Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+](C1C=CC=CC=1)([O-])=O.[OH:10][C:11]1[CH:16]=[C:15]([OH:17])[CH:14]=[C:13]([OH:18])[CH:12]=1.[Cl-].[Al+3].[Cl-].[Cl-].[CH3:23][CH:24]([CH2:29][CH2:30][CH2:31][CH:32]([CH3:34])[CH3:33])[CH2:25][C:26](Cl)=[O:27].Cl>C(=S)=S>[OH:10][C:11]1[CH:16]=[C:15]([OH:17])[CH:14]=[C:13]([OH:18])[C:12]=1[C:26]([CH2:25][CH:24]([CH3:23])[CH2:29][CH2:30][CH2:31][CH:32]([CH3:34])[CH3:33])=[O:27]
Reactant: Oc1cc(O)cc(O)c1
Reactant: CC(C)CCCC(C)CC(=O)Cl
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O=[N+]([O-])c1ccccc1
Solvent: S=C=S
Product: CC(C)CCCC(C)CC(=O)c1c(O)cc(O)cc1O
Temperature: 0 °C
Reaction time: 2 h
Yield: 63 %

Procedure:
Under the atmosphere of nitrogen, a solvent mixture of 27 ml of nitrobenzene and 23 ml of carbon disulfide was added to 6.613 g (52.4 mmol) of 1,3,5-trihydroxybenzene (1). To the mixture, 21 g (157.2 mmol, 3 equivalents) of granular aluminum chloride was added cooling with ice and stirred for two hours. Into the mixture thus formed, was added a nitrobenzene (8 ml) solution of 10.87 g (57.0 mmol, 1.09 equivalents) of 3,7-dimethyl-octanoyl chloride dropwise and were stirred at room temperature for 21 hours. The reaction mixture was poured into a cold dilute hydrochloric acid solution prepared by adding 5 ml of concentrated hydrochloric acid to 200 ml of ice and stirred and extracted from ether. The organic layer was washed with saturated brine, dried over sodium sulfate, and distilled under a reduced pressure to remove the solvent. To the residue of distillation, a large volume of water was added and were distilled under reduced pressure to remove nitrobenzene solvent by steam distillation method. The residue was extracted from ether, washed with saturated brine, dried over sodium sulfate, and distilled under a reduced pressure to remove the solvent and obtain a crude reaction product. By subjecting the crude product to silica gel column chromatography (using 100 g of Wako Gel C-200, elution with hexane:ethyl acetate=7:3), 9.25 g of (2,4,6-trihydroxyphenyl) (2,6-dimethylheptyl) ketone (6) was obtained in the form of an oily substance.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:39]=[CH:38][C:9]([CH2:10][NH:11][C:12]2[N:17]=[C:16]([O:18][CH2:19][C:20]([F:23])([F:22])[F:21])[N:15]=[C:14]([NH:24][C:25]3[CH:37]=[CH:36][C:28]([C:29]([O:31]C(C)(C)C)=[O:30])=[CH:27][CH:26]=3)[CH:13]=2)=[CH:8][CH:7]=1.Cl>O1CCOCC1>[Br:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[CH:8][C:9]([CH2:10][NH:11][C:12]2[N:17]=[C:16]([O:18][CH2:19][C:20]([F:23])([F:22])[F:21])[N:15]=[C:14]([NH:24][C:25]3[CH:26]=[CH:27][C:28]([C:29]([OH:31])=[O:30])=[CH:36][CH:37]=3)[CH:13]=2)=[CH:38][CH:39]=1
Reactant: CC(C)(C)OC(=O)c1ccc(Nc2cc(NCc3ccc(OCCCBr)cc3)nc(OCC(F)(F)F)n2)cc1
Agent: Cl
Solvent: C1COCCO1
Product: O=C(O)c1ccc(Nc2cc(NCc3ccc(OCCCBr)cc3)nc(OCC(F)(F)F)n2)cc1

