Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[C:2]([CH:4]([NH:12][C:13]([C@@H:15]1[CH2:20][CH2:19][CH2:18][CH2:17][C@@H:16]1[NH:21][C:22]([C:24]1[N:25]([CH3:33])[C:26]2[C:31]([CH:32]=1)=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:23])=[O:14])[CH2:5][CH:6]1[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1)#[N:3].[C:34](OC(=O)C)(=[O:36])[CH3:35]>CN(C=O)C.CN(C1C=CN=CC=1)C>[C:34]([N:9]1[CH2:10][CH2:11][CH:6]([CH2:5][CH:4]([NH:12][C:13]([C@@H:15]2[CH2:20][CH2:19][CH2:18][CH2:17][C@@H:16]2[NH:21][C:22]([C:24]2[N:25]([CH3:33])[C:26]3[C:31]([CH:32]=2)=[CH:30][CH:29]=[CH:28][CH:27]=3)=[O:23])=[O:14])[C:2]#[N:3])[CH2:7][CH2:8]1)(=[O:36])[CH3:35]
Reactant: CC(=O)OC(C)=O
Reactant: Cn1c(C(=O)N[C@H]2CCCC[C@H]2C(=O)NC(C#N)CC2CCNCC2)cc2ccccc21
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Product: CC(=O)N1CCC(CC(C#N)NC(=O)[C@@H]2CCCC[C@@H]2NC(=O)c2cc3ccccc3n2C)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 32.6 %

Procedure:
To a solution of 1-methyl-1H-indole-2-carboxylic acid {(1S,2R)-2-[(cyano-piperidin-4-ylmethyl-methyl)-carbamoyl]-cyclohexyl}-amide hydrochloride (0.50 g, 1.06 mmol) in 2 mL of DMF, was added 0.5 mL of TEA, acetic anhydride (0.15 mL, 1.59 mmol), and a few crystals of DMAP. The reaction mixture was stirred at ambient temperature for 1 hour, and partitioned between 50 mL of water and 50 mL of ethyl acetate. The separated organic layer was washed with water (2×50 mL), dried with sodium sulfate, filtered, concentrated, and purified by column chromatography (5:95, MeOH/CH2Cl2) to give 165 mg (33%) of 1-methyl-1H-indole-2-carboxylic acid ((1S,2R)-2-{[(1-acetyl-piperidin-4-ylmethyl)-cyano-methyl]-carbamoyl}-cyclohexyl)-amide as a white amorphous solid. MS: 478 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH2:5][CH2:6][CH:7]([C:14]([O:16][CH3:17])=[O:15])[C:8]2=[O:13].CC1(C)C2(CS(O)(=O)=O)C(CC1CC2)=O.C(OCC)(=O)C>CO>[OH:13][C@H:8]1[C:9]2[C:4](=[C:3]([O:2][CH3:1])[CH:12]=[CH:11][CH:10]=2)[CH2:5][CH2:6][C@@H:7]1[C:14]([O:16][CH3:17])=[O:15]
Reactant: COC(=O)C1CCc2c(OC)cccc2C1=O
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: CCOC(C)=O
Solvent: CO
Product: COC(=O)[C@H]1CCc2c(OC)cccc2[C@@H]1O
Yield: 98 %

Procedure:
A solution of methyl [5-methoxy-1-oxo-1,2,3,4-tetrahydro-2-naphthyl]formate (2.50 g), D-10-camphorsulfonic acid (124 mg), [RuCl2 (S)-binap]2NEt3 (90 mg) [cf. Tetrahedron Letters, Vol. 35, No. 26, pp 4559-4562, 1994], ethyl acetate (23.8 ml) and methanol (1.25 ml) was stirred under hydrogen (90 atm) at 50° C. for 40 hours. The reaction mixture was evaporated in vacuo and the residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=4:1) to give (1R,2S)-methyl [1-hydroxy-5-methoxy-1,2,3,4-tetrahydro-2-naphthyl]formate (2.47 g) as a white powder. mp: 87°-88° C.
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[Cl:11])[C:6]#[N:7].Cl.[C:13]([O:17][C:18](=[O:22])[CH2:19][NH:20][CH3:21])([CH3:16])([CH3:15])[CH3:14]>>[Cl:11][C:10]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[CH2:2][N:20]([CH3:21])[CH2:19][C:18]([O:17][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:22]
Reactant: N#Cc1ccc(Cl)c(CBr)c1
Reactant: CNCC(=O)OC(C)(C)C
Agent: Cl
Product: CN(CC(=O)OC(C)(C)C)Cc1cc(C#N)ccc1Cl

