Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si:1](Cl)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[Cl:9][C:10]1[N:11]=[C:12]([CH:15]([C:21]2[NH:22][C:23]([C:34]3[CH:39]=[CH:38][CH:37]=[C:36]([F:40])[CH:35]=3)=[C:24]3[C:29](=[O:30])[N:28]([CH3:31])[C:27](=[O:32])[N:26]([CH3:33])[C:25]=23)[CH2:16][CH:17]([OH:20])[CH2:18][OH:19])[S:13][CH:14]=1.N1C=CN=C1>CN(C1C=CN=CC=1)C.CN(C=O)C.CCOC(C)=O>[Si:1]([O:19][CH2:18][CH:17]([OH:20])[CH2:16][CH:15]([C:21]1[NH:22][C:23]([C:34]2[CH:39]=[CH:38][CH:37]=[C:36]([F:40])[CH:35]=2)=[C:24]2[C:29](=[O:30])[N:28]([CH3:31])[C:27](=[O:32])[N:26]([CH3:33])[C:25]=12)[C:12]1[S:13][CH:14]=[C:10]([Cl:9])[N:11]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: Cn1c(=O)c2c(-c3cccc(F)c3)[nH]c(C(CC(O)CO)c3nc(Cl)cs3)c2n(C)c1=O
Agent: CN(C)c1ccncc1
Agent: c1c[nH]cn1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cn1c(=O)c2c(-c3cccc(F)c3)[nH]c(C(CC(O)CO[Si](C)(C)C(C)(C)C)c3nc(Cl)cs3)c2n(C)c1=O
Temperature: 25 °C
Reaction time: 0.83 h

Procedure:
tert-Butyldimethylsilyl chloride (309 mg, 2.047 mmol) was added to a solution of 7-(1-(4-chlorothiazol-2-yl)-3,4-dihydroxybutyl)-5-(3-fluorophenyl)-1,3-dimethyl-1H-pyrrolo[3,4-d]pyrimidine-2,4(3H,6H)-dione (817 mg, 1.706 mmol), imidazole (232 mg, 3.41 mmol) and DMAP (20.84 mg, 0.171 mmol) in DMF (15 mL). The mixture was stirred at room temperature for 50 mins. A further portion of tert-butyldimethylsilyl chloride (100 mg, 0.662 mmol) was added and the mixture stirred for a further 1 hour. The reaction mixture was diluted with EtOAc and washed with 0.1M HCl(aq) (1×) and brine (3×). The organic phase was dried over sodium sulfate and evaporated under vacuum. Purification by chromatography on silica, eluting with 0-60% EtOAc/hexane, afforded the title compound as a mixture of diastereomers.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2([CH3:22])[CH2:17][C:16]3[C:11](=[C:12]([Cl:20])[C:13]([Cl:19])=[C:14]([OH:18])[CH:15]=3)[C:10]2=[O:21])=[CH:5][CH:4]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:30][C:31]([O:33]CC)=[O:32].[OH-].[Na+].Cl>CN(C)C=O.O>[O:21]=[C:10]1[C:11]2[C:16](=[CH:15][C:14]([O:18][CH2:30][C:31]([OH:33])=[O:32])=[C:13]([Cl:19])[C:12]=2[Cl:20])[CH2:17][C:9]1([C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)[CH3:22]
Reactant: CCOC(=O)CBr
Reactant: COc1ccc(C2(C)Cc3cc(O)c(Cl)c(Cl)c3C2=O)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(C2(C)Cc3cc(OCC(=O)O)c(Cl)c(Cl)c3C2=O)cc1
Temperature: 100 °C

