Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[C:9]3([CH2:16][CH2:15][CH2:14]3)[CH2:8][N:7]([CH:17]3[CH2:21][CH2:20][CH2:19][CH2:18]3)[C:6]=2[N:22]=1.[NH2:23][C:24]1[CH:32]=[CH:31][C:27]([C:28]([OH:30])=[O:29])=[CH:26][C:25]=1[O:33][CH3:34].C(O)(C(F)(F)F)=O>>[CH:17]1([N:7]2[CH2:8][C:9]3([CH2:16][CH2:15][CH2:14]3)[C:10](=[O:13])[N:11]([CH3:12])[C:5]3[CH:4]=[N:3][C:2]([NH:23][C:24]4[CH:32]=[CH:31][C:27]([C:28]([OH:30])=[O:29])=[CH:26][C:25]=4[O:33][CH3:34])=[N:22][C:6]2=3)[CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: CN1C(=O)C2(CCC2)CN(C2CCCC2)c2nc(Cl)ncc21
Reactant: COc1cc(C(=O)O)ccc1N
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC1(CCC1)C(=O)N2C
Yield: 75.2 %

Procedure:
2′-Chloro-9′-cyclopentyl-5′-methyl-8′,9′-dihydrospiro[cyclobutane-1,7′-pyrimido[4,5-b][1,4]diazepin]-6′(5′H)-one (Intermediate 4) (1.02 g, 3.18 mmol, 1 eq), 4-amino-3-methoxybenzoic acid (1.6 g, 9.5 mmol, 3 eq) and TFA (1.2 mL, 15.9 mmol, 5 eq) were heated to reflux in TFE (40 mL) for 24 hours. Solvent was evaporated in vacuo and the resulting residue was triturated with EtOAc to give 4-(9′-cyclopentyl-5′-methyl-6′-oxo-5′,6′,8′,9′-tetrahydrospiro[cyclobutane-1,7′-pyrimido[4,5-b][1,4]diazepine]-2′-ylamino)-3-methoxybenzoic acid (1.08 g, 75%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7]([CH2:17][C:18]3[N:23]=[C:22]([C:24](O)=[O:25])[CH:21]=[CH:20][CH:19]=3)=[C:8]([C:12]3[CH:16]=[CH:15][S:14][CH:13]=3)[NH:9]2)=[CH:5][CH:4]=1.[CH3:27][S:28]([NH2:31])(=[O:30])=[O:29].Cl.C(N=C=NCCCN(C)C)C>ClCCl.CN(C)C1C=CN=CC=1>[CH3:27][S:28]([NH:31][C:24]([C:22]1[CH:21]=[CH:20][CH:19]=[C:18]([CH2:17][C:7]2[C:6]3[C:10](=[CH:11][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)[NH:9][C:8]=2[C:12]2[CH:16]=[CH:15][S:14][CH:13]=2)[N:23]=1)=[O:25])(=[O:30])=[O:29]
Reactant: CS(N)(=O)=O
Reactant: COc1ccc2c(Cc3cccc(C(=O)O)n3)c(-c3ccsc3)[nH]c2c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: COc1ccc2c(Cc3cccc(C(=O)NS(C)(=O)=O)n3)c(-c3ccsc3)[nH]c2c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 39.7 %

