Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[N:12]=[C:11]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[N:10]=[C:9]([C:19]3[CH:24]=[CH:23][C:22]([NH:25][C:26](=[O:37])[NH:27][C:28]4[CH:36]=[CH:35][C:31]([C:32](O)=[O:33])=[CH:30][CH:29]=4)=[CH:21][CH:20]=3)[N:8]=2)[CH2:3][CH2:2]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:71][N:72]1[CH2:77][CH2:76][NH:75][CH2:74][CH2:73]1>CN1C(=O)CCC1>[O:1]1[CH2:6][CH2:5][N:4]([C:7]2[N:12]=[C:11]([N:13]3[CH2:14][CH2:15][O:16][CH2:17][CH2:18]3)[N:10]=[C:9]([C:19]3[CH:24]=[CH:23][C:22]([NH:25][C:26]([NH:27][C:28]4[CH:36]=[CH:35][C:31]([C:32]([N:75]5[CH2:76][CH2:77][N:72]([CH3:71])[CH2:73][CH2:74]5)=[O:33])=[CH:30][CH:29]=4)=[O:37])=[CH:21][CH:20]=3)[N:8]=2)[CH2:3][CH2:2]1
Reactant: CN1CCNCC1
Reactant: O=C(Nc1ccc(C(=O)O)cc1)Nc1ccc(-c2nc(N3CCOCC3)nc(N3CCOCC3)n2)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: CN1CCN(C(=O)c2ccc(NC(=O)Nc3ccc(-c4nc(N5CCOCC5)nc(N5CCOCC5)n4)cc3)cc2)CC1
Yield: 54.4 %

Procedure:
To a stirred solution of 4-(3-(4-(4,6-dimorpholino-1,3,5-triazin-2yl)phenyl)ureido)benzoic acid (150 mg; 0.297 mmol), Hunig's base (303 μL, 1.782 mmol), HBTU (563 mg, 1.485 mmol) in 2 mL of NMP was reacted according to example 68 with 1-methylpiperazine (132 μL, 1.188 mmol) to give 1-(4-(4,6-dimorpholino-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-methylpiperazine-1-carbonyl)phenyl)urea as a white solid (95 mg, 54% yield); MS (ESI) m/z=588.4.
Reaction SMILES: [O:1]=[C:2]1[CH:7]=[CH:6][N:5]([C:8]2[C:13]([C:14]([F:17])([F:16])[F:15])=[CH:12][C:11]([NH2:18])=[C:10]([NH2:19])[CH:9]=2)[CH:4]=[CH:3]1.[C:20](O)(=[O:24])[C:21](O)=[O:22].Cl>>[O:1]=[C:2]1[CH:3]=[CH:4][N:5]([C:8]2[CH:9]=[C:10]3[C:11](=[CH:12][C:13]=2[C:14]([F:16])([F:17])[F:15])[NH:18][C:21](=[O:22])[C:20](=[O:24])[NH:19]3)[CH:6]=[CH:7]1
Reactant: O=C(O)C(=O)O
Reactant: Nc1cc(-n2ccc(=O)cc2)c(C(F)(F)F)cc1N
Agent: Cl
Product: O=c1ccn(-c2cc3[nH]c(=O)c(=O)[nH]c3cc2C(F)(F)F)cc1
Yield: 60 %