Procedure:
The title compound was prepared following general procedure 10, starting from 3-(bromomethyl)-4-chlorobenzonitrile and sarcosine tert-butyl ester hydrochloride. It was obtained as a colorless oil (1.9 g, 86%). LC/MS (Method B): 295.1 (M+H)+.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([C:15]([CH3:18])([CH3:17])[CH3:16])[CH:14]=1)[O:11][CH:10]([C:19]([O:21]CCCC)=[O:20])[CH2:9][CH2:8]2)([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].CO>C1(C)C=CC=CC=1>[C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([C:15]([CH3:18])([CH3:17])[CH3:16])[CH:14]=1)[O:11][CH:10]([C:19]([OH:21])=[O:20])[CH2:9][CH2:8]2)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCCCOC(=O)C1CCc2cc(C(C)(C)C)cc(C(C)(C)C)c2O1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: Cc1ccccc1
Product: CC(C)(C)c1cc2c(c(C(C)(C)C)c1)OC(C(=O)O)CC2
Temperature: 70 °C
Yield: 98 %

Procedure:
To a toluene solution (183.0 g, 0.2 mol) of 6,8-di-t-butyl -2-butoxycarbonylchroman obtained in Example 2 were added 10% aqueous sodium hydroxide solution (120.0 g, 0.3 mol) and methanol (120 g), and the mixture was stirred while heating at 70° C. for 2 h. Toluene was added to the reaction mixture and the mixture was stirred and allowed to stand, and methanol and the like were removed from the aqueous layer. After the removal, aqueous sulfuric acid solution was added to the aqueous layer, and the mixture was extracted with toluene. The extract was concentrated under reduced pressure. The residue was quantitatively analyzed by liquid chromatography according to the internal standard method. As a result, 6,8-di-t-butyl-2-hydroxycarbonylchroman was obtained in a yield of 98% [net 56.92 g, 0.196 mol]. The 1H-NMR data of the obtained 6,8-di-t-butyl-2-hydroxycarbonylchroman are shown below.
Reaction SMILES: [CH2:1]([NH:8][CH2:9][P:10](=[O:17])([O:14][CH2:15][CH3:16])[O:11][CH2:12][CH3:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.Br[CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30]>C(#N)C>[CH2:1]([N:8]([CH2:9][P:10]([O:14][CH2:15][CH3:16])([O:11][CH2:12][CH3:13])=[O:17])[CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)CBr
Reactant: CCOP(=O)(CNCc1ccccc1)OCC
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CCOC(=O)CN(Cc1ccccc1)CP(=O)(OCC)OCC
Temperature: 25 °C

Procedure:
Into a 500-mL 3-necked round-bottom flask, was placed a solution of diethyl (benzylamino)methylphosphonate (intermediate 5.2) (12 g, 46.69 mmol, 1.00 equiv) in acetonitrile (150 mL), DIEA (12 g, 2.00 equiv). This was followed by the addition of ethyl 2-bromoacetate (8.4 g, 50.30 mmol, 1.10 equiv) dropwise with stirring. The mixture was stirred for 30 min at room temperature. The resulting solution was heated to reflux for 6 hr. The resulting mixture was cooled to room temperature and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:20 to 1:5). This resulted in 8.0 g (50%) of ethyl 2-(benzyl((diethoxyphosphoryl)methyl)amino)acetate as yellow oil.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][O:11][CH:10]([CH2:14][O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[O:22][CH2:23][CH3:24])[CH2:9]1)C1C=CC=CC=1.[ClH:25]>C(O)C.[Pd]>[ClH:25].[CH2:23]([O:22][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[O:15][CH2:14][CH:10]1[O:11][CH2:12][CH2:13][NH:8][CH2:9]1)[CH3:24]
Reactant: CCOc1ccccc1OCC1CN(Cc2ccccc2)CCO1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: CCOc1ccccc1OCC1CNCCO1
Yield: 96 %

