Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH3:29])[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2([C:22]3[CH:23]=[C:24]([CH3:28])[CH:25]=[CH:26][CH:27]=3)[CH:15]3[CH:11]([CH2:12][N:13](C(OC=C)=O)[CH2:14]3)[C:10](=[O:21])[CH2:9][CH2:8]2)[CH:2]=1.[ClH:30]>O1CCOCC1>[ClH:30].[C:1]1([CH3:29])[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2([C:22]3[CH:23]=[C:24]([CH3:28])[CH:25]=[CH:26][CH:27]=3)[CH:15]3[CH:11]([CH2:12][NH:13][CH2:14]3)[C:10](=[O:21])[CH2:9][CH2:8]2)[CH:2]=1
Reactant: C=COC(=O)N1CC2C(=O)CCC(c3cccc(C)c3)(c3cccc(C)c3)C2C1
Agent: Cl
Solvent: C1COCCO1
Product: Cc1cccc(C2(c3cccc(C)c3)CCC(=O)C3CNCC32)c1
Temperature: 60 °C
Reaction time: 16 h

Procedure:
(3aRS,7aRS)-7,7-bis-(3-tolyl)-2-vinyloxycarbonyl-4-perhydroisoindolone (7.4 g) is treated with a 6N solution (39 cc) of hydrochloric acid in dioxane for 30 minutes at 25° C. The solution is concentrated to dryness under reduced pressure (2.7 kPa) and the residue is taken up in ethanol (100 cc). The solution is heated at 60° C. for 2 hours and stirred for 16 hours at 25° C. and then concentrated to dryness under reduced pressure (2.7 kPa). The residue is solidified using isopropyl ether and the solid is washed, drained and dried. 7,7-bis-(3-Tolyl)-4-perhydroisoindolone hydrochloride (6.36 g) is obtained in the form of a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][C:5]2[NH:11][C:10](=[O:12])[C:9]([F:14])([F:13])[CH2:8][N:7]([CH:15]([CH3:17])[CH3:16])[C:6]=2[N:18]=1.[H-].[Na+].[CH3:21]I>CC(N(C)C)=O>[Cl:1][C:2]1[N:3]=[CH:4][C:5]2[N:11]([CH3:21])[C:10](=[O:12])[C:9]([F:14])([F:13])[CH2:8][N:7]([CH:15]([CH3:16])[CH3:17])[C:6]=2[N:18]=1
Reactant: CC(C)N1CC(F)(F)C(=O)Nc2cnc(Cl)nc21
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: CC(C)N1CC(F)(F)C(=O)N(C)c2cnc(Cl)nc21
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 89.6 %

Procedure:
2-chloro-7,7-difluoro-9-isopropyl-8,9-dihydro-5H-pyrimido[4,5-b][1,4]diazepin-6(7H)-one (0.800 g, 2.89 mmol) was dissolved in DMA (7 mL) and cooled to 0° C. under nitrogen. NaH (140 mg, 3.50 mmol) was added, the mixture was stirred for 20 min and MeI (0.23 mL, 3.61 mmol) was added dropwise. The reaction mixture was stirred at room temperature for 1 h and quenched with water (25 mL). The pH was adjusted to 1 (aq. HCl) and the mixture was extracted with ethyl acetate (4×20 mL). The comb organic extracts were concentrated in vacuo, dissolved in dichloromethane/trifluoroacetic acid (5:1, 6 ml) and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (80 g SiO2, hexanes:ethyl acetate 1:1) to afford the title compound as a yellow solid (0.753 g, 90%).
Reaction SMILES: [SH:1][CH2:2][CH2:3][OH:4].[CH3:5][C:6]1([CH3:9])[CH2:8][NH:7]1>C(COC)OC>[NH2:7][C:6]([CH3:9])([CH3:8])[CH2:5][S:1][CH2:2][CH2:3][OH:4]
Reactant: CC1(C)CN1
Reactant: OCCS
Solvent: COCCOC
Product: CC(C)(N)CSCCO
Temperature: 70 °C
Reaction time: 4 h

