Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O)(=O)/C=[CH:3]/[C:4](O)=[O:5].[N:9]1([CH2:14][CH2:15][CH2:16][NH:17][C:18]2[C:26]3[CH:27]=[CH:28][CH:29]=[C:24]4[C:25]=3[C:20](=[CH:21][CH:22]=[CH:23]4)[N:19]=2)[CH:13]=[N:12][CH:11]=[N:10]1.C(OC(=O)C)(=O)C>N1C=CC=CC=1>[N:19]1[C:20]2[C:25]3[C:24](=[CH:29][CH:28]=[CH:27][C:26]=3[C:18]=1[N:17]([CH2:16][CH2:15][CH2:14][N:9]1[CH:13]=[N:12][CH:11]=[N:10]1)[C:4](=[O:5])[CH3:3])[CH:23]=[CH:22][CH:21]=2
Reactant: O=C(O)/C=C/C(=O)O
Reactant: c1cc2c3c(cccc3c1)C(NCCCn1cncn1)=N2
Solvent: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)N(CCCn1cncn1)C1=Nc2cccc3cccc1c23
Temperature: -10 °C

Procedure:
Three and three-tenths grams of the free base of Example 69 and 10 ml of acetic anhydride were added to 5 ml of pyridine, and the mixture then refluxed for 15 minutes. The volatiles were removed in vacuo and the residue partitioned between 100 ml of dichloromethane and 100 ml of saturated NaHCO3 solution. The dichloromethane layer was dried over MgSO4. The dichloromethane solution was heated to boiling and hexane added until turbidity resulted (about 300 ml). The mixture was then cooled at -10° C. The precipitate of the title compound was collected, washed with hexane, and dried; yield, 1.9 grams; mp 128° C.-129° C.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]1([C:17](O)=O)[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1.[CH3:20][NH:21][CH3:22]>>[CH3:20][N:21]([CH3:22])[CH2:17][C:11]1([C:2]2[CH:3]=[CH:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH:1]=2)[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: O=C(O)C1(c2ccc3ccccc3c2)CCCCC1
Reactant: CNC
Product: CN(C)CC1(c2ccc3ccccc3c2)CCCCC1
Yield: 11 %

Procedure:
The title compound was synthesized from 1-(naphthalen-2-yl)cyclohexane-carboxylic acid and dimethyl amine using General Procedure G, followed by General Procedure E and was obtained in 11% yield as a clear oil. LCMS Rt=6.47 min, m/z=268 (M+1). 1H NMR (CDCl3, δ): 7.80 (m, 4H), 7.55 (dd, J=1.7, 8.6 Hz, 1H), 7.45 (m, 2H), 2.2 (m, 2H), 1.97 (s, 6H), 1.8-1.3 (m, 8H). 13C NMR (CDCl3, δ, mult): 133.4, 131.6, 127.9, 127.4, 127.2, 126.2, 126.1, 125.8, 125.5, 125.1, 72.6, 56.6, 48.4, 34.3, 26.6, 22.3.
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[CH2:7]/[N:8]=[CH:9]/[CH2:10][C:11]([CH3:19])([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH3:12])([CH3:4])([CH3:3])[CH3:2].[Cl:21][C:22]1[C:23]([F:40])=[C:24](/[CH:28]=[C:29](/[C:32]2[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][C:33]=2[F:39])\[C:30]#[N:31])[CH:25]=[CH:26][CH:27]=1.C(N(CC)CC)C>ClCCl>[C:1]([O:5][C:6]([CH:7]1[CH:28]([C:24]2[CH:25]=[CH:26][CH:27]=[C:22]([Cl:21])[C:23]=2[F:40])[C:29]([C:32]2[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][C:33]=2[F:39])([C:30]#[N:31])[CH:9]([CH2:10][C:11]([CH3:12])([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH3:19])[NH:8]1)=[O:20])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)C/N=C/CC(C)(C)c1ccccc1
Reactant: N#C/C(=C\c1cccc(Cl)c1F)c1ccc(Cl)cc1F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)C1NC(CC(C)(C)c2ccccc2)C(C#N)(c2ccc(Cl)cc2F)C1c1cccc(Cl)c1F
Yield: 22.2 %

