Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:3]([O:12][CH3:13])=[C:4]([O:10][CH3:11])[CH:5]=[C:6]([CH:9]=1)[CH:7]=O.C1(P(=[CH:33][CH:34]=[O:35])(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1C=CC=CC=1>[Br:1][C:2]1[CH:9]=[C:6]([CH:7]=[CH:33][CH:34]=[O:35])[CH:5]=[C:4]([O:10][CH3:11])[C:3]=1[O:12][CH3:13]
Reactant: COc1cc(C=O)cc(Br)c1OC
Reactant: O=CC=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: c1ccccc1
Product: COc1cc(C=CC=O)cc(Br)c1OC
Yield: 45 %

Procedure:
A mixture of 5-bromoveratraldehyde (100 mg, 0.41 mmol) and (triphenylphosphoranylidene)acetaldehyde (137 mg, 0.45 mmol) in dry benzene (2.5 ml) was refluxed for 9 h and the solvent was removed. The crude product was passed through a short silica gel column (bond-elute) (eluents: 10% ethyl acetate in hexane), giving 3-(3-bromo-4,5-dimethoxy-phenyl)-propenal (50 mg, 45%). 1H NMR (CDCl3): 9.68 (d, J=7.6 Hz, 1H), 7.36 (d, J =1.8 Hz, 1H), 7.34 (d, J=15.8 Hz, 1H), 7.03 (d, J=1.9 Hz, 1H), 6.62 (dd, J=7.6, 16.0 Hz, 1H), 3.913 (s, 3H), 3.907 (s, 3H) (the sample contained trace amount of starting material).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([CH2:12][N:13]2[CH2:18][CH2:17][CH:16]([CH2:19][N:20]([C@@H:27]3[CH2:29][C@H:28]3[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)C(=O)C(F)(F)F)[CH2:15][CH2:14]2)[CH:9]=[CH:8][C:3]=1[C:4]([O:6]C)=[O:5].[OH-].[Na+]>CO>[Cl:1][C:2]1[CH:11]=[C:10]([CH2:12][N:13]2[CH2:18][CH2:17][CH:16]([CH2:19][NH:20][C@@H:27]3[CH2:29][C@H:28]3[C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)[CH2:15][CH2:14]2)[CH:9]=[CH:8][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: COC(=O)c1ccc(CN2CCC(CN(C(=O)C(F)(F)F)[C@@H]3C[C@H]3c3ccccc3)CC2)cc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1ccc(CN2CCC(CN[C@@H]3C[C@H]3c3ccccc3)CC2)cc1Cl
Temperature: 25 °C
Reaction time: 18 h
Yield: 102.7 %