Procedure:
The title compound was prepared by hydrogenation of (±)-4-benzyl-2-[(2-ethoxyphenoxy)-methyl]morpholine over 5% Pd/C in ethanol: 1 M aqueous HCl 3:1. mp 176-179° C. Yield 96%.
Reaction SMILES: [Cl:1][C:2]1[N:9]=[CH:8][C:7]([CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])=[CH:6][C:3]=1[CH:4]=[O:5].C1N2CCN(CC2)C1.[C:23](#[N:26])[CH:24]=[CH2:25]>C(OCC)C>[Cl:1][C:2]1[C:3]([CH:4]([OH:5])[C:24](=[CH2:25])[C:23]#[N:26])=[CH:6][C:7]([CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])=[CH:8][N:9]=1
Reactant: CCCCCc1cnc(Cl)c(C=O)c1
Reactant: C=CC#N
Agent: C1CN2CCN1CC2
Solvent: CCOCC
Product: C=C(C#N)C(O)c1cc(CCCCC)cnc1Cl

Procedure:
To a mixture of 2-Chloro-5-pentylnicotinaldehyde (10 mmol, 2.11 g) and DABCO (10 mmol. 1.12 g) was added an acrylonitrile (60 mmol.) under neat conditions [solvent free conditions] at room temperature and the reaction progress was monitored by TLC. Upon completion of the reaction mixture (˜4-5 min.) was diluted with diethyl ether (300 ml.) and washed with water 3×50 ml. The organic layer was dried over Na2SO4 and concentrated, the residue was subjected to column chromatography over silica gel, eluting with ethyl acetate and hexane (2:8, v/v) to give the desired product in almost quantitative (2.62 g.).
Reaction SMILES: [CH:1](=[N:6][OH:7])[CH2:2][CH2:3][CH2:4][CH3:5].C(=NO)CCC.CN[C:16](NC)=[CH:17][C:18]([O:20][CH2:21][CH3:22])=[O:19]>>[CH2:21]([O:20][C:18]([C:17]1[C:1]([CH2:2][CH2:3][CH2:4][CH3:5])=[N:6][O:7][CH:16]=1)=[O:19])[CH3:22]
Reactant: CCOC(=O)C=C(NC)NC
Reactant: CCCCC=NO
Agent: CCCC=NO
Product: CCCCc1nocc1C(=O)OCC
Yield: 61 %

Procedure:
As described for example 1a except using valeraldehyde (12.4 mL, 116 mmol) instead of butyraldehyde, the penatnal oxime intermediate product (11.7 g, 99%) was obtained as a yellow solid and as a mixture of cis and trans isomers that was used directly without further purification. MS (EI): m/e=101.0 [M]+. Then as described for example 1b, except using (E and/or Z)-pentanal oxime (11.4 g, 113 mmol) instead of (E and/or Z)-butanal oxime, and using ethyl 3,3-dimethylaminoacrylate instead of ethyl (E)-3-(1-pyrrolidino)-2-butenoate, the title compound (13.6 g, 61%) was obtained as a yellow liquid after purification by chromatography (silica, 0 to 10% ethyl acetate in heptane). MS: m/e=198.1 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[CH:8][C:7](F)=[CH:6][C:5]=1[C:11]#[N:12].Cl.[CH3:15][NH:16][CH3:17].C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[CH:8][C:7]([N:16]([CH3:17])[CH3:15])=[CH:6][C:5]=1[C:11]#[N:12]
Reactant: CNC
Reactant: COC(=O)c1ccc(F)cc1C#N
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: COC(=O)c1ccc(N(C)C)cc1C#N
Temperature: 60 °C
Reaction time: 9 h
Yield: 85 %

