Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC1C=CC(S(O[CH2:12][C@@H:13]2[O:22][C:21]3[C:16](=[CH:17][CH:18]=[C:19]4[NH:25][C:24]([CH2:26][CH3:27])=[N:23][C:20]4=3)[O:15][CH2:14]2)(=O)=O)=CC=1.[NH:28]1[CH2:33][CH:32]=[C:31]([C:34]2[C:42]3[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=3)[NH:36][CH:35]=2)[CH2:30][CH2:29]1>CS(C)=O.C(OCC)(=O)C>[NH:36]1[C:37]2[C:42](=[CH:41][CH:40]=[CH:39][CH:38]=2)[C:34]([C:31]2[CH2:32][CH2:33][N:28]([CH2:12][CH:13]3[O:22][C:21]4[C:16](=[CH:17][CH:18]=[C:19]5[NH:25][C:24]([CH2:26][CH3:27])=[N:23][C:20]5=4)[O:15][CH2:14]3)[CH2:29][CH:30]=2)=[CH:35]1
Reactant: C1=C(c2c[nH]c3ccccc23)CCNC1
Reactant: CCc1nc2c3c(ccc2[nH]1)OC[C@H](COS(=O)(=O)c1ccc(C)cc1)O3
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CCc1nc2c3c(ccc2[nH]1)OCC(CN1CC=C(c2c[nH]c4ccccc24)CC1)O3
Temperature: 80 °C
Yield: 58.1 %

Procedure:
A mixture of 0.84 g (2.2 mmole) of [(8R)-2-ethyl-7,8-dihydro-3H-6,9-dioxa-1,3-diaza-cyclopenta[a]naphthalen-8-yl]methyl 4-methylbenzenesulfonate and 1.5 g (7.60 mmole) of 3-(1,2,3,6-tetrahydro-4-pyridinyl)-1H-indole in 10.0 mL of DMSO was heated at 80° C. under nitrogen for 6 hours. The reaction was allowed to come to room temperature, diluted to 500 mL with ethyl acetate, washed with 400 mL portions of saturated aqueous sodium bicarbonate, water and saturated brine, dried over sodium sulfate, filtered and evaporated in vacuum. The residue was column chromatographed on silica gel with 0-3% methanol in chloroform as eluant and the product fractions concentrated in vacuum to give 0.53 g of the desired compound as the free base. Recrystallization from ethanol with the addition of one equivalent of fumaric acid gave 0.46 g of the (S)-enantiomer of the title compound as a pale yellow solid fumarate, m.p. 231-232° C.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:4]([C:5]([OH:7])=[O:6])[C:3]=1[NH2:11].[Br:12]Br.CO.O>C(O)(=O)C>[NH2:11][C:3]1[C:2]([OH:1])=[CH:10][C:9]([Br:12])=[CH:8][C:4]=1[C:5]([OH:7])=[O:6]
Reactant: Nc1c(O)cccc1C(=O)O
Reactant: BrBr
Solvent: O
Solvent: CO
Solvent: CC(=O)O
Product: Nc1c(O)cc(Br)cc1C(=O)O
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 96 %

Procedure:
3-Hydroxyanthranilic acid (6.28 g, 41.0 mmol) was dissolved in acetic acid (550 ml), then a solution of bromine (13.1 g, 82.0 mmol) dissolved in acetic acid (50 ml) was gradually and dropwise added at room temperature, taking 20 minutes. After stirring at room temperature for 2.5 hours, methanol (70 ml) and water (300 ml) were added to the solution, followed by stirring at room temperature for 15 hours. The formed solid was collected by nitration, and dried under reduced pressure to obtain the entitled compound (9.129 g, 97%) as a brown powder.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH:8]=[C:9]([C:13]2[O:14][C:15]3[C:21]([C:22]([NH2:24])=[O:23])=[CH:20][CH:19]=[CH:18][C:16]=3[N:17]=2)[CH:10]=[CH:11][CH:12]=1.[H][H]>CO.O.[Pt](=O)=O>[NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[C:7]1[CH:8]=[C:9]([C:13]2[O:14][C:15]3[C:21]([C:22]([NH2:24])=[O:23])=[CH:20][CH:19]=[CH:18][C:16]=3[N:17]=2)[CH:10]=[CH:11][CH:12]=1
Reactant: [H][H]
Reactant: NC(=O)c1cccc2nc(-c3cccc(-c4ccccn4)c3)oc12
Agent: O=[Pt]=O
Solvent: O
Solvent: CO
Product: NC(=O)c1cccc2nc(-c3cccc(C4CCCCN4)c3)oc12
Yield: 33.3 %

