Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[CH:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([O:19][C:20](=[O:22])[CH3:21])[C@H:7]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([CH2:30][C:31]3[CH:36]=[CH:35][C:34]([O:37][CH2:38][CH3:39])=[CH:33][CH:32]=3)[CH:24]=2)[O:6]1)(=O)C.[BrH:40]>CC(O)=O.C(Cl)Cl>[C:16]([O:15][C@@H:9]1[C@@H:8]([O:19][C:20](=[O:22])[CH3:21])[C@H:7]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([CH2:30][C:31]3[CH:32]=[CH:33][C:34]([O:37][CH2:38][CH3:39])=[CH:35][CH:36]=3)[CH:24]=2)[O:6][C@@H:5]([Br:40])[C@H:10]1[O:11][C:12](=[O:14])[CH3:13])(=[O:18])[CH3:17]
Reactant: CCOc1ccc(Cc2cc([C@@H]3OC(OC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]3OC(C)=O)ccc2Cl)cc1
Reactant: Br
Solvent: ClCCl
Solvent: CC(=O)O
Product: CCOc1ccc(Cc2cc([C@@H]3O[C@@H](Br)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]3OC(C)=O)ccc2Cl)cc1
Reaction time: 0.5 h

Procedure:
The tetraacetate of step A (8.08 g, 14.4 mmol) was treated with 33% HBr in AcOH (30 ml) for 1 hour. The reaction was diluted with CH2Cl2 (60 ml), stirred for 30 minutes, diluted with more DCM, washed 3× with ice cold H2O and with sat. aq. NaHCO3 (with back extraction), dried over MgSO4, filtered, and concentrated under vacuum to give acetic acid (2S,3S,4R,5S,6S)-4,5-diacetoxy-2-bromo-6-[4-chloro-3-(4-ethoxy-benzyl)-phenyl]-tetrahydro-pyran-3-yl ester.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O.[F:19][C:20]1[CH:21]=[C:22]([N+:27]([O-:29])=[O:28])[CH:23]=[CH:24][C:25]=1F>C(OCC)(=O)C>[F:19][C:20]1[CH:21]=[C:22]([N+:27]([O-:29])=[O:28])[CH:23]=[CH:24][C:25]=1[O:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1
Reactant: Oc1cccnc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1ccc(Oc2cccnc2)c(F)c1
Temperature: 90 °C
Reaction time: 1 h

Procedure:
2.09 g of 3-hydroxypyridine and 5.52 g of potassium carbonate were added to a dimethylformamide (20 ml) solution of 3.18 g of 3,4-difluoronitrobenzene, and the reaction liquid was stirred at 90° C. for 1 hour. The reaction liquid was diluted with ethyl acetate, washed with water and saturated saline in order, and dried with anhydrous magnesium sulfate. The solvent was evaporated away under reduced pressure, and the resulting residue was purified through silica gel column chromatography (developing solvent: hexane/ethyl acetate=9/1) to obtain the entitled compound.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:9]=[C:8]([F:10])[C:7]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])=[C:6]([C:16]#[CH:17])[CH:5]=1.[C:18]([C:22]1[N:27]=[CH:26][C:25]([O:28][CH2:29][C:30](O)=[O:31])=[CH:24][CH:23]=1)([CH3:21])([CH3:20])[CH3:19].CN1C(=O)CCC1>C1COCC1>[C:18]([C:22]1[N:27]=[CH:26][C:25]([O:28][CH2:29][C:30]([NH:2][CH2:3][C:4]2[CH:9]=[C:8]([F:10])[C:7]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])=[C:6]([C:16]#[CH:17])[CH:5]=2)=[O:31])=[CH:24][CH:23]=1)([CH3:21])([CH3:19])[CH3:20]
Reactant: CC(C)(C)c1ccc(OCC(=O)O)cn1
Reactant: C#Cc1cc(CN)cc(F)c1NS(C)(=O)=O
Agent: Cl
Solvent: CN1CCCC1=O
Solvent: C1CCOC1
Product: C#Cc1cc(CNC(=O)COc2ccc(C(C)(C)C)nc2)cc(F)c1NS(C)(=O)=O
Yield: 33.3 %