Procedure:
Under an argon atmosphere, to a suspension of 6-(6-methoxy-2-thiophen-3-yl-1H-indol-3-ylmethyl)pyridine-2-carboxylic acid (45.5 mg) in dichloromethane (0.6 mL) were added methane sulfonamide (11.9 mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (23.9 mg), and 4-dimethylaminopyridine (15.3 mg), and this mixture was stirred at room temperature for 2 days. The reaction mixture was concentrated under reduced pressure. To the residue was added 10% aqueous citric acid solution, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution and saturated brine successively, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. To the residue was added ethanol, and this suspension was heated to reflux for 45 minutes to give a solution. This solution was left to be cooled. The precipitate was collected by filtration and dried under reduced pressure to obtain the title compound (21.9 mg). 1H-NMR (DMSO-d6) δ ppm: 3.38 (3H, s), 3.77 (3H, s), 4.47 (2H, s), 6.65 (1H, dd, J=2.3, 8.6 Hz), 6.85 (1H, d, J=2.3 Hz), 7.27-7.35 (1H, m), 7.42 (1H, d, J=8.6 Hz), 7.56 (1H, dd, J=1.3, 5.0 Hz), 7.67 (1H, dd, J=3.0, 5.0 Hz), 7.81-7.91 (3H, m), 11.17 (1H, s), 11.42-11.66 (1H, br).
Reaction SMILES: [N:1]1([C@@H:7]2[CH2:11][CH2:10][N:9](C(OC(C)(C)C)=O)[CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[ClH:19].O1CCOCC1>CO>[ClH:19].[ClH:19].[NH:9]1[CH2:10][CH2:11][C@@H:7]([N:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]2)[CH2:8]1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](N2CCCCC2)C1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: C1CCN([C@@H]2CCNC2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A stirred, room temperature solution of (R)-tert-butyl 3-(piperidin-1-yl)pyrrolidine-1-carboxylate (Reference Example 5b, 6.87 g, 27.0 mmol) in methanol (100 mL) was treated with 4 N HCl in dioxane (67.5 mL, 0.2700 mole). The reaction mixture was stirred at room temperature overnight, then volatiles were removed under reduced pressure. The resulting solid was crystallized from methanol/ether to provide (R)-1-(pyrrolidin-3-yl)piperidine dihydrochloride. 1H NMR (300 MHz, CD3OD) δ ppm 1.46-2.03 (m, 6H), 2.32-2.46 (m, 1H), 2.53-2.63 (m, 1H), 2.95-3.20 (m, 2H), 3.33-3.43 (m, 1H), 3.47-3.72 (m, 4H), 3.78-3.85 (m, 1H), 4.09 (pentet, J=8 Hz, 1H); MS (ESI) m/z 155 (M+H)+.
Reaction SMILES: O[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.N1C=CN=C1.[I:47]C1C=CC(CCCCCCCCCCCCCCCCCCO)=CC=1>C(Cl)Cl.C1C=CC=CC=1>[I:47][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19]
Reactant: CCOC(=O)CCCCCCCCCCCCCCCCO
Reactant: OCCCCCCCCCCCCCCCCCCc1ccc(I)cc1
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: c1ccccc1
Product: CCOC(=O)CCCCCCCCCCCCCCCCI
Temperature: 0 °C
Reaction time: 0.67 h
Yield: 90 %

Procedure:
Ethyl 17-hydroxy-heptadecanoate 79 (264 mg, 0.84 mmol), Ph3P (262 mg, 1 mmol) and imidazole (94 mg, 1.39 mmol) were dissolved in the mixture of CH2Cl2 (3 ml) and benzene (3 ml) and cooled to 0° C. Solid 12 (254 mg, 1 mmol) was added and the reaction mixture was stirred at 0° C. for 40 min. The reaction mixture was quenched by addition of MeOH (0.5 ml), diluted with EtOAc and washed with the aqueous NaHCO3—Na2S2O3 solution, dried over Na2SO4 and evaporated. Chromatography in hexane-EtOAc (97:3) afforded the product 80 (321 mg, 90%).
Reaction SMILES: [Si:1]([O:8][CH2:9][C@@H:10]([NH:13][C:14]([C:16]1[N:17]=[C:18]([N:21]2[CH2:24][CH:23]([OH:25])[CH2:22]2)[S:19][CH:20]=1)=[O:15])[CH2:11][CH3:12])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH3:26][S:27](Cl)(=[O:29])=[O:28].C(N(CC)CC)C>C(Cl)Cl>[Si:1]([O:8][CH2:9][C@@H:10]([NH:13][C:14]([C:16]1[N:17]=[C:18]([N:21]2[CH2:22][CH:23]([O:25][S:27]([CH3:26])(=[O:29])=[O:28])[CH2:24]2)[S:19][CH:20]=1)=[O:15])[CH2:11][CH3:12])([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:3])[CH3:2]
Reactant: CS(=O)(=O)Cl
Reactant: CC[C@@H](CO[Si](C)(C)C(C)(C)C)NC(=O)c1csc(N2CC(O)C2)n1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC[C@@H](CO[Si](C)(C)C(C)(C)C)NC(=O)c1csc(N2CC(OS(C)(=O)=O)C2)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 84.9 %

