Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([CH3:9])=[C:7]([CH3:10])[C:6]([O:11][CH3:12])=[C:5]([CH3:13])[C:4]=1[CH2:14][CH2:15][C@:16]([CH3:30])([OH:29])[CH2:17]OS(C1C=CC=CC=1C)(=O)=O.[OH-].[K+].C(Cl)Cl>C(O)C>[CH3:1][O:2][C:3]1[C:8]([CH3:9])=[C:7]([CH3:10])[C:6]([O:11][CH3:12])=[C:5]([CH3:13])[C:4]=1[CH2:14][CH2:15][C@:16]1([CH3:30])[O:29][CH2:17]1
Reactant: COc1c(C)c(C)c(OC)c(CC[C@](C)(O)COS(=O)(=O)c2ccccc2C)c1C
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: ClCCl
Product: COc1c(C)c(C)c(OC)c(CC[C@@]2(C)CO2)c1C
Reaction time: 0.17 h
Yield: 98 %

Procedure:
177 mg of (S)-4-(2',5'-dimethoxy-3',4',6'-trimethylphenyl)-2-methyl-1-toluylsulphonyloxy-2-butanol are dissolved in 1 ml of ethanol and treated with 0.3 ml of alcoholic potassium hydroxide solution (1.5N). The mixture is left to stand at room temperature for 10 minutes, 30 ml of methylene chloride are then added and the mixture is dried over anhydrous sodium sulphate and concentrated. There are obtained 105 mg of (S)-4-(2',5'-dimethoxy-3',4',6'-trimethylphenyl)-2-methyl-1,2-epoxy-butane, m.p. 47°-48° C. [α]D20 +4.91° (c=2.2% in CHCl3).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1[C:18]2[C:13](=[CH:14][N:15]=[C:16]([C:19]3[CH:20]=[N:21][N:22]([CH3:24])[CH:23]=3)[CH:17]=2)[N:12](C2CCCCO2)[N:11]=1.Cl>CO.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1[C:18]2[C:13](=[CH:14][N:15]=[C:16]([C:19]3[CH:20]=[N:21][N:22]([CH3:24])[CH:23]=3)[CH:17]=2)[NH:12][N:11]=1
Reactant: COc1ccc(F)c(-c2nn(C3CCCCO3)c3cnc(-c4cnn(C)c4)cc23)c1
Agent: Cl
Solvent: CO
Solvent: O
Product: COc1ccc(F)c(-c2n[nH]c3cnc(-c4cnn(C)c4)cc23)c1
Temperature: 60 °C
Reaction time: 72 h
Yield: 52.6 %

Procedure:
To a stirred mixture of 3-(2-fluoro-5-methoxyphenyl)-5-(1-methyl-1H-pyrazol-4-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-c]pyridine (37.0 mg, 0.09 mmol) in methanol (5.0 mL) was added 6 M HCl in water (0.66 mL). The reaction mixture was stirred at 60° C. for 3 days. Volatile solvent was evaporated in vacuo, and the crude was diluted into ethyl acetate (˜30 mL). The organic layer was washed with saturated aqueous sodium bicarbonate solution, water and brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. Trituration from ether-heptanes afforded 172 as a solid (15.3 mg, 52.1%). 1H NMR (400 MHz, DMSO) δ 13.88 (s, 1H), 9.06 (s, 1H), 8.25 (s, 1H), 7.97 (s, 1H), 7.88 (s, 1H), 7.36 (t, J=9.6 Hz, 1H), 7.31 (dd, J=5.7, 3.2 Hz, 1H), 7.09 (s, 1H), 3.88 (s, 3H), 3.83 (s, 3H). LC/MS: m/z 324.0 [M+1]
Reaction SMILES: [C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32](Cl)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:35][CH2:36][CH3:37])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[O:38]=[S:39]1(=[O:50])[CH2:43][CH2:42][CH:41]([N:44]2[CH2:49][CH2:48][NH:47][CH2:46][CH2:45]2)[CH2:40]1>>[C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:47]3[CH2:48][CH2:49][N:44]([CH:41]4[CH2:42][CH2:43][S:39](=[O:50])(=[O:38])[CH2:40]4)[CH2:45][CH2:46]3)=[O:33])[C@@:13]([C:25]3[CH:26]=[CH:27][C:28]([Cl:31])=[CH:29][CH:30]=3)([CH3:24])[C@@:14]([C:17]3[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=3)([CH3:16])[N:15]=2)=[C:7]([O:35][CH2:36][CH3:37])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)Cl
Reactant: O=S1(=O)CCC(N2CCNCC2)C1
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCN(C2CCS(=O)(=O)C2)CC1

