Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][NH:9][CH:10]=[CH2:11])=[CH:4][CH:3]=1.[CH3:12][S:13][C:14](SC)=[CH:15][N+:16]([O-:18])=[O:17]>C(O)C>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][N:9]([CH2:10][CH3:11])[C:14]([S:13][CH3:12])=[CH:15][N+:16]([O-:18])=[O:17])=[CH:4][CH:3]=1
Reactant: C=CNCc1ccc(Cl)nc1
Reactant: CSC(=C[N+](=O)[O-])SC
Solvent: CCO
Product: CCN(Cc1ccc(Cl)nc1)C(=C[N+](=O)[O-])SC

Procedure:
A mixture of N-((6-chloropyridin-3-yl)methyl)ethenamine and 1,1-dimethylthio-2-nitroethene is dissolved in ethanol and refluxed for 4-8 hours. After completion, the mixture is concentrated and purified by column chromatography to obtain N-((6-chloropyridin-3-yl)methyl)-N-ethyl-1-(methylthio)-2-nitroethenamine.
Reaction SMILES: [C:1]([C@@H:3]([NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH3:17])[CH:12]=2)=[CH:7][CH:6]=1)#[N:2].[N-:26]=[N+:27]=[N-:28].[Na+].O>C(O)(C)C.CCOC(C)=O.[Br-].[Zn+2].[Br-]>[C:21]([O:20][C:19](=[O:25])[NH:18][C@H:3]([C:1]1[NH:28][N:27]=[N:26][N:2]=1)[CH2:4][C:5]1[CH:6]=[CH:7][C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH3:17])[CH:12]=2)=[CH:9][CH:10]=1)([CH3:22])([CH3:24])[CH3:23]
Reactant: Cc1cccc(-c2ccc(C[C@@H](C#N)NC(=O)OC(C)(C)C)cc2)c1
Reactant: [N-]=[N+]=[N-]
Agent: [Br-]
Agent: [Na+]
Agent: [Zn+2]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CC(C)O
Product: Cc1cccc(-c2ccc(C[C@H](NC(=O)OC(C)(C)C)c3nnn[nH]3)cc2)c1
Temperature: 25 °C

Procedure:
(S)-tert-butyl 1-cyano-2-(3′-methylbiphenyl-4-yl)ethylcarbamate (0.81 g, 2.408 mmol), sodium azide (0.344 g, 5.30 mmol) and zinc bromide (0.325 g, 1.445 mmol) were refluxed in i-propanol (15 mL) and H2O (30 mL) for 6 hours. The reaction mixture was cooled to room temperature, diluted with EtOAc, and washed with 1M HCl and brine. The organic layer was dried over Na2SO4 and concentrated under reduced pressure. The obtained residue was purified by silica gel flash column chromatography (EtOAc/heptane->10% MeOH in DCM/DCM) to give [(S)-2-(3′-methyl-biphenyl-4-yl)-1-(1H-tetrazol-5-yl)-ethyl]-carbamic acid tert-butyl ester. 1H NMR (400 MHz, DMSO-d6) δ 1.30 (s, 9H), 2.36 (s, 3H), 3.10-3.21 (m, 1H), 3.24-3.31 (m, 1H), 4.96-5.15 (m, 1H), 7.15 (d, J=7.33 Hz, 1H), 7.27-7.35 (m, 3H), 7.39-7.46 (m, 2H), 7.55 (d, J=8.08 Hz, 2H), 7.65 (d, J=8.34 Hz, 1H); MS: m/z (MH+) 380; Retention time=1.51 min. (condition A)
Reaction SMILES: [N:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[NH:3][C:2]=1[CH2:10][NH:11]C(=O)OCC1C=CC=CC=1.[ClH:22].O1CCOCC1>CC(O)=O.CO.O1CCOCC1.[Pd]>[Cl-:22].[Cl-:22].[NH3+:11][CH2:10][C:2]1[NH:3][C:4]2=[NH+:5][CH:6]=[CH:7][CH:8]=[C:9]2[N:1]=1
Reactant: Cl
Reactant: O=C(NCc1nc2cccnc2[nH]1)OCc1ccccc1
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CO
Solvent: C1COCCO1
Product: [Cl-]
Product: [NH3+]Cc1nc2ccc[nH+]c2[nH]1
Reaction time: 20 h