Procedure:
To a solution of 1-{4-[(1S)-1-(t-butyldimethylsilyloxymethyl)propylcarbamoyl]-1,3-thiazol-2-yl}-3-hydroxyazetidine (1.00 mg, 2.59 mmol) (obtained as described in Reference Example 34(4)) in methylene chloride (50 ml) were added methanesulfonyl chloride (602 μl, 7.78 mmol) and triethylamine (1.09 ml, 7.78 mmol) in an ice bath. After stirring the mixture in the ice bath for 10 minutes, the mixture was stirred at room temperature for 3 hours. After checking the completion of the reaction, the reaction mixture was partitioned between ethyl acetate and saturated aqueous sodium hydrogencarbonate solution. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using n-hexane:ethyl acetate (2:1→1:2) as the eluant to afford 1-{4-[(1S)-1-(t-butyldimethylsilyloxymethyl)propylcarbamoyl]-1,3-thiazol-2-yl}-3-methanesulfonyloxyazetidine (1.02 g, yield 85%) as a pale yellow oil.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:3].C(Cl)Cl.[NH2:15][C:16]1[CH:17]=[CH:18][C:19]2[C:23]([Cl:24])=[C:22]([C:25]#[N:26])[S:21][C:20]=2[CH:27]=1>N1C=CC=CC=1>[C:2]([NH:15][C:16]1[CH:17]=[CH:18][C:19]2[C:23]([Cl:24])=[C:22]([C:25]#[N:26])[S:21][C:20]=2[CH:27]=1)([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:3]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: N#Cc1sc2cc(N)ccc2c1Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: N#Cc1sc2cc(NC(=O)OCc3ccccc3)ccc2c1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 19.0 g. of benzyl chloroformate in 100 ml. of methylene chloride was added to a stirred solution of 0.1 mole of the amine in 500 ml. of methylene chloride containing 20 ml. of pyridine. The reaction mixture was stirred overnight at room temperature and then concentrated to dryness in vacuo. The solid residue was triturated with 5% hydrochloric acid solution and then recrystallized from ethanol to yield 6-carbobenzyloxyamino-3-chlorobenzo[b]thiophene-2-carbonitrile, m.p. 155°-166° C.
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[CH:18][C:17]([N:20]3[CH2:24][C@H:23]([CH2:25]OS(C)(=O)=O)[O:22][C:21]3=[O:31])=[CH:16][C:15]=2[F:32])[CH2:10][CH2:9]1)=[O:7])([CH3:4])[CH3:3].[N-:33]=[N+:34]=[N-:35].[Na+]>CN(C)C=O.C(OCC)(=O)C>[CH3:4][C:2]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([C:14]2[CH:19]=[CH:18][C:17]([N:20]3[CH2:24][C@H:23]([CH2:25][N:33]=[N+:34]=[N-:35])[O:22][C:21]3=[O:31])=[CH:16][C:15]=2[F:32])[CH2:12][CH2:13]1)=[O:7])([CH3:1])[CH3:3]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(N3C[C@H](COS(C)(=O)=O)OC3=O)cc2F)CC1
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(N3C[C@H](CN=[N+]=[N-])OC3=O)cc2F)CC1
Temperature: 60 °C
Reaction time: 16 h

Procedure:
A mixture of (R)-(−)-4-[4-[5-[[(methylsulfonyl)oxy]methyl]-2-oxo-3-oxazolidinyl]-2-fluorophenyl]-1-piperidinecarboxylic acid 1,1-dimethylethyl ester (EXAMPLE 20, Step 6, 13.83 g) and sodium azide (7.62 g) in dry dimethylformamide (117 mL) under N2 is stirred at 60° C. for five hours and at ambient temperature for 16 hours. The mixture is then diluted with ethyl acetate (200 mL), washed with water (8×100 mL) and saline (100 mL), dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give the title compound, mp 109-110° C.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:6]=[C:7]([C:11]2[CH2:17][C:16](=[O:18])[NH:15][C:14]3[CH:19]=[C:20]([Cl:26])[C:21]([N:23]([CH3:25])[CH3:24])=[CH:22][C:13]=3[N:12]=2)[CH:8]=[CH:9][CH:10]=1)=O.[CH2:27]([NH:29][C:30]([NH2:32])=[S:31])[CH3:28]>C1COCC1.CCOC(C)=O>[Cl:26][C:20]1[C:21]([N:23]([CH3:25])[CH3:24])=[CH:22][C:13]2[N:12]=[C:11]([C:7]3[CH:8]=[CH:9][CH:10]=[C:5]([C:3]4[N:32]=[C:30]([NH:29][CH2:27][CH3:28])[S:31][CH:2]=4)[CH:6]=3)[CH2:17][C:16](=[O:18])[NH:15][C:14]=2[CH:19]=1
Reactant: CCNC(N)=S
Reactant: CN(C)c1cc2c(cc1Cl)NC(=O)CC(c1cccc(C(=O)CBr)c1)=N2
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCNc1nc(-c2cccc(C3=Nc4cc(N(C)C)c(Cl)cc4NC(=O)C3)c2)cs1
Temperature: 60 °C
Yield: 18.3 %

