Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3=[N:17][CH:18]=[CH:19][C:20]([C:21]4[CH:26]=[C:25]([O:27][CH3:28])[C:24]([F:29])=[CH:23][C:22]=4[O:30][CH2:31][CH:32]4[CH2:34][CH2:33]4)=[C:15]3[NH:14][C:13]=2[CH3:35])=[O:11])[CH2:5][CH2:4]1.C([O:39][CH2:40][C:41](Cl)=[O:42])(=O)C>>[CH:32]1([CH2:31][O:30][C:22]2[CH:23]=[C:24]([F:29])[C:25]([O:27][CH3:28])=[CH:26][C:21]=2[C:20]2[CH:19]=[CH:18][N:17]=[C:16]3[C:12]([C:10]([NH:9][C@H:6]4[CH2:7][CH2:8][C@H:3]([NH:2][C:40](=[O:39])[CH2:41][OH:42])[CH2:4][CH2:5]4)=[O:11])=[C:13]([CH3:35])[NH:14][C:15]=23)[CH2:33][CH2:34]1
Reactant: CC(=O)OCC(=O)Cl
Reactant: COc1cc(-c2ccnc3c(C(=O)N[C@H]4CC[C@H](N)CC4)c(C)[nH]c23)c(OCC2CC2)cc1F
Agent: Cl
Product: COc1cc(-c2ccnc3c(C(=O)N[C@H]4CC[C@H](NC(=O)CO)CC4)c(C)[nH]c23)c(OCC2CC2)cc1F

Procedure:
Starting from N-(trans-4-aminocyclohexyl)-7-[2-(cyclopropylmethoxy)-4-fluoro-5-methoxyphenyl]-2-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide hydrochloride (example D.f22) and commercially available 2-chloro-2-oxoethyl acetate the title compound is obtained as colorless solid.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]2[CH:9]=[CH:8][C:7]([CH3:10])=[N:6][N:5]2[CH:11]=1.Br[C:13]1[S:17][C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([CH3:24])[N:19]=2)=[CH:15][C:14]=1[CH3:25].C([O-])([O-])=O.[Cs+].[Cs+].N#N.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C(Cl)Cl.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CN(C=O)C>[CH3:1][C:2]1[N:3]=[C:4]2[CH:9]=[CH:8][C:7]([CH3:10])=[N:6][N:5]2[C:11]=1[C:13]1[S:17][C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([CH3:24])[N:19]=2)=[CH:15][C:14]=1[CH3:25]
Reactant: Cc1cccc(-c2cc(C)c(Br)s2)n1
Reactant: Cc1cn2nc(C)ccc2n1
Agent: [Pd]
Agent: N#N
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1cccc(-c2cc(C)c(-c3c(C)nc4ccc(C)nn34)s2)n1
Temperature: 130 °C
Yield: 39.8 %

Procedure:
A solution of 2,6-dimethyl-imidazo[1,2-b]pyridazine (below) (0.50 g, 3.39 mmol), 2-(5-bromo-4-methyl-thiophen-2-yl)-6-methyl-pyridine (1.00 g, 3.73 mmol), Cs2CO3 (2.32 g, 7.13 mmol) and DMF (5 mL) is de-gassed for 15 minutes with N2. Pd2(dba)3 (0.15 g, 0.16 mmol) and PPh3 (0.17 g, 0.65 mmol) is added and the solution is heated at 130° C. overnight. The solution is diluted with CH2Cl2 (30 mL) washed with water (2×25 mL), brine (25 mL) dried over MgSO4, filtered and concentrated. The residue is purified by ISCO column chromatography (100% EtOAc), followed by recrystallization from acetonitrile/water furnish the title compound (0.45 g, 1.35 mmol, 39%). 1H NMR (CDCl3), δ 2.13 (s, 3H), 2.50 (s, 3H), 2.53 (s, 3H), 2.57 (s, 3H), 6.90 (d, J=9.2 Hz, 1H), 7.01 (d, J=7.5 Hz, 1H), 7.46 (d, J=8.0 Hz, 1H), 7.52 (s, 1H), 7.56 (dd, J=8.0, 7.5 Hz, 1H), 7.77 (d, J=9.2 Hz, 1H). LC/MS (m/z): calcd. for C19H18N4S (M+H)+: 335.1; found: 335.1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH2:9][CH:10]([NH:12][C:13]2[C:18]([CH3:19])=[CH:17][CH:16]=[CH:15][C:14]=2[CH3:20])[CH3:11])=[CH:4][CH:3]=1.ClC(C)[CH2:23][NH:24]C1C=CC(Cl)=CC=1.CC1C=CC=C(C)C=1N.Cl>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:9][CH:10]([CH3:11])[N:12]([C:13]3[C:18]([CH3:19])=[CH:17][CH:16]=[CH:15][C:14]=3[CH3:20])[C:23]2=[NH:24])=[CH:4][CH:3]=1
Reactant: CC(Cl)CNc1ccc(Cl)cc1
Reactant: Cc1cccc(C)c1NC(C)CNc1ccc(Cl)cc1
Agent: Cc1cccc(C)c1N
Agent: Cl
Product: Cc1cccc(C)c1N1C(=N)N(c2ccc(Cl)cc2)CC1C
Yield: 50.9 %

