Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N+:4]([O-:27])[CH:5]=[C:6]([Cl:26])[C:7]=1[CH2:8][C@@H:9]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH:18]([F:20])[F:19])=[C:13]([O:21][CH2:22][CH:23]2[CH2:25][CH2:24]2)[CH:12]=1)[OH:10].[C:28]([O:32][C:33]([NH:35][CH2:36][C:37](O)=[O:38])=[O:34])([CH3:31])([CH3:30])[CH3:29].C(Cl)CCl>CN(C=O)C.CN(C1C=CN=CC=1)C.O>[C:28]([O:32][C:33]([NH:35][CH2:36][C:37]([O:10][C@H:9]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH:18]([F:20])[F:19])=[C:13]([O:21][CH2:22][CH:23]2[CH2:25][CH2:24]2)[CH:12]=1)[CH2:8][C:7]1[C:6]([Cl:26])=[CH:5][N+:4]([O-:27])=[CH:3][C:2]=1[Cl:1])=[O:38])=[O:34])([CH3:31])([CH3:30])[CH3:29]
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Reactant: [O-][n+]1cc(Cl)c(C[C@H](O)c2ccc(OC(F)F)c(OCC3CC3)c2)c(Cl)c1
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Solvent: O
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)NCC(=O)O[C@@H](Cc1c(Cl)c[n+]([O-])cc1Cl)c1ccc(OC(F)F)c(OCC2CC2)c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 72.9 %

Procedure:
(S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-hydroxyethyl)pyridine 1-oxide (80 mg; 0.19 mmol) was dissolved in DMF (2 ml), then 2-(tert-butoxycarbonylamino)acetic acid (70 mg, 0.4 mmol), EDC (60 mg, 0.3 mmol), and DMAP (30 mg, 0.25 mmol) were added. The reaction was stirred at RT for 6 hours, then it was diluted with water and extracted with EtOAc. The organic phase was extracted with HCl 1M and with K2CO3 sat, dried over Na2SO4 and evaporated under vacuum to give 80 mg of the desired compound (Yield: 74%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([N+:9]([O-])=O)[CH:6]=[CH:5][C:4]=1[C:12]1[S:13][C:14]2[CH:20]=[C:19]([O:21][CH3:22])[CH:18]=[CH:17][C:15]=2[N:16]=1.O.O.[Sn](Cl)Cl>CCO>[NH2:9][C:7]1[CH:6]=[CH:5][C:4]([C:12]2[S:13][C:14]3[CH:20]=[C:19]([O:21][CH3:22])[CH:18]=[CH:17][C:15]=3[N:16]=2)=[C:3]([O:2][CH3:1])[CH:8]=1
Reactant: COc1ccc2nc(-c3ccc([N+](=O)[O-])cc3OC)sc2c1
Agent: Cl[Sn]Cl
Solvent: O
Solvent: CCO
Product: COc1ccc2nc(-c3ccc(N)cc3OC)sc2c1
Yield: 88.1 %

Procedure:
Prepared as described in the Nitro Reduction section using 2-(2-methoxy-4-nitrophenyl)-6-methoxybenzothiazole (1.0 g, 3.13 mmol) and tin (II) dichloride dihydrate (5.66 g, 25.08 mmol) in EtOH (50 ml) to give the title compound (0.79 g, 89%) as a pale yellow solid after work-up and recrystallisation from EtOH.
Reaction SMILES: [N+:1]([C:4]1[CH:8]=[CH:7][NH:6][N:5]=1)([O-:3])=[O:2].[CH3:9][C:10]1([CH3:27])[O:14][C@H:13]([CH2:15]OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:12][O:11]1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(OCC)(=O)C>[CH3:9][C:10]1([CH3:27])[O:14][C@H:13]([CH2:15][N:6]2[CH:7]=[CH:8][C:4]([N+:1]([O-:3])=[O:2])=[N:5]2)[CH2:12][O:11]1
Reactant: Cc1ccc(S(=O)(=O)OC[C@@H]2COC(C)(C)O2)cc1
Reactant: O=[N+]([O-])c1cc[nH]n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC1(C)OC[C@@H](Cn2ccc([N+](=O)[O-])n2)O1
Temperature: 90 °C
Yield: 71.7 %

