Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C:5](Cl)(=[O:8])[CH2:6][CH3:7].[C:10]1([CH:16]([CH3:18])[CH3:17])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.Cl>O.ClCCCl>[CH:16]([C:10]1[CH:15]=[CH:14][C:13]([C:5](=[O:8])[CH2:6][CH3:7])=[CH:12][CH:11]=1)([CH3:18])[CH3:17]
Reactant: CC(C)c1ccccc1
Reactant: CCC(=O)Cl
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: ClCCCl
Product: CCC(=O)c1ccc(C(C)C)cc1
Temperature: 0 °C
Reaction time: 12 h
Yield: 83.4 %

Procedure:
525 ml of 1,2-dichloroethane and 209 g of aluminium chloride are added to a round flask, which is fitted with a stirrer, thermometer, condenser and dropping funnel. The mixture is cooled to 0° C. and 127 g of propionic acid chloride are allowed to drop in at 0°-5° C. within 3/4 hour. After the addition, the temperature is allowed to rise to +18° C. and then 157 g of cumene are added within 2 hours at 30° C. The mixture is left to stand for 12 hours and the product is then poured into a mixture of 800 g of ice, 130 ml of water and 130 ml of concentrated hydrochloric acid. The aqueous phase is separated and extracted with two 250 ml portions of dichloroethane. The combined organic phases are washed with three 200 ml portions of 2% sodium hydroxide and with 250 ml of water. The solvent is removed by evaporation under a vacuum and the residue (244 g) is distilled over a 10 cm column. There are obtained 192.1 g of p-isopropyl-propiophenone (yield: 83.2% of theory). B.p.=76°-77° C./0.15 mmHg; nD20 =1.5150; d420 =0.9645.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8]([C:10]2[CH2:11][CH2:12][O:13][C:14]3[CH:20]=[CH:19][C:18]([C:21]4[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=4)=[CH:17][C:15]=3[CH:16]=2)=[O:9])[CH2:3][CH2:2]1.[C:28]1([CH:37]=O)[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH:29]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[C:28]1([CH2:37][N:1]2[CH2:2][CH2:3][CH:4]([NH:7][C:8]([C:10]3[CH2:11][CH2:12][O:13][C:14]4[CH:20]=[CH:19][C:18]([C:21]5[CH:22]=[CH:23][C:24]([CH3:27])=[CH:25][CH:26]=5)=[CH:17][C:15]=4[CH:16]=3)=[O:9])[CH2:5][CH2:6]2)[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH:29]=1
Reactant: Cc1ccc(-c2ccc3c(c2)C=C(C(=O)NC2CCNCC2)CCO3)cc1
Reactant: O=CC1=CCCCCCCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: Cc1ccc(-c2ccc3c(c2)C=C(C(=O)NC2CCN(CC4=CCCCCCCC4)CC2)CCO3)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 38.8 %

