Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]([CH3:15])([CH3:14])[CH2:11][CH2:12][OH:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].CC(C)([O-])C.[K+].[F:22][C:23]1[CH:30]=[CH:29][C:28]([Br:31])=[CH:27][C:24]=1[CH2:25]Br.C(Cl)Cl>O1CCCC1>[C:1]([O:5][C:6]([NH:8][CH2:9][C:10]([CH3:15])([CH3:14])[CH2:11][CH2:12][O:13][CH2:25][C:24]1[CH:27]=[C:28]([Br:31])[CH:29]=[CH:30][C:23]=1[F:22])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(CCO)CNC(=O)OC(C)(C)C
Reactant: Fc1ccc(Br)cc1CBr
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC(C)(CCOCc1cc(Br)ccc1F)CNC(=O)OC(C)(C)C
Temperature: -45 °C
Reaction time: 0.5 h
Yield: 74.2 %

Procedure:
A stirred solution of 4-(t-butoxycarbonylamino)-3,3-dimethylbutan-1-ol (1.0 g, 4.60 mmol) in tetrahydrofuran (33 ml) at −45° C. was treated with potassium t-butoxide (1 M in tetrahydrofuran, 5.06 ml, 5.06 mmol). The anion was stirred for 30 minutes at −45° C., then cooled to −78° C. and treated with a tetrahydrofuran solution of 2-fluoro-5-bromobenzyl bromide (1.23 g, 4.60 mmol). The resulting yellow mixture was slowly warmed to 0° C. and stirred for about four hours. The cloudy reaction mixture was diluted wtih methylene chloride (100 ml) and washed with 1 M potassium carbonate. The organic fraction was dried over sodium sulfate, filtered, and the solvents were removed in vacuo. The residue was further purified by preparative high performance liquid chromatography to yield 1.38 grams (74%) of the title intermediate as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([Cl:10])[C:8]=1[Cl:9])[NH2:5].[C:11](=O)([O-])[O-].[K+].[K+].IC>C(#N)C>[CH3:11][NH:5][C:4]1[CH:3]=[C:2]([Cl:1])[C:8]([Cl:9])=[C:7]([Cl:10])[CH:6]=1
Reactant: O=C([O-])[O-]
Reactant: Nc1cc(Cl)c(Cl)c(Cl)c1
Agent: [K+]
Solvent: CC#N
Solvent: CI
Product: CNc1cc(Cl)c(Cl)c(Cl)c1
Temperature: 40 °C
Reaction time: 72 h
Yield: 41.9 %

Procedure:
To a 100 ml three neck round bottom flask was added 3,4,5-trichloroaniline (1.96 g), potassium carbonate (1.66 g), acetonitrile (25 mL) and iodomethane (1.42 g). The reaction mixture was stirred at 40° C. for 3 days under nitrogen in the dark. The reaction mixture was then quenched with ethyl acetate (50 ml) and filtered. The residue was washed with ethyl acetate (3×20 ml). The filtrate and the washings were combined and washed with water (3×30 ml). The organic layer was then filtered through anhydrous MgSO4 and evaporated under reduced pressure. The residue was dissolved in a minimum amount of ethyl acetate/hexane 1:12 and the solution was placed on a wet column of silica gel (80 g) and eluted with ethyl acetate/hexane 300 ml (1:12), 500 ml (1:8) to afford 0.88 g of N-methyl-3,4,5-trichloraniline (42%) as a white solid. The product was used directly for the condensation without characterization. To a 100 ml three neck round bottom flask was added anhydrous DMSO (5 ml), N-methyl-3,4,5-trichloroaniline (0.88 g) crude compound 117 (0.20 g) and anhydrous potassium carbonate (0.56 g). The reaction mixture was stirred at 45° C. for 24 h and then quenched with distilled water (15 ml). The resulting suspension was stirred at room temperature for 4 h and filtered. The residue was extracted with MeOH (100 ml) several times and the