Procedure:
N-(4-Aminomethyl-2-ethynyl-6-fluoro-phenyl)-methanesulfonamide HCl salt (120 mg, 0.43 mmol) was reacted with (6-tert-butyl-pyridin-3-yloxy)-acetic acid (90 mg) DMTMM (1.1 eq, 131 mg) and NMP (1.2 eq, 60 μl) in THF to give the title compound (62 mg, 33.3%) after purification by column chromatography (Hex EtOAc=2/3).
Reaction SMILES: [O:1]=[C:2]1[N:7]([NH2:8])[CH2:6][C:5]([CH3:9])=[N:4][NH:3]1.[CH3:10][C:11]1[C:16]([CH:17]=O)=[CH:15][CH:14]=[CH:13][N:12]=1>C(O)C.Cl>[O:1]=[C:2]1[N:7]([N:8]=[CH:17][C:16]2[C:11]([CH3:10])=[N:12][CH:13]=[CH:14][CH:15]=2)[CH2:6][C:5]([CH3:9])=[N:4][NH:3]1
Reactant: CC1=NNC(=O)N(N)C1
Reactant: Cc1ncccc1C=O
Agent: Cl
Solvent: CCO
Product: CC1=NNC(=O)N(N=Cc2cccnc2C)C1
Reaction time: 0.5 h

Procedure:
To a solution of 0.5 g (4 mmol) of 2,3,4,5-tetrahydro-3-oxo-4-amino-6-methyl-1,2,4-triazine in 250 ml of ethanol are added, at room temperature, 0.48 g (4 mmol) of 2-methylpyridine-3-carbaldehyde and 1 drop of concentrated HCl. The reaction mixture is stirred for 1/2 hour and then filtered. The isolated solid is washed with ether and dried, affording the title compound of formula ##STR26## in the form of a colourless solid; m.p. 226°-229° C. (yield: 0.6 g; 64%).
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.[H-].[Na+].Br[CH2:9][C:10]([C:12]1[CH:17]=[CH:16][C:15]([O:18][C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=2)=[CH:14][C:13]=1[Cl:26])=[O:11].Cl>C1COCC1.O>[Cl:26][C:13]1[CH:14]=[C:15]([O:18][C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=2)[CH:16]=[CH:17][C:12]=1[C:10](=[O:11])[CH2:9][N:1]1[CH:5]=[N:4][CH:3]=[N:2]1
Reactant: O=C(CBr)c1ccc(Oc2ccc(Cl)cc2)cc1Cl
Reactant: c1nc[nH]n1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: O=C(Cn1cncn1)c1ccc(Oc2ccc(Cl)cc2)cc1Cl
Reaction time: 2.5 h
Yield: 80.3 %

Procedure:
1,2,4-Triazole (249 g) was added carefully (small portions) to a mixture of sodium hydride (85 g) in THF (6000 mL). After 30 minutes a solution of 2-bromo-1-[2-chloro-4-(4-chlorophenoxy)phenyl]ethanone (1322 g) in THF (500 mL) was slowly added and the mixture was stirred for 150 min. The pH was adjusted to 7 with dil. hydrochloric acid whereupon water was added (3000 mL). The precipitate was filtered off and washed with MTBE. The organic phase was then concentrated and the resulting solid was filtered off to yield the desired material (1008 g).
Reaction SMILES: [NH2:1][C@@H:2]([C:5]([OH:7])=[O:6])[CH2:3][OH:4].[CH3:8][CH:9]([CH3:25])[C:10]([O:12][CH2:13][O:14][C:15](ON1C(=O)CCC1=O)=[O:16])=[O:11]>>[OH:4][CH2:3][C@@H:2]([NH:1][C:15]([O:14][CH2:13][O:12][C:10](=[O:11])[CH:9]([CH3:25])[CH3:8])=[O:16])[C:5]([OH:7])=[O:6]
Reactant: CC(C)C(=O)OCOC(=O)ON1C(=O)CCC1=O
Reactant: N[C@H](CO)C(=O)O
Product: CC(C)C(=O)OCOC(=O)N[C@H](CO)C(=O)O
Yield: 34 %