Procedure:
A stirred mixture of 2-(4-methoxyphenyl)-2-methyl-5-hydroxy-6,7-dichloro-1-indanone (2.6 g., 0.0077 mole), potassium carbonate (2.14 g., 0.0154 mole) and ethyl bromoacetate (2.58 g., 0.0154 mole) in dimethylformamide (60 ml.) is warmed at 55°-60° C. for 2.5 hrs., then treated with water (60 ml.),-10 N sodium hydroxide solution (3 ml., 0.03 mole) and heated at 100° C. for one hour. The reaction mixture is added slowly to crushed ice-water (600 ml.)-12 N hydrochloric acid (20 ml.) to precipitate 1.69 g. of [1-oxo-2-(4-methoxyphenyl)-2-methyl-6,7-dichloro-5-indanyloxy]acetic acid which melts at 173°-175° C. after crystallization from nitromethane.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][N:5]1[C:9]2[C:10]([N:14]([CH2:17][CH3:18])[CH2:15][CH3:16])=[CH:11][CH:12]=[CH:13][C:8]=2[N:7]=[C:6]1[C:19]([C:21]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=1[Cl:28])=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(C)C=CC=CC=1.CC(C)([O-])C.[K+]>C(#N)C.C(OCC)(=O)C.O1CCCC1>[Cl:28][C:22]1[CH:23]=[C:24]([Cl:27])[CH:25]=[CH:26][C:21]=1[C:19]1[C:6]2=[N:7][C:8]3[CH:13]=[CH:12][CH:11]=[C:10]([N:14]([CH2:17][CH3:18])[CH2:15][CH3:16])[C:9]=3[N:5]2[CH2:4][CH2:3][CH:2]=1
Reactant: CCN(CC)c1cccc2nc(C(=O)c3ccc(Cl)cc3Cl)n(CCCBr)c12
Agent: CC(C)(C)[O-]
Agent: [K+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Solvent: CC#N
Product: CCN(CC)c1cccc2nc3n(c12)CCC=C3c1ccc(Cl)cc1Cl
Reaction time: 1 h
Yield: 22.8 %

Procedure:
A solution of [1-(3-bromopropyl)-7-(diethylamino)-1H-benzimidazol-2-yl](2,4-dichlorophenyl)methanone (Reference example 211, 360 mg, 0.745 mmol) and triphenylphosphine (586 mg, 2.23 mmol) in acetonitrile (5 mL) was stirred for 60 h at 80° C. The reaction mixture was concentrated in vacuo. Toluene (5 mL), tetrahydrofuran (1 mL), and potassium tert-butoxide (85%, 83.6 mg, 0.745 mmol) was added at room temperature. After 1 h, the reaction mixture was diluted with ethyl acetate, washed with brine, dried over sodium sulfate, filtrated, and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with a 5-25% ethyl acetate/n-hexane gradient mixture to afford the desired product as pale yellow solid (65.5 mg, 0.170 mmol, 23%).
Reaction SMILES: C1C=C(Cl)C=C(C(OO)=[O:9])C=1.[CH2:12]([O:14][C:15](=[O:38])[O:16][C:17]1[CH:18]([CH2:31][CH:32]2[CH2:37][CH2:36][S:35][CH2:34][CH2:33]2)[NH:19][C:20](=[O:30])[C:21]=1[C:22]1[CH:27]=[C:26]([CH3:28])[CH:25]=[CH:24][C:23]=1[CH3:29])[CH3:13]>C(Cl)Cl>[CH2:12]([O:14][C:15](=[O:38])[O:16][C:17]1[CH:18]([CH2:31][CH:32]2[CH2:37][CH2:36][S:35](=[O:9])[CH2:34][CH2:33]2)[NH:19][C:20](=[O:30])[C:21]=1[C:22]1[CH:27]=[C:26]([CH3:28])[CH:25]=[CH:24][C:23]=1[CH3:29])[CH3:13]
Reactant: CCOC(=O)OC1=C(c2cc(C)ccc2C)C(=O)NC1CC1CCSCC1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CCOC(=O)OC1=C(c2cc(C)ccc2C)C(=O)NC1CC1CCS(=O)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of m-CPBA (189 mg, 1.1 mmol) in 5 ml of CH2Cl2 was added slowly to a stirred solution of carbonic acid 4-(2,5-dimethyl-phenyl)-5-oxo-2-(tetrahydro-thiopyran-4-ylmethyl)-2,5-dihydro-1H-pyrrol-3-yl ester ethyl ester (compound P1.2) (390 mg, 1.0 mmol) in 10 ml CH2Cl2 and the reaction mixture was stirred at room temperature for 1 h. Then, the resulting mixture was washed with saturated NaHCO3 (aq) and aqueous Na2S2O3, respectively. The organic layer was dried over sodium sulfate, filtered and concentrated under reduce pressure. The residue was purified by chromatography on silica gel. Yield: 100 mg of carbonic acid 4-(2,5-dimethyl-phenyl)-5-oxo-2-(1-oxo-hexahydro-1λ4-thiopyran-4-ylmethyl)-2,5-dihydro-1H-pyrrol-3-yl ester ethyl ester (compound P1.4) as a solid, mp 103-106° C.
Reaction SMILES: CC1C2C(O)=C(C(C)(C)C)C=CC=2OC=1.ClC1C=CC(C(C2C3OC(C(O)=O)=CC=3C=CC=2)=O)=CC=1.[CH3:37][C:38]1[C:42]2[C:43]([OH:60])=[C:44]([C:56]([CH3:59])([CH3:58])[CH3:57])[CH:45]=[C:46]([C:47](=[O:55])[C:48]3[CH:53]=[CH:52][C:51]([Cl:54])=[CH:50][CH:49]=3)[C:41]=2[O:40][C:39]=1C(O)=O.N1C2C(=CC=CC=2)C=CC=1.Cl>[Cu].C(OCC)(=O)C>[CH3:37][C:38]1[C:42]2[C:43]([OH:60])=[C:44]([C:56]([CH3:58])([CH3:57])[CH3:59])[CH:45]=[C:46]([C:47](=[O:55])[C:48]3[CH:53]=[CH:52][C:51]([Cl:54])=[CH:50][CH:49]=3)[C:41]=2[O:40][CH:39]=1
Reactant: Cc1c(C(=O)O)oc2c(C(=O)c3ccc(Cl)cc3)cc(C(C)(C)C)c(O)c12
Agent: [Cu]
Agent: Cc1coc2ccc(C(C)(C)C)c(O)c12
Agent: Cl
Solvent: c1ccc2ncccc2c1
Solvent: CCOC(C)=O
Product: Cc1coc2c(C(=O)c3ccc(Cl)cc3)cc(C(C)(C)C)c(O)c12
Temperature: 160 °C

