Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:16]2[C@H:15]3[CH2:17][C@H:14]3[CH2:13][C:12]=2[C:11]([C:18](O)=[O:19])=[N:10]1.[NH2:21][CH2:22][C:23]1([N:29]([CH3:31])[CH3:30])[CH2:28][S:26](=[O:27])[CH2:25][CH2:24]1>>[CH3:30][N:29]([CH3:31])[C:23]1([CH2:22][NH:21][C:18]([C:11]2[C:12]3[CH2:13][C@@H:14]4[CH2:17][C@@H:15]4[C:16]=3[N:9]([C:3]3[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=3[F:1])[N:10]=2)=[O:19])[CH2:24][CH2:25][S:26](=[O:27])[CH2:28]1
Reactant: O=C(O)c1nn(-c2ccc(F)cc2F)c2c1C[C@@H]1C[C@H]21
Reactant: CN(C)C1(CN)CCS(=O)C1
Product: CN(C)C1(CNC(=O)c2nn(-c3ccc(F)cc3F)c3c2C[C@@H]2C[C@H]32)CCS(=O)C1

Procedure:
The title compound was prepared in a manner similar to that described in Method G using Intermediate 3 (see Example 1.3) and 3-(aminomethyl)-3-(N,N-dimethylamino)tetramethylene sulfoxide LCMS m/z=435.4 [M+H]+; 1H NMR (400 MHz, CD3OD) δ ppm 0.48-0.51 (m, 1H), 1.21-1.28 (m, 1H), 2.20-2.28 (m, 1H), 2.35-2.40 (m, 1H), 2.41 (s, 3H), 2.47 (s, 3H), 2.50-2.58 (m, 1H), 2.71-2.80 (m, 1H), 2.90-3.10 (m, 3H), 3.15-3.20 (m, 1H), 3.30-3.38 (m, 2H, buried), 3.56-3.85 (m, 2H), 7.19-7.26 (m, 1H), 7.29-7.37 (m, 1H), 7.75-7.83 (m, 1H).
Reaction SMILES: [CH3:1][O-:2].[Na+].Br[C:5]1[N:6]([CH:21]2[CH2:26][CH2:25][CH2:24][CH2:23][O:22]2)[C:7]2[C:12]([N:13]=1)=[C:11]([NH2:14])[N:10]=[C:9]([NH:15][C@@H:16]([CH3:20])[CH2:17][CH2:18][CH3:19])[N:8]=2>CO>[CH3:20][C@H:16]([NH:15][C:9]1[N:8]=[C:7]2[C:12]([N:13]=[C:5]([O:2][CH3:1])[N:6]2[CH:21]2[CH2:26][CH2:25][CH2:24][CH2:23][O:22]2)=[C:11]([NH2:14])[N:10]=1)[CH2:17][CH2:18][CH3:19]
Reactant: CCC[C@H](C)Nc1nc(N)c2nc(Br)n(C3CCCCO3)c2n1
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: CCC[C@H](C)Nc1nc(N)c2nc(OC)n(C3CCCCO3)c2n1
Reaction time: 18 h

