Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Li])CCC.Br[C:7]1[N:12]=[C:11]([CH3:13])[C:10]([O:14][CH3:15])=[C:9]([CH3:16])[CH:8]=1.[Br:17][C:18]1[CH:23]=[C:22](/[C:24](/[C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([F:38])[C:33]=2[C:39]#[N:40])=[N:25]\S(C(C)(C)C)=O)[CH:21]=[CH:20][N:19]=1.Cl.C(OCC)C>C1COCC1.CO>[Br:17][C:18]1[CH:23]=[C:22]([C:24]2([C:7]3[CH:8]=[C:9]([CH3:16])[C:10]([O:14][CH3:15])=[C:11]([CH3:13])[N:12]=3)[C:32]3[C:33](=[C:34]([F:38])[CH:35]=[CH:36][CH:37]=3)[C:39]([NH2:40])=[N:25]2)[CH:21]=[CH:20][N:19]=1
Reactant: COc1c(C)cc(Br)nc1C
Reactant: CC(C)(C)S(=O)/N=C(\c1ccnc(Br)c1)c1cccc(F)c1C#N
Agent: Cl
Agent: [Li]CCCC
Solvent: CO
Solvent: C1CCOC1
Solvent: CCOCC
Product: COc1c(C)cc(C2(c3ccnc(Br)c3)N=C(N)c3c(F)cccc32)nc1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 103 %

Procedure:
n-Butyllithium (0.229 mL, 0.57 mmol) was added to 6-bromo-3-methoxy-2,4-dimethylpyridine (124 mg, 0.57 mmol) in THF (7 mL) at −78° C. under nitrogen atmosphere. The reaction was stirred for 30 min before (E)-N-((2-bromopyridin-4-yl)(2-cyano-3-fluorophenyl)methylene)-2-methylpropane-2-sulfinamide (180 mg, 0.44 mmol) in THF (2 mL) was added. The reaction was kept at −78° C. for 1 hour and then allowed to reach room temp. Methanol (5 mL) was added followed by hydrochloric acid in diethylether (1.323 mL, 1.32 mmol) and the reaction mixture was stirred 1 hour at room temperature. NaHCO3(sat) was added and the mixture was extracted with EtOAc (×2). The combined organic phases were dried and concentrated to give the title compound (200 mg, 97%), which was used without further purification. MS (ES+) m/z 441, 443 [M+1]+.
Reaction SMILES: Cl[C:2]1[C:3]2[C:10]([Cl:11])=[CH:9][N:8]([CH2:12][O:13][CH:14]([OH:18])[CH2:15][CH2:16][OH:17])[C:4]=2[N:5]=[CH:6][N:7]=1.[NH3:19]>>[NH2:19][C:2]1[C:3]2[C:10]([Cl:11])=[CH:9][N:8]([CH2:12][O:13][CH:14]([OH:18])[CH2:15][CH2:16][OH:17])[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: OCCC(O)OCn1cc(Cl)c2c(Cl)ncnc21
Reactant: N
Product: Nc1ncnc2c1c(Cl)cn2COC(O)CCO
Temperature: 135 °C

