Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[CH2:16][CH2:15][CH:14]([CH2:17][C:18](O)=[O:19])[N:6]3[C:7](=[O:13])[C:8](=[O:12])[NH:9][C:10]([CH:11]=1)=[C:5]23.[NH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[OH:28]>>[Br:1][C:2]1[CH:3]=[C:4]2[CH2:16][CH2:15][CH:14]([CH2:17][C:18](=[O:19])[NH:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[OH:28])[N:6]3[C:7](=[O:13])[C:8](=[O:12])[NH:9][C:10]([CH:11]=1)=[C:5]23
Reactant: O=C(O)CC1CCc2cc(Br)cc3[nH]c(=O)c(=O)n1c23
Reactant: Nc1ccccc1O
Product: O=C(CC1CCc2cc(Br)cc3[nH]c(=O)c(=O)n1c23)Nc1ccccc1O
Yield: 99 %

Procedure:
A procedure similar to that described in Example 5 was carried out with 9-bromo-5-carboxymethyl-6,7-dihydro-1H, 5H-pyrido[1,2,3-de]quinoxaline-2,3-dione (300 mg, 0.88 mmol) and o-aminophenol (110 mg, 1 mmol) to give 375 mg of the title compound (98%): mp 155° C. (dec); 1H NMR (270 MHz, DMSO-d6) δ12.07 (s, 1H), 9.71 (bs, 1H), 9.36 (s, 1H), 7.72 (d, 1H, J=7.2 Hz), 7.24 (bs, 1H), 7.17 (bs, 1H), 6.95 (dt, 1H, J=2, 7.2 Hz), 6.85 (dd, 1H, J=2, 7.2 Hz), 6.76 (dt, 1H, J=7.2, 2 Hz), 5.17~5.26 (m, 1H), 3.14 (ddd, 1H, J=17.1, 13.5, 4.5 Hz), 2.80 (dm, 1H, J=17.1 Hz), 2.78 (dd, 1H, J=14.4, 9 Hz), 2.64 (dd, 1H, J=14.4, 4.5 Hz), 2.10 (dm, 1H, J=13.5 Hz), 1.78~1.92 (m, 1H).
Reaction SMILES: [CH3:1][S:2][C:3](SC)=[C:4]([C:10]([C:12]1[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][C:13]=1[S:22]([CH3:25])(=[O:24])=[O:23])=[O:11])[C:5]([CH:7]1[CH2:9][CH2:8]1)=[O:6].Cl.[NH2:29]O.C([O-])(=O)C.[Na+]>ClCCl.C(O)C>[CH:7]1([C:5]2[O:6][N:29]=[C:3]([S:2][CH3:1])[C:4]=2[C:10](=[O:11])[C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][C:13]=2[S:22]([CH3:25])(=[O:24])=[O:23])[CH2:9][CH2:8]1
Reactant: NO
Reactant: CSC(SC)=C(C(=O)c1ccc(C(F)(F)F)cc1S(C)(=O)=O)C(=O)C1CC1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: CCO
Product: CSc1noc(C2CC2)c1C(=O)c1ccc(C(F)(F)F)cc1S(C)(=O)=O
Temperature: 20 °C
Reaction time: 48 h
Yield: 92.9 %

Procedure:
To a solution of 12.5 g (28.4 mmol) 2-(bis-methylsulfanylmethylene)-1 -cyclopropyl-3-(2-methanesulfonyl-4-trifluoromethylphenyl)propane-1,3-dione in 80 ml dichloromethane, 140 ml each of ethanol, 2.82 g (39.8 mmol) hydroxylamine hydrochloride and 3.4 g (41.2 mmol) anhydrous sodium acetate is successively added. The reaction mixture is then agitated for 48 hours at a temperature of 20° C. Then 50 ml dichloromethane, 50 ml ethanol, 1.4 g hydroxylamine hydrochloride and 1.7 g anhydrous sodium acetate are added, and the mixture is agitated for a further 3 days at 20° C. The reaction mixture is subsequently heated to a temperature of 30° C., and 2.8 g hydroxylamine hydrochloride and 3.4 g sodium acetate are added. After 18 hours' agitation at a temperature of 30° C., the solvents are distilled off and the residue taken up in 300 ml ethyl acetate. The organic phase is washed twice with water and once with concentrated aqueous sodium chloride solution. After the organic phase has been dried over sodium sulfate, it is treated with activated charcoal, filtered and evaporated to dryness. After recrystallization from a little diisopropylether, 10.7 g 5-cyclopropyl-3-methylsulfanyl-4-(2-methanesulfonyl-4-trifluoromethylbenzoyl)isoxazole is obtained in the form of crystalline solid matter with a melting point of 145-146° C.
