Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](Cl)(=[O:10])[C:2]1[C:3]([O:8][CH3:9])=[CH:4][CH:5]=[CH:6][CH:7]=1.N1C=CC=CC=1.[NH2:18][C:19]1[CH:40]=[CH:39][C:22]([CH2:23][O:24][C:25]2[CH:26]=[C:27]3[C:32](=[CH:33][CH:34]=2)[CH2:31][CH:30]([CH2:35][N:36]([CH3:38])[CH3:37])[CH2:29][CH2:28]3)=[CH:21][CH:20]=1.C(=O)([O-])[O-].[K+].[K+]>C(OCC)(=O)C>[CH3:38][N:36]([CH2:35][CH:30]1[CH2:29][CH2:28][C:27]2[C:32](=[CH:33][CH:34]=[C:25]([O:24][CH2:23][C:22]3[CH:21]=[CH:20][C:19]([NH:18][C:1](=[O:10])[C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=4[O:8][CH3:9])=[CH:40][CH:39]=3)[CH:26]=2)[CH2:31]1)[CH3:37]
Reactant: CN(C)CC1CCc2cc(OCc3ccc(N)cc3)ccc2C1
Reactant: COc1ccccc1C(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: COc1ccccc1C(=O)Nc1ccc(COc2ccc3c(c2)CCC(CN(C)C)C3)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
o-Anisoyl chloride (0.15 ml) was added dropwise to pyridine solution (4 ml) of 6-[(4-aminobenzyl)oxy]-2-[(N,N-dimethylamino)methyl]tetralin (200 mg) under ice-cooling, which was stirred at room temperature for 30 minutes. 10% aqueous potassium carbonate solution was added to the reaction mixture, and extraction was conducted using ethyl acetate. The organic layer was washed with water and saturated aqueous sodium chloride solution, dried, and then concentrated. The residue was purified using alumina column chromatography (development solvent; THF), and recrystallized (ethyl acetate-hexane) to give the titled compound (200 mg).
Reaction SMILES: [BH4-].[Na+].[Cl:3][C:4]1[CH:5]=[CH:6][C:7]2[C:8]3[C:17]([C:18](OCC)=[O:19])=[N:16][N:15]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[C:14](=[O:29])[C:9]=3[N:10]([CH3:13])[C:11]=2[CH:12]=1.CO>O1CCCC1>[Cl:3][C:4]1[CH:5]=[CH:6][C:7]2[C:8]3[C:17]([CH2:18][OH:19])=[N:16][N:15]([C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=4)[C:14](=[O:29])[C:9]=3[N:10]([CH3:13])[C:11]=2[CH:12]=1
Reactant: CCOC(=O)c1nn(-c2ccccc2)c(=O)c2c1c1ccc(Cl)cc1n2C
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: Cn1c2cc(Cl)ccc2c2c(CO)nn(-c3ccccc3)c(=O)c21

