Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[C:2]1([C:8]([C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=O)=O)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[S:18]([NH2:22])([NH2:21])(=[O:20])=[O:19]>CO>[C:2]1([C:8]2[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[N:22][S:18](=[O:20])(=[O:19])[N:21]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(C(=O)c1ccccc1)c1ccccc1
Reactant: NS(N)(=O)=O
Agent: Cl
Solvent: CO
Product: O=S1(=O)N=C(c2ccccc2)C(c2ccccc2)=N1
Temperature: 25 °C
Yield: 84416 %

Procedure:
Hydrogen chloride is bubbled through a solution of benzil (24 g, 0.11 mmol) and sulfamide (11 g, 0.11 mmol) in methanol (120 mL) for 2 h followed by heating to reflux for 2 h. The reaction mixture is cooled to RT, and the precipitate that formed is filtered to give 25.1 g of the product 14.
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:22])([F:21])[CH2:17]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][CH3:15])[C:9]=2[N:10]=1)([CH3:4])([CH3:3])[CH3:2].C(C1N=[C:29]([N:36]2[CH2:40][CH2:39][C:38](F)(F)[CH2:37]2)C2N=NNC=2N=1)(C)(C)C.Br.BrCCC1C=CC=CN=1>>[C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:21])([F:22])[CH2:17]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][CH2:15][C:40]3[CH:39]=[CH:38][CH:37]=[CH:29][N:36]=3)[C:9]=2[N:10]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn[nH]c2n1
Reactant: CCn1nnc2c(N3CCC(F)(F)C3)nc(C(C)(C)C)nc21
Agent: Br
Agent: BrCCc1ccccn1
Product: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nnn(CCc3ccccn3)c2n1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3-ethyl-3H-[1,2,3]triazolo[4,5-d]pyrimidine (example 61), the title compound was prepared from 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and 2-(2-bromoethyl)pyridine hydrobromide and isolated as colorless gum. MS (m/e): 387.4 (MH+).
Reaction SMILES: [SH:1][C:2]1[CH:3]=[C:4]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:5]([OH:14])=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:7]=1.[CH3:21][N:22]([CH2:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=1)[C:23](=[O:26])[CH:24]=[CH2:25]>C(N(CC)CC)C>[OH:14][C:5]1[C:6]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)=[CH:7][C:2]([S:1][CH2:25][CH2:24][C:23]([N:22]([CH3:21])[CH2:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=2)=[O:26])=[CH:3][C:4]=1[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: C=CC(=O)N(C)CCc1ccccn1
Reactant: Oc1c(-c2ccccc2)cc(S)cc1-c1ccccc1
Solvent: CCN(CC)CC
Product: CN(CCc1ccccn1)C(=O)CCSc1cc(-c2ccccc2)c(O)c(-c2ccccc2)c1

Procedure:
The title compound was prepared according to the method of Example 4 from the thiol of Example 16(2.78 g, 0.01 mole), N-methyl-N-[2-(2-pyridinyl)ethyl]-2-propenamide (1.90 g, 0.01 mold) and triethylamine (1.2 ml). Analysis calc. for C29H28O2N2S (468.54): Calc.: C, 74.32; H, 6.02; N, 5.98. Found: C, 73.93; H, 6.04; N, 6.16.
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][C:5]2[NH:6][C:7]([SH:9])=[N:8][C:4]=2[CH:3]=1.Cl.[CH:13]1([CH2:16][O:17][C:18]2[CH:23]=[CH:22][N:21]=[C:20]([CH2:24]Cl)[CH:19]=2)[CH2:15][CH2:14]1.[OH-].[Na+]>O.CO>[F:1][C:2]1[CH:11]=[CH:10][C:5]2[NH:6][C:7]([S:9][CH2:24][C:20]3[CH:19]=[C:18]([O:17][CH2:16][CH:13]4[CH2:15][CH2:14]4)[CH:23]=[CH:22][N:21]=3)=[N:8][C:4]=2[CH:3]=1
Reactant: Fc1ccc2[nH]c(S)nc2c1
Reactant: ClCc1cc(OCC2CC2)ccn1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Fc1ccc2[nH]c(SCc3cc(OCC4CC4)ccn3)nc2c1
Yield: 82.5 %