Reaction SMILES: [F:1][C:2]1([F:14])[CH2:7][CH2:6][CH:5]([CH2:8][C:9]([O:11]CC)=[O:10])[CH2:4][CH2:3]1.[OH-].[Na+]>C1COCC1.CO>[F:1][C:2]1([F:14])[CH2:3][CH2:4][CH:5]([CH2:8][C:9]([OH:11])=[O:10])[CH2:6][CH2:7]1
Reactant: CCOC(=O)CC1CCC(F)(F)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)CC1CCC(F)(F)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of ethyl 2-(4-oxocyclohexyl)acetate (0.4 g) in DCM (5 mL) was added Deoxo-Fluor® (0.881 mL) and EtOH (0.038 mL). The reaction mixture was stirred at rt for 16 h and then diluted with sat. NaHCO3 and EtOAc. The organic phase was washed with water, sat. NaCl and dried over anhydrous Na2SO4, filtered and dried to yield ethyl 2-(4,4-difluorocyclohexyl)acetate (0.4 g). To a solution of ethyl 2-(4,4-difluorocyclohexyl)acetate in THF/MeOH (2 mL) was added 1N NaOH (1 mL), and the reaction mixture was stirred at rt for 16 h. The reaction mixture was concentrated, then diluted with EtOAc and acidified with 1N HCl. The organic phase was washed with sat. NaCl, dried over anhydrous Na2SO4, filtered and concentrated to yield 2-(4,4-difluorocyclohexyl)acetic acid as a yellow solid. 1H NMR (400 MHz, DMSO-d6) ppm 12.13 (1H, br. s.), 2.06-2.28 (3H, m), 1.92-2.03 (1H, m), 1.72-1.91 (4H, m), 1.31-1.48 (1H, m), 1.10-1.31 (2H, m).
Reaction SMILES: Cl.[C:2](/[C:4](/[C:19]([NH:21][C:22]1[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=1)=[O:20])=[C:5](/[NH:8][C:9](=O)[C:10]1[CH:15]=[CH:14][C:13]([S:16][CH3:17])=[CH:12][CH:11]=1)\[S:6][CH3:7])#[N:3].C([OH:31])C>ClCCl>[OH:31][C:2]1[C:4]([C:19]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=2)=[O:20])=[C:5]([S:6][CH3:7])[N:8]=[C:9]([C:10]2[CH:15]=[CH:14][C:13]([S:16][CH3:17])=[CH:12][CH:11]=2)[N:3]=1
Reactant: CS/C(NC(=O)c1ccc(SC)cc1)=C(\C#N)C(=O)Nc1ccc(C)cc1
Reactant: CCO
Agent: Cl
Solvent: ClCCl
Product: CSc1ccc(-c2nc(O)c(C(=O)Nc3ccc(C)cc3)c(SC)n2)cc1
Yield: 90 %

Procedure:
Dry HCl gas was passed through a solution of N-[(1E)-2-Cyano-3-[(4-methylphenyl)amino]-1-(methylthio)-3-oxoprop-1-en-1-yl]-4-(methylthio)benzamide (2 g, 5 mmol, prepared according to the procedure described in preparation 1) in ethanol (50 ml) at 0° C. for 4 hours. The reaction mixture was then refluxed for 4 hours until completion; subsequently the resultant solid was filtered and washed with ethanol. The solid thus obtained was suspended in dichloromethane (50 ml), filtered, and finally dried under vacuum to yield the title compound (1.8 g, 90%, purity 99.78% by HPLC), m.p.: 302-305° C. 1H-NMR (CDCl3) δ (ppm): 2.29 (s, 3H), 2.33 (s, 3H), 2.63 (s, 3H), 7.12-7.14 (d, 2H), 7.23-7.26 (m, 2H), 7.47-7.49 (d, 2H), 8.13-8.15 (d, 2H), 11.38 (s, 1H, D2O exchangeable), 12.45 (s, 1H, D2O exchangeable). IR (KBr) cm−1: 3436, 3320, and 1646. MS m/z: 398.1(M++1).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][C:5](=[O:11])[NH:6]2.[Br:12]N1C(=O)CCC1=O.C(OCC)(=O)C.CCCCCC>C(#N)C>[Br:12][C:10]1[C:2]([CH3:1])=[C:3]2[C:7](=[CH:8][CH:9]=1)[NH:6][C:5](=[O:11])[CH2:4]2
