Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[S:11](Cl)(=[O:13])=[O:12])[CH:4]=[CH:3][CH:2]=1.[CH2:15]([O:17][C:18]([C:20]1([NH2:29])[CH2:28][C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH2:21]1)=[O:19])[CH3:16].CCN(C(C)C)C(C)C>C(Cl)Cl>[CH2:15]([O:17][C:18]([C:20]1([NH:29][S:11]([C:9]2[CH:8]=[CH:7][CH:6]=[C:5]3[C:10]=2[N:1]=[CH:2][CH:3]=[CH:4]3)(=[O:13])=[O:12])[CH2:28][C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH2:21]1)=[O:19])[CH3:16]
Reactant: O=S(=O)(Cl)c1cccc2cccnc12
Reactant: CCOC(=O)C1(N)Cc2ccccc2C1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C1(NS(=O)(=O)c2cccc3cccnc23)Cc2ccccc2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 35.1 %

Procedure:
To a solution of quinoline-8-sulfonyl chloride (400 mg, 1.76 mmol), 2-amino-indan-2-carboxylic acid ethyl ester (361 mg, 1.76 mmol) in anhydrous DCM (8 mL) is added DIPEA (291 μL, 1.76 mmol). The resulting solution is stirred at RT overnight. The reaction solution is diluted with DCM (40 mL), washed with water (1×5 mL) and brine (2×5 mL). The organic layer is dried over anhydrous Na2SO4 and concentrated in vacuo. The residue is purified by flash column chromatography (115 g silica gel, gradient elution: 5-50% EtOAc in heptane) to give a pure product (35) as white solid (245 mg, 35%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[NH:12][C:11](=O)[C:10]3[CH:14]=[CH:15][CH:16]=[CH:17][C:9]=3[S:8][C:7]=2[CH:18]=1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:20]>N1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[NH:12][C:11](=[S:20])[C:10]3[CH:14]=[CH:15][CH:16]=[CH:17][C:9]=3[S:8][C:7]=2[CH:18]=1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: COc1ccc2c(c1)Sc1ccccc1C(=O)N2
Solvent: c1ccncc1
Product: COc1ccc2c(c1)Sc1ccccc1C(=S)N2

Procedure:
To 7-methoxy-10,11-dihydrodibenzo[b,f][1,4]thiazepin-11-one (0.5 g, 1.95 mmol) in pyridine (10 ml) was added phosphorus pentasulphide (0.58 g, 0.675 equivalents) and the mixture was heated under reflux for 3.5 hours. The mixture was cooled and the pyridine was removed under reduced pressure, the residue washed with water and recrystallised from methanol to give the title compound as a yellow solid (0.38 g, m.p. 239°-241°, Rf 0.85 [silica, cyclohexane/ethyl acetate (1:1, v/v)].
Reaction SMILES: N[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][C:11]([CH3:14])([CH3:13])[C:10](=[O:15])[C:9]=2[C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]3[CH:33]=[CH:32][C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[N:25]=3)=[CH:18][CH:17]=2)=[CH:4][CH:3]=1.Cl.N([O-])=O.[Na+]>C(#N)C.O>[CH3:13][C:11]1([CH3:14])[C:10](=[O:15])[C:9]([C:16]2[CH:17]=[CH:18][C:19]([O:22][CH2:23][C:24]3[CH:33]=[CH:32][C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[N:25]=3)=[CH:20][CH:21]=2)=[C:8]([C:5]2[CH:6]=[CH:7][CH:2]=[CH:3][CH:4]=2)[O:12]1
