Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][CH:3]([NH:8][S:9]([C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1)(=[O:11])=[O:10])[C:4]([O:6][CH3:7])=[O:5].C(=O)([O-])[O-].[K+].[K+].Br[CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29].O>CN(C=O)C>[CH2:31]([O:30][C:28]([CH2:27][N:8]([S:9]([C:12]1[CH:13]=[CH:14][C:15]([O:18][CH3:19])=[CH:16][CH:17]=1)(=[O:11])=[O:10])[CH:3]([CH2:2][OH:1])[C:4]([O:6][CH3:7])=[O:5])=[O:29])[CH3:32]
Reactant: COC(=O)C(CO)NS(=O)(=O)c1ccc(OC)cc1
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CN(C(CO)C(=O)OC)S(=O)(=O)c1ccc(OC)cc1
Reaction time: 40 h
Yield: 54.1 %

Procedure:
The compound of Example 1 (7.2 g, 24.8 mmol) and anhydrous potassium carbonate (7 g, 50 mmol) were suspended in DMF (50 mL), and ethyl bromoacetate (4.5 Ml, 37 mmol) was added dropwise. After stirring for 40 hours, 50 ml of distilled water and 100 mL of ethyl acetated were introduced and stirred to separate layers. The supernatant was washed with a 1N HCl aqueous solution (50 mL), a saturated NaHCO3 aqueous solution (50 mL), and distilled water (100 mL), and it was dried and concentrated under reduced pressure. The mixture was separated using hexane and ethylacetate (2:1) in a silica gel column to obtain a yellow thick oily title compound (5.04 g, yield 54%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[C:9]2[C:17](OC)=[O:18])=[CH:4][CH:3]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3].C(C(C(C([O-])=O)O)O)([O-])=O.[K+].[Na+].C(OCC)C>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH:12]=[CH:11][C:10]([C:13]([F:14])([F:15])[F:16])=[C:9]2[CH2:17][OH:18])=[CH:6][CH:7]=1
Reactant: COC(=O)c1c(C(F)(F)F)ccn1-c1ccc(Cl)cc1
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: CCOCC
Product: OCc1c(C(F)(F)F)ccn1-c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of the product prepared in Step C (500 mg, 1.48 mmol, 1 eq) in THF (10 mL) at 0° C. under N2 was added LAH (1.48 mL of a 2 M solution in THF, 2.96 mmol, 2 eq). After 1 hr, saturated sodium potassium tartrate (5 mL) was added dropwise at first, the solution was warmed to room temperature, diethyl ether was added, the solution decanted from the solid, washed with brine, dried over MgSO4 and concentrated to yield (1-(4-chlorophenyl)-3-(trifluoromethyl)-1H-pyrrol-2-yl)methanol.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[C:12]([N:14]3[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]3)[CH:11]=[CH:10][C:9]=2[N+:20]([O-:22])=[O:21])[N:5]=[CH:4][N:3]=1.[CH3:23][C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][CH:31]=1)[CH2:27][NH2:28].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:23][C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][CH:31]=1)[CH2:27][NH:28][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[C:12]([N:14]3[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]3)[CH:11]=[CH:10][C:9]=2[N+:20]([O-:22])=[O:21])[N:5]=[CH:4][N:3]=1
Reactant: O=[N+]([O-])c1ccc(N2CCCCC2)cc1-c1cc(Cl)ncn1
Reactant: Cc1cccc(CN)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cccc(CNc2cc(-c3cc(N4CCCCC4)ccc3[N+](=O)[O-])ncn2)c1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
Into a 50-mL round-bottom flask, was placed a solution of 4-chloro-6-(2-nitro-5-(piperidin-1-yl)phenyl)pyrimidine 3.1b (500 mg, 1.57 mmol, 1.00 equiv) in N,N-dimethylformamide (10 mL), m-methylbenzylamine (285 mg, 2.36 mmol, 1.50 equiv), and potassium carbonate (650 mg, 4.71 mmol, 3.00 equiv). The resulting solution was stirred overnight at 80° C. The solids were filtered out. The resulting mixture was concentrated under vacuum. The residue was dissolved in 50 mL of ethyl acetate. The resulting mixture was washed with 2×50 mL of water. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column and eluted with ethyl acetate/petroleum ether (1:5). This resulted in 0.5 g (79%) of N-(3-methylbenzyl)-6-(2-nitro-5-(piperidin-1-yl)phenyl)pyrimidin-4-amine as yellow oil.
Reaction SMILES: [NH:1]([CH2:5][CH2:6][OH:7])[CH2:2][CH2:3][OH:4].O.[O:9]=[C:10]1[C:19](=[O:20])[NH:18][C:17]2[C:12](=[CH:13][CH:14]=[C:15]([S:21](Cl)(=[O:23])=[O:22])[CH:16]=2)[NH:11]1>>[OH:4][CH2:3][CH2:2][N:1]([CH2:5][CH2:6][OH:7])[S:21]([C:15]1[CH:16]=[C:17]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10](=[O:9])[C:19](=[O:20])[NH:18]2)(=[O:22])=[O:23]
Reactant: OCCNCCO
Reactant: O=c1[nH]c2ccc(S(=O)(=O)Cl)cc2[nH]c1=O
Solvent: O
Product: O=c1[nH]c2ccc(S(=O)(=O)N(CCO)CCO)cc2[nH]c1=O
Reaction time: 16 h
Yield: 51 %