Procedure:
To a solution of methyl 2-chloro-4-((4-((2,2,2-trifluoro-N-((1R,2S)-2-phenylcyclopropyl)acetamido)methyl)piperidin-1-yl)methyl)benzoate (31 mg, 0.061 mmol) in methanol (2 mL) was added sodium hydroxide (6M, 0.3 mL, 1.800 mmol), and the mixture was stirred at room temperature for 18 h. The mixture was purified using reverse-phase HPLC. The fractions containing the product as combined, treated with 1N HCl and concentrated. The residue was dried under vacuum to give 25 mg of product (HCl salt) as white solid. MS: (M+H)+=399.2. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.26 (d, 1H), 1.59 (dd, J=9.98, 3.66 Hz, 3H), 1.80-2.16 (m, 3H), 2.54-2.68 (m, 1H), 2.98 (br. s., 4H), 4.31 (br. s., 2H), 7.13-7.39 (m, 5H), 7.65 (d, J=7.83 Hz, 1H), 7.81-8.01 (m, 2H).
Reaction SMILES: [CH3:1][NH:2][C:3]([NH2:5])=[O:4].[C:6]([CH2:9][C:10](=O)[CH3:11])(=O)[CH3:7].S(=O)(=O)(O)O>C(O)C>[CH3:1][N:2]1[C:6]([CH3:7])=[CH:9][C:10]([CH3:11])=[N:5][C:3]1=[O:4]
Reactant: CNC(N)=O
Reactant: CC(=O)CC(C)=O
Agent: O=S(=O)(O)O
Solvent: CCO
Product: Cc1cc(C)n(C)c(=O)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
20.0 g (0.262 mol) of N-methylurea and 29.4 g (0.291 mol) of acetylacetone were together dissolved in 100 ml of absolute ethanol. 97 g of concentrated sulfuric acid were then added, and the reaction mixture heated up. The mixture was then after-stirred for 1 hour at room temperature. After just a short time, the hydrogen sulfate salt of the product precipitated out in the form of a pale, crystalline solid, which was filtered off. This salt was dissolved in a small amount of water and the solution was rendered neutral using 10% strength sodium hydroxide solution. Extraction was then carried out by shaking with chloroform, and the solvent was dried with magnesium sulfate. After removing the solvent on a rotary evaporator, the desired product was produced in the form of pale pink-colored crystals.
Reaction SMILES: Cl[CH2:2][C:3]1[C:4]([S:9][CH:10]([CH3:12])[CH3:11])=[N:5][CH:6]=[CH:7][CH:8]=1.C([O:15][C:16]([CH:18]1[CH2:20][CH:19]1[C:21]1[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][C:22]=1[Cl:28])=[O:17])C>>[Cl:28][C:22]1[CH:23]=[C:24]([O:27][CH2:2][C:3]2[C:4]([S:9][CH:10]([CH3:12])[CH3:11])=[N:5][CH:6]=[CH:7][CH:8]=2)[CH:25]=[CH:26][C:21]=1[CH:19]1[CH2:20][CH:18]1[C:16]([OH:17])=[O:15]
Reactant: CC(C)Sc1ncccc1CCl
Reactant: CCOC(=O)C1CC1c1ccc(O)cc1Cl
Product: CC(C)Sc1ncccc1COc1ccc(C2CC2C(=O)O)c(Cl)c1
Yield: 54.2 %

Procedure:
3-Chloromethyl-2-isopropylsulfanyl-pyridine (0.040 g, 0.20 mmol) obtained in Step C of Preparation Example 1 and 2-(2-chloro-4-hydroxy-phenyl)-cyclopropane carboxylic acid ethyl ester (0.047 g, 0.20 mmol) obtained in Step E of Preparation Example 45 were used to react sequentially in the same manner as in Steps A and B of Example 1 to obtain the title compound (0.041 g, 55%).
Reaction SMILES: [I:1][C:2]1[C:6]([CH:7]=O)=[CH:5][N:4]([CH:9]2[CH2:14][CH2:13][CH2:12][CH2:11][O:10]2)[N:3]=1.[CH3:15][NH:16][CH2:17][CH2:18][NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClC(Cl)C>[I:1][C:2]1[C:6]([CH2:7][N:16]([CH3:15])[CH2:17][CH2:18][NH:19][C:20](=[O:26])[O:21][C:22]([CH3:23])([CH3:24])[CH3:25])=[CH:5][N:4]([CH:9]2[CH2:14][CH2:13][CH2:12][CH2:11][O:10]2)[N:3]=1
Reactant: CNCCNC(=O)OC(C)(C)C
Reactant: O=Cc1cn(C2CCCCO2)nc1I
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Product: CN(CCNC(=O)OC(C)(C)C)Cc1cn(C2CCCCO2)nc1I
Temperature: 25 °C
Reaction time: 2 h
Yield: 83.5 %

Procedure:
A mixture of 3-iodo-1-(oxan-2-yl)-1H-pyrazole-4-carbaldehyde (3.2 g, 10.45 mmol, 1.00 equiv), tert-butyl N-[2-(methylamino)ethyl]carbamate (2.2 g, 12.63 mmol, 1.21 equiv) and NaBH(OAc)3 (6.65 g, 31.38 mmol, 3.00 equiv) in dichloroethane (30 mL) was stirred for 2 h at room temperature. The reaction was quenched with 50 mL of saturated aqueous sodium bicarbonate solution. The resulting mixture was extracted with 3×200 mL of dichloromethane. The combined organic layers was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified on a silica gel column eluted with 30-100% ethyl acetate in petroleum ether to give 4.05 g (83%) of tert-butyl (2-(((3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)methyl)(methyl)amino)ethyl)carbamate as a light yellow oil. 1H NMR (300 MHz, CDCl3): δ 7.48 (s, 1H), 5.35-5.30 (m, 1H), 4.13-4.03 (m, 1H), 3.71-3.63 (m, 1H), 3.36 (s, 2H), 3.26-3.25 (m, 2H), 2.52-2.49 (m, 2H), 2.21 (s, 3H), 2.09-2.01 (m, 3H), 1.68-1.58 (m, 3H), 1.44 (s, 9H) ppm. LCMS (method C, ESI): RT=0.58 min, m/z=465.0 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:21][CH2:20][C:19]2[C:18]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[N:12]([CH2:22][CH2:23][CH2:24]Cl)[C:11]=2[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:26]1([OH:32])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.CN(C=O)C.C([O-])([O-])=O.[K+].[K+]>CCOC(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:21][CH2:20][C:19]2[C:18]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[N:12]([CH2:22][CH2:23][CH2:24][O:32][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:11]=2[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Oc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCc2c(n(CCCCl)c3ccccc23)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCc2c(n(CCCOc3ccccc3)c3ccccc23)CC1
Temperature: 100 °C
Yield: 83.1 %