Procedure:
In a manner similar to the method described in Example 1c, [[3-methyl-3-phenyl-but-(E)-ylideneamino]-acetic acid tert-butyl ester prepared in Example 82a (2.3 g, 8.3 mmol) was reacted with (Z)-3-(3-chloro-2-fluoro-phenyl)-2-(4-chloro-2-fluoro-phenyl)-acrylonitrile (2.4 g, 7.7 mmol) prepared in Example 52a, AgF (0.7 g, 5.5 mmol), and triethylamine (2.1 g, 21 mmol) in dichloromethane (150 mL) at room temperature for 18 h to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2-methyl-2-phenyl-propyl)-pyrrolidine-2-carboxylic acid tert-butyl ester as a white foam (1 g, 22%).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5](/[CH:7]=[CH:8]/[C:9]([OH:11])=[O:10])[CH:4]=[N:3]1.OS(O)(=O)=O.[OH-].[Na+].[CH3:19]O>>[CH3:1][N:2]1[CH:6]=[C:5](/[CH:7]=[CH:8]/[C:9]([O:11][CH3:19])=[O:10])[CH:4]=[N:3]1
Reactant: Cn1cc(/C=C/C(=O)O)cn1
Reactant: CO
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: COC(=O)/C=C/c1cnn(C)c1
Temperature: 25 °C
Yield: 71.8 %

Procedure:
(2E)-3-(1-Methyl-1H-pyrazol-4-yl)-2-propenoic acid (7.5 g, 49.3 mmol) was added to a solution of H2SO4 (1.760 ml, 33.0 mmol) in methanol (40 ml), and the resultant mixture was refluxed for 4 h. It was cooled to room temperature, then poured into ice. The acid was neutralized with aqueous sodium hydroxide and extracted with DCM (80 ml×2). The organic phases were collected and combined, dried over MgSO4, and concentrated. The residue was washed with petroleum ether and concentrated to give the title compound (7 g, 71.8% yield). LCMS: rt=1.13 min, [M+H+]=167
Reaction SMILES: [H-].[Na+].[O:3]1[C:11]2[CH:10]=[CH:9][NH:8][C:7](=[O:12])[C:6]=2[CH:5]=[CH:4]1.C([O:15][CH:16]([O:19]CC)[CH2:17]Br)C.O>CN(C=O)C>[OH:15][CH:16]([OH:19])[CH2:17][N:8]1[CH:9]=[CH:10][C:11]2[O:3][CH:4]=[CH:5][C:6]=2[C:7]1=[O:12]
Reactant: O=c1[nH]ccc2occc12
Reactant: CCOC(CBr)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=c1c2ccoc2ccn1CC(O)O
Temperature: 0 °C

Procedure:
Sodium hydride (60% in oil, 0.36 g) was suspended in DMF(10 ml), and was cooled to 0° C. in an ice water bath. 5H-Furo[3,2-c]pyridin-4-one(1.0 g) was added thereto at the same temperature, and the mixture was stirred at 0° C. for an hour. Bromoacetaldehyde diethylacetal(2.6 ml) was added thereto, and the mixture was stirred at 80° C. for 5 hours. Water was added to the reaction liquid, followed by extraction by ethyl acetate. The organic layer was dried over sodium sulfate, and condensed under reduced pressure. A 3N-hydrochloric acid(5.8 ml) was added to an acetone solution (20 ml) of the residue, and the liquid was stirred at 60° C. for 5 hours. Water was added to the reaction liquid and stirred at room temperature. The precipitated insoluble matter was separated, washed with water, and dried to give the title compound(0.90 g) as a white solid.
Reaction SMILES: C1(C)C=CC=CC=1.Cl[C:9]1[N:14]=[N:13][C:12]2[O:15][C:16]3[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=3[O:18][C:11]=2[CH:10]=1.[C:23]1(/[CH:29]=[CH:30]/B(O)O)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(=O)([O-])[O-].[Na+].[Na+]>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.O>[C:23]1(/[CH:29]=[CH:30]/[C:9]2[N:14]=[N:13][C:12]3[O:15][C:16]4[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=4[O:18][C:11]=3[CH:10]=2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: OB(O)/C=C/c1ccccc1
Reactant: Clc1cc2c(nn1)Oc1ccccc1O2
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: Cc1ccccc1
Solvent: O
Product: C(=C/c1cc2c(nn1)Oc1ccccc1O2)\c1ccccc1
Temperature: 120 °C
Reaction time: 14 h
Yield: 49.2 %