Reactant: Cc1cccc2c1CC(=O)N2
Reactant: O=C1CCC(=O)N1Br
Solvent: CC#N
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: Cc1c(Br)ccc2c1CC(=O)N2
Temperature: 25 °C
Reaction time: 4 h
Yield: 21.7 %

Procedure:
4-Methyl-2-oxindole (5 g) in 40 mL of acetonitrile was treated with 7.26 g of N-bromosuccinimide and stirred at room temperature for 4 hours. Thin layer chromatography (ethyl acetate:hexane 1:2, silica gel) showed a mixture of 5-bromo (Rf 0.3) and 5,7-dibromo (Rf 0.5) products. Another 7.26 g of N-bromosuccinimide was added and the mixture stirred for 4 additional hours. The solid was collected by vacuum filtration, washed with 20 mL of acetonitrile and dried to give a 1:1 mixture of mono and dibromo compounds. The filtrate was concentrated and chromatographed on silica gel (ethyl acetate:hexane (1:2)) to give 1.67 g of 5-bromo-4-methyl-2-oxindole as a beige solid. The remaining 1:1 mixture of solids was recrystallized twice from glacial acetic acid to give 3.2 g of 5,7-dibromo-4-methyl-2-oxindole as a light orange solid. The filtrates from this material were chromatographed as above to give 0.6 g of 5-bromo-4-methyl-2-oxindole and 0.5 g of 5,7-dibromo-4-methyl-2-oxindole.
Reaction SMILES: [Cl-].C[SiH](C)C.[F:6][C:7]([F:17])([F:16])[C:8]1[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=1[CH2:10]Br.[Cl:18][C:19]1[CH:24]=[C:23](Cl)[N:22]=[CH:21][N:20]=1.O>O1CCCC1.BrC(Br)C.[Zn]>[Cl:18][C:19]1[CH:24]=[C:23]([CH2:10][C:9]2[CH:12]=[CH:13][CH:14]=[CH:15][C:8]=2[C:7]([F:17])([F:16])[F:6])[N:22]=[CH:21][N:20]=1
Reactant: FC(F)(F)c1ccccc1CBr
Reactant: Clc1cc(Cl)ncn1
Agent: CC(Br)Br
Agent: C[SiH](C)C
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: O
Product: FC(F)(F)c1ccccc1Cc1cc(Cl)ncn1
Reaction time: 0.33 h
Yield: 33.6 %

Procedure:
In 10 ml of tetrahydrofuran was suspended 1.3 g of zinc (powder), to which dibromoethane (2 drops) was added. The mixture was heated under reflux for 5 minutes, to which trimethylsilane chloride was added. The mixture was further heated under reflux for 5 minutes, to which a solution of 2.4 g of 2-trifluoromethylbenzyl bromide dissolved in 20 ml of tetrahydrofuran was slowly added with heating under reflux, followed by stirring for 20 minutes. (The solution thus obtained is referred to as solution F). In 10 ml of tetrahydrofuran were suspended 1.5 g of 4,6-dichloropyrimidine and 0.1 g of dichlorobistriphenylphosphine palladium, to which the above solution F was added, followed by heating under reflux for 3 hours and further stirring at room temperature for 12 hours. The reaction mixture was then poured into water and extracted three times with ethyl acetate. The organic layers were combined, washed with water, dried over anhydrous magnesium sulfate, and then concentrated. The residue was subjected to silica gel column chromatography to give 0.92 g of 4-chloro-6-(2-trifluoromethylbenzyl)pyrimidine.
