Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[N:7]=[N:6][C:5]([NH2:8])=[N:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[F:15][C:16]1[CH:17]=[C:18](B(O)O)[CH:19]=[C:20]([F:23])[C:21]=1[F:22]>>[C:9]1([C:3]2[N:4]=[C:5]([NH2:8])[N:6]=[N:7][C:2]=2[C:18]2[CH:17]=[C:16]([F:15])[C:21]([F:22])=[C:20]([F:23])[CH:19]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: OB(O)c1cc(F)c(F)c(F)c1
Reactant: Nc1nnc(Br)c(-c2ccccc2)n1
Product: Nc1nnc(-c2cc(F)c(F)c(F)c2)c(-c2ccccc2)n1
Yield: 36.4 %

Procedure:
5-Phenyl-6-(3,4,5-trifluorophenyl)-1,2,4-triazin-3-amine (131 mg, 37%) was prepared from 6-bromo-5-phenyl-1,2,4-triazin-3-amine (0.30 g, 1.19 mmol) and 3,4,5-trifluorophenylboronic acid (0.23 g, 1.30 mmol) according to the general procedure of Example 1.
Reaction SMILES: [C:1]([OH:10])(=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].S(Cl)([Cl:13])=O>>[C:1]([Cl:13])(=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCC(=O)O
Reactant: O=S(Cl)Cl
Product: CCCCCCCC(=O)Cl
Temperature: 40 °C

Procedure:
144.2 g of Octanoic Acid is charged at room temperature and heated to 40° C., then 154.64 g of Thionyl Chloride is added over a period of 1 hour and the reaction mixture is heated to reflux at 110° C. for 1½ hour to obtain crude Octanoyl Chloride.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1>S(Cl)(Cl)=O>[NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][C:5]([CH3:9])([CH3:6])[CH3:4])=[O:7])=[CH:4][CH:3]=1
Reactant: Nc1ccc(C(=O)O)cc1
Solvent: O=S(Cl)Cl
Product: CC(C)(C)OC(=O)c1ccc(N)cc1
Reaction time: 2 h

Procedure:
4-Aminobenzoic acid (5.0 g) was suspended in thionyl chloride (50 ml) and heated to a gentle reflux. After two hours the solution went completely clear, and so the reaction was allowed to cool and the thionyl chloride was removed under reduced pressure, the last traces by azeotrope with dichloromethane (3×50 ml). The resulting acid chloride was dissolved in more dichloromethane (50 ml) and a solution of t-butanol (15 ml) in dichloromethane (15 ml) was added to the stirred solution which was cooled in an ice bath. A solid white precipitate was formed--the hydrochloride salt of the title compound. This was isolated by evaporation of the dichloromethane, followed by suspension of the solid in ethyl acetate (100 ml) and filtration. The material was suspended in 10% aqueous sodium hydrogencarbonate solution (100 ml) and extracted into dichloromethane (3×100 ml). The organic layer was dried, filtered and evaporated to leave a pale cream solid (4.67 g, 66%), m.p. 106°-109° C. (lit. m.p. 109.5° C.) (R. Adams et al (1926) J. Amer. Chem. Soc., 48, 1758), the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:22][N:12]3[C:13](=[O:21])[NH:14][C:15]4[CH:16]=[CH:17][CH:18]=[CH:19][C:20]=4[C:11]3=[N:10][CH2:9]2)=[CH:4][CH:3]=1.[CH3:23][O:24][C:25]1[CH:30]=[CH:29][C:28]([N:31]=[C:32]=[O:33])=[CH:27][CH:26]=1>>[CH3:23][O:24][C:25]1[CH:30]=[CH:29][C:28]([NH:31][C:32]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([CH:8]3[CH2:22][N:12]4[C:13](=[O:21])[NH:14][C:15]5[CH:16]=[CH:17][CH:18]=[CH:19][C:20]=5[C:11]4=[N:10][CH2:9]3)=[CH:4][CH:3]=2)=[O:33])=[CH:27][CH:26]=1
Reactant: Nc1ccc(C2CN=C3c4ccccc4NC(=O)N3C2)cc1
Reactant: COc1ccc(N=C=O)cc1
Product: COc1ccc(NC(=O)Nc2ccc(C3CN=C4c5ccccc5NC(=O)N4C3)cc2)cc1
Yield: 81.4 %

