Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]2[N:12]([CH2:13][CH2:14]S)[CH2:11][C@@H:10]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[N:9]([S:23]([CH2:26][CH2:27][CH3:28])(=[O:25])=[O:24])[CH2:8][C:7]=2[CH:29]=1)#[N:2].[N-:30]=[N+:31]=[N-:32].[Na+]>CN(C=O)C.O>[N:30]([CH2:14][CH2:13][N:12]1[C:6]2[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:29][C:7]=2[CH2:8][N:9]([S:23]([CH2:26][CH2:27][CH3:28])(=[O:24])=[O:25])[C@H:10]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:11]1)=[N+:31]=[N-:32]
Reactant: [N-]=[N+]=[N-]
Reactant: CCCS(=O)(=O)N1Cc2cc(C#N)ccc2N(CCS)C[C@H]1Cc1ccccc1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCS(=O)(=O)N1Cc2cc(C#N)ccc2N(CCN=[N+]=[N-])C[C@H]1Cc1ccccc1
Temperature: 70 °C
Reaction time: 8 h

Procedure:
A mixture of Compound B of Example 27 (95.2 mg, 0.2 mmol) and sodium azide (15 mg, 0.23 mmol) in DMF (0.5 mL) was stirred at 70° C. overnight. The mixture was cooled to rt and diluted with water. The solid was collected, washed with water and dried to afford the title compound, 83 mg (95%) LC/MS: m/e (M+H)+=439.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH3:7]I.[Cl:9][C:10]1[N:18]=[C:17]2[C:13]([NH:14][C:15]([CH3:19])=[N:16]2)=[C:12]([Cl:20])[N:11]=1.O>C1COCC1>[Cl:9][C:10]1[N:18]=[C:17]2[C:13]([N:14]=[C:15]([CH3:19])[N:16]2[CH3:7])=[C:12]([Cl:20])[N:11]=1
Reactant: Cc1nc2nc(Cl)nc(Cl)c2[nH]1
Reactant: CI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1nc2c(Cl)nc(Cl)nc2n1C
Temperature: 25 °C
Reaction time: 5 h

Procedure:
Potassium carbonate (442 mg) and methyl iodide (0.17 mL) were added to a solution of 2,6-dichloro-8-methyl-7H-purine (500 mg) in THF (5 mL) under ice-cooling, and the mixture was stirred at room temperature for 5 hours. After the reaction mixture was ice-cooled, water was added thereto, extraction thereof was performed using EtOAc, and the extract was washed with water and saturated brine. The organic layer was dried over MgSO4 and filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (Hex:EtOAc=9:1 to 8:2), whereby 2,6-dichloro-8,9-dimethyl-9H-purine (310 mg) was obtained as a white solid.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=1)(C)(C)C.[H-].[Na+].Cl[C:21]1[CH:29]=[CH:28][C:24]([C:25]([NH2:27])=[O:26])=[CH:23][N:22]=1>CN(C=O)C>[NH2:7][CH2:8][CH2:9][C:10]1[CH:11]=[CH:12][C:13]([O:16][C:21]2[CH:29]=[CH:28][C:24]([C:25]([NH2:27])=[O:26])=[CH:23][N:22]=2)=[CH:14][CH:15]=1
Reactant: CC(C)(C)OC(=O)NCCc1ccc(O)cc1
Reactant: NC(=O)c1ccc(Cl)nc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: NCCc1ccc(Oc2ccc(C(N)=O)cn2)cc1