extracts which showed a major spot of the product on TLC were pooled and mixed with silica gel (2 g). The mixture was evaporated under reduced pressure and dried in vacuo. The residue was ground into fine powder and poured on top of a dry column of silica gel (40 g). The column was eluted with 3% MeOH in CHCl3. Fractions corresponding to a single spot of the product were pooled and evaporated. The residue was washed with ether and air dried to afford 0.06 g (16% for two steps) of compound 432 as a light yellow solid.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]3[C:18]4[C:13](=[N:14][CH:15]=[N:16][C:17]=4[NH2:19])[N:12]([CH3:20])[N:11]=3)=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[F:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[CH2:28][C:29](O)=[O:30].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.O>[F:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[CH2:28][C:29]([N:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]3[C:18]4[C:13](=[N:14][CH:15]=[N:16][C:17]=4[NH2:19])[N:12]([CH3:20])[N:11]=3)=[CH:7][CH:8]=2)[CH2:3][CH2:2]1)=[O:30]
Reactant: Cn1nc(-c2ccc3c(c2)CCN3)c2c(N)ncnc21
Reactant: O=C(O)Cc1ccccc1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cn1nc(-c2ccc3c(c2)CCN3C(=O)Cc2ccccc2F)c2c(N)ncnc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In a 20 mL vial, to the solution of 3-(2,3-dihydro-1H-indol-5-yl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine.2HCl (70 mg, 0.206 mmol), (2-fluorophenyl)acetic acid (31.8 mg, 0.206 mmol), HATU (78 mg, 0.206 mmol) in DMF (2 mL) was added Hunig's base (0.144 mL, 0.825 mmol). The mixture was stirred at room temperature for overnight. LCMS showed reaction was completed. The reaction was poured into water, white solid formed. The white solid was filtered to give the product. LC/MS (ES) m/z=403.2 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ ppm 3.25-3.32 (m, 2H), 3.91-3.99 (m, 5H), 4.31 (t, J=8.46 Hz, 2H), 7.16-7.24 (m, 2H), 7.32-7.39 (m, 2H), 7.44 (d, J=8.08 Hz, 1H), 7.53 (s, 1H), 8.15 (d, J=8.34 Hz, 1H), 8.25 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:22])=[CH:4][C:5]([F:21])=[C:6]([C:8]2[C:9](=[O:20])[N:10]([CH3:19])[C:11]3[C:16]([CH:17]=2)=[CH:15][N:14]=[C:13](Cl)[CH:12]=3)[CH:7]=1.[CH3:23][O:24][C:25]1[CH:33]=[CH:32][C:28]([CH2:29][NH:30][CH3:31])=[CH:27][CH:26]=1>>[CH3:23][O:24][C:25]1[CH:33]=[CH:32][C:28]([CH2:29][N:30]([CH3:31])[C:13]2[CH:12]=[C:11]3[C:16]([CH:17]=[C:8]([C:6]4[CH:7]=[C:2]([NH2:1])[C:3]([F:22])=[CH:4][C:5]=4[F:21])[C:9](=[O:20])[N:10]3[CH3:19])=[CH:15][N:14]=2)=[CH:27][CH:26]=1
Reactant: Cn1c(=O)c(-c2cc(N)c(F)cc2F)cc2cnc(Cl)cc21
Reactant: CNCc1ccc(OC)cc1
Product: COc1ccc(CN(C)c2cc3c(cn2)cc(-c2cc(N)c(F)cc2F)c(=O)n3C)cc1
Temperature: 200 °C
Yield: 91 %

Procedure:
3-(5-Amino-2,4-difluorophenyl)-7-chloro-1-methyl-1,6-naphthyridin-2(1H)-one (2.4 g, 7.5 mmol) and 4-methoxy-N-methylbenzyl amine (10 mL) were combined in a sealed vessel and heated to 200° C. overnight. The volatiles were removed in vacuo and the residue was purified by column chromatography to give 7-((4-methoxybenzyl)(methyl)amino)-3-(5-amino-2,4-difluorophenyl)-1-methyl-1,6-naphthyridin-2(1H)-one (3 g, 91% yield), which was used in the next step without further purification.