Procedure:
Tert-butyl 4-((6-((4-(3-bromopropoxy)benzyl)amino)-2-(2,2,2-trifluoroethoxy)pyrimidin-4-yl)amino)benzoate (90 mg, 0.15 mmol) and 4 N HCl in dioxane (2 mL) were stirred for 10 mins then concentrated under vacuum to give 4-((6-((4-(3-bromopropoxy)benzyl)amino)-2-(2,2,2-trifluoroethoxy)pyrimidin-4-yl)amino)benzoic acid which was carried to the next step without purification.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8](Br)=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2.[C:12]([Cu])#[N:13].N>CN(C=O)C.CO>[F:1][C:2]1[CH:10]=[CH:9][C:8]([C:12]#[N:13])=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2
Reactant: N#C[Cu]
Reactant: Fc1ccc(Br)c2[nH]ccc12
Agent: N
Solvent: CO
Solvent: CN(C)C=O
Product: N#Cc1ccc(F)c2cc[nH]c12
Temperature: 25 °C
Yield: 69.1 %

Procedure:
Intermediate 1 was prepared according to procedures described in Wallace, O. B. et al. PCT int. appl. WO0204440, and as described in Steps A-D below. Step A A mixture of 4-fluoro-7-bromoindole (600 mg, 2.8 mmol) and CuCN (1.004 g, 11.2 mmol) in DMF (4 ml) was refluxed for 16 hours. After cooling to room temperature, the reaction mixture was poured into a solution of ammonia in MeOH (30 ml, sat.) and the residue removed by filtration. The filtrate was added to a mixture of water (20 ml)/ammonia (20 ml, sat. aq.) and extracted with EtOAc/Ether (1/1) until TLC analysis showed no product in the aqueous phase. The combined organic extracts were washed with brine (2×200 ml) and water (200 ml), dried (MgSO4); evaporation in vacuo gave 4-fluoro-7-cyanoindole as a tan yellow solid (310 mg, 69%). Step B To a solution of KOH (13.04 g, 0.232 mol) in 14% H2O/EtOH (50 ml) was added 4-fluoro-7-cyanoindole (900 mg, 5.60 mmol). The resulting mixture was refluxed for 12 hours, slowly cooled to room temperature, and concentrated in vacuo to about 30 ml. The residue was acidified to pH 2 with HCl (˜5.5 N aq.). The precipitate was filtered, washed with excess of water, and dried under high vacuum to afford 4-fluoro-7-carboxyindole as a white solid (100% conversion). The material was used without further purification. Step C To a suspension of 4-fluoro-7-carboxyindole in a mixture of MeOH (18 ml)/PhH (62 ml) was added (trimethylsilyl)diazomethane (8.8 ml, 17.6 mmol, 2 M in hexane). The resulting mixture was stirred at room temperature for 30 min., quenched with excess acetic acid and evaporated in vacuo. The crude oily material was purified by flash chromatography using a gradient elution (Hexane to 10% EtOAc/Hexane) to afford 4-fluoro-7-carbomethoxy indole as a white solid (1.04 g, 83% two steps). Step D
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][S:9]([CH2:12][C:13]([OH:15])=O)(=[O:11])=[O:10])=[C:4]([C:16]([F:19])([F:18])[F:17])[CH:3]=1.Cl.[CH2:21]([O:23][C:24](=[O:28])[C@H:25]([CH3:27])[NH2:26])[CH3:22].O.OC1C2N=NNC=2C=CC=1.C(N(CC)CC)C>>[CH2:21]([O:23][C:24](=[O:28])[CH:25]([NH:26][C:13](=[O:15])[CH2:12][S:9](=[O:10])(=[O:11])[NH:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][C:4]=1[C:16]([F:19])([F:18])[F:17])[CH3:27])[CH3:22]
Reactant: CCOC(=O)[C@H](C)N
Reactant: O=C(O)CS(=O)(=O)Nc1ccc(F)cc1C(F)(F)F
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: O
Solvent: CCN(CC)CC
Product: CCOC(=O)C(C)NC(=O)CS(=O)(=O)Nc1ccc(F)cc1C(F)(F)F

