Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CO.[CH3:3][Si](C=[N+]=[N-])(C)C.[F:10][C:11]1[CH:34]=[CH:33][C:14]([CH2:15][N:16]2[CH2:25][CH2:24][C:23]3[C:22]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[N:21][CH:20]=[C:19]([OH:31])[C:18]=3[C:17]2=[O:32])=[CH:13][CH:12]=1.C(O)(=O)C>C(Cl)(Cl)Cl>[F:10][C:11]1[CH:34]=[CH:33][C:14]([CH2:15][N:16]2[CH2:25][CH2:24][C:23]3[C:22]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[N:21][CH:20]=[C:19]([O:31][CH3:3])[C:18]=3[C:17]2=[O:32])=[CH:13][CH:12]=1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: CCOC(=O)c1ncc(O)c2c1CCN(Cc1ccc(F)cc1)C2=O
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CCOC(=O)c1ncc(OC)c2c1CCN(Cc1ccc(F)cc1)C2=O
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of chloroform (10 mL) and methanol (10 mL) was added trimethylsilyl diazomethane (2.0 M in hexanes, 5 mL, 0.01 mole). After stirring for 10 minutes at room temperature, ethyl 6-(4-fluorobenzyl)-4-hydroxy-5-oxo-5,6,7,8-tetrahydro-2,6-naphthyridine-1-carboxylate (1.6 g, 3.5 mmol) in chloroform was added. After 7 hours, methanol (5 mL) and trimethylsilyl diazomethane (2.5 mL, 0.005 mole) was added to the reaction mixture. After 1 hour, glacial acetic acid (3 mL) was added with gas evolution observed. The solution was stirred for 0.5 hour. The product mixture was concentrated under vacuum. The residual material was subjected to column chromatography on silica gel eluting with 0-100% ethyl acetate in hexanes. The appropriate fractions were combined and concentrated to afford the title compound as a foam.
Reaction SMILES: [CH3:1][O:2][C@@H:3]1[CH2:8][CH2:7][C@H:6]([N:9]2[C:18]3[C:13](=[N:14][CH:15]=[C:16]([C:19]4[C:20]([CH3:36])=[N:21][C:22]([C:25]5[N:29](C6CCCCO6)[CH:28]=[N:27][N:26]=5)=[CH:23][CH:24]=4)[N:17]=3)[NH:12][C:11](=[O:37])[CH2:10]2)[CH2:5][CH2:4]1>C(O)C.Cl>[CH3:1][O:2][C@@H:3]1[CH2:8][CH2:7][C@H:6]([N:9]2[C:18]3[C:13](=[N:14][CH:15]=[C:16]([C:19]4[C:20]([CH3:36])=[N:21][C:22]([C:25]5[NH:29][CH:28]=[N:27][N:26]=5)=[CH:23][CH:24]=4)[N:17]=3)[NH:12][C:11](=[O:37])[CH2:10]2)[CH2:5][CH2:4]1
Reactant: CO[C@H]1CC[C@@H](N2CC(=O)Nc3ncc(-c4ccc(-c5nncn5C5CCCCO5)nc4C)nc32)CC1
Agent: Cl
Solvent: CCO
Product: CO[C@H]1CC[C@@H](N2CC(=O)Nc3ncc(-c4ccc(-c5nnc[nH]5)nc4C)nc32)CC1
Temperature: 80 °C
Reaction time: 2 h
Yield: 17.2 %

Procedure:
4-((cis)-4-Methoxycyclohexyl)-6-(2-methyl-6-(4-(tetrahydro-2H-pyran-2-yl)-4H-1,2,4-triazol-3-yl)pyridin-3-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one (0.279 g, 0.553 mmol) was diluted with ethanol (15 mL) and hydrogen chloride (4.0 N in dioxanes, 5 mL). The solution was stirred at 75° C. for 1 h and at 80° C. for 2 h. The solution was condensed to a slurry and diluted with ethanol and sonicated. The precipitate was filtered and washed with additional ethanol followed by acetonitrile. The crude solid was purified using reverse-phased semi-preparative HPLC (10-100% acetonitrile+0.1% TFA in water+0.1% TFA, over 30 min) to afford the title compound (0.040 g, 0.095 mmol, 17% yield). 1H NMR (400 MHz, METHANOL-d4) δ (ppm) 7.88-8.13 (m, 2H), 7.65 (s, 1H), 4.58 (s, 1H), 4.16 (s, 2H), 3.47 (br. s., 1H), 3.22-3.32 (m, 66H), 2.73 (s, 3H), 2.08 (br. s., 2H), 1.91 (br. s., 2H), 1.56 (br. s., 4H); MS (ESI) m/z 421.2 [M+1]+, mp 192-195° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:50])[CH2:4][NH:5][CH2:6][CH2:7][NH:8][C:9]([C@:11]12[CH2:46][CH2:45][C@@H:44]([C:47]([CH3:49])=[CH2:48])[C@@H:12]1[C@@H:13]1[C@@:26]([CH3:29])([CH2:27][CH2:28]2)[C@@:25]2([CH3:30])[C@@H:16]([C@:17]3([CH3:43])[C@@H:22]([CH2:23][CH2:24]2)[C:21]([CH3:32])([CH3:31])[C:20]([C:33]2[CH:42]=[CH:41][C:36]([C:37]([O:39][CH3:40])=[O:38])=[CH:35][CH:34]=2)=[CH:19][CH2:18]3)[CH2:15][CH2:14]1)=[O:10].I[CH2:52][CH3:53].C(=O)([O-])[O-].[K+].[K+]>C(#N)C.O1CCOCC1>[CH2:52]([N:5]([CH2:4][C:3]([O:2][CH3:1])=[O:50])[CH2:6][CH2:7][NH:8][C:9]([C@:11]12[CH2:46][CH2:45][C@@H:44]([C:47]([CH3:49])=[CH2:48])[C@@H:12]1[C@@H:13]1[C@@:26]([CH3:29])([CH2:27][CH2:28]2)[C@@:25]2([CH3:30])[C@@H:16]([C@:17]3([CH3:43])[C@@H:22]([CH2:23][CH2:24]2)[C:21]([CH3:32])([CH3:31])[C:20]([C:33]2[CH:34]=[CH:35][C:36]([C:37]([O:39][CH3:40])=[O:38])=[CH:41][CH:42]=2)=[CH:19][CH2:18]3)[CH2:15][CH2:14]1)=[O:10])[CH3:53]
Reactant: CCI
Reactant: C=C(C)[C@@H]1CC[C@]2(C(=O)NCCNCC(=O)OC)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
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: CC#N
Product: C=C(C)[C@@H]1CC[C@]2(C(=O)NCCN(CC)CC(=O)OC)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

Procedure:
A mixture of methyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(2-(2-methoxy-2-oxoethylamino)ethylcarbamoyl)-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 (50 mg, 0.071 mmol), iodoethane (0.047 mL, 0.571 mmol) and potassium carbonate (19.72 mg, 0.143 mmol) in acetonitrile (2.0 mL) and dioxane (2.0 mL) was heated up for 8 hours. LCMS indicated the formation of desired product and consumption of starting material. The reaction mixture was quenched with distilled water, extracted with DCM (3×3 mL). All the extracts were combined, dried over sodium sulfate, filtered and concentrated under reduced pressure to provide the crude intermediate methyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(2-(ethyl(2-methoxy-2-oxoethyl)amino)ethylcarbamoyl)-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. To