Procedure:
Following the general procedure for the synthesis of acyloxyalkyl carbamates, D-serine (161 mg, 1.5 mmol) and (2,5-dioxoazolidinyloxycarbonyloxy)methyl 2-methylpropanoate (330 mg, 1.3 mmol) were reacted to provide 110 mg (35% yield) of the title compound (32) as a white powder after work-up and mass-guided preparative HPLC purification. 1H NMR (CDCl3, 400 MHz): δ=6.61 (br s, 1H), 6.51 (d, 1H), 5.65 (m, 2H), 4.41 (m, 1H), 4.02 (m, 1H), 3.84 (m, 1H), 2.59 (m, 1H), 1.09 (d, 6H). MS (ESI) m/z 250.15 (M+H)+; 267.17 (M+NH4)+; 272.13 (M+Na)+; 248.12 (M−H)−.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:13][C:12]3[CH:14]=[C:15]([O:18][CH3:19])[CH:16]=[CH:17][C:11]=3[C:10]=2[C:20]2[CH:25]=[CH:24][CH:23]=[C:22](O)[CH:21]=2)=[CH:5][CH:4]=1.[Br:27][CH2:28][CH2:29][CH2:30][CH2:31]Br>CC(=O)CC>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:13][C:12]3[CH:14]=[C:15]([O:18][CH3:19])[CH:16]=[CH:17][C:11]=3[C:10]=2[C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([CH2:31][CH2:30][CH2:29][CH2:28][Br:27])[CH:21]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(-c2sc3cc(OC)ccc3c2-c2cccc(O)c2)cc1
Reactant: BrCCCCBr
Solvent: CCC(C)=O
Product: COc1ccc(-c2sc3cc(OC)ccc3c2-c2cccc(CCCCBr)c2)cc1

Procedure:
A slurry of 4.04 g (11 mmol) of 2-(4-Methoxyphenyl)-3-(3-hydroxyphenyl)-6-methoxybenzo[b]thiophene, 1,4-dibromobutane 26.3 mL (220 mmol), and 3.5 g (25.3 mmol) of K2 CO3 in 200 mL of 2-butanone was preapared. The reaction mixture was heated to reflux for two hours, then filtered, and evaporated to dryness. The resulting oil was chromatographed on a silica gel column eluted with a linear gradient begining with EtOAc-hexane (1:9) (v/v) and ending with EtOAc-hexane (1:4) (v/v). The desired fractions were combined and evaporated to a yellow oil. This yielded 5 g of the title compound.
Reaction SMILES: Cl[C:2]1[C:7]([N:8]([CH3:25])[C:9](=[O:24])[C:10]2[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[C:12]([S:20]([CH3:23])(=[O:22])=[O:21])[CH:11]=2)=[C:6]([C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][C:27]=2[O:33][CH3:34])[CH:5]=[CH:4][N:3]=1.[Cl-].C[Zn+].[CH3:38]N1CCN(C)C1=O.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1.CCOC(C)=O>[F:32][C:29]1[CH:30]=[CH:31][C:26]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([CH3:38])[C:7]=2[N:8]([CH3:25])[C:9](=[O:24])[C:10]2[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[C:12]([S:20]([CH3:23])(=[O:22])=[O:21])[CH:11]=2)=[C:27]([O:33][CH3:34])[CH:28]=1
Reactant: COc1cc(F)ccc1-c1ccnc(Cl)c1N(C)C(=O)c1cc(C(F)(F)F)cc(S(C)(=O)=O)c1
Reactant: CN1CCN(C)C1=O
Agent: C[Zn+]
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1cc(F)ccc1-c1ccnc(C)c1N(C)C(=O)c1cc(C(F)(F)F)cc(S(C)(=O)=O)c1
Temperature: 50 °C