Procedure:
2.5 g (66.1 mmol) of sodium borohydride are added to a solution of 4.04 g (10.6 mmol) of ethyl 7-chloro-5-methyl-4-oxo-3-phenyl-3,5-dihydro-4H-pyridazino[4,5-b]indole-1-carboxylate in 150 ml of tetrahydrofuran. 2.25 ml of methanol are then gradually added, with stirring, and then the mixture is heated under reflux for 5 h.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:16])=[C:6]([C:8]2([CH3:15])[NH:13][C:12](=O)[CH2:11][O:10][CH2:9]2)[CH:7]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:26])=CC=1>C1COCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:16])=[C:6]([C:8]2([CH3:15])[NH:13][C:12](=[S:26])[CH2:11][O:10][CH2:9]2)[CH:7]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CC1(c2cc(Br)ccc2F)COCC(=O)N1
Solvent: C1CCOC1
Product: CC1(c2cc(Br)ccc2F)COCC(=S)N1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
To a solution of 5-(5-bromo-2-fluoro-phenyl)-5-methyl-morpholin-3-one (CAS registry 1266784-13-7) (26.0 g, 82 mmol) in THF (520 ml) was added Lawesson's reagent (33.91 g, 82 mmol) and the reaction was heated for 2 h at reflux, then stirred for 14 h at rt. The solvent was evaporated and the title compound was prepurified by FC (toluene). Remaining impurities were removed by washing the toluene fractions with sat. aq. NaHCO3 soln. and water, the combined organic layers were dried over Na2SO4 and concentrated. Crude product was washed with MTBE and used in the next step without further purification.
Reaction SMILES: [C:1]([C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6](F)=[CH:5][CH:4]=1)#[N:2].[CH3:14][O:15][C:16](=[O:22])[C@@H:17]1[CH2:21][CH2:20][CH2:19][NH:18]1>>[CH3:14][O:15][C:16]([C@@H:17]1[CH2:21][CH2:20][CH2:19][N:18]1[C:6]1[C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]([C:1]#[N:2])=[CH:4][CH:5]=1)=[O:22]
Reactant: COC(=O)[C@@H]1CCCN1
Reactant: N#Cc1ccc(F)c2ccccc12
Product: COC(=O)[C@@H]1CCCN1c1ccc(C#N)c2ccccc12
Yield: 1.6 %

Procedure:
1-Cyano-4-fluoronaphthalene (109 mg, 0.64 mmol) and L-proline methyl ester (380 mg, 2.95 mmol) were heated to 60° C. for 2 days in a sealed vial. The crude product was concentrated in vacuo and purified by preparative TLC (ethyl acetate/n-heptane 1:3, 3× eluted) to afford the title compound (2.9 mg, 1.7%) as an off-white solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:16][CH:15]2[CH:10]([CH:11]=[CH:12][CH2:13][CH:14]2[CH2:17]OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[N-:29]=[N+:30]=[N-:31].[Na+]>CN(C)C=O>[C:1]([O:5][C:6]([N:8]1[CH2:16][CH:15]2[CH:10]([CH:11]=[CH:12][CH2:13][CH:14]2[CH2:17][N:29]=[N+:30]=[N-:31])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccc(S(=O)(=O)OCC2CC=CC3CN(C(=O)OC(C)(C)C)CC32)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CC2C=CCC(CN=[N+]=[N-])C2C1

Procedure:
A solution of 33 g (0.08 mol) of (1RS,2RS,6RS)-8-tert-butyloxycarbonyl-2-(4-toluenesulphonyloxymethyl)-8-azabicyclo[4.3.0]non-4-ene (title compound from Example K.5.) and 15.8 g (0.24 mol) of sodium azide in 200 ml of N,N-dimethylformamide is stirred at 70° C. for 40 h. After cooling, the solution is diluted with water (500 ml) and extracted three times with 250 ml of petroleum ether on each occasion. The combined organic phase is washed with 5% strength sodium hydrogen carbonate solution, dried (sodium sulphate) and concentrated.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:11])=[C:6]([CH:10]=1)[C:7](O)=O.[CH2:12]([C:15]1[S:16][CH:17]=[CH:18][CH:19]=1)[CH2:13][CH3:14]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:11])=[C:6]([CH2:7][C:17]2[S:16][C:15]([CH2:12][CH2:13][CH3:14])=[CH:19][CH:18]=2)[CH:10]=1
Reactant: O=C(O)c1cc(Br)ccc1Cl
Reactant: CCCc1cccs1
Product: CCCc1ccc(Cc2cc(Br)ccc2Cl)s1

Procedure:
5-Bromo-2-chlorobenzoic acid and 2-n-propylthiophene were used and treated in a manner similar to Reference Example 5 to give the target compound.
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[N:12]=[C:13]([C:16]([F:19])([F:18])[F:17])[S:14][CH:15]=1.[NH2:20][CH2:21][CH2:22][OH:23]>ClCCl>[F:17][C:16]([F:19])([F:18])[C:13]1[S:14][CH:15]=[C:11]([C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3][CH2:2][NH:20][CH2:21][CH2:22][OH:23])[N:12]=1
Reactant: FC(F)(F)c1nc(-c2ccccc2OCCBr)cs1
Reactant: NCCO
Solvent: ClCCl
Product: OCCNCCOc1ccccc1-c1csc(C(F)(F)F)n1
Temperature: 80 °C