Procedure:
234 g of 2-mercaptoethanol are dissolved in 90 ml of dimethoxyethane. 63.3 g of 2,2-dimethylaziridine are added dropwise to this solution and the mixture is stirred at 70° C. for 4 hours and concentrated, and the residue is distilled in a water jet vacuum. B.p.: 141°-142° C. (at 20 mbar); M.p.: 49°-51°;
Reaction SMILES: [OH:1][CH:2]1[CH2:7][C:6]([CH3:9])([CH3:8])[C:5]([CH:10]=[CH:11][C:12]([CH3:20])(O[Si](C)(C)C)[CH:13]=[CH2:14])=[C:4]([CH3:21])[C:3]1=[O:22].[C:23]1([S:29]([OH:31])=[O:30])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.[Na]>C(O)(=O)C>[OH:1][CH:2]1[CH2:7][C:6]([CH3:9])([CH3:8])[C:5]([CH:10]=[CH:11][C:12]([CH3:20])=[CH:13][CH2:14][S:29]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)(=[O:31])=[O:30])=[C:4]([CH3:21])[C:3]1=[O:22]
Reactant: C=CC(C)(C=CC1=C(C)C(=O)C(O)CC1(C)C)O[Si](C)(C)C
Reactant: O=S(O)c1ccccc1
Agent: [Na]
Solvent: CC(=O)O
Product: CC(C=CC1=C(C)C(=O)C(O)CC1(C)C)=CCS(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 1-(4-hydroxy-3-oxo-2,6,6-trimethyl-1-cyclo- hexen-1-yl)-3-methyl-3-trimethylsiloxy-1,4-pentadiene (200 mg, 0.62 mmol) in 1 ml glacial acetic acid is added benzenesulfinic acid, sodium salt (153 mg, 0.93 mmoles) and the mixture is stirred overnight at ambient temperature. The mixture is concentrated in vacuo and the remanecens is taken up in 10 ml diethylether and 10 ml 1M sodium hydroxide. The aqueous layer is separated and extracted twice with 10 ml diethylether. The combined ether phases are dried and concentrated in vacuo yielding the title compound as a slightly yellow oil.
Reaction SMILES: [CH2:1]([C:3]1[C:10]2[CH2:9][NH:8][C:7](=O)[C:6]=2[N:5]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[N:4]=1)[CH3:2].[H-].[Na+].CI.[CH3:23][OH:24].O1CCC[CH2:26]1>>[CH3:26][CH:9]1[N:8]([CH3:7])[C:23](=[O:24])[C:6]2[N:5]([C:12]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=3)[N:4]=[C:3]([CH2:1][CH3:2])[C:10]1=2
Reactant: C1CCOC1
Reactant: CO
Reactant: CCc1nn(-c2ccc(F)cc2)c2c1CNC2=O
Agent: [H-]
Agent: [Na+]
Solvent: CI
Product: CCc1nn(-c2ccc(F)cc2)c2c1C(C)N(C)C2=O
Temperature: 25 °C

Procedure:
A mixture of 3-ethyl-1-(4-fluorophenyl)-6-oxo-4,6-dihydro-1H-pyrazolo[3,4-c]pyrrole (0.20 g, 0.82 mmole) and 60% sodium hydride (0.49 g, 1.2 mmole) in anhydrous tetrahydrofuran (4 ml) was heated to reflux. After 45 minutes the reaction mixture was cooled to room temperature and methyl iodide (0.29 g, 2.0 mmole) added. The mixture was then heated to reflux over 16 hours. The mixture was treated with methanol (1 ml) and the solvent removed under reduced pressure. The crude residue was chromatographed on a silica column using 1:4 ethyl acetate/hexane as eluent to give 0.12 g of the title compound. Recrystallization from ether/petroleum ether gave white crystals. M.P. 65°-65° C., Anal. calcd. for C15H16FN3O: C, 65.92; H, 5.90; N, 15.37. Found: C, 66.15; H, 5.60; N, 15.53; MS m/z 274.
Reaction SMILES: [CH:1]1[C:6]2[CH2:7][NH:8][C:9]3[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=3[O:11][C:5]=2[CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[C:23]1([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:28]=[CH:27][C:26]([C:29](Cl)=[O:30])=[CH:25][CH:24]=1>C(Cl)Cl.C(Cl)(Cl)Cl>[C:23]1([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH:24]=[CH:25][C:26]([C:29]([N:8]2[CH2:7][C:6]3[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=3[O:11][C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]2=3)=[O:30])=[CH:27][CH:28]=1
Reactant: O=C(Cl)c1ccc(-c2ccccc2)cc1
Reactant: c1ccc2c(c1)CNc1ccccc1O2
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: O=C(c1ccc(-c2ccccc2)cc1)N1Cc2ccccc2Oc2ccccc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 83.6 %