Reaction SMILES: [Cl-].[Li+].C[Si](C[Mg]Cl)(C)C.[CH:10]1([Mg]Br)[CH2:14][CH2:13][CH2:12][CH2:11]1.[F:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][C:19]=1[C:26]1[C:27]([CH:42]=[O:43])=[CH:28][C:29]([O:32][CH2:33][C:34]2[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=2)=[CH:30][CH:31]=1.[Cl-].[NH4+]>C(OCC)C.C1COCC1.[Cl-].[Zn+2].[Cl-]>[CH:10]1([CH:42]([C:27]2[CH:28]=[C:29]([O:32][CH2:33][C:34]3[CH:35]=[CH:36][C:37]([O:40][CH3:41])=[CH:38][CH:39]=3)[CH:30]=[CH:31][C:26]=2[C:19]2[CH:20]=[C:21]([O:24][CH3:25])[CH:22]=[CH:23][C:18]=2[F:17])[OH:43])[CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: Br[Mg]C1CCCC1
Reactant: COc1ccc(COc2ccc(-c3cc(OC)ccc3F)c(C=O)c2)cc1
Agent: C[Si](C)(C)C[Mg]Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: COc1ccc(COc2ccc(-c3cc(OC)ccc3F)c(C(O)C3CCCC3)c2)cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a mixture of zinc chloride (34 mg), lithium chloride (117 mg) and THF (1 mL) was added a solution (1 M, 0.49 mL) of trimethylsilylmethylmagnesium chloride in diethyl ether, and the mixture was stirred at room temperature for 15 min. To the reaction mixture was added a solution (1 M, 2.7 mL) of cyclopentylmagnesium bromide in THF, and the mixture was stirred at room temperature for 45 min. To the reaction mixture was added a solution of 2′-fluoro-5′-methoxy-4-((4-methoxybenzyl)oxy)biphenyl-2-carbaldehyde (301 mg) obtained in Example 93, step 2, in THF (2 mL) at 0° C., and the mixture was stirred at 0° C. for 1 hr. To the reaction mixture was added saturated aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (40 mg) as a colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[C:9]1[CH:13]=[CH:12][O:11][CH:10]=1.[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:22](=[O:29])[CH2:23][O:24][CH2:25][C:26](O)=[O:27])=[C:17]([C:30]([O:32]C)=[O:31])[CH:16]=1>>[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:22](=[O:29])[CH2:23][O:24][CH2:25][C:26]([NH:6][C:5]2[CH:7]=[CH:8][C:2]([F:1])=[C:3]([C:9]3[CH:13]=[CH:12][O:11][CH:10]=3)[CH:4]=2)=[O:27])=[C:17]([CH:16]=1)[C:30]([OH:32])=[O:31]
Reactant: COC(=O)c1cc(Cl)ccc1NC(=O)COCC(=O)O
Reactant: Nc1ccc(F)c(-c2ccoc2)c1
Product: O=C(COCC(=O)Nc1ccc(Cl)cc1C(=O)O)Nc1ccc(F)c(-c2ccoc2)c1

Procedure:
Using the same method as in Example 15-(i), 4-fluoro-3-(furan-3-yl)aniline was reacted with the (2-([4-chloro-2-(methoxycarbonyl)phenyl]amino)-2-oxoethoxy)acetic acid obtained in Example 1-(i) to give 5-chloro-2-([(2-([4-fluoro-3-(furan-3-yl)phenyl]amino)-2-oxoethoxy)acetyl]amino)benzoic acid.methyl ester (yield: 52%).