Procedure:
To a solution of N-(2-chloro-4-(4-fluoro-2-methoxyphenyl)pyridin-3-yl)-N-methyl-3-(methylsulfonyl)-5-(trifluoromethyl)benzamide (0.1 g, 193 μmol, Example 212) in THF (3 mL) were added methylzinc(II)chloride (193 μL, 387 μmol), 1,3-dimethyl-2-imidazolidinone (DMI) (0.6 mL) and PEPPSI-IPr (CAS 905459-27-0) (2.7 mg, 3.87 μmol) and the reaction mixture was heated at 50° C. for 3 hours. The reaction mixture was poured on 10% aqueous citric acid solution and EtOAc and the layers were separated. The aqueous layer was extracted twice with EtOAc. The organic layers were washed with brine, dried over MgSO4, filtered and evaporated. The compound was purified by silica gel chromatography on a 10 g column using an MPLC (ISCO) system eluting with a gradient of n-heptane:EtOAc (100:0 to 0:100). The product was purified by preparative HPLC (Gemini NX column) using a gradient of MeOH:water (containing 0.1% formic acid) (20:80 to 98:2). The product was purified by preparative HPLC (Gemini NX column) using a gradient of MeOH:water (containing 0.05% triethylamine) (20:80 to 60:40). Colorless solid (0.035 g; 36%). MS (ESI): m/z=497.12 [M+H]+.
Reaction SMILES: B1(C)[O:8][C:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17]C=2)([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C@@H]2N1CCC2.B.C1COCC1.C1(=O)C2=C3C(=CC=C2)C=CC=C3C1.Cl>ClCCl.CO>[C@@H:7]1([OH:8])[C:9]2=[C:10]3[C:11](=[CH:12][CH:13]=[CH:14]2)[CH:17]=[CH:18][CH:19]=[C:20]3[CH2:15]1
Reactant: CB1OC(c2ccccc2)(c2ccccc2)[C@H]2CCCN12
Agent: B
Agent: Cl
Agent: O=C1Cc2cccc3cccc1c23
Solvent: C1CCOC1
Solvent: CO
Solvent: ClCCl
Product: O[C@H]1Cc2cccc3cccc1c23
Temperature: -30 °C
Reaction time: 0.75 h
Yield: 20.6 %

Procedure:
(R)-2-Methyl-CBS-oxazaboro-lidine (50 ml, 1 mol toluene solution) was cooled to −30° C., and a borane-THF complex (250 ml, 1 mol THF solution) was added. The mixture was stirred for 45 min. Acenaphthen-1-one (40 g, 240 mmol) was dissolved in dichloromethane (500 ml) and the solution was added dropwise. The mixture was stirred under cooling (−30° C.) for 2 hr. Then, methanol (80 ml) and 1N-hydrochloric acid (100 ml) were added under ice-cooling, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated aqueous ammonium chloride solution, dried over magnesium sulfate, and concentrated to give (S)-1-acenaphthenol (35 g) as pale-yellow crystals.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]2[NH:14][C:13]3[CH:15]=[CH:16][C:17]([C:19]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)=[O:20])=[CH:18][C:12]=3[N:11]=2)=[N:2]1.[H-].C([Al+]CC(C)C)C(C)C>O1CCCC1>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]2[NH:14][C:13]3[CH:15]=[CH:16][C:17]([CH:19]([C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=4)[OH:20])=[CH:18][C:12]=3[N:11]=2)=[N:2]1
Reactant: O=C(c1ccccc1)c1ccc2[nH]c(-c3n[nH]c4ccccc34)nc2c1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: C1CCOC1
Product: OC(c1ccccc1)c1ccc2[nH]c(-c3n[nH]c4ccccc34)nc2c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 80 %

