CH2:18])=[O:14])=[CH:9][CH:8]=1)=[O:6].Br[CH2:28][CH2:29][C:30]1([CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])[CH2:32][CH2:31]1.O>CN(C=O)C.C(OCC)(=O)C>[CH2:37]([O:36][C:34](=[O:35])[CH2:33][C:30]1([CH2:29][CH2:28][C:12]([CH2:11][C:10]2[CH:9]=[CH:8][C:7]([C:5]([O:4][CH3:3])=[O:6])=[CH:26][CH:25]=2)([C:19]([O:21][CH2:22][CH:23]=[CH2:24])=[O:20])[C:13]([O:15][CH2:16][CH:17]=[CH2:18])=[O:14])[CH2:31][CH2:32]1)[CH3:38]
Reactant: CCOC(=O)CC1(CCBr)CC1
Reactant: C=CCOC(=O)C(Cc1ccc(C(=O)OC)cc1)C(=O)OCC=C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: C=CCOC(=O)C(CCC1(CC(=O)OCC)CC1)(Cc1ccc(C(=O)OC)cc1)C(=O)OCC=C
Temperature: 40 °C
Reaction time: 0.5 h

Procedure:
Under argon and at 0° C., 1.67 g (41.62 mmol) of sodium hydride (60% strength dispersion in mineral oil) are added a little at a time to a solution of 10.87 g (32.70 mmol) of diallyl [4-(methoxycarbonyl)benzyl]malonate in 60 ml of anhhdrous DMF. The mixture is stirred at 40° C. for 30 min, and a solution of 6.99 g (29.73 mmol) of ethyl [1-(2-bromoethyl)cyclopropyl]acetate in 60 ml of anhydrous DMF is then added dropwise at this temperature. The reaction mixture is subsequently heated at 100° C. for 8 hours. After addition of 600 ml of water and 200 ml of ethyl acetate and phase separation, the aqueous phase is extracted twice with ethyl acetate. The organic phase is then washed five times with water and once with saturated sodium chloride solution and dried over anhydrous magnesium sulfate. The crude product is initially purified by flash chromatography (400 g of silica gel 60, mobile phase: cyclohexane/ethyl acetate 4:1), and then by preparative HPLC. This gives 4.87 g (28% of theory) of the title compound in the form of a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH:9]2[CH2:13][CH2:12][CH2:11][CH2:10]2)=[CH:6][C:5]([NH:14][C:15](=[O:19])[O:16][CH2:17][CH3:18])=[C:4]([F:20])[CH:3]=1.O[CH:22]([C:28](C)=C)[C:23](OCC)=O.C([OH:33])C.C1(C)C=CC=CC=1>C(N(CCCC)CCCC)CCC.CCCCCC>[Cl:1][C:2]1[C:7]([O:8][CH:9]2[CH2:10][CH2:11][CH2:12][CH2:13]2)=[CH:6][C:5]([N:14]2[C:18](=[O:33])[C:17](=[C:22]([CH3:28])[CH3:23])[O:16][C:15]2=[O:19])=[C:4]([F:20])[CH:3]=1
Reactant: CCO
Reactant: CCOC(=O)Nc1cc(OC2CCCC2)c(Cl)cc1F
Reactant: C=C(C)C(O)C(=O)OCC
Solvent: CCCCCC
Solvent: Cc1ccccc1
Solvent: CCCCN(CCCC)CCCC
Product: CC(C)=C1OC(=O)N(c2cc(OC3CCCC3)c(Cl)cc2F)C1=O
Temperature: 200 °C
Yield: 74.5 %

Procedure:
Ethyl N-(4-chloro-5-cyclopentyloxy-2-fluorphenyl)carbamate (674 g, 2.24 mmol), ferric chloride (3.7 g, 22.8 mmol) and tributylamine (21 g, 0.113 mol) were introduced into a three-necked flask (3 L) equipped with a mechanical stirrer and a Dean Stark, and the resulting mixture was heated to 200° C. with stirring to form a homogeneous solution. Then, ethyl 2-hydroxy-3-methyl-3-butenoate (484 g, 3.51 mol) was added dropwise over 5.5 hours, and after the addition, the solution was stirred for another 2.5 hours. The ethanol generated during the heating and stirring was distilled away by mean s of the Dean Stark . After completion of the reaction, the reaction mixture was allowed to cool to about 100° C., and then toluene (2.0 L) was added to form a solution. The solution was washed with 1N hydrochloric acid (1 L) and water (1 L). The organic layer was concentrated under reduced pressure, and the resulting oily crude product was crystallized in ethanol (3.85 L) acidified with sulfuric acid. The precipitated crystals were collected by filtration and washed with a small amount of acidic ethanol and then hexane to obtain 3-(4-chloro-5-cyclopentyloxy-2-fluorophenyl)-5-isopropylidene-1,3-oxazolidine-2,4-dione (590 g, yield 74.5%) as white crystals.
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH:10]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:11]([O:13][CH2:14][CH3:15])=[O:12]>C1C=CC=CC=1>[CH2:1]([NH:8][CH:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(Br)C(=O)OCC
Reactant: NCc1ccccc1
Solvent: c1ccccc1
Product: CCOC(=O)C(NCc1ccccc1)C(=O)OCC
Yield: 20.9 %