this intermediate in dioxane (1 mL) was added 1N sodium hydroxide (0.224 mL, 0.224 mmol). The reaction mixture was heated up at 78° C. for 3 hours until LCMS indicated the consumption of starting material. The reaction mixture was filtered and the clear solution was purified by prep HPLC to provide the title compound as a white solid (29 mg, 59%). LCMS: m/e 687.40 (M+H)+, 2.11 min (method 1). 1H NMR (500 MHz, Acetic Acid-d4) δ ppm 8.03 (d, J=8.24 Hz, 2H), 7.30 (d, J=8.24 Hz, 2H), 5.37 (d, J=4.58 Hz, 1H), 4.78 (s, 1H), 4.65 (s, 1H), 4.02 (s, 2H), 3.85-3.63 (m, 2H), 3.58-3.37 (m, 4H), 3.22-3.01 (m, 1H), 2.69-2.43 (m, 1H), 1.73 (s, 3H), 2.30-1.20 (m, 24H), 1.08 (s, 3H), 1.07 (s., 3H), 1.06 (s., 3H), 1.01 (s, 3H), 0.99 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([CH2:12][CH2:13][CH3:14])=[CH:5][C:6]=1[C:7]([O:9]CC)=O.Cl[C:16]1[N:21]=[CH:20][C:19]([C:22]([OH:24])=[O:23])=[CH:18][CH:17]=1>>[O:9]=[C:7]1[N:21]2[CH:20]=[C:19]([C:22]([OH:24])=[O:23])[CH:18]=[CH:17][C:16]2=[N:1][C:2]2[S:3][C:4]([CH2:12][CH2:13][CH3:14])=[CH:5][C:6]1=2
Reactant: O=C(O)c1ccc(Cl)nc1
Reactant: CCCc1cc(C(=O)OCC)c(N)s1
Product: CCCc1cc2c(=O)n3cc(C(=O)O)ccc3nc2s1
Temperature: 180 °C

Procedure:
A mixture of 2-amino-5-propyl-3-thiophenecarboxylic acid, ethyl ester, 7.4 g (0.035 mol) and 6-chloro-3-pyridinecarboxylic acid (Aldrich Chemical Company), 6.4 g (0.041 mol) is heated in an oil bath at 180° C. for two hours. The mixture is cooled, extracted with hot chloroform and the residue is dissolved in hot pyridine, cooled and 0.45 g of 4-oxo-2-propyl-4H-pyrido[1,2-a]thieno[2,3-d]pyrimidine-7-carboxylic acid is collected; mp 250°-254° C. after recrystallization from pyridine.
Reaction SMILES: Br[CH:2]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4].CCN(C(C)C)C(C)C.[NH:23]1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1>C(#N)C>[O:26]1[CH2:27][CH2:28][N:23]([CH:2]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:3]([O:5][CH2:6][CH3:7])=[O:4])[CH2:24][CH2:25]1
Reactant: C1COCCN1
Reactant: CCOC(=O)C(Br)c1ccccc1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C(c1ccccc1)N1CCOCC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 112.5 %

Procedure:
Ethyl 2-bromo-2-phenylacetate (0.22 ml, 1.23 mmol) was dissolved in acetonitrile (4.0 ml) and DIPEA (0.26 ml, 1.48 mmol) and morpholine (0.13 ml, 1.481 mmol) were sequentially added. The solution was stirred at room temperature for 1.5 hours. Acetonitrile was evaporated and the residue was purified by flash chromatography (petroleum ether/EtOAc=85/15) to obtain ethyl 2-morpholino-2-phenylacetate (345 mg, quantitative yield) as a colorless oil.