Procedure:
A mixture of 4-(3-bromoacetyl-phenyl)-8-chloro-7-dimethylamino-1,3-dihydro-benzo[b][1,4]diazepin-2-one (130 mg) (Example 193a) and N-ethyl-thiourea (31 mg) in THF (3 mL) was heated at 60° C. for 15 min. The mixture was diluted with AcOEt and washed with sat. NaHCO3 solution and with brine. The organic layer was dried and evaporated and the residue was purified by chromatography on silica gel using AcOEt/hexane (1:1) as eluent. The purified product was triturated with Et2O to give the title compound (24 mg) as yellow solid.
Reaction SMILES: Cl[CH:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][CH2:5][C:4]2[CH:13]=[CH:14][CH:15]=[CH:16][C:3]1=2.NC(N)=[S:19].[OH-].[Na+].S(=O)(=O)(O)O>C(O)C>[CH:13]1[C:4]2[CH2:5][CH2:6][C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[CH:2]([SH:19])[C:3]=2[CH:16]=[CH:15][CH:14]=1
Reactant: NC(N)=S
Reactant: ClC1c2ccccc2CCc2ccccc21
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: SC1c2ccccc2CCc2ccccc21
Temperature: 25 °C
Yield: 99.9 %

Procedure:
5-Chloro-10,11-dihydro-5H-dibenzo[a,d]cycloheptene (6.86 g, 0.030 mol) and thiourea (2.28 g, 0.030 mol) were dissolved in ethanol (50 ml) and heated at reflux temperature for 2.5 h. After cooling to room temperature, 2 N sodium hydroxide (20 ml) was added and the mixture was subsequently heated to reflux temperature under a nitrogen atmosphere for 2 h. The reaction mixture was cooled to room temperature, made acidic by addition of a slight excess of sulfuric acid and extracted with diethyl ether (50 ml). The organic phase was washed with water (50 ml) and brine (30 ml). Evaporation in vacuo afforded 6.78 g (100%) of 10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-thiol as an oil . The crude product was directly used in the next step without further purification.
Reaction SMILES: C(N(CCCC)CCCC)CCC.[CH2:14]([OH:20])[C:15]1[O:19][CH:18]=[CH:17][CH:16]=1.[C:21](OC(=O)C)(=[O:23])[CH3:22]>>[C:21]([O:20][CH2:14][C:15]1[O:19][CH:18]=[CH:17][CH:16]=1)(=[O:23])[CH3:22]
Reactant: CC(=O)OC(C)=O
Reactant: OCc1ccco1
Solvent: CCCCN(CCCC)CCCC
Product: CC(=O)OCc1ccco1
Yield: 98.2 %