Procedure:
A mixture of 3-methyl-4-hydroxy-5-tert-butylbenzofuran-7-p-chlorobenzoylbenzofuran-2-carboxylic acid, compound 18 (0.281 g, 0.73 mmol), copper (0.046 g, 0.73 mmol), and quinoline (1 mL) was heated to 160° C. until gas evolution had ceased. The reaction mixture was allowed to cool and poured into 2N HCl (25 mL). Ethyl acetate (25 mL) was added and the mixture was filtered through a pad of celite. The layers were separated and the aqueous layer reextracted with ethyl acetate (2×20 mL). The combined organic extracts were dried (Na2SO4) and concentrated. Flash chromatography using 10% ethyl acetate as eluant afforded 3-methyl-4-hydroxy-5-tert-butyl-7-p-chlorobenzoylbenzofuran, compound 19 as an oil which solidified on standing. 1H NMR d 1.50 (9H, s), 2.50 (3H, d, J=2 Hz), 5.79 (1H, s), 7.30 (1H, s), 7.46 (2H, d, J= 8 Hz), 7.66 (1H, s), 7.79 (2H, d, J=8 Hz).
Reaction SMILES: [CH3:1]/[C:2](/[CH:7]=[CH:8]/[C:9](/[F:22])=[C:10](\[CH3:21])/[CH:11]=[CH:12]/[C:13]1[C:17]([CH3:18])=[C:16]([CH3:19])[S:15][C:14]=1[CH3:20])=[CH:3]\[C:4](O)=[O:5].C[N:24](C)C=O.C(Cl)(=O)C(Cl)=O>C1C=CC=CC=1>[CH3:1]/[C:2](/[CH:7]=[CH:8]/[C:9](/[F:22])=[C:10](\[CH3:21])/[CH:11]=[CH:12]/[C:13]1[C:17]([CH3:18])=[C:16]([CH3:19])[S:15][C:14]=1[CH3:20])=[CH:3]\[C:4]([NH2:24])=[O:5]
Reactant: CN(C)C=O
Reactant: CC(/C=C/c1c(C)sc(C)c1C)=C(F)\C=C\C(C)=C\C(=O)O
Agent: O=C(Cl)C(=O)Cl
Solvent: c1ccccc1
Product: CC(/C=C/c1c(C)sc(C)c1C)=C(F)\C=C\C(C)=C\C(N)=O
Reaction time: 1 h