Procedure:
A mixture of 3-tert-butyloxycarbonyl-6-(3-chloropropyl)-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (213 mg), phenol (90 mg), DMF (2.0 mL), and K2CO3 (81 mg) was heated at 100° C. for 16 h, then allowed to cool to room temperature. The mixture was diluted with EtOAc (50 mL), then washed with water (3×10 mL). The organic layer was dried (MgSO4), filtered, and concentrated. Purification by flash chromatography (silica gel, 3:1 hexane:EtOAc) gave 205 mg of the title compound as an oil: 1H NMR (300 MHz, CDCl3) δ 7.45-7.55, 6.8-7.35, 4.33, 3.90, 3.55-3.75, 2.90-3.10, 2.12-2.28, 1.49; MS (ESI) m/z 421 (M+).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:15]3[C:22](Br)=[CH:21][N:20]([S:24]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)(=[O:26])=[O:25])[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[Na+].[Na+].[S:39]1[CH:43]=[CH:42][CH:41]=[C:40]1B(O)O>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:15]3[C:22]([C:40]4[S:39][CH:43]=[CH:42][CH:41]=4)=[CH:21][N:20]([S:24]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)(=[O:26])=[O:25])[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ncnc3c2c(Br)cn3S(=O)(=O)c2ccccc2)CC1
Reactant: OB(O)c1cccs1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: CC(C)(C)OC(=O)N1CCN(c2ncnc3c2c(-c2cccs2)cn3S(=O)(=O)c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 78.7 %

Procedure:
To a solution of 4-(7-Benzenesulfonyl-5-bromo-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-piperazine-1-carboxylic acid tert-butyl ester (150 mg, 0.29 mmol) in 4 mL DME (degassed with nitrogen prior to use) was added 0.94M aqueous Na2CO3 (0.61 mL, 0.57 mmol) and Pd(PPh3)4 (66 mg, 0.057 mmol). The reaction mixture was stirred 5 minutes, then 2-thiophene boronic acid (55 mg, 0.43 mmol) was added. The reaction mixture heated to reflux and stirred 16 hours, after which it was cooled to room temperature and DME was removed by rotary evaporation. The reaction mixture was diluted with H2O and extracted with DCM, and the combined extracts were dried (Na2SO4), filtered, and concentrated. The crude was purified on silica gel (8:1 to 4:1 hexanes:EtOAc) to furnish 4-(7-Benzenesulfonyl-5-thiophen-2-yl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-piperazine-1-carboxylic acid tert-butyl ester (120 mg, 79%) as a beige powder. LCMS (APCI+) m/z 526 [M+H]+; Rt: 3.25 min.
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[C@@H:7]1[CH2:11][C@H:10]([N:12]=[N+]=[N-])[CH2:9][N:8]1[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])([CH3:4])([CH3:3])[CH3:2].[H][H]>C(O)C.[Pd]>[C:1]([O:5][C:6](=[O:22])[C@@H:7]1[CH2:11][C@H:10]([NH2:12])[CH2:9][N:8]1[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)[C@@H]1C[C@H](N=[N+]=[N-])CN1C(=O)OC(C)(C)C
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)[C@@H]1C[C@H](N)CN1C(=O)OC(C)(C)C