Procedure:
Under the conditions of Example 2(a), 3.012 g (10 mmol) of 2-[2-[N-(4-Fluoro-2-trifluoromethylphenyl)sulfamoyl]acetic acid, 1.536 g (10 mmol) of L-alanine ethyl ester hydrochloride, 1.531 g (10 mmol) of hydroxybenzotriazole, hydrate, as well as 1.012 g (10 mmol) of triethylamine are reacted and worked up in analogous fashion. The crude product is chromatographed on silica gel. The title compound is eluted with ethyl acetate.
Reaction SMILES: [Mg].Br[C:3]1[S:4][CH:5]=[CH:6][CH:7]=1.Br[C:9]1[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][C:10]=1[F:16]>C1COCC1.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>[F:16][C:10]1[CH:11]=[C:12]([CH3:15])[CH:13]=[CH:14][C:9]=1[C:3]1[S:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccc(Br)c(F)c1
Reactant: Brc1cccs1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Mg]
Solvent: C1CCOC1
Product: Cc1ccc(-c2cccs2)c(F)c1
Temperature: 25 °C
Yield: 71.8 %

Procedure:
To a mixture of magnesium (0.25 g, 10.58 mmol) in anhydrous THF (5.3 mL) was added 2-bromothiophene (1.73 g, 10.58 mmol) dropwise. The mixture was heated at reflux under argon for 0.5 h. An additional 0.35 g of 2-bromothiophene was added to consume the remaining magnesium. The reaction mixture was heated for additional 1.5 h to afford a solution which was transferred to a mixture of 1-bromo-2-fluoro-4-methylbenzene (2.0 g, 10.58 mmol), Pd(PPh3)4 (0.61 g, 0.53 mmol), and THF (23.5 mL). The resulting mixture was heated under argon for 3 h. The reaction was allowed to cool to rt and quenched with water. The mixture was extracted with CH2Cl2. The organic layer was dried over MgSO4 and concentrated down under reduced pressure. The crude product was purified by flash column chromatography eluting with hexane to afford a colorless liquid (1.46 g, 72%): 1H NMR (CDCl3), δ 7.48-7.02 (m, 6H), 2.36 (s, 3H), GC/MS m/z 192 (M+, 100).
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]([CH2:7]P(OC)(OC)=O)=[O:6].[CH3:14][C:15]([NH:19][C:20]1[S:21][CH:22]=[C:23]([C:25]2[CH:32]=[CH:31][C:28]([C:29]#[N:30])=[CH:27][CH:26]=2)[N:24]=1)([CH3:18])[CH:16]=O>O1CCCC1>[C:29]([C:28]1[CH:27]=[CH:26][C:25]([C:23]2[N:24]=[C:20]([NH:19][C:15]([CH3:18])([CH3:16])/[CH:14]=[CH:7]/[C:5]([O:4][CH3:3])=[O:6])[S:21][CH:22]=2)=[CH:32][CH:31]=1)#[N:30]
Reactant: COC(=O)CP(=O)(OC)OC
Reactant: CC(C)(C=O)Nc1nc(-c2ccc(C#N)cc2)cs1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)/C=C/C(C)(C)Nc1nc(-c2ccc(C#N)cc2)cs1
Reaction time: 0.75 h
Yield: 92.6 %