Procedure:
Toluene (10 ml) was added to 3-chloro[1,4]benzodioxino[2,3-c]pyridazine (600 mg), and (E)-2-phenylvinylboronic acid (480 mg), tetrakis(triphenylphosphine)palladium (315 mg) and 2M aqueous sodium carbonate solution (1.6 mL) were added at room temperature. The reaction mixture was stirred at 120° C. for 14 hr. Water was added and the mixture was extracted with chloroform. The organic layer was washed with saturated aqueous ammonium chloride solution and saturated brine, dried over anhydrous magnesium sulfate and the solvent was concentrated under reduced pressure. The obtained residue was washed with a mixed solvent of hexane and ethyl acetate and filtered. The obtained solid was dried under reduced pressure to give 3-[(E)-2-phenylvinyl][1,4]benzodioxino[2,3-c]pyridazine (386 mg).
Reaction SMILES: [OH-].[Na+].S(O)(O)(=O)=O.[CH3:8][O:9][C:10](=[NH:12])[NH2:11].O.[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([N:21]=[C:22]=[O:23])=[CH:17][CH:16]=1>ClCCl>[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:22](=[O:23])[NH:12][C:10](=[NH:11])[O:9][CH3:8])=[CH:17][CH:16]=1
Reactant: O=C=Nc1ccc(Cl)cc1
Reactant: COC(=N)N
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: COC(=N)NC(=O)Nc1ccc(Cl)cc1
Temperature: 5 °C
Reaction time: 6 h

Procedure:
320 Parts of a 50% sodium hydroxide solution was added dropwise to 345 parts of 2-methylpseudourea hydrogen sulfate in a mixture of 3500 parts of water and 4000 parts of dichloromethane which mixture was maintained at approximately 5°C. by a cooling bath. 307 Parts of p-chlorophenyl isocyanate was added to the resulting mixture and the cooling bath was removed. The reaction mas was stirred vigorously for 6 hours at room temperature. The dichloromethane layer was separated, dried over anhydrous sodium sulfate, and evaporated under reduced pressure. The residue was triturated in hexane and the solid was collected by filtration affording 400 parts of methyl 4-(4-chlorophenyl)allophanimidate, m.p. 115°-117°C.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[C:5]([C:10]3[CH:11]=[C:12]([NH2:19])[C:13]4[CH:14]=[N:15][NH:16][C:17]=4[CH:18]=3)[CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[C:20]1([CH:28]=O)[C:21]([CH:26]=[O:27])=[CH:22][CH:23]=[CH:24][CH:25]=1>C(OCC)(=O)C.C(O)(=O)C>[NH:1]1[C:9]2[C:4](=[C:5]([C:10]3[CH:18]=[C:17]4[C:13]([CH:14]=[N:15][NH:16]4)=[C:12]([N:19]4[CH2:28][C:20]5[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=5)[C:26]4=[O:27])[CH:11]=3)[CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: O=Cc1ccccc1C=O
Reactant: Nc1cc(-c2cccc3[nH]ccc23)cc2[nH]ncc12
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: O=C1c2ccccc2CN1c1cc(-c2cccc3[nH]ccc23)cc2[nH]ncc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 13.6 %

