Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][CH2:11][C:12]1[CH:17]=[C:16]([Sn](C)(C)C)[N:15]=[C:14]([C:22]#[N:23])[N:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:24][C:25]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1Br)([F:27])[F:26]>CN(C)C=O.C(OCC)(=O)C.O>[CH2:1]([O:8][CH2:9][CH2:10][CH2:11][C:12]1[CH:17]=[C:16]([C:30]2[CH:31]=[CH:32][CH:33]=[C:28]([C:25]([F:27])([F:26])[F:24])[CH:29]=2)[N:15]=[C:14]([C:22]#[N:23])[N:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: FC(F)(F)c1ccccc1Br
Reactant: C[Sn](C)(C)c1cc(CCCOCc2ccccc2)nc(C#N)n1
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: N#Cc1nc(CCCOCc2ccccc2)cc(-c2cccc(C(F)(F)F)c2)n1

Procedure:
A solution of 4-(3-benzyloxy-propyl)-6-trimethylstannanyl-pyrimidine-2-carbonitrile (100 mg), trifluoromethylbromobenzene (36□μL) and 1,1′-(bistriphenylphosphino)ferrocenedichloropalladium(II) (16 mg) in dimethylformamide (5 mL) was heated in microwave at 150° C. for 5 min. The resulting suspension was diluted with ethyl acetate and water (20 mL), the organic layer being separated, dried over sodium sulphate and evaporated at reduced pressure. Flash silica chromatography afforded 4-(3-benzyloxy-propyl)-6-(3-trifluoromethyl-phenyl)-pyrimidine-2-carbonitrile as a yellow gum (47 mg).
Reaction SMILES: [Cl:1]C(Cl)(Cl)C(Cl)=O.[CH3:8][C:9]1[C:14]([CH3:15])=[C:13]([O:16][CH2:17][CH2:18][CH3:19])[CH:12]=[CH:11][N+:10]=1[O-].C(=O)=O.CCOCC>C(OC(C)C)(=O)C>[ClH:1].[Cl:1][CH2:8][C:9]1[C:14]([CH3:15])=[C:13]([O:16][CH2:17][CH2:18][CH3:19])[CH:12]=[CH:11][N:10]=1
Reactant: CCCOc1cc[n+]([O-])c(C)c1C
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Agent: O=C=O
Solvent: CCOCC
Solvent: CC(=O)OC(C)C
Product: CCCOc1ccnc(CCl)c1C
Product: Cl
Reaction time: 0.25 h

Procedure:
A solution of 23 ml of trichloroacetyl chloride in 50 ml of isopropyl acetate is added dropwise during 1 hour to a solution, boiling at reflux under argon, of 13 g of 2,3-dimethyl-4-propoxypyridine 1-oxide in 250 ml of isopropyl acetate. At the beginning the reaction exhibits a very exothermic character. During the addition of the first mol equivalent of trichloroacetyl chloride a vigorous evolution of carbon dioxide is observed. The solution is subsequently stirred under argon for a further 15 minutes at reflux temperature (oil-bath 130° ), cooled to 10° with ice. treated with 100 ml of ether and stirred for 1 hour while cooling with ice. The crystalline precipitate which separates during the entire reaction is filtered off under suction and washed with ice-cold isopropyl acetate and ether. Crystalline reaction product can again be obtained from the mother liquor. The 2-chloromethyl-3-methyl-4-propoxypyridine hydrochloride obtained is processed directly.
Reaction SMILES: S1C=CC=C1.C([OH:8])C.Cl.Cl.Cl.Cl[CH:13]([C:34]1[CH:45]=[CH:44][C:37]2[N:38]([CH2:42][CH3:43])[C:39]([CH3:41])=[N:40][C:36]=2[CH:35]=1)[CH2:14][N:15]1[CH2:20][CH2:19][N:18]([CH:21]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:17][CH2:16]1.[H][H]>[Pd].CO>[OH2:8].[C:28]1([CH:21]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[N:18]2[CH2:19][CH2:20][N:15]([CH2:14][CH2:13][C:34]3[CH:45]=[CH:44][C:37]4[N:38]([CH2:42][CH3:43])[C:39]([CH3:41])=[N:40][C:36]=4[CH:35]=3)[CH2:16][CH2:17]2)[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: [H][H]
Reactant: CCO
Reactant: CCn1c(C)nc2cc(C(Cl)CN3CCN(C(c4ccccc4)c4ccccc4)CC3)ccc21
Agent: [Pd]
Agent: Cl
Solvent: CO
Solvent: c1ccsc1
Product: CCn1c(C)nc2cc(CCN3CCN(C(c4ccccc4)c4ccccc4)CC3)ccc21
Product: O
Yield: 35.5 %

