Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:8]2[CH:9]=[C:10]([F:13])[CH:11]=[CH:12][C:7]=2[C:5](=[O:6])[C:4]([S+:14]([O-])[CH3:15])=[CH:3]1.FC1C=C2C(C(=S)C(C)=CN2C)=CC=1.[Cl:31]N1C(=O)CCC1=O>>[Cl:31][CH2:15][S:14][C:4]1[C:5](=[O:6])[C:7]2[C:8](=[CH:9][C:10]([F:13])=[CH:11][CH:12]=2)[N:2]([CH3:1])[CH:3]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: Cn1cc([S+](C)[O-])c(=O)c2ccc(F)cc21
Agent: Cc1cn(C)c2cc(F)ccc2c1=S
Product: Cn1cc(SCCl)c(=O)c2ccc(F)cc21

Procedure:
In other embodiments, the synthesis of racemic monochloroflosequinan is carried out as a three step procedure, as described in more detail in Example 2. Briefly, in the first step, racemic flosequinan is reduced to desoxyflosequinan (7-fluoro-1-methyl-3-methylthio-4-quinolone). In the second step, desoxyflosequinan is chlorinated using N-chlorosuccinimide, to produce chlorodesoxyflosequinan (3-chloromethylthio-7-fluoro-1-methyl-4-quinolone). In the third step, chlorodesoxyflosequinan is subjected to oxidation to produce 3-chloromethylsulfinyl-7-fluoro-1-methyl-4-quinolone (monochloroflosequinan). Such oxidation may be accomplished using hydrogen peroxide.
Reaction SMILES: [Br-].[PH4+].C1([C:9](C2C=CC=CC=2)(C2C=CC=CC=2)[CH2:10][O:11][C:12](=[O:16])[CH2:13][CH2:14][CH3:15])C=CC=CC=1.[H-].[Na+].[CH3:31][C:32]1[CH:47]=[CH:46][CH:45]=[C:44]([CH3:48])[C:33]=1[CH2:34][O:35][C:36]1[CH:37]=[C:38]([CH:41]=[CH:42][CH:43]=1)[CH:39]=O.O>CS(C)=O>[CH2:10]([O:11][C:12](=[O:16])[CH2:13][CH2:14][CH:15]=[CH:39][C:38]1[CH:41]=[CH:42][CH:43]=[C:36]([O:35][CH2:34][C:33]2[C:32]([CH3:31])=[CH:47][CH:46]=[CH:45][C:44]=2[CH3:48])[CH:37]=1)[CH3:9]
Reactant: Cc1cccc(C)c1COc1cccc(C=O)c1
Reactant: CCCC(=O)OCC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CCOC(=O)CCC=Cc1cccc(OCc2c(C)cccc2C)c1
Temperature: 26.700000762939453 °C
Reaction time: 0.5 h
Yield: 228 %