Reactant: CC1(C)OC(c2ccc(N)cc2)=C(c2ccc(OCc3ccc4ccccc4n3)cc2)C1=O
Agent: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: CC1(C)OC(c2ccccc2)=C(c2ccc(OCc3ccc4ccccc4n3)cc2)C1=O
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 23.7 %

Procedure:
To a stirred solution of 5-(4-aminophenyl)-2,2-dimethyl-4-(4-(quinolin-2-ylmethoxy)phenyl)furan-3(2H)-one (80 mg, 0.18 mmol) in ACN: H2O (6 mL, 1:1) was added conc HCl (0.2 mL) at 0° C. under N2 atmosphere. The reaction mixture was stirred at 0° C. for 10 min. After being stirred for 5 min then added NaNO2 in water and stirred for 40 min at 0° C. The reaction mixture was stirred at 70° C. for 2 h. After completion of starting material (by TLC), reaction mass was diluted with water and extracted with EtOAc (2×25 mL). Combined organic layers were washed with water (2×5 mL), brine and dried over anhydrous Na2SO4. After filtration and evaporation, the crude material was purified by silica gel column chromatography to afford 2,2-dimethyl-5-phenyl-4-(4-(quinolin-2-ylmethoxy)phenyl)furan-3(2H)-one (18 mg, 23%), as an off white solid. 1H NMR (400 MHz, CDCl3): δ 8.45 (d, J=8.5 Hz, 1H), 8.10 (d, J=7.9 Hz, 1H), 7.86 (d, J=8.4 Hz, 1H), 7.75-7.62 (m, 3H), 7.52 (t, J=8.2 Hz, 1H), 7.45 (d, J=8.5 Hz, 1H), 7.32 (d, J=7.5 Hz, 2H), 7.21 (d, J=7.4 Hz, 2H), 7.03 (d, J=7.5 Hz, 2H), 5.42 (s, 2H), 1.51 (s, 6H). MS: [M+Na]: m/z=444.1, [M+H]: m/z=422.1. HPLC: 98.72% (RT-2.83 min), Column: Acquity BEH-C-18, 50×2.1 mm, 1.7 um. Mobile Phase: 0.025% TFA in Water (A), ACN (B), Flow rate: 0.5 ml/min (Gradient).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].C([O-])([O-])=O.[K+].[K+].[Cl:23][C:24]1[N:29]=[C:28](Cl)[C:27]([Cl:31])=[CH:26][N:25]=1.O>C1COCC1>[Cl:23][C:24]1[N:29]=[C:28]([NH:1][C:2]2[CH:10]=[CH:9][C:8]([N:11]3[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]3)=[CH:7][C:3]=2[C:4]([NH2:6])=[O:5])[C:27]([Cl:31])=[CH:26][N:25]=1
Reactant: NC(=O)c1cc(N2CCCCC2)ccc1N
Reactant: Clc1ncc(Cl)c(Cl)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: NC(=O)c1cc(N2CCCCC2)ccc1Nc1nc(Cl)ncc1Cl
Reaction time: 72 h
Yield: 58.8 %

Procedure:
To a solution of 2-amino-5-piperidin-1-yl-benzamide (1.05 g, 4.6 mmol, Heterocyclic Comm. 2001, 7, 473-480) in THF (10 mL) was added K2CO3 (0.76 g, 5.5 mmol) and 2,4,5-trichloropyrimidine (0.84 g, 4.6 mmol). After stirring for 72 h, addition of water (5 mL) gave a precipitate that was removed by filtration and washed with water (5×3 mL) and ether (3×2 mL) to afford 2-(2,5-dichloro-pyrimidin-4-ylamino)-5-piperidin-1-yl-benzamide as a yellow solid (0.99 g) that was used without further purification in the subsequent step.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:15]2[O:14][CH2:13][CH2:12][CH2:11][O:10][C:9]=2[CH:8]=[C:7]([NH:16][C:17]([C:19]2[NH:20][C:21]3[C:26]([CH:27]=2)=[CH:25][C:24]([Cl:28])=[CH:23][CH:22]=3)=[O:18])[CH:6]=1)=[O:4].Cl>C1COCC1.O.[OH-].[K+]>[Cl:28][C:24]1[CH:25]=[C:26]2[C:21](=[CH:22][CH:23]=1)[NH:20][C:19]([C:17]([NH:16][C:7]1[CH:6]=[C:5]([C:3]([OH:4])=[O:2])[C:15]3[O:14][CH2:13][CH2:12][CH2:11][O:10][C:9]=3[CH:8]=1)=[O:18])=[CH:27]2