Procedure:
To 2 parts of a solution of 2 parts of thiophene in 40 parts of ethanol, are added 9 parts of 5-{1-chloro-2-[4-(diphenylmethyl)-1-piperazinyl]ethyl}-1-ethyl-2-methyl-1H-benzimidazole trihydrochloride and 240 parts of methanol. The whole is hydrogenated at normal pressure and at room temperature with 4 parts of palladium-on-charcoal catalyst 10%. After the calculated amount of hydrogen is taken up, the catalyst is filtered off and the filtrate is evaporated. The residue is taken up in 100 parts of water and the whole is alkalized with ammonium hydroxide. The product is extracted twice with dichloromethane. The combined extracts are dried, filtered and evaporated. The residue is purified by column-chromatography over silica gel using a mixture of trichloromethane and methanol (95:5 by volume) as eluent. The pure fractions are collected and the eluent is evaporated. The residue is crystallized from 2-propanol. The product is filtered off and dried, yielding 2.4 parts (35.5%) of 5-{2-[4 -(diphenylmethyl)-1-piperazinyl]ethyl}-1-ethyl-2-methyl-1H-benzimidazole monohydrate; mp. 95°-105° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH:14](Cl)[CH3:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[C:17]([N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1)(=[O:19])[CH3:18].C1C=CC=CC=1>O>[C:17]([N:20]1[CH2:25][CH2:24][N:23]([CH:14]([C:11]2[CH:12]=[CH:13][C:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)=[CH:9][CH:10]=2)[CH3:15])[CH2:22][CH2:21]1)(=[O:19])[CH3:18]
Reactant: CC(=O)N1CCNCC1
Reactant: CC(Cl)c1ccc(-c2ccc(Cl)cc2)cc1
Solvent: O
Solvent: c1ccccc1
Product: CC(=O)N1CCN(C(C)c2ccc(-c3ccc(Cl)cc3)cc2)CC1

Procedure:
With constant stirring, reflux a solution of 25.1g of 4'-chloro-4-(1-chloroethyl)[1,1']biphenyl, 51g of 1-acetyl piperazine and 400 ml of anhydrous benzene for 24 hours. Add 200 ml of water to the reaction mixture, separate the organic phase, water-wash (5 times with 200 mls of water). Dry (over sodium sulfate), concentrate (in vacuo) and recrystallize the resulting residue from ethyl acetate to obtain the desired product.
Reaction SMILES: [Cl:1][C:2]1[CH:33]=[CH:32][C:5]([CH2:6][O:7][C:8]2[CH:13]=[CH:12][N:11]([C:14]3[CH:15]=[CH:16][C:17]4[N:21]=[C:20]([CH:22]5[CH2:24][CH:23]5[C:25]([OH:28])([CH3:27])[CH3:26])[N:19]([CH3:29])[C:18]=4[CH:30]=3)[C:10](=[O:31])[CH:9]=2)=[CH:4][CH:3]=1.C(=O)=O.CCO.CC#N>>[Cl:1][C:2]1[CH:33]=[CH:32][C:5]([CH2:6][O:7][C:8]2[CH:13]=[CH:12][N:11]([C:14]3[CH:15]=[CH:16][C:17]4[N:21]=[C:20]([C@@H:22]5[CH2:24][C@@H:23]5[C:25]([OH:28])([CH3:27])[CH3:26])[N:19]([CH3:29])[C:18]=4[CH:30]=3)[C:10](=[O:31])[CH:9]=2)=[CH:4][CH:3]=1
Reactant: Cn1c(C2CC2C(C)(C)O)nc2ccc(-n3ccc(OCc4ccc(Cl)cc4)cc3=O)cc21
Agent: O=C=O
Solvent: CCO
Solvent: CC#N
Product: Cn1c([C@@H]2C[C@@H]2C(C)(C)O)nc2ccc(-n3ccc(OCc4ccc(Cl)cc4)cc3=O)cc21
Yield: 32.5 %