Procedure:
First, a mixture containing 300 mg of 4-(4-oxo-4H-pyridin-1-yl)-5-trifluoromethyl-1,2-phenylenediamine, 301 mg of oxalic acid, and 6 ml of 2N hydrochloric acid was refluxed by heating in an oil bath for 7 hours. The mixture was cooled and precipitated crystals were filtered. Then, 333 mg of the crude crystals thus obtained were recrystallized with a mixture of dimethylformamide and water to give 216 mg of 6-(4-oxo-4H-pyridin-1-yl)-7-trifluoromethyl-1,4-dihydroquinoxaline-2,3-dione.
Reaction SMILES: [CH3:1][N:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][C:5](=[O:12])[N:4]([C:13]2[CH:14]=[CH:15][C:16]3[S:20][N:19]=[C:18]([CH2:21][S:22][CH3:23])[C:17]=3[CH:24]=2)[C:3]1=[O:25].ClC1C=C(C=CC=1)C(OO)=[O:31].C(OCC)(=O)C>C(Cl)Cl>[CH3:1][N:2]1[C:7]([C:8]([F:9])([F:10])[F:11])=[CH:6][C:5](=[O:12])[N:4]([C:13]2[CH:14]=[CH:15][C:16]3[S:20][N:19]=[C:18]([CH2:21][S:22]([CH3:23])=[O:31])[C:17]=3[CH:24]=2)[C:3]1=[O:25]
Reactant: CSCc1nsc2ccc(-n3c(=O)cc(C(F)(F)F)n(C)c3=O)cc12
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: Cn1c(C(F)(F)F)cc(=O)n(-c2ccc3snc(CS(C)=O)c3c2)c1=O
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A solution of 1-methyl-3-{3-[(methylthio)methyl]-1,2-benzisothiazol-5-yl}-6-(trifluoromethyl)-2,4(1H,3H)-pyrimidinedione (0.740 g, 1.90 mmol) in methylene chloride is treated with 3-chloroperoxybenzoic acid (0.580 g, 60%, 2.00 mmol), stirred at room temperature for five minutes, diluted with additional methylene chloride, washed with 5% sodium carbonate solution, dried over anhydrous magnesium sulfate, and concentrated in vacuo to obtain a solid. Flash column chromatography of the solid using silica gel and a 10% ethyl acetate in methylene chloride solution gives the title product as a white solid which is identified by NMR spectral analysis.
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH3:5])[CH3:2].[Cl:6][CH:7]([C:11]1[CH:16]=[CH:15][C:14]([CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)=[C:13]([Cl:23])[CH:12]=1)[C:8]([OH:10])=[O:9]>CCCCCC>[CH2:1]([NH2+:3][CH2:4][CH3:5])[CH3:2].[Cl:6][CH:7]([C:11]1[CH:16]=[CH:15][C:14]([CH:17]2[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]2)=[C:13]([Cl:23])[CH:12]=1)[C:8]([O-:10])=[O:9]
Reactant: O=C(O)C(Cl)c1ccc(C2CCCCC2)c(Cl)c1
Reactant: CCNCC
Solvent: CCCCCC
Product: CC[NH2+]CC
Product: O=C([O-])C(Cl)c1ccc(C2CCCCC2)c(Cl)c1

Procedure:
Anhydrous diethylamine (0.11 moles) is added dropwise to a stirred solution of α,3-dichloro-4-cyclohexylphenylacetic acid (0.10 moles) in 100 ml. of n-hexane at 0° C. The precipitate is collected on a filter, washed with n-hexane, and dried in a vacuum desiccator to obtain α,3-dichloro-4-cyclohexylphenylacetic acid, diethylammonium salt.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.Cl.[C:15]([O:19][C:20](=[O:32])[C@H:21]([CH2:23][CH2:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[NH2:22])([CH3:18])([CH3:17])[CH3:16].ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C.C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C=O.CO>[N+:11]([C:9]1[CH:8]=[CH:7][C:3]([C:4]([NH:22][C@H:21]([C:20]([O:19][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:32])[CH2:23][CH2:24][C:25]([O:27][C:28]([CH3:31])([CH3:29])[CH3:30])=[O:26])=[O:6])=[C:2]([F:1])[CH:10]=1)([O-:13])=[O:12]
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1F
Reactant: CC(C)(C)OC(=O)CC[C@H](N)C(=O)OC(C)(C)C
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: CO
Product: CC(C)(C)OC(=O)CC[C@H](NC(=O)c1ccc([N+](=O)[O-])cc1F)C(=O)OC(C)(C)C
Reaction time: 0.25 h

