Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([S:9][C:10]2[CH:15]=[C:14]([N:16]=[C:17]=[S:18])[C:13]([F:19])=[CH:12][C:11]=2[Cl:20])[CH2:8][CH2:7][CH2:6]1)=[O:4].[NH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][NH:22]1>C(O)C>[CH3:1][O:2][C:3]([C:5]1([S:9][C:10]2[CH:15]=[C:14]([NH:16][C:17]([N:21]3[CH2:26][CH2:25][CH2:24][CH2:23][NH:22]3)=[S:18])[C:13]([F:19])=[CH:12][C:11]=2[Cl:20])[CH2:6][CH2:7][CH2:8]1)=[O:4]
Reactant: C1CCNNC1
Reactant: COC(=O)C1(Sc2cc(N=C=S)c(F)cc2Cl)CCC1
Solvent: CCO
Product: COC(=O)C1(Sc2cc(NC(=S)N3CCCCN3)c(F)cc2Cl)CCC1
Temperature: 25 °C
Yield: 65.5 %

Procedure:
While stirring at room temperature, a solution of 13.1 g of 1-(2-chloro-4-fluoro-5-isothiocyanato-phenylthio)-cyclobutanecarboxylic acid methyl ester obtained in accordance with Example P2 in 200 ml of ethanol is added dropwise to a solution of 4 g of hexahydropyridazine in 30 ml of ethanol. After stirring for 3 hours at room temperature, the reaction mixture is concentrated by evaporation in vacuo, yielding 10.8 g of 1-[2-chloro-4-fluoro-5-(1-hexahydropyridazinyl-thiocarbonylamino)-phenylthio]-cyclobutanecarboxylic acid methyl ester having a melting point of from +112° to +113° C.
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].[NH2:5][C:6]1[CH:19]=[CH:18][C:9]([CH2:10][NH:11][C:12](=[O:17])[C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:8][CH:7]=1.C(N(CC)CC)C>C1(C)C=CC=CC=1.C(Cl)Cl>[N:5]([C:6]1[CH:7]=[CH:8][C:9]([CH2:10][NH:11][C:12](=[O:17])[C:13]([CH3:15])([CH3:16])[CH3:14])=[CH:18][CH:19]=1)=[C:1]=[O:2]
Reactant: CC(C)(C)C(=O)NCc1ccc(N)cc1
Reactant: O=C(Cl)Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CC(C)(C)C(=O)NCc1ccc(N=C=O)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of phosgene (24.1 ml of a 1.93 M solution in toluene, 46.5 mmol) in methylene chloride (50 ml) cooled to 0° C. is added dropwise a solution of N-(4-amino-benzyl)-2,2-dimethyl-propionamide (8 g, 38.8 mmol) and triethyl amine (13.5 ml, 97 mmol) in methylene chloride (80 ml). The reaction mixture is allowed to slowly warm to 25° C. and stirred at this temperature for 18 hrs. The reaction mixture is filtered on dry cellite, under an argon atmosphere and the filtrate is concentrated in vacuo. The residue is dissolved in methylene chloride (380 ml) to provide a 0.1 M solution of N-(4-isocyanato-benzyl)-2,2-dimethyl-propionamide in methylene chloride which is used as is.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14](=[O:15])[CH:13]=[CH:12]O[C:10]=1[CH3:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OC1C(=O)C=COC=1C)C1C=CC=CC=1.C([N:36]1C=C[C:39](=[O:42])[C:38](O)=[C:37]1C)(=O)C.OCCCN.OCCN>>[CH2:1]([O:8][C:9]1[C:14](=[O:15])[CH:13]=[CH:12][N:36]([CH2:37][CH2:38][CH2:39][OH:42])[C:10]=1[CH3:16])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1occc(=O)c1OCc1ccccc1
Reactant: CC(=O)n1ccc(=O)c(O)c1C
Agent: NCCCO
Solvent: NCCO
Product: Cc1c(OCc2ccccc2)c(=O)ccn1CCCO