Procedure:
In a manner analogous to the method described in examples 8, (4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl chloride (example 51) was coupled with 1-(1,1-dioxo-tetrahydro-1λ6-thiophen-3-yl)-piperazine to give the title compound as a mixture of diastereomers.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:11])[C@@H:5]1[CH2:9][CH:8]([OH:10])[CH2:7][NH:6]1.Cl[C:13]([O:15][CH2:16][CH:17]=[CH2:18])=[O:14].[OH-].[Na+]>O.C1COCC1>[CH3:2][O:3][C:4](=[O:11])[C@@H:5]1[CH2:9][C@@H:8]([OH:10])[CH2:7][N:6]1[C:13]([O:15][CH2:16][CH:17]=[CH2:18])=[O:14]
Reactant: C=CCOC(=O)Cl
Reactant: COC(=O)[C@@H]1CC(O)CN1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: C=CCOC(=O)N1C[C@H](O)C[C@H]1C(=O)OC
Reaction time: 1 h
Yield: 86 %

Procedure:
To a solution of 4-hydroxyproline methyl ester hydrochloride (Rosen et al, Synthesis, 40, 1988) (60.4 mMol) in water (10 ml) and THF (20 ml), at 0° C., was added dropwise allyl chloroformate (70 mMol) in THF (20 ml). The solution was maintained at a slightly basic pH by the simultaneous addition of 4N sodium hydroxide (144 mMol). The mixture was stirred at 0° for 1 hour. The aqueous layer was separated and washed, twice, with dichloromethane (25 ml). The organic layers were combined, dried and evaporated to give N-allyloxycarbonyl hydroxyproline methyl ester as a pale yellow oil (86%): NMR (CDCl3) 2.2(m, 3H); 3.58(m, 2H); 3.73(2d, 3H); 4.54(m, 4H); 5.25(m, 2H); 5.9(m, 1H): M/S CI (M+H)+ =230.
Reaction SMILES: [F:1][C:2]1[CH:31]=[CH:30][C:5]([C:6]([NH:8][CH2:9][C:10]2([C:26]([F:29])([F:28])[F:27])[C:15]3[CH:16]=[C:17]([N:20]4[CH:24]=[CH:23][CH:22]=[N:21]4)[CH:18]=[CH:19][C:14]=3[NH:13][C:12](=[O:25])[O:11]2)=[O:7])=[CH:4][CH:3]=1.CCCCCC>C(O)C>[F:1][C:2]1[CH:31]=[CH:30][C:5]([C:6]([NH:8][CH2:9][C@:10]2([C:26]([F:28])([F:27])[F:29])[C:15]3[CH:16]=[C:17]([N:20]4[CH:24]=[CH:23][CH:22]=[N:21]4)[CH:18]=[CH:19][C:14]=3[NH:13][C:12](=[O:25])[O:11]2)=[O:7])=[CH:4][CH:3]=1
Reactant: O=C1Nc2ccc(-n3cccn3)cc2C(CNC(=O)c2ccc(F)cc2)(C(F)(F)F)O1
Solvent: CCO
Solvent: CCCCCC
Product: O=C1Nc2ccc(-n3cccn3)cc2[C@](CNC(=O)c2ccc(F)cc2)(C(F)(F)F)O1

