Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[C:2]1[N:3]=[C:4]2[CH:17]=[CH:16][C:15]([NH:18][NH:19][C:20]([C:22]3[CH:27]=[N:26][CH:25]=[CH:24][N:23]=3)=O)=[N:14][C:5]2=[N:6][C:7]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.P(Cl)(Cl)([Cl:30])=O>CC#N>[Cl:30][C:2]1[N:3]=[C:4]2[CH:17]=[CH:16][C:15]3=[N:18][N:19]=[C:20]([C:22]4[CH:27]=[N:26][CH:25]=[CH:24][N:23]=4)[N:14]3[C:5]2=[N:6][C:7]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=C(NNc1ccc2nc(O)c(-c3ccccc3)nc2n1)c1cnccn1
Solvent: CC#N
Product: Clc1nc2ccc3nnc(-c4cnccn4)n3c2nc1-c1ccccc1
Temperature: 100 °C

Procedure:
To a microwave vial was added N′-(2-hydroxy-3-phenylpyrido[2,3-b]pyrazin-6-yl)pyrazine-2-carbohydrazide (8-4, 0.412 g, 1.147 mmol), MeCN (5.0 mL), and finally phosphorus oxychloride (0.687 mL, 7.37 mmol). The reaction mixture was then heated to 100° C. in a hot oil bath (capped) overnight. The reaction mixture was then permitted to cool to room temperature, diluted with MeCN & concentrated in vacuo. The resulting residue was then suspended in ethyl acetate, washed with a saturated solution of sodium bicarbonate, followed by water, then brine, dried over sodium sulfate, filtered, and concentrated in vacuo to give 8-5 as a brown solid. HRMS (M+H)+: observed=360.0773, calculated=360.0759.
Reaction SMILES: [C:1]([Cu])#[N:2].Cl[C:5]1[N:10]=[CH:9][C:8]([CH2:11][OH:12])=[CH:7][C:6]=1[CH3:13].CC(OC)(C)C.N>CN(C=O)C>[OH:12][CH2:11][C:8]1[CH:7]=[C:6]([CH3:13])[C:5]([C:1]#[N:2])=[N:10][CH:9]=1
Reactant: N#C[Cu]
Reactant: Cc1cc(CO)cnc1Cl
Agent: N
Solvent: COC(C)(C)C
Solvent: CN(C)C=O
Product: Cc1cc(CO)cnc1C#N
Temperature: 250 °C
Reaction time: 0.58 h
Yield: 62.7 %

Procedure:
CuCN (54.3 mg, 0.607 mmol) was added to a solution of (6-chloro-5-methyl-3-pyridinyl)methanol (47.8 mg, 0.303 mmol) in anhydrous DMF (2 ml) and the mixture was stirred under microwave irradiation at 250° C. for 35 min. Full conversion was observed by HPLC. TBME and 28% NH3 were added. Extraction, drying (MgSO4), filtration, and removal of the solvent afforded 5-(hydroxymethyl)-3-methyl-2-pyridinecarbonitrile (28.2 mg, 0.190 mmol, 62.8% yield) pure enough to be used in the next step.
Reaction SMILES: CO[C:3](=[O:22])[C:4]1[C:9]([CH:10]=O)=[CH:8][C:7]([F:12])=[C:6]([F:13])[C:5]=1[NH:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[Cl:21].[OH:23][CH2:24][CH2:25][NH:26][NH2:27]>CCO>[Cl:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[NH:14][C:5]1[C:6]([F:13])=[C:7]([F:12])[CH:8]=[C:9]2[C:4]=1[C:3](=[O:22])[N:26]([CH2:25][CH2:24][OH:23])[N:27]=[CH:10]2
Reactant: NNCCO
Reactant: COC(=O)c1c(C=O)cc(F)c(F)c1Nc1ccccc1Cl
Solvent: CCO
Product: O=c1c2c(Nc3ccccc3Cl)c(F)c(F)cc2cnn1CCO
Temperature: 25 °C
Yield: 29.6 %

