Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[CH2:10][C:9](=O)[CH2:8][CH2:7]2.[CH2:13]([NH:16][CH2:17][CH:18]=[CH2:19])[CH:14]=[CH2:15].C1(C)C=CC(S(O)(=O)=O)=CC=1.C([BH3-])#N.[Na+].Cl.[OH-].[Na+]>C1(C)C=CC=CC=1.O1CCCC1.O>[CH2:13]([N:16]([CH2:17][CH:18]=[CH2:19])[CH:9]1[CH2:8][CH2:7][C:6]2[C:11](=[C:2]([Cl:1])[CH:3]=[CH:4][CH:5]=2)[CH2:10]1)[CH:14]=[CH2:15]
Reactant: C=CCNCC=C
Reactant: O=C1CCc2cccc(Cl)c2C1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Agent: [BH3-]C#N
Solvent: Cc1ccccc1
Solvent: O
Solvent: C1CCOC1
Product: C=CCN(CC=C)C1CCc2cccc(Cl)c2C1
Temperature: 25 °C
Yield: 23.4 %

Procedure:
To a solution of 8-chloro-2-tetralone (5.0 gm, 27.8 mMol) in toluene (50 mL) were added freshly distilled (b.p.=112° C.) diallylamine (7 mL, 56.7 mMol) and p-toluenesulfonic acid (500 mg), and the reaction mixture was stirred at reflux for 3 hours with constant water removal (Dean-Stark trap). The reaction mixture was then cooled to room temperature and volatiles removed in vacuo to give a brown-orange, viscous residue. To a solution of this residue in tetrahydrofuran (100 mL) was added sodium cyanoborohydride (3 gm, 47.7 mMol), and the resulting suspension was saturated with hydrogen chloride. The resulting mixture was stirred at room temperature for 18 hours. The reaction mixture was then poured into water (300 mL) and made basic with aqueous sodium hydroxide. After stirring for two hours at room temperature the reaction mixture was poured into ice and made strongly acidic with concentrated hydrochloric acid. The aqueous solution was extracted with diethyl ether and the organic phase discarded. The remaining aqueous was made strongly basic with aqueous sodium hydroxide and was extracted with dichloromethane. The combined organic extracts were dried over sodium sulfate and concentrated in vacuo to give a violet liquid. Purification on a basic alumina column (Activity I, dichloromethane) gave a colorless oil (1.7 gm, 24%). The hydrochloride salt was formed and recrystallized (ethanol/diethyl ether) to give a colorless solid (m.p.=117°-118° C.).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([NH:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]3[O:20][CH2:21][O:22][C:16]=3[CH:15]=2)[C:5]2[CH:10]=[C:9]([CH3:11])[S:8][C:6]=2[N:7]=1.[NH:23]1[CH:27]=[CH:26][N:25]=[CH:24]1.C1(O)C=CC=CC=1>>[N:23]1([C:2]2[N:3]=[C:4]([NH:12][CH2:13][C:14]3[CH:19]=[CH:18][C:17]4[O:20][CH2:21][O:22][C:16]=4[CH:15]=3)[C:5]3[CH:10]=[C:9]([CH3:11])[S:8][C:6]=3[N:7]=2)[CH:27]=[CH:26][N:25]=[CH:24]1
Reactant: c1c[nH]cn1
Reactant: Cc1cc2c(NCc3ccc4c(c3)OCO4)nc(Cl)nc2s1
Solvent: Oc1ccccc1
Product: Cc1cc2c(NCc3ccc4c(c3)OCO4)nc(-n3ccnc3)nc2s1
Yield: 184.9 %

