Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[CH:4]1[CH2:12][C:11]2[C:10](=O)[CH2:9][CH2:8][CH2:7][C:6]=2[O:5]1)C.C(OC(OCC)CC1C(=O)CCCC1=O)C.[NH3:30]>CO>[O:5]=[C:6]1[CH2:7][CH2:8][CH2:9][C:10]2[NH:30][CH:4]=[CH:12][C:11]1=2
Reactant: N
Reactant: CCOC1CC2=C(CCCC2=O)O1
Agent: CCOC(CC1C(=O)CCCC1=O)OCC
Solvent: CO
Product: O=C1CCCc2[nH]ccc21
Temperature: 100 °C
Reaction time: 16 h
Yield: 49 %

Procedure:
The reactions of Examples 1 and 3 were respectively repeated and the reaction products were admixed in a molar (1)/(2) ratio of 87.6:12.4. Then, 1014 mg of this mixture of 2-ethoxy-4-oxo-2,3,4,5,6,7-hexahydrocoumarone and 2-(2',2'-diethoxyethyl)-1,3-cyclohexanedione, 1.7 ml of liquid ammonia and 5.5 ml of methanol were admixed in a glass tube which was sealed and heated at 100° C. for 1 hour and, then, at 150° C. for 16 hours. The above procedure provided 357.6 mg of 4-oxo-4,5,6,7-tetrahydroindole (yield 49%).
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]([N:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)=[CH:5][CH:6]=1.CCN(C(C)C)C(C)C.Cl[C:23]([O:25][C:26]1[CH:31]=[CH:30][C:29]([N+:32]([O-:34])=[O:33])=[CH:28][CH:27]=1)=[O:24]>C(Cl)Cl>[C:4]1([N:7]2[CH2:8][CH2:9][N:10]([C:23]([O:25][C:26]3[CH:27]=[CH:28][C:29]([N+:32]([O-:34])=[O:33])=[CH:30][CH:31]=3)=[O:24])[CH2:11][CH2:12]2)[CH:3]=[CH:2][CH:1]=[CH:6][CH:5]=1
Reactant: c1ccc(N2CCNCC2)cc1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Oc1ccc([N+](=O)[O-])cc1)N1CCN(c2ccccc2)CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 102.4 %

Procedure:
To a solution of phenylpiperazine (12.0 g, 74.0 mmol) and DIPEA (13.5 mL, 81.6 mmol) in DCM (70 mL) at 0° C. add 4-nitrophenyl chloroformate (16.5 g, 81.71 mmol). The reaction mixture was stirred for 30 minutes at 0° C. and then washed with saturated sodium hydrogen carbonate solution (3×200 mL), dried (MgSO4) and concentrated in vacuo to give a 4-nitrophenyl 4-phenylpiperazine-1-carboxylate (24.8 g, 102%) as a yellow solid which was used without further purification.
Reaction SMILES: [F:1][C:2]1[C:7]([NH:8][CH2:9][C:10]2[CH:15]=[C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=3)[CH:13]=[C:12]([CH3:23])[C:11]=2[O:24][CH3:25])=[C:6]([F:26])[CH:5]=[CH:4][C:3]=1[OH:27].C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:35][C:36]([O:38][CH2:39][CH3:40])=[O:37]>CC(C)=O.O>[F:1][C:2]1[C:7]([NH:8][CH2:9][C:10]2[CH:15]=[C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=3)[CH:13]=[C:12]([CH3:23])[C:11]=2[O:24][CH3:25])=[C:6]([F:26])[CH:5]=[CH:4][C:3]=1[O:27][CH2:35][C:36]([O:38][CH2:39][CH3:40])=[O:37]
Reactant: COc1c(C)cc(-c2cccc(F)c2)cc1CNc1c(F)ccc(O)c1F
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Solvent: O
Product: CCOC(=O)COc1ccc(F)c(NCc2cc(-c3cccc(F)c3)cc(C)c2OC)c1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 107.1 %