Procedure:
To N-(4-piperidinyl)-7-(4-methylphenyl)-2,3-dihydro-1-benzooxepine-4-carboxamide (0.15 g) and cyclononene-1-carbaldehyde (0.085 g) dissolved in 1,2-dichloroethane (10 ml) was added under ice cooling sodium triacetoxyborohydride (0.12 g), and the resulting mixture was stirred at room temperature overnight under a nitrogen atmosphere. The reaction mixture was evaporated to remove the solvent, was neutralized with a 1 N aqueous solution of sodium hydroxide, was then concentrated and was extracted with ethyl acetate. The organic layer was washed with water and an aqueous saturated solution of sodium chloride, and was then dried with anhydrous magnesium sulfate. The resulting organic layer was evaporated under reduced pressure to remove the solvent. The residue was subjected to purification using a silica gel column (ethyl acetate) to obtain crude crystals. The crude crystals were recrystallized from ethyl acetate/hexane to obtain N-(1-(cyclononen-1-yl)methylpiperidin-4-yl)-7-(4-methylphenyl)-2,3-dihydro-1-benzooxepine-4-carboxamide (compound 59) (0.08 g) as colorless prisms.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.C[O-].[Na+].Br[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]>CN(C)C=O>[CH2:27]([O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1)[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH3:14]
Reactant: O=Cc1ccc(O)cc1
Reactant: CCCCCCCCCCCCCCBr
Agent: C[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCCCOc1ccc(C=O)cc1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To a stirred mixture of 50 g (0.41 mole) of p-hydroxybenzaldehyde, 22.2 g (0.41 mole) of sodium methoxide and 500 ml of dried dimethylformamide was added 114 g (0.41 mole) of 1-bromotetradecane. The mixture was refluxed for 3 hours, then allowed to stand at room temperature overnight after which it was poured into ice-water and extracted with diethyl ether. The ether layer was washed with water, 5% potassium hydroxide, and saline, and dried over sodium sulfate, filtered and evaporated. The residue is recrystallized from hexane to give 4-tetradecyloxybenzaldehyde.
Reaction SMILES: [N:1]([C@@H:4]1[CH2:9][CH2:8][C@@H:7]([C:10]([NH2:12])=[O:11])[CH2:6][C@H:5]1[OH:13])=[N+]=[N-].CO.[CH3:16][C:17]([OH:19])=[O:18]>[Pd]>[C:17]([OH:19])(=[O:18])[CH3:16].[NH2:1][C@@H:4]1[CH2:9][CH2:8][C@@H:7]([C:10]([NH2:12])=[O:11])[CH2:6][C@H:5]1[OH:13]
Reactant: [N-]=[N+]=N[C@@H]1CC[C@@H](C(N)=O)C[C@H]1O
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CO
Product: NC(=O)[C@@H]1CC[C@@H](N)[C@H](O)C1
Reaction time: 22 h

Procedure:
To (1R,3R,4R)-4-azido-3-hydroxy-cyclohexanecarboxylic acid amide (351c) (765 mg, 4.15 mmol) in MeOH/AcOH (9:1, 30 mL) was added Pd/C (10%, 300 mg), and the mixture hydrogenated under atmospheric pressure for 22 h. On completion of reaction the mixture was filtered through Celite®, the filter pad washed with MeOH, and the combined organic solutions concentrated in vacuo to give a white solid in quantitative yield.
Reaction SMILES: [CH2:1]([N:3]([CH2:31][CH3:32])[C:4]([C:6]1[CH:7]=[N:8][C:9]([C:12]2([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([NH2:30])[CH:25]=3)[CH2:17][CH2:16][N:15]([CH2:18][CH:19]([CH3:23])[CH2:20][CH2:21][CH3:22])[CH2:14][CH2:13]2)=[N:10][CH:11]=1)=[O:5])[CH3:2].N1C=CC=CC=1.[S:39](Cl)([CH3:42])(=[O:41])=[O:40]>C(Cl)Cl>[CH2:31]([N:3]([CH2:1][CH3:2])[C:4]([C:6]1[CH:7]=[N:8][C:9]([C:12]2([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([NH:30][S:39]([CH3:42])(=[O:41])=[O:40])[CH:25]=3)[CH2:17][CH2:16][N:15]([CH2:18][CH:19]([CH3:23])[CH2:20][CH2:21][CH3:22])[CH2:14][CH2:13]2)=[N:10][CH:11]=1)=[O:5])[CH3:32]
Reactant: CCCC(C)CN1CCC(c2cccc(N)c2)(c2ncc(C(=O)N(CC)CC)cn2)CC1
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCCC(C)CN1CCC(c2cccc(NS(C)(=O)=O)c2)(c2ncc(C(=O)N(CC)CC)cn2)CC1
Temperature: 25 °C
Reaction time: 48 h
Yield: 74.8 %