Procedure:
Benzylamine (18.3 g) and diethyl bromomalonate (20.3 g) were dissolved in dry benzene (100 ml), and the mixture was heated under reflux for 14 hours with stirring. The precipitated salt was removed by filtration from the reaction mixture. The filtrate was washed with dilute hydrochloric acid to remove the unreacted benzylamine. The benzene layer was washed with water three times, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography using hexane/ethyl acetate (4:1) as an eluent to give 4.7 g (yield 21%) of diethyl benzylaminomalonate having the following NMR data.
Reaction SMILES: [CH3:1][NH2:2].[CH3:3][C:4]1([CH3:19])[C:8](=O)[CH2:7][CH:6]([C:10]2[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[CH:12][C:11]=2[F:18])[CH2:5]1.O.[NH2:21]N.C(O)(=O)C>C(O)(C)C>[CH3:3][C:4]1([CH3:19])[C:8]2[NH:21][N:2]=[CH:1][C:7]=2[CH:6]([C:10]2[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[CH:12][C:11]=2[F:18])[CH2:5]1
Reactant: CC1(C)CC(c2ccc(C#N)cc2F)CC1=O
Reactant: CN
Reactant: NN
Solvent: O
Solvent: CC(C)O
Solvent: CC(=O)O
Product: CC1(C)CC(c2ccc(C#N)cc2F)c2cn[nH]c21
Temperature: 90 °C
Reaction time: 16 h
Yield: 99 %

Procedure:
Methanamine, 1,1-dimethoxy-N,N-dimethyl-(42.05 g, 352.84 mmol) is added to 4-(3,3-dimethyl-4-oxo-cyclopentyl)-3-fluoro-benzonitrile (34 g, 117.61 mmol) and the mixture is stirred at 90° C. for 16 hours. The mixture is cooled to ambient temperature and the excess DMF-DMA is evaporated to dryness. To the crude residue is added: isopropyl alcohol (163.20 mL), hydrazine monohydrate (11.78 g. 235.22 mmol), and acetic acid (20.22 mL, 352.84 mmol) and the mixture is stirred at 70° C. for 2 hours. The mixture is cooled to ambient temperature and the solvent evaporated to dryness. The mixture is poured into water (200 mL) and is extracted with MTBE (2×200 mL). The mixture is washed with brine, dried over MgSO4, filtered, and concentrated to dryness. The residue is purified by silica gel flash chromatography, eluting with hexane and 10% IPA to give the title compound (30 g, 99%). ES/MS (m/z) 256 (M+1), 1H NMR (300.16 MHz, DMSO) δ 12.62-12.60 (m, 1H), 7.82 (dd, J=1.5, 10.2 Hz, 1H), 7.62 (dd, J=1.5, 8.1 Hz, 1H), 7.42-7.34 (m, 1H), 4.52 (t, J=7.7 Hz, 1H), 2.73 (d, J=1.8 Hz, 1H), 2.07 (dd, J=8.1, 11.7 Hz, 1H), 1.25 (s, 6H).
Reaction SMILES: [S-:1][C:2]#[N:3].[K+].CC(C)=O.[C:9](Cl)(=[O:14])[C:10]([CH3:13])([CH3:12])[CH3:11].[CH:16]1([CH2:19][NH:20][CH:21]([C:23]2[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=2)[CH3:22])[CH2:18][CH2:17]1>>[C:9]([NH:3][C:2](=[S:1])[N:20]([CH2:19][CH:16]1[CH2:18][CH2:17]1)[CH:21]([C:23]1[CH:24]=[CH:25][N:26]=[CH:27][CH:28]=1)[CH3:22])(=[O:14])[C:10]([CH3:13])([CH3:12])[CH3:11]
Reactant: CC(C)(C)C(=O)Cl
Reactant: N#C[S-]
Reactant: CC(NCC1CC1)c1ccncc1
Agent: [K+]
Solvent: CC(C)=O
Product: CC(c1ccncc1)N(CC1CC1)C(=S)NC(=O)C(C)(C)C
Temperature: 0 °C
Reaction time: 5 h

