Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2]([N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([N+:14]([O-])=O)[CH:12]=2)[CH2:7][CH2:6]1)(=[O:4])=[O:3].C(O)C>[Pd].O1CCCC1>[CH3:1][S:2]([N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([NH2:14])[CH:12]=2)[CH2:7][CH2:6]1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)N1CCc2ccc([N+](=O)[O-])cc21
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: CS(=O)(=O)N1CCc2ccc(N)cc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 94.7 %

Procedure:
To 2.00 g of 1-methylsulfonyl-6-nitroindoline and a mixed solvent of 100 ml of ethanol and 100 ml of tetrahydrofuran was added 300 mg of 10% palladium/carbon under an argon atmosphere, followed by 3 hours of stirring at room temperature under a hydrogen atmosphere. The reaction solution was filtrated through celite and the organic solvent in the filtrate was removed under reduced pressure. To the residue was added 200 ml of a mixed solution of methanol, ethyl acetate, and tetrahydrofuran. Under an argon atmosphere, 1 g of 10% palladium/carbon was added and the whole was stirred at room temperature for 3 hours under a hydrogen atmosphere. The reaction solution was filtrated through celite and the organic solvent in the filtrate was removed under reduced pressure to obtain 1.66 g of 1-methylsulfonyl-6-aminoindoline as a pale yellow solid.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C@H:7]([NH:12][C:13](=[O:18])[C:14]([F:17])([F:16])[F:15])[C:8]([O:10][CH3:11])=[O:9].C(N(CC)C(C)C)(C)C.ClCCl.[CH2:31]=[C:32]1[O:36][C:34](=[O:35])[CH2:33]1>C(OCC)(=O)C>[CH3:11][O:10][C:8](=[O:9])[C@@H:7]([NH:12][C:13](=[O:18])[C:14]([F:16])([F:17])[F:15])[CH2:6][CH2:5][CH2:4][CH2:3][NH:2][C:34](=[O:35])[CH2:33][C:32](=[O:36])[CH3:31]
Reactant: C=C1CC(=O)O1
Reactant: COC(=O)[C@H](CCCCN)NC(=O)C(F)(F)F
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COC(=O)[C@H](CCCCNC(=O)CC(C)=O)NC(=O)C(F)(F)F
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To (S)-methyl 6-amino-2-(2,2,2-trifluoroacetamido)hexanoate hydrochloride (0.943 g, 3.22 mmol), N,N-diisopropyl ethylamine (DIEA, 1.39 mL) and dichloromethane (DCM, 10 mL) in a 40 mL glass vial was added diketene (0.37 mL) under N2 atmosphere, and the reaction was stirred at ambient temperature for 16 hours. The reaction mixture was diluted with ethyl acetate (EtOA), washed successively with H2O, 1 N HCl, H2O, sat aq Na2CO3, and sat aq NaCl, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by a SiO2 flash chromatography, affording (S)-methyl-6-(3-oxobutanamido)-2-(2,2,2-trifluoroacetamido)hexanoate (TU3000-012) as a yellow oil. MS (ESI+): calcd. 341.12. found 341.10 (MH+). H-NMR (400 MHz, CDCl3):1.33 (2H, m), 1.55 (2H, m), 1.89 (2H, m), 2.259(3H, s), 3.31 (2H, m), 3.410 (2H, s), 3.783 (3H, s), 4.543 (1H, dt, J=4.4, 8.0 Hz). 7.091 (1H, br.s), 7.279 (1H, br.d, J=7.6 Hz). F-NMR (376 MHz, CDCl3): −75.609.
Reaction SMILES: [CH3:1][S:2]([NH2:5])(=[O:4])=[O:3].[OH-].[Na+].Cl[CH2:9][C@@H:10]1[CH2:12][O:11]1.Cl>O>[O:11]1[CH2:12][C@@H:10]1[CH2:9][CH2:1][S:2]([NH2:5])(=[O:4])=[O:3]
Reactant: CS(N)(=O)=O
Reactant: ClC[C@@H]1CO1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: NS(=O)(=O)CC[C@H]1CO1
Reaction time: 2 h
Yield: 15.7 %

