Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[O:12])[N:10]([C@@H:13]([CH2:19][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:8](=[O:9])[C:7]2=[CH:26][CH:27]=1)([O-])=O>[Pd].C(O)C>[NH2:1][C:4]1[CH:5]=[C:6]2[C:11](=[O:12])[N:10]([C@@H:13]([CH2:19][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:8](=[O:9])[C:7]2=[CH:26][CH:27]=1
Reactant: CCOC(=O)CC[C@@H](C(=O)OCC)N1C(=O)c2ccc([N+](=O)[O-])cc2C1=O
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)CC[C@@H](C(=O)OCC)N1C(=O)c2ccc(N)cc2C1=O
Reaction time: 26 h
Yield: 88.8 %

Procedure:
A suspension of diethyl (S)-2-(4-nitrophthalimido)glutarate (35.6 g, 94.1 mmol) and 10% palladium on carbon (0.5 g) (Aldrich) in ethanol (200 ml) was shaken under a hydrogen atmosphere (40-50 psi) for 26 hours. The solution was filtered through celite and concentrated in vacuo. The residue was purified by chromatography on silica gel (250 g) eluting with diethyl ether:hexane (4:1) to give diethyl (S)-2-(4-aminophthalimido)glutarate as a viscous yellow oil (29.1 g). 1H NMR (DMSO-d6, 300 MHz) δ: 1.10 (t, J=7 Hz, 3H, ester CH3), 1.12 (t, J=7 Hz, 3H, ester CH3), 2.17-2.39 (m, 4H, glu CH2CH2), 3.87-3.98 (m, 2H, ester CH2), 4.05-4.18 (m, 2H, ester CH2), 4.75-4.82 (m, 1H, glu CH), 6.57 (br s, 2H, NH2), 6.82 (dd, J=8,2 Hz, 1H, Ar), 6.93 (d, J=2 Hz, 1H, Ar), 7.51 (d, J=8 Hz, 1H, Ar). Mass spectrum (CI-CH4) 349 (M+1, 40.8%), 303 (60.1%), 275 (100%). Anal. Calculated for C17H20N2O6 : C, 58.62; H, 5.79; N, 8.04. Found: C, 58.62; H, 5.80; N, 8.00.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[N:4][CH:5]=[C:6]([CH3:13])[C:7]=1[C:8]([O:10]CC)=[O:9].[OH-].[Na+].Cl>C(O)C.O>[CH3:1][C:2]1[N:3]=[N:4][CH:5]=[C:6]([CH3:13])[C:7]=1[C:8]([OH:10])=[O:9]
Reactant: CCOC(=O)c1c(C)cnnc1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cc1cnnc(C)c1C(=O)O
Temperature: 50 °C

Procedure:
To a solution of ethyl 3,5-dimethylpyridazine-4-carboxylate (600 mg, 3.3 mmol) in ethanol (1 mL) was added a solution of NaOH (166 mg, 4.16 mmol) in water (5 mL). The mixture was heated at 50° C. for 1 hour and a clear solution was obtained. The solution was acidified by addition of aq. HCl until pH 5 and all volatiles were removed in vacuo. The residue was extracted with DCM/MeOH 4/1. The extract was concentrated to dryness to afford Intermediate 50: 3,5-dimethylpyridazine-4-carboxylic acid (550 mg) as an off-white solid.
Reaction SMILES: [C:1]1([NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH2:7].[Br:9][C:10]1[CH:15]=[CH:14][C:13]([C:16](=O)[C:17]([C:19]2[CH:24]=[CH:23][C:22]([Br:25])=[CH:21][CH:20]=2)=O)=[CH:12][CH:11]=1>C(Cl)(Cl)Cl>[Br:9][C:10]1[CH:11]=[CH:12][C:13]([C:16]2[C:17]([C:19]3[CH:20]=[CH:21][C:22]([Br:25])=[CH:23][CH:24]=3)=[N:8][C:1]3[C:2](=[CH:3][CH:4]=[CH:5][CH:6]=3)[N:7]=2)=[CH:14][CH:15]=1
Reactant: Nc1ccccc1N
Reactant: O=C(C(=O)c1ccc(Br)cc1)c1ccc(Br)cc1
Solvent: ClC(Cl)Cl
Product: Brc1ccc(-c2nc3ccccc3nc2-c2ccc(Br)cc2)cc1
Yield: 92.3 %