Procedure:
3-Benzyloxy-2-methyl-4-pyrone, prepared as described under (J), is reacted with 3-hydroxypropylamine under substantially similar conditions to those described under (K) for reaction with 2-hydroxyethylamine to give 3-benzyloxy-1-(3'-hydroxypropyl)-2-methylpyrid-4-one. This is deprotected using the procedure described under (K) to give 3-hydroxy-1-(3'-hydroxypropyl)-2-methylpyrid-4-one as white crystals, m.p. 111°-113° C.; δmax (nujol) 1630, 3150, 3350 cm-1, δ(d6DMSO) 1.8 (m, 2H), 2.4 (s, 3H), 3.35 (t, 2H), 4.33 (t, 2H), 7.3 (d, 1H), 8.2 (d, 1H).
Reaction SMILES: [OH:1][CH:2]([CH2:20][OH:21])[CH2:3][NH:4][C:5](=[O:19])[C:6]1[CH:11]=[C:10](Cl)[C:9]([N+:13]([O-:15])=[O:14])=[CH:8][C:7]=1[N+:16]([O-:18])=[O:17].[NH:22]1[CH2:24][CH2:23]1>CCOC(C)=O>[OH:1][CH:2]([CH2:20][OH:21])[CH2:3][NH:4][C:5](=[O:19])[C:6]1[CH:11]=[C:10]([N:22]2[CH2:24][CH2:23]2)[C:9]([N+:13]([O-:15])=[O:14])=[CH:8][C:7]=1[N+:16]([O-:18])=[O:17]
Reactant: O=C(NCC(O)CO)c1cc(Cl)c([N+](=O)[O-])cc1[N+](=O)[O-]
Reactant: C1CN1
Solvent: CCOC(C)=O
Product: O=C(NCC(O)CO)c1cc(N2CC2)c([N+](=O)[O-])cc1[N+](=O)[O-]
Yield: 84.5 %

Procedure:
A solution of N-(2,3-dihydroxypropyl)-5-chloro-2,4-dinitrobenzamide (Friedlos et al., J. Med. Chem., 1997, 40, 1270-1275) (0.50 g, 1.56 mmol) and aziridine (1.00 g, 0.023 mol) in EtOAc (100 mL) was stirred at room temperature for 18 h. After washing with water the solution was worked up to give 2 (0.43 g, 84%): mp (EtOAc/petroleum ether) 145-147° C., 1H NMR [(CD3)2SO] δ8.74 (t, J=5.7 Hz, 1H, NH), 8.64 (s, 1H, H-3), 7.43 (s, 1H, H-6), 4.85 (d, J=4 9 Hz, 1H, OH), 4.58 (t, J=5 7 Hz, 1H, OH), 3 62 (m, 1H, CHOH), 3.44-3.36 (m, 2H, CH2OH), 3.39-3.36 (m, 1H, CONHCHH), 3.16-3.09 (m, 1H, CONHC), 2 48 (s, 4H, aziridine-H); 13C NMR δ164.19 (s), 152.98 (s), 139.70 (s), 138.89 (s), 137 53 (s), 124 57 (d), 122.58 (d), 70.02 (d), 63.70 (t), 42.73 (t), 29.91 (t). Anal. Calcd. for C12H14N4O7. C, 44.18;H, 4.33; N, 17.17%. Found: C, 44.22; H, 4.25; N, 17 40%.
Reaction SMILES: [C:1]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:6]=[CH:5][C:4]([C:7](O)=[O:8])=[CH:3][CH:2]=1.C(Cl)(=O)C([Cl:19])=O>C(Cl)Cl.CN(C=O)C>[C:1]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:6]=[CH:5][C:4]([C:7]([Cl:19])=[O:8])=[CH:3][CH:2]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1ccc(-c2ccccc2)cc1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)c1ccc(-c2ccccc2)cc1
Yield: 46 %