Procedure:
To a suspension of sodium hydride (60% in oil, 0.17 g, 4.5 mmol) in tetrahydrofuran (30 mL) was added trimethyl phosphonoacetate (0.75 mL, 5.2 mmol) dropwise and the mixture was stirred for 45 min. A solution of 4-{2-[(1,1-dimethyl-2-oxoethyl)amino]-1,3-thiazol-4-yl}benzonitrile (0.81 g, 3.0 mmol), prepared in step 1 of Example 83, in 5 mL of tetrahydrofuran was added and the mixture was stirred at 25° C. for 2 h. The reaction was quenched with saturated NH4Cl and diluted with ethyl acetate and washed with H2O, brine, dried over anhydrous MgSO4, filtered and concentrated. Flash chromatography (20% acetone/hexane) afforded methyl (2E)-4-{[4-(4-cyanophenyl)-1,3-thiazol-2-yl]amino}-4-methylpent-2-enoate (0.91 g, 93%) as a white solid. HRMS: calcd for C17H17N3O2S+H+, 328.11142; found (ESI, [M+H]+), 328.1135; Analytical HPLC: purity 100% at 210-370 nm, 9.9 min; 100% at 252 nm, 9.9 min; the Xterra® RP18 column, 3.5μ, 150×4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. pH=3.5/ACN+MeOH) for 10 min, hold 4 min.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[N:17]=[C:16]([NH:18][C:19]3[CH:20]=[C:21]4[C:25](=[CH:26][CH:27]=3)[N:24]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[N:23]=[CH:22]4)[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[N:35]([CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)=[C:36]=[O:37].CCN(CC)CC>C(Cl)Cl>[CH2:38]([NH:35][C:36](=[O:37])[NH:1][C:2]1[CH:3]=[C:4]([C:8]2[N:17]=[C:16]([NH:18][C:19]3[CH:20]=[C:21]4[C:25](=[CH:26][CH:27]=3)[N:24]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[N:23]=[CH:22]4)[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1)[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1
Reactant: CC(C)(C)OC(=O)n1ncc2cc(Nc3nc(-c4cccc(N)c4)nc4ccccc34)ccc21
Reactant: O=C=NCc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)n1ncc2cc(Nc3nc(-c4cccc(NC(=O)NCc5ccccc5)c4)nc4ccccc34)ccc21
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a suspension of tert-butyl 5-(2-(3-aminophenyl)quinazolin-4-ylamino)-1H-indazole-1-carboxylate (150 mg, 0.33 mmol) and 1-(isocyanatomethyl)benzene (162 μL, 1.32 mmol) in CH2Cl2 (2 mL) was added Et3N (1.38 mL, 9.9 mmol). The reaction mixture was stirred at RT for 4 h and concentrated in vacuo. The residue was triturated using MeOH and drops of CH2Cl2 to afford tert-butyl 5-(2-(3-(3-benzylureido)phenyl)quinazolin-4-ylamino)-1H-indazole-1-carboxylate. (100 mg, 52%)
Reaction SMILES: [C:1]1([N:7]2[CH:11]=[CH:10][CH:9]=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CN([CH:15]=[O:16])C.O=P(Cl)(Cl)Cl>>[C:1]1([N:7]2[CH:11]=[C:10]([CH:15]=[O:16])[CH:9]=[N:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: c1ccc(-n2cccn2)cc1
Reactant: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: O=Cc1cnn(-c2ccccc2)c1
Temperature: 106 °C
Reaction time: 0.17 h
Yield: 112.7 %

Procedure:
1-Phenyl-1H-pyrazole (250 mg, 1.7 mmol) was added to a cold (0-4° C.) solution of DMF (1.5 g, 1.6 mL, 9.7 mmol) and POCl3 (1.86 g, 1.1 mL, 19.2 mmol) and stirring continued for 10 minutes. The resulting mixture was heated at 106° C. for 2.5 hrs. The reaction mixture was cooled and quenched with ice cold water, basified with 20% aqueous NaOH solution, filtered the solid precipitated to afford 330 mg (crude) of 1-Phenyl-1H-pyrazole-4-carbaldehyde. 1H NMR (CDCl3): δ 10.0 (s, 1H), 8.45 (s, 1H), 8.2 (s, 1H), 7.75 (d, 2H), 7.55 (t, 2H), 7.45 (t, 1H).
Reaction SMILES: [N+]([O-])(O)=O.[N+:5]([O:8][CH2:9][CH2:10][NH2:11])([O-:7])=[O:6].[O:12]=[C:13]1[NH:17][CH:16]([C:18](O)=[O:19])[CH:15]([C:21]2[S:22][CH:23]=[CH:24][CH:25]=2)[S:14]1>>[N+:5]([O:8][CH2:9][CH2:10][NH:11][C:18]([CH:16]1[CH:15]([C:21]2[S:22][CH:23]=[CH:24][CH:25]=2)[S:14][C:13](=[O:12])[NH:17]1)=[O:19])([O-:7])=[O:6]
Reactant: NCCO[N+](=O)[O-]
Reactant: O=C1NC(C(=O)O)C(c2cccs2)S1
Solvent: O=[N+]([O-])O
Product: O=C1NC(C(=O)NCCO[N+](=O)[O-])C(c2cccs2)S1