Procedure:
To a cold solution of methanesulfonamide (10 g, 0.105 mol) in water (100 mL) in an ice bath was added sodium hydroxide as pellets (8.4 g, 0.21 mol) and then (S)-2-chloromethyloxirane (12.4 g, 0.158 mol). The mixture was stirred at the same temperature for 2 h, and at room temperature for 12 h and then concentrated hydrochloric acid (18 mL) was added. The product was isolated by extracting the aqueous layer with dichloromethane (2×300 mL). The organic layer was dried over MgSO4 and then evaporated to dryness, yielding a colorless liquid (2.5 g), which was used directly in the next step.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH:10]([OH:49])[CH2:11][S:12][C@H:13]3[C:16](=[O:17])[N:15]([C:18]4[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=4)[C@@H:14]3[C:25]3[CH:48]=[CH:47][C:28]([O:29][CH2:30][C:31](NCC(N[C@@H](C(O)=O)CCCCN)=O)=[O:32])=[CH:27][CH:26]=3)=[CH:9][C:4]=2[O:3][CH2:2]1.[BH4-].[Na+].C[OH:53]>>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH:10]([OH:49])[CH2:11][S:12][C@H:13]3[C:16](=[O:17])[N:15]([C:18]4[CH:19]=[CH:20][C:21]([F:24])=[CH:22][CH:23]=4)[C@@H:14]3[C:25]3[CH:48]=[CH:47][C:28]([O:29][CH2:30][C:31]([OH:32])=[O:53])=[CH:27][CH:26]=3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: NCCCC[C@@H](NC(=O)CNC(=O)COc1ccc([C@@H]2[C@@H](SCC(O)c3ccc4c(c3)OCO4)C(=O)N2c2ccc(F)cc2)cc1)C(=O)O
Reactant: CO
Agent: [BH4-]
Agent: [Na+]
Product: O=C(O)COc1ccc([C@@H]2[C@@H](SCC(O)c3ccc4c(c3)OCO4)C(=O)N2c2ccc(F)cc2)cc1

Procedure:
To a solution of {4-[(2R,3R)-3-{[2-(1,3-Benzodioxol-5-yl)-2-oxoethyl]thio}-1-(4-fluorophenyl)-4-oxoazetidin-2-yl]phenoxy}acetic acid (Method 7) (0.010 g, 0.020 mmol) in methanol (2 ml) was added NaBH4 (0.010 g, 0.265 mmol). After 15 min the reaction was quenched by the addition of an aqueous solution of hydrochloric acid (1M, 1 ml) and most of the methanol was removed under reduced pressure. The remaining solution was purified by preparative HPLC using a gradient of 20-60% MeCN in a 0.1M ammonium acetate buffer as eluent. Freeze-drying of the pure fractions gave the product.
Reaction SMILES: [I-].[Na+].Cl[Si](C)(C)C.[CH:8]1([N:12]2[CH:17]=[C:16]([O:18]C)[C:15](=[O:20])[C:14]([C:21]3[N:25]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[N:24]=[CH:23][CH:22]=3)=[N:13]2)[CH2:11][CH2:10][CH2:9]1.O>C(#N)C>[CH:8]1([N:12]2[CH:17]=[C:16]([OH:18])[C:15](=[O:20])[C:14]([C:21]3[N:25]([C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=4)[N:24]=[CH:23][CH:22]=3)=[N:13]2)[CH2:11][CH2:10][CH2:9]1
Reactant: COc1cn(C2CCC2)nc(-c2ccnn2-c2ccccc2)c1=O
Agent: C[Si](C)(C)Cl
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: O=c1c(O)cn(C2CCC2)nc1-c1ccnn1-c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 91.9 %