Procedure:
First 111.2 g (0.600 mole) tributyl amine and then 196.2 g (2.00 mole) distilled furfuryl alcohol were added to 224.6 g (2.20 mole) acetic anhydride. The temperature was allowed to rise to 35° C and was maintained at that for 5 hours. The mixture weighed 528.7 g and its concentration was 52.05%, i.e., the yield was 98.2%. The crude product was washed 3 times with 200 ml water. 5 ml HCl had been added to the second washing water. 264.7 g furfuryl acetate was obtained and its concentration was 95.6%, i.e., the yield was 90.3%.
Reaction SMILES: BrCCBr.Cl[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([Cl:12])[C:7]=1[CH3:13].[C:14]1(=[O:20])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1>O1CCCC1>[Cl:12][C:8]1[C:7]([CH3:13])=[C:6]([C:14]2([OH:20])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[CH:11]=[CH:10][CH:9]=1
Reactant: O=C1CCCCC1
Reactant: Cc1c(Cl)cccc1Cl
Solvent: BrCCBr
Solvent: C1CCOC1
Product: Cc1c(Cl)cccc1C1(O)CCCCC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
96 g (4 moles) of Mg turnings in 60 ml of absolute tetrahydrofuran (THF) are initially taken under a nitrogen atmosphere. 1 ml of 1,2-dibromoethane is added at 65° C., after which a solution of 644 g (4 moles) of 2,6-dichlorotoluene in 1.5 l of absolute THF is added dropwise in the course of 21/4 hours. Thereafter, the mixture is stirred for 4 hours under reflux and cooled to room temperature, and 352.8 g (3.6 moles) of cyclohexanone in 250 ml of absolute THF are added under nitrogen. When the reaction is complete, the Grignard reaction mixture is worked up in an aqueous medium in a conventional manner and the solvent is substantially removed by distillation under reduced pressure. The residue is subjected to incipient distillation (30°-107° C./0.27 mbar). The remaining crude product (676 g), which contains as much as 90% of 1-(3-chloro-2'-methylphenyl)-cyclohexanol, can be further purified by column chromatography using toluene as the mobile phase.
Reaction SMILES: [C:1]([C:3]1[S:7][C:6]([C:8]([OH:10])=O)=[CH:5][CH:4]=1)#[CH:2].[NH2:11][C@H:12]([CH2:30][O:31][CH3:32])[C:13]([NH:15][C:16]1[CH:21]=[CH:20][C:19]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][C:23]2=[O:28])=[C:18]([CH3:29])[CH:17]=1)=[O:14].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CN1CCOCC1>CN(C=O)C>[C:1]([C:3]1[S:7][C:6]([C:8]([NH:11][C@@H:12]([C:13](=[O:14])[NH:15][C:16]2[CH:21]=[CH:20][C:19]([N:22]3[CH2:27][CH2:26][O:25][CH2:24][C:23]3=[O:28])=[C:18]([CH3:29])[CH:17]=2)[CH2:30][O:31][CH3:32])=[O:10])=[CH:5][CH:4]=1)#[CH:2]
Reactant: COC[C@@H](N)C(=O)Nc1ccc(N2CCOCC2=O)c(C)c1
Reactant: C#Cc1ccc(C(=O)O)s1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: C#Cc1ccc(C(=O)N[C@H](COC)C(=O)Nc2ccc(N3CCOCC3=O)c(C)c2)s1

Procedure:
Prepared analogously to Example 1a from 5-ethynylthiophene-2-carboxylic acid and 2-(R)-amino-3-methoxy-N-[3-methyl-4-(3-oxomorpholin-4-yl)phenyl]propionamide with TBTU and NMM in DMF.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:18]([O:19][CH3:20])=[CH:17][C:6]2[CH2:7][C:8](=[O:16])[N:9]([CH2:12][CH2:13][CH:14]=O)[CH:10]=[CH:11][C:5]=2[CH:4]=1.[NH2:21][CH:22]1[CH2:31][CH2:30][C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:23]1>C(O)C.[Pd]>[CH3:1][O:2][C:3]1[C:18]([O:19][CH3:20])=[CH:17][C:6]2[CH2:7][C:8](=[O:16])[N:9]([CH2:12][CH2:13][CH2:14][NH:21][CH:22]3[CH2:31][CH2:30][C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[CH2:23]3)[CH2:10][CH2:11][C:5]=2[CH:4]=1
Reactant: NC1CCc2ccccc2C1
Reactant: COc1cc2c(cc1OC)CC(=O)N(CCC=O)C=C2
Agent: [Pd]
Solvent: CCO
Product: COc1cc2c(cc1OC)CC(=O)N(CCCNC1CCc3ccccc3C1)CC2

