Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN[C:3]([CH2:5]SP(OC)(OC)=S)=O.CCO[C:16]([CH2:18][CH:19]([S:25][P:26]([O:30][CH3:31])([O:28][CH3:29])=[S:27])[C:20]([O:22][CH2:23][CH3:24])=[O:21])=O.COP(S[CH2:39][C:40](N1CCOCC1)=O)(OC)=S.CN(C(CSP(OC)(OC)=S)=O)C=O>>[CH3:24][CH2:23][O:22][C:20]([CH:19]([S:25][P:26]([O:28][CH3:29])([O:30][CH3:31])=[S:27])[C:18]1[CH:16]=[CH:39][CH:40]=[CH:5][CH:3]=1)=[O:21]
Reactant: CCOC(=O)CC(SP(=S)(OC)OC)C(=O)OCC
Reactant: CNC(=O)CSP(=S)(OC)OC
Reactant: COP(=S)(OC)SCC(=O)N1CCOCC1
Agent: COP(=S)(OC)SCC(=O)N(C)C=O
Product: CCOC(=O)C(SP(=S)(OC)OC)c1ccccc1

Procedure:
dimethoate; malathion; morphothion and formothion.
Reaction SMILES: [C:1]1([CH3:12])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:8]=[N:9][NH:10][CH:11]=1.[CH:13](=O)[CH2:14][CH2:15][CH3:16].[CH:18]1([OH:24])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1.C1(C)C=CC(S(O)(=O)=O)=CC=1>O.C1CCCCC1>[CH:18]1([O:24][CH:13]([C:1]2([CH3:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]2[C:7]2[N:8]=[N:9][NH:10][CH:11]=2)[CH2:14][CH2:15][CH3:16])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: Cc1ccccc1-c1c[nH]nn1
Reactant: CCCC=O
Reactant: OC1CCCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: C1CCCCC1
Product: CCCC(OC1CCCCC1)C1(C)C=CC=CC1c1c[nH]nn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 91.5 %

Procedure:
A mixture of 133 parts tolyltriazole, 79.3 parts n-butyraldehyde, 100.1 parts cyclohexanol and 1.3 parts paratoluene sulphonic acid is heated in 600 parts cyclohexane with simultaneous azeotropic removal of the water formed during the reaction. The reaction is complete after 2 hours. Upon cooling to ambient temperature, the reaction mixture is washed with dilute sodium carbonate solution, then with water and finally dried over anhydrous magnesium sulphate. The dried reaction mixture is filtered and evaporated under reduced pressure and then stripped under vacuum (100° C./4 Pa) to yield 262.9 parts (91.5 %) of 1-(1-cyclohexyloxybutyl) tolyltriazole as a yellow oil. The product is distilled at 175° C./8 Pa to yield a pale yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][CH2:9][C:10]3([CH2:15][CH2:14][N:13]([CH3:16])[CH2:12][CH2:11]3)[C:5]2=[CH:4][CH:3]=1.[H-].[Na+].[F:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1F.[C:27]([OH:34])(=[O:33])/[CH:28]=[CH:29]\[C:30]([OH:32])=[O:31]>CCOCC.CS(C)=O>[C:27]([OH:34])(=[O:33])/[CH:28]=[CH:29]\[C:30]([OH:32])=[O:31].[Cl:1][C:2]1[CH:7]=[C:6]2[N:8]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=3[F:19])[CH2:9][C:10]3([CH2:15][CH2:14][N:13]([CH3:16])[CH2:12][CH2:11]3)[C:5]2=[CH:4][CH:3]=1
Reactant: Fc1ccccc1F
Reactant: CN1CCC2(CC1)CNc1cc(Cl)ccc12
Agent: O=C(O)/C=C\C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CS(C)=O
Product: CN1CCC2(CC1)CN(c1ccccc1F)c1cc(Cl)ccc12
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
A mixture of 6.3 g of 6-chloro-1'-methylspiro[indoline-3,4'-piperidine], Example 23b, 1.5 g of sodium hydride, 10 g of 0-difluorobenzene and 50 ml of dimethylsulfoxide is stirred at 60° C. under nitrogen for 30 minutes. Thereafter, the mixture is permitted to cool before adding ice-water. The biphasic mixture is extracted thrice with ether. The combined ether extracts are extracted with a large excess of dilute hydrochloric acid. The acidic extract is basified with concentrated ammonium hydroxide effecting a heavy oil. The oil is purified by passing through an alumina column, ether eluant, to provide a yellowish oil. The oil, in ether, is converted to its maleic acid salt which is recrystallized from an acetone-ether mixture providing off-white crystals, mp 166°-168° C. of 6-chloro-1-(2-fluorophenyl)-1'-methylspiro[indoline-3,4'-piperidine] maleate.
Reaction SMILES: [C:1](Cl)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[CH3:8][C:9]1([CH3:19])[C:14](=[O:15])[O:13][CH2:12][C:11]([CH3:18])([CH2:16][OH:17])[NH:10]1>CN(C)C1C=CN=CC=1.ClCCl>[CH3:8][C:9]1([CH3:19])[C:14](=[O:15])[O:13][CH2:12][C:11]([CH3:18])([CH2:16][O:17][C:1](=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3])[NH:10]1
Reactant: CC(C)(C)C(=O)Cl
Reactant: CC1(CO)COC(=O)C(C)(C)N1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC1(COC(=O)C(C)(C)C)COC(=O)C(C)(C)N1
Reaction time: 16 h