Procedure:
In a manner similar to the procedure described in Example 7, 3-(4-aminophenyl)-2,3,4,7-tetrahydro-6H-pyrimido[1,2-c]quinazolin-6-one (20.2 mg, 0.069 mmol) and 4-methoxyphenyl isocyanate (0.0098 mL, 0.076 mmol) were reacted to give the title compound as an off-white solid (24.8 mg, 81%). 1H NMR (DMSO-d6) δ: 10.68 (s, 1H), 8.55 (s, 1H), 8.44 (s, 1H), 7.98 (d, J=7.0 Hz, 1H), 7.40-7.45 (m, 3H), 7.33-7.36 (m, 2H), 7.22 (d, J=8.5 Hz, 2H), 7.06 (t, J=7.6 Hz, 1H), 7.01 (d, J=8.2 Hz, 1H), 6.85-6.88 (m, 2H), 4.22 (dt, J=12.6, 3.5 Hz, 1H), 3.69-3.75 (m, 4H), 3.50-3.58 (m, 2H), 2.92-2.99 (m, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][N:7]2[C:11]3=[N:12][C:13]([C:16]([O:18][CH3:19])=[O:17])=[CH:14][CH:15]=[C:10]3[N:9]=[C:8]2[CH3:20])=[C:4]([Cl:23])[CH:3]=1.N1C=CC=CC=1.[CH2:30]([S:34](Cl)(=[O:36])=[O:35])[CH2:31][CH2:32][CH3:33].O>ClCCl>[CH2:30]([S:34]([NH:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][N:7]2[C:11]3=[N:12][C:13]([C:16]([O:18][CH3:19])=[O:17])=[CH:14][CH:15]=[C:10]3[N:9]=[C:8]2[CH3:20])=[C:4]([Cl:23])[CH:3]=1)(=[O:36])=[O:35])[CH2:31][CH2:32][CH3:33]
Reactant: COC(=O)c1ccc2nc(C)n(Cc3ccc(N)cc3Cl)c2n1
Reactant: CCCCS(=O)(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: O
Product: CCCCS(=O)(=O)Nc1ccc(Cn2c(C)nc3ccc(C(=O)OC)nc32)c(Cl)c1
Temperature: 25 °C
Reaction time: 7 h

Procedure:
To a solution of methyl 3-(4-amino-2-chlorobenzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylate (300 mg) in dichloromethane (3.0 ml) was added pyridine (143 mg). To this suspension was added 1-butanesulfonyl chloride (156 mg) under ice-cooling and the mixture was stirred for 5 min and at room temperature for 7 hr. Water was added to the reaction mixture and extracted twice with chloroform. The combined organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate, filtrated, and concentrated under reduced pressure. Methanol was added to the residue. The mixture was crystallized, collected by filtration, and dried under reduced pressure to give methyl 3-(4-(N-(1-butanesulfonyl)amino)-2-chlorobenzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylate as ochroid crystals (287 mg).
Reaction SMILES: [F:1][CH:2]([F:16])[C:3]1[NH:4][C:5]2[C:10]([CH:11]=1)=[C:9]([C:12]#[N:13])[C:8]([C:14]#[N:15])=[CH:7][CH:6]=2.Br[CH:18]([CH3:23])[C:19]([O:21][CH3:22])=[O:20]>>[C:12]([C:9]1[C:8]([C:14]#[N:15])=[CH:7][CH:6]=[C:5]2[C:10]=1[CH:11]=[C:3]([CH:2]([F:1])[F:16])[N:4]2[CH:18]([CH3:23])[C:19]([O:21][CH3:22])=[O:20])#[N:13]
Reactant: N#Cc1ccc2[nH]c(C(F)F)cc2c1C#N
Reactant: COC(=O)C(C)Br
Product: COC(=O)C(C)n1c(C(F)F)cc2c(C#N)c(C#N)ccc21