Procedure:
A procedure similar to that described in Example 1 was repeated, but using 350 mg of N-(2-nitrooxyethyl)-amine nitrate and 400 mg of 2-oxo-5-(2-thienyl)thiazolidine-4-carboxylic acid, to obtain 260 mg of the title compound as colorless crystals, melting at 120°-122° C. (after recrystallization from ethanol).
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4](/[C:6](/Cl)=[N:7]\[OH:8])=[O:5].[Cl:10][C:11]1[CH:16]=[C:15]([C:17]([C:19](F)(F)F)=[CH2:18])[CH:14]=[C:13]([Cl:23])[CH:12]=1.C(=O)([O-])O.[Na+]>C(OC(=O)C)C>[CH2:2]([O:3][C:4]([C:6]1[CH2:18][C:17]([C:15]2[CH:14]=[C:13]([Cl:23])[CH:12]=[C:11]([Cl:10])[CH:16]=2)([CH3:19])[O:8][N:7]=1)=[O:5])[CH3:1]
Reactant: CCOC(=O)/C(Cl)=N\O
Reactant: C=C(c1cc(Cl)cc(Cl)c1)C(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CCOC(=O)C1=NOC(C)(c2cc(Cl)cc(Cl)c2)C1

Procedure:
A solution of ethyl chlorooximidoacetate (9.0 g, 59.1 mmol) in ethylacetate (30 ml) was added at ambient temperature with a syringe pump over a period of 40 h to a suspension of 1,3-dichloro-5-(3,3,3-trifluoroprop-1-en-2-yl)benzene (prepared according to WO 2005/085216) (9.5 g, 39.4 mmol) and sodium hydrogen carbonate (15.9 g, 189 mmol) in ethylacetate (85 ml). The reaction mixture was diluted with ethylacetate and washed with water. The organic phase was separated dried over sodium sulfate and concentrated. The residue was purified by chromatography over silica (cyclohexane/ethylacetate; 4/1) to give 8.9 of a yellow oil. 1H-NMR (CDCl3, 400 MHz): 7.45 (m, 3H), 4.49 (q, 2H), 3.96 (d, 1H), 3.59 (d, 1H), 1.40 (t, 3H).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C:5]1([CH3:14])[CH:10]=[CH:9][C:8]([C:11](Cl)=[O:12])=[CH:7][CH:6]=1.[C:15]1([S:21]([N:24]2[CH:28]=[CH:27][CH:26]=[CH:25]2)(=[O:23])=[O:22])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>ClC(Cl)C>[CH3:14][C:5]1[CH:10]=[CH:9][C:8]([C:11]([C:25]2[N:24]([S:21]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)(=[O:22])=[O:23])[CH:28]=[CH:27][CH:26]=2)=[O:12])=[CH:7][CH:6]=1
Reactant: Cc1ccc(C(=O)Cl)cc1
Reactant: O=S(=O)(c1ccccc1)n1cccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: CC(Cl)Cl
Product: Cc1ccc(C(=O)c2cccn2S(=O)(=O)c2ccccc2)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 105.1 %