Procedure:
To a mixture of 2-4 (52 g, 151.88 mmol) in 1000 mL of 1:1 AcOH/MeOH was added 20 g 10% Pd/C. The reaction mixture was stirred under 1 atm H2 for 20 hours. The mixture was filtered through a celite pad, concentrated, and then azeotroped with dioxane to give tan oil. The semisolid or thick oil was suspended in 200 mL dioxane and 200 mL 4.0 M HCl/dioxane was added to produce a tan suspension. The solid was collected, washed with dioxane (200 mL) and dried in vacuo to give 2-5 as a tan solid. 1H NMR (500 MHz, CD3OD) 8.75 (d, 1H, J=8 Hz), 8367 (d, 1H, J=6 Hz), 7.85 (m, 1H), 4.88 (s, 2H). HRMS (ES, M+1) calc'd 149.0822. found 149.0812.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]([CH:8]2[CH2:11][O:10][CH2:9]2)[C:4](=[O:12])[CH:3]=1.[OH:13][C:14]([CH3:47])([CH3:46])[CH2:15][C@@:16]1([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[O:21][C:20](=[O:22])[N:19]([C@H:23]([C:25]2[CH:30]=[CH:29][C:28](B3OC(C)(C)C(C)(C)O3)=[CH:27][CH:26]=2)[CH3:24])[CH2:18][CH2:17]1.C([O-])(O)=O.[Na+]>COCCOC.C(O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[OH:13][C:14]([CH3:46])([CH3:47])[CH2:15][C@@:16]1([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[O:21][C:20](=[O:22])[N:19]([C@H:23]([C:25]2[CH:26]=[CH:27][C:28]([C:2]3[CH:7]=[CH:6][N:5]([CH:8]4[CH2:11][O:10][CH2:9]4)[C:4](=[O:12])[CH:3]=3)=[CH:29][CH:30]=2)[CH3:24])[CH2:18][CH2:17]1
Reactant: O=c1cc(Br)ccn1C1COC1
Reactant: C[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: COCCOC
Product: C[C@@H](c1ccc(-c2ccn(C3COC3)c(=O)c2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Pd(PPh3)4 (10 mg) was added to a solution of 4-bromo-1-(oxetan-3-yl)pyridin-2(1H)-one (14 mg) in 1,2-dimethoxyethane (6 mL) under nitrogen. The formed mixture was stirred at room temperature for 1 h prior to the addition of (S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-{(S)-1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]ethyl}-1,3-oxazinan-2-one (24 mg) in ethanol (2 mL) followed by saturated aqueous NaHCO3 solution (2 mL). The mixture was stirred at 100° C. for 2 h. After cooling to room temperature, the reaction was quenched with water and the resulting mixture was extracted with ethyl acetate (3×). The combined organic phase was concentrated and the residue was purified by preparative HPLC to give the title compound. Yield: 14 mg (55% of theory); LC (method 4): tR=0.97 min; Mass spectrum (ESI+): m/z=445 [M-Me2CO+H]+; 1H NMR (CDCl3) δ 1.09 (s, 3H), 1.12 (s, 3H), 1.45 (d, 3H), 2.10-2.30 (m, 4H), 2.35 (m, 1H), 2.72 (m, 1H), 4.70 (m, 2H), 5.09 (m, 2H), 5.63 (m, 1H), 5.71 (m, 1H), 6.43 (m, 1H), 6.61 (m, 1H), 6.98 (d, 2H), 7.28 (m, 7H), 7.61 (d, 1H).
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26](O)=[O:27])=[CH:24][C:23]=4[CH2:31][CH3:32])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.ON1C2C=CC=CC=2N=N1.F[P-](F)(F)(F)(F)F.CN(C(N(C)C)=[N+]1C2C=CC=CC=2[N+]([O-])=N1)C.C(N(C(C)C)CC)(C)C.[NH2:76][CH:77]1[CH2:82][CH2:81][N:80]([C:83]([O:85][C:86]([CH3:89])([CH3:88])[CH3:87])=[O:84])[CH2:79][CH2:78]1>CN(C)C=O>[C:86]([O:85][C:83]([N:80]1[CH2:79][CH2:78][CH:77]([NH:76][C:26](=[O:27])[C:25]2[CH:29]=[CH:30][C:22]([NH:21][C:19]3[N:18]=[CH:17][C:8]4[N:9]([CH3:16])[C:10](=[O:15])[C:11]([F:13])([F:14])[CH2:12][N:6]([CH:1]5[CH2:5][CH2:4][CH2:3][CH2:2]5)[C:7]=4[N:20]=3)=[C:23]([CH2:31][CH3:32])[CH:24]=2)[CH2:82][CH2:81]1)=[O:84])([CH3:89])([CH3:88])[CH3:87]
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: CCc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Agent: CN(C)C(N(C)C)=[N+]1N=[N+]([O-])c2ccccc21
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCc1cc(C(=O)NC2CCN(C(=O)OC(C)(C)C)CC2)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Reaction time: 0.17 h
Yield: 93.4 %

