Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[CH2:7]/[N:8]=[CH:9]/[C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=1)([CH3:4])([CH3:3])[CH3:2].[Cl:18][C:19]1[CH:20]=[C:21](/[CH:25]=[C:26](/[C:29]2[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=2)\[C:27]#[N:28])[CH:22]=[CH:23][CH:24]=1.C(N(CC)CC)C>ClCCl>[C:1]([O:5][C:6]([CH:7]1[CH:25]([C:21]2[CH:22]=[CH:23][CH:24]=[C:19]([Cl:18])[CH:20]=2)[C:26]([C:29]2[CH:30]=[CH:31][C:32]([Cl:35])=[CH:33][CH:34]=2)([C:27]#[N:28])[CH:9]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[NH:8]1)=[O:17])([CH3:4])([CH3:2])[CH3:3]
Reactant: N#C/C(=C\c1cccc(Cl)c1)c1ccc(Cl)cc1
Reactant: CC(C)(C)OC(=O)C/N=C/c1cccc(Cl)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)C1NC(c2cccc(Cl)c2)C(C#N)(c2ccc(Cl)cc2)C1c1cccc(Cl)c1
Yield: 42.6 %

Procedure:
In a manner similar to the method described in Example 1c, {[1-(3-Chloro-phenyl)-meth-(E)-ylidene]-amino}-acetic acid tert-butyl ester prepared in Example 32a (2 g, 7.6 mmol) was reacted with (Z)-3-(3-chloro-phenyl)-2-(4-chloro-phenyl)-acrylonitrile (0.55 g, 2 mmol) prepared in Example 1b, AgF (1.3 g, 10 mmol), and triethylamine (1.9 g, 19 mmol) in dichloromethane (30 mL) at 50° C. for 20 h to give rac-(2R,3R,4R,5S)-3,5-bis-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-pyrrolidine-2-carboxylic acid tert-butyl ester as a white foam (0.45 g, 44%).
Reaction SMILES: O.[CH3:2][O:3][C:4]1[CH:5]=[C:6]([CH:14]2[O:18][C:17](=[N:19][NH2:20])[C:16](=C=O)[CH2:15]2)[CH:7]=[C:8]([O:12][CH3:13])[C:9]=1[O:10][CH3:11].[C:23](O)(=[O:25])C>CN(C)C=O>[OH:25][CH2:23][CH:15]1[C:14]([C:6]2[CH:7]=[C:8]([O:12][CH3:13])[C:9]([O:10][CH3:11])=[C:4]([O:3][CH3:2])[CH:5]=2)=[N:20][NH:19][C:17](=[O:18])[CH2:16]1
Reactant: COc1cc(C2CC(=C=O)C(=NN)O2)cc(OC)c1OC
Reactant: CC(=O)O
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(C2=NNC(=O)CC2CO)cc(OC)c1OC

Procedure:
7.0 g (0.222 mol) of the compound prepared in section (a) are stirred in 20 ml of dimethylformamide and 1 ml of acetic acid at 80° C. for 5 hours. After the mixture has been concentrated, the residue is taken up in methylene chloride, the methylene chloride mixture is washed with potassium carbonate solution and concentrated and the residue is recrystallised from ethanol.
Reaction SMILES: [C:1]([C@@H:5]([C@H:7]([C:9]([O:11]C)=O)[OH:8])[OH:6])([O:3]C)=O.[OH:13][CH2:14][C:15]([CH2:19][OH:20])([CH2:17][OH:18])[NH2:16]>CO>[OH:13][CH2:14][C:15]([NH:16][C:1](=[O:3])[C@@H:5]([C@H:7]([C:9]([NH:16][C:15]([CH2:19][OH:20])([CH2:17][OH:18])[CH2:14][OH:13])=[O:11])[OH:8])[OH:6])([CH2:19][OH:20])[CH2:17][OH:18]
Reactant: NC(CO)(CO)CO
Reactant: COC(=O)[C@H](O)[C@@H](O)C(=O)OC
Solvent: CO
Product: O=C(NC(CO)(CO)CO)[C@H](O)[C@@H](O)C(=O)NC(CO)(CO)CO

