Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[S:3][C:4]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][N:6]=1.[CH2:11]([N:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH3:10][O:9][C:7]([C:4]1[S:3][C:2]([N:21]2[CH2:22][CH2:23][N:18]([CH2:11][C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH2:19][CH2:20]2)=[N:6][CH:5]=1)=[O:8]
Reactant: c1ccc(CN2CCNCC2)cc1
Reactant: COC(=O)c1cnc(Br)s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)c1cnc(N2CCN(Cc3ccccc3)CC2)s1
Temperature: 80 °C
Yield: 72.1 %

Procedure:
To a solution of methyl 2-bromothiazole-5-carboxylate 1 (222 mg, 1.00 mmol) in acetonitrile (20 mL) were added N-benzyl piperazine 14b (211 mg, 1.20 mmol) and potassium carbonate (152 mg, 1.10 mmol) under a N2 atmosphere. The reaction mixture was heated to reflux at 80° C. for 10 h. The reaction mixture was filtered through Celite and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography using silica gel to give the compound 15b (229 mg, 72.7%).
Reaction SMILES: [O:1]=[CH:2][C@@H:3]([C@H:5]([C@H:7]([CH2:9][OH:10])[OH:8])[OH:6])[OH:4].O=C[C@@H]([C@@H]([C@H]([C@H](C)O)O)O)O.O=C[C@@H]([C@H]([C@@H]([C@@H](CO)O)O)O)O.OCC([C@H]([C@@H]([C@@H](CO)O)O)O)=O.C(O)[C@H]1O[C@H](O[C@]2(CO)O[C@H](CO)[C@@H](O)[C@@H]2O)[C@H](O)[C@@H](O)[C@@H]1O.C(O)[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)[C@H](O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@@H]1O.C([O-])(=O)C.C([O-])(=O)CC.C([O-])(=O)CCC.C([O-])(=O)C(C)O.OC1C=CC(C([O-])=O)=CC=1.NCCC(O)=O.N[C@H](C(O)=O)CC1N=CNC=1>C(O)C>[O:1]=[CH:2][C@@H:3]([C@H:5]([C@@H:7]([CH2:9][OH:10])[OH:8])[OH:6])[OH:4]
Reactant: O=C[C@H](O)[C@@H](O)[C@@H](O)CO
Agent: CC(=O)[O-]
Agent: CC(O)C(=O)[O-]
Agent: CCC(=O)[O-]
Solvent: CCO
Product: O=C[C@H](O)[C@@H](O)[C@H](O)CO

Procedure:
L-arabinose; L-rhamnose; D-glucose; D-fructose; sucrose; cellobiose; acetate; propionate; butyrate; DL-lactate; ethanol; para-hydroxybenzoate; β-alanine; L-histidine.
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[C:19]([O:23][C:24](=[O:42])[NH:25][C:26]1[CH:31]=[CH:30][C:29]([C:32](C)(C)[O:33][SiH2]C(C)(C)C)=[C:28]([CH3:41])[N:27]=1)([CH3:22])([CH3:21])[CH3:20].O>C1COCC1>[C:19]([O:23][C:24](=[O:42])[NH:25][C:26]1[CH:31]=[CH:30][C:29]([CH2:32][OH:33])=[C:28]([CH3:41])[N:27]=1)([CH3:22])([CH3:21])[CH3:20]
Reactant: Cc1nc(NC(=O)OC(C)(C)C)ccc1C(C)(C)O[SiH2]C(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1nc(NC(=O)OC(C)(C)C)ccc1CO
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.6 %

Procedure:
Tetrabutylammonium fluoride (19.6 g, 62.4 mmol) was added to a solution of [5-(tert-butyl-dimethyl-silanyloxymethyl)-6-methyl-pyridin-2-yl]-carbamic acid tert-butyl ester (10.5 g, 31.23 mmol) in THF (100 mL) and stirred at room temperature overnight. Water was added and the product extracted with chloroform. The organic phase was dried and concentrated under reduced pressure. Flash chromatography (MeOH/CH2Cl2, 2.5:77.5) gave (5-hydroxymethyl-6-methyl-pyridin-2-yl)-carbamic acid tert-butyl ester (6.0 g, 81%).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].C[C:8]1[C:14](=O)[C:13]2N3[C@@:20](OC)([C@H:21](COC(N)=O)[C:12]=2[C:10](=O)[C:9]=1OC)[C@H:19]1[NH:29][C@H]1C3>>[C:12]1([CH:21]2[CH2:20][CH:19]2[NH2:29])[CH:10]=[CH:9][CH:8]=[CH:14][CH:13]=1
Reactant: COC1=C(C)C(=O)C2=C(C1=O)[C@@H](COC(N)=O)[C@@]1(OC)[C@H]3N[C@H]3CN21
Agent: O=C([O-])[O-]
Agent: [K+]
Product: NC1CC1c1ccccc1

