Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH:11]=[C:10]([C:14]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[NH:16][CH:15]=2)[CH2:9]1)C1C=CC=CC=1>[Pd].C(O)=O.CO>[NH:8]1[CH2:13][CH2:12][CH2:11][CH:10]([C:14]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[NH:16][CH:15]=2)[CH2:9]1
Reactant: C1=C(c2c[nH]c3ccccc23)CN(Cc2ccccc2)CC1
Agent: [Pd]
Solvent: O=CO
Solvent: CO
Product: c1ccc2c(C3CCCNC3)c[nH]c2c1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A mixture of the 3-(1-benzyl-1,2,5,6-tetrahydro-pyridin-3-yl)-1H-indole obtained in Example 28 and 10% palladium on carbon in a mixture of formic acid and methanol is stirred at room temperature for 3 days and filtered through celite. The celite is washed with methanol. The filtrates are combined and concentrated in vacuo to afford the title product, identified by HPLC and mass spectral analyses.
Reaction SMILES: [OH:1][C:2]1[CH:15]=[CH:14][C:5]([C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.[CH2:16]([CH:18]1[O:20][CH2:19]1)Cl.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:16]([O:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:7])=[CH:14][CH:15]=1)[CH:18]1[O:20][CH2:19]1
Reactant: O=C(c1ccccc1)c1ccc(O)cc1
Reactant: ClCC1CO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=C(c1ccccc1)c1ccc(OCC2CO2)cc1
Temperature: 25 °C

Procedure:
As illustrated in FIG. 6, 100 mL of dried acetone were added to a dry, 250-mL round bottom flask, equipped with a magnetic stirrer, along with 15.05 grams of 4-hydroxybenzophenone, 32.1 grams of epichlorohydrin, and 6.2 grams of potassium carbonate. The solution was heated to reflux for 6 hours and then cooled to room temperature. The precipitated potassium chloride was filtered off, and the solution was evaporated to remove excess epichlorohydrin. The crude product was recrystallized from methanol. 1H NMR data confirmed the formation of the desired product.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=[O:10].S(Cl)(Cl)=O.[CH3:16]O>>[CH3:16][O:10][C:9](=[O:11])[CH2:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[Br:1]
Reactant: O=C(O)Cc1ccccc1Br
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)Cc1ccccc1Br
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
In a 250 mL round bottom flask, 5.0046 g (23.2729 mmol, 1.0 eq) of 2-(Bromophenyl)acetic acid was dissolved in 100 mL of clean, dry MeOH under N2 atmosphere. This solution was cooled to 0° C. using a wet ice bath and stirred for five minutes. To the stirring solution was added 2.55 mL (34.9093 mmol, 1.5 eq) of thionyl chloride dropwise over a period of five minutes. The reaction was then allowed to stir overnight, gradually warming to room temperature. The following morning, the solvent was removed under reduced pressure. The resultant deep yellow oil was taken up in 50 mL of DCM. The solution was then washed with 50 mL of saturated NaHCO3 (aq) solution. The organic layer immediately became colorless. The layers were separated and the organic layer was washed with brine (1×30 mL) and then dried over Na2SO4. The solution was decanted and then solvent was removed under reduced pressure. A clear oil was isolated. LCMS (m/e): 230 (M+H); 1H NMR (400 MHz, METHANOL-d4) δ ppm 3.69 (s, 3H) 3.82 (s, 2H) 7.10-7.25 (m, 1H) 7.26-7.40 (m, 2H) 7.58 (d, J=7.91 Hz, 1H).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:14]=[C:13]([O:15][CH3:16])[C:12]([O:17][CH2:18][CH2:19][N:20]3[CH:24]=[CH:23][N:22]=[N:21]3)=[C:11]([O:25][CH3:26])[CH:10]=2)[N:3]=1.[Cl:27][C:28]1[NH:29][C:30]2[CH:36]=[CH:35][CH:34]=[CH:33][C:31]=2[N:32]=1.C([O-])([O-])=O.[K+].[K+]>C(C#N)(C)=O>[Cl:27][C:28]1[N:32]([C:6]2[N:7]=[CH:2][N:3]=[C:4]([NH:8][C:9]3[CH:10]=[C:11]([O:25][CH3:26])[C:12]([O:17][CH2:18][CH2:19][N:20]4[CH:24]=[CH:23][N:22]=[N:21]4)=[C:13]([O:15][CH3:16])[CH:14]=3)[N:5]=2)[C:31]2[CH:33]=[CH:34][CH:35]=[CH:36][C:30]=2[N:29]=1
Reactant: COc1cc(Nc2ncnc(Cl)n2)cc(OC)c1OCCn1ccnn1
Reactant: Clc1nc2ccccc2[nH]1
Agent: CC(=O)C#N
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COc1cc(Nc2ncnc(-n3c(Cl)nc4ccccc43)n2)cc(OC)c1OCCn1ccnn1
Temperature: 70 °C