Procedure:
To a stirring solution of 2-[4-(3-Amino-phenyl)-1-(2-methyl-pentyl)-piperidin-4-yl]-pyrimidine-5-carboxylic acid diethylamide (50 mg, 0.114 mmol) and pyridine (0.01 mL, 0.13 mmol) in 5 mL CH2Cl2 at −5° C. was added mesyl chloride (0.01 mL, 0.13 mmol). The reaction warmed to room temperature and stirred 48 hours. The mixture was quenched with NaHCO3 and extracted with CH2Cl2 (3×10 mL). The combined organic layers were dried and concentrated. Purification of the resulting crude material by flash chromatography with 5% MeOH/CH2Cl2 afforded the desired product (44 mg). 1HNMR (400 MHz, CDCl3) δ 8.73 (s, 2H), 7.24-7.17 (comp, 3H), 7.07 (d, 1H), 3.55-3.51 (comp, 2H), 3.33-3.27 (comp, 2H), 3.02-2.94 (comp, 2H), 2.91 (s, 3H), 2.88-2.86 (comp, 2H), 2.45 (br s, 2H), 2.20-2.15 (comp, 4H), 1.68 (br s, 1H), 1.37-1.21 (comp, 10H), 1.05-0.99 (comp, 1H), 0.91-0.83 (comp, 6H); MS (M+1) 516.3.
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[C:6](C3OC(C)(C)C(C)(C)O3)[CH:7]=[CH:8][CH:9]=2)[CH2:3][CH2:2]1.[F:19][C:20]1[CH:21]=[C:22]([CH:32]([NH:34][C:35]([C:37]2[O:38][C:39](Br)=[CH:40][CH:41]=2)=[O:36])[CH3:33])[CH:23]=[C:24]([F:31])[C:25]=1[NH:26][S:27]([CH3:30])(=[O:29])=[O:28].C([O-])([O-])=O.[Cs+].[Cs+]>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>[F:19][C:20]1[CH:21]=[C:22]([CH:32]([NH:34][C:35]([C:37]2[O:38][C:39]([C:8]3[CH:7]=[CH:6][CH:5]=[C:4]([CH:1]4[CH2:3][CH2:2]4)[CH:9]=3)=[CH:40][CH:41]=2)=[O:36])[CH3:33])[CH:23]=[C:24]([F:31])[C:25]=1[NH:26][S:27]([CH3:30])(=[O:29])=[O:28]
Reactant: CC1(C)OC(c2cccc(C3CC3)c2)OC1(C)C
Reactant: CC(NC(=O)c1ccc(Br)o1)c1cc(F)c(NS(C)(=O)=O)c(F)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: CC(NC(=O)c1ccc(-c2cccc(C3CC3)c2)o1)c1cc(F)c(NS(C)(=O)=O)c(F)c1
Yield: 45.1 %

Procedure:
2-(3-Cyclopropyl-phenyl)-4,4,5,5-tetramethyl-[1,3]dioxolane (126 mg, 0.52 mmol) and 5-bromo-furan-2-carboxylic acid [1-(3,5-difluoro-4-methanesulfonylamino-phenyl)-ethyl]-amide (110 mg, 0.26 mmol) was reacted using Pd(PPh3)2Cl2 (14 mg, 0.02 mmol), Cs2CO3 (254 mg, 0.78 mmol) as described above to give the title compound (54 mg, 56%) after purification by recrystallization from n-Hex/EtOAc.
Reaction SMILES: [H-].[Na+].[NH:3]1[CH:7]=[N:6][CH:5]=[N:4]1.Cl[CH2:9][C:10]1[N:15]=[C:14]2[S:16][C:17]([CH3:20])=[C:18]([CH3:19])[C:13]2=[C:12]([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=2)[C:11]=1[C:28]([O:30][CH2:31][CH3:32])=[O:29].O>CN(C)C=O>[Cl:27][C:24]1[CH:25]=[CH:26][C:21]([C:12]2[C:11]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[C:10]([CH2:9][N:3]3[CH:7]=[N:6][CH:5]=[N:4]3)[N:15]=[C:14]3[S:16][C:17]([CH3:20])=[C:18]([CH3:19])[C:13]=23)=[CH:22][CH:23]=1
Reactant: c1nc[nH]n1
Reactant: CCOC(=O)c1c(CCl)nc2sc(C)c(C)c2c1-c1ccc(Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(Cn2cncn2)nc2sc(C)c(C)c2c1-c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 50.4 %