Procedure:
1-(4'-Chlorophenyl-amino)-2-(2',6'-dimethylphenylamino)-propane, applied as starting substance, is obtained with a yield of 50.9% by reacting N-(β-chloropropyl)-4-chloro-aniline, a compound prepared as described in Example 27, point (b), with 2,6-dimethylaniline according to the method given in Example 25, point (a). The hydrochloride of the product melts at 170°-178° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([N+:10]([O-])=O)[C:5]=1[C:13]([O:15][CH3:16])=[O:14].[H][H]>C(OCC)(=O)C.[Pd]>[CH3:1][O:2][C:3](=[O:17])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([NH2:10])[C:5]=1[C:13]([O:15][CH3:16])=[O:14]
Reactant: [H][H]
Reactant: COC(=O)c1cccc([N+](=O)[O-])c1C(=O)OC
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COC(=O)c1cccc(N)c1C(=O)OC
Yield: 86.9 %

Procedure:
To a solution of methyl-2-(methoxycarbonyl)-3-nitrobenzoate (23.8 g, 99.51 mmol) in ethyl acetate (200 ml) was added 10% Pd/C (1.8 g). The mixture was hydrogenated under 50 psi of hydrogen for 3 hours in a Parr Type Shaker. The mixture was filtered through Celite and the filtrate was concentrated in vacuo to yield an oil. The crude product was purified by flash chromatography (dichloromethane/ethyl acetate 95 to 5) to afford 18.1 g (87%) of the product as a brown oil: 1H NMR (CDCl3) δ 7.22 (t, J=7.6 Hz, 1H), 6.90 (d, J=7.2 Hz, 1H), 6.79 (d, J=8.7 Hz), 5.07 (b, 2H), 3.85 (s, 3H), 3.83 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1([C@H:11]([OH:13])[CH3:12])[CH2:10][O:9]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[N+:33]([C:36]1[CH:37]=[C:38]([CH:42]=[C:43]([N+:45]([O-:47])=[O:46])[CH:44]=1)[C:39](O)=[O:40])([O-:35])=[O:34].N(C(OCC)=O)=NC(OCC)=O.C(OC(C)C)(C)C>O1CCCC1.O.C(OCC)(=O)C>[N+:33]([C:36]1[CH:37]=[C:38]([CH:42]=[C:43]([N+:45]([O-:47])=[O:46])[CH:44]=1)[C:39]([O:13][C@H:11]([C@@:8]1([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[F:1])[CH2:10][O:9]1)[CH3:12])=[O:40])([O-:35])=[O:34]
Reactant: O=C(O)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Reactant: C[C@@H](O)C1(c2ccccc2F)CO1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CC(C)OC(C)C
Solvent: C1CCOC1
Product: C[C@H](OC(=O)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1)[C@@]1(c2ccccc2F)CO1
Temperature: 25 °C
Reaction time: 7 h