Procedure:
A solution of 2-fluoro-4-nitrobenzoic acid (6.26 g, 33.8 mmoles), (L)-glutamate di-tert-butyl ester hydrochloride (10.0 g, 33.8 mmoles), and 1-hydroxybenzotriazole (4.57 g, 33.8 mmoles) in dry dimethylformamide (150 mL) was stirred under nitrogen while triethylamine (3.42 g, 4.71 mL, 33.8 mmoles) was added in one portion. After 15 minutes, 1.3-dicyclohexylcarbodiimide (7.67 g, 37.2 mmoles) was added in portions during 1 minute. The reaction mixture was filtered after 20 hours and the solids rinsed with dichloromethane (1×50 mL). The filtrate was spin evaporated to an amber residue that was partitioned between dichloromethane and saturated bicarbonate solution (200 mL each). The organic phase was washed successively with saturated bicarbonate, 5% citric acid, and brine (1×200 mL each). The organic phase was then dried (MgSO4), filtered, spin evaporated, and dried (high vacuum) to an oily yellow solid (11.9 g, 83%) that showed a major spot on tlc (silica, 2:1 hexane/ethyl acetate, Rf =0.5). The product was purified by the flash chromatography technique to give a light green gum; yield, 9.7 g (67%); 1H-NMR (CDCl3) δ 1.42 (s, 9H), 1.50 (s, 9H), 2.02-2.41 (m, 4H), 4.72 (m, 1H), 7.44 (br t, 1H), 8.0-8.3 (m, 3H); uv (MeOH) 260 nm max (11000), 225 min (4710), 215 sh (7680); mass spec (CI) m/e 427 (24%), 371 (20), 315 (100).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[S:34])[NH:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:25]=[C:24]3[C:20]([CH2:21][N:22]([C@@H:27]([CH:31]([CH3:33])[CH3:32])[C:28]([OH:30])=[O:29])[C:23]3=[O:26])=[CH:19][CH:18]=2)=[CH:13][CH:12]=1.[Cl:35]C1C=CC(NC(=S)NC2C=CC(C3C=C4C(CN([C@@H](C(C)C)C(OC)=O)C4=O)=CC=3)=CC=2)=CC=1>>[Cl:35][C:7]1[CH:2]=[C:3]([NH:8][C:9](=[S:34])[NH:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:25]=[C:24]4[C:20]([CH2:21][N:22]([C@@H:27]([CH:31]([CH3:33])[CH3:32])[C:28]([OH:30])=[O:29])[C:23]4=[O:26])=[CH:19][CH:18]=3)=[CH:13][CH:12]=2)[CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=S)Nc4ccc(Cl)cc4)cc3)cc2C1=O
Reactant: CC(C)[C@@H](C(=O)O)N1Cc2ccc(-c3ccc(NC(=S)Nc4ccccc4F)cc3)cc2C1=O
Product: CC(C)[C@@H](C(=O)O)N1Cc2ccc(-c3ccc(NC(=S)Nc4cccc(Cl)c4)cc3)cc2C1=O
Yield: 86 %

Procedure:
The compound of example 64 was prepared analogous to compound of example 52 by hydrolysis of compound of example 63.
Reaction SMILES: COC1C=CC(CC(C2C=CC(OC)=CC=2)(C)C)=C(C=1)OC1C=CC(O)=CC=1.Cl.ClCCN1CCCCC1.C[O:40][C:41]1[CH:42]=[CH:43][C:44]([CH2:63][C:64]([C:67]2[CH:72]=[CH:71][C:70]([O:73]C)=[CH:69][CH:68]=2)([CH3:66])[CH3:65])=[C:45]([CH:62]=1)[O:46][C:47]1[CH:61]=[CH:60][C:50]([O:51][CH2:52][CH2:53][N:54]2[CH2:59][CH2:58][CH2:57][CH2:56][CH2:55]2)=[CH:49][CH:48]=1>>[OH:73][C:70]1[CH:71]=[CH:72][C:67]([C:64]([CH3:66])([CH3:65])[CH2:63][C:44]2[CH:43]=[CH:42][C:41]([OH:40])=[CH:62][C:45]=2[O:46][C:47]2[CH:61]=[CH:60][C:50]([O:51][CH2:52][CH2:53][N:54]3[CH2:55][CH2:56][CH2:57][CH2:58][CH2:59]3)=[CH:49][CH:48]=2)=[CH:68][CH:69]=1
Reactant: COc1ccc(C(C)(C)Cc2ccc(OC)cc2Oc2ccc(OCCN3CCCCC3)cc2)cc1
Agent: COc1ccc(C(C)(C)Cc2ccc(OC)cc2Oc2ccc(O)cc2)cc1
Agent: Cl
Agent: ClCCN1CCCCC1
Product: CC(C)(Cc1ccc(O)cc1Oc1ccc(OCCN2CCCCC2)cc1)c1ccc(O)cc1
Yield: 65.9 %

