Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:14])[NH:7][C:8]([CH2:12]Cl)=[N:9]2)=[CH:4][C:3]=1[CH3:15].[C:16]([O-:19])(=[O:18])[CH3:17].[Cs+]>CN(C=O)C>[C:16]([O:19][CH2:12][C:8]1[NH:7][C:6](=[O:14])[C:5]2[C:10](=[CH:11][C:2]([Cl:1])=[C:3]([CH3:15])[CH:4]=2)[N:9]=1)(=[O:18])[CH3:17]
Reactant: CC(=O)[O-]
Reactant: Cc1cc2c(=O)[nH]c(CCl)nc2cc1Cl
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(=O)OCc1nc2cc(Cl)c(C)cc2c(=O)[nH]1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A mixture of 7-chloro-2-chloromethyl-6-methyl-3,4-dihydroquinazolin-4-one (0.500 g, 2.06 mmol), anhydrous DMF (14 ml) and cesium acetate (1.58 g, 8.24 mmol) was placed in an oil bath preheated to 85° C., then stirred at this temperature for 2 hours and 15 min under argon. The reaction mixture was then allowed to cool to room temperature and the solvent was removed in vacuo. The residue was treated with hexanes (20 ml), collected by filtration, washed with hexanes (20 ml), water, and dried in vacuo over P2O5 (0.476 g, 87%), mp 220-225° C., 1H-NMR (DMSO-d6) 2.14 (s, 3H, CH3CO), 2.45 (s, 3H, 6-CH3), 4.95 (s, 2H, 2-CH2O), 7.70, 8.06 (2×s, 2H, 5-H and 8-H), 12.44 (s, 1H, N3—H).
Reaction SMILES: [CH3:1][C:2]1[C:15]2[N:14]([CH2:16][CH2:17][CH2:18][NH2:19])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[S:7](=[O:20])[C:6]=2[CH:5]=[CH:4][C:3]=1[CH3:21].[CH:22](=O)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.O>C1(C)C=CC=CC=1>[CH3:1][C:2]1[C:15]2[N:14]([CH2:16][CH2:17][CH2:18][NH:19][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[S:7](=[O:20])[C:6]=2[CH:5]=[CH:4][C:3]=1[CH3:21]
Reactant: O=Cc1ccccc1
Reactant: Cc1ccc2c(c1C)N(CCCN)c1ccccc1S2=O
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1ccc2c(c1C)N(CCCNCc1ccccc1)c1ccccc1S2=O
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 97.4 %

Procedure:
A solution of 1.5 g of 1,2-dimethyl-10-(3-aminopropyl)phenothiazine-5-oxide obtained in Example 8 and 580 mg of benzaldehyde in 60 ml of toluene was stirred under reflux for 2 hr while using a water separator. Then the mixture was cooled to room temperature and the solvent was evaporated under reduced pressure. After adding 60 ml of ethanol and sodium borohydride successively, the reaction mixture was stirred under ice cooling for 10 min. After adding water, the mixture was extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was washed with diethyl ether to give 1.9 g of the title compound.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[Cl:7][C:8]1[S:12][C:11]([C:13](O)=[O:14])=[CH:10][C:9]=1[N+:16]([O-:18])=[O:17].[N-:19]=[N+:20]=[N-:21].[Na+]>ClCCl.C(OCC)(=O)C>[Cl:7][C:8]1[S:12][C:11]([C:13]([N:19]=[N+:20]=[N-:21])=[O:14])=[CH:10][C:9]=1[N+:16]([O-:18])=[O:17]
Reactant: O=C(O)c1cc([N+](=O)[O-])c(Cl)s1
Reactant: [N-]=[N+]=[N-]
Agent: O=C(Cl)C(=O)Cl
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: [N-]=[N+]=NC(=O)c1cc([N+](=O)[O-])c(Cl)s1
Temperature: 25 °C
Reaction time: 4 h
Yield: 59.5 %