Procedure:
1,2-phenylenediamine (6.8 g) and 1,2-bis-(4-bromo-phenyl)-ethane-1,2-dione (22.1 g) were dissolved in 350 ml of chloroform and heated to reflux for three hours. The reaction solution was washed with 1N-hydrochloric acid, water, and a saturated aqueous solution of sodium chloride and dried with magnesium sulfate. Then the reaction was concentrated under reduced pressure to give 24.4 g of 2,3-bis(4-bromophenyl)quinoxaline as a white solid. The synthesis scheme and the structural formula are shown in a following formula (15).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]([S:11]([N:14]2[CH:27]([CH3:28])[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:20]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]2=3)(=[O:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].C(=O)([O-])[O-].[K+].[K+].I[CH2:36][CH3:37].[CH2:38](OCC)[CH3:39]>CN(C)C=O.O>[CH2:38]([O:1][C:2]1[CH:10]=[CH:9][C:8]([S:11]([N:14]2[CH:27]([CH3:28])[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:20]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]2=3)(=[O:13])=[O:12])=[CH:7][C:3]=1[C:4]([O:6][CH2:36][CH3:37])=[O:5])[CH3:39]
Reactant: CCOCC
Reactant: CCI
Reactant: CC1c2ccccc2-c2ccccc2N1S(=O)(=O)c1ccc(O)c(C(=O)O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc(S(=O)(=O)N2c3ccccc3-c3ccccc3C2C)ccc1OCC
Temperature: 25 °C
Reaction time: 8 h
Yield: 42 %

Procedure:
A stirred suspension of 2-hydroxy-5-[(6-methylphenanthridin-5(6H)-yl)sulfonyl]benzoic acid (0.5 g, 1.26 mmol) and anhydrous potassium carbonate (0.36 g, 2.6 mmol) in anhydrous N,N-dimethylformamide (5 mL) was treated drop-wise at room temperature under nitrogen with a solution of iodoethane (0.405 g, 2.6 mmol) in anhydrous N,N-dimethylformamide (1 mL). The mixture was stirred at room temperature overnight. The reaction was diluted with diethyl ether and water. The organic phase was separated and washed sequentially with a 1 N hydrochloric acid solution and water. After drying over anhydrous sodium sulfate, the organic phase was filtered through a short column of silica gel, and the filtrate evaporated in vacuo to yield a crude product (0.5 g). The crude product was purified by preparative chromatography on a Biotage® 40 Mi column of pre-packed silica gel (90 g), eluting with a mixture of methyl tert-butyl ether-hexane (15:85) at a flow rate of 40 mL/min to afford, after evaporation of the solvent, a colorless solid. Crystallization of the colorless solid from a mixture of diethyl ether-hexane yielded the title compound (0.239 g, 0.53 mmol, 42%) as a homogeneous, white powder, m.p. 113-115° C.;
Reaction SMILES: CS(O[CH2:6][CH2:7][O:8][C:9]1[C:17]2[C:12](=[N:13][CH:14]=[N:15][C:16]=2[NH:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[C:21]([CH3:33])[CH:20]=2)[NH:11][N:10]=1)(=O)=O.[CH3:34][N:35]1[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1>>[CH2:26]([O:25][C:22]1[CH:23]=[CH:24][C:19]([NH:18][C:16]2[N:15]=[CH:14][N:13]=[C:12]3[NH:11][N:10]=[C:9]([O:8][CH2:7][CH2:6][N:38]4[CH2:39][CH2:40][N:35]([CH3:34])[CH2:36][CH2:37]4)[C:17]=23)=[CH:20][C:21]=1[CH3:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: Cc1cc(Nc2ncnc3[nH]nc(OCCOS(C)(=O)=O)c23)ccc1OCc1ccccc1
Reactant: CN1CCNCC1
Product: Cc1cc(Nc2ncnc3[nH]nc(OCCN4CCN(C)CC4)c23)ccc1OCc1ccccc1
Yield: 55 %