Procedure:
Synthesized in a manner similar to Example 1 using 2-(difluoromethyl)-1H-indole-4,5-dicarbonitrile (see, for example, US2008139631A1) and methyl 2-bromopropanoate: MS (ESI): m/z 304 (M+H).
Reaction SMILES: [CH3:1][C:2]1[C:6]2[C:7](=[O:19])[N:8]([CH2:11][CH2:12][N:13]3[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]3)[CH2:9][CH2:10][C:5]=2[NH:4][C:3]=1[CH:20]=O.[NH:22]1[CH2:27][CH2:26][CH:25]([C:28]2[CH:36]=[CH:35][CH:34]=[C:33]3[C:29]=2[CH2:30][C:31](=[O:37])[NH:32]3)[CH2:24][CH2:23]1>>[CH3:1][C:2]1[C:6]2[C:7](=[O:19])[N:8]([CH2:11][CH2:12][N:13]3[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]3)[CH2:9][CH2:10][C:5]=2[NH:4][C:3]=1[CH:20]=[C:30]1[C:29]2[C:33](=[CH:34][CH:35]=[CH:36][C:28]=2[CH:25]2[CH2:24][CH2:23][NH:22][CH2:27][CH2:26]2)[NH:32][C:31]1=[O:37]
Reactant: O=C1Cc2c(cccc2C2CCNCC2)N1
Reactant: Cc1c(C=O)[nH]c2c1C(=O)N(CCN1CCCCC1)CC2
Product: Cc1c(C=C2C(=O)Nc3cccc(C4CCNCC4)c32)[nH]c2c1C(=O)N(CCN1CCCCC1)CC2
Yield: 27.9 %

Procedure:
The title compound was prepared under the same conditions as described in Example 25 with 3-methyl-4-oxo-5-(2-piperidin-1-yl-ethyl)-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine-2-carbaldehyde and 4-piperidin-4-yl-1,3-dihydro-indol-2-one as starting materials to give 3-methyl-2-(2-oxo-4-piperidin-4-yl-1,2-dihydro-indol-3-ylidenemethyl)-5-(2-piperidin-1-yl-ethyl)-1,5,6,7-tetrahydro-pyrrolo[3,2-c]pyridin-4-one (18 mg, 27.9%) as a yellow solid.
Reaction SMILES: BrCC1C=C(C=CC=1)[C:6]#[N:7].C(=O)([O-])[O-].[K+].[K+].Cl[C:18]1[CH:19]=[C:20]([CH:46]=[CH:47][C:48]=1OC)[CH2:21][N:22]1[CH2:27][CH2:26][CH:25]([NH:28][C:29]([N:31]2[CH2:36][CH2:35][C:34](=[CH:37][C:38]3[CH:43]=[C:42]([F:44])[CH:41]=[CH:40][C:39]=3[F:45])[CH2:33][CH2:32]2)=[O:30])[CH2:24][CH2:23]1.O>CN(C=O)C>[C:6]([C:18]1[CH:19]=[C:20]([CH:46]=[CH:47][CH:48]=1)[CH2:21][N:22]1[CH2:23][CH2:24][CH:25]([NH:28][C:29]([N:31]2[CH2:36][CH2:35][C:34](=[CH:37][C:38]3[CH:43]=[C:42]([F:44])[CH:41]=[CH:40][C:39]=3[F:45])[CH2:33][CH2:32]2)=[O:30])[CH2:26][CH2:27]1)#[N:7]
Reactant: COc1ccc(CN2CCC(NC(=O)N3CCC(=Cc4cc(F)ccc4F)CC3)CC2)cc1Cl
Reactant: N#Cc1cccc(CBr)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1cccc(CN2CCC(NC(=O)N3CCC(=Cc4cc(F)ccc4F)CC3)CC2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 41.4 %

