Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[C:2]1([C:18]2[C:19](=[O:25])[NH:20][C:21](=[O:24])[NH:22][CH:23]=2)[C:8]2[N:9]=[C:10]([CH3:12])[S:11][C:7]=2[CH2:6][CH2:5][C:4]2[CH:13]=[C:14]([CH3:17])[CH:15]=[CH:16][C:3]1=2.[H-].[Na+].Cl.Cl[CH2:30][CH2:31][N:32]1[CH2:36][CH2:35][CH2:34][CH2:33]1>CN(C)C=O.C(O)(=O)C>[CH3:12][C:10]1[S:11][C:7]2[CH:6]=[CH:5][C:4]3[CH:13]=[C:14]([CH3:17])[CH:15]=[CH:16][C:3]=3[CH:2]([C:18]3[C:19](=[O:25])[NH:20][C:21](=[O:24])[N:22]([CH2:30][CH2:31][N:32]4[CH2:36][CH2:35][CH2:34][CH2:33]4)[CH:23]=3)[C:8]=2[N:9]=1
Reactant: Cc1ccc2c(c1)CCc1sc(C)nc1C2(O)c1c[nH]c(=O)[nH]c1=O
Reactant: ClCCN1CCCC1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: Cc1ccc2c(c1)C=Cc1sc(C)nc1C2c1cn(CCN2CCCC2)c(=O)[nH]c1=O
Temperature: 50 °C

Procedure:
The product from example 18 step (ii) (1.44 g) was dissolved in dry N,N-dimethylformamide (20 ml) and treated cautiously with sodium hydride (60% dispersion by wt, 0.5 g) under nitrogen. After 10 min 1-(2-chloroethyl)pyrrolidine hydrochloride (0.8 g) was added and the whole heated at 50° C. for 16 h. The reaction mixture was partitioned between water and ethyl acetate. The organic layer was collected, dried over magnesium sulphate and solvent evaporated under reduced pressure. Purification was by flash chromatography eluting with 9:1 dichloromethane/methanol. The product obtained was dissolved in acetic acid (10 ml) and heated at 100° C. for 2 h. The solvent was removed under reduced pressure. Purification was by flash chromatography eluting with dichloromethane/methanol mixtures to give the subtitle product as pale yellow foam.
Reaction SMILES: [CH2:1]=[CH:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([NH2:12])(=[O:11])=[O:10])=[CH:5][CH:4]=1.C(N(CC)CC)C.[C:20]1([CH3:32])[CH:25]=[C:24]([CH3:26])[CH:23]=[C:22]([CH3:27])[C:21]=1[S:28](Cl)(=[O:30])=[O:29]>CN(C1C=CN=CC=1)C.C(#N)C>[C:20]1([CH3:32])[CH:25]=[C:24]([CH3:26])[CH:23]=[C:22]([CH3:27])[C:21]=1[S:28]([NH:12][S:9]([C:6]1[CH:5]=[CH:4][C:3]([CH:2]=[CH2:1])=[CH:8][CH:7]=1)(=[O:11])=[O:10])(=[O:29])=[O:30]
Reactant: Cc1cc(C)c(S(=O)(=O)Cl)c(C)c1
Reactant: C=Cc1ccc(S(N)(=O)=O)cc1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: C=Cc1ccc(S(=O)(=O)NS(=O)(=O)c2c(C)cc(C)cc2C)cc1
Yield: 64.7 %