Procedure:
Synthesized from 4-{5-methoxy-2-[2-(4-methoxyphenyl)-2-methylpropyl]phenoxy}phenol and 1-(2-chloroethyl)piperidine hydrochloride according to an analogous synthetic method to Preparation Example 40, 1-{2-{4-{5-methoxy-2-[2-(4-methoxyphenyl)-2-methylpropyl]phenoxy}phenoxy}ethyl}piperidine (190 mg) was used according to an analogous synthetic method to Example 779 described below to provide the title compound (118 mg).
Reaction SMILES: [Cl:1][C:2]1[N:3]([CH2:10][C@:11]2([CH3:14])[CH2:13][O:12]2)[CH:4]=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=1.[N:15]1([C:21]([O:23][CH2:24][CH:25]=[CH:26][C:27]2[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][CH:28]=2)=[O:22])[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1.O>CN(C=O)C>[Cl:1][C:2]1[N:3]([CH2:10][C@:11]([OH:12])([CH3:14])[CH2:13][N:18]2[CH2:17][CH2:16][N:15]([C:21]([O:23][CH2:24][CH:25]=[CH:26][C:27]3[CH:32]=[CH:31][C:30]([C:33]([F:35])([F:36])[F:34])=[CH:29][CH:28]=3)=[O:22])[CH2:20][CH2:19]2)[CH:4]=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=1
Reactant: C[C@@]1(Cn2cc([N+](=O)[O-])nc2Cl)CO1
Reactant: O=C(OCC=Cc1ccc(C(F)(F)F)cc1)N1CCNCC1
Solvent: CN(C)C=O
Solvent: O
Product: C[C@](O)(CN1CCN(C(=O)OCC=Cc2ccc(C(F)(F)F)cc2)CC1)Cn1cc([N+](=O)[O-])nc1Cl
Temperature: 52.5 °C
Reaction time: 24 h
Yield: 89.7 %

Procedure:
A mixture of (R)-2-chloro-1-(2-methyloxiran-2-ylmethyl)-4-nitroimidazole prepared in Example 12 (4.24 g, 19.48 mmol) and 3-(4-trifluoromethylphenyl)-2-propenyl piperazine-1-carboxylate (6.73 g, 21.41 mmol) in DMF (21 ml) were stirred at 50-55° C. for 24 hours. The reaction mixture was allowed to return to room temperature and poured into water (90 ml), and extracted with ethyl acetate (60 ml). The aqueous layer was extracted with ethyl acetate (60 ml) again. The organic phases were combined, washed with water (90 ml) 3 times and a saturated saline solution (60 ml), dried over sodium sulfate and then filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/n-hexane=1/1) to afford 3-(4-trifluoromethylphenyl)-2-propenyl (S)-4-[3-(2-chloro-4-nitroimidazol-1-yl)-2-hydroxy-2-methylpropyl]piperazine-1-carboxylate (9.29 g, yield 90%) as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[N:12][C:11]([NH:14][NH2:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.Cl[C:26]([O:28][CH2:29][CH3:30])=[O:27]>O1CCOCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:13]=[N:12][C:11]([NH:14][NH:15][C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:10][CH:9]=2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)Cl
Reactant: NNc1ccc(-c2ccc(Cl)cc2)nn1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: CCOC(=O)NNc1ccc(-c2ccc(Cl)cc2)nn1

Procedure:
A mixture of 1.0 g. of 6-(p-chlorophenyl)-3-hydrazinopyridazine and 0.65 g. of diisopropylethylamine in 25 ml. of dioxane are placed in a flask and warmed slightly. To this is added 0.5 g. (0.45 ml.) of ethyl chloroformate and the reaction is stirred for one hour. The dioxane is removed on a rotating evaporator and ethanol is added to the residue resulting in a precipitate. This precipitate is recrystallized from ethanol giving a yellow solid, m.p. 176°-180° C.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([NH:15][CH2:16][CH:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[C:7]([N+:12]([O-])=O)[CH:8]=[N:9]2)=[CH:4][CH:3]=1>C(#N)C.C(O)(C)C.[Pt]>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([NH:15][CH2:16][CH:17]3[CH2:18][CH2:19][O:20][CH2:21][CH2:22]3)=[C:7]([NH2:12])[CH:8]=[N:9]2)=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1cnc2cc(Br)ccc2c1NCC1CCOCC1
Agent: [Pt]
Solvent: CC(C)O
Solvent: CC#N
Product: Nc1cnc2cc(Br)ccc2c1NCC1CCOCC1
Reaction time: 2 h