Procedure:
A mixture of 6-(1H-indol-4-yl)-1H-indazol-4-amine (100 mg, 0.403 mmol) and 1,2-benzenedicarbaldehyde (54 mg, 0.403 mmol) in ethyl acetate (1 ml) and acetic acid (0.25 ml) was stirred under a nitrogen atmosphere at room temperature for 3 h then overnight at room temperature. The reaction mixture was diluted with ethyl acetate (20 ml) and washed with 5% sodium bicarbonate solution (10 ml). The phases were separated, and the aqueous phase was extracted with further ethyl acetate (20 ml). The combined organic extracts (which contained a small amount of insoluble solid) were dried over anhydrous sodium sulphate, filtered and evaporated to give a yellow foam. This was partially dissolved in ethyl acetate (20 ml) and pre-adsorbed on silica (1.5 g). This silica was then added to the top of a 20 g silica SPE cartridge. The cartridge was eluted on a Flashmaster (II) instrument using a gradient of 0-100% ethyl acetate in cyclohexane over 30 min. Appropriate fractions were combined and evaporated to give the title compound (20 mg) as a pale yellow solid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4](/[CH:7]=[CH:8]/[C:9]2[C:17]3[C:12](=[CH:13][C:14]([C@H:18]4[C@@:20]5([C:28]6[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=6)[NH:22][C:21]5=[O:29])[CH2:19]4)=[CH:15][CH:16]=3)[N:11](COCC[Si](C)(C)C)[N:10]=2)=[CH:3][CH:2]=1.B(F)(F)F.CCOCC>C(Cl)Cl>[N:1]1[CH:6]=[CH:5][C:4](/[CH:7]=[CH:8]/[C:9]2[C:17]3[C:12](=[CH:13][C:14]([C@H:18]4[C@@:20]5([C:28]6[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=6)[NH:22][C:21]5=[O:29])[CH2:19]4)=[CH:15][CH:16]=3)[NH:11][N:10]=2)=[CH:3][CH:2]=1
Reactant: C[Si](C)(C)CCOCn1nc(/C=C/c2ccncc2)c2ccc([C@@H]3C[C@@]34C(=O)Nc3ccccc34)cc21
Agent: FB(F)F
Solvent: ClCCl
Solvent: CCOCC
Product: O=C1Nc2ccccc2[C@]12C[C@H]2c1ccc2c(/C=C/c3ccncc3)n[nH]c2c1
Temperature: 50 °C
Reaction time: 2 h
Yield: 93.8 %

Procedure:
A dry-round bottom was charged with (1R*,2S*)-(E)-2-(3-(2-(pyridin-4-yl)vinyl)-1-((2-(trimethylsilyl)ethoxy) methyl)-1H-indazol-6-yl)spiro[cyclopropane-1,3′-indolin]-2′-one (320 mg, 0.62 mmol), and CH2Cl2 (15 mL) under an atmosphere of N2. Boron trifluoride etherate (1 mL) was added dropwise and the reaction was stirred for 2 h. Methylene chloride was removed in vacuo, and then 5 mL of a 2:1 mixture of EtOH/2M HCl was added and the reaction heated to 50° C. for 2 h. The reaction was cooled with an ice-bath and neutralized with NH4OH to pH˜8, the EtOH was removed and the resulting precipitate was collected. The product was purified by silica gel chromatography (85:15 CH2Cl2/MeOH) to give the title compound as a yellow solid (220 mg, 90%). 1H NMR (400 MHz, DMSO-d6) δ 13.31 (s, 1H), 10.63 (s, 1H), 8.57-8.50 (m, 2H), 8.10 (d, J=8.1 Hz, 1H), 7.80 (d, 1H, J=16.6 Hz), 7.75-7.70 (m, 2H), 7.50-7.42 (m, 2H), 7.09-6.99 (m, 2H), 6.85 (d, 1H, J=7.6 Hz), 6.53 (t, 1H, J=7.5 Hz), 6.01 (d, 1H, J=7.8 Hz) 3.23-3.19 (m, 1H), 2.35-2.31 (m, 1H), 2.02-1.98 (m, 1H); MS ESI 379.2 [M+H]+, calcd for [C24H18N4O+H]+ 379.4.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:10][C:11](=[O:19])[C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[C:20]([O:24][C:25](=[O:30])[C:26](Br)([CH3:28])[CH3:27])([CH3:23])([CH3:22])[CH3:21]>CN(C=O)C.O>[CH2:3]([O:10][C:11](=[O:19])[C:12]1[CH:13]=[CH:14][C:15]([O:18][C:26]([C:25]([O:24][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:30])([CH3:28])[CH3:27])=[CH:16][CH:17]=1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: O=C(OCc1ccccc1)c1ccc(O)cc1
Reactant: CC(C)(C)OC(=O)C(C)(C)Br
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)C(C)(C)Oc1ccc(C(=O)OCc2ccccc2)cc1
Temperature: 80 °C

