Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:26]=[CH:27][CH:28]=1)[CH2:5][C@@:6]([CH3:25])([C:21]([O:23][CH3:24])=[O:22])[N:7]=C(C1C=CC=CC=1)C1C=CC=CC=1.Cl>CO.C1COCC1>[NH3:7].[Br:1][C:2]1[CH:3]=[C:4]([CH:26]=[CH:27][CH:28]=1)[CH2:5][C@@:6]([CH3:25])([C:21]([O:23][CH3:24])=[O:22])[NH2:7]
Reactant: COC(=O)[C@](C)(Cc1cccc(Br)c1)N=C(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)[C@@](C)(N)Cc1cccc(Br)c1
Product: N
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of methyl 3-bromo-N-(diphenylmethylene)-α-methylphenylalaninate (2.95 g, 6.76 mmol) in MeOH (25 mL) and THF (25 mL) was added 6N HCl (3.4 mL, 20.3 mmol) and the reaction mixture was stirred at RT for 5 min, concentrated in vacuo and purified by ion exchange chromatography (SCX, 25 g, then 50 g, MeOH then 2M NH3 in MeOH) to provide methyl 3-bromo-α-methylphenylalaninate.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([C@H:14]3[CH2:16][C@H:15]3[CH2:17][OH:18])[CH2:10][CH2:9]2)=[N:6][CH:7]=1.[H-].[Na+].Br[CH2:22][C:23]1[CH:28]=[CH:27][C:26]([S:29][CH3:30])=[CH:25][CH:24]=1>CN(C=O)C>[Br:1][C:2]1[CH:3]=[N:4][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([C@H:14]3[CH2:16][C@H:15]3[CH2:17][O:18][CH2:22][C:23]3[CH:28]=[CH:27][C:26]([S:29][CH3:30])=[CH:25][CH:24]=3)[CH2:10][CH2:9]2)=[N:6][CH:7]=1
Reactant: OC[C@@H]1C[C@@H]1C1CCN(c2ncc(Br)cn2)CC1
Reactant: CSc1ccc(CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CSc1ccc(COC[C@@H]2C[C@@H]2C2CCN(c3ncc(Br)cn3)CC2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The product of step B (1.5 g, 4.8 mmol) was dissolved in DMF (15 mL), and sodium hydride (60 wt % dispersion in oil, 290 mg, 7.3 mmol) was added. After stirring at RT for 1 hour, (4-(bromomethyl)phenyl)(methyl)sulfane (1.35 g, 6.2 mmol) was added, and the resulting solution was stirred at RT for 18 h. The solution was partitioned between sat. NH4Cl and EtOAc. The aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine and dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (5/1 hexanes/EtOAc) to yield the title compound.
Reaction SMILES: [C:1]([CH:3]1[CH2:6][N:5]([C:7](=[O:40])[C@H:8]([NH:10][C:11]([C:13]2[C:21]3[C:16](=[N:17][CH:18]=[C:19]([C:22]4[S:30][C:29]5[C:24](=[N:25][CH:26]=[CH:27][C:28]=5Cl)[CH:23]=4)[N:20]=3)[N:15](COCC[Si](C)(C)C)[CH:14]=2)=[O:12])[CH3:9])[CH2:4]1)#[N:2].C(C1CN(C(=O)[C@H](NC([C:55]2[C:63]3[C:58](=NC=C(C4SC5C(=NC=CC=5Cl)C=4)N=3)[N:57](COCC[Si](C)(C)C)[CH:56]=2)=O)C2CC2)C1)#N>>[C:1]([CH:3]1[CH2:6][N:5]([C:7](=[O:40])[C@H:8]([NH:10][C:11]([C:13]2[C:21]3[C:16](=[N:17][CH:18]=[C:19]([C:22]4[S:30][C:29]5[C:24](=[N:25][CH:26]=[CH:27][C:28]=5[N:57]5[CH2:58][CH2:63][CH2:55][CH2:56]5)[CH:23]=4)[N:20]=3)[NH:15][CH:14]=2)=[O:12])[CH3:9])[CH2:4]1)#[N:2]
Reactant: C[Si](C)(C)CCOCn1cc(C(=O)N[C@@H](C(=O)N2CC(C#N)C2)C2CC2)c2nc(-c3cc4nccc(Cl)c4s3)cnc21
Reactant: C[C@@H](NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3cc4nccc(Cl)c4s3)nc12)C(=O)N1CC(C#N)C1
Product: C[C@@H](NC(=O)c1c[nH]c2ncc(-c3cc4nccc(N5CCCC5)c4s3)nc12)C(=O)N1CC(C#N)C1

Procedure:
Prepared according to the procedure outlined in Example 155 substituting 2-(7-chloro-thieno[3,2-b]pyridin-2-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-(3-cyano-azetidin-1-yl)-1-methyl-2-oxo-ethyl]-amide for 2-(7-chloro-thieno[3,2-b]pyridin-2-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-(3-cyano-azetidin-1-yl)-1-cyclopropyl-2-oxo-ethyl]-amide in step 1. MS: (M+H)+=501.