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]2[C:11](=[O:12])[CH:10]=[CH:9][C:7](=[O:8])[C:5]=2[CH:6]=1.[CH2:13]=[CH:14][CH:15]=[CH2:16]>>[CH2:13]1[C:10]2[C:11](=[O:12])[C:4]3[C:5](=[CH:6][CH:1]=[CH:2][CH:3]=3)[C:7](=[O:8])[C:9]=2[CH2:16][CH2:15][CH2:14]1
Reactant: O=C1C=CC(=O)c2ccccc21
Reactant: C=CC=C
Product: O=C1C2=C(CCCC2)C(=O)c2ccccc21

Procedure:
Process for the isolation of purified anthraquinone from crude anthraquinone which has been obtained by oxidation of naphthalene to give naphthoquinone, reaction of the oxidation product with butadiene to give tetrahydroanthraquinone, oxy-dehydrogenation of the reaction product with molecular oxygen to give a crude anthraquinone and optionally removal of naphthalene, phthalic anhydride and low-boiling substances from this crude anthraquinone, which comprises treating said crude anthraquinone with an oxygen compound of the elements of the first and/or second main group of the Periodic System in solid, pulverulent form and in an amount of 0.1 to 20% by weight relative to said crude anthraquinone at an elevated temperature, optionally in the presence of an organic solvent, and then isolating purified anthraquinone by subliming the pretreated anthraquinone in the presence of said oxygen compound at a temperature of about 190° to about 290° C. and a pressure of about 1 to about 90 mm Hg and then desubliming it under the same pressure, or by vaporizing the pretreated anthraquinone at a temperature of about 290° to about 380° C. and a pressure of about 90 to about 760 mm Hg and condensing the vapour under a pressure of about 90 to about 760 mm Hg.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:14][C:15]([CH3:30])([CH3:29])[C:16]([N:18]1[CH2:23][CH2:22][N:21]([C:24]([CH3:28])([CH3:27])[C:25]#[CH:26])[CH2:20][CH2:19]1)=[O:17].C(N(CC)CC)C>O1CCCC1.C(OCC)(=O)C.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[C:4]1([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=[C:2]([C:26]#[C:25][C:24]([N:21]2[CH2:20][CH2:19][N:18]([C:16](=[O:17])[C:15]([CH3:30])([CH3:29])[CH3:14])[CH2:23][CH2:22]2)([CH3:28])[CH3:27])[CH:3]=1
Reactant: Brc1cccc(-c2ccccc2)c1
Reactant: C#CC(C)(C)N1CCN(C(=O)C(C)(C)C)CC1
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)C(=O)N1CCN(C(C)(C)C#Cc2cccc(-c3ccccc3)c2)CC1
Reaction time: 0.25 h
Yield: 61.7 %

Procedure:
1.05 g (4.5 mmol) of 3-bromobiphenyl and 0.9 g (3.6 mmol) of 1-(2,2-dimethylpropanoyl)-4-(1,1-dimethylprop-2-yn-1-yl)piperazine, prepared in step 5.1., 0.75 ml (5.38 mmol) of triethylamine and 0.028 g (0.11 mmol) of triphenylphosphine are dissolved in 8 ml of tetrahydrofuran. Under an argon atmosphere, 0.126 g (0.18 mmol) of the dichloride complex of bis(triphenylphosphine) palladium is added. The mixture is stirred for 15 minutes and then 0.014 g (0.07 mmol) of cuprous iodide is added. The mixture is stirred at ambient temperature for 4 hours and then at 60° C. overnight. After cooling to temperature it is diluted with 25 ml of ethyl acetate and filtered on paper. The solid is rinsed with 4 times 10 ml of ethyl acetate. 4 g of silica are added to the filtrate, which is evaporated to dryness. The residue is purified by chromatography on silica gel, eluting with a 90/10 then 80/20 and 70/30 mixture of cyclohexane and ethyl acetate, to give 0.90 g (2.22 mmol) of product in the form of a orange-colored oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([S:9]([N:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)(=[O:11])=[O:10])[CH:5]=[CH:6][C:7]=1F.[F:17][C:18]1[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=1[OH:25].C(=O)([O-])[O-].[Cs+].[Cs+].O>CS(C)=O>[Br:1][C:2]1[CH:3]=[C:4]([S:9]([N:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)(=[O:11])=[O:10])[CH:5]=[CH:6][C:7]=1[O:25][C:19]1[CH:20]=[CH:21][C:22]([F:24])=[CH:23][C:18]=1[F:17]
Reactant: Oc1ccc(F)cc1F
Reactant: O=S(=O)(c1ccc(F)c(Br)c1)N1CCCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CS(C)=O
Product: O=S(=O)(c1ccc(Oc2ccc(F)cc2F)c(Br)c1)N1CCCC1
Yield: 82 %

Procedure:
A mixture of Example 299a (250 mg, 0.811 mmol), 2,4-difluorophenol (106 mg, 0.811 mmol) and cesium carbonate (317 mg, 0.973 mmol) in 5 mL dimethylsulfoxide was heated at 110° C. for 2 hours. Water was added and the mixture was extracted with ethyl acetate. The organic phase was washed with water (2×), saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated to give the title compound (278 mg, 82% yield), which was used without further purification.
