Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:20])[C:4]1[CH:9]=[CH:8][C:7](Cl)=[N:6][C:5]=1[NH:11][C:12]1[CH:17]=[CH:16][C:15]([Br:18])=[CH:14][C:13]=1[F:19].BrC1C=CC(NC2N=C(Cl)C=CC=2C(O)=[O:32])=C(F)C=1.C[Si](C=[N+]=[N-])(C)C>CO.C1C=CC=CC=1>[Br:18][C:15]1[CH:16]=[CH:17][C:12]([NH:11][C:5]2[NH:6][C:7](=[O:32])[CH:8]=[CH:9][C:4]=2[C:3]([OH:2])=[O:20])=[C:13]([F:19])[CH:14]=1
Reactant: COC(=O)c1ccc(Cl)nc1Nc1ccc(Br)cc1F
Reactant: O=C(O)c1ccc(Cl)nc1Nc1ccc(Br)cc1F
Agent: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Solvent: c1ccccc1
Product: O=C(O)c1ccc(=O)[nH]c1Nc1ccc(Br)cc1F
Reaction time: 1 h
Yield: 93 %

Procedure:
Preparation of 2-(4-bromo-2-fluorophenylamino)-6-chloro-nicotinic acid methyl ester: To a suspension of 2-(4-bromo-2-fluorophenylamino)-6-chloro-nicotinic acid (5.00 g, 14.5 mmol) in methanol/benzene (1:1, 100 mL) under N2 was added (trimethylsilyl)diazomethane (2.0 M solution in hexanes) dropwise until the bubbling caused by gas evolution ceased. Solids precipitated out of solution. The reaction was allowed to stir for 1 hour. Excess (trimethylsilyl)diazomethane was quenched by the dropwise addition of glacial acetic acid. The precipitated solids were filtered and washed with methanol. The filtrate was concentrated to a smaller volume and additional solids precipitated out of solution that were filtered and washed with methanol. The solids were combined and dried under vacuum to yield 4.82 g (93%) of pure desired product as a dark pink solid.
Reaction SMILES: [Cl:1][C:2](Cl)([O:4]C(=O)OC(Cl)(Cl)Cl)Cl.[N:13]1([CH:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)[CH2:17][CH2:16][CH2:15][CH2:14]1.C(N(CC)CC)C.C(Cl)(Cl)Cl>C1C=CC=CC=1>[N:13]1([CH:18]2[CH2:23][CH2:22][N:21]([C:2]([Cl:1])=[O:4])[CH2:20][CH2:19]2)[CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: C1CCN(C2CCNCC2)C1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: O=C(Cl)N1CCC(N2CCCC2)CC1
Temperature: 25 °C
Reaction time: 17 h
Yield: 29.2 %

Procedure:
Triphosgene (742 mg, 2.5 mmol) was dissolved in benzene (60 ml), followed by the addition of a solution of 4-pyrrolidinopiperidine (1.00 g, 6.5 mmol) in benzene and triethylamine (7.5 mmol). The resulting mixture was stirred at room temperature for 17 hours. Chloroform was added to the reaction mixture, and the thus-obtained mixture was washed with water. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by chromatography on a silica gel column (chloroform-acetone mixed solvent [1:2]), whereby 4-pyrrolidinopiperidinocarbonyl chloride (158 mg, 11%) was obtained.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[S:10][C:9]([CH:11]=O)=[CH:8][C:6]=2[N:7]=1.[OH:19][C:20]1([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1>>[Cl:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[S:10][C:9]([CH2:11][N:23]3[CH2:22][CH2:21][C:20]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)([OH:19])[CH2:25][CH2:24]3)=[CH:8][C:6]=2[N:7]=1
Reactant: OC1(c2ccccc2)CCNCC1
Reactant: O=Cc1cc2nc(Cl)nc(N3CCOCC3)c2s1
Product: OC1(c2ccccc2)CCN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CC1