Reaction SMILES: S(Cl)(Cl)=O.[Br:5][C:6]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:7]=1[C:8]([OH:10])=[O:9].[CH3:16]O>>[CH3:16][O:9][C:8](=[O:10])[C:7]1[CH:11]=[CH:12][C:13]([Cl:15])=[CH:14][C:6]=1[Br:5]
Reactant: CO
Reactant: O=C(O)c1ccc(Cl)cc1Br
Solvent: O=S(Cl)Cl
Product: COC(=O)c1ccc(Cl)cc1Br
Temperature: 0 °C
Yield: 99 %

Procedure:
To a 500 ml 2 necked RB flask containing anhydrous methanol (300 ml) was added thionyl chloride (29.2 ml, 400 mmol) dropwise at 0-5° C. (ice water bath) over 10 min. The ice water bath was removed, and 2-bromo-4-chloro-benzoic acid (25 g, 106 mmol) was added. The mixture was heated to mild reflux for 12 h. Progress of the reaction was monitored by TLC and LCMS. After completion of the reaction, the reaction mixture was concentrated. Crude product was dissolved in dichloromethane (DCM, 250 ml), washed with water (50 ml), sat. aq. NaHCO3 (50 ml), brine (50 ml), dried over sodium sulfate, and concentrated to give the 2-bromo-4-chloro-benzoic acid methyl ester (26 g, 99%), which was directly used in the following step.
Reaction SMILES: FC1C=CC(C[N:7]2C(=O)N(C3SC(C(O)=O)=C(C)N=3)C=N2)=CC=1.[F:24][C:25]1[CH:26]=[C:27]([CH:44]=[C:45]([F:47])[CH:46]=1)[CH2:28][N:29]1[CH2:33][CH2:32][N:31]([C:34]2[S:35][C:36]([C:40](O)=[O:41])=[C:37]([CH3:39])[N:38]=2)[C:30]1=[O:43]>>[F:47][C:45]1[CH:44]=[C:27]([CH:26]=[C:25]([F:24])[CH:46]=1)[CH2:28][N:29]1[CH2:33][CH2:32][N:31]([C:34]2[S:35][C:36]([C:40]([NH2:7])=[O:41])=[C:37]([CH3:39])[N:38]=2)[C:30]1=[O:43]
Reactant: Cc1nc(N2CCN(Cc3cc(F)cc(F)c3)C2=O)sc1C(=O)O
Reactant: Cc1nc(-n2cnn(Cc3ccc(F)cc3)c2=O)sc1C(=O)O
Product: Cc1nc(N2CCN(Cc3cc(F)cc(F)c3)C2=O)sc1C(N)=O

Procedure:
Following the procedure as described in Example 1, making variations as required to replace 2-(1-(4-fluorobenzyl)-5-oxo-1H-1,2,4-triazol-4(5H)-yl)-4-methylthiazole-5-carboxylic acid with 2-(3-(3,5-difluorobenzyl)-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid, the title compound was obtained as a colorless solid: mp >200° C.; 1H NMR (300 MHz, DMSO-d6) δ 7.32 (br s, 2H), 7.21-7.04 (m, 3H), 4.47 (s, 2H), 4.05-4.00 (m, 2H), 3.54-3.48 (m, 2H), 2.47 (s, 3H); MS (ES+) m/z 352.8 (M+1).