Procedure:
A solution of 2-chloro-6-methyl-4-(3,4-methylene dioxybenzylamino)-thieno-[2,3-d]-pyrimidine (1.67 g), imidazole (1.02 g) and phenol (2 g) are heated 5 hours at 150° C. After cooling, the residue is dissolved in C2Cl2. The solvent is removed, and the usual workup yields 2-(imidazol-1-yl)-6-methyl-4-(3,4-methylenedioxybenzylamino)-thieno-[2,3-d]-pyrimidine (3.38 g) Mp. 162° C.
Reaction SMILES: [Cl:1][C:2]1[C:10]([CH2:11][S:12][C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][C:14]=2[N+:20]([O-])=O)=[CH:9][C:5]2[O:6][CH2:7][O:8][C:4]=2[CH:3]=1.O.O.[Sn](Cl)Cl>C(O)C>[Cl:1][C:2]1[C:10]([CH2:11][S:12][C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][C:14]=2[NH2:20])=[CH:9][C:5]2[O:6][CH2:7][O:8][C:4]=2[CH:3]=1
Reactant: Cc1ccc(SCc2cc3c(cc2Cl)OCO3)c([N+](=O)[O-])c1
Agent: Cl[Sn]Cl
Solvent: CCO
Solvent: O
Product: Cc1ccc(SCc2cc3c(cc2Cl)OCO3)c(N)c1

Procedure:
The material from step 1 dissolved in ethanol (5 mL) was combined with a solution of tin dichloride dihydrate (12 mmol) in ethanol (5 mL) and heated to 70 for 5 h. The solvent was removed under a stream of nitrogen and the residue was redissolved in a mix of dichloromethane and 1 N NaOH solution. The mixture was applied to an Extrelut QE solid phase extraction column that was prepped with 1 N NaOH solution. The organic was collected and the solvent was removed under a stream of nitrogen. The residue was redissolved in diethyl ether and treated with 4 N HCl in dioxane. The precipate was collected to give the product as the HCl salt.
Reaction SMILES: [Br:1][C:2]1[N:6]2[N:7]=[C:8](Cl)[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1.[N:12]1[CH:17]=[CH:16][C:15]([CH2:18][NH2:19])=[CH:14][CH:13]=1.C(Cl)Cl.CO.[NH4+].[OH-]>>[Br:1][C:2]1[N:6]2[N:7]=[C:8]([NH:19][CH2:18][C:15]3[CH:16]=[CH:17][N:12]=[CH:13][CH:14]=3)[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1
Reactant: Clc1ccc2ncc(Br)n2n1
Reactant: NCc1ccncc1
Agent: [NH4+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CO
Product: Brc1cnc2ccc(NCc3ccncc3)nn12

Procedure:
Prepared from 3-bromo-6-chloroimidazo[1,2-b]pyridazine and pyridin-4-ylmethanamine according to general procedure 1 providing the intermediate (94 mg, 84%) as a yellow solid: Rf=0.28 (CH2Cl2/MeOH/NH4OH, 160:18:2); 1H NMR (500 MHz, CD3OD) δ 8.45-8.46 (m, 2H), 7.60 (d, J=9.7 Hz, 1H), 7.51-7.50 (m, 2H), 7.39 (s, 1H), 6.79 (d, J=9.7 Hz, 1H), 4.61 (s, 2H); ES-MS: (M+H)=304, 306 m/z.
Reaction SMILES: [CH3:1][Si:2]([CH3:11])([CH3:10])[CH2:3][CH2:4][CH2:5][S:6]([O-:9])(=[O:8])=[O:7].[Na+].C[Si](C)(C)CCCS([O-])(=O)=O>O>[CH3:10][Si:2]([CH3:1])([CH3:11])[CH2:3][CH2:4][CH2:5][S:6]([OH:9])(=[O:8])=[O:7]
Reactant: C[Si](C)(C)CCCS(=O)(=O)[O-]
Agent: [Na+]
Solvent: O
Product: C[Si](C)(C)CCCS(=O)(=O)O