Procedure:
Reaction between 2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidine-6-carbaldehyde 10 (Example 3) and 4-hydroxy-4-phenylpiperidine via General Procedure B-3 yielded 1-(2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-4-phenyl-piperidin-4-ol.
Reaction SMILES: [C:1](N[C@H](C(O)=O)CC1C=CC(C#N)=CC=1)(OC(C)(C)C)=O.NCC(N[C@H](C(N[C@H:39]([C:43]([O:45][C:46]([CH3:49])([CH3:48])C)=O)C(C)C)=O)[CH2:28][C:29](=[O:35])[O:30][C:31](C)(C)[CH3:32])=O>>[C:29]([O:30][CH2:31][CH3:32])(=[O:35])[CH3:28].[CH:46]([O:45][CH:43]([CH3:39])[CH3:1])([CH3:48])[CH3:49]
Reactant: CC(C)[C@H](NC(=O)[C@H](CC(=O)OC(C)(C)C)NC(=O)CN)C(=O)OC(C)(C)C
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(C#N)cc1)C(=O)O
Product: CC(C)OC(C)C
Product: CCOC(C)=O
Yield: 66 %

Procedure:
By coupling rac N-Boc-3-(p-cyanophenyl)alanine (French Published Specification 2593 814) and H-Gly-Asp(OtBu)-Val-OtBu there is obtained [N-Boc-3-(p-cyanophenyl)-DL-alanyl]-Gly-Asp(OtBu)-Val-OtBu, m.p. 140°-145° C. from ethyl acetate/isopropyl ether, yield: 66%.
Reaction SMILES: [I:1][C:2]1[CH:17]=[CH:16][C:5]2[NH:6][C:7]([CH2:12][C:13](O)=[O:14])=[N:8][S:9](=[O:11])(=[O:10])[C:4]=2[CH:3]=1.C([O:21][C:22]([C:24]1[N:25]([NH:29][CH2:30][CH2:31][CH:32]([CH3:34])[CH3:33])[CH:26]=[CH:27][CH:28]=1)=O)C=C.ClCCl.[O-]CC.[Na+].Cl>CN(C)C=O.C(O)C>[OH:21][C:22]1[C:24]2[N:25]([CH:26]=[CH:27][CH:28]=2)[N:29]([CH2:30][CH2:31][CH:32]([CH3:34])[CH3:33])[C:13](=[O:14])[C:12]=1[C:7]1[NH:6][C:5]2[CH:16]=[CH:17][C:2]([I:1])=[CH:3][C:4]=2[S:9](=[O:11])(=[O:10])[N:8]=1
Reactant: C=CCOC(=O)c1cccn1NCCC(C)C
Reactant: O=C(O)CC1=NS(=O)(=O)c2cc(I)ccc2N1
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: CCO
Solvent: CN(C)C=O
Product: CC(C)CCn1c(=O)c(C2=NS(=O)(=O)c3cc(I)ccc3N2)c(O)c2cccn21
Temperature: 25 °C
Reaction time: 2 h
Yield: 68.1 %

