Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[C:3]([O:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[C:10]([F:15])[CH:9]=1)(=[O:5])[CH3:4].[CH3:16][O:17][CH2:18][CH2:19][O:20][CH2:21]Cl.O>O1CCCC1.CN(C)C=O>[C:3]([O:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:16][O:17][CH2:18][CH2:19][O:20][CH3:21])=[C:10]([F:15])[CH:9]=1)(=[O:5])[CH3:4]
Reactant: COCCOCCl
Reactant: CC(=O)OCc1ccc(O)c(F)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: O
Product: COCCOCOc1ccc(COC(C)=O)cc1F
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 65.6 %

Procedure:
2.6 g (65.1 mmol) of 60% sodium hydride is added in portions to a solution at 0° C. of 10 g (54.3 mmol) of (3-fluoro-4-hydroxy-phenyl)-methyl acetate diluted in 50 ml of tetrahydrofuran and 50 ml of dimethylformamide. The reaction mixture is stirred at room temperature for 45 minutes and then 6.8 ml (59.7 mmol) of 2-methoxyethoxymethyl chloride is added dropwise. The reaction mixture is stirred at room temperature for 2 hours and then the reaction mixture is treated by adding water and extracted with ethyl acetate. The organic phases are combined, washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered, and evaporated. The raw product is purified by silica column chromatography, eluted with a heptane/ethyl acetate mixture 70/30. 9.7 g (65%) of [3-fluoro-4-(2-methoxy-ethoxymethoxy)-phenyl]-methyl acetate is obtained in the form of a colorless oil.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.[C:10]([OH:14])(=[O:13])[CH:11]=[CH2:12].C(NCC)C.Cl>[Pd].CN(C)C=O.C(OCC)C>[CH3:9][O:8][C:5]1[CH:6]=[CH:7][C:2]([CH:12]=[CH:11][C:10]([OH:14])=[O:13])=[CH:3][CH:4]=1
Reactant: COc1ccc(I)cc1
Reactant: C=CC(=O)O
Agent: [Pd]
Agent: Cl
Solvent: CCOCC
Solvent: CCNCC
Solvent: CN(C)C=O
Product: COc1ccc(C=CC(=O)O)cc1
Temperature: 140 °C
Reaction time: 4 h
Yield: 65 %

Procedure:
A mixture of 2.34 g (10 mmol) of p-iodoanisole, 0.756 g (10.5 mmol) of acrylic acid, 0.803 g (11 mmol) of diethylamine and 16 mg of palladium on charcoal in 4 ml of dimethylformamide is stirred at 140° C. for 4 hours. Subsequently, the mixture is worked up by adding diethyl ether and 2N hydrochloric acid, washing the separated organic phase with water and subsequently drying over anhydrous sodium sulphate, concentrating the organic phase under reduced pressure and recrystallizing the solid residue from ethanol. In this manner there is obtained p-methoxycinnamic acid in 65% yield. M.p. 170° C. (no depression upon mixing with a pure sample of this acid); 1H-NMR (CDCl3, 200 MHz): 3.85 ppm (s, 3H), 6.33 ppm (d, 15.5 Hz, 1H), 6.68-6.97 ppm (duplettoid, m 1H), 7.47-7.56 ppm (dupletteid m, 1H), 7.75 ppm (d, 15.5 Hz, 1H).
Reaction SMILES: O.[Na+].[Cl-].CN1[C@@H]2C[C@@H:11]([O:13][C:14]([CH:16]([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)CO)=[O:15])C[C@H]1CC2>>[C:14]([O:13][CH3:11])(=[O:15])[CH2:16][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:14][CH2:16][CH2:19][CH2:24][CH2:23][CH2:22][CH2:21][CH3:20]
Reactant: CN1[C@@H]2CC[C@H]1C[C@@H](OC(=O)C(CO)c1ccccc1)C2
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Product: CCCCCCCCCCCCCCCC(=O)OC