Procedure:
A solution of sodium methoxide in methanol (0.5M, 13 ml, 6.5 mmol) was added to a solution of 8-bromo-N2-[(1S)-1-methylbutyl]-9-(tetrahydro-2H-pyran-2-yl)-9H-purine-2,6-diamine (1.26 g, 3.29 mmol) in methanol (10 ml) and the resulting solution heated under reflux for 4 hours. More sodium methoxide in methanol (0.5M, 12 ml, 6 mmol) was then added and refluxing continued for a further 18 hours. The mixture was cooled and evaporated and the residue partitioned between ethyl acetate (75 ml) and water (75 ml). The aqueous phase was re-extracted with ethyl acetate (75 ml) and the combined organic phases were washed with saturated brine, dried over anhydrous magnesium sulphate and evaporated. The residue was dissolved in dichloromethane and purified on a 100 g aminopropyl (NH2) cartridge using a 0-100% ethyl acetate in cyclohexane gradient followed by a 0-20% methanol (+1% triethylamine) gradient over 15 mins. The product-containing fractions were combined and evaporated in vacuo to give the title compound as a white foam (0.848 g).
Reaction SMILES: C([O:3][C:4](=[O:36])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([S:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]3[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=3)=[C:16]([CH3:32])[CH:15]=2)=[CH:9][C:8]=1[CH2:33][CH2:34][CH3:35])C.[Li+].[OH-].O.Cl>C1COCC1>[CH3:32][C:16]1[CH:15]=[C:14]([S:13][C:10]2[CH:11]=[CH:12][C:7]([O:6][CH2:5][C:4]([OH:36])=[O:3])=[C:8]([CH2:33][CH2:34][CH3:35])[CH:9]=2)[CH:19]=[CH:18][C:17]=1[O:20][CH2:21][C:22]1[CH:23]=[CH:24][C:25]([C:28]([F:30])([F:31])[F:29])=[CH:26][CH:27]=1
Reactant: CCCc1cc(Sc2ccc(OCc3ccc(C(F)(F)F)cc3)c(C)c2)ccc1OCC(=O)OCC
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCCc1cc(Sc2ccc(OCc3ccc(C(F)(F)F)cc3)c(C)c2)ccc1OCC(=O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 78 %

Procedure:
Compound 4.5 (32.7 g, 63.0 mmol) was dissolved in THF (250 mL). To the solution was added 4N LiOH (31.5 mL, 126 mmol) and the reaction was stirred at room temperature for 1 h, after which time water (31.5 mL) was added, and the reaction mixture was stirred for 30 min. 2N HCl (70 mL) was then added to the reaction and the THF was removed in vacuo. The residue was diluted with hexane (250 mL) with stirring, and the deposited crystals were collected by filtration and recrystallized from EtOAc-hexane to provide 4 (24.12 g). MS APSI m/e: 489 (M−H). 1H NMR (400 MHz) (DMSO-d6) δ 12.90 (1H, brs); 7.76 (2H, d, J=8.2 Hz); 7.67 (2H, d, J=8.2 Hz); 7.20-7.05 (4H, m); 6.99 (1H, d, J=8.6 Hz); 6.81 (1H, d, J=8.4 Hz); 5.23 (2H, s); 4.68 (2H, s); 2.56-2.47 (2H, m); 2.18 (3H, s); 1.60-1.47 (2H, m); 0.85 (3H, t, J=7.4 Hz).
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11](F)[C:12]=3[F:14])[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2)[CH2:3][CH2:2]1.[CH3:21][N:22]([CH2:24][C:25]1[N:26]=[C:27]2[CH2:32][NH:31][CH2:30][CH2:29][N:28]2[CH:33]=1)[CH3:23]>>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11]([N:31]4[CH2:30][CH2:29][N:28]5[CH:33]=[C:25]([CH2:24][N:22]([CH3:23])[CH3:21])[N:26]=[C:27]5[CH2:32]4)[C:12]=3[F:14])[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2)[CH2:2][CH2:3]1
Reactant: O=C(O)c1cn(C2CC2)c2c(F)c(F)c(F)cc2c1=O
Reactant: CN(C)Cc1cn2c(n1)CNCC2
Product: CN(C)Cc1cn2c(n1)CN(c1c(F)cc3c(=O)c(C(=O)O)cn(C4CC4)c3c1F)CC2

Procedure:
Using 1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid and (2-dimethylaminomethyl-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine, the same procedure as in Production Example 1 was followed to yield the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[C:11](Cl)[C:12]3[C:17]([CH:18]=2)=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:5][CH:4]=1.[Cl-].[NH4+].O1CCC[CH2:23]1>Cl[Ni]Cl>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[C:11]([CH3:23])[C:12]3[C:17]([CH:18]=2)=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:5][CH:4]=1
Reactant: COc1ccc(-c2cc3ccccc3c(Cl)n2)cc1
Reactant: C1CCOC1
Agent: Cl[Ni]Cl
Agent: [Cl-]
Agent: [NH4+]
Product: COc1ccc(-c2cc3ccccc3c(C)n2)cc1
Yield: 100 %