Procedure:
A mixture of 2-(2-chlorophenylamino)-3,4-difluoro-6-formyl benzoic acid methyl ester (0.400 mg, 1.228 mmol) and 2-hydroxyethyl hydrazine (0.102 mL, 1.351 mmol) in EtOH (10 mL) was heated at reflux under N2 for 16 hours. After cooling to room temperature, a yellow precipitate formed which was collected by filtration. The yellow solid was washed with EtOH and dried to yield 0.128 g (30%) pure desired product.
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([NH2:14])=[CH:11][CH:12]=2)[C:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([CH3:15])[CH2:6][C:5]1([CH3:23])[CH3:22])(=[O:3])[CH3:2].[CH3:24][O:25][C:26]1[CH:34]=[CH:33][CH:32]=[CH:31][C:27]=1[C:28](Cl)=[O:29].C(N(CC)C(C)C)(C)C>O1CCCC1>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([NH:14][C:28](=[O:29])[C:27]3[CH:31]=[CH:32][CH:33]=[CH:34][C:26]=3[O:25][CH3:24])=[CH:11][CH:12]=2)[C:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([CH3:15])[CH2:6][C:5]1([CH3:23])[CH3:22])(=[O:3])[CH3:2]
Reactant: COc1ccccc1C(=O)Cl
Reactant: CC(=O)N1c2ccc(N)cc2C(C)(c2ccccc2)CC1(C)C
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccccc1C(=O)Nc1ccc2c(c1)C(C)(c1ccccc1)CC(C)(C)N2C(C)=O

Procedure:
Acylation of 1-acetyl-6-amino-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline (0.60 g) with 2-methoxybenzoyl chloride (1.0 g) and N,N-diisopropylethylamine (1.7 ml) in tetrahydrofuran (60 ml) was performed according to the method described in example 6.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[CH:4][C:3]=1[C:11]1[CH:16]=[CH:15][C:14]([CH:17]=O)=[CH:13][N:12]=1.[CH2:19]([NH2:27])[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[CH:4][C:3]=1[C:11]1[CH:16]=[CH:15][C:14]([CH2:17][NH:27][CH2:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:13][N:12]=1
Reactant: NCCc1ccccc1
Reactant: NC(=O)c1ccc(F)c(-c2ccc(C=O)cn2)c1
Product: NC(=O)c1ccc(F)c(-c2ccc(CNCCc3ccccc3)cn2)c1

Procedure:
Using the method outlined in Example 60, 4-fluoro-3-(5-formylpyridin-2-yl)benzamide (Preparation 13) and phenethylamine were converted to the title compound: RT=2.30 min; m/z (ES+)=350.0 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11](=O)[N:10]([CH2:13][CH3:14])[CH2:9][CH2:8][N:7]([CH2:15][CH3:16])[C:6]=2[CH:17]=1>O1CCOCC1.C1COCC1>[CH2:15]([N:7]1[C:6]2[CH:17]=[C:2]([NH2:1])[CH:3]=[CH:4][C:5]=2[CH2:11][N:10]([CH2:13][CH3:14])[CH2:9][CH2:8]1)[CH3:16]
Reactant: CCN1CCN(CC)c2cc(N)ccc2C1=O
Solvent: C1COCCO1
Solvent: C1CCOC1
Product: CCN1CCN(CC)c2cc(N)ccc2C1
Temperature: 75 °C
Reaction time: 18 h
Yield: 77.3 %