Procedure:
Compound 22a was prepared by heating the 4,5-dichloro-7-[(1,3-dihydroxypropoxy)methyl]pyrrolo[2,3-d]pyrimidine with saturated methanolic ammonia (15 mL) in a steel reaction vessel. The vessel was then heated to 135° C. for eight hours after which time the vessel was cooled and the solvent was removed in vacuo at 40° C. The resulting solid was then recrystallized from methanol to yield 0.28 g (61%). mp=175°-176.5° C. 1H NMR (DMSO-d6): δ3.22-3.50 (m, 5), 4.58 (t, 2, exchanges with D2O, OH); 5.57 (s, 2, C-1'); 6.88 (bs, 2, exchanges with D2O, NH2) 7.47 (s, 1, C6), 8.11 (s, 1, C-2). Anal. for C10H13N4O3Cl. (C,H,N).
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:14]=1[O:15][CH3:16])[N:11]=[C:10]([C:17]1[CH:22]=[CH:21][C:20]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[C:19]([F:29])[CH:18]=1)[N:9]=[C:8]2[NH:30][C:31]1[CH:32]=[C:33]2[C:37](=[CH:38][CH:39]=1)[N:36](C([O-])=O)[N:35]=[CH:34]2.[NH:43]1[CH2:47][CH2:46][CH2:45][CH2:44]1.O>CS(C)=O>[F:29][C:19]1[CH:18]=[C:17]([C:10]2[N:9]=[C:8]([NH:30][C:31]3[CH:32]=[C:33]4[C:37](=[CH:38][CH:39]=3)[NH:36][N:35]=[CH:34]4)[C:7]3[C:12](=[CH:13][C:14]([O:15][CH3:16])=[C:5]([O:4][CH2:3][CH2:2][N:43]4[CH2:47][CH2:46][CH2:45][CH2:44]4)[CH:6]=3)[N:11]=2)[CH:22]=[CH:21][C:20]=1[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: C1CCNC1
Reactant: COc1cc2nc(-c3ccc(-c4ccccc4)c(F)c3)nc(Nc3ccc4c(cnn4C(=O)[O-])c3)c2cc1OCCCl
Solvent: O
Solvent: CS(C)=O
Product: COc1cc2nc(-c3ccc(-c4ccccc4)c(F)c3)nc(Nc3ccc4[nH]ncc4c3)c2cc1OCCN1CCCC1
Temperature: 75 °C
Yield: 84.2 %

Procedure:
A mixture of 5-(6-(2-chloroethoxy)-2-(3-fluoro-4-(phenyl)phenyl)-7-methoxyquinazolin-4-ylamino)-1H-indazole-1-carboxylate (0.200 g, 0.31 mmol) and pyrrolidine (0.385 g, 5.41 mmol) in DMSO (1.5 mL) was heated at 75° C. for 1.5 h. The mixture was allowed to cool to RT, upon which it was poured into water (100 mL). The solid that formed was collected via filtration and purified by preparative TLC (SiO2, CH2Cl2:MeOH 9:1) to give the desired compound 2-(3-fluoro-4-(phenyl)phenyl)-N-(1H-indazol-5-yl)-7-methoxy-6-(2-(pyrrolidin-1-yl)ethoxy)quinazolin-4-amine (0.15 g, 0.261 mmol, 84%). MS 575.4 (M+1) HPLC retention time 5.40 mins.
Reaction SMILES: Br[N:2]1C(=O)CC[C:3]1=O.[Cl:9][C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[N:15]([CH2:19][C:20]([OH:22])=[O:21])[C:14]([CH3:23])=[C:13]2[C:24]1[C:33]2[C:28](=[CH:29][C:30]([Cl:34])=[CH:31][CH:32]=2)[N:27]=[CH:26][CH:25]=1.CN.C1COCC1>CN1C(=O)CCC1.ClCCl>[Cl:9][C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[N:15]([CH2:19][C:20]([OH:22])=[O:21])[C:14]([CH2:23][NH:2][CH3:3])=[C:13]2[C:24]1[C:33]2[C:28](=[CH:29][C:30]([Cl:34])=[CH:31][CH:32]=2)[N:27]=[CH:26][CH:25]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1c(-c2ccnc3cc(Cl)ccc23)c2cc(Cl)ccc2n1CC(=O)O
Agent: CN
Solvent: ClCCl
Solvent: CN1CCCC1=O
Solvent: C1CCOC1
Product: CNCc1c(-c2ccnc3cc(Cl)ccc23)c2cc(Cl)ccc2n1CC(=O)O
Reaction time: 1 h