Procedure:
A mixture of 4-[2-(2-bromoethoxy)phenyl]-2-(trifluoromethyl)-1,3-thiazole (C5) (115 mg, 0.327 mmol) and 2-aminoethanol (0.197 mL, 3.26 mmol) was heated to 80° C. for 3 hours. After cooling to room temperature, the reaction was diluted with dichloromethane and washed with 0.5 N aqueous sodium hydroxide solution, then with water. The organic layer was dried over magnesium sulfate, filtered, and concentrated in vacuo, yielding the title compound as a white solid. Yield: 113 mg, quantitative. 1H NMR (400 MHz, CDCl3) δ 2.88 (dd, J=5.2, 5.1 Hz, 2H), 3.15 (dd, J=5, 5 Hz, 2H), 3.68 (br dd, J=5, 5 Hz, 2H), 4.25 (dd, J=5, 5 Hz, 2H), 7.03 (br d, J=8.3 Hz, 1H), 7.08-7.12 (m, 1H), 7.33-7.38 (m, 1H), 8.18 (s, 1H), 8.21 (br d, J=7.9 Hz, 1H).
Reaction SMILES: Cl.[CH:2]([C:5]1[CH:6]=[C:7]([C@@H:11]([NH2:13])[CH3:12])[CH:8]=[CH:9][CH:10]=1)([CH3:4])[CH3:3].[Cl:14][C:15]1[CH:35]=[CH:34][C:18]([CH2:19][N:20]2[C:28]3[C:23](=[CH:24][C:25]([C:29](O)=[O:30])=[CH:26][CH:27]=3)[C:22]([CH3:32])=[C:21]2[CH3:33])=[CH:17][C:16]=1[O:36][C@@H:37]([CH2:42][CH3:43])[C:38]([O:40][CH3:41])=[O:39]>>[Cl:14][C:15]1[CH:35]=[CH:34][C:18]([CH2:19][N:20]2[C:28]3[C:23](=[CH:24][C:25]([C:29](=[O:30])[NH:13][C@H:11]([C:7]4[CH:8]=[CH:9][CH:10]=[C:5]([CH:2]([CH3:4])[CH3:3])[CH:6]=4)[CH3:12])=[CH:26][CH:27]=3)[C:22]([CH3:32])=[C:21]2[CH3:33])=[CH:17][C:16]=1[O:36][C@@H:37]([CH2:42][CH3:43])[C:38]([O:40][CH3:41])=[O:39]
Reactant: CC[C@H](Oc1cc(Cn2c(C)c(C)c3cc(C(=O)O)ccc32)ccc1Cl)C(=O)OC
Reactant: CC(C)c1cccc([C@H](C)N)c1
Agent: Cl
Product: CC[C@H](Oc1cc(Cn2c(C)c(C)c3cc(C(=O)N[C@@H](C)c4cccc(C(C)C)c4)ccc32)ccc1Cl)C(=O)OC

Procedure:
The title compound was prepared following the same protocol as described in Step 5, Example 36, using the (S)-1-(3-isopropylphenyl)ethanamine hydrochloride instead of the (S)-1-(3-cyclopropylphenyl)ethanamine hydrochloride and the (S)-1-(4-chloro-3-((1-methoxy-1-oxobutan-2-yl)oxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylic acid instead of the 1-(4-(2-methoxy-2-oxoethoxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylic acid.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([S:10]([NH:13][CH2:14][C:15]([NH2:17])=[O:16])(=[O:12])=[O:11])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].Cl[CH2:19][C:20]([NH2:22])=[O:21]>CN(C)C=O>[C:15]([CH2:14][N:13]([S:10]([C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1)(=[O:12])=[O:11])[CH2:19][C:20]([NH2:22])=[O:21])(=[O:16])[NH2:17]
Reactant: NC(=O)CNS(=O)(=O)c1cccc([N+](=O)[O-])c1
Reactant: NC(=O)CCl
Solvent: CN(C)C=O
Product: NC(=O)CN(CC(N)=O)S(=O)(=O)c1cccc([N+](=O)[O-])c1