Procedure:
To a solution of 8-Amino-1,4-diethyl-1,2,3,4-tetrahydro-benzo[e][1,4]diazepin-5one (22.0 g, 0.0944 mol) in dioxane (400 mL) was added borane dimethyl sulfide complex solution (2 M in THF, 118 mL, 0.236 mol) and heated at 75° C. for 4 hr. The reaction was quenched with ethanol (100 mL) and stirred at room temperature for 18 hr., then evaporated. To the residue was added hydrazine hydrate (100 mL) and heated at 95° C. for 4 hr. After evaporation, toluene (50 mL) and ethanol (50 mL) were added, distilled and the reaction evaporated. The residue was extracted with DCM, evaporated, dissolved in ether, filtered and evaporated to give 1,4-Diethyl-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-8-ylamine as an oil (16.0 g, 84%). LCMS (m/e) 220 (M+1); 1H-NMR (DMSO, 400 MHz) δ 6.79-6.71 (d, 1H, J=7.83 Hz), 6.49 (br, 1H), 6.01-5.99 (d, 1H, J=7.83 Hz), 4.79 (s, 2H), 3.07-3.02 (q, 2H, J=6.82 Hz), 2.85-2.83 (t, 2H, J=8.08 Hz), 2.70-2.68 (t, 2H, J=8.09 Hz), 1.13-1.10 (t, 3H, J=7.07 Hz), 1.00-0.97 (t, 3H, J=7.32 Hz), 712d) 5-Chloro-N*2*-(1,4-diethyl-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-8-yl)-N*4*-(2-methoxy-4-morpholin-4-yl-phenyl)-pyrimidin-2,4-diamine was prepared from 1,4-Diethyl-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-8-ylamine (0.068 g, 0.00023 mol) and (2,5-Dichloro-pyrimidin-4-yl)-(2-methoxy-4-morpholin-4-yl-phenyl)-amine (0.081 g, 0.00023 mol), camphorsulfonic acid (0.0187 g, 0.0008 mol) and methoxyethanol (10 mL). The mixture was heated at 95° C. for 18 hr. The reaction was evaporated and the residue treated with a 10% sodium carbonate solution and DCM, separated, washed, dried and evaporated to give a solid. This material was chromatographed on a silica gel prep plate with THF/methanol (10-1) giving the product as a tan solid (0.053 g, 43%). Mp 165-166° C. LCMS (m/e) 538 (M); 1H-NMR (DMSO, 400 MHz) δ 9.07 (s, 1H), 8.05 (s, 1H), 8.01 (s, 1H), 7.65 (d, 1H), 7.15-7.13 (d, 1H, J=8.33 Hz), 7.01 (s, 1H), 6.84-6.82 (d, 1H, J=8.08 Hz), 6.69 (s, 1H), 6.49-6.47 (d, 1H, J=8.59 Hz), 3.80 (s, 3H), 3.76 (t, 2H, J=4.05), 3.54 (s, 2H), 3.14 (t, 3H), 3.01-2.99 (q, 2H, J=7.07 Hz), 2.90-2.84 (m, 2H), 2.78-2.69 (m, 2H), 2.40-2.30 (m, 2H), 1.11-1.08 (t, 3H, J=6.57 Hz), 1.03-1.00 (t, 3H, J=7.33).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:8]=[C:7]([CH:15]([C:22]2[CH:27]=[CH:26][C:25]([C:28]#[N:29])=[CH:24][CH:23]=2)N2CCCCC2)[C:6]=1O)([CH3:4])([CH3:3])[CH3:2].[CH:31]([OH:33])=[O:32]>C1(C)C=CC=CC=1>[C:11]([C:9]1[CH:10]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[C:6]2[O:32][C:31](=[O:33])[CH:15]([C:22]3[CH:23]=[CH:24][C:25]([C:28]#[N:29])=[CH:26][CH:27]=3)[C:7]=2[CH:8]=1)([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)c1cc(C(c2ccc(C#N)cc2)N2CCCCC2)c(O)c(C(C)(C)C)c1
Reactant: O=CO
Solvent: Cc1ccccc1
Product: CC(C)(C)c1cc2c(c(C(C)(C)C)c1)OC(=O)C2c1ccc(C#N)cc1
Temperature: 140 °C
Yield: 79.4 %