Procedure:
This compound was prepared by the procedure described in Example 1, except that the potassium carbonate was omitted. From 125 mg. of mitomycin A and 85 mg. of 2-phenylcyclopropylamine was obtained 70 mg. (63%) of the desired product decomposing at temperatures above 250° C. and providing the following analysis:
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=O)[C:5]([OH:11])=[CH:4][CH:3]=1.[CH3:12][C:13]([C:16]1[CH:17]=[C:18]([CH:20]=[C:21]([C:23]([CH3:26])([CH3:25])[CH3:24])[CH:22]=1)[NH2:19])([CH3:15])[CH3:14]>>[CH3:15][C:13]([C:16]1[CH:17]=[C:18]([NH:19][C:7](=[O:9])[C:6]2[CH:10]=[C:2]([Br:1])[CH:3]=[CH:4][C:5]=2[OH:11])[CH:20]=[C:21]([C:23]([CH3:26])([CH3:25])[CH3:24])[CH:22]=1)([CH3:12])[CH3:14]
Reactant: CC(C)(C)c1cc(N)cc(C(C)(C)C)c1
Reactant: O=C(O)c1cc(Br)ccc1O
Product: CC(C)(C)c1cc(NC(=O)c2cc(Br)ccc2O)cc(C(C)(C)C)c1
Yield: 45.2 %

Procedure:
Using 5-bromosalicylic acid and 3,5-bis[(1,1-dimethyl)ethyl]aniline as the raw materials, the same operation as the example 16 gave the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[N:12][N:13]=[CH:14][C:15]1[NH:19][C:18]([CH3:20])=[C:17]([C:21]([NH:23][CH2:24][CH2:25][CH2:26][CH2:27][C:28](O)=[O:29])=[O:22])[C:16]=1[CH3:31].Cl.C(N=C=NCCCN(C)C)C.OC1C2N=NNC=2C=CC=1.C(N(CC)CC)C.[F:61][C:62]1[CH:67]=[CH:66][C:65]([NH2:68])=[C:64]([NH2:69])[CH:63]=1>[Cl-].[Na+].O.CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[N:12][N:13]=[CH:14][C:15]1[NH:19][C:18]([CH3:20])=[C:17]([C:21]([NH:23][CH2:24][CH2:25][CH2:26][CH2:27][C:28]([NH:68][C:65]2[CH:66]=[CH:67][C:62]([F:61])=[CH:63][C:64]=2[NH2:69])=[O:29])=[O:22])[C:16]=1[CH3:31]
Reactant: Cc1[nH]c(C=NN=C2C(=O)Nc3ccc(F)cc32)c(C)c1C(=O)NCCCCC(=O)O
Reactant: Nc1ccc(F)cc1N
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1[nH]c(C=NN=C2C(=O)Nc3ccc(F)cc32)c(C)c1C(=O)NCCCCC(=O)Nc1ccc(F)cc1N
Temperature: 25 °C
Reaction time: 24 h
Yield: 82 %