Procedure:
To a cooled (0° C.) solution of 1.0 g of 10,11-dihydrodibenz[b,f][1,4]oxazepine and 7 ml of triethylamine in 30 ml of CH2Cl2 under argon is added dropwise 2.0 g of [1,1'-biphenyl]-4-carbonyl chloride. The mixture is stirred at room temperature for 16 hours and diluted with 50 ml of CHCl3. The mixture is washed with 30 ml each of H2O, 2NHCl, H2O, saturated NaHCO3, H2O, and dried (Na2SO4). Solvent is removed under vacuum to give 1.6 g of a yellow solid, m.p. 93°-95° C; Mass spectrum (CI), 378(MH+).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([O:13][CH2:14][C:15]([OH:17])=[O:16])[CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[C:18](=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([O:13][CH2:14][C:15]([O:17][CH3:18])=[O:16])[CH2:9][CH2:10][CH2:11][CH2:12]2)=[CH:6][CH:7]=1
Reactant: O=C(O)COC1(c2ccc(Br)cc2)CCCC1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)COC1(c2ccc(Br)cc2)CCCC1
Temperature: 25 °C
Reaction time: 40 h

Procedure:
To an ambient solution of Example 30B (200 mg, 0.668 mmol) in N,N-dimethylformamide (4 mL) was added iodomethahe (0.208 mL. 3.34 mmol) and potassium carbonate (184 mg, 1.34 mmol). The mixture was stirred at room temperature for 40 h, and then diluted with water (10 mL) and ethyl acetate (20 mL). The layers were separated, and the organic was washed with water (3×10 mL), brine (1×10 mL), dried over sodium sulfate, and concentrated under reduced pressure to give the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.67-1.72 (m, 2 H), 1.74-1.84 (m, 4 H), 2.10 (m, 2 H), 3.58 (s, 3 H), 3.67-3.70 (m, 2 H), 7.34-7.40 (m, 2 H), 7.51-7.57 (m, 2 H).
Reaction SMILES: C[C@@:2]1([C:5]2[CH:6]=[N:7][CH:8]=[CH:9][CH:10]=2)[CH2:4][O:3]1.[NH2:11][C@H:12]([CH3:27])[CH2:13][C:14]1[C:22]2[C:17](=[C:18]([C:23]([O:25][CH3:26])=[O:24])[CH:19]=[CH:20][CH:21]=2)[NH:16][CH:15]=1.N1C=CN=C1.[CH2:33]([Si:35](Cl)([CH2:38][CH3:39])[CH2:36][CH3:37])[CH3:34]>CO.CN(C)C1C=CN=CC=1.C(OCC)(=O)C>[N:7]1[CH:8]=[CH:9][CH:10]=[C:5]([C@@H:2]([O:3][Si:35]([CH2:38][CH3:39])([CH2:36][CH3:37])[CH2:33][CH3:34])[CH2:4][NH:11][C@H:12]([CH3:27])[CH2:13][C:14]2[C:22]3[C:17](=[C:18]([C:23]([O:25][CH3:26])=[O:24])[CH:19]=[CH:20][CH:21]=3)[NH:16][CH:15]=2)[CH:6]=1
Reactant: C[C@@]1(c2cccnc2)CO1
Reactant: COC(=O)c1cccc2c(C[C@@H](C)N)c[nH]c12
Reactant: CC[Si](Cl)(CC)CC
Agent: CN(C)c1ccncc1
Agent: c1c[nH]cn1
Solvent: CO
Solvent: CCOC(C)=O
Product: CC[Si](CC)(CC)O[C@@H](CN[C@H](C)Cc1c[nH]c2c(C(=O)OC)cccc12)c1cccnc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 24.3 %