Procedure:
The procedure described in Example 55 was repeated using 2-[(4-{[4-(benzyloxy)-3-methylphenyl]amino}-1H-pyrazolo[3,4-d]pyrimidin-3-yl)oxy]ethyl methanesulfonate (prepared as described in Example 110) and N-methylpiperazine to give the title compound in 55% yield; NMR Spectrum: 2.10 (s, 3H), 2.22 (s, 3H), 2.22-2.55 (m, 8H), 2.77 (t, 2H), 4.41 (t, 2H), 5.13 (s, 2H), 7.01 (d, 1H), 7.31-7.48 (m, 7H), 8.17 (s, 1H), 8.24 (s, 1H); Mass Spectrum: 474 (MH+).
Reaction SMILES: C1[C:6]([C:7]([OH:9])=[O:8])=[CH:5][C:4]2C([O:12][C:13](=[O:14])[C:3]=2C=1)=O.CCOCCOC(C)=O.C1(O)C=CC=CC=1>>[C:13]([OH:14])(=[O:12])[CH2:3][CH2:4][CH2:5][CH2:6][C:7]([OH:9])=[O:8]
Reactant: O=C(O)c1ccc2c(c1)C(=O)OC2=O
Solvent: CCOCCOC(C)=O
Solvent: Oc1ccccc1
Product: O=C(O)CCCCC(=O)O
Yield: 59.2 %

Procedure:
A solution is formed by mixing 60.0 grams of trimellitic acid anhydride and 132.0 grams of p,p' diphenyl methane diisocyanate and 110.0 grams of cellosolve acetate and 4.8 grams of phenol by heating the mixture. At approximately 145°C. a clear, homogeneous solution is obtained. Once clarity is obtained 27.0 grams of adipic acid is added slowly. The temperature of the mixture is raised to approximately 160°C. and slow reflux is maintained. After approximately 100 minutes, a brownish-yellow viscous resin is obtained and 396.2 grams of phenol are added to quench and stop the reaction. The solution is maintained at 130°C. until all the resin is dissolved. The resultant solution is cooled to room temperature and filtered. The viscosity of the product at 25°C. was measured at about 890 cps, utilizing a Brookfield viscometer, and a resin solution of approximately 30% weight resin.
Reaction SMILES: [C:1]1([CH:9]=[CH:8][CH:7]=[C:5](O)[C:3]=1[OH:4])O.[CH3:10][C:11](C)=[O:12].C(C(C)=O)C>CO>[C:5]1([CH3:10])[C:3]([OH:4])=[CH:1][CH:9]=[CH:8][CH:7]=1.[CH2:11]=[O:12]
Reactant: CC(C)=O
Reactant: Oc1cccc(O)c1O
Solvent: CO
Solvent: CCC(C)=O
Product: C=O
Product: Cc1ccccc1O

Procedure:
A composition consisting of 0.9 g of an ester of naphthoquinone-1,2-diazide-4-sulfonyl chloride with a pyrogallol-acetone resin, 0.05 g of Victoria Pure Blue BOH, 2.0 g of a novolac resin obtained from cresol and formaldehyde (meta:para=6:4; weight-average molecular weight, 1,800), 20 g of methyl ethyl ketone, and 7 g of methyl alcohol was applied to the hydrophilic layer. Thus, a positive type lithographic printing plate precursor of Example 8 was obtained.
Reaction SMILES: N[C:2]1[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[C:7]([CH3:14])=[CH:6][C:3]=1[C:4]#[N:5].N(OCCC(C)C)=O>C1COCC1.CC(OC)(C)C>[CH3:14][C:7]1[CH:6]=[C:3]([CH:2]=[CH:9][C:8]=1[C:10]([F:11])([F:12])[F:13])[C:4]#[N:5]
Reactant: Cc1cc(C#N)c(N)cc1C(F)(F)F
Agent: CC(C)CCON=O
Solvent: C1CCOC1
Solvent: COC(C)(C)C
Product: Cc1cc(C#N)ccc1C(F)(F)F
Temperature: 23 °C
Yield: 92.8 %