Procedure:
To a stirred solution of 4.03 g (22.5 mmol) 2-Cyano-4-fluoro-benzoic acid methyl ester (J. Med. Chem., 35; 24; (1992); 4613-4627) and 60.0 ml dimethylsulphoxid were added 2.23 g (27.0 mmol) dimethylamine hydrochloride and 6.54 g (47.3 mmol) potassium carbonate. The reaction mixture was stirred for 9 h at 60° C. in an autoclave and was concentrated with high vacuum rotation evaporator at 65° C. The residue was diluted with dichloromethane, washed twice with water. The combined water phases were extracted with dichloromethane. The combined dichloromethane phases were washed with diluted sodium hydrogen carbonate solution, dried with sodium sulphate and concentrated. The oily crude was purified by column chromatography and the desired product 9a was obtained in 85% yield (3.90 g, 19.1 mmol).
Reaction SMILES: [C:1]([O:4][C@@H:5]1[CH2:22][CH2:21][C@@:20]2([CH3:23])[C@H:7]([CH2:8][CH2:9][C@@H:10]3[C@@H:19]2[CH2:18][C@H:17]([O:24][C:25](=[O:27])[CH3:26])[C@@:15]2([CH3:16])[C@H:11]3[CH2:12][CH2:13][C@@H:14]2[C:28](=[CH2:44])CC=C(C2C=CC=CC=2)C2C=CC=CC=2)[CH2:6]1)(=[O:3])[CH3:2].I([O-])(=O)(=O)=[O:46].[Na+]>C(Cl)(Cl)(Cl)Cl.C(#N)C.O.C(Cl)Cl.O.[Ru](Cl)(Cl)Cl>[C:28]([C@H:14]1[CH2:13][CH2:12][C@H:11]2[C@H:10]3[C@H:19]([CH2:18][C@H:17]([O:24][C:25](=[O:27])[CH3:26])[C@:15]12[CH3:16])[C@:20]1([CH3:23])[C@@H:7]([CH2:6][C@H:5]([O:4][C:1](=[O:3])[CH3:2])[CH2:22][CH2:21]1)[CH2:8][CH2:9]3)(=[O:46])[CH3:44]
Reactant: C=C(CC=C(c1ccccc1)c1ccccc1)[C@H]1CC[C@H]2[C@@H]3CC[C@@H]4C[C@H](OC(C)=O)CC[C@]4(C)[C@H]3C[C@H](OC(C)=O)[C@]12C
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: Cl[Ru](Cl)Cl
Agent: [Na+]
Solvent: ClC(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: O
Product: CC(=O)O[C@@H]1CC[C@@]2(C)[C@H](CC[C@@H]3[C@@H]2C[C@H](OC(C)=O)[C@]2(C)[C@@H](C(C)=O)CC[C@@H]32)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of the crude 3α, 12α-diacetoxy-17β-[(1,1-diphenyl)-1,4-pentadien-4-yl]-5β-androstane (43.6 g) in carbon tetrachloride (110 ml), acetonitrile (110 ml) and water (146 ml) is added sodium periodate (46.8 g) and ruthenium(III) chloride hydrate (0.373 g). The mixture is stirred vigorously at room temperature for about 1 hour, sodium periodate (5.0 g) and ruthenium(III) chloride hydrate (0.10 g) are added and stirring continued for about 30 minutes. The mixture is diluted with methylene chloride, washed with water, dried over magnesium sulfate, filtered and concentrated in vacuo. The crude product is purified by flash chromatography in 5% ether in methylene chloride and further purified by flash chromatography in 25% ethyl acetate in hexane to give the desired product.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][C:7]([C:11]#[N:12])=[CH:8][CH:9]=2)[CH2:4][CH2:3]1.[BrH:13].BrBr.S(=O)(O)[O-].[Na+]>C(O)(=O)C.O>[Br:13][CH:3]1[CH2:4][C:5]2[C:10](=[CH:9][CH:8]=[C:7]([C:11]#[N:12])[CH:6]=2)[C:2]1=[O:1]
Reactant: Br
Reactant: N#Cc1ccc2c(c1)CCC2=O
Agent: BrBr
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: N#Cc1ccc2c(c1)CC(Br)C2=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
3.93 g of 1-oxoindane-5-carbonitrile are dissolved in 40 ml of glacial acetic acid and, after addition of 0.1 ml of hydrobromic acid (48% strength in water), at room temperature a solution of 1.34 ml of bromine in 8 ml of acetic acid is added dropwise. The reaction mixture is stirred at room temperature for 3 h and then added to a mixture of 20 g of ice and 40 g of water, 0.5 g of sodium bisulfite is added and the mixture is extracted by shaking twice with 50 ml of dichloromethane each time. The organic phase is washed with 50 ml of water, dried over magnesium sulfate, concentrated in vacuo and chromatographed on silica gel with toluene/ethyl acetate 25/1. 2-Bromo-l-oxoindane-5-carbonitrile is obtained with a melting point of 115-118° C.
Reaction SMILES: [CH2:1]([C:8]1[C:13]([C:14]#[C:15][C:16]23[CH2:22][CH:19]([CH2:20]C2)CC3O)=[CH:12][CH:11]=[C:10]([N:24]2[CH2:28][C@@H:27]([O:29][CH3:30])[C@H:26]([OH:31])[CH2:25]2)[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1CCCCC1.CCCCCC.C([Li])(CC)C.[N:49]12[CH2:56][CH2:55][CH:52]([CH2:53][CH2:54]1)[C:51](=[O:57])[CH2:50]2>O1CCCC1>[CH2:1]([C:8]1[C:13]([C:14]2[CH:20]=[CH:19][C:22]([C:51]3([OH:57])[CH:52]4[CH2:55][CH2:56][N:49]([CH2:54][CH2:53]4)[CH2:50]3)=[CH:16][CH:15]=2)=[CH:12][CH:11]=[C:10]([N:24]2[CH2:28][C@@H:27]([O:29][CH3:30])[C@H:26]([OH:31])[CH2:25]2)[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CO[C@@H]1CN(c2ccc(C#CC34CCC(CC3O)C4)c(Cc3ccccc3)n2)C[C@H]1O
Reactant: O=C1CN2CCC1CC2
Agent: [Li]C(C)CC
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: C1CCCCC1
Product: CO[C@@H]1CN(c2ccc(-c3ccc(C4(O)CN5CCC4CC5)cc3)c(Cc3ccccc3)n2)C[C@H]1O
Temperature: -90 °C
Reaction time: 0.67 h
Yield: 18.5 %