Procedure:
Basal gastric acidity was determined by pyloric ligation under ether anaesthesia followed by gastric lavage with normal saline. Except for the control group, all the rats received 3 doses (1, 3 & 5 mg/kg) of the said compound and standard antagonist atropine (0.01, 0.05 & 0.1 mg/kg) subcutaneously 15 minutes prior to pyloric ligation. Three hours later the animals were killed and the stomach was tied at the oesophageal junction and removed. The contents were collected by cutting along the greater curvature and the free acidity was determined by titration against 0.01 normal NaOH using Topfers reagent as indicator.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH:10]=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:12]1([CH2:18][CH2:19][CH2:20][Mg]Br)[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1.[Cl-].[NH4+]>C(OCC)C>[CH:12]1([CH2:18][CH2:19][CH2:20][CH:10]([CH2:9][O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[OH:11])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: O=CCOCc1ccccc1
Reactant: Br[Mg]CCCC1CCCCC1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Product: OC(CCCC1CCCCC1)COCc1ccccc1
Reaction time: 0.5 h
Yield: 68 %

Procedure:
A solution of 1.01 g (6.73 mmol) of 2-benzyloxyacetaldehyde in 6 ml of diethyl ether was added dropwise over a period of 3 minutes to 14 ml (8.6 mmol) of a 0.6M diethyl ether solution of 3-cyclohexylpropylmagnesium bromide, whilst ice-cooling, and the resulting mixture was stirred for 30 minutes at the same temperature and then for 10 minutes at room temperature. In order to stop the reaction, a saturated aqueous solution of ammonium chloride was added to the reaction mixture. The reaction mixture was then diluted with diethyl ether, and the diluted mixture was washed with water and with a saturated aqueous solution of sodium chloride, in that order. The organic phase was dried over anhydrous magnesium sulfate, and the solvent was removed by distillation under reduced pressure. The resulting residue was purified by column chromatography through 150 g of silica gel, using a 1:3 by volume mixture of ethyl acetate and hexane as the eluent, to give 1.27 g (yield 68%) of the title alcohol derivative as an oil.
Reaction SMILES: [CH3:1][N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:12]([OH:14])=[O:13])[C:3]1=[O:15].C(Cl)(=O)C(Cl)=O.[C:22]1(=O)[CH2:27][CH2:26][CH2:25][C:24](=[O:28])[CH2:23]1.C(N(CC)CC)C>ClCCl.CN(C)C=O>[CH3:1][N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:12]([O:14][C:22]2[CH2:27][CH2:26][CH2:25][C:24](=[O:28])[CH:23]=2)=[O:13])[C:3]1=[O:15]
Reactant: Cn1c(=O)c(C(=O)O)nc2ccccc21
Reactant: O=C1CCCC(=O)C1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cn1c(=O)c(C(=O)OC2=CC(=O)CCC2)nc2ccccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 93.9 %

Procedure:
4.6 g (22.5 mmol) of 1-methyl-2-oxo-1,2-dihydroquinoxaline-3-carboxylic acid was dissolved in dichloromethane (200 mL), and N,N-dimethylformamide (0.5 mL) and 4.3 g (33.9 mmol) of oxalyl chloride were added thereto. The mixture was stirred for 1 hour at room temperature. The reaction mixture was concentrated under reduced pressure, and the obtained residue was dissolved in dichloromethane (100 mL). This solution was added dropwise at room temperature to a solution prepared by dissolving 2.8 g (25.0 mmol) of 1,3-cyclohexanedione and 2.7 g (26.7 mmol) of triethylamine in dichloromethane (100 mL). The mixture was stirred for 1 hour at room temperature, and then, the reaction mixture was washed with water, and dried over anhydrous sodium sulfate. The inorganic matter was separated by filtration, and then the solvent was distilled off under reduced pressure, to obtain 6.3 g (yield 94%) of 3-oxo-1-cyclohexenyl 1-methyl-2-oxo-1,2-dihydroquinoxaline-3-carboxylate as a yellow solid.
Reaction SMILES: C[O:2][C:3](=[O:23])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([NH:12][C:13](=[O:22])[CH:14]=[CH:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:7]=1.[OH-].[Na+]>O1CCCC1.O>[C:16]1([CH:15]=[CH:14][C:13]([NH:12][C:8]2[CH:7]=[C:6]([CH:11]=[CH:10][CH:9]=2)[O:5][CH2:4][C:3]([OH:23])=[O:2])=[O:22])[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: COC(=O)COc1cccc(NC(=O)C=Cc2ccccc2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)COc1cccc(NC(=O)C=Cc2ccccc2)c1
Temperature: 35 °C
Reaction time: 3 h
Yield: 91.7 %