Procedure:
Using 55.0 g (0.3 mol) of p-styrenesulfonamide, 3.7 g (0.03 mol) of 4-(N,N-dimethylamino)pyridine, 82.0 g (0.81 mol) of triethylamine, 91.8 g (0.42 mol) of 2-mesitylenesulfonyl chloride, and 500 ml of acetonitrile, reaction was conducted in the same manner as in Synthesis Example 1. As a result, 70.9 g of N-(2-mesitylenesulfonyl) -p-styrenesulfonamide was obtained (yield, 64.7%; light-yellow crystals; m.p., 146.5-147° C.).
Reaction SMILES: [Cl:1][C:2]1[C:6]2[N:7]([C:17](Cl)=[O:18])[C:8]3[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=3[NH:10][C:11](=[O:12])[C:5]=2[N:4]([CH3:20])[CH:3]=1.[CH2:21]([N:24]([CH2:28][CH:29]1[CH2:34][CH2:33][CH2:32][CH2:31][N:30]1[CH2:35][CH2:36][NH2:37])[CH2:25][CH2:26][CH3:27])[CH2:22][CH3:23]>>[Cl:1][C:2]1[C:6]2[N:7]([C:17]([NH:37][CH2:36][CH2:35][N:30]3[CH2:31][CH2:32][CH2:33][CH2:34][CH:29]3[CH2:28][N:24]([CH2:21][CH2:22][CH3:23])[CH2:25][CH2:26][CH3:27])=[O:18])[C:8]3[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=3[NH:10][C:11](=[O:12])[C:5]=2[N:4]([CH3:20])[CH:3]=1
Reactant: Cn1cc(Cl)c2c1C(=O)Nc1ccccc1N2C(=O)Cl
Reactant: CCCN(CCC)CC1CCCCN1CCN
Product: CCCN(CCC)CC1CCCCN1CCNC(=O)N1c2ccccc2NC(=O)c2c1c(Cl)cn2C
Yield: 57 %

Procedure:
Prepared analogously to Example 2 from 3-chloro-4-(chlorocarbonyl)-1-methyl-1,4,9,10-tetrahydro-pyrrolo[3,2-b][1,5]benzodiazepin-10-one and 2-[2-[(dipropylamino)methyl]-piperidin-1-yl]ethanamine in a yield of 57% of theory.
Reaction SMILES: [CH2:1]([N:4]([CH2:25][CH2:26][CH3:27])[C:5]1[N:6]([CH3:24])[C:7](=[O:23])[C:8]2[C:13]([C:14]3[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][C:15]=3[F:21])=[CH:12][N:11]([CH3:22])[C:9]=2[N:10]=1)[CH2:2][CH3:3].[H-].[Na+].I[CH3:31]>CN(C)C=O>[CH2:25]([N:4]([CH2:1][CH2:2][CH3:3])[C:5]1[N:6]([CH3:24])[C:7](=[O:23])[C:8]2[C:13]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:31])=[CH:16][C:15]=3[F:21])=[CH:12][N:11]([CH3:22])[C:9]=2[N:10]=1)[CH2:26][CH3:27]
Reactant: CCCN(CCC)c1nc2c(c(-c3ccc(O)cc3F)cn2C)c(=O)n1C
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCN(CCC)c1nc2c(c(-c3ccc(OC)cc3F)cn2C)c(=O)n1C
Reaction time: 0.5 h
Yield: 74 %

Procedure:
To a solution of 2-(dipropylamino)-5-(2-fluoro-4-hydroxyphenyl)-3,7-dimethyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one (30 mg, 0.0805 mmol) in N,N-dimethylformamide (0.5 ml) were added sodium hydride (66% dispersion in oil; 3.2 mg, 0.0886 mmol) and iodomethane (0.006 ml, 0.0886 ml) at 0° C., and the mixture was stirred at the same temperature for 30 minutes. The reaction mixture was diluted with ice-cold water and extracted with ethyl acetate (×1). The organic layer was washed with water (×1) and brine (×1), dried over sodium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with a 20% hexane/ethyl acetate mixture. The desired fractions were concentrated in vacuo to give 23 mg (74%) of the title compound as an oil.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][CH2:7]Br)=[CH:4][CH:3]=1.[CH3:11][NH2:12]>CO>[CH3:11][NH:12][CH2:7][CH2:6][C:5]1[CH:9]=[CH:10][C:2]([OH:1])=[CH:3][CH:4]=1
Reactant: Oc1ccc(CCBr)cc1
Reactant: CN
Solvent: CO
Product: CNCCc1ccc(O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 80 %