Reaction SMILES: [Br:1][C:2]1[C:3]([O:21][CH3:22])=[CH:4][C:5]2[NH:11][C:10](=O)[CH2:9][N:8]=[C:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[Cl:19])[C:6]=2[CH:20]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:32])=CC=1>COCCOC>[Br:1][C:2]1[C:3]([O:21][CH3:22])=[CH:4][C:5]2[NH:11][C:10](=[S:32])[CH2:9][N:8]=[C:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[Cl:19])[C:6]=2[CH:20]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: COc1cc2c(cc1Br)C(c1ccccc1Cl)=NCC(=O)N2
Solvent: COCCOC
Product: COc1cc2c(cc1Br)C(c1ccccc1Cl)=NCC(=S)N2
Temperature: 85 °C
Yield: 81.1 %

Procedure:
A mixture of 2.0 g (0.0053 mole) of 7-bromo-5-(2-chlorophenyl)-1,3-dihydro-8-methoxy-2H-1,4-benzodiazepin-2-one (Id), 200 mL of 1,2-dimethoxyethane and 2.13 g (0.0053 mole) of Lawesson's reagent (2,4-bis(4-methoxyphenyl)-2,4-disulfide-1,3,2,4-dithiadiphosphetane) was heated at 85° C. for 1 hour, then cooled and poured onto ice cold sodium bicarbonate solution. The mixture was extracted twice with ethyl acetate-methanol (9:1), and the organic layers washed successively with water and brine. The combined extracts were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Trituration of the residue with ethyl acetate provided 1.7 g of 7-bromo-5-(2-chlorophenyl)-1,3-dihydro-8-methoxy-2H-1,4-benzodiazepin-2-thione (IId). MH+/Z=395.
Reaction SMILES: [O:1]=[S:2]1(=[O:27])[N:7]=[CH:6][C:5]2[CH:8]=[C:9]([CH2:12][N:13](C3C=CC=CC=3C#N)[N:14]3[CH:18]=[CH:17][N:16]=[CH:15]3)[CH:10]=[CH:11][C:4]=2[O:3]1.[BH4-].[Na+].[NH4+:30].[Cl-].O>CO>[O:1]=[S:2]1(=[O:27])[NH:7][CH2:6][C:5]2[CH:8]=[C:9]([CH2:12][N:13]([C:10]3[CH:9]=[CH:8][C:5]([C:6]#[N:30])=[CH:4][CH:11]=3)[N:14]3[CH:18]=[CH:17][N:16]=[CH:15]3)[CH:10]=[CH:11][C:4]=2[O:3]1
Reactant: [NH4+]
Reactant: N#Cc1ccccc1N(Cc1ccc2c(c1)C=NS(=O)(=O)O2)n1ccnc1
Agent: [BH4-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: N#Cc1ccc(N(Cc2ccc3c(c2)CNS(=O)(=O)O3)n2ccnc2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 82 %

Procedure:
To a suspension of +[N-[(2,2-dioxido-1,2,3-benzoxathiazin-6-yl)methyl]-N-(1H-imidazol-1-yl)amino]benzonitrile (0.40 g, 1.05 mmol) in methanol (8 ml) was added portionwise NaBH4 (0.08 g, 2.11 mmol) and the reaction mixture was stirred at room temperature for 3 h. After addition of a saturated solution of NH4Cl (3 ml) and water (40 ml), the precipitate obtained was filtered, washed with water and dried to give a white solid. Crystallization from ethyl acetate with ethanol yielded the expected product (0.40 g, 82%, mp: 190° C.).
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:12][CH2:11][N:10]2[CH:5]([CH2:6][CH2:7][CH2:8][CH2:9]2)[CH2:4]1.[CH2:13]([N:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:17]([C:24](O)=[O:25])=[CH:16]1)[CH3:14]>>[CH2:4]1[CH:5]2[N:10]([CH2:9][CH2:8][CH2:7][CH2:6]2)[CH2:11][CH2:12][CH:3]1[CH2:2][O:1][C:24]([C:17]1[C:18]2[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:15]([CH2:13][CH3:14])[CH:16]=1)=[O:25]
Reactant: OCC1CCN2CCCCC2C1
Reactant: CCn1cc(C(=O)O)c2ccccc21
Product: CCn1cc(C(=O)OCC2CCN3CCCCC3C2)c2ccccc21

Procedure:
eq-2-Hydroxymethylquinolizidine (N. J. Leonard et al, J. Org. Chem., 1957, 22, 1445) was reacted with the acid chloride of 1-ethylindole-3-carboxylic acid using the method of Example 1. The product was chromatographed on silica gel eluting with ethyl acetate to afford the title compound (E16) as a pale yellow oil. This was converted to its hydrochloride salt mp 168°-172° C.