Procedure:
To a suspension of [3-(3-phenyl-acryloylamino)-phenoxy]-acetic acid methyl ester (8) (0.345 g, 1.1 mmol) in tetrahydrofuran (6 ml) a solution of NaOH (0.130 g, 3.3 mmol) in water (6 ml) was added and the resulting mixture was stirred for 3 hours at 35° C. Tetrahydrofuran was evaporated and the remaining water mixture was acidified with 2N HCl to pH 3. The precipitate was filtered off and dried to give 0.300 g (92%) of the title product 9, which was used in the next step without an additional purification.
Reaction SMILES: [C:1]([CH2:3][C:4]([N:6]([CH:18]1[CH2:20][CH2:19]1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([I:16])=[CH:12][C:11]=1[F:17])=[O:8])=[O:5])#[N:2].[OH-].[Na+]>O>[NH2:2][C:1]1[N:9]([C:10]2[CH:15]=[CH:14][C:13]([I:16])=[CH:12][C:11]=2[F:17])[C:7](=[O:8])[N:6]([CH:18]2[CH2:19][CH2:20]2)[C:4](=[O:5])[CH:3]=1
Reactant: N#CCC(=O)N(C(=O)Nc1ccc(I)cc1F)C1CC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Nc1cc(=O)n(C2CC2)c(=O)n1-c1ccc(I)cc1F
Temperature: 80 °C
Yield: 92.7 %

Procedure:
To 1-(2-cyano-acetyl)-1-cyclopropyl-3-(2-fluoro-4-iodo-phenyl)-urea 74 (192 g) were added water (962 ml) and 2N aqueous sodium hydroxide solution (24.9 ml), and the mixture was stirred with heating at 80° C. for 1 hr. After allowing to cool to room temperature, the crystals were collected by filtration and dried to give 6-amino-3-cyclopropyl-1-(2-fluoro-4-iodo-phenyl)-1H-pyrimidine-2,4-dione 75 (178 g, yield from 48, 88%) as pale-yellow crystals.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH:11]([N:13]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([Br:22])[CH:17]=2)[CH3:14])[CH2:10][CH:9]1[C:23]([OH:25])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[N:40]1([C:46]2[CH:53]=[CH:52][CH:51]=[CH:50][C:47]=2[C:48]#[N:49])[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1.CCN(CC)CC>CN(C=O)C>[CH2:1]([N:8]1[CH2:12][CH:11]([N:13]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([Br:22])[CH:17]=2)[CH3:14])[CH2:10][CH:9]1[C:23]([N:43]1[CH2:42][CH2:41][N:40]([C:46]2[CH:53]=[CH:52][CH:51]=[CH:50][C:47]=2[C:48]#[N:49])[CH2:45][CH2:44]1)=[O:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN(Cc1cccc(Br)c1)C1CC(C(=O)O)N(Cc2ccccc2)C1
Reactant: N#Cc1ccccc1N1CCNCC1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: CN(Cc1cccc(Br)c1)C1CC(C(=O)N2CCN(c3ccccc3C#N)CC2)N(Cc2ccccc2)C1
Reaction time: 8 h
Yield: 15.3 %