Procedure:
A solution of sodium 3-(trimethylsilyl)-1-propanesulfonate (13 grams, 59.5 mmol) dissolved in demineralized water (75 ml) was added dropwise into a short column packed with an excess (15-20 times the molar amount of 3-(trimethylsilyl)-1-propanesulfonate) of Tulsion T-42 MP(H+) acidic ion exchange resin. Then the resin bed was washed with water until the pH of the solution eluting from the column was about 5 to 6. The water solution of the free 3-(trimethylsilyl)-1-propanesulfonic acid thus obtained was neutralized with tetra-n-butylphosphonium hydroxide until the pH of the solution was about 5 to 5.5. The resulting mixture was extracted with chloroform (three times) and the combined chloroform washes was washed with water (three times). The chloroform layer was separated, dried with anhydrous sodium sulfate, and concentrated under reduced pressure to remove solvent and other volatiles. The residual material was finally dried at 40° C. and 0.1 mm Hg to afford tetra-n-butylphosphonium 3-(trimethylsilyl)-1-propanesulfonate as a white solid. The yield of the product was 26.9 grams, or 99% of the theoretical amount. Proton NMR spectrum of the compound indicated that it was the desired compound.
Reaction SMILES: [CH2:1]([NH:8][C:9](=[O:44])[NH:10][C:11]1[CH:12]=[C:13]([C:17]2[N:26]=[C:25]([NH:27][C:28]3[CH:29]=[C:30]4[C:34](=[CH:35][CH:36]=3)[N:33](C(OC(C)(C)C)=O)[N:32]=[CH:31]4)[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:18]=2)[CH:14]=[CH:15][CH:16]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH:33]1[C:34]2[C:30](=[CH:29][C:28]([NH:27][C:25]3[C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[N:18]=[C:17]([C:13]4[CH:12]=[C:11]([NH:10][C:9]([NH:8][CH2:1][C:2]5[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=5)=[O:44])[CH:16]=[CH:15][CH:14]=4)[N:26]=3)=[CH:36][CH:35]=2)[CH:31]=[N:32]1
Reactant: CC(C)(C)OC(=O)n1ncc2cc(Nc3nc(-c4cccc(NC(=O)NCc5ccccc5)c4)nc4ccccc34)ccc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(NCc1ccccc1)Nc1cccc(-c2nc(Nc3ccc4[nH]ncc4c3)c3ccccc3n2)c1

Procedure:
To tert-butyl 5-(2-(3-(3-benzylureido)phenyl)quinazolin-4-ylamino)-1H-indazole-1-carboxylate (30 mg, 0.051 mmol) was added a solution of 1:1 TFA:CH2Cl2 (2 mL) and stirred at RT for 2 h. The reaction mixture was concentrated in vacuo and left under high vacuum for several hours. The crude product was triturated with ethyl ether to afford 1-(3-(4-(1H-indazol-5-ylamino)quinazolin-2-yl)phenyl)-3-benzylurea. (25 mg, 100%)
Reaction SMILES: N[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2NC2C=CC=C(Cl)C=2)[NH:4][N:3]=1.C(O)(=O)C.S1C=CN=C1C1C=CC(C=O)=CC=1>CO>[NH:4]1[C:5]2=[N:6][CH:7]=[N:8][CH:9]=[C:10]2[CH:2]=[N:3]1
Reactant: Nc1n[nH]c2ncnc(Nc3cccc(Cl)c3)c12
Agent: O=Cc1ccc(-c2nccs2)cc1
Solvent: CO
Solvent: CC(=O)O
Product: c1ncc2cn[nH]c2n1

Procedure:
Analogously to Example 32, 521 mg (2.00 mmol) of 3-amino-4-(3-chlorophenylamino)-1H-pyrazolo[3,4-d]pyrimidine (see Step 1.6) and 343 μl of acetic acid are dissolved in 50 ml of methanol and reacted with 567 mg (3.0 mmol) of 4-(thiazol-2-yl)-benzaldehyde to form 4-(3chloro-phenylamino)-3t{4-(thiazol-2-yl)-phen-1-yl)methyleneamino]-1H-pyrazolo[3,4-d]pyrimidine. The above intermediate is reduced in 30 ml of DMEU with 16 ml (16 mmol) of DIBAL-H and worked up analogously. The crude product is dissolved in THF/methanol; 20 g of silica gel are added and the mixture is dried to a powder. Application to a silica gel column and elution with CH2Cl2/methanol/H2O/acetic acid (85:13:1.5:0.5) yield 4-(3-chloro-phenylamino)-3-[4-(thiazol-2-yl)-benzylamino]-1H-pyrazolo[3,4-d]pyrimidine; m.p. 241-243° C.; TLC: Rf=0.44 (CHCl3/methanol/H2O/acetic acid=85:13:1.5:0.5); HPLC: tRet(grad20-100)=9.0; FAB-MS: (M+H)+=434.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:14]3[CH:15]=[C:16]([CH3:22])[C:17]([C:20]#[N:21])=[C:18]([CH3:19])[C:13]=3[N:12]=[C:11]2[CH2:23][CH3:24])=[CH:6][CH:5]=1.[OH-:25].[Na+]>OS(O)(=O)=O>[Cl:1][CH2:2][CH2:3][C:4]1[CH:5]=[CH:6][C:7]([N:10]2[C:14]3[CH:15]=[C:16]([CH3:22])[C:17]([C:20]([NH2:21])=[O:25])=[C:18]([CH3:19])[C:13]=3[N:12]=[C:11]2[CH2:23][CH3:24])=[CH:8][CH:9]=1
Reactant: CCc1nc2c(C)c(C#N)c(C)cc2n1-c1ccc(CCCl)cc1
Reactant: [OH-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: CCc1nc2c(C)c(C(N)=O)c(C)cc2n1-c1ccc(CCCl)cc1
Yield: 83 %