Procedure:
To 5-fluoro-2-mercapto-1H-benzimidazole (0.88 g, 0.0051 mol) in methanol (25 ml) NaOH (0.2 g, 0.0051 mol) dissolved in H2O (1 ml) and 4-cyclopropylmethoxy-2-chloromethyl-pyridine hydrochloride (0.91 g, 0.0046 mol) dissolved in methanol (10 ml) were added in the given order. The mixture was heated to boiling and NaOH (0.2 g, 0.005 mol) dissolved in H2O (1 ml) was added and the mixture was refluxed for 1 hour. After evaporation of methanol, CH1Cl2 (75 ml) and H2O (50 ml) were added and pH adjusted to 10. The mixture was vigorously stirred, the phases were separated, the organic phase was dried over Na2SO4 and evaporated giving the desired product (1.25 g, 72%). NMR data for the product is given below.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:19]([CH3:20])=[CH:18][C:17]([CH2:21][CH2:22][CH3:23])=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.Cl.C(OCC)(=O)C.[OH-].[Na+]>C(Cl)(Cl)Cl>[CH3:20][C:19]1[C:14]([N:11]2[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)=[N:15][CH:16]=[C:17]([CH2:21][CH2:22][CH3:23])[CH:18]=1
Reactant: CCCc1cnc(N2CCN(C(=O)OC(C)(C)C)CC2)c(C)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: ClC(Cl)Cl
Product: CCCc1cnc(N2CCNCC2)c(C)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.4 %

Procedure:
To a mixture of 4-(5-bromo-3-methylpyridin-2-yl)piperazine-1-carboxylic acid tert-butyl ester (6.7 g), bis(tricyclohexylphosphine)palladium (II) dichloride (148 mg), tripotassium phosphate (13 g) and cis-1-propene-1-boronic acid (2.6 g) were added toluene (60 mL) and water (3 mL), and the mixture was refluxed for 8 hr. After cooling, the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and the solvent was evaporated. The residue was purified by column chromatography (hexane:ethyl acetate) to give 4-[3-methyl-5-propenylpyridin-2-yl]piperazine-1-carboxylic acid tert-butyl ester (6 g). 4-[3-Methyl-5-propenylpyridin-2-yl]piperazine-1-carboxylic acid tert-butyl ester (6 g) was dissolved in ethanol (40 mL), 5% palladium carbon-ethylenediamine complex (1.2 g) was added, and the mixture was stirred under a hydrogen atmosphere at room temperature overnight. After celite filtration, the solvent in the filtrate was evaporated to give 4-[3-methyl-5-propylpyridin-2-yl]piperazine-1-carboxylic acid tert-butyl ester (6 g). 4-[3-Methyl-5-propylpyridin-2-yl]piperazine-1-carboxylic acid tert-butyl ester (6 g) was dissolved in chloroform (10 mL), 4N hydrogen chloride/ethyl acetate (10 mL) was added, and the mixture was stirred at room temperature overnight. To the reaction mixture was added 1N aqueous sodium hydroxide solution (40 mL), and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, and the solvent was evaporated to give the title compound (2.9 g).
Reaction SMILES: [CH2:1]([NH:8][CH2:9][CH:10](O)[C:11]1[C:16]([F:17])=[CH:15][C:14]([O:18][CH3:19])=[C:13]([O:20][CH3:21])[CH:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(=O)(=O)(O)O.C([O-])(=O)C.[Na+]>FC(F)(F)C(O)=O>[F:17][C:16]1[C:11]([CH:10]2[C:7]3[C:2](=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH2:1][NH:8][CH2:9]2)=[CH:12][C:13]([O:20][CH3:21])=[C:14]([O:18][CH3:19])[CH:15]=1
Reactant: COc1cc(F)c(C(O)CNCc2ccccc2)cc1OC
Agent: CC(=O)[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(F)c(C2CNCc3ccccc32)cc1OC
Reaction time: 1.17 h
Yield: 100.3 %