Procedure:
To a stirring mixture of 1-benzyl-4-[(3-bromo-benzyl)-methyl-amino]-pyrrolidine-2-carboxylic acid (0.2 mmol), EDC (0.3 mmol) and HOBT (0.3 mmol) in 3 mL of dry DMF were added 2-piperazin-1-yl-benzonitrile (0.24 mmol) and NEt3 (0.6 mmol), and the reaction mixture was stirred overnight and subsequently subjected to preparative HPLC purification on reversed phase eluting with a acetonitrile/water (0.05% NEt3) gradient. 17.5 mg of title product was obtained in 15.2% yield as brown oil.
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[NH2:12][CH2:13][CH:14]([C:23]1[CH:24]=[N:25][C:26]([N:29]([CH3:31])[CH3:30])=[N:27][CH:28]=1)[N:15]1[CH2:20][CH2:19][C:18]([F:22])([F:21])[CH2:17][CH2:16]1>>[Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:12][CH2:13][CH:14]([N:15]1[CH2:16][CH2:17][C:18]([F:21])([F:22])[CH2:19][CH2:20]1)[C:23]1[CH:24]=[N:25][C:26]([N:29]([CH3:31])[CH3:30])=[N:27][CH:28]=1)=[O:6]
Reactant: O=C(O)c1cccc(Cl)c1Cl
Reactant: CN(C)c1ncc(C(CN)N2CCC(F)(F)CC2)cn1
Product: CN(C)c1ncc(C(CNC(=O)c2cccc(Cl)c2Cl)N2CCC(F)(F)CC2)cn1

Procedure:
From 2,3-dichlorobenzoic acid and 5-(2-amino-1-(4,4-difluoropiperidin-1-yl)ethyl)-N,N-dimethylpyrimidin-2-amine.
Reaction SMILES: [CH:1]([OH:4])([CH3:3])[CH3:2].[Na].[Br:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9](Br)[N:8]=1>>[Br:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([O:4][CH:1]([CH3:3])[CH3:2])[N:8]=1
Reactant: Brc1cccc(Br)n1
Reactant: CC(C)O
Agent: [Na]
Product: CC(C)Oc1cccc(Br)n1
Temperature: 80 °C

Procedure:
The compound was prepared in a manner similar to that described in WO 02/076983 (page 80). Dry isopropanol (25 mL, 42.2 mmole) was placed in an oven-dried 250 ml 3 necked flask under nitrogen, sodium spheres (0.5 g, 21.1 mmol) were added and the reaction was heated to 80° C. to dissolve the sodium. 2,6 dibromopyridine (10 g, 42.2 mmole) was added as a solid and the reaction was heated at 95° C. After heating for ˜2.5 hr the reaction was cooled and partitioned between ether and water. The organic layer was evaporated to give a solid plus oil, the mixture was suspended in hexanes, cooled, and filtered to remove the solid. The filtrate was evaporated carefully and chromatographed on silica eluting with hexanes to give the product as a clear, colorless oil.
Reaction SMILES: [C:1]1(/[CH:7]=[CH:8]/[C:9]2[C:10]([NH2:15])=[N:11][CH:12]=[CH:13][CH:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([S:24](Cl)(=[O:26])=[O:25])=[CH:20][CH:19]=1>N1C=CC=CC=1>[CH3:16][O:17][C:18]1[CH:19]=[CH:20][C:21]([S:24]([NH:15][C:10]2[C:9](/[CH:8]=[CH:7]/[C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[CH:14][CH:13]=[CH:12][N:11]=2)(=[O:26])=[O:25])=[CH:22][CH:23]=1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Reactant: Nc1ncccc1/C=C/c1ccccc1
Solvent: c1ccncc1
Product: COc1ccc(S(=O)(=O)Nc2ncccc2/C=C/c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 51.5 %