Procedure:
7-Bromo-3-nitro-N-(tetrahydro-2H-pyran-4-ylmethyl)quinolin-4-amine (20 g, 55 mmol) was dissolved in a mixture of acetonitrile (500 mL) and isopropyl alcohol (50 mL) and the solution was placed in a pressure bottle. Platinum on carbon (5%, 2 g) was then added and the reaction mixture was shaken under H2 at 48 PSI (3.3×105 Pa). After 2 hours, the reaction mixture was filtered through a pad of CELITE filter agent. The pad was rinsed with acetonitrile and the combined filtrates were concentrated under reduced pressure to give 7-bromo-N4-(tetrahydro-2H-pyran-4-ylmethyl)quinoline-3,4-diamine which was carried forward without further purification assuming quantitative yield.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][CH:18]3[CH2:23][CH2:22][CH2:21][NH:20][CH2:19]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:24]#[N:25].Cl.[CH3:27][CH:28]([O:30][C:31]1[CH:36]=[CH:35][C:34]([NH:37][C:38]([N:40]2[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]2)=[O:39])=[CH:33][CH:32]=1)[CH3:29]>CN(C=O)C>[C:24]([C:3]1[CH:4]=[N:5][C:6]2[C:11]([C:2]=1[N:43]1[CH2:42][CH2:41][N:40]([C:38]([NH:37][C:34]3[CH:35]=[CH:36][C:31]([O:30][CH:28]([CH3:29])[CH3:27])=[CH:32][CH:33]=3)=[O:39])[CH2:45][CH2:44]1)=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][CH2:15][CH2:16][CH2:17][CH:18]1[CH2:23][CH2:22][CH2:21][NH:20][CH2:19]1)[CH:7]=2)#[N:25]
Reactant: CC(C)Oc1ccc(NC(=O)N2CCNCC2)cc1
Reactant: COc1cc2c(Cl)c(C#N)cnc2cc1OCCCC1CCCNC1
Agent: Cl
Solvent: CN(C)C=O
Product: COc1cc2c(N3CCN(C(=O)Nc4ccc(OC(C)C)cc4)CC3)c(C#N)cnc2cc1OCCCC1CCCNC1
Temperature: 40 °C

Procedure:
To the DMF solution (3 mL) of the 4-chloroquinoline (0.175 g, 0.487 mmol) from step A added K2CO3 (0.155 g, 1.10 mmol) followed by N-[4-(methylethoxy)phenyl]piperazinylcarboxamide hydrochloride (0.169 g, 0.535 mmol). The reaction mixture was heated to 40° C. overnight, during that period starting materials were consumed. After cooling diluted with EtOAc/water and the layers were separated. The organic layer was dried, filtered and evaporated to afford desired product as a crude residue. The crude residue was purified by RP-HPLC to afford {4-[3-cyano-6-methoxy-7-(3-piperidylpropoxy)quinolin-4-yl)piperazinyl}-N-[4-(methylethoxy)phenyl]carboxamide as the desired product (0.195 g, 69%). MS(ES) 587.3 (M+H)
Reaction SMILES: [C:1]1(=[N:7][OH:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH2:17][CH2:18][N:19]([CH2:22][CH2:23][CH2:24][C:25](OCC)=O)[CH2:20][CH:21]=2)=[CH:12][CH:11]=1>>[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][CH2:24][C:25]3[O:8][N:7]=[C:1]4[CH2:6][CH2:5][CH2:4][CH2:3][C:2]=34)[CH2:18][CH:17]=2)=[CH:12][CH:11]=1
Reactant: ON=C1CCCCC1
Reactant: CCOC(=O)CCCN1CC=C(c2ccc(Cl)cc2)CC1
Product: Clc1ccc(C2=CCN(CCCc3onc4c3CCCC4)CC2)cc1