Procedure:
Sodium hydride (60% in oil, 0.158 g) was added to a solution of 1H-1,2,4-triazole (0.252 g) in N,N-dimethylformamide (DMF) (15 ml). The mixture was stirred for 15 minutes at room temperature, to which was added ethyl 6-chloromethyl-4-(4-chlorophenyl)-2,3-dimethylthieno[2,3-b]pyridine-5-carboxylate (1.2 g). The mixture was stirred for 35 minutes at 80° C. The reaction mixture was poured into water, which was subjected to extraction with ethyl acetate. The ethyl acetate layer was washed with water and dried (MgSO4), then the solvent was distilled off. The residue was subjected to column chromatography on silica gel. From the fraction eluted with dichloromethane-ethyl acetate (20:1, v/v), was obtained ethyl 4-(4-chlorophenyl)-2,3-dimethyl-6-(1,2,4-triazol-1-ylmethyl)thieno[2,3-b]pyridine-5-carboxylate (0.655 g, 50%). Recrystallization from ethanol gave colorless prisms, m.p.144°-145° C.
Reaction SMILES: C([Si]([O:8][CH2:9][C:10]1[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[CH:13]=[CH:12][C:11]=1[N:19]=[C:20]=S)(C)C)(C)(C)C.[NH2:22][C:23]1[C:31]2[O:30][C:29]([CH3:33])([CH3:32])[CH2:28][C:27]=2[CH:26]=[CH:25][CH:24]=1>>[CH3:32][C:29]1([CH3:33])[CH2:28][C:27]2[CH:26]=[CH:25][CH:24]=[C:23]([NH:22][C:20]3[O:8][CH2:9][C:10]4[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[CH:13]=[CH:12][C:11]=4[N:19]=3)[C:31]=2[O:30]1
Reactant: CC(C)(C)[Si](C)(C)OCc1cc([N+](=O)[O-])ccc1N=C=S
Reactant: CC1(C)Cc2cccc(N)c2O1
Product: CC1(C)Cc2cccc(NC3=Nc4ccc([N+](=O)[O-])cc4CO3)c2O1
Yield: 67 %

Procedure:
Prepared from tert-butyl-(2-isothiocyanato-5-nitro-benzyloxy)-dimethyl-silane (Example C1) (3.75 g, 11 mmol) and 7-amino-2,3-dihydro-2,2-dimethylbenzofuran (CAS 68298-46-4) (1.86 g, 11 mmol) according to the procedure described for Example 1. Obtained the title compound as a yellow solid (2.5 g, 65%), MS (ISP) m/e=340.3 [(M+H)+].
Reaction SMILES: Cl.[C:2]([C:4]1([NH:10][C:11]([CH:13]([NH:21][C:22]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)=[O:23])[CH2:14][CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)=[O:12])[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1)#[N:3].[CH3:30][N:31]1[CH2:36][CH2:35][N:34]([C:37](Cl)=[O:38])[CH2:33][CH2:32]1.CN1CCOCC1>C(Cl)Cl>[C:2]([C:4]1([NH:10][C:11]([CH:13]([NH:21][C:22]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)=[O:23])[CH2:14][CH:15]2[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]2)=[O:12])[CH2:5][CH2:6][N:7]([C:37]([N:34]2[CH2:35][CH2:36][N:31]([CH3:30])[CH2:32][CH2:33]2)=[O:38])[CH2:8][CH2:9]1)#[N:3]
Reactant: N#CC1(NC(=O)C(CC2CCCCC2)NC(=O)N2CCOCC2)CCNCC1
Reactant: CN1CCN(C(=O)Cl)CC1
Agent: Cl
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CN1CCN(C(=O)N2CCC(C#N)(NC(=O)C(CC3CCCCC3)NC(=O)N3CCOCC3)CC2)CC1

