Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:5][C:6](=[O:18])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1[C:16]#[CH:17])(C)(C)C.Br[C:20]1[CH:21]=[C:22]([S:26]([CH2:29][CH2:30][OH:31])(=[O:28])=[O:27])[CH:23]=[CH:24][CH:25]=1>>[Cl:15][C:12]1[CH:13]=[CH:14][C:9]([O:8][CH2:7][C:6]([OH:5])=[O:18])=[C:10]([C:16]#[C:17][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([S:26]([CH2:29][CH2:30][OH:31])(=[O:28])=[O:27])[CH:21]=2)[CH:11]=1
Reactant: C#Cc1cc(Cl)ccc1OCC(=O)OC(C)(C)C
Reactant: O=S(=O)(CCO)c1cccc(Br)c1
Product: O=C(O)COc1ccc(Cl)cc1C#Cc1cccc(S(=O)(=O)CCO)c1

Procedure:
Following the general method as outlined in Example 10, starting from tert-butyl(4-chloro-2-ethynylphenoxy)acetate (Intermediate 3) and 2-(3-bromo-benzenesulfonyl)-ethanol (Intermediate 7), the title compound was obtained as a beige solid after purification by preparative HPLC.
Reaction SMILES: [OH:1][C@@H:2]([CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:3]([OH:5])=[O:4].O.[C:14]1(C)C=CC(S(O)(=O)=O)=CC=1.O>CO>[OH:1][C@@H:2]([CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:3]([O:5][CH3:14])=[O:4]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: O=C(O)[C@@H](O)Cc1ccccc1
Solvent: O
Solvent: CO
Product: COC(=O)[C@@H](O)Cc1ccccc1
Yield: 98 %

Procedure:
A solution of commercially available (S)-2-hydroxy-3-phenylpropionic acid (5.0 g, 30.1 mmol) and p-toluenesulfonic acid hydrate (1g) in methanol (125 mL) was refluxed with removal of water using 3A molecular sieves for 17 h. The solution was concentrated and dissolved in ether. The ether solution was washed with saturated sodium bicarbonate, brine and concentrated to provide the title compound as a white solid (5.32 g, 98%): NMR (CDCl3): δ 7.36-7.20 (m, 5H), 4.47 (ddd, J=5, 6, 7 Hz, 1H), 3.78 (s, 3H), 3.14 (dd, J=5, 14 Hz, 1H), 2.97 (dd, J=7, 14 Hz), 2.69 (d, J=6 Hz, 1H).
Reaction SMILES: N=[C:2]1[N:6]([C:7]2[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[C:9]([C:15]([F:18])([F:17])[F:16])[CH:8]=2)[C:5](=[O:19])[C:4]2([CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)[NH:3]1.Cl.C(=O)([O-])[OH:27].[Na+]>C(O)C>[O:27]=[C:2]1[N:6]([C:7]2[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[C:9]([C:15]([F:18])([F:17])[F:16])[CH:8]=2)[C:5](=[O:19])[C:4]2([CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)[NH:3]1
Reactant: O=C([O-])O
Reactant: N#Cc1ccc(N2C(=N)NC3(CCCCC3)C2=O)cc1C(F)(F)F
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: N#Cc1ccc(N2C(=O)NC3(CCCCC3)C2=O)cc1C(F)(F)F
Temperature: 25 °C