Procedure:
A solution of 11.33 g (28.0 mmol) of compound (206), prepared according to Example 3a, in 150 ml of dry toluene is degassed using argon and then 33.6 mg (0.057 mmol) of dichloro-[1,3-bis(diphenylphosphino)propane]palladium(II) and 4.22 ml (112 mmol) of formic acid are added. The autoclave is flushed with carbon monoxide and sealed, and a carbon monoxide pressure of 6 bar is then applied. The reaction mixture is maintained at 140° C. for 14 hours. After cooling to room temperature, the reaction mixture is poured into water and extracted three times using ethyl acetate. The organic phases are combined, dried over sodium sulfate and concentrated using a vacuum rotary evaporator. Filtration of the residue on silica gel using ethyl acetate and crystallisation of the pure fractions from methanol yields 7.72 g (79%) of compound (106) (Table 1), m.p. 136-137° C. Molecular weight C23H25NO2 (347.46). Analysis, calculated: C 79.51; H 7.25; N 4.03%. Analysis, found: C 79.36; H 6.98; N 3.82%. 1HNMR (300 MHz, CDCl3, ppm): 1.23 (s, 9H); 1.36 (s, 9H); 4.83 (s, 1H); 6.95 (m, 1H); 7.31 (m, 3H); 7.61 (d, 2H).
Reaction SMILES: [C:1]1([CH:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:8]#[N:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[S:18]([N:28]1[CH2:32][CH2:31][CH:30](OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:29]1)([C:21]1[CH:27]=[CH:26][C:24]([CH3:25])=[CH:23][CH:22]=1)(=[O:20])=[O:19]>C1(C)C=CC=CC=1>[C:8]([C:7]([CH:31]1[CH2:30][CH2:29][N:28]([S:18]([C:21]2[CH:27]=[CH:26][C:24]([CH3:25])=[CH:23][CH:22]=2)(=[O:20])=[O:19])[CH2:32]1)([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)#[N:9]
Reactant: N#CC(c1ccccc1)c1ccccc1
Reactant: Cc1ccc(S(=O)(=O)OC2CCN(S(=O)(=O)c3ccc(C)cc3)C2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: Cc1ccc(S(=O)(=O)N2CCC(C(C#N)(c3ccccc3)c3ccccc3)C2)cc1
Temperature: 25 °C

Procedure:
Diphenylacetonitrile (17.1 g) was added to a stirred suspension of sodium hydride (4 g of a 60% suspension in mineral oil) in anhydrous toluene (250 ml) and the mixture was heated under reflux for 2 hours. On cooling to room temperature, 1-tosyl-3-(R,S)-tosyloxypyrrolidine (28 g--see Preparation 5) was added in portions and the mixture heated under reflux for 3 hours. The mixture was diluted with toluene (150 ml), washed with 5% aqueous sodium hydroxide (2×100 ml) and brine (150 ml) then dried (MgSO4) and concentrated in vacuo to give a solid which was purified by trituration with methanol to give the title compound as a colourless microcrystalline powder, yield 18 g, m.p. 186°-187° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1.I[C:13]1[C:21]2[C:16](=[N:17][CH:18]=[N:19][C:20]=2[NH2:22])[N:15]([CH:23]([CH3:25])[CH3:24])[N:14]=1.C([O-])([O-])=O.[Na+].[Na+]>CCO.COCCOC.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>[CH:23]([N:15]1[C:16]2=[N:17][CH:18]=[N:19][C:20]([NH2:22])=[C:21]2[C:13]([C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)=[N:14]1)([CH3:25])[CH3:24]
Reactant: COc1ccc(B(O)O)cc1
Reactant: CC(C)n1nc(I)c2c(N)ncnc21
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: COCCOC
Solvent: CCO
Product: COc1ccc(-c2nn(C(C)C)c3ncnc(N)c23)cc1
Temperature: 80 °C
Yield: 15.9 %