Procedure:
5-(5-(((5-fluoro-2-oxoindolin-3-ylidene)hydrazono)methyl)-2,4-dimethyl-1H-pyrrole-3-carboxamido)-pentanoic acid (427 mg, 1 mmol), and 8 ml of DMF were stirred at room temperature while 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (394 mg, 2 mmol), hydroxy-benzotriazole (162 mg, 1.2 mmol), triethylamine (404 mg, 4 mmol) and 4-fluoro-o-phenylenediamine (151 mg, 1.2 mmol) were added. The mixture was stirred for 24 hours at room temperature. The mixture was diluted with 400 mL of brine. The solids were collected by vacuum filtration, washed with water and dried under vacuum to give the title compound (439 mg, 82% yield) as a red solid. LC-MS (m/z) 536 (M+1).
Reaction SMILES: [NH:1]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19][NH:18][CH2:17][CH2:16][NH:15][CH2:14][CH2:13][NH:12][CH2:11][CH2:10][CH2:9][NH:8][CH2:7][CH2:6][NH:5][CH2:4][CH2:3][CH2:2]1.[F:24][C:25]([OH2+])([F:27])[F:26]>>[F:24][C:25]([F:27])([F:26])[N:1]1[CH2:23][CH2:22][N:21]([C:25]([F:27])([F:26])[F:24])[CH2:20][CH2:19][N:18]([C:25]([F:27])([F:26])[F:24])[CH2:17][CH2:16][N:15]([C:25]([F:27])([F:26])[F:24])[CH2:14][CH2:13][N:12]([C:25]([F:27])([F:26])[F:24])[CH2:11][CH2:10][CH2:9][N:8]([C:25]([F:27])([F:26])[F:24])[CH2:7][CH2:6][N:5]([C:25]([F:27])([F:26])[F:24])[CH2:4][CH2:3][CH2:2]1
Reactant: C1CNCCNCCCNCCNCCNCCNCCNC1
Reactant: [OH2+]C(F)(F)F
Product: FC(F)(F)N1CCCN(C(F)(F)F)CCN(C(F)(F)F)CCN(C(F)(F)F)CCN(C(F)(F)F)CCN(C(F)(F)F)CCCN(C(F)(F)F)CC1
Yield: 50.2 %

Procedure:
8 g (0.024 mol) of 1,5,8,12,15,18,21-Heptaazacyclotricosane and 90.9 g (0.168 mol) of the trifluoromethyl oxonium salt were refluxed in an argon atmosphere for 3 hours to produce 9.7 g of 1,5,8,12,15,18,21-Heptakis(trifluoromethyl)-1,5,8,12,15,18,21-heptaazacyclotricosane represented by Formula 12 below.
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]([CH3:15])[C:12](Cl)=[O:13])=[CH:7][CH:6]=1)[CH:2]([CH3:4])[CH3:3].[CH3:16][C:17]1[CH:24]=[CH:23][C:20]([CH2:21][OH:22])=[CH:19][CH:18]=1.CN(C)C.O>O1CCCC1>[CH3:16][C:17]1[CH:24]=[CH:23][C:20]([CH2:21][O:22][C:12](=[O:13])[CH:11]([C:8]2[CH:9]=[CH:10][C:5]([CH2:1][CH:2]([CH3:4])[CH3:3])=[CH:6][CH:7]=2)[CH3:15])=[CH:19][CH:18]=1
Reactant: Cc1ccc(CO)cc1
Reactant: CC(C)Cc1ccc(C(C)C(=O)Cl)cc1
Agent: CN(C)C
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc(COC(=O)C(C)c2ccc(CC(C)C)cc2)cc1
Yield: 84.5 %

Procedure:
To a solution of 5.4 g of 2-(4-isobutylphenyl)propionic acid chloride and 3.5 g of p-methylbenzyl alcohol in 30 ml of tetrahydrofuran was added 3.7 g of trimethylamine, dropwise under cooling, and reacted at room temperature for 2 hours. After the reaction was complete, the crystals produced were removed by filtration. The filtrate was freed of solvent by distillation to leave a residue, to which was added water. The resulting mixture was extracted with ether, and the extract was dehydrated and freed of solvent by distillation to give an oily residue. This residue was then distilled in vacuo to yield 6.3 g of 2-(4-isobutylphenyl)propionic acid-p-methylbenzyl ester as a colorless oil, boiling at 139°-140° C./0.1 mmHg. Mass spectrum: parent ion 310 m/e.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][C:8]([NH:10][C:11]2[CH:24]=[CH:23][C:22]3[NH:21][C:20]4[C:15](=[CH:16][C:17]([NH:25][C:26](=[O:34])[CH2:27][CH2:28][N:29]5[CH2:33][CH2:32][CH2:31][CH2:30]5)=[CH:18][CH:19]=4)[C:14](=O)[C:13]=3[CH:12]=2)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.O=P(Cl)(Cl)[Cl:38]>C(OCC)C>[Cl:38][C:14]1[C:15]2[C:20]([N:21]=[C:22]3[C:13]=1[CH:12]=[C:11]([NH:10][C:8](=[O:9])[CH2:7][CH2:6][N:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1)[CH:24]=[CH:23]3)=[CH:19][CH:18]=[C:17]([NH:25][C:26](=[O:34])[CH2:27][CH2:28][N:29]1[CH2:33][CH2:32][CH2:31][CH2:30]1)[CH:16]=2
Reactant: O=C(CCN1CCCC1)Nc1ccc2[nH]c3ccc(NC(=O)CCN4CCCC4)cc3c(=O)c2c1
Reactant: O=P(Cl)(Cl)Cl
Solvent: CCOCC
Product: O=C(CCN1CCCC1)Nc1ccc2nc3ccc(NC(=O)CCN4CCCC4)cc3c(Cl)c2c1