Procedure:
Under nitrogen atmosphere, to a suspension of aluminum chloride (4.62 g) in dichloroethane (50 mL) was added a solution of p-toluoyl chloride (4.91 g) in dichloroethane (5 mL) at room temperature over a period of 10 minutes. After stirring for 30 minutes, to the mixture was added a solution of 1-benzenesulfonyl-1H-pyrrole (6.00 g) in dichloroethane (10 mL) over a period of 10 minutes. The mixture was stirred at room temperature for 2 hours, and the reaction mixture was poured into ice water, and the aqueous layer was extracted twice with methylene chloride. The organic layers were combined, dried, filtered and concentrated. The residue was purified by silica gel column chromatography to give (1-benzenesulfonyl-1H-pyrrol-2-yl) (4- methyl-phenyl) ketone (9.9 g, 100%).
Reaction SMILES: C(N(CC)CC)C.[NH2:8][C:9]1[CH:10]=[C:11]([CH:24]=[CH:25][C:26]=1[CH3:27])[C:12]([NH:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([N:21]([CH3:23])[CH3:22])[CH:16]=1)=[O:13].[CH3:28][C:29]1[O:33][N:32]=[C:31]([C:34](Cl)=[O:35])[CH:30]=1>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH3:22][N:21]([CH3:23])[C:17]1[CH:16]=[C:15]([NH:14][C:12](=[O:13])[C:11]2[CH:24]=[CH:25][C:26]([CH3:27])=[C:9]([NH:8][C:34]([C:31]3[CH:30]=[C:29]([CH3:28])[O:33][N:32]=3)=[O:35])[CH:10]=2)[CH:20]=[CH:19][CH:18]=1
Reactant: Cc1cc(C(=O)Cl)no1
Reactant: Cc1ccc(C(=O)Nc2cccc(N(C)C)c2)cc1N
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc(C(=O)Nc2cc(C(=O)Nc3cccc(N(C)C)c3)ccc2C)no1
Yield: 71.2 %

Procedure:
Triethylamine (0.129 ml) was added to a stirred mixture of 3-amino-N-(3-dimethylaminophenyl)-4-methylbenzamide (0.1 g), 4-dimethylaminopyridine (5 mg), 5-methylisoxazol-3-ylcarbonyl chloride (0.081 g) and methylene chloride (3 ml) and the resultant mixture was stirred at ambient temperature for 16 hours. The mixture was diluted with methylene chloride (10 ml), washed with a saturated aqueous sodium bicarbonate solution and dried over magnesium sulphate. The organic solution was evaporated and the residue was triturated under isohexane. The resultant solid was dried at 55° C. under vacuum to give the title compound as a solid (0.1 g); NMR Spectrum: (CDCl3) 2.42 (s, 3H), 2.55 (s, 3H), 2.97 (s, 6H), 6.55 (m, 2H), 6.89 (d, 1H), 7.23 (m, 2H), 7.36 (d, 1H), 7.72 (d, 1H), 7.84 (broad s, 1H), 8.55 (broad s, 2H); Mass Spectrum: M+H+ 379.
Reaction SMILES: [C:1]([OH:6])(=[O:5])[C:2]([OH:4])=[O:3].[CH3:7][CH:8]([NH:20][CH2:21][CH:22]([OH:37])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[O:29]CC1C=CC=CC=1)[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([O:18][CH3:19])[CH:11]=1.CO>[H][H].[C].[Pd]>[C:1]([OH:6])(=[O:5])[C:2]([OH:4])=[O:3].[CH3:7][CH:8]([NH:20][CH2:21][CH:22]([OH:37])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[OH:29])[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([O:18][CH3:19])[CH:11]=1
Reactant: [H][H]
Reactant: COc1ccc(CC(C)NCC(O)c2ccccc2OCc2ccccc2)cc1OC
Agent: [Pd]
Agent: O=C(O)C(=O)O
Solvent: CO
Product: COc1ccc(CC(C)NCC(O)c2ccccc2O)cc1OC