Procedure:
To a solution of 2-amino-5-methyl-4-trifluoromethyl-benzonitrile from step 4 (23.34 g, 117 mmol) in dry THF (350 mL) was added isoamyl nitrite (34.3 mL, 257 mmol) and the mixture was refluxed for 20 h. Additional isoamyl nitrite (16.6 mL, 129 mmol) was added and the mixture was refluxed for further 20 h. The mixture was cooled to 23° C. and diluted with TBME, the organic layer was washed with 1 N HCl, sat. NaHCO3-sol. and brine, dried over Na2SO4. Removal of the solvent in vacuum left a brown oil (25.82 g), which was purified by bulb to bulb distillation to give a yellow liquid (20.11 g), which was finally purified by distillation to give the title compound as a yellow liquid (17.10 g, 79%; bp 38-42° C. at 0.8 mbar). MS (EI) 185.1 [M].
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[C:6]([C:13]1[O:17][N:16]=[C:15]([CH3:18])[CH:14]=1)=[C:5]2[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[C:25](OC(=O)C)(=[O:27])[CH3:26].CCN(CC)CC>C1COCC1>[CH3:18][C:15]1[CH:14]=[C:13]([C:6]2[C:7](=[O:12])[NH:8][C:9]3[C:4]([C:5]=2[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[CH:3][C:2]([NH:1][C:25](=[O:27])[CH3:26])=[CH:11][CH:10]=3)[O:17][N:16]=1
Reactant: Cc1cc(-c2c(-c3ccccc3)c3cc(N)ccc3[nH]c2=O)on1
Reactant: CC(=O)OC(C)=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=O)Nc1ccc2[nH]c(=O)c(-c3cc(C)no3)c(-c3ccccc3)c2c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 49.1 %

Procedure:
A flask charged with 6-amino-3-(3-methyl-isoxazol-5-yl)-4-phenyl-1H-quinolin-2-one (0.027 mg, 0.085 mmol)(Example 52), acetic anhydride (0.01 mL, 0.100 mmol), NEt3 (0.018 mL, 0.13 mmol) and 1 mL of THF was stirred for 6 hrs at 25° C. The title compound was eluted from a 5 g SPE with 100% EtAc to give 0.015 g (50%) of a white solid. 1H NMR (400 MHz, CDCl3) 12.30 (s, 1H), 8.06 (s, 1H), 7.72 (m, 1H), 7.36 (m, 5H), 7.14 (m, 2H), 6.36 (s, 1H), 2.22 (s, 3H), 2.02 (s, 3H). Mass spectrum (ESI, m/z) calcd. for C21H17N3O3 359.1, found 360.2 (M+H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]3[C:14]4C=CC=C[C:13]=4[S:12][C:11]=13)[N:8]=[CH:7][N:6]=[C:5]2[NH:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([Br:26])[CH:21]=1.C(O)(=O)C=C.C(N(CC)CC)C.Cl.CN(C)CCCN=C=NCC>CN(C=O)C>[NH2:1][C:2]1[C:11]2[S:12][C:4]3[C:5]([NH:19][C:20]4[CH:25]=[CH:24][CH:23]=[C:22]([Br:26])[CH:21]=4)=[N:6][CH:7]=[N:8][C:9]=3[C:10]=2[CH:14]=[CH:13][CH:3]=1
Reactant: Nc1cc2c(Nc3cccc(Br)c3)ncnc2c2c1sc1ccccc12
Agent: C=CC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Nc1cccc2c1sc1c(Nc3cccc(Br)c3)ncnc12
Temperature: 25 °C
Yield: 30.8 %