Procedure:
2-(3-(Pyridin-2-yl)phenyl)benzo[d]oxazole-7-carboxamide (90 mg, 0.28 mmol) and platinum (IV) oxide monohydrate (45 mg) in methanol (20 mL) was purged with 20 atm of hydrogen at 50° C. for 24 h. Then the mixture was filtered and adjusted to pH=9. The solvent was removed in vacuum. The crude was purified by chromatography (petroleum ether/ethyl acetate=1:1). 30 mg of 2-(3-(piperidin-2-yl)phenyl)benzo[d]oxazole-7-carboxamide was obtained, yield: 33%. 1H-NMR (400 MHz, DMSO-d6) δ 1.35-1.38 (m, 1H), 1.45-1.47 (m, 2H), 1.58-1.60 (m, 1H), 1.75-1.82 (m, 2H); 2.68-2.69 (m, 1H); 3.08-3.10 (d, J=9.6 Hz, 1H); 3.66-3.69 (m, 1H); 7.48-7.50 (t, J=6.0 Hz, 1H), 7.55-7.58 (d, J=6.4 Hz, 1H), 7.63-7.64 (d, J=5.6 Hz, 1H); 7.79-7.81 (m, 1H); 7.86 (brs, 1H); 7.94 (brs, 1H); 7.95-7.97 (m, 1H); 8.16-8.18 (m, 1H); 8.302 (s, 1H); LC-MS (ESI) m/z: 322 (M+1)+.
Reaction SMILES: C[C:2]1([C:18]([O-])=[O:19])[CH2:7][CH2:6][N:5]([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])[CH2:4][CH2:3]1.CC(C[AlH]CC(C)C)C.CO.[Cl-].[Na+]>C1(C)C=CC=CC=1>[CH:18]([CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][CH2:11][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[O:9])[CH2:4][CH2:3]1)=[O:19]
Reactant: CC1(C(=O)[O-])CCN(C(=O)OCc2ccccc2)CC1
Agent: CC(C)C[AlH]CC(C)C
Agent: [Cl-]
Agent: [Na+]
Solvent: CO
Solvent: Cc1ccccc1
Product: O=CC1CCN(C(=O)OCc2ccccc2)CC1
Reaction time: 1 h