Procedure:
To a stirred solution of 2,4-difluoro-3-[[5-(3-fluorophenyl)-2-methoxy-3-methyl-phenyl]methylamino]phenol (47 mg, 0.13 mmol, 1.0 eq) in acetone (5 mL) was added Cs2CO3 (61.5 mg, 0.19 mmol, 1.5 eq). The resulting mixture was stirred for 30 min at room temperature then ethyl bromoacetate (25.2 mg, 0.15 mmol, 1.2 eq) was added. The resulting mixture was stirred for 1 h then diluted with water and extracted with EtOAc. The combined organic extracts were washed with water and brine, dried (Na2SO4) and evaporated in vacuo. The residue was purified by column chromatography (petroleum ether:EtOAc, 1:0 to 20:1) to give the title compound as an oil (64 mg, 86%).
Reaction SMILES: O([C@H]1CC[C@H](C[NH:12][C:13](=[O:21])[CH2:14][CH2:15][C:16]([N:18](C)C)=[O:17])CC1)[N+]([O-])=O.[O:22]([C@H:26]1[CH2:31][CH2:30][C@H:29](CNC(=O)CCC(O)=O)[CH2:28][CH2:27]1)[N+:23]([O-:25])=[O:24].CNC>>[O:22]([C@H:26]1[CH2:27][CH2:28][C@H:29]([NH:12][C:13](=[O:21])[CH2:14][CH2:15][C:16]([NH2:18])=[O:17])[CH2:30][CH2:31]1)[N+:23]([O-:25])=[O:24]
Reactant: O=C(O)CCC(=O)NC[C@H]1CC[C@H](O[N+](=O)[O-])CC1
Reactant: CN(C)C(=O)CCC(=O)NC[C@H]1CC[C@H](O[N+](=O)[O-])CC1
Agent: CNC
Product: NC(=O)CCC(=O)N[C@H]1CC[C@H](O[N+](=O)[O-])CC1

Procedure:
N-(trans-4-nitroxycyclohexylmethyl)-N',N'-dimethylsuccinic acid diamide from N-(trans-4-nitroxycyclohexylmethyl)-succinic acid monoamide and dimethylamine melting point: 70°-71° C. (ether), yield: 40%
Reaction SMILES: Cl[CH2:2][C:3]([N:5]([CH2:7][CH:8]([O:11][CH3:12])[O:9][CH3:10])[CH3:6])=[O:4].[NH2:13][C@H:14]1[CH2:19][CH2:18][C@H:17]([OH:20])[CH2:16][CH2:15]1.C(=O)([O-])[O-].[Na+].[Na+].[I-].[K+]>C(#N)C>[OH:20][C@H:17]1[CH2:18][CH2:19][C@H:14]([NH:13][CH2:2][C:3]([N:5]([CH2:7][CH:8]([O:11][CH3:12])[O:9][CH3:10])[CH3:6])=[O:4])[CH2:15][CH2:16]1
Reactant: N[C@H]1CC[C@H](O)CC1
Reactant: COC(CN(C)C(=O)CCl)OC
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Product: COC(CN(C)C(=O)CN[C@H]1CC[C@H](O)CC1)OC
Temperature: 85 °C
Reaction time: 16.5 h

Procedure:
15.0 g 2-chloro-N-(2,2-dimethoxy-ethyl)-N-methyl-acetamide in 80 ml acetonitrile are added dropwise within one hour to a suspension of 10.6 g (trans)-4-aminocyclohexanol, 16.25 g sodium carbonate and 0.64 g potassium iodide in 220 ml acetonitrile which has been warmed to 85° C. The mixture is stirred for one hour at 85° C. and for 16.5 hours at ambient temperature. It is filtered off and the filtrate is evaporated down. The residue is purified by chromatography and then recrystallised from methyl-tert-butylether and cyclohexane.
Reaction SMILES: [NH4+:1].[Cl:2][C:3]1[CH:4]=[C:5]([CH:24]=[CH:25][C:26]=1[Cl:27])[CH:6]=[CH:7][S:8]([N:11]=[C:12](Cl)[C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([O:21][CH3:22])[CH:14]=1)(=[O:10])=[O:9]>C1C=CC=CC=1>[Cl:2][C:3]1[CH:4]=[C:5]([CH:24]=[CH:25][C:26]=1[Cl:27])[CH:6]=[CH:7][S:8]([NH:11][C:12](=[NH:1])[C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([O:21][CH3:22])[CH:14]=1)(=[O:10])=[O:9]
Reactant: [NH4+]
Reactant: COc1ccc(C(Cl)=NS(=O)(=O)C=Cc2ccc(Cl)c(Cl)c2)cc1OC
Solvent: c1ccccc1
Product: COc1ccc(C(=N)NS(=O)(=O)C=Cc2ccc(Cl)c(Cl)c2)cc1OC
Yield: 96 %