Procedure:
oxalyl chloride (460 mg, 3.62 mmol) followed by N,N-dimethylformide (0.05 mL) was added to a solution of 5-chloro-4-nitrothiophene-2-carboxylic acid (1.0 g, 14.0 mmol) in dichloromethane (20 mL) under nitrogen atmosphere and the resulting mixture was stirred at ambient temperature for 4 hours. TLC analysis showed no acid remaining so the mixture was allowed to be concentrated in vacuo. The resulting acid chloride was dissolved in dry tetrahydrofuran (10 mL). Sodium azide (190 mg, 2.89 mmol) was added to the above solution. The resulting mixture was stirred at ambient temperature for 10 hours. After this time, TLC analysis showed no acid chloride remaining so the mixture was diluted with ethyl acetate and washed with water and brine. The organic layer was separated, dried (Na2SO4), filtered and the solvent was removed to afford the title product as a brown solid (400 mg, 59% yield). 1H NMR (400 MHz, d6-DMSO) δ: 8.23 (2H, s).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH3:15])=[N:5][CH:6]=[CH:7][C:8]=1[N:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.C(N(CC)CC)C.[CH3:23][CH:24]([CH3:30])/[CH:25]=[CH:26]/[C:27](Cl)=[O:28]>ClCCl>[CH3:1][O:2][C:3]1[C:4]([CH3:15])=[N:5][CH:6]=[CH:7][C:8]=1[N:9]1[CH2:10][CH2:11][N:12]([C:27](=[O:28])/[CH:26]=[CH:25]/[CH:24]([CH3:30])[CH3:23])[CH2:13][CH2:14]1
Reactant: CC(C)/C=C/C(=O)Cl
Reactant: COc1c(N2CCNCC2)ccnc1C
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1c(N2CCN(C(=O)/C=C/C(C)C)CC2)ccnc1C
Yield: 7 %

Procedure:
1-(3-Methoxy-2-methyl-4-pyridyl)piperazine (20.7 mg, 0.1 mmol) was dissolved in dichloromethane (1 ml), triethylamine was added (1 ml of a 0.12 M solution in dichloromethane) followed by a solution of (E)-4-methylpent-2-enoyl chloride (1 ml, 0.12 M in dichloromethane). The mixture was shaken briefly, washed with 5% sodium bicarbonate solution (2×), water and evaporated to dryness. The raw product was purified by preparative HPLC (gradient of water containing 0.1% ammonia and acetonitrile) to yield 2.2 mg of a solid (0.007 mmol, 7%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9][C:10]2[O:11][C:12]([CH:15]=O)=[CH:13][CH:14]=2)=[CH:5][CH:4]=1.[C:17]([NH:21][OH:22])([CH3:20])([CH3:19])[CH3:18]>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([S:9][C:10]2[O:11][C:12]([CH:15]=[N+:21]([C:17]([CH3:20])([CH3:19])[CH3:18])[O-:22])=[CH:13][CH:14]=2)=[CH:7][CH:8]=1
Reactant: CC(C)(C)NO
Reactant: COc1ccc(Sc2ccc(C=O)o2)cc1
Product: COc1ccc(Sc2ccc(C=[N+]([O-])C(C)(C)C)o2)cc1
Yield: 86.2 %

Procedure:
2-(4-Methoxyphenylthio)-5-furaldehyde (24.50 g) was mixed with N-tert-butylhydroxylamine (15.0 g, 168.16 mmol), molecular sieves (100 g) and silica gel (20 g) in CDCl3 (500 mL). The mixture was refluxed overnight under argon gas, and then filtered and concentrated on a rotary evaporator. The residue was recrystallized from hexanes (435 mL) to afford the title compound as yellowish crystals (27.52 g, yield 78.8%), m.p. 91.7° C. (Rf=0.15 on a silica gel plate using hexanes/EtOAc, 2:1, v:v, as the eluant).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[NH:11]1[CH2:15][CH2:14][CH2:13][CH2:12]1>O1CCOCC1>[N:11]1([C:2]2[CH:7]=[CH:6][N:5]=[CH:4][C:3]=2[N+:8]([O-:10])=[O:9])[CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: C1CCNC1
Reactant: O=[N+]([O-])c1cnccc1Cl
Solvent: C1COCCO1
Product: O=[N+]([O-])c1cnccc1N1CCCC1
Reaction time: 0.5 h
Yield: 95.4 %