Procedure:
To a mixture of 280 mg of 2-(4-bromophenyl)-6-methyl-1,3,6,2-dioxyazaborocane (Production Example 14) and 10 ml of tetrahydrofuran was added dropwise 2 ml of a 1 M cyclohexane-hexane solution of sec-butyllithium under nitrogen atmosphere while cooling in a liquid nitrogen-tetrahydrofuran bath at −90° C., followed by stirring as it was for 40 minutes. Then, a solution of 130 mg of 3-quinuclidinone in 1 ml of tetrahydrofuran was added to the mixture, the liquid nitrogen-tetrahydrofuran bath was removed and the mixture was stirred at room temperature for 30 minutes. 1 ml of an aqueous ammonium chloride solution was added to the reaction mixture, followed by evaporating. To the residue were added 5 ml of methanol, 2 ml of a 5 Maqueous solution of potassium carbonate, 220 mg of 2-benzyl-3-iodo-6-[(3R,4R)-3-hydroxy-4-methoxypyrrolidin-1-yl]pyridine hydrochloride and 5 ml of diethoxymethane, followed by heating under stirring under nitrogen atmosphere in an oil bath at 60° C. for 3 hours. The reaction mixture was extracted with ethyl acetate-water, and the organic layer was washed with water and brine, dried over anhydrous magnesium sulfate and then evaporated. The residue was subjected to column chromatography using NH-silica gel with 50% ethyl acetate-hexane and 0–5% methanol-ethyl acetate, to give 60 mg of the title compound.
Reaction SMILES: [CH3:1][N:2]([CH3:12])[CH:3]=[CH:4][C:5](=[O:11])[C:6]([O:8][CH2:9][CH3:10])=[O:7].[F:13][B-:14]([F:17])([F:16])[F:15].[CH2:18]([O+](CC)CC)[CH3:19]>C(Cl)Cl>[F:13][B-:14]([F:17])([F:16])[F:15].[CH2:18]([O:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=[N+:2]([CH3:1])[CH3:12])[CH3:19]
Reactant: CC[O+](CC)CC
Reactant: CCOC(=O)C(=O)C=CN(C)C
Agent: F[B-](F)(F)F
Solvent: ClCCl
Product: CCOC(=O)C(=CC=[N+](C)C)OCC
Temperature: 10 °C
Reaction time: 5 h