Procedure:
A solution of methyl (R)-(pyridin-3-yl)oxirane (1.17 g, 9.7 mmol) and methyl (R)-3-(2-aminopropyl)-1H-indole-7-carboxylate (1.50 g, 6.5 mmol) in methanol (10 mL) is stirred at 100° C. for 2 hours under sealed conditions, and the mixture is cooled and concentrated. The residue is dissolved in N,N-dimethylformamide (20 mL), and thereto are added imidazole (1.70 g, 25 mmol) and 4-dimethylaminopyridine (61 mg, 0.5 mmol) and triethylsilyl chloride (3.25 mL, 19.4 mmol). The mixture is stirred at room temperature for 3 hours, and thereto are added ethyl acetate. The mixture is washed with a saturated aqueous sodium hydrogen carbonate solution, water, and a saturated brine, dried over sodium sulfate, and concentrated. The residue is purified by silica gel column chromatography (methanol/chloroform=1/50) to give the desired methyl 3-[(2R)-2-(2-pyridin-3-yl-(2 R)-2-(triethylsilyloxy)ethyl-amino)propyl]-1H-indole-7-carboxylate (0.74 g, yield: 24%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[CH:7]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:6]2.C([O-])([O-])=O.[K+].[K+].Br[CH2:25][CH2:26][F:27]>CC(N(C)C)=O>[F:27][CH2:26][CH2:25][C:7]1([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:6][C:5]2[C:9](=[CH:10][CH:11]=[C:3]([O:2][CH3:1])[CH:4]=2)[C:8]1=[O:12]
Reactant: CCOC(=O)C1Cc2cc(OC)ccc2C1=O
Reactant: FCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: CCOC(=O)C1(CCF)Cc2cc(OC)ccc2C1=O
Temperature: 65 °C
Reaction time: 20 h

Procedure:
To a mixture of ethyl 5-methoxy-1-oxoindane-2-carboxylate (crude product from the preceding two reactions, ˜190 mmol), K2CO3 (53.8 g, 389 mmol) and KI (64.7 g, 390 mmol) in anhydrous dimethylacetamide (792 mL) was added 1-bromo-2-fluoroethane (18.4 mL, 247 mmol) and the mixture was stirred and heated at 65° C. After 20 hours, analysis of an aliquot by NMR showed the reaction to be complete. After cooling to room temperature, most of the dimethylacetamide was removed by evaporation at reduced pressure. The residue was partitioned between EtOAc and water and the organic phase was washed with water (4 times) and brine and dried over Na2SO4. Filtration and removal of the solvent under reduced pressure gave crude ethyl 2-(2-fluoroethyl)-5-methoxy-1-oxoindane-2-carboxylate which was used in the next step without purification.
Reaction SMILES: F[C:2]1[CH:14]=[C:13]([NH2:15])[CH:12]=[CH:11][C:3]=1[CH:4]=[CH:5][C:6]([O:8][CH2:9][CH3:10])=[O:7].Br[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32].C(=O)([O-])[O-].[K+].[K+]>CN(C)P(N(C)C)(N(C)C)=O.O>[CH2:32]([NH:15][C:13]1[CH:12]=[CH:11][C:3]([CH:4]=[CH:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:2][CH:14]=1)[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH3:17]
Reactant: CCOC(=O)C=Cc1ccc(N)cc1F
Reactant: CCCCCCCCCCCCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: O
Product: CCCCCCCCCCCCCCCCNc1ccc(C=CC(=O)OCC)cc1
Temperature: 60 °C

