Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:28]=[CH:27][C:6]([CH2:7][N:8]2[C:12]3=[N:13][CH:14]=[CH:15][C:16]([O:17][C:18]4[CH:23]=[CH:22][C:21]([NH2:24])=[CH:20][C:19]=4[F:25])=[C:11]3[C:10](I)=[N:9]2)=[CH:5][CH:4]=1.C([O-])([O-])=O.[Cs+].[Cs+].[N:35]1([C:41]([C:43]2[CH:48]=[CH:47][C:46](B(O)O)=[CH:45][CH:44]=2)=[O:42])[CH2:40][CH2:39][O:38][CH2:37][CH2:36]1>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:24][C:21]1[CH:22]=[CH:23][C:18]([O:17][C:16]2[CH:15]=[CH:14][N:13]=[C:12]3[N:8]([CH2:7][C:6]4[CH:27]=[CH:28][C:3]([O:2][CH3:1])=[CH:4][CH:5]=4)[N:9]=[C:10]([C:46]4[CH:45]=[CH:44][C:43]([C:41]([N:35]5[CH2:40][CH2:39][O:38][CH2:37][CH2:36]5)=[O:42])=[CH:48][CH:47]=4)[C:11]=23)=[C:19]([F:25])[CH:20]=1
Reactant: O=C(c1ccc(B(O)O)cc1)N1CCOCC1
Reactant: COc1ccc(Cn2nc(I)c3c(Oc4ccc(N)cc4F)ccnc32)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: COCCOC
Product: COc1ccc(Cn2nc(-c3ccc(C(=O)N4CCOCC4)cc3)c3c(Oc4ccc(N)cc4F)ccnc32)cc1
Temperature: 85 °C
Yield: 11.5 %

Procedure:
A mixture of 4-(1-(4-methoxybenzyl)-3-iodo-1H-pyrazolo[3,4-b]pyridin-4-yloxy)-3-fluorobenzenamine (0.30 g, 0.612 mmol; prepared as in Example 7, Step B), Cs2CO3 (0.299 g, 0.918 mmol), and 4-(morpholine-4-carbonyl)phenylboronic acid (0.151 g, 0.643 mmol) in DME (3 mL) was degassed under nitrogen for 10 minutes and tetrakistriphenylphosphinepalladium (0.035 g, 0.03 mmol) was added. The reaction mixture was heated at 85° C. for 15 hours. The precipitate was removed by filtration with a mixture of EtOAc and MeOH. The filtrate was concentrated and the crude material was purified by silica gel flash column chromatography (1% MeOH in CH2Cl2) to afford 39 mg (12%) of the desired product. LRMS (APCI pos) m/e 554.1 (M+1).
Reaction SMILES: Cl[C:2]1[C:7]([CH2:8][CH3:9])=[C:6]([O:10][C:11]2[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[S:13][CH:12]=2)[N:5]=[C:4]([C:20]2[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=2)[N:3]=1.CO.C(N(CC)CC)C>[Pd].C(OCC)(=O)C>[CH2:8]([C:7]1[CH:2]=[N:3][C:4]([C:20]2[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=2)=[N:5][C:6]=1[O:10][C:11]1[CH:15]=[C:14]([C:16]([F:17])([F:19])[F:18])[S:13][CH:12]=1)[CH3:9]
Reactant: CCc1c(Cl)nc(-c2ccc(C(F)(F)F)cc2)nc1Oc1csc(C(F)(F)F)c1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CO
Product: CCc1cnc(-c2ccc(C(F)(F)F)cc2)nc1Oc1csc(C(F)(F)F)c1