Procedure:
Ethyl 4-dimethylamino-2-oxo-3-butenoate (675 g) is added in the course of 3 hours, while the temperature is maintained at approximately 10° C., to a solution, cooled to 10° C. and through which a stream of argon is passed, of triethyloxonium tetrafluoroborate (862 g) in methylene chloride. The reaction medium is then stirred for 5 hours at a temperature in the region of 20° C. The solution of N-(3-ethoxy-3-ethoxycarbonylpropenylidene)-N-methylmethanaminium tetrafluoroborate thereby obtained is stored under an argon atmosphere, and is used immediately in the subsequent syntheses.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:45][CH3:46])[CH2:4][NH:5][C@:6]12[CH2:41][CH2:40][C@@H:39]([C:42]([CH3:44])=[CH2:43])[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([CH3:38])[C@@H:17]([CH2:18][CH2:19]2)[C:16]([CH3:27])([CH3:26])[C:15]([C:28]2[CH:37]=[CH:36][C:31]([C:32]([O:34]C)=[O:33])=[CH:30][CH:29]=2)=[CH:14][CH2:13]3)[CH2:10][CH2:9]1.[OH-].[Na+]>O1CCOCC1.CO>[CH3:1][O:2][CH:3]([O:45][CH3:46])[CH2:4][NH:5][C@:6]12[CH2:41][CH2:40][C@@H:39]([C:42]([CH3:44])=[CH2:43])[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([CH3:38])[C@@H:17]([CH2:18][CH2:19]2)[C:16]([CH3:27])([CH3:26])[C:15]([C:28]2[CH:29]=[CH:30][C:31]([C:32]([OH:34])=[O:33])=[CH:36][CH:37]=2)=[CH:14][CH2:13]3)[CH2:10][CH2:9]1
Reactant: C=C(C)[C@@H]1CC[C@]2(NCC(OC)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: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1COCCO1
Product: C=C(C)[C@@H]1CC[C@]2(NCC(OC)OC)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
Temperature: 85 °C
Yield: 65 %