Procedure:
1-Bromo-2,5-pyrrolidinedione (125 mg) was added to a solution of the product from Example 27 step b) (250 mg) in NMP (0.5 ml) and dichloromethane (5 ml), and the solution stirred for 30 min. 2M methylamine/THF (3.25 ml) was then added and the solution stirred for 1 hour. The mixture was diluted with dichloromethane (20 ml), washed with saturated aqueous sodium bicarbonate and water. The organic layer was dried (MgSO4), filtered, evaporated in vacuo and the residue purified by reverse phase HPLC. After evaporation in vacuo the oily residue was treated with ether to give a solid, filtered off and dried to yield the title compound as a white solid (60 mg).
Reaction SMILES: [CH:1]1([C:4]([Cl:6])=[O:5])[CH2:3][CH2:2]1.[Cl:7][C:8]1[CH:33]=[CH:32][C:11]2[N:12]3[C:16]([CH2:17][NH:18][CH2:19][C:10]=2[CH:9]=1)=[N:15][N:14]=[C:13]3[CH:20]1[CH2:25][CH2:24][N:23]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=2)[CH2:22][CH2:21]1>>[ClH:6].[ClH:7].[Cl:7][C:8]1[CH:33]=[CH:32][C:11]2[N:12]3[C:16]([CH2:17][N:18]([C:4]([CH:1]4[CH2:3][CH2:2]4)=[O:5])[CH2:19][C:10]=2[CH:9]=1)=[N:15][N:14]=[C:13]3[CH:20]1[CH2:21][CH2:22][N:23]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=2)[CH2:24][CH2:25]1
Reactant: Clc1ccc2c(c1)CNCc1nnc(C3CCN(c4ccccn4)CC3)n1-2
Reactant: O=C(Cl)C1CC1
Product: Cl
Product: O=C(C1CC1)N1Cc2cc(Cl)ccc2-n2c(nnc2C2CCN(c3ccccn3)CC2)C1
Yield: 50 %

Procedure:
The title compound was prepared from Cyclopropanecarbonyl chloride and the amine of example 4, in 50% yield, using the procedure described in example 8.
Reaction SMILES: [F:1][C:2]([F:39])([F:38])[C:3]1[CH:4]=[C:5]([C:13]2[S:14][C:15]([C:24]3[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:27]=[C:26]([C:34]([F:37])([F:36])[F:35])[CH:25]=3)=[C:16]([N+:21]([O-])=O)[C:17]=2[N+:18]([O-])=O)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.BrC1SC(Br)=C([N+]([O-])=O)C=1[N+]([O-])=O.FC(F)(F)C1C=C([Sn](CCCC)(CCCC)CCCC)C=C(C(F)(F)F)C=1.O.O.[Sn](Cl)Cl>C(O)C>[F:12][C:9]([F:10])([F:11])[C:7]1[CH:6]=[C:5]([C:13]2[S:14][C:15]([C:24]3[CH:29]=[C:28]([C:30]([F:31])([F:32])[F:33])[CH:27]=[C:26]([C:34]([F:37])([F:36])[F:35])[CH:25]=3)=[C:16]([NH2:21])[C:17]=2[NH2:18])[CH:4]=[C:3]([C:2]([F:39])([F:38])[F:1])[CH:8]=1
Reactant: O=[N+]([O-])c1c(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)sc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)c1[N+](=O)[O-]
Agent: CCCC[Sn](CCCC)(CCCC)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: Cl[Sn]Cl
Agent: O=[N+]([O-])c1c(Br)sc(Br)c1[N+](=O)[O-]
Solvent: O
Solvent: CCO
Product: Nc1c(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)sc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)c1N

Procedure:
2,5-Bis-(3,5-bis-trifluoromethyl-phenyl)-3,4-dinitro-thiophene was made by Stille coupling reaction of 2,5-dibromo-3,4-dinitro-thiophene and 3,5-bis-trifluoromethyl-phenyl-tributyl-stannane. It was reduced with tin (II) chloride dihydrate in ethanol to give 2,5-bis-(3,5-bis-trifluoromethyl-phenyl)-thiophene-3,4-diamine. The diamine was reacted with hexaketocyclohexane octahydrate to give compound A. The product is a red-brown solid. It is soluble in common organic solvents such as dichloromethane and THF. It was purified by flash chromatography on silica gel and crystallization in ethanol. The purified product had elemental analysis data consistent with the formula for the desired compound.
Reaction SMILES: [Br:1]N1C(=O)NC(=O)N(Br)C1=O.[F:12][C:13]1[C:18]([OH:19])=[C:17]([CH:20]=[O:21])[CH:16]=[CH:15][C:14]=1[C:22]1[CH:27]=[CH:26][C:25]([F:28])=[CH:24][C:23]=1[F:29].S([O-])([O-])(=O)=S.[Na+].[Na+]>CN(C=O)C>[Br:1][C:15]1[C:14]([C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][C:23]=2[F:29])=[C:13]([F:12])[C:18]([OH:19])=[C:17]([CH:20]=[O:21])[CH:16]=1
Reactant: O=c1[nH]c(=O)n(Br)c(=O)n1Br
Reactant: O=Cc1ccc(-c2ccc(F)cc2F)c(F)c1O
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=Cc1cc(Br)c(-c2ccc(F)cc2F)c(F)c1O
Reaction time: 3 h
Yield: 121.3 %