Procedure:
To a mixture of 0.040 g (0.0899 mmole) of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-ethyl-benzoic acid (I-194) and 6 mL of dimethylformamide was added 0.0182 g (0.135 mmole) of 1-hydroxybenzotriazole, 0.0520 g (0.135 mmole) of 1-[bis(dimethylamino)methylene]-1H-benzotriazolium-3-oxide hexafluorophosphate and 0.047 g (0.359 mmole) of diisopropylethylamine. The mixture was stirred for 10 minutes, then 0.0270 g (0.135 mmole) of 4-amino-1-Boc-piperidine was added. The reaction mixture was stirred for 2 hours and then concentrated under reduced pressure. The residue was dissolved in 80 mL of ethyl acetate and washed three times with 10 mL of 1M sodium hydroxide, twice with 15 mL of brine, dried, filtered and concentrated under reduced pressure. Purification by silica gel chromatography, eluting with dichloromethane-methanol (gradient, 95:5-90:10) gave 0.0527 g of 4-[4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-ethyl-benzoylamino]-piperidine-1-carboxylic acid tert-butyl ester (I-201) as a white solid.
Reaction SMILES: [CH:1]1([NH:6][CH2:7][C:8]([OH:16])([CH2:14][CH3:15])[C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:17](Br)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C([O-])([O-])=O.[K+].[K+].CCOC(C)=O>C(#N)C>[CH2:17]([N:6]([CH2:7][C:8]([OH:16])([CH2:14][CH3:15])[C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:1]1[CH2:2][CH2:3][CH2:4][CH2:5]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CCOC(=O)C(O)(CC)CNC1CCCC1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CCOC(=O)C(O)(CC)CN(Cc1ccccc1)C1CCCC1
Temperature: 80 °C
Yield: 75.7 %

Procedure:
To ethyl 2-((cyclopentylamino)methyl)-2-hydroxybutanoate (2.7 g, 12 mmol) in 50 ml of acetonitrile at room temperature, was added benzyl bromide (2.1 ml, 18 mmol) dropwise, followed by K2CO3 (5 g, 35 mmol). The reaction mixture was heated at 80° C. for 18 h. It was then diluted to EtOAc, washed by brine and water. Organic extract dried and concentrated to a residue, which was purified on silica gel column chromatographically (Hex/EtOAc=100:1 to 4:1) to give 2.9 g product (77%). [M+H] calc'd for C19H29NO3, 320; found 320.
Reaction SMILES: ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[F:23][C:24]([F:28])([F:27])[CH2:25][NH2:26].[Cl:29][C:30]1[CH:35]=[CH:34][N:33]=[C:32]([C:36](O)=[O:37])[CH:31]=1>O.ClCCl>[F:23][C:24]([F:28])([F:27])[CH2:25][NH:26][C:36]([C:32]1[CH:31]=[C:30]([Cl:29])[CH:35]=[CH:34][N:33]=1)=[O:37]
Reactant: O=C(O)c1cc(Cl)ccn1
Reactant: NCC(F)(F)F
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClCCl
Product: O=C(NCC(F)(F)F)c1cc(Cl)ccn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 57.5 %