Procedure:
A mixture of one g of α-[(α-methyl-3,4-dimethoxyphenethylamino)methyl]-2-benzyloxybenzylalcohol oxalate [the diastereoisomer of M.p. 152°-153° C. (decomp.)], 0.2 g of 10% palladium-carbon and 15 ml of 90% aqueous methanol is shaken at room temperature in hydrogen atmosphere under atmospheric pressure. After hydrogen uptake is completed, insoluble materials are removed by filtration, and the filtrate is condensed. The residue thus obtained is recrystallized from ethanol. 0.72 g of α-[(α-methyl-3,4-dimethoxyphenethylamino)methyl]-2-hydroxybenzylalcohol oxalate [the diastereoisomer of M.p. 155°-156° C. (decomp.)] is obtained.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.C(COC)OC.CC(C)([O-])C.[Na+].Br[CH2:28][C:29]1[CH:34]=[CH:33][C:32]([O:35][C:36]([F:39])([F:38])[F:37])=[CH:31][CH:30]=1>O>[F:37][C:36]([F:38])([F:39])[O:35][C:32]1[CH:33]=[CH:34][C:29]([CH2:28][O:1][CH:2]2[CH2:3][CH2:4][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:6][CH2:7]2)=[CH:30][CH:31]=1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: FC(F)(F)Oc1ccc(CBr)cc1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: CC(C)(C)OC(=O)N1CCC(OCc2ccc(OC(F)(F)F)cc2)CC1
Temperature: 9.5 °C
Reaction time: 0.5 h

Procedure:
10.00 kg of tert-butyl 4-hydroxypiperidin-1-carboxylate, 40 L of dimethoxyethane and 9.55 kg of sodium tert-butoxide were mixed, and stirred at 2 to 17° C. for 30 min. The mixture was mixed with 13.31 kg of 4-bromomethyl-1-trifluoromethoxybenzene and 10 L of dimethoxyethane at 12 to 14° C., and stirred at 21 to 23° C. for 3 hours. The reaction mixture was diluted with 100 L of water; extracted with 100 L of ethyl acetate; and the organic layer was washed with 100 L of a 1% NaCl aqueous solution twice. The organic layer was concentrated under reduced pressure to quantitatively obtain 19.21 kg of a yellow oily target substance.
Reaction SMILES: CS(O[CH2:6][C:7]1[N:12]=[CH:11][C:10]2[N:13]=[CH:14][N:15]([C:16]3[S:17][C:18]([C:34](=[O:36])[NH2:35])=[C:19]([O:21][C@@H:22]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[C:30]([F:33])([F:32])[F:31])[CH3:23])[CH:20]=3)[C:9]=2[CH:8]=1)(=O)=O.[N:37]1([CH2:43][C:44]([N:46]2[CH2:51][CH2:50][O:49][CH2:48][CH2:47]2)=[O:45])[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1>ClCCl>[N:46]1([C:44](=[O:45])[CH2:43][N:37]2[CH2:38][CH2:39][N:40]([CH2:6][C:7]3[N:12]=[CH:11][C:10]4[N:13]=[CH:14][N:15]([C:16]5[S:17][C:18]([C:34]([NH2:35])=[O:36])=[C:19]([O:21][C@@H:22]([C:24]6[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=6[C:30]([F:33])([F:31])[F:32])[CH3:23])[CH:20]=5)[C:9]=4[CH:8]=3)[CH2:41][CH2:42]2)[CH2:47][CH2:48][O:49][CH2:50][CH2:51]1
Reactant: O=C(CN1CCNCC1)N1CCOCC1
Reactant: C[C@@H](Oc1cc(-n2cnc3cnc(COS(C)(=O)=O)cc32)sc1C(N)=O)c1ccccc1C(F)(F)F
Solvent: ClCCl
Product: C[C@@H](Oc1cc(-n2cnc3cnc(CN4CCN(CC(=O)N5CCOCC5)CC4)cc32)sc1C(N)=O)c1ccccc1C(F)(F)F

Procedure:
In a similar manner as described for example 58, 108 mg of [1-(5-carbamoyl-4-{(1R)-1-[2-(trifluoromethyl)phenyl]ethoxy}-2-thienyl)-1H-imidazo[4,5-c]pyridin-6-yl]methyl methanesulfonate and 213.3 mg of 4-(piperazin-1-ylacetyl)morpholine in 2.5 ml dichloromethane give the title compound.
Reaction SMILES: [Cl:1][C:2](Cl)([Cl:6])C([O-])=O.[Na+].[O:9]([CH:16]=[CH:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>COCCOC>[O:9]([CH:16]1[CH:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:2]1([Cl:6])[Cl:1])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=C([O-])C(Cl)(Cl)Cl
Reactant: CCOC(=O)C=COc1ccccc1
Agent: [Na+]
Solvent: COCCOC
Product: CCOC(=O)C1C(Oc2ccccc2)C1(Cl)Cl