Procedure:
By the same reaction and treatment as m Example 48 using cyclohexanone oxime and ethyl 4-(4-(4-chlorophenyl)-1,2,3,6-tetrahydropyridin-1-yl)-n-butyrate, 3-(3-(4-(4-chlorophenyl)-1,2,3,6-tetrahydropyridin-1-yl)propyl)-4,5,6,7-tetrahydrobenzo[c]isoxazole is obtained.
Reaction SMILES: [C:1]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8]#[N:9].[CH3:16][S:17]([N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1)(=[O:19])=[O:18]>C(O)C>[C:1]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8]([N:23]1[CH2:24][CH2:25][N:20]([S:17]([CH3:16])(=[O:19])=[O:18])[CH2:21][CH2:22]1)=[NH:9]
Reactant: N#CNc1ccccc1-c1ccccc1
Reactant: CS(=O)(=O)N1CCNCC1
Solvent: CCO
Product: CS(=O)(=O)N1CCN(C(=N)Nc2ccccc2-c2ccccc2)CC1

Procedure:
A mixture of 2-biphenylylcyanamide (3.8 g), 1-methanesulphonylpiperazine (3.8 g) and ethanol (60 ml) was heated at 90°-95° C. for 12 hours to give N-(2-biphenylyl)-4-methanesulphonylpiperazine-1-carboxamidine (m.p. 178°-180° C.) which was recrystallized from ethanol.
Reaction SMILES: [CH2:1]([N:4]([CH2:20][CH2:21][CH3:22])[CH:5]1[CH2:19][C:8]2=[CH:9][C:10]3[C:11](=[O:18])[N:12]([CH3:17])[C:13](=O)[C:14]=3[CH:15]=[C:7]2[CH2:6]1)[CH2:2][CH3:3].Cl>CC(O)=O.[Zn]>[CH2:20]([N:4]([CH2:1][CH2:2][CH3:3])[CH:5]1[CH2:19][C:8]2=[CH:9][C:10]3[C:11](=[O:18])[N:12]([CH3:17])[CH2:13][C:14]=3[CH:15]=[C:7]2[CH2:6]1)[CH2:21][CH3:22]
Reactant: CCCN(CCC)C1Cc2cc3c(cc2C1)C(=O)N(C)C3=O
Agent: Cl
Agent: [Zn]
Solvent: CC(=O)O
Product: CCCN(CCC)C1Cc2cc3c(cc2C1)C(=O)N(C)C3

Procedure:
Using procedure 47, the 6-(dipropylamino)-6,7-dihydro-2-methylcyclopent[f]isoindole-1,3(2H,5H)-dione (120, 0.13 g, 0.4 mmol) was reduced with Zinc dust (0.26 g, 4.0 mmol) in glacial HOAc (10 mL). Purification via crystallization from EtOAc/MeOH gave an off-white solid that was converted to an HCl salt and recrystallized from EtOAc/MeOH to give 126 as a white solid (m.p. 242-243° C.).
Reaction SMILES: [CH3:1][N:2]([CH2:4][CH2:5][OH:6])[CH3:3].[C:7](=O)([O:10][CH:11]([CH3:13])[CH3:12])[O:8]C>CO>[C:7](=[O:8])([O:6][CH2:5][CH2:4][N:2]([CH3:3])[CH3:1])[O:10][CH:11]([CH3:13])[CH3:12]
Reactant: COC(=O)OC(C)C
Reactant: CN(C)CCO
Solvent: CO
Product: CC(C)OC(=O)OCCN(C)C