Procedure:
Sodium hydride (0.664 g, 26.28 mmol) was added to a solution of 4-hydroxy-benzoic acid benzyl ester (5.0 g, 21.90 mmol) and 2-bromo-2-methyl-propionic acid tert-butyl ester (5.86 g, 26.28 mmol) in DMF (50 mL). The resulting mixture was warmed up to 80° C. and stirred for 1 h before additional 2-bromo-2-methyl-propionic acid tert-butyl ester (5.86 g, 26.28 mmol) and sodium hydride (0.664 g, 26.28 mmol) was added. After 18 h at 80° C. about 50% product could be detected by LC-MS. The reaction mixture was diluted with water and extracted with Et2O. The combined organic layers were dried (Mg504) and evaporated and the desired product was isolated from the remaining mixture by HPLC. The title compound was obtained as an oil (2.5 g, 30.8%). 1H NMR (500 MHz, CDCl3): δ 7.96 (d, 2H), 7.43 (d, 2H), 7.37 (t, 2H), 7.33 (d, 1H), 6.82 (d, 2H), 5.32 (s, 2H), 1.60 (s, 6H), 1.40 (s, 9H).
Reaction SMILES: [CH2:1](Br)[CH3:2].[OH:4][C:5]1[CH:14]=[C:13]2[C:8]([N:9]=[CH:10][C:11]([O:15][CH2:16][CH2:17][N:18]3[CH2:23][CH2:22][CH:21]([NH:24][C:25]([C:27]4[CH:28]=[CH:29][C:30]5[S:35][CH2:34][C:33](=[O:36])[NH:32][C:31]=5[CH:37]=4)=[O:26])[CH2:20][CH2:19]3)=[N:12]2)=[CH:7][CH:6]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:1]([O:4][C:5]1[CH:14]=[C:13]2[C:8]([N:9]=[CH:10][C:11]([O:15][CH2:16][CH2:17][N:18]3[CH2:23][CH2:22][CH:21]([NH:24][C:25]([C:27]4[CH:28]=[CH:29][C:30]5[S:35][CH2:34][C:33](=[O:36])[NH:32][C:31]=5[CH:37]=4)=[O:26])[CH2:20][CH2:19]3)=[N:12]2)=[CH:7][CH:6]=1)[CH3:2]
Reactant: O=C1CSc2ccc(C(=O)NC3CCN(CCOc4cnc5ccc(O)cc5n4)CC3)cc2N1
Reactant: CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOc1ccc2ncc(OCCN3CCC(NC(=O)c4ccc5c(c4)NC(=O)CS5)CC3)nc2c1
Temperature: 60 °C
Reaction time: 3 h
Yield: 18.5 %