Procedure:
A solution of 2.63g (0.021 mol) of pivaloyl chloride is added dropwise to a solution of 3.5 g (0.02 mol) of 3,3,5-trimethyl-5-hydroxymethylmorpholin-2-one (prepared in accordance with J. T. Lai.: Synthesis 122 (1984)) and 0.lg of 4-dimethylaminopyridine in 20 ml of dichloromethane at 15° C. After stirring for 16 hours, another 0.75 ml of pivaloyl chloride is added and the reaction mixture is stirred for 24 hours.
Reaction SMILES: [CH2:1]([O:8][C:9]1[N:17]=[CH:16][CH:15]=[CH:14][C:10]=1[C:11]([OH:13])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(C(C)C)C(C)C)C.[CH:51]1[C:63]2[CH:62]([CH2:64][O:65][C:66](=[O:83])[NH:67][C:68]3[CH:73]=[CH:72][C:71]([NH2:74])=[C:70]([O:75][CH2:76][C:77]4[CH:82]=[CH:81][CH:80]=[CH:79][CH:78]=4)[CH:69]=3)[C:61]3[C:56](=[CH:57][CH:58]=[CH:59][CH:60]=3)[C:55]=2[CH:54]=[CH:53][CH:52]=1>CN(C=O)C.CCOC(C)=O>[CH:51]1[C:63]2[CH:62]([CH2:64][O:65][C:66](=[O:83])[NH:67][C:68]3[CH:73]=[CH:72][C:71]([NH:74][C:11]([C:10]4[C:9]([O:8][CH2:1][C:2]5[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=5)=[N:17][CH:16]=[CH:15][CH:14]=4)=[O:13])=[C:70]([O:75][CH2:76][C:77]4[CH:78]=[CH:79][CH:80]=[CH:81][CH:82]=4)[CH:69]=3)[C:61]3[C:56](=[CH:57][CH:58]=[CH:59][CH:60]=3)[C:55]=2[CH:54]=[CH:53][CH:52]=1
Reactant: O=C(O)c1cccnc1OCc1ccccc1
Reactant: Nc1ccc(NC(=O)OCC2c3ccccc3-c3ccccc32)cc1OCc1ccccc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1ccc(NC(=O)c2cccnc2OCc2ccccc2)c(OCc2ccccc2)c1)OCC1c2ccccc2-c2ccccc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 98 %