Procedure:
A solution (4S)-1-(tert-butyloxycarbonyl)-4-azido-L-proline tert-butyl ester (185 mg, 0.611 mmol) in 90% ethanol (15 mL) was hydrogenated in the presence of 10% palladium-on-charcoal (40 mg) under a balloon atmosphere of hydrogen gas for one hour. The catalyst was removed by filtration through Celite, the filter washed with methanol, and the combined filtrate and washings evaporated. The title compound was obtained as a colorless oil after drying under high vacuum; yield 145 mg (86%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[N:5]=[C:4]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[N:3]=1.[CH3:15][NH:16][C:17]([NH:19][C:20]1[CH:25]=[CH:24][C:23](B2OC(C)(C)C(C)(C)O2)=[CH:22][CH:21]=1)=[O:18].C([O-])([O-])=O.[Na+].[Na+]>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:8][C:6]1[N:5]=[C:4]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[N:3]=[C:2]([C:23]2[CH:22]=[CH:21][C:20]([NH:19][C:17]([NH:16][CH3:15])=[O:18])=[CH:25][CH:24]=2)[N:7]=1
Reactant: CNC(=O)Nc1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Reactant: Clc1nc(Cl)nc(N2CCOCC2)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: CNC(=O)Nc1ccc(-c2nc(Cl)nc(N3CCOCC3)n2)cc1
Yield: 34 %

Procedure:
A mixture of compound 4-(4,6-dichloro-1,3,5-triazin-2-yl)morpholine (10 g, 42.7 mmol), Pd (PPh3)4 (2.46 g, 2.1 mmol), 1-methyl-3-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-urea. (11.7 g, 42.4 mmol) and 1N Na2CO3(168 mL, 168 mmol)in degassed 1,2-dimethoxyethane (400 mL) was heated to 65° C. for 8 hours under N2 atmosphere. The reaction mixture filtered, diluted with water, extracted with ethyl acetate and washed with water, brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. Crude product was purified by silica gel (100-200 mesh) column chromatography using 20-60% ethyl acetate in pet-ether as an eluent. To give 1-(4-(4-chloro-6-morpholino-1,3,5-triazin-2-yl)phenyl)-3-methylurea (5.0 g, 34% yield).
Reaction SMILES: [CH3:1][C:2]1[C:10]2[CH2:9][O:8][C:7](=[O:11])[C:6]=2[CH:5]=[CH:4][C:3]=1[C@@H:12]1[CH2:14][O:13]1.[CH3:15][C:16]1[C:24]2[CH2:23][O:22][C:21](=[O:25])[C:20]=2[CH:19]=[CH:18][C:17]=1[CH2:26][CH2:27][N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1>>[OH:13][C@H:12]([C:3]1[CH:4]=[CH:5][C:6]2[C:7](=[O:11])[O:8][CH2:9][C:10]=2[C:2]=1[CH3:1])[CH2:14][N:31]1[CH2:32][CH2:33][N:28]([CH2:27][CH2:26][C:17]2[CH:18]=[CH:19][C:20]3[C:21](=[O:25])[O:22][CH2:23][C:24]=3[C:16]=2[CH3:15])[CH2:29][CH2:30]1
Reactant: Cc1c([C@@H]2CO2)ccc2c1COC2=O
Reactant: Cc1c(CCN2CCNCC2)ccc2c1COC2=O
Product: Cc1c(CCN2CCN(C[C@H](O)c3ccc4c(c3C)COC4=O)CC2)ccc2c1COC2=O

Procedure:
5-((1R)-1-hydroxy-2-{4-[2-(4-methyl-1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl]piperazin-1-yl}ethyl)-4-methyl-2-benzofuran-1(3H)-one was prepared in a similar fashion to that described for the synthesis of EXAMPLE 12 starting from 4-methyl-5-[(2R)-oxiran-2-yl]-2-benzofuran-1(3H)-one and 4-methyl-5-(2-piperazin-1-ylethyl)-2-benzofuran-1(3H)-one.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([CH2:8][C:9]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)=O)[CH:5]=[CH:4][CH:3]=1.Cl.[NH2:19][OH:20].[OH-].[Na+]>CO>[Cl:1][C:2]1[N:7]=[C:6]([CH2:8][C:9]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)=[N:19][OH:20])[CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cc1cccc(Cl)n1)c1ccc(F)cc1
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: ON=C(Cc1cccc(Cl)n1)c1ccc(F)cc1
Temperature: 25 °C
Yield: 85.6 %