Procedure:
Ammonium gas is bubbled through a solution of N-(3,4-dichlorostyrylsulfonyl)-3,4-dimethoxybenzimidoyl chloride (8.7 g., 0.02 mole) in 100 ml. of dry benzene for a period of 1 hr. The solvent evaporated under reduced pressure and the solid residue stirred with 50 ml. of water and filtered affords 8.0 g. (96% yield) of N-(3,4-DICHLOROSTYRYLSULFONYL)-3,4-DIMETHOXYBENZAMIDINE, m.p. 205°-210° C. A sample crystallized from acetonitrile has a melting point of m.p. 208°-211° C.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[C:8]([C:11]3[CH2:12][CH2:13][N:14]([CH2:17][CH3:18])[CH2:15][CH:16]=3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1.[F:19][C:20]1[CH:28]=[CH:27][C:23]([C:24](Cl)=[O:25])=[CH:22][CH:21]=1>>[F:19][C:20]1[CH:28]=[CH:27][C:23]([C:24]([NH:1][C:2]2[N:7]=[C:6]3[C:8]([C:11]4[CH2:12][CH2:13][N:14]([CH2:17][CH3:18])[CH2:15][CH:16]=4)=[CH:9][NH:10][C:5]3=[CH:4][CH:3]=2)=[O:25])=[CH:22][CH:21]=1
Reactant: CCN1CC=C(c2c[nH]c3ccc(N)nc23)CC1
Reactant: O=C(Cl)c1ccc(F)cc1
Product: CCN1CC=C(c2c[nH]c3ccc(NC(=O)c4ccc(F)cc4)nc23)CC1

Procedure:
Beginning with 0.015 gm (0.062 mMol) 5-amino-3-(1-ethyl-1,2,3,6-tetrahydropyridin-4-yl)pyrrolo[3,2-b]pyridine and 0.008 mL (0.068 mMol) 4-fluorobenzoyl chloride, the title compound was prepared essentially by the procedure described in Example 7.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([N+:11]([O-])=O)=[CH:8][CH:9]=2)[CH:4]=[C:3]1[C:14]([O:16][CH2:17][CH3:18])=[O:15].C([O-])=O.[NH4+]>[Pd].C(O)C.O>[NH2:11][C:7]1[CH:6]=[C:5]2[C:10](=[CH:9][CH:8]=1)[N:2]([CH3:1])[C:3]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:4]2
Reactant: CCOC(=O)c1cc2cc([N+](=O)[O-])ccc2n1C
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: CCOC(=O)c1cc2cc(N)ccc2n1C
Temperature: 20 °C
Reaction time: 18 h
Yield: 85.7 %

Procedure:
Alternative A. To a mixture of ethyl 1-methyl-5-nitro-1H-indole-2-carboxylate (420 g), from step (a) or commercial sources, and 10% palladium on carbon catalyst (50% wet) (42 g) in ethanol (4200 mL) was added a solution of ammonium formate (541.59) in demineralized water (840 mL) at between 25-35° C. over 3 hours. The mixture was stirred for 18 hours at 20° C., and then filtered, washing the solids with ethanol (2100 mL). The combined filtrate and washings were concentrated to 840 mL under vacuum at about 20° C. The resulting slurry was granulated at 5° C., filtered, washed with chilled ethanol (420 mL), and dried to give product ethyl 5-amino-1-methyl-1H-indole-2-carboxylate (316.5 g, 86%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[N:9][C:8](O)=[CH:7][N:6]=1)=[O:4].P(Br)(Br)([Br:14])=O>CO>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[N:9][C:8]([Br:14])=[CH:7][N:6]=1)=[O:4]
Reactant: COC(=O)c1cnc(O)cn1
Reactant: O=P(Br)(Br)Br
Solvent: CO
Product: COC(=O)c1cnc(Br)cn1