Reaction SMILES: [CH2:1]([NH:4][C:5]1[S:6][CH:7]=[C:8]([CH:10]=O)[N:9]=1)[CH:2]=[CH2:3].[S:12]1[CH2:18][C:16](=[O:17])[N:15]([CH2:19][C:20]([OH:22])=[O:21])[C:13]1=[S:14].[Cl-].[NH4+].N>C(O)C>[CH2:1]([NH:4][C:5]1[S:6][CH:7]=[C:8]([CH:10]=[C:18]2[S:12][C:13](=[S:14])[N:15]([CH2:19][C:20]([OH:22])=[O:21])[C:16]2=[O:17])[N:9]=1)[CH:2]=[CH2:3]
Reactant: C=CCNc1nc(C=O)cs1
Reactant: O=C(O)CN1C(=O)CSC1=S
Agent: N
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Product: C=CCNc1nc(C=C2SC(=S)N(CC(=O)O)C2=O)cs1

Procedure:
The reaction described in Example 1 was repeated, but using 3.0 g of 2-allylaminothiazole-4-carbaldehyde, 2.8 g of rhodanine-3-acetic acid, 2.1 g of ammonium chloride, 2.1 ml of 28% v/v aqueous ammonia and 70 ml of ethanol giving 3.3 g of the title compound as brown needles.
Reaction SMILES: C([O:3][C:4]([C:6]1[O:7][C:8]2[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][N:18]3[CH2:23][CH2:22][C:21]([F:25])([F:24])[CH2:20][CH2:19]3)=[CH:11][C:9]=2[CH:10]=1)=[O:5])C.[OH-].[Li+]>C1COCC1.O>[F:25][C:21]1([F:24])[CH2:22][CH2:23][N:18]([CH2:17][CH2:16][O:15][C:12]2[CH:13]=[CH:14][C:8]3[O:7][C:6]([C:4]([OH:5])=[O:3])=[CH:10][C:9]=3[CH:11]=2)[CH2:19][CH2:20]1
Reactant: CCOC(=O)c1cc2cc(OCCN3CCC(F)(F)CC3)ccc2o1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1cc2cc(OCCN3CCC(F)(F)CC3)ccc2o1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 4,4-difluoropiperidine hydrochloride (1 g, 6.3 mmol) in THF (20 mL) was added methylbromoacetate (0.63 mL, 6.6 mmol) and triethylamine (2.65 mL, 19.0 mmol). The reaction was heated at reflux for 4 h. The reaction was diluted with water (50 mL) and the product extracted with ethyl acetate (3×20 mL). The combined organic fractions were washed with brine, dried over magnesium sulphate and concentrated in vacuo to yield (4,4-difluoropiperidin-1-yl)acetic acid methyl ester as a brown oil (1.17 g, 96%). MS 194 (M+H)+. To a solution of (4,4-dfluompiperidin-1-yl)acetic acid methyl ester (1.17 g, 6.1 mmol) in THF (15 mL) at 0° C. was added potion wise lithium aluminium hydride (0.46 g, 12.2 mmol). Once the effervescence had ceased the reaction was heated at 60° C. for 1.5 h. The reaction was quenched with water (10 mL) followed by sodium hydroxide solution (2N, 10 mL) then water (10 mL). The reaction was filtered and the filtrate extracted with ethyl acetate (3×20 mL). The combined organic fractions were washed with brine, dried over magnesium sulphate and concentrated in vacuo to yield 2-(4,4-difluoropiperidin-1-yl)-ethanol as a brown oil (0.99 g, 99%). MS 166 (M+H)+. To a solution of diisopropylazodicarboxylate (0.36 mL, 1.82 mmol) in DCM (20 mL) was added polymer supported triphenylphosphine (728 mg, 2.18 mmol). The reaction was stirred at RT for 10 min. 5-Hydroxybenzofuran-2-carboxylic acid ethyl ester (025 g, 1.21 mmol) and 2-(4,4-difluoropiperidin-1-yl)-ethanol (210 mg, 1.27 mmol) were added and the reaction stirred at RT for 16 h. The reaction was filtered and the filtrate concentrated in vacuo. The product was purified on silica eluting with 50% tert-butyl methyl ether in n-heptane to yield 5-[2-(4,4-difluoropiperidin-1-yl)ethoxy]benzofuran-2-carboxylic acid ethyl ester as a yellow solid (375 mg, 88%). MS 354 (M+H)+. To a solution of 5-[2-(4,4-difluoropiperidin-1-yl)ethoxy]benzofuran-2-carboxylic acid ethyl ester (375 mg, 1.06 mmol) in THF (5 mL) and water (1 mL) was added lithium hydroxide (34 mg, 2.12 mmol). The reaction was stirred at RT for 16 h. The THF was removed in vacuo and the remaining aqueous solution dried overnight in a freeze dryer to yield the crude title compound as a brown solid. MS 326 (M+H. 5.3 min) and used for coupling onto H2N-Leu-P1 without any further purification.