Procedure:
To a solution of sodium iodide (2.11 g) in acetonitrile (84.3 mL) was added at room temperature chlorotrimethylsilane (1.78 mL) and the mixture was stirred for 30 min. Then, 1-cyclobutyl-5-methoxy-3-(1-phenyl-1H-pyrazol-5-yl)pyridazin-4(1H)-one (0.91 g) was added, and the mixture was stirred at room temperature for 30 min, and further refluxed for 3 hr. The reaction mixture was allowed to cool to room temperature, water was added, and the mixture was stirred for 30 min, and extracted with ethyl acetate. The organic layer was washed with aqueous sodium thiosulfate solution and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was triturated with diisopropyl ether, and collected by filtration to give the title compound (800 mg).
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.O1CCCC1.[Si]([O:31][CH2:32][C@@H:33]1[N:40]([C:41](=[O:77])[C@@H:42]2[CH2:46][C@@H:45]([F:47])[CH2:44][N:43]2[C:48]([C:50]2[S:54][C:53]3=[N:55][C@:56]([C:67]4[CH:68]=[N:69][C:70]([Cl:73])=[CH:71][CH:72]=4)([CH3:66])[C@@H:57]([C:58]4[CH:63]=[CH:62][C:61]([Cl:64])=[C:60]([F:65])[CH:59]=4)[N:52]3[C:51]=2[CH:74]([CH3:76])[CH3:75])=[O:49])[CH2:39][C:36]2([CH2:38][CH2:37]2)[N:35](C(=O)C(F)(F)F)[CH2:34]1)(C(C)(C)C)(C)C>C(OCC)(=O)C>[Cl:64][C:61]1[CH:62]=[CH:63][C:58]([C@H:57]2[N:52]3[C:53]([S:54][C:50]([C:48]([N:43]4[CH2:44][C@H:45]([F:47])[CH2:46][C@H:42]4[C:41]([N:40]4[CH2:39][C:36]5([CH2:37][CH2:38]5)[NH:35][CH2:34][C@@H:33]4[CH2:32][OH:31])=[O:77])=[O:49])=[C:51]3[CH:74]([CH3:75])[CH3:76])=[N:55][C@:56]2([C:67]2[CH:68]=[N:69][C:70]([Cl:73])=[CH:71][CH:72]=2)[CH3:66])=[CH:59][C:60]=1[F:65]
Reactant: CC(C)C1=C(C(=O)N2C[C@H](F)C[C@H]2C(=O)N2CC3(CC3)N(C(=O)C(F)(F)F)C[C@@H]2CO[Si](C)(C)C(C)(C)C)SC2=N[C@@](C)(c3ccc(Cl)nc3)[C@@H](c3ccc(Cl)c(F)c3)N21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)C1=C(C(=O)N2C[C@H](F)C[C@H]2C(=O)N2CC3(CC3)NC[C@@H]2CO)SC2=N[C@@](C)(c3ccc(Cl)nc3)[C@@H](c3ccc(Cl)c(F)c3)N21
Temperature: 25 °C
Reaction time: 3 h
Yield: 51.6 %

Procedure:
Tetra-n-butylammonium fluoride (1 M tetrahydrofuran solution) (0.42 ml, 0.42 mmol) was added to a tetrahydrofuran (4 ml) solution of the compound (255 mg, 0.28 mmol) obtained in Step 1 above and the resulting mixture was stirred at room temperature for 3 hours. The solvent was concentrated under reduced pressure, then the residue obtained was diluted with ethyl acetate and the organic layer was washed with saturated aqueous sodium bicarbonate solution and saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue obtained was purified by NH-silica gel column chromatography [chloroform:methanol=40:1 (v/v)] to give the title compound (102 mg, 52%) as a colorless solid.
Reaction SMILES: [CH2:1]([N:8]([C@@H:16]([CH2:19][CH2:20][CH2:21][N:22]([CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH:17]=[O:18])[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH3:52]>>[CH2:23]([N:22]([CH2:21][CH2:20][CH2:19][C@H:16]([N:8]([CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C@H:17]([OH:18])[CH2:52][CH2:51][CH2:50][CH2:49][CH2:48][CH2:47][CH2:46][CH2:45][CH2:44][CH2:43][CH2:42][CH2:41][CH2:40][CH2:39][CH3:38])[CH2:30][C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: O=C[C@H](CCCN(Cc1ccccc1)Cc1ccccc1)N(Cc1ccccc1)Cc1ccccc1
Reactant: CCCCCCCCCCCCCCCBr
Product: CCCCCCCCCCCCCCC[C@@H](O)[C@H](CCCN(Cc1ccccc1)Cc1ccccc1)N(Cc1ccccc1)Cc1ccccc1