Procedure:
Dibromoisocyanuric acid (2.25 g) was added at room temperature to a DMF (90 mL) solution of 2,2′,4′-trifluoro-3-hydroxybiphenyl-4-carbaldehyde (3.29 g), and the mixture was stirred at the same temperature as above for 3 hours in a nitrogen atmosphere. A saturated aqueous solution of sodium thiosulfate was added to the reaction mixture at room temperature, followed by extraction with ethyl acetate. The obtained organic layer was washed with water and saturated saline in this order and dried over anhydrous magnesium sulfate, and then, the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) and diol-supported silica gel column chromatography (hexane/ethyl acetate) in this order to obtain the title compound (3.15 g).
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[NH2:12][C:13]1[S:14][CH:15]=[C:16]([CH3:18])[N:17]=1.[CH3:19][Si](C=[N+]=[N-])(C)C>N1C=CC=CC=1.CO.O1CCCC1>[CH3:19][N:12]([C:13]1[S:14][CH:15]=[C:16]([CH3:18])[N:17]=1)[S:8]([C:5]1[CH:6]=[CH:7][C:2]([I:1])=[CH:3][CH:4]=1)(=[O:10])=[O:9]
Reactant: Cc1csc(N)n1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: O=S(=O)(Cl)c1ccc(I)cc1
Solvent: CO
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: Cc1csc(N(C)S(=O)(=O)c2ccc(I)cc2)n1
Reaction time: 1 h

Procedure:
760 mg of N1-(4-methyl-1,3-thiazol-2-yl)-4-iodo-1-benzene sulfonamide obtained by reacting 4-iodobenzenesulfonyl chloride with 2-amino-4-methylthiazole in pyridine was dissolved in a solvent mixture of 5 mL methanol and 3 mL tetrahydrofuran, then 1.1 mL (trimethylsilyl)diazomethane (2 M hexane solution) was added thereto, and the mixture was stirred for 1 hour. The solvent was evaporated and purified with an NH silica gel column, to give 335 mg of the title compound as a pale yellow solid.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:11]=1)[C:6](Cl)=[O:7].[CH3:18][NH:19][C:20]1[CH:21]=[N:22][CH:23]=[CH:24][C:25]=1[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[CH3:32].CCN(C(C)C)C(C)C>C(Cl)Cl>[CH3:18][N:19]([C:20]1[CH:21]=[N:22][CH:23]=[CH:24][C:25]=1[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[CH3:32])[C:6](=[O:7])[C:5]1[CH:4]=[C:3]([C:2]([F:17])([F:16])[F:1])[CH:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:9]=1
Reactant: CNc1cnccc1-c1ccccc1C
Reactant: O=C(Cl)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccccc1-c1ccncc1N(C)C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reaction time: 8 h