Procedure:
To a solution of 10.51 g (0.1 mole) of diethanolamine in 40 ml of water 5.21 g (0.02 mole) of 1,2,3,4-tetrahydro-2,3-dioxo-6-quinoxalinesulfonyl chloride are added in small portions, under stirring. The mixture is stirred at room temperature for 10 hours and allowed to stand for 16 hours. The separated crystals are filtered, washed successively with water and acetone, dried, dissolved in a slight amount of hot dimethyl sulfoxide and precipitated from the solution with water. Thus 3.37 g (51%) of N.N-bis-(2-hydroxyethyl)-1,2,3,4-tetrahydro-2,3-dioxo-6-quinoxaline sulfonamide are obtained, m.p.: 272-276° C.
Reaction SMILES: [CH2:1]([Si:4]([CH3:7])([CH3:6])[CH3:5])[CH:2]=[CH2:3].[C:8]1([PH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>>[CH3:5][Si:4]([CH2:1][CH2:2][CH2:3][P:14]([C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([CH3:7])[CH3:6]
Reactant: c1ccc(Pc2ccccc2)cc1
Reactant: C=CC[Si](C)(C)C
Product: C[Si](C)(C)CCCP(c1ccccc1)c1ccccc1
Yield: 50 %

Procedure:
A mixture of 22.8 g (0.2 mole) allyl trimethyl silane and 37.2 g (0.2 mole) diphenyl phosphine was reacted for 158 hours in the manner described in Example 1. A subsequent fractional distillation, yielded the desired pure adduct as a clear, colorless liquid. The distillation yield was 50%. The product had a boiling point of 150° C. at 0.10 mm.
Reaction SMILES: [CH3:1][NH:2][NH2:3].Cl[CH2:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[S:15][CH:16]=[C:17]([C:19]3[CH2:23][CH:22]([C:24]4[C:29]([F:30])=[CH:28][CH:27]=[CH:26][C:25]=4[F:31])[O:21][N:20]=3)[N:18]=2)[CH2:10][CH2:9]1)=[O:7]>O1CCCC1>[F:31][C:25]1[CH:26]=[CH:27][CH:28]=[C:29]([F:30])[C:24]=1[CH:22]1[O:21][N:20]=[C:19]([C:17]2[N:18]=[C:14]([CH:11]3[CH2:10][CH2:9][N:8]([C:6](=[O:7])[CH2:5][N:2]([CH3:1])[NH2:3])[CH2:13][CH2:12]3)[S:15][CH:16]=2)[CH2:23]1
Reactant: CNN
Reactant: O=C(CCl)N1CCC(c2nc(C3=NOC(c4c(F)cccc4F)C3)cs2)CC1
Solvent: C1CCOC1
Product: CN(N)CC(=O)N1CCC(c2nc(C3=NOC(c4c(F)cccc4F)C3)cs2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of methyl hydrazine (532 μL, 10.0 mmol) in tetrahydrofuran (1 mL) at 0° C. was added dropwise a solution of 2-chloro-1-[4-[4-[5-(2,6-difluorophenyl)-4,5-dihydro-3-isoxazolyl]-2-thiazolyl]-1-piperidinyl]ethanone (i.e. the product of Example 2, Step A) (425 