Procedure:
To a solution of methyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(2,2-dimethoxyethylamino)-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 (0.025 g, 0.040 mmol) in 1,4-dioxane (1 mL) was added NaOH (1N) (0.198 mL, 0.198 mmol). The mixture was heated to 85° C. After 6 h of heating, the mixture was cooled to rt, the reaction mixture was diluted with MeOH and was purified by prep HPLC. The fractions containing the expected product were combined and were concentrated under reduced pressure to give the title compound (17 mg, 0.026 mmol, 66.1% yield) as a clear film. LCMS: m/e 618.8 (M+H)+, 2.28 min (method 11). 1H NMR (500 MHz, CHLOROFORM-d) d ppm 7.99 (d, J=7.93 Hz, 2H), 7.20 (d, J=7.93 Hz, 2H), 5.28 (d, J=4.88 Hz, 1H), 5.12 (br. s., 1H), 4.72 (s, 1H), 4.58 (s, 1H), 4.53 (t, J=5.49 Hz, 1H), 3.44 (s, 3H), 3.41 (s, 3H), 2.64-2.74 (m, 2H), 2.60 (dd, J=11.44, 6.56 Hz, 1H), 1.97-2.13 (m, 2H), 1.86-1.95 (m, 2H), 1.81 (dd, J=12.51, 8.24 Hz, 1H), 1.68 (s, 3H), 1.11 (s, 3H), 0.98 (s, 3H), 0.97 (br. s., 3H), 0.95-1.72 (m, 17H), 0.93 (br. s., 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:17][C:18]2[C:19]3[N:26]([CH2:27][C:28]4[CH:36]=[CH:35][C:31]([C:32]([OH:34])=O)=[CH:30][CH:29]=4)[CH:25]=[CH:24][C:20]=3[N:21]=[CH:22][N:23]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=1.[OH:37][CH:38]1[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]1.O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>CN(C)C=O.C(N(CC)CC)C>[Cl:1][C:2]1[CH:3]=[C:4]([NH:17][C:18]2[C:19]3[N:26]([CH2:27][C:28]4[CH:36]=[CH:35][C:31]([C:32]([N:41]5[CH2:42][CH2:43][CH:38]([OH:37])[CH2:39][CH2:40]5)=[O:34])=[CH:30][CH:29]=4)[CH:25]=[CH:24][C:20]=3[N:21]=[CH:22][N:23]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=1
Reactant: O=C(O)c1ccc(Cn2ccc3ncnc(Nc4ccc(OCc5cccc(F)c5)c(Cl)c4)c32)cc1
Reactant: OC1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(c1ccc(Cn2ccc3ncnc(Nc4ccc(OCc5cccc(F)c5)c(Cl)c4)c32)cc1)N1CCC(O)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.1 %

Procedure:
To a mixture of 4-{[4-({3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl]methyl}benzoic acid (150 mg), 4-hydroxypiperidine (33.2 mg) and 1-hydroxybenzotriazole monohydrate (60 mg) in N,N-dimethylformamide (3 mL) were added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (86 mg) and triethylamine (0.208 mL) at room temperature and the mixture was stirred overnight at room temperature. The mixture was partitioned between ethyl acetate (50 mL) and water (30 mL). The organic layer washed with saturated brine (30 mL), dried over magnesium sulfate, and concentrated under reduced pressure. The residue was separated and purified by basic silica gel column chromatography (eluent, ethyl acetate:methanol=100:0→ethyl acetate:methanol=80:20), and crystallized from diisopropyl ether to give the title compound (168 mg).
Reaction SMILES: C1C(=O)N([Br:8])C(=O)C1.[Cl:9][C:10]1[C:11]([F:36])=[C:12]([N:16]2[C:23](=[O:24])[C:22]3[CH:21]=[CH:20][N:19]([CH:25]([CH3:27])[CH3:26])[C:18]=3[CH:17]2[C:28]2[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][C:29]=2[CH3:35])[CH:13]=[CH:14][CH:15]=1>C(Cl)(Cl)(Cl)Cl.CCOC(C)=O>[Br:8][C:20]1[N:19]([CH:25]([CH3:27])[CH3:26])[C:18]2[CH:17]([C:28]3[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][C:29]=3[CH3:35])[N:16]([C:12]3[CH:13]=[CH:14][CH:15]=[C:10]([Cl:9])[C:11]=3[F:36])[C:23](=[O:24])[C:22]=2[CH:21]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cc(Cl)ccc1C1c2c(ccn2C(C)C)C(=O)N1c1cccc(Cl)c1F
Solvent: ClC(Cl)(Cl)Cl
Solvent: CCOC(C)=O
Product: Cc1cc(Cl)ccc1C1c2c(cc(Br)n2C(C)C)C(=O)N1c1cccc(Cl)c1F
Reaction time: 1.5 h