Procedure:
A solution of 1-[4-(2-chloroethyl)phenyl]-2-ethyl-4,6-dimethyl-1H-benzimidazole-5-carbonitrile (Example 329, step 6, 997 mg, 2.95 mmol) in c.H2SO4 (50 ml) was stirred at 80° C. for 15 h. The mixture was poured onto ice and was neutralized with NaOH. The mixture was extracted with ethyl acetate (600 ml). The organic layer was washed with brine (300 ml), then dried (Na2SO4). The solvent was removed to afford 871 mg (83%) of the title compound as white solids.
Reaction SMILES: [H-].[Na+].Cl[CH2:4][CH2:5][NH:6][C:7]([C:9]1[N:10]=[C:11](/[CH:21]=[CH:22]/[C:23]2[CH:28]=[CH:27][C:26]([N:29]3[CH:33]=[C:32]([CH3:34])[N:31]=[CH:30]3)=[C:25]([O:35][CH3:36])[CH:24]=2)[NH:12][C:13]=1[C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=1)=[O:8].C(OCC)(=O)C.O.C(=O)(O)[O-].[Na+]>CN(C=O)C>[F:20][C:17]1[CH:18]=[CH:19][C:14]([C:13]2[N:12]=[C:11](/[CH:21]=[CH:22]/[C:23]3[CH:28]=[CH:27][C:26]([N:29]4[CH:33]=[C:32]([CH3:34])[N:31]=[CH:30]4)=[C:25]([O:35][CH3:36])[CH:24]=3)[N:10]3[CH2:4][CH2:5][NH:6][C:7](=[O:8])[C:9]=23)=[CH:15][CH:16]=1
Reactant: COc1cc(/C=C/c2nc(C(=O)NCCCl)c(-c3ccc(F)cc3)[nH]2)ccc1-n1cnc(C)c1
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(/C=C/c2nc(-c3ccc(F)cc3)c3n2CCNC3=O)ccc1-n1cnc(C)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 72.1 %

Procedure:
Sodium hydride (containing mineral oil at 60%, 3 mg) was added to a solution of 5-(4-fluorophenyl)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-1H-imidazole-4-carboxylic acid (2-chloroethyl)amide (15 mg) in DMF (2 mL) at room temperature, and the reaction solution was stirred at room temperature for 30 minutes. Ethyl acetate and saturated sodium bicarbonate water were added to the reaction solution, and the organic layer was separated. The resulting organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (carrier: Chromatorex™ NH; elution solvent: ethyl acetate->ethyl acetate:methanol=5:1) to obtain 10 mg of the title compound. The property values of the compound are as follows.
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.[CH3:13][CH2:14][O:15][C:16]([CH3:18])=[O:17].[CH2:19]([O:26][C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([CH:33]=[CH:34][N+:35]([O-:37])=[O:36])[CH:28]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C1COCC1>[CH2:14]([O:15][C:16](=[O:17])[CH2:18][CH:33]([C:29]1[CH:30]=[CH:31][CH:32]=[C:27]([O:26][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:28]=1)[CH2:34][N+:35]([O-:37])=[O:36])[CH3:13]
Reactant: O=[N+]([O-])C=Cc1cccc(OCc2ccccc2)c1
Reactant: CCOC(C)=O
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CCOC(=O)CC(C[N+](=O)[O-])c1cccc(OCc2ccccc2)c1
Temperature: -78 °C