Procedure:
2-Benzyloxy-nicotinic acid (423) (0.157 g, 0.687 mmol) was dissolved in DMF (4 mL), 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyl-uronium hexafluorophosphate (HBTU) (0.273 g, 0.721 mmol) was added followed by iPr2EtN (0.143 mL, 0.824 mmol) and the mixture was shaken in a Teflon septum capped 40 mL vial at room temperature for 25 minutes. (4-Amino-3-benzyloxy-phenyl)-carbamic acid 9H-fluoren-9-ylmethyl ester (65) (0.3 g, 0.687 mmol) was added and the mixture was shaken at room temperature for 16 h. LC-MS indicated complete coupling at this point. The mixture was diluted with EtOAc (25 mL), washed with water (15 mL), NaHCO3 (aqueous saturated, 15 mL) and brine (15 mL) via extraction, dried over MgSO4 and concentrated to give a brown oil. Purification by flash chromatography (eluding with 15–100% EtOAc/hexane in 30 minutes) gave the desired product (424) as a yellow powder upon concentration (0.436 g, 0.673 mmol, 98% yield). LC-MS (ESI): (exact mass: 647.24) m/e=648.3 [M+1]+ (100%).
Reaction SMILES: [CH2:1](N(CC)CC)[CH3:2].Cl[CH:9]1[C:14](CC)([C:15]([O:17][CH2:18][CH3:19])=[S:16])[CH:13]=[N:12][C:11]([CH3:22])=[N:10]1.[CH3:23][O:24][C:25]1[CH:26]=[C:27]([CH:31]=[CH:32][C:33]=1[O:34][CH3:35])[CH2:28][CH2:29][NH2:30].O>C1(C)C=CC=CC=1>[CH3:23][O:24][C:25]1[CH:26]=[C:27]([CH2:28][CH2:29][NH:30][C:13]2[C:14]([C:15]([O:17][CH2:18][CH3:19])=[S:16])=[C:9]([CH2:1][CH3:2])[N:10]=[C:11]([CH3:22])[N:12]=2)[CH:31]=[CH:32][C:33]=1[O:34][CH3:35]
Reactant: COc1ccc(CCN)cc1OC
Reactant: CCOC(=S)C1(CC)C=NC(C)=NC1Cl
Reactant: CCN(CC)CC
Solvent: O
Solvent: Cc1ccccc1
Product: CCOC(=S)c1c(CC)nc(C)nc1NCCc1ccc(OC)c(OC)c1
Temperature: 25 °C
Reaction time: 14 h
Yield: 50.7 %

Procedure:
Triethylamine (0.17 g, 1.68 mmol) was added to a solution of ethyl 4-chloro-5-ethyl-2-methylthiopyrimidine-5-carboxylate (0.21 g, 0.81 mmol) in toluene (4 ml), followed by addition of 3,4-dimethoxyphenethylamine (0.18 g, 0.99 mmol). The mixture was stirred at room temperature for 14 hours. The reaction mixture was poured into water, extracted with ethyl acetate and dried over magnesium sulfate. After evaporation of the solvent, the residue was purified by column chromatography on silica gel eluting with n-hexane/ethyl acetate (=8/2 ) to give the desired ethyl 4-(2-(3,4-dimethoxyphenyl)ethylamino)-6-ethyl-2-methylthiopyrimidine-5-carboxylate (0.16 g, 49%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[Cl:10])[CH2:5][NH2:6].[Cl:11][C:12]1[N:13]=[C:14](Cl)[C:15]2[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[S:18][C:16]=2[N:17]=1>>[Cl:11][C:12]1[N:13]=[C:14]([NH:6][CH2:5][C:4]2[CH:7]=[CH:8][C:9]([Cl:10])=[C:2]([Cl:1])[CH:3]=2)[C:15]2[CH:20]=[C:19]([C:21]([F:23])([F:24])[F:22])[S:18][C:16]=2[N:17]=1
Reactant: FC(F)(F)c1cc2c(Cl)nc(Cl)nc2s1
Reactant: NCc1ccc(Cl)c(Cl)c1
Product: FC(F)(F)c1cc2c(NCc3ccc(Cl)c(Cl)c3)nc(Cl)nc2s1

Procedure:
Following the procedure of Example 1, the reaction of 3,4-dichlorobenzylamine with 2,4-dichloro-6-trifluoromethyl-thieno-[2,3-d]-pyrimidine yields 2-chloro-6-trifluoromethyl-4-(3,4-dichlorobenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4][C:3]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12].Br[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=1>C(OCC)(=O)C.ClCCl>[N:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[NH:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4][C:3]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: CCOC(=O)c1[nH]c2ccccc2c1N
Reactant: Brc1ccccn1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCOC(=O)c1[nH]c2ccccc2c1Nc1ccccn1
Yield: 14.8 %