Reaction SMILES: [C:1]1([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:6]=[CH:5][C:4]([CH:7]([NH:14][CH3:15])[CH2:8][N:9]2[CH2:13][CH2:12][CH2:11][CH2:10]2)=[CH:3][CH:2]=1.[O:22]=[C:23]1[N:28]([CH2:29][C:30]([OH:32])=O)[C:27]2[CH:33]=[C:34]([O:37][C:38]([F:41])([F:40])[F:39])[CH:35]=[CH:36][C:26]=2[O:25][CH2:24]1.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.FC(F)(F)C(O)=O>CN(C)C=O.CC#N.O>[C:1]1([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:6]=[CH:5][C:4]([CH:7]([N:14]([CH3:15])[C:30](=[O:32])[CH2:29][N:28]2[C:27]3[CH:33]=[C:34]([O:37][C:38]([F:41])([F:40])[F:39])[CH:35]=[CH:36][C:26]=3[O:25][CH2:24][C:23]2=[O:22])[CH2:8][N:9]2[CH2:13][CH2:12][CH2:11][CH2:10]2)=[CH:3][CH:2]=1
Reactant: CNC(CN1CCCC1)c1ccc(-c2ccccc2)cc1
Reactant: O=C(O)CN1C(=O)COc2ccc(OC(F)(F)F)cc21
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CC#N
Solvent: O
Product: CN(C(=O)CN1C(=O)COc2ccc(OC(F)(F)F)cc21)C(CN1CCCC1)c1ccc(-c2ccccc2)cc1
Reaction time: 0.25 h
Yield: 51.6 %

Procedure:
[1-(4-biphenylyl)-2-(1-pyrrolidinyl)ethyl]methylamine (0.087 g, 0.31 mmol) and {3-oxo-6-[(trifluoromethyl)oxy]-2,3-dihydro-4H-1,4-benzoxazin-4-yl}acetic acid (0.1 g, 0.34 mmol) were dissolved in 1 mL of dimethylformamide. Triethylamine (0.13 mL, 0.93 mmol) was delivered to the room temperature mixture, and the solution was allowed to stir for several minutes before a separate solution of 1H-1,2,3-benzotriazol-1-yloxy-tris(dimethylamino)-phosphonium hexafluorophosphate (BOP reagent, 0.150 g, 0.34 mmol) dissolved in 1 mL of dimethylformamide was added at room temperature to the mixture. The reaction was maintained at that temperature for 18 hours, before it was determined to be complete by LCMS (two Aquasil C18, 20×1 mm columns were run in sequence, 4 minutes at 0.1 mL/min, 1-99% CH3CN/H2O with 0.018% trifluoroacetic acid, ES) Rt=2.0 min and m/e 554 [M+1]+. The reaction mixture was filtered through a 0.45 μm PTFE Acrodisk and the crude residue was purified by prep HPLC (Waters, 50×100 mm, 84 mL/min, A: acetonitrile B: water (pH=10, NH4OH), A: 10 to 99% over 15 min, UV detection at 214 nm) to give the title compound (0.087 g. 0.16 mmol, 46%) as an off-white amorphous solid. MS (ES) m/e 554 [M+H]+.