Procedure:
To a solution of biphenyl-4-carboxylic acid (2.1 mmol) in dry CH2Cl2 (5.3 mL) and dry DMF (1 mL), kept at 0° C. under N2, was added oxalyl chloride (0.3 mL, 3.13 mmol). The mixture was reacted 20 min at 0° C. and 2 h at room temperature, then concentrated to give crude biphenyl-4-carbonyl chloride as a light-yellow solid. An amount of his sample (2 mmol) were dissolved in dry THF (20 mL) and the resulting solution added dropwise, at 0° C., to a suspension obtained by mixing 3 (1.3 mmol), Et3N (1.143 mL, 8.2 mmol) and dry THF (3 mL) at 0° C. under N2. The ensuing mixture was reacted at 0° C. for 30 min and at room temperature for 3 h, then evaporated. Purification by flash-chromatography (cyclohexane/EtOAc 1:1) and recrystallization gave pure URB894 as an ivory coloured solid. Yield 46%. Mp 218-220° C. (acetone/petroleum ether; sealed capillary tube; decomposition of the sample with changing of colour and shrinking of the mass was noted starting from 146° C.); [α]D20=−20° (c 0.55, CH3CN). MS (EI): m/z 267 (M+), 222, 181, 167 (100). IR (Nujol) 3270, 1827, 1641, 1540 cm−1; 1H NMR (d6-acetone) δ 4.53-4.65 (m, 2H), 4.50-4.59 (m, 1H), 7.38-7.55 (m, 3H), 7.70-7.84 (m, 4H), 8.00-8.07 (m, 2H), 8.68 (br d, 1H, J=7 Hz) ppm. 13C NMR (d6-acetone): δ 58.8, 65.1, 126.9, 127.0, 128.0, 128.1, 129.0, 131.9, 139.7, 144.4, 166.4, 169.2 ppm.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([CH:15]=[CH:16][CH:17]=1)[O:6][C:7]([CH3:14])([CH3:13])[C:8]([O:10]CC)=[O:9])=O.[NH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[SH:25].[OH-].[Na+]>CO>[S:25]1[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[N:18]=[C:1]1[C:3]1[CH:4]=[C:5]([CH:15]=[CH:16][CH:17]=1)[O:6][C:7]([CH3:13])([CH3:14])[C:8]([OH:10])=[O:9]
Reactant: CCOC(=O)C(C)(C)Oc1cccc(C=O)c1
Reactant: Nc1ccccc1S
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(Oc1cccc(-c2nc3ccccc3s2)c1)C(=O)O
Temperature: 25 °C
Reaction time: 22 h
Yield: 67.7 %

Procedure:
In a methanol solvent, a solution including Compound 97b (1.0 eq.) and 2-aminothiophenol (1.0 eq.) was stirred at room temperature for 22 hours. After methanol was evaporated, the residual was purified by silica gel column chromatography using hexane and ethyl acetate (14:1) as a developer. The obtained product was dissolved with 1,4-dioxane, and then, 1 N NaOH (1.5 eq.) was added thereto. The reaction mixture was stirred at room temperature for 17 hours, and 1,4-dioxane was evaporated. The reaction mixture was stirred at room temperature for 17 hours, and 1,4-dioxane was evaporated therefrom. The residual was distributed between ethyl acetate and water, an aqueous layer was acidified with 6 N HCl. The produced precipitate was filtered and washed with water to obtain Compound 120.
Reaction SMILES: [C:1]1([CH3:26])[CH:6]=[C:5]([CH3:7])[CH:4]=[C:3]([CH3:8])[C:2]=1[NH:9][C:10]1[S:11][C:12]2[C:18]([C:19]([O:21]C)=[O:20])=[CH:17][C:16]([N+:23]([O-:25])=[O:24])=[CH:15][C:13]=2[N:14]=1.[OH-].[Na+]>CO.C1COCC1>[C:1]1([CH3:26])[CH:6]=[C:5]([CH3:7])[CH:4]=[C:3]([CH3:8])[C:2]=1[NH:9][C:10]1[S:11][C:12]2[C:18]([C:19]([OH:21])=[O:20])=[CH:17][C:16]([N+:23]([O-:25])=[O:24])=[CH:15][C:13]=2[N:14]=1
Reactant: COC(=O)c1cc([N+](=O)[O-])cc2nc(Nc3c(C)cc(C)cc3C)sc12
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1cc(C)c(Nc2nc3cc([N+](=O)[O-])cc(C(=O)O)c3s2)c(C)c1
Temperature: 50 °C
Reaction time: 3 h
Yield: 80 %