Reaction SMILES: [Cl:1][S:2]([OH:5])(=O)=[O:3].[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][C:14](=[O:16])[CH3:15])=[CH:9][CH:8]=1>>[Cl:6][C:7]1[CH:8]=[CH:9][C:10]([CH2:13][C:14](=[O:16])[CH3:15])=[CH:11][C:12]=1[S:2]([Cl:1])(=[O:5])=[O:3]
Reactant: O=S(=O)(O)Cl
Reactant: CC(=O)Cc1ccc(Cl)cc1
Product: CC(=O)Cc1ccc(Cl)c(S(=O)(=O)Cl)c1
Temperature: 25 °C

Procedure:
To chlorosulfonic acid (25 ml, excess) cooled at −10° C. is added dropwise 4-chlorophenyl acetone (1.0 g, 5.93 mmol). The temperature is kept below 0° C. throughout the addition. The reaction mixture is then left to warm up to room temperature overnight. The reaction mixture is poured carefully onto ice (1500 ml). Once the ice is melted, the aqueous layer is extracted with dichloromethane (3×250 ml). The combined organic layers are dried over MgSO4, filtered and concentrated to afford the titled compound as an off-white solid.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:9]#[N:10])=[N:4][CH:5]=[C:6](Cl)[CH:7]=1.[C:11]([C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][CH3:22])=[CH:15][CH:14]=1)#[CH:12].C(N(CC)CC)C>CN(C=O)C.C(OCC)(=O)C.[OH-].[NH4+].[Cu]I>[Cl:1][C:2]1[C:3]([C:9]#[N:10])=[N:4][CH:5]=[C:6]([C:12]#[C:11][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][CH3:22])=[CH:15][CH:14]=2)[CH:7]=1
Reactant: C#Cc1ccc(OCCC)cc1
Reactant: N#Cc1ncc(Cl)cc1Cl
Agent: [Cu]I
Agent: [NH4+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCOc1ccc(C#Cc2cnc(C#N)c(Cl)c2)cc1
Temperature: 25 °C

Procedure:
A solution of 3,5-dichloropicolinonitrile (1.0 eq.), 1-ethynyl-4-propoxybenzene (commercially available) (1.0 eq.), trans-dichlororbis(triphenylphosphine)palladium (II) (10 mol %), copper (I) iodide (20 mol %), and triethylamine (5.0 eq.) in DMF (0.3 M) was stirred at 50° C. for 3 hours. After cooling to ambient temperature, the reaction mixture was diluted with ethyl acetate and 10% aqueous ammonium hydroxide. The two phases were separated, and the aqueous layer was extracted twice with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous MgSO4, and concentrated en vaccuo. The crude material was purified by flash chromatography on a COMBIFLASH® system (ISCO) using 0-10% ethyl acetate in hexane to give 3-chloro-5-((4-propoxyphenyl)ethynyl)picolinonitrile as a white solid.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=O.S(Cl)(Cl)=O.