Procedure:
1.10 g of the product obtained in Stage 2 above, 3 ml of 6N hydrochloric acid and 8 ml of ethanol are introduced, the mixture is taken to reflux for one hour, cooled down to ambient temperature, neutralized by the addition of sodium hydrogen carbonate, extracted with ethyl acetate. The organic phases are combined, washed with water, dried, filtered and concentrated. After chromatography on silica eluting with methylene chloride-acetone: 9-1, then recrystallization from isopropanol, 470 mg of expected product (white solid) is obtained. M.p.=187° C.
Reaction SMILES: [CH:1]([N:4]1[C:8]([CH:9]2[C:18](=O)[C:17]3[C:16]([C:20]([O:22]CC)=O)=[CH:15][CH:14]=[CH:13][C:12]=3[NH:11][CH:10]2[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:7][N:6]=[CH:5]1)([CH3:3])[CH3:2].O.[NH2:32][NH2:33]>CO>[CH:1]([N:4]1[C:8]([CH:9]2[C:18]3=[N:32][NH:33][C:20](=[O:22])[C:16]4[CH:15]=[CH:14][CH:13]=[C:12]([C:17]=43)[NH:11][CH:10]2[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:7][N:6]=[CH:5]1)([CH3:2])[CH3:3]
Reactant: NN
Reactant: CCOC(=O)c1cccc2c1C(=O)C(c1cncn1C(C)C)C(c1ccccc1)N2
Solvent: O
Solvent: CO
Product: CC(C)n1cncc1C1c2n[nH]c(=O)c3cccc(c23)NC1c1ccccc1
Temperature: 50 °C
Reaction time: 8 h
Yield: 13 %

Procedure:
A suspension of ethyl 3-(1-isopropyl-1H-imidazol-5-yl)-4-oxo-2-phenyl-1,2,3,4-tetrahydroquinoline-5-carboxylate (770 mg, 1.9 mmol) and hydrazine monohydrate (6 ml, 85%) were added in methanol (10 mL) and stirred at 50° C. overnight. The mixture was filtered, and the white solid was washed with methanol and dried to give 9-(1-isopropyl-1H-imidazol-5-yl)-8-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one (90 mg, yield 13%). 1H-NMR (400 MHz, DMSO-d) δ (ppm): 0.82-0.84 (d, J=6.8 Hz, 3H), 1.27-1.29 (d, J=6.4 Hz, 3H), 3.30-3.33 (t, J=6.6 Hz, 1H), 4.67-4.70 (d, J=11.2 Hz, 1H), 4.92-4.95 (d, J=11.2 Hz, 1H), 6.80 (s, 1H), 7.01 (s, 1H), 7.16-7.18 (s, 1H), 7.24-7.28 (m, 3H), 7.31 (s, 1H), 7.36-7.39 (m, 3H), 7.55-7.59 (m, 1H); LC-MS (ESI) m/z: 372 (M+1)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:15])[CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11].[H-].[Na+].[F:18][C:19]([F:29])([F:28])[C:20]1[CH:27]=[CH:26][C:23]([CH2:24]Br)=[CH:22][CH:21]=1.O>COCCOC>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:15])[CH:9]([CH2:24][C:23]1[CH:22]=[CH:21][C:20]([C:19]([F:18])([F:28])[F:29])=[CH:27][CH:26]=1)[C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: FC(F)(F)c1ccc(CBr)cc1
Reactant: CCOC(=O)CC(=O)c1ccccc1F
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: CCOC(=O)C(Cc1ccc(C(F)(F)F)cc1)C(=O)c1ccccc1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 73.4 %