Procedure:
4-Fluoro-N-{[2-oxo-6-(1H-pyrazol-1-yl)-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-4-yl]methyl}benzamide was subjected to optical resolution by HPLC (Chiralpack AD-H, n-hexane:ethanol=4:1), and a fraction eluted at a later time was concentrated, whereby the objective compound was obtained.
Reaction SMILES: [Li+].CC([N-]C(C)C)C.[CH:9]([N:12]([C:20]1[S:21][CH:22]=[CH:23][N:24]=1)[C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:11])[CH3:10].[CH2:25]([Sn:29](Cl)([CH2:34][CH2:35][CH2:36][CH3:37])[CH2:30][CH2:31][CH2:32][CH3:33])[CH2:26][CH2:27][CH3:28]>C1COCC1>[CH:9]([N:12]([C:20]1[S:21][C:22]([Sn:29]([CH2:30][CH2:31][CH2:32][CH3:33])([CH2:34][CH2:35][CH2:36][CH3:37])[CH2:25][CH2:26][CH2:27][CH3:28])=[CH:23][N:24]=1)[C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:16])[CH3:17])([CH3:11])[CH3:10]
Reactant: CC(C)N(C(=O)OC(C)(C)C)c1nccs1
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1cnc(N(C(=O)OC(C)(C)C)C(C)C)s1
Temperature: -78 °C
Reaction time: 2 h
Yield: 40.3 %

Procedure:
LDA (0.55M 1.1 mmol, 2M) was added to a RBF containing THF (5 mL) cooled to −78° C. A solution of tert-butyl isopropyl(thiazol-2-yl)carbamate (242 mg, 1 mmol) in THF (5 mL) was added via cannula and the resulting solution stirred for 2 h at −78° C. Tributyltin chloride (0.27 mL, 1 mmol) was added and the reaction mixture allowed to slowly warm to room temperature then stirred overnight. The reaction mixture was then quenched with NH4Cl (2 mL, sat. aq.) and diluted with water. The mixture was then extracted with EtOAc (3×25 mL) and the combined organic extracts were dried (Na2SO4), filtered and concentrated in vacuo. The product was isolated via column chromatography (SiO2, 2% EtOAc/heptane) to afford the product (214 mg, 40% yield) as a colorless oil.
Reaction SMILES: Cl.C(OCC)(=O)C.C([O:12][C:13]1[C:14]([CH2:19][N:20]2[CH2:25][CH2:24][CH:23]([C:26](=[O:38])[CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[C:34]([F:37])([F:36])[F:35])[CH2:22][CH2:21]2)=[N:15][CH:16]=[CH:17][N:18]=1)(C)(C)C.[OH-].[Na+]>ClCCl>[F:37][C:34]([F:35])([F:36])[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=1[CH2:27][C:26]([CH:23]1[CH2:22][CH2:21][N:20]([CH2:19][C:14]2[C:13](=[O:12])[NH:18][CH:17]=[CH:16][N:15]=2)[CH2:25][CH2:24]1)=[O:38]
Reactant: CC(C)(C)Oc1nccnc1CN1CCC(C(=O)Cc2ccccc2C(F)(F)F)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: O=C(Cc1ccccc1C(F)(F)F)C1CCN(Cc2ncc[nH]c2=O)CC1
Reaction time: 0.5 h
Yield: 71.5 %

Procedure:
After adding 3 ml of 4N hydrogen chloride/ethyl acetate to 249 mg of 1-[1-(3-tert-butoxy-2-pyrazinylmethyl)piperidin-4-yl]-2-[2-(trifluoromethyl)phenyl]ethanone while cooling on ice, the mixture was stirred for 30 minutes. A 2N sodium hydroxide solution was added to the reaction solution for neutralization, and extraction was performed with dichloromethane. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. Diethyl ether was added to the residue and the mixture was filtered to obtain the title compound (155 mg, 71% yield).
Reaction SMILES: [SH-:1].[Na+].[CH2:3]([S:5]([C:8]1[CH:13]=[CH:12][C:11](F)=[C:10]([Cl:15])[CH:9]=1)(=[O:7])=[O:6])[CH3:4]>CN(C=O)C.[OH-].[Na+]>[Cl:15][C:10]1[CH:9]=[C:8]([S:5]([CH2:3][CH3:4])(=[O:7])=[O:6])[CH:13]=[CH:12][C:11]=1[SH:1]
Reactant: [SH-]
Reactant: CCS(=O)(=O)c1ccc(F)c(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: CCS(=O)(=O)c1ccc(S)c(Cl)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Sodium hydrosulphide (0.252 g) was added to the product from example 4 step (i) (11.0 g) in dry DMF (10 ml) and stirred at RT for 2 h. The mixture was diluted with 2M sodium hydroxide solution and extracted with diethylether. The aqueous layer was acidified with 2M hydrochloric acid, extracted with ethyl acetate, dried and evaporated under reduced pressure, crude yield 1.60 g.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[OH:9].C(=O)([O-])[O-].[K+].[K+].Br[CH2:17][CH2:18]Br>CN(C)C=O>[CH3:8][C:5]1[CH:6]=[CH:7][C:2]2[NH:1][CH2:17][CH2:18][O:9][C:3]=2[CH:4]=1
Reactant: BrCCBr
Reactant: Cc1ccc(N)c(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1ccc2c(c1)OCCN2
Temperature: 130 °C
Reaction time: 11 h