Procedure:
The title compound is prepared from morpholine-4-carboxylic acid [1-(4-cyano-piperidin-4-ylcarbamoyl)-2-cyclohexyl-ethyl]-amide hydrochloride and 4-methyl-piperzine carbonyl chloride in the presence of a tertiary amine base such as N-methylmorpholine in a solvent such as methylene chloride.
Reaction SMILES: [F:1][C:2]([F:26])([C:16]([F:25])([F:24])[C:17]([F:23])([F:22])[C:18]([F:21])([F:20])[F:19])[CH2:3][CH2:4][CH:5]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:6]([O:8][CH2:9][CH3:10])=[O:7].[H-].[Na+].I[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH:35]=[CH2:36].O>CS(C)=O>[CH2:36]([C:5]([CH2:4][CH2:3][C:2]([F:26])([F:1])[C:16]([F:24])([F:25])[C:17]([F:22])([F:23])[C:18]([F:21])([F:20])[F:19])([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH2:35][CH2:34][CH2:33][CH2:32][CH:31]=[CH2:30]
Reactant: C=CCCCCCI
Reactant: CCOC(=O)C(CCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F)C(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: C=CCCCCCC(CCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F)(C(=O)OCC)C(=O)OCC
Temperature: 25 °C
Reaction time: 1 h
Yield: 86 %

Procedure:
The diethyl 2-(3,3,4,4,5,5,6,6,6-nonafluorohexyl)-malonate prepared in Step 1 of Example 2 (1.2 g, 3.0 mmol) was slowly added dropwise to a suspension of 60% sodium hydride (288 mg, 12 mmol) in anhydrous dimethyl sulfoxide (20 ml) at 0° C., followed by stirring for 1 hour at room temperature. After 7-iodohept-1-ene (795 mg, 2.5 mmol) was slowly added dropwise, the reaction mixture was stirred for 12 hours at room temperature. Water was added to the reaction mixture, which was then extracted twice with ethyl acetate. The combined organic layers were washed with water and saturated aqueous sodium chloride, and then dried over anhydrous magnesium sulfate. After distilling off the solvent, the residue was purified by silica gel column chromatography (eluent: ethyl acetate/hexane=1/40) to give diethyl 2-(6-heptenyl)-2-(3,3,4,4,5,5,6,6,6-nonafluorohexyl)malonate (1.08 g, Yield 73%).
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][N:12]2[CH2:17][CH2:16][CH:15]([C:18]([C:20]3[CH:25]=[CH:24][C:23]([O:26][C:27]([F:30])([F:29])[F:28])=[CH:22][CH:21]=3)=[O:19])[CH2:14][CH2:13]2)=[CH:7][CH:6]=1)[CH2:2][CH3:3].[Cl:31][C:32]1[CH:37]=[CH:36][C:35]([Mg]Br)=[CH:34][CH:33]=1.[Cl-].[NH4+]>O1CCCC1>[CH2:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][N:12]2[CH2:17][CH2:16][CH:15]([C:18]([C:20]3[CH:21]=[CH:22][C:23]([O:26][C:27]([F:30])([F:28])[F:29])=[CH:24][CH:25]=3)([C:35]3[CH:36]=[CH:37][C:32]([Cl:31])=[CH:33][CH:34]=3)[OH:19])[CH2:14][CH2:13]2)=[CH:7][CH:6]=1)[CH2:2][CH3:3]
Reactant: CCCOc1ccc(CN2CCC(C(=O)c3ccc(OC(F)(F)F)cc3)CC2)cc1
Reactant: Clc1ccc([Mg]Br)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCCOc1ccc(CN2CCC(C(O)(c3ccc(Cl)cc3)c3ccc(OC(F)(F)F)cc3)CC2)cc1
Temperature: 65 °C
Reaction time: 3.5 h