Procedure:
Treat [2-(4-hydroxyphenyl)ethyl]carbamic acid tert-butyl ester (534.3 mg, 2.2 mmol) with NaH (80% in mineral oil, 78.0 mg (2.6 mmol) in anhydrous DMF (10 mL) at room temperature for 30 minutes. Add 6-chloronicotinamide (343.8 mg, 2.2 mmol) and heat the mixture at 80° C. overnight. Quench the reaction with H2O and concentrate to dryness, using xylenes to remove DMF as an azeotrope. Suspend the residue in MeOH and filter with thorough MeOH and CH2Cl2 rinse. Concentrate the filtrate and purify by flash chromatography, eluting with 75:15:10 EtOAc/CH2Cl2/2.0 M NH3 in MeOH. Deprotect the BOC group with 1:1 TFA/CH2Cl2 (16 mL) at room temperature overnight. Concentrate and purify by an SCX column, washing with MeOH and then eluting with 2.0 M NH3 in MeOH: MS ES+ 297.9 (M+H+K)+, HRMS calcd for Cl14H16N3O2 258.1243 (M+H)+, found 258.1235, time 0.40 min; HPLC [YMC-Pack Pro C-18 (150×4.6 mm, S-5 microm), 0.1% TFA/acetonitrile in 0.1% TFA/water at 1.0 mL/min, 5-95% over 19 min], tR=6.93 min, 100% purity.
Reaction SMILES: O1CCOCC1.O.[C:8]1(=[O:14])[CH2:13][CH2:12][CH2:11][CH:10]=[CH:9]1.[C:15]1(B(O)O)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C(OCC)(=O)C>[C:15]1([C@H:10]2[CH2:11][CH2:12][CH2:13][C:8](=[O:14])[CH2:9]2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=C1C=CCCC1
Reactant: OB(O)c1ccccc1
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: O
Product: O=C1CCC[C@H](c2ccccc2)C1
Temperature: 100 °C

Procedure:
1 ml of dioxane, 0.1 ml of distilled water and 0.4 mmol of cyclohexenone are added to 3.1 mg of Rh(acac)(C2H4)2, 0.012 mmol of compound I.1 and 2 mmol of phenylboronic acid under argon. The reaction mixture is heated at 100° C. for 5 hours. After it has returned to room temperature, the solvents are evaporated off under reduced pressure. The residue obtained is dissolved in 20 ml of ethyl acetate, washed with 5 ml of saturated aqueous sodium hydrogencarbonate solution and then dried over sodium sulfate. The solvents are then evaporated off under reduced pressure. The product is purified by filtration on silica to isolate (S)-3-phenylcyclohexanone, which is characterized by the 1H NMR spectrum below.
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([C@@H:11]([O:15][C:16]2[CH:40]=[CH:39][C:19]([C:20]([C:22]3[CH:23]=[C:24]([CH2:31][CH2:32][CH2:33][C:34]([O:36]CC)=[O:35])[N:25]4[C:30]=3[CH:29]=[CH:28][CH:27]=[CH:26]4)=[O:21])=[CH:18][CH:17]=2)[CH2:12][CH2:13][CH3:14])=[CH:7][CH:6]=1)[CH:2]([CH3:4])[CH3:3].[OH-].[Na+].C(OCC)(=O)C.Cl>C(O)C.O1CCOCC1>[CH2:1]([C:5]1[CH:6]=[CH:7][C:8]([C@@H:11]([O:15][C:16]2[CH:17]=[CH:18][C:19]([C:20]([C:22]3[CH:23]=[C:24]([CH2:31][CH2:32][CH2:33][C:34]([OH:36])=[O:35])[N:25]4[C:30]=3[CH:29]=[CH:28][CH:27]=[CH:26]4)=[O:21])=[CH:39][CH:40]=2)[CH2:12][CH2:13][CH3:14])=[CH:9][CH:10]=1)[CH:2]([CH3:4])[CH3:3]
Reactant: CCC[C@H](Oc1ccc(C(=O)c2cc(CCCC(=O)OCC)n3ccccc23)cc1)c1ccc(CC(C)C)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CCC[C@H](Oc1ccc(C(=O)c2cc(CCCC(=O)O)n3ccccc23)cc1)c1ccc(CC(C)C)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 86.8 %