Procedure:
To a solution of 2-amino-5-methylphenol (5.0 g) in N,N-dimethylformamide (50 ml), potassium carbonate (28.3 g) and 1,2-dibromoethane (10.6 ml) were added and stirred at 130° C. for 11 hours. After insoluble materials were filtered off, the filtrate was diluted with ethyl acetate and washed sequentially with water and brine. The organic layer was dried over anhydrous sodium sulfate and then filtered to remove the desiccant, followed by distilling off the solvent under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluting solvent: n-hexane:ethyl acetate=20:1 to 9:1) to give the titled compound, i.e., 7-methyl-3,4-dihydro-2H-1,4-benzoxazine (980 mg) as a brown oil.
Reaction SMILES: Br[C:2]1[C:11]([NH:12][CH3:13])=[C:10]([F:14])[CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][N:6]([C:16]1[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=1)[C:7]2=[O:15].[C:25]([Cu])#[N:26].[C-]#N.[K+]>CN1C(=O)CCC1>[F:14][C:10]1[C:11]([NH:12][CH3:13])=[C:2]([C:25]#[N:26])[C:3]2[CH:4]=[CH:5][N:6]([C:16]3[CH:17]=[CH:18][C:19]([N+:22]([O-:24])=[O:23])=[CH:20][CH:21]=3)[C:7](=[O:15])[C:8]=2[CH:9]=1
Reactant: CNc1c(F)cc2c(=O)n(-c3ccc([N+](=O)[O-])cc3)ccc2c1Br
Reactant: N#C[Cu]
Agent: [C-]#N
Agent: [K+]
Solvent: CN1CCCC1=O
Product: CNc1c(F)cc2c(=O)n(-c3ccc([N+](=O)[O-])cc3)ccc2c1C#N
Temperature: 50 °C
Yield: 130 %

Procedure:
A 110 mg (0.28 mmol) portion of 5-Bromo-7-fluoro-6-methylamino-2-(4-nitro-phenyl)-2H-isoquinolin-1-one (Example 107) and 55 mg (2.2 equiv) of CuCN in 1.4 mL of NMP was heated to 200° C. for 2 h. After cooling to 50° C., 10 mL of 10% aq KCN was added, and mixture was stirred, filtered, washed with water and dried to give 123 mg (130%) of 7-Fluoro-6-methylamino-2-(4-nitro-phenyl)-1-oxo-1,2-dihydro-isoquinoline-5-carbonitrile. A 50 mg (0.15 mmol) portion of this 5-cyano material was reduced with 36 mg of Raney Nickel (Aldrich) in 1:1:2 water/AcOH/pyridine containing 58 mg of sodium hypophosphite. The reaction was then extracted 3 times with ethyl acetate, drying over Na2SO4 (anh.), and concentration in vacuo afforded 10 mg (20%) of the resulting aniline. This material was then coupled using the method described in Example 13 to give 7.8 mg (46%) of 5-chloro-N-[({4-[5-cyano-7-fluoro-6-(methylamino)-1-oxoisoquinolin-2(1H)-yl]phenyl}amino)carbonyl]thiophene-2-sulfonamide. ES-MS (M+H)+=532.1 (Cl).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[CH:9]([CH3:28])[C:10]([C:16]1[CH:17]=[CH:18][C:19]2[O:24][CH2:23][C:22](=[O:25])[N:21]([CH3:26])[C:20]=2[CH:27]=1)([OH:15])[C:11]([F:14])([F:13])[F:12].[C:29]([C:31]1[CH:32]=[C:33](B(O)O)[CH:34]=[CH:35][C:36]=1[F:37])#[N:30]>C([O-])(=O)C.[Cu+2].C([O-])(=O)C.N1C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:33]2[CH:34]=[CH:35][C:36]([F:37])=[C:31]([CH:32]=2)[C:29]#[N:30])=[CH:4][C:3]=1[CH:9]([CH3:28])[C:10]([OH:15])([C:16]1[CH:17]=[CH:18][C:19]2[O:24][CH2:23][C:22](=[O:25])[N:21]([CH3:26])[C:20]=2[CH:27]=1)[C:11]([F:12])([F:13])[F:14]
Reactant: CC(c1cc(O)ccc1Cl)C(O)(c1ccc2c(c1)N(C)C(=O)CO2)C(F)(F)F
Reactant: N#Cc1cc(B(O)O)ccc1F
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Product: CC(c1cc(Oc2ccc(F)c(C#N)c2)ccc1Cl)C(O)(c1ccc2c(c1)N(C)C(=O)CO2)C(F)(F)F