Procedure:
A solution of 3-nitro-1H-pyrazole (Intermediate 2, 12.0 g, 106 mmol) in N,N-dimethylformamide (150 mL) was treated with para-toluenesulfonic acid (S)-2,2-dimethyl-[1,3]dioxolan-4-ylmethyl ester (25.5 g, 89.0 mmol), and potassium carbonate (24.5 g, 178 mmol). The reaction mixture was heated to 90° C. for 6 h under nitrogen. After this time, the reaction mixture was diluted with ethyl acetate, washed with water and a saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered, rinsed and concentrated in vacuo. Silica gel column chromatography (ISCO 120 g, 5-30% ethyl acetate/hexanes) afforded 1-((R)-2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)-3-nitro-1H-pyrazole (14.5 g, 73%) as a light yellow oil; ESI-LRMS m/e calcd for C9H13N3O4 [M+H+] 228, found 228 [M+H+].
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:4]=[C:5]([NH:9][N:10]=[C:11]([C:14]#[N:15])[C:12]#[N:13])[CH:6]=[CH:7][CH:8]=1.FC(F)(F)C1C=C(C=CC=1)N.C(#N)CC#N.O.[NH2:35][NH2:36]>>[NH2:15][C:14]1[C:11](=[N:10][NH:9][C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:1])([F:16])[F:17])[CH:4]=2)[C:12]([NH2:13])=[N:36][N:35]=1
Reactant: N#CC(C#N)=NNc1cccc(C(F)(F)F)c1
Reactant: NN
Agent: Nc1cccc(C(F)(F)F)c1
Solvent: N#CCC#N
Solvent: O
Product: NC1=NN=C(N)C1=NNc1cccc(C(F)(F)F)c1
Yield: 31 %

Procedure:
This compound was prepared using 119 mg (0.5 mmol) of 2-[(3-trifluoromethylphenyl)-hydrazono]malononitrile, which was derived from 3-(trifluoromethyl)aniline (125 μL, 1.0 mmol) and malononitrile (1.5 mmol) as described in Example 8, and hydrazine hydrate. Precipitate formed in the reaction tube approximately 10 min after the addition of hydrazine hydrate. The resulting solid was isolated by filtration, washed with ethanol, and dried to yield 43 mg (31%) of the title compound as a yellow solid.
Reaction SMILES: [CH3:1][CH:2]([NH:11][C:12]([C:14]1[C:22]2[C:17](=[N:18][CH:19]=[C:20]([C:23]3[C:31]4[C:26](=[CH:27][C:28]([F:32])=[CH:29][CH:30]=4)[N:25]([CH3:33])[N:24]=3)[N:21]=2)[N:16](COCC[Si](C)(C)C)[CH:15]=1)=[O:13])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.C(Cl)Cl.C(N)CN.O>C(O)(C(F)(F)F)=O>[CH3:1][CH:2]([NH:11][C:12]([C:14]1[C:22]2[C:17](=[N:18][CH:19]=[C:20]([C:23]3[C:31]4[C:26](=[CH:27][C:28]([F:32])=[CH:29][CH:30]=4)[N:25]([CH3:33])[N:24]=3)[N:21]=2)[NH:16][CH:15]=1)=[O:13])[CH2:3][O:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: CC(COc1ccccc1)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(C)c4cc(F)ccc34)nc12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: NCCN
Product: CC(COc1ccccc1)NC(=O)c1c[nH]c2ncc(-c3nn(C)c4cc(F)ccc34)nc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 0.1 %

Procedure:
2-(6-Fluoro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (1-methyl-2-phenoxy-ethyl)-amide (80 mg, 0.139 mol) was dissolved in a 4:6 solution of TFA:DCM (6.5 mL). After stirring at room temperature overnight, the volatiles were removed under reduced pressure. The crude material was then dissolved in dichloromethane and treated with ethylenediamine (837 mg, 13.9 mmol). After stirring at room temperature overnight, water was added and the resulting precipitate was collected by filtration to provide 35 mg (57%) of 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (1-methyl-2-phenoxy-ethyl)-amide as a yellow solid.
Reaction SMILES: [F:1][C:2]([F:13])([C:9]([F:12])([F:11])[F:10])[CH2:3][CH2:4][CH2:5][C:6](O)=[O:7].B.CSC.C(N(CC)CC)C.[CH3:25][S:26](Cl)(=[O:28])=[O:27]>O1CCCC1.O.CO>[CH3:25][S:26]([O:7][CH2:6][CH2:5][CH2:4][CH2:3][C:2]([F:13])([F:1])[C:9]([F:12])([F:11])[F:10])(=[O:28])=[O:27]
Reactant: CS(=O)(=O)Cl
Reactant: O=C(O)CCCC(F)(F)C(F)(F)F
Agent: B
Solvent: CO
Solvent: O
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCCCCC(F)(F)C(F)(F)F
Temperature: -30 °C
Reaction time: 3 h
Yield: 81.1 %