Procedure:
4-Chloro-3-nitropyridine (2.02 g, 12.7 mmol) was suspended in 15 ml of 1,4-dioxane. The suspension was cooled a little in an ice bath, and then pyrrolidine (2.1 ml, 25.3 mmol) was added dropwise thereto. The temperature of the suspension was returned to room temperature, and the suspension was stirred for 30 minutes, followed by removal of the solvent by distillation under reduced pressure. The residue was purified by silica gel column chromatography (eluent: ethyl acetate) to obtain 2.34 g of a yellow solid (yield: 95.4%).
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[CH:22][C:5]([CH2:6][C:7]2[C:12]([Cl:13])=[CH:11][C:10]([N:14]3[C:19](=[O:20])[NH:18][CH2:17][CH:16]=[N:15]3)=[CH:9][C:8]=2[Cl:21])=[CH:4][CH:3]=1.[Cr](Cl)([O-])(=O)=[O:25].[NH+]1C=CC=CC=1>O1CCCC1>[Cl:1][C:2]1[CH:23]=[CH:22][C:5]([CH2:6][C:7]2[C:12]([Cl:13])=[CH:11][C:10]([N:14]3[C:19](=[O:20])[NH:18][C:17](=[O:25])[CH:16]=[N:15]3)=[CH:9][C:8]=2[Cl:21])=[CH:4][CH:3]=1
Reactant: O=[Cr](=O)([O-])Cl
Reactant: O=C1NCC=NN1c1cc(Cl)c(Cc2ccc(Cl)cc2)c(Cl)c1
Agent: c1cc[nH+]cc1
Solvent: C1CCOC1
Product: O=c1cnn(-c2cc(Cl)c(Cc3ccc(Cl)cc3)c(Cl)c2)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.5 %

Procedure:
In 30 ml of tetrahydrofuran was dissolved 2.6 g of 2-[4-(4-chlorobenzyl)-3,5-dichlorophenyl]-4,5-dihydro-1,2,4-triazin-3(2H)-one. To the solution was added 4.5 g of pyridinium chlorochromate. The mixture was stirred at room temperature overnight, after which the insoluble matter was filtered off. The filtrate was concentrated. The residue was purified by column chromatography (Merck Silica Gel 60; chloroform-ethanol=20:1) to provide 2.2 g of the title compound as colorless crystals, m.p. 175-176° C.
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cl:32][C:33]1[C:34]([C:40]2[CH:45]=[CH:44][C:43]([O:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH3:54])=[CH:42][CH:41]=2)=[N:35][CH:36]=[C:37]([OH:39])[CH:38]=1.[CH2:55](O)[CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH3:62]>O1CCCC1>[Cl:32][C:33]1[C:34]([C:40]2[CH:41]=[CH:42][C:43]([O:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH3:54])=[CH:44][CH:45]=2)=[N:35][CH:36]=[C:37]([O:39][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH3:62])[CH:38]=1
Reactant: CCCCCCCCOc1ccc(-c2ncc(O)cc2Cl)cc1
Reactant: CCCCCCCCO
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCCCCCCCOc1ccc(-c2ncc(OCCCCCCCC)cc2Cl)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 56.5 %