Procedure:
3-Bromomethylbenzonitrile (160 mg, 0.81 mmol) was dissolved in DMF (3.0 mL), and potassium carbonate (220 mg, 1.62 mmol) and the compound (300 mg, 0.81 mmol) obtained in Example 36 (1) were added thereto, followed by stirring overnight while heating at room temperature. Water was added to the reaction mixture, and after extraction with chloroform, the extract was washed with water and a saturated sodium chloride aqueous solution, and dried over anhydrous magnesium sulfate. After the desiccant was filtered off, the residue obtained by evaporation under reduced pressure was purified using medium pressure silica gel flash column chromatography (methanol:chloroform=1:200), thereby giving the title compound (151 mg, 42%) as a white solid.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[NH:11][C:12]([C:14]2[N:18]3[CH:19]=[CH:20][C:21]([CH2:23][CH:24]=[O:25])=[CH:22][C:17]3=[N:16][CH:15]=2)=[O:13])[N:4]([CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([CH3:33])[N:28]=2)[N:3]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CCO>[OH:25][CH2:24][CH2:23][C:21]1[CH:20]=[CH:19][N:18]2[C:14]([C:12]([NH:11][C:9]3[CH:8]=[CH:7][CH:6]=[C:5]4[C:10]=3[C:2]([CH3:1])=[N:3][N:4]4[CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([CH3:33])[N:28]=3)=[O:13])=[CH:15][N:16]=[C:17]2[CH:22]=1
Reactant: Cc1cccc(Cn2nc(C)c3c(NC(=O)c4cnc5cc(CC=O)ccn45)cccc32)n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCO
Product: Cc1cccc(Cn2nc(C)c3c(NC(=O)c4cnc5cc(CCO)ccn45)cccc32)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 76.4 %

Procedure:
A solution of N-(3-methyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-yl)-7-(2-oxoethyl)imidazo[1,2-a]pyridine-3-carboxamide (5 mg, 0.011 mmol) in 0.5 mL absolute EtOH was treated at ambient temperature with 3 equivalents of sodium triacetoxyborohydride. The reaction mixture was stirred overnight at ambient temperature, after which another 10 equivalents reducing agent were added. Stirring was continued until starting material was consumed. The reaction was quenched with excess saturated aqueous sodium bicarbonate solution, and extracted with DCM and EtOAc. The combined organic extracts were dried over anhydrous sodium sulfate, and concentrated. The crude product was subjected to preparative thin-layer chromatography on silica with 5% MeOH/DCM as eluent to afford 3.7 mg of product as a white solid. MS (ES+APCI) m/z=441 (M+H) detected.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][O:8][C:9]1[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[CH:11][CH:10]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][O:8][C:9]1[CH:16]=[CH:15][C:12]([CH2:13][NH2:14])=[CH:11][CH:10]=1
Reactant: N#Cc1ccc(OCc2ccccn2)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: NCc1ccc(OCc2ccccn2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 90 %