Procedure:
reacting 2-(3-Nitro-benzenesulfonylamino)-acetamide with ClCH2CONH2 in the presence of N,N-Dimethylformamide and a base to provide 2-[Carbamoylmethyl-(3-nitro-benzenesulfonyl)-amino]acetamide;
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]([CH:19]3[CH2:24][NH:23][CH2:22][CH2:21][NH:20]3)=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:25]([N:27]1[C:36]2[C:31](=[CH:32][C:33]([F:38])=[C:34](F)[CH:35]=2)[C:30](=[O:39])[C:29]([C:40]([OH:42])=[O:41])=[CH:28]1)[CH3:26]>N1C=CC=CC=1>[CH2:25]([N:27]1[C:36]2[C:31](=[CH:32][C:33]([F:38])=[C:34]([N:23]3[CH2:22][CH2:21][NH:20][CH:19]([C:12]4[C:13]5[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=5)[N:10]([S:7]([C:1]5[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=5)(=[O:9])=[O:8])[CH:11]=4)[CH2:24]3)[CH:35]=2)[C:30](=[O:39])[C:29]([C:40]([OH:42])=[O:41])=[CH:28]1)[CH3:26]
Reactant: O=S(=O)(c1ccccc1)n1cc(C2CNCCN2)c2ccccc21
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(F)cc21
Solvent: c1ccncc1
Product: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCNC(c4cn(S(=O)(=O)c5ccccc5)c5ccccc45)C3)cc21
Temperature: 95 °C
Yield: 84.5 %

Procedure:
A mixture of 4.092 g of 1-(phenylsulfonyl)-3-(2-piperazinyl)-1H-indole and 1.012 g of 1-ethyl-6,7-difluoro1,4-dihydro-4-oxo-3-quinolinecarboxylic acid in 5 ml of pyridine was heated at 95° C. for 3 hours, then cooled and the solid collected, washed with methanol and ether, giving 1.94 g of 1-ethyl-6-fluoro-1,4-dihydro-4-oxo-7-[3-[1-(phenylsulfonyl)-1H-indol-3-yl]-1-piperazinyl]-3-quinolinecarboxylic acid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1F)[C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]([Cl:18])([F:17])[F:16])=[CH:10][CH:9]=1)=[O:6].Cl.Cl.[NH2:25][C@H:26]1[CH2:30][NH:29][CH2:28][C@@H:27]1[OH:31].C([O-])([O-])=O.[Na+].[Na+]>CS(C)=O>[NH2:25][C@@H:26]1[C@@H:27]([OH:31])[CH2:28][N:29]([C:21]2[CH:20]=[CH:19][C:4]([C:5]([NH:7][C:8]3[CH:13]=[CH:12][C:11]([O:14][C:15]([Cl:18])([F:17])[F:16])=[CH:10][CH:9]=3)=[O:6])=[CH:3][C:2]=2[Br:1])[CH2:30]1
Reactant: N[C@H]1CNC[C@@H]1O
Reactant: O=C(Nc1ccc(OC(F)(F)Cl)cc1)c1ccc(F)c(Br)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CS(C)=O
Product: N[C@H]1CN(c2ccc(C(=O)Nc3ccc(OC(F)(F)Cl)cc3)cc2Br)C[C@@H]1O
Temperature: 100 °C
Reaction time: 40 h

