Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[Cl:2][CH2:3][CH2:4][N:5]([C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]([NH:18][C@H:19]([C:29]([O:31]C(C)(C)C)=[O:30])[CH2:20][CH2:21][C:22]([O:24]C(C)(C)C)=[O:23])=[O:17])=[CH:11][CH:10]=1)[CH2:6][CH2:7][Cl:8]>CCOCC.C(OCC)(=O)C>[ClH:2].[Cl:2][CH2:3][CH2:4][N:5]([C:9]1[CH:10]=[CH:11][C:12]([NH:15][C:16]([NH:18][C@H:19]([C:29]([OH:31])=[O:30])[CH2:20][CH2:21][C:22]([OH:24])=[O:23])=[O:17])=[CH:13][CH:14]=1)[CH2:6][CH2:7][Cl:8]
Reactant: CC(C)(C)OC(=O)CC[C@H](NC(=O)Nc1ccc(N(CCCl)CCCl)cc1)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: O=C(O)CC[C@H](NC(=O)Nc1ccc(N(CCCl)CCCl)cc1)C(=O)O
Yield: 186.3 %

Procedure:
A saturated solution of hydrogen chloride in ether (120 ml) was added to a solution of ditertbutyl N-(-4-[N,N-bis-(2-chloroethyl)amino]-phenylcarbamoyl)-L-glutamate (4.4 g) in ethyl acetate (20 ml). After 1 hour at ambient temperature the mixture was evaporated to a solid. This solid was triturated with ether to obtain N-(4-[N,N-bis(2-chloroethyl)amino]phenylcarbamoyl)-L-glutamic acid hydrochloride (3.5 g) as a grey solid m.p=148-150° C. (see Scheme 3) NMR: 7.2 (d) 2H; 6.7 (d) 2H); 4.2 (n) 1H; 3.7 (m) 8H; 2.4-1.8 (m) 4H;
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][N:10]1[CH:14]=[C:13]([C:15]2[CH:20]=[C:19]([C:21]([NH2:23])=O)[CH:18]=[CH:17][N:16]=2)[N:12]=[CH:11]1.N1C=CC=CC=1.C(OC(C(F)(F)F)=O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][N:10]1[CH:14]=[C:13]([C:15]2[CH:20]=[C:19]([C:21]#[N:23])[CH:18]=[CH:17][N:16]=2)[N:12]=[CH:11]1
Reactant: NC(=O)c1ccnc(-c2cn(CCc3ccccc3Cl)cn2)c1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Solvent: c1ccncc1
Product: N#Cc1ccnc(-c2cn(CCc3ccccc3Cl)cn2)c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 53 %

Procedure:
To a solution of 2-[1-[2-(2-chlorophenyl)ethyl]imidazol-4-yl]pyridine-4-carboxamide (1 eq) and pyridine (3 eq) in DCM was added TFAA (2 eq) slowly at 0° C., then the mixture was stirred for 2 hr at 0° C., the solution was washed by H2O, NaHCO3 and brine. The collected organic fractions were concentrated and purified by FCC (PE/EA=1/4) to give the title compound (53%). [M+H] Calc'd for C17H13ClN4, 309. Found, 309.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[NH:4][C:5]1[CH:10]=[C:9]([C:11]([C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)=[O:12])[CH:8]=[C:7](Br)[CH:6]=1.CC1(C)C(C)(C)OB([C:29]2[CH:37]=[CH:36][CH:35]=[C:34]3[C:30]=2[CH:31]=[CH:32][N:33]3[Si:38]([CH:45]([CH3:47])[CH3:46])([CH:42]([CH3:44])[CH3:43])[CH:39]([CH3:41])[CH3:40])O1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.Cl[Pd-](P(C1CC2CC1CC2)C1CC2CC1CC2)C1C=CC=CC=1C1C=CC=CC=1N(C)C>[CH3:1][O:2][C:3](=[O:20])[NH:4][C:5]1[CH:6]=[C:7]([C:29]2[CH:37]=[CH:36][CH:35]=[C:34]3[C:30]=2[CH:31]=[CH:32][N:33]3[Si:38]([CH:42]([CH3:44])[CH3:43])([CH:45]([CH3:47])[CH3:46])[CH:39]([CH3:40])[CH3:41])[CH:8]=[C:9]([C:11]([C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)=[O:12])[CH:10]=1
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1ccc2c(B3OC(C)(C)C(C)(C)O3)cccc21
Reactant: COC(=O)Nc1cc(Br)cc(C(=O)c2cccnc2)c1
Agent: CN(C)c1ccccc1-c1ccccc1[Pd-](Cl)P(C1CC2CCC1C2)C1CC2CCC1C2
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: COC(=O)Nc1cc(C(=O)c2cccnc2)cc(-c2cccc3c2ccn3[Si](C(C)C)(C(C)C)C(C)C)c1
Yield: 70.6 %