Procedure:
Here, 3-[7,8-dimethoxy-1,3-dihydro-2H-3-benzazepin-2-on-3-yl]-propionaldehyde (1.5 g, 0.0054 mol) and 2-amino-1,2,3,4-tetrahydronaphthalene (0.8 g, 0.0054 mol) are hydrogenated in ethanol (150 ml) in the presence of 10% palladium/charcoal (0.5 g) for 15 hours under pressure (5 bar) at 60° C. The catalyst is removed by suction filtering, the filtrate is concentrated in vacuo and the residue is purified over silica gel by column chromatography with methylene chloride and increasing amounts of ethanol (up to 4%). The clean fractions are concentrated by evaporation and the hydrochloride is precipitated from acetone. Yield: 1.35 g. Mp: 229°-230° C.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:9]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:10])=[N:4][C:5](Br)=[CH:6][N:7]=1.[CH2:18]([S:20]([N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1)(=[O:22])=[O:21])[CH3:19]>>[NH2:1][C:2]1[C:3]([C:9]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:10])=[N:4][C:5]([N:26]2[CH2:25][CH2:24][N:23]([S:20]([CH2:18][CH3:19])(=[O:21])=[O:22])[CH2:28][CH2:27]2)=[CH:6][N:7]=1
Reactant: Nc1ncc(Br)nc1C(=O)Nc1ccccc1
Reactant: CCS(=O)(=O)N1CCNCC1
Product: CCS(=O)(=O)N1CCN(c2cnc(N)c(C(=O)Nc3ccccc3)n2)CC1
Yield: 58 %

Procedure:
3-amino-6-bromo-N-phenyl-pyrazine-2-carboxamide (50 mg, 0.1706 mmol) was heated in neat 1-ethylsulfonylpiperazine (excess) at 190° C. for 115 mins in the microwave. The mixture was partitioned between water and EtOAc and the aqueous layer separated. The organic phase was dried (MgSO4) and concentrated in vacuo. The resultant residue was purified by reverse phase preparative HPLC [Waters Sunfire C18, 10 uM, 100A column, gradient 10%-95% B (solvent A: 0.05% TFA in water, solvent B: CH3CN) over 16 minutes at 25 mL/min]. The fractions were collected and freeze-dried to give the title compound (41.2 mg, 58% Yield).
Reaction SMILES: Br[C:2]1[O:6][C:5]([C:7]([OH:9])=[O:8])=[CH:4][CH:3]=1.[CH2:10]([OH:28])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH:18]=[CH:19][CH2:20][CH:21]=[CH:22][CH2:23][CH:24]=[CH:25][CH2:26][CH3:27].CC(C)([O-])C.[K+].C(O)(C)(C)C>C1(C)C=CC=CC=1>[CH2:10]([O:28][C:2]1[O:6][C:5]([C:7]([OH:9])=[O:8])=[CH:4][CH:3]=1)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH:18]=[CH:19][CH2:20][CH:21]=[CH:22][CH2:23][CH:24]=[CH:25][CH2:26][CH3:27]
Reactant: O=C(O)c1ccc(Br)o1
Reactant: CCC=CCC=CCC=CCCCCCCCCO
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Solvent: Cc1ccccc1
Product: CCC=CCC=CCC=CCCCCCCCCOc1ccc(C(=O)O)o1
Temperature: 110 °C

Procedure:
A mixture of 57.0 g (0.300 mole) of 5-bromo-2-furoic acid, 119.0 g (0.450 mole) of 9,12,15-octadecatrienol, and 84.0 g (0.750 mole) of potassium tert-butoxide in dry toluene is stirred with heating. The tert-butanol formed in the reaction is allowed to distill off and the mixture is refluxed at 110° C with stirring for 48 hours. The mixture is allowed to cool, then is acidified with acetic acid and diluted with ice-water. The toluene organic layer is separated, washed with water, then extracted three times with 5% sodium bicarbonate solution. The combined aqueous extracts are cooled and acidified with 10% HCl solution to give 5-(9,12,15-octadecatrien-1-yloxy)-2-furoic acid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH:15][CH:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1.C(O)(=O)C>C(O)C.[Pt]>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:19]2[CH2:20][CH2:21][CH:16]([OH:15])[CH2:17][CH2:18]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: OC1CCNCC1
Agent: [Pt]
Solvent: CC(=O)O
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC(N2CCC(O)CC2)CC1
Reaction time: 6 h
Yield: 13.7 %