Procedure:
A solution of 5-hydroxy-pyrazine-2-carboxylic acid methyl ester (2.56 g, 16.61 mmol) in phosphorous oxybromide 9.9 g, 34.9 mmol) were heated at 90° C. for 70 mins. The reaction was allowed to cool and the resulting solid carefully dissolved in methanol and then the solvent was evaporated in vacuo. The residue was partitioned between EtOAc and sat. NaHCO3 and the organic extracts were washed with brine, dried (Na2SO4) and evaporated in vacuo. The residue was chromatographed (silica gel, EtOAc:Hexanes 40:60) to afford the title compound.
Reaction SMILES: [NH2:1][C:2]1[C:31]([O:32][CH2:33][C:34]([F:37])([F:36])[F:35])=[CH:30][C:5]([CH2:6][C@H:7]2[C@H:15]3[C@@H:11]([N:12]([CH2:17][C:18]4[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([CH3:27])([CH3:26])[CH3:25])[CH:19]=4)[C:13](=[O:16])[O:14]3)[CH2:10][S:9](=[O:29])(=[O:28])[CH2:8]2)=[CH:4][C:3]=1[F:38].[Cl:39][CH2:40][C:41](Cl)=[O:42]>C1(C)C=CC=CC=1>[C:24]([C:20]1[CH:19]=[C:18]([CH:23]=[CH:22][CH:21]=1)[CH2:17][N:12]1[C@@H:11]2[C@H:15]([C@H:7]([CH2:6][C:5]3[CH:30]=[C:31]([O:32][CH2:33][C:34]([F:36])([F:37])[F:35])[C:2]([NH:1][C:41](=[O:42])[CH2:40][Cl:39])=[C:3]([F:38])[CH:4]=3)[CH2:8][S:9](=[O:29])(=[O:28])[CH2:10]2)[O:14][C:13]1=[O:16])([CH3:27])([CH3:25])[CH3:26]
Reactant: CC(C)(C)c1cccc(CN2C(=O)O[C@H]3[C@H](Cc4cc(F)c(N)c(OCC(F)(F)F)c4)CS(=O)(=O)C[C@@H]32)c1
Reactant: O=C(Cl)CCl
Solvent: Cc1ccccc1
Product: CC(C)(C)c1cccc(CN2C(=O)O[C@H]3[C@H](Cc4cc(F)c(NC(=O)CCl)c(OCC(F)(F)F)c4)CS(=O)(=O)C[C@@H]32)c1

Procedure:
The title compound was prepared in analogous manner as described for example 8p) from (3aR,7S,7aS)-7-[4-amino-3-fluoro-5-(2,2,2-trifluoro-ethoxy)-benzyl]-3-(3-tert-butyl-benzyl)-5,5-dioxo-hexahydro-1-oxa-5lambda*6*-thia-3-aza-inden-2-one (400 mg, 0.716 mmol) and chloroacetylchloride (324 mg, 2.86 mmol) to yield a white foam: TLC Rf=0.40 (toluene-ETA 85:15); ESIMS [M+NH4]+=652, 654, [M−H]−=633, 635; UPLC RtD=1.861 min; 1H NMR (600 MHz, DMSO-d6): δ 9.64 (s, 1H, NH), 7.41 (s, 1H), 7.33 (d, 1H), 7.28 (t, 1H), 7.13 (d, 1H), 6.91 (s, 1H), 6.88 (d, 1H), 4.74 (q, 2H), 4.43 (d, 1H), 4.25-4.18 (m, 4H), 3.78 (d, 1H), 3.65 (t, 1H), 3.50 (t, 1H), 3.17 (t, 1H), 2.99 (m, 2H), 2.56 (m, 2H), 1.25 (s, 9H).
Reaction SMILES: [OH:1][C:2]1[C:7]([CH:8]=[O:9])=[CH:6][C:5]([O:10][CH3:11])=[N:4][CH:3]=1.Cl.Cl[CH2:14][C:15]1[C:16]([C:21]2[N:25]([CH:26]([CH3:28])[CH3:27])[N:24]=[CH:23][CH:22]=2)=[N:17][CH:18]=[CH:19][CH:20]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH:26]([N:25]1[C:21]([C:16]2[C:15]([CH2:14][O:1][C:2]3[C:7]([CH:8]=[O:9])=[CH:6][C:5]([O:10][CH3:11])=[N:4][CH:3]=3)=[CH:20][CH:19]=[CH:18][N:17]=2)=[CH:22][CH:23]=[N:24]1)([CH3:28])[CH3:27]
Reactant: CC(C)n1nccc1-c1ncccc1CCl
Reactant: COc1cc(C=O)c(O)cn1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc(C=O)c(OCc2cccnc2-c2ccnn2C(C)C)cn1
Temperature: 70 °C
Yield: 64.9 %