Procedure:
[3-Bromo-5-(pyridine-3-carbonyl)-phenyl]-carbamic acid methyl ester (316 mg, 0.94 mmol), 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1-triisopropylsilanyl-1H-indole (0.377 mg, 0.94 mmol) and chloro(di-2-norbornylphosphino)(2′dimethylamino-1,1′-biphenyl-2-yl)palladium (II) (53 mg, 0.094 mmol) were dissolved in dioxane (6 mL) under nitrogen. Aqueous 2M K3PO4 (1 mL, 1.2 mmol) was added and the mixture was heated at reflux overnight. The reaction mixture was filtered through Celite® and the solvent was removed. The product was chromatographed to give 0.350 g (70% yield) of [3-(pyridine-3-carbonyl)-5-(1-triisopropylsilanyl-1H-indol-4-yl)-phenyl]-carbamic acid methyl ester.
Reaction SMILES: C[CH:2](C)[C@@H:3]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:17]3[CH:22]=[CH:21][C:20]([NH:23][C:24]([NH:26][C:27]4[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:36])([F:35])[F:34])[CH:28]=4)=[O:25])=[CH:19][CH:18]=3)[CH:14]=2)[C:9]1=[O:37])[C:4]([O:6][CH3:7])=[O:5].BrC1C=C2C(=CC=1)C(=O)N([C@@H](C)C(OC)=O)C2.CC1(C)C(C)(C)OB(C2C=CC(NC(NC3C=CC=C(C(F)(F)F)C=3)=O)=CC=2)O1>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl>[O:37]=[C:9]1[C:10]2[C:15](=[CH:14][C:13]([C:17]3[CH:18]=[CH:19][C:20]([NH:23][C:24]([NH:26][C:27]4[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:34])([F:36])[F:35])[CH:28]=4)=[O:25])=[CH:21][CH:22]=3)=[CH:12][CH:11]=2)[CH2:16][N:8]1[C@@H:3]([CH3:2])[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)[C@@H](C(C)C)N1Cc2cc(-c3ccc(NC(=O)Nc4cccc(C(F)(F)F)c4)cc3)ccc2C1=O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC1(C)OB(c2ccc(NC(=O)Nc3cccc(C(F)(F)F)c3)cc2)OC1(C)C
Solvent: ClCCl
Product: COC(=O)[C@H](C)N1Cc2cc(-c3ccc(NC(=O)Nc4cccc(C(F)(F)F)c4)cc3)ccc2C1=O

Procedure:
The compound of example 366 was prepared analogous to compound of example 360 by reaction of the compound of example 365, compound of example 357 and Pd(dppf)Cl2: CH2Cl2.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([N+:16]([O-:18])=[O:17])[C:7](OC)=[C:8]2[C:13]=1[CH2:12][CH2:11][CH2:10][CH2:9]2)(=[O:3])[CH3:2].[NH3:19]>CS(C)=O>[C:1]([C:4]1[CH:5]=[C:6]([N+:16]([O-:18])=[O:17])[C:7]([NH2:19])=[C:8]2[C:13]=1[CH2:12][CH2:11][CH2:10][CH2:9]2)(=[O:3])[CH3:2]
Reactant: N
Reactant: COc1c([N+](=O)[O-])cc(C(C)=O)c2c1CCCC2
Solvent: CS(C)=O
Product: CC(=O)c1cc([N+](=O)[O-])c(N)c2c1CCCC2
Temperature: 0 °C
Yield: 75 %