Procedure:
2,7-Bisamidoacridone BR-ACO-16 (1 g, 2.1 mmol) was treated with refluxing POCl3 for 3 hr. The reaction was cooled, and anhydrous diethyl ether was added to precipitate product. Solids were filtered from solution to give the desired product JM-ACI-43 (750 mg, 72%) as a yellow solid.
Reaction SMILES: [C:1]1([S:7]([C:10]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([Cl:19])[CH:17]=3)[NH:12][C:11]=2[C:20]([O:22]CC)=O)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl-].[NH4+:26]>[OH-].[NH4+]>[C:1]1([S:7]([C:10]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([Cl:19])[CH:17]=3)[NH:12][C:11]=2[C:20]([NH2:26])=[O:22])(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: [NH4+]
Reactant: CCOC(=O)c1[nH]c2ccc(Cl)cc2c1S(=O)(=O)c1ccccc1
Agent: [Cl-]
Agent: [OH-]
Product: NC(=O)c1[nH]c2ccc(Cl)cc2c1S(=O)(=O)c1ccccc1
Temperature: 100 °C

Procedure:
A suspension of ethyl 3-phenylsulfonyl-5-chloroindole-2-carboxylate (596 mg, 1.64 mmol) in aqueous conc. ammonium hydroxide (10 mL) containing ammonium chloride (28 mg) was heated at 100° C. for 3 hours in a sealed screw-top tube. The sealed tube was cooled in an ice bath as product crystallized out. The product was collected by filtration, rinsed with ice water, and dried to give the product, mp 253°-254° C.
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:5][C:6]=1[C:7](OCC)=[O:8].[H-].[Al+3].[Li+].[H-].[H-].[H-].Cl.O>O1CCCC1>[CH3:1][C:2]1[O:3][C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:5][C:6]=1[CH2:7][OH:8]
Reactant: CCOC(=O)c1cc(-c2ccccc2)oc1C
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1oc(-c2ccccc2)cc1CO
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 100.9 %

Procedure:
A solution of ethyl 2-methyl-5-phenyl-3-furancarboxylate (5.7 g) in tetrahydrofuran (30 mL) was added dropwise to a suspension of lithium aluminum hydride (1.0 g) in tetrahydrofuran (30 mL) at 0° C. and, after the completion of the dropwise addition, the mixture was stirred at 0° C. for 30 min. The reaction mixture was treated with 1N hydrochloric acid, poured into water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure to give the title compound (4.7 g, 100%) as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:29]2[NH:33][N:32]=[N:31][N:30]=2)[N:5]([C:7]2[CH:28]=[CH:27][C:10]([CH2:11][N:12]3[C:16]4=[N:17][CH:18]=[CH:19][C:20]([CH3:21])=[C:15]4[N:14]=[C:13]3S(CC)(=O)=O)=[CH:9][CH:8]=2)[CH:6]=1.[O-:34][CH2:35][CH3:36].[Na+].Cl(O)(=O)=O>C(O)C.ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([C:29]2[NH:30][N:31]=[N:32][N:33]=2)[N:5]([C:7]2[CH:8]=[CH:9][C:10]([CH2:11][N:12]3[C:16]4=[N:17][CH:18]=[CH:19][C:20]([CH3:21])=[C:15]4[N:14]=[C:13]3[O:34][CH2:35][CH3:36])=[CH:27][CH:28]=2)[CH:6]=1
Reactant: CCS(=O)(=O)c1nc2c(C)ccnc2n1Cc1ccc(-n2cc(Cl)cc2-c2nnn[nH]2)cc1
Reactant: CC[O-]
Agent: [Na+]
Agent: [O-][Cl+2]([O-])O
Solvent: ClCCl
Solvent: CCO
Product: CCOc1nc2c(C)ccnc2n1Cc1ccc(-n2cc(Cl)cc2-c2nnn[nH]2)cc1