Reactant: COC(=O)c1cc(NC(=O)c2cc3cc(Cl)ccc3[nH]2)cc2c1OCCCO2
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(Nc1cc2c(c(C(=O)O)c1)OCCCO2)c1cc2cc(Cl)ccc2[nH]1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
8-[(5-Chloro-1H-indole-2-carbonyl)amino]-3,4-dihydro-2H-benzo[b][1,4]dioxepine-6-carboxylic acid methyl ester (120 mg) was dissolved in a mixture of THF/water and 0.3 mL of 1N KOH. The reaction was stirred at room temperature overnight, made acidic with 1N HCl and then extracted with EtOAc. The organic extract was washed with water, brine and dried with MgSO4. This afforded 35 mg of product. MS POS: M+ 387/389.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH2:26][CH3:27])[CH2:23][CH2:22][C:21]([C:28]([NH:30][C:31]4[CH:36]=[CH:35][C:34]([S:37][CH2:38][C:39]5[N:43]6[CH:44]=[CH:45][CH:46]=[CH:47][C:42]6=[N:41][C:40]=5[CH3:48])=[CH:33][CH:32]=4)=[O:29])=[CH:20][C:19]=3[CH:49]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].ClC1C=CC=C(C(OO)=[O:58])C=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>ClCCl>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH2:26][CH3:27])[CH2:23][CH2:22][C:21]([C:28]([NH:30][C:31]4[CH:32]=[CH:33][C:34]([S:37]([CH2:38][C:39]5[N:43]6[CH:44]=[CH:45][CH:46]=[CH:47][C:42]6=[N:41][C:40]=5[CH3:48])=[O:58])=[CH:35][CH:36]=4)=[O:29])=[CH:20][C:19]=3[CH:49]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(SCc4c(C)nc5ccccn45)cc2)CCN3CCC)cc1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(S(=O)Cc4c(C)nc5ccccn45)cc2)CCN3CCC)cc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 67.5 %

Procedure:
To a solution of 7-[4-(2-butoxyethoxy)phenyl]-N-[4-(2-methylimidazo[1,2-a]pyridin-3-ylmethylthio)phenyl]-1-propyl-2,3-dihydro-1H-benzazepine-4-carboxamide (0.96 g) in dichloromethane (10 ml) was added dropwise a solution of 3-chloroperbenzoic acid (70%, 0.52 g) in dichloromethane (10 ml) at −78° C. The mixture was stirred for 1 hour at −78° C., sodium thiosulfate solution was added to the mixture at room temperature and the mixture was stirred for several minutes. The mixture was extracted with ethyl acetate, and the organic layer was washed with sodium bicarbonate solution and saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The obtained residue was separated and purified by column chromatography (basic silica gel, ethyl acetate:hexane 3:1→ethyl acetate), and was further recrystallized from ethyl acetate-diisopropylether, to give 7-[4-(2-butoxyethoxy)phenyl]-N-[4-(2-methylimidazo[1,2-a]pyridin-3-ylmethylsulfinyl)phenyl]-1-propyl-2,3-dihydro-1H-benzazepine-4-carboxamide (Compound 165) (663.1 mg) as yellow crystals.