Procedure:
A solution of 8-acetyl-1,2,3,4-tetrahydro-5-methoxy-6nitronaphthalene (1.0 g, 4 mmol) in 15 ml of dry dimethylsulfoxide was heated to 100° C. and ammonia was passed into the solution for 3 h. After the solution was added to 100 ml of ice-water, the crude solid was filtered off and washed with water. Recrystallization from ethanol afforded 0.71 g (75%) of the pure title compound M.p. 170°-172° C.; 1H-NMR (DMSO-d6): 1.47-1.93 (m, 4H, 2CH2), 2.27-2.63 (m, 2H, CH2), 2.48 (s, 3H, COCH3), 2.70-3.03 (m, 2H, CH2), 7.50 (broad s, 2H, NH2), 8.33 (s, 1H, H-7).
Reaction SMILES: O[CH:2]([CH:5]1[CH2:10][CH2:9][CH:8]2[CH:6]1[CH2:7]2)[C:3]#[N:4].N1C=CC=CC=1.S(Cl)(Cl)=O>O>[C:3]([CH:2]=[C:5]1[CH2:10][CH2:9][CH:8]2[CH:6]1[CH2:7]2)#[N:4]
Reactant: N#CC(O)C1CCC2CC21
Solvent: c1ccncc1
Solvent: O=S(Cl)Cl
Solvent: O
Product: N#CC=C1CCC2CC12
Temperature: 25 °C

Procedure:
0.078 Mole of 2-hydroxy-2-(bicyclo[3.1.0]hex-2-yl)acetonitrile is dissolved in 200 ml. of anhydrous pyridine under nitrogen, and cooled to -50° C. 0.0942 Mole of thionyl chloride is added dropwise and the mixture allowed to warm to room temperature and then recooled to 0° C. Excess thionyl chloride is then decomposed by the addition of 2 ml. of water. The pyridine is removed by evaporation under vacuum and the resulting residue dissolved in 300 ml. of ethyl acetate. The ethyl acetate solution is then washed twice with water, dried over anhydrous magnesium sulfate, and filtered. The filtrate is evaporated to dryness, under vacuum, and the resulting residue is chromatographed with silica gel eluting with 10% ethyl acetate-90%, vol., hexane, affording 2-(cyanomethylene)bicyclo[3.1.0]hexane.
Reaction SMILES: C([NH:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]2[N:16]=[C:17]([C:20]3[CH:25]=[C:24]([C:26]4[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][CH:27]=4)[CH:23]=[C:22]([CH3:36])[N:21]=3)[S:18][CH:19]=2)[CH:10]=1)(=[O:8])=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[CH3:36][C:22]1[N:21]=[C:20]([C:17]2[S:18][CH:19]=[C:15]([C:11]3[CH:10]=[C:9]([S:6]([NH2:5])(=[O:7])=[O:8])[CH:14]=[CH:13][CH:12]=3)[N:16]=2)[CH:25]=[C:24]([C:26]2[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:33])[F:34])=[CH:28][CH:27]=2)[CH:23]=1
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2nc(-c3cccc(S(=O)(=O)NC(C)(C)C)c3)cs2)n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2nc(-c3cccc(S(N)(=O)=O)c3)cs2)n1
Temperature: 25 °C
Reaction time: 15 h
Yield: 55.9 %