Procedure:
A solution of (4-Methoxyphenylboronic acid (17 mg, 0.11 mmol) in EtOH (3.3 mL) was added to a solution of 3-iodo-1-isopropyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (30 mg, 0.10 mmol) in DME (12 mL). Pd(PPh3)4 (30 mg, 0.03 mmol) and saturated Na2CO3 (1.9 mL) were added and the reaction was heated to 80° C. under an argon atmosphere overnight. After cooling, the reaction was extracted with saturated NaCl and CH2Cl2. Organic phases were combined, concentrated in vacuo and purified by RP-HPLC (MeCN:H2O:0.1% TFA) to yield BA48 (4.5 mg, 16% yield). ESI-MS (M+H)+ m/z calcd 284.1, found 284.1.
Reaction SMILES: [Cl:1][C:2]1[C:7](=[O:8])[NH:6][C:5]([CH2:9][C:10]([O-:12])=O)=[N:4][C:3]=1[N:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1.[Na+].[CH3:20][C@H:21]1[CH2:29][C:28]2[C:23](=[CH:24][CH:25]=[CH:26][C:27]=2[F:30])[NH:22]1>>[Cl:1][C:2]1[C:7](=[O:8])[NH:6][C:5]([CH2:9][C:10]([N:22]2[C:23]3[C:28](=[C:27]([F:30])[CH:26]=[CH:25][CH:24]=3)[CH2:29][C@@H:21]2[CH3:20])=[O:12])=[N:4][C:3]=1[N:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1
Reactant: O=C([O-])Cc1nc(N2CCOCC2)c(Cl)c(=O)[nH]1
Reactant: C[C@H]1Cc2c(F)cccc2N1
Agent: [Na+]
Product: C[C@H]1Cc2c(F)cccc2N1C(=O)Cc1nc(N2CCOCC2)c(Cl)c(=O)[nH]1
Yield: 33.4 %

Procedure:
The product is prepared by following the procedure described in example 1a (step 5a) using 220 mg of sodium (5-chloro-4-morpholin-4-yl-6-oxo-1,6-dihydropyrimidin-2-yl)acetate and 110 mg of (S)-2-methyl-4-fluoro-2,3-dihydro-1H-indole (which can be prepared according to Krasnov, V. P. et al. (Mendeleev Commun. 2002, 12(1), 27-28)). After silica column purification: eluent 99/01 then 98/02 then 97/03 dichloromethane/methanol, 99 mg of 5-chloro-2-[2-((S)-2-methyl-4-fluoro-2,3-dihydroindol-1-yl)-2-oxoethyl]-6-morpholin-4-yl-3H-pyrimidin-4-one are obtained in the form of a solid, the characteristics of which are the following:
Reaction SMILES: CCC[C:4]1[C:5]2[N:14]=[C:13](C3C=C(S(N4CCN(C)CC4)(=O)=O)C=CC=3OCC)[NH:12][C:10](=O)[C:6]=2[N:7](C)[N:8]=1.[OH-:34].[Na+]>>[N:7]1[C:6]2[CH:10]=[N:12][CH:13]=[N:14][C:5]=2[C:4](=[O:34])[N:8]=1
Reactant: CCCc1nn(C)c2c(=O)[nH]c(-c3cc(S(=O)(=O)N4CCN(C)CC4)ccc3OCC)nc12
Reactant: [OH-]
Agent: [Na+]
Product: O=C1N=Nc2cncnc21
Yield: 77 %

Procedure:
Drug preparation: Sildenafil was synthesized in 6 steps according to reported procedures (Terrett et al., 1996) (U.S. Pat. No. 5,346,901. 1994). Briefly, commercially available 2-ethoxybenzoic acid was converted to 2-ethoxybenzoyl chloride with thionyl chloride. Reaction of 2-ethoxybenzoyl chloride with 4-amino-1-methyl-3-N-propylpyrazole-5-carboxamide yielded the amide in 90% yield. Cyclization of the amide using NaOH afforded pyrazolopyrimidinone in 77% yield. Chlorosulfonylation of the pyrazolopyrimidinone in chlorosulfonic acid, followed by reaction with N-methylpiperazine provided sildenafil in 90% yield. Tadalafil was also synthesized according to reported procedures (Daugan et al., 2003b). Briefly, D-tryptophan methyl ester reacted with piperonal under Pictet-Spengler reaction condition (TFA/CH2Cl2/MeOH) and the resulting product condensed with chloroacetyl chloride to provide acylated intermediate. Reaction of the intermediate with N-methyl amine provided tadalafil. Tadalafil was diluted in 0.1% DMSO.
Reaction SMILES: O[C:2]1[CH:17]=[C:16]([OH:18])[CH:15]=[CH:14][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][C:7]=1[OH:13])=O.C([O-])(=O)C.[Na+].Cl.[C:25]([C:27]1[CH:32]=[CH:31][C:30]([NH:33][NH2:34])=[CH:29][CH:28]=1)#[N:26]>>[OH:13][C:7]1[CH:8]=[C:9]([OH:12])[CH:10]=[CH:11][C:6]=1[C:4]1[C:3]2[C:2](=[CH:17][C:16]([OH:18])=[CH:15][CH:14]=2)[N:33]([C:30]2[CH:31]=[CH:32][C:27]([C:25]#[N:26])=[CH:28][CH:29]=2)[N:34]=1
Reactant: N#Cc1ccc(NN)cc1
Reactant: O=C(c1ccc(O)cc1O)c1ccc(O)cc1O
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Product: N#Cc1ccc(-n2nc(-c3ccc(O)cc3O)c3ccc(O)cc32)cc1
Yield: 7 %