Procedure:
To a solution of 4(pyridine-2-ylmethoxy)-benzonitrile described in Preparation Example 170 (1.2 g, 5.70 mmol) in tetrahydrofuran (30 mL) was added lithium aluminum hydride (0.22 g, 5.80 mmol), and the solution was stirred for 2 hours 30 minutes at room temperature. Ice water was added to the reaction solution, which was then stirred for 30 minutes. This mixture was filtered through Celite pad, and washed with ethyl acetate. The filtrate was partitioned, this organic layer was dried over anhydrous magnesium sulfate, then, concentrated, and the title compound (1.1 g, 5.13 mmol, 90%) was obtained.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH:2]1[C:10]([O:12][CH2:13][CH3:14])=[O:11].C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[CH2:25](Br)[CH:26]=[CH2:27]>C1COCC1>[CH2:27]([C:2]1([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:1][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3]1)[CH:26]=[CH2:25]
Reactant: C=CCBr
Reactant: CCOC(=O)C1Cc2ccccc2C1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: C=CCC1(C(=O)OCC)Cc2ccccc2C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of ethyl indane-2-carboxylate [Schaaf et al., J. Med. Chem. 1983, 26, 328-334] (6.87 g, 36.1 mmol) in THF (100 mL) at −78° C. was added sodium bis(trimethylsilyl)amide (1.0 M in THF, 39.7 mL, 39.7 mmol) dropwise over 20 min. The resulting yellow solution was stirred for 1 h, and then allyl bromide (3.75 mL, 43.3 mmol) was added over 5 min. Stirring was continued for 1.5 h at −78° C., and then the reaction was quenched by the addition of saturated NH4Cl and warmed to ambient temperature. The reaction mixture was partitioned between saturated NH4Cl (100 mL) and EtOAc (100 mL). The aqueous phase was further extracted with EtOAc (2×50 mL), and the combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel chromatography, eluting with a gradient of hexane:EtOAc—100:0 to 75:25, to give the title compound. MS: m/Z=231 (M+1).
Reaction SMILES: C([O:8][C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:19][CH3:20])[CH:15]=2)[C:10]=1[O:21][C:22]1[CH:37]=[CH:36][C:25]([O:26][CH2:27][CH2:28][N:29]2[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]2)=[CH:24][CH:23]=1)C1C=CC=CC=1.C([O-])=O.[NH4+]>C(OCC)(=O)C.CO.[Pd]>[N:29]1([CH2:28][CH2:27][O:26][C:25]2[CH:24]=[CH:23][C:22]([O:21][C:10]3[C:11]4[C:16](=[CH:15][C:14]([O:19][CH3:20])=[CH:13][CH:12]=4)[CH:17]=[CH:18][C:9]=3[OH:8])=[CH:37][CH:36]=2)[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1
Reactant: COc1ccc2c(Oc3ccc(OCCN4CCCCCC4)cc3)c(OCc3ccccc3)ccc2c1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: CO
Product: COc1ccc2c(Oc3ccc(OCCN4CCCCCC4)cc3)c(O)ccc2c1
Temperature: 25 °C
Yield: 97.5 %

Procedure:
Dissolve 1-{2-[4-(2-benzyloxy-6-methoxy-naphthalen-1-yloxy)-phenoxy]-ethyl}-azepane (19 g, 38 mmol) in ethyl acetate (500 mL) and methanol (600 ml Heat the mixture to obtain a clear solution. Cool to room temperature. Add ammonium formate (30 g, 476 mmol) and palladium on carbon (2 g, 1.9 mmol). Heat to reflux for 30 minutes. Add ammonium formate (7 g, 111 mmol) and palladium on carbon (0.7 g, 0.7 mmol). Heat to reflux for 30 minutes. Filter the suspension through a pad of celite and elute with ethyl acetate (500 mL). Evaporate solvent under reduced pressure and add water (100 mL). Dilute the mixture with ethyl acetate (500 mL) and separate layers. Wash the organic layer with saturated sodium bicarbonate solution (2×200 mL), dry with magnesium sulfate, filter and evaporate solvent under reduced pressure to give 15.1 g (97%) of 1-[4-(2-azepan-1-yl-ethoxy)-phenoxy]-6-methoxy-naphthalen-2-ol.
Reaction SMILES: S(Cl)(Cl)=O.[CH3:5][O:6][C:7]1[C:15]([O:16][CH3:17])=[C:14]([O:18][CH3:19])[CH:13]=[CH:12][C:8]=1[C:9]([OH:11])=O.[N:20]1([C:26]([S:28][CH3:29])=[S:27])[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1.C(N(CC)CC)C>ClCCl>[CH3:5][O:6][C:7]1[C:15]([O:16][CH3:17])=[C:14]([O:18][CH3:19])[CH:13]=[CH:12][C:8]=1[C:9]([N:23]1[CH2:24][CH2:25][N:20]([C:26]([S:28][CH3:29])=[S:27])[CH2:21][CH2:22]1)=[O:11]
Reactant: CSC(=S)N1CCNCC1
Reactant: COc1ccc(C(=O)O)c(OC)c1OC
Solvent: O=S(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(C(=O)N2CCN(C(=S)SC)CC2)c(OC)c1OC
Reaction time: 8 h
Yield: 51.6 %