Procedure:
To a mixture of methyl 2-mesitylamino-5-nitro-1,3-benzothiazole-7-carboxylate (230 mg, 0.619 mmol) (prepared in example 19) in methanol (5 ml) and THF (5 ml) was added 1 N NaOH solution (2.48 ml, 2.48 mmol). The mixture was stirred at 50° C. for 3 h. The solvent was evaporated under vacuum and the aqueous residue was neutralized with 1N HCl solution. The resulting precipitate was collected by filtration and dried under vacuum to afford 177 mg of the title compound.
Reaction SMILES: F[C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1.[O:13]1[C:17]2([CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)[O:16][CH2:15][CH2:14]1.C(N(CC)CC)C.C(OCC)(=O)C>CN(C)C(=O)C>[O:13]1[C:17]2([CH2:22][CH2:21][N:20]([C:2]3[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=3)[CH2:19][CH2:18]2)[O:16][CH2:15][CH2:14]1
Reactant: C1CC2(CCN1)OCCO2
Reactant: CCOC(=O)c1ccc(F)cc1
Solvent: CCN(CC)CC
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: CCOC(=O)c1ccc(N2CCC3(CC2)OCCO3)cc1

Procedure:
Ethyl 4-fluorobenzoate (11.65 g, 69.3 mmol), 1,4-dioxa-8-azaspiro[4.5]decane (9.92 g, 69.3 mmol), and triethylamine (9.66 mL, 69.3 mmol) in N,N-dimethylacetamide (80 mL) were stirred at 80° C. for 24 hours. The reaction was cooled, poured into ethyl acetate, washed with 3× water and brine, and concentrated to afford the title compound.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.[CH2:15]([O:17][C:18]([C:20]1[C:21](=[O:40])[C:22]2[CH:27]=[N:26][C:25](S(C)(=O)=O)=[N:24][C:23]=2[N:32]([CH:34]2[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]2)[CH:33]=1)=[O:19])[CH3:16]>>[CH2:15]([O:17][C:18]([C:20]1[C:21](=[O:40])[C:22]2[CH:27]=[N:26][C:25]([NH:14][C:11]3[CH:12]=[CH:13][C:8]([N:5]4[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH2:6]4)=[CH:9][CH:10]=3)=[N:24][C:23]=2[N:32]([CH:34]2[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]2)[CH:33]=1)=[O:19])[CH3:16]
Reactant: CCOC(=O)c1cn(C2CCCCC2)c2nc(S(C)(=O)=O)ncc2c1=O
Reactant: CN1CCN(c2ccc(N)cc2)CC1
Product: CCOC(=O)c1cn(C2CCCCC2)c2nc(Nc3ccc(N4CCN(C)CC4)cc3)ncc2c1=O

Procedure:
Using the procedure outlined in Example 1(g) the title compound was prepared from 4-(4-methyl-piperazin-1-yl)-phenylamine (50 mg, 0.26 mmol) and 8-cyclohexyl-2-methanesulfonyl-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester (from Example 17(e), 100 mg, 0.26 mmol). The title compound was obtained as a yellow solid (80 mg, 63%). 1H NMR (400 MHz, CDCl3) δ (ppm): 9.25 (s, 1H), 8.44 (s, 1H), 7.56 (br, 1H), 7.43 (d, J=8.9 Hz, 2H), 6.87 (d, J=9.0 Hz, 2H), 5.00 (m, 1H), 4.32 (q, J=7.1 Hz, 2H), 3.16 (t, J=4.9 Hz, 4H), 2.55 (t, J=4.9 Hz, 4H), 2.30 (s, 3H), 1.94 (m, 4H), 1.76 (m, 1H), 1.62 (m, 2H), 1.42 (m, 2H), 1.34 (t, J=7.1 Hz, 3H), 1.21 (m, 1H).
Reaction SMILES: [OH:1][CH2:2][C:3](=[O:8])[CH2:4][CH2:5][CH2:6][CH3:7].CN(C)C=O.N1C=CN=C1.Cl[Si:20]([CH2:25][CH3:26])([CH2:23][CH3:24])[CH2:21][CH3:22]>O>[CH2:21]([Si:20]([CH2:25][CH3:26])([CH2:23][CH3:24])[O:1][CH2:2][C:3](=[O:8])[CH2:4][CH2:5][CH2:6][CH3:7])[CH3:22]
Reactant: CC[Si](Cl)(CC)CC
Reactant: CCCCC(=O)CO
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: CCCCC(=O)CO[Si](CC)(CC)CC