Procedure:
A suspension of 1.78 g of dimethyl L-tartrate and 4.85 g of tris-hydroxymethyl-methylamine in 50 ml of methanol was heated under reflux for 6 days and then concentrated. The residue was purified by chromatography over silica gel with ethyl acetate/methanol/water as the eluent and gave N,N'-bis-(2-hydroxy-1,1-bis-hydroxymethyl-ethyl)-L-tartaramide, [a]+101.00 (c 0.4; dimethyl sulfoxide), MS: m/z 357.3 ([M+H]+).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:28])=[C:4]([CH:8]2[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[CH:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:10][NH:9]2)[CH:5]=[CH:6][CH:7]=1.[CH3:29][O:30][C:31](=[O:41])[C:32]1[CH:37]=[CH:36][C:35]([C:38](Cl)=[O:39])=[CH:34][CH:33]=1.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH3:29][O:30][C:31](=[O:41])[C:32]1[CH:37]=[CH:36][C:35]([C:38]([N:9]2[CH2:10][C@@H:11]([CH2:23][C:24]([CH3:25])([CH3:27])[CH3:26])[C@@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:8]2[C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=2[F:28])=[O:39])=[CH:34][CH:33]=1
Reactant: CC(C)(C)CC1CNC(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Reactant: COC(=O)c1ccc(C(=O)Cl)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)c1ccc(C(=O)N2C[C@@H](CC(C)(C)C)[C@](C#N)(c3ccc(Cl)cc3F)[C@H]2c2cccc(Cl)c2F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 98 %

Procedure:
A mixture of rac-(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-4-(2,2-dimethyl-propyl)-pyrrolidine-3-carbonitrile (100.0 mg, 0.23 mmol), 4-chlorocarbonyl-benzoic acid methyl ester (60.0 mg, 0.30 mmol), iPr2NEt (0.12 mL, 0.69 mmol) in CH2Cl2 (5 mL) was stirred at rt overnight. The mixture was then diluted with CH2Cl2 and washed with water, brine. The organic phase was separated, filtered and dried over Na2SO4. The mixture was then concentrated and the residue was purified by flash column (1%-15% AcOEt in Hex) to give rac-4-[(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano-4-(2,2-dimethyl-propyl)-pyrrolidine-1-carbonyl]-benzoic acid methyl ester (132.0 mg, 98.0%).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]1[N:13]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]3[CH2:21][CH2:22][NH:23][CH2:24][CH:25]=3)[CH:15]=2)[N:12]=[C:11]([C:26]([C:32]([F:35])([F:34])[F:33])([C:28]([F:31])([F:30])[F:29])[OH:27])[CH2:10]1.[CH3:36][S:37](Cl)(=[O:39])=[O:38].C(N(CC)CC)C>ClCCl>[Cl:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]1[N:13]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]3[CH2:21][CH2:22][N:23]([S:37]([CH3:36])(=[O:39])=[O:38])[CH2:24][CH:25]=3)[CH:15]=2)[N:12]=[C:11]([C:26]([C:32]([F:35])([F:33])[F:34])([C:28]([F:29])([F:30])[F:31])[OH:27])[CH2:10]1
Reactant: CS(=O)(=O)Cl
Reactant: OC(C1=NN(c2cccc(C3=CCNCC3)c2)C(c2ccccc2Cl)C1)(C(F)(F)F)C(F)(F)F
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)N1CC=C(c2cccc(N3N=C(C(O)(C(F)(F)F)C(F)(F)F)CC3c3ccccc3Cl)c2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 43.7 %