Procedure:
To a solution of 2-(6-chloro-2-pyridinyl)-1-(4-fluorophenyl)ethanone (74.9 g, 299.8 mmol) in methanol (900 mL) was added hydroxylamine hydrochloride (104 g, 1.49 mol) followed by sodium hydroxide (600 mL, 10% aqueous, 1.5 mol). The resultant suspension was heated to reflux for 2 hours and then cooled to room temperature. The mixture was concentrated in vacuo and the residue taken up in ether and water. The organic layer was washed with brine. The aqueous layer was extracted with ether and the combined organics were dried over magnesium sulfate. Filtration and concentration gave a solid residue which was purified by recrystallization from ethyl acetate-hexanes to provide 2-(6-chloro-2-pyridinyl)-1-(4-fluorophenyl)ethanone oxime (67.9 g, 86%) as a white solid. 1H NMR (CDCl3): δ 8.69 (s, 1 H), 7.71 (dd, 2 H), 7.53 (t, 1 H), 7.18-7.16 (m, 2 H), 7.03 (t, 2 H), 4.37 (s, 2 H); 19F NMR (CDCl3) δ −111.77; MS m/z 265 (M+1).
Reaction SMILES: [OH-].[Li+].[O:3]=[C:4]1[NH:10][C:9]2[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=2[CH2:7][CH2:6][N:5]1[CH:15]1[CH2:20][CH2:19][N:18]([C:21]([O:23][C@@H:24]([C:38]([O:40]CC)=[O:39])[CH2:25][C:26]2[CH:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[C:29]([NH2:36])=[C:28]([Cl:37])[CH:27]=2)=[O:22])[CH2:17][CH2:16]1.C1COCC1.Cl>O>[O:3]=[C:4]1[NH:10][C:9]2[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=2[CH2:7][CH2:6][N:5]1[CH:15]1[CH2:20][CH2:19][N:18]([C:21]([O:23][C@@H:24]([C:38]([OH:40])=[O:39])[CH2:25][C:26]2[CH:31]=[C:30]([C:32]([F:35])([F:33])[F:34])[C:29]([NH2:36])=[C:28]([Cl:37])[CH:27]=2)=[O:22])[CH2:17][CH2:16]1
Reactant: CCOC(=O)[C@@H](Cc1cc(Cl)c(N)c(C(F)(F)F)c1)OC(=O)N1CCC(N2CCc3ccccc3NC2=O)CC1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Nc1c(Cl)cc(C[C@@H](OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)O)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 804 mg (33.5 mmol) lithium hydroxide dissolved in 80 ml of water was added dropwise to a mixture of 13.0 g (22.3 mmol) (R)-2-(4-amino-3-chloro-5-trifluoromethyl-phenyl)-1-ethoxycarbonyl-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-benzo[d]-[1,3]diazepin-3-yl)-piperidine-1-carboxylate and 120 ml THF. The mixture was stirred for 3 hours at ambient temperature, freed from THF under reduced pressure, combined with 150 ml of water, and acidified by the addition of aqueous 4-molar hydrochloric acid solution. Then the aqueous phase was extracted with 300 ml of ethyl acetate, the organic phase was dried and evaporated down under reduced pressure. The residue was recrystallised from 50 ml isopropanol.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)[OH:9])[CH:5]=[CH:6][CH:7]=1.Cl.Cl[CH2:20][C:21]1[CH:30]=[CH:29][C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[N:22]=1.[OH-].[K+]>O.C(O)C>[CH3:17][O:16][C:13]1[CH:14]=[CH:15][C:10]([CH:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([O:1][CH2:20][C:21]3[CH:30]=[CH:29][C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[N:22]=3)[CH:3]=2)[OH:9])=[CH:11][CH:12]=1
Reactant: ClCc1ccc2ccccc2n1
Reactant: COc1ccc(C(O)c2cccc(O)c2)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: COc1ccc(C(O)c2cccc(OCc3ccc4ccccc4n3)c2)cc1