Procedure:
(1RS,2SR)-4-((4-Chlorobenzyl)oxy)-1-(2-(2-(2-hydroxypropan-2-yl)cyclopropyl)-1-methyl-1H-benzimidazol-6-yl)pyridin-2(1H)-one (0.830 g) was resolved by a preparative SFC (CHIRALPAK AYH, CO2/EtOH/CH3CN=600/200/200) to give a white solid (355 mg, >99% ee). This solid was recrystallized from IPA to give the title compound (270 mg) as a white solid.
Reaction SMILES: C(N(CC)CC)C.C1(C2C=CC=CC=2)C=CC=CC=1P(C(C)(C)C)C(C)(C)C.Br[C:30]1[CH:31]=[CH:32][C:33]([C:36]#[C:37][CH2:38][OH:39])=[N:34][CH:35]=1.[Cl:40][C:41]1[CH:46]=[CH:45][C:44](OB(O)O)=[CH:43][CH:42]=1>CN(C=O)C.O.CC([O-])=O.CC([O-])=O.[Pd+2]>[Cl:40][C:41]1[CH:46]=[CH:45][C:44]([C:30]2[CH:31]=[CH:32][C:33]([C:36]#[C:37][CH2:38][OH:39])=[N:34][CH:35]=2)=[CH:43][CH:42]=1
Reactant: OB(O)Oc1ccc(Cl)cc1
Reactant: OCC#Cc1ccc(Br)cn1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: OCC#Cc1ccc(-c2ccc(Cl)cc2)cn1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
Under an N2 atmosphere 1 mL (7.22 mmol) triethylamine, 23 mg (0.1 mmol) Pd(OAc)2 and 57.5 mg (0.19 mmol) biphenyl-2-yl-di-tert-butyl-phosphane are added to a solution of 500 mg (2.36 mmol) 3-(5-bromo-pyridin-2-yl)-prop-2-yn-1-ol and 600 mg (3.72 mmol) 4-chlorophenyl-boric acid in 10 mL DMF and 2.5 mL water and the reaction mixture is stirred for 8 h at 60° C. Then 400 mg (2.48 mmol) 4-chlorophenyl-boric acid are added and the mixture is stirred for a further 19 h at 60° C. The mixture is evaporated down i. vac., the residue is combined with 10 mL water and 10 mL EtOAc, the aqueous phase is saturated with NaCl, the organic phase is separated off and dried over Na2SO4. After the desiccant and solvent have been eliminated the residue is purified by chromatography (silica gel, cyc/EtOAc3 2:1).
Reaction SMILES: [Br:1][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][C:5]([NH2:12])=[C:4]([I:13])[CH:3]=1.[C:14]1(C)[CH:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[CH:16][CH:15]=1.[OH-].[Na+].[F-].[CH2:28]([N+](CCCC)(CCCC)CCCC)CCC>N1C=CC=CC=1.C(OCC)(=O)C.O1CCCC1>[Br:1][C:2]1[C:7]([C:8]([F:10])([F:11])[F:9])=[CH:6][C:5]([NH:12][S:20]([C:17]2[C:18]#[C:19][CH:14]=[CH:15][C:16]=2[CH3:28])(=[O:21])=[O:22])=[C:4]([I:13])[CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: Nc1cc(C(F)(F)F)c(Br)cc1I
Reactant: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: Cc1ccc#cc1S(=O)(=O)Nc1cc(C(F)(F)F)c(Br)cc1I
Temperature: 25 °C
Reaction time: 16 h
Yield: 95 %