Procedure:
To a solution of 6-amino-4-[(3-bromophenyl)amino]-benzothieno-quinazoline (130 mg, 0.35 mmol), acrylic acid (0.05 mL, 0.73 mmol), and triethylamine (0.1 mL, 0.72 mmol) in DMF (3 mL) stirred under N2 at 0° C. was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (144 mg, 0.75 mmol). The reaction gradually warmed up to 25° C. and was quenched with water after 20 hours. The formed yellow solid was collected and purified by sonication with acetone to give the desired product (40 mg, 27%), mp 216.4-217.2° C. 1H NMR [(CD3)2SO]: δ10.64 (s, 1H, NH), 9.84 (s, 1H, NH), 8.77 (s, 1H, H2), 8.73 (d, J=1.5 Hz, 1H, H6), 8.31 (d, 1H, J=8.8 Hz, H8), 8.20 (s, 1H, H2′), 7.84 (d, J=8.3 Hz, 1H, H6′), 7.67 (dd, J=8.6, 1.7 Hz, 1H, H9), 7.34 (t, J=7.8 Hz, 1H, H5′), 7.28 (d, J=8.1 Hz, 1H, H4′), 6.50 (dd, J=16.9, 10.0 Hz, 1H, ═CH), 6.34 (dd, J=17.1, 1.7 Hz, 1H, ═CH2), 5.83 (dd, J=10, 1.7 Hz, 1H ═CH2).
Reaction SMILES: Br[C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][C:8]([Br:15])=[CH:9][CH:10]=3)[N:5]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:4]=2[CH:3]=1.[CH3:22][O:23][C:24]1[CH:25]=[CH:26][C:27](B(O)O)=[C:28]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH:29]=1.C([O-])([O-])=O.[Na+].[Na+].CCO>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1(C)C=CC=CC=1>[Br:15][C:8]1[CH:9]=[CH:10][C:11]2[C:12]3[C:4](=[CH:3][C:2]([C:27]4[CH:26]=[CH:25][C:24]([O:23][CH3:22])=[CH:29][C:28]=4[C:30]4[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=4)=[CH:14][CH:13]=3)[N:5]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:6]=2[CH:7]=1
Reactant: COc1ccc(B(O)O)c(-c2ccccc2)c1
Reactant: Brc1ccc2c3ccc(Br)cc3n(-c3ccccc3)c2c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: COc1ccc(-c2ccc3c4ccc(Br)cc4n(-c4ccccc4)c3c2)c(-c2ccccc2)c1
Temperature: 110 °C
Yield: 59 %

Procedure:
A mixture of 4 g (10 mmol) of 2,7-dibromo-9-phenyl-9H-carbazole, 75 g (12 mmol) of 5-methoxybiphenyl-2-ylboronic acid, 0.12 g (0.1 mmol) of tetrakis(triphenylphosphine)palladium, 15 ml of 2M Na2CO3, 20 ml of EtOH and 60 ml toluene was degassed and placed under nitrogen, and then heated at 110° C. for 8 h. After finishing the reaction, the mixture was allowed to cool to room temperature. The reaction mixture was extracted with ethyl acetate and water, dried with anhydrous magnesium sulfate, the solvent was evaporated in vacuum. The residue was purified by column chromatography on silica (hexane-dichloromethane) afforded a white solid (3 g, 5.9 mmol, 59%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:15]=[CH:16][C:17]=1Cl)[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:8])([O-:3])=[O:2].[CH2:19]([NH:21][CH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1)[CH3:20]>>[N+:1]([C:4]1[CH:5]=[C:6]([CH:15]=[CH:16][C:17]=1[N:21]([CH2:19][CH3:20])[CH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1)[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:8])([O-:3])=[O:2]
Reactant: CCNC1CCCCC1
Reactant: O=C(c1ccccc1)c1ccc(Cl)c([N+](=O)[O-])c1
Product: CCN(c1ccc(C(=O)c2ccccc2)cc1[N+](=O)[O-])C1CCCCC1