Procedure:
1-hydroxybenzotriazole (0.53 g, 3.5 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (WSC) (0.67 g, 3.5 mmol) and 2,2,2-trifluoroethyl amine (0.51 ml. 6.35 mmol) were added to a dichloromethane solution (5 ml) of 4-chloropyridine-2-carboxylic acid (0.5 g, 3.17 mmol) and the mixture was stirred at room temperature for one hour. Water was added to the reaction solution, which was then extracted with ethyl acetate. The extraction solution with ethyl acetate was dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=11:1→5:1). The purified product was concentrated to dryness under reduced pressure to obtain N-(2,2,2-trifluoroethyl)-4-chloropyridine-2-carboxamide (435 mg) as white powder.
Reaction SMILES: C([N:8]1[CH2:15][CH2:14][C:13]2([F:16])[CH:9]1[CH2:10][N:11]([CH3:17])[CH2:12]2)C1C=CC=CC=1>C(O)C.[Pd]>[F:16][C:13]12[CH2:12][N:11]([CH3:17])[CH2:10][CH:9]1[NH:8][CH2:15][CH2:14]2
Reactant: CN1CC2N(Cc3ccccc3)CCC2(F)C1
Agent: [Pd]
Solvent: CCO
Product: CN1CC2NCCC2(F)C1

Procedure:
11 g (43.7 mmol, 93%) of 2-benzyl-5-fluoro-7-methyl-2,7-diazabicyclo[3.3.0]octane in 100 ml of ethanol are hydrogenated on 2 g of palladium/active carbon (10% Pd) at 100° C. and 100 bar. The catalyst is filtered off with suction, the filtrate is concentrated, and the residue is distilled.
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[C:13]2[C:8](=[N:9][CH:10]=[CH:11][CH:12]=2)[NH:7][CH:6]=1)[CH3:3].[CH2:14]([O:16][C:17]1[CH:22]=[CH:21][C:20]([N:23]2[CH2:28]CNC[CH2:24]2)=[CH:19][CH:18]=1)[CH3:15]>C1(C)C=CC=CC=1>[CH2:14]([O:16][C:17]1[CH:22]=[CH:21][C:20]([N:23]2[CH2:24][CH2:1][N:2]([CH2:4][C:5]3[C:13]4[C:8](=[N:9][CH:10]=[CH:11][CH:12]=4)[NH:7][CH:6]=3)[CH2:3][CH2:28]2)=[CH:19][CH:18]=1)[CH3:15]
Reactant: CCOc1ccc(N2CCNCC2)cc1
Reactant: CN(C)Cc1c[nH]c2ncccc12
Solvent: Cc1ccccc1
Product: CCOc1ccc(N2CCN(Cc3c[nH]c4ncccc34)CC2)cc1
Yield: 67 %