Procedure:
3,5-Bis-trifluoromethylbenzoyl chloride (36 mg, 0.13 mmol, CAS RN 1271-19-8) was added to a solution of methyl-(4-o-tolyl-pyridin-3-yl)-amine (20 mg, 0.10 mmol) and DIPEA (40 μL, 0.23 mmol) in CH2Cl2 (1 mL). The reaction mixture was stirred overnight and then loaded directly onto a silica gel column and eluted with 50% EtOAc in n-hexane to yield the desired product as a waxy solid (23 mg, 41%). MS (ESI): m/z=439.0 [M+H]+.
Reaction SMILES: [C:1]1([P:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:20]([O:22][C:23]1[CH:30]=[CH:29][CH:28]=[C:27]([O:31][CH2:32][CH3:33])[C:24]=1[CH2:25][Br:26])[CH3:21].C(OCC)C>C1(C)C=CC=CC=1>[Br-:26].[CH2:32]([O:31][C:27]1[CH:28]=[CH:29][CH:30]=[C:23]([O:22][CH2:20][CH3:21])[C:24]=1[CH2:25][P+:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[CH3:33]
Reactant: CCOc1cccc(OCC)c1CBr
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: CCOc1cccc(OCC)c1C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Product: [Br-]
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of triphenylphosphine (1.31 g, 5.01 mmol) in toluene (6.5 mL) was added 2,6-diethoxybenzyl bromide (1.3 g, 5.01 mmol) and the mixture stirred at room temperature overnight. Diethyl ether was added and the solid was collected by filtration to give (2,6-diethoxybenzyl)triphenylphosphonium bromide as an off-white solid. Yield (1.58 g, 60%): 1H NMR (400 MHz, DMSO-d6) δ 7.83-7.87 (m, 3H), 7.68 (ddd, J=7.6, 7.6, 3.2 Hz, 6H), 7.55 (d, J=7.6 Hz, 3H), 7.52 (d, J=7.2 Hz, 3H), 7.18 (ddd, 0.1=8.4, 8.4, 2.4 Hz, 1H), 6.45 (d, J=8.4 Hz, 2H), 4.66 (d, J=14.0 Hz, 2H), 3.65 (q, J=6.8 Hz, 4H), 1.01 (t, J=6.8 Hz, 6H).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)[N:5]=[CH:4][N:3]=1.[CH3:18][C:19]1[CH:28]=[N:27][C:26]2[C:25]([OH:29])=[CH:24][CH:23]=[CH:22][C:21]=2[N:20]=1.[H-].[Na+]>CN(C=O)C>[CH3:18][C:19]1[CH:28]=[N:27][C:26]2[C:21](=[CH:22][CH:23]=[CH:24][C:25]=2[O:29][C:2]2[CH:7]=[C:6]([C:8]3[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=3)[N:5]=[CH:4][N:3]=2)[N:20]=1
Reactant: Cc1cnc2c(O)cccc2n1
Reactant: FC(F)(F)c1ccc(-c2cc(Cl)ncn2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cnc2c(Oc3cc(-c4ccc(C(F)(F)F)cc4)ncn3)cccc2n1

Procedure:
The title compound was prepared analogous to the procedure in Example 29 using 4-chloro-6-(4-trifluoromethyl-phenyl)-pyrimidine, (Example 2(a), Method A), (0.20 g, 0.77 mmol), 2-methyl-quinoxalin-5-ol (0.14 g, 0.85 mmol, J. Med. Chem, 1988, 41, 4062.) DMF (3 mL), and a 60% dispersion of sodium hydride in mineral oil (0.040 g, 1.0 mmol, Aldrich). Purification by flash chromatography (0→75% EtOAc/hexanes) gave the title compound as an ivory powder. Mp: 135–141° C., MS (ESI, pos. ion) m/z: 383 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[O:11]1[CH2:15][CH2:14][O:13][CH:12]1[CH2:16][CH2:17][C@H:18]1[CH2:23][CH2:22][C@H:21]([C@H:24]2[CH2:29][CH2:28][C@H:27]([OH:30])[CH2:26][CH2:25]2)[CH2:20][CH2:19]1>N1C=CC=CC=1>[O:11]1[CH2:15][CH2:14][O:13][CH:12]1[CH2:16][CH2:17][C@H:18]1[CH2:19][CH2:20][C@H:21]([C@H:24]2[CH2:29][CH2:28][C@H:27]([O:30][C:6](=[O:7])[C:5]3[CH:9]=[CH:10][C:2]([F:1])=[CH:3][CH:4]=3)[CH2:26][CH2:25]2)[CH2:22][CH2:23]1
Reactant: O[C@H]1CC[C@H]([C@H]2CC[C@H](CCC3OCCO3)CC2)CC1
Reactant: O=C(Cl)c1ccc(F)cc1
Solvent: c1ccncc1
Product: O=C(O[C@H]1CC[C@H]([C@H]2CC[C@H](CCC3OCCO3)CC2)CC1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A solution of 1.7 g of 4-fluorobenzoyl chloride in 5 ml of pyridine is treated with 2.8 g of trans-4-[trans-4-[2-(1,3-dioxolan-2-yl)ethyl]cyclohexyl]cyclohexanol (prepared according to Example 3) and stirred at room temperature for 12 hours. Thereafter, the reaction mixture is poured on to ice-water and extracted three times with diethyl ether. The organic phases are washed in succession with saturated sodium hydrogen carbonate solution, with 10 percent hydrochloric acid, with saturated sodium hydrogen carbonate solution and with water, then dried over magnesium sulfate, filtered and concentrated. Chromatographic purification of the resulting crude product on silica gel with ethyl acetate/petroleum ether (vol. 3:97) gives 4-fluorobenzoic acid trans-4-[trans-4-[2-(1,3-dioxolan-2-yl)ethyl]cyclohexyl]cyclohexyl ester.
Reaction SMILES: CO[C:3]([C:5]1([CH2:11][CH2:12][NH:13][C:14]2[C:15]([CH3:31])=[N:16][C:17]([N:20]3[CH2:24][CH2:23][C@@H:22]([N:25]4[CH2:29][CH2:28][CH2:27][C@@H:26]4[CH3:30])[CH2:21]3)=[CH:18][CH:19]=2)[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1)=[O:4]>CO.C(Cl)Cl>[CH3:31][C:15]1[C:14]([N:13]2[CH2:12][CH2:11][C:5]3([CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]3)[C:3]2=[O:4])=[CH:19][CH:18]=[C:17]([N:20]2[CH2:24][CH2:23][C@@H:22]([N:25]3[CH2:29][CH2:28][CH2:27][C@@H:26]3[CH3:30])[CH2:21]2)[N:16]=1.[NH3:13]
Reactant: COC(=O)C1(CCNc2ccc(N3CC[C@@H](N4CCC[C@@H]4C)C3)nc2C)CCCCC1
Solvent: CO
Solvent: ClCCl
Product: Cc1nc(N2CC[C@@H](N3CCC[C@@H]3C)C2)ccc1N1CCC2(CCCCC2)C1=O
Product: N
Yield: 5 %