Procedure:
0.6 ml (3.8 mmol) of diethyl azodicarboxylate is added dropwise at 0° C. to 1.00 g (3.80 mmol) of triphenylphosphine in 15 ml of tetrahydrofuran, and the mixture is stirred at room temperature for 30 minutes. 0.78 g (2.5 mmol) of 3-chloro-5-hydroxy-2-(4-octyloxyphenyl)-pyridine and 0.6 ml (3.8 mmol) of 1-octanol are subsequently added. After a reaction time of 18 hours at room temperature, the solvent is removed by distillation and the residue is purified by chromatography (silica gel, dichloromethane). Recrystallization from acetonitrile gives 0.63 g of 3-chloro-5-octyloxy-2-(4-octyloxyphenyl)pyridine. ##STR19## The compound has the phase sequence: X 32.2 (6.5) N 17 I.
Reaction SMILES: CN1C(S[CH2:8][C:9]([OH:11])=[O:10])=NN=N1.O[N:13]1[C:17](=[O:18])[CH2:16][CH2:15][C:14]1=[O:19].C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C=O>[O:19]=[C:14]1[CH2:15][CH2:16][C:17](=[O:18])[N:13]1[O:11][C:9](=[O:10])[CH3:8]
Reactant: O=C1CCC(=O)N1O
Reactant: Cn1nnnc1SCC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CN(C)C=O
Product: CC(=O)ON1C(=O)CCC1=O
Reaction time: 120 h

Procedure:
5.2 g (885 mmol) (1-methyl-1H-tetrazol-5-ylsulfanyl)-acetic acid (CAS Reg. No 55862-52-7; Saito, Seiki et al, Synlett (1993), 2, 139-40 ; 29) were dissolved in 100 ml dimetylformamide. Then 3.44 g (32.84 mmol) N-hydroxysuccinimide were added. Then 6.78 g N,N'-dicyclohexylcarbodiimid were added. After a few minutes white crystals were obtained. The suspension was stirred for further five days. The crystals were filtered off. Dimethylformamide was removed in vacuum. The residue was taken up in 60 ml ethyl acetate at 60° C., filtered off, washed with 30 ml ethylacetate (three times) and dried at high vacuum. 1-Methyl-1H-tetrazol-5-ylsulfanyl)-acetic acid 2,5-dioxo-pyrrolidin-1-yl ester was obtained.
Reaction SMILES: [BH4-].[Na+].[C:3]([C:6]1[CH:13]=[C:12]([Cl:14])[C:9]([C:10]#[N:11])=[C:8]([CH:15]2[O:19][C:18](=[O:20])[NH:17][CH2:16]2)[C:7]=1[O:21][CH2:22][CH3:23])(=[O:5])[CH3:4].CO>>[Cl:14][C:12]1[C:9]([C:10]#[N:11])=[C:8]([CH:15]2[O:19][C:18](=[O:20])[NH:17][CH2:16]2)[C:7]([O:21][CH2:22][CH3:23])=[C:6]([CH:3]([OH:5])[CH3:4])[CH:13]=1
Reactant: CCOc1c(C(C)=O)cc(Cl)c(C#N)c1C1CNC(=O)O1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CCOc1c(C(C)O)cc(Cl)c(C#N)c1C1CNC(=O)O1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Sodium tetrahydroborate (19 mg, 0.50 mmol) was added to a mixture of 4-acetyl-6-chloro-3-ethoxy-2-(2-oxo-1,3-oxazolidin-5-yl)benzonitrile (100 mg, 0.34 mmol) (racemic mixture from step 3) in methanol (1.6 mL, 38 mmol) at 0° C. and the reaction mixture was stirred at room temperature for 10 minutes and evaporated. The residue was diluted with ethyl acetate, washed with 1 N HCl, brine, dried over sodium sulfate, filtered and concentrated to give the desired compound as a mixture of four diastereomers, 58 mg, 55%. LCMS calculated for C14H16ClN2O4 (M+H)+: m/z=311.1; found: 311.1.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:28])[C@@H:5]([CH2:12][C:13]1[C:14]([CH2:23][O:24][C:25](=[O:27])[CH3:26])=[C:15]2[C:19](=[C:20](Br)[CH:21]=1)[NH:18][N:17]=[CH:16]2)[CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH3:2].[CH3:29][Sn](C)(C)C>>[CH2:1]([O:3][C:4](=[O:28])[C@@H:5]([CH2:12][C:13]1[C:14]([CH2:23][O:24][C:25](=[O:27])[CH3:26])=[C:15]2[C:19](=[C:20]([CH3:29])[CH:21]=1)[NH:18][N:17]=[CH:16]2)[CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH3:2]
Reactant: C[Sn](C)(C)C
Reactant: CCOC(=O)C[C@H](Cc1cc(Br)c2[nH]ncc2c1COC(C)=O)C(=O)OCC
Product: CCOC(=O)C[C@H](Cc1cc(C)c2[nH]ncc2c1COC(C)=O)C(=O)OCC
Yield: 68 %