Procedure:
α-[(benzylamino)methyl]-6-fluoro-3,4-dimethoxybenzyl alcohol (1.25 g) was dissolved in 8.75 ml of trifluoroacetic acid, and after adding thereto 0.37 ml of conc. sulfuric acid under ice-cooling, the mixture was stirred for 70 minutes. Then, 1.07 g of sodium acetate was added to the mixture, and the reaction mixture was concentrated. To the residue, was added chloroform and water, and the mixture was basified by addition of conc. aqueous ammonia under ice-cooling. By a separating procedure, the chloroform layer was collected, washed with saturated aqueous NaCl solution, and dried over anhydrous sodium sulfate. The solvent was removed by distillation, giving 1.18 g of 4-(6-fluoro-3,4-dimethoxyphenyl)-1,2,3,4-tetrahydroisoquinoline as a syrupy matter.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.[CH:11](=O)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.CO>[BH4-].[Na+]>[CH2:11]([NH:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: NCCc1ccc(O)cc1
Reactant: O=Cc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: Oc1ccc(CCNCc2ccccc2)cc1

Procedure:
According to Scheme 2, tyramine is treated with benzaldehyde in sodium borohydride, molecular sieves, and methanol to produce the reductive amination product 4-(benzylamino-ethyl)-phenol (8). The phenol 8 is treated with cesium carbonate and 4-fluorobenzonitrile in DMF to yield the corresponding biarylether 9. The nitrile functionality of the biaryl ether may be converted to the acetate 10 with methyl lithium followed by hydrolysis in aqueous sulfuric acid. The acetate 10 is oxidized with MCPBA to yield acetic acid 4-[4-(2-benzylamino-ethyl)-phenoxy]-phenyl ester (11).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][C@H:3]([NH:6][C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10])[CH2:2]1.I[CH2:15][CH3:16].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH2:15]([N:1]1[CH2:5][CH2:4][C@H:3]([NH:6][C:7](=[O:13])[O:8][C:9]([CH3:10])([CH3:12])[CH3:11])[CH2:2]1)[CH3:16]
Reactant: CCI
Reactant: CC(C)(C)OC(=O)N[C@H]1CCNC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCN1CC[C@H](NC(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 17 h
Yield: 73.9 %

Procedure:
A mixture of tert butyl (S)-pyrrolidin-3-ylcarbamate (1.048 g), iodoethane (0.90 g) and potassium carbonate (1.55 g) in acetonitrile (15 mL) was stirred at room temperature for 17 hours then filtered. The filtrate was concentrated in vacuo and the residue was triturated with DCM and filtered. The filtrate was concentrated in vacuo and the residue was purified by chromatography on silica, eluting with a mixture of methanol and DCM with a gradient of 0-35% to give tert-butyl ((S)-1-ethylpyrrolidin-3-yl)carbamate (0.891 g) as a light coloured gum.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)=[C:8]([Cl:18])[CH:7]=1)[CH3:2].[CH2:20]([O:22][C:23](=[O:26])[CH:24]=[CH2:25])[CH3:21].[Na].C(O)(=O)C>C(O)C>[CH2:1]([O:3][C:4](=[O:19])[CH:5]([C:6]1[CH:11]=[CH:10][C:9]([CH:12]2[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]2)=[C:8]([Cl:18])[CH:7]=1)[CH2:25][CH2:24][C:23]([O:22][CH2:20][CH3:21])=[O:26])[CH3:2]
Reactant: C=CC(=O)OCC
Reactant: CCOC(=O)Cc1ccc(C2CCCCC2)c(Cl)c1
Agent: [Na]
Solvent: CCO
Solvent: CC(=O)O
Product: CCOC(=O)CCC(C(=O)OCC)c1ccc(C2CCCCC2)c(Cl)c1
Temperature: 0 °C
Yield: 44.2 %