Procedure:
(7-Iodo-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)-acetic acid (Example 4b, 0.2 g, 0.546 mmol) was dissolved in N,N-dimethylformamide (2.7 mL). 1-(3-Methyl-butylamino)-1H-pyrrole-2-carboxylic acid allyl ester (Example 1c, 0.129 g, 0.546 mmol) was added followed by a 1.0 M solution of N,N-dicyclohexylcarbodiimide in dichloromethane (0.574 mL, 0.574 mmol). The mixture was stirred at 25° C. for 2 h. N,N-Dicyclohexylurea precipitation was visible at this point. The mixture was diluted with dichloromethane (5 mL) and filtered under reduced pressure. The filtrate was washed with 1.0 M aqueous hydrochloric acid solution (2×10 mL), saturated aqueous brine solution (10 mL), dried over magnesium sulfate, filtered and concentrated in vacuo to afford a golden oil. The oil was dissolved in ethanol (2.7 mL). A 21% solution of sodium ethoxide in ethanol (0.448 mL) was added and the mixture was stirred at 80° C. for 4 h. Additional sodium ethoxide in ethanol (0.448 mL) was added and the mixture was stirred at 80° C. for 4 h. Upon cooling to 25° C., the pH was adjusted to approximately 6 by the addition of 3.0 M aqueous hydrochloric acid solution. Immediate precipitation was observed. Methanol (3 mL) was added and the mixture was shaken vigorously. The solid was collected by vacuum filtration, rinsed with methanol (3×2 mL) and dried in vacuo for 16 h to afford the desired product, 4-hydroxy-3-(7-iodo-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)-1-(3-methyl-butyl)-pyrrolo[1,2-b]pyridazin-2-one (0.196 g, 0.372 mmol, 68% yield) as a white powder. LC-MS (ESI) calcd for C19H19IN4O4S. found 526.02. found 527.15 [M+H+].
Reaction SMILES: [CH2:1]([N:8]1[CH2:14][C:13]2[N:15]=[CH:16][C:17]([NH2:19])=[N:18][C:12]=2[O:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:20][C:21](=O)[CH2:22][CH2:23][C:24](=O)[CH3:25].C(O)(=O)C.C1(C)C=CC=CC=1>C(OCC)(=O)C>[CH2:1]([N:8]1[CH2:14][C:13]2[N:15]=[CH:16][C:17]([N:19]3[C:24]([CH3:25])=[CH:23][CH:22]=[C:21]3[CH3:20])=[N:18][C:12]=2[O:11][CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1cnc2c(n1)OCCN(Cc1ccccc1)C2
Reactant: CC(=O)CCC(C)=O
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: Cc1ccc(C)n1-c1cnc2c(n1)OCCN(Cc1ccccc1)C2
Temperature: 80 °C
Reaction time: 24 h
Yield: 46 %

Procedure:
A mixture of 8-benzyl-6,7,8,9-tetrahydropyrazino[2,3-f][1,4]oxazepin-3-amine (100 mg), 2,5-hexanedione (50 μL), acetic acid (164 μL) and toluene (3 mL) was stirred at 80° C. for 24 hr. The mixture was diluted with ethyl acetate at room temperature, and the organic layer was washed with water and saturated brine, dried over magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography (solvent gradient: 10→100% ethyl acetate/hexane) to give the title compound (60 mg, 46%) as a pale-yellow oil.
Reaction SMILES: [CH2:1]([N:8]([CH3:25])[C:9]([CH2:11][CH2:12][C:13]([N:15]1[CH2:19][CH2:18][CH2:17][C@H:16]1[CH:20]([OH:24])[C:21]([OH:23])=[O:22])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:32](Br)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.CS(C)=O>O>[CH2:32]([O:22][C:21](=[O:23])[CH:20]([C@@H:16]1[CH2:17][CH2:18][CH2:19][N:15]1[C:13](=[O:14])[CH2:12][CH2:11][C:9](=[O:10])[N:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[CH3:25])[OH:24])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: BrCc1ccccc1
Reactant: CN(Cc1ccccc1)C(=O)CCC(=O)N1CCC[C@H]1C(O)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CN(Cc1ccccc1)C(=O)CCC(=O)N1CCC[C@H]1C(O)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of (2RS)-2-[(2S)-1-[3-(N-benzyl-N-methlcarbamoyl)propanoyl]pyrrolidin-2-yl]-2-hydroxyacetic acid (134 mg), potassium carbonate (64 mg), benzyl bromide (51 μl) and DMSO (1 ml) was stirred for 1 hr at room temperature. Water was added to the mixture. The mixture was extracted with a mixture of hexane and EtOAc (1:1). The extract was washed, dried and evaporated. The residue was purified by column chromatography on silica gel (hexane-EtOAc) to give the title compound (141 mg) having the following physical data:
Reaction SMILES: [CH2:1]([C:5]1[N:9]([C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:17]([NH:19][CH2:20][CH3:21])=[O:18])=[CH:12][CH:11]=2)[N:8]=[N:7][C:6]=1[C:22]([NH:24][CH:25]1[CH2:27][CH2:26]1)=[O:23])CC=C.C(#N)C.O.C[N+]1([O-])CC[O:36]CC1.[CH3:40][C:41]([CH3:43])=[O:42]>[Os](=O)(=O)(=O)=O>[CH:25]1([NH:24][C:22]([C:6]2[N:7]=[N:8][N:9]([C:10]3[CH:15]=[CH:14][C:13]([NH:16][C:17]([NH:19][CH2:20][CH3:21])=[O:18])=[CH:12][CH:11]=3)[C:5]=2[CH2:1][CH2:40][CH:41]([OH:42])[CH2:43][OH:36])=[O:23])[CH2:27][CH2:26]1
Reactant: C[N+]1([O-])CCOCC1
Reactant: CC(C)=O
Reactant: C=CCCc1c(C(=O)NC2CC2)nnn1-c1ccc(NC(=O)NCC)cc1
Agent: O=[Os](=O)(=O)=O
Solvent: O
Solvent: CC#N
Product: CCNC(=O)Nc1ccc(-n2nnc(C(=O)NC3CC3)c2CCC(O)CO)cc1
Temperature: 25 °C
Reaction time: 96 h
Yield: 23 %