Procedure:
According to the method of Example 26, from aldehyde 23 (503 mg, 1.05 mmol) and 1-bromopentadecane (768; mg, 2.64 mmol), alcohol 77 was obtained as a colorless oil (350 mg, 48% yield).
Reaction SMILES: Cl.[C:2]([NH:6][NH2:7])([CH3:5])([CH3:4])[CH3:3].C(=O)([O-])[O-].[K+].[K+].C(Cl)(Cl)(Cl)Cl.[CH3:19][O:20][P:21]([O-:24])[O:22][CH3:23]>[Cl-].C([N+](CC)(CC)CC1C=CC=CC=1)C.ClCCl>[C:2]([NH:6][NH:7][P:21]([O:22][CH3:23])([O:20][CH3:19])=[O:24])([CH3:5])([CH3:4])[CH3:3]
Reactant: COP([O-])OC
Reactant: CC(C)(C)NN
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: ClC(Cl)(Cl)Cl
Solvent: ClCCl
Product: COP(=O)(NNC(C)(C)C)OC
Yield: 73.9 %

Procedure:
A mixture of t-butylhydrazine hydrochloride (12.46 g, 0.1 mole), potassium carbonate (27.64 g, 0.2 mole) and triethylbenzyl ammonium chloride (0.3 g, 0.0013 mole) was stirred vigorously at reflux with dichloromethane (100 ml) and carbon tetrachloride (60 ml) for 30 minutes. A solution of dimethylphosphite (11.0 g, 0.1 mole) in dichloromethane (20 ml) was then added dropwise to this refluxing mixture and the mixture stirred and refluxed for an additional 20 hours. The mixture was then filtered and the filtrate dried over anhydrous magnesium sulfate. The dried filtrate, then was evaporated down to a viscous oil which was subjected to high vacuum for 2 or 3 hours to yield 14.5 g of a solid product, m.pt. 61°-8° C.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[CH:9][CH:10]=[C:6]2[N:5]=[C:4]([CH:11]2[CH2:16][CH2:15][S:14][CH2:13][CH2:12]2)[CH:3]=1.[NH3:17]>CO>[S:14]1[CH2:15][CH2:16][CH:11]([C:4]2[CH:3]=[C:2]([NH2:17])[N:7]3[N:8]=[CH:9][CH:10]=[C:6]3[N:5]=2)[CH2:12][CH2:13]1
Reactant: N
Reactant: Clc1cc(C2CCSCC2)nc2ccnn12
Solvent: CO
Product: Nc1cc(C2CCSCC2)nc2ccnn12
Temperature: 80 °C

Procedure:
A mixture of 7-chloro-5-(tetrahydro-2H-thiopyran-4-yl)pyrazolo[1,5-a]pyrimidine (Int-1c, 1.52 g, 6.0 mmol) in a solution of ammonia in MeOH (7 N, 20 mL) was heated in sealed vessel at 80° C. for 5 h. The reaction mixture was cooled down and concentrated. The residue was dried in high vacuum and used for the next step without further purification. LC/MS RT=0.92 Min (5 min method). Mass calculated for, M+H 235.09, observed 235.09.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH3:12])[C:7](=[O:13])[NH:6][CH2:5]2.[Si:14]([O:21][C@:22]1([C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([SH:35])[CH:30]=2)[CH2:27][CH2:26][O:25][C@@H:24]([CH3:28])[CH2:23]1)([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15]>>[Si:14]([O:21][C@:22]1([C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([S:35][C:2]3[CH:3]=[C:4]4[C:9](=[CH:10][CH:11]=3)[N:8]([CH3:12])[C:7](=[O:13])[NH:6][CH2:5]4)[CH:30]=2)[CH2:27][CH2:26][O:25][C@@H:24]([CH3:28])[CH2:23]1)([C:17]([CH3:20])([CH3:18])[CH3:19])([CH3:16])[CH3:15]
Reactant: CN1C(=O)NCc2cc(I)ccc21
Reactant: C[C@H]1C[C@@](O[Si](C)(C)C(C)(C)C)(c2cccc(S)c2)CCO1
Product: C[C@H]1C[C@@](O[Si](C)(C)C(C)(C)C)(c2cccc(Sc3ccc4c(c3)CNC(=O)N4C)c2)CCO1
Yield: 41 %