Procedure:
5,5,6,6,6-Pentafluorohexanoic acid (95 g, 460.92 mmol) was dissolved in anhydrous tetrahydrofuran (1L) and cooled to −30° C. To this solution, borane-methyl sulfide complex (10 M in THF, 92.2 ml, 921.84 mmol) was slowly added dropwise, followed by stirring for 3 hours at room temperature. After treatment with methanol at 0° C., water was added to the reaction mixture, which was then extracted twice with ether. The combined organic layers were washed with water and saturated aqueous sodium chloride, and then dried over anhydrous magnesium sulfate. After distilling off the solvent, the resulting residue was dissolved in dichloromethane (1500 ml), and triethylamine (160.6 ml, 1.15 mol) and methanesulfonyl chloride (46.4 ml, 599.19 mmol) were added dropwise thereto at 0° C., followed by stirring for 1 hour. After the reaction was completed, water was added to the reaction mixture, which was then extracted twice with dichloromethane. The combined organic layers were washed with water and saturated aqueous sodium chloride, and then dried over anhydrous magnesium sulfate. After distilling off the solvent, the residue was purified by silica gel column chromatography (eluent: ethyl acetate/hexane=1/4) to give 1-methanesulfonyloxy-5,5,6,6,6-pentafluorohexane (101 g, Yield 81%).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][S:16]([CH3:19])(=[O:18])=[O:17])[CH:10]=2)[N:3]=1.[CH:20]1([O:23][C:24]2[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:25]=2B2OC(C)(C)C(C)(C)O2)[CH2:22][CH2:21]1.C(=O)([O-])[O-].[K+].[K+]>COCCOC>[CH:20]1([O:23][C:24]2[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:25]=2[C:2]2[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]3[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][S:16]([CH3:19])(=[O:18])=[O:17])[CH:10]=3)[N:3]=2)[CH2:22][CH2:21]1
Reactant: CS(=O)(=O)Cc1cccc(Nc2ncnc(Cl)n2)c1
Reactant: CC1(C)OB(c2ccc(F)cc2OC2CC2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Product: CS(=O)(=O)Cc1cccc(Nc2ncnc(-c3ccc(F)cc3OC3CC3)n2)c1
Temperature: 100 °C
Reaction time: 1 h
Yield: 26.8 %

Procedure:
A mixture of 4-chloro-N-{3-[(methylsulfonyl)methyl]phenyl}-1,3,5-triazin-2-amine (134 mg), (Intermediate 1.4), 2-[2-(cyclopropyloxy)-4-fluorophenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (150 mg; 0.539 mmol) and Pd(dppf)C12 (55 mg; 0.06 mmol) in 1,2-dimethoxyethane (2.0 ml) and 2 M solution of potassium carbonate (0.45 ml) was degassed using argon. The batch was stirred under argon for 1 hour at 100° C. After cooling the batch was diluted with ethyl acetate (35 ml) and THF (35 ml). The organic phase was washed with brine, dried (sodium sulfate) and concentrated. The residue was purified by preparative HPLC to give the desired product (38 mg; 0.12 mmol).
Reaction SMILES: [N:1]1([C:12]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:13])[CH2:6][CH2:5][CH2:4][CH:3]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:2]1.[CH3:22][Si]([N-][Si](C)(C)C)(C)C.[Li+].CI.[Cl-].[NH4+]>C1COCC1>[CH3:22][C:3]1([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:4][CH2:5][CH2:6][N:1]([C:12]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:13])[CH2:2]1
Reactant: CCOC(=O)C1CCCN(C(=O)OCc2ccccc2)C1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [Li+]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CI
Product: CCOC(=O)C1(C)CCCN(C(=O)OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 98.6 %