Procedure:
In analogy to Example 5, 6-[2-(2-chloro-5-hydroxy-phenyl)-1-hydroxy-1-trifluoromethyl-propyl]-4-methyl-4H-benzo[1,4]oxazin-3-one (Example 1, step 4) was reacted with 3-cyano-4-fluorophenylboronic acid, copper-(II)-acetate and pyridine to give the title compound as an off-white solid. MS (m/e)=535.2 [M+H+].
Reaction SMILES: C(=O)([O-])[O-].[Ca+2].[NH2:6][C:7]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][C:8]=1[C:9]([O:11][CH2:12][CH3:13])=[O:10].Cl.[C:20](Cl)(Cl)=[S:21]>O.ClC(Cl)Cl>[OH:18][C:15]1[CH:16]=[CH:17][C:7]([N:6]=[C:20]=[S:21])=[C:8]([CH:14]=1)[C:9]([O:11][CH2:12][CH3:13])=[O:10]
Reactant: CCOC(=O)c1cc(O)ccc1N
Reactant: S=C(Cl)Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: O
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1cc(O)ccc1N=C=S
Temperature: 10 °C
Reaction time: 0.25 h
Yield: 67.1 %

Procedure:
To a stirred mixture of 5 parts of calcium carbonate, 18.75 parts of trichloromethane and 12.5 parts of water were added 3.6 parts of ethyl 2-amino-5-hydroxybenzoate. 3 Parts of concentrate hydrochloric acid and 10 parts of water were added and the whole was stirred for 15 minutes under nitrogen atmosphere. After cooling in an ice bath at 10° C., 2.6 parts of carbonothioic dichloride were added dropwise, during a period of 20 minutes, at 10°-15° C. The whole was allowed to reach room temperature and stirring was continued for 2 hours. 300 Parts of trichloromethane and 200 parts of water were added. The organic layer was separated, washed with a hydrochloric acid solution 1N and with a sodium hydrogen carbonate solution 10%, dried, filtered and evaporated. The residue was crystallized from 45 parts of benzene. The product was filtered off and dried, yielding 3.0 parts (67.1%) of ethyl 5-hydroxy-2-isothiocyanatobenzoate (18).
Reaction SMILES: [C:1]([O:4][C@H:5]1[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:14](=[CH:15][C:16](=[O:26])[CH:17](I)[C@@H:18]1[CH3:24])[CH2:13][CH2:12]3)(=[O:3])[CH3:2].C(=O)([O-])[O-].[Li+].[Li+].O>CN(C)C=O>[C:1]([O:4][C@H:5]1[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:14](=[CH:15][C:16](=[O:26])[CH:17]=[C:18]1[CH3:24])[CH2:13][CH2:12]3)(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@H]1CC[C@H]2[C@@H]3CCC4=CC(=O)C(I)[C@H](C)[C@]4(C)[C@H]3CC[C@]12C
Agent: O=C([O-])[O-]
Agent: [Li+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)O[C@H]1CC[C@H]2[C@@H]3CCC4=CC(=O)C=C(C)[C@]4(C)[C@H]3CC[C@]12C