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:4]=[C:5]([NH:9][C:10]2[NH:11][C:12]([C:15]3[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=3)=[N:13][N:14]=2)[CH:6]=[CH:7][CH:8]=1.C([O-])([O-])=O.[Cs+].[Cs+].[NH2:30][C:31]1[CH:36]=[C:35](Cl)[N:34]=[CH:33][N:32]=1.CO>O1CCOCC1>[F:23][C:2]([F:22])([F:1])[C:3]1[CH:4]=[C:5]([NH:9][C:10]2[NH:11][C:12]([C:15]3[CH:20]=[CH:19][C:18]([O:21][C:35]4[N:34]=[CH:33][N:32]=[C:31]([NH2:30])[CH:36]=4)=[CH:17][CH:16]=3)=[N:13][N:14]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: Oc1ccc(-c2nnc(Nc3cccc(C(F)(F)F)c3)[nH]2)cc1
Reactant: Nc1cc(Cl)ncn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CO
Solvent: C1COCCO1
Product: Nc1cc(Oc2ccc(-c3nnc(Nc4cccc(C(F)(F)F)c4)[nH]3)cc2)ncn1
Yield: 59.8 %

Procedure:
4-(5-{[3-(trifluoromethyl)phenyl]amino}-4H-1,2,4-triazol-3-yl)phenol (100 mg, 0.31 mmol) was dissolved in 3 mL of anhydrous dioxane in 2-5 mL microwave vial (Personal Chemistry). Solid Cs2CO3 (101.7 mg, 0.31 mmol) was added, followed by 4-amino-6-chloro-pyrimidine (48.5 mg, 0.37 mmol). The vial was capped and microwaved at 200° C., for 5 min. Then ca. 3 mL of MeOH was added to dissolve the formed suspension. The resulting reddish-brown solution was transferred into a round-bottom flask and solvent was removed in vacuo. The residue was re-dissolved in 3 mL of DMF, filtered through 0.22 u syringe filter and purified by reverse phase preparative HPLC using acetonitrile/water system with 0.01% of TFA. The fractions, containing the product, were collected and partitioned between EtOAc and saturated aqueous NaHCO3. Ethyl acetate layer was washed with brine, dried over anhydrous sodium sulfate and filtered. Solvent was removed in vacuo to give the title compound as a white solid (76.6 mg).
Reaction SMILES: Cl[C:2]1[C:11]([CH3:12])=[C:10]([Cl:13])[C:9]2[C:4](=[CH:5][C:6]([F:15])=[CH:7][C:8]=2[F:14])[N:3]=1.[CH:16]1([CH2:19][O:20][C:21]2[CH:26]=[CH:25][C:24](B3OC(C)(C)C(C)(C)O3)=[CH:23][N:22]=2)[CH2:18][CH2:17]1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1>[Cl:13][C:10]1[C:9]2[C:4](=[CH:5][C:6]([F:15])=[CH:7][C:8]=2[F:14])[N:3]=[C:2]([C:24]2[CH:23]=[N:22][C:21]([O:20][CH2:19][CH:16]3[CH2:17][CH2:18]3)=[CH:26][CH:25]=2)[C:11]=1[CH3:12]
Reactant: Cc1c(Cl)nc2cc(F)cc(F)c2c1Cl
Reactant: CC1(C)OB(c2ccc(OCC3CC3)nc2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: Cc1c(-c2ccc(OCC3CC3)nc2)nc2cc(F)cc(F)c2c1Cl

Procedure:
The Suzuki coupled product was prepared according to Procedure F using 2,4-dichloro-5,7-difluoro-3-methylquinoline (0.5 g, 2.0 mmol), 2-(cyclopropylmethoxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (0.666 g, 2.42 mmol), palladium tetrakistriphenylphosphine (0.23 g, 0.20 mmol), potassium carbonate (0.84 g, 6.1 mmol) in toluene (4.0 mL) at 100° C. for 18.3 h to give 4-chloro-2-(6-(cyclopropylmethoxy)pyridin-3-yl)-5,7-difluoro-3-methylquinoline as a light yellow solid. Mass Spectrum (ESI) m/e=361.1 (M+1).