Procedure:
To a stirred solution of 3-[4-[4-chloro-2-(1H-tetrazol-5-yl)-1-pyrrolyl]benzyl]-2-ethylsulfonyl-7-methyl-3H-imidazo[4,5-b]pyridine (209 mg) in ethanol(2 ml) was added 1N sodium ethoxide solution in ethanol (1.02 ml) and dichloromethane(30 ml) at room temperature and the resulting mixture was heated under reflux for two hours. After cooling, the mixture was treated with 7% aqueous hydrogenchloric acid and the organic phase was washed with water and dried over anhydrous magnesium sulfute. After filtration the solvent was removed in vauo and the residue was purified by preparative thin layer chromatography eluting with dichloromethane-methanol(8:1 v/v) to give 3-[4-[4-chloro-2-(1H-tetrazol-5-yl)-1-pyrrolyl]benzyl]-2-ethoxy-7-methyl-3H-imidazo[4,5-b]pyridine(97 mg) as a amorphous solid which was powderized by treating with diethylether.
Reaction SMILES: [C:1]([C:3]([C:6]1[CH:7]=[C:8]([CH:29]=[CH:30][CH:31]=1)[C:9]([NH:11][C:12]1[CH:17]=[CH:16][C:15]([CH3:18])=[C:14]([O:19][C:20]2[CH:21]=[N:22][C:23]([N+:26]([O-])=O)=[CH:24][CH:25]=2)[CH:13]=1)=[O:10])([CH3:5])[CH3:4])#[N:2]>CO.[C].[Pd]>[NH2:26][C:23]1[N:22]=[CH:21][C:20]([O:19][C:14]2[CH:13]=[C:12]([NH:11][C:9](=[O:10])[C:8]3[CH:29]=[CH:30][CH:31]=[C:6]([C:3]([C:1]#[N:2])([CH3:5])[CH3:4])[CH:7]=3)[CH:17]=[CH:16][C:15]=2[CH3:18])=[CH:25][CH:24]=1
Reactant: Cc1ccc(NC(=O)c2cccc(C(C)(C)C#N)c2)cc1Oc1ccc([N+](=O)[O-])nc1
Agent: [Pd]
Solvent: CO
Product: Cc1ccc(NC(=O)c2cccc(C(C)(C)C#N)c2)cc1Oc1ccc(N)nc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 78.1 %

Procedure:
To a solution of 3-(1-cyano-1-methylethyl)-N-{4-methyl-3-[(6-nitropyridin-3-yl)oxy]phenyl}benzamide (6.68 g, 16.0 mmol) in methanol (150 mL) was added 10% palladium-carbon (850 mg), and the mixture was stirred at room temperature for 16 hr under a hydrogen atmosphere (2.0 atm). The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was recrystallized from ethyl acetate and hexane to give the title compound (4.83 g, 78%) as colorless crystals.
Reaction SMILES: [CH2:1]([N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[NH:10][C:9]1=[NH:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:18]([O:20][C:21](=[O:33])[C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH2:29][CH2:30][CH2:31]Cl)[CH:23]=1)[CH3:19]>CC(=O)CC>[CH2:18]([O:20][C:21](=[O:33])[C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH2:29][CH2:30][CH2:31][N:10]2[C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:8]([CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[C:9]2=[NH:17])[CH:23]=1)[CH3:19]
Reactant: CCOC(=O)c1cccc(OCCCCl)c1
Reactant: N=c1[nH]c2ccccc2n1Cc1ccccc1
Solvent: CCC(C)=O
Product: CCOC(=O)c1cccc(OCCCn2c(=N)n(Cc3ccccc3)c3ccccc32)c1
Temperature: 85 °C
Yield: 74.1 %