Procedure:
using an analogous procedure to that described in Example 5, 6-iodo-1-methyl-2-oxo-1,2,3,4-tetrahydroquinazoline was reacted with (2S,4R)-4-(tert-butyldimethylsilyloxy)-4-(3-mercaptophenyl)-2methyltetrahydropyran to give (2S,4R)-4-(tert-butyldimethylsilyloxy)2-methyl-4-[3-(1-methyl-2-oxo-1,2,3,4-tetrahydroquinazolin-6-ylthio)phenyl]tetrahydropyran in 41% yield as a foam. A mixture of the material so formed (0.12 g) and tetrabutylammonium fluoride (1M in THF, 5 ml) was stirred and heated to reflux for 2 hours. The mixture was cooled to ambient temperature and partitioned between ethyl acetate and water. The organic solution was dried (Na2SO4) and evaporated. The residue was purified by column chromatography using increasingly polar mixtures of methylene chloride and methanol as eluent. There was thus obtained (2S,4R)-4-hydroxy-2-methyl-4-[3-(1-methyl-2-oxo-1,2,3,4-tetrahydroquinazolin-6-ylthio)phenyl]tetrahydropyran (0.07 g) as a gum;
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][C:5]([CH3:26])([CH3:25])[CH2:6][N:7]1[C:19]2[C:18]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[N:12]=[C:11]([NH2:20])[C:10]=2[N:9]=[C:8]1[CH2:21][O:22][CH2:23][CH3:24].C(N(CC)CC)C.[C:34](Cl)(=[O:36])[CH3:35]>C(Cl)Cl>[NH2:20][C:11]1[C:10]2[N:9]=[C:8]([CH2:21][O:22][CH2:23][CH3:24])[N:7]([CH2:6][C:5]([CH3:25])([O:4][CH2:3][CH2:2][NH:1][C:34](=[O:36])[CH3:35])[CH3:26])[C:19]=2[C:18]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[N:12]=1
Reactant: CC(=O)Cl
Reactant: CCOCc1nc2c(N)nc3ccccc3c2n1CC(C)(C)OCCN
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOCc1nc2c(N)nc3ccccc3c2n1CC(C)(C)OCCNC(C)=O
Temperature: 25 °C
Reaction time: 18 h
Yield: 53.1 %

Procedure:
1-(2-(2-Aminoethoxy)-2-methylpropyl)-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-4-amine (32 mg, 89.5 μmol) was combined with DCM (1.0 mL) to give a colorless solution. To this solution was added triethylamine (25.0 μL, 179 μmol) and acetyl chloride (7.00 μL, 98.5 μmol) and the reaction mixture was stirred 18 hours at room temperature. After concentrating the mixture in vacuo the residue was purified by flash chromatography (silica gel-NH2, 0% to 10% methanol in DCM) to give the title compound (19 mg, 53%) as white foam; LC-MS (UV peak area, ESI) 97%, 400.2348 (MH+).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[CH:9]=2)[N:5]=[C:4]2[CH2:15][CH2:16][CH2:17][C:3]=12.[NH2:18][C:19]1[CH:33]=[CH:32][C:22]([CH2:23][C:24]([CH3:31])([C:28]([NH2:30])=[O:29])[C:25]([NH2:27])=[O:26])=[CH:21][CH:20]=1.Cl.O1CCOCC1>CN1C(=O)CCC1.O.C(=O)(O)[O-].[Na+].ClCCl.CO>[Cl:14][C:10]1[CH:9]=[C:8]([C:6]2[N:5]=[C:4]3[CH2:15][CH2:16][CH2:17][C:3]3=[C:2]([NH:18][C:19]3[CH:20]=[CH:21][C:22]([CH2:23][C:24]([CH3:31])([C:25]([NH2:27])=[O:26])[C:28]([NH2:30])=[O:29])=[CH:32][CH:33]=3)[CH:7]=2)[CH:13]=[CH:12][CH:11]=1
Reactant: Clc1cccc(-c2cc(Cl)c3c(n2)CCC3)c1
Reactant: CC(Cc1ccc(N)cc1)(C(N)=O)C(N)=O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: C1COCCO1
Solvent: CO
Product: CC(Cc1ccc(Nc2cc(-c3cccc(Cl)c3)nc3c2CCC3)cc1)(C(N)=O)C(N)=O
Temperature: 150 °C
Yield: 70.3 %