Procedure:
A solution of 4-Chloro-5-ethyl-2-(α,α,α-trifluoro-p-tolyl)-6-{[5-(trifluoromethyl)-3-thienyl]oxy}pyrimidine (1.06 g, 2.34 mmol) in a 1:1 mixture of methanol:ethyl acetate is treated with triethylamine (0.80 ml, 5.86 mmol) and 10% Pd-C (0.32 g, 30 wt %). The resultant mixture is placed on a PARR hydrogenator at 50 psi for 2 hours (reaction is complete by TLC). The resultant mixture is filtered. The filtrate is concentrated. The 20/80) to give the title product as a white solid, 0.69 9 (70%), mp 67-68° C. identified by 1HNMR, 13CNMR, 19FNMR, mass spectral and elemental analyses.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([S:19]C(=O)N(C)C)=[CH:15][CH:14]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[K+]>CO.O>[C:1]([O:5][C:6](=[O:7])[NH:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]1[CH:14]=[CH:15][C:16]([SH:19])=[CH:17][CH:18]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CN(C)C(=O)Sc1ccc(CCCCNC(=O)OC(C)(C)C)cc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)NCCCCc1ccc(S)cc1
Temperature: 25 °C
Yield: 45.3 %

Procedure:
N-tert-Butoxycarbonyl-4-[4-(dimethylcarbamoylthio)phenyl]butylamine 37 (0.35 g, 1.02 mmol) was dissolved in MeOH (8 mL). KOH (0.19 g, 3.4 mmol) dissolved in water (2 ml) was added. The mixture was stirred under reflux for 6 h and cooled to room temperature. The solvent was removed under reduced pressure. The residue was dissolved in water and acidified with 5% aqueous HCl to pH ˜5. The solvent was removed again under reduced pressure and the residue was purified by flash chromatography over silica gel (hexane/ethyl acetate, 3:1, v/v) to give the desired thiophenol 38 (0.13 g, 45%) as a clear oil. 1H NMR (300 MHz, CDCl3) δ 1.43 (s, 9H), 1.49 (m, 2H) 1.59 (m, 2H), 2.57 (t, 2H), 3.12 (m, 2H), 3.38 (s, 1H), 4.47 (br s, 1H), 7.04 (d, 2H), 7.19 (d, 2H).
Reaction SMILES: C([N:8]1[C:16]2[C:11](=[CH:12][C:13]([C:17]#[N:18])=[CH:14][CH:15]=2)[C:10]([C@H:19]2[CH2:23][CH2:22][C@@H:21]([N:24]([CH2:26]C3C=CC=CC=3)[CH3:25])[CH2:20]2)=[CH:9]1)(OC(C)(C)C)=O.C=O.C(O)(=O)C>[Pd].C(Cl)Cl.CO>[CH3:25][N:24]([CH3:26])[C@@H:21]1[CH2:22][CH2:23][C@H:19]([C:10]2[C:11]3[C:16](=[CH:15][CH:14]=[C:13]([C:17]#[N:18])[CH:12]=3)[NH:8][CH:9]=2)[CH2:20]1
Reactant: CN(Cc1ccccc1)[C@@H]1CC[C@H](c2cn(C(=O)OC(C)(C)C)c3ccc(C#N)cc23)C1
Agent: [Pd]
Agent: C=O
Solvent: CO
Solvent: CC(=O)O
Solvent: ClCCl
Product: CN(C)[C@@H]1CC[C@H](c2c[nH]c3ccc(C#N)cc23)C1
Reaction time: 4 h
Yield: 39.5 %

Procedure:
A mixture of cis-1-BOC-3-[3-(N-benzyl-N-methylamino)-cyclopentyl]-1H-indole-5-carbonitrile (500 mg, 1.2 mMol), 10% palladium on carbon (200 mg), formaldehyde (1.2 mL of 30% aqueous, 12 mMol), and acetic acid (0.1 mL) in methylene chloride (10 mL) and methanol (20 mL) was stirred under hydrogen (balloon pressure) for 4 h. The mixture was filtered and the filtrate was concentrated in vacuo. The residue was dissolved in methylene chloride (10 mL) and trifluoroacetic acid (3 mL) and stirred for 18 h. The solution was concentrated in vacuo, and the residue was dissolved in ethyl acetate. The ethyl acetate solution was washed with aqueous NaHCO3, and then brine, and dried over magnesium sulfate. The solution was concentrated to give the crude product which was purified by preparative HPLC to give cis-3-(3-dimethylaminocyclopentyl)-1H-indole-5-carbonitrile (120 mg, 40%).
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH2:12][CH2:13][O:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][O:20][CH2:21][CH2:22][C:23]([OH:25])=O.C(Cl)(=O)C([Cl:29])=O>C(Cl)Cl.CN(C=O)C>[O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH2:12][CH2:13][O:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][O:20][CH2:21][CH2:22][C:23]([Cl:29])=[O:25]
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)CCOCCOCCOCCN1C(=O)c2ccccc2C1=O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)CCOCCOCCOCCN1C(=O)c2ccccc2C1=O