Procedure:
Ethyl bromide (12.8 μL, 0.17 mmol, 1.1 eq) is added at room temperature to a stirred solution of 3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxylic acid {1-[2-(7-hydroxy-quinoxalin-2-yloxy)-ethyl]-piperidin-4-yl}-amide (75 mg, 0.16 mmol, 1.0 eq) in N,N-dimethylformamide (2 mL), followed by potassium carbonate (28.1 mg, 0.20 mmol, 1.3 eq). After 3 hours stirring at 60° C., solvent is evaporated and the residue is extracted with dichloromethane (3×5 mL) and water (5 mL). The combined organic layers are dried over sodium sulfate, filtered and concentrated to give a residue that is purified by preparative HPLC to afford 3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxylic acid {1-[2-(7-ethoxy-quinoxalin-2-yloxy)-ethyl]-piperidin-4-yl}-amide as a white powder (15 mg, 18% yield).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][CH:8]=[C:9]2[CH:18]([C:19]3[O:20][C:21]([S:24][C:25]4[NH:26][C:27]5[CH:33]=[C:32]6[O:34][C:35]([F:38])([F:37])[O:36][C:31]6=[CH:30][C:28]=5[N:29]=4)=[CH:22][CH:23]=3)[C:17]3[C:16](=[O:39])[CH2:15][N:14](OC(C)(C)C)[CH2:13][C:12]=3[NH:11][C:10]=12)=[O:5])[CH3:2].[ClH:45]>O1CCOCC1>[ClH:45].[CH2:1]([O:3][C:4]([C:6]1[NH:7][CH:8]=[C:9]2[CH:18]([C:19]3[O:20][C:21]([S:24][C:25]4[NH:26][C:27]5[CH:33]=[C:32]6[O:34][C:35]([F:38])([F:37])[O:36][C:31]6=[CH:30][C:28]=5[N:29]=4)=[CH:22][CH:23]=3)[C:17]3[C:16](=[O:39])[CH2:15][NH:14][CH2:13][C:12]=3[NH:11][C:10]=12)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1[nH]cc2c1NC1=C(C(=O)CN(OC(C)(C)C)C1)C2c1ccc(Sc2nc3cc4c(cc3[nH]2)OC(F)(F)O4)o1
Agent: Cl
Solvent: C1COCCO1
Product: CCOC(=O)c1[nH]cc2c1NC1=C(C(=O)CNC1)C2c1ccc(Sc2nc3cc4c(cc3[nH]2)OC(F)(F)O4)o1
Temperature: 25 °C
Reaction time: 16 h
Yield: 98 %

Procedure:
170 mg of 6-tert-butyloxy-9-[5-(2,2-difluoro-5H-[1,3]dioxolo[4′,5′:4,5]benzo[1,2-d]imidazol-6-ylsulfanyl)-furan-2-yl]-8-oxo-2,4,5,7,8,9-hexahydro-pyrrolo[3,4-b]-1,7-naphthyridine-3-carboxylic acid ethyl ester (example 140) are dissolved in 10 ml of dioxane and combined with 0.94 ml of 4N HCl in dioxane. The reaction mixture is stirred for 16 hours at room temperature. The formed insoluble material is collected by filtration, washed with dioxane (10 ml), diisopropyl ether (10 ml) and pentane (10 ml) and dried under vacuum to yield 150 mg of 9-[5-(2,2-difluoro-5H-[1,3]dioxolo[4′,5′:4,5]benzo[1,2-d]imidazol-6-ylsulfanyl)-furan-2-yl]-8-oxo-4,5,6,7,8,9-hexahydro-2H-pyrrolo[3,4-b]-1,7-naphthyridine-3-carboxylic acid ethyl ester hydrochloride. Yield=98%. Analytical LC/MS (method B): m/z=554 (negative ion mode [M−H]−), m/z=556 (positive ion mode [M+H]+)
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([N:8]2[CH2:10][CH2:9]2)=[O:7])=[CH:4][CH:3]=1.[C:13]1([N:19]2[C:23]3([CH2:28][CH2:27][NH:26][CH2:25][CH2:24]3)[C:22](=[O:29])[NH:21][CH2:20]2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C1C=CC=CC=1>CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([NH:8][CH2:10][CH2:9][N:26]2[CH2:25][CH2:24][C:23]3([N:19]([C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=4)[CH2:20][NH:21][C:22]3=[O:29])[CH2:28][CH2:27]2)=[O:7])=[CH:11][CH:12]=1
Reactant: O=C(c1ccc(Cl)cc1)N1CC1
Reactant: O=C1NCN(c2ccccc2)C12CCNCC2
Solvent: c1ccccc1
Solvent: CO
Product: O=C(NCCN1CCC2(CC1)C(=O)NCN2c1ccccc1)c1ccc(Cl)cc1