Procedure:
A mixture of triphenylethylbutyrate phosphonium bromide (10.06 g, 22 mmol) and sodium hydride (0.581 g, 24.2 mmol) in dimethyl sulfoxide (45 ml) was stirred for 30 minutes under nitrogen. The reaction mixture was heated to 26.7° C. and 3-(2,6-Dimethylbenzyloxy)benzaldehyde (3.89 g, 16.2 mmol) diluted in dimethyl sulfoxide (15 ml) was added dropwise over 3 minutes. The reaction mixture was stirred for 3 hours at 50° C. A mixture of triphenylethylbutyrate phosphonium bromide (3.20 g, 70 mmol) and sodium hydride (0.185 g) in dimethyl sulfoxide (10 ml) was stirred under nitrogen for 30 minutes. This mixture was added, in bolus to the above reaction mixture at room temperature. The reaction mixture was stirred for Z hours at 50° C., cooled to room temperature and poured over ice (50 g) and water (50 ml) mixture. The aqueous mixture was extracted with ethyl acetate (3×125 ml). The combined organic layer was dried over Na2SO4, filtered and concentrated to afford the 12.5 g of brown oil. The oil was dissolved in 30 ml of hexanes:ethyl acetate (95:5) and chromatographed on a Biotage 75S silica gel column to give 4.9 g of a yellow oil. The yellow oil was subjected to another silica gel column chromatography eluting with hexane:chloroform (1:1) to hexane:ethyl acetate (9:1) to afford 3.40 g (62%) of a faint yellow oil product which solidified upon standing.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][C:12](/[C:18](/[C:26]#[N:27])=[CH:19]/[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:13][CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(O)C>[C:1]([O:5][C:6]([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][C:12]([CH:18]([C:26]#[N:27])[CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:13][CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(/C(C#N)=C/c3ccccc3)cc2C1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCc2ccc(C(C#N)Cc3ccccc3)cc2C1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a suspension of 0.178 mmol of (Z)-tert-butyl-7-(1-cyano-2-phenylvinyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate in 2 ml ethanol were added at 0° C. 0.178 mmol of sodium borohydride. The mixture was allowed to warm to room temperature and stirred for 3 d. The mixture was poured on ice water and citric acid (5%) was added until acidic. The aqueous phase was extracted with EtOAc. The combined organic phase was washed with brine, dried over MgSO4, and filtered. Evaporation of the solvent gave 61.2 mg (95%) of a crude slightly yellow oil, that was directly submitted to Boc deprotection.
Reaction SMILES: Br[C:2]1[C:3]([CH2:8][C:9]2([OH:25])[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([CH3:18])[CH:16]=3)[N:11]([CH2:19][CH2:20][CH:21](C)C)[C:10]2=[O:24])=[N:4][CH:5]=[CH:6][CH:7]=1.CC1C=C2C(=CC=1)N(CCC)[C:31](=[O:39])C2=O.COC1C=CC(C)=NC=1>>[OH:25][C:9]1([CH2:8][C:3]2[CH:2]=[CH:7][C:6]([O:39][CH3:31])=[CH:5][N:4]=2)[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([CH3:18])[CH:16]=2)[N:11]([CH2:19][CH2:20][CH3:21])[C:10]1=[O:24]
Reactant: CCCN1C(=O)C(=O)c2cc(C)ccc21
Reactant: Cc1ccc2c(c1)C(O)(Cc1ncccc1Br)C(=O)N2CCC(C)C
Agent: COc1ccc(C)nc1
Product: CCCN1C(=O)C(O)(Cc2ccc(OC)cn2)c2cc(C)ccc21

Procedure:
This compound was prepared in an analogous manner to 3-((3-bromopyridin-2-yl)methyl)-3-hydroxy-1-isopentyl-5-methylindolin-2-one using 5-methyl-1-propylindoline-2,3-dione and 5-methoxy-2-methylpyridine. 1H-NMR δ 8.3 (s, 1H), 7.20 (d, 1H), 7.08 (d, 1H), 6.98 (d, 1H), 6.73 (m, 2H), 4.2 (bs, OH), 3.92 (s, 3H), 3.61 (m, 2H), 3.23 (d, 1H), 3.12 (d, 1H), 2.62 (s, 3H), 1.70 (m, 2H), 0.97 (t, 3H). Calculated mass for C19H22N2O3, 326.16. Observed, 327.1 (M+1).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([S:12][CH2:13][CH2:14][O:15][CH3:16])=[N:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:36][S:37]([CH2:40][CH2:41][CH2:42]O)(=[O:39])=[O:38].N(C(OCC)=O)=NC(OCC)=O>C(Cl)Cl>[CH3:16][O:15][CH2:14][CH2:13][S:12][C:6]1[C:5]2[C:10](=[CH:11][C:2]([O:1][CH2:42][CH2:41][CH2:40][S:37]([CH3:36])(=[O:39])=[O:38])=[CH:3][CH:4]=2)[N:9]=[CH:8][N:7]=1
Reactant: CS(=O)(=O)CCCO
Reactant: COCCSc1ncnc2cc(O)ccc12
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COCCSc1ncnc2cc(OCCCS(C)(=O)=O)ccc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 70.9 %