Procedure:
13 g. of 3-nitro-4-chloro-benzophenone are reacted with 15 ml. of N-ethyl-N-cyclohexylamine as described in Example 2. The crude product is recrystallized from n-hexane to yield 15.3 g of pure, crystalline 3-nitro-4-(N-ethyl-N-cyclohexylamino)-benzophenone; m.p. 91.5°-92° C.
Reaction SMILES: [OH2:1].C([O:6]C([NH:9][C@@H:10]([CH3:28])[C:11]([NH:13][C@@:14]1([C:25]([OH:27])=[O:26])[CH2:21][C:18]2([CH2:20][CH2:19]2)[C@@H:17]2[C@H:15]1[C@H:16]2[C:22]([OH:24])=[O:23])=[O:12])=O)(C)(C)C.Cl.[OH-].[Na+]>C(O)C>[OH2:6].[OH2:1].[NH2:9][C@@H:10]([CH3:28])[C:11]([NH:13][C@@:14]1([C:25]([OH:27])=[O:26])[CH2:21][C:18]2([CH2:19][CH2:20]2)[C@@H:17]2[C@H:15]1[C@H:16]2[C:22]([OH:24])=[O:23])=[O:12]
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@@]1(C(=O)O)CC2(CC2)[C@H]2[C@H](C(=O)O)[C@H]21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: C[C@H](N)C(=O)N[C@@]1(C(=O)O)CC2(CC2)[C@H]2[C@H](C(=O)O)[C@H]21
Temperature: 25 °C
Yield: 81.6 %

Procedure:
Charge water (32 mL, 8 volumes) and (1S,2S,5R,6S)-2-[[(2S)-2-(tert-butoxy carbonylamino)propanoyl]amino]spiro[bicyclo[3.1.0]hexane-4,1′-cyclopropane]-2,6-dicarboxylic acid (3.99 g, 10.4 mmol) to a reactor followed by concentrated HCl (1.80 mL, 2.0 equivalents) and then heat the reaction to 45-55° C. until the reaction complete (monitor by HPLC). Cool the reaction mixture to 20-30° C. and adjust the pH to approximately 3.6 with 5 N NaOH. Add absolute ethanol (15 mL, 3.75 volumes) over at least 30 minutes between 20-30° C. to the resulting slurry. Allow the resulting slurry to granulate between 20-30° C. for at least 12 hours. Cool the mixture between −5-5° C. and allow it to granulate for at least 60 minutes. Filter the resulting solids and wash the cake with 30% absolute ethanol in water (2×9 mL, 2.25 volumes). Dry the solids under reduced pressure at 35° C. for at least 12 hours, and then allow the resulting solids to stay on the balance until no additional weight change for at least 2 hours to provide the title compound as a white solid (2.71 g, 8.51 mmol, 81.6%). 1H NMR (D2O, 400 MHz): δ 3.90 (q, J=7.2, 1H), 2.56 (dd, J=6.5, 2.9, 1H), 1.74-1.66 (m, 2H), 1.62-1.54 (m, 2H), 1.39 (d, J=7.1, 3H), 0.61-0.56 (m, 1H), 0.55-0.49 (m, 1H), 0.40-0.30 (m, 2H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[CH:10](=O)[CH2:11][CH2:12][CH3:13]>CO.O>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH:10]([C:3]2[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[NH:1][CH:2]=2)[CH2:11][CH2:12][CH3:13])=[CH:2]1
Reactant: c1ccc2[nH]ccc2c1
Reactant: CCCC=O
Solvent: O
Solvent: CO
Product: CCCC(c1c[nH]c2ccccc12)c1c[nH]c2ccccc12