[C:15]([O:18][CH:19]1[O:33][C@H:32]([CH2:34][O:35][C:36](=[O:38])[CH3:37])[C@@H:27]([O:28][C:29](=[O:31])[CH3:30])[C@H:22]([O:23][C:24](=[O:26])[CH3:25])[C@H:20]1[NH2:21])(=[O:17])[CH3:16].Cl>C1C=CC=CC=1.N1C=CC=CC=1>[I:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([NH:21][C@@H:20]1[C@@H:22]([O:23][C:24](=[O:26])[CH3:25])[C@H:27]([O:28][C:29](=[O:31])[CH3:30])[C@@H:32]([CH2:34][O:35][C:36](=[O:38])[CH3:37])[O:33][CH:19]1[O:18][C:15](=[O:17])[CH3:16])=[O:7]
Reactant: O=C(O)c1cccc(I)c1
Reactant: CC(=O)OC[C@H]1OC(OC(C)=O)[C@H](N)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: Cl
Solvent: O=S(Cl)Cl
Solvent: c1ccccc1
Solvent: c1ccncc1
Product: CC(=O)OC[C@H]1OC(OC(C)=O)[C@H](NC(=O)c2cccc(I)c2)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 65 °C
Reaction time: 24 h
Yield: 45.1 %

Procedure:
A mixture of m-iodobenzoic acid (1.6 g; 6.45×10-3 mol) and thionyl chloride (10 ml) was stirred at 65° C. for 24 hours, benzene was added thereto, and excessive thionyl chloride was removed by distillation under reduced pressure. The thus prepared m-iodobenzoyl chloride was dissolved in benzene (2 ml), and a solution of 1,3,4,6-tetra-O-acetyl-D-glucosamine (2 g; 5.76×10-3 mol) in benzene (10 ml) and pyridine (2 ml) was added thereto, followed by stirring for 48 hours. The resulting mixture was neutralized with 0.1N hydrochloric acid and extracted with chloroform, followed by crystallization from methanol to give N-(m-iodobenzoyl)-1,3,4,6-tetra-O-acetyl-D-glucosamine (ABGA) (1.50 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]=[C:12]=[O:13])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[NH2:14][C:15]1[C:23]([O:24][CH3:25])=[CH:22][CH:21]=[CH:20][C:16]=1[C:17](O)=[O:18]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([N:11]2[C:17](=[O:18])[C:16]3[C:15](=[C:23]([O:24][CH3:25])[CH:22]=[CH:21][CH:20]=3)[NH:14][C:12]2=[O:13])(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: O=C=NS(=O)(=O)c1ccc(Cl)cc1
Reactant: COc1cccc(C(=O)O)c1N
Product: COc1cccc2c(=O)n(S(=O)(=O)c3ccc(Cl)cc3)c(=O)[nH]c12
Yield: 83.9 %

Procedure:
2.00 g (9.19 mmol) of 4-chlorobenzenesulfonylisocyanate and 1.40 g (8.38 mmol) of 2-amino-3-methoxybenzoic acid were treated in the same way as in Example 1 to obtain 2.58 g of the above-identified compound (yield 84.0%). Properties: colorless crystal, Melting point: 220°-222° C., PMR (δppm, DMSO-d6): 3.88 (3H,s), 7.16 (1H,t), 7.32 (1H,d), 7.43 (1H,d), 7.76 (2H,d), 8.17 (2H,d), 10.95 (1H,br).