Procedure:
The 5-(2-chloro-phenyl)-1-[3-(1,2,3,6-tetrahydropyridin-4-yl)-phenyl]-3-[di-(trifluoromethyl)-hydroxy-methyl]-4,5-dihydro-1H-pyrazole hydrochloride (30.0 mg, 0.055 mmol) in the form of a yellow liquid, methanesulfonyl chloride (7.6 mg, 0.066 mmol), and triethylamine (31.0 uL, 0.221 mmol) were added to dichloromethane (1.0 mL). The reaction mixture was stirred at room temperature for 16 hours, washed with distilled water and brine, dried on anhydrous magnesium sulfate, and then concentrated under reduced pressure to give a yellow liquid residue. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=2/1) to give 14.0 mg of the titled compound as a yellow liquid.
Reaction SMILES: [C:1]([C:3]1[S:4][C:5]2[CH:11]=[C:10]([OH:12])[CH:9]=[CH:8][C:6]=2[N:7]=1)#[N:2].C(=O)([O-])[O-].[K+].[K+].[F:19][C:20]([F:30])([F:29])[C:21]1[CH:28]=[CH:27][CH:26]=[CH:25][C:22]=1[CH2:23]Br>CC(C)=O>[C:1]([C:3]1[S:4][C:5]2[CH:11]=[C:10]([O:12][CH2:23][C:22]3[CH:25]=[CH:26][CH:27]=[CH:28][C:21]=3[C:20]([F:19])([F:29])[F:30])[CH:9]=[CH:8][C:6]=2[N:7]=1)#[N:2]
Reactant: N#Cc1nc2ccc(O)cc2s1
Reactant: FC(F)(F)c1ccccc1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: N#Cc1nc2ccc(OCc3ccccc3C(F)(F)F)cc2s1
Temperature: 25 °C
Reaction time: 5 h
Yield: 77.9 %

Procedure:
To a solution of 2-cyano-6-hydroxybenzothiazole (100 mg, 0.568 mmol) in 10 mL of acetone was added potassium carbonate (157 mg, 1.14 mmol), followed by 2-(trifluoromethyl)benzyl bromide (204 mg, 0.852 mmol). The mixture was then stirred at RT for about 5 hrs. The solvent was then removed under reduced pressure and the residue was dissolved in dichloromethane. The resultant solution was then extracted with dichloromethane. The organic phase was dried over sodium sulfate and purified by flash chromatography using dichloromethane. 148 mg of product was obtained.
Reaction SMILES: [Cl:1][C:2]1[C:3](=[O:22])[N:4]([CH:19]([CH3:21])[CH3:20])[N:5]=[CH:6][C:7]=1[NH:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]([OH:18])=O)=[CH:12][CH:11]=1.[CH2:23]([NH:26][CH2:27][CH2:28][CH3:29])[CH2:24][CH3:25]>CN(C)C=O>[Cl:1][C:2]1[C:3](=[O:22])[N:4]([CH:19]([CH3:21])[CH3:20])[N:5]=[CH:6][C:7]=1[NH:8][CH2:9][C:10]1[CH:11]=[CH:12][C:13]([C:16]([N:26]([CH2:27][CH2:28][CH3:29])[CH2:23][CH2:24][CH3:25])=[O:18])=[CH:14][CH:15]=1
Reactant: CC(C)n1ncc(NCc2ccc(C(=O)O)cc2)c(Cl)c1=O
Reactant: CCCNCCC
Solvent: CN(C)C=O
Product: CCCN(CCC)C(=O)c1ccc(CNc2cnn(C(C)C)c(=O)c2Cl)cc1
Reaction time: 8 h

Procedure:
A mixture of 322 mg of 4-chloro-5-(4-carboxy-benzylamino)-2-i-propyl-3(2H)pyridazinone obtained from 2-i-propyl-4,5-dichloro-3(2H)pyrisazinone and 4-carbonxybenzylamine, 194 mg of N,N'-carbonyldiimidazole and 5 ml of dimethylformamide, was stirred at room temperature for one hour. A solution obtained by dissolving 100 mg of di-n-propylamine in 1 ml of dimethylformamide was added thereto, and the mixture was stirred at the same temperature overnight. The solvent was distilled off under reduced pressure, and the pale yellow oily substance thereby obtained was extracted with chloroform. The extract was washed successively with diluted hydrochloric acid, water, a 5% sodium hydroxide aqueous solution and a saturated sodium chloride aqueous solution, and dried over sodium sulfate, and then the solvent was distilled off to obtain a pale yellow oily substance. This substance was subjected to silica gel column chromatography and eluted with benzene:ethyl acetate (2:5, v/v). The colorless viscous oily substance thereby obtained was crystallized from ether-n-hexane to obtain 108 mg of the above identified compound having a melting point of from 78° to 81° C. as colorless crystals.
Reaction SMILES: [CH:1]12[CH2:7][CH:4]([CH:5]=[CH:6]1)[C:3](=[O:8])[NH:2]2.[C:9](OC=C)(=O)[CH3:10]>[Na+].[Na+].Cl[Pd+2](Cl)(Cl)Cl>[CH:9]([N:2]1[C:3](=[O:8])[CH:4]2[CH2:7][CH:1]1[CH:6]=[CH:5]2)=[CH2:10]
Reactant: O=C1NC2C=CC1C2
Reactant: C=COC(C)=O
Agent: Cl[Pd]Cl
Agent: [Na+]
Product: C=CN1C(=O)C2C=CC1C2