Procedure:
A solution of 0.6 gram (0.0014 mole) of N-(4-propoxyphenylmethyl)-4-(4-trifluoromethoxyphenyicarbonyl)piperidine in 15 mL of tetrahydrofuran was stirred, and to the stirred solution was slowly added 1.8 mL of 4-chlorophenylmagnesium bromide (0.0018 mole-1M in diethyl ether). Upon completion of the addition, the reaction mixture was warmed to 65° C., where it was stirred for 3.5 hours. After this time the reaction mixture was allowed to cool to ambient temperature, where it stirred for about 18 hours. The reaction mixture was then poured into a mixture of 50 mL of ice and 75 mL of an aqueous solution saturated with ammonium chloride. The mixture was stirred until the ice melted and then extracted with ethyl acetate. The extract was dried with sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to a residue, which was dissolved in boiling petroleum ether and treated with decolorizing carbon. Diatomaceous earth was stirred in, and the mixture was filtered through a pad of activated magnesium silicate. The magnesium silicate pad was washed with 30% acetone in methylene chloride. The filtrate and wash were combined and concentrated under reduced pressure, yielding 0.4 gram of N-(4-propoxyphenylmethyl)-4-[(4-trifluoromethoxyphenyl)(4-chlorophenyl)hydroxymethyl]piperidine. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:16])[CH3:15])[C:11]([F:17])=[CH:10][C:9]=1[N+:18]([O-])=O)([CH3:4])([CH3:3])[CH3:2]>[Pd]>[C:1]([O:5][C:6](=[O:21])[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:16])[CH3:15])[C:11]([F:17])=[CH:10][C:9]=1[NH2:18])([CH3:4])([CH3:2])[CH3:3]
Reactant: CN(C)c1cc(NC(=O)OC(C)(C)C)c([N+](=O)[O-])cc1F
Agent: [Pd]
Product: CN(C)c1cc(NC(=O)OC(C)(C)C)c(N)cc1F

Procedure:
The title compound was prepared from (5-dimethylamino-4-fluoro-2-nitro-phenyl)-carbamic acid tert.-butyl ester (Example C11) (4.88 g, 16 mmol) by hydrogenation with 10% Pd/C according to the general procedure J (method a). Obtained as a green solid (4.55 g).
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:12]1[C:38]([CH3:39])=[CH:37][C:15]2[N:16]=[C:17]([C:19]3[CH:24]=[CH:23][N:22]=[C:21]([C:25]4[CH:26]=[C:27]5[C:32](=[CH:33][CH:34]=4)[N:31]([CH3:35])[C:30](=[O:36])[CH:29]=[CH:28]5)[CH:20]=3)[S:18][C:14]=2[C:13]=1[C:40]1[CH:45]=[CH:44][C:43]([Cl:46])=[CH:42][CH:41]=1)[C:7]([O:9]CC)=[O:8])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>C1COCC1.CO>[C:1]([O:5][C@@H:6]([C:12]1[C:38]([CH3:39])=[CH:37][C:15]2[N:16]=[C:17]([C:19]3[CH:24]=[CH:23][N:22]=[C:21]([C:25]4[CH:26]=[C:27]5[C:32](=[CH:33][CH:34]=4)[N:31]([CH3:35])[C:30](=[O:36])[CH:29]=[CH:28]5)[CH:20]=3)[S:18][C:14]=2[C:13]=1[C:40]1[CH:45]=[CH:44][C:43]([Cl:46])=[CH:42][CH:41]=1)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3ccnc(-c4ccc5c(ccc(=O)n5C)c4)c3)sc2c1-c1ccc(Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cc2nc(-c3ccnc(-c4ccc5c(ccc(=O)n5C)c4)c3)sc2c(-c2ccc(Cl)cc2)c1[C@H](OC(C)(C)C)C(=O)O
Temperature: 50 °C
Reaction time: 2 h