Procedure:
To a solution of the crude 1-hydroxy-hexan-2-one (prepared in Example 1) in 80 ml. of dimethylformamide at 0° C. is added with stirring, 40.8 g. of imidazole and 45.21 g. of chlorotriethylsilane. The mixture is stirred at 0° C. for 5 minutes and then at room temperature overnight, then poured into cold water and extracted with petroleum ether. The petroleum ether solution is washed with water, then saturated sodium bicarbonate solution and then dried over magnesium sulfate. The solvent is removed and the residue is distilled. The fraction boiling at 95°-103° C. (0.7 mm.) is collected giving the desired product as a cloudy colorless liquid.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4]([NH:12][C:13]2[CH:27]=[CH:26][C:16]([CH2:17][P:18](=[O:25])([O:22][CH2:23][CH3:24])[O:19][CH2:20][CH3:21])=[CH:15][C:14]=2[O:28][CH3:29])[N:3]=1.[NH2:30][C:31]1[CH:32]=[CH:33][C:34]([N:42]2[CH2:47][CH2:46][NH:45][CH:44]([C:48]([O:50]C)=[O:49])[CH2:43]2)=[C:35]2[C:39]=1[C:38](=[O:40])[N:37]([CH3:41])[CH2:36]2.[F:52][C:53]([F:58])([F:57])[C:54]([OH:56])=[O:55].C(O)C(F)(F)F.O.[OH-].[Li+]>O.CO.C1COCC1>[CH2:20]([O:19][P:18]([CH2:17][C:16]1[CH:26]=[CH:27][C:13]([NH:12][C:4]2[N:3]=[C:2]([NH:30][C:31]3[CH:32]=[CH:33][C:34]([N:42]4[CH2:47][CH2:46][NH:45][CH:44]([C:48]([OH:50])=[O:49])[CH2:43]4)=[C:35]4[C:39]=3[C:38](=[O:40])[N:37]([CH3:41])[CH2:36]4)[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=2)=[C:14]([O:28][CH3:29])[CH:15]=1)([O:22][CH2:23][CH3:24])=[O:25])[CH3:21].[F:52][C:53]([F:58])([F:57])[C:54]([OH:56])=[O:55]
Reactant: COC(=O)C1CN(c2ccc(N)c3c2CN(C)C3=O)CCN1
Reactant: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Cl)n2)c(OC)c1)OCC
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: OCC(F)(F)F
Solvent: O=C(O)C(F)(F)F
Product: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(N4CCNC(C(=O)O)C4)c4c3C(=O)N(C)C4)n2)c(OC)c1)OCC
Temperature: 105 °C
Reaction time: 8 h