Procedure:
2-(2-Fluorophenyl)-2-[(l1R)-1-(3,4,5,6-tetrahydro-2H-pyran-2-yl)oxyethyl] oxirane (synthesized by the method described in EP0548553A) was converted into (1R)-1-[2-(2-fluorophenyl)-2-oxiranyl]ethanol by the method described in Reference Example 1. To an ice-cooled solution of this compound (34.77 g) in tetrahydrofuran (600 ml) were added triphenylphosphine (127.21 g), 3,5-dinitrobenzoic acid (102.88 g) and diethyl azodicarboxylate (84.47 g). The mixture was stirred at room temperature for 7 hours under an argon atmosphere, and then ethyl acetate (600 ml), diisopropyl ether (100 ml) and water (800 ml) were added. The separated aqueous layer was extracted with ethyl acetate (600 ml, 400 ml). The organic layers were combined, washed with water and a saturated aqueous solution of sodium chloride successively, dried over anhydrous magnesium sulfate and concentrated. The residue was purified by silica gel chromatography (eluent: hexane/ethyl acetate=5/1) and recrystallized from ethyl acetate to give [(1S)-1-[(2R)-2-(2-fluorophenyl)-2-oxiranyl]ethyl] 3,5-dinitrobenzoate (23.15 g) as colorless needles.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9](=[O:44])[NH:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([N:18]2[C:22]([NH:23][C:24]([NH:26][C:27]3[CH:32]=[CH:31][C:30]([O:33][C:34]4[CH:39]=[CH:38][N:37]=[CH:36][CH:35]=4)=[CH:29][CH:28]=3)=[O:25])=[CH:21][C:20]([C:40]([CH3:43])([CH3:42])[CH3:41])=[N:19]2)=[CH:14][CH:13]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C1COCC1>[NH2:7][CH2:8][C:9]([NH:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([N:18]2[C:22]([NH:23][C:24]([NH:26][C:27]3[CH:32]=[CH:31][C:30]([O:33][C:34]4[CH:35]=[CH:36][N:37]=[CH:38][CH:39]=4)=[CH:29][CH:28]=3)=[O:25])=[CH:21][C:20]([C:40]([CH3:43])([CH3:42])[CH3:41])=[N:19]2)=[CH:14][CH:13]=1)=[O:44]
Reactant: CC(C)(C)OC(=O)NCC(=O)NCc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)Nc2ccc(Oc3ccncc3)cc2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Product: CC(C)(C)c1cc(NC(=O)Nc2ccc(Oc3ccncc3)cc2)n(-c2ccc(CNC(=O)CN)cc2)n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 19.5 %

Procedure:
To a solution of {[4-(3-tert-butyl-5-{3-[4-(pyridin-4-yloxy)-phenyl]-ureido}-pyrazol-1-yl)-benzylcarbamoyl]-methyl}-carbamic acid tert-butyl ester (60 mg, 0.10 mmol) in THF (5 mL) was added TFA (3 mL), and the resulting mixture was stirred at room temperature for 18 h. The reaction mixture was partitioned between EtOAc (20 mL) and saturated NaHCO3 aqueous solution (20 mL), and the organic layer was removed and washed with brine, dried over Na2SO4, and concentrated at reduced pressure. The residue was purified by preparative TLC (90:10 CH2Cl2/MeOH) to give 10 mg (20%) of the desired product. 1H-NMR (DMSO-d6) δ 8.72 (s, 1H), 8.32 (d, J=5.7 Hz, 2H), 8.02 (s, 1H), 7.53 to 7.30 (m, 6H), 6.96 (d, J=6.6 Hz, 2H), 6.73 (d, J=6.3 Hz, 2H), 6.32 (s, 1H), 4.36 (s, 2H), 3.70 (S, 2H), 1.18 (s, 9H); MS LC-MS [M+H]+=513, RT=2.01 min.
Reaction SMILES: [CH3:1][NH:2][C:3]([O:5][C@@H:6]([CH2:27][O:28]C(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH2:7][O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])=[O:4].FC(F)(F)C(O)=O>ClCCl>[CH3:1][NH:2][C:3]([O:5][C@@H:6]([CH2:27][OH:28])[CH2:7][O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])=[O:4]
Reactant: CCCCCCCCCCCCCCCCCCOC[C@H](COC(c1ccccc1)(c1ccccc1)c1ccccc1)OC(=O)NC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCCCCCCCCCCCCCCCCOC[C@H](CO)OC(=O)NC