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[CH:14]=[C:13]2[C:8]([CH:9]=[C:10]([CH:15]=O)[CH2:11][O:12]2)=[CH:7][CH:6]=1.[NH:17]1[CH2:22][CH2:21][CH2:20][C@@H:19]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:18]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>ClC(Cl)C>[CH3:1][O:2][CH2:3][O:4][C:5]1[CH:14]=[C:13]2[C:8]([CH:9]=[C:10]([CH2:15][N:17]3[CH2:22][CH2:21][CH2:20][C@@H:19]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:18]3)[CH2:11][O:12]2)=[CH:7][CH:6]=1
Reactant: COCOc1ccc2c(c1)OCC(C=O)=C2
Reactant: CCOC(=O)[C@@H]1CCCNC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(Cl)Cl
Product: CCOC(=O)[C@@H]1CCCN(CC2=Cc3ccc(OCOC)cc3OC2)C1
Temperature: 80 °C
Reaction time: 4 h

Procedure:
To a solution of 7-(methoxymethoxy)-2H-chromene-3-carbaldehyde (5.00 g) and ethyl (3R)-piperidine-3-carboxylate (4.20 mL) in dichloroethane (150 mL) was added sodium triacetoxyborohydride (12.0 g), followed by stirring at 80° C. for 4 hours. The reaction liquid was cooled to room temperature and then saturated aqueous NaHCO3 was added thereto, followed by extraction with chloroform. The organic layer was washed with brine and dried over anhydrous sodium sulfate, and the vehicle was evaporated. The residue was purified by silica gel column chromatography (hexane:EtOAc=4:1) to obtain ethyl (3R)-1-{[7-(methoxymethoxy)-2H-chromen-3-yl]methyl}piperidine-3-carboxylate (7.30 g) as a yellow oily substance.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][CH:3]=1.Cl[C:11]1[C:12]2[C:25]([CH3:26])=[C:24]([CH3:27])[S:23][C:13]=2[N:14]=[C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=2)[N:16]=1>>[N:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[C:15]1[N:16]=[C:11]([NH:7][CH2:6][C:5]2[CH:8]=[CH:9][C:2]([F:1])=[CH:3][CH:4]=2)[C:12]2[C:25]([CH3:26])=[C:24]([CH3:27])[S:23][C:13]=2[N:14]=1
Reactant: Cc1sc2nc(-c3ccccn3)nc(Cl)c2c1C
Reactant: NCc1ccc(F)cc1
Product: Cc1sc2nc(-c3ccccn3)nc(NCc3ccc(F)cc3)c2c1C

Procedure:
With the procedure of Example 1, the reaction of 4-fluorobenzylamine with 4-chloro-2-(pyridin-2-yl)-5,6-dimethyl-thieno-[2,3-d]-pyrimidine yields 2-(pyridin-2-yl)-4-(4-fluorobenzylamino)-5,6-dimethyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [CH2:1]([O:3][C:4]1[N:13]=[C:12]([O:14][CH:15]2[CH2:32][CH:31]3[CH:17]([C:18](=[O:38])[N:19]([CH3:37])[CH2:20][CH2:21][CH2:22][CH2:23][CH:24]=[CH:25][CH:26]4[C:28]([C:34]([OH:36])=O)([NH:29][C:30]3=[O:33])[CH2:27]4)[CH2:16]2)[C:11]2[C:6](=[C:7]([CH3:41])[C:8]([O:39][CH3:40])=[CH:9][CH:10]=2)[N:5]=1)[CH3:2].[CH:42]1([S:45]([NH2:48])(=[O:47])=[O:46])[CH2:44][CH2:43]1>>[CH2:1]([O:3][C:4]1[N:13]=[C:12]([O:14][CH:15]2[CH2:32][CH:31]3[CH:17]([C:18](=[O:38])[N:19]([CH3:37])[CH2:20][CH2:21][CH2:22][CH2:23][CH:24]=[CH:25][CH:26]4[C:28]([C:34]([NH:48][S:45]([CH:42]5[CH2:44][CH2:43]5)(=[O:47])=[O:46])=[O:36])([NH:29][C:30]3=[O:33])[CH2:27]4)[CH2:16]2)[C:11]2[C:6](=[C:7]([CH3:41])[C:8]([O:39][CH3:40])=[CH:9][CH:10]=2)[N:5]=1)[CH3:2]