Procedure:
3-Bromo-N-(4-(chlorodifluoromethoxy)phenyl)-4-fluorobenzamide (240 mg, 0.596 mmol) and TEA (0.332 mL, 2.384 mmol) were added to a vial containing DMSO (0.5 mL). (3S,4S)-4-aminopyrrolidin-3-ol dihydrochloride (Stage 245.2, 128 mg, 0.715 mmol) was added. The RM was stirred at 100° C. for 40 h. The RM was treated with sat. aq. Na2CO3 (50 mL) and was extracted with EtOAc. The combined extracts were washed with water (30 mL) and brine (30 mL), dried over Na2SO4, filtered and the filtrate was evaporated off under reduced pressure to give a crude product that was purified by flash chromatography (from 100% EtOAc to EtOAc/EtOH/NH3 aq. 90:9:1) to afford the title product as a beige solid. HPLC (Condition 10) tR=6.08 min, UPLC-MS (Condition 3) tR=0.82 min, m/z=476.1/478.1 [M+H]+.
Reaction SMILES: [N:1](OC(C)(C)C)=[O:2].Cl.[CH3:9][O:10][N:11]=[C:12]1[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[O:14][CH2:13]1>C(OCC)(=O)C>[CH3:9][O:10][N:11]=[C:12]1[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[O:14][C:13]1=[N:1][OH:2]
Reactant: CC(C)(C)ON=O
Reactant: CON=C1COc2ccccc21
Agent: Cl
Solvent: CCOC(C)=O
Product: CON=C1C(=NO)Oc2ccccc21
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 57.3 %

Procedure:
At -10° C., 2 g (0.019 mol) of tert-butyl nitrite are added dropwise to 30 ml of ethyl acetate which is saturated with dry hydrogen chloride, and the mixture is stirred at this temperature for 15 minutes. At -10° C., 1.6 g (0.0098 mol) of benzofuran-3-one O-methyl-oxime dissolved in 5 ml of ethyl acetate are then added, the temperature is allowed to increase to 0° C. and the mixture is stirred at this temperature for 30 minutes. The crystalline product is filtered off, affording 1.08 g of crystalline benzofuran-2,3-dione 3-(O-methyl-oxime) 2-oxime as a mixture of two stereoisomers comprising, according to HPLC analysis, 54.7% (56% of theory) of isomer B and 42.9% of isomer A.
Reaction SMILES: Br[C:2]1[S:3][C:4]([Br:7])=[CH:5][N:6]=1.C([O-])([O-])=O.[K+].[K+].[CH2:14]([SH:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>CN(C=O)C.O>[CH2:14]([S:21][C:2]1[S:3][C:4]([Br:7])=[CH:5][N:6]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: Brc1cnc(Br)s1
Reactant: SCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Brc1cnc(SCc2ccccc2)s1
Temperature: 25 °C
Yield: 97.6 %

Procedure:
To a solution of 2,5-dibromothiazole (2.0 g, 8.23 mmol) in DMF (15 mL) was added K2CO3 (1.16 g, 8.40 mmol) followed by benzyl mercaptan (1.07 g, 8.40 mmol) in DMF (10 mL) over a period of 20 min. The reaction mixture was stirred at RT for over night. After this time, the reaction mixture was diluted with water and extracted in EtOAc. The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure. The resulting crude product was purified by silica gel chromatography (0.2% EtOAc in hexane) to yield 2-(benzylthio)-5-bromothiazole (2.3 g, 97.5% yield) as a brown solid. 1H NMR (400 MHz, DMSO-d6, δ): 7.56 (s, 1H); 7.25-7.36 (m, 5H); 4.39 (s, 2H). 1H LCMS Method V: Retention time 2.319 min, [M+1]=286.
Reaction SMILES: [C-:1]#[N:2].[K+].CN(C)[CH2:6][C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][C:14]=2[N+:16]([O-:18])=[O:17])[NH:9][CH:8]=1>O.CN(C=O)C>[N+:16]([C:14]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:15]=1[C:7]([CH2:6][C:1]#[N:2])=[CH:8][NH:9]2)([O-:18])=[O:17]
Reactant: CN(C)Cc1c[nH]c2cccc([N+](=O)[O-])c12
Reactant: [C-]#N
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: N#CCc1c[nH]c2cccc([N+](=O)[O-])c12
Temperature: 25 °C