Procedure:
3-(4-Methoxyphenyl)-1-chloroisoquinoline (3.25 g) was dissolved in tetrahydrofuran (30 ml), followed by the addition of 3.0M ethylmagnesium bromide diethyl ether solution (12 ml) and NiCl2 (dppp) (50 mg) at 0° C. After the mixture was reacted overnight at room temperature, the resulting reaction solution was poured into an aqueous solution of saturated ammonium chloride and extracted with ethyl acetate. The resulting organic layer was washed with water and brine, dried and evaporated, to give 3-(4-methoxyphenyl)-1-methylisoquinoline as an oil (3.3 g, yield; 100%).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10](=O)[C:11](OCC2C=CC=CC=2)=[O:12])=[CH:2]1.[BH4-].[Na+]>C(O)(C)C.O>[OH:12][CH2:11][CH2:10][C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[NH:1][CH:2]=1
Reactant: O=C(OCc1ccccc1)C(=O)c1c[nH]c2ccccc12
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)O
Product: OCCc1c[nH]c2ccccc12
Reaction time: 4 h

Procedure:
A suspension of benzyl 3-indolylglyoxylate (55.8 g.) and sodium borohydride (22.7 g.) in isopropanol (560 ml.) was heated to reflux over a period of 40 minutes and stirred at that temperature for 4 hours. After cooling the mixture was diluted with water (1.2 l.) and extracted with dichloromethane. The extract was washed with water and the solvent evaporated under reduced pressure to yield a viscous oil. This was distilled at 0.5 - 1 mm. pressure and the friction which distilled at a vapour temperature of 160°-190° was crystallised from toluene (100 ml.), giving the title compound as white crystals, mp. 57°-90°. Yield 24.3 g. (75.5%).
Reaction SMILES: C1C2C(COC(=O)[NH:17][CH:18]3[CH2:23][CH2:22][N:21]([C:24](=[O:51])[C:25]4[CH:30]=[CH:29][C:28]([NH:31][C:32]5[N:33]=[CH:34][C:35]6[N:41]([CH3:42])[C:40](=[O:43])[C:39]([F:45])([F:44])[CH2:38][N:37]([CH:46]7[CH2:49][CH2:48][CH2:47]7)[C:36]=6[N:50]=5)=[CH:27][CH:26]=4)[CH2:20][CH2:19]3)C3C(=CC=CC=3)C=2C=CC=1.N1CCCCC1>ClCCl>[NH2:17][CH:18]1[CH2:23][CH2:22][N:21]([C:24]([C:25]2[CH:30]=[CH:29][C:28]([NH:31][C:32]3[N:33]=[CH:34][C:35]4[N:41]([CH3:42])[C:40](=[O:43])[C:39]([F:44])([F:45])[CH2:38][N:37]([CH:46]5[CH2:47][CH2:48][CH2:49]5)[C:36]=4[N:50]=3)=[CH:27][CH:26]=2)=[O:51])[CH2:20][CH2:19]1
Reactant: CN1C(=O)C(F)(F)CN(C2CCC2)c2nc(Nc3ccc(C(=O)N4CCC(NC(=O)OCC5c6ccccc6-c6ccccc65)CC4)cc3)ncc21
Solvent: ClCCl
Solvent: C1CCNCC1
Product: CN1C(=O)C(F)(F)CN(C2CCC2)c2nc(Nc3ccc(C(=O)N4CCC(N)CC4)cc3)ncc21
Reaction time: 1 h
Yield: 25.2 %