mg, 1.0 mmol) in tetrahydrofuran (5 mL). The reaction mixture was stirred at room temperature overnight, and then concentrated under reduced pressure. The resulting residue was dissolved in dichloromethane, washed with water and saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered and concentrated under reduced pressure to provide the title compound as an oil (0.59 g weight including residual tetrahydrofuran), which was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][C:5]2[C:6]3[C:7](=[CH:18][NH:19][CH:20]=3)[CH2:8][N:9]=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[F:17])[C:4]=2[CH:3]=1.[CH3:23]C(C)([O-])C.[K+].CI.O>CN(C)C=O>[Cl:1][C:2]1[CH:22]=[CH:21][C:5]2[C:6]3[C:7](=[CH:18][N:19]([CH3:23])[CH:20]=3)[CH2:8][N:9]=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[F:17])[C:4]=2[CH:3]=1
Reactant: CC(C)(C)[O-]
Reactant: Fc1ccccc1C1=NCc2c[nH]cc2-c2ccc(Cl)cc21
Agent: [K+]
Solvent: O
Solvent: CI
Solvent: CN(C)C=O
Product: Cn1cc2c(c1)-c1ccc(Cl)cc1C(c1ccccc1F)=NC2
Temperature: 0 °C

Procedure:
In one portion, 0.7 g (2.2 mmole) of 8-chloro-6-(2-fluorophenyl)-2H,4H-pyrrolo[3,4-d][2]benzazepine was added to a solution of 0.3 g (2.6 mmole) of potassium t-butoxide in 30 ml of dry dimethylformamide which was cooled to 0° C. After stirring for 15 minutes 1.0 ml (16 mmole) of methyl iodide was added, and the mixture was allowed to warm to room temperature. Water was added, and the mixture was extracted with methylene chloride. The methylene chloride solution was washed with water, dried over anhydrous sodium sulfate, and concentrated at reduced pressure to give a yellow oil. Purification by column chromatography (silica gel, 20 g; eluent 5% ether in methylene chloride) gave a tan solid (mp 142°-144° C.). Recrystallization from a mixture of ether and petroleum ether gave cream colored prisms, mp 144°-146° C.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][C:18]([F:21])([F:20])[F:19])=[CH:13][CH:12]=2)=[CH:6][CH:5]=1)([O-])=O>[Pt].C(O)C>[F:19][C:18]([F:20])([F:21])[O:17][C:14]1[CH:13]=[CH:12][C:11]([O:10][C:7]2[CH:8]=[CH:9][C:4]([NH2:1])=[CH:5][CH:6]=2)=[CH:16][CH:15]=1
Reactant: O=[N+]([O-])c1ccc(Oc2ccc(OC(F)(F)F)cc2)cc1
Agent: [Pt]
Solvent: CCO
Product: Nc1ccc(Oc2ccc(OC(F)(F)F)cc2)cc1
Reaction time: 3 h
Yield: 94.1 %