Procedure:
In a nitrogen atmosphere, 10 ml (138 mmol.) of thionyl chloride was added to 1.00 g (4.71 mmol.) of 2,3,4-trimethoxybenzoic acid. The mixture was refluxed under heating for 2 hours. The solvent was distilled off under reduced pressure. To the residue was added 10 ml of dry benzene, and the mixture was placed under reduced pressure to distill off benzene. This procedure was repeated once. To the residue was dropwise added at room temperature a solution of 0.88 g (4.74 mmol., purity 95%) of methyl 1-piperazinecarbodithioate in 12 ml of dichloromethane. In the course of the addition, 0.48 g (4.74 mmol.) of triethylamine was added to the mixture. The resulting mixture was then stirred overnight. The reaction mixture was washed successively with 1-N hydrochloric acid and a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and placed under pressure to distill off the solvent. The residue was crystallized from acetone. The crystals were collected by filtration. The filtrate was concentrated, and additional crystals were further precipitated from the concentrated filtrate by addition of a small amount of ethanol. These crystalline portions were combined to give 0.90 g of the desired compound as a white crystalline product, m.p. 149°-150° C. (decomp.), yield 51.6%.
Reaction SMILES: CN(C)C(=O)C[NH:5][C@:6]12[CH2:40][CH2:39][C@@H:38]([C:41]([CH3:43])=[CH2:42])[C@@H:7]1[C@@H:8]1[C@@:21]([CH3:24])([CH2:22][CH2:23]2)[C@@:20]2([CH3:25])[C@@H:11]([C@:12]3([CH3:37])[C@@H:17]([CH2:18][CH2:19]2)[C:16]([CH3:27])([CH3:26])[C:15]([C:28]2[CH:36]=[CH:35][C:31]([C:32]([OH:34])=[O:33])=[CH:30][CH:29]=2)=[CH:14][CH2:13]3)[CH2:10][CH2:9]1.Cl[CH2:47][CH2:48][C:49]1[CH:54]=[CH:53][N:52]=[CH:51][CH:50]=1>>[CH3:24][C@:21]12[C@@:20]3([CH3:25])[C@@H:11]([C@:12]4([CH3:37])[C@@H:17]([CH2:18][CH2:19]3)[C:16]([CH3:26])([CH3:27])[C:15]([C:28]3[CH:36]=[CH:35][C:31]([C:32]([OH:34])=[O:33])=[CH:30][CH:29]=3)=[CH:14][CH2:13]4)[CH2:10][CH2:9][C@@H:8]1[C@H:7]1[C@H:38]([C:41]([CH3:43])=[CH2:42])[CH2:39][CH2:40][C@:6]1([NH:5][CH2:47][CH2:48][C:49]1[CH:54]=[CH:53][N:52]=[CH:51][CH:50]=1)[CH2:23][CH2:22]2
Reactant: C=C(C)[C@@H]1CC[C@]2(NCC(=O)N(C)C)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Reactant: ClCCc1ccncc1
Product: C=C(C)[C@@H]1CC[C@]2(NCCc3ccncc3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12