Procedure:
Diethyl (4-{[4-chloro-5-(trifluoromethyl)pyrimidin-2-yl]amino}-3-methoxybenzyl)phosphonate (18 mg, 0.039 mmol), methyl 4-(7-amino-2-methyl-1-oxo-2,3-dihydro-1H-isoindol-4-yl)piperazine-2-carboxylate (Compound 287A, 6.0 mg, 0.020 mmol), trifluoroacetic acid (4.6 μL, 0.060 mmol) and 0.5 mL trifluoroethanol were mixed. The mixture was heated in microwave 105° C. for 30 minutes. Solvent was evaporated. To the crude solid was added, 0.1 mL THF, 0.1 mL methanol, 0.1 mL water and lithium hydroxide monohydrate (8.3 mg, 0.20 mmol). The mixture was stirred at room temperature overnight. The crude material was purified by MDP to obtain the title compound as a trifluoroacetic acid salt (1.1 mg, 7.9% yield). 1H NMR (400 MHz, methanol-d4) δ=1.28 (t, J=7.3 Hz, 6 H), 3.18 (s, 3 H), 3.21-3.24 (m, 1 H), 3.33 (d, J=21.7 Hz, 2 H), 3.37-3.43 (m, 2 H), 3.45-3.51 (m, 1 H), 3.55-3.61 (m, 2 H), 3.90 (s, 3 H), 4.06-4.11 (m, 4 H), 4.32-4.39 (m, 1 H), 4.44-4.59 (m, 2 H), 6.99 (d, J=7.8 Hz, 1 H), 7.09 (s, 1 H), 7.25 (d, J=8.8 Hz, 1 H), 7.75 (d, J=8.3 Hz, 1 H), 8.35 (s, 1 H), 8.49 (br. s., 1 H). MS (ES+): m/z 708.26 (100) [MH+]; HPLC: tR=0.77 min (UPLC, purity).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:12][C:11]([CH3:14])([CH3:13])[C:10]([CH2:15][NH2:16])=[C:9]([N:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]3=[O:23])[C:8]=2[CH:24]=1)([O-:3])=[O:2].[CH2:25]([N:27]=[C:28]=[O:29])[CH3:26].O>ClCCl>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:12][C:11]([CH3:13])([CH3:14])[C:10]([CH2:15][NH:16][C:28]([NH:27][CH2:25][CH3:26])=[O:29])=[C:9]([N:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]3=[O:23])[C:8]=2[CH:24]=1)([O-:3])=[O:2]
Reactant: CC1(C)Oc2ccc([N+](=O)[O-])cc2C(n2ccccc2=O)=C1CN
Reactant: CCN=C=O
Solvent: ClCCl
Solvent: O
Product: CCNC(=O)NCC1=C(n2ccccc2=O)c2cc([N+](=O)[O-])ccc2OC1(C)C
Yield: 55.8 %

Procedure:
A solution of 6-nitro-2,2-dimethyl-3-aminomethyl-4-(2-oxo-1,2-dihydropyridin-1-yl)-2H-1-benzopyran (0.5 g, 1.53 mmol) in dichloromethane (10 ml) was stirred with ethyl isocyanate (0.12 ml, 1.53 mmol) at room temperature for two hours. Water was added and the organic phase separated, dried and evaporated to give crude product, which was chromatographed on silica gel, eluting with dichloromethane/methanol (95/5) to give 0.34 g of 6-nitro-2,2-dimethyl-3-(N'-ethylureido)methyl-4-(2-oxo-1,2-dihydropyridin-1-yl)-2H-1-benzopyran, m.p. 197° C.
Reaction SMILES: [CH2:1]1[O:9][CH:2]1[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH2:10]([CH2:12][NH2:13])[OH:11]>>[OH:11][CH2:10][CH2:12][NH:13][CH2:1][CH:2]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:9]
Reactant: NCCO
Reactant: c1ccc(C2CO2)cc1
Product: OCCNCC(O)c1ccccc1
Temperature: 125 °C
Reaction time: 16 h
Yield: 19 %

Procedure:
A mixture of styrene oxide (2.40 g, 0.020 mole) and ethanolamine (1.22 g, 0.020 mole) was heated at 125° C. in an oil bath for 2 hr. An NMR analysis showed no styrene oxide remaining. On standing at ambient temperature for 16 hrs, partial solidification occurred. The material was triturated with ethyl acetate, giving a white solid which was collected by filtration and washed with isopropyl ether. A small amount of second crop was obtained from the filtrate for a total of 0.82 g (23%). Recrystallization from ethyl acetate-isopropyl ether gave 0.69 g of a white solid, m.p. 96°-98° C.
Reaction SMILES: [NH2:1][NH:2][C:3]([NH2:5])=[S:4].[Cl:6][CH2:7][CH2:8][CH2:9][C:10]([C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1)=O>CO.Cl.O>[CH3:19][O:18][C:15]1[CH:16]=[CH:17][C:12]([C:10](=[N:1][NH:2][C:3](=[S:4])[NH2:5])[CH2:9][CH2:8][CH2:7][Cl:6])=[CH:13][CH:14]=1
Reactant: COc1ccc(C(=O)CCCCl)cc1
Reactant: NNC(N)=S
Agent: Cl
Solvent: O
Solvent: CO
Product: COc1ccc(C(CCCCl)=NNC(N)=S)cc1
Reaction time: 72 h
Yield: 63 %