Procedure:
To a solution of 1-benzyl-1,3-dihydro-benzoimidazol-2-ylideneamine (247 mg, 1.10 mmol) in 2-butanone (40 ml) was added 3-(3-chloro-propoxy)-benzoic acid ethyl ester (0.40 g, 1.65 mmol) and KI (0.55 g, 3.32 mmol). The reaction was heated to 85° C. where it was maintained for 54 h. After this time, the mixture was cooled to rt and filtered. The filtrate was concentrated under reduced pressure and combined with the collected solid, washed with diethyl ether and petroleum ether and dried to provide 3-[3-(3-benzyl-2-imino-2,3-dihydro-benzoimidazol-1-yl)-propoxy]-benzoic acid ethyl ester (350 mg, 74%). HPLC-MS 430 [M+1]+.
Reaction SMILES: C1CO[C:3]2([CH2:20][CH2:19][C@@:18]3([CH3:21])[CH:5]([C@@H:6]([CH2:31][OH:32])[C:7](=[O:30])[C@@H:8]4[C@@H:17]3[CH2:16][CH2:15][C@@:13]3([CH3:14])[C@H:9]4[CH2:10][CH2:11][C@@H:12]3[O:22][Si](C(C)(C)C)(C)C)[C:4]2([CH3:34])[CH3:33])[O:2]1>CO>[CH3:33][C:4]1([CH3:34])[C:3](=[O:2])[CH2:20][CH2:19][C@@:18]2([CH3:21])[CH:5]1[C@@H:6]([CH2:31][OH:32])[C@@H:7]([OH:30])[C@@H:8]1[C@@H:17]2[CH2:16][CH2:15][C@@:13]2([CH3:14])[C@H:9]1[CH2:10][CH2:11][C@@H:12]2[OH:22]
Reactant: CC1(C)C2[C@@H](CO)C(=O)[C@H]3[C@@H]4CC[C@H](O[Si](C)(C)C(C)(C)C)[C@@]4(C)CC[C@@H]3[C@@]2(C)CCC12OCCO2
Solvent: CO
Product: CC1(C)C(=O)CC[C@@]2(C)C1[C@@H](CO)[C@@H](O)[C@H]1[C@@H]3CC[C@H](O)[C@@]3(C)CC[C@@H]12
Temperature: 25 °C
Reaction time: 1 h
Yield: 76 %

Procedure:
To a stirred solution of 3,3-(ethylenedioxy)-4,4-dimethyl-6α-hydroxymethyl-17β-tert-butyldimethylsilyloxyandrostan-7-one (Preparation 9—Step 5, 1.0 g) in MeOH (40 ml) NaBH4 (140 mg) was added at 0° C. and the mixture was warmed to RT. After 1 h the mixture was quenched by addition of 5% NaH2PO4 and extracted with DCM. The combined organic extracts were washed with brine, dried over Na2SO4 and evaporated to dryness. The residue was dissolved in dioxane (20 ml) and 1N HCl (10 ml) was added. The resulting mixture was stirred at RT for 1 h and evaporated to dryness. The residue was purified by flash chromatography (SiO2, n-hexane/AcOEt 25/75) to give 4,4-dimethyl-6α-hydroxymethyl-7α,17β-dihydroxyandrostan-3-one in 76% yield.
Reaction SMILES: [C:1]1(=[O:16])[N:5]([CH2:6][CH2:7][CH2:8][CH:9]=O)[C:4](=[O:11])[C:3]2=[CH:12][CH:13]=[CH:14][CH:15]=[C:2]12.[CH3:17][O:18][C:19]1[CH:28]=[C:27]2[C:22]([CH2:23][CH2:24][NH:25][CH2:26]2)=[CH:21][CH:20]=1>>[CH3:17][O:18][C:19]1[CH:28]=[C:27]2[C:22]([CH2:23][CH2:24][N:25]([CH2:9][CH2:8][CH2:7][CH2:6][N:5]3[C:4](=[O:11])[C:3]4=[CH:12][CH:13]=[CH:14][CH:15]=[C:2]4[C:1]3=[O:16])[CH2:26]2)=[CH:21][CH:20]=1
Reactant: O=CCCCN1C(=O)c2ccccc2C1=O
Reactant: COc1ccc2c(c1)CNCC2
Product: COc1ccc2c(c1)CN(CCCCN1C(=O)c3ccccc3C1=O)CC2