Procedure:
4-Bromo-2-iodo-5-trifluoromethyl-phenylamine (366 mg, 1.0 mmol) and p-toluene sulfonyl chloride (286 mg, 1.5 mmol, 1.5 eq.) were dissolved in anhydrous pyridine (2.5 ml). This was stirred at room temperature for 16 hours. An aqueous solution of 1 M sodium hydroxide was added to the reaction mixture, and this was stirred for five minutes. The reaction mixture was diluted with ethyl acetate. The organic layer was isolated, and washed with an aqueous solution of 1 M hydrochloric acid and an aqueous solution saturated with sodium chloride, and dried over anhydrous sodium sulfate. The desiccant was removed by filtration, and concentration was performed. Then, the residue obtained by concentration under reduced pressure was dissolved in tetrahydrofuran (THF) (2.5 ml), and then a tetrahydrofuran (THF) solution of 1 M tetrabutylammonium fluoride was added thereto. This was stirred at room temperature for 17 hours. The reaction mixture was diluted with ethyl acetate. The organic layer was isolated, and washed with water and an aqueous solution saturated with sodium chloride, and then dried over anhydrous sodium sulfate. The desiccant was removed by filtration and concentration was performed. Then, the residue obtained by concentration under reduced pressure was purified by silica gel column chromatography. Thus, N-(4-bromo-2-iodo-5-trifluoromethyl-phenyl)-4-methyl benzynesulfonamide was obtained as a pale brown solid (494 mg, three-step yield of 95%).
Reaction SMILES: [OH:1][C@@H:2]([C@H:4]1[C:24](=[O:25])[N:6]2[C:7]([C:21]([O-:23])=[O:22])=[C:8]([S:11]/[CH:12]=[CH:13]\[C:14]3[S:15][CH:16]=[C:17]([CH2:19][OH:20])[N:18]=3)[C@H:9]([CH3:10])[C@H:5]12)[CH3:3].[Na+].[CH:27]1([O:33][C:34]([O:36][CH:37](I)[CH3:38])=[O:35])[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1>>[OH:1][C@@H:2]([C@H:4]1[C:24](=[O:25])[N:6]2[C:7]([C:21]([O:23][CH:37]([O:36][C:34]([O:33][CH:27]3[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]3)=[O:35])[CH3:38])=[O:22])=[C:8]([S:11]/[CH:12]=[CH:13]\[C:14]3[S:15][CH:16]=[C:17]([CH2:19][OH:20])[N:18]=3)[C@H:9]([CH3:10])[C@H:5]12)[CH3:3]
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)[O-])=C(S/C=C\c3nc(CO)cs3)[C@H](C)[C@H]12
Reactant: CC(I)OC(=O)OC1CCCCC1
Agent: [Na+]
Product: CC(OC(=O)OC1CCCCC1)OC(=O)C1=C(S/C=C\c2nc(CO)cs2)[C@H](C)[C@@H]2[C@@H]([C@@H](C)O)C(=O)N12
Yield: 89.9 %

Procedure:
In the same manner as in Example 81, 52.7 mg of the title compound was prepared from 42.9 mg of sodium (1R,5S,6S)-6-((1R)-1-hydroxyethyl)-2-[[(Z)-2-(4-hydroxymethylthiazol-2-yl)ethen-1-yl]thio]-1-methyl-1-carbapen-2-em-3-carboxylate and 48 mg of 1-(cyclohexyloxycarbonyloxy)ethyl iodide.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([CH3:12])[CH:11]=1)[NH:8][C:7](=[O:13])[CH:6]=[CH:5]2.[CH:14]([NH:16][NH:17][CH:18]=O)=O>>[N:16]1[N:17]=[CH:18][N:1]([C:2]2[CH:3]=[C:4]3[C:9](=[C:10]([CH3:12])[CH:11]=2)[NH:8][C:7](=[O:13])[CH:6]=[CH:5]3)[CH:14]=1
Reactant: O=CNNC=O
Reactant: Cc1cc(N)cc2ccc(=O)[nH]c12
Product: Cc1cc(-n2cnnc2)cc2ccc(=O)[nH]c12

Procedure:
A mixture of 6-amino-8-methyl-2-(1H)-quinolone (0.485 g) and 1,2-diformylhydrazine (0.245 g) was stirred and heated in a melt at 200° for 1 hour. The residue was then triturated with hot isopropanol, cooled and filtered and the solid residue was recrystallized from chloroform-isopropanol to afford 6-(1,2,4-triazol-4-yl)-8-methyl-2-(1H)-quinolone 0.25H2O, m.p. 369°-371° (0.112 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:20])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([OH:16])=O)=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18].[CH3:21][N:22]1[CH2:27][CH2:26][CH2:25][CH:24]([NH2:28])[CH2:23]1>>[Cl:20][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([Cl:1])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([NH:28][CH:24]2[CH2:25][CH2:26][CH2:27][N:22]([CH3:21])[CH2:23]2)=[O:16])=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18]
Reactant: O=C(O)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1
Reactant: CN1CCCC(N)C1
Product: CN1CCCC(NC(=O)c2cc([N+](=O)[O-])c(Sc3c(Cl)cncc3Cl)s2)C1