Procedure:
A mixture of 40.5 g of 3-chloro-4-cyclohexylphenylacetic acid ethyl ester and 16 g of acrylic acid ethyl ester is added dropwise to a solution of 3.6 g of sodium in 60 ml of ethanol. The solution is refluxed overnight and then poured into a mixture of 10 ml of glacial acetic acid and 170 ml of ice water. The ethanol is distilled off and the residue extracted with ethyl acetate and evaporated; the residue is distilled under a high vacuum, to yield 24.3 g of 2-(3-chloro-4-cyclohexylphenyl)-glutaric acid diethyl ester boiling at 203°-205°C under 0.4 mm Hg pressure.
Reaction SMILES: [OH:1][C:2]([CH3:41])([CH3:40])[CH:3]([CH3:39])[O:4][C@H:5]1[CH2:10][CH2:9][C@H:8]([N:11]2[C:16](=[O:17])[C:15]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]4[C:26]([C:31]#[N:32])=[CH:27][CH:28]=[CH:29][CH:30]=4)=[CH:21][CH:20]=3)=[C:14]([CH2:33][CH2:34][CH3:35])[N:13]3[N:36]=[CH:37][N:38]=[C:12]23)[CH2:7][CH2:6]1.C[Si]([N:46]=[N+:47]=[N-:48])(C)C.C([Sn](=O)CCCC)CCC.C1(C)C=CC=CC=1>O.C(OCC)(=O)C>[OH:1][C:2]([CH3:40])([CH3:41])[CH:3]([CH3:39])[O:4][C@H:5]1[CH2:10][CH2:9][C@H:8]([N:11]2[C:16](=[O:17])[C:15]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=4[C:31]4[NH:48][N:47]=[N:46][N:32]=4)=[CH:21][CH:20]=3)=[C:14]([CH2:33][CH2:34][CH3:35])[N:13]3[N:36]=[CH:37][N:38]=[C:12]23)[CH2:7][CH2:6]1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](OC(C)C(C)(C)O)CC2)c2ncnn12
Agent: CCCC[Sn](=O)CCCC
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: O
Product: CCCc1c(Cc2ccc(-c3ccccc3-c3nnn[nH]3)cc2)c(=O)n([C@H]2CC[C@H](OC(C)C(C)(C)O)CC2)c2ncnn12
Temperature: 110 °C
Reaction time: 88 h

Procedure:
A mixture of 4′-({4-[trans-4-(2-hydroxy-1,2-dimethylpropoxy)cyclohexyl]-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile (0.33 g), trimethylsilylazide (1.9 g), dibutyltinoxide (0.14 g) and toluene (15 mL) was stirred at 110° C. for 88 hr. Ethyl acetate and water were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was dissolved in tetrahydrofuran (10 mL). Tetrabutylammonium fluoride (2.3 mL, 1.0 M tetrahydrofuran solution) was added, and the mixture was stirred at 70° C. for 1 hr. The reaction mixture was added to 1 M hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography and recrystallized (ethyl acetate-diisopropyl ether) to give the title compound as a colorless solid (0.10 g, 30%).
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH2:19][C:20]3[N:21]=[C:22]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[O:23][C:24]=3[CH3:25])[CH:13]=2)[CH:7]=[N:6][CH:5]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].S([O-])([O-])(=O)=O.[Na+].[Na+]>O1CCCC1>[CH3:25][C:24]1[O:23][C:22]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)=[N:21][C:20]=1[CH2:19][O:18][C:14]1[CH:13]=[C:12]([CH:17]=[CH:16][CH:15]=1)[CH2:11][O:10][C:8]1[CH:9]=[C:4]([CH2:3][OH:2])[CH:5]=[N:6][CH:7]=1
Reactant: COC(=O)c1cncc(OCc2cccc(OCc3nc(-c4ccccc4)oc3C)c2)c1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: Cc1oc(-c2ccccc2)nc1COc1cccc(COc2cncc(CO)c2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 100.5 %

Procedure:
To a mixture of methyl-5-[3-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]nicotinate (0.50 g) and tetrahydrofuran (10 mL) was added lithium aluminum hydride (0.045 g) under ice-cooling, and the mixture was stirred at room temperature for 3 hrs. Sodium sulfate 1.0 hydrate (0.39 g) was added to the mixture and the mixture was further stirred at room temperature for 30 min. The insoluble materials were removed by filtration, and the filtrate was concentrated to give crystals (0.47 g, 98%) of [5-[3-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]-3-pyridyl]methanol. Recrystallization from ethyl acetate-hexane gave colorless needle crystals. melting point: 145-146° C.
Reaction SMILES: [CH3:1][C@H:2]1[C:7](=[O:8])[O:6][CH2:5][C:4]([CH3:10])([CH3:9])[NH:3]1.[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([Mg]Br)=[CH:14][CH:13]=1.[NH4+].[Cl-].CCOC(C)=O>C1COCC1>[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([C@:7]2([OH:8])[O:6][CH2:5][C:4]([CH3:10])([CH3:9])[NH:3][C@H:2]2[CH3:1])=[CH:14][CH:13]=1
Reactant: Clc1ccc([Mg]Br)cc1
Reactant: C[C@@H]1NC(C)(C)COC1=O
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C[C@@H]1NC(C)(C)CO[C@@]1(O)c1ccc(Cl)cc1
Temperature: -78 °C
Reaction time: 2 h
Yield: 28.2 %