Procedure:
Heat a mixture of ethyl 3-aminoindole-2-carboxylate (250 mg, 1.2 mmol) and 2-bromopyridine (1.0 mL, 10 mmol) at 150° C. for 1 h. Cool the reaction and partition between aqueous ammonium chloride and ethyl acetate. Separate the organic layer and concentrate to afford a crude mixture. Flash chromatograph the mixture on silica gel eluting with 25% ethyl acetate/dichloromethane to afford 50 mg of the title compound: MS 282(M+H).
Reaction SMILES: Cl.Cl.[Cl:3][C:4]1[CH:5]=[N:6][C:7]2[NH:8][C:9]3[CH:10]=[CH:11][CH:12]=[C:13]([CH:26]=3)[CH2:14][CH2:15][C:16]3[CH:24]=[C:20]([NH:21][C:22]=1[N:23]=2)[CH:19]=[CH:18][C:17]=3[NH2:25].C(N(CC)C(C)C)(C)C.[C:36](Cl)(Cl)=[O:37].C1(C)C=CC=CC=1.[NH2:47][CH2:48][CH2:49][NH:50][C:51]([O:53][C:54]([CH3:57])([CH3:56])[CH3:55])=[O:52]>C(Cl)Cl>[Cl:3][C:4]1[CH:5]=[N:6][C:7]2[NH:8][C:9]3[CH:10]=[CH:11][CH:12]=[C:13]([CH:26]=3)[CH2:14][CH2:15][C:16]3[CH:24]=[C:20]([NH:21][C:22]=1[N:23]=2)[CH:19]=[CH:18][C:17]=3[NH:25][C:36]([NH:47][CH2:48][CH2:49][NH:50][C:51](=[O:52])[O:53][C:54]([CH3:57])([CH3:56])[CH3:55])=[O:37]
Reactant: CC(C)(C)OC(=O)NCCN
Reactant: O=C(Cl)Cl
Reactant: Nc1ccc2cc1CCc1cccc(c1)Nc1ncc(Cl)c(n1)N2
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)NCCNC(=O)Nc1ccc2cc1CCc1cccc(c1)Nc1ncc(Cl)c(n1)N2
Reaction time: 2 h
Yield: 81 %

Procedure:
To a solution of 6-chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-amine dihydrochloride (314 mg, 0.764 mmol) in DCM (3.4 mL) were added N,N-diisopropylethylamine (0.53 mL, 3.1 mmol) and 20% phosgene in toluene (0.53 mL, 0.99 mmol). After stirring for 2 hours, N-(2-aminoethyl)(tert-butoxy)carboxamide (0.182 mL, 1.15 mmol) was added to reaction flask and stirred overnight. The resulting precipitate was filtered and washed with DCM to yield the desired product (326 mg, 81%). LCMS calculated for C26H31ClN7O3(M+H)+: m/z=524.3.
Reaction SMILES: [CH3:1][CH:2]([CH2:6][CH2:7][CH2:8][C:9]([CH3:12])([CH3:11])[CH3:10])[CH2:3][CH2:4][OH:5].[Cr](O)(O)(=O)=O.C(O)(C)C>N1C=CC=CC=1.[OH-].[K+]>[CH3:1][CH:2]([CH2:6][CH2:7][CH2:8][C:9]([CH3:10])([CH3:12])[CH3:11])[CH2:3][CH:4]=[O:5]
Reactant: CC(CCO)CCCC(C)(C)C
Agent: O=[Cr](=O)(O)O
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: c1ccncc1
Product: CC(CC=O)CCCC(C)(C)C
Reaction time: 2 h

Procedure:
Five grams of 3,7,7-trimethyloctan-1-ol in 50 ml. of dry pyridine is added to a mixture of chromic acid (5 g.) in pyridine (50 ml.) with stirring. After two hours, isopropanol (10 ml.) is added and after a further 30 minutes, the mixture is diluted with 0.5% aqueous potassium hydroxide solution and extracted with ether. The ethereal extract is washed, dried and evaporated to yield 3,7,7-trimethyloctan-1-al.
Reaction SMILES: [CH3:1][O:2][P:3]([O:6]C)[O:4][CH3:5].[CH3:8][S:9][C:10]1[CH:17]=[CH:16][C:13]([CH2:14]Cl)=[CH:12][CH:11]=1>>[CH3:8][S:9][C:10]1[CH:17]=[CH:16][C:13]([CH2:14][P:3](=[O:6])([O:4][CH3:5])[O:2][CH3:1])=[CH:12][CH:11]=1
Reactant: CSc1ccc(CCl)cc1
Reactant: COP(OC)OC
Product: COP(=O)(Cc1ccc(SC)cc1)OC
Temperature: 25 °C