Procedure:
Thiosemicarbazide (6.4 g, 70 mmol) was added under nitrogen to a solution of 4-chloro-4'-methoxybutyrophenone (10.0 g, 47 mmol) in 150 mL of methanol plus 12.7 mL of 1 N HCl plus 11.8 mL of water and the reaction stirred for approximately three days (over the weekend). The solid formed was collected by filtration and dissolved in methylene chloride. The organic solution was washed multiple times with water, dried (MgSO4) and the solvent removed under reduced pressure to give a white solid. Recrystallization of the solid from isopropyl alcohol gave 8.46 g (63%) of the title compound as a light yellow solid, mp 137-140° C.
Reaction SMILES: [CH3:1][CH:2]([S:4][C:5]1[CH:10]=[CH:9][C:8](B(O)O)=[CH:7][CH:6]=1)[CH3:3].Br[C:15]1[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH:23]2[CH2:28][CH2:27][N:26]([C:29]([O:31][CH:32]([CH3:34])[CH3:33])=[O:30])[CH2:25][CH2:24]2)=[CH:17][CH:16]=1>>[CH3:1][CH:2]([S:4][C:5]1[CH:10]=[CH:9][C:8]([C:15]2[CH:16]=[CH:17][C:18]([O:21][CH2:22][CH:23]3[CH2:24][CH2:25][N:26]([C:29]([O:31][CH:32]([CH3:34])[CH3:33])=[O:30])[CH2:27][CH2:28]3)=[CH:19][CH:20]=2)=[CH:7][CH:6]=1)[CH3:3]
Reactant: CC(C)Sc1ccc(B(O)O)cc1
Reactant: CC(C)OC(=O)N1CCC(COc2ccc(Br)cc2)CC1
Product: CC(C)OC(=O)N1CCC(COc2ccc(-c3ccc(SC(C)C)cc3)cc2)CC1
Yield: 16.6 %

Procedure:
The title compound (7.1 mg, 17%) was prepared from {4-[(1-methylethyl)thio]phenyl}boronic acid (19.6 mg, 0.1 mmol) and 1-methylethyl 4-{[(4-bromophenyl)oxy]methyl}-1-piperidinecarboxylate (Example 9, Step 2, 36 mg, 0.10 mmol) in a manner similar to Example 9, Step 3. LRMS (ESI), m/z 450 (M+Na).
Reaction SMILES: Cl.Cl.Cl.[CH3:4][N:5]([CH2:7][C:8]1[CH:13]=[CH:12][N:11]=[C:10]([CH2:14][S:15][C:16](=N)N)[CH:9]=1)[CH3:6].ClC[CH2:21][C:22]#[N:23].[OH-].[Na+]>O.C(O)C>[CH3:6][N:5]([CH2:7][C:8]1[CH:13]=[CH:12][N:11]=[C:10]([CH2:14][S:15][CH2:16][CH2:21][C:22]#[N:23])[CH:9]=1)[CH3:4]
Reactant: N#CCCCl
Reactant: CN(C)Cc1ccnc(CSC(=N)N)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CN(C)Cc1ccnc(CSCCC#N)c1
Reaction time: 7 h
Yield: 89.9 %