Procedure:
A suspension of 0.40 g. (0.12 mmol) of 2E,4E,6Z,8E-3,7-dimethyl-6-fluoro-9-(2,4,5-trimethyl-3-thienyl)-2,4,6,8-nonatetraenoic acid in 12 ml. of dry benzene was stirred at 23° C. under argon while about 5 mg. of dimethylformamide were added thereto followed by 0.24 g. (0.19 mmole) of oxalyl chloride in 3 ml. of dry benzene. After 1 hour of stirring, dry ammonia was bubbled into the resulting orange solution until a bright yellow color persisted. The reaction mixture was poured into water, extracted with ethyl acetate, washed with water, dried with magnesium sulfate, filtered, and evaporated to give a crude orange solid. This material was purified by chromatography on silica gel using ethyl acetate-hexane (2:3 parts by volume) as the elutant. One crystallization from ethyl acetate gave 70 mg. (18% yield) of pure 2E,4E,6Z,8E-3,7-dimethyl-6-fluoro-9-(2,4,5-trimethyl-3-thienyl)-2,4,6,8-nonatetraenamide, m.p. 212°-215° C.
Reaction SMILES: CC1(C)[O:6][C:5](=[O:7])[CH:4]([CH:8]([CH2:12][CH2:13][CH2:14][CH3:15])[C:9]([OH:11])=O)[O:3]1.[NH:17]1[CH2:21][CH2:20][CH2:19][CH:18]1[C:22]1[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=1>>[OH:3][C@@H:4]([C@H:8]([C:9]([N:17]1[CH2:21][CH2:20][CH2:19][CH:18]1[C:22]1[CH:23]=[CH:24][N:25]=[CH:26][CH:27]=1)=[O:11])[CH2:12][CH2:13][CH2:14][CH3:15])[C:5]([OH:6])=[O:7]
Reactant: c1cc(C2CCCN2)ccn1
Reactant: CCCCC(C(=O)O)C1OC(C)(C)OC1=O
Product: CCCC[C@@H](C(=O)N1CCCC1c1ccncc1)[C@H](O)C(=O)O

Procedure:
The title compound is prepared from 2-(2,2-dimethyl-4-oxo-1,3-dioxolan-5-yl)hexanoic acid B-5 and commercially available 4-pyrrolidin-2-yl-pyridine A-5 according to General Procedure B.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:18]2[CH:19]=[C:20]([C:25]3[CH:30]=[C:29]([C:31]4[CH:32]=[N:33][N:34]([CH3:36])[CH:35]=4)[N:28]=[CH:27][C:26]=3[NH2:37])[C:21](F)=[N:22][CH:23]=2)[CH:6]=[C:7]([O:16][CH3:17])[C:8]=1[CH2:9][N:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+]>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:18]2[CH:23]=[N:22][C:21]3[NH:37][C:26]4[CH:27]=[N:28][C:29]([C:31]5[CH:32]=[N:33][N:34]([CH3:36])[CH:35]=5)=[CH:30][C:25]=4[C:20]=3[CH:19]=2)[CH:6]=[C:7]([O:16][CH3:17])[C:8]=1[CH2:9][N:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: COc1cc(-c2cnc(F)c(-c3cc(-c4cnn(C)c4)ncc3N)c2)cc(OC)c1CN1CCCCC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1cc(-c2cnc3[nH]c4cnc(-c5cnn(C)c5)cc4c3c2)cc(OC)c1CN1CCCCC1
Reaction time: 0.5 h
Yield: 14.6 %