Procedure:
Prepared from 4-phthalimidobutyraldehyde (15.96 g, 0.074 mol) and 7-methoxy-1,2,3,4-tetrahydroisoquinoline (10 g, 0.061 mol) using a procedure similar to that of Example 1 (13.5 g, 60%).
Reaction SMILES: Cl[C:2]1[C:3]2[NH:10][C:9]([CH3:11])=[C:8]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:4]=2[N:5]=[CH:6][N:7]=1.[CH:17]1([CH2:20][O:21][C:22]2[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:23]=2B2OC(C)(C)C(C)(C)O2)[CH2:19][CH2:18]1>>[CH:17]1([CH2:20][O:21][C:22]2[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:23]=2[C:2]2[C:3]3[NH:10][C:9]([CH3:11])=[C:8]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:4]=3[N:5]=[CH:6][N:7]=2)[CH2:18][CH2:19]1
Reactant: CCOC(=O)c1c(C)[nH]c2c(Cl)ncnc12
Reactant: CC1(C)OB(c2ccc(F)cc2OCC2CC2)OC1(C)C
Product: CCOC(=O)c1c(C)[nH]c2c(-c3ccc(F)cc3OCC3CC3)ncnc12

Procedure:
Starting from ethyl 4-chloro-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylate (example A4) and 2-(2-cyclopropylmethoxy-4-fluoro-phenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (example B.c3) the title compound is obtained as off-white solid.
Reaction SMILES: [CH3:1][N:2]([CH3:26])[C:3]1[CH:4]=[C:5]([CH:9]=[C:10](/[CH:12]=[CH:13]/[C:14]2[CH:19]=[C:18]([CH3:20])[C:17]([O:21][CH2:22][O:23][CH3:24])=[C:16]([CH3:25])[CH:15]=2)[CH:11]=1)[C:6]([OH:8])=O.C1CCC(N=C=NC2CCCCC2)CC1.[F:42][C:43]1[CH:48]=[CH:47][C:46]([SH:49])=[CH:45][CH:44]=1>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:1][N:2]([CH3:26])[C:3]1[CH:4]=[C:5]([CH:9]=[C:10](/[CH:12]=[CH:13]/[C:14]2[CH:15]=[C:16]([CH3:25])[C:17]([O:21][CH2:22][O:23][CH3:24])=[C:18]([CH3:20])[CH:19]=2)[CH:11]=1)[C:6](=[O:8])[S:49][C:46]1[CH:47]=[CH:48][C:43]([F:42])=[CH:44][CH:45]=1
Reactant: COCOc1c(C)cc(/C=C/c2cc(C(=O)O)cc(N(C)C)c2)cc1C
Reactant: Fc1ccc(S)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: COCOc1c(C)cc(/C=C/c2cc(C(=O)Sc3ccc(F)cc3)cc(N(C)C)c2)cc1C
Reaction time: 18 h

Procedure:
To a solution of Compound 5 (80 mg, 0.225 mmol) in DCM (3 mL) were added DCC (70 mg, 0.338 mmol), DMAP (5.5 mg, 0.045 mmol), and 4-fluorobenzenethiol (37 μL, 0.338 mmol) at room temperature. The reaction mixture was stirred overnight (about 18 hours) and filtered through Celite. The filtrate was washed with brine, and dried with Na2SO4. The solution was filtered and concentrated. The residue was subjected to chromatography over silica gel (Hexanes/EtOAc=8/1) to give (E)-S-4-fluorophenyl 3-(dimethylamino)-5-(4-(methoxymethoxy)-3,5-dimethylstyryl)benzothioate.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]#[N:11])=[CH:4][C:3]=1[CH2:12][OH:13].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]#[N:11])=[CH:4][C:3]=1[CH:12]=[O:13]
Reactant: N#CCCc1ccc(Cl)c(CO)c1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: N#CCCc1ccc(Cl)c(C=O)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 3-[4-chloro-3-(hydroxymethyl)phenyl]propanenitrile from the previous step (1 eq.) in CH2Cl2 (0.1 M) was added Dess-Martin periodinane (1.1 eq.) portionwise. The resulting suspension was stirred at RT for 2 h. The reaction was quenched with MeOH and H2O. The organic layer was separated and the aqueous layer was back-extracted with EtOAc. The combined organic extracts were washed sat. aq. NaHCO3 and brine, dried over Na2SO4 and filtered. Concentration of the filtrate in vacuo afforded the title compound as a pale yellow oil.
Reaction SMILES: [S:1]1[CH2:5][CH2:4][CH:3]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][N:11]2C(=O)C3C(=CC=CC=3)C2=O)[S:2]1.[Cl:22][CH2:23][S:24](Cl)(=[O:26])=[O:25]>C1(C)C=CC=CC=1.CO.C(N)CCC.O1CCCC1.C(N(CC)CC)C>[Cl:22][CH2:23][S:24]([NH:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH:3]1[CH2:4][CH2:5][S:1][S:2]1)(=[O:26])=[O:25]
Reactant: O=C1c2ccccc2C(=O)N1CCCCCC1CCSS1
Reactant: O=S(=O)(Cl)CCl
Solvent: Cc1ccccc1
Solvent: CCCCN
Solvent: CO
Product: O=S(=O)(CCl)NCCCCCC1CCSS1