Reaction SMILES: [H-].[Na+].[CH2:3]([SH:5])[CH3:4].CN(C=O)C.Cl[C:12]1[C:13]([C:22]([NH:24][C:25]2[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][N:26]=2)=[O:23])=[N:14][CH:15]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:17]=1>O>[CH2:3]([S:5][C:12]1[C:13]([C:22]([NH:24][C:25]2[CH:30]=[CH:29][C:28]([C:31]([F:32])([F:33])[F:34])=[CH:27][N:26]=2)=[O:23])=[N:14][CH:15]=[C:16]([C:18]([F:19])([F:20])[F:21])[CH:17]=1)[CH3:4]
Reactant: O=C(Nc1ccc(C(F)(F)F)cn1)c1ncc(C(F)(F)F)cc1Cl
Reactant: CCS
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCSc1cc(C(F)(F)F)cnc1C(=O)Nc1ccc(C(F)(F)F)cn1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 107.4 %

Procedure:
0.37 g of 60% sodium hydride (oil-based) was added to a mixture of 0.34 g of ethyl mercaptan and 3 mL of DMF under ice cooling, and the mixture was stirred at room temperature for 10 minutes. 1.35 g of 3-chloro-5-trifluoromethyl-N-(5-trifluoromethylpyridin-2-yl)picolinamide was added to the reaction mixture, and the mixture was stirred at room temperature for 3 hours. Water was poured to the reaction mixture, and the precipitated solid was taken by filtration and dried under reduced pressure to obtain 1.55 g of 3-ethylsulfanyl-5-trifluoromethyl-N-(5-trifluoromethylpyridin-2-yl)picolinamide (hereinafter, referred to as Compound of Present Invention 1).
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[CH:15]=[CH:14][CH:13]=[C:12]([NH2:17])[C:11]=2[C:10]([CH2:18][CH3:19])=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:20]N1C(=O)CCC1=O>C(#N)C>[CH2:1]([N:8]1[C:16]2[CH:15]=[CH:14][C:13]([Cl:20])=[C:12]([NH2:17])[C:11]=2[C:10]([CH2:18][CH3:19])=[N:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: CCc1nn(Cc2ccccc2)c2cccc(N)c12
Solvent: CC#N
Product: CCc1nn(Cc2ccccc2)c2ccc(Cl)c(N)c12
Temperature: 60 °C
Reaction time: 16 h

Procedure:
To a reaction vial was added 1-benzyl-3-ethyl-1H-indazol-4-amine (20.0 mg, 0.0796 mmol) (prepared as in Example 2, steps A-B), N-chlorosuccinimide (12.8 mg, 0.0955 mmol) and acetonitrile (0.4 mL). The reaction vial was sealed and heated, with magnetic stirring, at 60° C. for 4 hours. The mixture was stirred at ambient temperature for 16 hours. The solvent was removed under a stream of nitrogen. The resulting material was purified using preparative thin layer chromatography on silica, eluting with 5% methanol in chloroform containing 0.5% ammonium chloride solution. The desired mono-chlorination product, 1-benzyl-5-chloro-3-ethyl-1H-indazol-4-amine (MS, APCI, m/z=286.1, M+H) was isolated as lower eluting component (8.7 mg).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[C:4]([CH3:11])[CH:3]=1.[NH4+].[Cl-].Cl.O1CCOCC1>[Fe].CC(OC)(C)C.C(O)C>[Br:1][C:2]1[CH:7]=[C:6]([CH:5]=[C:4]([CH3:11])[CH:3]=1)[NH2:8]
Reactant: Cc1cc(Br)cc([N+](=O)[O-])c1
Agent: [Fe]
Agent: Cl
Agent: [Cl-]
Solvent: C1COCCO1
Solvent: COC(C)(C)C
Solvent: CCO
Product: Cc1cc(N)cc(Br)c1
Temperature: 25 °C

Procedure:
In 2 L flask outfitted with condenser and stir bar was added 1-bromo-3-methyl-5-nitrobenzene (50.0 g, 231 mmol), ethanol (967 mL), and saturated aqueous NH4Cl (141 mL). The system was evacuated and flushed with N2(g) and then iron (38.8 g, 694 mmol) was added before heating the reaction to reflux for 2 days. The reaction was cooled to room temperature and CELITE (15 g) was added to the flask. This was then filtered through CELITE, washing the cake with ethanol (500 mL) and ethyl acetate (500 mL). The filtrate was concentrated and the solvent was removed. The residue was diluted with ethyl acetate (500 mL) and water (500 mL). After cutting the layers, the organic was washed with saturated aqueous NaHCO3 (400 mL) and then brine (400 mL), before drying over sodium sulfate and concentrating. MTBE (˜500 mL) was added to the resultant residue and HCl in dioxane (4 M, 57.9 mL, 231 mmol) was added dropwise at RT over 30 min. The resultant precipitate was collected by filtration. This creme colored solid was placed in a beaker and was dissolved in ethyl acetate and partitioned with saturated aqueous NaHCO3 and then 10% NH4OH (aq). The organic was cut and dried over sodium sulfate before concentrating to dryness. 3-Bromo-5-methylaniline was isolated as a brown oil. MS APCI calc'd for C7H9BrN [M+H]+ 186. found 186/188.