Procedure:
A solution of 5-(3,5-dimethoxy-4-piperidin-1-ylmethyl-phenyl)-2-fluoro-6′-(1-methyl-1H-pyrazol-4-yl)-[3,4]bipyridinyl-3′-ylamine (490 mg, 0.98 mmol) in anhydrous THF (16.7 mL) was added dropwise over 10 minutes to a solution of sodium bis(trimethylsilyl)amide (1N solution in THF, 2.9 mL, 2.9 mmol). After 30 minutes, the reaction was quenched by the addition of saturated aqueous potassium fluoride solution (5 mL) and concentrated under reduced pressure to afford a brown residue. The resultant brown residue was partitioned between ethyl acetate (75 mL) and water (50 mL). The organic phase was separated, dried over sodium sulfate, filtered and evaporated in vacuo to afford a residue that was purified by flash chromatography (silica, 50 g column, Biotage, 0-20% methanol in DCM) to afford the title compound as an off-white solid (69 mg, 15%). 1H NMR (CDCl3 plus CD3OD, 300 MHz): 8.86 (d, J=1.1 Hz, 1H), 8.84-8.80 (m, 2H), 8.37 (d, J=1.1 Hz, 1H), 8.09 (s, 1H), 8.06 (d, J=0.8 Hz, 1H), 6.91 (s, 2H), 4.01 (s, 3H), 3.96 (s, 6H), 3.74 (s, 2H), 2.64-2.50 (m, 4H), 1.65-1.56 (m, 4H), 1.49-1.37 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[CH:4][CH:3]=1.Br[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(=O)([O-])[O-].[Na+].[Na+].[Cl-].[Li+]>O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:4][CH:3]=1
Reactant: Brc1ccccc1
Reactant: OB(O)c1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Clc1ccc(-c2ccccc2)cc1
Yield: 97 %

Procedure:
A mixture of 100 mmol of p-chlorophenylboronic acid (15.7 g), 98 mmol of bromobenzene (15.4 g), 110 mmol of anhydrous sodium carbonate (11.7 g), 0.1 mmol of trans-di-μ-acetato-bis[2-[bis(1,1-dimethylethyl)phosphino]-2 methylpropyl-C,P]dipalladium (0.2 mol %), 10 mmol of lithium chloride (0.43 g) and 100 ml of tetrahydrofuran was refluxed for 2.5 hours. After distilling off as much of the THF as possible under atmospheric pressure and replacing it by 100 ml of toluene, the mixture was hydrolyzed with 150 ml of water. The aqueous phase was extracted with a further 50 ml of toluene and the organic phase was washed with 50 ml of water. Distillation of the combined organic phases gave 4-chlorobiphehyl in a yield of 97% (based on bromobenzene).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1F.[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1)=[O:18])([CH3:15])([CH3:14])[CH3:13].CN(C)C=O.O>C(Cl)(Cl)Cl>[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][N:22]([C:7]2[CH:6]=[CH:5][C:4]([N+:9]([O-:11])=[O:10])=[CH:3][C:2]=2[Cl:1])[CH2:21][CH2:20]1)=[O:18])([CH3:15])([CH3:13])[CH3:14]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=[N+]([O-])c1ccc(F)c(Cl)c1
Solvent: CN(C)C=O
Solvent: O
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)N1CCN(c2ccc([N+](=O)[O-])cc2Cl)CC1
Temperature: 130 °C
Reaction time: 0.5 h
Yield: 64.7 %