Procedure:
A mixture of 0.220 g (0.31 mmole) of {1-[4-(9-cyclobutyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-benzoyl]-piperidin-4-yl}-carbamic acid 9H-fluoren-9-ylmethyl ester, 1 mL of piperidine and 5 mL of dichloromethane was stirred for 1 hour and then concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with dichloromethane-methanol-ammonium hydroxide (92:8:0.3) to give 0.038 g of 2-[4-(4-amino-piperidine-1-carbonyl)-phenylamino]-9-cyclobutyl-7,7-difluoro-5-methyl-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (I-15).
Reaction SMILES: [F:1][C:2]([F:10])([F:9])[C:3](=O)[CH2:4][C:5](=O)[CH3:6].[CH3:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([NH:19][NH2:20])=[CH:15][CH:14]=1.Cl>COCCO.C(O)(=O)C>[F:1][C:2]([F:10])([F:9])[C:3]1[CH:4]=[C:5]([CH3:6])[N:19]([C:16]2[CH:17]=[CH:18][C:13]([O:12][CH3:11])=[CH:14][CH:15]=2)[N:20]=1
Reactant: CC(=O)CC(=O)C(F)(F)F
Reactant: COc1ccc(NN)cc1
Agent: Cl
Solvent: COCCO
Solvent: CC(=O)O
Product: COc1ccc(-n2nc(C(F)(F)F)cc2C)cc1
Yield: 87.8 %

Procedure:
A mixture of 1,1,1-trifluoro-2,4-pentanedione (0.02 mol, 2.4 mL) and 4-methoxyphenyl hydrazine.HCl (4.54 g, 1.3 eq.) in 2-methoxyethanol (100 mL) and acetic acid (30 mL) was refluxed for 6 h. The reaction mixture was evaporated and purified by flash chromatography on a silica gel column (400 g) eluted with 4:1 hexane:ethyl acetate to give 4.5 g of pure product (88%).
Reaction SMILES: Br[C:2]1[C:19]([F:20])=[CH:18][C:5]2[O:6][CH2:7][CH2:8][C:9]3[CH:13]=[C:12]([C:14]([O:16][CH3:17])=[O:15])[S:11][C:10]=3[C:4]=2[CH:3]=1.[C:21]([C@:23]1([OH:30])[CH2:27][CH2:26][N:25]([CH3:28])[C:24]1=[O:29])#[CH:22]>>[F:20][C:19]1[C:2]([C:22]#[C:21][C@:23]2([OH:30])[CH2:27][CH2:26][N:25]([CH3:28])[C:24]2=[O:29])=[CH:3][C:4]2[C:10]3[S:11][C:12]([C:14]([O:16][CH3:17])=[O:15])=[CH:13][C:9]=3[CH2:8][CH2:7][O:6][C:5]=2[CH:18]=1
Reactant: COC(=O)c1cc2c(s1)-c1cc(Br)c(F)cc1OCC2
Reactant: C#C[C@]1(O)CCN(C)C1=O
Product: COC(=O)c1cc2c(s1)-c1cc(C#C[C@]3(O)CCN(C)C3=O)c(F)cc1OCC2

Procedure:
Methyl 9-bromo-8-fluoro-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2-carboxylate was reacted with (3R)-3-ethynyl-3-hydroxy-1-methyl-pyrrolidin-2-one similarly to as described in General Procedure F with non-critical modifications to afford (R)-methyl 8-fluoro-9-((3-hydroxy-1-methyl-2-oxopyrrolidin-3-yl)ethynyl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2-carboxylate. Crude (R)-methyl 8-fluoro-9-((3-hydroxy-1-methyl-2-oxopyrrolidin-3-yl)ethynyl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2-carboxylate was to General Procedure M subjected to afford 26 mg (21%) of 8-fluoro-9-[2-[(3R)-3-hydroxy-1-methyl-2-oxo-pyrrolidin-3-yl]ethynyl]-4,5-dihydrothieno[3,2-d][1]benzoxepine-2-carboxamide.
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([Br:13])=[CH:9][CH:8]=2)[N:6]=1.[CH2:14]([NH2:17])[CH2:15][NH2:16].C([O-])(O)=O.[Na+]>>[Br:13][C:10]1[CH:11]=[CH:12][C:7]([C:5]2[N:6]=[C:2]([NH:16][CH2:15][CH2:14][NH2:17])[S:3][CH:4]=2)=[CH:8][CH:9]=1
Reactant: Brc1ccc(-c2csc(Br)n2)cc1
Reactant: NCCN
Agent: O=C([O-])O
Agent: [Na+]
Product: NCCNc1nc(-c2ccc(Br)cc2)cs1
Temperature: 130 °C
Yield: 97.4 %