Procedure:
Into a 50-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a solution of 3-(2-(2-(2-(1,3-dioxoisoindolin-2-yl)ethoxy)ethoxy)ethoxy)propanoic acid (700 mg, 1.99 mmol, 1.00 equiv) in anhydrous DCM (30.0 mL), then oxalyl dichloride (0.7 mL) was added dropwise at room temperature. Two drops of anhydrous DMF were then added. The resulting solution was heated to reflux for 40 min. The solvent was removed under vacuum to yield 750 mg of 3-(2-(2-(2-(1,3-dioxoisoindolin-2-yl)ethoxy)ethoxy)ethoxy)propanoyl chloride as pale yellow oil, which was used directly for the next reaction step without further purification.
Reaction SMILES: [F:1][C:2]1[CH:24]=[CH:23][C:5]([C:6]([NH:8][C:9]2[CH:10]=[C:11]3[C:19](=[CH:20][CH:21]=2)[NH:18][C:17]2[CH2:16][CH2:15][CH:14]([NH2:22])[CH2:13][C:12]3=2)=[O:7])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:31][N:32]1[CH:36]=[C:35]([CH2:37][CH2:38]OS(C)(=O)=O)[CH:34]=[N:33]1>CN(C)C=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([NH:8][C:9]2[CH:10]=[C:11]3[C:19](=[CH:20][CH:21]=2)[NH:18][C:17]2[CH2:16][CH2:15][CH:14]([NH:22][CH2:38][CH2:37][C:35]4[CH:34]=[N:33][N:32]([CH3:31])[CH:36]=4)[CH2:13][C:12]3=2)=[O:7])=[CH:23][CH:24]=1
Reactant: NC1CCc2[nH]c3ccc(NC(=O)c4ccc(F)cc4)cc3c2C1
Reactant: Cn1cc(CCOS(C)(=O)=O)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cn1cc(CCNC2CCc3[nH]c4ccc(NC(=O)c5ccc(F)cc5)cc4c3C2)cn1
Temperature: 67.5 °C
Reaction time: 18 h
Yield: 33.6 %

Procedure:
To a mixture of 0.40 gm (1.24 mMol) 6-(4-fluorobenzoyl)amino-3-amino-1,2,3,4-tetrahydro-9H-carbazole and 0.257 gm (1.86 mMol) potassium carbonate in 8.0 mL dimethylform-amide were added 0.303 gm (1.49 mMol) 2-(1-methyl-1H-pyrazol-4-yl)-1-mesyloxyethane in 2.0 mL dimethylformamide and the mixture was stirred at 60-75° C. for 18 hours. An additional 0.101 gm (0.50 mMol) 2-(1-methyl-1H-pyrazol-4-yl)-1-mesyloxyethane were added and the reaction heated to 150° C. After 1.5 hours the reaction mixture was cooled to room temperature and was then partitioned between water and dichloromethane. The aqueous phase was extracted again with dichloromethane. The combined organic phases were dried over sodium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel chromatography, eluting with 95:5:0.5 dichloromethane:methanol:ammonium hydroxide. Fractions shown to contain product were combined and concentrated under reduced pressure to give 0.180 gm (33.6%) of 6-(4-fluorobenzoyl)amino-3-(2-(1-methyl-1H-pyrazol-4-yl)ethyl)amino-1,2,3,4-tetrahydro-9H-carbazole. The corresponding hydrochloride salt was prepared to provide the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C@H:10](OS(C)(=O)=O)/[CH:11]=[CH:12]/[C:13]([O:15][CH3:16])=[O:14])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(OC(N[C@@H]([CH2:50][C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1)[C@@H](OS(C)(=O)=O)/C=C/C(OC)=O)=O)(C)(C)C.CCCCCC>C(OCC)(=O)C>[CH2:50]([C@@H:12](/[CH:11]=[CH:10]/[C@@H:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:13]([O:15][CH3:16])=[O:14])[C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1
Reactant: COC(=O)/C=C/[C@@H](OS(C)(=O)=O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Reactant: COC(=O)/C=C/[C@H](OS(C)(=O)=O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: COC(=O)[C@H](/C=C/[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C)Cc1ccccc1
Yield: 90 %