Procedure:
To a dry round bottom flask was added 2.7 mL of diisopropylamine and 20 mL THF. The mixture was cooled to −78° C. with stirring. A solution of n-BuLi (11.4 mL, 1.6 M) was added dropwise and the resulting solution was stirred for 20 min. EtOAc (1.5 mL) was added slowly to quench and the mixture was stirred for an additional 20 min. 1-Benzyloxy-3-(2-nitrovinyl)benzene (3.4 g, 13 mmol) in 50 mL THF was then added and the solution was stirred for 2 h. The mixture was warmed to r.t., quenched with sat. NH4Cl solution (50 mL), extracted with EtOAc, washed with brine, dried over MgSO4, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel to give 3.2 g of the desired product.
Reaction SMILES: Cl[C:2]1[N:7]([CH3:8])[C:6](=[N:9][C:10]2[C:15]([CH3:16])=[CH:14][C:13]([CH3:17])=[CH:12][C:11]=2[CH3:18])[CH:5]=[C:4]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([O:27][CH3:28])[CH:20]=2)[N:3]=1.[NH:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1>C(O)C>[CH3:28][O:27][C:21]1[CH:20]=[C:19]([C:4]2[N:3]=[C:2]([N:29]3[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]3)[N:7]([CH3:8])[C:6](=[N:9][C:10]3[C:15]([CH3:16])=[CH:14][C:13]([CH3:17])=[CH:12][C:11]=3[CH3:18])[CH:5]=2)[CH:24]=[CH:23][C:22]=1[O:25][CH3:26]
Reactant: C1CNCCN1
Reactant: COc1ccc(-c2cc(=Nc3c(C)cc(C)cc3C)n(C)c(Cl)n2)cc1OC
Solvent: CCO
Product: COc1ccc(-c2cc(=Nc3c(C)cc(C)cc3C)n(C)c(N3CCNCC3)n2)cc1OC
Temperature: 25 °C
Yield: 57.3 %

Procedure:
To a suspension of 2-chloro-3,4-dihydro-6-(3,4-dimethoxyphenyl)-3-methyl-4-(2,4,6-trimethylphenylimino)pyrimidine (1.07 g) in ethanol (10 ml) was added piperazine (0.70 g). The mixture was refluxed for 3 hours, cooled to ambient temperature. The mixture was evaporated, and the residue was dissolved in chloroform and washed with aqueous sodium bicarbonate solution. The organic layer was dried over magnesium sulfate and evaporated. The residue was chromatographed on silica gel using a mixture of chloroform and methanol (95:5) to give 3,4-dihydro-6-(3,4-dimethoxyphenyl)-3-methyl-2-(1-piperazinyl)-4-(2,4,6-trimethylphenylimino)pyrimidine (0.69 g).
Reaction SMILES: [NH2:1][C@:2]12[CH2:37][CH2:36][C@@H:35]([C:38]([CH3:40])=[CH2:39])[C@@H:3]1[C@@H:4]1[C@@:17]([CH3:20])([CH2:18][CH2:19]2)[C@@:16]2([CH3:21])[C@@H:7]([C@:8]3([CH3:34])[C@@H:13]([CH2:14][CH2:15]2)[C:12]([CH3:23])([CH3:22])[C:11]([C:24]2[CH:33]=[CH:32][C:27]([C:28]([O:30]C)=[O:29])=[CH:26][CH:25]=2)=[CH:10][CH2:9]3)[CH2:6][CH2:5]1.CN(C)CCC(N[C@]12CC[C@@H](C(C)=C)[C@@H]1[C@@H]1[C@@](C)(CC2)[C@@]2(C)[C@@H]([C@]3(C)[C@@H](CC2)C(C)(C)C(C2C=CC(C(O)=O)=CC=2)=CC3)CC1)=O.Cl.[CH3:88][N:89]([CH3:96])[CH2:90][CH2:91][CH2:92][C:93](O)=[O:94]>>[CH3:88][N:89]([CH3:96])[CH2:90][CH2:91][CH2:92][C:93]([NH:1][C@:2]12[CH2:37][CH2:36][C@@H:35]([C:38]([CH3:40])=[CH2:39])[C@@H:3]1[C@@H:4]1[C@@:17]([CH3:20])([CH2:18][CH2:19]2)[C@@:16]2([CH3:21])[C@@H:7]([C@:8]3([CH3:34])[C@@H:13]([CH2:14][CH2:15]2)[C:12]([CH3:23])([CH3:22])[C:11]([C:24]2[CH:33]=[CH:32][C:27]([C:28]([OH:30])=[O:29])=[CH:26][CH:25]=2)=[CH:10][CH2:9]3)[CH2:6][CH2:5]1)=[O:94]
Reactant: CN(C)CCCC(=O)O
Reactant: C=C(C)[C@@H]1CC[C@]2(N)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: C=C(C)[C@@H]1CC[C@]2(NC(=O)CCN(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
Agent: Cl
Product: C=C(C)[C@@H]1CC[C@]2(NC(=O)CCCN(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
Yield: 26 %