Procedure:
The title compound was synthesized in essentially the same manner using the procedures as set forth in Step 2 of Example 1, by cyclizing 1-{2-[2-methyl-6-((2S,3′R)-2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-pyridin-3-ylamino]-ethyl}-cyclohexanecarboxylic acid methyl ester (94 mg, 0.22 mmol) to obtain 35.6 mg (41% yield over two steps) of the title compound after flash column chromatography (5% 7N NH3 in MeOH/CH2Cl2).
Reaction SMILES: [CH:1](=[O:10])[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C(C1C(=O)C(Cl)=C(Cl)[C:15](=[O:16])C=1C#N)#N.CO>C1(C)C=CC=CC=1>[C:1]([O:16][CH3:15])(=[O:10])[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Reactant: O=CC=Cc1ccccc1
Solvent: CO
Solvent: Cc1ccccc1
Product: COC(=O)C=Cc1ccccc1
Yield: 96 %

Procedure:
A homogeneous mixture containing cinnamaldehyde (7.5 mmol), DDQ (11.3 mmol), MeOH (15 mL) and toluene (10 mL) is taken in a round bottom flask and catalytic amount of neutral alumina (0.1 g) is added to it. The mixture is refluxed for 6 hrs under Dean Stark apparatus. After completion of the reaction (observed by TLC and by GC analysis), the reaction mixture is filtered and washed with MeOH (5 ml×2). Concentrate the filtrate under reduced pressure and the crude product thus obtained is loaded on a neutral alumina column and eluted with diethyl ether. Methyl cinnamate is isolated in 96% yield whose NMR values are found matching with reported values as in example 1.
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH2:5][CH:4]([CH2:8][NH:9][C:10]([C@H:12]2[CH2:16][CH2:15][CH2:14][N:13]2[C:17]([C@@H:19]2[CH2:23][CH2:22][CH2:21][N:20]2[C:24](=[O:45])[CH2:25][C:26]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[O:18])=[O:11])[CH2:3]1.[CH2:46]=O>>[CH3:46][N:2]1[CH2:7][CH2:6][CH2:5][CH:4]([CH2:8][NH:9][C:10]([C@H:12]2[CH2:16][CH2:15][CH2:14][N:13]2[C:17]([C@@H:19]2[CH2:23][CH2:22][CH2:21][N:20]2[C:24](=[O:45])[CH2:25][C:26]([C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[O:18])=[O:11])[CH2:3]1
Reactant: O=C(NCC1CCCNC1)[C@H]1CCCN1C(=O)[C@@H]1CCCN1C(=O)CC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: C=O
Agent: Cl
Product: CN1CCCC(CNC(=O)[C@H]2CCCN2C(=O)[C@@H]2CCCN2C(=O)CC(c2ccccc2)(c2ccccc2)c2ccccc2)C1