Procedure:
A mixture of 5-hydroxy-2-methoxyisonicotinaldehyde (395 mg, 2.58 mmol, 1 eq.), 3-(chloromethyl)-2-(1-isopropyl-1H-pyrazol-5-yl)pyridine hydrochloride (700 mg, 2.58 mmol, 1 eq.), and K2CO3 (1.4 g, 10.32 mmol, 4 eq.) in DMF (10.0 mL) was heated at 70° C. for 2 h. The mixture was cooled, filtered, concentrated, and purified on silica gel using a mixture of EtOAc and hexanes as eluent to give 5-((2-(1-isopropyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)-2-methoxyisonicotinaldehyde (590 mg, 65%) as an off-white solid. 1H NMR (400 MHz, CDCl3) δ 10.41 (s, 1H), 8.76 (dd, J=4.7, 1.6 Hz, 1H), 8.04 (dd, J=7.9, 1.6 Hz, 1H), 7.90 (s, 1H), 7.61 (d, J=1.8 Hz, 1H), 7.44 (dd, J=7.9, 4.8 Hz, 1H), 7.10 (s, 1H), 6.37 (d, J=1.8 Hz, 1H), 5.14 (s, 2H), 4.65 (sep, J=6.6 Hz, 1H), 3.91 (s, 3H), 1.49 (d, J=6.6 Hz, 6H). LRMS (M+H+) m/z 353.1.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9][C:10]2[CH:22]=[CH:21][C:13]3[O:14][C:15]([CH3:20])([CH3:19])[C:16]([CH3:18])=[CH:17][C:12]=3[CH:11]=2)=[CH:5][CH:4]=1.[I-].[Li+]>N1C(C)=CC(C)=CC=1C.ClCCl>[OH:2][C:3]1[CH:4]=[CH:5][C:6]([S:9][C:10]2[CH:22]=[CH:21][C:13]3[O:14][C:15]([CH3:19])([CH3:20])[C:16]([CH3:18])=[CH:17][C:12]=3[CH:11]=2)=[CH:7][CH:8]=1
Reactant: COc1ccc(Sc2ccc3c(c2)C=C(C)C(C)(C)O3)cc1
Agent: [I-]
Agent: [Li+]
Solvent: Cc1cc(C)nc(C)c1
Solvent: ClCCl
Product: CC1=Cc2cc(Sc3ccc(O)cc3)ccc2OC1(C)C
Reaction time: 72 h
Yield: 77.7 %

Procedure:
6-(4-Methoxyphenyl)thio-2,2,3-trimethyl-2H-benzo[b]pyran (7.816 g) (see Preparation 5) was dissolved in dry 2,4,6-collidine (30 ml), anhydrous lithium iodide (10.04 g) was added and the mixture was heated under reflux under a nitrogen atmosphere for 48 hours. A further portion of lithium iodide (9.06 g). was then added and heating was continued for another 72 hours. After cooling, the mixture was taken up in dichloromethane and washed with 2N aqueous hydrochloric acid solution (×3). The organic layer was separated, dried (anhydrous sodium sulphate), the solvent removed under reduced pressure and the residue was chromatographed on silica using dichloromethane as the eluent to yield 6-(4-hydroxyphenyl)thio-2,2,3-trimethyl-2H-benzo[b]pyran (5.799 g) as an oil.
Reaction SMILES: [N+:1]([C:4]1[CH:18]=[CH:17][C:7]([CH2:8][NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:6][CH:5]=1)([O-])=O.C(O)C.O.[Cl-].[NH4+]>O1CCOCC1>[NH2:1][C:4]1[CH:18]=[CH:17][C:7]([CH2:8][NH:9][C:10](=[O:16])[O:11][C:12]([CH3:14])([CH3:15])[CH3:13])=[CH:6][CH:5]=1
Reactant: CC(C)(C)OC(=O)NCc1ccc([N+](=O)[O-])cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)NCc1ccc(N)cc1
Temperature: 25 °C
Yield: 99 %