Procedure:
A solution of 1-benzyl 4-methylpiperidine-1,4-dicarboxylate (10 g) in toluene (100 ml), under nitrogen, was cooled to −78° C. Then DIBAL-H (60.9 ml) was added dropwise at −78° C., and the mixture was stirred for 1 h at that temperature (TLC monitoring). Because the reaction was incomplete, a further 0.2 eq. of DIBAL-H was added and stirring was carried out for a further 30 min (TLC monitoring: some starting material and the corresponding alcohol were detectable). Methanol (40 ml) followed by sat. sodium chloride solution (40 ml) were added slowly to the reaction mixture at −78° C. The mixture was filtered over celite, and the solvent was removed under vacuum. The residue was extracted with ethyl acetate (3×75 ml), dried (Na2SO4) and concentrated under vacuum. The crude product so obtained was purified by column chromatography (silica gel, 20% ethyl acetate/hexane). Yield: 4.3 g (49%)
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][C:17]=2[N+:23]([O-:25])=[O:24])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH3:28]I>CN(C)C=O>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([N:15]([CH3:28])[C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][C:17]=2[N+:23]([O-:25])=[O:24])=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CI
Reactant: Cc1ccc(Nc2ccc(OCc3ccccc3)cc2)c([N+](=O)[O-])c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc(N(C)c2ccc(OCc3ccccc3)cc2)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
A solution of the product from Example 133A (229.4 mg, 0.6861 mmol) in anhydrous N,N-dimethylformamide (3 mL) was added to a suspension of sodium hydride (60% dispersion in mineral oil, 55 mg, 1.372 mmol) in N,N-dimethylformamide (3 mL) at room temperature under a nitrogen atmosphere. The reaction was stirred at room temperature for 1 hour, then added methyl iodide (0.171 mL, 2.744 mmol) and let stir at room temperature for 2 hours. The solvent was removed by rotary evaporation under vacuum. The residue was taken up in water (30 mL) and extracted with methylene chloride (50 mL). The organic phase was washed with water (30 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated by rotary evaporation under vacuum to afford the title compound as a maroon-colored solid (239 mg, 100%).
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[CH:6][C:5]([C:9]2[C:10]([CH3:15])=[N:11][O:12][C:13]=2[CH3:14])=[CH:4][C:3]=1[S:16]([NH:19][CH:20]1[CH2:24][CH2:23][CH2:22][CH2:21]1)(=[O:18])=[O:17].C1N=CN([C:30](N2C=NC=C2)=[O:31])C=1>CN(C=O)C>[CH:20]1([NH:19][S:16]([C:3]2[C:2]3[NH:1][C:30](=[O:31])[NH:8][C:7]=3[CH:6]=[C:5]([C:9]3[C:10]([CH3:15])=[N:11][O:12][C:13]=3[CH3:14])[CH:4]=2)(=[O:17])=[O:18])[CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Cc1noc(C)c1-c1cc(N)c(N)c(S(=O)(=O)NC2CCCC2)c1
Solvent: CN(C)C=O
Product: Cc1noc(C)c1-c1cc(S(=O)(=O)NC2CCCC2)c2[nH]c(=O)[nH]c2c1
Temperature: 150 °C

Procedure:
2,3-Diamino-N-cyclopentyl-5-(3,5-dimethylisoxazol-4-yl)benzenesulfonamide (58 mg, 0.17 mmol) was dissolved in DMF (2 mL). To the solution was added CDI (360 mg, 4 mmol) and TEA (1 mL). The reaction was heated at 150° C. in microwave for 10 h. The solvent was evaporated and the residue was purified by preparative HPLC (0-100% CH3CN/H2O) to afford N-cyclopentyl-6-(3,5-dimethylisoxazol-4-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-4-sulfonamide.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]2[CH2:14][C@@H:15]([C:17]([OH:19])=O)[CH2:16][C@H:10]2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N=C=NCCCN(C)C)C.O.OC1C2N=NNC=2C=CC=1.[C:42]1([CH:48]([C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=2)[NH2:49])[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1>ClCCl.O>[CH:48]([NH:49][C:17]([C@@H:15]1[CH2:14][N:11]2[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:9][C@@H:10]2[CH2:16]1)=[O:19])([C:50]1[CH:51]=[CH:52][CH:53]=[CH:54][CH:55]=1)[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1
Reactant: NC(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCN2C[C@@H](C(=O)O)C[C@H]2C1
Agent: CCN=C=NCCCN(C)C
Agent: Oc1cccc2[nH]nnc12
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN2C[C@@H](C(=O)NC(c3ccccc3)c3ccccc3)C[C@H]2C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (7S,8aS)-2-(tert-butoxycarbonyl)octahydropyrrolo[1,2-a]pyrazine-7-carboxylic acid (80 mg, 0.296 mmol) in dichloromethane (2 mL) was added a solution of 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide (68.9 mg, 0.444 mmol) and hydroxybenzotriazole hydrate (40.0 mg, 0.296 mmol) in dichloromethane (1 mL). The mixture was stirred at room temperature for 1 hour and then diphenylmethanamine (54.2 mg, 0.296 mmol) was added. After stirring for three days the mixture was poured into water (10 mL). The mixture was extracted with dichloromethane (3×5 mL), the organic fractions were concentrated and the residue was purified by flash chromatography (dichloromethane/methanol=25:1) to give the title compound. MS (ESI) m/z 436 (M+H)+.
Reaction SMILES: B(O)(O)O.C([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][C:17]=1[O:18]C(=O)C)[NH:14][CH:13]=[CH:12]2)(=O)C>C(O)(=O)C>[OH:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][C:17]=1[OH:18])[NH:14][CH:13]=[CH:12]2
Reactant: CC(=O)Oc1cc2cc[nH]c2cc1OC(C)=O
Agent: OB(O)O
Solvent: CC(=O)O
Product: Oc1cc2cc[nH]c2cc1O