Procedure:
Dissolve under argon 2.9 g of potassium thiocyanate in 30 mol of acetone in a 100-ml three-necked flask. Cool to 0° C. and add 3.4 ml of pivaloyl chloride dropwise. Stir at 0° C. for 5 hours and then add 4.8 g of N-(cyclopropylmethyl)-1-(4-pyridyl)ethylamine (Compound 61). Stir at room temperature overnight. Evaporate to dryness. The residue is taken up in water and extracted into methylene chloride. Dry over anhydrous sodium sulphate and evaporate to dryness. The powder obtained is washed with hexane and filtered off.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:14](=O)[CH3:15])[CH:5]=[N:6][C:7]=1[O:8][CH2:9][C:10]([F:13])([F:12])[F:11].[CH3:17][C:18]([S@:21]([NH2:23])=[O:22])([CH3:20])[CH3:19]>>[F:1][C:2]1[CH:3]=[C:4]([CH:14]([NH:23][S@@:21]([C:18]([CH3:20])([CH3:19])[CH3:17])=[O:22])[CH3:15])[CH:5]=[N:6][C:7]=1[O:8][CH2:9][C:10]([F:13])([F:12])[F:11]
Reactant: CC(C)(C)[S@](N)=O
Reactant: CC(=O)c1cnc(OCC(F)(F)F)c(F)c1
Product: CC(N[S@](=O)C(C)(C)C)c1cnc(OCC(F)(F)F)c(F)c1
Yield: 78 %

Procedure:
The title compound is prepared in 78% yield (0.17 g, white solid) from 1-(5-fluoro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethanone (0.15 g, 0.65 mmol, Step-4) and (R)-2-methylpropane-2-sulfinamide in a similar manner to Step-4 of Amine-1.
Reaction SMILES: N1C=CC=CC=1.[C:7](OC(=O)C)(=[O:9])[CH3:8].[C:14]([N:24]1[CH2:27][CH:26]([C:28]2[CH:33]=[CH:32][C:31]([N:34]3[CH2:38][C@H:37]([CH2:39][NH2:40])[O:36][C:35]3=[O:41])=[CH:30][C:29]=2[F:42])[CH2:25]1)([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15]>CN(C)C1C=CN=CC=1.C(Cl)Cl>[F:42][C:29]1[CH:30]=[C:31]([N:34]2[CH2:38][C@H:37]([CH2:39][NH:40][C:7](=[O:9])[CH3:8])[O:36][C:35]2=[O:41])[CH:32]=[CH:33][C:28]=1[CH:26]1[CH2:27][N:24]([C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:15])[CH2:25]1
Reactant: CC(=O)OC(C)=O
Reactant: NC[C@H]1CN(c2ccc(C3CN(C(=O)OCc4ccccc4)C3)c(F)c2)C(=O)O1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)NC[C@H]1CN(c2ccc(C3CN(C(=O)OCc4ccccc4)C3)c(F)c2)C(=O)O1
Reaction time: 1 h

Procedure:
Pyridine (1.0 mL), acetic anhydride (1.0 mL) and a few crystals of 4-dimethylaminopyridine were added to a stirred solution of (S)-(−)-N-carbobenzyloxy-3-[2-fluoro-4-[5-aminomethyl-2-oxo-3-oxazolidinyl]phenyl]azetidine (Example 81, Step 8, 1.42 g, 3.56 mmol) in methylene chloride (30 mL), then stirred for 1 hr. The solvents were removed at 38°/0.75 mm and the residue chromatographed over silica gel (50 g, 40-60 μm) eluting with 1-2% methanol-chloroform. The title compound was isolated as a white foam. FAB-HRMS: theory 442.1778 (M+1); meas. 442.1777.
Reaction SMILES: [C:1]1([CH:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=2)[C:8]#[N:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-:16].[Na+]>S(=O)(=O)(O)O>[C:1]1([CH:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=2)[C:8]([NH2:9])=[O:16])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: N#CC(c1ccccc1)c1ccccn1
Reactant: [OH-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: NC(=O)C(c1ccccc1)c1ccccn1
Temperature: 0 °C
Yield: 86 %