Procedure:
Prepared according to the procedure described for example 44 from 5-[(3,5-dichloro-4-pyridyl)sulfanyl]-4-nitro-thiophene-2-carboxylic acid (35 mg, 0.1 mmol) and 1-methylpiperidin-3-amine (13.7 mg, 0.12 mmol). The title compound was obtained as a solid (23.0 mg, 51% yield). MS m/z: 447.02, 449.02 [M+H]+.
Reaction SMILES: O.O.Cl.[NH2:4][C:5]1[N:14]=[C:13]([NH2:15])[C:12]2[C:7](=[N:8][CH:9]=[C:10]([CH2:16][N:17]([CH3:27])[C:18]3[CH:26]=[CH:25][C:21]([C:22](O)=[O:23])=[CH:20][CH:19]=3)[N:11]=2)[N:6]=1.NC1N=C(N)C2C(=NC=C(CN(C3C=CC(C(O)=O)=CC=3)C)N=2)N=1.O.O.C(P(=O)(OCC)OCC)#N.CCN(C(C)C)C(C)C.C(O)(=O)C(O)=O.[CH2:79]([O:81][P:82]([CH2:87][CH2:88][NH2:89])(=[O:86])[O:83][CH2:84][CH3:85])[CH3:80]>CN(C=O)C>[CH2:84]([O:83][P:82]([CH2:87][CH2:88][NH:89][C:22](=[O:23])[C:21]1[CH:20]=[CH:19][C:18]([N:17]([CH2:16][C:10]2[N:11]=[C:12]3[C:7](=[N:8][CH:9]=2)[N:6]=[C:5]([NH2:4])[N:14]=[C:13]3[NH2:15])[CH3:27])=[CH:26][CH:25]=1)(=[O:86])[O:81][CH2:79][CH3:80])[CH3:85]
Reactant: CCOP(=O)(CCN)OCC
Reactant: CN(Cc1cnc2nc(N)nc(N)c2n1)c1ccc(C(=O)O)cc1
Agent: CCOP(=O)(C#N)OCC
Agent: Cl
Agent: O=C(O)C(=O)O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CCOP(=O)(CCNC(=O)c1ccc(N(C)Cc2cnc3nc(N)nc(N)c3n2)cc1)OCC
Temperature: 25 °C
Reaction time: 4 h
Yield: 24.2 %