Procedure:
To 1-benzyl 3-ethyl piperidine-1,3-dicarboxylate (3.0 g, 10.3 mmol) in THF (20 mL) was added lithium bis(trimethylsilyl)amide (12.9 mL, 12.9 mmol) in THF at −78° C., and the reaction was stirred at this temperature for 20 minutes. MeI (0.867 mL, 13.9 mmol) was added, and the reaction was warmed to room temperature. After 2 hours at room temperature, the mixture was poured onto saturated ammonium chloride (20 mL) and extracted with ether, washed with brine and dried over sodium sulfate. After removal of the solvent, the residue was purified by chromatography on silica gel (hexane:ethyl acetate 5:1) to give 1-benzyl 3-ethyl 3-methylpiperidine-1,3-dicarboxylate (3.1 g, 98% yield) as an oil.
Reaction SMILES: [N+:1]([C:4]1[C:5]([NH2:11])=[C:6]([NH2:10])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[C:12]1([CH3:22])[CH:17]=[CH:16][C:15]([S:18](Cl)(=[O:20])=[O:19])=[CH:14][CH:13]=1.O>N1C=CC=CC=1>[NH2:11][C:5]1[C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=[CH:7][C:6]=1[NH:10][S:18]([C:15]1[CH:16]=[CH:17][C:12]([CH3:22])=[CH:13][CH:14]=1)(=[O:20])=[O:19]
Reactant: Nc1cccc([N+](=O)[O-])c1N
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Solvent: O
Product: Cc1ccc(S(=O)(=O)Nc2cccc([N+](=O)[O-])c2N)cc1

Procedure:
0.1 mol (15.3 g) of 3-nitro-ortho-phenylenediamine is dissolved in 50 ml of pyridine, and 0.11 mol (21 g) of para-toluenesulphonyl chloride is then added gradually, whilst stirring, at between 40° and 45° C. When the addition has ended, the stirring is maintained for 15 minutes and the reaction medium is then poured into 250 ml of iced water. The expected product precipitates. It is filtered off, washed with water and recrystallised from acetic acid. It melts at 195° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([Cl:10])[C:5]([C:8]#[N:9])=[N:6][CH:7]=1.[OH:11][C@H:12]1[C@@H:19]2[N:15]([C:16](=[O:33])N(C3C4CCCCC=4C(C#N)=CC=3)[C:18]2=[O:20])[CH2:14][CH2:13]1>>[Cl:10][C:4]1[C:5]([C:8]#[N:9])=[N:6][CH:7]=[C:2]([N:1]2[C:18](=[O:20])[C@@H:19]3[C@H:12]([OH:11])[CH2:13][CH2:14][N:15]3[C:16]2=[O:33])[CH:3]=1
Reactant: N#Cc1ccc(N2C(=O)[C@@H]3[C@H](O)CCN3C2=O)c2c1CCCC2
Reactant: N#Cc1ncc(N)cc1Cl
Product: N#Cc1ncc(N2C(=O)[C@@H]3[C@H](O)CCN3C2=O)cc1Cl

Procedure:
The title compound was synthesized from compound 44D by procedures analogous to those described for Examples 2E to 2F. HPLC: 100% at 1.67 min. (retention time) (Conditions: Shim-Pak VP-ODS (4.6×50 mm); Eluted with 0% to 100% B, 4 min gradient, 1 min hold. (A=90% H2O—10% MeOH—0.1% H3PO4 and B=10% H2O—90% MeOH—0.1% H3PO4); Flow rate at 4 mL/min UV detection at 220 nm); MS(ES) m/z 293 [M+H]+.
Reaction SMILES: [CH2:1]([C:3]1[NH:7][N:6]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=2)[C:5](=[O:15])[C:4]=1[C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH3:2].F[C:22](F)(F)S(OC)(=O)=O>>[CH2:1]([C:3]1[N:7]([CH3:22])[N:6]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=2)[C:5](=[O:15])[C:4]=1[C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH3:2]
Reactant: COS(=O)(=O)C(F)(F)F
Reactant: CCOC(=O)c1c(CC)[nH]n(-c2ccc(F)cc2)c1=O
Product: CCOC(=O)c1c(CC)n(C)n(-c2ccc(F)cc2)c1=O
Yield: 57 %