Procedure:
A mixture of 3-dimethylaminomethyl-1H-pyrrolo[2,3-b]pyridine [prepared by the method of M. M. Robinson and B. L. Robinson, J. Am. Chem. Soc., 1955, 77, 457] (0.40 g, 2.28 mmol) and 1-(4-ethoxyphenyl)piperazine (0.495 g, 2.40 mmol) in toluene (10 ml) was heated at reflux under nitrogen for 7 h. The mixture was allowed to cool and the crystallised product collected. Recrystallisation from methanol afforded the title compound (0.513 g, 67%), m.p. 179°-180° C.; (Found: C, 71.27; H, 7.19; N, 16.59. C20H24N4O requires C, 71.40; H, 7.19; N, 16.65%); δH (DMSO-d6) 1.27 (3H, t, J 7.0 Hz, ArOCH2CH3), 2.52 (4H, m, 2×piperazinyl CH2), 2.98 (4H, m, 2×piperazinyl CH2), 3.67 (2H, s, CH2N), 3.92 (2H, q, J 7.0 Hz, ArOCH2CH3), 6.80 (4H, m, ArH), 7.04 (1H, dd, J 7.8, 4.6 Hz, 5-H), 7.37 (1H, d, J 2.1 Hz, 2-H), 8.04 (1H, dd, J 7.8, 1.3 Hz, 4-H), 8.19 (1H, dd, J 4.6, 1.3 Hz, 6-H), and 11.46 (1H, br s, NH); m/z (CI+, NH3) 337 (M+1)+.
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][NH:5][C@H:4]([C:7]([OH:9])=[O:8])[CH2:3]1.[CH2:10]=O.[H][H]>[Pd].O.CO>[CH3:10][N:5]1[CH2:6][C@H:2]([OH:1])[CH2:3][C@H:4]1[C:7]([OH:9])=[O:8]
Reactant: [H][H]
Reactant: C=O
Reactant: O=C(O)[C@@H]1C[C@@H](O)CN1
Agent: [Pd]
Solvent: CO
Solvent: O
Product: CN1C[C@H](O)C[C@H]1C(=O)O
Reaction time: 8 h

Procedure:
A suspension of 10% palladium on carbon in water (25 ml) was added to a suspension of trans-4-hydroxy-L-proline (6.576 g., 50.10 mmol) in methanol (100 ml) and 37% aqueous formaldehyde (16 ml, 213.5 mmol) in a Parr bottle. The bottle was pressurized to 50 psi with hydrogen and shaken overnight. The catalyst was removed by filtration through a pad of celite which was washed thoroughly with methanol (100 ml). Evaporation of the methanol and excess formaldehyde yielded N-methyl-trans-4-hydroxy-L-proline as a white solid which was recrystallized from methanol/diethyl ether to give 6.425 g. of white needles, m.p. 236°-238 ° (decomposition with gas evolution).
Reaction SMILES: C([Li])CCCCC.[CH3:8][O:9][C:10]([NH:12][C@@H:13]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:14]([O:16]C)=O)=[O:11].Cl[Si](C)(C)C.Br[CH2:31][Cl:32].Cl>CCCCCC.O1CCCC1.O>[CH2:18]([C@H:13]([NH:12][C:10](=[O:11])[O:9][CH3:8])[C:14](=[O:16])[CH2:31][Cl:32])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: ClCBr
Reactant: COC(=O)N[C@@H](Cc1ccccc1)C(=O)OC
Agent: C[Si](C)(C)Cl
Agent: Cl
Agent: [Li]CCCCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)N[C@@H](Cc1ccccc1)C(=O)CCl
Yield: 70 %