Procedure:
To 250 mg of 4-hydroxyphenethyl bromide in a round-bottomed flask, a 10 M excess of MeNH2 (6.2 mL of 2M in MeOH) was added and the solution was stirred at r.t. overnight. After filtration, the solvent was removed to give a brown oil in 80% yield. TLC (EtAc:MeOH, 9:1 v/v): RF=0.33. 1H NMR, δ: 9.42 (s, 1H), 7.10 (d, 2H), 6.75 (d, 2 H), 3.60 (s, 3H), 2.84 (t, 2H), 2.60 (t, 2H), 1.90 (s, 1H). 13C NMR, δ: 167.5, 131.2, 128.3, 112.4, 41.5, 36.4, 35.0. Anal. calcd for C9H13NO: C, 71.49; H, 8.67; N, 9.26%. Found; C, 71.50; H, 8.80; N, 9.20%.
Reaction SMILES: [CH3:1][CH:2]([CH3:5])[CH2:3][OH:4].[H-].[Na+].[N+:8]([C:11]1[CH:18]=[CH:17][CH:16]=[C:15]([N+]([O-])=O)[C:12]=1[C:13]#[N:14])([O-:10])=[O:9]>C1COCC1>[CH2:3]([O:4][C:15]1[CH:16]=[CH:17][CH:18]=[C:11]([N+:8]([O-:10])=[O:9])[C:12]=1[C:13]#[N:14])[CH:2]([CH3:5])[CH3:1]
Reactant: N#Cc1c([N+](=O)[O-])cccc1[N+](=O)[O-]
Reactant: CC(C)CO
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)COc1cccc([N+](=O)[O-])c1C#N
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 149.8 %

Procedure:
To a solution of 2-methylpropan-1-ol (9.6 mL, 0.104 mol) in anhydrous THF (200 mL) was added NaH (60% in mineral oil, 4.565 g, 0.114 mol) in small portions at 0° C. under N2. After it was stirred at room temperature for 30 min, the reaction mixture was cooled down to −70 C. and 2,6-dinitrobenzonitrile (20.0 g, 0.104 mol) was added portionwise. After the addition was complete, the reaction mixture was stirred at −70° C.—RT overnight, then poured into ice water (600 mL). The resultant precipitate was collected by filtration and rinsed with water, hexane, and air dried to provide 2-isobutoxy-6-nitrobenzonitrile as a light yellow solid (34.3 g, 100%). 1H NMR (400 MHz, DMSO-d6) δ 1.0 (d, J=6.8 Hz, 6H), 2.04-2.11 (m, 1H), 4.02 (d, J=6.8 Hz, 2H), 7.69-7.71 (m, 1H), 7.84-7.90 (m, 2H). MS 221 (MH+).
Reaction SMILES: [C:1]1([OH:11])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[Cl:12][CH2:13][CH2:14][CH2:15][C:16](O)=[O:17].B(F)(F)F.CCOCC>O>[Cl:12][CH2:13][CH2:14][CH2:15][C:16]([C:2]1[CH:3]=[CH:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:1]=1[OH:11])=[O:17]
Reactant: O=C(O)CCCCl
Reactant: Oc1cccc2ccccc12
Agent: FB(F)F
Solvent: CCOCC
Solvent: O
Product: O=C(CCCCl)c1ccc2ccccc2c1O
Reaction time: 0.5 h
Yield: 38.2 %

Procedure:
A mixture of 1-naphthol (15.14 g, 0.105 mole), 4-chlorobutyric acid (9.90 mL, 0.100 mole), and boron trifluoride etherate (75 mL) was heated on a steam bath for 4 hours. The mixture was then treated slowly with 100 mL of water, and heating continued for 30 minutes. The mixture was poured into water, stirred, and the solution decanted. The residue was triturated with water, then crystallized from ethanol to provide the title compound (9.50 g, 38%) as a pale green solid, mp 73°-79°.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C@H:9]2[CH2:14][CH2:13][C@H:12]([OH:15])[CH2:11][CH2:10]2)[C:5]([N+:16]([O-:18])=[O:17])=[CH:4][CH:3]=1.FC(F)(F)C([O-])=[O:22]>>[OH:15][C@H:12]1[CH2:13][CH2:14][C@H:9]([NH:8][C:6]2[N:7]=[C:2]([OH:22])[CH:3]=[CH:4][C:5]=2[N+:16]([O-:18])=[O:17])[CH2:10][CH2:11]1
Reactant: O=C([O-])C(F)(F)F
Reactant: O=[N+]([O-])c1ccc(Cl)nc1N[C@H]1CC[C@H](O)CC1
Product: O=[N+]([O-])c1ccc(O)nc1N[C@H]1CC[C@H](O)CC1