Procedure:
(4-Chloro-[1,3,5]triazin-2-yl)-[3,5-dimethoxy-4-(2-[1,2,3]triazol-1-yl-ethoxy)phenyl]amine (407 mg, 1.076 mmol) is combined with 2-chlorobenzimidazole (164 mg, 1.076 mmol) and K2CO3(179 mg, 1.292 mmol) in AcCN (10 ml) and heated at 65 to 75° C. for 4 to 20 hours. The mix is concentrated down under reduced pressure and treated with water. A white precipitate forms which is filtered and dried under vacuum, giving [4-(2-chloro-benzimidazol-1-yl)-[1,3,5]triazin-2-yl]-[3,5-dimethoxy-4-(2-[1,2,3]triazol-1-yl-ethoxy)phenyl]-amine.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:12]1[CH:17]=[CH:16][C:15]([NH:18][C:19]([N:21]([C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([C:30]([F:33])([F:32])[F:31])[CH:24]=3)[OH:22])=[O:20])=[CH:14][CH:13]=1)[CH:7]=[CH:6]2.Cl[C:35]([O:37][CH2:38][CH2:39][O:40][CH3:41])=[O:36]>>[CH3:41][O:40][CH2:39][CH2:38][O:37][C:35](=[O:36])[NH:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:12]1[CH:13]=[CH:14][C:15]([NH:18][C:19]([N:21]([C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([C:30]([F:33])([F:32])[F:31])[CH:24]=3)[OH:22])=[O:20])=[CH:16][CH:17]=1)[CH:7]=[CH:6]2
Reactant: Nc1ccc2c(ccn2-c2ccc(NC(=O)N(O)c3ccc(Cl)c(C(F)(F)F)c3)cc2)c1
Reactant: COCCOC(=O)Cl
Agent: Cl
Product: COCCOC(=O)Nc1ccc2c(ccn2-c2ccc(NC(=O)N(O)c3ccc(Cl)c(C(F)(F)F)c3)cc2)c1

Procedure:
The title compound can be synthesized from 1-[4-(5-aminoindol-1-yl)phenyl]-3-(4-chloro-3-(trifluoromethyl)phenyl)-3-hydroxyurea hydrochloride and 2-methoxyethyl chloroformate by using the same techniques as in Example 41.
Reaction SMILES: Cl[C:2]1[CH:12]=[C:6]2[N:7]([CH3:11])[CH2:8][CH2:9][CH2:10][N:5]2[C:4](=[O:13])[N:3]=1.[F:14][C:15]1[CH:16]=[C:17]([CH:28]=[CH:29][C:30]=1[F:31])[O:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][OH:26])=[CH:21][C:20]=1[F:27]>>[F:14][C:15]1[CH:16]=[C:17]([CH:28]=[CH:29][C:30]=1[F:31])[O:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][O:26][C:2]2[CH:12]=[C:6]3[N:7]([CH3:11])[CH2:8][CH2:9][CH2:10][N:5]3[C:4](=[O:13])[N:3]=2)=[CH:21][C:20]=1[F:27]
Reactant: OCc1ccc(Oc2ccc(F)c(F)c2)c(F)c1
Reactant: CN1CCCn2c1cc(Cl)nc2=O
Product: CN1CCCn2c1cc(OCc1ccc(Oc3ccc(F)c(F)c3)c(F)c1)nc2=O