Procedure:
Potassium cyanide (9.20 g, 141 mmol) in H2O (80 mL) was added to a solution of N,N-dimethyl-1-(4-nitro-1H-indol-3-yl)methanamine from Step A (3.10 g, 14.1 mmol) in DMF (80 mL) and the mixture was heated at reflux for 1 h, then cooled to ambient temperature and partitioned between H2O (200 mL) and EtOAc (400 mL). The organic layer was dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by silica gel chromatography, eluting with a gradient of hexane:EtOAc—100:0 to 0:100, to give the title compound. MS: m/z=265 (M+Na+CH3CN).
Reaction SMILES: [CH3:1][P:2](=[O:7])([O:5][CH3:6])[O:3][CH3:4].C([Li])CCC.[F:13][CH:14]([CH2:20][CH2:21][CH2:22][CH3:23])[C:15](OCC)=[O:16].S(=O)(=O)(O)O>CCCCCC.O1CCCC1>[CH3:4][O:3][P:2]([CH2:1][C:15](=[O:16])[CH:14]([F:13])[CH2:20][CH2:21][CH2:22][CH3:23])(=[O:7])[O:5][CH3:6]
Reactant: COP(C)(=O)OC
Reactant: CCCCC(F)C(=O)OCC
Agent: O=S(=O)(O)O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCCCC(F)C(=O)CP(=O)(OC)OC
Reaction time: 0.08 h
Yield: 80.5 %

Procedure:
To a solution of 7.7 g. (0.06 mole) of dimethyl methyl-phosphonate in 80 ml. of tetrahydrofuran at -73° C. was added dropwise 43.4 ml. of a 1.42 molar solution of butyl lithium in hexane. After stirring for 5 minutes, a solution of 4 g. (0.03 mole) of ethyl 2-fluorohexanoate in 20 ml. of tetrahydrofuran was added dropwise. The resulting solution was then allowed to warm to 0° and then acidified (pH3) with 2 N sulfuric acid. The mixture was then extracted with hexane, the hexane solution washed with a saturated sodium chloride solution and then dried (MgSO4). The solvent was then removed under reduced pressure and the residue distilled to give 5.8 g of dimethyl(2-oxo-3-fluoroheptyl)phosphonate, b.p. 116°-118°/0.4 mm.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[C:6](I)[CH:5]=[CH:4][N:3]=1.Cl.[NH:11]1[CH2:16][CH2:15][C:14]2([C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH2:18][O:17]2)[CH2:13][CH2:12]1.CCN(C(C)C)C(C)C.C([O-])(O)=O.[Na+]>CC#N>[Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([N:11]2[CH2:16][CH2:15][C:14]3([C:24]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=4[CH2:18][O:17]3)[CH2:13][CH2:12]2)[CH:5]=[CH:4][N:3]=1
Reactant: Clc1nccc(I)c1Cl
Reactant: c1ccc2c(c1)COC21CCNCC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: Clc1nccc(N2CCC3(CC2)OCc2ccccc23)c1Cl
Temperature: 110 °C

Procedure:
A mixture of D10 (1 g, 3.655 mmol), spiro[isobenzofuran-1(3H),4′-piperidine], hydrochloride [CAS 37663-44-8] (0.83 g, 4.386 mmol) and DIPEA (1.273 ml, 7.309 mmol) in CH3CN (9 ml) was heated in a sealed tube at 110° C. for 16 h. The mixture was then treated with NaHCO3 (aqueous sat. solution) and extracted with EtOAc. The organic layer was separated, dried (Na2SO4) and concentrated in vacuo. The crude product was purified by column chromatography (silica gel; DCM/EtOAc up to 2% as eluent). The desired fractions were collected and concentrated in vacuo to yield intermediate compound D21 (0.199 g, 16%) as a white solid. M.P. 160.8° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:15])[S:13][CH:14]=2)=[CH:4][N:3]=1.[CH3:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1B(O)O.C(=O)([O-])[O-].[K+].[K+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:15])[S:13][CH:14]=2)=[CH:4][N:3]=1
Reactant: Cc1ccccc1B(O)O
Reactant: Cc1nc(C#Cc2ccc(Cl)nc2)cs1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1nc(C#Cc2ccc(-c3ccccc3C)nc2)cs1
Temperature: 80 °C