Procedure:
From trans-4-(6-chloro-3-nitropyridin-2-ylamino)cyclohexanol, trifluoroacetate, prepared in a similar manner as the one described in Example 1.3, Step B, the title compound was obtained. LCMS m/z=254.4 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([SH:8])[CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.Br[CH2:17][C:18]1[CH:22]=[CH:21][S:20][C:19]=1[C:23]([O:25][CH3:26])=[O:24].C(=O)([O-])O.[Na+]>ClCCl>[NH2:1][C:2]1[CH:3]=[C:4]([S:8][CH2:17][C:18]2[CH:22]=[CH:21][S:20][C:19]=2[C:23]([O:25][CH3:26])=[O:24])[CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1sccc1CBr
Reactant: Nc1cccc(S)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1sccc1CSc1cccc(N)c1
Reaction time: 0.5 h
Yield: 92.3 %

Procedure:
To a solution of 3-aminothiophenol (2.3 g, 18.7 mmol) and triethylamine (3.12 ml, 22.4 mmol) in dichloromethane (30 ml) was slowly added methyl 3-bromomethylthiophene-2-carboxylate (6.24 g, 22.4 mmol) under ice-cooling, followed by stirring for 30 minutes. After the reaction was completed, a saturated aqueous solution of sodium hydrogen carbonate was added to the reaction mixture. The organic layer was washed successively with a saturated aqueous solution of sodium hydrogen carbonate and a saturated aqueous solution of sodium chloride, and then dried over anhydrous magnesium sulfate. After the drying agent was filtered off, the organic layer was concentrated under reduced pressure. The obtained oily substance was purified by silica gel column chromatography (hexane/ethyl acetate=7/1) to give oily methyl 3-(3-aminophenylthiomethyl)thiophene-2-carboxylate (4.82 g, 92%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]([N+:10]([O-:12])=[O:11])=[C:6]([CH:9]=1)[CH:7]=[O:8].IC.[C:15](=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:15][O:1][C:2]1[CH:3]=[CH:4][C:5]([N+:10]([O-:12])=[O:11])=[C:6]([CH:9]=1)[CH:7]=[O:8]
Reactant: O=C([O-])[O-]
Reactant: O=Cc1cc(O)ccc1[N+](=O)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: COc1ccc([N+](=O)[O-])c(C=O)c1

Procedure:
In this scheme 5-hydroxy-2-nitrobenzaldehyde 1 is reacted in DMF with iodomethane and potassium carbonate to yield 5-methoxy-2-nitrobenzaldehyde 2. The methoxybenzaldehyde is heated with p-toluene sulfonic acid monohydrate (catalytic amount) in toluene to obtain the dioxane derivative 3, which is hydrogenated to give 2-(1,3-dioxolan-2yl)-4-methoxyphenylamine 4. Following conversion to the ethoxycarboxamide 5 and then to the formyl carboxamide 6,6-methoxyquinazolin-2-ol 7 is obtained by ring closure with ammonia. Reaction with phosphorus oxychloride then yields the desired 2-chloro-6-methoxyquinazoline intermediate 8.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][O:7][C:8]2=[C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([Cl:20])[CH:18]=3)[NH:13][C:12]2=[O:21])=[CH:4][CH:3]=1.C(N(CC)C(C)C)(C)C.[C:31](Cl)(=[O:33])[CH3:32]>C1COCC1>[Cl:20][C:17]1[CH:18]=[C:19]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12](=[O:21])[C:11]2=[C:8]1[C:9]2[C:5](=[CH:4][CH:3]=[C:2]([NH:1][C:31](=[O:33])[CH3:32])[CH:10]=2)[CH2:6][O:7]1
Reactant: Nc1ccc2c(c1)C(=C1C(=O)Nc3ccc(Cl)cc31)OC2
Reactant: CC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)Nc1ccc2c(c1)C(=C1C(=O)Nc3ccc(Cl)cc31)OC2
Temperature: 25 °C
Reaction time: 3 h
Yield: 72.8 %