Procedure:
A mixture of ethyl 2-fluoro-4-aminocinnamate, one equivalent of 1-bromohexadecane and one equivalent of anhydrous potassium carbonate in hexamethylphosphoramide is heated for 20 hours at 60° C. The mixture is then cooled, diluted with water and extracted with ether. The combined ether extracts are dried, filtered and evaporated to provide ethyl 4-hexadecylaminocinnamate. The ester is hydrolyzed with sodium hydroxide in a 1:9 water:ethanol solution at steam bath temperatures for 10 hours. The hot solution is then acidified with acetic acid, cooled and filtered and the solid is washed with water. Recrystallization from chloroform yields 2-fluoro-4-(hexadecylamino)cinnamic acid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[S:14][C:13]3[C:8](=[N:9][CH:10]=[C:11]([C:23]#[N:24])[C:12]=3[NH:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([Br:22])[CH:17]=3)[C:6]=2[CH:7]=1.Cl.CN(C)CCCN=C=NCC.[C:37](O)(=[O:40])[CH:38]=[CH2:39].C(N(C(C)C)CC)(C)C>CN(C)C=O.O1CCCC1>[Br:22][C:18]1[CH:17]=[C:16]([CH:21]=[CH:20][CH:19]=1)[NH:15][C:12]1[C:11]([C:23]#[N:24])=[CH:10][N:9]=[C:8]2[C:6]3[CH:7]=[C:2]([NH:1][C:37](=[O:40])[CH:38]=[CH2:39])[CH:3]=[CH:4][C:5]=3[S:14][C:13]=12
Reactant: N#Cc1cnc2c(sc3ccc(N)cc32)c1Nc1cccc(Br)c1
Reactant: C=CC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: C=CC(=O)Nc1ccc2sc3c(Nc4cccc(Br)c4)c(C#N)cnc3c2c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 36.8 %

Procedure:
To a 0° C. solution of 164 mg (0.417 mmol) of 8-amino-4-(3-bromoanilino)-[1]benzothieno[3,2-b]pyridine-3-carbonitrile and 120 mg (0.626 mmol) of 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride in 2 mL of dimethylformamide and 2 mL of tetrahydrofuran is added 0.045 mL (0.656 mmol) of acrylic acid followed by 0.110 mL (0.633 mmol) of diisopropylethylamine. The reaction mixture is stirred at room temperature for 4 hours then partitioned between methylene choride and water. The aqueous layer is extracted with additional methylene chloride and the organic layers are combined, dried over magnesium sulfate, filtered and concentrated in vacuo. The residue is purified by flash chromatography, eluting with a gradient of 95:5 methylene chloride/methanol to 9:1 methylene chloride/methanol, to provide 69 mg of N-[4-(3-bromoanilino)-3-cyano[1]benzothieno[3,2-b]pyridin-8-yl]acrylamide as a light tan solid, mp>300° C. dec.
Reaction SMILES: OCCN1CCN(CC(NC2C(SC)=NC(C)=CC=2SC)=O)CC1.O[CH2:26][CH2:27][N:28]1[CH2:33][CH2:32][N:31]([CH2:34][C:35]([NH:37][C:38]2[C:39]([O:51][CH2:52][C:53]([F:56])([F:55])[F:54])=[N:40][C:41]([CH3:50])=[CH:42][C:43]=2[O:44][CH2:45][C:46]([F:49])([F:48])[F:47])=[O:36])[CH2:30][CH2:29]1.SC1NC2C=CC=CC=2N=1.[F:67][C:68]1[C:77]([F:78])=[CH:76][C:71]2[N:72]=[C:73]([SH:75])[NH:74][C:70]=2[CH:69]=1>>[F:78][C:77]1[C:68]([F:67])=[CH:69][C:70]2[N:74]=[C:73]([S:75][CH2:26][CH2:27][N:28]3[CH2:33][CH2:32][N:31]([CH2:34][C:35]([NH:37][C:38]4[C:39]([O:51][CH2:52][C:53]([F:56])([F:54])[F:55])=[N:40][C:41]([CH3:50])=[CH:42][C:43]=4[O:44][CH2:45][C:46]([F:47])([F:48])[F:49])=[O:36])[CH2:30][CH2:29]3)[NH:72][C:71]=2[CH:76]=1
Reactant: Fc1cc2nc(S)[nH]c2cc1F
Reactant: Cc1cc(OCC(F)(F)F)c(NC(=O)CN2CCN(CCO)CC2)c(OCC(F)(F)F)n1
Agent: CSc1cc(C)nc(SC)c1NC(=O)CN1CCN(CCO)CC1
Agent: Sc1nc2ccccc2[nH]1
Product: Cc1cc(OCC(F)(F)F)c(NC(=O)CN2CCN(CCSc3nc4cc(F)c(F)cc4[nH]3)CC2)c(OCC(F)(F)F)n1