Procedure:
To a solution of 4-[(2,4-diamino-pteridin-6-ylmethyl)-methyl-amino]-benzoic acid hemihydrochloride dihydrate (61.2 mg, 161 μmol) in DMF (2.8 mL) were added diethyl cyanophosphonate (31.8 μL, 210 μmol) and DIEA (27.8 μL, 161 μmol). The solution was stirred at ambient temperature for 4 hours, when diethyl(aminoethyl)phosphonate oxalate (43.8 mg, 161 μmol) was added. The solution was stirred for 3 additional hours, by which time complete consumption of the starting materials was observed. The reaction was worked up by removal of the solvent in vacuo and purifying the residue by silica gel chromatography using MeOH—CH2Cl2 (10-30%). The product collected from this chromatography step was sufficiently pure to be carried on to the next reaction. A small amount of the product (32 mg) was re-purified by RP HPLC on C18 column using H2O/acetonitrile (2-95%) to provide 19 mg (70%) of the pure product. 1H NMR (300 MHz, DMSO-d6) δ 1.21 (t, 6H, J=7 Hz), 1.95-2.05 (m, 2H), 3.20 (s, 3H), 3.13-3.22 (m, 2H), 3.98 (appt septet, 4H, J=7 Hz), 4.79 (s, 2H), 6.80 (d, 2H, J=9 Hz), 7.65 (d, 2H, J=9 Hz), 8.20 (br s, 1H), 8.60 (s, 1H). 31P (121.4 MHz, DMSO-d6) δ 28.9. MS (m/z) 489.2 [M+H]+, 511.2 [M+Na]+.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[CH2:20][CH2:19][N:18]([C:21]3[N:22]=[C:23]([N:31]4[CH2:35][CH2:34][CH2:33][C@H:32]4[CH2:36][NH2:37])[C:24]4[S:29](=[O:30])[CH2:28][CH2:27][C:25]=4[N:26]=3)[CH2:17][CH2:16]2)=[CH:11][CH:10]=1.[C:38]1([N:44]=[C:45]=[O:46])[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>ClCCl>[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[CH2:16][CH2:17][N:18]([C:21]3[N:22]=[C:23]([N:31]4[CH2:35][CH2:34][CH2:33][C@H:32]4[CH2:36][NH:37][C:45]([NH:44][C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=4)=[O:46])[C:24]4[S:29](=[O:30])[CH2:28][CH2:27][C:25]=4[N:26]=3)[CH2:19][CH2:20]2)=[CH:11][CH:10]=1
Reactant: NC[C@@H]1CCCN1c1nc(N2CCN(c3ccc(Cl)cc3)CC2)nc2c1S(=O)CC2
Reactant: O=C=Nc1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(NC[C@@H]1CCCN1c1nc(N2CCN(c3ccc(Cl)cc3)CC2)nc2c1S(=O)CC2)Nc1ccccc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
100 mg C—((S)-1-{2-[4-(4-chloro-phenyl)-piperazin-1-yl]-5-oxo-6,7-dihydro-5H-5λ4-thieno[3,2-d]pyrimidin-4-yl}-pyrrolidin-2-yl)-methylamine trifluoroacetate, Diastereomer 2 (Example 226) (see scheme 3, 3.17.2) are placed in 2 ml dichloromethane and 30 μl phenylisocyanate are added. The reaction mixture is stirred for 4 hours at ambient temperature and then evaporated to dryness. The product is purified by preparative HPLC (method A). 64 mg of the product are obtained as a powder. Analytical HPLC-MS (method D): RT=1.33 min.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:26]=[C:27]([O:31][CH3:32])[C:28]=1[O:29][CH3:30])[C:6]([N:8]([CH2:16][C:17]([CH3:25])=[CH:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:9][CH2:10][CH:11]1[CH2:15][CH2:14][CH2:13][NH:12]1)=[O:7].[CH:33](=O)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.C(O)(=O)C.C([BH3-])#N.[Na+]>CO>[CH2:33]([N:12]1[CH2:13][CH2:14][CH2:15][CH:11]1[CH2:10][CH2:9][N:8]([CH2:16][C:17]([CH3:25])=[CH:18][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)[C:6](=[O:7])[C:5]1[CH:26]=[C:27]([O:31][CH3:32])[C:28]([O:29][CH3:30])=[C:3]([O:2][CH3:1])[CH:4]=1)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: O=Cc1ccccc1
Reactant: COc1cc(C(=O)N(CCC2CCCN2)CC(C)=Cc2ccccc2)cc(OC)c1OC
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: COc1cc(C(=O)N(CCC2CCCN2Cc2ccccc2)CC(C)=Cc2ccccc2)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
3,4,5-Trimethoxy-N-(2-methyl-3-phenyl-allyl)-N-(2-pyrrolidin-2-yl-ethyl)-benzamide 0.11 g (2.5 mmol) and freshly distilled benzaldehyde 0.026 g (2.5 mmol) was taken in 10 ml of dry methanol. Acetic acid 0.022 ml (3.7 mmol) was added at 0° C. The reaction mixture was stirred at room temperature for 30 min and sodium cyanoborohydride 0.023 g (3.7 mmol) was added at 0° C. The reaction mixture was gradually warmed to room temperature and stirred for 14 hr. The reaction mixture was concentrated, and the residue was diluted with water and extracted with chloroform (3×20 ml). Organic layer was washed with 10% NaHCO3 solution, water and brine, dried over anhydrous sodium sulfate, concentrated and the residue was purified by column chromatography over silica gel to yield the pure desired compound. This was converted to its hydrochloride salt using dry HCl in ether to obtain 90 mg of product. Yield: 63%.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].[CH2:10](Cl)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(=O)([O-])[O-].[Na+].[Na+]>CC(C)=O.CCCCCC.C(OCC)(=O)C>[CH2:10]([O:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: ClCc1ccccc1
Reactant: O=Cc1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: O=Cc1cccc(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 83.9 %

Procedure:
24.2 g (0.2 mol) of 3-hydroxybenzaldehyde and 25.32 g (0.2 mol) of benzyl chloride were placed in 500 ml of acetone and 21.2 g (0.2 mol) of sodium carbonate was added thereto. The resulting solution was stirred for 12 to 24 hours with heating, cooled to room temperature. The solvent was removed under a reduced pressure and the residue thus obtained was washed with water and the extracted with ethyl acetate twice. The organic layer was dried and the solvent was removed under a reduced pressure to obtain a residue. The residue was subjected to column chromatography using a mixture of n-hexane and ethyl acetate (9:1) as an eluent to obtain 35.6 g (yield 84%) of the title compound as a colorless liquid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[N:12][C:11]([N:14]([CH3:16])[NH2:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.Cl[C:27]([O:29][CH2:30][CH3:31])=[O:28]>O1CCOCC1>[CH3:16][N:14]([C:11]1[N:12]=[N:13][C:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)=[CH:9][CH:10]=1)[NH:15][C:27]([O:29][CH2:30][CH3:31])=[O:28]
Reactant: CN(N)c1ccc(-c2ccc(Cl)cc2)nn1
Reactant: CCOC(=O)Cl
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)NN(C)c1ccc(-c2ccc(Cl)cc2)nn1
Reaction time: 1 h