Reaction SMILES: [CH:1]1([N:8]([C@H:19]2[CH2:24][CH2:23][C@H:22]([CH3:25])[CH2:21][CH2:20]2)[C:9]([NH:11][C:12]2[S:13][C:14]([CH:17]=O)=[CH:15][N:16]=2)=[O:10])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl-].[CH3:27][O:28][C:29]([CH2:31][CH2:32][S:33]([N:36]1[CH2:41][CH2:40][NH2+:39][CH2:38][CH2:37]1)(=[O:35])=[O:34])=[O:30]>>[CH3:27][O:28][C:29](=[O:30])[CH2:31][CH2:32][S:33]([N:36]1[CH2:37][CH2:38][N:39]([CH2:17][C:14]2[S:13][C:12]([NH:11][C:9]([N:8]([CH:1]3[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)[C@H:19]3[CH2:20][CH2:21][C@H:22]([CH3:25])[CH2:23][CH2:24]3)=[O:10])=[N:16][CH:15]=2)[CH2:40][CH2:41]1)(=[O:34])=[O:35]
Reactant: C[C@H]1CC[C@H](N(C(=O)Nc2ncc(C=O)s2)C2CCCCCC2)CC1
Reactant: COC(=O)CCS(=O)(=O)N1CC[NH2+]CC1
Agent: [Cl-]
Product: COC(=O)CCS(=O)(=O)N1CCN(Cc2cnc(NC(=O)N(C3CCCCCC3)[C@H]3CC[C@H](C)CC3)s2)CC1

Procedure:
Prepared in 65% (380 mg) yield as described in general procedure (B) from trans-1-cycloheptyl-3-(5-formyl-thiazol-2-yl)-1-(4-methyl-cyclohexyl)-urea (364 mg, 1.0 mmol) and 4-(2-methoxycarbonyl-ethanesulfonyl)-piperazin-1-ium chloride (273 mg, 1 mmol).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([CH3:14])[C:10]=1[C:11]([OH:13])=O)=[O:5])[CH3:2].Cl.[CH3:16][C:17]1[O:21][C:20]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[N:19][C:18]=1[CH2:28][CH2:29][NH2:30].CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O.C(N(CC)C(C)C)(C)C.OS([O-])(=O)=O.[K+]>C1COCC1>[CH3:14][N:9]1[C:10]([C:11](=[O:13])[NH:30][CH2:29][CH2:28][C:18]2[N:19]=[C:20]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[O:21][C:17]=2[CH3:16])=[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH:7]=[N:8]1
Reactant: CCOC(=O)c1cnn(C)c1C(=O)O
Reactant: Cc1oc(-c2ccccc2)nc1CCN
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: Cl
Agent: O=S(=O)([O-])O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCOC(=O)c1cnn(C)c1C(=O)NCCc1nc(-c2ccccc2)oc1C
Temperature: 70 °C
Reaction time: 2 h
Yield: 76.3 %

Procedure:
To a suspension of 4-(ethoxycarbonyl)-1-methyl-1H-pyrazole-5-carboxylic acid (500 mg, 2.52 mmol, prepared as described in US 2011/0071128) in THF (12.5 mL) were added 2-(5-methyl-2-phenyloxazol-4-yl)ethanamine hydrochloride (602 mg, 2.52 mmol), 1-propanephosphonic acid cyclic anhydride (4.01 g, 3.75 mL, 6.31 mmol) and N,N-diisopropylethylamine (2.61 g, 3.53 mL, 20.2 mmol) at RT. The mixture was stirred at 70° C. for 2 h, poured into KHSO4 (10% aqueous solution, 50 mL) and extracted with ethyl acetate (2×75 mL). The organic phases were washed with water (50 mL) and brine (50 mL). The combined organic layer was dried over MgSO4 and concentrated in vacuo to give 735 mg crude product. The product was obtained after purification by flash chromatography (using silica gel and an ethyl acetate/heptane gradient) as white solid (410 mg, 1.07 mmol, 42.5%).