Procedure:
In the same manner as in Reference Example 64 and using ethyl 5-ethyl-2-(4-fluorophenyl)-3-oxo-2,3-dihydro-1H-pyrazole-4-carboxylate (3.1 g, 11 mmol) and methyl trifluoromethanesulfonate (3.7 mL) as starting materials, the title compound (1.9 g, 57%) was obtained as a pale-yellow solid.
Reaction SMILES: COC1C=CC(C[N:8]2[CH:12]=[C:11]([C:13]3[N:14]=[C:15]([NH:18][C:19]4[N:24]=[C:23]([CH3:25])[CH:22]=[CH:21][N:20]=4)[S:16][CH:17]=3)[C:10]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[N:9]2)=CC=1.O>C(O)(C(F)(F)F)=O>[CH3:25][C:23]1[CH:22]=[CH:21][N:20]=[C:19]([NH:18][C:15]2[S:16][CH:17]=[C:13]([C:11]3[C:10]([C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=4)=[N:9][NH:8][CH:12]=3)[N:14]=2)[N:24]=1
Reactant: COc1ccc(Cn2cc(-c3csc(Nc4nccc(C)n4)n3)c(-c3ccccc3)n2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: Cc1ccnc(Nc2nc(-c3c[nH]nc3-c3ccccc3)cs2)n1
Yield: 52.9 %

Procedure:
According to Scheme 12 Step 2: A solution of 4-(1-(4-methoxybenzyl)-3-phenyl-1H-pyrazol-4-yl)-N-(4-methylpyrimidin-2-yl)thiazol-2-amine (0.17 mmol, 77 mg) in TFA (1 mL) was stirred at 150° C. for 5 minutes under microwave heating. Water was added and was extracted with DCM. The organic layer was dried over MgSO4, was filtered and was concentrated. The crude compound was purified by flash chromatography with silica gel using DCM/AcOEt (100:10 to 50:50) to yield N-(4-methylpyrimidin-2-yl)-4-(3-phenyl-1H-pyrazol-4-yl)thiazol-2-amine (90 μmol, 30 mg, 50%) as a yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][C:10]#[N:11])[CH:6]=[CH:7][CH:8]=1.[H-].[Na+].Br[CH:15]([CH3:17])[CH3:16]>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]([CH:15]([CH3:17])[CH3:16])[C:10]#[N:11])[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(CC#N)c1
Reactant: CC(C)Br
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cccc(C(C#N)C(C)C)c1
Yield: 79.8 %

Procedure:
By working in a way similar to that described in example 16 but using 3-methoxy-phenyl-acetonitrile (4.4 g, 30 mmoles), anhydrous DMF (40 ml), NaH (55-65%, 1.44 g, 36.3 mmoles) and 2-bromo-propane (4.46 g, 36.3 mmoles), 4.53 g of the title compound were obtained (yield: 79.9%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([N:7]=[CH:8][C:9](=[O:13])[NH:10]2)=[CH:5][CH:4]=1.[H-].[Li+].Br[CH2:17][CH2:18][CH2:19][CH2:20][O:21][Si:22]([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23].[I-].[Na+]>CN(C)C=O.C(OCC)(=O)C>[Si:22]([O:21][CH2:20][CH2:19][CH2:18][CH2:17][N:10]1[C:11]2[C:6](=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[CH:12]=2)[N:7]=[CH:8][C:9]1=[O:13])([C:25]([CH3:26])([CH3:27])[CH3:28])([CH3:23])[CH3:24]
Reactant: COc1ccc2ncc(=O)[nH]c2c1
Reactant: CC(C)(C)[Si](C)(C)OCCCCBr
Agent: [H-]
Agent: [I-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1ccc2ncc(=O)n(CCCCO[Si](C)(C)C(C)(C)C)c2c1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 44 %