Reaction SMILES: [Si:1]([O:8][CH2:9][C@@H:10]1[CH2:14][CH2:13][C@H:12]([CH2:15][O:16][Si:17]([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18])[N:11]1[C:24]1[N:29]=[C:28]([C:30]2[CH:35]=[CH:34][C:33]([N+:36]([O-])=O)=[CH:32][CH:31]=2)[N:27]=[C:26]([N:39]2[CH:44]3[CH2:45][CH2:46][CH:40]2[CH2:41][O:42][CH2:43]3)[N:25]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[H][H]>[Pd].O1CCCC1>[CH:40]12[N:39]([C:26]3[N:25]=[C:24]([N:11]4[C@@H:12]([CH2:15][O:16][Si:17]([C:20]([CH3:22])([CH3:23])[CH3:21])([CH3:19])[CH3:18])[CH2:13][CH2:14][C@H:10]4[CH2:9][O:8][Si:1]([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:3])[CH3:2])[N:29]=[C:28]([C:30]4[CH:35]=[CH:34][C:33]([NH2:36])=[CH:32][CH:31]=4)[N:27]=3)[CH:44]([CH2:45][CH2:46]1)[CH2:43][O:42][CH2:41]2
Reactant: [H][H]
Reactant: CC(C)(C)[Si](C)(C)OC[C@H]1CC[C@@H](CO[Si](C)(C)C(C)(C)C)N1c1nc(-c2ccc([N+](=O)[O-])cc2)nc(N2C3CCC2COC3)n1
Agent: [Pd]
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OC[C@H]1CC[C@@H](CO[Si](C)(C)C(C)(C)C)N1c1nc(-c2ccc(N)cc2)nc(N2C3CCC2COC3)n1
Yield: 54.6 %

Procedure:
A suspension of palladium on charcoal (10%, 50 mg) and 8-(4-((2S,5R)-2,5-bis((tert-butyldimethylsilyloxy)methyl)pyrrolidin-1-yl)-6-(4-nitrophenyl)-1,3,5-triazin-2-yl)-3-oxa-8-azabicyclo[3.2.1]octane (0.55 g, 1.2 mmol) in tetrahydrofuran (20 mL) was stirred under a balloon of hydrogen overnight. The mixture was filtered through a pad of Celite™ diatomaceous earth and concentrated under reduced pressure to provide the title compound as a tan foam (0.42 g, 80%). MS (ES+)=642.4 (M+H)+
Reaction SMILES: II.Br[CH2:4][CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[C:9]([O:15][CH3:16])[CH:8]=1.[CH3:17][O:18][C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][C:26]=1[O:27][CH3:28])[CH:22]=[O:23].[NH4+].[Cl-]>C1COCC1.O>[CH3:17][O:18][C:19]1[CH:20]=[C:21]([CH:22]([OH:23])[CH2:4][CH2:5][CH2:6][C:7]2[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[C:9]([O:15][CH3:16])[CH:8]=2)[CH:24]=[CH:25][C:26]=1[O:27][CH3:28]
Reactant: COc1ccc(C=O)cc1OC
Reactant: COc1ccc(CCCBr)cc1OC
Agent: II
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(CCCC(O)c2ccc(OC)c(OC)c2)cc1OC
Temperature: 0 °C

Procedure:
Under N2, Mg powder (21.15 g, 0.87 gram-atom) was added to a 5 1, 3-neck flask fitted with a mechanical stirrer, condenser, and septum inlet. The Mg was covered with dry THF (200 cc), stirring was begun and a trace of iodine was added followed by about 20 cc then dropwise addition of a solution of 1-bromo,3-(3,4-dimethoxyphenyl)propane (222 g, 0.857 mole) from which all traces of water had been removed in dry THF (1150 cc) at a rate to maintain gentle reflux over a period of 2.5 hours. The resulting dark grey solution was stirred and refluxed for 45 minutes and then cooled to 0° C. With stirring a solution of dried 3,4-dimethoxybenzaldehyde (149.5 g, 0.899 mole) in dry THF (150 cc) was added dropwise over 1 hour at 0° C.-3° C. The resulting mixture was stirred overnight at room temperature, cooled to 0° C., and treated over 1/2 hour at 0°-5° C. with saturated NH4Cl solution (100 cc). The nitrogen atmosphere was discontinued at this point. After standing at room temperature for several hours, the mixture was filtered and the solids were air-dried overnight. The filtrate was evaporated in vacuo to a syrup. The solids were extracted with CH2Cl2 (500 cc) by stirring for a few hours and filtering. The filtrate was combined with the syrup from above and the mixture was diluted with CH2Cl2 (1:1) The organic solution was washed with H2O (3 ×500 cc), dried (Na ), and evaporated in vacuo to a light orange syrup; yield: 300 g (>100%).