Procedure:
Using the procedure of Example 8 but replacing the resultant compound of Example 7 with the resultant compound of Example 14 provided, after silica gel chromatography using 6:1 hexane:ethyl acetate, the desired compound (m.p. 84°-85° C., R 0.73, 2:1 hexane:ethyl acetate) in 90% yield. 1H NMR (CDCl3) 1.41 s, 9 H), 2.7-2.8 (m, 3 H), 3.01 (dd, J=14, 8 Hz, 1 H), 3.26 (q, J=7 Hz, 1 H), 3.61 (s, 3 H), 4.37 (m, 2 H), 5.42 (br d, 1 H), 5.56 (dd, J=15, 8 Hz, 1 H), 7.03-7.12 (m, 4 H), 7.2-7.3 (m, 6 H).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:15]2[CH:24]=[CH:23][C:18]([C:19]([O:21]C)=[O:20])=[C:17]([F:25])[CH:16]=2)=[N:4][C:5]([C:8]2[CH:9]=[N:10][N:11]([CH2:13][CH3:14])[CH:12]=2)=[CH:6][N:7]=1.[Li+].[OH-].Cl>CO.C1COCC1>[NH2:1][C:2]1[C:3]([C:15]2[CH:24]=[CH:23][C:18]([C:19]([OH:21])=[O:20])=[C:17]([F:25])[CH:16]=2)=[N:4][C:5]([C:8]2[CH:9]=[N:10][N:11]([CH2:13][CH3:14])[CH:12]=2)=[CH:6][N:7]=1
Reactant: CCn1cc(-c2cnc(N)c(-c3ccc(C(=O)OC)c(F)c3)n2)cn1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCn1cc(-c2cnc(N)c(-c3ccc(C(=O)O)c(F)c3)n2)cn1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To methyl 4-(3-amino-6-(1-ethyl-1H-pyrazol-4-yl)pyrazin-2-yl)-2-fluorobenzoate (25 mg, 0.073 mmol) in MeOH (1 mL) and THF (2 mL) was added 1 M LiOH (0.220 mL, 0.2 20 mmol). The reaction mixture was stirred at room temperature for 4 h. The pH of reaction mixture was adjusted to ˜4 by 2 N HCl. The product was extracted with ethyl acetate twice. The combined organics extracts were washed with brine, dried over sodium sulfate, filtered, and evaporated. The residue was proceeded to next step without further purification. LCMS (m/z): 328.1 (MH+), 0.607 min.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C([O-])([O-])=O.[K+].[K+].[F:13][C:14]1[CH:21]=[C:20](F)[CH:19]=[CH:18][C:15]=1[C:16]#[N:17]>CC#N.CCOC(C)=O>[F:13][C:14]1[CH:21]=[C:20]([N:1]2[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]2)[CH:19]=[CH:18][C:15]=1[C:16]#[N:17]
Reactant: C1CNCCN1
Reactant: N#Cc1ccc(F)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: N#Cc1ccc(N2CCNCC2)cc1F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Piperazine (20.0 g, 232.3 mmol) and K2CO3 (16.0 g, 118.5 mmol) are dissolved in CH3CN (85 ml). 2,4-Difluoro-benzonitrile (8.5 g, 61.1 mmol) is added and the mixture is stirred for 2 h at rt, then diluted with AcOEt and washed with water. The organic layer is separated, dried over Na2SO4 and evaporated. Excess piperazine is removed by MPLC (100 g silica gel, eluent CH2Cl2:MeOH 85:15). A second chromatographic purification (300 g silica gel, eluent toluene:EtOH:AcOH 4:4:1) yields the acetate salt of 2-fluoro-4-(piperazin-1-yl)-benzonitrile that is crystallized from AcOEt, filtered off and washed with ether. The free base is isolated by extraction with sat. aq. Na2CO3 solution/AcOEt.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH2:11][C:12]3[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=3)=[N:9][N:10]=2)[N:7]=1.[NH:19]1[CH:23]=[CH:22][N:21]=[CH:20]1>>[N:19]1([C:2]2[CH:3]=[CH:4][C:5]3[N:6]([C:8]([CH2:11][C:12]4[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=4)=[N:9][N:10]=3)[N:7]=2)[CH:23]=[CH:22][N:21]=[CH:20]1
Reactant: c1c[nH]cn1
Reactant: Oc1ccc(Cc2nnc3ccc(Cl)nn23)cc1
Product: Oc1ccc(Cc2nnc3ccc(-n4ccnc4)nn23)cc1