Procedure:
A 10-mL microwave vial was charged with 4-chloro-2-(3-chlorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridine (0.100 g, 0.38 mmol), 2-(4-aminobenzyl)-2-methylmalonamide (0.167 g, 0.75 mmol) and 4M HCl in dioxane (0.095 mL, 0.38 mmol) in NMP (4 mL). The resulting mixture was heated at 150° C. under microwave irradiation for 8 h. After this time, the reaction mixture was cooled, diluted with water (20 mL) and saturated aqueous sodium bicarbonate (20 mL) affording a solid. The solid was isolated by filtration and chromatography on silica using dichloromethane/methanol (10:0 to 9:1) as eluent to afford 2-(4-((2-(3-chlorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)amino)benzyl)-2-methylmalonamide (0.12 g, 72%) as an off-white solid. MW=448.94. 1H NMR (DMSO-d6, 300 MHz) δ 8.10 (s, 1H), 7.92-7.89 (m, 1H), 7.74 (dt, J=6.6, 2.1 Hz, 1H), 7.48-7.39 (m, 2H), 7.23 (s, 2H), 7.20-7.10 (m, 7H), 3.05 (s, 2H), 2.91 (t, J=7.8 Hz, 2H), 2.81 (t, J=7.2 Hz, 2H), 2.08 (quin, J=7.2 Hz, 2H), 1.14 (s, 3H). Treatment with 1.25M HCl in methanol (0.44 mL, 0.55 mmol) afforded the title compound (0.11 g, 84%) as an off-white solid. MW=485.41. M.p. 162-165° C. 1H NMR (DMSO-d6, 500 MHz) δ 14.01 (br s, 1H), 9.17 (s, 1H), 7.89 (t, J=2.0 Hz, 1H), 7.00 (dt, J=4.5, 1.5 Hz, 1H), 7.60-7.52 (m, 2H), 7.28-7.20 (m, 6H), 7.15 (s, 2H), 7.05 (s, 1H), 3.10 (s, 2H), 3.06 (t, J=7.5 Hz, 2H), 2.87 (d, J=7.5 Hz, 2H), 2.18 (quin, J=7.5 Hz, 2H), 1.15 (s, 3H); APCI MS m/z 449 [M+H]+.
Reaction SMILES: [CH3:1][N:2]1[CH2:24][CH2:23][C:5]2[N:6]([CH2:14][CH:15]([C:17]3[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=3)[OH:16])[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.[C:25](O)(=[O:29])[CH:26]([CH3:28])[CH3:27].CCN=C=NCCCN(C)C.Cl>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:25]([O:16][CH:15]([C:17]1[CH:18]=[CH:19][N:20]=[CH:21][CH:22]=1)[CH2:14][N:6]1[C:7]2[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=2[C:4]2[CH2:3][N:2]([CH3:1])[CH2:24][CH2:23][C:5]1=2)(=[O:29])[CH:26]([CH3:28])[CH3:27]
Reactant: Cc1ccc2c(c1)c1c(n2CC(O)c2ccncc2)CCN(C)C1
Reactant: CC(C)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: Cc1ccc2c(c1)c1c(n2CC(OC(=O)C(C)C)c2ccncc2)CCN(C)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 51.1 %