Procedure:
At the completion of the reaction, which will generally require from about 30 minutes to about 3 hours, preferably from about 45 minutes to about 2 hours, the reaction system may be acidified to a pH of about 5 or less, preferably about 4.5, by the addition of acetic acid. The reaction mixture is then extracted, preferably after filtration, with ether or dichloromethane one or more times, under a nitrogen gas atmosphere, to recover the product 5,6-dihydroxyindole. According to a particular feature of the invention, the isolated yield of 5,6-dihydroxyindole can be further increased by carrying out the isolation of the product 5,6-dihydroxyindole by adding to the acetic acid mixture a compound which will protect the hydroxy groups to give the product compound in a form which is more stable in air. For example, addition of acetic anhydride to the filtered mixture gives 5,6-diacetoxyindole on heating. It is also possible to form the borate ester ##STR8## by addition of boric acid to the acetic acid reaction mixture. Generally, any protecting group which is stable to acetic acid can be added to the filtered reaction mixture to give the protected 5,6-dihydroxyindole.
Reaction SMILES: [CH:1]([NH:4][C:5]1[CH:9]=[C:8]([NH2:10])[NH:7][N:6]=1)([CH3:3])[CH3:2].O.[N+:12]([CH:15]([CH:18]=O)[CH:16]=O)([O-:14])=[O:13].[Na].C(O)(=O)C>O>[CH:1]([NH:4][C:5]1[C:9]2[C:8](=[N:10][CH:16]=[C:15]([N+:12]([O-:14])=[O:13])[CH:18]=2)[NH:7][N:6]=1)([CH3:3])[CH3:2]
Reactant: CC(C)Nc1cc(N)[nH]n1
Reactant: O=CC(C=O)[N+](=O)[O-]
Agent: [Na]
Solvent: CC(=O)O
Solvent: O
Product: CC(C)Nc1n[nH]c2ncc([N+](=O)[O-])cc12
Temperature: 25 °C
Yield: 59.4 %

Procedure:
A solution of N3-isopropyl-1H-pyrazole-3,5-diamine (0.231 g, 1.85 mmol) and sodium nitromalonaldehyde monohydrate (0.307 g, 1.95 mmol) in water (20 mL) was heated to 100° C. overnight. The reaction mixture was cooled to room temperature, and the pH was adjusted to about 6 with acetic acid. The resulting solids were collected by filtration, washed with water and dried in vacuo to give N-isopropyl-5-nitro-1H-pyrazolo[3,4-b]pyridin-3-amine (0.243 g, 59%). m/z (APCI-neg) M−1=220.3.
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[NH2:5][C:6]1[CH:7]=[C:8]([CH:10]=[CH:11][C:12]=1[CH3:13])[NH2:9].C[O:15][C:16](=O)[C:17]1[CH:22]=[CH:21][C:20]([CH2:23][N:24]2[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]2)=[CH:19][CH:18]=1.C(C(C(C([O-])=O)O)O)([O-])=O.[Na+].[K+].C([O-])(O)=O.[Na+]>C1(C)C=CC=CC=1.C(#N)C.COC(C)(C)C>[NH2:5][C:6]1[CH:7]=[C:8]([NH:9][C:16](=[O:15])[C:17]2[CH:18]=[CH:19][C:20]([CH2:23][N:24]3[CH2:25][CH2:26][N:27]([CH3:30])[CH2:28][CH2:29]3)=[CH:21][CH:22]=2)[CH:10]=[CH:11][C:12]=1[CH3:13]
Reactant: COC(=O)c1ccc(CN2CCN(C)CC2)cc1
Reactant: Cc1ccc(N)cc1N
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: O=C([O-])O
Agent: [Al+3]
Solvent: CC#N
Solvent: Cc1ccccc1
Solvent: COC(C)(C)C
Product: Cc1ccc(NC(=O)c2ccc(CN3CCN(C)CC3)cc2)cc1N
Temperature: 40 °C
Reaction time: 8 h
Yield: 81.3 %