Procedure:
To a solution of 3-(6-Amino-3H-isobenzofuran-1-ylidene)-5-chloro-1,3-dihydro-indol-2-one (56.5 mg, 0.189 mmol) and N,N-diisopropylethylamine (98.8 μL, 0.567 mmol) in 2.5 mL THF was added acetyl chloride (13.4 μL, 0.189 mmol). After stirring at room temperature for 3 h, the mixture was filtered and rinsed with isopropanol and hexanes/EtOAc (7:3) to give the title compound (46.9 mg, 73%) as a yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4](I)[CH:3]=1.[N:9]1[CH:14]=[CH:13][CH:12]=[C:11](B(O)O)[CH:10]=1.C([O-])([O-])=O.[K+].[K+]>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.O1CCOCC1>[Br:1][C:2]1[CH:3]=[C:4]([C:11]2[CH:10]=[N:9][CH:14]=[CH:13][CH:12]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Brc1cccc(I)c1
Reactant: OB(O)c1cccnc1
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: [K+]
Solvent: C1COCCO1
Product: Brc1cccc(-c2cccnc2)c1
Temperature: 100 °C
Yield: 0.1 %

Procedure:
1-bromo-3-iodobenzene (1.118 g, 3.95 mol) and 3-pyridine boronic acid (0.559 g, 4.54 mol) were added to a 100 mL three neck round bottom flask. To this flask, dioxane (20 mL) and aqueous K2CO3 (2 N, 20 mL) were added. The mixture was stirred and degassed with a steam of argon for 30 minutes. Then under argon atmosphere, 50 mg (0.04 mmol) of Pd(PPh3)4 (1%) was added. The mixture was heated to 100° C. and stirred overnight. The next day, the solvent was removed by roto-evaporation and the residue was suspended into an equal amount of water (50 mL) and CH2Cl2 (50 mL). The organic layer was separated from aqueous layer and washed with brine (50 mL×3). After drying over Na2SO4, and removal of the drying agent, about 0.92 g of 3-(3-bromophenyl)pyridine product (100%) was afforded. 1H NMR (400 MHz, CDC3) 8.85 (s, 1H), 8.65 (d, 1H), 7.87 (d, 1H), 7.75 (s, 1H), 7.57-7.52 (m, 2H), 7.41-7.35 (m, 2H).
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[NH:14][N:13]=[C:12]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)[C:11]=2[CH2:10][CH2:9]1)=O)(C)(C)C.[Br:25][C:26]1[CH:33]=[CH:32][C:29]([CH2:30]Br)=[CH:28][CH:27]=1>>[Br:25][C:26]1[CH:33]=[CH:32][C:29]([CH2:30][N:14]2[C:15]3[CH2:16][CH2:17][NH:8][CH2:9][CH2:10][C:11]=3[C:12]([C:18]3[CH:19]=[CH:20][C:21]([Cl:24])=[CH:22][CH:23]=3)=[N:13]2)=[CH:28][CH:27]=1
Reactant: BrCc1ccc(Br)cc1
Reactant: CC(C)(C)OC(=O)N1CCc2[nH]nc(-c3ccc(Cl)cc3)c2CC1
Product: Clc1ccc(-c2nn(Cc3ccc(Br)cc3)c3c2CCNCC3)cc1
Yield: 25.6 %