Procedure:
2-(S)-(4-Acetoxymethyl-7-bromo-1H-indazol-5-ylmethyl)-succinic acid diethyl ester (350 mg, 0.77 mmol) and tetramethyltin (150 μL, 1.1 mmol) were reacted in a manner analogous to the preparation of [4-Methyl-9-(2,2-dimethyl-propyl)-8-oxo-3,6,7,8,9,10-hexahydro-2,3,9-triaza-(S)-cyclohepta[e]inden-7-yl]-acetic acid methyl ester. Title compound was obtained as pale yellow solid in 68% yield. MS m/e (M−H)−=389.1.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([CH3:11])=[C:7]2[C:3]=1[CH:4]=[C:5]([C:12]([O:14]CC)=[O:13])[NH:6]2.[OH-].[K+].[CH2:19](O)C>O>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([CH3:11])=[C:7]2[C:3]=1[C:4]([CH3:19])=[C:5]([C:12]([OH:14])=[O:13])[NH:6]2
Reactant: CCO
Reactant: CCOC(=O)c1cc2c(Cl)ccc(C)c2[nH]1
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: Cc1ccc(Cl)c2c(C)c(C(=O)O)[nH]c12
Yield: 68 %

Procedure:
In 20 ml of ethanol and 5 ml of water were dissolved 1.50 g (6.0 mmol) of ethyl 4-chloro-7-methylindole-2-carboxylate and 0.5 g (9.0 mmol) of potassium hydroxide. The reaction mixture was refluxed for 4 hours. The solution was concentrated and then 1N HCl aqueous solution was added. The precipitates were separated by filtration, dissolved in 50 ml of diethyl ether and extracted with 30 ml of aqueous sodium hydrogencarbonate solution three times. The extract was washed with 30 ml of diethyl ether. The water layers were made acid with 1N HCl aqueous solution and extracted with 30 ml of diethyl ether three times. The extract was dried over anhydrous magnesium sulfate and concentrated to provide 0.91 g of beige crystals. Yield: 68%
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[C:8]([C:13]([F:16])([F:15])[F:14])[CH:7]=1)=[O:4].[N:17]1[CH:22]=[CH:21][C:20]([O:23][C:24]2[CH:29]=[CH:28][C:27]([NH2:30])=[CH:26][CH:25]=2)=[CH:19][CH:18]=1.C(N(C(C)C)C(C)C)C>CN(C)C=O>[Cl:12][C:9]1[CH:10]=[CH:11][C:6]([NH:5][C:3](=[O:4])[CH2:2][NH:30][C:27]2[CH:26]=[CH:25][C:24]([O:23][C:20]3[CH:21]=[CH:22][N:17]=[CH:18][CH:19]=3)=[CH:29][CH:28]=2)=[CH:7][C:8]=1[C:13]([F:16])([F:15])[F:14]
Reactant: O=C(CCl)Nc1ccc(Cl)c(C(F)(F)F)c1
Reactant: Nc1ccc(Oc2ccncc2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(CNc1ccc(Oc2ccncc2)cc1)Nc1ccc(Cl)c(C(F)(F)F)c1
Temperature: 100 °C
Yield: 4.7 %