Reactant: CCOc1nc(OC2CC3C(=O)NC4(C(=O)O)CC4C=CCCCCN(C)C(=O)C3C2)c2ccc(OC)c(C)c2n1
Reactant: NS(=O)(=O)C1CC1
Product: CCOc1nc(OC2CC3C(=O)NC4(C(=O)NS(=O)(=O)C5CC5)CC4C=CCCCCN(C)C(=O)C3C2)c2ccc(OC)c(C)c2n1

Procedure:
The acid (149) was reacted with cyclopropylsulfonamide according to the procedure described in example 147, which gave the title compound, m/z=670 (M+H)+.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[CH2:15][CH2:14][N:13]([C:16]([O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[O:17])[CH2:12][CH:11]2[O:26][CH2:27][C:28]2[CH:29]=[CH:30][C:31]3[O:36][CH2:35][CH2:34][N:33]([CH2:37][CH2:38][CH2:39][O:40][CH3:41])[C:32]=3[CH:42]=2)=[CH:6][CH:5]=1)(O)=[O:2].[O:43]([CH2:50][CH2:51][NH2:52])[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1.Cl.CN(C)CCCN=C=NCC.O>CN(C)C=O.CN(C)C1C=CN=CC=1>[CH3:41][O:40][CH2:39][CH2:38][CH2:37][N:33]1[C:32]2[CH:42]=[C:28]([CH2:27][O:26][CH:11]3[CH:10]([C:7]4[CH:6]=[CH:5][C:4]([C:1](=[O:2])[NH:52][CH2:51][CH2:50][O:43][C:44]5[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=5)=[CH:9][CH:8]=4)[CH2:15][CH2:14][N:13]([C:16]([O:18][CH2:19][C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=4)=[O:17])[CH2:12]3)[CH:29]=[CH:30][C:31]=2[O:36][CH2:35][CH2:34]1
Reactant: NCCOc1ccccc1
Reactant: COCCCN1CCOc2ccc(COC3CN(C(=O)OCc4ccccc4)CCC3c3ccc(C(=O)O)cc3)cc21
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Product: COCCCN1CCOc2ccc(COC3CN(C(=O)OCc4ccccc4)CCC3c3ccc(C(=O)NCCOc4ccccc4)cc3)cc21
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A solution of 0.36 g of benzyl 4-(4-carboxyphenyl)-3-[4-(3-methoxypropyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]piperidine-1-carboxylate and 0.125 g of 2-phenoxyethylamine in 5 ml of N,N-dimethylformamide is admixed under argon with 0.172 g of 3-dimethylaminopropyl ethyl carbodiimide hydrochloride and 0.0037 g of 4-dimethylaminopyridine. The reaction solution is stirred at room temperature over 3 days, subsequently poured onto 25 ml of water and extracted with 50 ml of tert-butyl methyl ether. The organic phase is dried over potassium carbonate, filtered and concentrated. The title compound is obtained as a yellow oil from the residue by means of flash chromatography (SiO2 60F). Rf=0.16 (2:1 EtOAc-heptane); Rt=5.18.
Reaction SMILES: [OH:1][N:2]=[C:3]([C:5]1[CH:13]=[CH:12][C:8]2[NH:9][CH:10]=[N:11][C:7]=2[CH:6]=1)[NH2:4].[F:14]C1C2NC=NC=2C=C(C#N)C=1>>[F:14][C:12]1[C:8]2[NH:9][CH:10]=[N:11][C:7]=2[CH:6]=[C:5]([C:3](=[N:2][OH:1])[NH2:4])[CH:13]=1
Reactant: NC(=NO)c1ccc2[nH]cnc2c1
Reactant: N#Cc1cc(F)c2[nH]cnc2c1
Product: NC(=NO)c1cc(F)c2[nH]cnc2c1

Procedure:
The title compound was prepared following the procedure described for Intermediate 1, step 2, but starting from 7-fluoro-1H-benzimidazole-5-carbonitrile obtained in step 2 (750 mg; 4.65 mmol) as a beige solid (814 mg, 90%). 1H NMR (DMSO-d6) δ 12.88 (bs, 1H), 9.67 (s, 1H), 9.30 (s, 1H), 7.68 (s, 1H), 7.33-7.29 (m, 1H), 5.89 (s, 2H). LC/MS (Method B): 195.1 (M+H)+.