Procedure:
The title compound was prepared by a method similar to Step 7 of Example 1 using (2R)-N-(3-piperidylmethyl)-1-{(2S)-1-(3,3,3-triphenylpropanoyl)pyrrolidin-2-yl}carbonylpyrrolidine-2-carboxamide monohydrochloride and 37% aqueous formaldehyde solution. The compound was obtained as a white solid.
Reaction SMILES: ClC(Cl)(O[C:5](=[O:11])OC(Cl)(Cl)Cl)Cl.[C:13]1([CH3:29])[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[C@@H:19]1[NH:24][CH2:23][CH2:22][N:21]2[C:25](=[O:28])[CH2:26][CH2:27][C@@H:20]12.[CH:30]([C:33]1[CH:34]=[C:35]([C@H:43]([NH:45][CH3:46])[CH3:44])[CH:36]=[C:37]([C:39]([F:42])([F:41])[F:40])[CH:38]=1)([CH3:32])[CH3:31]>CCOC(C)=O.CN(C1C=CN=CC=1)C>[CH:30]([C:33]1[CH:34]=[C:35]([C@H:43]([N:45]([CH3:46])[C:5]([N:24]2[CH2:23][CH2:22][N:21]3[C:25](=[O:28])[CH2:26][CH2:27][C@H:20]3[C@@H:19]2[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[CH3:29])=[O:11])[CH3:44])[CH:36]=[C:37]([C:39]([F:40])([F:41])[F:42])[CH:38]=1)([CH3:32])[CH3:31]
Reactant: CN[C@H](C)c1cc(C(C)C)cc(C(F)(F)F)c1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: Cc1ccccc1[C@@H]1NCCN2C(=O)CC[C@@H]12
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Product: Cc1ccccc1[C@H]1[C@@H]2CCC(=O)N2CCN1C(=O)N(C)[C@H](C)c1cc(C(C)C)cc(C(F)(F)F)c1
Reaction time: 1.5 h
Yield: 49.4 %

Procedure:
To a solution of triphosgene (72 mg, 0.242 mmol) in EtOAc (5 mL) at 0° C. was added solution of (1S,8aS)-1-o-tolylhexahydropyrrolo[1,2-a]pyrazin-6(7H)-one (112 mg, 0.484 mmol), DMAP (6.2 mg, 0.05 mmol) and TEA (151 mg, 1.5 mmol) in EtOAc (15 mL). The mixture was stirred for 1.5 h, followed by addition of (R)-1-(3-isopropyl-5-(trifluoromethyl)phenyl)-N-methylethanamine (142 mg, 0.58 mmol) in EtOAc (10 mL) and TEA (151 mg, 1.5 mmol). The reaction was then stirred at 50° C. for 48 h and quenched with water. The resulting mixture was extracted with EtOAc. The combined organic layer was washed with 1 N aqueous HCl solution, dried over anhydrous Na2SO4 and then concentrated in high vacuum. The residue was purified by silica gel chromatography (DCM/MeOH=20/1 to 10/1) to give the title compound (60 mg, yield: 25%) as yellow solid. 1H-NMR (400 MHz, CDCl3) δ ppm 7.37 (s, 1H), 7.27 (d, J=6 Hz, 2H), 7.15 (m, 5H), 5.48 (m, 1H), 4.08 (m, 2H), 3.71 (m, 1H), 2.87 (m, 4H), 2.67 (s, 3H), 2.56 (s, 3H), 2.37 (m, 2H), 1.82 (m, 1H), 1.64 (m, 1H), 1.35 (d, 3H), 1.22 (m, 3H); m/z (ES+): 502 [M+H]+.
Reaction SMILES: [CH:1]1[C:6]([OH:7])=[CH:5][CH:4]=[C:3]([CH3:8])[CH:2]=1.[CH3:9][O:10][C:11]1[CH:12]=[C:13]([C:19]2[C:24]([C:25]([N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)=[O:26])=[CH:23][N:22]=[C:21](S(C)(=O)=O)[N:20]=2)[CH:14]=[CH:15][C:16]=1[O:17][CH3:18]>C(#N)C>[CH3:9][O:10][C:11]1[CH:12]=[C:13]([C:19]2[C:24]([C:25]([N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)=[O:26])=[CH:23][N:22]=[C:21]([O:7][C:6]3[CH:1]=[CH:2][C:3]([CH3:8])=[CH:4][CH:5]=3)[N:20]=2)[CH:14]=[CH:15][C:16]=1[O:17][CH3:18]
Reactant: COc1ccc(-c2nc(S(C)(=O)=O)ncc2C(=O)N2CCOCC2)cc1OC
Reactant: Cc1ccc(O)cc1
Solvent: CC#N
Product: COc1ccc(-c2nc(Oc3ccc(C)cc3)ncc2C(=O)N2CCOCC2)cc1OC
Temperature: 65 °C
Yield: 75 %