Procedure:
A solution of 0.57 g of (R)-2-O-(methyl-carbamoyl)-1-O-octadecyl-3-O-tritylglycerine in 15 ml of dichloromethane is treated with 0.5 ml of trifluoroacetic acid. The solution is washed with water and with sodium bicarbonate, dried and evaporated. The residue is recrystallized from dichloromethane-n-hexane. There is obtained (S)-2-O-(methylcarbamoyl)-1-O-octadecylglycerine of melting point 68°-69° C.
Reaction SMILES: [CH2:1]1[CH2:5][O:4][CH2:3][CH2:2]1.S(=O)(=O)(O)O.OS(O)(=O)=O.O=S(=O)=O>O>[CH3:1][CH2:5][CH2:1][CH2:5][O:4][C@H:3]([CH2:2][OH:4])[CH2:3][CH3:2]
Reactant: C1CCOC1
Agent: O=S(=O)(O)O
Agent: O=S(=O)=O
Solvent: O
Product: CCCCO[C@@H](CC)CO
Reaction time: 2 h
Yield: 54.8 %

Procedure:
To 360 g of THF (water content approximately 50 ppm) was added dropwise while cooling fuming sulfuric acid containing 25 wt % of free SO3 (25% oleum) in the amounts shown in Table 1, after which FSA was further added dropwise thereto. The temperature of the THF increased by the dropwise addition of the FSA. The polymerization was assumed to be initiated at the point when the systems reached the temperatures shown in Table 1, and the polymerization was continued at at these temperatures for the times shown in Table 1. After completion of the polymerization, the polymerization solution was mixed with 360 g of hot water at 60° C. to suspend the reaction, after which a hydrolysis reaction was conducted at 90° C. for 2 hours. Then, the unreacted THF was removed by distillation, after which calcium hydroxide was added thereto to neutralize the acids in the polymerization solution. A 100 g of toluene was added to the solution, and water contained therein was removed by azeotropic distillation. The toluene solution containing the dehydrated PTMG was filtered with a filter aid, after which the toluene was distilled off under reduced pressure to obtain about 200 g of PTMG.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C([O:9][C:10](=O)[CH2:11][C:12]([CH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1)([OH:14])[CH3:13])C>CCOCC>[CH:15]1([C:12]([OH:14])([CH3:13])[CH2:11][CH2:10][OH:9])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: CCOC(=O)CC(C)(O)C1CCCCC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: CC(O)(CCO)C1CCCCC1
Yield: 86.4 %

Procedure:
To a slurry of lithium aluminium hydride (6.39 g, 0.168 mol) in ether (250 ml), in an atmosphere of nitrogen and cooled in an ice-bath was added dropwise ethyl-3-cyclohexyl-3-hydroxybutyrate (36 g, 0.168 mol) in ether (100 ml). After complete addition of the ester the resultant mixture was boiled at reflux for 1 hr, then cooled in an ice-bath. Excess lithium aluminium hydride was destroyed by successive dropwise addition of water (7 ml), 10% sodium hydroxide solution (7 ml) and water (21 ml). The reaction mixture was filtered, the filter cake washed with ether (2×100 ml) and the filtrate washed with saturated sodium chloride solution (1×250 ml) and then dried (Na2SO4). This mixture was filtered and the filtrate evaporated in vacuo to remove ether to give 3-cyclohexylbutane-1,3-diol (25 g) as an oil.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][N:9]=2)[CH:4]=[CH:3][C:2]=1[CH:11]=O.Br.Br.Br.[CH2:16]([C:18]1[C:19]([C:26]2[CH:34]=[C:33]3[C:29]([C:30]([C:35]4[NH:36][C:37]5[CH2:42][CH2:41][NH:40][CH2:39][C:38]=5[N:43]=4)=[N:31][NH:32]3)=[CH:28][CH:27]=2)=[CH:20][C:21]([F:25])=[C:22]([OH:24])[CH:23]=1)[CH3:17]>>[CH2:16]([C:18]1[C:19]([C:26]2[CH:34]=[C:33]3[C:29]([C:30]([C:35]4[NH:36][C:37]5[CH2:42][CH2:41][N:40]([CH2:11][C:2]6[CH:3]=[CH:4][C:5]7[C:10](=[N:9][CH:8]=[CH:7][CH:6]=7)[N:1]=6)[CH2:39][C:38]=5[N:43]=4)=[N:31][NH:32]3)=[CH:28][CH:27]=2)=[CH:20][C:21]([F:25])=[C:22]([OH:24])[CH:23]=1)[CH3:17]
Reactant: CCc1cc(O)c(F)cc1-c1ccc2c(-c3nc4c([nH]3)CCNC4)n[nH]c2c1
Reactant: O=Cc1ccc2cccnc2n1
Agent: Br
Product: CCc1cc(O)c(F)cc1-c1ccc2c(-c3nc4c([nH]3)CCN(Cc3ccc5cccnc5n3)C4)n[nH]c2c1
Yield: 32.8 %