Procedure:
A mixture of 1-nitro-4-[4-(trifluoromethoxy)phenoxy]benzene (4.18 g, 13.970 mmol), 10% platinum-activated charcoal (270 mg) and ethanol (40 ml) was stirred for 3 hours under hydrogen atmosphere. The reaction mixture was filtered through celite. The residue obtained by concentration of the filtrate under reduced pressure was purified by column chromatography on silica gel (n-hexane:ethyl acetate=3:1) to give the title compound (3.54 g, 93.9%) as a yellow oil.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:16]([C:17]3[CH:22]=[CH:21][N:20]=[C:19]([NH:23][C:24]4[CH:33]=[C:32]5[C:27]([CH2:28][CH2:29][N:30]([CH3:34])[CH2:31]5)=[CH:26][CH:25]=4)[N:18]=3)=[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][N:10]3[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[S:35]1[CH:39]=[CH:38][CH:37]=[C:36]1[CH2:40][C:41](Cl)=[O:42]>>[CH3:34][N:30]1[CH2:29][CH2:28][C:27]2[C:32](=[CH:33][C:24]([NH:23][C:19]3[N:18]=[C:17]([C:16]4[C:8]([C:4]5[CH:3]=[C:2]([NH:1][C:41](=[O:42])[CH2:40][C:36]6[S:35][CH:39]=[CH:38][CH:37]=6)[CH:7]=[CH:6][CH:5]=5)=[N:9][N:10]5[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=45)[CH:22]=[CH:21][N:20]=3)=[CH:25][CH:26]=2)[CH2:31]1
Reactant: CN1CCc2ccc(Nc3nccc(-c4c(-c5cccc(N)c5)nn5ccccc45)n3)cc2C1
Reactant: O=C(Cl)Cc1cccs1
Product: CN1CCc2ccc(Nc3nccc(-c4c(-c5cccc(NC(=O)Cc6cccs6)c5)nn5ccccc45)n3)cc2C1
Yield: 89 %

Procedure:
The title compound was prepared from N-{4-[2-(3-aminophenyl)pyrazolo[1,5-a]pyridin-3-yl]-2-pyrimidinyl}-2-methyl-1,2,3,4-tetrahydro-7-isoquinolinamine and 2-thiopheneacetyl chloride using acylation conditions described in Example 1, Step F to generate the product in 89% yield. 1H NMR (400 MHz, DMSO-d6): δ 2.31 (s, 3H), 2.57 (t, 2H, J=5.7 Hz), 2.74 (t, 2H, J=5.6 Hz), 3.38 (s, 2H), 3.88 (s, 2H), 6.47 (d, 1H, J=5.3 Hz), 6.97 (m, 3H), 7.13 (t, 1H, J=6.8 Hz), 7.27 (d, 1H, J=7.5 Hz), 7.38-7.50 (m, 5H), 7.75 (d, 1H, J=8.1 Hz), 7.90 (s, 1H), 8.23 (d, 1H, J=5.3 Hz), 8.46 (d, 1H, J=8.6 Hz), 8.83 (d, 1H, J=7.0 Hz), 9.43 (s, 1H), 10.36 (s, 1H). ES-LC/MS m/z=572 [M+H]+.
Reaction SMILES: [CH:1]1[C:10]2[CH:9]=[CH:8][CH:7]=[C:6]([SH:11])[C:5]=2[CH:4]=[CH:3][N:2]=1.Cl[C:13]1[C:24]([N+:25]([O-:27])=[O:26])=[CH:23][C:16]2[N:17]([CH2:21][CH3:22])[C:18]([CH3:20])=[N:19][C:15]=2[CH:14]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH2:21]([N:17]1[C:16]2[CH:23]=[C:24]([N+:25]([O-:27])=[O:26])[C:13]([S:11][C:6]3[CH:7]=[CH:8][CH:9]=[C:10]4[C:5]=3[CH:4]=[CH:3][N:2]=[CH:1]4)=[CH:14][C:15]=2[N:19]=[C:18]1[CH3:20])[CH3:22]
Reactant: CCn1c(C)nc2cc(Cl)c([N+](=O)[O-])cc21
Reactant: Sc1cccc2cnccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCn1c(C)nc2cc(Sc3cccc4cnccc34)c([N+](=O)[O-])cc21
Temperature: 130 °C
Reaction time: 3 h
Yield: 42.5 %