Procedure:
The title compound was prepared by a procedure similar to that described for E1 starting from 8-chloro-1-methyl-3,4-dihydro-1H-pyrimido[1,6-a]pyrimidin-6(2H)-one and (4-(3,4-difluorophenoxy)-3-fluorophenyl)methanol.
Reaction SMILES: [OH:1][C:2]1[CH:14]=[CH:13][C:5]2[C:6]([CH2:9][C:10]([OH:12])=[O:11])=[CH:7][O:8][C:4]=2[C:3]=1[CH3:15].OS(O)(=O)=O.[CH3:21]O>>[CH3:21][O:11][C:10](=[O:12])[CH2:9][C:6]1[C:5]2[CH:13]=[CH:14][C:2]([OH:1])=[C:3]([CH3:15])[C:4]=2[O:8][CH:7]=1
Reactant: CO
Reactant: Cc1c(O)ccc2c(CC(=O)O)coc12
Agent: O=S(=O)(O)O
Product: COC(=O)Cc1coc2c(C)c(O)ccc12
Temperature: 60 °C
Reaction time: 1 h

Procedure:
To a mixture of (6-hydroxy-7-methyl-1-benzofuran-3-yl)acetic acid (2.61 g) in MeOH (80 mL) was added conc. H2SO4 (0.135 mL). The mixture was stirred at 60° C. for 1 h. The mixture was concentrated. The mixture was neutralized with saturated aqueous NaHCO3 and extracted with EtOAc. The combined organic layer was washed with brine, dried over MgSO4, and concentrated in vacuo. The residue was purified by silica gel column chromatography (EtOAc/hexane) to give the title compound (2.52 g).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Cl[C:8]1[C:13]([C:14]#[N:15])=[CH:12][CH:11]=[CH:10][N:9]=1>O>[C:14]([C:13]1[C:8]([N:1]2[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]2)=[N:9][CH:10]=[CH:11][CH:12]=1)#[N:15]
Reactant: N#Cc1cccnc1Cl
Reactant: C1CNCCN1
Solvent: O
Product: N#Cc1cccnc1N1CCNCC1
Temperature: 150 °C
Reaction time: 2 h
Yield: 89.1 %

Procedure:
Piperazine (125 g) was melted by heating at 150° C. and 2-chloro-3-cyanopyridine (20.0 g) was added thereto. The mixture was stirred at 110° C. for 2 hr. Water was added to the reaction mixture and the mixture was extracted with chloroform. The extract was washed with brine, dried and concentrated under reduced pressure to give 1-(3-cyano-2-pyridyl)piperazine (24.2 g) as a brown solid.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH3:11])(=[O:10])=[O:9])=[CH:4][C:3]=1[C:12]([N:14]1[CH2:19][CH2:18][N:17]([C:20]2[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=2)[CH2:16][CH2:15]1)=[O:13].[NH:30]1[CH:34]=[CH:33][N:32]=[CH:31]1>>[N:30]1([C:2]2[CH:7]=[CH:6][C:5]([S:8]([CH3:11])(=[O:10])=[O:9])=[CH:4][C:3]=2[C:12]([N:14]2[CH2:19][CH2:18][N:17]([C:20]3[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=3)[CH2:16][CH2:15]2)=[O:13])[CH:34]=[CH:33][N:32]=[CH:31]1
Reactant: c1c[nH]cn1
Reactant: CS(=O)(=O)c1ccc(I)c(C(=O)N2CCN(c3ccc(C(F)(F)F)cc3)CC2)c1
Product: CS(=O)(=O)c1ccc(-n2ccnc2)c(C(=O)N2CCN(c3ccc(C(F)(F)F)cc3)CC2)c1