Procedure:
To a solution of ethyl 3-(2-fluorophenyl)-3-oxopropionate (20 g, 95 mmol) in 1,2-dimethoxyethane (100 ml) was added sodium hydride (60% in oil, 3.80 g, 95 mmol) under ice-cooling and the mixture was stirred at room temperature for 30 min. To the reaction solution was dropwise added a solution of 4-trifluoromethylbenzyl bromide (22.7 g, 95 mmol) in 1,2-dimethoxyethane (50 ml) and the reaction solution was stirred at room temperature for 4 hrs. The reaction solution was poured into water (300 ml) and extracted with ethyl acetate (500 ml×2). The extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (toluene:hexane=1:1-toluene) to give ethyl 3-(2-fluorophenyl)-3-oxo-2-((4-(trifluoromethyl)phenyl)methyl)propionate (25.7 g, 73%) as a colorless oil.
Reaction SMILES: [CH3:1][C:2]([CH2:9][CH2:10][C:11]([CH3:15])=[C:12]([CH3:14])[CH3:13])=[CH:3][CH2:4][CH2:5][C:6](=[O:8])[CH3:7].ClC1C=CC=C(C(OO)=[O:24])C=1>C(Cl)Cl>[O:24]1[C:12]([CH3:14])([CH3:13])[C:11]1([CH3:15])[CH2:10][CH2:9][C:2]([CH3:1])=[CH:3][CH2:4][CH2:5][C:6](=[O:8])[CH3:7]
Reactant: CC(=O)CCC=C(C)CCC(C)=C(C)C
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CC(=O)CCC=C(C)CCC1(C)OC1(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 100 g. of 6,9,10-trimethyl-undeca-5,9-dien-2-one in 2,000 ml. of methylene chloride, there was added, while cooling with ice, 100 g. of m-chloro perbenzoic acid. The resulting mixture was allowed to stand while constantly stirring at room temperature for 1 hour. The resulting mixture was diluted with 1,000 ml. of methylene chloride. The resulting solution was washed with ice-cold 1-N sodium hydroxide solution and with a saturated sodium chloride solution, dried over sodium sulfate and evaporated. The residue was fractionally distilled under high vacuum. There was obtained 9,10-epoxy-6,9,10-trimethyl-undec-5-en-2-one. B.p. 89°-91°C./0.07 mm Hg; nD20 = 1.4656.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[C:8]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)(=[O:12])[CH:9]([CH3:11])O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>C(Cl)Cl.CCCCCC>[N:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[O:1][CH:9]([CH3:11])[C:8]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12]
Reactant: CC(O)C(=O)OCc1ccccc1
Reactant: Oc1ccccn1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCCCCC
Solvent: ClCCl
Product: CC(Oc1ccccn1)C(=O)OCc1ccccc1
Temperature: 25 °C

Procedure:
To a mixture of 2-hydroxypyridine (2.9 g, 30 mmol), benzyl lactate (5.0 g, 21 mmol) and triphenylphosphine (12 g, 47 mmol) in 100 mL of methylene chloride was added diethylazodicarboxylate (7.8 mL, 45 mmol) at 0° C. The reaction was allowed to warm to room temperature for 4 h. The resulting mixture was diluted with hexane (100 mL) and concentrated with 20 g of silica gel. The material was loaded onto a silica gel column, which was eluted with 10% ethyl acetate in hexane to give the title compound. 1H NMR (500 MHz, CD3OD): δ 8.00 (dd, 1H), 7.68 (ddd, 1H), 7.36-7.28 (m, 5 H), 6.94 (dd, 1H), 6.84 (dd, 1H), 5.30 (q, 1H), 5.18 (s, 2H), 1.59 (d, 3H). LC-MS: m/e 258 (M+H)+ (3.3 min).
Reaction SMILES: Br[C:2](Br)=[CH:3][C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[C:6]([O:12][CH2:13][CH3:14])[CH:5]=1.[Li]CCCC>>[CH2:13]([O:12][C:6]1[CH:5]=[C:4]([C:3]#[CH:2])[CH:9]=[CH:8][C:7]=1[O:10][CH3:11])[CH3:14]
Reactant: CCOc1cc(C=C(Br)Br)ccc1OC
Agent: [Li]CCCC
Product: C#Cc1ccc(OC)c(OCC)c1
Yield: 99.2 %