Procedure:
The title compound was prepared in 26% yield from methyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-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 following the same procedure as described for the preparation of 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(3-(dimethylamino)propanamido)-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, except 4-(dimethylamino)butyric acid hydrochloride was used instead of 3-(dimethylamino)propionic acid hydrochloride in Step 1. LCMS: m/e 643.4 (M+H)+, 4.19 min (method 8). 1H NMR (500 MHz, METHANOL-d4) δ=7.95 (d, J=8.2 Hz, 2H), 7.24 (d, J=8.5 Hz, 2H), 5.33 (dd, J=1.7, 6.3 Hz, 1H), 4.80 (d, J=1.5 Hz, 1H), 4.67 (s, 1H), 3.21-3.14 (m, 2H), 2.93 (s, 6H), 2.82-2.67 (m, 2H), 2.49 (t, J=6.9 Hz, 2H), 2.41 (dd, J=8.2, 12.2 Hz, 1H), 2.18 (dd, J=6.4, 17.1 Hz, 1H), 2.06-1.96 (m, 3H), 1.96-1.86 (m, 1H), 1.85-1.79 (m, 1H), 1.77 (br. s., 1H), 1.75 (s, 3H), 1.73-1.69 (m, 1H), 1.64-1.56 (m, 3H), 1.55-1.48 (m, 4H), 1.47-1.38 (m, 3H), 1.35 (d, J=12.2 Hz, 1H), 1.33-1.27 (m, 1H), 1.21-1.17 (m, 1H), 1.15 (s, 3H), 1.12 (d, J=3.4 Hz, 1H), 1.07 (s, 6H), 0.99 (s, 3H), 0.97 (s, 3H).
Reaction SMILES: [CH:1]1[C:6]([NH:7][NH2:8])=[CH:5][CH:4]=[C:3]([S:9]([NH2:12])(=[O:11])=[O:10])[CH:2]=1.Cl.[CH3:14][O:15][C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][CH:25]=1)[C:22](=O)[C:21](=[C:27](O)[C:28]([F:31])([F:30])[F:29])[CH2:20][CH2:19]2>C(O)C>[CH3:14][O:15][C:16]1[CH:25]=[CH:24][C:23]2[C:22]3[N:7]([C:6]4[CH:1]=[CH:2][C:3]([S:9]([NH2:12])(=[O:10])=[O:11])=[CH:4][CH:5]=4)[N:8]=[C:27]([C:28]([F:30])([F:29])[F:31])[C:21]=3[CH2:20][CH2:19][C:18]=2[CH:17]=1
Reactant: COc1ccc2c(c1)CCC(=C(O)C(F)(F)F)C2=O
Reactant: NNc1ccc(S(N)(=O)=O)cc1
Agent: Cl
Solvent: CCO
Product: COc1ccc2c(c1)CCc1c(C(F)(F)F)nn(-c3ccc(S(N)(=O)=O)cc3)c1-2
Reaction time: 16 h
Yield: 88.5 %