Procedure:
reacting 2-(N,N-dimethylamino)ethanol with the methyl isopropyl carbonate formed in step i) in the presence of a transesterification catalyst to form isopropyl 2-dimethylaminoethyl carbonate and methanol, under such conditions that the 2-(N,N-dimethylamino)ethanol also reacts with the diisopropyl carbonate formed in step i) to form more isopropyl 2-dimethylaminoethyl carbonate,
Reaction SMILES: C[O:2][C:3](=[O:23])[C:4]1[C:9]([CH3:10])=[CH:8][C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=2)=[N:6][C:5]=1[O:21]C.B(Br)(Br)Br.CO>C(Cl)Cl>[CH3:10][C:9]1[CH:8]=[C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:19])([F:20])[F:18])[CH:12]=2)[NH:6][C:5](=[O:21])[C:4]=1[C:3]([OH:23])=[O:2]
Reactant: COC(=O)c1c(C)cc(-c2cccc(C(F)(F)F)c2)nc1OC
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: CO
Product: Cc1cc(-c2cccc(C(F)(F)F)c2)[nH]c(=O)c1C(=O)O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 0.325 g (1.0 mmol) of 2-methoxy-4-methyl-6-(3-trifluoromethyl-phenyl)-nicotinic acid methyl ester (intermediate 12C) in 10 ml of CH2Cl2 was cooled down to 0° C., 2.0 ml (2.0 mmol) of a solution of boron tribromide (1 molar in CH2Cl2) was added drop by drop and the reaction mixture was subsequently warmed up to RT. After two hours, 1.0 ml of MeOH was added and 90 min later, the reaction mixture was evaporated. The crude intermediate formed was used without purification in the next step.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15](=[O:18])[CH2:16]Br)=[CH:11][C:10]=1[N+:19]([O-:21])=[O:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CS(C)=[O:24]>>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([CH:16]=[O:24])=[O:18])=[CH:11][C:10]=1[N+:19]([O-:21])=[O:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CS(C)=O
Reactant: O=C(CBr)c1ccc(OCc2ccccc2)c([N+](=O)[O-])c1
Product: O=CC(=O)c1ccc(OCc2ccccc2)c([N+](=O)[O-])c1
Reaction time: 72 h

Procedure:
1-(4-Benzyloxy-3-nitrophenyl)-2-bromoethanone (12.6 g) was dissolved in dimethyl sulphoxide (40 ml) and the solution was allowed to stand at room temperature for 3 days. The solution was poured onto ice and the product was collected as the hydrate (8.7 g). τ(d6DMSO) 4.58 (2H, s), 4.33 (1H, s), 2.25-2.65 (6H, m), 2.07 (2H, br), 1.30-1.87 (2H, m).
Reaction SMILES: [C:1]1([S:11]([C:14]2[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([CH:23]=O)[CH:21]=3)[NH:16][N:15]=2)(=[O:13])=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[CH3:25][NH:26][CH2:27][CH2:28][N:29]([CH3:31])[CH3:30].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C>[CH3:30][N:29]([CH3:31])[CH2:28][CH2:27][N:26]([CH3:25])[CH2:23][C:20]1[CH:21]=[C:22]2[C:17](=[CH:18][CH:19]=1)[NH:16][N:15]=[C:14]2[S:11]([C:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1)(=[O:13])=[O:12]
Reactant: O=Cc1ccc2[nH]nc(S(=O)(=O)c3cccc4ccccc34)c2c1
Reactant: CNCCN(C)C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Product: CN(C)CCN(C)Cc1ccc2[nH]nc(S(=O)(=O)c3cccc4ccccc34)c2c1

Procedure:
3-(Naphthalene-1-sulfonyl)-1H-indazole-5-carbaldehyde (0.17 g, 0.5 mmol), trimethyl ethylene diamine (0.6 mmol) and sodium triacetoxyborohydride (0.7 mmol) in dichloroethane (5 mL) was stirred at room temperature for 24 hrs. After completion, the solvent was removed in vacuo, crude material dispersed in water and the pH brought to 3.4. Solid material was filtered off and washed with cold water to afford after drying the target material as a free base. The latter was converted into hydrochloride salt by dissolution in methanol, followed by treatment with the excess of 2N HCl and the evacuation of the volatiles in vacuo to afford the title compound hydrochloride salt, mp>200° C.; MS (APPI) 423 [M+H]
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].[C:19](=[S:21])=[S:20]>CO>[CH3:12][O:11][C:7]1[CH:6]=[C:5]([N:13]2[CH2:18][CH2:17][N:16]([C:19]([SH:21])=[S:20])[CH2:15][CH2:14]2)[CH:4]=[C:3]([O:2][CH3:1])[C:8]=1[O:9][CH3:10]
Reactant: S=C=S
Reactant: COc1cc(N2CCNCC2)cc(OC)c1OC
Solvent: CO
Product: COc1cc(N2CCN(C(=S)S)CC2)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 77.7 %