Procedure:
2-Bromo-4-(4-bromophenyl)-1,3-thiazole (2.0 g, 6.2 mmol), prepared in step 2 of Example 1, was dissolved in ethylenediamine (10.0 mL, 185 mmol) and heated to 130° C. for 2 h. The mixture was cooled and poured into saturated NaHCO3 and extracted with ether. The ether extracts were combined and washed with water, brine, dried over anhydrous MgSO4, filtered and concentrated under reduced pressure to give N-[4-(4-bromophenyl)-1,3-thiazol-2-yl]ethane-1,2-diamine (1.8 g, 97%) as a yellow solid. HRMS: calcd for C11H12BrN3S+H+, 298.00080; found (ESI, [M+H]+), 298.0012. Analytical HPLC: retention time 7.0 min, 210-370 nm the Xterra® RP18 column, 3.5μ, 150×4.6 mm 40 C 85/15-5/95 (Ammon. Form. Buff. pH=3.5/ACN+MeOH) for 10 min, hold 4 min, 1.2 mL/min 5 μL injection.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=4[Cl:22])[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:23]([OH:26])[CH2:24][CH3:25])=[CH:4][CH:3]=1.[H-].[Na+].[CH:29]1([CH2:32]Br)[CH2:31][CH2:30]1>CN(C)C=O>[Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=4[Cl:22])[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:23]([O:26][CH2:32][CH:29]2[CH2:31][CH2:30]2)[CH2:24][CH3:25])=[CH:4][CH:3]=1
Reactant: CCC(O)c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl
Reactant: BrCC1CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCC(OCC1CC1)c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 90.8 %

Procedure:
To a solution of 1-[9-chloro-1-(2,4-dichlorophenyl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazol-6-yl]propan-1-ol (120.0 mg, 0.292 mmol) in N,N-dimethylformamide (1.5 mL) was added sodium hydride (23.4 mg, 0.584 mmol) at 0° C. After 20 min, to the mixture was added cyclopropylmethyl bromide (0.14 mL, 1.46 mmol). The reaction mixture was stirred at room temperature for 1 day. The mixture was quenched with water and extracted with ethyl acetate (×3). The combined organic layer was washed with water (×2) and brine (×1), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with a 0-30% ethyl acetate/n-hexane gradient mixture. The resulting solid was recrystallized from n-hexane to give the title compound as a colorless powder (123.0 mg, 0.265 mmol, 91%).
Reaction SMILES: C(NCC)C.[CH2:6]([CH2:8][NH2:9])[OH:7].[C:10]1([C:16]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)Cl)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C(O)(C)C>[C:16]([NH:9][CH2:8][CH2:6][OH:7])([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)([C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: NCCO
Solvent: CC(C)O
Solvent: CCNCC
Product: OCCNC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 85.7 %