Procedure:
To a solution of ethyl 4-[1-[4-[(S)-1-(4-isobutylphenyl)butoxy]benzoyl]indolizin-3-yl]butyrate (282 mg) in ethanol (3 ml) and 1,4-dioxane (3 ml) was added 1N aqueous solution of sodium hydroxide (2 ml). The mixture was stirred at room temperature for 2 hours, and then poured into a mixture of ethyl acetate and 0.5N hydrochloric acid. The organic layer was separated, washed with water and brine, dried over magnesium sulfate and evaporated to give 4-[1-[4-[(S)-1-(4-isobutylphenyl)butoxy]benzoyl]- indolizin-3-yl]butyric acid (232 mg) as powder.
Reaction SMILES: [C:1]1([C:7]2[O:11][N:10]=[CH:9][C:8]=2/[CH:12]=[CH:13]/[C:14]([OH:16])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:17]([N:19](CC)CC)[CH3:18].C(Cl)(=O)OCC.C(N)C>O.O1CCCC1>[CH2:17]([NH:19][C:14](=[O:16])/[CH:13]=[CH:12]/[C:8]1[CH:9]=[N:10][O:11][C:7]=1[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[CH3:18]
Reactant: CCN(CC)CC
Reactant: O=C(O)/C=C/c1cnoc1-c1ccccc1
Agent: CCN
Agent: CCOC(=O)Cl
Solvent: C1CCOC1
Solvent: O
Product: CCNC(=O)/C=C/c1cnoc1-c1ccccc1
Temperature: -20 °C
Reaction time: 1 h
Yield: 91 %

Procedure:
To a mixture of (E)-3-(5-phenyl-4-isoxazolyl)propenoic acid (0.76 g), triethylamine (0.8 ml) and tetrahydrofuran (50 ml) was added ethyl chlorocarbonate (0.4 ml) at −30° C. and the mixture was stirred at −20° C. for 1 hr. To the obtained mixture was added aqueous ethylamine solution (1 ml), and the mixture was stirred at room temperature for 1 hr. The reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with dilute hydrochloric acid, saturated aqueous sodium hydrogencarbonate and then saturated brine, dried (MgSO4) and concentrated to give (E)-N-ethyl-3-(5-phenyl-4-isoxazolyl)propenamide (0.78 g, yield 91%) as colorless crystals. The crystals were recrystallized from acetone-hexane. melting point: 156–157° C.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[C:7]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[NH:8]2)=[CH:4][C:3]=1[CH3:16].[H-].[Na+].Cl[CH2:20][C:21]#[N:22].O>CN(C=O)C.C(OCC)(=O)C>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[C:7]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[N:8]2[CH2:20][C:21]#[N:22])=[CH:4][C:3]=1[CH3:16]
Reactant: N#CCCl
Reactant: CCOC(=O)c1cc2cc(C)c(Cl)cc2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cc2cc(C)c(Cl)cc2n1CC#N
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
A solution of ethyl 6-chloro-5-methylindole-2-carboxylate (1.5 g, 6.3 mmol) in DMF (30 mL) was added dropwise to a stirred suspension of sodium hydride (60%, 0.39 g, 10 mmol) in DMF (20 mL) at room temperature under Ar. The reaction was then cooled to 0° C. and stirred for 45 min then chloroacetonitrile (0.81 mL, 13 mmol) was added in one portion. The reaction was heated to 75° C. and stirred for 1 h. After allowing to cool to room temperature the mixture was poured into water (200 mL) and with ethyl acetate (3×100 mL). The combined organic extracts were washed with brine (1×100 mL), dried (magnesium sulfate), filtered and the solvent removed under vacuum to leave the crude product which was used immediately.
Reaction SMILES: [CH:1]([CH:4]1[CH2:8][CH2:7][C:6](=O)[CH:5]1[C:10]([O:12][CH3:13])=[O:11])([CH3:3])[CH3:2].C([O-])(=O)C.[NH4+:18]>CO>[NH2:18][C:6]1[CH2:7][CH2:8][CH:4]([CH:1]([CH3:3])[CH3:2])[C:5]=1[C:10]([O:12][CH3:13])=[O:11]
Reactant: [NH4+]
Reactant: COC(=O)C1C(=O)CCC1C(C)C
Agent: CC(=O)[O-]
Solvent: CO
Product: COC(=O)C1=C(N)CCC1C(C)C
Temperature: 50 °C
Reaction time: 8 h
Yield: 60.9 %

