Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[OH:11][CH2:12][CH2:13][CH2:14][N:15]([CH3:23])[C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19].C(N(CC)CC)C>ClCCl.[Cl-].[Na+].O>[CH3:23][N:15]([CH2:14][CH2:13][CH:12]=[O:11])[C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:19])[CH3:20]
Reactant: CN(CCCO)C(=O)OC(C)(C)C
Agent: O=C(Cl)C(=O)Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CN(CCC=O)C(=O)OC(C)(C)C
Temperature: -78 °C
Yield: 100.7 %

Procedure:
Dimethylsulfoxide (6.22 ml, 87.6 mmol) was dissolved in dry dichloromethane (100 ml) under nitrogen and the solution was cooled to −78° C. with stirring. Oxalyl chloride (3.95 ml, 45.4 mmol) was then added dropwise and the solution was stirred at −78° C. for a further 30 minutes when effervescence had ceased. A solution of (3-hydroxypropyl)methylcarbamic acid, 1,1-dimethylethyl ester (6.62 g, 35.0 mmol) in dichloromethane (100 ml) was then added dropwise at −78° C. The resultant solution was stirred at −78° C. for 45 minutes, then a solution of triethylamine (24.4 ml, 175 mmol) in dichloromethane (50 ml) was added. The resultant solution was allowed to warm to room temperature and stirred for a further 18 h. The reaction mixture was then poured into brine and extracted with dichloromethane three times. The combined organic fractions were then washed with brine and dried over magnesium sulfate. The solvent was evaporated and the residue triturated with diethyl ether and filtered. The solvent was evaporated to give the title compound (6.60 g, 100%) as an orange oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[CH2:4][N:5]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH2:6][C:7]([O:9][CH3:10])=[O:8].C[O-].[Na+].[CH3:27][C:28](=[CH:30][CH2:31][CH2:32]/[C:33](=[CH:35]/CO)/[CH3:34])[CH3:29].CO>C1(C)C=CC=CC=1>[CH2:10]([O:9][C:7](=[O:8])[CH2:6][N:5]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH2:4][C:3]([O:2][CH2:1]/[CH:35]=[C:33](/[CH2:32][CH2:31][CH:30]=[C:28]([CH3:27])[CH3:29])\[CH3:34])=[O:23])/[CH:27]=[C:28](/[CH2:30][CH2:31][CH:32]=[C:33]([CH3:35])[CH3:34])\[CH3:29]
Reactant: CCCCCCCCCCCCN(CC(=O)OC)CC(=O)OC
Reactant: CC(C)=CCC/C(C)=C/CO
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: Cc1ccccc1
Product: CCCCCCCCCCCCN(CC(=O)OC/C=C(\C)CCC=C(C)C)CC(=O)OC/C=C(\C)CCC=C(C)C
Reaction time: 1 h

Procedure:
To a mixture of N-dodecyl-N-(2-methoxy-2-oxoethyl)glycine methyl ester (6.59 g, 20 mmol, 1 eq) in toluene (80 ml) under argon was slowly added some sodium methoxide (0.27 g, 0.005 mol, 2*0.125 eq) and geraniol (7.3 ml, 42 mmol, 2*1.05 eq). The mixture was heated under vacuum (10 mm Hg) and the methanol produced by the transesterification reaction was distilled with toluene over two hours after which the reaction appeared completed by 1H NMR. Any remaining toluene was evaporated under vacuum. Diethyl ether was added (200 ml) and the mixture stored at 4° C. for one hour prior to filtration. The filtrate was then concentrated under vacuum yielding to the expected N-dodecyl-N-(2-geranyloxy-2-oxoethyl)glycine geranyl ester as a light brown oil (quantitative yield).
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[S:10][C:11]3[CH2:12][CH2:13][O:14][C:15]4[CH:22]=[C:21]([C:23]#[N:24])[CH:20]=[CH:19][C:16]=4[C:17]=3[N:18]=2)=[N:7][C:6]([CH3:25])=[N:5]1)([CH3:3])[CH3:2].[AlH4-].[Li+]>O1CCCC1>[CH:1]([N:4]1[C:8]([C:9]2[S:10][C:11]3[CH2:12][CH2:13][O:14][C:15]4[CH:22]=[C:21]([CH2:23][NH2:24])[CH:20]=[CH:19][C:16]=4[C:17]=3[N:18]=2)=[N:7][C:6]([CH3:25])=[N:5]1)([CH3:3])[CH3:2]
Reactant: Cc1nc(-c2nc3c(s2)CCOc2cc(C#N)ccc2-3)n(C(C)C)n1
Agent: [AlH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1nc(-c2nc3c(s2)CCOc2cc(CN)ccc2-3)n(C(C)C)n1
Reaction time: 2 h
Yield: 47.2 %