Procedure:
The title compound was prepared from 4-(6-Chloro-[1,2,4]triazolo[4,3-b]pyridazin-3-ylmethyl) -phenol (Example 45: step a) and imidazole as described in Example 43. 1H-NMR (CD3OD): δ 9.78 (1H, t, J=1.3 Hz), 8.54 (1H, d, J=9.9 Hz), 8.38 (1H, t, J=1.8 Hz), 7.97 (1H, d, J=9.9 Hz), 7.83 (1H, dd, J=1.3, 1.8 Hz), 7.23 (2H, d, J=8.6 Hz), 6.72 (2H, d, J=8.6 Hz), 4.53 (s, 2H). ESI-MS (m/z): Calcd. for C15H12N6O: 292.1; found: 293.2 (M+H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[NH:7][S:8](=[O:25])(=[O:24])[NH:9][CH2:10][CH2:11][O:12][N:13]1C(=O)C2C(=CC=CC=2)C1=O)([CH3:4])([CH3:3])[CH3:2].C(Cl)Cl.O.NN>C(O)C>[NH2:13][O:12][CH2:11][CH2:10][NH:9][S:8]([NH:7][C:6](=[O:26])[O:5][C:1]([CH3:3])([CH3:2])[CH3:4])(=[O:25])=[O:24]
Reactant: CC(C)(C)OC(=O)NS(=O)(=O)NCCON1C(=O)c2ccccc2C1=O
Agent: NN
Solvent: O
Solvent: ClCCl
Solvent: CCO
Product: CC(C)(C)OC(=O)NS(=O)(=O)NCCON
Temperature: 25 °C
Reaction time: 8 h
Yield: 43.8 %

Procedure:
To a mixture of tert-butyl({2-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)oxy]ethyl}sulfamoyl)carbamate 77 (0.62 g, 1.61 mmol) in a solution of DCM (10 mL) and ethanol (2 mL) was added hydrazine hydrate (0.092 mL, 1.61 mmol) at room temperature. The mixture was stirred at room temperature overnight, filtered and concentrated to provide a residue which was subjected to chromatography to give 78 (0.18 g, 44%) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([CH2:18][C:19]([CH3:25])([CH3:24])[C:20]([O:22]C)=[O:21])=[C:14]([CH3:17])[CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.Cl>[OH-].[Na+].CO.CS(C)=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([CH2:18][C:19]([CH3:25])([CH3:24])[C:20]([OH:22])=[O:21])=[C:14]([CH3:17])[CH:15]=3)[CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: COC(=O)C(C)(C)Cc1cc2cnn(-c3ccc(F)cc3)c2cc1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CS(C)=O
Product: Cc1cc2c(cnn2-c2ccc(F)cc2)cc1CC(C)(C)C(=O)O
Yield: 77.7 %