Procedure:
A solution of methyl 2-isopropyl-5-oxocyclopentanecarboxylate (5.4 g, 29.31 mmol) in MeOH (145 mL) was treated with ammonium acetate (22.59 g, 293.1 mmol), and the mixture was heated to 50° C. for 2 hours and stirred at room temperature overnight. The solvents were removed under reduced pressure, and the crude residue was taken up in DCM and H2O. The combined organics were washed with brine, dried Na2SO4, filtered, and concentrated. The crude residue was purified by column chromatography (5 then 15% EtOAc/Hexane) to yield pure methyl 2-amino-5-isopropylcyclopent-1-enecarboxylate (3.27 g, 61%). LCMS (APCI+) m/z 184.0 [M+H]+; Rt=3.51 min.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[N:8]([CH2:11][C@H:12]3[CH2:17][CH2:16][C@H:15]([CH3:18])[CH2:14][CH2:13]3)[CH:9]=[N:10][C:6]=2[CH:5]=[C:4]([Cl:19])[N:3]=1.[O:20]1[CH2:25][CH2:24][NH:23][C@@H:22]2[CH2:26][CH2:27][CH2:28][C@@H:21]12.C([Sn](CCCC)(CCCC)C1N=NC=CC=1)CCC>>[ClH:1].[Cl:1][C:2]1[C:7]2[N:8]([CH2:11][C@H:12]3[CH2:17][CH2:16][C@H:15]([CH3:18])[CH2:14][CH2:13]3)[C:9]([N:23]3[CH2:24][CH2:25][O:20][C@@H:21]4[CH2:28][CH2:27][CH2:26][C@@H:22]34)=[N:10][C:6]=2[CH:5]=[C:4]([Cl:19])[N:3]=1
Reactant: C1C[C@H]2NCCO[C@@H]2C1
Reactant: C[C@H]1CC[C@H](Cn2cnc3cc(Cl)nc(Cl)c32)CC1
Agent: CCCC[Sn](CCCC)(CCCC)c1cccnn1
Product: C[C@H]1CC[C@H](Cn2c(N3CCO[C@@H]4CCC[C@H]43)nc3cc(Cl)nc(Cl)c32)CC1
Product: Cl

Procedure:
Using a procedure analagous to that described in Example 2.1 (Steps 1 and 2) and starting with 4,6-dichloro-3-((trans-4-methylcyclohexyl)methyl)-3H-imidazo[4,5-c]pyridine (Preparative Example 2.3) and (trans)-octahydrocyclopenta[b][1,4]oxazine.HCl (purchased from Enamine), 4,6-dichloro-2-[(trans)-hexahydrocyclopenta[b][1,4]oxazin-4(4aH)-yl]-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridine (racemic) was prepared. Preparative Example 18.2 3-(tributylstannanyl)pyridazine
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([S:10]([C:13]3[CH:14]=[C:15]([OH:33])[C:16]4[O:25][C:24]5[CH2:23][CH2:22][N:21]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:20][C:19]=5[C:17]=4[CH:18]=3)(=[O:12])=[O:11])=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[OH-].[Na+].Cl[C:37]([O:39][CH2:40][CH3:41])=[O:38]>O.ClCCl>[CH2:40]([O:39][C:37]([N:1]1[C:9]2[C:4](=[CH:5][C:6]([S:10]([C:13]3[CH:14]=[C:15]([OH:33])[C:16]4[O:25][C:24]5[CH2:23][CH2:22][N:21]([C:26]([O:28][C:29]([CH3:30])([CH3:32])[CH3:31])=[O:27])[CH2:20][C:19]=5[C:17]=4[CH:18]=3)(=[O:12])=[O:11])=[CH:7][CH:8]=2)[CH:3]=[CH:2]1)=[O:38])[CH3:41]
Reactant: CC(C)(C)OC(=O)N1CCc2oc3c(O)cc(S(=O)(=O)c4ccc5[nH]ccc5c4)cc3c2C1
Reactant: CCOC(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)n1ccc2cc(S(=O)(=O)c3cc(O)c4oc5c(c4c3)CN(C(=O)OC(C)(C)C)CC5)ccc21
Reaction time: 2 h
Yield: 29.2 %