Procedure:
A solution of 15 (357 mg, 2.50 mmol) in dry THF (2.5 mL, 1M) under an N2 atmosphere was cooled to −78° C. and treated with 4-chlorophenylmagnesium bromide (2 equiv., 5.00 mmol, 5.00 mL, 1M solution in ether). The reaction mixture was stirred at −78° C. for 2 h. A saturated aqueous solution of NH4Cl was added to the reaction vessel, and the mixture was allowed to warm to room temperature. EtOAc was added and the organic layer was separated and the aqueous phase was extracted with EtOAc (trice). The combined organic extracts were washed (water, brine), dried (Na2SO4) and concentrated. The residue was purified by column chromatography on silica gel using CH2Cl2 to CH2Cl2-MeOH (90:10) as the eluent to afford 180 mg (29%) of 4i as a white solid: [α]23D +33° (c 0.4, CHCl3): 1H NMR (CDCl3) δ 7.54 (d, 2H, J=8.5 Hz), 7.32 (d, 2H, J=8.5 Hz), 3.83 (d, 1H, J=11.3 Hz), 3.40 (d, 1H, J=11.3 Hz), 3.18 (q, 1H, J=6.5 Hz), 1.38 (s, 3H), 1.08 (s, 3H), 0.78 (d, 3H, J=6.5 Hz); 13C NMR (CDCl3) δ 128.5, 128.1, 127.6, 127.2, 101.6, 95.9, 69.5, 53.4, 49.7, 27.3, 22.8, 16.4; LCMS (ESI) m/z 256.3 [(M+H)+, M=C13H18ClNO2].
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH:4]1[N:9]([CH2:10][C:11]([C:13]2[C:14]([CH3:23])=[C:15]3[C:19](=[CH:20][CH:21]=2)[C:18](=[O:22])[O:17][CH2:16]3)=[O:12])[CH2:8][CH2:7][N:6]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:5]1.[BH4-].[Na+]>CO>[OH:12][CH:11]([C:13]1[C:14]([CH3:23])=[C:15]2[C:19](=[CH:20][CH:21]=1)[C:18](=[O:22])[O:17][CH2:16]2)[CH2:10][N:9]1[CH2:8][CH2:7][N:6]([C:24]([O:26][C:27]([CH3:28])([CH3:29])[CH3:30])=[O:25])[CH2:5][CH:4]1[CH2:3][CH2:2][OH:1]
Reactant: Cc1c(C(=O)CN2CCN(C(=O)OC(C)(C)C)CC2CCO)ccc2c1COC2=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: Cc1c(C(O)CN2CCN(C(=O)OC(C)(C)C)CC2CCO)ccc2c1COC2=O
Temperature: 25 °C

Procedure:
tert-Butyl 3-(2-hydroxyethyl)-4-(2-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)-2-oxoethyl)piperazine-1-carboxylate (6.16 g, 14.7 mmol) was dissolved in methanol (100 mL) at 0° C. and then NaBH4 (1.67 g, 44.2 mmol) was added. The reaction mixture was warmed up to RT. After ten minutes, TLC showed no SM left. The methanol was evaporated and the residue was taken up with brine and extracted with ethyl acetate twice. The combined organic layers were dried with MgSO4, filtered and concentrated. The crude product was chromatographed through an ISCO 330 g Redi-sep column and eluted with 5% MeOH/DCM to yield the title compound: LC-MS (IE, m/z): 421[M+1]+.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:15]([CH:16]=[O:17])=[CH:14][N:13](C3CCCCO3)[N:12]=2)=[CH:7][CH:6]=1)([CH3:3])[CH3:2].[ClH:24]>>[ClH:24].[CH:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:15]([CH:16]=[O:17])=[CH:14][NH:13][N:12]=2)=[CH:7][CH:6]=1)([CH3:3])[CH3:2]
Reactant: CC(C)Oc1ccc(-c2nn(C3CCCCO3)cc2C=O)cc1
Agent: Cl
Product: CC(C)Oc1ccc(-c2n[nH]cc2C=O)cc1
Yield: 98 %