Procedure:
To a solution of 2-(1,2,3,4-tetrahydro-2,8-dimethylpyrido[4,3-b]indol-5-yl)-1-(pyridin-4-yl)ethanol (500 mg, 1.55 mmol) and isobutyric acid (274 mg, 3.1 mmol) in DCM (100 mL) were added EDC.HCl (657 mg, 3.4 mmol), DMAP (19 mg, 0.16 mmol) and TEA (346 mg, 3.4 mmol). The reaction mixture was stirred at RT for 16 h and washed with water. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (4% MeOH-DCM) followed by reverse phase purification to yield 2-(1,2,3,4-tetrahydro-2,8-dimethylpyrido[4,3-b]indol-5-yl)-1-(pyridin-4-yl)ethyl isobutyrate (310 mg). 1H NMR (CDCl3, freebase) δ (ppm): 8.53 (d, 2H), 7.2 (d, 1H), 7.18 (s, 1H), 7.04 (d, 2H), 6.97 (d, 1H), 5.98 (t, 1H), 4.4 (dd, 1H), 4.14 (dd, 1H), 3.64 (q, 2H), 2.73 (m, 2H), 2.6 (m, 1H), 2.49 (s, 3H), 2.43 (s, 3H), 2.37 (m, 1H), 1.15 (d, 3H), 1.09 (d, 3H). Separation by chiral HPLC provided enantiomers 54a and 54b.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:20]2[CH:21]=[C:22]([CH:27]=[CH:28][N:29]=2)[C:23]([O:25]C)=[O:24])[CH:6]=[CH:7][C:8]=1[N:9]1[CH:13]=[C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:11]=[N:10]1)#[N:2].[OH-].[Na+].Cl>CO.C1COCC1>[C:1]([C:3]1[CH:4]=[C:5]([C:20]2[CH:21]=[C:22]([CH:27]=[CH:28][N:29]=2)[C:23]([OH:25])=[O:24])[CH:6]=[CH:7][C:8]=1[N:9]1[CH:13]=[C:12]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:11]=[N:10]1)#[N:2]
Reactant: COC(=O)c1ccnc(-c2ccc(-n3cc(-c4ccccc4)nn3)c(C#N)c2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: N#Cc1cc(-c2cc(C(=O)O)ccn2)ccc1-n1cc(-c2ccccc2)nn1
Yield: 34.6 %

Procedure:
12 mg of methyl 2-[3-cyano-4-(4-phenyl-1H-1,2,3-triazol-1-yl)phenyl]isonicotinate was dissolved in a mixture of 234 μl of methanol and 351 μl of THF, then 61 μl of aqueous 1 M sodium hydroxide solution was added, followed by heating under reflux for 3 hours. The reaction mixture was cooled, and neutralized with 61 μl of 1 M hydrochloric acid, then extracted with a mixture of 2-propanol and chloroform (1:4). The organic layer was washed with brine. The solvent of the organic layer was removed under reduced pressure, and the resulting residue was recrystallized from a mixture of 2-propanol and chloroform (1:4) to obtain 4 mg of 2-[3-cyano-4-(4-phenyl-1H-1,2,3-triazol-1-yl)phenyl]isonicotinic acid.
Reaction SMILES: COC1C=CC(C[N:8]2[CH:12]=[C:11]([NH:13][C:14](=[O:26])[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[O:21][C:22]([F:25])([F:24])[F:23])[C:10]([C:27]3[NH:31][C:30]4[CH:32]=[CH:33][C:34]([CH2:36][N:37]5[CH2:42][CH2:41][O:40][CH2:39][CH2:38]5)=[CH:35][C:29]=4[N:28]=3)=[N:9]2)=CC=1.C1(OC)C=CC=CC=1>FC(F)(F)C(O)=O>[N:37]1([CH2:36][C:34]2[CH:33]=[CH:32][C:30]3[NH:31][C:27]([C:10]4[C:11]([NH:13][C:14](=[O:26])[C:15]5[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=5[O:21][C:22]([F:23])([F:24])[F:25])=[CH:12][NH:8][N:9]=4)=[N:28][C:29]=3[CH:35]=2)[CH2:38][CH2:39][O:40][CH2:41][CH2:42]1
Reactant: COc1ccc(Cn2cc(NC(=O)c3ccccc3OC(F)(F)F)c(-c3nc4cc(CN5CCOCC5)ccc4[nH]3)n2)cc1
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1c[nH]nc1-c1nc2cc(CN3CCOCC3)ccc2[nH]1)c1ccccc1OC(F)(F)F
Temperature: 140 °C
Yield: 29.9 %