Procedure:
A stirred solution of [2-(indazol-3-yl)-1H-benzoimidazol-5-yl]-phenyl-methanone [200 mg, Example 234(c)] in tetrahydrofuran (10 mL), at −78° C. and under an atmosphere of nitrogen, was treated dropwise with a solution of diisobutylaluminium hydride in tetrahydrofuran (1.18 mL, 1N). The reaction mixture was warmed to ambient temperature, then stirred for 16 hours and then partitioned between ether and sodium hydroxide solution (2N). The organic phase was washed with water, then with brine, then dried over magnesium sulfate and then evaporated. The residue was subjected to flash column chromatography on silica eluting with a mixture of ethyl acetate and hexane (3:1, v/v) to give [2-(indazol-3-yl)-1H-benzoimidazol-5-yl]-phenyl-methanol (161 mg) as a white solid. LC-MS (Method D): RT=21.89 minutes, 341.3 (M+H)+.
Reaction SMILES: C([NH:9][C:10]1[NH:11][N:12]([C:17]2[C:22]([Cl:23])=[CH:21][C:20]([Cl:24])=[CH:19][C:18]=2[Cl:25])[C:13](=[O:16])[C:14]=1Br)(=O)C1C=CC=CC=1.[NH:26]1[CH:30]=[CH:29][CH:28]=[N:27]1.C(C1C(O)=C(C(C)(C)C)C=C(C)C=1)(C)(C)C.O.O.O.O.O.O.O.O.[OH-].[Ba+2].[OH-].[OH-].[Na+].Cl>CO.CN1CCCC1=O>[NH2:9][C:10]1[NH:11][N:12]([C:17]2[C:18]([Cl:25])=[CH:19][C:20]([Cl:24])=[CH:21][C:22]=2[Cl:23])[C:13](=[O:16])[C:14]=1[N:26]1[CH:30]=[CH:29][CH:28]=[N:27]1
Reactant: O=C(Nc1[nH]n(-c2c(Cl)cc(Cl)cc2Cl)c(=O)c1Br)c1ccccc1
Reactant: c1cn[nH]c1
Agent: Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Agent: Cl
Agent: [Ba+2]
Solvent: CN1CCCC1=O
Solvent: CO
Solvent: O
Product: Nc1[nH]n(-c2c(Cl)cc(Cl)cc2Cl)c(=O)c1-n1cccn1
Temperature: 75 °C
Yield: 73 %

Procedure:
200 g of 3-benzoylamino-4-bromo-1-(2,4,6-trichlorophenyl)-5- pyrazolone, 59 g of pyrazol, 14 g of 2,6-di-t-butyl-p-cresol and 100 mL of N-methylpyrrolidone were mixed, and the resultant reaction mixture was heated at 75° C. under a nitrogen gas flow while agitated. The reaction mixture was cooled to 45° C., and 400 mL of methanol, 25 g of barium hydroxide octahydrate and 138 g of a 25% (W/V) aqueous solution of sodium hydroxide were added to the reaction mixture. The resultant mixture was agitated for six hours at an internal temperature of 65° C. After the reaction mixture was cooled to 45° C., 500 mL of concentrated hydrochloric acid were added to the mixture, and precipitated insoluble substances (barium chloride and sodium chloride) were eliminated by filtration. The filtrate was extracted twice with toluene, and the aqueous phase after the extraction was neutralized by adding a 25% (W/V) aqueous solution of sodium hydroxide so that the pH value of the aqueous phase became 3.5. Precipitated crystals were separated by filtration, and the obtained crystals were washed and dried to obtain 109 g of desired 3-amino-4-(1-pyrazolyl)-1-(2,4,6-trichlorophenyl)-5-pyrazolone (yield: 73.3%) as gray-white powder.
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[C:22](I)[CH:21]=[CH:20][C:3]=1[CH2:4][N:5]1[C:9]2[CH:10]=[C:11]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:12]=[CH:13][C:8]=2[N:7]=[C:6]1[CH3:19].[CH2:25]=[CH:26][CH2:27][CH2:28][CH2:29][CH3:30].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CCCC)CCCC)CCC>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CN(C)C=O>[Cl:1][C:2]1[CH:23]=[C:22]([CH:25]=[CH:26][CH2:27][CH2:28][CH2:29][CH3:30])[CH:21]=[CH:20][C:3]=1[CH2:4][N:5]1[C:9]2[CH:10]=[C:11]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:12]=[CH:13][C:8]=2[N:7]=[C:6]1[CH3:19]
Reactant: C=CCCCC
Reactant: CCOC(=O)c1ccc2nc(C)n(Cc3ccc(I)cc3Cl)c2c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCCCN(CCCC)CCCC
Solvent: CN(C)C=O
Product: CCCCC=Cc1ccc(Cn2c(C)nc3ccc(C(=O)OCC)cc32)c(Cl)c1
Temperature: 60 °C
Reaction time: 8 h
Yield: 90.5 %