Procedure:
C4 (7.0 g, 27.7 mmol) was dissolved in dioxane (325 mL), ethanol (240 mL), and water (160 mL). The resultant solution was then treated with Fe(0) powder (7.12 g, 127.4 mmol) and ammonium chloride (5.33 g, 99.7 mmol), and the resultant mixture was stirred at 70° C. for 4 hours. The reaction mixture was cooled to 25° C., filtered through Celite®, and washed with EtOAc. The organic solvents were evaporated, and the resultant aqueous residue was extracted with EtOAc. The combined organic layers were dried over MgSO4, filtered, and concentrated to provide C5 as a yellow solid. Yield: 6.52 g, 99% yield. 1H NMR (400 MHz, d6-DMSO) δ: 7.146 (t, 1H), 6.87 (d, 2H), 6.48 (d, 2H), 4.95 (s, 2H), 3.92 (d, 2H), 1.38 (s, 9H).
Reaction SMILES: [NH2:1][C:2]1[CH:20]=[CH:19][CH:18]=[CH:17][C:3]=1[CH2:4][NH:5]C(=O)C1C=CC=CC=1[N+]([O-])=O.[N+](C1C=CC=CC=1C(Cl)=O)([O-])=O>>[NH2:1][C:2]1[CH:20]=[CH:19][CH:18]=[CH:17][C:3]=1[CH2:4][NH2:5]
Reactant: Nc1ccccc1CNC(=O)c1ccccc1[N+](=O)[O-]
Agent: O=C(Cl)c1ccccc1[N+](=O)[O-]
Product: NCc1ccccc1N

Procedure:
N-(2-Aminobenzyl)-2-nitrobenzamide was itself obtained as a solid, m.p. 112-113° C., in 80% yield using a similar procedure to that described for the starting material of Example 24, that is by reacting 2-nitrobenzoyl chloride with 2-aminobenzyl (J.Amer.Chem.Soc., 1949, 71, 2137) except that, after the work-up described therein was complete, the residue was triturated in a mixture of diethyl ether/methylene chloride/methanol (1/1/ few drops v/v). The crystalline solid, formed by reaction of the acid chloride with both of the amino groups of 2-aminobenzylamine, was filtered off and discarded. The residual solution was concentrated and N-(2-aminobenzyl)-2-nitrobenzamide was precipitated by the addition of diethyl ether.
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[C:3]1[CH:27]=[CH:26][C:6]2=[N:7][N:8]([C:10]3[CH:11]=[C:12]([CH:18]=[C:19]([C:22]([CH3:25])([CH3:24])[CH3:23])[C:20]=3[OH:21])[CH2:13][CH2:14][C:15]([OH:17])=[O:16])[N:9]=[C:5]2[CH:4]=1.[CH2:30](O)[CH2:31][CH2:32][CH2:33][CH2:34][CH:35]([CH3:37])[CH3:36].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>>[F:29][C:2]([C:3]1[C:4]2[C:5](=[N:9][N:8]([C:10]3[CH:11]=[C:12]([CH:18]=[C:19]([C:22]([CH3:25])([CH3:24])[CH3:23])[C:20]=3[OH:21])[CH2:13][CH2:14][C:15]([O:17][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH:35]([CH3:37])[CH3:36])=[O:16])[N:7]=2)[CH:6]=[CH:26][CH:27]=1)([F:28])[F:1]
Reactant: CC(C)CCCCCO
Reactant: CC(C)(C)c1cc(CCC(=O)O)cc(-n2nc3ccc(C(F)(F)F)cc3n2)c1O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Product: CC(C)CCCCCOC(=O)CCc1cc(-n2nc3cccc(C(F)(F)F)c3n2)c(O)c(C(C)(C)C)c1
Yield: 99.5 %