Procedure:
To a stirred solution of (S)-ethyl 2-tert-butoxy-2-(7-(4-chlorophenyl)-5-methyl-2-(2-(1-methyl-2-oxo-1,2-dihydroquinolin-6-yl)pyridin-4-yl)benzo[d]thiazol-6-yl)acetate (5.2 mg, 0.008 mmol) in THF (0.4 mL) and methanol (0.4 mL) was added 1N NaOH solution (0.4 mL, excess). The reaction mixture was stirred at 50° C. for 2 h and then purified by reverse phase HPLC, eluting by 0-100% acetonitrile in H2O with 0.1% TFA to give the desired product. LCMS-ESI+ (m/z): [M+H]+ calcd for C35H31ClN3O4S: 624.2; found: 624.2. 1H NMR (400 MHz, CDCl3) δ 8.88 (d, J=5.2 Hz, 1H), 8.49 (s, 1H), 8.41 (s, 1H), 8.36 (d, J=7.6 Hz, 1H), 8.00 (s, 1H), 7.94 (s, 1H), 7.85 (d, J=9.6 Hz, 1H), 7.74 (d, J=6.8 Hz, 1H), 7.58-7.47 (m, 4H), 6.81 (d, J=9.6 Hz, 1H), 5.35 (s, 1H), 3.79 (s, 3H), 2.63 (s, 3H), 1.03 (s, 9H).
Reaction SMILES: C[O:2][C:3]1[CH:32]=[CH:31][C:6]2[NH:7][C:8](=[O:30])[CH:9]([CH2:11][CH2:12][CH2:13][CH2:14][N:15]3[CH2:20][CH2:19][CH:18]([C:21](=[O:29])[C:22]4[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=4)[CH2:17][CH2:16]3)[S:10][C:5]=2[CH:4]=1.B(Br)(Br)Br.C(=O)([O-])O.[Na+].C(Cl)(Cl)Cl>ClCCl>[OH:2][C:3]1[CH:32]=[CH:31][C:6]2[NH:7][C:8](=[O:30])[CH:9]([CH2:11][CH2:12][CH2:13][CH2:14][N:15]3[CH2:16][CH2:17][CH:18]([C:21](=[O:29])[C:22]4[CH:23]=[CH:24][C:25]([F:28])=[CH:26][CH:27]=4)[CH2:19][CH2:20]3)[S:10][C:5]=2[CH:4]=1
Reactant: COc1ccc2c(c1)SC(CCCCN1CCC(C(=O)c3ccc(F)cc3)CC1)C(=O)N2
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: O=C(c1ccc(F)cc1)C1CCN(CCCCC2Sc3cc(O)ccc3NC2=O)CC1
Reaction time: 0.5 h