Procedure:
To a solution of 5-(3-buten-1-yl)-N-cyclopropyl-1-(4-{[(ethylamino)carbonyl]amino}phenyl)-1H-1,2,3-triazole-4-carboxamide obtained in Example 41 in acetone (3 ml)-acetonitrile (3 ml)—water (3 ml) were added N-methylmorpholine N-oxide (0.18 g) and microencapsulated osmium tetroxide (containing 10%, 0.5 g). The reaction mixture was stirred at room temperature for 4 days, and the insoluble material was filtered off. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column (ethyl acetate/methanol=9/1 to ethyl acetate/methanol=7/3). The resultant product was recrystallized from ethyl acetate/hexane to give the title compound as colorless crystals (0.12 g, 23%).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](Cl)[C:5]([C:9]#[N:10])=[C:4]([CH3:11])[N:3]=1.[NH2:12][C@H:13]([C:15]1[N:20]=[C:19]2[CH:21]=[CH:22][N:23]([CH3:24])[C:18]2=[CH:17][C:16]=1[N:25]1[CH2:29][CH2:28][C@H:27]([N:30]([CH3:38])[C:31](=[O:37])[O:32][C:33]([CH3:36])([CH3:35])[CH3:34])[CH2:26]1)[CH3:14].C(N(CC)CC)C>CS(C)=O>[NH2:1][C:2]1[N:7]=[C:6]([NH:12][C@H:13]([C:15]2[N:20]=[C:19]3[CH:21]=[CH:22][N:23]([CH3:24])[C:18]3=[CH:17][C:16]=2[N:25]2[CH2:29][CH2:28][C@H:27]([N:30]([CH3:38])[C:31](=[O:37])[O:32][C:33]([CH3:35])([CH3:34])[CH3:36])[CH2:26]2)[CH3:14])[C:5]([C:9]#[N:10])=[C:4]([CH3:11])[N:3]=1
Reactant: Cc1nc(N)nc(Cl)c1C#N
Reactant: C[C@H](N)c1nc2ccn(C)c2cc1N1CC[C@H](N(C)C(=O)OC(C)(C)C)C1
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: Cc1nc(N)nc(N[C@@H](C)c2nc3ccn(C)c3cc2N2CC[C@H](N(C)C(=O)OC(C)(C)C)C2)c1C#N
Temperature: 90 °C
Yield: 67.8 %