Procedure:
7-Methoxyquinoxalin-2(1H)-one (synthesized with reference to WO2009/1126; 400 mg, 2.27 mmol) was dissolved in N,N-dimethylformamide (8 ml). The solution was cooled in an ice bath, lithium hydride (purity 90%, 26 mg, 2.95 mmol) was then added thereto and the mixture was stirred at room temperature for 40 minutes. The reaction solution was cooled in an ice bath again, (4-bromobutoxy)(tert-butyl)dimethylsilane (synthesized with reference to Journal of Medicinal Chemistry, 2008, vol. 51, No. 18, pages 5690-5701; 580 mg, 2.17 mmol) and sodium iodide (442 mg, 2.95 mmol) were added thereto, and the mixture was stirred overnight at room temperature. The reaction mixture was diluted with ethyl acetate, washed sequentially with saturated sodium chloride solution (×2), water and saturated sodium chloride solution, dried over anhydrous magnesium sulfate and the solvent was removed under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane/ethyl acetate) to yield 363 mg (44%) of the title compound in the form of a light yellow syrup.
Reaction SMILES: C[O:2][C:3](=[O:42])[C@@H:4]([NH:8][S:9]([C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:23]=[CH:22][C:21]([NH:24][C:25]([C:27]3[O:28][C:29]4[CH:36]=[CH:35][C:34]([C:37]([Cl:39])=[CH2:38])=[C:33]([O:40][CH3:41])[C:30]=4[C:31]=3[CH3:32])=[O:26])=[CH:20][CH:19]=2)=[CH:14][CH:13]=1)(=[O:11])=[O:10])[CH:5]([CH3:7])[CH3:6].[Li+].[OH-]>C1COCC1>[Cl:39][C:37]([C:34]1[CH:35]=[CH:36][C:29]2[O:28][C:27]([C:25]([NH:24][C:21]3[CH:22]=[CH:23][C:18]([C:15]4[CH:14]=[CH:13][C:12]([S:9]([NH:8][C@@H:4]([CH:5]([CH3:7])[CH3:6])[C:3]([OH:42])=[O:2])(=[O:11])=[O:10])=[CH:17][CH:16]=4)=[CH:19][CH:20]=3)=[O:26])=[C:31]([CH3:32])[C:30]=2[C:33]=1[O:40][CH3:41])=[CH2:38]
Reactant: C=C(Cl)c1ccc2oc(C(=O)Nc3ccc(-c4ccc(S(=O)(=O)N[C@H](C(=O)OC)C(C)C)cc4)cc3)c(C)c2c1OC
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: C=C(Cl)c1ccc2oc(C(=O)Nc3ccc(-c4ccc(S(=O)(=O)N[C@H](C(=O)O)C(C)C)cc4)cc3)c(C)c2c1OC
Temperature: 25 °C
Reaction time: 72 h
Yield: 81.2 %

Procedure:
To (S)-2-(4′-{[5-(1-chloro-vinyl)-4-methoxy-3-methyl-benzofuran-2-carbonyl]-amino}-biphenyl-4-sulfonylamino)-3-methyl-butyric acid methyl ester (29 mg) was added 0.5 mL of THF and 2 mL of LiOH solution (3.6 g LiOH/50 mL MeOH/50 mL H2O). The mixture was stirred at room temperature for 3 days. The solvents were removed under vacuum and the residue was triturated with 2 mL of 2N HCl and filtered. The solid product was dried under vacuum. 23 mg of desired (S)-2-(4′-{[5-(1-chloro-vinyl)-4-methoxy-3-methyl-benzofuran-2-carbonyl]-amino}-biphenyl-4-sulfonylamino)-3-methyl-butyric acid, obtained as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.8 (dd, J=12.9, 6.8 Hz, 6 H) 2.0 (m, 1 H) 2.7 (s, 3 H) 3.6 (dd, J=9.3, 6.1 Hz, 1 H) 4.0 (s, 3 H) 5.9 (d, J=2.3 Hz, 1 H) 6.7 (d, J=2.3 Hz, 1 H) 7.0 (d, J=8.6 Hz, 1 H) 7.7 (d, J=8.6 Hz, 1 H) 7.8 (m, 8 H) 8.1 (d, 1 H) 10.3 (s, 1 H) 12.6 (s, 1 H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[C:4]([F:11])[CH:3]=1.[Cl:12][C:13]1[C:18]([Cl:19])=[CH:17][CH:16]=[CH:15][C:14]=1[O:20][CH3:21].[Al+3].[Cl-].[Cl-].[Cl-].Cl>ClCCCl>[Cl:19][C:18]1[C:13]([Cl:12])=[C:14]([O:20][CH3:21])[CH:15]=[CH:16][C:17]=1[C:6]([C:5]1[CH:9]=[CH:10][C:2]([Cl:1])=[CH:3][C:4]=1[F:11])=[O:7]
Reactant: O=C(Cl)c1ccc(Cl)cc1F
Reactant: COc1cccc(Cl)c1Cl
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: COc1ccc(C(=O)c2ccc(Cl)cc2F)c(Cl)c1Cl
Temperature: 40 °C