Procedure:
675 mg (=0.0015 m) of 7-methoxy-2-(4-[4-(4-fluorobenzoyl)-piperidin-1-yl]-butyl)-2H-1,4benzothiazine-3(4H)-one (see Example 18) prepared analogously to Example 4 were placed in 5 ml of dichloromethane with exclusion of moisture. After cooling to -5° C. a solution of 1.10 g of boron tribromide in 1 ml of methylene chloride was added dropwise with stirring. Stirring was then continued for a further 30 minutes at room temperature. The reaction mixture was worked up by adding it with stirring to a mixture of ice and aqueous sodium hydrogen carbonate solution. 200 ml of chloroform were then added. The resulting organic solution was washed with water, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The title compound was obtained from the remaining residue by fractional column chromatography. The fractions containing the title compound were concentrated and treated with ether. 55 mg of 7-hydroxy-2-{4-[4-(4-fluorobenzoyl)-piperazin-1-yl]-butyl} -2H-1,4-benzothiazine-3(4H)-one were obtained.
Reaction SMILES: [C:1]([O:5][CH:6]([C:11]1[C:12]([C:21]2[CH:22]=[C:23]3[C:28](=[CH:29][CH:30]=2)[O:27][CH2:26][CH2:25][CH2:24]3)=[C:13]2[CH:20]=[CH:19][NH:18][C:14]2=[N:15][C:16]=1[CH3:17])[C:7]([O:9]C)=[O:8])([CH3:4])([CH3:3])[CH3:2].[F:31][C:32]1[CH:39]=[C:38]([C:40]([F:43])([F:42])[F:41])[CH:37]=[CH:36][C:33]=1[CH2:34]Br>>[C:1]([O:5][CH:6]([C:11]1[C:12]([C:21]2[CH:22]=[C:23]3[C:28](=[CH:29][CH:30]=2)[O:27][CH2:26][CH2:25][CH2:24]3)=[C:13]2[CH:20]=[CH:19][N:18]([CH2:34][C:33]3[CH:36]=[CH:37][C:38]([C:40]([F:41])([F:43])[F:42])=[CH:39][C:32]=3[F:31])[C:14]2=[N:15][C:16]=1[CH3:17])[C:7]([OH:9])=[O:8])([CH3:2])([CH3:3])[CH3:4]
Reactant: Fc1cc(C(F)(F)F)ccc1CBr
Reactant: COC(=O)C(OC(C)(C)C)c1c(C)nc2[nH]ccc2c1-c1ccc2c(c1)CCCO2
Product: Cc1nc2c(ccn2Cc2ccc(C(F)(F)F)cc2F)c(-c2ccc3c(c2)CCCO3)c1C(OC(C)(C)C)C(=O)O

Procedure:
The title compound was prepared in a manner similar to that described in Example 27, Step H from methyl 2-(tert-butoxy)-2-(4-(chroman-6-yl)-6-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)acetate and 2-fluoro-4-(trifluoromethyl)benzyl bromide. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.49-7.41 (m, 1 H), 7.39-7.28 (m, 3 H), 7.25-7.18 (m, 1 H), 7.14-7.10 (m, 1 H), 6.93 (dd, J=3.9, 8.4 Hz, 1 H), 6.29 (dd, J=3.5, 12.1 Hz, 1 H), 5.70-5.62 (m, 1 H), 5.62-5.52 (m, 2 H), 4.33-4.25 (m, 2 H), 2.96-2.77 (m, 2 H), 2.73 (s, 3 H), 2.16-2.03 (m, 2 H), 1.01-0.92 (s, 9 H); LC/MS (m/z) ES+=571 (M+1).
Reaction SMILES: [N@:1]1([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])[CH2:3][CH:2]1[C:4]([O:6][CH3:7])=[O:5].[C:18]1([CH:24]([OH:26])[CH3:25])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.B(F)(F)F.CCOCC>ClCCl>[CH3:7][O:6][C:4](=[O:5])[CH:2]([NH:1][C:8]([O:10][CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)=[O:9])[CH2:3][O:26][CH:24]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH3:25]
Reactant: CC(O)c1ccccc1
Reactant: COC(=O)C1CN1C(=O)OCc1ccccc1
Agent: FB(F)F
Solvent: ClCCl
Solvent: CCOCC
Product: COC(=O)C(COC(C)c1ccccc1)NC(=O)OCc1ccccc1
Reaction time: 1 h
Yield: 46.9 %

Procedure:
To a stirred solution of 1-benzyl 2-methyl (S)-(−)-1,2-aziridinedicarboxylate (1.88 g) in dichloromethane (30 ml) were added at 0° C. 1-phenyl-ethanol (9.77 g) and boron trifluoride etherate (2.0 ml). After stirring the mixture for one hour the cooling bath was removed and stirring was continued overnight. Then the reaction mixture was poured onto saturated sodium bicarbonate solution and extracted with ethyl acetate. The combined organic layers were washed with brine, dried (MgSO4) and concentrated. The crude product was purified by column chromatography (SiO2; gradient: heptane/EtOAc 100:0->90:10) to give S)-2-benzyloxycarbonylamino-3-(1-phenyl-ethoxy)-propionic acid methyl ester (1.34 g, 47%) as a light yellow oil. MS (ISP): 358.2 ([M+H]+)).