Procedure:
A solution of 2-azabicyclo[2.2.1]hept-5-en-3-one (0.5 g, 4.6 mmole) in vinyl acetate (3 ml, 33 mmole) with sodium tetrachloropalladate (15 mg, 0.05 mmole) was refluxed for 5 days. The product, Compound 6, was isolated by evaporation of the volatiles. Analysis by Gas Liquid Chromatography-Mass Spectrometry (GLC-MS) was consistent with the predicted molecular weight.
Reaction SMILES: [F:1][C:2]1[C:10]2[S:9][C:8](S(C)(=O)=O)=[N:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[NH3:15]>C(O)C>[NH2:15][C:8]1[S:9][C:10]2[C:2]([F:1])=[CH:3][CH:4]=[CH:5][C:6]=2[N:7]=1
Reactant: N
Reactant: CS(=O)(=O)c1nc2cccc(F)c2s1
Solvent: CCO
Product: Nc1nc2cccc(F)c2s1
Temperature: 160 °C

Procedure:
A mixture of 7-fluoro-2-methylsulfonyl-1,3-benzothiazole (500 mg, 2.16 mmol) in 10 mL ethanol and 20% ethanolic ammonia (20 mL) was heated at 160° C. in a sealed tube for 12 h. It was cooled to RT, ethanol was removed under reduced pressure, and the brownish residue was purified by column chromatography (5% to 10% methanol in methylene chloride) to afford the title compound. 1H-NMR (CDCl3, 300 MHz): δ=7.35 (d, J=7.5 Hz, 1H), 7.33-7.37 (m, 1H), 6.93-6.84 (m, 1H), 5.30 (brs, 2H).
Reaction SMILES: C([Li])CCC.[N:6]1([CH2:10][CH2:11][CH2:12][O:13][C:14]2[CH:19]=[CH:18][C:17](Br)=[CH:16][N:15]=2)[CH2:9][CH2:8][CH2:7]1.C(O[B:25]1[O:29][C:28]([CH3:31])([CH3:30])[C:27]([CH3:33])([CH3:32])[O:26]1)(C)C>C1COCC1>[N:6]1([CH2:10][CH2:11][CH2:12][O:13][C:14]2[CH:19]=[CH:18][C:17]([B:25]3[O:29][C:28]([CH3:31])([CH3:30])[C:27]([CH3:33])([CH3:32])[O:26]3)=[CH:16][N:15]=2)[CH2:9][CH2:8][CH2:7]1
Reactant: Brc1ccc(OCCCN2CCC2)nc1
Reactant: CC(C)OB1OC(C)(C)C(C)(C)O1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC1(C)OB(c2ccc(OCCCN3CCC3)nc2)OC1(C)C
Temperature: -78 °C
Reaction time: 1 h
Yield: 81.2 %

Procedure:
n-Butyl lithium (4.65 mL, 11.62 mmol) was added to 2-[3-(azetidin-yl)propoxy]-5-bromopyridine (2.1 g, 7.74 mmol) and 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (2.161 g, 11.62 mmol) in THF (50 ml) at −78° C. over a period of 10 minutes and the resulting solution stirred at −78° C. for 1 h. The reaction was quenched with sat. Na2SO4 (10 mL) and the solvent removed in vacuo. The residue was dissolved in DCM (100 mL), dried over Na2SO4, filtered and evaporated to afford the desired material (2.00 g, 81%) as a white solid. Mass Spectrum: m/z (ES+)[M+H]+=319.
Reaction SMILES: [NH2:1][C@@H:2]([CH3:11])[C@@H:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[OH:4].[F:12][C:13]1[CH:18]=[CH:17][C:16]([N:19]2[C:27]3[C:22](=[CH:23][C:24](I)=[C:25]([CH3:28])[CH:26]=3)[CH:21]=[N:20]2)=[CH:15][CH:14]=1>>[F:12][C:13]1[CH:14]=[CH:15][C:16]([N:19]2[C:27]3[C:22](=[CH:23][C:24]([O:4][C@H:3]([C:5]4[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=4)[C@@H:2]([NH2:1])[CH3:11])=[C:25]([CH3:28])[CH:26]=3)[CH:21]=[N:20]2)=[CH:17][CH:18]=1
Reactant: Cc1cc2c(cnn2-c2ccc(F)cc2)cc1I
Reactant: C[C@H](N)[C@H](O)c1ccccc1
Product: Cc1cc2c(cnn2-c2ccc(F)cc2)cc1O[C@H](c1ccccc1)[C@H](C)N