Reaction SMILES: [C:1]1([SH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CC(C)([O-])C.[K+].[CH3:14][O:15][C:16](=[O:25])[C:17]1[CH:22]=[CH:21][C:20]([CH2:23]Br)=[CH:19][CH:18]=1>CN(C=O)C>[CH3:14][O:15][C:16](=[O:25])[C:17]1[CH:22]=[CH:21][C:20]([CH2:23][S:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[CH:19][CH:18]=1
Reactant: Sc1ccccc1
Reactant: COC(=O)c1ccc(CBr)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(CSc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 81 %

Procedure:
To a mixture of benzenethiol (1.3 mL, 13.1 mmol) and potassium tert-butoxide (1.47 g, 13.1 mmol) in DMF (50 mL) at 0° C. was added 4-(bromomethyl)benzoic acid methyl ester (3.0 g, 13.1 mmol), and the mixture was stirred at room temperature for 1 hour. After stirring at 80-90° C. overnight, the reaction mixture was evaporated to dryness under reduced pressure. The residue was dissolved in water (30 mL) and extracted with CH2Cl2 (200 mL). The organic layer was dried (MgSO4) and evaporated under reduced pressure. The crude product was purified by MPLC on silica gel (10% EtOAc in hexanes) to afford the titled compound (2.74 g, 81%) as a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH:15]1[CH2:18][CH2:17][CH2:16]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:15]2[CH2:18][CH2:17][CH2:16]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: C1CNC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Product: CC(C)(C)OC(=O)N1CCC(N2CCC2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 93.7 %

Procedure:
To a solution of 4-oxo-piperidine-1-carboxylic acid tert-butyl ester (1.75 g, 8.88 mmol) in dichloroethane (80 mL) was added azetidine (0.6 g, 10.53 mmol) and the mixture was stirred at RT for 30 min. Sodium triacetoxyborohydride (3.9 g, 18.44 mmol) was added and the resulting solution was stirred at RT for 18 h. The reaction mixture was partitioned between water and DCM and the layers separated. The organic layer was extracted further with DCM and the combined aqueous layers were concentrated in vacuo. The resultant white semi-solid was suspended in DCM and a saturated aqueous solution of NaHCO3 was added. The layers were thoroughly mixed, the organic layer isolated and the aqueous layer further extracted with DCM. The combined organic layers were washed with brine, dried (Na2SO4) and concentrated in vacuo to give 4-azetidin-1-yl-piperidine-1-carboxylic acid tert-butyl ester as a white solid (2.0 g, 95%). BOC-deprotection of 4-azetidin-1-yl-piperidine-1-carboxylic acid tert-butyl ester (400 mg, 1.67 mmol) using TFA:DCM (1:4) gave the title compound as a yellow oil (185 mg, 79%)
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[CH:22][C:5]([O:6][CH:7]2[CH2:12][CH2:11][N:10]([C:13]([CH:15]3[CH2:19][CH:18]([OH:20])[CH:17]([OH:21])[CH2:16]3)=O)[CH2:9][CH2:8]2)=[C:4]([CH3:24])[CH:3]=1.B.CO>O1CCCC1>[Cl:1][C:2]1[CH:23]=[CH:22][C:5]([O:6][CH:7]2[CH2:8][CH2:9][N:10]([CH2:13][CH:15]3[CH2:16][CH:17]([OH:21])[CH:18]([OH:20])[CH2:19]3)[CH2:11][CH2:12]2)=[C:4]([CH3:24])[CH:3]=1