Procedure:
The title compound (0.032 g) was prepared from 3-(4-chloro-phenyl)-4,5,7,8-tetrahydro-1H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (Example 103, Step B; 0.3 mmol) using 4-bromobenzyl bromide (0.3 mmol) in place of 2-chloromethyl-thiophene. MS (ESI): exact mass calculated for C20H19BrClN3, 415.05; found, m/z 418.0 [M+H]+. 1H NMR (500 MHz, CD3OD): 7.48-7.40 (m, 6H), 6.92 (d, J=8.4 Hz, 2H), 5.28 (s, 2H), 3.32-3.30 (br m, 4H), 3.03-3.01 (br m, 4H).
Reaction SMILES: [OH:1][C@@H:2]1[CH2:7][N:6]([C:8]([O:10][CH3:11])=[O:9])[C@H:5]([C:12]([N:14]2[CH2:19][CH2:18][N:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:16][CH2:15]2)=[O:13])[C@@H:4]([C:26]([O:28][CH3:29])=[O:27])[CH2:3]1.CC(C)([O-])C.[K+].[CH3:36][C:37]([O:40][C:41](=[O:44])[CH2:42]Br)([CH3:39])[CH3:38]>O1CCCC1>[C:37]([O:40][C:41](=[O:44])[CH2:42][O:1][C@@H:2]1[CH2:7][N:6]([C:8]([O:10][CH3:11])=[O:9])[C@H:5]([C:12]([N:14]2[CH2:19][CH2:18][N:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:16][CH2:15]2)=[O:13])[C@@H:4]([C:26]([O:28][CH3:29])=[O:27])[CH2:3]1)([CH3:39])([CH3:38])[CH3:36]
Reactant: COC(=O)[C@H]1C[C@H](O)CN(C(=O)OC)[C@@H]1C(=O)N1CCN(c2ccccc2)CC1
Reactant: CC(C)(C)OC(=O)CBr
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: COC(=O)[C@H]1C[C@H](OCC(=O)OC(C)(C)C)CN(C(=O)OC)[C@@H]1C(=O)N1CCN(c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of dimethyl (2S,3S,5S)-5-hydroxy-2-[(4-phenylpiperazin-1-yl)carbonyl]piperidine-1,3-dicarboxylate (50.0 mg, 0.000123 mol) in tetrahydrofuran (0.50 mL, 0.0062 mol) was added 1.00 M of potassium tert-butoxide in tetrahydrofuran (0.150 mL). After stirred at rt for 30 min, to the mixture was added bromo-acetic acid 1,1-dimethylethyl ester (0.0228 mL, 0.000154 mol). The resulting mixture was stirred at rt overnight and then concentrated to dry.
Reaction SMILES: [OH:1][C:2]([C:5]1([C:11]#[N:12])[CH2:9][CH:8]=[C:7]([CH3:10])[CH2:6]1)([CH3:4])[CH3:3].ClC1C=CC=C(C(OO)=[O:21])C=1>C(Cl)Cl.C(=O)(O)[O-].[Na+]>[OH:1][C:2]([C:5]1([C:11]#[N:12])[CH2:9][CH:8]2[C:7]([CH3:10])([O:21]2)[CH2:6]1)([CH3:4])[CH3:3]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC1=CCC(C#N)(C(C)(C)O)C1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC12CC(C#N)(C(C)(C)O)CC1O2
Reaction time: 8 h
Yield: 111.1 %

Procedure:
To a stirred mixture of 11.65 g of 1-(1-hydroxy-1-methylethyl)-3-methyl-3-cyclopentene-1-carbonitrile in 700 ml of methylene chloride and 210 ml of aqueous sodium bicarbonate was added portionwise at 25°-35° C. 15.3 g of 85% m-chloroperbenzoic acid. After stirring overnight, the phases were separated and the organic phase was washed successively with 200 ml of 1N sodium hydroxide, 200 ml of water and 200 ml of saturated aqueous sodium chloride, dried (MgSO4), and concentrated in vacuo to leave 14.2 g of a colorless oil, as a 1.2;1.0 mixture of diastereomeric epoxides. These diastereomers were separated by flash silica gel column chromatography using 2:8:40 tetrahydrofuran/ethyl acetate/hexane as eluent to give 5.1 g of the less polar (1α,3β,5α) isomer as a colorless oil and using 2:15:33 ratio of the same solvents to give 5.4 g of the more polar (1α,3α,5α)isomer as a colorless oil.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[CH:11]=[C:10]([C:12]#[N:13])[CH:9]=[CH:8][N:7]=2)[N:3]=[CH:2]1.BrC[CH2:16][CH2:17][O:18][CH2:19]CCBr>>[CH3:19][O:18][CH2:17][CH2:16][N:1]1[CH:5]=[C:4]([C:6]2[CH:11]=[C:10]([C:12]#[N:13])[CH:9]=[CH:8][N:7]=2)[N:3]=[CH:2]1
Reactant: BrCCCOCCCBr
Reactant: N#Cc1ccnc(-c2c[nH]cn2)c1
Product: COCCn1cnc(-c2cc(C#N)ccn2)c1