Procedure:
15.4 ml of a 2.6 molar solution of hexyllithium in hexane were added dropwise at -80° C. to a solution of 9.50 g of methyl (S)-2-methoxycarbonylamino-3-phenyl-propionate in 60 ml of tetrahydrofuran. Subsequently, the mixture was treated with 5.60 ml of chlorotrimethylsilane. The resulting suspension was stirred and treated with 3.22 ml of bromochloromethane. Subsequently, 18.4 ml of hexyllithlum solution were added. The solution was treated at -80° C. with 11 ml of 20% methanolic hydrochloric acid, warmed to 220 and diluted with 100 ml of water and 40 ml of tetrahydrofuran. The phases were separated and the organic phase was washed with saturated sodium chloride solution, dried and concentrated. The residue was recrystallized from ethyl acetate and hexane and the crystallizate was dried, there being obtained 7.20 g (70%) of pure methyl (S)-(1-benzyl-3-chloro-2-oxopropyl)-carbamate, m.p. 122°-123° C. IR (KBr): 3336s (NH), 1737s and 1686s (C=O), 1535s (amide II).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[N:3]=1.[C:10]([O:14][C:15]([N:17]1[CH2:22][CH2:21][CH:20]([NH2:23])[CH2:19][CH2:18]1)=[O:16])([CH3:13])([CH3:12])[CH3:11].C(N(C(C)C)C(C)C)C>C(#N)C.CC(N(C)C)=O>[C:10]([O:14][C:15]([N:17]1[CH2:22][CH2:21][CH:20]([NH:23][C:2]2[N:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[N:3]=2)[CH2:19][CH2:18]1)=[O:16])([CH3:13])([CH3:11])[CH3:12]
Reactant: Cc1cc(C)nc(Cl)n1
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Solvent: CC(=O)N(C)C
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(C)nc(NC2CCN(C(=O)OC(C)(C)C)CC2)n1
Reaction time: 0.5 h

Procedure:
A mixture of 2-chloro-4,6-dimethyl-pyrimidine (1.50 g, 10.52 mmol, 1.0 equiv; commercially available), 4-amino-piperidine-1-carboxylic acid tert-butyl ester (2.53 g, 12.62 mmol, 1.2 equiv; commercially available) and N-ethyl diisopropylamine (2.15 mL, 1.63 g, 12.62 mmol, 1.2 equiv) in acetonitrile (8 mL) and DMAc (2 mL) was heated by microwave irradiation to 160° C. for 1 h and then to 180° C. for 30 min. The reaction mixture was concentrated 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 1.47 g (46%) of the title compound. MS (ISP): 307.5 [M+H]+.
Reaction SMILES: C(Br)Br.[CH2:4](N(CC)CC)C.[C:11]1([S:17][CH2:18][NH:19][C:20](=[S:22])[S-:21])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[K+].S1CCS1>O.CN(C)C=O>[C:11]1([S:17][CH2:18][N:19]=[C:20]2[S:21][CH2:4][S:22]2)[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: CCN(CC)CC
Reactant: S=C([S-])NCSc1ccccc1
Agent: C1CSS1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: BrCBr
Solvent: O
Product: c1ccc(SCN=C2SCS2)cc1
Reaction time: 2 h

Procedure:
To a mixture of 28.2 g. of methylene bromide and 10.9 g. of triethylamine in 250 ml. of dimethylformamide was added, in portions, 27.3 g. of potassium phenylthiomethyldithiocarbamate keeping the reaction temperature below 30°C. by cooling. After another 2 hours, the mixture was poured into water and extracted with ethylene chloride. The ethylene chloride mixture was washed with water, dried, and saturated with dry hydrogen chloride. The resulting salt was collected by filtration and washed with acetone. The salt, on stirring with a mixture of 100 ml. of water and 300 ml. of chloroform, dissolved and removal and concentration of the chloroform layer gave 8.5 g. of the dithietane as a white solid, m.p. 50°-52°C.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:18]([OH:20])=O)=[N:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][CH:9]=2)=[CH:6][N:7]=1.C(OP(C#N)(OCC)=O)C.[NH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.C(N(CC)CC)C>COCCOC.O>[NH2:1][C:2]1[C:3]([C:18]([NH:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[O:20])=[N:4][C:5]([C:8]2[CH:9]=[CH:10][C:11]([S:14]([CH3:17])(=[O:15])=[O:16])=[CH:12][CH:13]=2)=[CH:6][N:7]=1
Reactant: CS(=O)(=O)c1ccc(-c2cnc(N)c(C(=O)O)n2)cc1
Reactant: Nc1ccccc1
Agent: CCOP(=O)(C#N)OCC
Solvent: CCN(CC)CC
Solvent: O
Solvent: COCCOC
Product: CS(=O)(=O)c1ccc(-c2cnc(N)c(C(=O)Nc3ccccc3)n2)cc1
Yield: 99.8 %