Procedure:
A mixture of 1-(2-chloro-4-iodobenzyl)-6-(ethoxycarbonyl)-2-methylbenzimidazole (1.21 g), 1-hexene (1.12 g), palladium acetate (II) (0.09 g), triphenylphosphine (0.21 g), tri-n-butylamine (1.49 g), and N,N-dimethylformamide (15 ml) was stirred overnight at 60° C. The reaction mixture was concentrated under reduced pressure and the resulting residue was purified by silica gel column chromatography (eluate: hexane/ethyl acetate=1/2) to obtain 1-(2-chloro-4-(1-hexen-1-yl)benzyl)-6-(ethoxycarbonyl)-2-methyl-benzimidazole (0.99 g). In accordance with the method of Production Example 5, this product was immediately converted to the desired compound (0.64 g) containing about 10% of 6-carboxy-1-(2-chloro-4-(1-hexen-2-yl)benzyl)-2-methyl-benzimidazole. This compound was immediately subjected to the next step.
Reaction SMILES: C([Si](C)(C)[O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:14]=[C:15]3[C:20](=[CH:21][CH:22]=2)[C:19]([N+:23]([O-:25])=[O:24])=[C:18]([OH:26])[CH:17]=[CH:16]3)=[CH:9][CH:8]=1)(C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1.O>[OH:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]2[CH:14]=[C:15]3[C:20](=[CH:21][CH:22]=2)[C:19]([N+:23]([O-:25])=[O:24])=[C:18]([OH:26])[CH:17]=[CH:16]3)=[CH:11][CH:12]=1
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(-c2ccc3c([N+](=O)[O-])c(O)ccc3c2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: O=[N+]([O-])c1c(O)ccc2cc(-c3ccc(O)cc3)ccc12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 60.5 %

Procedure:
To a solution of 6-[4-(tert-Butyl-dimethyl-silanyloxy)-phenyl]-1-nitro-2-naphthol (302 mg, 0.764 mmol) in THF (12 mL) was added TBAF (0.92 mL, 0.917 mmol, 1.0 M solution in THF). The solution was stirred for 10 minutes at room temperature, poured in water. The mixture was extracted with ethyl acetate. The combined organic layers were washed with brine, dried anhydrous Na2SO4, filtered, evaporation of the solvent, and purification on a silica column (20%-40% ethyl acetate-hexane) yielded 130 mg (61%) of a orange solid. An analytical sample was further purified by recrystallization with ethyl acetate-hexane to yield the title compound as a orange solid:: mp 199-201° C.; 1H NMR (DMDO-d6): δ 6.89(2H, d, J=8.51 Hz), 7.33 (1H, d, J=9.05 Hz), 7.62 (1H, d, J=8.94 Hz), 7.63(2H, d, 8.48 Hz), 7.91 (1H, dd, J=8.87 Hz, J=1.59 Hz), 8.06 (1H, d, 9.18 Hz), 8.17 (1H, d, J=1.31 Hz), 9.64(1H, s), 11.40 (1H,s); MS (ESI) m/z280 (M−H)−.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][O:14]1)[N:8]=[C:7]2[C:19]1[NH:23][C:22]2[CH:24]=[C:25]([CH2:28][N:29]3[CH2:34][CH2:33][O:32][CH2:31][CH2:30]3)[CH:26]=[CH:27][C:21]=2[N:20]=1)([O-])=O.[H][H]>C(O)C.[Pd]>[O:32]1[CH2:33][CH2:34][N:29]([CH2:28][C:25]2[CH:26]=[CH:27][C:21]3[N:20]=[C:19]([C:7]4[C:6]5[C:10](=[CH:11][CH:12]=[C:4]([NH2:1])[CH:5]=5)[N:9]([CH:13]5[CH2:18][CH2:17][CH2:16][CH2:15][O:14]5)[N:8]=4)[NH:23][C:22]=3[CH:24]=2)[CH2:30][CH2:31]1
Reactant: [H][H]
Reactant: O=[N+]([O-])c1ccc2c(c1)c(-c1nc3ccc(CN4CCOCC4)cc3[nH]1)nn2C1CCCCO1
Agent: [Pd]
Solvent: CCO
Product: Nc1ccc2c(c1)c(-c1nc3ccc(CN4CCOCC4)cc3[nH]1)nn2C1CCCCO1
Yield: 80.7 %