Procedure:
Acetonitrile (10 ml) potassium carbonate (0.5 g), paracresol (2.7 g) and the pyrimidine obtained in Example 432 (1 g) are placed in a reactor together with 3 drops of TDA--1[tris(3,6-dioxaheptyl)amine] as catalyst. The mixture is heated to 65° C. for one hour, and the solvent is evaporated. The mixture is taken up in water and extracted with ether, dried over MgSO4 and evaporated. A white solid is obtained in a yield of 75%, m.p. 152° C.
Reaction SMILES: [C:1]([C:9]1[O:13][C:12]([CH:14]=O)=[CH:11][CH:10]=1)#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].C(O)(=O)[CH2:17][C:18]([OH:20])=[O:19]>>[C:1]([C:9]1[O:13][C:12](/[CH:14]=[CH:17]/[C:18]([OH:20])=[O:19])=[CH:11][CH:10]=1)#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: O=C(O)CC(=O)O
Reactant: CCCCCCC#Cc1ccc(C=O)o1
Product: CCCCCCC#Cc1ccc(/C=C/C(=O)O)o1
Yield: 88.2 %

Procedure:
Reaction of 5-(1-octynyl)furan-2-carboxaldehyde (0.72 g, 3.5 mmole from example 8) with malonic acid (0.73 g, 7 mmole) as described in Example 2 gave 0.76 g (88%) of the title compound, mp(Hexane) 100°-100.5° C. νmax (mull) 2650 (broad), 1695, 1630, 1565, 1510, 1410, 1300, 1235, 1210 cm-1 ; δ(CDCl3) 0.90(3H, t, 6.8 Hz), 1.32(4H, m), 1.44(2H, m), 1.62(2H, m), 2.47(2H, t, J=6.5 Hz), 6.38(1H, d, J=15 Hz), 6.54(1H, d, J=3 Hz), 6.64(1H, d, J=3 Hz), 7.48(1H, d, J=15 Hz), 10.53 (1H, broad).
Reaction SMILES: [N+:1](=[C:3]([C:8](=O)[CH2:9][O:10][CH3:11])[C:4]([O:6][CH3:7])=[O:5])=[N-:2].[NH4+]=[S:14]>>[CH3:11][O:10][CH2:9][C:8]1[S:14][N:2]=[N:1][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: COCC(=O)C(=[N+]=[N-])C(=O)OC
Product: COCc1snnc1C(=O)OC
Reaction time: 0.5 h
Yield: 85.8 %

Procedure:
Methyl 2-diazo-4-methoxy-3-oxobutanoate (4.5 g, 0.026 mol) was cooled in an ice bath and ammonium sulfide (8.0 g, 0.12 mol) (40-48%) was added drop-wise over 2 minutes. White precipitate formed. The slurry was stirred for 30 minutes, and then purified by flash chromatography to give the desired product (4.2 g, 85%) as a light oil, that crystallized readily upon standing. 1H NMR (400 MHz, CD3OD): δ 5.02 (s, 2H), 3.98 (s, 3H), 3.57 (s, 3H). MF═C6H8N2O3S; LCMS calculated for C6H9N2O3S(M+H)+: m/z=189.0.