Procedure:
A solution of (RS)-phenyl-pyridin-2-yl-acetonitrile (0.928 g, 4.80 mmol) in 5 ml of conc. sulfuric acid was stirred overnight at room temperature. The mixture is poured on 100 g of ice, the pH is adjusted to 8-9 by addition of 28% sodium hydroxide solution and the product is extracted with ethyl acetate/water. After drying (MgSO4) and concentration, the crude material is purified by flash chromatography on silicagel using ethyl acetate as eluant to yield 0.878 g (4.14 mmol, 86%) of (RS)-phenyl-pyridin-2-yl-acetamide as a white solid, m.p. 134° C. and MS: m/e=213.2 (M+H+).
Reaction SMILES: [CH2:1]([C:4]1[NH:5][C:6]2[C:11]([CH:12]=1)=[CH:10][CH:9]=[C:8]([C:13]([O:15][CH3:16])=[O:14])[CH:7]=2)[CH2:2][CH3:3].[CH3:17][O:18][CH2:19][C:20](O)=[O:21].C(Cl)(Cl)(Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCCl>[CH3:17][O:18][CH2:19][C:20]([C:12]1[C:11]2[C:6](=[CH:7][C:8]([C:13]([O:15][CH3:16])=[O:14])=[CH:9][CH:10]=2)[NH:5][C:4]=1[CH2:1][CH2:2][CH3:3])=[O:21]
Reactant: CCCc1cc2ccc(C(=O)OC)cc2[nH]1
Reactant: COCC(=O)O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCCl
Solvent: ClC(Cl)(Cl)Cl
Product: CCCc1[nH]c2cc(C(=O)OC)ccc2c1C(=O)COC

Procedure:
To a mixture of methyl 2-propylindole-6-carboxylate (10 g), methoxyacetic acid (4.6 ml) and carbontetrachloride (13.4 ml) in 1,2-dichloroethane (45 ml) was added slowly triphenylphosphine (16.7 g) in 1,2-dichloroethane (30 ml) over 1 hour under reflux, and the resulting mixture was heated under reflux for additional 8 hours. After evaporation of solvent, the residue was chromatographed on silica gel eluting with a mixture of hexane and ethyl acetate (1:1) and triturated with diethyl ether to give methyl 3-methoxyacetyl-2-propylindole-6-carboxylate (8.11 g).
Reaction SMILES: [C:1]1([C:7]#[C:8][C:9]2[CH2:13][C:12]3([CH2:18][CH2:17][N:16](C(OC(C)(C)C)=O)[CH2:15][CH2:14]3)[O:11][N:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.FC(F)(F)C(O)=O.O.[OH-].[Na+]>C(Cl)Cl>[C:1]1([C:7]#[C:8][C:9]2[CH2:13][C:12]3([CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)[O:11][N:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CC(C#Cc1ccccc1)=NO2
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C(#Cc1ccccc1)C1=NOC2(CCNCC2)C1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of Compound 1b (200 mg, 0.59 mmol) in CH2Cl2 (12 mL) stirred at 0° C. was added trifluoroacetic acid (452 μl, 5.87 mmol) and the reaction mixture was stirred at 25° C. for 24 h, until the complete conversion of the reactant was observed by LC-MS. Water was added followed by 3N aq. NaOH to give a alkaline pH. Separation of the organic layer and extraction of the aqueous layer with CH2Cl2, washing with brine and drying over Na2SO4 the combined organic layers, afforded the title compound as beige solid, used in the next step without further purification.
Reaction SMILES: [C:1]([C:4]1[CH:24]=[CH:23][CH:22]=[CH:21][C:5]=1[O:6][C:7]1[CH:12]=[N:11][N:10](C2CCCCO2)[C:9](=[O:19])[C:8]=1[Cl:20])(=[O:3])[CH3:2].Cl.O>CO>[C:1]([C:4]1[CH:24]=[CH:23][CH:22]=[CH:21][C:5]=1[O:6][C:7]1[CH:12]=[N:11][NH:10][C:9](=[O:19])[C:8]=1[Cl:20])(=[O:3])[CH3:2]
Reactant: CC(=O)c1ccccc1Oc1cnn(C2CCCCO2)c(=O)c1Cl
Agent: Cl
Solvent: CO
Solvent: O
Product: CC(=O)c1ccccc1Oc1cn[nH]c(=O)c1Cl
Yield: 79.1 %

Procedure:
A solution of 5-(2-acetyl-phenoxy)-4-chloro-2-(tetrahydro-pyran-2-yl)-2H-pyridazin-3-one (15.0 g, 0.043 mol), concentrated hydrochloric acid (30 mL), water (45 mL) and methanol (130 mL) was heated at reflux for 2 h. At this time, the reaction was concentrated in vacuo. The residue was charged with water (200 mL) and then basified with a saturated aqueous sodium bicarbonate solution. The resulting material was collected by filtration, rinsed with water and petroleum ether, and dried to afford 5-(2-acetyl-phenoxy)-4-chloro-2H-pyridazin-3-one (9.0 g, 79%); ESI-MS 265 [M+H+].