Procedure:
The reaction and treatments of Example 12 were repeated, except that 2-[4-(2-hydroxyethyl)piperazin-1-yl]-N-[2,4-bis(methylthio)-6-methylpyridin-3-yl]acetamide was replaced by 2-[4-(2-hydroxyethyl)piperazin-1-yl]-N-[2,4-bis(2,2,2-trifluoroethoxy)-6-methylpyridin-3-yl]acetamide, and 2-mercaptobenzimidazole was replaced by 5,6-difluoro-2-mercaptobenzimidazole, to thereby yield the title compound as a colorless foamed substance.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[N:11]([C:12]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[O:13])[CH2:10][C:9](=[O:22])[NH:8][C:7]=2[N:23]=1.[H-].[Na+].[N+](C1C=C(S(O[CH2:39][C@@H:40]2[CH2:42][O:41]2)(=O)=O)C=CC=1)([O-])=O>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[N:11]([C:12]([O:14][CH2:15][C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)=[O:13])[CH2:10][C:9](=[O:22])[N:8]([CH2:39][C@@H:40]3[CH2:42][O:41]3)[C:7]=2[N:23]=1
Reactant: COc1ccc2c(n1)NC(=O)CN2C(=O)OCc1ccccc1
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)OC[C@@H]2CO2)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc2c(n1)N(C[C@@H]1CO1)C(=O)CN2C(=O)OCc1ccccc1
Temperature: 25 °C
Yield: 130.6 %

Procedure:
Phenylmethyl 6-(methyloxy)-3-oxo-3,4-dihydropyrido[2,3-b]pyrazine-1(2H)-carboxylate (11 g, 35.1 mmol) was dissolved in DMF (300 ml) at room temperature under argon to give a yellow solution. The solution was then cooled with an ice bath and treated with sodium hydride (1.685 g, 42.1 mmol). The solution was allowed to warm to room temperature. After 20 minutes (2S)-2-oxiranylmethyl 3-nitrobenzenesulfonate (9.56 g, 36.9 mmol) was added. After 1 h all the starting material was consumed so the reaction was treated with a saturated solution of sodium bicarbonate (350 ml) and the aqueous layer was extracted with DCM (3×400 ml). The combined organic layers were dried on magnesium sulphate, filtered and evaporated to afford a light brown oil (16.93 g). The product was used as crude in the next step.
Reaction SMILES: Br[C:2]1[C:3]2[C:4]3[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]=3[CH:12]=[CH:13][CH:14]=2.[CH3:15][N:16](C)C=O>>[C:15]([C:2]1[C:3]2[C:4]3[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]=3[CH:12]=[CH:13][CH:14]=2)#[N:16]
Reactant: CN(C)C=O
Reactant: O=C1Nc2ccc(Br)c3cccc1c23
Product: N#Cc1ccc2c3c(cccc13)C(=O)N2