Procedure:
Prepared according to Method B from 2,2′,4,4′-tetrahydroxybenzophenone (0.123 g, 0.5 mmol), sodium acetate (0.041 g, 0.5 mmol) and 4-cyanophenylhydrazine hydrochloride (0.085 g, 0.5 mmol) to give 0.012 g of product as a yellow solid MS (APCI) m/z 343 (M−.).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[CH2:5][C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][CH3:16])[CH:13]=2)[NH:8][C:7]=1[CH2:17][CH3:18])[CH3:2].[H-].[Na+].[Cl:22][C:23]1[CH:24]=[C:25]([CH:28]=[CH:29][CH:30]=1)[CH2:26]Cl>O>[CH2:1]([O:3][C:4](=[O:19])[CH2:5][C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][CH3:16])[CH:13]=2)[N:8]([CH2:26][C:25]2[CH:28]=[CH:29][CH:30]=[C:23]([Cl:22])[CH:24]=2)[C:7]=1[CH2:17][CH3:18])[CH3:2]
Reactant: CCOC(=O)Cc1c(CC)[nH]c2ccc(OC)cc12
Reactant: ClCc1cccc(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: CCOC(=O)Cc1c(CC)n(Cc2cccc(Cl)c2)c2ccc(OC)cc12
Reaction time: 0.5 h
Yield: 74.6 %

Procedure:
2-Ethyl-5-methoxy-1H-indole-3-acetic acid ethyl ester (1.82 g, 7.4 mmol) was added to 296 mg (7.4 mmol) of NaH/mineral oil (previously washed with hexane), the mixture stirred for 0.5 hours and 0.93 mL (7.4 mmol) of 3-chlorobenzyl chloride added. After 21 hours, water was added and the mixture extracted with ethyl acetate. The ethyl acetate was washed with brine, dried (MgSO4) and concentrated at reduced pressure. The residue was chromatographed on silica gel eluting with 20% EtOAc/hexane to give 2.13 g (75% yield) of 1-[(3-chlorophenyl)methyl]-2-ethyl-5-methoxy-1H-indole-3-acetic acid ethyl ester as an oil.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][CH:9]=1)[NH2:6].N1C=CN=C1.[Si:15](Cl)([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16].O>CN(C=O)C>[Si:15]([O:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][CH:9]=1)[NH2:6])([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16]
Reactant: Nc1cccc(CO)c1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)[Si](C)(C)OCc1cccc(N)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 62.4 %

Procedure:
To 1.00 g (8.1 mmol) of 3-hydroxymethylaniline in 25 mL of DMF was added 0.61 g (8.9 mmol) of imidazole and 1.35 g (8.9 mmol) of tert-butyldimethylsilyl chloride. The reaction was stirred at room temperature for 18 h and poured into 12 volumes of water. The product was extracted with ether and the combined organic layers were washed successively with water and brine, dried over sodium sulfate, filtered and concentrated to a golden oil. The oil was purified by flash chromatography eluting with a 20% ethyl acetate/hexanes mixture to give 1.2 g (62%) of the title compound as a colorless oil.
Reaction SMILES: CS(O[CH2:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:23]=[CH:22][C:14]2[C:15]([CH3:21])([CH3:20])[O:16][C:17](=[O:19])[NH:18][C:13]=2[CH:12]=1)(=O)=O.[C:24]1([SH:30])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[C:24]1([S:30][CH2:6][CH2:7][CH2:8][CH2:9][O:10][C:11]2[CH:23]=[CH:22][C:14]3[C:15]([CH3:20])([CH3:21])[O:16][C:17](=[O:19])[NH:18][C:13]=3[CH:12]=2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: CC1(C)OC(=O)Nc2cc(OCCCCOS(C)(=O)=O)ccc21
Reactant: Sc1ccccc1
Product: CC1(C)OC(=O)Nc2cc(OCCCCSc3ccccc3)ccc21