Reaction SMILES: [C:1]([NH:8][CH2:9][CH2:10][CH2:11][OH:12])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C(N(CC)CC)C.[CH3:20][S:21](Cl)(=[O:23])=[O:22].O>ClCCl>[CH3:20][S:21]([O:12][CH2:11][CH2:10][CH2:9][NH:8][C:1]([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2])(=[O:23])=[O:22]
Reactant: CC(C)(C)OC(=O)NCCCO
Reactant: CS(=O)(=O)Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCCCOS(C)(=O)=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 89.9 %

Procedure:
To a solution of 3-(Boc-amino)-propanol (10 g, 57.5 mmol) in dichloromethane (100 mL) was added triethylamine (11.6 g, 115 mmol) at 0° C., then methanesulfonyl chloride (7.9 g, 69 mmol) was dropwise added. The resulting mixture was stirred for 1 hour at 0° C., poured into water, and then extracted with dichloromethane for 3 times (100 mL for each time). The organic phases were combined, dried and concentrated to afford the product 3-(tert-butyloxycarbonylamino)propyl methanesulfonate (13.1 g, yield: 94%). The characterization of the resulting product was as follows: 1HNMR (400 MHz, CDCl3): δ=4.76 (s, 1H), 4.26 (t, J=6.4 Hz, 2H), 3.22-3.24 (m, 2H), 3.00 (s, 3H), 1.89-1.92 (m, 2H), 1.41 (s, 9H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:14][C:13]2[C:12]([Cl:15])=[CH:11][N:10]=[CH:9][C:8]=2[C:7]=1[NH2:16])=[O:5])[CH3:2].[F:17][C:18]1[CH:23]=[C:22]([Si:24]([CH3:27])([CH3:26])[CH3:25])[CH:21]=[CH:20][C:19]=1OS(C(F)(F)F)(=O)=O.C(=O)([O-])[O-].[Cs+].[Cs+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>C1(C)C=CC=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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH2:1]([O:3][C:4]([C:6]1[NH:14][C:13]2[C:12]([Cl:15])=[CH:11][N:10]=[CH:9][C:8]=2[C:7]=1[NH:16][C:19]1[CH:20]=[CH:21][C:22]([Si:24]([CH3:26])([CH3:25])[CH3:27])=[CH:23][C:18]=1[F:17])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1[nH]c2c(Cl)cncc2c1N
Reactant: C[Si](C)(C)c1ccc(OS(=O)(=O)C(F)(F)F)c(F)c1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: CCOC(=O)c1[nH]c2c(Cl)cncc2c1Nc1ccc([Si](C)(C)C)cc1F
Temperature: 150 °C
Yield: 49.5 %

Procedure:
To a solution of 3-amino-7-chloro-1H-pyrrolo[3,2-c]pyridine-2-carboxylic acid ethyl ester (1.0 g, 4.18 mmol) and trifluoromethanesulfonic acid 2-fluoro-4-trimethylsilanyl-phenyl ester (1.45 g, 4.59 mmol) in toluene (18 ml) was added cesium carbonate (1.90 g, 5.85 mmol) before the mixture was degassed. Pd2dba3 (382 mg, 0.418 mmol) and Xantphos (482 mg, 0.835 mmol) were then added and the vessel was flushed with argon. The resultant reaction mixture was heated at 150° C. under microwave irradiation for 31 min, cooled and filtered through Hyflo washing with ethyl acetate. The filtrate was washed with saturated sodium bicarbonate, the organic layer dried (MgSO4) and concentrated in vacuo. Purification of the resultant residue by flash chromatography (Si-PPC, dichloromethane:ethyl acetate gradient 1:0 to 5:1) afforded the title compound as a pale yellow solid (0.84 g, 50%). LCMS (method B): RT=3.75 min, M+H+=406.