Procedure:
4-Sulfonamidophenylhydrazine hydrochloride (4.35 g, 19.4 mmol) was added to a stirred solution of 3,4-dihydro-6-methoxy-2-[2,2,2-trifluoro-1-hydroxyethylidene]-1(2H)-naphthalenone from Step 1 (5.06 g, 18.6 mmol) in ethanol (100 mL). The reaction was heated to reflux and stirred for 16 hours. The reaction mixture was filtered and washed with ethanol to give the desired pyrazole as a white solid (6.97 g, 88%): mp 277°-278° C.; 1H NMR (acetone d6) 300 MHz 8.09 (d, J=8.7 Hz, 2H) 7.80 (d, J=8.9 Hz, 2H) 7.00 (d, J=2.6 Hz, 1H) 6.78 (m, 3H) 6.69 (dd, J=8.7 Hz J=2.6 Hz, 1H) 3.81 (s, 3H) 3.04 (m, 2H) 2.84 (m, 2H); 19F NMR (acetone d6) 300 MHz -62.43 (s). Mass Spectrum M+ =423.0838.
Reaction SMILES: [N:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH:10]=O)=[CH:9][C:4]=2[NH:3][CH:2]=1.[NH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].CC(O)=O>>[NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][NH:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: Nc1ccccc1
Reactant: O=Cc1ccc2nc[nH]c2c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Product: c1ccc(NCc2ccc3[nH]cnc3c2)cc1

Procedure:
The compound was synthesized starting from benzimidazol-5-carbaldehyde (146 mg; 1 mmol; 1 eq.), aniline (0.095 ml; 1 mmol; 1 eq.), NaBH(AcO)3 (318 mg; 1.5 mmol; 1.5 eq.) and AcOH (0.095 ml; 1.5 mmol; 1.5 eq.) as described above. Yield: 0.160 g (71%); MS m/z: 224.3 [M+H]+; 1H-NMR (400 MHz, DMSO d6): δ 4.34-4.35 (m, 2H); 6.20.6.21 (m, 1H); 6.45-6.49 (m, 1H); 6.57-6.59 (m, 1H); 6.98-7.02 (m, 1H); 7.17-7.26 (m, 2H); 7.39-7.43 (m, 1H); 7.49-7.52 (m, 2H); 12.34-12.39 (br m, 1H); HPLC (METHOD [A]): rt 8.16 min (97.3%)
Reaction SMILES: C(N1CC[CH2:6][CH:5](CCN2C(OC)=NC3C2=NC(O[C@@H](C)CCC)=NC=3N)[CH2:4]1)C.[CH3:29][C@H:30]([O:34][C:35]1[N:43]=[C:42]2[C:38]([N:39]=[C:40]([O:51][CH3:52])[N:41]2[CH2:44][CH:45]2[CH2:50][CH2:49][NH:48][CH2:47][CH2:46]2)=[C:37]([NH2:53])[N:36]=1)[CH2:31][CH2:32][CH3:33].IC(C)C>>[CH3:29][C@H:30]([O:34][C:35]1[N:43]=[C:42]2[C:38]([N:39]=[C:40]([O:51][CH3:52])[N:41]2[CH2:44][CH:45]2[CH2:46][CH2:47][N:48]([CH:5]([CH3:6])[CH3:4])[CH2:49][CH2:50]2)=[C:37]([NH2:53])[N:36]=1)[CH2:31][CH2:32][CH3:33]
Reactant: CCC[C@H](C)Oc1nc(N)c2nc(OC)n(CCC3CCCN(CC)C3)c2n1
Reactant: CCC[C@H](C)Oc1nc(N)c2nc(OC)n(CC3CCNCC3)c2n1
Solvent: CC(C)I
Product: CCC[C@H](C)Oc1nc(N)c2nc(OC)n(CC3CCN(C(C)C)CC3)c2n1