Procedure:
1.4 g (3 mmol) of 17α-acetoxy-2-iodo-1α-methyl-androst-4-en-3-one of example 11 and 0.443 g (6 mmol) of anhydrous lithium carbonate are stirred in 6 ml of dimethylformamide for 1 hour at 120° C. under nitrogen atmosphere. After cooling, it is added to water and extracted with ethyl acetate. The ethyl acetate solution is dried on sodium sulfate and then concentrated by evaporation. The residue is chromatographed on silica gel with ethyl acetate/hexane as mobile solvent. After concentration by evaporation of the fractions, 0.95 g (92% of theory) of 17β-acetoxy-1-methyl-androsta-1,4-dien-3-one of melting point 173° C. is obtained.
Reaction SMILES: [N:1]1([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]([C:16]3[O:17][C:18]4[C:23]([C:24](=[O:26])[CH:25]=3)=[CH:22][C:21]([O:27][CH3:28])=[CH:20][C:19]=4[N:29]3[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][CH2:30]3)=[O:15])=[CH:9][CH:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH2:36]([N:38]=[C:39]=[O:40])[CH3:37]>>[CH2:36]([NH:38][C:39]([N:4]1[CH2:5][CH2:6][N:1]([C:7]2[CH:8]=[CH:9][C:10]([NH:13][C:14]([C:16]3[O:17][C:18]4[C:23]([C:24](=[O:26])[CH:25]=3)=[CH:22][C:21]([O:27][CH3:28])=[CH:20][C:19]=4[N:29]3[CH2:30][CH2:31][N:32]([CH3:35])[CH2:33][CH2:34]3)=[O:15])=[CH:11][CH:12]=2)[CH2:2][CH2:3]1)=[O:40])[CH3:37]
Reactant: CCN=C=O
Reactant: COc1cc(N2CCN(C)CC2)c2oc(C(=O)Nc3ccc(N4CCNCC4)cc3)cc(=O)c2c1
Product: CCNC(=O)N1CCN(c2ccc(NC(=O)c3cc(=O)c4cc(OC)cc(N5CCN(C)CC5)c4o3)cc2)CC1