Procedure:
The title compound was prepared according to the procedure described for example 199 from (2-Iodo-5-methanesulfonyl-phenyl)-[4-(4-trifluoromethyl-phenyl)-piperazin-1-yl]-methanone (compound CK) and imidazole (20%, light grey solid, MS (m/e): 479.2 (M+H, 100%)
Reaction SMILES: Cl.Cl.[O:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[C:11]([CH:12]3[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C@H:20]4[CH2:25][CH2:24][C@H:23]([NH2:26])[CH2:22][CH2:21]4)[CH2:14][CH2:13]3)[C:6]=2[CH2:5][CH2:4]1.[O:27]1[C:31]2[CH:32]=[CH:33][C:34]([C:36](O)=[O:37])=[CH:35][C:30]=2[O:29][CH2:28]1>>[O:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[C:11]([CH:12]3[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C@H:20]4[CH2:21][CH2:22][C@H:23]([NH:26][C:36]([C:34]5[CH:33]=[CH:32][C:31]6[O:27][CH2:28][O:29][C:30]=6[CH:35]=5)=[O:37])[CH2:24][CH2:25]4)[CH2:14][CH2:13]3)[C:6]=2[CH2:5][CH2:4]1
Reactant: N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3CCO4)CC2)CC1
Reactant: O=C(O)c1ccc2c(c1)OCO2
Agent: Cl
Product: O=C(N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3CCO4)CC2)CC1)c1ccc2c(c1)OCO2

Procedure:
The title compound, off-white solid (97 mg, 82%), MS (ISP) m/z=477.3 [(M+H)+], mp 233° C., was prepared in accordance with the general method of example 1 from trans-4-{2-[4-(2,3-dihydro-benzofuran-4-yl)-piperidin-1-yl]-ethyl}-cyclohexylamine dihydrochloride (intermediate B) (100 mg, 0.25 mmol) and benzo[1,3]dioxole-5-carboxylic acid.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:13][CH:12]=3)=[CH:9][NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[H-].[Na+].CC1C=CC(S(O[CH:37]2[CH2:41][CH2:40][N:39]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH2:38]2)(=O)=O)=CC=1>CN(C=O)C.CCOC(C)=O.CO>[NH2:1][C:2]1[C:3]2[C:10]([C:11]3[CH:12]=[CH:13][C:14]([O:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:15][CH:16]=3)=[CH:9][N:8]([CH:41]3[CH2:37][CH2:38][N:39]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH2:40]3)[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: Cc1ccc(S(=O)(=O)OC2CCN(C(=O)OC(C)(C)C)C2)cc1
Reactant: Nc1ncnc2[nH]cc(-c3ccc(Oc4ccccc4)cc3)c12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(n2cc(-c3ccc(Oc4ccccc4)cc3)c3c(N)ncnc32)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 32.1 %