Procedure:
The reaction was carried out as described in Example 60, but using 3 ml of a solution of 1.6 mmol of 2-[5-(1,2-dithiolan-3-yl)pentyl]isoindoline-1,3-dione (prepared as described in Example 58) in toluene, 2 ml of methanol, 2 ml of butylamine, 5 ml of anhydrous tetrahydrofuran, 0.33 ml of triethylamine and 0.21 ml of chloromethanesulfonyl chloride. The solvent was removed from the reaction mixture by evaporation under reduced pressure, and water was added to the residue, after which it was extracted with ethyl acetate. The extraction solution was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. The ethyl acetate was removed from the extraction solution by evaporation under reduced pressure, and the residue was subjected to silica gel column chromatography, using 2:5 and 2:3 by volume mixtures of ethyl acetate and hexane as the eluent. The ethyl acetate was removed from the eluate solution by evaporation under reduced pressure, and the residue was dissolved in dioxane and then lyophilised, to obtain 42 mg of the title compound as a brown oil having an Rf value of 0.29 (silica gel thin layer chromatography; using a 2:5 by volume mixture of ethyl acetate and hexane as developing solvent).
Reaction SMILES: [CH3:1][N:2]1[CH2:25][CH2:24][C:5]2[N:6]([CH2:14][CH:15]([C:17]3[CH:18]=[N:19][C:20]([CH3:23])=[CH:21][CH:22]=3)O)[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.S(=O)(=O)(O)O.[OH-].[K+]>>[CH3:1][N:2]1[CH2:25][CH2:24][C:5]2[N:6](/[CH:14]=[CH:15]/[C:17]3[CH:18]=[N:19][C:20]([CH3:23])=[CH:21][CH:22]=3)[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1
Reactant: Cc1ccc2c(c1)c1c(n2CC(O)c2ccc(C)nc2)CCN(C)C1
Agent: O=S(=O)(O)O
Agent: [K+]
Agent: [OH-]
Product: Cc1ccc2c(c1)c1c(n2/C=C/c2ccc(C)nc2)CCN(C)C1
Temperature: 5 °C

Procedure:
2-(1,2,3,4-Tetrahydro-2,8-dimethylpyrido[4,3-b]indol-5-yl)-1-(6-methylpyridin-3-yl)ethanol (1 g, 2.98 mmol, 1 eq) was refluxed with 25% sulfuric acid (7 mL) for 2 h. The reaction mixture was cooled to 5° C. with an ice-water bath. KOH (15% aq. solution) was added dropwise to the reaction mixture until pH 9-10 was achieved. The reaction mixture was extracted with EtOAc (3×10 mL). The combined organic layers were washed with water (10 mL) followed by brine, dried over sodium sulfate and evaporated under vacuum. The crude product was purified by column chromatography over silica gel (100-200 mesh) using a gradient of MeOH-EtOAc (0-10%). 1H NMR (CD3OD, TFA salt) δ (ppm): 8.8 (s, 1H), 8.55 (d, 1H), 7.95 (d, 1H), 7.75 (m, 2H), 7.35 (s, 1H), 7.28 (d, 1H), 7.0 (d, 1H), 4.8 (bs, 1H), 4.4 (bs, 1H), 3.9 (bs, 1H), 3.6 (bs, 1H), 3.4 (t, 2H), 3.15 (s, 3H), 2.75 (s, 3H), 2.45 (s, 3H).