Procedure:
Prepared analogously to Example 210 from 7-(4-methanesulfonyloxy-butoxy)-4,4-dimethyl-4H-3,1-benzoxazin-2-one and thiophenol.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][NH:5][C:6]1[CH:11]=[N:10][CH:9]=[CH:8][N:7]=1.[C:12]([N:20]=[C:21]=[S:22])(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[C:12]([NH:20][C:21]([NH:1][CH2:2][CH2:3][CH2:4][NH:5][C:6]1[CH:11]=[N:10][CH:9]=[CH:8][N:7]=1)=[S:22])(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C(N=C=S)c1ccccc1
Reactant: NCCCNc1cnccn1
Product: O=C(NC(=S)NCCCNc1cnccn1)c1ccccc1

Procedure:
Reacting 2-(3-aminopropylamino)pyrazine with benzoyl isothiocyanate by the procedure of Example 46 gives N-benzoyl-N'-[3-(2-pyrazinylamino)propyl]thiourea. Removing the benzoyl group by the procedure of Example 46 gives N-[3-(2-pyrazinylamino)propyl]thiourea.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10](Cl)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[NH2:13][C:14]1[CH:18]=[C:17]([CH:19]2[CH2:23][CH2:22][CH2:21][CH2:20]2)[NH:16][N:15]=1.C(N(CC)CC)C>C(O)C>[Cl:1][C:2]1[N:11]=[C:10]([NH:13][C:14]2[NH:15][N:16]=[C:17]([CH:19]3[CH2:23][CH2:22][CH2:21][CH2:20]3)[CH:18]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: Clc1nc(Cl)c2ccccc2n1
Reactant: Nc1cc(C2CCCC2)[nH]n1
Solvent: CCO
Solvent: CCN(CC)CC
Product: Clc1nc(Nc2cc(C3CCCC3)n[nH]2)c2ccccc2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 66.1 %

Procedure:
2,4-Dichloroquinazoline (0.657 g, 3.3 mmol) in ethanol (9 ml) was treated with 3-amino-5-cyclopentyl pyrazole (0.5 g, 3.3 mmol) and triethylamine (0.46 ml, 3.3 mmol) and stirred overnight at room temperature. The mixture was filtered and the solid washed with ethanol to give (2-chloro-quinazolin-4-yl)-(5-cyclopentyl-2H-pyrazol-3-yl)-amine as colourless crystals (684 mg, 66%).
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[C:10]2[C:5](=[CH:6][C:7]([N+:15]([O-:17])=[O:16])=[C:8]([NH:11]C(=O)C)[CH:9]=2)[NH:4][C:3]1=[O:18].Br[CH2:21]/[CH:22]=[CH:23]/[CH2:24][CH3:25].CC([O-])(C)C.[K+].C1CCN2C(=NCCC2)CC1>CO>[NH2:11][C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][C:7]=1[N+:15]([O-:17])=[O:16])[N:4]([CH2:21]/[CH:22]=[CH:23]/[CH2:24][CH3:25])[C:3](=[O:18])[C:2]2([CH3:1])[CH3:19]
Reactant: CC/C=C/CBr
Reactant: CC(=O)Nc1cc2c(cc1[N+](=O)[O-])NC(=O)C2(C)C
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCC2=NCCCN2CC1
Solvent: CO
Product: CC/C=C/CN1C(=O)C(C)(C)c2cc(N)c([N+](=O)[O-])cc21
Yield: 37.1 %