Procedure:
According to the General Procedure E, 2,2-dibromo-1-(3-ethoxy-4-methoxyphenyl)ethene (5.00 g, 14.88 mmol) and n-BuLi (20.46 ml, 32.74 mmol) are converted to give after workup and chromatography (SiO2, PE/EE=5:1, Rf=0.31) the title compound (2.60 g, 14.76 mmol, 99%) as a colorless solid. M.p. 95-96° C.;
Reaction SMILES: [N:1]1([C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:11])[CH2:9][CH2:8][CH2:7][CH2:6][C@@H:2]1[C:3](O)=[O:4].C([N:22](CC)CC)C.ClC(OCC(C)C)=O.N>C(OCC)(=O)C>[N:1]1([C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:11])[CH2:9][CH2:8][CH2:7][CH2:6][C@@H:2]1[C:3]([NH2:22])=[O:4]
Reactant: O=C(O)[C@H]1CCCCN1C(=O)OCc1ccccc1
Reactant: CCN(CC)CC
Agent: CC(C)COC(=O)Cl
Agent: N
Solvent: CCOC(C)=O
Product: NC(=O)[C@H]1CCCCN1C(=O)OCc1ccccc1
Temperature: -20 °C
Reaction time: 0.25 h
Yield: 87.7 %

Procedure:
13.15 g (50 mmoles) of Z-D-Pip-OH (L. Balaspiri et al.: Monatsh. Chem. 101, 177/1970/) are dissolved in 100 ml of ethyl acetate, 7.0 ml (50 mmoles) of triethylamine are added, and the solution is cooled to -20° C. 6.5 ml (50 mmoles) of isobutyl chloroformate are added dropwise to the stirred solution at the same temperature, thereafter the mixture is stirred for 15 minutes, and then gaseous ammonia is introduced into the mixture at -10° C. for 1.5 hours. The separated precipitate is filtered off, the filtrate is washed with n hydrochloric acid, n sodium hydrocarbonate solution and water, dried over anhydrous sodium sulfate and evaporated. The residue is crystallized from a mixture of ethyl acetate and ether to obtain 11.5 g (88%) of Z-D-Pip-NH2 ; m.p.: 114°-115° C., Rf2 =0.50, [α]D25 =+32.0° (c=1%, in methanol).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[CH:6]=[CH:7][CH:8]=1.Br[CH2:16][C:17]#[N:18]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:9]2[CH2:14][CH2:13][N:12]([CH2:16][C:17]#[N:18])[CH2:11][CH2:10]2)[CH:6]=[CH:7][CH:8]=1
Reactant: N#CCBr
Reactant: COc1cccc(N2CCNCC2)c1
Product: COc1cccc(N2CCN(CC#N)CC2)c1

Procedure:
The title compound is synthesized by coupling of 1-(3-Methoxy-phenyl)-piperazine and bromoacetonitrile analogously to the preparation of Intermediate 149.2 as a white solid; ES-MS: M+=232.2: AtRet=2.62.
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[C:3]([CH2:18][C:19]1([CH3:29])[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:22][CH2:21][CH2:20]1)([OH:17])[CH:4]=[N:5][C:6]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:7]=1[CH:8]=[CH:9][C:10]([CH3:16])=[N:11]2.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])[O-].[Na+].[Na+].C(OCC)(=O)C>C(O)(=O)C>[F:31][C:2]([F:1])([F:30])[C:3]([CH2:18][C:19]1([CH3:29])[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:22][CH2:21][CH2:20]1)([OH:17])[CH2:4][NH:5][C:6]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:7]=1[CH:8]=[CH:9][C:10]([CH3:16])=[N:11]2
Reactant: Cc1ccc2c(N=CC(O)(CC3(C)CCCc4ccccc43)C(F)(F)F)cccc2n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: Cc1ccc2c(NCC(O)(CC3(C)CCCc4ccccc43)C(F)(F)F)cccc2n1
Reaction time: 4 h
Yield: 71.3 %