Procedure:
A solution of AlCl3 (1000 mg, 7.5 mmol) in toluene (3 ml) and acetonitrile (3.0 ml) at 0° C. under an atmosphere of argon is treated dropwise with a solution of 3-amino-4-methyl-aniline (470 mg, 6.0 mmol) in toluene (6 ml). The resulting brown solution is heated at 40° C. A solution of 4-(4-methyl-piperazin-1-ylmethyl)-benzoic acid methyl ester (745 mg, 3.0 mmol) in toluene (2 ml) is then added dropwise over a period of 30 min. The resulting mixture is stirred at 40° C. for 8 hrs and then cooled at 0° C. An aqueous saturated potassium-sodium tartrate (30 ml) and aqueous saturated NaHCO3 (40 ml) and t-butyl methyl ether (60 ml) are added sequentially. The organic phase is separated and washed with aqueous saturated NaCl. The aqueous phases are back-extracted with t-butyl methyl ether. The organic phases are combined, dried over MgSO4 and concentrated in vacuo. Purification by flash-chromatography (SiO2, CH2Cl2/MeOH 90:10+1% aq. NH3) gives 825 mg of the title compound (75%) as yellowish crystals.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:8]([C:23]2([OH:29])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)[CH2:9][N:10]2[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]2)[CH:5]=[CH:6][CH:7]=1.[CH2:30]([Sn](CCCC)(CCCC)C=C)[CH2:31]CC>C1(C)C=CC=CC=1.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>[OH:29][C:23]1([CH:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([CH:30]=[CH2:31])[CH:3]=2)[CH2:9][N:10]2[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]2)[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Reactant: CC(C)(C)OC(=O)N1CCN(CC(c2cccc(Br)c2)C2(O)CCCCC2)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: C=Cc1cccc(C(CN2CCN(C(=O)OC(C)(C)C)CC2)C2(O)CCCCC2)c1
Yield: 89.2 %

Procedure:
A mixture of tert-butyl 4-[2-(3-bromophenyl)-2-(1-hydroxycyclohexyl)ethyl]piperazine-1-carboxylate (see Example 135, step 2) (141 mg, 0.300 mmol), tributyl(vinyl)tin (114 mg, 0.360 mmol, 1.2 equivalent), and tetrakis(triphenylphosphine)palladium (17 mg, 0.015 mmol, 5 mol %) in toluene (3 mL) was heated at reflux under nitrogen until all starting material was consumed and precipitation of black palladium occurred (1-2 h). Filtration through Celite® and purification via flash column chromatography (silica, gradient from 0% ethyl acetate/hexane to 10% ethyl acetate/hexane) yielded 111 mg (90%) tert-butyl 4-[2-(1-hydroxycyclohexyl)-2-(3-vinylphenyl)ethyl]piperazine-1-carboxylate as a viscous colorless oil. MS (ES) m/z 415.4 ([M+H]+); HRMS: calcd for C25H38N2O3, 414.2882; found (ESI), 415.2966.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][NH2:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].N1([C:17]([O:19][C@H:20]2[CH2:37][CH2:36][C@@:35]3([CH3:38])[CH:22]([C:23](=[O:40])[CH2:24][C@@H:25]4[C@@H:34]3[CH2:33][CH2:32][C@@:30]3([CH3:31])[C@H:26]4[CH2:27][CH2:28][C:29]3=[O:39])[CH2:21]2)=[O:18])C=CN=C1.O>C(Cl)Cl.CC(O)C>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][NH:11][C:17]([O:19][C@H:20]1[CH2:37][CH2:36][C@@:35]2([CH3:38])[CH:22]([C:23](=[O:40])[CH2:24][C@@H:25]3[C@@H:34]2[CH2:33][CH2:32][C@@:30]2([CH3:31])[C@H:26]3[CH2:27][CH2:28][C:29]2=[O:39])[CH2:21]1)=[O:18])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NCCN
Reactant: C[C@]12CC[C@H](OC(=O)n3ccnc3)CC1C(=O)C[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Solvent: O
Solvent: ClCCl
Solvent: CC(C)O
Product: CC(C)(C)OC(=O)NCCNC(=O)O[C@H]1CC[C@@]2(C)C(C1)C(=O)C[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Temperature: 25 °C
Yield: 76 %