Procedure:
A mixture of the product of step B (90 mg, 0.19 mmol), sodium hydroxide (31 mg, 0.76 mmol) tetrabutylammonium hydrogen sulfate (13 mg, 0.04 mmol) and water (2 drops) in dichloromethane (10 mL) was stirred at ambient temperature for 5 min under an argon atmosphere before addition of ethyl chloroformate (24 μL, 0.25 mmol). The reaction mixture was stirred for 2 h before quenching with aqueous ammonium chloride (15 mL) and extracted with dichloromethane. The organic extract was washed with brine, dried over sodium sulfate and concentrated in vacuo. The residue was purified by flash column chromatography (SiO2, 30:70 hexane/ethyl acetate) to give tert-butyl 8-((1-(ethoxycarbonyl)-1H-indol-5-yl)sulfonyl)-6-hydroxy-3,4-dihydrobenzofuro[3,2-c]pyridine-2(1H)-carboxylate (30 mg, 29%) as a yellow solid: 1H NMR (CDCl3, 400 MHz) δ 8.25 (d, J=8.8 Hz, 1H), 8.20 (s, 1H), 7.85 (d, J=8.4 Hz, 1H), 7.78-7.52 (m, 2H), 7.43 (d, J=1.6 Hz, 1H), 6.70-6.63 (m, 1H), 4.54 (s, 2H), 4.50 (q, J=7.2 Hz, 2H), 3.89-3.72 (m, 2H), 2.91-2.77 (m, 2H), 1.51 (s, 9H), 1.46 (t, J=7.2 Hz, 3H).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[C:7](Br)[CH:8]=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:13]([NH:15][CH2:16][CH2:17][CH3:18])=[O:14].[Cl:19][C:20]1[C:25]([Cl:26])=[CH:24][CH:23]=[CH:22][C:21]=1B(O)O>>[NH2:1][C:2]1[C:11]2[C:6](=[C:7]([C:24]3[CH:23]=[CH:22][CH:21]=[C:20]([Cl:19])[C:25]=3[Cl:26])[CH:8]=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:13]([NH:15][CH2:16][CH2:17][CH3:18])=[O:14]
Reactant: CCCNC(=O)c1nnc2c(Br)cccc2c1N
Reactant: OB(O)c1cccc(Cl)c1Cl
Product: CCCNC(=O)c1nnc2c(-c3cccc(Cl)c3Cl)cccc2c1N
Yield: 80.6 %

Procedure:
Using method A, 4-amino-8-bromo-N-propyl-cinnoline-3-carboxamide (100 mg, 0.33 mmol) and 2,3-dichlorophenyl boronic acid (185 mg, 0.97 mmol) were reacted to afford the title compound (99.8 mg, 83.1% yield) as a pale-yellow solid. 1H NMR (300 MHz, CDCl3) δ 8.52 (br, 1H), 7.96 (dd, J=7.6 Hz, J′=2.1 Hz, 1H), 7.66-7.78 (m, 2H), 7.53 (dd, J=6.3 Hz, J′=3.3 Hz, 1H), 7.28-7.35 (m, 2H), 3.45 (q, J=6.7 Hz, 2H), 1.64 (m, J=7.3 Hz, 2H), 0.99 (t, J=7.4 Hz, 3H) MS APCI, m/z=375/377 (M+H) HPLC 2.19 min.
Reaction SMILES: O[C:2]1([CH3:13])[CH:7]([CH3:8])[C:6]([CH3:10])([CH3:9])[CH2:5][CH2:4][C:3]1([CH3:12])[CH3:11].C1(C)C=CC(S(O)(=O)=O)=CC=1.O.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC=CC=1>[CH3:8][C:7]1[C:6]([CH3:10])([CH3:9])[CH2:5][CH2:4][C:3]([CH3:12])([CH3:11])[C:2]=1[CH3:13]
Reactant: CC1C(C)(C)CCC(C)(C)C1(C)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: c1ccccc1
Product: CC1=C(C)C(C)(C)CCC1(C)C
Yield: 89.9 %