Procedure:
A mixture consisting of 9.9 grams of 6-bromobenz(cd)indol-2one, 5 grams of cuprous cyanide and 100 ml of dry dimethylformamide was stirred and heated under reflux for 20 hours. The hot mixture was filtered, and the filtrate, after cooling, gave 3.2 grams of 6-cyanobenz (cd)indol-2-one, m.p. 315° C., with decomposition. Treatment of the latter compound with 2.2 grams of phosphorous pentasulfide in 100 ml of refluxing pyridine for 18 hours, concentrating to dryness and treating with water gave 2.8 grams of crude 6-cyanobenz(cd)indol-2-thione. A portion recrystallized from acetic acid melted above 320° C. 2.8 grams of 6-cyanobenz(cd)indol-2-thione, 1.7 grams of 3-(1H-imidazolyl)propylamine, 4.2 grams of mercuric acetate, 100 ml of ethanol and 20 ml of dimethylformamide were combined and heated under reflux for 7 hours. The hot reaction mixture was filtered through diatomaceous earth, and the cake washed with 25 ml of hot dimethylformamide. The filtrate was then concentrated to dryness in vacuo. The residue was shaken with 50 ml of 5N sodium hydroxide and the mixture extracted three times with 100 ml portions of chloroform. The combined chloroform extracts were dried over sodium sulfate and the chloroform removed in vacuo. The yellow residue was recrystallized from methanol, yielding 1.9 g of N-(3-(1H-imidazol-1-yl)propyl)-2-aminobenz(cd)indol-6-carbonitrile melting at 214°C.-215° C. and analyzing as the 1/4 hydiate.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([C:12]3([CH3:17])[O:16][CH2:15][CH2:14][O:13]3)=[CH:8][C:7]=2[C:18]2[C:19]3[NH:26][C:25]([CH3:27])=[C:24]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[C:20]=3[N:21]=[CH:22][N:23]=2)[CH2:3][CH2:2]1.Cl[CH2:34][O:35][CH2:36][CH2:37][Si:38]([CH3:41])([CH3:40])[CH3:39]>>[CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([C:12]3([CH3:17])[O:13][CH2:14][CH2:15][O:16]3)=[CH:8][C:7]=2[C:18]2[C:19]3[N:26]([CH2:34][O:35][CH2:36][CH2:37][Si:38]([CH3:41])([CH3:40])[CH3:39])[C:25]([CH3:27])=[C:24]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[C:20]=3[N:21]=[CH:22][N:23]=2)[CH2:3][CH2:2]1
Reactant: C[Si](C)(C)CCOCCl
Reactant: CCOC(=O)c1c(C)[nH]c2c(-c3cc(C4(C)OCCO4)ccc3OCC3CC3)ncnc12
Product: CCOC(=O)c1c(C)n(COCC[Si](C)(C)C)c2c(-c3cc(C4(C)OCCO4)ccc3OCC3CC3)ncnc12

Procedure:
Starting from ethyl 4-[2-(cyclopropylmethoxy)-5-(2-methyl-1,3-dioxolan-2-yl)phenyl]-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylate (example D.a13) and commercially available (2-chloromethoxy-ethyl)-trimethyl-silane the title compound is obtained as yellow viscous oil.
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]3[C:14]([C:15](Cl)=[C:6]2[CH:5]=[N:4]1)=[CH:13][C:12]([N+:17]([O-:19])=[O:18])=[CH:11][CH:10]=3)[CH3:2].C(N(CC)CC)C.[OH:27][CH:28]1[CH2:33][CH2:32][CH2:31][CH:30]([CH2:34][NH2:35])[CH2:29]1.[NH4+].[OH-]>C1COCC1.CS(C)=O>[CH2:1]([N:3]1[C:7]2=[N:8][C:9]3[C:14]([C:15]([NH:35][CH2:34][CH:30]4[CH2:31][CH2:32][CH2:33][CH:28]([OH:27])[CH2:29]4)=[C:6]2[CH:5]=[N:4]1)=[CH:13][C:12]([N+:17]([O-:19])=[O:18])=[CH:11][CH:10]=3)[CH3:2]
Reactant: CCn1ncc2c(Cl)c3cc([N+](=O)[O-])ccc3nc21
Reactant: NCC1CCCC(O)C1
Agent: [NH4+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: C1CCOC1
Product: CCn1ncc2c(NCC3CCCC(O)C3)c3cc([N+](=O)[O-])ccc3nc21
Temperature: 110 °C
Yield: 10.5 %