Procedure:
To a cooled and stirred solution of N-tert-butyl-3-{2-[6-methyl-4-(4-trifluoromethyl-phenyl)-pyridin-2-yl]-thiazol-4-yl}-benzenesulfonamide (example 263) (0.40 g, 0.753 mmol) in dichloromethane (10 mL) was added TFA (10 mL) and the reaction mixture was allowed to stir at room temperature for 15 h. The mixture was evaporated to dryness and saturated NaHCO3 solution (5 mL), diethyl ether and heptane were added. The mixture was stirred at room temperature for 1 h, the precipitate was collected by filtration, washed with water and heptane/diethyl ether and dried to yield the title compound as a white solid (0.20 g, 56%). MS (ISP) 474.1 [(M+H)+]; mp>250° C.
Reaction SMILES: [CH:1]1([C:5](Cl)=[O:6])[CH2:4][CH2:3][CH2:2]1.[CH:8]1[C:20]2[CH:19]([CH2:21][O:22][C:23]([NH:25][C@@H:26]([CH2:30][NH2:31])[C:27]([OH:29])=[O:28])=[O:24])[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]=2[CH:11]=[CH:10][CH:9]=1>C1COCC1.[OH-].[Na+]>[CH:17]1[C:18]2[CH:19]([CH2:21][O:22][C:23]([NH:25][C@@H:26]([CH2:30][NH:31][C:5]([CH:1]3[CH2:4][CH2:3][CH2:2]3)=[O:6])[C:27]([OH:29])=[O:28])=[O:24])[C:20]3[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=3)[C:13]=2[CH:14]=[CH:15][CH:16]=1
Reactant: NC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Reactant: O=C(Cl)C1CCC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(N[C@@H](CNC(=O)C1CCC1)C(=O)O)OCC1c2ccccc2-c2ccccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Cyclobutanecarbonyl chloride (72.7 mg, 0.613 mmol) and NaOH (0.735 mL, 0.735 mmol) were dropped at the same time to a stirred solution of (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-aminopropanoic acid (200 mg, 0.613 mmol) in THF (1.5 mL) and NaOH (1N, 0.8 mL) at 0° C. The reaction mixture was allowed to stir at rt for 1 h at which time LC-MS showed the desired product peak. The reaction solution was acidified with 1N HCl and extracted with EtOAc (60 mL×1). The crude was purified via flash chromatography (ISCO, silica gel, 12 g column; flow rate 30 mL/min, 100% DCM to 20% MeOH/DCM). Fractions containing the desired product were combined and dried via centrifugal evaporation to provide the title compound (156 mg, 61%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH2:6]Cl.C([O-])([O-])=O.[Cs+].[Cs+].[CH3:17][O:18][C:19]1[CH:20]=[C:21]([C:25]([C:34]2([OH:40])[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]2)=[CH:26][CH2:27][N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)[CH:22]=[CH:23][CH:24]=1.C(N(CC)CC)C>CN(C=O)C>[CH3:17][O:18][C:19]1[CH:20]=[C:21]([C:25]([C:34]2([OH:40])[CH2:35][CH2:36][CH2:37][CH2:38][CH2:39]2)=[CH:26][CH2:27][N:28]2[CH2:29][CH2:30][N:31]([CH2:6][C:5]3[CH:8]=[CH:9][CH:10]=[C:3]([O:2][CH3:1])[CH:4]=3)[CH2:32][CH2:33]2)[CH:22]=[CH:23][CH:24]=1
Reactant: COc1cccc(CCl)c1
Reactant: COc1cccc(C(=CCN2CCNCC2)C2(O)CCCCC2)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1cccc(CN2CCN(CC=C(c3cccc(OC)c3)C3(O)CCCCC3)CC2)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
3-Methoxybenzyl chloride (1.28 g, 7.5 mol) and Cs2CO3 (5.9 g, 18 mmole) were added to a solution of 1-[1-(3-methoxyphenyl)-3-(1-piperazinyl)-1-propenyl]cyclohexanol (2.0 g, 6 mmole) in DMF (50 mL) and the mixture stirred at room temperature for one hour. Triethylamine (0.25 mL) was then added and the reaction mixture stirred overnight. The solvent was evaporated and the residue dissolved in chloroform. The solution was washed with water and the water back-extracted with chloroform. The combined organic solution was washed with brine, dried over magnesium sulfate and evaporated. The product was purified using column chromatography with chloroform as eluent and the purified title compound was converted to the hydrochloride. Yield 530 mg, m.p. 169°-171° C.
Reaction SMILES: [CH3:1][C:2]1[C:6]2[C:7](=[O:19])[N:8]([CH2:12][CH2:13][N:14]3[CH2:18][CH2:17][CH2:16][CH2:15]3)[CH2:9][CH2:10][CH2:11][C:5]=2[NH:4][C:3]=1[CH:20]=O.[F:22][C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][C:31]=1[NH:32][C:33](=[O:37])[CH2:34][O:35][CH3:36])[NH:28][C:27](=[O:38])[CH2:26]2>>[F:22][C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][C:31]=1[NH:32][C:33](=[O:37])[CH2:34][O:35][CH3:36])[NH:28][C:27](=[O:38])/[C:26]/2=[CH:20]\[C:3]1[NH:4][C:5]2[CH2:11][CH2:10][CH2:9][N:8]([CH2:12][CH2:13][N:14]3[CH2:15][CH2:16][CH2:17][CH2:18]3)[C:7](=[O:19])[C:6]=2[C:2]=1[CH3:1]
Reactant: Cc1c(C=O)[nH]c2c1C(=O)N(CCN1CCCC1)CCC2
Reactant: COCC(=O)Nc1cc2c(cc1F)CC(=O)N2
Product: COCC(=O)Nc1cc2c(cc1F)/C(=C/c1[nH]c3c(c1C)C(=O)N(CCN1CCCC1)CCC3)C(=O)N2
Yield: 63.7 %