Reaction SMILES: [NH2:1][C:2]([NH2:4])=[O:3].S(=O)(=O)(O)[OH:6].ClC1N=[C:15](Cl)[C:14]([CH:18](Br)[CH3:19])=[CH:13]N=1>>[CH2:18]([C:14]1[C:13](=[O:6])[NH:1][C:2](=[O:3])[NH:4][CH:15]=1)[CH3:19]
Reactant: CC(Br)c1cnc(Cl)nc1Cl
Reactant: NC(N)=O
Reactant: O=S(=O)(O)O
Product: CCc1c[nH]c(=O)[nH]c1=O
Temperature: 11.5 °C
Reaction time: 0.5 h

Procedure:
Urea (19.39 g, 0.32 mol) (J. T. Baker) was added over 20 minutes to fuming sulfuric acid (26–29.5% free SO3, 135 mL, 2.65 mol) (Aldrich) with cooling in an ice water bath maintaining the reaction temperature between 8 to 15° C. After stirring for an additional 30 minutes, ethyl 2-formylbutyrate (46.55 g, 0.32 mol) (from Example 1c, supra) was added over 18 minutes keeping the reaction at the same temperature. After stirring for another 30 minutes, a second portion of urea (15.07 g, 0.25 mol) was added over 10 minutes at the same temperature. The reaction mixture was then stirred at room temperature for 65 hours, and at 90–100° C. for 2 hours (gas evolution was observed, and reaction was exothermic, with reaction temperature rising to 110° C.). The mixture was cooled to 30° C. with an ice-water bath. Ice (270 g) was added slowly keeping the reaction below 35° C. The mixture was then cooled to 5° C. and stirred for 20 minutes. The solid formed was collected by filtration, washed with cold water, hexanes, and diethyl ether and dried by suction to give 5-ethyl uracil. (Yield 38.85 g, 85.9%).
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][C:5]([O:6][CH2:7][C:8]([OH:10])=O)=[CH:4][CH:3]=1.[NH2:13][CH2:14][CH2:15][N:16]1[C:20]([CH3:21])=[CH:19][CH:18]=[C:17]1[CH3:22].C(N(CC)CC)C.CP(OP(CC)(C)=O)(CC)=O>CN(C)C=O>[CH3:22][C:17]1[N:16]([CH2:15][CH2:14][NH:13][C:8](=[O:10])[CH2:7][O:6][C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:12][CH:11]=2)[C:20]([CH3:21])=[CH:19][CH:18]=1
Reactant: O=C(O)COc1ccc(Cl)cc1
Reactant: Cc1ccc(C)n1CCN
Agent: CCP(C)(=O)OP(C)(=O)CC
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1ccc(C)n1CCNC(=O)COc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
9.3 g (0.05 mol) of 4-chlorophenoxyacetic acid, 6.9 g (0.05 mol) of 1-(2-aminoethyl)-2,5-dimethylpyrrole and 35 ml of triethylamine are dissolved in 50 ml of dimethylformamide. At -5° to 0° C., 20 ml of methylethylphosphinic anhydride are added dropwise, and the mixture is then stirred at room temperature for 3 h. The reaction mixture is poured into ice-cold aqueous sodium bicarbonate solution, and the mixture is extracted with methylene chloride and the extract is concentrated. The residue is chromatographed over a 20 cm silica gel column using a 1:1 methylene chloride/ethyl acetate mixture as the mobile phase, and the product is crystallized using ligroin. Yield: 10.5 g (69% of theory), Melting point: 75°-77° C. Elemental analysis: C16H19CLN2O2 (306.80) calculated: C 62.6 H 6.2 CL 11.6 N 9.1 0 10.4 found: C 62.7 H 6.4 CL 11.7 N 9.2 0 10.4
Reaction SMILES: F[C:2]1[CH:8]=[C:7]([F:9])[C:6]([F:10])=[CH:5][C:3]=1[NH2:4].CCO[C:14]([S-:16])=[S:15].[K+].Cl>CN(C)C=O.O>[F:10][C:6]1[C:7]([F:9])=[CH:8][C:2]2[S:15][C:14]([SH:16])=[N:4][C:3]=2[CH:5]=1