Procedure:
To a solution of 1,1,1-trifluoro-3-[(2-methyl-5-quinolinyl)imino]-2-[(1-methyl-1,2,3,4-tetrahydro-1-naphthalenyl)methyl]-2-propanol (intermediate 8) (130 mg, 0.30 mmol) in glacial acetic acid (4 ml) stirred under nitrogen at 21° C., was added sodium triacetoxyborohydride (254 mg, 1.2 mmol) portionwise over 25 min and the solution was stirred for a further 4 h. The solution was then carefully added to a mixture of saturated aqueous sodium carbonate (50 ml) and ethyl acetate (30 ml) and stirred for 10 min, when effervescence had finished. The layers were separated and the aqueous layer re-extracted with ethyl acetate (30 ml) and the combined organic layers were washed with saturated sodium carbonate (15 ml), water (2×30 ml) and saturated brine (30 ml), dried over anhydrous sodium sulphate and evaporated. The crude product was purified on a 50 g silica cartridge using a Flashmaster 2 system with a 0-100% gradient of ethyl acetate in cyclohexane over 80 min to give the title compound (91.6 mg, 71%) as a mixture of diastereomers.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[C:8]([CH:11]3[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1.Cl.[N:19]1[CH:24]=[CH:23][C:22]([C:25](Cl)=[O:26])=[CH:21][CH:20]=1>>[N:19]1[CH:24]=[CH:23][C:22]([C:25]([NH:1][C:2]2[N:7]=[C:6]3[C:8]([CH:11]4[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]4)=[CH:9][NH:10][C:5]3=[CH:4][CH:3]=2)=[O:26])=[CH:21][CH:20]=1
Reactant: CN1CCC(c2c[nH]c3ccc(N)nc23)CC1
Reactant: O=C(Cl)c1ccncc1
Agent: Cl
Product: CN1CCC(c2c[nH]c3ccc(NC(=O)c4ccncc4)nc23)CC1
Yield: 56 %

Procedure:
Beginning with 0.065 gm (0.282 mMol) 5-amino-3-(1-methylpiperidin-4-yl)pyrrolo[3,2-b]pyridine and 0.106 gm (0.593 mMol) 4-pyridinecarbonyl chloride hydrochloride, 0.053 gm (56%) of the title compound was recovered as an amorphous solid by the procedure described in Example 16.
Reaction SMILES: CS(O[CH2:6][CH2:7][C:8]1[C:17]([CH3:18])=[CH:16][C:11]2[C:12](=[O:15])[O:13][CH2:14][C:10]=2[CH:9]=1)(=O)=O.C1CCN2C(=NCCC2)CC1>C(Cl)Cl>[CH:7]([C:8]1[C:17]([CH3:18])=[CH:16][C:11]2[C:12](=[O:15])[O:13][CH2:14][C:10]=2[CH:9]=1)=[CH2:6]
Reactant: Cc1cc2c(cc1CCOS(C)(=O)=O)COC2=O
Solvent: ClCCl
Solvent: C1CCC2=NCCCN2CC1
Product: C=Cc1cc2c(cc1C)C(=O)OC2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 2-(6-methyl-1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl methanesulfonate (2.0 g, 7.4 mmol) and TEA (5 mL) in DCM (50 mL) was added DBU (5 mL) slowly at 0° C. The mixture was stirred at r.t. overnight, and then diluted with 50 mL of DCM, washed with 2 N HCl in three times and brine. The organic layer was dried and concentrated to dryness. The residue was purified by prep-TLC to give 5-ethenyl-6-methyl-2-benzofuran-1(3H)-one.
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]([CH3:11])[C:5]([NH:7][N+:8]([O-:10])=[O:9])=[NH:6].[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19]Cl)=[CH:15][N:14]=1>CN(C=O)C>[Cl:12][C:13]1[N:14]=[CH:15][C:16]([CH2:19][NH:6][C:5]([N:4]([CH3:11])[CH3:3])=[N:7][N+:8]([O-:10])=[O:9])=[CH:17][CH:18]=1
Reactant: ClCc1ccc(Cl)nc1
Reactant: CN(C)C(=N)N[N+](=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C)C(=N[N+](=O)[O-])NCc1ccc(Cl)nc1
Reaction time: 0.17 h
Yield: 31.9 %