Procedure:
A solution of 7-hydroxy-4-(2-methoxyethylsulphanyl)quinazoline (0.1 g, 3.8 mmol) in methylene chloride (20nil) containing triphenylphosphine (1.7 g, 6.36 mmol), 3-(methylsulphonyl)-1-propanol (0.85 g, 6 mmol) and diethyl azodicarboxylate (1.05 ml, 6.36 mmol) was stirred for 3 hours at ambient temperature. After partial evaporation of the methylene chloride, ethyl acetate was added. The precipitate was collected by filtration, washed with ether and dried under vacuum to give 4-(2-methoxyethylsulphanyl)-7-(3-methylsulphonylpropoxy)quinazoline (960 mg, 71%).
Reaction SMILES: [CH:1]([C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][CH:4]=1)=O.Cl.[O:14]([NH2:16])[CH3:15]>>[CH3:15][O:14][N:16]=[CH:1][C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][CH:4]=1
Reactant: COC(=O)c1ccc(C=O)cc1
Reactant: CON
Agent: Cl
Product: CON=Cc1ccc(C(=O)OC)cc1
Yield: 96 %

Procedure:
Reaction of methyl 4-formylbenzoate with methoxylamine hydrochloride as described in the preparation of Compound 44-A gave the title oxime ether (96% yield) as a white solid (mixture of E- and Z-isomers). The E-isomer was obtained as white crystals from hexane; mp 66–67° C. (Lit. mp 65–66° C., Cooks, Org. Mass Spectrum., 5, 1971, 687). 1HNMR 400 MHz (DMSO-d6) δ (ppm): (E-isomer) 3.86 (3H, s, OCH3), 3.93 (3H, s, OCH3), 7.75 (2H, d, aromatics), 7.98 (2H, d, aromatics), 8.32 (1H, s, CH).
Reaction SMILES: [CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:63])=[CH:43][CH:44]2[CH2:49][CH2:48][C:47](=[CH:50][C:51]([O:53][CH2:54][C:55]3[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=3)=[O:52])[CH:46]([O:61][CH3:62])[CH2:45]2)[CH:7]([CH3:64])[CH:6]([O:65][Si](C(C)(C)C)(C)C)[CH2:5][C:4]1=[O:73])[CH3:2]>C(#N)C>[CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:63])=[CH:43][CH:44]2[CH2:49][CH2:48][C:47](=[CH:50][C:51]([O:53][CH2:54][C:55]3[CH:56]=[CH:57][CH:58]=[CH:59][CH:60]=3)=[O:52])[CH:46]([O:61][CH3:62])[CH2:45]2)[CH:7]([CH3:64])[CH:6]([OH:65])[CH2:5][C:4]1=[O:73])[CH3:2]
Reactant: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(=CC(=O)OCc4ccccc4)C(OC)C3)C(C)C(O[Si](C)(C)C(C)(C)C)CC1=O)C(C)CC2OC
Solvent: CC#N
Product: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(=CC(=O)OCc4ccccc4)C(OC)C3)C(C)C(O)CC1=O)C(C)CC2OC
Yield: 85.4 %

Procedure:
A solution of 0.200 g (0.193 mmole) of 17-ethyl-1-hydroxy-12-[2'-(4"-[benzyloxycarbonylmethylidenyl]-3"-methoxycyclohexyl)-1'-methylvinyl]-14-tert-butyldimethylsilyloxy-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone in 5 mL of 10% (48% aqueous HF)-acetonitrile was stirred at room temperature for 8 hr. The reaction was quenched by addition of 5 mL of trimethylethoxy-silane and the solution was concentrated under vacuum. The residue was purified by flash chromatography (silica gel, 1.5 cm×10 cm) using 20% acetoneohexane and the product lyophilized from benzene to afford 0.152 g (85%) of the title compound as a colorless solid; NMR (CDCl3) indicated a 9:1 mixture of olefin isomers; MS (FAB) 921 (M+Li).
Reaction SMILES: C[C@H](N)C1C=CC=CC=1.[O:10]1[C:14]2[CH:15]=[CH:16][C:17]([CH:19]([C:35]3[C:43]4[C:38](=[CH:39][C:40]([C:44]([OH:46])=[O:45])=[CH:41][CH:42]=4)[N:37]([CH3:47])[CH:36]=3)[C:20]([NH:22][S:23]([C:26]3[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][C:27]=3[O:33][CH3:34])(=[O:25])=[O:24])=[O:21])=[CH:18][C:13]=2[O:12][CH2:11]1>O1CCCC1.COCCOC>[O:10]1[C:14]2[CH:15]=[CH:16][C:17]([C@@H:19]([C:35]3[C:43]4[C:38](=[CH:39][C:40]([C:44]([OH:46])=[O:45])=[CH:41][CH:42]=4)[N:37]([CH3:47])[CH:36]=3)[C:20]([NH:22][S:23]([C:26]3[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][C:27]=3[O:33][CH3:34])(=[O:24])=[O:25])=[O:21])=[CH:18][C:13]=2[O:12][CH2:11]1
Reactant: COc1cc(C)ccc1S(=O)(=O)NC(=O)C(c1ccc2c(c1)OCO2)c1cn(C)c2cc(C(=O)O)ccc12
Agent: C[C@H](N)c1ccccc1
Solvent: COCCOC
Solvent: C1CCOC1
Product: COc1cc(C)ccc1S(=O)(=O)NC(=O)[C@@H](c1ccc2c(c1)OCO2)c1cn(C)c2cc(C(=O)O)ccc12
Temperature: 55 °C