Procedure:
2-chloro-5-[(2-methyl-1,3-thiazol-4-yl)ethynyl]pyridine (1.0 mmol, 234 mg), 2-methylphenylboronic acid (2.0 mmol, 272 mg), dichlorobis(triphenylphosphine)palladium(II) (0.05 mmol, 35 mg), and potassium carbonate (3.5 mmol, 500 ing) were added to deoxygenated DME:water (1:1, 5 mL) at room temperature. The reaction was heated for 18 h at 80° C., then partitioned in a separatory funnel with EtOAc (100 mL) and water (30 mL). The organic layer was washed with one additional portion of water (20 mL) and the combined aqueous layers back extracted with EtOAc (50 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo. The crude residue was chromatographed on SiO2, eluting with a 0% to 60% EtOAc gradient in hexanes, to afford the title compound as a tan solid, which was dissolved in ether and precipitated as the hydrochloride salt with 1M HCl in ether. 1H-NMR (CD3OD, 500 MHz) δ 9.14 (s, 1H), 8.76 (d, 1H), 8.18 (d, 1H), 8.03 (s, 1H), 7.44-7.61 (m, 4H), 2.76 (s, 3H), 2.26 (s, 3H). MS (ESI) 291.2 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:20][C:21]([O:23]C2C(F)=C(F)C(F)=C(F)C=2F)=O)[CH:6]=[CH:7][C:8]=1[NH:9][C:10]([NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH3:19])=[O:11].[N+:35]([C:38]1[CH:39]=[C:40]([CH:45]=[CH:46][C:47]=1[O:48][CH2:49][C@@H:50]([NH2:52])[CH3:51])[C:41]([O:43][CH3:44])=[O:42])([O-:37])=[O:36]>CN(C=O)C.CCOC(C)=O>[N+:35]([C:38]1[CH:39]=[C:40]([CH:45]=[CH:46][C:47]=1[O:48][CH2:49][C@@H:50]([NH:52][C:21](=[O:23])[CH2:20][C:5]1[CH:6]=[CH:7][C:8]([NH:9][C:10]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[CH3:19])=[O:11])=[C:3]([O:2][CH3:1])[CH:4]=1)[CH3:51])[C:41]([O:43][CH3:44])=[O:42])([O-:37])=[O:36]
Reactant: COc1cc(CC(=O)Oc2c(F)c(F)c(F)c(F)c2F)ccc1NC(=O)Nc1ccccc1C
Reactant: COC(=O)c1ccc(OC[C@H](C)N)c([N+](=O)[O-])c1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(OC[C@H](C)NC(=O)Cc2ccc(NC(=O)Nc3ccccc3C)c(OC)c2)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 45.8 %