Procedure:
A mixture of 3-chloro-4-fluoronitrobenzene (5 g, 27.1 mmol), 1-piperazinecarboxylic acid t-butyl ester (5 g, 26.8 mmol) and dimethylformamide (10 mL) was stirred for 3 hours and 30 minutes at an external temperature of 130° C. After adding water to the air-cooled reaction mixture, extraction was performed 3 times with chloroform. The organic layers were washed with brine and dried over anhydrous magnesium sulfate. The desiccant was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel colurn chromatography (ethyl acetate/heptane) to give 5.93 g of the title compound as a yellow solid.
Reaction SMILES: [C:1]([C:4]1[C:12]2[O:11][CH2:10][C:9]([CH3:14])([CH3:13])[C:8]=2[CH:7]=[C:6]([Br:15])[CH:5]=1)(=O)[CH3:2].C([SiH](CC)CC)C.CO.C(=O)(O)[O-].[Na+]>FC(F)(F)C(O)=O.O>[Br:15][C:6]1[CH:5]=[C:4]([CH2:1][CH3:2])[C:12]2[O:11][CH2:10][C:9]([CH3:13])([CH3:14])[C:8]=2[CH:7]=1
Reactant: CC(=O)c1cc(Br)cc2c1OCC2(C)C
Agent: CC[SiH](CC)CC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: CO
Product: CCc1cc(Br)cc2c1OCC2(C)C
Temperature: 55 °C
Yield: 86.2 %

Procedure:
A solution of 7-acetyl-5-bromo-3,3-dimethyl-2,3-dihydro-benzofuran (Intermediate 13, 0.125 g, 0.5 mmol) in 3 mL of trifluoroacetic acid was treated with triethyl silane (0.9 mL, 11.3 mmol) and the resulting clear, colorless solution was heated at 55° C. for 2 h. The reaction mixture was cooled, treated with 6 mL each of methanol and water, neutralized cautiously with saturated sodium bicarbonate solution and extracted with hexanes. The organic extract was dried over anhydrous sodium sulfate, filtered and evaporated to an oil. Flash column chromatography using 2% ethyl acetate in hexane as the eluent afforded the title compound (0.11 g, 93%) as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[CH:4][C:3]=1[C:11](=[O:13])[CH3:12].[Cl-].[NH4+].O>[Fe].CO>[NH2:8][C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([C:11](=[O:13])[CH3:12])[CH:4]=1
Reactant: CC(=O)c1cc([N+](=O)[O-])ccc1Cl
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CO
Product: CC(=O)c1cc(N)ccc1Cl
Temperature: 70 °C
Reaction time: 1 h
Yield: 93.4 %

Procedure:
2.01 g (10.1 mmol) of 1-(2-chloro-5-nitro-phenyl)-ethanone, 2.54 g (47.5 mmol) of ammonium chloride and 1.99 g (35.7 mmol) of iron powder were added to a mixture of 6 mL of water and 12 mL of methanol. The slurry was stirred at 70° C. for 1 h, and then cooled down, filtered through a pad of celite and concentrated down under reduced pressure. The residue was taken up in 60 mL ethyl acetate and 60 mL of water. The aqueous layer was extracted with 40 mL of ethyl acetate and the combined organic layers were evaporated under reduced pressure. The residue was filtered through a pad of silica gel eluting with a 7:3 mixture of ethyl acetate-hexanes to give 1.6 g (94%) of the pure product as a white solid. LC-MSD, m/z for C8H8ClNO [M+H]+=170.0, 172.0;
Reaction SMILES: [CH2:1]([N:3]([CH2:23][CH3:24])[C:4]1[CH:22]=[CH:21][CH:20]=[CH:19][C:5]=1[CH2:6][S:7][C:8]1[C:17]([CH3:18])=[N:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]=1)[CH3:2].ClC1C=CC=C(C(OO)=[O:33])C=1>C(Cl)(Cl)Cl>[CH2:23]([N:3]([CH2:1][CH3:2])[C:4]1[CH:22]=[CH:21][CH:20]=[CH:19][C:5]=1[CH2:6][S:7]([C:8]1[C:17]([CH3:18])=[N:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]=1)=[O:33])[CH3:24]
Reactant: CCN(CC)c1ccccc1CSc1nc2ccccc2nc1C
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Product: CCN(CC)c1ccccc1CS(=O)c1nc2ccccc2nc1C
Yield: 67.4 %