Procedure:
NBS (1.926 mmol) was added to a mixture of 5-(3-chloro-2-fluoro-phenyl)-6-(4-chloro-2-methyl-phenyl)-1-isopropyl-5,6-dihydro-1H-pyrrolo[3,4-b]pyrrol-4-one (Step A1) (1.965 mmol) in CCl4 (65 mL). After 1.5 h, the reaction mixture was diluted with EtOAc and successively washed with a saturated aqueous solution of NaHCO3, water and brine, dried (Na2SO4), filtered and concentrated. The residue was purified using a RediSep® silica gel column to afford the title compound as a white solid. tR: 5.69 min (HPLC 1); ESI-MS: tR=1.39 min, [M+H]+ 495/497/499 (LC-MS 1); TLC: Rf=0.12 (CH2Cl2).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[C:9]([NH:10][C@H:11]([CH2:14][CH:15]([CH3:17])[CH3:16])[CH2:12][OH:13])=[N:8][C:7]([SH:18])=[N:6][C:5]=2[N:19]=1.Cl[CH:21]([C:23]1[CH:28]=[CH:27][C:26]([F:29])=[CH:25][N:24]=1)[CH3:22]>>[NH2:1][C:2]1[S:3][C:4]2[C:9]([NH:10][C@H:11]([CH2:14][CH:15]([CH3:16])[CH3:17])[CH2:12][OH:13])=[N:8][C:7]([S:18][CH:21]([C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][N:24]=3)[CH3:22])=[N:6][C:5]=2[N:19]=1
Reactant: CC(Cl)c1ccc(F)cn1
Reactant: CC(C)C[C@H](CO)Nc1nc(S)nc2nc(N)sc12
Product: CC(C)C[C@H](CO)Nc1nc(SC(C)c2ccc(F)cn2)nc2nc(N)sc12
Yield: 19.7 %

Procedure:
The title compound was prepared according to General method A starting from (2R)-2-[(2-amino-5-mercapto[1,3]thiazolo[4,5-d]pyrimidin-7-yl)amino]-4-methylpentan-1-ol (21 mg, 0.072 mmol) and 2-(1-chloroethyl)-5-fluoropyridine (8 mg, 0.048 mmol). Purification by preparative HPLC yielded 4 mg (21% yield) of the title compound as a mixture of diastereomers.
Reaction SMILES: C(OC([NH:11][CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][C@H:21]([O:27][CH2:28][CH3:29])[C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:16][CH:15]=1)=O)C1C=CC=CC=1>C(OCC)(=O)C.[Pd]>[NH2:11][CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][C@H:21]([O:27][CH2:28][CH3:29])[C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:16][CH:15]=1
Reactant: CCOC(=O)[C@H](Cc1ccc(CCNC(=O)OCc2ccccc2)cc1)OCC
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCOC(=O)[C@H](Cc1ccc(CCN)cc1)OCC
Yield: 52 %

Procedure:
Ethyl (2S)-3-[4-(2-{[(benzyloxy)carbonyl]amino}ethyl)phenyl]-2-ethoxypropanoate (2.45 g, 6.14 mmol) was hydrogenated for 2.5 hours at atmospheric pressure in ethyl acetate (51 ml) using Pd/C (1 spoon) as catalyst. After filtration on hyflo, the solvent was evaporated in vacuo. The crude product was purified by chromatography on silica gel using THF:methanol (NH3-saturated) (gradient 25:1–1:25) as eluent. The first fractions containing the product was filtered on Millipore filter and combined with the later fractions containing product to give 0.84 g (yield 52%, including a by-product) of the desired product.