Procedure:
To a solution of 2-(2-Isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-8-carbonitrile (0.500 g, 0.00142 mol) in Tetrahydrofuran (14 mL) was added Lithium tetrahydroaluminate (0.00569 mol, 1M in THF, 5.7 mL), dropwise at 0° C. The reaction was stirred for 2 hours and quenched with saturated Na2SO4 until H2 evolution ceased. MgSO4 was added and the whole was diluted with copious amounts of methylene chloride, filtered over celite, and concentrated in vacuo. The crude was purified by flash chromatography (1-15% MeOH in DCM spiked with Et3N) to afford 532 as a yellow solid (238 mg). MS(ESI+) 356.1
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:16]2[CH:17]=[C:18](C=CC(Cl)=O)[CH:19]=[CH:20][CH:21]=2)=[CH:4][C:5]2[C:6]([CH3:15])([CH3:14])[CH2:7][CH2:8][C:9]([CH3:13])([CH3:12])[C:10]=2[CH:11]=1.[OH:27][C:28]1[CH:34]=[CH:33][C:31]([NH2:32])=[CH:30][CH:29]=1>>[OH:27][C:28]1[CH:34]=[CH:33][C:31]([NH:32][C:28](=[O:27])[C:29]([C:18]2[CH:19]=[CH:20][CH:21]=[C:16]([C:3]3[C:2]([CH3:1])=[CH:11][C:10]4[C:9]([CH3:12])([CH3:13])[CH2:8][CH2:7][C:6]([CH3:14])([CH3:15])[C:5]=4[CH:4]=3)[CH:17]=2)=[CH2:30])=[CH:30][CH:29]=1
Reactant: Nc1ccc(O)cc1
Reactant: Cc1cc2c(cc1-c1cccc(C=CC(=O)Cl)c1)C(C)(C)CCC2(C)C
Product: C=C(C(=O)Nc1ccc(O)cc1)c1cccc(-c2cc3c(cc2C)C(C)(C)CCC3(C)C)c1

Procedure:
In similar manner to Example 27(a), by reaction of 1.2 g (3.2 mmol) of 3-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)phenylacryloyl chloride with 349 mg (3.2 mmol) of 4-hydroxyaniline, 810 mg of (57%) of N-(4-hydroxyphenyl)-3-(3,5,5,8,8-pentamethyl-5,6,7,6-tetrahydro-2-naphthyl)phenylacrylamide are obtained, with a melting point of 240-1° C.
Reaction SMILES: [Cl:1][O-].[Na+].[Cl:4][C:5]1[N:10]=[CH:9][C:8]2[CH:11]=[N:12][NH:13][C:7]=2[CH:6]=1.O.S([O-])([O-])=O.[Na+].[Na+]>CCO>[Cl:1][C:11]1[C:8]2[CH:9]=[N:10][C:5]([Cl:4])=[CH:6][C:7]=2[NH:13][N:12]=1
Reactant: [O-]Cl
Reactant: Clc1cc2[nH]ncc2cn1
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Clc1cc2[nH]nc(Cl)c2cn1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 94.8 %