Procedure:
The mixture of 20.9 g (113 mmol) sodium trichloroacetate, 15.4 g (80 mmol) ethyl 3-phenoxy-2-propenoate and 50 ml dry 1,2-dimethoxyethane is heated under reflux for 10 hr, under nitrogen. The mixture is filtered and solvent removed. The residue is purified by chromatography on silica gel, giving ethyl 3-phenoxy-2,2-dichlorocyclopropanecarboxylate, which is then hydrolyzed, as in Example 3, to give the corresponding carboxylic acid.
Reaction SMILES: O[C@H:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:11][C:12](=[O:17])[N:13]([CH2:15][CH3:16])[CH3:14])[CH:9]=2)[CH2:4][CH2:3]1.C(N(CC)CC)C.[CH2:25]([NH2:28])[C:26]#[CH:27]>ClCCl>[CH2:25]([NH:28][C@@H:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:11][C:12](=[O:17])[N:13]([CH2:15][CH3:16])[CH3:14])[CH:9]=2)[CH2:4][CH2:3]1)[C:26]#[CH:27]
Reactant: CCN(C)C(=O)Oc1ccc2c(c1)[C@H](O)CC2
Reactant: C#CCN
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C#CCN[C@H]1CCc2ccc(OC(=O)N(C)CC)cc21
Temperature: 25 °C
Yield: 70.3 %

Procedure:
Methanesulfonyl anhydride (1.544 g, 8.9 mmol) as a solution in dichloromethane (7.5 mL+2.5 mL) was added to a stirred solution of (R)-ethyl-methyl-carbamic acid 3-hydroxy-indan-5-yl ester (1.04 g, 4.4 mmol) and triethylamine (2.5 mL, 17.7 mmol) in dichloromethane (10 mL) at −35° C. (external) over 10 minutes. The reaction was maintained at this temperature for 45 minutes before propargylamine (3.0 mL, 44.3 mmol) was added. The reaction was allowed to warm slowly to room temperature overnight before being partitioned between ethyl acetate (100 mL) and ice-water (100 mL). The organic material was concentrated under reduced pressure to afford a brown oil which was partitioned between methyl tert-butyl ether (50 mL) and aqueous hydrochloric acid (1M, 50 mL). The aqueous layer was basified by addition of aqueous sodium hydroxide solution (2M, 40 mL) before being extracted with ethyl acetate (50 mL). This final organic extract was dried (MgSO4), filtered and concentrated under reduced pressure to afford the title compound (842 mg, 70%). 1H NMR (400 MHz, CDCl3) δ ppm 7.19 (1H, d, J 8, Ar), 7.09 (1H, s, Ar), 6.94 (1H, brd, J, 8, Ar), 4.39 (1H, dd, J 6 and 6, NHCH), 3.55 (1H, Dd, J 17 and 2, NCHH), 3.49 (1H, Dd, J 17 and 2, NCHH), 3.46 (rotamer A, 1H, q, J 8, MeCHHN), 3.40 (rotamer B, 1H, q, J 7, MeCHHN), 3.06 (rotamer A, 1.5H, s, MeN), 3.03-2.95 [2.5H, m, NCHCH2CHH and rotamer B, Me, incl. at 2.98 (rotamer B, 1.5H, s, MeN)], 2.83-2.75 (1H, m, NCHCH2CHH), 2.48-2.39 (1H, m, NCHCHH), 2.25 (1H, t, J 2, ≡CH), 1.92-1.83 (1H, m, NCHCHH), 1.23 (rotamer A, 1.5H, t, J 7, MeN) and 1.18 (rotamer B, 1.5H, t, J 7, MeN). Analysis of this material by chiral LC indicated it to be 62% e.e.