Procedure:
A 2.0 g. portion of 6-(p-chlorophenyl)-3-(1-methylhydrazino)pyridazine and 1.30 g. of diisopropylethylamine in 50 ml. of dioxane is warmed slightly in a flask. A 1.0 g. portion of ethyl chloroformate is added and the reaction mixture is stirred for one hour. The dioxane is removed on a rotary evaporator, ethanol and water are added to the residue and a precipitate results. The solid is recrystallized from ethanol to give a pure white solid, m.p. 170°-172° C.
Reaction SMILES: [C:1]([O:5][CH2:6][CH3:7])(=[O:4])[C:2]#[CH:3].[NH:8]1[CH2:12][CH2:11][CH2:10][CH2:9]1>C1C=CC=CC=1>[N:8]1([CH:3]=[CH:2][C:1]([O:5][CH2:6][CH3:7])=[O:4])[CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: C1CCNC1
Reactant: C#CC(=O)OCC
Solvent: c1ccccc1
Product: CCOC(=O)C=CN1CCCC1
Reaction time: 8 h
Yield: 69 %

Procedure:
A solution of 29.43 g of ethyl propiolate (0.30 mol) in 200 ml of benzene was held at 25° in a water bath with magnetic stirring. A solution of 21.34 g of pyrrolidine in 50 ml of benzene was added dropwise over a period of 45 minutes, during which time the temperature rose to 35°. The clear brown solution was stirred overnight and the solvent under reduced pressure at 55°. The residue was distilled under reduced pressure to give 35.05 g of yellow oil, boiling point 110° (0.4 torr), which crystallized upon standing. The yellow solid was recrystallized from petroleum ether to give 31.36 (62%) of yellowish platelets, m.p. 37.5°-39.5°.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[C:7]([CH:12]=[CH:13][N:14]=1)[C:8](OC)=[O:9])(=[O:3])[CH3:2].[NH2:15][NH2:16].[N:17]([O-])=O.[Na+]>CO>[C:1]([NH:4][C:5]1[CH:6]=[C:7]([CH:12]=[CH:13][N:14]=1)[C:8]([N:15]=[N+:16]=[N-:17])=[O:9])(=[O:3])[CH3:2]
Reactant: NN
Reactant: COC(=O)c1ccnc(NC(C)=O)c1
Reactant: O=N[O-]
Agent: [Na+]
Solvent: CO
Product: CC(=O)Nc1cc(C(=O)N=[N+]=[N-])ccn1
Temperature: 0 °C
Reaction time: 1 h
Yield: 68.8 %

Procedure:
To a suspension of Intermediate 62A (0.250 g, 1.29 mmol) in MeOH (2 mL) at room temperature was added anhydrous hydrazine (0.048 mL, 1.55 mmol), and the mixture was heated to reflux for 1 hour. The suspension was cooled and filtered, washing the solid with MeOH. The solid was dried in vacuo and used immediately. The acyl hydrazide was suspended in 2N HCl (5 mL) and cooled to 0° C., whereupon sodium nitrite (0.533 g, 7.72 mmol) was added slowly in portions with vigorous stirring. The resulting solution stirred for 1 hour at 0° C. The reaction was then quenched by carefully adding solid sodium bicarbonate to pH 6, whereupon a precipitate formed. The solid was filtered, washed with cold water, and dried in vacuo overnight to provide Intermediate 62B (0.182 g, 68% yield) as a white solid. HPLC: Rt=2.345 min. (YMC S5 ODS 4.6×50 mm, 10-90% aqueous methanol containing 0.2% H3PO4, 4 min. gradient, monitored at 220 nm). 1H NMR (400 MHz, DMSO-d6) δ ppm 10.82 (1H, s), 8.58 (1H, s), 8.52 (1H, d, J=5.29 Hz), 7.51 (1H, dd, J=5.16, 1.64 Hz), 2.11 (3H, s).