Procedure:
and (b) A mixture of 1-ethyl-6-nitro-4-chloro-1H-pyrazolo[3,4-b]quinoline (2.7 g, 17.8 mmol), triethylamine (3 ml, 0.02 mol), DMSO (15 ml) and 3-hydroxycyclohexylmethylamine (4.97 g, 18 mmol) is heated at 110° C. overnight. The reaction mixture is poured into ice water (200 ml)/NH4OH (10 ml) and the solid which forms is collected by filtration. The filtrate is then extracted with CH2Cl2 (2×100 ml). The solid is stirred and sonicated with CH2Cl2 (2×200 ml), and any solids which did not go into solution are collected by filtration. All of the above CH2Cl2 filtrates and extracts are combined, washed with water and evaporated. The residue is slurried with ethyl acetate (10-15 ml)/ether (20 ml) and a red colored solid is collected by filtration and washed with ether. The solid is purified by column chromatography (2×) on silica gel (note that the solid is preloaded onto 50-100 g of silica gel) eluting with 40% THF/cyclohexane and each of the diastereomers which is isolated is dissolved in hot THF, filtered and the solvent is evaporated. Each of the residues is slurried with ethanol (5 ml), filtered and dried to afford 0.69 g of 1-ethyl-6-nitro-N-(3-hydroxycyclohexylmethyl)-1H-pyrazolo[3,4-b]quinolin-4-amine (the RS,SR diastereomer which is labelled as Example 36(a)), m.p. 236°-238° C. and 2.23 g of 1-ethyl-6-nitro-N-(3-hydroxycyclohexylmethyl)-1H-pyrazolo[3,4-b]quinolin-4-amine (the RR,SS diastereomer which is labelled as Example 36(b)), m.p. 247°-248° C.
Reaction SMILES: S(=O)(=O)(O)O.O.[NH2:7][NH2:8].[CH3:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]([CH3:18])=O)=[CH:12][CH:11]=1.[Cl:19][C:20]1[CH:27]=[CH:26][C:23]([CH:24]=O)=[CH:22][CH:21]=1.[I-].[Na+]>>[Cl:19][C:20]1[CH:27]=[CH:26][C:23]([C:24]2[CH:18]=[C:16]([C:13]3[CH:14]=[CH:15][C:10]([CH3:9])=[CH:11][CH:12]=3)[NH:8][N:7]=2)=[CH:22][CH:21]=1
Reactant: NN
Reactant: O=Cc1ccc(Cl)cc1
Reactant: CC(=O)c1ccc(C)cc1
Agent: O=S(=O)(O)O
Agent: [I-]
Agent: [Na+]
Solvent: O
Product: Cc1ccc(-c2cc(-c3ccc(Cl)cc3)n[nH]2)cc1
Reaction time: 2.5 h
Yield: 92 %

Procedure:
326.7 parts (2 mol) of sulfuric acid were initiially introduced into the stirring flask. 37.5 parts (0.75 mol) of hydrazine hydrate, 100 parts (0.75 mol) of 4-methylacetophenone, 105 parts (0.75 mol) of 4-chlorobenzaldehyde and 1 part (0.0067 mol) of sodium iodide were meteredin in succession at room temperature. The reaction mixture was brought to 140° C. by distilling off water and kept at 140° C. for 2.5 hours. 140 parts of water were distilled off. The mixture was diluted with500 parts of water and neutralized with 500 parts (12.5 mol) of 20% strength by weight sodium hydroxide solution. After filtering off the solid it was washed until sulfate-free and dried. 189 parts of 3-(4-chlorophenyl)-5-(4-methylphenyl)pyrazole having a purity of 98% (HPLC) were obtained, which corresponds to a yield of 92% of theory. M.p.:228° C.