Procedure:
The title compound was prepared from [1,8]naphthyridine-2-carbaldehyde (31 mg, 198 μmol) and 5-ethyl-2-fluoro-4-[3-(4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridin-2-yl)-1H-indazol-6-yl]-phenol trihydrobromide salt (Preparation 25, 50 mg, 132 μmol) using the method of Example 22. The crude material was purified by HPLC Method B to afford 22.5 mg of the title compound.
Reaction SMILES: [ClH:1].Cl.[Cl:3][C:4]1C(C2SC3C=CC=C(C(N)=O)C=3C=2)=NC(NCCC2CCN(C)CC2)=NC=1.[CH3:32][NH:33][C:34]([C:36]1[C:44]2[CH:43]=[C:42]([C:45]3[C:50]([CH3:51])=[CH:49][N:48]=[C:47]([NH:52][CH2:53][CH2:54][CH2:55][N:56]4[CH2:61][CH2:60][NH:59][C@@H:58]([CH3:62])[CH2:57]4)[N:46]=3)[S:41][C:40]=2[CH:39]=[CH:38][CH:37]=1)=[O:35]>>[ClH:3].[ClH:1].[ClH:3].[CH3:32][NH:33][C:34]([C:36]1[C:44]2[CH:43]=[C:42]([C:45]3[C:50]([CH3:51])=[CH:49][N:48]=[C:47]([NH:52][CH2:53][CH2:54][CH2:55][N:56]4[CH2:61][CH2:60][N:59]([CH3:4])[C@@H:58]([CH3:62])[CH2:57]4)[N:46]=3)[S:41][C:40]=2[CH:39]=[CH:38][CH:37]=1)=[O:35]
Reactant: CNC(=O)c1cccc2sc(-c3nc(NCCCN4CCN[C@@H](C)C4)ncc3C)cc12
Reactant: CN1CCC(CCNc2ncc(Cl)c(-c3cc4c(C(N)=O)cccc4s3)n2)CC1
Agent: Cl
Product: CNC(=O)c1cccc2sc(-c3nc(NCCCN4CCN(C)[C@@H](C)C4)ncc3C)cc12

Procedure:
Using the method of 2-{5-chloro-2-[2-(1-methylpiperidin-4-yl)-ethylamino]-pyrimidin-4-yl}-benzo[b]thiophene-4-carboxylic acid amide di-hydrochloride, the title compound is synthesized from (S)-2-{5-methyl-2-[3-(3-methylpiperazin-1-yl)-propylamino]-pyrimidin-4-yl}-benzo[b]thiophene-4-carboxylic acid methylamide and isolated as a yellow solid. ES+(m/z) 453 [M(free base)+H].
Reaction SMILES: Br.CS(O[C@H:7]1[C:26]2[C@:21]([CH3:28])([CH2:22][CH2:23][C:24](=[O:27])[CH:25]=2)[C@@H:20]2[C@H:9]([C@H:10]3[C@:17]([CH3:29])([CH2:18][CH2:19]2)[C@@:13]([OH:30])([C:14](=[O:16])[CH3:15])[C:12](=[CH2:31])[CH2:11]3)[C@H:8]1OS(C)(=O)=O)(=O)=O.[N-:37]=[N+:38]=[N-:39].[Na+]>C(O)(=O)C.CN(C)C=O>[N:37]([C:7]1[C:26]2[C@:21]([CH3:28])([CH2:22][CH2:23][C:24](=[O:27])[CH:25]=2)[C@@H:20]2[C@H:9]([C@H:10]3[C@:17]([CH3:29])([CH2:18][CH2:19]2)[C@@:13]([OH:30])([C:14](=[O:16])[CH3:15])[C:12](=[CH2:31])[CH2:11]3)[CH:8]=1)=[N+:38]=[N-:39]
Reactant: [N-]=[N+]=[N-]
Reactant: C=C1C[C@H]2[C@@H]3[C@@H](OS(C)(=O)=O)[C@@H](OS(C)(=O)=O)C4=CC(=O)CC[C@]4(C)[C@H]3CC[C@]2(C)[C@@]1(O)C(C)=O
Agent: Br
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: C=C1C[C@H]2[C@@H]3C=C(N=[N+]=[N-])C4=CC(=O)CC[C@]4(C)[C@H]3CC[C@]2(C)[C@@]1(O)C(C)=O