Procedure:
5-Isoquinolinethiol 500 mg (3.1 mmol) was dissolved in DMF 20 ml, 5-chloro-1-ethyl-2-methyl-6-nitro-1H-benzo[d]imidazole 910 mg (3.1 mmol) and potassium carbonate 1.29 g (9.3 mmol) were added, and the mixture was stirred for 3 hours at 130° C. The reaction mixture was concentrated under reduced pressure, the residue was crystallized with ethyl acetate, and 1-ethyl-5-(5-isoquinolylsulfanyl)-2-methyl-6-nitro-1H-benzo[d]imidazole 480 mg (42.3%) was obtained.
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH:13]2[O:18][C:17]3[CH:19]=[C:20]([N+:23]([O-:25])=[O:24])[CH:21]=[CH:22][C:16]=3[O:15][CH2:14]2)(=O)=O)=CC=1.[CH2:26]([NH2:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>CCCCCCC>[CH2:26]([NH:33][CH2:12][CH:13]1[O:18][C:17]2[CH:19]=[C:20]([N+:23]([O-:25])=[O:24])[CH:21]=[CH:22][C:16]=2[O:15][CH2:14]1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: Cc1ccc(S(=O)(=O)OCC2COc3ccc([N+](=O)[O-])cc3O2)cc1
Reactant: NCc1ccccc1
Solvent: CCCCCCC
Product: O=[N+]([O-])c1ccc2c(c1)OC(CNCc1ccccc1)CO2
Temperature: 95 °C
Yield: 98.5 %

Procedure:
A 200 mL round bottomed flask equipped with a magnetic stir bar is charged with [7-nitro-2,3-dihydro-1,4-benzodioxin-2-yl]methyl 4-methylbenzenesulfonate (40.0 g, 110 mmol) and benzylamine (35.2 g, 328 mmol). The mixture is heated to 95° C. for 3 h, and then heating is discontinued. Once the temperature of the solution is 80° C., heptane (300 mL) is added slowly, with rapid stirring. Once the suspension is cooled to rt, the solid is collected by vacuum filtration, and the filter cake is washed several times with heptane and suction dried to give the title compound (32.55 g, 100%) as a yellow powder. LCMS (Basic Method): 1.93 min, 301 (M+H)+. 1H NMR (300 MHz, DMSO-d6) δ 7.77-7.70 (m, 1H), 7.47-7.18 (m, 6H), 7.10-7.06 (m, 1H), 4.47 (dd, J=2.5, 11.5 Hz, 1H), 4.37-4.29 (m, 1H), 4.15 (dd, J=7.1, 11.5 Hz, 1H), 3.73 (s, 2H), 2.43 (br s, 1H), 2.82-2.70 (m, 2H).
Reaction SMILES: [CH3:1][NH2:2].[NH2:3][C:4]1[C:5]([F:27])=[CH:6][C:7]([F:26])=[C:8]([N:10]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17](F)[C:18]=3[F:20])[C:13](=[O:22])[C:12]([C:23]([OH:25])=[O:24])=[CH:11]2)[CH:9]=1>N1C=CC=CC=1>[NH2:3][C:4]1[C:5]([F:27])=[CH:6][C:7]([F:26])=[C:8]([N:10]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([NH:2][CH3:1])[C:18]=3[F:20])[C:13](=[O:22])[C:12]([C:23]([OH:25])=[O:24])=[CH:11]2)[CH:9]=1
Reactant: CN
Reactant: Nc1cc(-n2cc(C(=O)O)c(=O)c3ccc(F)c(F)c32)c(F)cc1F
Solvent: c1ccncc1
Product: CNc1ccc2c(=O)c(C(=O)O)cn(-c3cc(N)c(F)cc3F)c2c1F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A 40% aqueous solution (100 mg) of methylamine and 1-(5-amino-2,4-difluorophenyl)-7,8-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (100 mg) were added to pyridine (2 ml), and the mixture was stirred at room temperature for 2 hours. The solvent was distilled off under reduced pressure, ethanol (2 ml) was added to the residue, and solids were collected by filtration to obtain the title compound (40 mg) as an orange powder.
Reaction SMILES: Br[C:2]([CH3:9])([CH3:8])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[CH2:10]([SH:13])[CH:11]=[CH2:12].[OH-].[K+]>C(O)C>[CH2:6]([O:5][C:3](=[O:4])[C:2]([S:13][CH2:10][CH:11]=[CH2:12])([CH3:9])[CH3:8])[CH3:7]
Reactant: CCOC(=O)C(C)(C)Br
Reactant: C=CCS
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: C=CCSC(C)(C)C(=O)OCC
Yield: 35 %