Procedure:
To a solution of S-(4-dimethylaminomethyl-2pyridylmethyl)isothiourea trihydrochloride (21.54 g) and 3-chloropropionitrile (8.01 g) in water (90 ml) and ethanol (65 ml) at 0° C (ice-salt bath) under nitrogen, was added dropwise over 30 minutes, a solution of sodium hydroxide (11.5 g) in water (120 ml), keeping the temperature below 3° C. After having been stirred for 7 hours and allowed to stand for 20 hours, the solution was extracted with 3:1 chloroform:ethanol (3×160 ml). The combined extracts were washed with water and dried (MgSO4) Solvent was evaporated at reduced pressure and the residue vacuum-distilled to give 3-(4-dimethylaminomethy-2-pyridyl-methylthio)propionitrile (13.66 g) as a pale yellow liquid, b.p.0.005 mm 148°-152° C.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:18]=[CH:17][CH:16]=[CH:15][C:5]=1[CH2:6][CH:7]1[CH2:12][CH2:11][CH:10]([CH2:13][OH:14])[CH2:9][CH2:8]1.[F:19][C:20]1[CH:27]=[CH:26][CH:25]=[C:24](F)[C:21]=1[C:22]#[N:23]>CN(C)C=O>[F:19][C:20]1[CH:27]=[CH:26][CH:25]=[C:24]([O:14][CH2:13][CH:10]2[CH2:9][CH2:8][CH:7]([CH2:6][C:5]3[CH:15]=[CH:16][CH:17]=[CH:18][C:4]=3[F:3])[CH2:12][CH2:11]2)[C:21]=1[C:22]#[N:23]
Reactant: N#Cc1c(F)cccc1F
Reactant: OCC1CCC(Cc2ccccc2F)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#Cc1c(F)cccc1OCC1CCC(Cc2ccccc2F)CC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 97.5 %

Procedure:
In an 18 mL vial, sodium hydride was suspended in 2 mL dry dimethylformamide and chilled to 0° C. under nitrogen flow. 4-(2-Fluorobenzyl)cyclohexylmethanol (155 mg; 0.7 mmol) was added over 2 minutes and warmed to room temperature for 2 hours. Mixture was then added to a 0° C. mixture of 2,6-difluorobenzonitrile (97 mg; 0.7 mmol) in 2 mL of dimethylformamide over 1 minute and mixture continued to stir an additional 2 hours. Mixture was quenched over 10 g of ice and extracted 3× ethyl acetate 20 mL each. Combined organics were washed 5× water, brine and dried over MgSO4. Colorless oil was obtained and purified by flash chromatography (20:1) with 0-5% ethyl acetate in hexanes to give 233 mg of title compound. (98% yield).
Reaction SMILES: Br[C:2]1[CH:7]=[N:6][CH:5]=[C:4]([Br:8])[N:3]=1.CS(C)=O.N12CCCN=C1CCCCC2.[OH:24][C:25]1[CH:32]=[CH:31][CH:30]=[CH:29][C:26]=1[CH2:27][NH2:28]>C(OCC)(=O)C>[Br:8][C:4]1[N:3]=[C:2]([NH:28][CH2:27][C:26]2[CH:29]=[CH:30][CH:31]=[CH:32][C:25]=2[OH:24])[CH:7]=[N:6][CH:5]=1
Reactant: Brc1cncc(Br)n1
Reactant: NCc1ccccc1O
Solvent: C1CCC2=NCCCN2CC1
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: Oc1ccccc1CNc1cncc(Br)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Introduced into a 50 ml round-bottomed flask is 1 g (4.2 mmol) of 2,6-dibromopyrazine (starting material 3), to which 15 ml of dimethyl sulphoxide, 638 mg (4.2 mmol, 1eq) of 1,8-diazabicyclo[5.4.0]undec-7-ene, and 1.03 g (8.4 mmol, 2 eq) of 2-hydroxybenzylamine (starting material 4) are added; the mixture is left stirring for 2 h at room temperature. The reaction medium is diluted with 50 ml of ethyl acetate and then the mixture is washed with 50 ml of a saturated solution of ammonium chloride, and then twice with 50 ml of water. The organic phases are dried over magnesium sulphate, filtered and concentrated to dryness. The residue is purified by chromatography over silica with, as eluent, a heptane/ethyl acetate (8/2) mixture. 2-[(6-Bromopyrazin-2-ylamino)methyl]phenol is obtained in the form of a white solid.