Procedure:
Prepared similarly to Intermediate 46 from 2-{[(1S)-1-methylbutyl]oxy}-8-(methyloxy)-9-(4-piperidinylmethyl)-9H-purin-6-amine and 2-iodopropane.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([CH:12]([CH:20]2[CH2:24][CH2:23][CH2:22][CH2:21]2)[C:13]([O:15]C(C)(C)C)=[O:14])=[CH:8][CH:7]=1)(=[O:3])[CH3:2].FC(F)(F)C(O)=O>ClCCl>[C:1]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([CH:12]([CH:20]2[CH2:24][CH2:23][CH2:22][CH2:21]2)[C:13]([OH:15])=[O:14])=[CH:8][CH:7]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OCc1ccc(C(C(=O)OC(C)(C)C)C2CCCC2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)OCc1ccc(C(C(=O)O)C2CCCC2)cc1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 91 %

Procedure:
11.70 g (35.19 mmol) of tert-butyl [4-(acetoxymethyl)phenyl](cyclopentyl)acetate were dissolved in 108.5 ml of dichloromethane, the mixture was cooled to 0° C. and 39.2 ml of trifluoroacetic acid were added. The reaction mixture was stirred first at 0° C. for 1.5 h and then at RT for 1.5 h and then concentrated under reduced pressure. The residue was taken up in 50 ml of dichloromethane and the solution was washed four times with in each case 30 ml of water. The organic phase was dried over magnesium sulphate and concentrated under reduced pressure and the residue was dried under high vacuum. This gave 9.83 g of the target compound as a crude product (about 90% pure, yield 91% of theory).
Reaction SMILES: [OH:1][CH:2]([C:22]1[C:30]([CH2:31][O:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[CH:29][C:28]([CH3:39])=[C:27]2[C:23]=1[CH:24]=[CH:25][N:26]2[S:40]([C:43]1[CH:49]=[CH:48][C:46]([CH3:47])=[CH:45][CH:44]=1)(=[O:42])=[O:41])[C:3]1[N:7](COCC[Si](C)(C)C)[C:6]2[CH:16]=[CH:17][C:18]([C:20]#[N:21])=[CH:19][C:5]=2[N:4]=1.OC(C1C(COC2C=CC=CC=2)=CC(C)=C2C=1C=CN2S(C1C=CC(C)=CC=1)(=O)=O)C1N(COCC[Si](C)(C)C)C2C=C(C#N)C=CC=2N=1.B(F)(F)F.O(CC)CC>C(Cl)Cl>[OH:1][CH:2]([C:22]1[C:30]([CH2:31][O:32][C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)=[CH:29][C:28]([CH3:39])=[C:27]2[C:23]=1[CH:24]=[CH:25][N:26]2[S:40]([C:43]1[CH:44]=[CH:45][C:46]([CH3:47])=[CH:48][CH:49]=1)(=[O:41])=[O:42])[C:3]1[NH:7][C:6]2[CH:16]=[CH:17][C:18]([C:20]#[N:21])=[CH:19][C:5]=2[N:4]=1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(C(O)c4nc5cc(C#N)ccc5n4COCC[Si](C)(C)C)c(COc4ccccc4)cc(C)c32)cc1
Agent: Cc1ccc(S(=O)(=O)n2ccc3c(C(O)c4nc5ccc(C#N)cc5n4COCC[Si](C)(C)C)c(COc4ccccc4)cc(C)c32)cc1
Agent: FB(F)F
Solvent: CCOCC
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)n2ccc3c(C(O)c4nc5cc(C#N)ccc5[nH]4)c(COc4ccccc4)cc(C)c32)cc1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To a solution of (±)-2-(hydroxy(7-methyl-5-(phenoxymethyl)-1-tosyl-1H-indol-4-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-5-carbonitrile and (±)-2-(hydroxy(7-methyl-5-(phenoxymethyl)-1-tosyl-1H-indol-4-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-6-carbonitrile (160 mg, 0.231 mmol) in CH2Cl2 (2 mL) was added BF3—OEt2 (0.059 mL, 0.462 mmol) at 0° C., and then the mixture was stirred at room temperature for 2.5 h. The reaction was quenched by 7N NH3 in MeOH. The mixture was filtered off through SiO2. The SiO2 cake was washed with CH2Cl2/MeOH (c.a. 6/1). The combined organics were concentrated to give the title compound, without need of further purification. MS (ESI+) m/z 563.3 (M+H).