Procedure:
To a solution of 4-amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidine (2.0 g, 6.6 mmol) in dry DMF (120 ml) under nitrogen at 0° C. was added NaH (0.264 g, 60% dispeersion, 6.6 mmol) and then reaction mixture warmed to room temperature and stirred for 1 hr. tert-butyl 3-[(4-methylphenyl)sulfonyl]oxy-1-pyrrolidinecarboxylate (2.25 g, 6.6 mmol) was added portionwise and the mixture heated at 95° C. for 72 hr. Quench with water and extract with EtOAc (4×100 ml). Wash the combined organic solutions with water (4×100 ml) and brine (2×100 ml). The organics were dried (sodium sulphate), filtered and evaporated to leave a solid which was dissolved in EtOAc/MeOH and adsorbed onto silica. Purification using flash silica gel column chromatography with 5% MeOH/EtOAc as eluent gave in F 17-25 tert-butyl 3-[4-amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]-1-pyrrolidinecarboxylate (1.0 g, 32%) as a white solid m.pt. 168-170° C. Rf in 9:1 EtOAc: MeOH=0.46. 1H NMR (d6 DMSO, 250 MHz): 8.17 (1H, s), 7.38-7.50 (5H, m), 6.19 (2H, bs), 5.31 (1H, m), 3.77 (1H, m), 3.42-3.60 (3H, m), 2.38 (2H, m), 1.40 (9H, s). Mass spec. 471.2250 (C27H29O3N5) IR (KBr disc): 3130, 1683, 1585, 1404, 1245 cm−1.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH:7]1([C:12]([N:14]2[CH2:18][C:17]34[CH2:28][CH:21]([C:22]5[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=5[C:16]3=[CH:15]2)[C:20]2[CH:29]=[CH:30][CH:31]=[CH:32][C:19]4=2)=O)[CH2:11][CH2:10][CH2:9][CH2:8]1.[H-].[OH-].[Na+]>CCOCC.O>[CH:7]1([CH2:12][N:14]2[CH2:18][C:17]34[CH2:28][CH:21]([C:22]5[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=5[C:16]3=[CH:15]2)[C:20]2[CH:29]=[CH:30][CH:31]=[CH:32][C:19]4=2)[CH2:8][CH2:9][CH2:10][CH2:11]1
Reactant: O=C(C1CCCC1)N1C=C2c3ccccc3C3CC2(C1)c1ccccc13
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: O
Product: C1=C2c3ccccc3C3CC2(CN1CC1CCCC1)c1ccccc13
Temperature: 25 °C
Reaction time: 6 h
Yield: 59.9 %

Procedure:
To a cooled slurry of 0.40 g of lithium aluminum hydride in 30 ml of ether is added 1.55 g of 9b and the mixture is stirred at room temperature for 6 hours. The excess hydride is decomposed by the addition of 0.4 ml of water, followed by 0.4 ml of 15% aqueous sodium hydroxide solution and 1.2 ml of water. The mixture is filtered and the filtrate is concentrated. Crystallization of the residue from isopropyl alcohol gives 0.89 g of 2-cyclopentylmethyl-2,3-dihydro-8H-3a,8-methanodibenzo[3,4:6,7]cyclohepta[1,2-c]pyrrole (8e), identical by infrared and nmr spectroscopy with the product obtained in Example 8. Reduction of 8e as described in Example 8 gives 2-cycopentylmethyl-2,3,8,12b-tetrahydro-1H-3a,8-methanodibenzo[3,4:6,7]cyclohepta[1,2-c]pyrrole.
Reaction SMILES: [BH4-].[Na+].[ClH:3].[CH3:4][O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[N:12]1[CH2:17][CH2:16][N:15]([CH2:18][C:19]([C:21]2[C:30]3[O:29][C:28]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)=[C:27]([CH3:37])[C:26](=[O:38])[C:25]=3[CH:24]=[CH:23][CH:22]=2)=[O:20])[CH2:14][CH2:13]1.Cl.[OH-].[Na+]>CO>[ClH:3].[OH:20][CH:19]([C:21]1[C:30]2[O:29][C:28]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)=[C:27]([CH3:37])[C:26](=[O:38])[C:25]=2[CH:24]=[CH:23][CH:22]=1)[CH2:18][N:15]1[CH2:16][CH2:17][N:12]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[O:5][CH3:4])[CH2:13][CH2:14]1
Reactant: COc1ccccc1N1CCN(CC(=O)c2cccc3c(=O)c(C)c(-c4ccccc4)oc23)CC1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COc1ccccc1N1CCN(CC(O)c2cccc3c(=O)c(C)c(-c4ccccc4)oc23)CC1
Reaction time: 1.5 h
Yield: 61 %