Procedure:
The title compound was prepared following the method described above for the synthesis of 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(2-(dimethylamino)-2-oxoethylamino)-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)benzoic acid using 4-(2-chloroethyl)pyridine as the alkylating reagent in Step 1. The product was isolated as an off white solid (10 mg, 2.9%). LCMS: m/e 635.40 (M+H)+, 2.31 min (method 13). 1H NMR (400 MHz, METHANOL-d4) δ 8.83 (d, J=5.8 Hz, 2H), 8.06 (d, J=6.0 Hz, 2H), 7.95 (d, J=8.5 Hz, 2H), 7.25 (d, J=8.3 Hz, 2H), 5.33 (d, J=4.5 Hz, 1H), 4.90 (s, 1H), 4.76 (s, 1H), 3.57-3.46 (m, 4H), 2.86-2.75 (m, 1H), 2.27-2.08 (m, 5H), 2.05-1.89 (m, 2H), 1.79 (s, 3H), 1.85-1.67 (m, 4H), 1.66-1.49 (m, 7H), 1.45-1.23 (m, 4H), 1.21 (s, 3H), 1.14 (s, 3H), 1.09 (s, 3H), 1.00 (s, 3H), 0.98 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH2:9][CH2:10][C:11]([OH:13])=O)=[C:4]([N+:14]([O-:16])=[O:15])[CH:3]=1.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[C:6]2[C:5](=[C:4]([N+:14]([O-:16])=[O:15])[CH:3]=1)[NH:8][CH2:9][CH2:10][C:11]2=[O:13]
Reactant: O=C(O)CCNc1ccc(Cl)cc1[N+](=O)[O-]
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: Cc1ccccc1
Product: O=C1CCNc2c1cc(Cl)cc2[N+](=O)[O-]
Yield: 67.5 %

Procedure:
Starting from 3-(4-chloro-2-nitrophenylamino)propionic acid (40.0 g), phosphorus pentoxide (70.0 g) and toluene (300 ml), 6-chloro-2,3-dihydro-8-nitro-4(1H)-quinolinone (yield 25.0 g) was obtained in a manner similar to Step 1 of Example 1.
Reaction SMILES: ClC1C(C(=O)N(CCCC)CCCC)=NN(C2C=CC(C(=O)NS(C3C=CC4C(=CC=CC=4)C=3)(=O)=O)=CC=2C(O)=O)C=1C.[Cl:44][C:45]1[C:46]([C:87](=[O:97])[N:88]([CH2:93][CH2:94][CH2:95][CH3:96])[CH2:89][CH2:90][CH2:91][CH3:92])=[N:47][N:48]([C:51]2[CH:61]=[CH:60][C:59]([C:62](=[O:86])[NH:63][S:64]([C:67]3[CH:76]=[CH:75][C:74]4[C:69](=[C:70]([O:77][CH2:78][CH2:79][N:80]5[CH2:85][CH2:84][O:83][CH2:82][CH2:81]5)[CH:71]=[CH:72][CH:73]=4)[CH:68]=3)(=[O:66])=[O:65])=[CH:58][C:52]=2[C:53]([O:55]CC)=[O:54])[C:49]=1[CH3:50]>>[Cl:44][C:45]1[C:46]([C:87](=[O:97])[N:88]([CH2:89][CH2:90][CH2:91][CH3:92])[CH2:93][CH2:94][CH2:95][CH3:96])=[N:47][N:48]([C:51]2[CH:61]=[CH:60][C:59]([C:62](=[O:86])[NH:63][S:64]([C:67]3[CH:76]=[CH:75][C:74]4[C:69](=[C:70]([O:77][CH2:78][CH2:79][N:80]5[CH2:81][CH2:82][O:83][CH2:84][CH2:85]5)[CH:71]=[CH:72][CH:73]=4)[CH:68]=3)(=[O:66])=[O:65])=[CH:58][C:52]=2[C:53]([OH:55])=[O:54])[C:49]=1[CH3:50]
Reactant: CCCCN(CCCC)C(=O)c1nn(-c2ccc(C(=O)NS(=O)(=O)c3ccc4cccc(OCCN5CCOCC5)c4c3)cc2C(=O)OCC)c(C)c1Cl
Agent: CCCCN(CCCC)C(=O)c1nn(-c2ccc(C(=O)NS(=O)(=O)c3ccc4ccccc4c3)cc2C(=O)O)c(C)c1Cl
Product: CCCCN(CCCC)C(=O)c1nn(-c2ccc(C(=O)NS(=O)(=O)c3ccc4cccc(OCCN5CCOCC5)c4c3)cc2C(=O)O)c(C)c1Cl
Yield: 99.9 %