Procedure:
To a suspension of 0.44 g of 60% sodium hydride (in mineral oil) in 10 ml of DMF was added 1.32 g of N,N- dimethyl-N'-nitroguanidine during 20 minutes at room temperature. After stirring for 10 minutes, 1.62 g of 2-chloro-5-(chloromethyl)pyridine was added to the mixture in 5 minutes, and stirred for 2 hours at room temperature and for 4 hours in an oil bath of 60° C. After filtering insoluble materials off, the filtrate was concentrated. The resulting residue was purified by a column chromatography [developing solvent: dichloromethane-ethyl acetate (5:1-3:1)] to obtain 0.82 g of 1-(6-chloro-3-pyridylmethyl)-3,3-dimethyl-2-nitroguanidine (Compound No. 6).
Reaction SMILES: [Na].Cl[C:3]1[C:7]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)=[N:6][S:5][N:4]=1.[CH3:14][OH:15]>>[CH3:14][O:15][C:3]1[C:7]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)=[N:6][S:5][N:4]=1
Reactant: Clc1nsnc1-c1cccnc1
Reactant: CO
Agent: [Na]
Product: COc1nsnc1-c1cccnc1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
To a solution of sodium (460 mg, 20 mmol) in methanol (10 ml) was added 3-(3-chloro-1,2,5-thiadiazol-4-yl)pyridine (750 mg, 3.8 mmol). The mixture was stirred at 50° C. for 1 h and evaporated. The residue was dissolved in water and extracted with methylene chloride. The combined organic phases were dried and evaporated to give the title compound, which crystallized with petroleum ether in a 630 mg (86%) yield.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1C=O.[CH:10](OC)([O:13][CH3:14])[O:11][CH3:12]>CO.Cl>[CH3:12][O:11][CH:10]([O:13][CH3:14])[C:3]1[CH:6]=[CH:7][CH:8]=[CH:9][C:2]=1[Br:1]
Reactant: COC(OC)OC
Reactant: O=Cc1ccccc1Br
Agent: Cl
Solvent: CO
Product: COC(OC)c1ccccc1Br
Yield: 84.1 %

Procedure:
A solution of 2-bromobenzaldehyde (451.9 g, 2.44 mol), trimethyl orthoformate (324 g, 3.05 mol) and concentrated hydrochloric acid (4.0 ml, 0.05 mol) in methanol (2 L) was refluxed for four hours. The volatile components were evaporated on the rotary evaporator and the residue dried over anhydrous potassium carbonate, filtered, and distilled (66°-72° C. at 0.1-0.2 mm) to give 474.1 g (84%) of the 2-Bromobenzaldehyde Dimethyl Acetal compound as a colorless oil. 'H NMR (CDCl3): 3.35 (s, 6, OCH3), 5.50 (s, 1, CH), 7.5 (m, 4, Ar--H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:14])[NH:7][CH:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[Cl:15][C:16]1[CH:23]=[CH:22][C:19]([CH:20]=O)=[CH:18][C:17]=1[O:24][CH2:25][CH3:26].C(O)(=O)C.C([BH3-])#N.[Na+]>C(O)C>[C:1]([O:5][C:6](=[O:14])[NH:7][CH:8]1[CH2:13][CH2:12][N:11]([CH2:20][C:19]2[CH:22]=[CH:23][C:16]([Cl:15])=[C:17]([O:24][CH2:25][CH3:26])[CH:18]=2)[CH2:10][CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Reactant: CCOc1cc(C=O)ccc1Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)O
Product: CCOc1cc(CN2CCC(NC(=O)OC(C)(C)C)CC2)ccc1Cl
Temperature: 100 °C