Procedure:
The acid prepared in Example 39 (8 g, 0.02 mol), EXXAL® 8 (isooctanol isomers, Exxon, 5 g, 0.038 mol), p-toluenesulfonic acid hydrate (0.5 g, 0.0026 mol) and xylenes (100 mL) are charged to a reactor and refluxed for six hours. TLC shows when the reaction is complete. The solvent is removed and the resulting oil is chromatographed on silical gel. The title compound is obtained in 99.5% yield as a light yellow oil.
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:10]1[C:11]2[CH:24]=[C:23]([Cl:25])[S:22][C:12]=2[N:13]=[C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)[N:15]=1>>[N:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[C:14]1[N:15]=[C:10]([NH:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:11]2[CH:24]=[C:23]([Cl:25])[S:22][C:12]=2[N:13]=1
Reactant: Clc1cc2c(Cl)nc(-c3ccccn3)nc2s1
Reactant: NCc1ccccc1
Product: Clc1cc2c(NCc3ccccc3)nc(-c3ccccn3)nc2s1

Procedure:
With the procedure of Example 1, the reaction of benzylamine with 4-chloro-2-(pyridin-2-yl)-6-chloro-thieno-[2,3-d]-pyrimidine yields 2-(pyridin-2-yl)-4-benzylamino-6-chloro-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [CH:1]1([C:5]2[CH:11]=[CH:10][C:8]([NH2:9])=[CH:7][C:6]=2[C:12]([F:15])([F:14])[F:13])[CH2:4][CH2:3][CH2:2]1.C(=O)([O-])O.[Na+].[I:21]Cl.S(S([O-])=O)([O-])(=O)=O.[Na+].[Na+]>C(Cl)(Cl)Cl.O.CO>[CH:1]1([C:5]2[C:6]([C:12]([F:13])([F:14])[F:15])=[CH:7][C:8]([NH2:9])=[C:10]([I:21])[CH:11]=2)[CH2:2][CH2:3][CH2:4]1
Reactant: ClI
Reactant: Nc1ccc(C2CCC2)c(C(F)(F)F)c1
Agent: O=C([O-])O
Agent: O=S([O-])S(=O)(=O)[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: ClC(Cl)Cl
Product: Nc1cc(C(F)(F)F)c(C2CCC2)cc1I
Temperature: 25 °C
Reaction time: 2 h
Yield: 97.9 %

Procedure:
To a mixture of the compound (1.34 g) obtained in step (2) above, sodium hydrogencarbonate (628 mg), chloroform (32.0 mL) and methanol (8.00 mL), a solution of iodine monochloride (1.21 g) in chloroform (8.00 mL) was added dropwise at room temperature over a period of 30 minutes. The resulting mixture was stirred at room temperature for two hours. After adding a solution of 25% sodium metabisulfite in water (20.0 g) under cooling with ice, the mixture was stirred at room temperature for 30 minutes. The reaction mixture was extracted with chloroform and the combined organic layers were dried over anhydrous magnesium sulfate. After removing the desiccant by filtration, the filtrate was concentrated under reduced pressure to give 4-cyclobutyl-2-iodo-5-(trifluoromethyl)aniline as a brown oil (2.08 g).
Reaction SMILES: [NH:1]([C:3]1[N:8]=[CH:7][CH:6]=[CH:5][N:4]=1)[NH2:2].[F:9][C:10]([F:20])([F:19])[C:11](=O)[CH2:12][C:13](OCC)=[O:14]>C(O)(=O)C>[N:4]1[CH:5]=[CH:6][CH:7]=[N:8][C:3]=1[N:1]1[C:13]([OH:14])=[CH:12][C:11]([C:10]([F:20])([F:19])[F:9])=[N:2]1
Reactant: NNc1ncccn1
Reactant: CCOC(=O)CC(=O)C(F)(F)F
Solvent: CC(=O)O
Product: Oc1cc(C(F)(F)F)nn1-c1ncccn1
Yield: 33.8 %