Procedure:
A mixture of pentafluorophenyl 3-methoxy-4-[N′-(2-methylphenyl)ureido]phenylacetate (591 mg, 1.23 mmol), methyl (S)-3-nitro-4-(2-amino-1-propoxy)benzoate (313 mg, 1.23 mmol), and Et3 N (257 mL, 1.84 mmol) in DMF (5 mL) was stirred at room temp for 2 days. The mixture was diluted with EtOAc, washed with 0.5 N HCl, brine, dried over Na2SO4, and evaporated. The residue was purified by column chromatography on silica-gel with 5% MeOH in CHCl3 as eluent to give 310 mg (46%) methyl (S)-3-nitro-4-[2-[3-methoxy-4-[N′-(2-methylphenyl)ureido]phenyl acetylamino]-1-propoxy]benzoate as a gum. 1H-NMR (CDCl3) δ 1.28 (d, 3 H, J=6.8 Hz), 2.31 (s, 3 H), 3.49 (s, 2H), 3.71 (s, 3 H), 3.92 (s, 3 H), 4.14–4.16 (m, 2 H), 4.38–4.41 (m, 1 H), 5.88–5.90 (m, 1 H), 6.49 (s, 1 H), 6.70–6.71 (m, 1 H), 6.77–6.79 (m, 1 H), 7.05–7.30 (m, 4 H), 7.55–7.57 (m, 1 H), 8.02–8.06 (m, 2 H), 8.16–8.19 (m, 1 H), 8.51–8.52 (m, 1 H); MS (FAB) m/z 551 (M++1).
Reaction SMILES: [CH:1]1([NH:6][C:7]2[CH:8]=[C:9]([CH2:24][S:25]([CH3:28])(=[O:27])=[O:26])[CH:10]=[C:11]3[C:15]=2[NH:14][C:13]([C:16]2[S:17][CH2:18][C@@H:19]([CH2:21][CH2:22]I)[N:20]=2)=[CH:12]3)[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:29]([N:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1)(=[O:31])[CH3:30]>>[CH:1]1([NH:6][C:7]2[CH:8]=[C:9]([CH2:24][S:25]([CH3:28])(=[O:27])=[O:26])[CH:10]=[C:11]3[C:15]=2[NH:14][C:13]([C:16]2[S:17][CH2:18][C@@H:19]([CH2:21][CH2:22][N:35]4[CH2:36][CH2:37][N:32]([C:29](=[O:31])[CH3:30])[CH2:33][CH2:34]4)[N:20]=2)=[CH:12]3)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(=O)N1CCNCC1
Reactant: CS(=O)(=O)Cc1cc(NC2CCCC2)c2[nH]c(C3=N[C@H](CCI)CS3)cc2c1
Product: CC(=O)N1CCN(CC[C@@H]2CSC(c3cc4cc(CS(C)(=O)=O)cc(NC5CCCC5)c4[nH]3)=N2)CC1

Procedure:
Cyclopentyl-{2-[(R)-4-(2-iodo-ethyl)-4,5-dihydro-thiazol-2-yl]-5-methanesulfonylmethyl-1H-indol-7-yl}-amine prepared in Step A of Example 156 and acetylpiperazine were reacted according to the same procedure as Step B of Example 156 to give the title compound.
Reaction SMILES: [CH3:1][C:2]([N:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[NH:6][C:5]1=[O:13])=[CH2:3].[H-].[Na+].Br[CH2:17][CH2:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21].O>CN(C)C=O>[CH3:3][C:2]([N:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]([CH2:17][CH2:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:5]1=[O:13])=[CH2:1]
Reactant: CCOC(=O)CCCBr
Reactant: C=C(C)n1c(=O)[nH]c2ccccc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C=C(C)n1c(=O)n(CCCC(=O)OCC)c2ccccc21
Reaction time: 0.5 h
Yield: 104.9 %

Procedure:
A solution of 19 g of 1,3-dihydro-1-(1-methylethenyl)-2H-benzimidazol-2-one [described in J. Chem. Soc. Perkins, 1982, p. 261] in 150 ml of dimethylformamide was added with stirring at 20° C.±2° C. to 5.75 g of sodium hydride as a 50% suspension in oil and 10 ml of dimethylformamide and the mixture was stirred for another 30 minutes. 23.4 g of ethyl 4-bromo-butyrate were added to the mixture over 15 minutes and the mixture was stirred at room temperature for 4 hours and was poured into 800 ml of iced water. The mixture was extracted with ether and the organic phase was washed with water, dried and evaporated to dryness under reduced pressure to obtain 33 g of ethyl 2,3-dihydro-3-(1-methyl-ethenyl)-2-oxo-1H-benzimidazol-1-butanoate.