Procedure:
A mixture of piperidin-4-yl-carbamic acid tert-butyl ester (5.0 g, 25.0 mmol, 1.0 equiv; commercially available), 4-chloro-3-ethoxy-benzaldehyde (5.54 g, 30.0 mmol, 1.2 equiv; intermediate E2, vide infra) and acetic acid (5.7 mL, 6.01 g, 100.0 mmol, 4.0 equiv) in ethanol (25 mL) was heated by microwave irradiation to 100° C. for 5 min. Sodium cyanoborohydride (3.14 g, 50.0 mmol, 2.0 equiv), dissolved in ethanol (10 mL), was added and the reaction mixture heated by microwave irradiation to 100° C. for an additional time period of 10 min. The solvent was removed under reduced pressure and the crude reaction product extracted from a solution of 1 M NaOH (100 mL) with ethyl acetate (3×100 mL). The combined organic phases were dried over MgSO4, concentrated by evaporation under reduced pressure and the crude material purified by silica column chromatography using a MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of heptane/ethyl acetate providing 3.91 g (42%) of the title compound. MS (ISP): 369.0 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([OH:13])=O)=[CH:5]2.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.[CH3:36][O:37][C:38](=[O:52])[CH2:39][NH:40][C:41](=[O:51])[CH:42]([NH2:50])[CH2:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1>C(#N)C>[CH3:36][O:37][C:38](=[O:52])[CH2:39][NH:40][C:41](=[O:51])[CH:42]([NH:50][C:11]([C:6]1[NH:7][C:8]2[C:4]([CH:5]=1)=[CH:3][C:2]([Cl:1])=[CH:10][CH:9]=2)=[O:13])[CH2:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1
Reactant: O=C(O)c1cc2cc(Cl)ccc2[nH]1
Reactant: COC(=O)CNC(=O)C(N)Cc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CC#N
Product: COC(=O)CNC(=O)C(Cc1ccccc1)NC(=O)c1cc2cc(Cl)ccc2[nH]1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
To 5.0 mmol of 5-chloro-1H-indole-2-carboxylic acid (50 mL of a 0.1 M solution in acetonitrile) was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (50 mL of a 0.10 M solution in acetonitrile, 5.0 mmol), 1-hydroxybenzotriazole (50 mL of a 0.10 M solution in acetonitrile, 5.0 mmol), followed by (2-amino-3-phenyl-propionylamino)-acetic acid methyl ester (50 mL of a 0.10 M solution in acetonitrile, 5.0 mmol). The reaction was agitated overnight at 80° C. and then concentrated to dryness to give the title compound.
Reaction SMILES: [CH:1](=O)[CH:2]([CH3:4])[CH3:3].[NH2:6][CH2:7][C:8]1[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=1.O>C1C=CC=CC=1>[CH:1](=[C:12]1[CH:13]=[C:8]([CH2:7][NH2:6])[CH:9]=[CH:10][NH:11]1)[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)C=O
Reactant: NCc1ccncc1
Solvent: O
Solvent: c1ccccc1
Product: CC(C)C=C1C=C(CN)C=CN1
Yield: 91.7 %

Procedure:
227 g (3.15 mols) of isobutyraldehyde is added dropwise, within 1.5 hours, to a solution of 324 g (3.0 mols) of 4-aminomethylpyridine in 300 ml of benzene, the addition being made in a manner ensuring that the temperature in the solution does not exceed 35° C. The water which has formed (about 39 g) is separated, and the benzene (with residual water) is distilled off under a slight water-jet vacuum. The residue is distilled in an oil-pump vacuum. After a small preliminary fraction of 5 g, there is obtained 445 g (2.75 mols) of isobutylidene-4-aminomethylpyridine as a slightly yellowish main fraction, corresponding to a yield of 91.5% of theory; b.p. 81.5°-82° C./133 Pa; nD° =1.5105.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].O[CH2:7][CH2:8][N:9]1[CH2:14][CH2:13][C:12]([C:26]([O:28][CH3:29])=[O:27])([N:15]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:16](=[O:19])[CH2:17][CH3:18])[CH2:11][CH2:10]1.C(N(CC)CC)C>C(OCC)(=O)C>[CH3:1][S:2]([CH2:7][CH2:8][N:9]1[CH2:10][CH2:11][C:12]([C:26]([O:28][CH3:29])=[O:27])([N:15]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:16](=[O:19])[CH2:17][CH3:18])[CH2:13][CH2:14]1)(=[O:4])=[O:3]
Reactant: CCC(=O)N(c1ccccc1)C1(C(=O)OC)CCN(CCO)CC1
Reactant: CS(=O)(=O)Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CCC(=O)N(c1ccccc1)C1(C(=O)OC)CCN(CCS(C)(=O)=O)CC1
Reaction time: 8 h
Yield: 44.6 %