Procedure:
Sodium hypochlorite (121 mL, 195 mmol) was gradually added to a suspension of 6-chloro-1H-pyrazolo[4,3-c]pyridine (10 g, 65.1 mmol) in EtOH (100 mL) at 0° C. The reaction mixture was then stirred at room temperature for 10 minutes. Water and sodium sulfite (24.62 g, 195 mmol) were added, forming a clear solution, and the mixture was extracted with EtOAc. The organic phase was concentrated in vacuo to give 3,6-dichloro-1H-pyrazolo[4,3-c]pyridine (11.6 g, 61.7 mmol, 95% yield). MS ESI calc'd. for C6H4Cl2N3 [M+H]+ 188, found 188.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[C:12]([CH:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[CH:11]=[CH:10][C:9]=2[NH:20][C:21]([C:23]2[O:24][C:25]([C:28]#[N:29])=[CH:26][CH:27]=2)=[O:22])[CH2:4][CH2:3]1.CCN(CC)CC.[C:37](OC(=O)C)(=[O:39])[CH3:38]>C(Cl)Cl>[C:37]([N:17]1[CH2:16][CH2:15][CH:14]([C:12]2[CH:11]=[CH:10][C:9]([NH:20][C:21]([C:23]3[O:24][C:25]([C:28]#[N:29])=[CH:26][CH:27]=3)=[O:22])=[C:8]([N:5]3[CH2:6][CH2:7][CH:2]([CH3:1])[CH2:3][CH2:4]3)[CH:13]=2)[CH2:19][CH2:18]1)(=[O:39])[CH3:38]
Reactant: CC(=O)OC(C)=O
Reactant: CC1CCN(c2cc(C3CCNCC3)ccc2NC(=O)c2ccc(C#N)o2)CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)N1CCC(c2ccc(NC(=O)c3ccc(C#N)o3)c(N3CCC(C)CC3)c2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 74 %

Procedure:
A flask was charged with 5-cyano-furan-2-carboxylic acid [2-(4-methyl-piperidin-1-yl)-4-piperidin-4-yl-phenyl]-amide (0.035 g, 56 μmol) (as prepared in Example 34, step (b)), NEt3 (31.0 μL, 225 μmol), acetic anhydride (6.5 μL, 62 μmol), and DCM (0.5 mL) and stirred at RT for 1 h. The title compound was eluted from a 10-g SPE cartridge (silica) with 5% MeOH/DCM to give 18 mg (75%) of a white solid. 1H-NMR (400 MHz, CDCl3): δ 9.78 (s, 1H), 8.34 (d, 1H), 7.24 (m, 2H), 7.01 (m, 2H), 4.80 (m, 2H), 3.96. (m, 2H), 3.20 (t, 1H), 2.98 (m, 2H), 2.70 (m, 4H), 2.28 (s, 3H), 1.88 (m, 4H), 1.60 (m, 5H), 1.10 (d, 3H). Mass spectrum (ESI, m/z): Calcd. for C25H30N4O3, 435.2 (M+H), found 435.2.
Reaction SMILES: [C:1]([CH2:3][NH:4][C:5](=O)[C:6]1[CH:11]=[CH:10][N:9]=[CH:8][CH:7]=1)#[N:2].P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:14].C1C=CC=CC=1>>[N:9]1[CH:10]=[CH:11][C:6]([C:5]2[S:14][C:1]([NH2:2])=[CH:3][N:4]=2)=[CH:7][CH:8]=1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: N#CCNC(=O)c1ccncc1
Solvent: c1ccccc1
Product: Nc1cnc(-c2ccncc2)s1
Yield: 100.5 %

Procedure:
A mixture of N-(cyanomethyl)isonicotinamide (0.665 g, 4.1 mmol) and phosphorus pentasulfide (1.8 g, 8.3 mmol) in benzene (5.00 ml, 56 mmol) was allowed to refluxed for 24 hours. The mixture was concentrated and the residue was purified by CombiFlash using 0-10% methanol/DCM to give 730 mg of 2-(pyridin-4-yl)thiazol-5-amine 5.3C. 400 MHz 1H NMR (CD3OD) δ: 8.51 (d, J=8.0 Hz, 2H), 7.72 (d, J=8.0 Hz, 2H), 7.07 (s, 1H). LCMS (ES+) m/z 178.
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([S:12](Cl)(=[O:14])=[O:13])=[CH:4][CH:3]=1.[CH:16]1([NH2:22])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1.C(N(CC)CC)C>C(Cl)Cl>[CH:16]1([NH:22][S:12]([C:5]2[C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[C:2]([CH3:1])=[CH:3][CH:4]=2)(=[O:14])=[O:13])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: Cc1ccc(S(=O)(=O)Cl)c2ccccc12
Reactant: NC1CCCCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)NC2CCCCC2)c2ccccc12
Yield: 65.9 %