Procedure:
To a 25 mL pear flask were added 2-amino-4-chloro-6-methylpyrimidine-5-carbonitrile (63.4 mg, 0.376 mmol) and tert-butyl ((S)-1-(5-((S)-1-aminoethyl)-1-methyl-1H-pyrrolo[3,2-b]pyridin-6-yl)pyrrolidin-3-yl)(methyl)carbamate (78 mg, 0.21 mmol) in DMSO (1.0 mL). Triethylamine (146 μL, 1.04 mmol) was added to the mixture, which was then heated to 90° C. for 2 hours. The reaction mixture was partitioned between saturated NaHCO3 and ethyl acetate. The aqueous layer was extracted with ethyl acetate. The organic layers were combined, dried over MgSO4, filtered, and concentrated. The residue was purified by liquid chromatography (SiO2, 25-100% EtOAc/heptanes gradient) to give the title compound as a foam (72 mg, 68%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.36-1.48 (m, 12H), 1.93-2.05 (m, 2H), 2.17-2.30 (m, 4H), 2.92 (s, 3H), 2.97-3.13 (m, 2H), 3.16-3.29 (m, 2H), 3.80 (s, 3H), 4.84 (br s, 1H), 5.71-5.89 (m, 1H), 6.39-6.55 (m, 1H), 6.84 (br s, 1H), 6.96 (d, J=7.58 Hz, 1H), 7.16 (br s, 1H), 7.55 (d, J=3.03 Hz, 1H), 7.85 (s, 1H); ESI-MS m/z [M+H]+ calc'd for C26H35N9O2, 506. found 506.
Reaction SMILES: CCOC(/N=N/C(OCC)=O)=O.[F:13][C:14]1[CH:15]=[CH:16][C:17]([N+:21]([O-:23])=[O:22])=[C:18]([OH:20])[CH:19]=1.[CH3:24][O:25][CH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH:27]1O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1.C(Cl)Cl>[F:13][C:14]1[CH:15]=[CH:16][C:17]([N+:21]([O-:23])=[O:22])=[C:18]([O:20][C@@H:27]2[CH2:28][CH2:29][CH2:30][CH2:31][C@@H:26]2[O:25][CH3:24])[CH:19]=1
Reactant: COC1CCCCC1O
Reactant: O=[N+]([O-])c1ccc(F)cc1O
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: C1CCOC1
Product: CO[C@H]1CCCC[C@H]1Oc1cc(F)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 48 h

Procedure:
2.36 ml DEAD were added to an ice-cooled solution of the 1.57 g 5-fluoro-2-nitrophenol, 1.95 ml 2-methoxycyclohexanol and 3.93 g triphenylphosphine in 30 ml THF. The reaction mixture was allowed to warm to rt overnight. The mixture was stirred additional 48 hours. Then the reaction mixture was diluted with methylene chloride and washed with 10% aq. potassium carbonate solution. The organic phase was passed through a hydrophobic frit and evaporated. Purification was achieved by silica gel column chromatography (solvent:10:1 iso-hexane: EtOAc).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=2)[N:5]=[C:4]([N:13]2[CH2:19][C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[S:16](=[O:25])(=[O:24])[CH2:15][CH2:14]2)[CH:3]=1.[NH2:26][C@H:27]([C:29]([OH:31])=[O:30])[CH3:28]>C1(O)C=CC=CC=1>[O:24]=[S:16]1(=[O:25])[C:17]2[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=2[CH2:19][N:13]([C:4]2[CH:3]=[C:2]([NH:26][C@H:27]([C:29]([OH:31])=[O:30])[CH3:28])[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=3)[N:5]=2)[CH2:14][CH2:15]1
Reactant: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(Cl)c2c1
Reactant: C[C@H](N)C(=O)O
Solvent: Oc1ccccc1
Product: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(N[C@@H](C)C(=O)O)c2c1
Temperature: 150 °C