Procedure:
A solution of methanesulfonyl chloride 0.374 g, 3.3 mmol in ethyl acetate (3 ml was added to a mixture of 1-(2-hydroxyethyl)-4-methoxycarbonyl-4-(N'-phenylpropionamido)piperidine (1.0 g, 3 mmol) and triethylamine. The resulting mixture was stirred overnight. The reaction mixture was filtered and the filtrate was concentrated under vacuum to give an oily residue. The residue was chromatographed on silica gel (290 g; ethyl acetate/hexane: 1:4) to yield 1-(2-methanesulfonylethyl)-4-methoxycarbonyl-4-(N'-phenyl-propionamido)piperidine (0.53 g, 43%) as an oil.
Reaction SMILES: [CH:1]1([NH:4][C:5]([C:7]2[N:12]=[C:11]([C:13]3[CH2:14][CH2:15][N:16]([S:19]([C:22]4[CH:27]=[CH:26][C:25]([O:28][C:29]([F:32])([F:31])[F:30])=[CH:24][CH:23]=4)(=[O:21])=[O:20])[CH2:17][CH:18]=3)[CH:10]=[CH:9][CH:8]=2)=[O:6])[CH2:3][CH2:2]1.FC(F)(F)C1C=C(S([Cl:44])(=O)=O)C=CC=1>>[CH:1]1([NH:4][C:5]([C:7]2[N:12]=[C:11]([C:13]3[CH2:18][CH2:17][N:16]([S:19]([C:22]4[CH:23]=[CH:24][C:25]([O:28][C:29]([F:31])([F:30])[F:32])=[CH:26][CH:27]=4)(=[O:21])=[O:20])[CH2:15][CH:14]=3)[CH:10]=[CH:9][C:8]=2[Cl:44])=[O:6])[CH2:3][CH2:2]1
Reactant: O=C(NC1CC1)c1cccc(C2=CCN(S(=O)(=O)c3ccc(OC(F)(F)F)cc3)CC2)n1
Reactant: O=S(=O)(Cl)c1cccc(C(F)(F)F)c1
Product: O=C(NC1CC1)c1nc(C2=CCN(S(=O)(=O)c3ccc(OC(F)(F)F)cc3)CC2)ccc1Cl

Procedure:
Similarly, 5-chloro-1′-(4-trifluoromethoxybenzenesulfonyl)-1′,2′,3′,6′-tetra-hydro-[2,4′]bipyridinyl-6-carboxylic acid cyclopropylamide was synthesized using 4-trifluoromethoxybenzenesulfonyl chloride at the last step instead of 3-trifluoromethylbenzenesulfonyl chloride. 1H NMR (400 MHz, CD3OD): δ 7.99 (m, 2H), 7.85 (d, 1H, J=8.4 Hz), 7.59 (d, 1H, J=8.4 Hz), 7.54 (m, 2H), 6.72 (m, 1H), 3.87 (m, 2H), 3.39 (t, 2H, J=5.6 Hz), 2.87 (m, 1H), 2.73 (m, 2H), 0.83 (m, 2H), 0.66 (m, 2H); MS: 502 (M+H+).