Procedure:
In a manner similar to that described in Example 26, treat 6β,7β-dimethanesulfonyloxy-16β-methyl-16α,17α-oxido-4-pregnene-3,20-dione with hydrogen bromide in acetic acid; treat the resulting 6β,7β-dimethanesulfonyloxy-16-methylene-17α-hydroxy-4-pregnene-3,20-dione with sodium azide in dimethylformamide to obtain 6-azido-16-methylene-17α-hydroxy-4,6-pregnadiene-3,20-dione.
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[S:3]([NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([CH2:13][C:14]2[C:23](=[O:24])[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([O:25]C)[CH:21]=3)[O:16][C:15]=2[CH3:27])[CH:8]=1)(=[O:5])=[O:4].Br.C(O)(=O)C.O>ClCCl.CO>[F:28][C:2]([F:1])([F:29])[S:3]([NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([CH2:13][C:14]2[C:23](=[O:24])[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([OH:25])[CH:21]=3)[O:16][C:15]=2[CH3:27])[CH:8]=1)(=[O:4])=[O:5]
Reactant: COc1ccc2oc(C)c(Cc3cccc(NS(=O)(=O)C(F)(F)F)c3)c(=O)c2c1
Agent: Br
Solvent: CO
Solvent: ClCCl
Solvent: CC(=O)O
Product: Cc1oc2ccc(O)cc2c(=O)c1Cc1cccc(NS(=O)(=O)C(F)(F)F)c1
Reaction time: 1 h
Yield: 93.1 %

Procedure:
A mixture of 2.1 g (4.91 mmole) of the product from Example 125, 25 mL 48% hydrobromic acid and 25 mL glacial acetic acid was refluxed for 18 hours. The mixture was poured into a stirred slurry of ice and water and stirred for 1 hour. The mixture was filtered, and the filtrant washed with water and dried to give a solid. Flash chromatography on silica gel eluting with 5% methanol in dichloromethane afforded 1.89 g (93%) the title product as a solid, mp 232°-234° C.
Reaction SMILES: S(=O)(=O)(O)O.[CH3:6][C:7]1[C:8](=[O:18])[C:9]2[C:14]([C:15](=[O:17])[CH:16]=1)=[CH:13][CH:12]=[CH:11][CH:10]=2.[CH3:19][O:20][CH2:21][CH2:22]O>[Zn].C1(C)C=CC=CC=1>[CH3:19][O:20][CH2:21][CH2:22][O:17][C:15]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([OH:18])=[C:7]([CH3:6])[CH:16]=1
Reactant: CC1=CC(=O)c2ccccc2C1=O
Reactant: COCCO
Agent: O=S(=O)(O)O
Agent: [Zn]
Solvent: Cc1ccccc1
Product: COCCOc1cc(C)c(O)c2ccccc12
Temperature: 100 °C
Reaction time: 5 h
Yield: 76 %