Reactant: Cc1cc(Cl)ccc1OC1CCN(C(=O)C2CC(O)C(O)C2)CC1
Agent: B
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cc(Cl)ccc1OC1CCN(CC2CC(O)C(O)C2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.6 %

Procedure:
4-{[4-(4-Chloro-2-methylphenoxy)piperidin-1-yl]carbonyl}cyclopentane-1,2-diol (32.0 g) was dissolved in tetrahydrofuran (100 mL) and stirred, at room temperature, under nitrogen. Borane (1 M solution in THF; 300 mL) was added dropwise and then the reaction mixture was heated under reflux for 2 h. The reaction mixture was allowed to cool slightly and methanol (60 mL) was added carefully. Heating was resumed and continued overnight. The reaction mixture was concentrated in vacuo and the residue was purified using SCX resin:Non-basic impurities were eluted with methanol then product was eluted with 0.7 M ammonia in methanol. Solvent was removed in vacuo to give the title compound (30 g) as a mixture of 2 stereoisomers.
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.[C:49]([O:53][C:54]([NH:56][C:57]1([C:62]([O:64][CH2:65][CH3:66])=[O:63])[CH2:59][CH:58]1[CH:60]=[CH2:61])=[O:55])([CH3:52])([CH3:51])[CH3:50].C1(N(C)C2CCCCC2)CCCCC1>O1CCOCC1.C(OCC)C.[Pd].C(P(C(C)(C)C)C(C)(C)C)(C)(C)C.C(P(C(C)(C)C)C(C)(C)C)(C)(C)C>[C:49]([O:53][C:54]([NH:56][C:57]1([C:62]([O:64][CH2:65][CH3:66])=[O:63])[CH2:59][CH:58]1/[CH:60]=[CH:61]/[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[CH2:36][CH2:37][S:38](=[O:42])(=[O:41])[CH2:39][CH2:40]1)[CH2:15][CH2:14]3)[CH2:11][CH2:10]2)=[O:55])([CH3:52])([CH3:50])[CH3:51]
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: C=CC1CC1(NC(=O)OC(C)(C)C)C(=O)OCC
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: CN(C1CCCCC1)C1CCCCC1
Solvent: CCOCC
Solvent: C1COCCO1
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(/C=C/C6CC6(NC(=O)OC(C)(C)C)C(=O)OCC)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 110 °C

Procedure:
The mixture of (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 (50 mg, 0.070 mmol), ethyl 1-((tert-butoxycarbonyl)amino)-2-vinylcyclopropanecarboxylate (17.76 mg, 0.070 mmol) and N-cyclohexyl-N-methylcyclohexanamine (0.018 mL, 0.083 mmol) in dioxane (1 mL) was placed in a sealable pressure tube and N2 was bubbled through the solution for 10 min. Bis(tri-tertbutylphosphine) Palladium(0) (0.355 mg, 0.695 μmol) was added to the reaction mixture and the tube was sealed, and heated to 110° C. for 4 h. After cooling to rt, the crude reaction mixture was diluted with diethyl ether and filtered. The filtrate was concentrated and purified using a flash silica gel column (4 g; eluted with ethyl acetate in hexane from 0 to 45%) to give the title compound as a yellow film (13 mg, 22.7%). MS: m/e 824.55 (M+H)+, 2.625 min (method 4). 1H NMR (400 MHz, CHLOROFORM-d) δ 7.23-5.36 (m, 2H), 5.27-5.12 (m, 1H), 4.72 (br. s., 1H), 4.61 (br. s., 1H), 4.26 (m, 2H), 3.24-2.92 (m, 8H), 2.72-2.45 (m, 5H), 2.32-1.76 (m, 11H), 1.68 (br. s., 3H), 1.53-0.74 (m, 42H).