Procedure:
A mixture of 3-amino-6-(4-methylsulfonylphenyl)pyrazine-2-carboxylic acid (1.5 g, 5.114 mmol), diethoxyphosphorylformonitrile (926.8 mg, 849.5 μL, 5.114 mmol), aniline (476.2 mg, 465.9 μL, 5.114 mmol) and triethylamine (1.035 g, 1.426 mL, 10.23 mmol) was stirred in DME (18.75 mL) at 120° C. for 18 hours. After this time water was added and the resultant solid collected by filtration and triturated with acetone to give the desired product (1.88 g, 71% Yield). 1H NMR (400.0 MHz, DMSO) δ 10.47 (s, 1H), 9.04 (s, 1H), 8.51 (d, J=8.4 Hz, 2H), 8.01 (d, J=8.4 Hz, 2H), 7.89 (s, 2H), 7.82 (d, J=7.9 Hz, 2H), 7.41 (t, J=7.8 Hz, 2H), 7.18 (t, J=7.3 Hz, 1H) and 3.28 (s, 3H) ppm; MS (ES+) 369.0.
Reaction SMILES: C(O[C:5](=[O:7])[CH3:6])(=O)C.N1C=CC=CC=1.[CH2:14]([NH2:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C(Cl)Cl>[CH2:14]([NH:21][C:5](=[O:7])[CH3:6])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: NCc1ccccc1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)NCc1ccccc1
Reaction time: 1 h
Yield: 10.3 %

Procedure:
To a suspension of P-HOBT 1 (0.212 g, 0.125 mmol) in CH2Cl2 (5 mL) was added acetic anhydride (0.216 g, 0.200 mL, 2.12 mmol, 17 equiv.) and pyridine (0.234 g, 0.240 mL, 2.96 mmol, 24 equiv.). The suspension was subsequently rocked for 60 minutes at 25° C. The polymer was then filtered and washed with CH2Cl2 (3×5 mL), NMP (3×5 mL), CH2Cl2 (3×5 mL), and anhydrous Et2O (3×5 mL). The polymer was re-suspended in CH2Cl2 (5 mL) and benzylamine (0.0098 g, 0.010 mL, 0.91 mmol, 0.73 equiv. based on P-HOBT) was added. The suspension was rocked at 25° C. for 4 h. The polymer was then filtered and washed with CH2Cl2 (4×5 mL). The filtrate and washings were combined and concentrated to yield 0.014 g (100%) of N-benzylacetamide as a white solid.
Reaction SMILES: [C:1](=O)([O:33]C1C=CC([N+]([O-])=O)=CC=1)[O:2][CH:3]([CH3:32])[C:4](=[C:13]1[CH2:16][N:15]([CH:17]([C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=2)[C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)[CH2:14]1)[C:5]1[CH:10]=[C:9]([F:11])[CH:8]=[C:7]([F:12])[CH:6]=1.[CH:44]([NH2:47])([CH3:46])[CH3:45]>C(Cl)Cl>[CH:44]([NH:47][C:1](=[O:33])[O:2][CH:3]([CH3:32])[C:4](=[C:13]1[CH2:14][N:15]([CH:17]([C:25]2[CH:26]=[CH:27][C:28]([Cl:31])=[CH:29][CH:30]=2)[C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)[CH2:16]1)[C:5]1[CH:10]=[C:9]([F:11])[CH:8]=[C:7]([F:12])[CH:6]=1)([CH3:46])[CH3:45]
Reactant: CC(OC(=O)Oc1ccc([N+](=O)[O-])cc1)C(=C1CN(C(c2ccc(Cl)cc2)c2ccc(Cl)cc2)C1)c1cc(F)cc(F)c1
Reactant: CC(C)N
Solvent: ClCCl
Product: CC(C)NC(=O)OC(C)C(=C1CN(C(c2ccc(Cl)cc2)c2ccc(Cl)cc2)C1)c1cc(F)cc(F)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 45 mg (0.073 mmol) of 2-{1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene}-2-(3,5-difluorophenyl)-1-methylethyl 4-nitrophenyl carbonate in 3 mL of methylene chloride was added 0.3 mL of isopropylamine and the reaction was stirred for 4 h at rt, followed by concentration and purification of the residue by silica gel chromatography with hexanes/ethyl acetate=4:1 to afford the title compound as white solid. Mass Spectrum: m/e=545 (M+1 35Cl, 35Cl) and 547 (M+1 35Cl, 37Cl).
Reaction SMILES: C[Al](C)C.[CH3:5][N:6]1[CH2:12][CH2:11][C:10]2[CH:13]=[C:14]([NH2:17])[CH:15]=[CH:16][C:9]=2[CH2:8][CH2:7]1.C([O:20][C:21]([C:23]([NH:29][C:30]([C:32]1[S:33][C:34]([Cl:37])=[CH:35][CH:36]=1)=[O:31])([CH3:28])[CH2:24][CH2:25][O:26][CH3:27])=O)C>C1(C)C=CC=CC=1.ClCCl>[CH3:27][O:26][CH2:25][CH2:24][C:23]([NH:29][C:30]([C:32]1[S:33][C:34]([Cl:37])=[CH:35][CH:36]=1)=[O:31])([CH3:28])[C:21](=[O:20])[NH:17][C:14]1[CH:15]=[CH:16][C:9]2[CH2:8][CH2:7][N:6]([CH3:5])[CH2:12][CH2:11][C:10]=2[CH:13]=1
Reactant: CCOC(=O)C(C)(CCOC)NC(=O)c1ccc(Cl)s1
Reactant: CN1CCc2ccc(N)cc2CC1
Agent: C[Al](C)C
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: COCCC(C)(NC(=O)c1ccc(Cl)s1)C(=O)Nc1ccc2c(c1)CCN(C)CC2
Reaction time: 0.25 h