Procedure:
282 mg of indole (2.4 mmol) were dissolved in 10 ml of CH3OH and 5 ml of H2O; 72 mg (1 mmol) of butyraldehyde and 240 mg of dysprosium triflate-(CF3SO3)3Dy-(0.393 mmol) were added.
Reaction SMILES: [CH2:1]([CH:3]([CH2:32][CH3:33])[C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([N:13]2[CH2:18][CH2:17][CH:16]([C:19](O)([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:20][CH2:21][CH2:22][CH3:23])[CH2:15][CH2:14]2)=[C:9]([F:31])[CH:8]=1)=[O:5])[CH3:2].[SiH](CC)(CC)CC.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:32]([CH:3]([CH2:1][CH3:2])[C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([N:13]2[CH2:18][CH2:17][CH:16]([CH:19]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:20][CH2:21][CH2:22][CH3:23])[CH2:15][CH2:14]2)=[C:9]([F:31])[CH:8]=1)=[O:5])[CH3:33]
Reactant: CCCCC(O)(c1ccccc1)C1CCN(c2ccc(NC(=O)C(CC)CC)cc2F)CC1
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCCC(c1ccccc1)C1CCN(c2ccc(NC(=O)C(CC)CC)cc2F)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 55.5 %

Procedure:
To a solution of 2-ethyl-N-{3-fluoro-4-[4-(1-hydroxy-1-phenyl-pentyl)-piperidin-1-yl]-phenyl}-butyramide (17 mg, 0.037 mmol) and Et3SiH (0.025 mL) in DCM (0.15 mL) was added TFA (0.25 mL). The mixture was stirred at 25° C. for 0.5 h and purified by PTLC to provide the title compound (9 mg, 55%). MS: 439.4. 1H NMR (CDCl3): 7.40 (dd, J=14.0, 2.5, 1H), 7.32-7.25 (m, 2H), 7.22-7.17 (m, 1H), 7.14-7.06 (m, 3H), 7.02 (s, 1H), 7.06 (t, J=9.2, 1H), 3.47-3.22 (m, 2H), 2.65-2.55 (m, 1H), 2.52-2.43 (m, 1H), 2.38-2.30 (m, 1H), 2.03 (m, 2H), 1.88-1.15 (m, 12H), 1.10-0.98 (m, 2H), 0.92 (t, J=7.4, 6H), 0.81 (t, J=7.3, 3H).
Reaction SMILES: O[CH2:2][CH2:3][NH:4][C@:5]12[CH2:40][CH2:39][C@@H:38]([C:41]([CH3:43])=[CH2:42])[C@@H:6]1[C@@H:7]1[C@@:20]([CH3:23])([CH2:21][CH2:22]2)[C@@:19]2([CH3:24])[C@@H:10]([C@:11]3([CH3:37])[C@@H:16]([CH2:17][CH2:18]2)[C:15]([CH3:26])([CH3:25])[C:14]([C:27]2[CH:36]=[CH:35][C:30]([C:31]([O:33][CH3:34])=[O:32])=[CH:29][CH:28]=2)=[CH:13][CH2:12]3)[CH2:9][CH2:8]1.S(Cl)([Cl:46])=O>ClC(Cl)C>[Cl:46][CH2:2][CH2:3][NH:4][C@:5]12[CH2:40][CH2:39][C@@H:38]([C:41]([CH3:43])=[CH2:42])[C@@H:6]1[C@@H:7]1[C@@:20]([CH3:23])([CH2:21][CH2:22]2)[C@@:19]2([CH3:24])[C@@H:10]([C@:11]3([CH3:37])[C@@H:16]([CH2:17][CH2:18]2)[C:15]([CH3:26])([CH3:25])[C:14]([C:27]2[CH:36]=[CH:35][C:30]([C:31]([O:33][CH3:34])=[O:32])=[CH:29][CH:28]=2)=[CH:13][CH2:12]3)[CH2:9][CH2:8]1
Reactant: C=C(C)[C@@H]1CC[C@]2(NCCO)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Reactant: O=S(Cl)Cl
Solvent: CC(Cl)Cl
Product: C=C(C)[C@@H]1CC[C@]2(NCCCl)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 60 °C
Yield: 90 %