Procedure:
The title compound was prepared under the same conditions as described in step 4 of Example 28 with 3-methyl-4-oxo-5-(2-pyrrolidin-1-yl-ethyl)-1,4,5,6,7,8-hexahydro-pyrrolo[3,2-c]azepine-2-carbaldehyde 28c obtained from step 3 of Example 28 and N-(5-fluoro-2-oxo-2,3-dihydro-1H-indol-6-yl)-2-methoxy-acetamide 7a obtained from step 1 of Example 7 as starting materials to obtain (Z)—N-{5-fluoro-3-[3-methyl-4-oxo-5-(2-pyrrolidin-1-yl-ethyl)-1,4,5,6,7,8-hexahydro-pyrrolo[3,2-c]azepin-2-ylmethylene]-2-oxo-2,3-dihydro-1H-indol-6-yl}-2-methoxy-acetamide 52 (45 mg, yield 63.7%) as a yellow solid.
Reaction SMILES: ClCC[CH2:4][CH:5]([O:11]C(=O)C)CCCCC.C(Br)CCCC.[Cl:21][CH2:22][CH2:23][CH2:24][C:25](=[O:34])[CH2:26][CH2:27][CH2:28][CH2:29][C:30]([F:33])([F:32])[F:31].ClCCCC(O)CCCCC(F)(F)F>>[Cl:21][CH2:22][CH2:23][CH2:24][CH:25]([O:34][C:5](=[O:11])[CH3:4])[CH2:26][CH2:27][CH2:28][CH2:29][C:30]([F:31])([F:32])[F:33]
Reactant: CCCCCC(CCCCl)OC(C)=O
Reactant: O=C(CCCCl)CCCCC(F)(F)F
Agent: OC(CCCCl)CCCCC(F)(F)F
Solvent: CCCCCBr
Product: CC(=O)OC(CCCCl)CCCCC(F)(F)F