Procedure:
In 10 ml of pyridine was dissolved 0.8 g of the (E)-3-(2-phenylethenyl)-2-aminopyridine obtained in Reference Example 1. To this solution was added 0.92 g of p-methoxyphenylsulfonyl chloride gradually under ice-cooling and the mixture was stirred at room temperature overnight. After completion of the reaction, the solvent was evaporated off and the resulting residue was purified by silica gel column chromatography (eluent: CHCl3 /MeOH=9/1). The crystal crop thus obtained was recrystallized from ethanol to provide 0.77 g of the desired compound (yellow plates). m.p. 152-155° C. Elemental analysis for C20H19N2O3S
Reaction SMILES: C([O:3][C:4](=[O:35])[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][CH2:16][CH2:17][C:18]3[N:19]([CH3:34])[N:20]=[C:21]([C:23]4[CH:28]=[CH:27][C:26]([O:29][C:30]([F:33])([F:32])[F:31])=[CH:25][CH:24]=4)[CH:22]=3)[CH:13]=2)[CH:8]=[CH:7]1)C.[Li+].[OH-]>>[CH3:34][N:19]1[C:18]([CH2:17][CH2:16][O:15][C:12]2[CH:13]=[C:14]3[C:9]([CH:8]=[CH:7][N:6]3[CH2:5][C:4]([OH:35])=[O:3])=[CH:10][CH:11]=2)=[CH:22][C:21]([C:23]2[CH:28]=[CH:27][C:26]([O:29][C:30]([F:31])([F:33])[F:32])=[CH:25][CH:24]=2)=[N:20]1
Reactant: CCOC(=O)Cn1ccc2ccc(OCCc3cc(-c4ccc(OC(F)(F)F)cc4)nn3C)cc21
Agent: [Li+]
Agent: [OH-]
Product: Cn1nc(-c2ccc(OC(F)(F)F)cc2)cc1CCOc1ccc2ccn(CC(=O)O)c2c1

Procedure:
In analogy to the procedure described in example 1 f], (6-{2-[2-methyl-5-(4-trifluoromethoxy-phenyl)-2H-pyrazol-3-yl]-ethoxy}-indol-1-yl)-acetic acid ethyl ester was treated with LiOH to obtain (6-{2-[2-methyl-5-(4-trifluoromethoxy-phenyl)-2H-pyrazol-3-yl]-ethoxy}-indol-1-yl)-acetic acid as colorless crystals.
Reaction SMILES: [CH3:1][C@H:2]([O:6][C:7]1[CH:8]=[C:9]([CH:13]=[C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:15]=1)[C:10]([OH:12])=O)[CH2:3][O:4][CH3:5].C(Cl)(=O)C(Cl)=O.[NH2:30][C:31]1[CH:36]=[N:35][C:34]([CH3:37])=[CH:33][N:32]=1.N1C=CC=CC=1>CN(C=O)C.C(Cl)Cl>[CH3:1][C@H:2]([O:6][C:7]1[CH:8]=[C:9]([CH:13]=[C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:15]=1)[C:10]([NH:30][C:31]1[CH:36]=[N:35][C:34]([CH3:37])=[CH:33][N:32]=1)=[O:12])[CH2:3][O:4][CH3:5]
Reactant: Cc1cnc(N)cn1
Reactant: COC[C@H](C)Oc1cc(OCc2ccccc2)cc(C(=O)O)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: c1ccncc1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COC[C@H](C)Oc1cc(OCc2ccccc2)cc(C(=O)Nc2cnc(C)cn2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 98.2 %

Procedure:
DMF (2 drops) was added to a solution of 3-{[(1S)-1-methyl-2-(methyloxy)ethyl]oxy}-5-[(phenylmethyl)oxy]benzoic acid (6.0 g, 19.0 mmol) and oxalyl chloride (1.99 mL, 22.8 mmol) in DCM (40 mL) The mixture was stirred at ambient temperature for 2 hours and the DCM and excess oxalyl chloride evaporated in vacuo. The residual acid chloride was dissolved in DCM and added dropwise to 2-amino-5 methylpyrazine [Tett lett. 2002, 9287-90] (2.28 g, 19.8 mmol) and pyridine (2.56 mL, 38 mmol) in DCM (40 mL), at 0° C. Stirred at ambient temperature for 24 hours. The DCM was evaporated in vacuo, and the residue partitioned between ethyl acetate (100 mL) and 1N hydrochloric acid (50 mL). The ethyl acetate layer was washed sequentially with saturated aqueous sodium hydrogen carbonate (50 mL) and brine (50 mL), dried (MgSO4), and evaporated in vacuo. The residue was chromatographed on silica, eluting with a gradient of 30-100% ethyl acetate in isohexane, to give the desired compound (7.6 g)
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([C@@H:8]2[CH2:12][CH2:11][CH2:10][N:9]2[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[NH:5][C:6]=1Br.[O-]S([O-])=O.[Na+].[Na+]>O1CCOCC1.O>[Br:1][C:2]1[NH:3][C:4]([C@@H:8]2[CH2:12][CH2:11][CH2:10][N:9]2[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[N:5][CH:6]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1c1nc(Br)c(Br)[nH]1
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCC[C@H]1c1ncc(Br)[nH]1
Yield: 52.2 %