Procedure:
25.9 g of 1-hydroxy-1,2,2,5,5,6-hexamethylcyclohexane are dissolved in 600 ml of benzene and, after the addition of a spatula tip of p-toluenesulphonic acid, held at boiling temperature on a water separator for 3 hours. The mixture is cooled, treated with sodium carbonate, stirred briefly, filtered and the benzene is distilled off at normal pressure. Distillation of the residue gives 21 g of 1,2,3,3,6,6-hexamethyl-1-cyclohexene as a colourless liquid of boiling point 65°-67° C./10 mm Hg.
Reaction SMILES: [C:1]1([C:7]2[O:8][C:9]([CH2:22][CH2:23][CH3:24])=[C:10]([CH2:12][O:13][C:14]3[CH:21]=[CH:20][C:17]([CH:18]=[O:19])=[CH:16][CH:15]=3)[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O1CCCC1.C(O)C.[BH4-].[Na+]>O>[C:1]1([C:7]2[O:8][C:9]([CH2:22][CH2:23][CH3:24])=[C:10]([CH2:12][O:13][C:14]3[CH:15]=[CH:16][C:17]([CH2:18][OH:19])=[CH:20][CH:21]=3)[N:11]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCCc1oc(-c2ccccc2)nc1COc1ccc(C=O)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: C1CCOC1
Product: CCCc1oc(-c2ccccc2)nc1COc1ccc(CO)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 66.3 %

Procedure:
To a mixture of 4-[(2-phenyl-5-propyl-4-oxazolyl)methoxy]benzaldehyde (2.40 g), tetrahydrofuran (30 ml) and ethanol (10 mL) was added sodium borohydride (0.28 g) at room temperature and the mixture was stirred at room temperature for 1 hr. To, the reaction mixture was added water and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated. The obtained residue was subjected to silica gel column chromatography to give crystals (1.60 g, 66%) of [4-[(2-phenyl-5-propyl-4-oxazolyl)methoxy]phenyl]methanol from a fraction eluted with ethyl acetate-hexane (1:1, v/v). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 79-80° C.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH2:7][CH2:6][CH2:5]2.[CH:12]([O:15][C:16]1[CH:24]=[CH:23][C:22]([S:25]([CH3:28])(=[O:27])=[O:26])=[CH:21][C:17]=1[C:18](O)=[O:19])([CH3:14])[CH3:13]>CC(O)=O>[CH:12]([O:15][C:16]1[CH:24]=[CH:23][C:22]([S:25]([CH3:28])(=[O:27])=[O:26])=[CH:21][C:17]=1[C:18]([N:8]1[C:9]2[C:4](=[CH:3][C:2]([CH3:1])=[CH:11][CH:10]=2)[CH2:5][CH2:6][CH2:7]1)=[O:19])([CH3:14])[CH3:13]
Reactant: CC(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)O
Reactant: Cc1ccc2c(c1)CCCN2
Solvent: CC(=O)O
Product: Cc1ccc2c(c1)CCCN2C(=O)c1cc(S(C)(=O)=O)ccc1OC(C)C

Procedure:
Prepared in analogy to example 1.1 from 6-methyl-1,2,3,4-tetrahydro-quinoline (CA [91-61-2]) and 2-isopropoxy-5-methanesulfonyl-benzoic acid (Example 2.1). MS (m/e): 445.9 (M+CH3COOH).
Reaction SMILES: C([O:3][C:4]([C:6]1([NH:16][C:17]([C:19]2[C:28]3[CH2:27][CH2:26][CH2:25][CH2:24][C:23]=3[CH:22]=[CH:21][CH:20]=2)=[O:18])[CH2:14][C:13]2[CH:12]=[N:11][C:10]([CH3:15])=[CH:9][C:8]=2[CH2:7]1)=[O:5])C.[OH-].[K+]>CCO.O>[CH3:15][C:10]1[N:11]=[CH:12][C:13]2[CH2:14][C:6]([NH:16][C:17]([C:19]3[C:28]4[CH2:27][CH2:26][CH2:25][CH2:24][C:23]=4[CH:22]=[CH:21][CH:20]=3)=[O:18])([C:4]([OH:5])=[O:3])[CH2:7][C:8]=2[CH:9]=1
Reactant: CCOC(=O)C1(NC(=O)c2cccc3c2CCCC3)Cc2cnc(C)cc2C1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cc1cc2c(cn1)CC(NC(=O)c1cccc3c1CCCC3)(C(=O)O)C2
Temperature: 25 °C
Reaction time: 3 h
Yield: 22 %