Procedure:
A mixture of 3.7 g (0.016 mol) 1-(3-hydroxyphenyl)-1-(4-methoxyphenyl)methanol, 3.4 g (0.016 mol) 2-chloromethylquinoline hydrochloride and 2 g (0.036 mol) KOH in 5 ml water and 50 ml ethanol was heated over steam bath for a period of 4 hours. Reaction mixture was concentrated to dryness and slurried into water and extracted with methylene chloride. The methylene chloride extract was washed with water, dried over MgSO4 and concentrated to dryness under reduced pressure to obtain oily material. Repeated recrystallization from ethyl acetate, acetonitrite and isopropanol gave desired produce 1.1 g. m.p. 70°-80° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]([O:8][CH2:9][CH2:10][O:11][C:12]2[N:17]=[CH:16][N:15]=[C:14]([NH:18][S:19](=[O:33])(=[O:32])[NH:20][CH:21]([O:24]CC3C=CC=CC=3)[CH2:22][CH3:23])[C:13]=2[C:34]2[CH:39]=[CH:38][C:37]([Br:40])=[CH:36][CH:35]=2)=[N:6][CH:7]=1.B(Br)(Br)Br.CO>C(Cl)Cl.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>[Br:1][C:2]1[CH:7]=[N:6][C:5]([O:8][CH2:9][CH2:10][O:11][C:12]2[N:17]=[CH:16][N:15]=[C:14]([NH:18][S:19](=[O:32])(=[O:33])[NH:20][CH:21]([OH:24])[CH2:22][CH3:23])[C:13]=2[C:34]2[CH:35]=[CH:36][C:37]([Br:40])=[CH:38][CH:39]=2)=[N:4][CH:3]=1
Reactant: CCC(NS(=O)(=O)Nc1ncnc(OCCOc2ncc(Br)cn2)c1-c1ccc(Br)cc1)OCc1ccccc1
Agent: BrB(Br)Br
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CO
Solvent: ClCCl
Product: CCC(O)NS(=O)(=O)Nc1ncnc(OCCOc2ncc(Br)cn2)c1-c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.5 %

Procedure:
A solution of 1-benzyloxypropanesulfamic acid[6-(2-(5-bromopyrimid-2-yloxy)-ethoxy)-5-(4-bromophenyl)-pyrimidin-4-yl]-amide (283 mg, 0.408 mmol) in DCM (15 mL) is cooled to −78° C. an then slowly treated with BBr3 (0.816 mL of a 1 M solution in DCM). The reaction mixture is allowed to warm to rt and stirring is continued for 1 h. Methanol (approx. 10 mL) is added to the suspension and stirring is continued for another 10 min before the mixture is diluted with 10% aq. citric acid solution (75 mL) and extracted with DCM (2×75 mL). The organic extracts are washed with water (50 mL), dried over MgSO4, filtered and concentrated. The crude product is purified on prep. tlc plates (silica gel, DCM with 10% methanol) to afford 1-hydroxypropanesulfamic acid[6-(2-(5-bromopyrimid-2-yloxy)-ethoxy)-5-(4-bromophenyl)-pyrimidin-4-yl]-amide (223 mg) as a pale grey foam. LC-MS: tR=0.92 min, [M+H]+=602.87; 1H NMR (CDCl3): δ 8.48 (s, 2H), 8.44 (s, 1H), 7.58-7.54 (m, 2H), 7.18-7.13 (m, 2H), 6.91 (s, 1H), 5.93 (t, J=6.4 Hz, 2H), 4.75-4.70 (m, 2H), 4.65-4.60 (m, 2H), 3.75 (t, J=5.2 Hz, 2H), 3.17 (q, J=6.4 Hz, 2H), 1.85-1.76 (m, 3H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1/[CH:7]=[N:8]/[OH:9].[Cl:10]N1C(=O)CCC1=O.O>CN(C)C=O>[OH:9][N:8]=[C:7]([Cl:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: O/N=C/c1ccccn1
Solvent: O
Solvent: CN(C)C=O
Product: ON=C(Cl)c1ccccn1
Temperature: 60 °C
Reaction time: 1 h
Yield: 74.5 %