Procedure:
This compound was prepared from 6-methoxy-8-(4-methyl-piperazin-1-yl)-4-oxo-4H-chromene-2-carboxylic acid (4-piperazin-1-yl-phenyl)-amide (Example 43) and commercially available ethyl isocyanate (Aldrich) via the parallel synthesis described above.
Reaction SMILES: [CH2:1]([N:3]([CH2:37][CH3:38])[C:4]([NH:6][C:7]1[C:8]([C:18]2[NH:22][C:21]3[CH:23]=[C:24]([O:28][CH2:29][CH2:30][N:31]4[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]4)[C:25]([F:27])=[CH:26][C:20]=3[N:19]=2)=[N:9][N:10](C2CCCCO2)[CH:11]=1)=[O:5])[CH3:2].[F:39][C:40]([F:45])([F:44])[C:41]([OH:43])=[O:42]>ClCCl>[F:39][C:40]([F:45])([F:44])[C:41]([OH:43])=[O:42].[CH2:37]([N:3]([CH2:1][CH3:2])[C:4]([NH:6][C:7]1[C:8]([C:18]2[NH:22][C:21]3[CH:23]=[C:24]([O:28][CH2:29][CH2:30][N:31]4[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]4)[C:25]([F:27])=[CH:26][C:20]=3[N:19]=2)=[N:9][NH:10][CH:11]=1)=[O:5])[CH3:38]
Reactant: CCN(CC)C(=O)Nc1cn(C2CCCCO2)nc1-c1nc2cc(F)c(OCCN3CCCCC3)cc2[nH]1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCN(CC)C(=O)Nc1c[nH]nc1-c1nc2cc(F)c(OCCN3CCCCC3)cc2[nH]1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 38 mg of 1,1-diethyl-3-{3-[5-fluoro-6-(2-piperidin-1-ylethoxy)-1H-benzimidazol-2-yl]-1-(tetrahydropyran-2-yl)-1H-pyrazol-4-yl}urea is solubilized in 2 mL of dichloromethane and then 500 μl of trifluoroacetic acid are added. The reaction medium is stirred at ambient temperature overnight. The solvent is evaporated off under vacuum in a rotary evaporator and the crude is reacted again in 500 μL of dichloromethane and 500 μL of trifluoroacetic acid at ambient temperature for one hour. After concentration of the solvent in a rotary evaporator, the reaction crude is purified by flash chromatography on a 4 g silica cartridge, eluent: 100/0 to 90/10 dichloromethane/-methanol. 20 mg of 1,1-diethyl-3-{3-[5-fluoro-6-(2-piperidin-1-ylethoxy)-1H-benzimidazol-2-yl]-1H-pyrazol-4-yl}urea trifluoroacetate are isolated in the form of a yellow solid. 1H NMR (400 MHz, DMSO-d6, δ in ppm), for this batch, we observe a 60%-40% resolution of tautomers with: 1.24 (m, 6H); from 1.32 to 1.93 (m, 6H); 3.06 (broad m, 2H); from 3.23 to 3.68 (broad m, 4H); 3.41 (m, 4H); 4.44 (broad m, 2H); 7.21 (d, J=8.0 Hz, 0.6H); 7.32 (d, J=11.0 Hz, 0.4H); 7.38 (d, J=8.0 Hz, 0.4H); 7.49 (d, J=11.0 Hz, 0.6H); 8.01 (s, 1H); 9.32 (broad m, 1H); 9.74 (s, 0.4H); 9.77 (s, 0.6H); 13.0 (s, 1.6H); 13.05 (s, 0.4H).
Reaction SMILES: [CH3:1][S:2]([O:5][C:6]1[CH:7]=[CH:8][C:9]2[O:13][CH:12](N3CCOCC3)[C:11]([CH3:21])([CH3:20])[C:10]=2[CH:22]=1)(=[O:4])=[O:3].[OH2:23]>Cl>[CH3:1][S:2]([O:5][C:6]1[CH:7]=[CH:8][C:9]2[O:13][CH:12]([OH:23])[C:11]([CH3:21])([CH3:20])[C:10]=2[CH:22]=1)(=[O:4])=[O:3]
Reactant: O
Reactant: CC1(C)c2cc(OS(C)(=O)=O)ccc2OC1N1CCOCC1
Agent: Cl
Product: CC1(C)c2cc(OS(C)(=O)=O)ccc2OC1O

Procedure:
A suspension of 2,3-dihydro-3,3-dimethyl-2-morpholinobenzofuran-5-yl methanesulphonate (product of Example 2) (24.9 parts) in water (50 parts) and hydrochloric acid (22.4 parts) was rapidly heated to 90°-100° C. and then cooled after 2 minutes. The crude product was extracted into ether (3×60 parts) and the extracts washed with water (2×50 parts), dried with sodium sulphate and evaporated to leave a gum which crystallised to give 2,3-dihydro-3,3-dimethyl-2-hydroxybenzofuran-5-yl methanesulphonate, m.p. 69°-72° C. (16 parts)
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][C:9]([N+:13]([O-:15])=[O:14])=[CH:10][CH:11]=2)[C:6](=[C:16](OCC)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:5]1=[O:26])(=O)C.[N:27]1([CH2:33][C:34]2[CH:35]=[C:36]([CH:38]=[CH:39][CH:40]=2)[NH2:37])[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1.[OH-].[Na+]>CN(C=O)C.CO>[N:27]1([CH2:33][C:34]2[CH:35]=[C:36]([NH:37]/[C:16](=[C:6]3\[C:5](=[O:26])[NH:4][C:12]4[C:7]\3=[CH:8][C:9]([N+:13]([O-:15])=[O:14])=[CH:10][CH:11]=4)/[C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:38]=[CH:39][CH:40]=2)[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1
Reactant: Nc1cccc(CN2CCCCC2)c1
Reactant: CCOC(=C1C(=O)N(C(C)=O)c2ccc([N+](=O)[O-])cc21)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CN(C)C=O
Product: O=C1Nc2ccc([N+](=O)[O-])cc2/C1=C(/Nc1cccc(CN2CCCCC2)c1)c1ccccc1