Procedure:
4-((2-(5-Nitro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)-1H-benzo[d]imidazol-6-yl)methyl)morpholine (20 mg, 0.043 mmol) was added to the 10% Pd/C (5 mg) in ethanol (10 mL) and then hydrogen gas (60 psi) was applied for 6 h at room temperature. The reaction mixture was filtered through Celite, and the solvent was removed in vacuo. Purification by flash chromatography (5% CH3OH/CH2Cl2) afforded the title compound (15 mg) as a white solid.
Reaction SMILES: [BH4-].[Li+].C[Si](C)(C)Cl.[C:8]1([N:14]2[C:18]([CH2:19][C:20]#[N:21])=[N:17][C:16]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[N:15]2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>C1COCC1>[C:8]1([N:14]2[C:18]([CH2:19][CH2:20][NH2:21])=[N:17][C:16]([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)=[N:15]2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: N#CCc1nc(-c2ccccc2)nn1-c1ccccc1
Agent: C[Si](C)(C)Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: NCCc1nc(-c2ccccc2)nn1-c1ccccc1
Temperature: 60 °C
Reaction time: 1.5 h

Procedure:
To lithium borohydride (2M solution in THF, 899 μL, 1.8 mmol) was added dropwise trimethylchlorosilane (391 mg, 460 μL, 3.6 mmol) over a period of 5 min at 0-5° C., followed by the dropwise addition of a solution of 2-(1,3-diphenyl-1H-1,2,4-triazol-5-yl)acetonitrile (117 mg, 449 μmol) in THF (1.5 mL). The ice bath was removed after 10 min and the mixture was stirred at 60° C. for 1.5 h. The reaction mixture was cooled to 0-5° C. and 1 mL MeOH was added slowly (bubbling!). After 10 min the ice bath was removed and the mixture was allowed to warm up to RT. The mixture was poured into NaOH (1M aqueous solution, 15 mL) and extracted with dichloromethane (3×50 mL). The combined organic phase was dried over MgSO4, filtered and evaporated to give the product (118 mg with 90% purity, 402 μmol, 89.4%) as yellow viscous oil which was used without further purification.
Reaction SMILES: [N:1]([CH:4]1[CH2:17][C:6]2([CH2:9][N:8]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:7]2)[CH2:5]1)=[N+]=[N-]>C(O)C.[Pd].CC([O-])=O.CC([O-])=O.[Pb+2]>[NH2:1][CH:4]1[CH2:5][C:6]2([CH2:9][N:8]([C:10]([O:12][C:13]([CH3:15])([CH3:14])[CH3:16])=[O:11])[CH2:7]2)[CH2:17]1
Reactant: CC(C)(C)OC(=O)N1CC2(CC(N=[N+]=[N-])C2)C1
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Pb+2]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CC2(CC(N)C2)C1
Yield: 58 %