Reaction SMILES: [N+:1]([C:4]1[CH:42]=[CH:41][CH:40]=[CH:39][C:5]=1[CH2:6][O:7][C:8]([CH2:10][P:11]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[N:12]1[CH:15]([CH2:16][C:17](O)=[O:18])[CH2:14][C:13]1=[O:20])=[O:9])([O-:3])=[O:2].C(Cl)(=O)C([Cl:46])=O>C(Cl)Cl.CN(C=O)C>[N+:1]([C:4]1[CH:42]=[CH:41][CH:40]=[CH:39][C:5]=1[CH2:6][O:7][C:8]([CH2:10][P:11]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[N:12]1[CH:15]([CH2:16][C:17]([Cl:46])=[O:18])[CH2:14][C:13]1=[O:20])=[O:9])([O-:3])=[O:2]
Reactant: O=C(O)CC1CC(=O)N1P(CC(=O)OCc1ccccc1[N+](=O)[O-])(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)CC1CC(=O)N1P(CC(=O)OCc1ccccc1[N+](=O)[O-])(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
From Step A, 1-(o-nitrobenzyloxycarbonylmethyltriphenylphosphoranyl)-4-(carboxymethyl)-2-azetidinone (0.851 g) is dissolved in 20 ml CH2Cl2 and cooled to 0° C. under N2. Oxalyl chloride (0.8 ml) is added dropwise over 5 min and then 1 drop of DMF is added. The mixture is stirred at 0° C. for 5 min and then at 25° C. for 15 min. The solvent and excess oxalyl chloride are evaporated under reduced pressure. The residue is the desired acid chloride which is used without purification in the next step.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:12][C:11]3[CH:13]=[CH:14][C:15]([N:17]([CH2:19][CH2:20][O:21][CH3:22])C)=[CH:16][C:10]=3[N:9]=2)=[CH:4][C:3]=1[N+:23]([O-])=O.[C:26]([O:29][CH2:30]C)(=O)C.CO>[Pd]>[CH3:26][O:29][CH2:30][CH2:22][O:21][CH2:20][CH2:19][NH:17][C:15]1[CH:14]=[CH:13][C:11]2[NH:12][C:8]([C:5]3[CH:4]=[C:3]([NH2:23])[C:2]([NH2:1])=[CH:7][CH:6]=3)=[N:9][C:10]=2[CH:16]=1
Reactant: CCOC(C)=O
Reactant: COCCN(C)c1ccc2[nH]c(-c3ccc(N)c([N+](=O)[O-])c3)nc2c1
Agent: [Pd]
Solvent: CO
Product: COCCOCCNc1ccc2[nH]c(-c3ccc(N)c(N)c3)nc2c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of [2-(4-amino-3-nitro-phenyl)-1H-benzoimidazol-5-yl]-(2-methoxy-ethyl)-methyl-amine (0.8 g, 2.1 mmol) in 4:1 ethyl acetate/methanol (50 ml) under nitrogen, was added 5% palladium on carbon (100 mg) and the mixture was first evacuated and then stirred at room temperature under an atmosphere of hydrogen for 1 day. The reaction mixture was then filtered through Celite, washed with 1:1 ethyl acetate/methanol (10 mL) and the combined filtrate and washings were concentrated to give the crude 4-{5-[2-(2-methoxy-ethoxy)-ethylamino]-1H-benzoimidazol-2-yl}-benzene-1,2-diamine as a thick oil that was used in the next step without any purification.