Procedure:
First, dimethyl (4-methylthiobenzyl)phosphonate was synthesized, as follows: Trimethylphosphite (206 g, 1.66 mol) was stirred at reflux, and 245 g (1.42 mol) of 4-methylmercaptobenzyl chloride (prepared as described in Ulman, et al. U.S. Pat. No. 4,792,208, Example 1) was added dropwise over 30 min. The mixture was kept at reflux for 4 hours, and then cooled to room temperature. Dimethyl (4-methylthiobenzyl)phosphonate was obtained by fractional distillation at reduced pressure. The yield was 263 grams, which is 75% of theoretical.
Reaction SMILES: C[O:2][C:3](=[O:16])[C:4]([CH3:15])([CH3:14])[CH2:5][NH:6]C(OC(C)(C)C)=O.[OH-].[Na+].Cl.[C:20]([OH:26])([C:22]([F:25])([F:24])[F:23])=[O:21]>CO.C(Cl)Cl>[OH:26][C:20]([C:22]([F:25])([F:24])[F:23])=[O:21].[NH2:6][CH2:5][C:4]([CH3:15])([CH3:14])[C:3]([OH:16])=[O:2]
Reactant: COC(=O)C(C)(C)CNC(=O)OC(C)(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Solvent: ClCCl
Product: CC(C)(CN)C(=O)O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 3-tert-butoxycarbonylamino-2,2-dimethyl-propionic acid methyl ester (2.5 g, 10.8 mmol) in MeOH (30 mL) was added 1 M NaOH (27 mL, 27 mmol), and the resulting mixture was stirred at r.t. for 16 h. 1 M HCl was added until pH was ˜3, and the mixture was extracted with EtOAc. The organic layer was dried over MgSO4 and concentrated. The residue obtained was dissolved CH2Cl2 (10 mL), and TFA (7 mL) was added. The resulting mixture was stirred at r.t. for 3 days, then concentrated to dryness to give 2.1 g of the title compound as a gray solid. 1H NMR (DMSO-d6, 200 MHz): δ ppm=7.8 (br s, 3H), 2.80-3.00 (m, 2H), 1.18 (s, 6H).
Reaction SMILES: [C@H:1]([NH:5][CH2:6][C:7]1[NH:8][C:9](=[O:17])[C:10]2[CH2:16][O:15][CH2:14][CH2:13][C:11]=2[N:12]=1)([CH2:3][CH3:4])[CH3:2].[F:18][C:19]1[CH:36]=[CH:35][C:22]([C:23]([CH:25]2[CH2:30][CH2:29][N:28]([CH2:31][C:32](O)=[O:33])[CH2:27][CH2:26]2)=[O:24])=[CH:21][CH:20]=1>>[C@H:1]([N:5]([CH2:6][C:7]1[NH:8][C:9](=[O:17])[C:10]2[CH2:16][O:15][CH2:14][CH2:13][C:11]=2[N:12]=1)[C:32](=[O:33])[CH2:31][N:28]1[CH2:29][CH2:30][CH:25]([C:23](=[O:24])[C:22]2[CH:21]=[CH:20][C:19]([F:18])=[CH:36][CH:35]=2)[CH2:26][CH2:27]1)([CH2:3][CH3:4])[CH3:2]
Reactant: O=C(O)CN1CCC(C(=O)c2ccc(F)cc2)CC1
Reactant: CC[C@@H](C)NCc1nc2c(c(=O)[nH]1)COCC2
Product: CC[C@@H](C)N(Cc1nc2c(c(=O)[nH]1)COCC2)C(=O)CN1CCC(C(=O)c2ccc(F)cc2)CC1