Procedure:
To a solution of 4-methyl-naphthalene-1-sulfonyl chloride (2.4 g, 10.0 mmol) in CH2Cl2 (30 mL), was added cyclohexylamine (1.4 g, 11.0 mmol) and triethylamine (2.8 mL, 20.0 mmol) and the resultant solution was stirred at room temperature overnight. The solution was quenched with water and extracted with CH2Cl2 (3×30 mL). The combined organic layers were dried over Na2SO4 and concentrated in vacuo. The resulting residue was purified by Flash column chromatography (hexane/ethyl acetate, gradient elution) to give the title compound 40 (2.0 g) as a yellow solid. 1H NMR (300 MHz, CDCl3) δ 8.63 (d, 1H), 8.18 (d, 1H), 8.10 (d, 1H), 7.64 (m, 2H), 7.38 (d, 1H), 3.08 (m, 1H), 2.76 (s, 3H), 1.52 (m, 5H), 1.09 (m, 5H); LC/MS m/z 304 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:22][C@@H:23]2[C@@H:28]3[CH2:29][C@@H:25]([CH:26]=[CH:27]3)[C@@H:24]2[C:30]([NH2:32])=[O:31])=[C:4]2[N:10]=[C:9]([C:11]3[CH:12]=[N:13][N:14]([CH:16]4[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]4)[CH:15]=3)[NH:8][C:5]2=[N:6][CH:7]=1.[CH2:33]([N:35]=[C:36]=[O:37])[CH3:34]>>[CH2:33]([NH:35][C:36]([N:19]1[CH2:20][CH2:21][CH:16]([N:14]2[CH:15]=[C:11]([C:9]3[NH:8][C:5]4=[N:6][CH:7]=[C:2]([Cl:1])[C:3]([NH:22][C@H:23]5[C@@H:24]([C:30](=[O:31])[NH2:32])[C@H:25]6[CH2:29][C@@H:28]5[CH:27]=[CH:26]6)=[C:4]4[N:10]=3)[CH:12]=[N:13]2)[CH2:17][CH2:18]1)=[O:37])[CH3:34]
Reactant: NC(=O)[C@@H]1[C@H](Nc2c(Cl)cnc3[nH]c(-c4cnn(C5CCNCC5)c4)nc23)[C@H]2C=C[C@@H]1C2
Reactant: CCN=C=O
Product: CCNC(=O)N1CCC(n2cc(-c3nc4c(N[C@H]5[C@@H](C(N)=O)[C@@H]6C=C[C@H]5C6)c(Cl)cnc4[nH]3)cn2)CC1

Procedure:
In a similar fashion as for the synthesis of Compound LXI, (1S,2S,3R,4R)-3-[6-Chloro-2-(1-piperidin-4-yl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridine-7-ylamino]-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid amide was reacted with ethyl isocyanate to afford the title compound as a white lyophilate (70%). 1H NMR (d-chloroform): 8.36 (d, J=8 Hz, 1H), 8.11 (s, 2H), 7.87 (s, 1H), 6.47 (m, 1H), 6.42 (m, 1H), 5.81 (br s, 1H), 5.45 (br s, 1H), 5.36 (m, 1H), 4.42 (m, 2H), 4.15 (m, 2H), 3.33 (m, 2H), 3.17 (s, 1H), 3.02 (m, 3H), 2.67 (d, J=9 Hz, 1H), 2.33 (d, J=9 Hz, 1H), 2.23 (m, 2H), 2.10 (m, 3H), 1.69 (d, J=8 Hz, 1H), 1.20 (t, J=9 Hz, 1H). MS: 524.21 (M+H). HPLC retention time: 1.96 minutes (G Method).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[H-].[Na+].[Cl:12][C:13]1[CH:14]=[C:15]([C:22]([CH3:32])([CH3:31])[CH2:23][C:24]2([C:27]([F:30])([F:29])[F:28])[CH2:26][O:25]2)[C:16]2[O:20][CH2:19][CH2:18][C:17]=2[CH:21]=1>CN(C=O)C.C(OCC)(=O)C>[Cl:12][C:13]1[CH:14]=[C:15]([C:22]([CH3:32])([CH3:31])[CH2:23][C:24]([CH2:26][N:1]2[C:9]3[C:4](=[N:5][CH:6]=[CH:7][CH:8]=3)[CH:3]=[CH:2]2)([OH:25])[C:27]([F:28])([F:29])[F:30])[C:16]2[O:20][CH2:19][CH2:18][C:17]=2[CH:21]=1
Reactant: CC(C)(CC1(C(F)(F)F)CO1)c1cc(Cl)cc2c1OCC2
Reactant: c1cnc2cc[nH]c2c1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(CC(O)(Cn1ccc2ncccc21)C(F)(F)F)c1cc(Cl)cc2c1OCC2
Reaction time: 0.5 h
Yield: 44.9 %