Procedure:
Ethyl 2-bromoisobutyrate (40.0 g, 0.205 mole), allyl mercaptan (16.8 g, 0.0226 mole), potassium hydroxide (14.4 g, 0.226 mole), ethyl alcohol (100 g) were combined and reaction mixture was refluxed for six hours prior to quenching. Crude yield: 79.3%; Distilled yield: 35.0%.
Reaction SMILES: [C:1]1(B(O)O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[C:11]1[CH:12]=[C:13]2[O:19][C:18]([N:20]3[CH:26]4[CH2:27][CH2:28][N:23]([CH2:24][CH2:25]4)[CH2:22][CH2:21]3)=[N:17][C:14]2=[N:15][CH:16]=1>>[C:1]1([C:11]2[CH:12]=[C:13]3[O:19][C:18]([N:20]4[CH:26]5[CH2:25][CH2:24][N:23]([CH2:28][CH2:27]5)[CH2:22][CH2:21]4)=[N:17][C:14]3=[N:15][CH:16]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Brc1cnc2nc(N3CCN4CCC3CC4)oc2c1
Reactant: OB(O)c1ccccc1
Product: c1ccc(-c2cnc3nc(N4CCN5CCC4CC5)oc3c2)cc1
Yield: 27 %

Procedure:
The title compound was prepared according to the procedure detailed in Example 44 using phenyl boronic acid and 4-(6-bromo-oxazolo[4,5-b]pyridin-2-yl)-1,4-diaza-bicyclo[3.2.2]nonane (prepared in Example 47) in 27% yield: 1H NMR (CDCl3, 400 MHz) δ 8.48 (d, 1H, J=2.1 Hz), 7.62 (d, 1H, J=2.1 Hz), 7.57-7.55 (m, 2H), 7.47-7.43 (m, 2H), 7.40-7.34 (m, 1H), 4.62 (br s, 1H), 4.00 (t, 2H, J=5.8 Hz), 3.20-3.15 (m, 4H), 3.08-3.01 (m, 2H), 2.19-2.08 (m, 2H), 1.90-1.81 (m, 2H); MS (Cl) m/z 321.2 (M+1).
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[N:13]=[C:12](Cl)[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([N+:15]([O-:17])=[O:16])[CH:10]=2)[N:5]=1.C(O)(=[O:20])C>>[Cl:3][C:4]1[NH:13][C:12](=[O:20])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([N+:15]([O-:17])=[O:16])[CH:10]=2)[N:5]=1
Reactant: O=[N+]([O-])c1ccc2nc(Cl)nc(Cl)c2c1
Reactant: CC(=O)O
Agent: [Na+]
Agent: [OH-]
Product: O=c1[nH]c(Cl)nc2ccc([N+](=O)[O-])cc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 89.6 %