Procedure:
(S)-(−)-α-Methylbenzylamine (0.53 kg) was added over a period of 15 minutes to a stirred suspension of 3-{1-(1,3-benzodioxol-5-yl)-2-[(2-methoxy4-methylphenyl)sulfonylamino]-2-oxoethyl}-1-methyl-1H-indole-6-carboxylic acid (from step (c), 1.17 kg, 2.18 moles) in tetrahydrofuran (6.5 liters, 5.5 ml/g) and 1,2-dimethoxyethane (6.5 liters, 5.5 ml/g) at 60° C. under a nitrogen atmosphere. The resulting solution was allowed to cool to 55° C., seeded with 13.6 g of the (S)-(−)-α-methylbenzylamine salt of the title compound of Example 1 (prepared by conventional methods) and stirred for 24 h. The resulting suspension was allowed to cool to 45° C. over a period of 48 h and stirred at this temperature for an additional 48 h. The suspension was allowed to cool to room temperature and the precipitated (S)-(−)-α-methylbenzylamine salt (of the title compound) collected by filtration (1.316 kg, 84%, ratio of (S)-(−)-α-methylbenzylamine to (S)-(+)-acid in the salt 1.5:1). The salt was partitioned between ethyl acetate (6.8 liters), tetrahydrofuran (1.4 liters) and 1M hydrochloric acid (6.8 liters) and the organic phase was separated and then washed with 1M hydrochloric acid (3×0.9 liters) and water (2×0.7 liters). The organic phase was dried by azeotropic distillation with ethyl acetate at constant volume, concentrated to a volume of 3.5 liters and then n-hexane (3.5 liters) added. The precipitated product was granulated at 0° C. for 1 h and filtered to give the title compound as a white crystalline solid (0.936 kg, 91.6%). The enantiomeric excess of the compound was found to be >94% using chiral stationary phase HPLC.
Reaction SMILES: [CH3:1][CH:2]([CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4].ClC1C=CC=C(C(OO)=O)C=1.C[Si]([C:30]#[N:31])(C)C.CN(C)C(Cl)=O>C(OCC)(=O)C.O>[C:30]([C:11]1[N:10]=[C:9]([CH2:8][CH:2]([CH3:1])[C:3]([O:5][CH2:6][CH3:7])=[O:4])[CH:14]=[CH:13][CH:12]=1)#[N:31]
Reactant: CCOC(=O)C(C)Cc1ccccn1
Reactant: C[Si](C)(C)C#N
Agent: CN(C)C(=O)Cl
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: O
Solvent: CCOC(C)=O
Product: CCOC(=O)C(C)Cc1cccc(C#N)n1
Temperature: 25 °C
Reaction time: 14 h
Yield: 70.5 %