Procedure:
A solution of 1H-pyrrolo[3,2-b]pyridine (33.0 mg, 0.279 mmol) in 4 mL of DMF was treated with NaH (60% in mineral oil, 16.8 mg, 0.419 mmol) at room temperature. After 30 minutes, 5-chloro-7-[1,1-dimethyl-2-(2-trifluoromethyloxiranyl)ethyl]-2,3-dihydrobenzofuran (188 mg, 0.558 mmol) was added and the resulting mixture was stirred overnight. The reaction was then diluted with 5 mL of ethyl acetate and quenched with 5 mL of saturated ammonium chloride solution. The aqueous layer was extracted with 5 mL of ethyl acetate. The combined organic layers were dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue was triturated with diethyl ether to afford 55.0 mg (45% yield) of the title product as white solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([OH:10])=O)=[N:6][CH:7]=1.Cl.Cl.[NH:13]1[CH2:18][CH2:17][CH:16]([C:19]2[NH:23][C:22]3[CH:24]=[CH:25][CH:26]=[CH:27][C:21]=3[N:20]=2)[CH2:15][CH2:14]1.Cl.C(N=C=N)C.C(N(CC)CC)C>ClC(Cl)C.CN(C)C1C=CN=CC=1>[NH:20]1[C:21]2[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=2[N:23]=[C:19]1[CH:16]1[CH2:17][CH2:18][N:13]([C:8]([C:5]2[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][N:6]=2)=[O:10])[CH2:14][CH2:15]1
Reactant: c1ccc2[nH]c(C3CCNCC3)nc2c1
Reactant: O=C(O)c1ccc(Br)cn1
Agent: CCN=C=N
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CC(Cl)Cl
Solvent: CCN(CC)CC
Product: O=C(c1ccc(Br)cn1)N1CCC(c2nc3ccccc3[nH]2)CC1
Yield: 14 %

Procedure:
To a stirred mixture of 5-bromopyridine-2-carboxylic acid (177 mg, 0.88 mmol) and 2-(piperidin-4-yl)-1H-benzimidazole dihydrochloride (200 mg, 0.73 mmol) in dichloroethane (5 mL) is added ethylcarbodiimide hydrochloride (168 mg, 0.88 mmol), triethylamine (0.25 mL, 1.82 mmol) and 4-dimethylaminopyridine (44.6 mg, 0.36 mmol). After 3 h the reaction mixture is washed with saturated aqueous NaHCO3, water and brine. The organic layer is dried over Na2SO4, filtered and concentrated under reduced pressure. Trituration from hot EtOAc gives 39.4 mg of [4-(1H-benzimidazol-2-yl)piperidin-1-yl](5-bromopyridin-2-yl)methanone.
Reaction SMILES: C([O:4][CH2:5][C:6](=[O:32])[C@@:7]12[O:31][CH2:30][O:29][C@@H:8]1[CH2:9][C@@H:10]1[C@:24]2([CH3:25])[CH2:23][C@H:22]([OH:26])[C@@:21]2([F:27])[C@H:11]1[CH2:12][CH2:13][C:14]1[C@:19]2([CH3:20])[CH:18]=[CH:17][C:16](=[O:28])[CH:15]=1)(=O)C>Cl(O)(=O)(=O)=O.CO.C(Cl)Cl>[F:27][C@:21]12[C@@H:22]([OH:26])[CH2:23][C@@:24]3([CH3:25])[C@@H:10]([CH2:9][C@H:8]4[O:29][CH2:30][O:31][C@:7]43[C:6](=[O:32])[CH2:5][OH:4])[C@@H:11]1[CH2:12][CH2:13][C:14]1[C@:19]2([CH3:20])[CH:18]=[CH:17][C:16](=[O:28])[CH:15]=1
Reactant: CC(=O)OCC(=O)[C@@]12OCO[C@@H]1C[C@H]1[C@@H]3CCC4=CC(=O)C=C[C@]4(C)[C@@]3(F)[C@@H](O)C[C@@]12C
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: ClCCl
Solvent: CO
Product: C[C@]12C=CC(=O)C=C1CC[C@H]1[C@@H]3C[C@H]4OCO[C@@]4(C(=O)CO)[C@@]3(C)C[C@H](O)[C@@]12F
Yield: 65 %