Procedure:
In a nitrogen atmosphere, 1.9 g of 1-(3,4,5-trimethoxyphenyl)piperazine wasdissolved in 10 ml of methanol. To the solution was dropwise added under chilling with ice 0.46 ml of carbon disulfide. After the addition was complete, the mixture was stirred at room temperature for 2 hours. Precipitated crystals were collected by filtration to give 1.9 g of the desired compound as a gray-brown powder, m.p. 183°-190° C. (decomp.), yield 77.7%.
Reaction SMILES: CO[C:3](=[O:28])[CH:4](Br)[CH2:5][C:6]1[CH:7]=[CH:8][C:9]([O:12][CH2:13][CH2:14][C:15]2[N:16]=[C:17]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[S:18][C:19]=2[CH3:20])=[N:10][CH:11]=1.[NH2:29][C:30](N)=[S:31].C([OH:35])C.Cl>O>[CH3:20][C:19]1[S:18][C:17]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[N:16][C:15]=1[CH2:14][CH2:13][O:12][C:9]1[CH:8]=[CH:7][C:6]([CH2:5][CH:4]2[S:31][C:30](=[O:35])[NH:29][C:3]2=[O:28])=[CH:11][N:10]=1
Reactant: COC(=O)C(Br)Cc1ccc(OCCc2nc(-c3ccccc3)sc2C)nc1
Reactant: CCO
Reactant: NC(N)=S
Agent: Cl
Solvent: O
Product: Cc1sc(-c2ccccc2)nc1CCOc1ccc(CC2SC(=O)NC2=O)cn1
Yield: 51 %

Procedure:
A mixture of 2-bromo-3-[2-[2-(5-methyl-2-phenyl-4-thiazolyl)ethoxy]-5-pyridyl]propionic acid methyl ester (1.40 g), thiourea (0.25 g) and ethanol (20 ml) was heated for 4.5 hours while refluxing, followed by addition of 2N hydrochloric acid (20 ml) and heating for 18 more hours under refluxing conditions. The reaction mixture was added to water and extracted with dichloromethane. After the dichloromethane layer was washed with water and dried (MgSO4), the solvent was distilled off. The residual crystal was recrystallized from ethanol-chloroform to yield 5-[[2-[2-(5-methyl-2-phenyl-4-thiazolyl)ethoxy]-5-pyridyl]methyl]-2,4-thiazolidinedione (0.66 g, 51%) as a colorless crystal.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:20])=[C:6]([C@:8]2([CH3:19])[CH2:13][C@@H:12]([C:14]([F:17])([F:16])[F:15])[O:11][C:10]([NH2:18])=[N:9]2)[CH:7]=1.[F:21][CH:22]([F:32])[C:23]1[N:24]=[CH:25][C:26]([C:29](O)=[O:30])=[N:27][CH:28]=1>>[NH2:18][C:10]1[O:11][C@H:12]([C:14]([F:16])([F:17])[F:15])[CH2:13][C@:8]([C:6]2[CH:7]=[C:2]([NH:1][C:29]([C:26]3[CH:25]=[N:24][C:23]([CH:22]([F:32])[F:21])=[CH:28][N:27]=3)=[O:30])[CH:3]=[CH:4][C:5]=2[F:20])([CH3:19])[N:9]=1
Reactant: C[C@@]1(c2cc(N)ccc2F)C[C@@H](C(F)(F)F)OC(N)=N1
Reactant: O=C(O)c1cnc(C(F)F)cn1
Product: C[C@@]1(c2cc(NC(=O)c3cnc(C(F)F)cn3)ccc2F)C[C@@H](C(F)(F)F)OC(N)=N1

Procedure:
The coupling of (4S,6S)-4-(5-amino-2-fluorophenyl)-4-methyl-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-2-amine (XI-1) and 5-(difluoromethyl)pyrazine-2-carboxylic acid [J. M. Ellard et al. WO2011009898 (2011)] following General Procedure F yielded the title compound as a colorless solid. MS: m/z=448.5 [M+H]+.