Procedure:
1.36 g of sodium borohydride was added portionwise at 0° to +5° C. to a solution of 15.5 g of the compound prepared in Example 1 in 1500 ml of methanol. After stirring for 90 minutes at 0° to +5° C., 3N aqueous hydrochloric acid solution was added in order slightly to acidify the reaction mixture, which was then stripped in vacuo. The residue was shaken with 2N aqueous sodium hydroxide solution and extracted with chloroform. The organic layer was dried on anhydrous sodium sulfate/calcium chloride, filtered, acidified with ethanolic hydrogen chloride and stripped in vacuo. After washing with diethyl ether, the crude product was crystallized from ethanol to give 9.5 g of title compound, m.p. 248°-249° C.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].S([O-])([O-])(=O)=O.[Mg+2].[CH:15](=O)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.CC1C=CC(S(O)(=O)=O)=CC=1>CCOCC>[CH:15](=[N:4]/[C:3]1[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=1[F:1])\[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=Cc1ccccc1
Reactant: Nc1ccccc1F
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: CCOCC
Product: Fc1ccccc1/N=C/c1ccccc1

Procedure:
Dissolved 2-fluoroaniline (2.0 mL, 20.8 mmol, 1.05 eq) in 40 mL of anhydrous ether. Added Magnesium Sulfate (7146 mg, 59.3 mmol, 4 eq), 7 g of powdered mol sieves, and benzaldehyde (2.0 mL, 19.8 mmol). To this mixture was added pTsOH (18.8 mg, 98.9 μmol, 0.005 eq) and heated to reflux overnight. The reaction was cooled, filtered and concentrated to yield (E)-N-benzylidene-2-fluorobenzenamine. 1H NMR (400 MHz, CDCl3) δ ppm 8.55 (s, 1H), 7.95 (m, 2H), 7.52 (m, 5H), 7.18 (m, 4H).
Reaction SMILES: [CH3:1][S:2]([C:5]1[S:9][C:8]([N:10]=[C:11]=[O:12])=[N:7][N:6]=1)(=[O:4])=[O:3].[CH2:13]([NH:16][CH:17]([CH2:20][O:21][CH3:22])[CH:18]=[O:19])[CH2:14][CH3:15]>C1C=CC=CC=1>[CH2:13]([N:16]([CH:17]([CH2:20][O:21][CH3:22])[CH:18]=[O:19])[C:11]([NH:10][C:8]1[S:9][C:5]([S:2]([CH3:1])(=[O:4])=[O:3])=[N:6][N:7]=1)=[O:12])[CH2:14][CH3:15]
Reactant: CS(=O)(=O)c1nnc(N=C=O)s1
Reactant: CCCNC(C=O)COC
Solvent: c1ccccc1
Product: CCCN(C(=O)Nc1nnc(S(C)(=O)=O)s1)C(C=O)COC

Procedure:
5-Methylsulfonyl-1,3,4-thiadiazol-2-yl isocyanate dimer (0.05 mole), the dimethyl acetal of 2-propylamino-3-methoxypropionaldehyde (0.1 mole) and benzene (60 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. The reaction mixture is heated at reflux for a period of about 30 minutes. After this time the mixture is stripped of benzene under reduced pressure to yield a solid product as the residue. This residue is then recrystallized to yield the desired product the dimethyl acetal of 2-[1-propyl-3-(5-methylsulfonyl-1,3,4-thiadiazol-2-yl)ureido]-3-methoxypropionaldehyde.
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8]CC)=O)=[CH:4][CH:3]=1.[CH2:13]([CH2:15][NH2:16])[OH:14]>C(O)C>[OH:14][CH2:13][CH2:15][NH:16][C:6](=[O:8])[C:5]1[CH:4]=[CH:3][C:2]([NH2:1])=[CH:12][CH:11]=1
Reactant: NCCO
Reactant: CCOC(=O)c1ccc(N)cc1
Solvent: CCO
Product: Nc1ccc(C(=O)NCCO)cc1