Procedure:
Aqueous 2M NaOH (22.2 mL, 44.4 mmol) was added to 2,4-dichloro-6-nitro-quinazoline (3.61 g, 14.8 mmol). The mixture was sonicated, stirred at room temperature for 3 h, and filtered, rinsing with water (60 mL). Acetic acid (3.81 mL, 66.6 mmol) was added to the filtrate to yield a precipitate, which was collected and dried in a vacuum oven to yield the titled compound (2.99 g, 90% yield). This compound did not yield MS data. 1H NMR (400 MHz, CDCl3): 9.07 (s, 1H), 8.56 (d, J=8.9 Hz, 1H), 7.78 (d, J=8.8 Hz, 1H).
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH2:8][CH3:9])=[C:6]([NH:10][C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])[CH:5]=[CH:4][C:3]=1[OH:17].Cl.[CH:19](OCC)(OCC)OCC>CO>[CH2:8]([C:7]1[C:2]2[N:1]=[CH:19][O:17][C:3]=2[CH:4]=[CH:5][C:6]=1[NH:10][C:11](=[O:16])[C:12]([F:13])([F:14])[F:15])[CH3:9]
Reactant: CCOC(OCC)OCC
Reactant: CCc1c(NC(=O)C(F)(F)F)ccc(O)c1N
Agent: Cl
Solvent: CO
Product: CCc1c(NC(=O)C(F)(F)F)ccc2ocnc12
Temperature: 90 °C

Procedure:
A mixture of 2-amino-3-ethyl-4-trifluoroacetamidophenol (18.15 mmol) and concentrated hydrochloric acid (45 mL) in methanol (5.2 mL) is treated with triethyl orthoformate (27.2 mmol). A simple distillation apparatus is attached and the mixture is heated with an oil bath to 90° C. and methanol is distilled from the reaction. The reaction mixture is cooled to room temperature and distributed between ethyl ether (200 mL) and water (20 mL). The ether layer is washed with a 0.1 M aqueous solution of sodium hydroxide (20 mL), dried over magnesium sulfate and concentrated under reduced pressure to yield 4-ethyl-5-trifluoroacetamidobenzoxazole.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=CC(S(O)(=O)=O)=CC=1.[Cl:12][CH2:13][CH:14]([OH:17])[CH2:15][OH:16]>CC(C)=O>[Cl:12][CH2:13][CH:14]1[CH2:15][O:16][C:1]([CH3:6])([CH3:11])[O:17]1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: OCC(O)CCl
Solvent: CC(C)=O
Product: CC1(C)OCC(CCl)O1
Temperature: 25 °C
Reaction time: 12 h
Yield: 8177 %

Procedure:
p-Toluenesulfonic acid (1.79 g) was added to a mixture of 3-chloro-1,2-propanediol (104.49 g, 0.945 mol) and acetone (1500 ml) and the resulting mixture was stirred for 12 hours at 25° C. After completion of the reaction, acetone was removed in vacuo and the crude product was distilled to give 128.01 g of 4-chloromethyl-2,2-dimethyl-1,3-dioxolane (yield 89%, b.p. 45° C. at 5 mmHg).
Reaction SMILES: [CH2:1]([N:8]([CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH:9]([CH:13]([O:18][C:19]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=1[N+:26]([O-])=O)[C:14]([F:17])([F:16])[F:15])[C:10]([OH:12])=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CO.[Ni]>[NH2:26][C:20]1[CH:21]=[C:22]([F:25])[CH:23]=[CH:24][C:19]=1[O:18][CH:13]([C:14]([F:15])([F:16])[F:17])[CH:9]([N:8]([CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:10]([OH:12])=[O:11]
Reactant: O=C(O)C(C(Oc1ccc(F)cc1[N+](=O)[O-])C(F)(F)F)N(Cc1ccccc1)Cc1ccccc1
Agent: [Ni]
Solvent: CO
Product: Nc1cc(F)ccc1OC(C(C(=O)O)N(Cc1ccccc1)Cc1ccccc1)C(F)(F)F