Procedure:
In 50 ml of chloroform was dissolved 1.7 g of 2-(2-diethylaminobenzylthio)-3-methylquinoxaline. To the chilled solution kept at -10° C. was portionwise added 1.21 g of m-chloroperbenzoic acid (purity: 80%). The reaction liquid was then washed successively with saturated aqueous NaHCO3 solution, water and saturated aqueous sodium chloride solution, and dried over sodium sulfate. The sodium sulfate was then removed by filtration, and the solvent was evaporated under reduced pressure from the filtrate. The residual oil was purified by silica gel column chromatography (hexane/acetone) to give 1.2 g of 2-(2-diethylaminobenzylsulfinyl)-3-methylquinoxaline as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[C:7]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[NH:8]2)=[CH:4][CH:3]=1.CC(C)([O-])C.[K+].Cl[C:24](=[O:33])[CH2:25][C@@H:26]([CH3:32])[CH2:27][C:28]([O:30][CH3:31])=[O:29].[Cl-].[NH4+]>C(Cl)Cl.C1COCC1.C(OCC)(=O)C>[CH3:31][O:30][C:28](=[O:29])[CH2:27][C@H:26]([CH3:32])[CH2:25][C:24]([N:8]1[C:9]2[C:5](=[CH:4][CH:3]=[C:2]([Cl:1])[CH:10]=2)[CH:6]=[C:7]1[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])=[O:33]
Reactant: COC(=O)C[C@H](C)CC(=O)Cl
Reactant: CCCCCCc1cc2ccc(Cl)cc2[nH]1
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCCCCCc1cc2ccc(Cl)cc2n1C(=O)C[C@@H](C)CC(=O)OC
Reaction time: 0.5 h

Procedure:
To the cold solution of 6-Chloro-2-hexyl-1H-indole in methylene chloride was added solution of potassium tert-butoxide in THF and stirred for 30 minutes. Then (S)-methyl 5-chloro-3-methyl-5-oxopentanoate in methylene chloride was added to the reaction mixture and was stirred for 3 hours. The reaction mixture was then treated with saturated ammonium chloride and ethyl acetate. The product was purified by column chromatography.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[C:8](F)[C:5]([C:6]#[N:7])=[C:4]([F:11])[CH:3]=1.Cl.[NH2:13][CH2:14][C:15]([NH2:17])=[O:16].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]([F:11])[C:5]([C:6]#[N:7])=[C:8]([NH:13][CH2:14][C:15]([NH2:17])=[O:16])[CH:9]=1
Reactant: N#Cc1c(F)cc(Br)cc1F
Reactant: NCC(N)=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#Cc1c(F)cc(Br)cc1NCC(N)=O
Temperature: 70 °C
Yield: 84 %