Procedure:
Following general procedure of Example 4, the title compound was prepared (11 mg) from (R)-2-((sec-butylamino)methyl)-7,8-dihydro-3H-pyrano[4,3-d]pyrimidin-4(5H)-one and 2-(4-(4-fluorobenzoyl)piperidin-1-yl)acetic acid. Exact mass calculated for C26H33FN4O4 484.6. found 485.4 (ESI, M+H); 1H NMR (400 MHz, dichloromethane-d2) δ ppm 7.87-8.07 (m, 2H) 7.16 (t, J=8.59 Hz, 2H) 4.41-4.58 (m, 2H) 4.19-4.41 (m, 3H) 4.13 (d, J=7.07 Hz, 1H) 3.82-3.99 (m, 2H) 3.34 (br. s., 2H) 3.25 (br. s., 1H) 3.13 (br. s., 1H) 2.87-3.07 (m, 1H) 2.55-2.69 (m, 2H) 2.25 (br. s., 2H) 1.98 (br. s., 1H) 1.88 (br. s., 2H) 1.72 (br. s., 1H) 1.16-1.28 (m, 3H) 1.09 (d, J=6.57 Hz, 1H) 0.69-0.89 (m, 3H).
Reaction SMILES: [I:1][C:2]1[N:6]([CH2:7][CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:5]=[N:4][C:3]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.IC1N=CN(CCC2C=CC=CC=2)C=1C1C=CC=CC=1.[Li+].CC([N-]C(C)C)C.CN([CH:52]=[O:53])C>C1COCC1>[I:1][C:2]1[N:6]([CH2:7][CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:5]([CH:52]=[O:53])=[N:4][C:3]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CN(C)C=O
Reactant: Ic1c(-c2ccccc2)ncn1CCc1ccccc1
Agent: CC(C)[N-]C(C)C
Agent: Ic1ncn(CCc2ccccc2)c1-c1ccccc1
Agent: [Li+]
Solvent: C1CCOC1
Product: O=Cc1nc(-c2ccccc2)c(I)n1CCc1ccccc1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
A solution of the mixture of 5-iodo-1-phenethyl-4-phenylimidazole and 4-iodo-1-phenethyl-5-phenylimidazole (example 247C) (0.7 g, 1.87 mmoles) in THF (9 mL) under argon is cooled to −78° C. A 2.0M LDA solution (1.9 mL, 3.8 mmoles) is added dropwise. After 30 minutes at −78° C., DMF (0.9 mL, 3.8 mmoles) is added dropwise. The reaction mixture is allowed to reach 0° C., then it is quenched by adding a half-saturated NaHCO3 solution. The aqueous phase is extracted three times with AcOEt. The organic phase is washed with water, brine, dried over magnesium sulphate, filtered and the solvent is removed under reduced pressure. The residue is re-crystallized from AcOEt to give 5-iodo-1-phenethyl-4-phenylimidazole-2-carbaldehyde.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:12]=[CH:11][C:8]([CH:9]=O)=[C:7]([F:13])[CH:6]=1)[CH:2]=[CH2:3].[CH3:14][C:15]1[C:21]([N+:22]([O-:24])=[O:23])=[CH:20][CH:19]=[CH:18][C:16]=1[NH2:17]>>[CH2:1]([O:4][C:5]1[CH:12]=[CH:11][C:8]([CH2:9][NH:17][C:16]2[CH:18]=[CH:19][CH:20]=[C:21]([N+:22]([O-:24])=[O:23])[C:15]=2[CH3:14])=[C:7]([F:13])[CH:6]=1)[CH:2]=[CH2:3]
Reactant: C=CCOc1ccc(C=O)c(F)c1
Reactant: Cc1c(N)cccc1[N+](=O)[O-]
Product: C=CCOc1ccc(CNc2cccc([N+](=O)[O-])c2C)c(F)c1

Procedure:
The product from Example 53B and 2-methyl-3-nitroaniline were processed as described in Example 6A to provide the title compound. MS (ESI−) m/z 315 (M−H)−.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][NH:11][C:12]2[N:17]=[C:16]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=3[Cl:25])[C:15](NC(=O)CNC)=[CH:14][N:13]=2)[CH:5]=[CH:4][C:3]=1[N+:32]([O-:34])=[O:33].ClC1C=C(Cl)C=CC=1C(=O)CCl.C1(=O)[NH:51]C(=O)C2=CC=CC=C12.C(O[N:63]([CH2:67][C:68]([OH:70])=O)[C:64](C)=O)(C)(C)C>>[NH2:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][NH:11][C:12]2[N:17]=[C:16]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=3[Cl:25])[C:15]([CH:67]([NH:63][CH3:64])[C:68]([NH2:51])=[O:70])=[CH:14][N:13]=2)[CH:5]=[CH:4][C:3]=1[N+:32]([O-:34])=[O:33]
Reactant: CNCC(=O)Nc1cnc(NCCNc2ccc([N+](=O)[O-])c(N)n2)nc1-c1ccc(Cl)cc1Cl
Reactant: O=C1NC(=O)c2ccccc21
Reactant: CC(=O)N(CC(=O)O)OC(C)(C)C
Agent: O=C(CCl)c1ccc(Cl)cc1Cl
Product: CNC(C(N)=O)c1cnc(NCCNc2ccc([N+](=O)[O-])c(N)n2)nc1-c1ccc(Cl)cc1Cl