Procedure:
A solution of 3-(4-isopropoxyphenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-4-carbaldehyde (7.4 g, 23.56 mmol) in 3M methanolic HCl (74 mL) was stirred at rt for 3 h. The resulting solution was concentrated and triturated using diethyl ether (50 mL×3) to afford 3-(4-isopropoxyphenyl)-1H-pyrazole-4-carbaldehyde hydrochloride (5.3 g, yield 98%). LCMS (method C): RT=1.96 min, m/z=231.1 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:17])=[C:6]([CH:8]=[N:9][C:10]([O:12][Si](C)(C)C)=[CH2:11])[CH:7]=1.C(OC([N:25]1[C:33]2[C:28](=[CH:29][CH:30]=[C:31]([Cl:34])[CH:32]=2)/[C:27](=[CH:35]/[C:36]2[CH:41]=[C:40]([Cl:42])[CH:39]=[CH:38][C:37]=2[O:43][CH2:44][C:45]2([CH3:49])[CH2:48][O:47][CH2:46]2)/[C:26]1=[O:50])=O)(C)(C)C>C1(C)C=CC=CC=1>[Cl:34][C:31]1[CH:32]=[C:33]2[NH:25][C:26](=[O:50])[C:27]3([CH:35]([C:36]4[CH:41]=[C:40]([Cl:42])[CH:39]=[CH:38][C:37]=4[O:43][CH2:44][C:45]4([CH3:49])[CH2:48][O:47][CH2:46]4)[CH2:12][C:10](=[O:11])[NH:9][CH:8]3[C:6]3[CH:7]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=3[CH3:17])[C:28]2=[CH:29][CH:30]=1
Reactant: CC1(COc2ccc(Cl)cc2/C=C2\C(=O)N(C(=O)OC(C)(C)C)c3cc(Cl)ccc32)COC1
Reactant: C=C(N=Cc1cc(F)ccc1C)O[Si](C)(C)C
Solvent: Cc1ccccc1
Product: Cc1ccc(F)cc1C1NC(=O)CC(c2cc(Cl)ccc2OCC2(C)COC2)C12C(=O)Nc1cc(Cl)ccc12
Temperature: 140 °C
Reaction time: 3 h
Yield: 1.5 %

Procedure:
To a solution of 1-(5-fluoro-2-methyl-phenyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene (7.1 mmol) in anhydrous toluene (7 mL) was added E/Z-6-Chloro-3-[5-chloro-2-(3-methyl-oxetan-3-ylmethoxy)-benzylidene]-2-oxo-2,3-dihydro-indole-1-carboxylic acid tert-butyl ester (0.7 g, 1.4 mmol). The solution was stirred under Ar in a sealed tube at 140° C. for 3 h. After the solution was cooled to room temperature and concentrated, the residue was purified by chromatography (DCM:CH3OH=50:1) to give crude product. The crude product was purified again by Prep-HPLC to give title compound as a white solid (12 mg).
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]2[C:11](=[O:19])[CH:12]([CH2:15]N(C)C)[CH2:13][CH2:14][C:3]=12.[CH3:20][C:21]1[NH:22][CH:23]=[CH:24][N:25]=1.Cl.C(O)(C)C>C(Cl)Cl>[CH3:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]2[C:11](=[O:19])[CH:12]([CH2:15][N:22]3[CH:23]=[CH:24][N:25]=[C:21]3[CH3:20])[CH2:13][CH2:14][C:3]=12
Reactant: Cc1ncc[nH]1
Reactant: Cc1c2n(c3ccccc13)C(=O)C(CN(C)C)CC2
Agent: Cl
Solvent: CC(C)O
Solvent: ClCCl
Product: Cc1c2n(c3ccccc13)C(=O)C(Cn1ccnc1C)CC2
Temperature: 100 °C
Yield: 53.8 %