Procedure:
12.6 (58.3 mmol) 4-bromo-2,6-difluorobenzonitrile, 6.8 g (61.5 mmol) glycinamide hydrochloride and 16.1 g (116.5 mmol) K2CO3 were suspended in 50 ml DMF and heated at 70° C. for 18 h. Having cooled down to room temperature, the solvent was concentrated and water was added. The resulting precipitate was sucked off and washed with water. 13.3 g (84%) 2-(5-bromo-2-cyano-3-fluorophenylamino)acetamide was obtained. ESI-MS [m/z]: 272, 274 [M+H]+
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[CH3:11][N:12]([CH:21]1[CH2:25][CH:24]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:23]([CH2:32][OH:33])[CH2:22]1)[C:13](=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(N(CC)C(C)C)(C)C>ClCCl>[CH3:11][N:12]([CH:21]1[CH2:25][CH:24]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:23]([CH:32]=[O:33])[CH2:22]1)[C:13](=[O:20])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CN(C(=O)c1ccccc1)C1CC(CO)C(c2ccccc2)C1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CS(C)=O
Product: CN(C(=O)c1ccccc1)C1CC(C=O)C(c2ccccc2)C1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Oxalyl chloride (0.884 mL, 10.2 mmol) was dissolved in dichloromethane (30 mL) and chilled to −78°. Dimethylsulfoxide (1.44 mL, 10.3 mmol) was added slowly and the solution was aged 15 minutes. A solution of 1-(RS)-(N-(methyl)-N-(benzoyl)amino)-3-(SR)-(hydroxymethyl)4-(SR)-phenylcyclopentane (1.26 g, 4.1 mmol), the higher Rf isomer from Step C, in methylene chloride (3 mL) was added slowly and the solution was aged for one hour. N,N-diisopropylethylamine (7.09 mL, 40.7 mmol) was added to the solution. After aging 10 minutes at −78°, the bath was removed and the solution was warmed to ambient temperature over one hour. The organic layers were washed sequentially with 1N HCl, water and brine, then dried over sodium sulfate and concentrated to afford the crude title compound which was essentially the same as Example 11, Step D.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[CH:11]=[CH:12][C:13]([NH:17][CH:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)=[C:14]([CH:16]=1)[NH2:15].[CH:24](=O)[C:25]1[C:26]([O:31][CH3:32])=[CH:27][CH:28]=[CH:29][CH:30]=1.OOS([O-])=O.[K+].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[CH:11]=[CH:12][C:13]2[N:17]([CH:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)[C:24]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[O:31][CH3:32])=[N:15][C:14]=2[CH:16]=1
Reactant: COc1ccccc1C=O
Reactant: Nc1cc(-c2nc3ccccc3o2)ccc1NC1CCOCC1
Agent: O=C([O-])[O-]
Agent: O=S([O-])OO
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccccc1-c1nc2cc(-c3nc4ccccc4o3)ccc2n1C1CCOCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 82.4 %

Procedure:
To a solution of 5-(benzoxazol-2-yl)-2-(tetrahydropyran-4-yl)aminoaniline (see Working Example 20-2) (150 mg, 0.485 mmol) in dimethylformamide (3 mL) was added o-anisaldehyde (79.2 mg, 0.582 mmol) and oxone (179 mg, 0.291 mmol), and this was stirred at room temperature for 2 hours. After the reaction was complete, aqueous potassium carbonate solution was added, and after this was filtered and washed with water, drying yielded the title compound (170 mg, 82% yield) as pale yellow crystals.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C@@H:11]1[CH2:16][CH2:15][C@H:14]([C:17]([OH:19])=O)[CH2:13][CH2:12]1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C.[CH2:41]([NH2:48])[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1>CN(C=O)C>[CH2:41]([NH:48][C:17]([C@H:14]1[CH2:13][CH2:12][C@@H:11]([NH:10][C:2]2[NH:3][C:4]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[N:1]=2)[CH2:16][CH2:15]1)=[O:19])[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1
Reactant: NCc1ccccc1
Reactant: O=C(O)[C@H]1CC[C@@H](Nc2nc3ccccc3[nH]2)CC1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(NCc1ccccc1)[C@H]1CC[C@@H](Nc2nc3ccccc3[nH]2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of cis 4-(1H-benzimidazol-2-ylamino)-cyclohexanecarboxylic acid (L) (20 mg, 0.07 mmol) in DMF (0.2 mL) was added EDC (26 mg,,0.14 mmol), HOBt (18 mg, 0.14 mmol), triethylamine (0.019 mL, 0.14 mmol) and benzyl amine (0.007 mL, 0.7 mmol). The reaction mixture was stirred at room temperature for 1 h followed by quenching with aqueous NaHCO3 and EtOAc. The layers were separated and the organic was washed twice with water, dried over Na2SO4, filtered and concentrated. Purification of the crude oil by preparative reverse-phase HPLC gave cis 4-(1H-benzimidazol-2-ylamino)-cyclohexanecarboxylic acid benzylamide (Example 10) (12 mg): 1H NMR (300 MHz, CD3OD) δ7.40-7.20 (m, 9 H), 4.39 (s, 2 H), 3.81 (m, I H), 2.45 (m, 1 H), 2.02-1.77 (m, 8 H); mass spectrum m/z 349 [(M+H)+; calcd for C21H25N4O: 349].