Reaction SMILES: CON(C)[C:4]([C:6]1[CH:10]=[C:9]([CH2:11][CH3:12])[N:8]([CH3:13])[N:7]=1)=[O:5].[CH3:15][Mg]Br.[Cl-].[NH4+]>O1CCCC1.CCOCC>[C:4]([C:6]1[CH:10]=[C:9]([CH2:11][CH3:12])[N:8]([CH3:13])[N:7]=1)(=[O:5])[CH3:15]
Reactant: CCc1cc(C(=O)N(C)OC)nn1C
Reactant: C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCc1cc(C(C)=O)nn1C
Temperature: 0 °C
Reaction time: 2 h
Yield: 88 %

Procedure:
N-Methoxy-N-methyl-5-ethyl-1-methylpyrazole-3-carboxamide (2.9 g) in dry tetrahydrofuran (100 ml), under argon was cooled to -20 ° C. and treated with methylmagnesium bromide (9.8 ml of a 3M solution in ether). A precipitate was initially formed that re-dissolved on complete addition. The reaction mixture was stirred at 0° C. for 2 h. and then poured into saturated ammonium chloride. The aqueous phase was extracted with ethyl acetate and the combined organic phases washed with brine, dried over anhydrous magnesium sulphate and concentrated to a brown oil. The crude product was purified by silica gel chromatography eluting with 50% ethyl acetate/hexane to give the title compound as a pale brown oil, (1.97 g, 88%); (Found: M+, 152.0950. C8H12N2O requires M 152.0950); nmax (CH2Cl2) 1693. 1472, 1376 and 1352 cm-1 ; dH (CDCl3) 1.28 (3H, t, J7.4 Hz), 2.54 (3H, s), 2.61 (2H, q, J7.4 Hz), 3.84 (3H, s) and 6.56 (1H, s).
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][C:4]=1[Cl:10].Cl[C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13]>N1C=CC=CC=1>[Cl:10][C:4]1[CH:5]=[C:6]([OH:9])[CH:7]=[CH:8][C:3]=1[NH:2][C:12](=[O:13])[O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: Nc1ccc(O)cc1Cl
Agent: Cl
Solvent: c1ccncc1
Product: O=C(Nc1ccc(O)cc1Cl)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-amino-3-chlorophenol hydrochloride (3.00 g) in pyridine (20.0 mL) were added benzyl chloroformate (2.62 mL) under ice-cooling, followed by stirring at room temperature overnight. The reaction mixture was concentrated under reduced pressure, and then the residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain benzyl (2-chloro-4-hydroxyphenyl)carbamate (1.59 g).