Reaction SMILES: [O:1]=[C:2]1[NH:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[O:5][CH2:4][C@H:3]1[NH:13][C:14]([NH:16][C:17]1[CH:18]=[C:19]([CH3:23])[CH:20]=[CH:21][CH:22]=1)=[O:15].I[CH2:25][C:26]([N:28]1[CH2:33][CH:32]([CH3:34])[CH2:31][CH:30]([CH3:35])[CH2:29]1)=[O:27]>C1COCC1>[CH3:35][CH:30]1[CH2:31][CH:32]([CH3:34])[CH2:33][N:28]([C:26](=[O:27])[CH2:25][N:8]2[C:7]3[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=3[O:5][CH2:4][C@@H:3]([NH:13][C:14]([NH:16][C:17]3[CH:18]=[C:19]([CH3:23])[CH:20]=[CH:21][CH:22]=3)=[O:15])[C:2]2=[O:1])[CH2:29]1
Reactant: CC1CC(C)CN(C(=O)CI)C1
Reactant: Cc1cccc(NC(=O)N[C@@H]2COc3ccccc3NC2=O)c1
Solvent: C1CCOC1
Product: Cc1cccc(NC(=O)N[C@@H]2COc3ccccc3N(CC(=O)N3CC(C)CC(C)C3)C2=O)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 72 %

Procedure:
A solution of 0.100 g (0.000325M) (R)-(8-oxo-6,7,8,9-tetrahydro-5-oxa-9-aza-benzocyclohepten-7-yl)-3-m-tolyl-urea in 5 ml of THF was cooled to -78° C. under a nitrogen atmosphere. To this solution was added dropwise 0.321 mL (0.000325M) of lithium bis-hexamethyldisilylamide (1M solution in THF) and the reaction was stirred for 15 minutes. To this mixture was added 0.090 ml (0.000325M) of N-iodoacetyl-3,5-dimethyl piperidine. After addition was complete, the reaction was warmed to room temperature and stirred for 30 minutes. The reaction mixture was quenched with 5 mL of water, and extracted with ethyl acetate. The ethyl acetate extracts were dried and evaporated. The residue was chromatographed on 15 g of silica using 10:1 chloroform:methanol as the eluant. The appropriate fractions were combined and evaporated to yield 109 mg (72% yield) of product as a white solid.