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[CH:14]=[C:13]2[C@@H:8]([CH2:9][C:10]3[C:11]4[C:18]([NH:19][CH:20]=3)=[CH:17][CH:16]=[CH:15][C:12]=42)[N:7](C#N)[CH2:6]1)=[O:4].O>C(O)(=O)C.CO.C(Cl)Cl.[Zn]>[CH3:1][O:2][C:3]([C@@H:5]1[CH:14]=[C:13]2[C@@H:8]([CH2:9][C:10]3[C:11]4[C:18]([NH:19][CH:20]=3)=[CH:17][CH:16]=[CH:15][C:12]=42)[NH:7][CH2:6]1)=[O:4]
Reactant: COC(=O)[C@@H]1C=C2c3cccc4[nH]cc(c34)C[C@H]2N(C#N)C1
Agent: [Zn]
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: CO
Product: COC(=O)[C@@H]1C=C2c3cccc4[nH]cc(c34)C[C@H]2NC1

Procedure:
To a 100 ml round-bottom flask containing a solution of (6aR,9R)-7-Cyano-4,6,6a,7,8,9-hexahydro-indolo[4,3-fg]quinoline-9-carboxylic acid methyl ester (1.57 g, 5.35 mmol) in acetic acid (20 ml) is added water (4 ml) and zinc (1.5 g). The reaction mixture is refluxed at 100° C. for 3 hours by which time TLC in 20% methanol/DCM showed conversion of starting material to give product as a mixture of diastereomers. The reaction mixture is filtered to remove the zinc and the filter paper is washed thoroughly with water (200 ml) and ethyl acetate (200 ml). The aqueous phase is made basic with the addition of solid sodium hydrogen carbonate. The phases are then extracted and allowed to separate. The aqueous phase is re-extracted with ethyl acetate (2×100 ml) and the combined organic phases washed with brine (200 ml), dried (MgSO4), filtered at the pump and concentrated in vacuo to give a beige coloured foam. Purification is carried out by Normal Phase Flash column chromatography (Biotage Flash 40, 40 g cartridge) using 10% methanol/dichloromethane to achieve separation. Product is isolated as a beige foam.
Reaction SMILES: [N+:1]([CH2:3][C:4]([O:6]C)=O)#[C-:2].[NH:8]1[CH2:12][CH2:11][C@@H:10]([OH:13])[CH2:9]1>CO>[OH:13][C@@H:10]1[CH2:11][CH2:12][N:8]([C:4](=[O:6])[CH2:3][N+:1]#[C-:2])[CH2:9]1
Reactant: O[C@@H]1CCNC1
Reactant: [C-]#[N+]CC(=O)OC
Solvent: CO
Product: [C-]#[N+]CC(=O)N1CC[C@@H](O)C1
Yield: 49 %

Procedure:
To stirred and cooled (0° C.) methyl isocyanoacetate (96% technical grade, 1.7 g, 17.21 mmol) was slowly added (R)-(+)-3-pyrrolidinol (1.5 g, 17.21 mmol) and MeOH (5 mL). The mixture was stirred for 3 h at RT and concentrated. Brine was added (30 mL) and the mixture was extracted with EtOAc (3×50 mL), dried over MgSO4, filtered and evaporated to obtained crude 1-((R)-3-hydroxypyrrolidin-1-yl)-2-isocyanoethanone VIB 01172 (1.3 g, 49% yield) as a yellow solid.
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH:7]=[CH2:8].[CH2:9]([O:11][SiH:12]([O:16][CH2:17][CH3:18])[O:13][CH2:14][CH3:15])[CH3:10].C([Si](C=C)(C)O[Si](C)(C)C)=C>C1(C)C=CC=CC=1>[CH2:8]([Si:12]([O:16][CH2:17][CH3:18])([O:13][CH2:14][CH3:15])[O:11][CH2:9][CH3:10])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH3:1]
Reactant: CCO[SiH](OCC)OCC
Reactant: C=CCCCCCC
Agent: C=C[Si](C)(C=C)O[Si](C)(C)C
Solvent: Cc1ccccc1
Product: CCCCCCCC[Si](OCC)(OCC)OCC
Temperature: 50 °C
Yield: 0.4 %

Procedure:
224 mg Of octene-1, 329 mg of triethoxysilane, and 400 mg of toluene were placed in a glass reaction tube. Next, 0.001 ml of a toluene solution of a 0-valent platinum complex of divinyltetramethyldisiloxane (platinum content: 0.4 wt %) was added to this mixture. The reaction tube was sealed with Teflon tape and heated for 30 minutes in an oil bath at 50° C. When the contents were analyzed by GC-MS following cooling, the conversion rate of octene-1 was 0.5% and n-octyltriethoxysilane was produced at a yield of 0.4%.