Procedure:
N-(tert-Butoxycarbonyl)ethylendiamine (0.20 mL) was added to a solution of 3β-(1-imidazolylcarbonyloxy)androstane-6,17-dione (200 mg) in CH2Cl2 (10 mL) and 2-propanol (1 mL). After heating under reflux for 9 hr, the mixture was cooled to room temperature and water was added. The organic layer was separated, dried over Na2SO4 and evaporated to dryness. The residue was purified by flash chromatography (SiO2; CH2Cl2:EtOAc 1:1) to give 3β-[N-(2-tert-butoxycarbonylaminoethyl)-carbamoyloxy]androstane-6,17-dione (184 mg, 76%). 1H-NMR (300 MHz, CDCl3, ppm from TMS): δ 5.02 (1H, bb), 4.84 (1H, bb), 4.56 (1H, m), 3.27 (4H, m), 2.50-1.20 (20H, m), 1.45 (9H, s), 0.87 (3H, s), 0.80 (3H, s).
Reaction SMILES: [Br:1][C:2]1[CH:6]=[CH:5][N:4](S(C2C=CC=CC=2)(=O)=O)[C:3]=1[C:16]([O:18][CH3:19])=[O:17].C[O-].[Na+].[Cl-].[NH4+]>CO>[Br:1][C:2]1[CH:6]=[CH:5][NH:4][C:3]=1[C:16]([O:18][CH3:19])=[O:17]
Reactant: COC(=O)c1c(Br)ccn1S(=O)(=O)c1ccccc1
Agent: C[O-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Product: COC(=O)c1[nH]ccc1Br
Temperature: 0 °C
Reaction time: 4 h
Yield: 85 %