Procedure:
A mixture of Example 126D (12.5 g, 31.5 mmol) in dioxane (400 mL) and H2O (400 mL) had a solution of Na2SO3 (43.7 g, 347 mmol) in H2O (400 mL) added and was heated to reflux for 21 hours. The mixture was concentrated to half volume and extracted with CH2Cl2 (3×200 mL). The organic was then washed with brine, dried (MgSO4), filtered and concentrated. Purification by trituration (CH2Cl2, tBuOMe, and Hexanes) afforded 5.2 g (52%) of the title compound. MS (ESI) m/z 317 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([CH2:12][N:13]1[C:19](=[O:20])[C@@H:18]([NH:21][C:22](=[O:34])[C@@H:23]([N:25]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH3:26])[CH3:24])[CH2:17][O:16][C:15]3[C:35]([C:39]([O:41][CH3:42])=[O:40])=[CH:36][CH:37]=[CH:38][C:14]1=3)=[C:7]([O:43][CH3:44])[CH:6]=[CH:5]2>CO.[Pd]>[C:30]([O:29][C:27]([N:25]([CH3:26])[C@@H:23]([CH3:24])[C:22]([NH:21][C@H:18]1[CH2:17][O:16][C:15]2[C:35]([C:39]([O:41][CH3:42])=[O:40])=[CH:36][CH:37]=[CH:38][C:14]=2[N:13]([CH2:12][C:8]2[C:9]3[C:4](=[CH:3][CH:2]=[CH:11][CH:10]=3)[CH:5]=[CH:6][C:7]=2[O:43][CH3:44])[C:19]1=[O:20])=[O:34])=[O:28])([CH3:32])([CH3:33])[CH3:31]
Reactant: COC(=O)c1cccc2c1OC[C@H](NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)C(=O)N2Cc1c(OC)ccc2cc(Br)ccc12
Agent: [Pd]
Solvent: CO
Product: COC(=O)c1cccc2c1OC[C@H](NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)C(=O)N2Cc1c(OC)ccc2ccccc12
Reaction time: 8 h
Yield: 107.8 %

Procedure:
A mixture of (S)-methyl 5-((6-bromo-2-methoxynaphthalen-1-yl)methyl)-3-((S)-2-(tert-butoxycarbonyl(methyl)amino)propanamido)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-9-carboxylate (100 mg, 149 μmol, Eq: 1.00) and 10% Pd/C (5.22 mg, 4.92 μmol, Eq: 0.033) in MeOH (5 mL) was hydrogenated at RT overnight. The mixture was filtered through Celite and the filtrate concentrated to afford (S)-methyl 3-((S)-2-(tert-butoxycarbonyl(methyl)amino)propanamido)-5-((2-methoxynaphthalen-1-yl)methyl)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-9-carboxylate (95 mg, 97%) as a tan foam.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([O:14][CH:15]2[CH2:19][CH2:18][O:17][CH2:16]2)=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=O)[NH:8][N:7]=[CH:6]2.P(Cl)(Cl)([Cl:22])=O>>[Cl:22][C:9]1[C:10]2[C:5](=[C:4]([O:14][CH:15]3[CH2:19][CH2:18][O:17][CH2:16]3)[C:3]([O:2][CH3:1])=[CH:12][CH:11]=2)[CH:6]=[N:7][N:8]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1ccc2c(=O)[nH]ncc2c1OC1CCOC1
Product: COc1ccc2c(Cl)nncc2c1OC1CCOC1
Yield: 88 %