Procedure:
Ethyl 2-methyl-3-(2-pyridyl)propionate (1.0 g, 5.2 mmol) was dissolved in ethyl acetate (4 ml), and 3-chloroperbenzoic acid (ca. 77%, 1.2 g, 5.2 mmol) was added thereto. The reaction mixture was stirred at room temperature for 14 hrs and subjected to a silica gel (50 g) column chromatography. The fractions eluted with ethyl acetate-ethanol (4:1, v/v) were collected and concentrated. The residue was dissolved in acetonitrile (10 ml), and trimethylsilyl cyanide (0.95 g, 9.6 mmol) and N,N-dimethylcarbamoyl chloride (0.77 g, 7.2 mmol) were added thereto. The reaction mixture was stirred at room temperature for 16 hrs and combined with ethyl acetate and water. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated, and the residue was subjected to a silica gel (50 g) column chromatography. The fractions eluted with hexane-ethyl acetate (4:1, v/v) were collected and concentrated to give the titled compound (0.80 g, 76%).
Reaction SMILES: C[O:2][C:3]1[C:11]2[CH:10]=[C:9]([C:12]3[O:16][N:15]=[C:14]([CH3:17])[CH:13]=3)[O:8][C:7]=2[CH:6]=[CH:5][CH:4]=1.B(Br)(Br)Br>>[OH:2][C:3]1[C:11]2[CH:10]=[C:9]([C:12]3[O:16][N:15]=[C:14]([CH3:17])[CH:13]=3)[O:8][C:7]=2[CH:6]=[CH:5][CH:4]=1
Reactant: COc1cccc2oc(-c3cc(C)no3)cc12
Agent: BrB(Br)Br
Product: Cc1cc(-c2cc3c(O)cccc3o2)on1
Yield: 92.3 %

Procedure:
By the reactions in the same manner as in Starting Material Synthesis Example 5 using 5-(4-methoxybenzo(b)furan-2-yl)-3-methylisoxazole (3.0 g) and boron tribromide (7.6 ml), the title compound (2.6 g) was obtained as pale-yellow crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]([CH2:6][N:7]([CH:12]2[CH2:16][CH2:15][NH:14][CH2:13]2)[CH2:8][C:9]([NH2:11])=[O:10])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:26][CH2:27]/[CH:28]=[C:29]1/[C:30]2[CH:43]=[C:42]([C:44]([OH:47])([CH3:46])[CH3:45])[CH:41]=[CH:40][C:31]=2[O:32][CH2:33][C:34]2[N:39]=[CH:38][CH:37]=[CH:36][C:35]/1=2>C(#N)C.O>[Cl:1][C:2]1[CH:18]=[CH:17][C:5]([CH2:6][N:7]([CH:12]2[CH2:16][CH2:15][N:14]([CH2:26][CH2:27][CH:28]=[C:29]3[C:35]4[CH:36]=[CH:37][CH:38]=[N:39][C:34]=4[CH2:33][O:32][C:31]4[CH:40]=[CH:41][C:42]([C:44]([OH:47])([CH3:46])[CH3:45])=[CH:43][C:30]3=4)[CH2:13]2)[CH2:8][C:9]([NH2:11])=[O:10])=[CH:4][CH:3]=1
Reactant: NC(=O)CN(Cc1ccc(Cl)cc1)C1CCNC1
Reactant: CC(C)(O)c1ccc2c(c1)/C(=C/CCBr)c1cccnc1CO2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CC(C)(O)c1ccc2c(c1)C(=CCCN1CCC(N(CC(N)=O)Cc3ccc(Cl)cc3)C1)c1cccnc1CO2
Temperature: 50 °C
Reaction time: 24 h