Procedure:
Prepared as described in Example 1 from (1R,2S)-2-amino-1-phenylpropan-1-ol (257 mg, 1.70 mmol), and 1-(4-fluorophenyl)-5-iodo-6-methylindazole (200 mg, 0.57 mmol). Yield 169 mg (79%).
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[C:8]([NH2:10])[N:7]=[C:6]([NH2:11])[CH:5]=1.[NH3:13]>CO>[NH2:11][C:6]1[CH:5]=[C:4]([CH:9]=[C:8]([NH2:10])[N:7]=1)[C:3]([NH2:13])=[O:2]
Reactant: N
Reactant: COC(=O)c1cc(N)nc(N)c1
Solvent: CO
Product: NC(=O)c1cc(N)nc(N)c1
Temperature: 62 °C

Procedure:
A solution of 3.9 g (20 mmol) 2,6-diamino-isonicotinic acid methyl ester in 200 ml methanol was treated for 1 at 0° C. with gaseous ammonia. The mixture was heated for 36 h at 62° C. in an autoclave (4 bar) and afterwards filtered through decalite and evaporated to dryness. 3.5 g (quant.) of the title compound was obtained as a yellow solid.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[C:9]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20]Br)=[CH:16][CH:15]=2)=[CH:10][CH:11]=[CH:12][CH:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:22]1(=[O:32])[NH:26][C:25](=[O:27])[C:24]2=[CH:28][CH:29]=[CH:30][CH:31]=[C:23]12.[K]>CN(C=O)C>[C:1]([O:5][C:6]([C:8]1[C:9]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][N:26]3[C:22](=[O:32])[C:23]4[C:24](=[CH:28][CH:29]=[CH:30][CH:31]=4)[C:25]3=[O:27])=[CH:16][CH:15]=2)=[CH:10][CH:11]=[CH:12][CH:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: CC(C)(C)OC(=O)c1ccccc1-c1ccc(CBr)cc1
Agent: [K]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)c1ccccc1-c1ccc(CN2C(=O)c3ccccc3C2=O)cc1
Temperature: 50 °C

Procedure:
4′-Bromomethylbiphenyl-2-carboxylic acid t-butyl ester (4.0 g, 11.5 mmol) and potassium phthalimide were combined and dissolved in DMF (30 mL), and the mixture was heated at 50° C. for two days. The mixture was then cooled to room temperature and the reaction quenched with water (30 mL). The mixture was then extracted with EtOAc, and washed with a 10% aqueous lithium chloride solution. The organic layer was dried over MgSO4, filtered and concentrated to obtain intermediate (22a) (4.8 g). MS m/z: [M+H+] calcd for C26H23NO4, 414.5; found 414.3.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][S:6]([NH:9][C:10]1[C:11](F)=[C:12]([CH:17]=[C:18]([N+:20]([O-:22])=[O:21])[CH:19]=1)[C:13]([O:15][CH3:16])=[O:14])(=[O:8])=[O:7].CCN(CC)CC.[CH3:31][OH:32]>>[O:7]=[S:6]1(=[O:8])[CH2:5][CH2:4][CH2:3][CH2:2][N:9]1[C:10]1[C:11]([O:32][CH3:31])=[C:12]([CH:17]=[C:18]([N+:20]([O-:22])=[O:21])[CH:19]=1)[C:13]([O:15][CH3:16])=[O:14]
Reactant: CO
Reactant: COC(=O)c1cc([N+](=O)[O-])cc(NS(=O)(=O)CCCCCl)c1F
Solvent: CCN(CC)CC
Product: COC(=O)c1cc([N+](=O)[O-])cc(N2CCCCS2(=O)=O)c1OC
Temperature: 25 °C
Yield: 55 %