Procedure:
4.9g of concentrated sulfuric acid were added dropwise, with stirring, to a mixture of 4.75 g (27.6 mmole) of 2-methyl-1,4-naphthoquinone, 2.71 g (41.4 mmole) of zinc powder, 15 mL of 2-methoxyethanol and 15 mL of toluene, in an ice bath. After the addition was completed, the reaction mixture was stirred for 5 hours at 100° C. The reaction product was extracted with ethyl acetate, washed with water, then brine, dried over sodium sulfate, filtered, then evaporated under reduced pressure to give 4.87 g (76% yield) of the title compound. The resultant product had a melting point of 100-101° C. and an 1HNMR as follows: (300 Hz, DMSO-d6) δ 2.33 (s, 3H), 3.34 (s, 3H), 3.79 (t, 2H, J=4.5 Hz), 4.21 (t, 2H, J=4.5 Hz), 6.78(s, 1H), 7.47 (m, 2H), 8.08 (d, 1H, J=8.0 Hz), 8.14 (d, 1H, J=8.0 Hz), 8.54 (s, 1H). The mass spectrum showed a molecular ion at m/z 232.
Reaction SMILES: ClC1N=C(C)N([CH2:8][C:9]2[S:24][C:12]3[N:13]([CH2:20][CH:21]([CH3:23])[CH3:22])[C:14](=[O:19])[N:15]([CH3:18])[C:16](=[O:17])[C:11]=3[C:10]=2[C:25]([N:27]([O:29][CH3:30])[CH3:28])=[O:26])C=1Cl.[O:32]1[C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=2[NH:34][C:33]1=[O:41]>>[CH3:30][O:29][N:27]([CH3:28])[C:25]([C:10]1[C:11]2[C:16](=[O:17])[N:15]([CH3:18])[C:14](=[O:19])[N:13]([CH2:20][CH:21]([CH3:23])[CH3:22])[C:12]=2[S:24][C:9]=1[CH2:8][N:34]1[C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=2[O:32][C:33]1=[O:41])=[O:26]
Reactant: CON(C)C(=O)c1c(Cn2c(C)nc(Cl)c2Cl)sc2c1c(=O)n(C)c(=O)n2CC(C)C
Reactant: O=c1[nH]c2ccccc2o1
Product: CON(C)C(=O)c1c(Cn2c(=O)oc3ccccc32)sc2c1c(=O)n(C)c(=O)n2CC(C)C

Procedure:
The subtitle compound was synthesised by the method of example 1 c) using the product of example 1 part b) and benzoxazolone. The product was isolated by SiO2 chromatography eluting with ethyl acetate/i-hexane (3:2), followed by recrystallisation with diethyl ether to so give the sub-title compound.
Reaction SMILES: C(N(CC)CC)C.[C:8]([O:12][C:13]([N:15]1[CH2:19][CH2:18][CH:17]([OH:20])[CH2:16]1)=[O:14])([CH3:11])([CH3:10])[CH3:9].[CH3:21][S:22](Cl)(=[O:24])=[O:23]>C(OCC)C>[CH3:21][S:22]([OH:24])(=[O:12])=[O:23].[C:8]([O:12][C:13]([N:15]1[CH2:19][CH2:18][CH:17]([OH:20])[CH2:16]1)=[O:14])([CH3:11])([CH3:9])[CH3:10]
Reactant: CS(=O)(=O)Cl
Agent: CC(C)(C)OC(=O)N1CCC(O)C1
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CS(=O)(=O)O
Reaction time: 2 h