Procedure:
To a solution of 2-[(4-chloro-benzyl)-pyrrolidin-3-yl-amino]-acetamide (0.21 g, 0.8 mmol) in acetonitrile:water (4:1) was added potassium carbonate (0.6 mmol) and (E)-2-[5-(3-bromo-propylidene)-5,11-dihydro-10-oxa-1-aza-dibenzo[a,d]cyclohepten-7-yl]-propan-2-ol (0.15 g, 0.4 mmol) and the resulting mixture was stirred at 50° C. for 24 h. The reaction mixture was concentrated in vacuo, diluted with ethyl acetate, and dried over sodium sulfate. The crude product was purified by HPLC. 1H-NMR (CDCl3) δ: 1.35 (6H, s), 1.55-1.75 (1H, m), 1.80-2.00 (1H, m), 2.20-2.85 (8H, m), 2.90-3.10 (2H, d), 3.30-3.50 (1H, m), 3.60 (1H, d), 4.80-5.30 (2H, br, s), 6.10 (1H, t), 6.70 (1H, dd), 7.00-7.45 (7H, m), 7.70 (1H, dd), 8.50 (1H, dd). ESI-MS m/z: 562 (M+1), UV retention time: 1.31 min.
Reaction SMILES: Br[C:2]1[CH:28]=[C:27]([F:29])[C:5]2[N:6]([CH2:9][C:10]3[CH:26]=[CH:25][C:13]4[N:14]=[C:15]([NH:17][C@@H:18]5[CH2:23][CH2:22][CH2:21][CH2:20][C@H:19]5[OH:24])[S:16][C:12]=4[CH:11]=3)[CH:7]=[N:8][C:4]=2[CH:3]=1.[CH3:30][N:31](C=O)C>[C-]#N.[Zn+2].[C-]#N.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:29][C:27]1[C:5]2[N:6]([CH2:9][C:10]3[CH:26]=[CH:25][C:13]4[N:14]=[C:15]([NH:17][C@@H:18]5[CH2:23][CH2:22][CH2:21][CH2:20][C@H:19]5[OH:24])[S:16][C:12]=4[CH:11]=3)[CH:7]=[N:8][C:4]=2[CH:3]=[C:2]([C:30]#[N:31])[CH:28]=1
Reactant: CN(C)C=O
Reactant: O[C@@H]1CCCC[C@H]1Nc1nc2ccc(Cn3cnc4cc(Br)cc(F)c43)cc2s1
Agent: [Fe+2]
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: N#Cc1cc(F)c2c(c1)ncn2Cc1ccc2nc(N[C@@H]3CCCC[C@H]3O)sc2c1
Temperature: 100 °C
Reaction time: 15 h
Yield: 2 %

Procedure:
A stirred mixture of (1R,2R)-2-((6-((5-bromo-7-fluoro-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol (150 mg, 0.316 mmol) from Example 203, zinc cyanide (111 mg, 0.948 mmol), 1,1′-bis(diphenylphosphino)ferrocene (35 mg, 0.0632 mmol) and anhydrous DMF (2 mL) was purged with a stream of argon. To the mixture was added palladium(trisdibenzylideneacetone) (0) (29 mg, 0.0316 mmol) and the mixture was heated in a sealed tube 100° C. for 6 h. The mixture was cooled and additional zinc cyanide (111 mg, 0.948 mmol), 1,1′-bis(diphenylphosphino)ferrocene (35 mg, 0.0632 mmol), and palladium(trisdibenzylideneacetone) (0) (29 mg, 0.0316 mmol) were added, and heating in a sealed tube was continued at 100° C. for 15 h. The mixture was cooled to rt and purified directly by reverse-phase preparative HPLC using a mixture of water (5% CH3CN, 0.05% HOAc) and CH3CN (0.05% HOAc) as the mobile phase and Varian Pursuit XRs diphenyl column as the stationary phase to afford (7-fluoro-1-((2-(((1R,2R)-2-hydroxycyclohexyl)amino)benzo[d]thiazol-6-yl)methyl)-1H-benzo[d]imidazole-5-carbonitrile (2.6 mg, 2%) as a white solid. 1H NMR (500 MHz, DMSO-d6) δ 8.70 (s, 1H), 8.13 (s, 1H), 8.02 (d, J=7.6 Hz, 1H), 7.63 (d, J=11.1 Hz, 1H), 7.57 (s, 1H), 7.29 (d, J=8.1 Hz, 1H), 7.10 (d, J=8.1 Hz, 1H), 5.58 (s, 2H), 4.77 (br s, 1H), 3.50 (br m, 1H), 3.30 (br m, 1H), 2.02 (m, 1H), 1.87 (m, 1H), 1.55-1.67 (m, 2H), 1.12-1.32 (m, 4H); LCMS (ESI) m/z 422 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:11])[CH2:5][NH:6][C:7](=[O:10])[CH2:8][NH2:9])[CH3:2].C1(=O)N([O:17][C:18](=O)[C:19]([O:22][C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=2)([CH3:21])[CH3:20])C(=O)CC1>>[CH2:1]([O:3][C:4](=[O:11])[CH2:5][NH:6][C:7](=[O:10])[CH2:8][NH:9][C:18](=[O:17])[C:19]([O:22][C:23]1[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=1)([CH3:21])[CH3:20])[CH3:2]
Reactant: CCOC(=O)CNC(=O)CN
Reactant: CC(C)(Oc1ccc(Cl)cc1)C(=O)ON1C(=O)CCC1=O
Product: CCOC(=O)CNC(=O)CNC(=O)C(C)(C)Oc1ccc(Cl)cc1