Procedure:
1-tert-Butoxycarbonyl-4-piperidone (3 g, 0.0151 mol, 1 eq) and 4-hydroxypiperidine (1.56 g, 0.0154 mol, 1 eq) were stirred at room temperature in ethanol (10 ml) and acetic acid (1 ml) for 30 minutes. To the solution was added 0.4 g of 5% platinum on carbon type 117 Johnson Matthey catalyst. The reaction was then hydrogenated under a pressure of 3 bar at room temperature for 6 hours. The reaction was filtered through CELITE™ and washed with ethanol (40 ml). The 4-(hydroxy)-[1,4′]bipiperidinyl-1′-carboxylic acid tert-butyl ester (13.7% purity by HPLC area %) was not isolated.
Reaction SMILES: [N:1]1[C:6]2[CH:7]=[CH:8][N:9]=[CH:10][C:5]=2[C:4](=[S:11])[NH:3][CH:2]=1.[CH2:12](N(CC)CC)C.IC>CS(C)=O>[CH3:12][S:11][C:4]1[C:5]2[CH:10]=[N:9][CH:8]=[CH:7][C:6]=2[N:1]=[CH:2][N:3]=1
Reactant: CCN(CC)CC
Reactant: S=c1[nH]cnc2ccncc12
Solvent: CI
Solvent: CS(C)=O
Product: CSc1ncnc2ccncc12
Temperature: 25 °C
Reaction time: 12 h
Yield: 156.7 %

Procedure:
A mixture of 3H-pyrido[4,3-d]pyrimidin-4-thione (676 mg, 4.14 mmol), triethylamine (1.4 mL, 10.31 mmol), DMSO (4 mL), and iodomethane (0.48 mL, 7.72 mmol) is stirred for 12 h under N2 at 25° C. The mixture is poured onto water and extracted with EtOAc. The organic extracts are dried (MgSO4), and the solvent is removed under reduced pressure to yield 4-methylthiopyrido[4,3-d]pyrimidine (1.15 g, quant.) as a brown solid. 1H NMR (DMSO) δ 9.52 (1H, s), 9.16 (1H, s), 8.95 (1H, d, J=6 Hz), 7.86 (1H, d, J=8 Hz), 2.75 (1H, s).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[F:10])[C:5]#[N:6].[Cl-].[OH:12][NH3+:13].C(=O)(O)[O-].[Na+]>C(O)C.O>[F:1][C:2]1[CH:3]=[C:4]([C:5](=[N:13][OH:12])[NH2:6])[CH:7]=[CH:8][C:9]=1[F:10]
Reactant: [NH3+]O
Reactant: N#Cc1ccc(F)c(F)c1
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: NC(=NO)c1ccc(F)c(F)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
1.0 g (7.2 mmol) of 3,4-difluorobenzonitrile was initially charged in 30 ml of ethanol, and a solution of 0.5 g (7.2 mmol) of hydroxylammonium chloride and 0.6 g (7.2 mmol) of sodium bicarbonate in 11 ml of water was added at RT. The reaction mixture was stirred at RT for 16 h, concentrated under reduced pressure and reacted without further purification.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[F:8].C([Li])CCC.[F:14][CH:15]([F:21])[C:16](OCC)=[O:17].[NH4+].[Cl-]>C1COCC1>[F:14][CH:15]([F:21])[C:16]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[F:8])=[O:17]
Reactant: Fc1ccccc1Br
Reactant: CCOC(=O)C(F)F
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: O=C(c1ccccc1F)C(F)F
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 56.3 %

Procedure:
To a solution of 1-bromo-2-fluorobenzene (10.00 g, 57.14 mmol) in THF (200 mL) was added n-butyllithium (2.5 M, 24.00 mL) drop-wise at −78° C. over a period of 15 minutes under N2. The mixture was stirred at −78° C. for 30 min. Ethyl 2,2-difluoroacetate (10.64 g, 85.71 mmol) was added dropwise at −78° C. and stirred for 2 hours at −78° C. TLC showed no starting material remained. Saturated aqueous NH4Cl (15 mL) was added dropwise at −78° C. The reaction mixture was warmed to 25° C., extracted with ethyl acetate (100 mL, three times). The combined organic phases were washed with brine (30 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel (petroleum ether: ethyl acetate=95:5) to afford 2,2-difluoro-1-(2-fluorophenyl)ethan-1-one (5.60 g, 47.8% yield, 85% purity). 1H NMR (CDCl3, 400 MHz): δ 7.99-7.95 (m, 1H), 7.70-7.64 (m, 1H), 7.33 (t, J=7.6 Hz 2H), 7.24 (dd, J=10.8, 8.4 Hz, 1H), 6.59-6.32 (m, 1H).