Procedure:
A mixture of isopropanol (750 ml), diethylamine (75 ml), ethanolamine (98%, 62.3 g, 1 mole) and triphenylchloromethane (97%, 143.7 g, 0.50 moles) was stirred at room temperature for 3 hours. The resulting solution was then poured into ice-cold water (4 l) under continuous stirring and the resulting precipitate was filtered off and dried. The crude product was digested in toluene (340 ml), then filtered off and dried in vacuo at 60° C. Thus 130 g (85%) of the pure desired compound were obtained.
Reaction SMILES: [CH2:1]([C:3]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)([OH:12])[C:4](=[O:11])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[OH:2].[CH3:19][CH:20]1OC(C)OC(C)O1>C1(C)C=CC(S(O)(=O)=O)=CC=1.C1C=CC=CC=1>[CH3:19][CH:20]1[O:12][C:3]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)([C:4](=[O:11])[C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH2:1][O:2]1
Reactant: CC1OC(C)OC(C)O1
Reactant: O=C(c1ccccc1)C(O)(CO)c1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Product: CC1OCC(C(=O)c2ccccc2)(c2ccccc2)O1
Reaction time: 0.5 h
Yield: 107.3 %

Procedure:
A solution of 10.0 grams (41 millimoles)αmethylol benzoin, 20.0 grams (45 millimoles) paraldehyde, 0.5 grams p-toluenesulfonic acid and 100 ml. benzene was heated with magnetic stirring to 80°-90° C for 30 minutes under a Dean-Stark trap under conditions such that refluxing occurred, but the vapors condensed before reaching the trap. The temperature of the reaction mixture was then gradually raised to 120°-130° C and 8 ml. water was collected. The reaction mixture was then saturated with ammonia gas, the resulting salt precipitate removed by filtration on a Buchner funnel to provide a benzene solution of the reaction product. The benzene solvent was removed under vacuum. A yield of 11.8 grams of a yellow oil was obtained. The yellow oil was chromatographed on silica gel with 5% ethyl ether in n-hexane elution to provide 9.5 grams of an odorous yellow oil which distilled at 125°-130° C at 20μ vacuum pressure to provide 6.5 grams of a light yellow oil product.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[CH:10]=[C:9]([CH:11]=O)[S:8][C:6]=2[N:7]=1.[CH3:19][O:20][CH2:21][CH2:22][N:23]([CH3:30])[CH:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1>>[Cl:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[CH:10]=[C:9]([CH2:11][N:27]3[CH2:28][CH2:29][CH:24]([N:23]([CH2:22][CH2:21][O:20][CH3:19])[CH3:30])[CH2:25][CH2:26]3)[S:8][C:6]=2[N:7]=1
Reactant: COCCN(C)C1CCNCC1
Reactant: O=Cc1cc2c(N3CCOCC3)nc(Cl)nc2s1
Product: COCCN(C)C1CCN(Cc2cc3c(N4CCOCC4)nc(Cl)nc3s2)CC1

Procedure:
Reaction between 2-chloro-4-morpholin-4-yl-thieno[2,3-d]pyrimidine-6-carbaldehyde (General Procedure D-2) and (2-methoxy-ethyl)-methyl-piperidin-4-yl-amine using General Procedure B-3 yielded 1-((2-chloro-4-morpholinothieno[2,3-d]pyrimidin-6-yl)methyl)-N-(2-methoxyethyl)-N-methylpiperidin-4-amine.
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:31]=[CH:30][C:16]([CH2:17][NH:18][C:19]3[CH:29]=[CH:28][C:22]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:21][CH:20]=3)=[CH:15][CH:14]=2)=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].[C:32](Cl)(=[O:38])[CH2:33][CH2:34][CH2:35][CH2:36][CH3:37]>>[CH2:1]([C:5]1[CH:6]=[CH:7][C:8]([C:11]#[C:12][C:13]2[CH:14]=[CH:15][C:16]([CH2:17][N:18]([C:32](=[O:38])[CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])[C:19]3[CH:20]=[CH:21][C:22]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:28][CH:29]=3)=[CH:30][CH:31]=2)=[CH:9][CH:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1ccc(C#Cc2ccc(CNc3ccc(C(=O)OCC)cc3)cc2)cc1
Reactant: CCCCCC(=O)Cl
Product: CCCCCC(=O)N(Cc1ccc(C#Cc2ccc(CCCC)cc2)cc1)c1ccc(C(=O)OCC)cc1