Procedure:
Methyl 3-bromo-1-(phenylsulfonyl)-1H-pyrrole-2-carboxylate (6.59 g, 19.15 mmol) was dissolved in 132 mL anhydrous methanol under nitrogen atmosphere and it was cooled at 0° C. Sodium methoxide (1.55 g, 28.69 mmol) was added and the reaction mixture was stirred at room temperature for 4 h. The reaction was poured into a saturated ammonium chloride solution and extracted twice with ethyl acetate. The organics were combined and washed with water, brine, dried over sodium sulphate, filtered and evaporated under reduced pressure. The crude was purified using SP1® Purification System (0% to 30%, hexane-ethyl acetate) to obtain 3.32 g (85% yield) of the title compound as a white solid.
Reaction SMILES: C[O:2][C:3]([C:5]1[S:6][C:7]([C:27]#[C:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[CH:8][C:9]=1[N:10]([CH:20]1[CH2:25][CH2:24][CH:23](Br)[CH2:22][CH2:21]1)[C:11]([CH:13]1[CH2:18][CH2:17][CH:16]([CH3:19])[CH2:15][CH2:14]1)=[O:12])=[O:4].[CH3:33][N:34]1[CH:38]=[N:37][N:36]=[C:35]1[SH:39].C1CCN2C(=NCCC2)CC1.[Br-].[OH-].[K+].Cl>O1CCOCC1>[CH3:31][C:29]([CH3:30])([CH3:32])[C:28]#[C:27][C:7]1[S:6][C:5]([C:3]([OH:2])=[O:4])=[C:9]([N:10]([C:11]([CH:13]2[CH2:14][CH2:15][CH:16]([CH3:19])[CH2:17][CH2:18]2)=[O:12])[CH:20]2[CH2:25][CH2:24][CH:23]([S:39][C:35]3[N:34]([CH3:33])[CH:38]=[N:37][N:36]=3)[CH2:22][CH2:21]2)[CH:8]=1
Reactant: COC(=O)c1sc(C#CC(C)(C)C)cc1N(C(=O)C1CCC(C)CC1)C1CCC(Br)CC1
Reactant: Cn1cnnc1S
Agent: Cl
Agent: [Br-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: C1CCC2=NCCCN2CC1
Product: CC1CCC(C(=O)N(c2cc(C#CC(C)(C)C)sc2C(=O)O)C2CCC(Sc3nncn3C)CC2)CC1
Temperature: 25 °C

Procedure:
3-[(4-Bromo-cyclohexyl)-(4-methyl-cyclohexanecarbonyl)-amino]-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylic acid methyl ester (75 mg, 0.143 mmol, 1.0 eq.) was weighed into a round-bottomed flask containing 1,4-dioxane (2 mL) and purged with N2. 4-Methyl-4H-[1,2,4]triazole-3-thiol (83 mg, 0.718 mmol, 5.0 eq.) and DBU (107 μL, 0.718 mmol, 5 eq.) were then added to the solution. The reaction was stirred at 80° C. until the complete consumption of bromide. The solution was then cooled to room temperature and 50% KOH (1.0 mL) was added to the flask. The reaction was heated at 40° C. for 2 h. The reaction was cooled to 0° C. and acidified with 2 N HCl. After removing volatiles, the residue was purified by reverse phase preparative HPLC to afford Example 1 (5-(3,3-dimethyl-but-1-ynyl)-3-{(4-methyl-cyclohexanecarbonyl)-[4-(4-methyl-4H-[1,2,4]triazol-3-ylsulfanyl)-cyclohexyl]-amino}-thiophene-2-carboxylic acid, 32 mg, 41%).
Reaction SMILES: N[C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([Br:9])=[C:4]([CH3:10])[N:3]=1.N([O-])=O.[Na+].[ClH:15]>>[Br:9][C:5]1[C:4]([CH3:10])=[N:3][C:2]([Cl:15])=[CH:7][C:6]=1[CH3:8]
Reactant: Cc1cc(N)nc(C)c1Br
Reactant: Cl
Agent: O=N[O-]
Agent: [Na+]
Product: Cc1cc(Cl)nc(C)c1Br
Temperature: -10 °C
Reaction time: 0.25 h