Procedure:
18.0 g of 21-acetoxy-9α-fluoro-11β-hydroxy-16α,17α-methylenedioxy-1,4-pregnadiene-3,20-dione is stirred in a mixture of 216 ml of 60% perchloric acid and 720 ml of methanol at room temperature for 18 hours. The reaction solution is diluted with methylene chloride and poured on water. After extraction with methylene chloride, neutralizing, washing, drying, and concentration of the organic extracts, 14.0 g of a crude product is obtained which is recrystallized from hexane/acetone, yielding 10.6 g of 9α-fluoro-11β,21-dihydroxy-16α,17α-methylenedioxy-1,4-pregnadiene-3,20-dione, mp 262° C.
Reaction SMILES: [OH-:1].[Na+].[Cl:3][C:4]1[C:5]([OH:17])=[CH:6][CH:7]=[C:8]2[C:13]=1[O:12][C:11](=[O:14])[CH:10]=[C:9]2[CH2:15]Cl>Cl>[Cl:3][C:4]1[C:13]2[O:12][CH:15]=[C:9]([CH2:10][C:11]([OH:14])=[O:1])[C:8]=2[CH:7]=[CH:6][C:5]=1[OH:17]
Reactant: [OH-]
Reactant: O=c1cc(CCl)c2ccc(O)c(Cl)c2o1
Agent: Cl
Agent: [Na+]
Product: O=C(O)Cc1coc2c(Cl)c(O)ccc12
Temperature: 100 °C
Reaction time: 1 h

Procedure:
A mixture of 1N NaOH (56.7 mL) and 8-chloro-4-(chloromethyl)-7-hydroxy-2H-chromen-2-one (2.78 g) was stirred at 100° C. for 1 h. After cooling, the reaction mixture was acidified with 6N HCl (10 mL). The precipitate was collected by filtration to give the title compound (1.65 g).
Reaction SMILES: [Na].C([O:4][C:5]1[C:10]([F:11])=[CH:9][CH:8]=[CH:7][C:6]=1[O:12][CH2:13][C@@H:14]1[O:16][CH2:15]1)=O>CO>[F:11][C:10]1[C:5]2[O:4][C@@H:14]([CH2:15][OH:16])[CH2:13][O:12][C:6]=2[CH:7]=[CH:8][CH:9]=1
Reactant: O=COc1c(F)cccc1OC[C@H]1CO1
Agent: [Na]
Solvent: CO
Product: OC[C@H]1COc2cccc(F)c2O1
Temperature: 25 °C
Reaction time: 1 h
Yield: 67.6 %

Procedure:
Sodium metal (0.89 g) was dissolved in methanol (100 ml) and a solution of (R)-2-(2,3-epoxypropoxy)-6-fluorophenyl formate (6.56 g, prepared as described above) in methanol (100 ml) added dropwise. The mixture was stirred for one hour at ambient temperature then heated under reflux for two hours, allowed to stand for 3 days, and then heated under reflux for 4 hours. The solvent was removed in vacuo, water (100 ml) was added and the mixture extracted with ethyl acetate (4×100 ml). The combined extracts were washed with brine (100 ml), dried over magnesium sulphate and the solvent evaporated in vacuo to give crude (S)-8-fluoro-1,4-benzodioxan-2-ylmethanol (3.85 g) which was used without further purification.
Reaction SMILES: C1O[C:8]2[CH:7]=[CH:6][C:5]([N+:10]([O-:12])=[O:11])=[CH:4][C:3]=2[O:2]1.[NH3:13].COCCOCCOC>O>[NH2:13][C:8]1[CH:7]=[CH:6][C:5]([N+:10]([O-:12])=[O:11])=[CH:4][C:3]=1[OH:2]
Reactant: N
Reactant: O=[N+]([O-])c1ccc2c(c1)OCO2
Solvent: COCCOCCOC
Solvent: O
Product: Nc1ccc([N+](=O)[O-])cc1O
Temperature: 100 °C
Reaction time: 0.5 h