Procedure:
Prepared analogously to Example 82 from 1-acetyl-3-(1-ethoxy-1-phenyl-methylidene)-5-nitro-2-indolinone and 3-piperidinomethyl-aniline in DMF and subsequent treatment with sodium hydroxide solution in methanol.
Reaction SMILES: CS(O[CH2:6][C@H:7]1[CH2:15][C:10]2([O:14][CH2:13][CH2:12][O:11]2)[CH2:9][C@H:8]1[CH2:16]OS(C)(=O)=O)(=O)=O.[CH2:22]([NH2:26])[CH2:23][CH2:24][CH3:25]>>[CH2:22]([N:26]1[CH2:6][C@@H:7]2[CH2:15][C:10]3([CH2:9][C@@H:8]2[CH2:16]1)[O:11][CH2:12][CH2:13][O:14]3)[CH2:23][CH2:24][CH3:25]
Reactant: CCCCN
Reactant: CS(=O)(=O)OC[C@@H]1CC2(C[C@@H]1COS(C)(=O)=O)OCCO2
Product: CCCCN1C[C@@H]2CC3(C[C@@H]2C1)OCCO3
Temperature: 90 °C

Procedure:
A suspension of methanesulfonic acid (7R,8S)-8-methanesulfonyloxymethyl-1,4-dioxaspiro-[4.4]non-7-ylmethyl ester (0.250 g, 0.73 mmol) in n-butylamine (1 ml) is heated at 90° C. for 3 hours. The reaction is evaporated and partitioned between EtOAc and 2M aqueous NaOH. The organic phase is washed with brine, dried (MgSO4) and evaporated. The crude product is purified by flash chromatography, eluting with EtOAc to afford (3aR,6aS)-2-butylspiro[hexahydrocyclopenta[c]pyrrole-5(1H),2′-[1,3]dioxolane], M+226.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[C:15]2[CH:16]=[N:17][CH:18]=[C:19]([OH:20])[C:14]=2[C:13]2[CH:21]=[C:22]([Br:25])[CH:23]=[N:24][C:12]1=2)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:26]([O:30][C:31]([N:33]1[CH2:38][CH2:37][CH:36](O)[CH2:35][CH2:34]1)=[O:32])([CH3:29])([CH3:28])[CH3:27].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[CH2:1]([O:8][C:9]([N:11]1[C:15]2[CH:16]=[N:17][CH:18]=[C:19]([O:20][CH:36]3[CH2:37][CH2:38][N:33]([C:31]([O:30][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:32])[CH2:34][CH2:35]3)[C:14]=2[C:13]2[CH:21]=[C:22]([Br:25])[CH:23]=[N:24][C:12]1=2)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(OCc1ccccc1)n1c2cncc(O)c2c2cc(Br)cnc21
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(Oc2cncc3c2c2cc(Br)cnc2n3C(=O)OCc2ccccc2)CC1
Temperature: 50 °C
Yield: 99.1 %

Procedure:
A solution of 3-bromo-5-hydroxy-dipyrido[2,3-b;4′,3′-d]pyrrole-9-carboxylic acid benzyl ester (234 mg, 0.59 mmol), 4-hydroxypiperidine-1-carboxylic acid tert-butyl ester (295 mg, 1.47 mmol) and triphenylphosphine (390 mg, 1.47 mmol) in anhydrous THF (7 mL) was treated dropwise with diethyl azodicarboxylate (295 mg, 1.47 mmol). On complete addition the mixture was heated at 50° C. for 1 hour. The mixture was concentrated in-vacuo and the resultant residue was purified by flash chromatography (silica, 12 g cartridge, ISCO, 0-7% methanol in dichloromethane). The appropriate fractions were collected and evaporated to afford the title compound as an orange oil (0.34 g, 100%). LCMS (Method B): RT=4.76 min, M+H+=581/583. 1H NMR (400 MHz, CDCl3): 9.27 (s, 1H), 8.80 (d, J=2.3 Hz, 1H), 8.61 (d, J=2.3 Hz, 1H), 8.32 (s, 1H), 7.60 (d, J=7.3 Hz, 2H), 7.43-7.36 (m, 3H), 5.64 (s, 2H), 4.89 (m, 1H), 3.40-3.39 (m, 2H), 3.02 (ddd, J=13.5, 9.8, 3.4 Hz, 2H), 2.21-1.80 (m, 4H), 1.46 (s, 9H).