Procedure:
The mixture of 3-methyl-6-[(5,6,7,8-tetrahydro-naphthalene-1-carbonyl)-amino]-6,7-dihydro-5H-[2]pyrindine-6-carboxylic acid ethyl ester (82) and KOH (1 g, 17.9 mmol) in EtOH (5 mL) and water (0.3 mL) under a water bath. The water bath is removed when KOH is completely dissolved and the resulting reaction solution is stirred at RT for 3 h. After concentration in vacuo, the residue is dissolved in water (20 mL) and acidified with conc. HCl dropwise until no more precipitate came out of the water. After the filtration, the solid is purified by HPLC to give a pure product (83) as colorless oil (20 mg, 22%).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[CH:21]=[CH:20][C:19]([N+:22]([O-])=O)=[CH:18][C:11]=1[O:12][CH2:13][CH2:14][N:15]([CH3:17])[CH3:16].O.O.[Sn](Cl)Cl.CO>CCO>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][C:11]=1[O:12][CH2:13][CH2:14][N:15]([CH3:17])[CH3:16]
Reactant: CN(C)CCOc1cc([N+](=O)[O-])ccc1-c1nc2ccccc2s1
Agent: Cl[Sn]Cl
Solvent: O
Solvent: CO
Solvent: CCO
Product: CN(C)CCOc1cc(N)ccc1-c1nc2ccccc2s1
Yield: 76 %

Procedure:
Prepared as described in the Nitro Reduction section using 2-[2-(1,3-benzothiazol-2-yl)-5-nitrophenoxy]-N,N-dimethylethanamine (0.073 g, 0.21 mmol) and tin (II) dichloride dihydrate (0.38 g, 1.7 mmol) in EtOH (7 ml) to give the title compound (0.05 g, 75%) as a cream-coloured solid after work-up and flash chromatography (MeOH).
Reaction SMILES: C1C=CC(C2C=CC=CC=2)=CC=1.C1C=CC(OC2C=CC=CC=2)=CC=1.C1(OC2C=CC=CC=2)C=CC=CC=1.C([O:43][C:44](=O)[CH:45]=[C:46]([NH:59][C:60]1[CH:65]=[CH:64][C:63]([NH:66][C:67](=[O:69])[CH3:68])=[CH:62][CH:61]=1)[C:47]1[CH:52]=[CH:51][C:50]([CH:53]2[CH2:58][CH2:57][CH2:56][CH2:55][CH2:54]2)=[CH:49][CH:48]=1)CCC>CCCCCC>[CH:53]1([C:50]2[CH:49]=[CH:48][C:47]([C:46]3[CH:45]=[C:44]([OH:43])[C:65]4[C:60](=[CH:61][CH:62]=[C:63]([NH:66][C:67](=[O:69])[CH3:68])[CH:64]=4)[N:59]=3)=[CH:52][CH:51]=2)[CH2:54][CH2:55][CH2:56][CH2:57][CH2:58]1
Reactant: CCCCOC(=O)C=C(Nc1ccc(NC(C)=O)cc1)c1ccc(C2CCCCC2)cc1
Solvent: c1ccc(-c2ccccc2)cc1
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: CCCCCC
Product: CC(=O)Nc1ccc2nc(-c3ccc(C4CCCCC4)cc3)cc(O)c2c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Into a 2 L three-neck round-bottom flask equipped with a condenser, magnetic stirrer, thermocouple, heating mantle with a variable voltage controller, and a nitrogen inlet, was charged 1.2 L of Dowtherm A (a eutectic mixture of 26.5% diphenyl and 73.5% diphenyl oxide). The Dowtherm A was then preheated to 250° C. To this was cautiously added in small portions 48 g (0.11 moles) of 3-(4-acetylamino-phenylamino)-3-(4-cyclohexylphenyl)-acrylic acid butyl ester. As portions were added gas was evolved and foaming occurred. Crystals of product begin to form and adhere to the sides. After all the material had been added the heating of the reaction was continued for 1 hour. The mixture was then cooled to room temperature and hexane was added. The solid product was collected by vacuum filtration and washed with hexane. After drying in a vacuum oven, 35.7 g (90%) of product was recovered.
Reaction SMILES: C([O:8][C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1[CH:11]=[C:12]([C:19]([OH:21])=O)[N:13]2[CH3:18])C1C=CC=CC=1.[Cl:22][C:23]1[CH:30]=[CH:29][C:26]([CH2:27][NH2:28])=[CH:25][CH:24]=1>>[Cl:22][C:23]1[CH:30]=[CH:29][C:26]([CH2:27][NH:28][C:19]([C:12]2[N:13]([CH3:18])[C:14]3[C:10]([CH:11]=2)=[C:9]([OH:8])[CH:17]=[CH:16][CH:15]=3)=[O:21])=[CH:25][CH:24]=1
Reactant: NCc1ccc(Cl)cc1
Reactant: Cn1c(C(=O)O)cc2c(OCc3ccccc3)cccc21
Product: Cn1c(C(=O)NCc2ccc(Cl)cc2)cc2c(O)cccc21