Procedure:
5.00 g (10.2 mmol) (2S,3S and 2R,3R)-2-dibenzylamino-4,4,4-trifluoro-3-(4-fluoro-2-nitro-phenoxy)-butyric acid acid in 300 ml methanol were hydrogenated with 1.19 g Raney-Nickel. Filtration and removal of the solvent by distillation yielded 4.19 g (89%) racemic (2S,3S and 2R,3R)-3-(2-amino-4-fluoro-phenoxy)-2-dibenzylamino-4,4,4-trifluoro-butyric acid as light yellow oil, MS m/e (%): 461.2 (M−H+, 100).
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:22])[C:8]=2[NH:12][C:13](=[O:21])[CH2:14][CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)[N:3]=1.[NH:23]1[CH2:28][CH2:27][CH:26]([CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH2:25][CH2:24]1>>[Cl:22][C:7]1[C:8]([NH:12][C:13](=[O:21])[CH2:14][CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)=[C:9]2[C:4](=[CH:5][CH:6]=1)[N:3]=[C:2]([N:23]1[CH2:28][CH2:27][CH:26]([CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH2:25][CH2:24]1)[CH:11]=[CH:10]2
Reactant: O=C(CC1CCCCC1)Nc1c(Cl)ccc2nc(Cl)ccc12
Reactant: CCOC(=O)CC1CCNCC1
Product: CCOC(=O)CC1CCN(c2ccc3c(NC(=O)CC4CCCCC4)c(Cl)ccc3n2)CC1
Yield: 53.6 %

Procedure:
Prepared according to the method of example 30, using N-(2,6-dichloro-5-quinolinyl)-cyclohexaneacetamide (prepared as in Example 1(a)) (200 mg) and 4-piperidineacetic acid, ethyl ester (305 mg). The reaction mixture was evaporated to dryness, the residue was suspended in methanol and the solid collected by filtration to afford the sub-title compound (150 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[F:10].[C:11]([O:15][CH3:16])(=[O:14])[CH:12]=[CH2:13].N12CCN(CC1)CC2>C(#N)C>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]([OH:7])[C:12](=[CH2:13])[C:11]([O:15][CH3:16])=[O:14])=[CH:4][C:3]=1[F:10]
Reactant: C=CC(=O)OC
Reactant: O=Cc1ccc(Cl)c(F)c1
Agent: C1CN2CCN1CC2
Solvent: CC#N
Product: C=C(C(=O)OC)C(O)c1ccc(Cl)c(F)c1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of 4-chloro-3-fluorobenzaldehyde (50.0 g) and methyl acrylate (42.6 mL) in acetonitrile (158 mL) was added 1,4-diazabicyclo[2.2.2]octane (10.6 g), and the mixture was stirred at room temperature for 3 days. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (hexane/ethyl acetate) to give the title compound (69.1 g).
Reaction SMILES: [OH:1][C@@H:2]([C:13]([O:26][CH3:27])([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:3]([O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:4].C(O)(=O)[CH2:29][OH:30]>ClCCl.C1(C)C=CC(S(O)(=O)=O)=CC=1>[C:20]1([C:13]2([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[C@@H:2]([C:3]([O:5][CH2:6][C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)=[O:4])[O:1][C:29](=[O:30])[CH2:27][O:26]2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=C(O)CO
Reactant: COC(c1ccccc1)(c1ccccc1)[C@H](O)C(=O)OCc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Product: O=C1COC(c2ccccc2)(c2ccccc2)[C@@H](C(=O)OCc2ccccc2)O1
Yield: 54 %

Procedure:
38 g (100 mmol) of the benzyl (S)-2-hydroxy-3-methoxy-3,3-diphenylpropionate were added to 9.8 g (130 mmol) of glycolic acid, and the mixture was stirred with 300 mg of anhydrous para-toluenesulfonic acid at 70° C. on a rotary evaporator under reduced pressure for 20 minutes. The content of the flask was taken up in dichloromethane, the acid was separated off using sodium hydrogen sulfate solution, the organic phase was separated off and dried and the solvent was distilled off. The residue was recrystallized from ether, and 21 g (54 mmol) of product were isolated.