Procedure:
0.60 ml of a 2M solution of trimethylaluminium in toluene are added to a mixture of 130 mg (0.738 mmol) 3-methyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamine in dichloromethane and stirred for 15 min. Then the mixture is added to 233 mg (0.729 mmol) 5-chloro-thiophene-2-carboxylic acid-N-(1-ethoxycarbonyl-3-methoxy-1-methyl-propyl)-amide and stirred for 3 days. Then it is poured onto ice water/2 N NaOH, extracted several times with ethyl acetate and dried with sodium sulphate. The crude product is purified by chromatography.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([Cl:9])[CH:8]=1)[NH2:5].[CH2:10]([C:12](=O)[C:13]([O-:15])=[O:14])[CH3:11].[F:17][C:18]1[CH:25]=[CH:24][C:21](C=C)=[CH:20][CH:19]=1.FC(F)(F)C(O)=O.[OH-].[Na+]>C(#N)C.C(O)C>[Cl:1][C:2]1[CH:8]=[C:7]([Cl:9])[CH:6]=[C:4]2[C:3]=1[CH:11]([C:21]1[CH:24]=[CH:25][C:18]([F:17])=[CH:19][CH:20]=1)[CH2:10][CH:12]([C:13]([OH:15])=[O:14])[NH:5]2
Reactant: C=Cc1ccc(F)cc1
Reactant: Nc1cc(Cl)cc(Cl)c1
Reactant: CCC(=O)C(=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Solvent: CCO
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)C1CC(c2ccc(F)cc2)c2c(Cl)cc(Cl)cc2N1

Procedure:
Compound 31 was prepared by the basic process from 5.0 mmol 3,5-dichloroaniline, 5.5 mmol ethylglyoxalate solution (50% toluene), 15.0 mmol 4-fluorostyrene and 5.0 mmol trifluoroacetic acid in 30.0 ml acetonitrile. Subsequent saponification was carried out using 1.0 ml of sodium hydroxide solution (6N water) in 20.0 ml of ethanol.