Reactant: Nc1cc(F)c(F)cc1F
Reactant: CCOC(=S)[S-]
Agent: Cl
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Fc1cc2nc(S)sc2cc1F
Temperature: 95 °C
Yield: 39.8 %

Procedure:
A mixture of 1 g (6.80 mmol) 2,4,5-trifluoroaniline and 1.33 g (8.16 mmol) potassium ethylxanthogenate in 5 mL dry N,N-dimethylformamide was heated in a 95° C. oil bath for 7 h. The reaction mixture was cooled to room temperature and diluted with water (15 mL). The mixture was acidified with aqueous HCl 2N. The precipitate was collected by filtration, washed with water and dried to provide 0.55 g (40%) of the titled compound as a light yellow solid. MS(m/e): 201.9 (M−H+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[NH:9][C:10]1[NH:11][C:12]2[C:18]3[CH2:19][C:20]([CH3:23])([CH3:22])[O:21][C:17]=3[C:16]([C:24]([O:26]C)=O)=[CH:15][C:13]=2[N:14]=1.[F:28][C:29]1[C:35]([F:36])=[C:34]([F:37])[CH:33]=[CH:32][C:30]=1[NH2:31].C[Al](C)C>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[NH:9][C:10]1[NH:11][C:12]2[C:18]3[CH2:19][C:20]([CH3:23])([CH3:22])[O:21][C:17]=3[C:16]([C:24]([NH:31][C:30]3[CH:32]=[CH:33][C:34]([F:37])=[C:35]([F:36])[C:29]=3[F:28])=[O:26])=[CH:15][C:13]=2[N:14]=1
Reactant: Nc1ccc(F)c(F)c1F
Reactant: COC(=O)c1cc2nc(Nc3c(C)cccc3Cl)[nH]c2c2c1OC(C)(C)C2
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Product: Cc1cccc(Cl)c1Nc1nc2cc(C(=O)Nc3ccc(F)c(F)c3F)c3c(c2[nH]1)CC(C)(C)O3
Yield: 48.2 %

Procedure:
The title compound was prepared by following the procedure as described for Example-137 by using methyl 2-[(2-chloro-6-methylphenyl)amino]-7,7-dimethyl-7,8-dihydro-1H-furo[3,2-e]benzimidazole-5-carboxylate (Step-1 of Intermediate-35, 0.200 g, 0.414 mmol) and 2,3,4-trifluoroaniline (0.090 g, 0.602 mmol), trimethyl aluminium (2M solution in toluene) (1 mL) and dry toluene (5.0 mL) to afford 0.100 g of the desired product. 1HNMR (DMSO-d6): δ 1.55 (s, 6H), 2.24 (s, 3H), 3.13 (s, 2H), 7.25-7.43 (m, 4H), 7.52 (s, 1H), 8.24 (m, 1H), 9.10 (m, 1H), 10.06 (s, 1H), 10.96 (m, 1H): MS [M+H]+: 501.04.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([S:52]([CH:55]2[CH2:57][CH2:56]2)(=[O:54])=[O:53])=[C:6]([CH2:8][N:9]([CH3:51])[C:10]([CH:12]([NH:24][C:25]2[CH:26]=[C:27]3[C:32](=[CH:33][C:34]=2[F:35])[C:31]([N:36]([C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[C:37](=[O:43])[O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[N:30][CH:29]=[CH:28]3)[C:13]2[CH:18]=[CH:17][C:16]([C@@H:19]([CH3:22])[CH2:20][OH:21])=[C:15]([CH3:23])[CH:14]=2)=[O:11])[CH:7]=1.[C:58](Cl)(Cl)=[O:59]>C(#N)C.ClCCl>[C:39]([O:38][C:37]([N:36]([C:31]1[C:32]2[C:27](=[CH:26][C:25]([NH:24][C@H:12]3[C:10](=[O:11])[N:9]([CH3:51])[CH2:8][C:6]4[CH:7]=[C:2]([CH:3]=[CH:4][C:5]=4[S:52]([CH:55]4[CH2:56][CH2:57]4)(=[O:54])=[O:53])[NH:1][C:58](=[O:59])[O:21][CH2:20][C@H:19]([CH3:22])[C:16]4[CH:17]=[CH:18][C:13]3=[CH:14][C:15]=4[CH3:23])=[C:34]([F:35])[CH:33]=2)[CH:28]=[CH:29][N:30]=1)[C:44](=[O:45])[O:46][C:47]([CH3:48])([CH3:49])[CH3:50])=[O:43])([CH3:41])([CH3:40])[CH3:42]
Reactant: Cc1cc(C(Nc2cc3ccnc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c3cc2F)C(=O)N(C)Cc2cc(N)ccc2S(=O)(=O)C2CC2)ccc1[C@@H](C)CO