Procedure:
To a solution of methyl 3-{[(4-chlorobutyl)sulfonyl]amino}-2-fluoro-5-nitrobenzoate (D146) (1.5 g, 4.1 mmol, 1 equiv) in MeOH (30 ml) was added NEt3 (1.2 ml 8.6 mmol, 2.1 equiv) and the resulting solution was refluxed for 15 h then cooled to room temperature and concentrated in vacuo. The residue was dissolved in AcOEt and the organic phase was washed with a 2N aqueous HCl solution, dried over MgSO4 and concentrated in vacuo. The residue was triturated with AcOEt/Et2O to give methyl 3-(1,1-dioxidotetrahydro-2H-1,2-thiazin-2-yl)-2-(methyloxy)-5-nitrobenzoate (D149) (1.2 g, 55%) as a light brown solid which was used in the next step without further purification. [M+H]+=345.1, RT2.80 min.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12](=[O:15])[CH2:13][CH3:14])=[C:5]2[NH:16][C@H:17]1[CH2:22][CH2:21][C@H:20]([N:23]([CH3:25])[CH3:24])[CH2:19][CH2:18]1.[Cl:26][C:27]1[CH:32]=[C:31](B2OC(C)(C)C(C)(C)O2)[CH:30]=[C:29]([Cl:42])[C:28]=1[OH:43]>>[Cl:42][C:29]1[CH:30]=[C:31]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[CH:7][C:6]([C:12](=[O:15])[CH2:13][CH3:14])=[C:5]3[NH:16][C@H:17]2[CH2:22][CH2:21][C@H:20]([N:23]([CH3:25])[CH3:24])[CH2:19][CH2:18]2)[CH:32]=[C:27]([Cl:26])[C:28]=1[OH:43]
Reactant: CC1(C)OB(c2cc(Cl)c(O)c(Cl)c2)OC1(C)C
Reactant: CCC(=O)c1cnc2ccc(Br)cc2c1N[C@H]1CC[C@H](N(C)C)CC1
Product: CCC(=O)c1cnc2ccc(-c3cc(Cl)c(O)c(Cl)c3)cc2c1N[C@H]1CC[C@H](N(C)C)CC1

Procedure:
Following general procedure M, 1-(6-bromo-4-((trans-4-(dimethylamino)cyclohexyl)amino)quinolin-3-yl)propan-1-one (125 mg, 0.31 mmol) was reacted with 2,6-dichloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (98 mg, 0.34 mmol) to afford the desired product (74 mg, 49%) as a yellow solid. 1H NMR (500 MHz, DMSO d6) δ 10.58 (d, J=7.9 Hz, 1H), 8.96 (s, 1H), 8.30 (d, J=2.1 Hz, 1H), 8.03 (dd, J=8.7, 1.9 Hz, 1H), 7.84 (d, J=8.7 Hz, 1H), 7.771 (s, 2H), 4.19-4.15 (br s, 1H), 3.13 (q, J=7.2 Hz, 2H), 2.56-2.51 (m, 1H), 2.32 (s, 6H), 2.26-2.22 (m, 2H), 1.96-1.89 (m, 2H), 1.56-1.47 (m, 4H), 1.14 (t, J=7.2 Hz, 3H). APCI MS m/z 486 [C26H29Cl2N3O2+H]+; HPLC>99% (AUC), tR=8.28 min.
Reaction SMILES: C([NH:8][C:9]1[C:10]([CH3:28])=[C:11]([CH3:27])[C:12]2[O:16][CH:15]=[C:14]([C:17]3[CH:22]=[CH:21][C:20]([CH2:23][CH3:24])=[CH:19][CH:18]=3)[C:13]=2[C:25]=1[CH3:26])C1C=CC=CC=1>C(OCC)(=O)C.CCCCCC>[CH2:23]([C:20]1[CH:21]=[CH:22][C:17]([C:14]2[C:13]3[C:25]([CH3:26])=[C:9]([NH2:8])[C:10]([CH3:28])=[C:11]([CH3:27])[C:12]=3[O:16][CH:15]=2)=[CH:18][CH:19]=1)[CH3:24]
Reactant: CCc1ccc(-c2coc3c(C)c(C)c(NCc4ccccc4)c(C)c23)cc1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CCc1ccc(-c2coc3c(C)c(C)c(N)c(C)c23)cc1
Yield: 85 %