Procedure:
A mixture of 1.82 parts of 1-(4-chlorobenzoyl)aziridine, 2.32 parts of 1-phenyl-1,3,8-triazaspiro[4,5]decan-4-one, 10.8 parts of benzene an 1.6 parts of methanol is stirred and refluxed for 1.50 hours. The reaction mixture is cooled and upon scratching, the product solidifies. It is filtered off, washed with benzene and crystallized from 2-propanol, yielding 1.53 parts of 4-chloro-N-[2-(4-oxo-1-phenyl-1,3,8-triazaspiro[4,5]dec-8-yl)ethyl]benzamide; mp. 200.6° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([S:8]([CH3:11])(=[O:10])=[O:9])[CH:5]=[CH:4][C:3]=1[N:12]1[C:16]2=[N:17][CH:18]=[N:19][C:20](O)=[C:15]2[CH:14]=[N:13]1.O=P(Cl)(Cl)[Cl:24].CN(C)C1C=CC=CC=1>>[Cl:24][C:20]1[N:19]=[CH:18][N:17]=[C:16]2[N:12]([C:3]3[CH:4]=[CH:5][C:6]([S:8]([CH3:11])(=[O:10])=[O:9])=[CH:7][C:2]=3[F:1])[N:13]=[CH:14][C:15]=12
Reactant: CS(=O)(=O)c1ccc(-n2ncc3c(O)ncnc32)c(F)c1
Reactant: O=P(Cl)(Cl)Cl
Solvent: CN(C)c1ccccc1
Product: CS(=O)(=O)c1ccc(-n2ncc3c(Cl)ncnc32)c(F)c1
Yield: 95.2 %