Procedure:
The titled compound was prepared following the procedure B using ethyl 4-({4-[(4-butylphenyl)ethynyl]benzyl}amino)benzoate and hexanoyl chloride as a yellow oil (92%). 1H NMR (CDCl3, 300 MHz) δ 8.00 (d, J=8.3 Hz, 2H), 7.41 (m, 4H), 7.14 (m, 4H), 7.03 (d, J=8.7 Hz, 2H), 4.89 (s, 2H), 4.37 (q, J=7.2 Hz, 2H), 2.60 (t, J=7.5 Hz, 2H), 2.06 (t, J=7.5 Hz, 2H), 1.67-1.55 (m, 4H), 1.43-1.10 (m, 9H), 0.91 (t, J=7.2 Hz, 3H), 0.82 (t, J=7.0 Hz, 3H). M+ (ESI): 510.5. HPLC, Rt: 6.14 min (Purity: 98.2%).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:13]2[CH2:18][N:17]([C:19]([N:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)=[O:20])[CH2:16][CH:15]([C:27](O)=[O:28])[CH2:14]2)[CH:5]=[CH:6][C:7]=1[O:8][C:9]([F:12])([F:11])[F:10].O[N:31]=[C:32]([NH2:36])[CH:33]([CH3:35])[CH3:34]>>[CH3:1][C:2]1[CH:3]=[C:4]([CH:13]2[CH2:14][CH:15]([C:27]3[O:28][N:36]=[C:32]([CH:33]([CH3:35])[CH3:34])[N:31]=3)[CH2:16][N:17]([C:19]([N:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)=[O:20])[CH2:18]2)[CH:5]=[CH:6][C:7]=1[O:8][C:9]([F:11])([F:10])[F:12]
Reactant: CC(C)C(N)=NO
Reactant: Cc1cc(C2CC(C(=O)O)CN(C(=O)N3CCOCC3)C2)ccc1OC(F)(F)F
Product: Cc1cc(C2CC(c3nc(C(C)C)no3)CN(C(=O)N3CCOCC3)C2)ccc1OC(F)(F)F

Procedure:
500 mg (1.15 mmol) of the compound from Example 167A and 130 mg (1.27 mmol) of N′-hydroxy-2-methylpropanimidamide were reacted according to the General Method 1. Yield: 286 mg (51% of theory)
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH3:7][C:8]1[NH:12][C:11]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:10]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:9]=1[C:24]([O:26][CH2:27][CH3:28])=[O:25].[CH2:29]([O:31][CH2:32][CH2:33]I)[CH3:30]>C(#N)C>[CH2:29]([O:31][CH2:32][CH2:33][N:12]1[C:8]([CH3:7])=[C:9]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[C:10]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[C:11]1[C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH3:30]
Reactant: CCOCCI
Reactant: CCOC(=O)c1[nH]c(C)c(C(=O)OCC)c1-c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOCCn1c(C)c(C(=O)OCC)c(-c2ccccc2)c1C(=O)OCC
Yield: 100.8 %

Procedure:
Potassium carbonate (1.82 g, 13.3 mmol) was added to a solution of diethyl 5-methyl-3-phenyl-1H-pyrrole-2,4-dicarboxylate (1.0 g, 3.32 mmol) and 1-ethoxy-2-iodo-ethane (1.98 g, 9.96 mmol) in acetonitrile (20 mL) and the mixture heated at reflux for 72 h. The inorganic salts were filtered off and the filtrate was concentrated in vacuo to afford diethyl 1-(2-ethoxyethyl)-5-methyl-3-phenyl-pyrrole-2,4-dicarboxylate (1.25 g, quantitative).
Reaction SMILES: [Cl:1][C:2]1[C:14]([N:15]([CH3:17])[CH3:16])=[CH:13][C:5]([CH:6](O)CS(C)(=O)=O)=[CH:4][C:3]=1[N:18]([CH3:20])[CH3:19].C[O-].[Na+].[NH:24]([CH2:31][CH2:32][C:33]#[N:34])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>CS(C)=O>[NH:24]([CH:31]=[C:32]([CH2:6][C:5]1[CH:13]=[C:14]([N:15]([CH3:16])[CH3:17])[C:2]([Cl:1])=[C:3]([N:18]([CH3:19])[CH3:20])[CH:4]=1)[C:33]#[N:34])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: N#CCCNc1ccccc1
Reactant: CN(C)c1cc(C(O)CS(C)(=O)=O)cc(N(C)C)c1Cl
Agent: C[O-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CN(C)c1cc(CC(C#N)=CNc2ccccc2)cc(N(C)C)c1Cl