Procedure:
The mixture of 4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (150 mg, 0.40 mmol, prepared in analogy to the one in Example 2-1) and L-alanine (360 mg, 4.0 mmol) in phenol (360 mg) was heated at 150° C. overnight. After being cooled to room temperature, the mixture was purified by preparative HPLC to afford the pure product as a solid. MS obsd. (ESI+) [(M+H)+] 426, 1H NMR (400 MHz, CD3OD) δ ppm 8.16-7.92 (m, 3 H), 7.84 (d, J=8.34 Hz, 1 H), 7.78-7.62 (m, 1 H), 7.61-7.42 (m, 2 H), 5.86 (s, 1 H), 5.24 (brs, 2 H), 4.65-4.35 (m, 3 H), 3.69 (brs, 2 H), 3.37 (s, 3 H), 2.53-2.39 (m, 3 H), 1.76-1.57 (m, 3 H).
Reaction SMILES: [CH3:1][C:2]1([CH3:24])[C:19](=O)[CH2:18][CH2:17][C@@:16]2([CH3:21])[C@@:3]1([OH:23])[CH2:4][CH2:5][C@@H:6]1[C@@H:15]2[CH2:14][CH2:13][C@@:11]2([CH3:12])[C@H:7]1[CH2:8][CH2:9][C@@H:10]2[OH:22].[ClH:25].Cl.[NH:27]1[CH2:31][CH2:30][C@@H:29]([O:32][NH2:33])[CH2:28]1>>[ClH:25].[NH:27]1[CH2:31][CH2:30][C@@H:29]([O:32]/[N:33]=[C:19]2/[C:2]([CH3:1])([CH3:24])[C@@:3]3([OH:23])[C@:16]([CH3:21])([CH2:17][CH2:18]/2)[C@@H:15]2[C@H:6]([C@H:7]4[C@@:11]([CH2:13][CH2:14]2)([CH3:12])[C@@H:10]([OH:22])[CH2:9][CH2:8]4)[CH2:5][CH2:4]3)[CH2:28]1
Reactant: CC1(C)C(=O)CC[C@]2(C)[C@H]3CC[C@]4(C)[C@@H](O)CC[C@H]4[C@@H]3CC[C@@]12O
Reactant: NO[C@@H]1CCNC1
Agent: Cl
Product: CC1(C)/C(=N/O[C@@H]2CCNC2)CC[C@]2(C)[C@H]3CC[C@]4(C)[C@@H](O)CC[C@H]4[C@@H]3CC[C@@]12O

Procedure:
The title compound was obtained in 51% yield following the procedure described in Example 2 and starting from 4,4-dimethyl-5α,17β-dihydroxyandrostan-3-one (Preparation 28, 33 mg) and 3-(R)-pyrrolidinyloxyamine dihydrochloride (Preparation 12, 69 mg). The crude product was triturated with Et2O and the resulting precipitate was filtered to give the title compound I-by.
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH:11]=[CH2:12].[CH:13]1([NH2:16])[CH2:15][CH2:14]1.O.Cl.C1(N)CC1>C1COCC1>[CH:13]1([NH:16][C:2]2[N:10]=[CH:9][N:8]=[C:7]3[C:3]=2[N:4]=[CH:5][N:6]3[CH:11]=[CH2:12])[CH2:15][CH2:14]1
Reactant: C=Cn1cnc2c(Cl)ncnc21
Reactant: NC1CC1
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: C=Cn1cnc2c(NC3CC3)ncnc21
Temperature: 25 °C
Reaction time: 5 h

Procedure:
6-Chloro-9-vinylpurine (0.54 g, 3 mmol) was mixed with cyclopropylamine (1.71 g, 30 mmol) in THF (10 mL) and the mixture was stirred for 5 h at rt. Water was added to dissolve the white precipitate (cyclopropylamine hydrochloride). The aqueous layer was extracted with ethyl acetate and the combined organic layers were dried over sodium sulfate, concentrated on a rotavap, and then recrystallized from EtOAc/hexanes yielding the desired product.
Reaction SMILES: C(OC([NH:11][C:12]([CH3:30])([CH3:29])[CH2:13][NH:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:22]([CH3:28])[CH2:23][C:24](=[O:27])[NH:25][N:26]=2)=[CH:17][CH:16]=1)=O)C1C=CC=CC=1.[H][H]>[C].[Pd].CO>[NH2:11][C:12]([CH3:29])([CH3:30])[CH2:13][NH:14][C:15]1[CH:16]=[CH:17][C:18]([C:21]2[CH:22]([CH3:28])[CH2:23][C:24](=[O:27])[NH:25][N:26]=2)=[CH:19][CH:20]=1
Reactant: [H][H]
Reactant: CC1CC(=O)NN=C1c1ccc(NCC(C)(C)NC(=O)OCc2ccccc2)cc1
Agent: [Pd]
Solvent: CO
Product: CC1CC(=O)NN=C1c1ccc(NCC(C)(C)N)cc1
Yield: 89.3 %