Procedure:
N-[2-({2-[(6-amino-5-nitro(2-pyridyl))amino]ethyl}amino)-4-(2,4-dichlorophenyl)pyrimidin-5-yl]-2-(methylamino)acetamide was made in accordance with the foregoing procedures through steps A using 1-(2,4-dichlorophenyl)-2-chloroethan-1-one and phthalimide, B, C using amino{2-[(6-amino-5-nitro(2-pyridyl))-amino]ethyl}carboxamidine, D, E, F using 2-[(tert-butoxy)-N-methylcarbonylamino]acetic acid, and G.
Reaction SMILES: [F:1][C:2]1[CH:14]=[C:12]2[C:13]3[N:8]([CH:9]=[C:10]([C:16]([OH:18])=[O:17])[C:11]2=[O:15])[CH:7]([CH3:19])[CH2:6][CH2:5][C:4]=3[C:3]=1[Br:20].[NH:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1.CN(C)P(=O)(N(C)C)N(C)C.C(O)(=O)C>O>[BrH:20].[N:21]1([C:3]2[C:4]3=[C:13]4[N:8]([CH:7]([CH3:19])[CH2:6][CH2:5]3)[CH:9]=[C:10]([C:16]([OH:18])=[O:17])[C:11](=[O:15])[C:12]4=[CH:14][C:2]=2[F:1])[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1
Reactant: CC1CCc2c(Br)c(F)cc3c(=O)c(C(=O)O)cn1c23
Reactant: C1CNCCN1
Solvent: O
Solvent: CC(=O)O
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: Br
Product: CC1CCc2c(N3CCNCC3)c(F)cc3c(=O)c(C(=O)O)cn1c23
Yield: 71.8 %

Procedure:
A mixture of 3 g of 9-fluoro-8-bromo-5-methyl-6,7-dihydro-1-oxo-1H,5H-benzo[ij]quinolizine-2-carboxylic acid, 3.8 g of anhydrous piperazine and 30 ml of hexamethylphosphoric triamide was heated at 150° to 160° C. on a water bath for 5 hours in an argon stream. After completion of the reaction the solvent was removed under reduced pressure and 20 ml of ethyl acetate was added to the residue. The crystals precipitated were collected by filtration. The crystals thus-obtained were dissolved in 300 ml of water and the solution was adjusted to a pH of 4 with acetic acid. After adding activated carbon to the solution and filtering, the filtrate was concentrated under reduced pressure. Recrystallization of the crude crystals precipitated from isopropanol-water (2:1 by volume) gave 2.7 g of 8-(1-piperazinyl)-9-fluoro-5-methyl-6,7-dihydro-1-oxo-benzo[ij]quinolizine-2-carboxylic acid hydrobromide as rhombic crystals having a melting point of 300° C. or more.
Reaction SMILES: [N+]([O-])(O)=O.[F:5][C:6]([F:21])([O:10][C:11]1[CH:12]=[C:13]([NH:17][C:18]([NH2:20])=[NH:19])[CH:14]=[CH:15][CH:16]=1)[CH:7]([F:9])[F:8].CN(C)[CH:24]=[CH:25][C:26]([C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([O:34][CH2:35][CH3:36])[CH:29]=1)=O.[OH-].[Na+]>CC(O)C>[F:5][C:6]([F:21])([O:10][C:11]1[CH:12]=[C:13]([NH:17][C:18]2[N:20]=[C:26]([C:28]3[CH:33]=[CH:32][CH:31]=[C:30]([O:34][CH2:35][CH3:36])[CH:29]=3)[CH:25]=[CH:24][N:19]=2)[CH:14]=[CH:15][CH:16]=1)[CH:7]([F:8])[F:9]
Reactant: N=C(N)Nc1cccc(OC(F)(F)C(F)F)c1
Reactant: CCOc1cccc(C(=O)C=CN(C)C)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: O=[N+]([O-])O
Product: CCOc1cccc(-c2ccnc(Nc3cccc(OC(F)(F)C(F)F)c3)n2)c1
Temperature: 25 °C