Reaction SMILES: ON1C2C=CC=CC=2N=N1.[N:11]1([C:16]2[N:17]=[CH:18][C:19]3[CH:24]([C:25]([OH:27])=O)[CH2:23][CH2:22][C:20]=3[N:21]=2)[CH:15]=[N:14][N:13]=[N:12]1.C(Cl)CCl.[F:32][C:33]1[C:38]([C:39]#[N:40])=[C:37]([CH3:41])[C:36]([C@H:42]2[O:47][CH2:46][C@H:45]3[CH2:48][NH:49][CH2:50][CH2:51][N:44]3[CH2:43]2)=[CH:35][CH:34]=1.C(N(CC)CC)C>ClCCl.CCOC(C)=O>[F:32][C:33]1[C:38]([C:39]#[N:40])=[C:37]([CH3:41])[C:36]([C@H:42]2[O:47][CH2:46][C@H:45]3[CH2:48][N:49]([C:25]([CH:24]4[C:19]5[CH:18]=[N:17][C:16]([N:11]6[CH:15]=[N:14][N:13]=[N:12]6)=[N:21][C:20]=5[CH2:22][CH2:23]4)=[O:27])[CH2:50][CH2:51][N:44]3[CH2:43]2)=[CH:35][CH:34]=1
Reactant: Cc1c([C@@H]2CN3CCNC[C@@H]3CO2)ccc(F)c1C#N
Reactant: O=C(O)C1CCc2nc(-n3cnnn3)ncc21
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: Cc1c([C@@H]2CN3CCN(C(=O)C4CCc5nc(-n6cnnn6)ncc54)C[C@@H]3CO2)ccc(F)c1C#N
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1-Hydroxybenzotriazole (173 mg, 1.280 mmol) was added to a suspension of 2-(1H-tetrazol-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-5-carboxylic acid [I-67] (200 mg, 0.861 mmol) in dichloromethane (2 mL) followed by EDC (331 mg, 1.73 mmol), 6-fluoro-2-methyl-3-[(3R,9aR)-octahydropyrazino[2,1-c][1,4]oxazin-3-yl]benzonitrile [I-40D] (551 mg, 1.095 mmol) and triethylamine (0.70 mL, 5.0 mmol). The reaction mixture was stirred at RT overnight. The reaction mixture was diluted with EtOAc and washed with saturated NaHCO3 solution, water and brine, dried (MgSO4), filtered, and the solvent evaporated to afford the title compound as a mixture of two diastereomers. The crude product was purified by MPLC on silica (24 g cartridge) using CH2Cl2 (A) and CH2Cl2:MeOH 90:10 (B) with gradient elution from 100% A to 100% B over 12 CV's to afford the title compound as a mixture of 2 diastereomers. LC/MS 490 (M+H). The mixture of diastereomers was purified by preparative chiral HPLC (SFC) on a Chiralcel AS column, 100 bar, 40% MeOH (0.2% DEA)/CO2, 35° C. to afford the two separated aza-indane diastereomers of the title compound: Isomer 2C (faster eluting) and Isomer 2D (slower eluting). Each isomer was dissolved separately in 1 mL of dichloromethane and 1 eq. 1 M HCl in ether was added. The solvent was evaporated to yield the hydrochloride salts of each isomer. Isomer 2C HCl salt: NMR 600 MHz (CD3OD) (mixture amide rotamers) 9.988 (s, 0.6H); 9.975 (s, 0.4H); 8.73 (s, 0.6H); 8.67 (s, 0.4H); 7.94 (dd, 1H); 7.31 (app t, 1H); 5.15 (d, 1H); 4.80 (t, 0.5H); 4.75 (d, 0.5H); 4.65-4.70 (m, 1H); 4.47 (d, 0.5H); 4.32-4.38 (m, 1H); 4.19-4.29 (m, 2H); 3.84-3.98 (m, 2H 3.57-3.72 (m, 2H); 3.44-3.54 (m, 2H); 3.31-3.38 (m, 0.5H); 3.23 (t, 2H); 2.69-2.86 (m, 1H); 2.62 (s, 3H); 2.33-2.42 (m, 0.5H); 2.20-2.28 (m, 0.5H). LC/MS 531 (M+H+CH3CN). Isomer 2D HCl salt: NMR 500 MHz (CD3OD) (mixture amide rotamers) 9.98 (s, 1H); 8.72 (s, 0.6H)); 8.69 (s, 0.4H); 7.91-7.96 (m, 1H); 7.30 (q, 1H); 5.14-5.18 (m, 1H); 472-4.78 (m, 1.5H); 4.65 (d, 0.5H); 4.49 (d, 0.5H); 4.35 (d, 1H); 4.21-4.30 (m, 2H); 3.32-3.95 (m, 6.5H); 3.18-3.27 (m, 2H); 2.71-2.79 (m, 1H); 2.62 (s, 3H); 2.35-2.42 (m, 0.5H); 2.18-2.26 (m, 0.5H). LC/MS 531 (M+H+CH3CN).