Procedure:
A mixture of 6-[4-(2-benzyloxycarbonylamino-2-methylpropylamino)phenyl]-5-methyl-4,5-dihydro-3(2H)-pyridazinone (0.50 g), 10% palladium-carbon (0.50 g) and methanol (40 ml) was stirred in a stream of hydrogen for 3 hours. The catalyst was removed by filtration, and the filtrate was concentrated under reduced pressure to give 6-[4-(2-amino-2-methylpropyl amino)phenyl]-5-methyl-4,5-dihydro-3(2H)-pyridazinone(0.30 g).
Reaction SMILES: I.CS[C:4](=[N:18][CH3:19])[NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1.[CH3:20][O:21][CH2:22][CH2:23][NH2:24].C(O)C.[C:28]([OH:35])(=[O:34])/[CH:29]=[CH:30]/[C:31]([OH:33])=[O:32]>CO>[C:28]([OH:35])(=[O:34])/[CH:29]=[CH:30]/[C:31]([OH:33])=[O:32].[CH3:19][NH:18][C:4]([NH:24][CH2:23][CH2:22][O:21][CH3:20])=[N:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1
Reactant: CN=C(Nc1ccccc1N1CCOCC1)SC
Reactant: COCCN
Agent: I
Agent: O=C(O)/C=C/C(=O)O
Solvent: CCO
Solvent: CO
Product: CNC(=Nc1ccccc1N1CCOCC1)NCCOC

Procedure:
A mixture of 2-methyl-1-(2-morpholinophenyl)-3-methyl-2-thiopseudourea hydroiodide (3.9 g prepared as described in Example 210), 2-methoxyethylamine (0.82 g) and ethanol (25 ml) was stored at ambient temperature for three months to yield an oil which was dissolved in methanol and treated with fumaric acid to give 1-methyl-2-(2-morpholinophenyl)-3-(2-methoxyethyl)guanidine monofumarate (m.p. 158°-160° C.) which was recrystallised from a 1:2 mixture of methanol and ether.
Reaction SMILES: [Cl:1][C:2]1[CH:7]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=2)[C:6](Cl)([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)[CH:5]=[N:4][N:3]=1.N1C=CC=CC=1.O.[NH2:30][NH2:31]>O>[Cl:1][C:2]1[N:3]=[N:4][C:5]([NH:30][NH2:31])=[C:6]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)[C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=1
Reactant: ClC1=NN=CC(Cl)(c2ccc(Cl)cc2)C1c1ccc(Cl)cc1
Reactant: NN
Solvent: c1ccncc1
Solvent: O
Product: NNc1nnc(Cl)c(-c2ccc(Cl)cc2)c1-c1ccc(Cl)cc1
Temperature: 120 °C
Reaction time: 1 h
Yield: 82.9 %

Procedure:
To a r.b. flask was added 3,5-dichloro-4,5-bis(4-chlorophenyl)pyridazine (4.5 gm, 12.2 mmol), pyridine (20 ml) and hydrazine monohydrate (1.494 gm, 30.49 mmol). The reaction mixture was stirred at 120° C. for 1 h. After this time, the reaction mixture was cooled to RT Water (400 ml) was then added and a solid precipitated. The solution was filtered and the solid was collected and air dried overnight to give the title compound, 1-(6-chloro-4,5-bis(4-chlorophenyl)pyridazin-3-yl)hydrazine (3.7 gm, 83% yield) as a solid. MS (M+H)=364.9.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]([N:5]1[CH2:11][CH2:10][C:9]2[CH:12]=[C:13]([OH:19])[C:14]([N+:16]([O-:18])=[O:17])=[CH:15][C:8]=2[CH2:7][CH2:6]1)=[O:4].[C:22](=O)([O-])[O-].[K+].[K+].CI>CN(C=O)C>[F:21][C:2]([F:1])([F:20])[C:3]([N:5]1[CH2:11][CH2:10][C:9]2[CH:12]=[C:13]([O:19][CH3:22])[C:14]([N+:16]([O-:18])=[O:17])=[CH:15][C:8]=2[CH2:7][CH2:6]1)=[O:4]
Reactant: O=C(N1CCc2cc(O)c([N+](=O)[O-])cc2CC1)C(F)(F)F
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: COc1cc2c(cc1[N+](=O)[O-])CCN(C(=O)C(F)(F)F)CC2
Reaction time: 8 h