Procedure:
Operating analogously to example 7 starting from 6-methoxy-5-(tetrahydro-furan-3-yloxy)-2H-phthalazin-1-one (1.73 g, 6.6 mmoles) and phosphoryl chloride (6.7 ml, 73 mmoles), 1.63 g of the title product were obtained (yield: 88%).
Reaction SMILES: [C:1]1([C:7]2[C:8]([C:16]3[CH:23]=[CH:22][C:19]([CH:20]=O)=[CH:18][CH:17]=3)=[N:9][C:10]3[N:11]([N:13]=[CH:14][CH:15]=3)[CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[NH:25]1[CH2:30][CH2:29][CH:28]([C:31]2[NH:35][C:34]3[CH:36]=[C:37]([C:40]([F:43])([F:42])[F:41])[CH:38]=[CH:39][C:33]=3[N:32]=2)[CH2:27][CH2:26]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[C:1]1([C:7]2[C:8]([C:16]3[CH:23]=[CH:22][C:19]([CH2:20][N:25]4[CH2:30][CH2:29][CH:28]([C:31]5[NH:35][C:34]6[CH:36]=[C:37]([C:40]([F:43])([F:42])[F:41])[CH:38]=[CH:39][C:33]=6[N:32]=5)[CH2:27][CH2:26]4)=[CH:18][CH:17]=3)=[N:9][C:10]3[N:11]([N:13]=[CH:14][CH:15]=3)[CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=Cc1ccc(-c2nc3ccnn3cc2-c2ccccc2)cc1
Reactant: FC(F)(F)c1ccc2nc(C3CCNCC3)[nH]c2c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Product: FC(F)(F)c1ccc2nc(C3CCN(Cc4ccc(-c5nc6ccnn6cc5-c5ccccc5)cc4)CC3)[nH]c2c1
Reaction time: 8 h
Yield: 44.8 %

Procedure:
250 mg (0.84 mmol) 4-(6-phenylpyrazolo[1,5-a]pyrimidin-5-yl)benzaldehyde and 308 mg (1 mmol) 2-piperidine-4-yl-6-trifluoromethyl-1H-benzimidazole hydrochloride salt were treated as previously described. Additional NaBH(OAc)3 has been added after one, two and three hours (two equivalents each). After a further hour stirring at room temperature additional 31 mg 2-piperidine-4-yl-6-trifluoromethyl-1H-benzimidazole hydrochloride salt and two equivalents NaBH(OAc)3 were added. After stirring overnight and two further additions of NaBH(OAc)3 the solvents were evaporated. Workup and purification yields 208 mg of the desired compound.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([N:10]2[CH:14]=[C:13]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:12]=[N:11]2)[CH:6]=[CH:7][C:8]=1[OH:9])#[N:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:27][C@@H:28]([CH3:31])[CH2:29][CH3:30].O>CN(C)C=O.C(OCC)(=O)C>[C:1]([C:3]1[CH:4]=[C:5]([N:10]2[CH:14]=[C:13]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:12]=[N:11]2)[CH:6]=[CH:7][C:8]=1[O:9][CH2:27][C@@H:28]([CH3:31])[CH2:29][CH3:30])#[N:2]
Reactant: CCOC(=O)c1cnn(-c2ccc(O)c(C#N)c2)c1
Reactant: CC[C@H](C)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cnn(-c2ccc(OC[C@@H](C)CC)c(C#N)c2)c1
Temperature: 90 °C
Yield: 89.1 %

Procedure:
To a solution (10 ml) of ethyl 1-(3-cyano-4-hydroxyphenyl)pyrazole-4-carboxylate (1.5 g) in dimethylformamide were added potassium carbonate (0.91 g) and (S)-(+)-1-bromo-2-methylbutane (1 g) with stirring, and the mixture was heated at 90° C. for 2 hours. After the completion of the reaction, the reaction mixture was poured into water and the mixture was acted with ethyl acetate, washed with water and dried over magnesium sulfate. The solvent was evaporated under reduced pressure and the obtained residue was recrystallized from isopropyl ether to give 1.7 g of ethyl 1-(3-cyano-4-((S)-2-methylbutoxy)phenyl)pyrazole-4-carboxylate, melting point 105-106° C.