Procedure:
The process is performed according to the procedure described in Example 6 (step 6.4.). Starting with 0.638 g (2.68 mmol) of tert-butyl 6-azido-2-azaspiro[3.3]heptane-2-carboxylate, obtained in step 11.5., in 11 mL of ethanol, 0.276 g (1.34 mmol) of Lindlar catalyst (PdCaCO3) is added. After purification on a column of silica gel, eluting with a 98/2/0.2 mixture of dichloromethane, methanol and 28% aqueous ammonia, 0.330 g of pure product is obtained in the form of a white powder.
Reaction SMILES: [F:1][C:2]1[C:3]([CH2:14][N:15]([CH3:23])[C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:4][NH:5][C:6]=1[C:7]1[C:8]([F:13])=[N:9][CH:10]=[CH:11][CH:12]=1.[H-].[Na+].[CH2:26]([O:33][C:34]1[CH:39]=[CH:38][C:37]([S:40](Cl)(=[O:42])=[O:41])=[CH:36][CH:35]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>O1CCCC1.O>[CH2:26]([O:33][C:34]1[CH:39]=[CH:38][C:37]([S:40]([N:5]2[C:6]([C:7]3[C:8]([F:13])=[N:9][CH:10]=[CH:11][CH:12]=3)=[C:2]([F:1])[C:3]([CH2:14][N:15]([CH3:23])[C:16](=[O:22])[O:17][C:18]([CH3:19])([CH3:20])[CH3:21])=[CH:4]2)(=[O:42])=[O:41])=[CH:36][CH:35]=1)[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: O=S(=O)(Cl)c1ccc(OCc2ccccc2)cc1
Reactant: CN(Cc1c[nH]c(-c2cccnc2F)c1F)C(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CN(Cc1cn(S(=O)(=O)c2ccc(OCc3ccccc3)cc2)c(-c2cccnc2F)c1F)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 102.2 %

Procedure:
To a solution of tert-butyl {[4-fluoro-5-(2-fluoropyridin-3-yl)-1H-pyrrol-3-yl]methyl}methylcarbamate (200 mg) in tetrahydrofuran (10 mL) was added sodium hydride (60% in oil, 50 mg), and the mixture was stirred at room temperature for 10 min. 4-(Benzyloxy)benzenesulfonyl chloride (210 mg) was added and the mixture was further stirred for 30 min. The reaction mixture was diluted with water, and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=7:3→1:1) to give the title compound as a colorless oil (yield 360 mg, quantitative).
Reaction SMILES: C(O)=O.[NH2:4][CH2:5][CH2:6][C:7]1[CH:27]=[CH:26][C:10]([NH:11][CH:12]2[CH2:17][CH2:16][N:15]([C:18]([NH:20][CH2:21][C:22]([F:25])([F:24])[F:23])=[O:19])[CH2:14][CH2:13]2)=[CH:9][CH:8]=1.C([Si]([O:45][C:46]1[CH:51]=[CH:50][C:49]([O:52][CH2:53][CH:54]2[CH2:56][O:55]2)=[CH:48][CH:47]=1)(C1C=CC=CC=1)C1C=CC=CC=1)(C)(C)C>>[F:24][C:22]([F:25])([F:23])[CH2:21][NH:20][C:18]([N:15]1[CH2:16][CH2:17][CH:12]([NH:11][C:10]2[CH:9]=[CH:8][C:7]([CH2:6][CH2:5][NH:4][CH2:56][C@H:54]([OH:55])[CH2:53][O:52][C:49]3[CH:50]=[CH:51][C:46]([OH:45])=[CH:47][CH:48]=3)=[CH:27][CH:26]=2)[CH2:13][CH2:14]1)=[O:19]
Reactant: CC(C)(C)[Si](Oc1ccc(OCC2CO2)cc1)(c1ccccc1)c1ccccc1
Reactant: NCCc1ccc(NC2CCN(C(=O)NCC(F)(F)F)CC2)cc1
Solvent: O=CO
Product: O=C(NCC(F)(F)F)N1CCC(Nc2ccc(CCNC[C@H](O)COc3ccc(O)cc3)cc2)CC1
Yield: 18.1 %

Procedure:
4-[4-(2-Aminoethyl)anilino]-N-(2,2,2-trifluoroethyl)-1-piperidinecarboxamide formate (0.60 g, 1.53 mmol) was reacted with tert-butyl-(4-oxiranylmethoxy-phenoxy)-diphenyl-silane (0.550 g, 1.38 mmol) according to Procedure G to give the title compound (eluant: 20:1 chloroform-methanol) (0.188 g, 0.25 mmol).