Procedure:
Following a procedure analogous to that for the synthesis of Intermediate 91F, ethyl 2-(4-chloro-3-(dibutylcarbamoyl)-5-methyl-1H-pyrazol-1-yl)-5-(8-(2-morpholinoethoxy)naphthalen-2-ylsulfonylcarbamoyl)benzoate (105 mg, 0.13 mmol) was converted to the title compound (98 mg, 97%). MS(ESI+) m/z 754.2 (M+H)+.
Reaction SMILES: [C:1]([O:6][CH2:7][CH3:8])(=[O:5])[C@H:2]([CH3:4])[OH:3].[H-].[Na+].[CH2:11](Br)[CH:12]=[CH2:13]>C1COCC1>[CH2:13]([O:3][CH:2]([CH3:4])[C:1]([O:6][CH2:7][CH3:8])=[O:5])[CH:12]=[CH2:11]
Reactant: CCOC(=O)[C@H](C)O
Reactant: C=CCBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C=CCOC(C)C(=O)OCC
Yield: 100.2 %

Procedure:
23.6 g (0.2 mol) of ethyl (S)-(−)-lactate, dissolved in 100 ml of THF, are added to a suspension of 8.0 g (0.2 mol) of NaH in 150 ml THF. When the addition is complete, 36.3 g (0.3 mol) of allyl bromide, dissolved in 10 ml of THF, are added dropwise. Some KI is then added and the mixture is refluxed for 16 h. The mixture is then cooled and the reaction is quenched with 100 ml of 2N HCl. The aqueous phase is extracted twice more with Et2O before the combined organic phases are dried over Na2SO4. The mixture is then filtered and the filtrate is evaporated to dryness on a rotary evaporator, giving 31.7 g of crude product (GC purity 89.0%), which is used in the next reactions without further purification.
Reaction SMILES: [C:1]([NH:5][C:6](=[O:27])[CH:7]([S:25][CH3:26])[O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[N:15]=[CH:14][C:13]([C:19]#[C:20][Si](C)(C)C)=[CH:12]2)([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+]>CO.C(OCC)(=O)C>[C:1]([NH:5][C:6](=[O:27])[CH:7]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[N:15]=[CH:14][C:13]([C:19]#[CH:20])=[CH:12]2)[S:25][CH3:26])([CH3:4])([CH3:3])[CH3:2]
Reactant: CSC(Oc1ccc2ncc(C#C[Si](C)(C)C)cc2c1)C(=O)NC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CCOC(C)=O
Product: C#Cc1cnc2ccc(OC(SC)C(=O)NC(C)(C)C)cc2c1
Reaction time: 1 h
Yield: 70.9 %

Procedure:
A solution of N-tert-Butyl-2-methylsulfanyl-2-(3-trimethylsilanylethynyl-quinolin-6-yloxy)-acetamide (215 mg) in methanol (5 ml) was treated with potassium carbonate (18 mg) at room temperature. The reaction mixture was stirred for 1 h. The reaction mixture was diluted with ethyl acetate and washed with 30 ml sat. aq. sodium hydrogen carbonate. The aqueous layer was extracted with 3×50 ml ethyl acetate. The organic layers were combined, dried over sodium sulfate, filtered and evaporated. The residue was purified by column chromatography (heptane/ethyl acetate 6:4) to give N-tert-Butyl-2-(3-ethynyl-quinolin-6-yloxy)-2-methylsulfanyl-acetamide (125 mg) as brownish solid.