Procedure:
From 4-benzyloxy-1-methyl-1H-indole-2-carboxylic acid and 4-chlorobenzylamine the title compound was prepared by a method analogous to that described in Example 11. MS ES (M++H)=315 and 317.
Reaction SMILES: Br[C:2]1[CH:36]=[CH:35][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([S:13]([N:16](CC3C=CC(OC)=CC=3OC)[C:17]3[S:18][CH:19]=[CH:20][N:21]=3)(=[O:15])=[O:14])=[CH:9][C:8]=2[C:33]#[N:34])=[C:4]([C:37]2[N:38]([CH3:42])[N:39]=[CH:40][CH:41]=2)[CH:3]=1.[CH3:43][O:44][C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][C:46]=1B(O)O.C(=O)([O-])[O-].[K+].[K+].FC(F)(F)C(O)=O>C1(C)C=CC=CC=1.C(Cl)Cl.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:33]([C:8]1[CH:9]=[C:10]([S:13]([NH:16][C:17]2[S:18][CH:19]=[CH:20][N:21]=2)(=[O:15])=[O:14])[CH:11]=[CH:12][C:7]=1[O:6][C:5]1[CH:35]=[CH:36][C:2]([C:46]2[CH:47]=[CH:48][CH:49]=[CH:50][C:45]=2[O:44][CH3:43])=[CH:3][C:4]=1[C:37]1[N:38]([CH3:42])[N:39]=[CH:40][CH:41]=1)#[N:34]
Reactant: COc1ccccc1B(O)O
Reactant: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc(Oc3ccc(Br)cc3-c3ccnn3C)c(C#N)c2)c(OC)c1
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: [K+]
Solvent: Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccccc1-c1ccc(Oc2ccc(S(=O)(=O)Nc3nccs3)cc2C#N)c(-c2ccnn2C)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 62.1 %

Procedure:
To a solution of 4-[4-bromo-2-(2-methyl-2H-pyrazol-3-yl)-phenoxy]-3-cyano-N-(2,4-dimethoxy-benzyl)-N-thiazol-2-yl-benzenesulfonamide (Preparation 88, 98.5 mg, 0.148 mmol), 2-methoxyphenylboronic acid (48 mg, 0.32 mmol), and potassium carbonate (62.5 mg, 0.452 mmol) in toluene (3 mL) was added tetrakis(triphenylphosphine)palladium(0) (22.5 mg, 0.0195 mmol) and the mixture was sparged two times with argon. The reaction mixture was then heated at reflux for 4.5 hours and then allowed to cool to room temperature. The reaction mixture was diluted with ethyl acetate and washed with water and saturated sodium chloride solution. The organic layer was dried over anhydrous MgSO4, filtered, and concentrated in vacuo. The residue was purified by automated flash column chromatography using a 0-100% EtOAc/hexanes gradient to give a clear oil. This oil was dissolved in methylene chloride (5 mL) and treated with trifluoroacetic acid (1 mL, 10 mmol). After stirring for 1 hour, the reaction mixture was concentrated in vacuo and purified by automated flash column chromatography (0%-5% methanol in dichloromethane gradient elution) to yield the title compound (50 mg, 61%) as a white solid.