Procedure:
The title compound was prepared 2-(1H-imidazol-4-yl)pyridine-4-carbonitrile and 2-bromo-ethylmethylether according to the procedure for the preparation of Example 35, part A. [M+H] Calc'd for C12H12N4O, 229. Found, 229.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][N:7]=1.[N+:12]([CH:15]=[C:16](SC)[S:17][CH3:18])([O-:14])=[O:13]>N1C=CC=CC=1>[N+:12]([CH:15]=[C:16]([S:17][CH3:18])[NH:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][N:7]=1)([O-:14])=[O:13]
Reactant: NCCCCc1ccccn1
Reactant: CSC(=C[N+](=O)[O-])SC
Solvent: c1ccncc1
Product: CSC(=C[N+](=O)[O-])NCCCCc1ccccn1

Procedure:
2-(4-Aminobutyl)pyridine was reacted with 1-nitro-2,2-bis-methylthio-ethylene in pyridine at 60° for 3.5 hours. Concentration of the reaction mixture and crystallisation yielded 1-nitro-2-methylthio-2-[4-(2-pyridyl)butylamino]ethylene, m.p. 78°.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[C:10]2[C:15]([N:16]=[C:17]3[C:22]=1[C:21](=[O:23])[CH2:20][CH2:19][CH2:18]3)=[CH:14][C:13]([Cl:24])=[CH:12][CH:11]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[CH2:1]([NH:8][C:9]1[C:10]2[C:15]([N:16]=[C:17]3[C:22]=1[CH:21]([OH:23])[CH2:20][CH2:19][CH2:18]3)=[CH:14][C:13]([Cl:24])=[CH:12][CH:11]=2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CCCc2nc3cc(Cl)ccc3c(NCc3ccccc3)c21
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OC1CCCc2nc3cc(Cl)ccc3c(NCc3ccccc3)c21
Temperature: 10 °C
Reaction time: 1 h
Yield: 73.4 %

Procedure:
In 100 ml of dry THF was added 2.90 g of 9-benzylamino-6-chloro-3,4-dihydroacridin-1(2H)-one. The mechanically stirred solution was cooled with ice under nitrogen and 4.3 ml of 1M lithium aluminum hydride solution in THF was added dropwise over 10 minutes. After 1 hour of stirring at 10° C., the reaction was complete by TLC, so it quenched with 1 ml of saturated ammonium chloride solution. The organic salts were filtered off and the filtrate was evaporated to a solid. The solid was recrystallized from 1:1 dichloromethane/pentane to yield 2.14 g of solid, mp 163° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[C:4]1[C:9]([F:10])=[CH:8][C:7](F)=[CH:6][C:5]=1[NH:12][C:13](=[O:24])[CH2:14][C:15]1[CH:23]=[CH:22][C:18]2[O:19][CH2:20][O:21][C:17]=2[CH:16]=1.[CH3:26][N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1>CS(C)=O>[CH3:1][O:2][C:3](=[O:25])[C:4]1[C:9]([F:10])=[CH:8][C:7]([N:30]2[CH2:31][CH2:32][N:27]([CH3:26])[CH2:28][CH2:29]2)=[CH:6][C:5]=1[NH:12][C:13](=[O:24])[CH2:14][C:15]1[CH:23]=[CH:22][C:18]2[O:19][CH2:20][O:21][C:17]=2[CH:16]=1
Reactant: COC(=O)c1c(F)cc(F)cc1NC(=O)Cc1ccc2c(c1)OCO2
Reactant: CN1CCNCC1
Solvent: CS(C)=O
Product: COC(=O)c1c(F)cc(N2CCN(C)CC2)cc1NC(=O)Cc1ccc2c(c1)OCO2
Temperature: 80 °C
Reaction time: 3 h
Yield: 24.4 %