Procedure:
165.2 parts of ethyl p-aminobenzoate are dissolved in 150 parts of ethanolamine and ethanol is then distilled off at 160° C. The volatile constituents are subsequently stripped off in vacuo and the resulting residue is recrystallised from isopropanol. p-Aminobenzoic acid β-hydroxyethylamide of melting point 116° C. is obtained.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[S:21][C:9]3[N:10]=[C:11]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)[N:12]=[C:13]([CH3:14])[C:8]=3[C:6]=2[N:7]=1.[NH:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1>O1CCCC1>[Cl:1][C:2]1[N:3]=[C:4]([N:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)[C:5]2[S:21][C:9]3[N:10]=[C:11]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)[N:12]=[C:13]([CH3:14])[C:8]=3[C:6]=2[N:7]=1
Reactant: C1CNCCN1
Reactant: Cc1nc(-c2ccccc2)nc2sc3c(Cl)nc(Cl)nc3c12
Solvent: C1CCOC1
Product: Cc1nc(-c2ccccc2)nc2sc3c(N4CCNCC4)nc(Cl)nc3c12
Yield: 43.9 %

Procedure:
3.0 g (8.6 mmol) 2,4-dichloro-9-methyl-7-phenyl-thieno[2,3-d:4,5-d′]dipyrimidine and 2.0 g (23.2 mmol) piperazine are added by stirring to 40 ml tetrahydrofuran at room temperature for 6 h. Thereafter, the solvent is removed, the residue is suspended in water, sucked off, washed with 40 ml water and dried. 1.5 g (44%) 2-chloro-9-methyl-4-piperazin-1-yl-7-phenyl-thieno[2,3-d:4,5-d′]dipyrimidine is obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][CH3:9])[N:3]=1.C(C1C=CN=C(N2[CH2:23][CH2:22][N:21]([C:24]3[CH:29]=[CH:28][C:27]([NH2:30])=[CH:26][CH:25]=3)[CH2:20][CH2:19]2)C=1)C>>[CH2:8]([C:4]1[N:3]=[C:2]([N:1]2[CH2:19][CH2:20][N:21]([C:24]3[CH:25]=[CH:26][C:27]([NH2:30])=[CH:28][CH:29]=3)[CH2:22][CH2:23]2)[CH:7]=[CH:6][CH:5]=1)[CH3:9]
Reactant: CCc1cccc(N)n1
Reactant: CCc1ccnc(N2CCN(c3ccc(N)cc3)CC2)c1
Product: CCc1cccc(N2CCN(c3ccc(N)cc3)CC2)n1

Procedure:
From 2-amino-6-ethylpyridine, in the same manner as 4-[4-(4-ethyl-pyridin-2-yl)-piperazin-1-yl]-phenylamine.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]3[CH2:17][CH2:16][CH2:15][C:14]([C:18](O)=[O:19])=[CH:13][C:12]=3[CH:21]=2)=[CH:4][CH:3]=1.C(Cl)(C(Cl)=O)=O.O1CCCCC1[O:34][CH2:35][C:36]1[CH:42]=[CH:41][C:39]([NH2:40])=[CH:38][CH:37]=1.C(N(CC)CC)C>O1CCCC1.O.CN(C=O)C>[OH:34][CH2:35][C:36]1[CH:37]=[CH:38][C:39]([NH:40][C:18]([CH:14]2[CH2:15][CH:16]=[CH:17][C:11]3[CH:10]=[CH:9][C:8]([C:5]4[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][CH:6]=4)=[CH:21][C:12]=3[CH2:13]2)=[O:19])=[CH:41][CH:42]=1
Reactant: Cc1ccc(-c2ccc3c(c2)C=C(C(=O)O)CCC3)cc1
Reactant: Nc1ccc(COC2CCCCO2)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: Cc1ccc(-c2ccc3c(c2)CC(C(=O)Nc2ccc(CO)cc2)CC=C3)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 55.5 %