Procedure:
A mixture of N-[1-(4-methoxy-benzyl)-3-(5-morpholin-4-ylmethyl-1H-benzimidazol-2-yl)-1H-pyrazol-4-yl]-2-trifluoromethoxy-benzamide (50 mg) and anisole (25 μl) in trifluoroacetic acid (1 ml) was heated at 140° C. (100 W) for 20 min in a CEM Discover™ microwave synthesiser. The reaction mixture was evaporated and then azeotroped with toluene (2×10 ml). To the crude material was added EtOAc (5 ml) and the mixture neutralised with saturated aqueous sodium hydrogen carbonate. The organic portion was washed with water, dried (MgSO4) and reduced in vacuo. The residue was purified by flash column chromatography [SiO2, CH2Cl2-MeOH (100:0-95:5)] to give N-[3-(5-morpholin-4-ylmethyl-1H-benzimidazol-2-yl)-1H-pyrazol-4-yl]-2-trifluoromethoxy-benzamide (12 mg) as a white solid. (LC/MS: Rt 2.06, [M+H]+ 487).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([NH:12][C@@H:13]([CH2:23][CH:24]([CH3:26])[CH3:25])[CH2:14][O:15][Si](C(C)(C)C)(C)C)[CH:9]([F:11])[F:10])=[CH:4][CH:3]=1.C1C=CN=CC=1.F.C(=O)(O)[O-].[Na+].C(OCC)(=O)C>CC#N>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([NH:12][C@@H:13]([CH2:23][CH:24]([CH3:26])[CH3:25])[CH2:14][OH:15])[CH:9]([F:11])[F:10])=[CH:4][CH:3]=1
Reactant: CC(C)C[C@@H](CO[Si](C)(C)C(C)(C)C)N[C@@H](c1ccc(Br)cc1)C(F)F
Agent: F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CC(C)C[C@@H](CO)N[C@@H](c1ccc(Br)cc1)C(F)F
Temperature: 0 °C

Procedure:
n-BuLi (2.5 M in hexanes, 1.43 mL) was added to a −70° C. THF (8.5 mL) solution of 1,4-dibromobenzene (884 mg) and the mixture was stirred for 15 minutes. A THF (8.5 mL) solution of (2S)-1-{[tert-butyl(dimethyl)silyl]oxy}-4-methyl-N-[(1E)-2,2-difluoroethylidene]pentan-2-amine (1.0 g) was then added dropwise and the mixture was stirred for 1.5 hours. The mixture was then poured slowly into an icy saturated aqueous solution of ammonium chloride under vigorous stirring and was extracted with 3 portions of ethyl acetate. The combined organic layers were washed with brine, dried with magnesium sulfate and the solvent was removed in vacuo to yield a residue, which was purified on SiO2 using a gradient of hexanes and ethyl acetate (90:10 to 75:25) as eluent to yield (2S)—N-[(1S)-1-(4-bromophenyl)-2,2-difluoroethyl]-1-{[tert-butyl(dimethyl)silyl]oxy}-4-methylpentan-2-amine. (2S)—N-[(1S)-1-(4-Bromophenyl)-2,2-difluoroethyl]-1-{[tert-butyl(dimethyl)silyl]oxy}-4-methylpentan-2-amine (200 mg) was dissolved in CH3CN (4 mL) and the solution was cooled to 0° C. HF-pyridine (40 μL) was added dropwise and the mixture was reacted for 16 hours. The mixture was poured into a saturated solution of sodium bicarbonate, ethyl acetate was added and the resultant mixture was vigorously shaken. The organic layer was separated and the aqueous further extracted with ethyl acetate (2×50 mL). The combined organic layers were washed with brine, dried with magnesium sulfate and the solvent was removed in vacuo to yield a residue which was purified on SiO2 using a gradient of hexanes and ethyl acetate (80:20 to 60:40) as eluent to yield the title compound.