Procedure:
Using N-benzyl-3-(4-ethylphenyl)-4,6,7-trimethyl-1-benzofuran-5-amine obtained in Reference Example 281, the title compound was synthesized in the same manner as in Reference Example 30. Yield 85%. Melting point: 68-69° C. (ethyl acetate-hexane).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[C:4]([NH2:9])[CH:3]=1.[N:10]([CH:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:16][CH2:15][CH2:14]1)=[C:11]=S>>[F:1][C:2]1[CH:7]=[CH:6][C:5]2[N:8]=[C:11]([NH:10][CH:13]3[C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[CH2:16][CH2:15][CH2:14]3)[NH:9][C:4]=2[CH:3]=1
Reactant: S=C=NC1CCCc2ccccc21
Reactant: Nc1ccc(F)cc1N
Product: Fc1ccc2nc(NC3CCCc4ccccc43)[nH]c2c1

Procedure:
The title compound was prepared from 4-fluorophenylenediamine and 1-isothiocyanato-1,2,3,4-tetrahydronaphthalene by Procedure D. The title compound was isolated by column chromatography as the free base and as a mixture of enantiomers (solid, mp 220-221° C.). MS(ES+) m/z 282 ([M+1]+, 100).
Reaction SMILES: [CH3:1][C:2]([CH3:31])([CH3:30])[CH2:3][NH:4][C:5]1[C:6]([NH2:29])=[N:7][C:8]([C:12]2[C:20]3[C:15](=[N:16][CH:17]=[CH:18][CH:19]=3)[N:14]([CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[F:28])[N:13]=2)=[N:9][C:10]=1[NH2:11].C1N=CN([C:37](N2C=NC=C2)=[O:38])C=1.C(N(CC)CC)C>CN(C)C=O>[NH2:29][C:6]1[N:7]=[C:8]([C:12]2[C:20]3[C:15](=[N:16][CH:17]=[CH:18][CH:19]=3)[N:14]([CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[F:28])[N:13]=2)[N:9]=[C:10]2[C:5]=1[N:4]([CH2:3][C:2]([CH3:31])([CH3:30])[CH3:1])[C:37](=[O:38])[NH:11]2
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CC(C)(C)CNc1c(N)nc(-c2nn(Cc3ccccc3F)c3ncccc23)nc1N
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)Cn1c(=O)[nH]c2nc(-c3nn(Cc4ccccc4F)c4ncccc34)nc(N)c21
Temperature: 100 °C
Reaction time: 8 h

Procedure:
447 mg (0.94 mmol) of the compound from example 64A were initially charged in dimethylformamide (5 ml), then 758 mg (4.68 mmol) of N,N-carbonyldiimidazole and 1.57 ml (11.23 mmol) of triethylamine were added and the mixture was stirred at 100° C. overnight. The reaction mixture was purified directly by means of preparative HPLC (eluent: methanol/water with 0.1% formic acid gradient). This gave 163 mg (39% of theory) of the title compound in solid form.
Reaction SMILES: [CH:1]([O:4][C:5]([C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[N:12]([CH2:16][C:17]1[CH:21]=[C:20]([C:22]3[S:23][C:24]([Cl:27])=[CH:25][CH:26]=3)[O:19][N:18]=1)[C:11]([C:28]([O:30]CC)=[O:29])=[CH:10]2)=[O:6])([CH3:3])[CH3:2].[Li+].[OH-]>C1COCC1.CO>[CH:1]([O:4][C:5]([C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[N:12]([CH2:16][C:17]1[CH:21]=[C:20]([C:22]3[S:23][C:24]([Cl:27])=[CH:25][CH:26]=3)[O:19][N:18]=1)[C:11]([C:28]([OH:30])=[O:29])=[CH:10]2)=[O:6])([CH3:3])[CH3:2]
Reactant: CCOC(=O)c1cc2cc(C(=O)OC(C)C)ccc2n1Cc1cc(-c2ccc(Cl)s2)on1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)OC(=O)c1ccc2c(c1)cc(C(=O)O)n2Cc1cc(-c2ccc(Cl)s2)on1
Reaction time: 2 h