Procedure:
To a colorless, homogeneous solution of (E)-picolinaldehyde oxime (6.75 g, 55.3 mmol) in N,N-dimethylformamide (55 mL) at room temperature was added N-chlorosuccinimide (7.38 g, 55.3 mmol) portion-wise. After the addition of ˜⅕ of the NCS, the reaction mixture was immersed in an oil bath at 60° C., and the remaining NCS was added portion-wise over 1.5 h. After the addition was complete, the homogeneous reaction mixture was stirred for 60 min. at 60° C. and was then cooled to room temperature. Water (400 mL) was added, and the aqueous mixture was extracted with ether (3×200 mL). The organic layer was collected, washed with water (2×200 mL), washed with a saturated aqueous solution of brine (100 mL), and dried over anhydrous magnesium sulfate. Concentration under reduced pressure afforded N-hydroxypicolinimidoyl chloride (6.45 g, 41.2 mmol, 75% yield) as a tan solid. The compound had an HPLC retention time=0.515 min.—Column: CHROMOLITH® SpeedROD 4.6×50 mm (4 min.); Solvent A=10% MeOH, 90% H2O, 0.1% TFA; Solvent B=90% MeOH, 10% H2O, 0.1% TFA. LC/MS M+1=156.8. 1H NMR (400 MHz, CDCl3) δ ppm 7.37-7.43 (m, 1H), 7.80 (td, J=7.78, 1.76 Hz, 1H), 7.91-7.97 (m, 1H), 8.72 (d, J=4.02 Hz, 1H), and 9.85 (br. s., 1H).
Reaction SMILES: [C:1]([O:7][C:8]1[CH:9]=[C:10]([CH2:21][CH2:22][NH:23][C:24]([O:26][CH2:27]Cl)=[O:25])[CH:11]=[CH:12][C:13]=1[O:14][C:15](=[O:20])[C:16]([CH3:19])([CH3:18])[CH3:17])(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[C:29]([OH:37])(=[O:36])[C:30]1[CH:35]=[CH:34][CH:33]=[N:32][CH:31]=1.C(N(CC)CC)C>CN(C)C=O>[N:32]1[CH:33]=[CH:34][CH:35]=[C:30]([C:29]([O:37][CH2:27][O:26][C:24]([NH:23][CH2:22][CH2:21][C:10]2[CH:11]=[CH:12][C:13]([O:14][C:15](=[O:20])[C:16]([CH3:17])([CH3:19])[CH3:18])=[C:8]([O:7][C:1](=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3])[CH:9]=2)=[O:25])=[O:36])[CH:31]=1
Reactant: O=C(O)c1cccnc1
Reactant: CC(C)(C)C(=O)Oc1ccc(CCNC(=O)OCCl)cc1OC(=O)C(C)(C)C
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)C(=O)Oc1ccc(CCNC(=O)OCOC(=O)c2cccnc2)cc1OC(=O)C(C)(C)C
Reaction time: 96 h

Procedure:
The chloromethyl carbamate prepared in Example 112 (1.26 g, 3.04 mmol) was combined with 10 mL of dry dimethylformamide and that mixture was added to a premixed solution of nicotinic acid (375 mg, 3.04 mmol) and triethylamine (445 mL, 5% excess) in 15 mL of dry dimethylformamide at room temperature. The reaction mixture was stirred for 4 days, then the precipitate which formed was removed by filtration. The filtrate was evaporated to dryness and the residue was taken up in 20 mL of methylene chloride. That solution was washed twice with 10 mL portions of water. Removal of the solvent in vacuo afforded the title compound of the formula: ##STR143## The identity of the product was confirmed by NMR.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:6]=[C:7]([CH3:11])[CH:8]=[CH:9][CH:10]=1)(=[O:3])[CH3:2].[Br:12]N1C(=O)CCC1=O>ClC(Cl)(Cl)Cl.N(C(C)(C)C#N)=NC(C)(C)C#N>[C:1]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH2:11][Br:12])[CH:6]=1)(=[O:3])[CH3:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(=O)Oc1cccc(C)c1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: CC(=O)Oc1cccc(CBr)c1
Temperature: 25 °C
Yield: 100.4 %

Procedure:
A suspension of m-tolyl acetate (583 mg), N-bromosuccinimide (691 mg) and α,α′-azobis(isobutyronitrile) (13 mg) in tetrachloromethane (10 mL) was refluxed for 1 hour. The reaction mixture was cooled to room temperature, and the insoluble material was removed by filtration. The filtrate was concentrated to give the title compound (893 mg).