Procedure:
A mixture of methyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-hydroxyethyl)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)benzoate (1400 mg, 2.381 mmol) and thionyl chloride (1.738 mL, 23.81 mmol) in dichloroethane (15 mL) was heated to 60° C. for 2 h. The reaction mixture was concentrated under reduced pressure to provide the desired product as a brown solid (1.3 g, 90%), which was taken to the next step without further purification. LCMS: m/e 606.48 (M+H)+, 2.46 min (method 5).
Reaction SMILES: [CH:1]([C@H:4]1[C@@H:8]2[C@@H:9]3[C@@:22]([CH3:25])([CH2:23][CH2:24][C@@:7]2([C:38]([O:40][CH2:41][C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)=[O:39])[CH2:6][CH2:5]1)[C@@:21]1([CH3:26])[C@@H:12]([C@:13]2([CH3:37])[C@@H:18]([CH2:19][CH2:20]1)[C:17]([CH3:28])([CH3:27])[C:16](OS(C(F)(F)F)(=O)=O)=[CH:15][CH2:14]2)[CH2:11][CH2:10]3)([CH3:3])[CH3:2].[CH3:48][O:49][C:50]([C:52]1[CH:57]=[CH:56][C:55](B(O)O)=[CH:54][CH:53]=1)=[O:51].C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:1]([C@H:4]1[C@@H:8]2[C@@H:9]3[C@@:22]([CH3:25])([CH2:23][CH2:24][C@@:7]2([C:38]([O:40][CH2:41][C:42]2[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=2)=[O:39])[CH2:6][CH2:5]1)[C@@:21]1([CH3:26])[C@@H:12]([C@:13]2([CH3:37])[C@@H:18]([CH2:19][CH2:20]1)[C:17]([CH3:27])([CH3:28])[C:16]([C:55]1[CH:56]=[CH:57][C:52]([C:50]([O:49][CH3:48])=[O:51])=[CH:53][CH:54]=1)=[CH:15][CH2:14]2)[CH2:11][CH2:10]3)([CH3:3])[CH3:2]
Reactant: COC(=O)c1ccc(B(O)O)cc1
Reactant: CC(C)[C@@H]1CC[C@]2(C(=O)OCc3ccccc3)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
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: COC(=O)c1ccc(C2=CC[C@]3(C)[C@H]4CC[C@@H]5[C@H]6[C@H](C(C)C)CC[C@]6(C(=O)OCc6ccccc6)CC[C@@]5(C)[C@]4(C)CC[C@H]3C2(C)C)cc1
Temperature: 90 °C
Yield: 88.9 %

Procedure:
A mixture of (1S,3aS,5aR,5bR,7aR,11aR,11bR,13aR,13bR)-benzyl 1-isopropyl-5a,5b,8,8,11a-pentamethyl-9-(trifluoromethylsulfonyloxy)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysene-3a-carboxylate (3.5 g, 5.16 mmol), 4-(methoxycarbonyl)phenylboronic acid (1.206 g, 6.70 mmol), Pd(Ph3P)4 (0.179 g, 0.155 mmol) and sodium carbonate (1.639 g, 15.47 mmol) in dioxane (20 mL) and water (20 mL) was heated up at 90° C. for 2 h. TLC indicated starting material was consumed and a new spot was present. The reaction mixture was purified by biotage with 0-10% ethyl acetate/hexanes to provide the title compound as white solid (3.05 g, 89%). 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 7.92 (d, J=8.24 Hz, 2H), 7.48-7.28 (m, 5H), 7.19 (d, J=7.93 Hz, 2H), 5.28 (dd, J=6.26, 1.68 Hz, 1H), 5.19-5.00 (m, 2H), 3.90 (s, 3H), 2.38-2.20 (m, 3H), 2.11 (dd, J=17.09, 6.41 Hz, 1H), 1.89-1.75 (m, 2H), 1.72-1.61 (m, 2H), 1.53-1.07 (m, 16H), 0.95 (s, 6H), 0.92 (s, 3H), 0.90 (s, 3H), 0.85 (d, J=6.71 Hz, 3H), 0.80 (s, 3H), 0.75 (d, 3H).