Procedure:
To a solution of 6.21 g 1-[5-(5-Chloro-thiophen-2-yl)-isoxazol-3-ylmethyl]-1H-indole-2,5-dicarboxylic acid 2-ethyl ester 5-isopropyl ester in 100 ml THF and 40 ml MeOH 52 ml of an aqueous 1 M LiOH solution were added and stirred for 2 h. The organic solvents were removed under reduced pressure and the residue acidified with 2 M hydrochloric acid to pH 2. The precipitated product was collected by filtration and dried over P2O5 in vacuo to yield a white solid. Yield: 5.77 g.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][C:7](=[C:10]2[C:16]3=[N:17][CH:18]=[C:19]([C:21]([CH3:24])([CH3:23])[CH3:22])[CH:20]=[C:15]3[CH2:14][CH2:13][C:12]3[CH:25]=[C:26]([Cl:29])[CH:27]=[CH:28][C:11]2=3)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].ClC1C=C(C=CC=1)C(OO)=[O:35].[OH-].[Na+]>C(Cl)Cl>[C:1]([N+:4]1([O-:35])[CH2:9][CH2:8][C:7](=[C:10]2[C:16]3=[N:17][CH:18]=[C:19]([C:21]([CH3:24])([CH3:23])[CH3:22])[CH:20]=[C:15]3[CH2:14][CH2:13][C:12]3[CH:25]=[C:26]([Cl:29])[CH:27]=[CH:28][C:11]2=3)[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC(=O)N1CCC(=C2c3ccc(Cl)cc3CCc3cc(C(C)(C)C)cnc32)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CC(=O)[N+]1([O-])CCC(=C2c3ccc(Cl)cc3CCc3cc(C(C)(C)C)cnc32)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 41.7 %

Procedure:
To a mixture of 450 mg of 1-acetyl-4-(8-chloro-5,6-dihydro-3-(1,1-dimethylethyl)-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)-piperidine in 30 ml of dry methylene chloride at -10° C. and under a nitrogen atmosphere was added 260 mg of 3-chloroperoxybenzoic acid in four portions ten minutes apart (mCPBA). The reaction mixture was kept at -10° C. for 3 hours and then slowly warmed to room temperature. The next day the mixture was poured into 1.0 N aqueous sodium hydroxide and extracted 3 times with methylene chloride. The combined organic portions were dried over magnesium sulfate, filtered and concentrated in vacuo to give a product which was purified via flash chromatography and triturated with pentane to give 195 mg (42%) of the title compound as a glass.
Reaction SMILES: [F:1][C:2]1[C:3]([C:10]([F:13])([F:12])[F:11])=[N:4][CH:5]=[CH:6][C:7]=1[CH:8]=O.Cl.[NH2:15][OH:16].C([O-])(=O)C.[NH4+]>CO.O>[F:1][C:2]1[C:3]([C:10]([F:13])([F:12])[F:11])=[N:4][CH:5]=[CH:6][C:7]=1[CH:8]=[N:15][OH:16]
Reactant: NO
Reactant: O=Cc1ccnc(C(F)(F)F)c1F
Agent: CC(=O)[O-]
Agent: Cl
Agent: [NH4+]
Solvent: O
Solvent: CO
Product: ON=Cc1ccnc(C(F)(F)F)c1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 3-fluoro-2-trifluoromethyl-pyridine-4-carbaldehyde (0.495 g, 2.05 mmol) in MeOH (17.6 mL) and water (2.9 mL) were added hydroxylamine hydrochloride (0.214 g, 3.08 mmol) and ammonium acetate (0.474 g, 6.15 mmol), and the resulting mixture was stirred at RT overnight. Volatile were removed in vacuo, and the residue was suspended in CH2Cl2/MeOH 9:1. The precipitate was filtered off, washed with CH2Cl2 and dried to afford the title compound as a white solid. MS (LC/MS): 209.0 [M+H]+; tR (HPLC conditions c): 4.28 min.