Procedure:
A solution of 146.1 mg (0.54 mmol) of compound 9 in dimethylformamide (DMF) is given to a solution of 100 mg (0.54 mmol) of compound 2 and 0.1 ml (0.59 mmol) N-Ethyl-diisopropylamine in DMF. The reaction mixture is heated to 100° C. for 6 h, then evaporated and the residue is purified by preparative HPLC to yield 10.7 mg (5%) colourless solid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]([C:12]1[N:13]=[CH:14][NH:15][C:16]=1[C:17]([NH:19][C:20]1[NH:24][C:23]2[CH:25]=[CH:26][C:27]([O:29][CH2:30][C:31](OCC)=[O:32])=[CH:28][C:22]=2[N:21]=1)=[O:18])=[O:11].[NH2:36][CH2:37][CH:38]([OH:41])[CH2:39][OH:40].CC(N(C)C)=O>C1COCC1>[OH:41][CH:38]([CH2:39][OH:40])[CH2:37][NH:36][C:31](=[O:32])[CH2:30][O:29][C:27]1[CH:26]=[CH:25][C:23]2[N:24]=[C:20]([NH:19][C:17]([C:16]3[NH:15][CH:14]=[N:13][C:12]=3[C:10]([NH:9][C:3]3[CH:4]=[CH:5][C:6]([CH3:8])=[CH:7][C:2]=3[CH3:1])=[O:11])=[O:18])[NH:21][C:22]=2[CH:28]=1
Reactant: NCC(O)CO
Reactant: CCOC(=O)COc1ccc2[nH]c(NC(=O)c3[nH]cnc3C(=O)Nc3ccc(C)cc3C)nc2c1
Solvent: C1CCOC1
Solvent: CC(=O)N(C)C
Product: Cc1ccc(NC(=O)c2nc[nH]c2C(=O)Nc2nc3ccc(OCC(=O)NCC(O)CO)cc3[nH]2)c(C)c1
Temperature: 90 °C
Yield: 24.5 %

Procedure:
To a seal tube was added ethyl 2-(2-(4-(2,4-dimethylphenylcarbamoyl)-1H-imidazole-5-carboxamido)-1H-benzo[d]imidazol-5-yloxy)acetate (230 mg, 0.5 mmol), 3-aminopropane-1,2-diol (180 mg, 2 mmol), DMA (3 mL) and THF (3 mL), the mixture was heated to 90° C. overnight. The reaction was allowed to cool to room temperature, concentrated under reduced pressure and purified by preparative reverse phase HPLC (aqueous ammonium acetate—acetonitrile) to give 64 mg of N5-[6-({2-[(2,3-dihydroxypropyl)amino]-2-oxoethyl}oxy)-1H benzimidazol-2-yl]-N4-(2,4-dimethylphenyl)-1H-imidazole-4,5-dicarboxamide as the desired product. 1H-NMR (DMSO-d6) δ 8.05 (s, 1H), 7.68 (d, 2H), 7.43 (s, br 2H), 7.05 (dd, 2H), 6.93 (d, 2H), 4.31 (m, 1H), 2.65 (m, 2H), 2.29 (q, 2H), 2.14 (m, 2H), 1.88 (m, 2H), 1.59 (m, 2H), 0.95 (t, 3H). MS (EI): 474 (MH+).
Reaction SMILES: [CH:1](=[C:8]1[C:24](=[O:25])[C:23]2([CH3:26])[CH:10]([CH:11]3[CH:20]([CH2:21][CH2:22]2)[C:19]2[CH:18]=[CH:17][C:16]([OH:27])=[CH:15][C:14]=2[CH2:13][CH2:12]3)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+]>C(O)C.C1COCC1>[CH:1](=[C:8]1[CH:24]([OH:25])[C:23]2([CH3:26])[CH:10]([CH:11]3[CH:20]([CH2:21][CH2:22]2)[C:19]2[CH:18]=[CH:17][C:16]([OH:27])=[CH:15][C:14]=2[CH2:13][CH2:12]3)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC12CCC3c4ccc(O)cc4CCC3C1CC(=Cc1ccccc1)C2=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Product: CC12CCC3c4ccc(O)cc4CCC3C1CC(=Cc1ccccc1)C2O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
16-Benzylidene-3-hydroxy-13-methyl-6,7,8,9,11,12,13,14,15,16-decahydro-cyclopenta[a]phenanthren-17-one (179 mg, 0.50 mmol, CAB01122) was dissolved in ethanol (10 ml) and THF (10 ml). The resulting light yellow solution was cooled to 0° C. (ice bath) and sodium borohydride (100 mg, 2.64 mmol) was added. The reaction mixture was stirred overnight at room temperature, the solvents were removed under reduced pressure and the residue was dissolved in ethyl acetate (40 ml). The organic solution was washed with water (2×25 ml) and brine (25 ml), dried over sodium sulphate and concentrated under reduced pressure. The residue was dissolved in a small amount of ethyl acetate and precipitated by addition of hexane. The white solid was filtered off and dried under high vacuum. Yield 175 mg (97%). 1H-NMR (d6-DMSO, 270 MHz), δ: 0.61 (s, 3H), 1.20-1.50 (m, 5H), 1.82-0.98 (m, 2H), 2.20-2.35 (m, 3H), 2.58-2.82 (m, 3H), 3.95-4.05 (m, 1H, H-17), 5.15 (d, J=6.2 Hz, 1H), 6.43 (s, 1H), 6.46 (d, J=2.3 Hz, 1H), 6.52 (dd, J=8.2, 2.3 Hz, 1H), 7.06 (d, J=8.2 Hz, 1H), 7.15-7.20 (m, 1H), 7.31-7.41 (m, 4H). LRMS (FAB+): 343.2 (80), 360.2 (100, [M]+). LRMS (FAB−): 359.3 (100, (M−H]−). HRMS (FAB+) 360.209709 C25H28O2 requires 360.208930
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:12]=[CH:13][CH:14]=1)[O:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][O:7]1.[Li][CH2:16]CCC.CI>C1COCC1>[F:1][C:2]1[C:3]([CH3:16])=[C:4]([CH:12]=[CH:13][CH:14]=1)[O:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][O:7]1
Reactant: Fc1cccc(OC2CCCCO2)c1
Reactant: [Li]CCCC
Solvent: C1CCOC1
Solvent: CI
Product: Cc1c(F)cccc1OC1CCCCO1
Temperature: -78 °C
Reaction time: 0.75 h
Yield: 90.1 %