Procedure:
By following the procedure described for 1-chloro-4-acetoxynonane (Example A) but substituting 1-bromo-5,5,5-trifluoropentane for amyl bromide, there is obtained in succession: 1-chloro-9,9,9-trifluoro-4-nonanone, 1-chloro-9,9,9-trifluoro-4-nonanol, and 1-chloro-4-acetoxy- 9,9,9-trifluoronane.
Reaction SMILES: [CH2:1]([Li])CCC.[F:6][C:7]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:8]=1[C:14]1([C:17]([C:19]2[CH:20]=[CH:21][C:22]([S:25][CH3:26])=[N:23][CH:24]=2)=O)[CH2:16][O:15]1>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1>[F:6][C:7]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:8]=1[C:14]1([C:17]([C:19]2[CH:20]=[CH:21][C:22]([S:25][CH3:26])=[N:23][CH:24]=2)=[CH2:1])[CH2:16][O:15]1
Reactant: CSc1ccc(C(=O)C2(c3ccc(F)cc3F)CO2)cn1
Reactant: [Li]CCCC
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: C1CCOC1
Product: C=C(c1ccc(SC)nc1)C1(c2ccc(F)cc2F)CO1
Temperature: 0 °C
Reaction time: 18 h
Yield: 90.7 %

Procedure:
A suspension of methyltriphenylphosphonium bromide (5.0 g, 14 mmol) in THF (70 ml) was treated with n-butyllithium (2.5M solution in hexane, 5.6 ml, 14 mmol) under an atmosphere of nitrogen at -70° C. After 15 minutes at -70° C. the mixture was warmed to 0° C. and then was treated dropwise with a solution of the product of part (v) (3.9 g, 13 mmol) in THF (40 ml). The mixture was stirred at room temperature for 18 hours and then evaporated under reduced pressure. The residue was partitioned between dichloromethane (50 ml) and water (30 ml). The organic phase was dried (MgSO4) and evaporated under reduced pressure. The crude product was purified by flash chromatography on silica by elution with ether/hexane (1:4) to provide the title compound as an orange oil, (3.6 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([CH3:9])[N:6]=[C:5]([NH2:10])[CH:4]=1.Br[CH2:12][C:13](=O)[C:14]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:15]>O1CCCC1.CCOCC>[CH3:1][O:2][C:3]1[N:8]=[C:7]([CH3:9])[N:6]2[CH:12]=[C:13]([C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[O:15])[N:10]=[C:5]2[CH:4]=1
Reactant: COc1cc(N)nc(C)n1
Reactant: O=C(CBr)C(=O)c1ccccc1
Solvent: CCOCC
Solvent: C1CCOC1
Product: COc1cc2nc(C(=O)c3ccccc3)cn2c(C)n1
Reaction time: 8 h
Yield: 66.9 %

Procedure:
A stirred solution of 2.1 g of 6-methoxy-2-methyl-4-pyrimidinamine in dry tetrahydrofuran was treated with a solution of 5.4 g of 3-bromo-1-phenyl-1,2-propanedione in 5 ml of dry ether. After stirring overnight, the mixture was chilled and the precipitated salt filtered off. A suspension of the salt in dry ethanol was refluxed for 1.5 hours, chilled, and filtered. The solid was shaken with a mixture of chloroform and aqueous sodium bicarbonate and the organic layer was evaporated to dryness under reduced pressure. The residue was chromatographed in ethyl acetate on silica to obtain 2.7 g of (7-methoxy-5-methyl-imidazo[1,2-c]pyrimidin-2-yl)-phenylmethanone as a yellow crystalline solid melting at 165°-7° C.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[N:5]=[CH:6][S:7][C:8]=1[CH:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[OH:10].[CH3:17]I>CN(C)C=O>[CH3:3][C:4]1[N:5]=[CH:6][S:7][C:8]=1[CH:9]([O:10][CH3:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CI
Reactant: Cc1ncsc1C(O)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(c1ccccc1)c1scnc1C
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Sodium hydride (80% dispersion in mineral oil, 80 mg) was added to a stirred solution of 1-(4-methyl-5-thiazolyl)-1-phenyl-methanol (500 mg) in dry N,N-dimethylformamide (10 ml) at 0° C. After 10 minutes, methyl iodide (0.15 ml) was added. The mixture was allowed to warm to room temperature and after a further 30 minutes the mixture was evaporated to dryness. The residue was purified by flash chromatography to give the title compound.
Reaction SMILES: Cl.[C:2]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][CH:9]=[C:8]2[CH2:14][CH2:15][CH2:16][CH2:17][N:18]1[CH2:23][CH2:22][C:21]2[C:24]3[CH:30]=[CH:29][CH:28]=[CH:27][C:25]=3[O:26][C:20]=2[CH2:19]1)([OH:4])=[O:3].[CH2:31](O)[CH3:32]>>[CH2:31]([O:3][C:2]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][CH:9]=[C:8]2[CH2:14][CH2:15][CH2:16][CH2:17][N:18]1[CH2:23][CH2:22][C:21]2[C:24]3[CH:30]=[CH:29][CH:28]=[CH:27][C:25]=3[O:26][C:20]=2[CH2:19]1)=[O:4])[CH3:32]
Reactant: O=C(O)c1ccc2[nH]cc(CCCCN3CCc4c(oc5ccccc45)C3)c2c1
Reactant: CCO
Agent: Cl
Product: CCOC(=O)c1ccc2[nH]cc(CCCCN3CCc4c(oc5ccccc45)C3)c2c1
Reaction time: 48 h