Procedure:
Triethylamine (4.5 ml, 32.0 mmol) was added to a stirred solution of, N-(tert-butoxy-carbonyl)-3-hydroxypyrrolidine (2.00 g, 10.7 mmol) in diethyl ether (100 ml) and the reaction was cooled to 0° C. before addition of methanesulphonyl chloride (1.65 ml, 21.4 mmol) and stirring for 2 hours, warming from 0° C. to ambient temperature. The reaction was filtered, the filtrate was washed with 1.0 N hydrochloric acid (100 ml) and with brine (100 ml) before being dried over magnesium sulphate. Solvent evaporation in vacuo yielded N-(tert-butoxycarbonyl)-3-hydroxypyrrolidine methanesulphonate (2.9 g, 100% yield) as a colourless oil:
Reaction SMILES: Br[C:2]1[N:10]=[CH:9][C:8]2[NH:7][C:6]3[N:11]=[CH:12][C:13]([C:15]4[CH:20]=[CH:19][C:18]([CH2:21][N:22]5[C@H:27]([CH3:28])[CH2:26][CH2:25][CH2:24][C@@H:23]5[CH3:29])=[CH:17][CH:16]=4)=[CH:14][C:5]=3[C:4]=2[CH:3]=1.[CH3:30][N:31]1[CH:35]=[C:34](B2OC(C)(C)C(C)(C)O2)[CH:33]=[N:32]1>C(=O)([O-])[O-].[Na+].[Na+].C(#N)C.C(OCC)(=O)C>[CH3:29][C@H:23]1[CH2:24][CH2:25][CH2:26][C@@H:27]([CH3:28])[N:22]1[CH2:21][C:18]1[CH:19]=[CH:20][C:15]([C:13]2[CH:12]=[N:11][C:6]3[NH:7][C:8]4[CH:9]=[N:10][C:2]([C:34]5[CH:33]=[N:32][N:31]([CH3:30])[CH:35]=5)=[CH:3][C:4]=4[C:5]=3[CH:14]=2)=[CH:16][CH:17]=1
Reactant: C[C@@H]1CCC[C@H](C)N1Cc1ccc(-c2cnc3[nH]c4cnc(Br)cc4c3c2)cc1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: C[C@@H]1CCC[C@H](C)N1Cc1ccc(-c2cnc3[nH]c4cnc(-c5cnn(C)c5)cc4c3c2)cc1
Temperature: 130 °C
Yield: 31.1 %

Procedure:
A degassed mixture of 6-bromo-3-[4-((2S,6R)-2,6-dimethyl-piperidin-1-ylmethyl)-phenyl]-9H-dipyrido[2,3-b;4′,3′-d]pyrrole (223 mg, 0.50 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (208 mg, 1.0 mmol), 1,1′-[bis(diphenylphosphino)ferrocene]dichloropalladium(II) (41 mg, 0.05 mmol) in 2N aqueous sodium carbonate solution (6 mL) and acetonitrile (6 mL) was heated under microwave irradiation at 130° C. for 20 minutes. The cooled reaction mixture was diluted with ethyl acetate (100 mL) and washed with water (75 mL). The organic phase was separated, dried over sodium sulfate, filtered and evaporated in vacuo to afford a residue that was purified by flash chromatography (silica, 25 g column, Biotage, 0-15% methanol in DCM) to afford the title compound as a white solid (70 mg, 31%). 1H NMR (CDCl3 plus CD3OD, 300 MHz): 8.85 (d, J=1.1 Hz, 1H), 8.82-8.77 (m, 2H), 8.33 (d, J=1.1 Hz, 1H), 8.08 (s, 1H), 8.06 (d, J=0.8 Hz, 1H), 7.71-7.65 (m, 2H), 7.56-7.51 (m, 2H), 4.00 (d, J=1.9 Hz, 5H), 2.65-2.52 (m, 2H), 1.72-1.60 (m, 3H), 1.47-1.30 (m, 3H), 1.25 (d, J=6.2 Hz, 6H).
Reaction SMILES: [C:1]1([C:7]([C:9]2[N:17](S(C3C=CC=CC=3)(=O)=O)[C:12]3=[CH:13][N:14]=[CH:15][CH:16]=[C:11]3[CH:10]=2)=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+]>CCO>[C:1]1([C:7]([C:9]2[NH:17][C:12]3=[CH:13][N:14]=[CH:15][CH:16]=[C:11]3[CH:10]=2)=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(c1ccccc1)c1cc2ccncc2n1S(=O)(=O)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(c1ccccc1)c1cc2ccncc2[nH]1
Reaction time: 14 h
Yield: 84.1 %

Procedure:
Phenyl[1-(phenylsulfonyl)-1H-pyrrolo[2,3-c]pyridin-2-yl]methanone (Reference Example 13) (2.2 g, 6.1 mmol) and 10% aq NaOH (70 mL) in EtOH (135 mL) was heated to reflux. After 14 h, the mixture was concentrated under reduced pressure to remove most of the EtOH. The mixture was diluted with H2O (50 mL) and extracted with EtOAc (2×100 mL). The combined extracts were washed with saturated NaCl (25 mL), dried (Na2SO4) and concentrated under reduced pressure. Trituration in EtOAc/diethyl ether gave phenyl(1H-pyrrolo[2,3-c]pyridin-2-yl)methanone (1.14 g, 83%).