Procedure:
A mixture of 2 g (9 mmol) of 2-hydrazinopyrimidine and ethyl trifluoroacetoacetate (2.6 ml; 9.1 mmol) in 10 ml of acetic acid was refluxed for 60 hours with stirring under nitrogen and then cooled. The mixture was concentrated in vacuo, the residue was diluted with 100 ml of water, and the mixture was extracted with ethyl acetate (3×). The combined organic layer was dried over magnesium sulfate, and concentrated in vacuo. The resulting residue was dried in vacuo to afford 700 mg of 1-(2-pyrimidinyl)-3-trifluoromethyl-5-hydroxypyrazole as a red gum.
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][O:7][C:8]2[CH:13]=[CH:12][NH:11][C:10](=[O:14])[CH:9]=2)=[CH:4][CH:3]=1.[CH:17]1([C:20]2[N:21]=[C:22]3[CH:27]=[CH:26][C:25](I)=[CH:24][N:23]3[C:29]=2[CH3:30])[CH2:19][CH2:18]1.CNCCNC.C(=O)([O-])[O-].[K+].[K+].N>[Cu](I)I.CS(C)=O>[Cl:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][O:7][C:8]2[CH:13]=[CH:12][N:11]([C:25]3[CH:26]=[CH:27][C:22]4[N:23]([C:29]([CH3:30])=[C:20]([CH:17]5[CH2:19][CH2:18]5)[N:21]=4)[CH:24]=3)[C:10](=[O:14])[CH:9]=2)=[CH:4][CH:3]=1
Reactant: Cc1c(C2CC2)nc2ccc(I)cn12
Reactant: O=c1cc(OCc2ccc(Cl)cc2)cc[nH]1
Agent: I[Cu]I
Agent: CNCCNC
Agent: N
Solvent: CS(C)=O
Product: Cc1c(C2CC2)nc2ccc(-n3ccc(OCc4ccc(Cl)cc4)cc3=O)cn12
Temperature: 110 °C
Yield: 55.2 %

Procedure:
Then a mixture of 4-((4-chlorobenzyl)oxy)pyridin-2(1H)-one (1.0 g), 2-cyclopropyl-6-iodo-3-methylimidazo[1,2-a]pyridine (1.27 g), N,N′-dimethylethylenediamine (0.48 ml), copper iodide (0.81 g), potassium carbonate (1.76 g) and DMSO (13 ml) was heated at 110° C. under microwave irradiation for 1 h. Other two batches using 200 mg and 1 g of 4-((4-chlorobenzyl)oxy)pyridin-2(1H)-one were conducted. Then these reaction mixtures were combined, and poured into 14% NH3 solution. The mixture was extracted with 1:1 mixture of EtOAc and THF. The extract was washed with brine, dried over MgSO4, concentrated, and purified by silica gel column chromatography (hexane/EtOAc then EtOAc/MeOH), followed by NH silica gel column chromatography (hexane/EtOAc) to give the title compound as a white solid (950 mg).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:30])[C@H:4]([C:6]1[CH:7]=[C:8]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][C:17]=2[CH2:26][NH:27][CH2:28][CH3:29])[CH:9]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:11]=1)[CH3:5].[CH2:31]([N:38]=[C:39]=[O:40])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>>[CH3:1][O:2][C:3](=[O:30])[C@H:4]([C:6]1[CH:7]=[C:8]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:23])([F:24])[F:25])=[CH:18][C:17]=2[CH2:26][N:27]([CH2:28][CH3:29])[C:39]([NH:38][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[O:40])[CH:9]=[C:10]([C:12]([F:14])([F:15])[F:13])[CH:11]=1)[CH3:5]
Reactant: CCNCc1cc(C(F)(F)F)ccc1-c1cc([C@H](C)C(=O)OC)cc(C(F)(F)F)c1
Reactant: O=C=NCc1ccccc1
Product: CCN(Cc1cc(C(F)(F)F)ccc1-c1cc([C@H](C)C(=O)OC)cc(C(F)(F)F)c1)C(=O)NCc1ccccc1

Procedure:
Prepared according to the procedure described in Example 43, Step 3, using the following starting materials: (S)-2-(2′-ethylaminomethyl-5,4′-bis-trifluoromethyl-biphenyl-3-yl)-propionic acid methyl ester and benzyl isocyanate.