Procedure:
To a solution of 2-(4-methylphenyl)-6,7-dihydro-5H-benzocycloheptene-8-carboxylic acid (35.0 g, 0.126 mol) in tetrahydrofuran (THF) (280 ml) were added (COCl)2 (21.9 ml, 0.251 mol) and DMF (0.7 ml) at 0° C. Under nitrogen atmosphere, the mixture was stirred at room temperature for 4 hours. After the reaction completed, The solvent was evaporated, and to the residue was added THF (315 ml). To a solution of the acid chloride was added a solution of 4-(2-tetrahydropyranyloxymethyl)aniline (28.1 g, 0.138 mol) and triethylamine (Et3N) (26.3 ml, 0.189 mol) in THF (105 ml) at 0° C., and the mixture was stirred under nitrogen atmosphere, at room temperature for 2 hours. After the reaction completed, to the mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated NaCl solution and dried with MgSO4. The solvent was evaporated and the residue was dissolved in methanol (MeOH) (470 ml). To the mixture was dropwise added 6N HCl (5.9 ml) at room temperature, and the mixture was stirred for 1 hour. After the reaction completed, the mixture was neutralized with saturated NaHCO3 solution, and the solvent was removed. The residue was washed with water and then acetone/isopropylether (10:1; 60 ml), and the resulting precipitate was filtered, which was dissolved in THF. The mixture was dried with MgSO4, and the solvent was evaporated. The resulting powder was washed twice with hexane:ethyl acetate (10:1; 50 ml) to give N-(4-hydroxymethylphenyl)-3-(4-methylphenyl)-6,7-dihydro-5H-benzocycloheptene-6-carboxamide (26.8 g, 56%) as white powder.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.[H-].[Na+].Br[CH2:11][CH:12]([N:19]1[C:23]2[CH:24]=[C:25]([F:29])[C:26]([F:28])=[CH:27][C:22]=2[N:21]=[C:20]1[C:30]1[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=1)[CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1.Cl>CN(C)C=O.C(OCC)(=O)C>[Cl:36][C:33]1[CH:34]=[CH:35][C:30]([C:20]2[N:19]([CH:12]([CH:13]3[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]3)[CH2:11][O:1][C:2]3[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=3)[C:23]3[CH:24]=[C:25]([F:29])[C:26]([F:28])=[CH:27][C:22]=3[N:21]=2)=[CH:31][CH:32]=1
Reactant: Oc1cccnc1
Reactant: Fc1cc2nc(-c3ccc(Cl)cc3)n(C(CBr)C3CCCCC3)c2cc1F
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Fc1cc2nc(-c3ccc(Cl)cc3)n(C(COc3cccnc3)C3CCCCC3)c2cc1F
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 65 %

Procedure:
To a solution of 46 mg (0.48 mmol) 3-hydroxypyridine in 3 mL N,N-dimethylformamide were added 21 mg (0.48 mmol, 55% dispersion in mineral oil) sodium hydride. The reaction mixture was stirred for 10 min. at room temperature. To this suspension 0.2 g (0.44 mmol) 1-(2-bromo-1-cyclohexyl-ethyl)-2-(4-chloro-phenyl)-5,6-difluoro-1H-benzoimidazole (Ex. 34, int.) were added and the reaction mixture stirred for 4 days at room temperature. The reaction mixture was poured on 30 mL 1N hydrochloric acid and 30 mL ethyl acetate and the phases separated. The aqueous layer was extracted with 30 mL ethyl acetate. The combined organic layers were washed twice with 30 mL water and once with 30 mL brine, dried over magnesium sulfate, filtered and evaporated. The residue was purified by silica gel chromatography using a MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of n-heptane:ethyl acetate (100:0 to 60:40) to give the desired compound as white solid (65%). MS (Turbo Spray): m/z=468.2 [M+H].