Procedure:
HCl is passed for 2 hours into a solution of 3.88 g of 2-[4-(5-carboxy-3-indolyl)butyl]-1,2,3,4-tetrahydrobenzofuro[2,3-c]pyridine in 50 ml of absolute ethanol. The mixture is then allowed to stand at 20° for 48 hours, the usual working up is carried out, and 2-[4-(5-ethoxycarbonyl-3-indolyl)butyl]-1,2,3,4-tetrahydrobenzofuro[2,3-c]pyridine is obtained.
Reaction SMILES: C(O[C:4]([N:6]1[CH2:11][CH2:10][C@H:9]([O:12][C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)[C@H:8]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:7]1)=O)C.[H-].[Al+3].[Li+].[H-].[H-].[H-].S([O-])([O-])(=O)=O.[Na+].[Na+].[C:39]([OH:46])(=[O:45])/[CH:40]=[CH:41]/[C:42]([OH:44])=[O:43]>O1CCCC1.CCOCC.C(O)C>[C:39]([OH:46])(=[O:45])/[CH:40]=[CH:41]/[C:42]([OH:44])=[O:43].[CH3:4][N:6]1[CH2:11][CH2:10][C@H:9]([O:12][C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)[C@H:8]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:7]1
Reactant: CCOC(=O)N1CC[C@H](Oc2ccc(C)cc2)[C@H](c2ccccc2)C1
Agent: O=C(O)/C=C/C(=O)O
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1ccc(O[C@H]2CCN(C)C[C@H]2c2ccccc2)cc1
Temperature: 5 °C