Procedure:
A mixture of 15.7 g. of 4-chloro-3,5-bis(dimethylamino)-α-[(methylsulfonyl)methyl]benzyl alcohol, 2.8 g. of sodium methylate and 7.1 g. of β-anilinopropionitrile in 31 ml. of dimethylsulfoxide was stirred with the exclusion of moisture for 5 hours at 50° C. The mixture was poured into 200 ml. of water, the precipitated oil extracted with ethyl acetate, the ethyl acetate solution dried over sodium sulfate and evaporated in vacuo. By purification of the residue over aluminum oxide with benzene and recrystallization from ethyl acetate/petroleum ether, there was obtained α-(anilinomethylene)-4-chloro-3,5-bis(dimethylamino)hydrocinnamonitrile, having a melting point of 168° C.
Reaction SMILES: [H-].[Na+].[NH:3]1[CH2:8][CH2:7][S:6][CH2:5][C:4]1=[O:9].[Br:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][CH2:19]Br)=[CH:13][N:12]=1>CN(C=O)C>[Br:10][C:11]1[N:12]=[CH:13][C:14]([CH2:17][CH2:18][CH2:19][N:3]2[CH2:8][CH2:7][S:6][CH2:5][C:4]2=[O:9])=[CH:15][CH:16]=1
Reactant: BrCCCc1ccc(Br)nc1
Reactant: O=C1CSCCN1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1CSCCN1CCCc1ccc(Br)nc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
60.2 mg (1.38 mmol) of sodium hydride (55% suspension in mineral oil) were added to 161.7 mg (1.38 mmol) of thiomorpholin-3-one in 5 ml of DMF, and the mixture was stirred at room temperature for 15 min. Subsequently, 350 mg (1.25 mmol) of 2-bromo-5-(3-bromopropyl)pyridine were added. The reaction mixture was stirred for 3.5 h, concentrated, admixed with water and extracted with ethyl acetate. The organic phase was separated and concentrated. Yield: 421 mg.
Reaction SMILES: C([Li])CCC.[F:6][C:7]1[CH:8]=[C:9]([O:13][CH3:14])[CH:10]=[CH:11][CH:12]=1.[CH:15](=[O:18])[CH2:16][CH3:17].Cl>CCCCCC.O1CCCC1>[F:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH3:14])[C:8]=1[CH:15]([OH:18])[CH2:16][CH3:17]
Reactant: COc1cccc(F)c1
Reactant: CCC=O
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCC(O)c1c(F)cccc1OC
Reaction time: 1 h
Yield: 85.6 %

Procedure:
66.7 ml (106.8 mmol) of a 1.6N butyllithium solution in hexane were added at -78° to a solution of 12 g (95.14 mmol) of 3-fluoroanisole in 240 ml of anhydrous tetrahydrofuran and the mixture was stirred for one hour. Subsequently, 21 ml (288 mmol) of propionaldehyde were added dropwise thereto at -78°, the mixture was stirred for one hour and the solution was left to come to room temperature. The mixture was poured into 240 ml of 1 N HCl and extracted twice with 250 ml of diethyl ether each time After drying over sodium sulfate concentration was carried out in a vacuum. The crude product obtained was purified by column chromatography on silica gel (dichloromethane/hexane 1:1). There were obtained 15 g (86%) of 1-(2-fluoro-6-methoxy-phenyl)-propan-1-ol as a pale yellow oil.