Procedure:
1-(2-Fluoro-4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-ol (0.774 g, 2.51 mmol) was suspended in POCl3 (23 mL, 251 mmol) and dimethylaniline (0.69 mL) and the mixture brought to reflux for 18 h. The solvent was concentrated under reduced pressure and the residue loaded to a column of silica gel. The product was eluted using 5% ethyl acetate/dichloromethane. Removal of solvent afforded 4-chloro-1-(2-fluoro-4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidine as a white solid (0.781 g, 95%). 1H NMR (400 MHz DMSO-d6) δ (ppm): 9.14 (s, 1H); 9.07 (s, 1H); 8.34 (d, 1H); 8.24 (m, 1H); 8.20 (m, 1H); 3.55(s, 3H). Exact mass calculated for C12H8ClFN4O2S 326, found 327.2 (MH+, 100%).
Reaction SMILES: [C:1]([O:4][C@@:5]1([CH2:26][CH2:27][CH3:28])[CH2:10][CH2:9][C@H:8]2[C@H:11]3[C@H:21]([CH2:22][CH2:23][C@:6]12[CH3:7])[C@:19]1([CH3:20])[C@H:14]([CH2:15][C@@H:16](O)[CH2:17][C@@H:18]1[CH3:24])[CH2:13][CH2:12]3)(=[O:3])[CH3:2].[CH3:29][O:30][CH2:31]OC.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O>ClCCl>[C:1]([O:4][C@@:5]1([CH2:26][CH2:27][CH3:28])[CH2:10][CH2:9][C@H:8]2[C@H:11]3[C@H:21]([CH2:22][CH2:23][C@:6]12[CH3:7])[C@:19]1([CH3:20])[C@H:14]([CH2:15][C@@H:16]([CH2:29][O:30][CH3:31])[CH2:17][C@@H:18]1[CH3:24])[CH2:13][CH2:12]3)(=[O:3])[CH3:2]
Reactant: COCOC
Reactant: CCC[C@]1(OC(C)=O)CC[C@H]2[C@@H]3CC[C@H]4C[C@@H](O)C[C@H](C)[C@]4(C)[C@H]3CC[C@@]21C
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: ClCCl
Product: CCC[C@]1(OC(C)=O)CC[C@H]2[C@@H]3CC[C@H]4C[C@@H](COC)C[C@H](C)[C@]4(C)[C@H]3CC[C@@]21C
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
400 mg of 17β-acetoxy-1α-methyl-17α-n-propyl-5α-androstan-3β-ol is combined in 2.8 ml of absolute dichloromethane and 1.8 ml of formaldehyde dimethylacetal with a mixture of 600 mg of kieselguhr W 20 and 300 mg of phosphorus pentoxide and stirred for 45 minutes at room temperature. The mixture is vacuum-filtered from the insoluble components and washed with dichloromethane containing 3-5% triethylamine. The crude product obtained after evaporation is chromatographed on silica gel, thus producing 280 mg of 17β-acetoxy-3β-methoxymethyl-1α-methyl-17α-n-propyl-5α-androstane.
Reaction SMILES: [CH2:1]1[CH2:11][C:9](=O)[C:8]2[C:3](=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:2]1.[CH2:12]([O:14][C:15](=[O:23])[C:16]1[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=1)[CH3:13].C1C=CC=CC=1>O>[C:9]1(=[N:22][C:19]2[CH:18]=[CH:17][C:16]([C:15]([O:14][CH2:12][CH3:13])=[O:23])=[CH:21][CH:20]=2)[C:8]2[C:3](=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:2][CH2:1][CH2:11]1
Reactant: CCOC(=O)c1ccc(N)cc1
Reactant: O=C1CCCc2ccccc21
Solvent: O
Solvent: c1ccccc1
Product: CCOC(=O)c1ccc(N=C2CCCc3ccccc32)cc1

Procedure:
A solution of α-tetralone (40 ml), ethyl-p-amino-benzoate (42 g) and benzene (100 ml) was refluxed in the presence of molecular sieve (100 g) with the continuous removal of water. The crude product was crystallized from ethanol to give N-(1,2,3,4-tetrahydonaphthylidene)-p-carbethoxyaniline (XXVIII). XXVIII had a.m.p. of 108.5° C.
Reaction SMILES: [N+:1]([C:4]1[CH:8]=[CH:7][N:6]([CH2:9][CH2:10][CH3:11])[N:5]=1)([O-])=O.CO.[H][H]>C(OCC)(=O)C.[Pd]>[CH2:9]([N:6]1[CH:7]=[CH:8][C:4]([NH2:1])=[N:5]1)[CH2:10][CH3:11]
Reactant: CCCn1ccc([N+](=O)[O-])n1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: CCCn1ccc(N)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 73.1 %

Procedure:
3-Nitro-1-propyl-1H-pyrazole (92 mg, 0.59 mmol) was dissolved in ethyl acetate (3 mL) and methanol (3 mL) was added. Palladium, 10 wt. % on carbon, wet (˜50 mg) was added to the mixture. The vial was charged with hydrogen gas (via balloon) and the mixture stirred for 16 h at 25° C. The mixture was passed through a plug of celite and concentrated in vacuo followed by purification by flash column chromatography (Merck silica gel 60, 40-63 μm; 25% ethyl acetate/hexanes to 70% ethyl acetate/hexanes) afforded 1-propyl-1H-pyrazol-3-ylamine (54 mg, 73%) as a golden oil: LC-MS (ESI) m/e calcd for C6H11N3 [M+] 125.10, found 126.3 [M+H+], 251.3 [2M+H+].