Procedure:
A solution of 0.18 mol (30 g) of 3,4-methylenedioxynitrobenzene in a mixture of 240 ml of 28% strength ammonia solution and 240 ml of diethylene glycol dimethyl ether is heated at 100° C. for 28 hours in an autoclave. After cooling, 480 ml of water are added. The unreacted initial product precipitates. It is recovered by filtration and the filtrate is then neutralised with hydrochloric acid. After filtration, the filtrate is extracted with ethyl acetate. The ethyl acetate is driven off in vacuo. The residue is treated with 25 ml of acetic anhydride and then kept in a boiling water-bath for 30 minutes. After cooling, the expected product is isolated in the form of the acetyl derivative. This acetyl derivative is hydrolysed with 45 ml of hydrochloric acid of density 1.17, at 90° C. for one hour. After dilution and neutralisation of the solution containing hydrochloric acid, 2-amino-5-nitrophenol is isolated by filtration.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].C1([Mg]Cl)C=CC=CC=1.[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([S:26]([N:29]([C:33]2[C:34]([CH:40]=[O:41])=[N:35][CH:36]=[C:37]([Cl:39])[CH:38]=2)[CH2:30][O:31][CH3:32])(=[O:28])=[O:27])=[CH:22][C:21]=1[C:42]([F:45])([F:44])[F:43]>C1COCC1>[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([S:26]([N:29]([C:33]2[C:34]([CH:40]([OH:41])[C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=3[N+:8]([O-:10])=[O:9])=[N:35][CH:36]=[C:37]([Cl:39])[CH:38]=2)[CH2:30][O:31][CH3:32])(=[O:28])=[O:27])=[CH:22][C:21]=1[C:42]([F:43])([F:45])[F:44]
Reactant: O=[N+]([O-])c1ccccc1I
Reactant: COCN(c1cc(Cl)cnc1C=O)S(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Agent: Cl[Mg]c1ccccc1
Solvent: C1CCOC1
Product: COCN(c1cc(Cl)cnc1C(O)c1ccccc1[N+](=O)[O-])S(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a stirred solution of 1-iodo-2-nitro-benzene (769 mg, 3.08 mmol) in anhydrous THF (3 mL) was added 2 M phenylmagnesium chloride in THF (1.62 mL, 3.24 mmol) at −40° C. under an atmosphere of nitrogen. It was stirred at the same temperature for 15 minutes and then 4-chloro-N-(5-chloro-2-formyl-pyridin-3-yl)-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamide (1.04 g, 2.36 mmol) was added in one portion and the progress of the reaction was followed by LCMS. The reaction mixture was warmed to room temperature and stirred for 3 h. It was then quenched with saturated aqueous NH4Cl (2 mL), and extracted with EtOAc. The combined extracts were dried (Na2SO4), filtered and concentrated under reduced pressure to provide crude 4-chloro-N-{5-chloro-2-[hydroxy-(2-nitro-phenyl)-methyl]-pyridin-3-yl}-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamide, which was used in the following step without any purification. Mass spectrum m/z: 566.3 (M+H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[F:12])[C:5]([O:7]C)=O.[CH2:13]([NH2:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.N1CCCN2CCCN=C12.BrC1C=CC2N(N=CC=2C(NC2C=C(C(=O)NCC3C=CC=CC=3N3CCN(C)CC3)C=CC=2C)=O)C=1>>[NH2:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[F:12])[C:5]([NH:20][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:7]
Reactant: NCc1ccccc1
Reactant: COC(=O)c1ccc(F)c(N)c1
Agent: C1CN=C2NCCCN2C1
Agent: Cc1ccc(C(=O)NCc2ccccc2N2CCN(C)CC2)cc1NC(=O)c1cnn2cc(Br)ccc12
Product: Nc1cc(C(=O)NCc2ccccc2)ccc1F