Procedure:
To a solution of 2-(2-benzo[1,3]dioxol-5-yl-acetylamino)-4,6-difluoro-benzoic acid methyl ester (0.50 g, 1.43 mmol) in dimethylsulfoxide (8 mL) was added N-methylpiperazine (0.20 mL, 2.86 mmol). The reaction was stirred at 80° C. for 3 h then cooled at room temperature. The solid precipitated was filtered and washed with a mixture H2O/EtOH 1/1, to provide after drying the title compound (0.15 g, 25% yield).
Reaction SMILES: [O:1]=[C:2]([CH2:9][CH2:10][CH3:11])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].OCC[C:15]#[N:16]>>[O:1]=[C:2]([CH2:9][CH2:10][CH3:11])[CH2:3][C:4]([O:6][CH2:7][CH2:8][C:15]#[N:16])=[O:5]
Reactant: N#CCCO
Reactant: CCCC(=O)CC(=O)OCC
Product: CCCC(=O)CC(=O)OCCC#N
Temperature: 192.5 °C

Procedure:
A mixture of ethyl 3-oxohexanoate (33.7 mmol) and 3-hydroxypropionitrile (28.1 mmol) were placed in a round bottom flask (magnetically stirred) equipped with a short distillation path. The resulting mixture was gradually heated to 180-205° C. in an oil bath. The distillate was collected. The mixture was then cooled to room temperature and the residue was distilled under reduced pressure to give 2-cyanoethyl 3-oxohexanoate.
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][CH2:5][CH2:6][S:7][C:8]1[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=1.C(N(CC)CC)C.[CH3:21][O:22][C:23]1[CH:24]=[C:25]([CH:29]=[C:30]([O:32][CH3:33])[CH:31]=1)[C:26](Cl)=[O:27]>C(Cl)Cl>[CH3:33][O:32][C:30]1[CH:29]=[C:25]([CH:24]=[C:23]([O:22][CH3:21])[CH:31]=1)[C:26]([NH:3][CH2:4][CH2:5][CH2:6][S:7][C:8]1[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=1)=[O:27]
Reactant: COc1cc(OC)cc(C(=O)Cl)c1
Reactant: NCCCSc1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc(OC)cc(C(=O)NCCCSc2ccncc2)c1
Yield: 87.7 %

Procedure:
To a solution of 1.00 g (4.15 mmol) of 4-(3-aminopropylthio)pyridine dihydrochloride and 2.77 ml (19.8 mmol) of triethylamine in 40 ml of methylene chloride was added 995 mg (4.96 mmol) of 3,5-dimethoxybenzoyl chloride under ice-cooling with stirring and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was washed with an aqueous saturated sodium bicarbonate solution and water and dried. The solvent was distilled off. The residue was purified by column chromatography (eluent: ethyl acetate) to obtain 1.21 g of the desired compound (87.7%, pale yellow powder), mp: 110.0°-111.0° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[CH:7]([O:11][C:12](=[O:14])[CH3:13])[C:8]([CH3:10])=[O:9])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH2:18](Br)[CH2:19][CH3:20]>CN(C=O)C>[C:1]([O:5][C:6](=[O:15])[C:7]([O:11][C:12](=[O:14])[CH3:13])([C:8](=[O:9])[CH3:10])[CH2:18][CH2:19][CH3:20])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(=O)OC(C(C)=O)C(=O)OC(C)(C)C
Reactant: CCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCC(OC(C)=O)(C(C)=O)C(=O)OC(C)(C)C
Yield: 70.5 %

Procedure:
According to the general alkylation method, tert-butyl-2-acetoxy-aceto-acetate (219a) (7.12 g, 32.9 mmol), NaH (900 mg, 37.5 mmol) and propylbromide (4.05 g, 32.9 mmol) were reacted in DMF (64 mL) to give 2-acetoxy-2-acetyl-pentanoic-acid-tert-butylester (250h) (6.00 g, 23.2 mmol, 71%) as a slightly yellow oil after Kugelrohr distillation at 160° C. and 1.0 mbar. Then, 250h (6.00 g, 23.2 mmol) and 393 mg (2.07 mmol) p-TsOH.H2O were stirred in 60 mL benzene according to decarboxylation method A. Kugelrohr distillation at 1.0 mbar and 150° C., followed by column chromatography (diethylether:petroleum ether=1:8) gave 251h (2.00 g, 12.6 mmol, 54%) as a colorless oil.