Procedure:
A mixture of 8,9-dihydro-10-methyl-7-(dimethylaminomethyl)pyrido[1,2-a]indol-6(7H)-one (0.65 g), 2-methylimidazole (0.76 g), 2N hydrochloric acid (1.27 ml), and isopropyl alcohol (4 ml) was heated at 100° C. for 3 hours and 15 minutes. After evaporation of the solvent, the residue obtained was dissolved in methylene chloride. The methylene chloride solution was washed with water and brine, dried over anhydrous magnesium sulfate, and evaporated in vacuo. Purification with neutral alumina column chromatography (0.5% methanol-methylene chloride), followed by recrystallization with ethyl acetate-hexane, gave 8,9-dihydro-10-methyl-7-[(2-methyl-1H-imidazol-1-yl)methyl]pyrido[1,2-a]indol-6(7H)-one (0.40 g).
Reaction SMILES: CO[CH:3](OC)[CH2:4][NH:5][CH2:6][C:7]1[CH:12]=[C:11]([O:13][CH3:14])[C:10]([O:15][CH3:16])=[CH:9][C:8]=1[NH2:17].[N:20]#[C:21]Br.Cl>C(O)C>[CH3:14][O:13][C:11]1[CH:12]=[C:7]2[C:8](=[CH:9][C:10]=1[O:15][CH3:16])[NH:17][C:21]1=[N:20][CH:3]=[CH:4][N:5]1[CH2:6]2
Reactant: N#CBr
Reactant: COc1cc(N)c(CNCC(OC)OC)cc1OC
Agent: Cl
Solvent: CCO
Product: COc1cc2c(cc1OC)Nc1nccn1C2
Reaction time: 2 h

Procedure:
1.1 g of N-(2,2-dimethoxyethyl)-2-amino-4,5-dimethoxybenzylamine and 0.5 g of cyanogen bromide are heated under reflux over-night in 10 ml of 95% ethanol. 5 ml of 5 N hydrochloric acid are then added, and the solution is left to stand at room temperature for 2 hours. After the reaction solution is concentrated in a vacuum it is made alkaline with dilute caustic soda. The little compound is obtained in crystalline form, and is crystallised from ethyl acetate. M.p. 215°-217° (from ethanol).
Reaction SMILES: C([Si](C)(C)OCC[C:9]1[CH:14]=[C:13]([C:15]([C:17]2[C:22]([N:23](COC)[S:24]([C:27]3[CH:32]=[CH:31][C:30]([Cl:33])=[C:29]([C:34]([F:37])([F:36])[F:35])[CH:28]=3)(=[O:26])=[O:25])=[CH:21][C:20]([Cl:41])=[CH:19][N:18]=2)=[O:16])[CH:12]=[CH:11][N:10]=1)(C)(C)C.O.[O:45]1CC[O:48][CH2:47][CH2:46]1>Cl>[Cl:33][C:30]1[CH:31]=[CH:32][C:27]([S:24]([NH:23][C:22]2[C:17]([C:15]([C:13]3[CH:12]=[CH:11][N:10]=[C:9]([O:45][CH2:46][CH2:47][OH:48])[CH:14]=3)=[O:16])=[N:18][CH:19]=[C:20]([Cl:41])[CH:21]=2)(=[O:25])=[O:26])=[CH:28][C:29]=1[C:34]([F:37])([F:36])[F:35]
Reactant: C1COCCO1
Reactant: COCN(c1cc(Cl)cnc1C(=O)c1ccnc(CCO[Si](C)(C)C(C)(C)C)c1)S(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Agent: Cl
Solvent: O
Product: O=C(c1ccnc(OCCO)c1)c1ncc(Cl)cc1NS(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Temperature: 25 °C

Procedure:
A solution of N-(2-{2-[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-pyridine-4-carbonyl}-5-chloro-pyridin-3-yl)-4-chloro-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamide in 4N HCl in dioxane (4 mL) and water (1 mL) was stirred at 100° C. for overnight. The reaction mixture was cooled to room temperature, evaporated to dryness and treated with saturated aqueous NaHCO3 solution till pH 7-8. The mixture was extracted with EtOAc (2×25 mL), dried (anhydrous Na2SO4) and concentrated. The crude product was purified by HPLC. 1H NMR (400 MHz, CDCl3) δ 10.82 (s, 1H), 8.35 (m, 1H), 8.24 (m, 1H), 8.15-8.18 (m, 2H), 7.96 (m, 1H), 7.63 (m, 1H), 7.17 (m, 1H), 7.09 (m, 1H), 4.51 (m, 2H), 3.97 (m, 2H), 3.09 (m, 1H); MS: (M+H)/z=535.9.