Procedure:
1.30 g (4.27 mmol) of 2,2,2-trifluoro-1-(7-hydroxy-8-nitro-1,2,4,5-tetrahydro-benzo[d]azepin-3-yl)-ethanone are dissolved in 20 ml DMF. At room temperature 0.59 g (4.27 mmol) potassium carbonate and 0.26 ml (4.27 mmol) methyliodide are added and the mixture is stirred overnight. Then it is filtered and the filtrate is concentrated by evaporation i.vac., the residue is triturated with water and suction filtered and dried in the circulating air dryer at 45° C.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](O)(=O)=O)=[CH:3][CH:2]=1.O.C(OCC)(=[O:15])C.[CH3:19][C:20]([CH3:22])=O>>[CH3:22][C:20]1[S:7][C:4]2[CH:3]=[CH:2][C:1]([CH:11]=[O:15])=[CH:6][C:5]=2[CH:19]=1
Reactant: CC(C)=O
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: CCOC(C)=O
Solvent: O
Product: Cc1cc2cc(C=O)ccc2s1
Reaction time: 0.5 h

Procedure:
A catalytic amount of p-toluenesulfonic acid is added to a solution of 1.5 g of 2-methyl-5-(1,3-dioxoran-2-yl)benzo[b]thiophene in 20 ml of acetone at room temperature, at which temperature the resulting mixture is stirred for 30 minutes. After the reaction, the solvent is removed from the reaction mixture by distillation under reduced pressure. The residue obtained are added 20 ml of water and 20 ml of ethyl acetate, after which the resulting organic layer is separated, washed successively with water and a saturated saline solution and then dried over anhydrous magnesium sulfate. The solvent is thereafter removed from the thus dried layer by distillation under reduced pressure, to obtain 1.15 g of colorless, solid 2-methylbenzo[b]thiophene-5-carbaldehyde.
Reaction SMILES: [NH2:1][C@@:2]1([C:11]([OH:13])=[O:12])[CH2:7][CH2:6][C@@H:5]2[C@H:3]1[C@H:4]2[C:8]([OH:10])=[O:9].O1CCOCC1.Cl[C:21]([O:23][CH2:24][CH:25]=[CH2:26])=[O:22]>C(=O)(O)[O-].[Na+].O>[CH2:24]([O:23][C:21]([NH:1][C@@:2]1([C:11]([OH:13])=[O:12])[CH2:7][CH2:6][C@@H:5]2[C@H:3]1[C@H:4]2[C:8]([OH:10])=[O:9])=[O:22])[CH:25]=[CH2:26]
Reactant: C=CCOC(=O)Cl
Reactant: N[C@@]1(C(=O)O)CC[C@H]2[C@H](C(=O)O)[C@H]21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: C=CCOC(=O)N[C@@]1(C(=O)O)CC[C@H]2[C@H](C(=O)O)[C@H]21
Reaction time: 8 h
Yield: 67.3 %

Procedure:
(1S,2S,5R,6S)-2-Amino-bicyclo[3.1.0]hexane-2,6-dicarboxylic acid (15.0 g, 73.9 mmol) was slowly dissolved in 250 mL of saturated sodium bicarbonate. After complete solution, dioxane (100 mL) and allyl chloroformate (15.7 mL, 147.8 mmol) were added at room temperature and the mixture was stirred overnight. The reaction mixture was diluted with water (100 mL) and washed with three portions of ethyl acetate. The organic layer was extracted once with saturated sodium bicarbonate. The combined aqueous layers were acidified to pH 1 with 4N hydrochloric acid and extracted with two portions of ethyl acetate. The organic layer was dried over magnesium sulfate, filtered and concentrated to provide the title compound as an oil (13.4 g, 67% yield).