Procedure:
926.1 mg (3.69 mmol) of 3-(1,1,2,2-tetrafluoro-ethoxy)-phenyl-guanidine nitrate are added to a solution of 801.1 mg (3.69 mmol) of 3-dimethylamino-1-(3-ethoxy-phenyl)-2-propen-1-one in 10 ml of 2-propanol. After the addition of 162.2 mg (4.05 mmol) of sodium hydroxide, the reaction mixture is boiled under reflux for 20 h. After cooling to RT, the reaction product is isolated by filtration and washed with 1-propanol, ethyl acetate and water. After chromatography (hexane:ethyl acetate=7:3), N-[3-(1,1,2,2-tetrafluoro-ethoxy)-phenyl]-4-(3-ethoxy-phenyl)-2-pyrimidineamine is obtained; Rf =0.72 (methylene chloride:methanol=98:2), m.p. 88°-96°.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][S:12]([N:15]2[CH2:20][CH2:19][C:18]3[CH:21]=[CH:22][O:23][C:17]=3[CH2:16]2)(=[O:14])=[O:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:24][NH:25][CH3:26].[CH2:27]=O>C(O)(=O)C>[CH3:24][N:25]([CH2:27][C:22]1[O:23][C:17]2[CH2:16][N:15]([S:12]([CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)(=[O:14])=[O:13])[CH2:20][CH2:19][C:18]=2[CH:21]=1)[CH3:26]
Reactant: C=O
Reactant: CNC
Reactant: O=S(=O)(CCCCCc1ccccc1)N1CCc2ccoc2C1
Solvent: CC(=O)O
Product: CN(C)Cc1cc2c(o1)CN(S(=O)(=O)CCCCCc1ccccc1)CC2
Temperature: 100 °C
Reaction time: 1 h

Procedure:
To a solution of 0.181 g (0.543 mmol) of 6-(5-phenylpentylsulfonyl)-4,5,6,7-tetrahydrofuro[2,3-c]pyridine in 20 ml of acetic acid, 59 mg (0.65 mmol) of 50% aqueous dimethylamine and 53 mg (0.65 mmol) of 37% aqueous formaldehyde were added, followed by stirring at 100° C. for 1 hour. After the solvent was distilled off under reduced pressure, the residual solution was alkalified with aqueous sodium hydroxide and extracted with dichloromethane 3 times. The combined organic layer was dried over anhydrous magnesium sulfate; the solvent was distilled off under reduced pressure. The resulting crude product was purified by silica gel column chromatography (ethyl acetate to ethyl acetate/methanol=4/1) to yield the desired product.
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[C:5]([C:6]([O:8]C)=O)=[CH:4][N:3]=1.[CH3:16][N:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1.[Cl:23][C:24]1[CH:32]=[CH:31][C:27]([CH2:28][CH2:29][NH2:30])=[CH:26][CH:25]=1>>[Cl:23][C:24]1[CH:32]=[CH:31][C:27]([CH2:28][CH2:29][NH:30][C:6](=[O:8])[C:5]2[C:10]([C:12]([F:15])([F:14])[F:13])=[CH:11][C:2]([N:20]3[CH2:21][CH2:22][N:17]([CH3:16])[CH2:18][CH2:19]3)=[N:3][CH:4]=2)=[CH:26][CH:25]=1
Reactant: COC(=O)c1cnc(Cl)cc1C(F)(F)F
Reactant: CN1CCNCC1
Reactant: NCCc1ccc(Cl)cc1
Product: CN1CCN(c2cc(C(F)(F)F)c(C(=O)NCCc3ccc(Cl)cc3)cn2)CC1

Procedure:
In analogy to example 1 methyl 6-chloro-4-(trifluoromethyl)nicotinate was reacted with N-methylpiperazine and then, using 4-chlorophenethylamine in the coupling step, converted to N-[2-(4-chloro-phenyl)-ethyl]-6-(4-methyl-piperazin-1-yl)-4-trifluoro-methyl-nicotinamide. Off-white solid. MS (ISP): 427.2 ([M+H]+)