Procedure:
A stirred solution of 2-amino-5-bromo-4,6-dimethylpyridine (65 g, 323 mmol) in 37% hydrochloric acid (780 ml) was cooled to −10° C. Sodium nitrite (66.9 g, 970 mmol) was added in small portions over 10 min. The reaction was stirred for 15 min at −10° C. and then warmed to room temperature. After stirring for 1 hour at r.t., the reaction was quenched by pouring into ice/water (4 L). The mixture was stirred for 5 minutes and then extracted with EtOAc (4 L). The organic extract was washed with water (4 L) and brine (2 L). The organic layer was dried over Na2SO4, filtered, and concentrated. The resulting white solid was dissolved in CH2Cl2 (200 mL) and heptanes (700 mL) were added. The solution was stirred for 20 minutes and then filtered to remove solids. The filtrate was concentrated and the residue was purified by flash chromatography on silica gel with 0 to 15% EtOAc/heptanes to afford 3-bromo-6-chloro-2,4-dimethylpyridine. LCMS=219.9 and 221.9 (M+H)+ 1H NMR (CDCl3, 500 MHz) δ 7.05 (s, 1H), 2.65 (s, 3H), 2.39 (s, 3H).
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7](=[O:16])[C:8]2[CH:15]=[CH:14][CH:13]=[N:12][C:9]=2[NH:10][N:11]=1)=[O:5])C.C(OC(=O)C(=[N+]=[N-])C(C1C(Cl)=NC=CC=1)=O)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(OC(C)C)(C)C>[O:16]=[C:7]1[C:6]([C:4]([OH:5])=[O:3])=[N:11][NH:10][C:9]2[N:12]=[CH:13][CH:14]=[CH:15][C:8]1=2
Reactant: CCOC(=O)c1n[nH]c2ncccc2c1=O
Agent: CCOC(=O)C(=[N+]=[N-])C(=O)c1cccnc1Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC(C)OC(C)C
Product: O=C(O)c1n[nH]c2ncccc2c1=O
Temperature: 25 °C
Reaction time: 18 h
Yield: 158.3 %

Procedure:
4-Oxo-1,4-dihydropyrido[2,3-c]pyridazine-3-carboxylic acid ethyl ester—3-(2-Chloropyridin-3-yl)-2-diazo-3-oxopropionic acid ethyl ester (5 g) in diisopropyl ether (150 ml) was treated with triphenylphosphine (5.7 g) and stirred at ambient temperature for 18 hours. The resulting solid was filtered off and dried in vacuo then treated with methanol (250 ml) and water (50 ml) and heated under reflux for 2 hours. The methanol was distilled off and the resulting aqueous extracted with EtOAc. The organic was dried and evaporated. Chromatography (EtOAc/hexane) gave title compound (3.2 g). MS (−ve ion chemical ionisation) m/z 218 ([M−H]−, 100%).
Reaction SMILES: [OH-].[Na+].[CH3:3][O:4][C:5]1[CH:6]=[C:7]([CH:23]=[CH:24][C:25]=1[N+:26]([O-:28])=[O:27])[C:8]([C:10]1[N:14]2[CH:15]=[C:16]([C:19]([O:21]C)=[O:20])[CH:17]=[CH:18][C:13]2=[CH:12][N:11]=1)=[O:9]>O1CCOCC1.CO>[CH3:3][O:4][C:5]1[CH:6]=[C:7]([CH:23]=[CH:24][C:25]=1[N+:26]([O-:28])=[O:27])[C:8]([C:10]1[N:14]2[CH:15]=[C:16]([C:19]([OH:21])=[O:20])[CH:17]=[CH:18][C:13]2=[CH:12][N:11]=1)=[O:9]
Reactant: COC(=O)c1ccc2cnc(C(=O)c3ccc([N+](=O)[O-])c(OC)c3)n2c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CO
Product: COc1cc(C(=O)c2ncc3ccc(C(=O)O)cn23)ccc1[N+](=O)[O-]
Temperature: 60 °C

Procedure:
1.64 ml (1.64 mmol) of a 1N aqueous sodium hydroxide solution are added to 530 mg (1.49 mmol) of methyl 3-(3-methoxy-4-nitrobenzoyl)imidazo[1,5-a]pyridine-6-carboxylate obtained in example 4 in a mixture of 20 ml of dioxane and 10 ml of methanol. The reaction medium is heated at 60° C. for 3 hours and then concentrated under reduced pressure. The residue is taken up in water and the aqueous phase obtained is washed with dichloromethane and then neutralized by addition of 1.64 ml of 1N hydrochloric acid. The precipitate formed is filtered off, washed with water and then dried. 405 mg of a yellow solid are collected. Melting point: 313° C.; 1H NMR (d6-DMSO): 4.01 (3H, s), 7.78 (1H, d), 7.98 (1H, s), 8.06-8.10 (3H, m), 8.15 (1H, s), 10.28 (1H, s)