Procedure:
To a chilled solution (−78° C.) of 9.33 g (47.55 mmol) of 2-(3-fluorophenoxy)-tetrahydro-2H-pyran in 150 mL of THF was added 38 mL (95.1 mmols) of n-BuLi (2.5 M soln in hexanes). The reaction mixture was stirred at −78° C. for 45 minutes and slowly added 11.9 mL (190.2 mmol) of methyl iodide via syringe. The reaction was allowed to warm to room temperature and was stirred overnight. Quenched reaction with satd ammonium chloride and transferred to a round bottom flask. Removed volatiles in vacuo and partitioned mixture between EtOAc and water. Separated layers and washed organics with water (×2) and brine. Dried over Na2SO4, filtered, and concd to afford a 9.01 g (90%) of a yellow oil: 1H NMR (CDCl3/400 MHz) 1.46-2.09 (m, 6H), 2.21 (d, 3H, J=2.0 Hz), 3.60-3.65 (m, 1H), 3.86-3.92 (m, 1H), 5.44 (t, 1H, J=3.2 Hz), 6.70 (t, 1H, J=8.8 Hz), 6.90 (d, 1H, J=8.4 Hz), 7.08 (dd, 1H, J=8.0, 15.2 Hz); HRMS (EI+) m/z calcd for (C12H15FO2) 210.1056, found 210.1070.
Reaction SMILES: [Na].[C:2]1([CH:8]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:9]2[CH2:14][CH2:13][CH:12]([CH2:15][C:16]#[N:17])[CH2:11][CH2:10]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(=O)(=O)(O)O.[OH-].[Na+]>C1COCC1>[C:2]1([CH:8]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:9]2[CH2:14][CH2:13][CH:12]([CH2:15][CH2:16][NH2:17])[CH2:11][CH2:10]2)[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N#CCC1CCN(C(c2ccccc2)c2ccccc2)CC1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [Na]
Solvent: C1CCOC1
Product: NCCC1CCN(C(c2ccccc2)c2ccccc2)CC1
Temperature: 0 °C
Reaction time: 48 h