Reactant: O=C(Cl)Cl
Solvent: ClCCl
Solvent: CC#N
Product: Cc1cc2ccc1[C@@H](C)COC(=O)Nc1ccc(S(=O)(=O)C3CC3)c(c1)CN(C)C(=O)[C@@H]2Nc1cc2ccnc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c2cc1F
Temperature: 0 °C
Reaction time: 0.67 h
Yield: 36.4 %

Procedure:
To a solution of 26A (80 mg, 0.099 mmol) in acetonitrile (6 mL) and dichloromethane (3 mL) at 0° C., was added phosgene solution (20% in toluene, 0.063 mL, 0.119 mmol) dropwise. The mixture was stirred at 0° C. for 40 min, then at rt for 30 min. Extra phosgene was removed by bubbling Ar though the reaction mixture (30 min). The mixture was added dropwise via syringe pump into a solution of TEA (0.111 mL, 0.794 mmol) in dichloromethane (40 ml) at rt over 3.0 h. The solution was stirred at rt overnight, quenched with 0.5 N HCl, extracted with CH2Cl2. The organic layer was washed with water and dried over sodium sulfate, then concentrated. The crude residue was purified by flash chromatography (30-100% EtOAc/hexanes) to give a mixture of diastereoisomers (70 mg, 0.084 mmol, 85% yield). The diastereomers were separated by a prep chiral HPLC (R,R-Whelk-O column 21.1×250 mm) to give 26B (30 mg, 0.036 mmol, 42.9% yield). MS (ESI) m/z: [M+1]+. 19F NMR (376 MHz, CDCl3) d ppm −128.71 (s, 1F).
Reaction SMILES: CC1(C)CCCC(C)(C)N1.C(=O)=O.[Li][CH2:15][CH2:16][CH2:17][CH3:18].[C:19]([OH:27])(=[O:26])[C:20]1C=[CH:24][N:23]=[CH:22][CH:21]=1.C(=O)CC>C1COCC1>[CH2:17]([CH:16]1[C:15]2[CH:24]=[N:23][CH:22]=[CH:21][C:20]=2[C:19](=[O:26])[O:27]1)[CH3:18]
Reactant: [Li]CCCC
Reactant: O=C(O)c1ccncc1
Agent: CC1(C)CCCC(C)(C)N1
Agent: O=C=O
Solvent: C1CCOC1
Solvent: CCC=O
Product: CCC1OC(=O)c2ccncc21
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 10 %

Procedure:
A solution of 2,2,6,6-tetramethyl-piperidine (20.3 ml, 120 mmol) in a 250 ml round bottomed flask equipped with a magnetic stirrer, is put under argon atmosphere and 60 ml of dry THF is added. The reaction mixture is cooled to −78° C. by adding a controlled amount of dry ice to an acetone bath. The cooled reaction mixture is treated dropwise with nBuLi solution (64 mL of a 2.5 M solution in hexanes, 160 mmol) and the reaction is let stir at −78° C. for 0.5 h. A solution of isonicotinic acid (4.92 g, 40 mmol) in THF (60 mL) is added dropwise to the reaction at −78° C. The reaction is stirred at −78° C. for 1 h and is then warmed to −20° C. The reaction mixture is treated with propionaldehyde (7.2 ml, 100 mmol, 2.5 eq) dropwise at −50° C. The reaction is stirred at −20° C. for 2 h and warmed to room temperature overnight. The reaction mixture is concentrated and the residue is dissolved in water and ether. The aqueous layer is collected and extracted with dichloromethane and ether (6×50 ml). The aqueous phase is concentrated and the residue is dissolved in EtOH (30 mL) and acetic acid (2 mL) and heated at reflux overnight under argon. The reaction mixture is cooled to room temperature and concentrated. The residue is purified by chromatography (silica gel, MeOH/chloroform) to give the title compound (0.674 g, 10%) as an oil.