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:8]([CH3:46])([CH3:45])[C@H:9]2[C@:22]([CH3:25])([CH2:23][CH:24]=1)[C@@H:21]1[C@:12]([CH3:44])([C@@:13]3([CH3:43])[C@H:18]([CH2:19][CH2:20]1)[C@H:17]1[C@H:26]([C:29]([CH3:31])=[CH2:30])[CH2:27][CH2:28][C@:16]1([NH:32][CH2:33][CH2:34][N:35]1[CH2:40][CH2:39][S:38](=[O:42])(=[O:41])[CH2:37][CH2:36]1)[CH2:15][CH2:14]3)[CH2:11][CH2:10]2)(=O)=O.[CH3:49][C:50]1([C:65]([O:67][CH2:68][CH3:69])=[O:66])[O:55][CH2:54][C:53](B2OC(C)(C)C(C)(C)O2)=[CH:52][O:51]1>>[O:42]=[S:38]1(=[O:41])[CH2:39][CH2:40][N:35]([CH2:34][CH2:33][NH:32][C@:16]23[CH2:28][CH2:27][C@@H:26]([C:29]([CH3:31])=[CH2:30])[C@@H:17]2[C@@H:18]2[C@@:13]([CH3:43])([CH2:14][CH2:15]3)[C@@:12]3([CH3:44])[C@@H:21]([C@:22]4([CH3:25])[C@@H:9]([CH2:10][CH2:11]3)[C:8]([CH3:45])([CH3:46])[C:7]([C:53]3[CH2:54][O:55][C:50]([CH3:49])([C:65]([O:67][CH2:68][CH3:69])=[O:66])[O:51][CH:52]=3)=[CH:24][CH2:23]4)[CH2:20][CH2:19]2)[CH2:36][CH2:37]1
Reactant: C=C(C)[C@@H]1CC[C@]2(NCCN3CCS(=O)(=O)CC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(OS(=O)(=O)C(F)(F)F)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Reactant: CCOC(=O)C1(C)OC=C(B2OC(C)(C)C(C)(C)O2)CO1
Product: C=C(C)[C@@H]1CC[C@]2(NCCN3CCS(=O)(=O)CC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(C6=COC(C)(C(=O)OCC)OC6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Yield: 13.3 %

Procedure:
The title compound was prepared following the method described in step 1 for the preparation of Example 1, using (1R,3aS,5aR,5bR,7aR,11aR,11bR,13aR,13bR)-3a-((2-(1,1-dioxidothiomorpholino)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl trifluoromethanesulfonate and ethyl 2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4H-1,3-dioxine-2-carboxylate as the reactants. The product was isolated as a mixture of diasteromers in 13.3% yield. MS: m/e 741.55 (M+H)+, 2.72 min (method 8). 1H NMR (400 MHz, CHLOROFORM-d) δ 6.35-6.30 (m, 1H), 5.36 (d, J=5.5 Hz, 1H), 4.73 (s, 1H), 4.60 (s, 1H), 4.42 (ddd, J=15.4, 7.6, 1.4 Hz, 1H), 4.33-4.21 (m, 2H), 4.20-4.12 (m, 1H), 3.14-3.00 (m, 11H), 2.80-2.47 (m, 2H), 2.12-1.73 (m, 2H), 1.69 (s, 3H), 1.62 (s, 3H), 1.55-1.19 (m, 11H), 1.10-1.02 (m, 12H), 1.00-0.94 (m, 6H), 0.92-0.87 (m, 3H), 0.86-0.78 (m, 6H).
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[CH2:8][CH2:7][CH2:6][C:5]1=[O:9].[H-].[Na+].Br[C:13]1[CH:18]=[CH:17][C:16]([Br:19])=[CH:15][N:14]=1.[OH-].[Na+]>CN1C(=O)CCC1.O>[Br:19][C:16]1[CH:17]=[CH:18][C:13]([O:1][CH2:2][CH2:3][N:4]2[CH2:8][CH2:7][CH2:6][C:5]2=[O:9])=[N:14][CH:15]=1
Reactant: O=C1CCCN1CCO
Reactant: Brc1ccc(Br)nc1
Agent: [H-]
Agent: [Na+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Solvent: O
Product: O=C1CCCN1CCOc1ccc(Br)cn1
Temperature: 80 °C

Procedure:
2.45 g (19 mmol) of 1-(2-hydroxyethyl)-pyrrolidin-2-one and 0.83 g (19 mmol) of sodium hydride (55% in mineral oil) in 10 ml of NMP were stirred at room temperature for 1 h. 3.0 g (12.7 mmol) of 2,5-dibromopyridine were added, and the mixture was heated to 80° C. for 2 h. Water was added, and the mixture was extracted with ethyl acetate. The combined organic phases were dried and concentrated. The remaining oil was taken up in 200 ml of tert-butyl methyl ether and treated with a solution of hydrogen chloride in diethyl ether. The resulting greasy solid was isolated by decantation of the solvent and treated with a 25% aqueous sodium hydroxide solution. The product was extracted with ethyl acetate, and the combined organic phases were dried and concentrated. Yield: 2.75 g.