Procedure:
The title compound was prepared from methyl 3-amino-4-fluorobenzoate, benzylamine and 2,3,4,6,7,8-hexahydro-1H-pyrimido[1,2-a]pyrimidine analogously to 3-amino-4-methyl-N-(2-(4-methylpiperazin-1-yl)benzyl)benzamide (Intermediate 4A, step 1);
Reaction SMILES: [CH2:1]([N:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:13]3[N:14]=[N:15][N:16]([C:19]4[C:20]([F:25])=[N:21][CH:22]=[CH:23][CH:24]=4)[C:17]=3[CH3:18])[CH:9]=2)[C:4]1=[O:26])[CH3:2].[H][H]>[C].[Pd].C(O)C>[CH2:1]([N:3]1[CH2:12][CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:13]3[N:14]=[N:15][N:16]([C:19]4[C:20]([F:25])=[N:21][CH:22]=[CH:23][CH:24]=4)[C:17]=3[CH3:18])[CH:9]=2)[C:4]1=[O:26])[CH3:2]
Reactant: CCn1ccc2cc(-c3nnn(-c4cccnc4F)c3C)ccc2c1=O
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CCN1CCc2cc(-c3nnn(-c4cccnc4F)c3C)ccc2C1=O
Yield: 19.9 %

Procedure:
20 mg of palladium carbon was added to 10 ml solution of ethanol with 5 mg of 4-(2-ethyl-1-oxo-isoquinoline-6-yl)-1-(2-fluoropyridine-3-yl)-5-methyl-1H-[1,2,3]triazole, hydrogen was added under 4 atm of hydrogen atmosphere. 8 hours later, the reaction solution was filtrated and after distilling out the solvents of the filtrate under reduced pressure, the residues were separated and purified by thin-layer chromatography (chloroform/methanol=10/1) to obtain 1 mg of the above compound as a white solid.
Reaction SMILES: [O-]CC.[Na+].[Cl:5][CH:6]([CH2:16][C:17](Cl)([Cl:19])[Cl:18])[C:7]([CH3:15])([CH3:14])[CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10].Cl>CN(C)C=O>[Cl:5][CH:6]([CH:16]=[C:17]([Cl:18])[Cl:19])[C:7]([CH3:15])([CH3:14])[CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10]
Reactant: CCOC(=O)CC(C)(C)C(Cl)CC(Cl)(Cl)Cl
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)CC(C)(C)C(Cl)C=C(Cl)Cl
Temperature: 0 °C
Yield: 66.2 %

Procedure:
A solution of 2.04 g of sodium ethoxide in 60 ml of dimethylformamide was added to a hot solution (140°) of 3.1 g of ethyl 4,6,6,6-tetrachloro-3,3-dimethylhexanoate in 20 ml of dimethylformamide. The mixture was maintained at 140° for 2 hours, then cooled to 0°, neutralized with dry hydrogen chloride and poured into ice water. The aqueous mixture was extracted with ether, and the extract was washed successively with saturated aqueous sodium bicarbonate and sodium chloride. The washed extract was dried over magnesium sulfate and distilled to give 1.81 g (77% yield) of ethyl 4,6,6-trichloro-3,3-dimethyl-5-hexenoate, b.p. 98°-101°/0.6 mm.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([N+:11]([O-:13])=[O:12])[CH:10]=1)[NH:7]C(=O)[C:5]2=[O:15].[OH:16]O.Cl>[OH-].[Na+].O>[NH2:7][C:8]1[C:9]([N+:11]([O-:13])=[O:12])=[CH:10][C:2]([CH3:1])=[CH:3][C:4]=1[C:5]([OH:15])=[O:16]
Reactant: Cc1cc2c(c([N+](=O)[O-])c1)NC(=O)C2=O
Reactant: OO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1cc(C(=O)O)c(N)c([N+](=O)[O-])c1
Reaction time: 12 h
Yield: 85 %

Procedure:
A solution of 5-methyl-7-nitro-1H-indole-2,3-dione (6.5 g, 0.0315 mol) in 2N NaOH (35 mL) was cooled to 20° C. and a 30% aq. solution of H2O2 (6.5 mL) was added slowly over a period of 15 min. The reaction mixture was brought to room temperature and stirred for 12 h, then diluted with water (75 mL). The pH was adjusted to 2 with conc. HCl. The formed precipitate was filtered and dried in a vacuum oven to get 5.3 g of the required product as a yellow coloured solid (85%).