Reaction SMILES: [ClH:1].C1(S[C:9]2[S:10][C:11]([CH2:14][N:15]3[C:20](=[N:21][N+:22]([O-:24])=[O:23])[N:19]([CH3:25])[CH2:18][O:17][CH2:16]3)=[CH:12][N:13]=2)CCCCC1.ClCl>ClC1C=CC=CC=1>[Cl:1][C:9]1[S:10][C:11]([CH2:14][N:15]2[C:20](=[N:21][N+:22]([O-:24])=[O:23])[N:19]([CH3:25])[CH2:18][O:17][CH2:16]2)=[CH:12][N:13]=1
Reactant: CN1COCN(Cc2cnc(SC3CCCCC3)s2)C1=N[N+](=O)[O-]
Reactant: Cl
Agent: ClCl
Solvent: Clc1ccccc1
Product: CN1COCN(Cc2cnc(Cl)s2)C1=N[N+](=O)[O-]
Reaction time: 2 h
Yield: 92.4 %

Procedure:
To a mixture of 300 g of aqueous hydrochloric acid (32%) and 150 g of chlorobenzene are added with stirring 186 g of 3-(2-cyclohexylthiothiazol-5-ylmethyl)-5-methyl-4-nitroimino-perhydro-1,3,5-oxadiazine within 5 minutes. 124 g of chlorine are then passed into the mixture at 20 to 25° over a period of 4 hours. After stirring for a further 2 hours, the excess of chlorine is removed by introduction of nitrogen, and the aqueous phase (containing the title compound in hydrochloride form) is separated off and adjusted to pH 5 with aqueous sodium hydroxide solution (30%). The crystalline precipitate is filtered off, washed with water and dried at 50° in vacuo, yielding 135 g of the title compound (purity: 97%) melting at 132 to 135°.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[CH:11][C:12]2[C:13]3[N:21]=[C:20]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=4)[CH:19]=[C:18]([C:32]([O:34][CH3:35])=[O:33])[C:14]=3[NH:15][C:16]=2[CH:17]=1)C1C=CC=CC=1>C(O)(C(F)(F)F)=O.O.C(Cl)Cl>[OH:8][C:9]1[CH:10]=[CH:11][C:12]2[C:13]3[N:21]=[C:20]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=4)[CH:19]=[C:18]([C:32]([O:34][CH3:35])=[O:33])[C:14]=3[NH:15][C:16]=2[CH:17]=1
Reactant: COC(=O)c1cc(-c2cccc(C(F)(F)F)c2)nc2c1[nH]c1cc(OCc3ccccc3)ccc12
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: ClCCl
Product: COC(=O)c1cc(-c2cccc(C(F)(F)F)c2)nc2c1[nH]c1cc(O)ccc12
Yield: 110.9 %

Procedure:
A solution of methyl 7-(benzyloxy)-2-(3-(trifluoromethyl)phenyl)-5H-pyrido[3,2-b]indole-4-carboxylate (1.0 g, 2.1 mmol) in TFA (8.3 mL) and water (2.3 mL) was heated at 90° C. for 3 hrs. The solvent was removed to leave an orange solid. This was suspended in DCM:hexane=1:1 and then collected by filtration to give crude methyl 7-hydroxy-2-(3-(trifluoromethyl)phenyl)-5H-pyrido [3,2-b]indole-4-carboxylate (0.9 g) as a yellow solid that was used as such. MS (ESI) m/z 387.09 (M+H). 1H NMR (500 MHz, DMSO-d6) δ ppm 11.49 (1H, s), 8.53 (1H, s), 8.49 (1H, d, J=7.02 Hz), 8.30 (1H, s), 8.11 (1H, d, J=8.24 Hz), 7.75-7.80 (2H, m), 7.13 (1H, d, J=1.83 Hz), 6.81 (1H, dd, J=8.39, 1.98 Hz), 4.07 (3H, s).