Procedure:
Analogously to general procedure (I) N-(3,3-dimethyl-6-nitro-2-oxo-2,3-dihydro-1H-indol-5-yl)-acetamide (1.47 g) is alkylated using (E)-1-bromo-2-pentene (1 g; 6.71 mmol) and KOtBu (0.75 g; 6.71 mmol) at RT for 20 h. After aqueous work-up and flash chromatography on silica gel eluting with light petroleum/EtOAc (2.5:1) the pure alkylated acetamide (0.85 g; 2.58 mmol) is de-acetylated under reflux conditions using DBU (0.6 ml) in MeOH (60 ml). (E)-5-amino-3,3-dimethyl-6-nitro-1-(pent-2-enyl)-1,3-dihydro-indol-2-one (0.6 g) is obtained after an aqueous work-up.
Reaction SMILES: [O:1]=[C:2]1[CH2:6][S:5][CH2:4][CH:3]1[C:7]([O:9][CH3:10])=[O:8].[Cl:11][C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][CH:19]=1)[CH:15]=O.N1CCCCC1>CO>[Cl:11][C:12]1[CH:13]=[C:14]([CH2:15][C:6]2[S:5][CH:4]=[C:3]([C:7]([O:9][CH3:10])=[O:8])[C:2]=2[OH:1])[CH:17]=[CH:18][CH:19]=1
Reactant: O=Cc1cccc(Cl)c1
Reactant: COC(=O)C1CSCC1=O
Solvent: CO
Solvent: C1CCNCC1
Product: COC(=O)c1csc(Cc2cccc(Cl)c2)c1O
Temperature: 25 °C
Yield: 68.4 %

Procedure:
Methyl 4-oxotetrahydrothiophene-3-carboxylate (18.5 g) and 3-chlorobenzaldehyde (48.5 g) were heated at 100° C. with piperidine (4 ml) for 15 minutes and then allowed to cool to room temperature. The resulting yellow solid was stirred in methanol (300 ml) for 18 hours and collected. The yellow solid was suspended in ethanol (300 m) and dichloromethane (200 ml), para-toluenesulfonic acid(10 g) was added and the suspension was heated at reflux for 48 hours. The reaction mixture was allowed to cool and was then concentrated. The residue was purified by chromatography, eluting with 10:1 isohexane:dichloromethane, to give the sub-title compound (22.32 g).
Reaction SMILES: [N+:1]([C:4]1[CH:16]=[CH:15][C:7]([O:8][CH:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[C:6]([C:17]([F:20])([F:19])[F:18])[CH:5]=1)([O-:3])=[O:2].[O:21]1[CH2:24][C:23](=O)[CH2:22]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>ClCCCl.C(Cl)Cl>[N+:1]([C:4]1[CH:16]=[CH:15][C:7]([O:8][CH:9]2[CH2:14][CH2:13][N:12]([CH:23]3[CH2:24][O:21][CH2:22]3)[CH2:11][CH2:10]2)=[C:6]([C:17]([F:20])([F:18])[F:19])[CH:5]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(OC2CCNCC2)c(C(F)(F)F)c1
Reactant: O=C1COC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: ClCCCl
Product: O=[N+]([O-])c1ccc(OC2CCN(C3COC3)CC2)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 77 %

Procedure:
A solution of 4-(4-nitro-2-(trifluoromethyl)phenoxy)piperidine (1.0 g, 1.0 eq, 3.5 mmol) and oxetan-3-one (0.35 g, 1.4 eq, 4.8 mmol) in 1,2-dichloroethane (50 mL) was stirred at room temperature for 30 minutes. Sodium triacetoxyborohydride (1.3 g, 1.8 eq, 6.2 mmol) was added in portions to the above solution and the heterogeneous mixture was stirred at room temperature overnight. The reaction mixture was diluted with CH2Cl2 (50 mL) and pardoned with aqueous saturated NaHCO3 solution (100 mL). The layers were separated and the organic layer was washed with brine solution (2×50 mL). The combined organic layers were dried over Na2SO4. Removal of the solvents and purification of the crude mixture by column chromatography on silica gel (ISCO System) using 20% MeOH in CH2Cl2/CH2Cl2 (gradient system from 0:1 to 1:9) as eluent gave the product in 77% yield.