Procedure:
Likewise, by following the procedure of Example 1 but replacing proline methyl ester hydrochloride with glycylglycine ethyl ester and replacing the "activated ester" N-{N-[2-(p-chlorophenoxy)-2-methylpropionyl]glycine} succinimido ester with an equivalent amount of the "activated ester", 2-(p-chlorophenoxy)-2-methyl-propionic acid succinimido ester, obtained in an analogous manner as the aforementioned "activated ester", N-{N-[2-(p-chlorophenoxy)-2-methylpropionyl]glycyl}glycine ethyl ester again is obtained.
Reaction SMILES: C([C@H:8]([C@H:14]([CH3:18])[CH:15]([CH3:17])[CH3:16])[CH2:9][O:10][C:11](=[O:13])[CH3:12])C1C=CC=CC=1.C(#N)C.C(Cl)(Cl)(Cl)Cl.I([O-])(=O)(=O)=O.[Na+]>C(Cl)Cl.O>[CH3:18][C@@H:14]([C@@H:8]1[CH2:9][O:10][C:11](=[O:13])[CH2:12]1)[CH:15]([CH3:17])[CH3:16]
Reactant: CC(=O)OC[C@H](Cc1ccccc1)[C@H](C)C(C)C
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: O
Solvent: CC#N
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)[C@@H](C)[C@@H]1COC(=O)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 158.8 %

Procedure:
To a solution of aromatic compound 179 (5.0 g, 20.16 mmol) in HPLC grade acetonitrile (60 mL), carbon tetrachloride (60 mL), and water (120 mL) was added sodium periodate (86.24 g, 403.32 mmol, 20 equiv.), followed by RuCl3 (414 mg, 10 mol %). The mixture was stirred vigorously overnight at room temperature, and diluted with methylene chloride (400 mL). The mixture was filtered through a pad of Celite to remove the solid precipitate. The organic portion was separated, and the aqueous was further extracted with methylene chloride. After the combined organic portions concentrated, the residue was dissolved in ether and applied to a column of Florisil. The compound was eluted with 3% methanol in ether, evaporated to a paste that was dissolved in methanol (100 mL). Potassium carbonate (8.0 g) was added, and the mixture was refluxed for 6 hours. The solvent was evaporated, and the solid residue was dissolved in water. The pH was adjusted to 2 by the careful addition of concentrated HCl while being cooled in ice water bath and stirred. Chloroform (200 mL) was added to the solution and stirred as such overnight at room temperature. The organic phase was separated, and the aqueous portion was further extracted with chloroform. After drying, the solvent was evaporated to give the lactone 180 5.0 g. NMR (CDCl3) δ 4.36 (app. t, 1H, CHaHbO), 3.85 (app. t, 1H, CHaHbO), 2.46 (mn, 2H, CHcHd C═O), 2.13 (m, 2H, CHCH2C═O), 1.60 (m, 1H, CH(Me)2), 1.35 (m, 1H, CH3CHCH(Me)2), 0.86 (d, 3H, CH3) and 0.72 (t, 3H, CH3).
Reaction SMILES: [N:1]([C@@H:4]1[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6][C@H:5]1[OH:14])=[N+]=[N-]>CO.[Pd]>[NH2:1][C@@H:4]1[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6][C@H:5]1[OH:14]
Reactant: [N-]=[N+]=N[C@@H]1Cc2ccccc2C[C@H]1O
Agent: [Pd]
Solvent: CO
Product: N[C@@H]1Cc2ccccc2C[C@H]1O
Yield: 102 %

Procedure:
A stirring mixture of trans 3-azido-2-hydroxy-1,2,3,4-tetrahydronaphthalene (2.5 g, about 75% pure) dissolved in methanol (132 mL) and 10% palladium on carbon (250 mg) was hydrogenated for 2 h under a hydrogen balloon at room temperature. The reaction mixture was filtered through Celite®, rinsing with methanol, and then evaporated under vacuum to provide the title compound (2.2 g, 72% pure).