Procedure:
To a mixture of 46 g of 4-chloro-2-fluorobenzoyl chloride and 38.9 g of 2,3-dichloroanisole in 150 ml of 1,2-dichloroethane, 32 g of AlCl3 is added gradually. The mixture is warmed to 40° C. with a vigorous evolution of gas. The mixture is poured into concentrated HCl and ice. The organic layer is separated and the aqueous layer is extracted with additional organic solvent. The combined organic extracts are washed with water, dried over Na2SO4 and evaporated. The crude product is triturated with hexane to give 2,3-dichloro-4-methoxy-4'-chloro-2'-fluorobenzophenone. An analytical sample is recrystallized from EtOH, mp 115°-116° C.
Reaction SMILES: [C:1]12([C:11]([NH2:13])=O)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.S(C)C.CO>C1COCC1>[C:1]12([CH2:11][NH2:13])[CH2:8][CH:7]3[CH2:6][CH:5]([CH2:4][CH:3]([CH2:9]3)[CH2:2]1)[CH2:10]2
Reactant: NC(=O)C12CC3CC(CC(C3)C1)C2
Solvent: CO
Solvent: CSC
Solvent: C1CCOC1
Product: NCC12CC3CC(CC(C3)C1)C2
Temperature: 25 °C
Yield: 59 %

Procedure:
To a solution of admantane-1-carboxamide (2 g, 11.17 mmol) in THF (50 mL) was added BH3.Me2S (10.2 M, 3.4 mL, 34.7 mmol) under nitrogen. The mixture was heated at reflux overnight. The solution was cooled to rt. Methanol (20 mL) was added to the solution. The mixture was concentrated under vacuum to give crude product, which was purified by chromatography on silica gel to afford (1-adamantyl)methylamine (1.09 g, 59%). 1H NMR (CDCl3, 400 MHz): δ=1.44-1.96 (m, 15H), 2.30 (s, 2H).
Reaction SMILES: COCCO[AlH2-]OCCOC.[Na+].[H-].[H-].COCCO[Al+]OCCOC.[Na+].C[O:28][C:29](=O)[C:30]1[CH:35]=[CH:34][C:33]([O:36][CH2:37][CH:38]=[C:39]([CH2:41][CH2:42][CH:43]=[C:44]([CH2:46][CH2:47][CH:48]=[C:49]([CH3:51])[CH3:50])[CH3:45])[CH3:40])=[CH:32][CH:31]=1.[OH-].[Na+].[H][H]>C1(C)C=CC=CC=1.CC(O)C.O>[CH2:37]([O:36][C:33]1[CH:32]=[CH:31][C:30]([CH2:29][OH:28])=[CH:35][CH:34]=1)[CH:38]=[C:39]([CH2:41][CH2:42][CH:43]=[C:44]([CH2:46][CH2:47][CH:48]=[C:49]([CH3:51])[CH3:50])[CH3:45])[CH3:40]
Reactant: COC(=O)c1ccc(OCC=C(C)CCC=C(C)CCC=C(C)C)cc1
Reactant: [H][H]
Agent: COCCO[Al+]OCCOC
Agent: COCCO[AlH2-]OCCOC
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CC(C)O
Product: CC(C)=CCCC(C)=CCCC(C)=CCOc1ccc(CO)cc1

Procedure:
4 g (14 mmol) Vitride®, which is 70% sodium bis-(2-methoxy-ethoxy)-aluminum dihydride, were added dropwise with stirring and cooling with ice at 5° to 15° C. to a solution of 5 g (14 mmol) 4-farnesyloxybenzoic acid methyl ester in 30 ml toluene. The mixture was then heated for 2 hours to the boiling temperature, cooled and 10% sodium hydroxide solution added dropwise while cooling with ice (until the evolution of hydrogen stopped). After approx. 10 ml water and a few drops 2-propanol had been added, the toluene phase was separated off, the aqueous phase was washed twice with toluene and, after drying with sodium sulfate, was concentrated by evaporation. The residue was chromatographed on silica gel (Merck) (eluent: methylene chloride/methanol 99:1). 4-farnesyloxybenzyl alcohol having a refractive index n20 of 1.5305 was obtained in a yield of 3.6 g (78% of the theoretical).