Procedure:
A solution of 3.12 g of cis-1-ethoxycarbonyl-3-phenyl-4-(4-tolyloxy)piperidine in 55 ml of anhydrous tetrahydrofuran is added dropwise under nitrogen to a suspension of 1.05 g of lithium aluminum hydride in 55 ml of tetrahydrofuran. The resulting mixture is refluxed for 2 hours, cooled to 5° C. and diluted with 100 ml of anhydrous ether. Saturated sodium sulfate solution is added dropwise with cooling until a flocculent white precipitate forms. The solid is filtered, washed with ether, and the filtrate is concentrated in vacuo to a colorless oil. The oil is dissolved in 150 ml of ether, washed with 100 ml of saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated in vacuo to afford a colorless oil. This oil is dissolved in ether (100 ml) and treated dropwise with a solution of 1.12 g of fumaric acid in a mixture of ether (100 ml) and ethanol (25 ml). The solvent is removed in vacuo, and the residue is triturated into solid with ether. The crystalline solid is filtered, washed with ether and dried. The filtrate is concentrated in vacuo to an oil and 1 ml of ethanol is added followed by approximately 5 ml of ether. The solution is seeded with the crystalline solid and another 5 ml of ether is slowly added. The solution is scratched to afford a second crop of salt. The two crops are combined and recrystallized by dissolving in 100 ml of boiling ethyl acetate, filtering the solution hot and boiling the filtrate down to a volume of 50 ml. The solid is filtered, washed with ethyl acetate and ether and dried to afford product as colorless crystals, mp 148°-150° C.
Reaction SMILES: CS(C)=O.FC(F)(F)C(OC(=O)C(F)(F)F)=O.[NH:18]1[CH:22]=[CH:21][N:20]=[C:19]1[CH:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH:24]1[OH:29].[OH-].[Na+]>C(Cl)Cl.C(N(CC)CC)C>[NH:18]1[CH:22]=[CH:21][N:20]=[C:19]1[CH:23]1[CH2:28][CH2:27][CH2:26][CH2:25][C:24]1=[O:29]
Reactant: OC1CCCCC1c1ncc[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: O=C1CCCCC1c1ncc[nH]1
Temperature: -76 °C
Reaction time: 0.17 h
Yield: 19.4 %

Procedure:
Dimethylsulfoxide (8.46 g) was mixed with methylene chloride (35 ml) and cooled to -76° C. with stirring and after dropwise addition of a diluted solution of trifluoroacetic anhydride (19.71 g) in methylene chloride (10 ml), stirred for 1 hour. A solution of of 2-imidazolylcyclohexanol (IVa) (12.0 g) in methylene chloride (100 ml) was added dropwise thereto for 10 minutes. The mixture was made to react at -76°--20° C. for 1.5 hours, cooled to -55° C. and after dropwise addition of triethylamine (30 ml) at -55° C., stirred for 1 hour at -55° C. After addition of a 5% sodium hydroxide solution, the mixture was extracted with methylene chloride. The extract was washed with water, dried and evaporated. The residue was applied to column chromatography on slica gel (100 g). From Chloroform-methanol (100:1) fraction, 2-imidazolyl cyclohexanone (IIa) (2.3 g) was obtained. Mp. 104°-105° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:22]=[CH:21][CH:20]=[CH:19][C:4]=1[CH2:5][NH:6][C:7](=[O:18])[C:8]1[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=1.C1N2CN3CN(C2)CN1C3.O.[C:34](=O)(O)[O-:35].[Na+]>FC(F)(F)C(O)=O.C(OCC)(=O)C>[CH:34]([C:20]1[CH:21]=[CH:22][C:3]([O:2][CH3:1])=[C:4]([CH:19]=1)[CH2:5][NH:6][C:7](=[O:18])[C:8]1[CH:13]=[CH:12][C:11]([C:14]([F:16])([F:17])[F:15])=[CH:10][CH:9]=1)=[O:35]
Reactant: COc1ccccc1CNC(=O)c1ccc(C(F)(F)F)cc1
Reactant: O=C([O-])O
Agent: C1N2CN3CN1CN(C2)C3
Agent: [Na+]
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Product: COc1ccc(C=O)cc1CNC(=O)c1ccc(C(F)(F)F)cc1

Procedure:
8.7 g of N1-(2-methoxybenzyl)-4-(trifluoromethyl)benzamide was dissolved in 20 ml trifluoroacetic acid, and 3.9 g of hexamethylene tetramine was added, and the mixture was reacted at 85° C. for 3 hours. The reaction solution was returned to room temperature, and water and ethyl acetate were added, and further sodium bicarbonate was added until the pH reached 8. After extracting with ethyl acetate, the extract was washed with brine, dried over anhydrous magnesium sulfate and the solvent was evapoarated. The residue was subjected to silica gel column chromatography, and from fractions eluted with hexane-ethyl acetate (2:1), 4.2 g of N1-(5-formyl-2-methoxybenzyl)-4-(trifluoromethyl)benzamide was obtained.