Procedure:
2.2 g (58.2 mmol) sodium borohydroxide are suspended in 50 ml abs. THF and cooled to ca. 0° C. under moisture exclusion. 6.7 g (23.1 mmol) (1-diphenylmethylpiperidin-4-yl)-acetonitrile are added and the mixture is subsequently cooled to −5° C. to −10° C. and added dropwise to 1.5 ml (26.7 mmol) 95% sulfuric acid (vigorous foaming). The suspension is left to stand for two days at RT without further cooling. Under renewed cooling to ca. 0° C., 40 ml 2 M sodium hydroxide solution is added dropwise. The aqueous phase is extracted with 30 ml THF and thereafter the combined organic phases are washed twice, each with 30 ml saturated NaCl solution, dried over sodium sulfate and the solution is removed under vacuum. The residue is chromatographically purified over silica gel with CHCl3/CH3OH/N4OH (90/10/1). Yield: 3.9 g (57%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH:6]=[O:7].[Br:11]Br.O>C(O)(=O)C>[Br:11][C:8]1[CH:9]=[CH:10][C:3]([O:2][CH3:1])=[CH:4][C:5]=1[CH:6]=[O:7]
Reactant: COc1cccc(C=O)c1
Reactant: BrBr
Solvent: CC(=O)O
Solvent: O
Product: COc1ccc(Br)c(C=O)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 87 %

Procedure:
50 g of 3-methoxybenzaldehyde are dissolved in 245 ml of acetic acid. 22 ml of bromine are added dropwise at 0° C., the medium is stirred at room temperature for 4 hours, and then left overnight at room temperature. 300 ml of water are added to the solution and the expected product crystallizes. After filtration and washing with water and drying, 68 g of 2-bromo-5-methoxybenzaldehyde having the empirical formula C8H7Br.O2 are obtained (M=114 g).
Reaction SMILES: O.O.O.O.O.O.O.[Cl-].[Ce+3].[Cl-].[Cl-].[BH4-].[Na+].[C:14]([O:18][C:19]([C@H:21]1[C@H:25]([C:26]([CH:28]=[O:29])=[CH2:27])[CH2:24][N:23]([C:30]([O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[O:31])[CH2:22]1)=[O:20])([CH3:17])([CH3:16])[CH3:15]>C(O)C>[C:14]([O:18][C:19]([C@H:21]1[C@H:25]([C:26]([CH2:28][OH:29])=[CH2:27])[CH2:24][N:23]([C:30]([O:32][CH2:33][C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)=[O:31])[CH2:22]1)=[O:20])([CH3:17])([CH3:15])[CH3:16]
Reactant: C=C(C=O)[C@@H]1CN(C(=O)OCc2ccccc2)C[C@H]1C(=O)OC(C)(C)C
Agent: [BH4-]
Agent: [Ce+3]
Agent: [Cl-]
Solvent: CCO
Solvent: O
Product: C=C(CO)[C@@H]1CN(C(=O)OCc2ccccc2)C[C@H]1C(=O)OC(C)(C)C
Reaction time: 0.17 h
Yield: 76.3 %

Procedure:
Cerium (III) chloride heptahydrate (57.0 g, 153 mmol) was dissolved in ethanol (700 mL). Sodium borohydride (5.79 g, 153 mmol) was added at 0° C., and the mixture was stirred for 10 minutes. A solution of (3S,4R)-1-benzyloxycarbonyl-4-(1-formylvinyl)pyrrolidine-3-carboxylic acid tert-butyl ester (55.0 g, 153 mmol) in ethanol (700 mL) was added dropwise to the reaction solution at 0° C., and the mixture was stirred at room temperature for three hours. The reaction solution was extracted with a 10% citric acid solution, water, and ethyl acetate. Then, the organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=24:1→2:1) to give 42.2 g of the title compound as a colorless oil.