Procedure:
Methyl 3-(1-(4-fluorophenyl)-6-methyl-1H-indazol-5-yl)-2,2-dimethylpropanoate (121 mg, 0.355 mmol) was heated to 100 C overnight in a mixture of 2 M NaOH/MeOH/DMSO (1:1:1). The next day, the reaction was cooled, acidified to pH 5 with HCl and extracted 2×EtOAc. The organic layers were washed with water×2, dried over MgSO4, filtered, and concentrated in vacuo to give 90 mg (80% yield) of acid 3-(1-(4-fluorophenyl)-6-methyl-1H-indazol-5-yl)-2,2-dimethylpropanoic acid. MS found: (M+H)+=327.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:10][F:11])[C:5]([CH:8]=[O:9])=[N:6][CH:7]=1.[OH-:12].[Na+]>C1COCC1.O>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:10][F:11])[C:5]([C:8]([OH:12])=[O:9])=[N:6][CH:7]=1
Reactant: [OH-]
Reactant: O=Cc1ncc(Cl)cc1CF
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1ncc(Cl)cc1CF
Reaction time: 0.17 h

Procedure:
To a solution of 5-chloro-3-(fluoromethyl)picolinaldehyde (55 mg, 0.32 mmol) in THF (2 mL) and water (4 mL) was added solid NaOH (13 mg) at 0° C. After 10 min, KMNO4 (100 mg) was added in one portion. After additional 10 min, the reaction mixture was filtered through a pad of celite. The celite was washed with 1 M HCl (10 mL), water and EtOAc. The phases were separated and the aqueous phase was extracted with EtOAc. The combined organic layers were dried over MgSO4 and the filtrate was concentrated under reduced pressure. The title compound was obtained as a yellow residue and taken onto the next step without further purification. LC/MS m/z=172.1 [M+H]+.
Reaction SMILES: [C:1]([C:3]1([NH:6][C:7]([C@@H:9]2[CH2:13][C@@H:12]([S:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[O:21][CH3:22])[CH2:11][N:10]2C(OC(C)(C)C)=O)=[O:8])[CH2:5][CH2:4]1)#[N:2]>C(O)=O>[C:1]([C:3]1([NH:6][C:7]([C@@H:9]2[CH2:13][C@@H:12]([S:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[O:21][CH3:22])[CH2:11][NH:10]2)=[O:8])[CH2:5][CH2:4]1)#[N:2]
Reactant: COc1ccccc1S[C@@H]1C[C@@H](C(=O)NC2(C#N)CC2)N(C(=O)OC(C)(C)C)C1
Solvent: O=CO
Product: COc1ccccc1S[C@H]1CN[C@H](C(=O)NC2(C#N)CC2)C1
Yield: 79 %

Procedure:
The reaction of the amide 11C with formic acid yielded (2S,4R)-N-(1-cyanocyclopropyl)-4-(2-methoxyphenylthio)pyrrolidine-2-carboxamide as a light yellow viscous oil (79%). MS ISP (m/e): 318.2 (100) [(M+H)]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([S:20]([NH2:23])(=[O:22])=[O:21])[CH:5]=[CH:6][C:7]=1[O:8][C@H:9]1[CH2:13][CH2:12][CH2:11][C@@H:10]1[C:14]1[N:18]([CH3:19])[N:17]=[CH:16][CH:15]=1.Br[C:25]1[S:26][CH:27]=[CH:28][N:29]=1.CN[C@@H]1CCCC[C@H]1NC.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.[Cu](I)I>[F:1][C:2]1[CH:3]=[C:4]([S:20]([NH:23][C:25]2[S:26][CH:27]=[CH:28][N:29]=2)(=[O:21])=[O:22])[CH:5]=[CH:6][C:7]=1[O:8][C@H:9]1[CH2:13][CH2:12][CH2:11][C@@H:10]1[C:14]1[N:18]([CH3:19])[N:17]=[CH:16][CH:15]=1
Reactant: Brc1nccs1
Reactant: Cn1nccc1[C@H]1CCC[C@@H]1Oc1ccc(S(N)(=O)=O)cc1F
Agent: I[Cu]I
Agent: CN[C@@H]1CCCC[C@H]1NC
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: Cn1nccc1[C@H]1CCC[C@@H]1Oc1ccc(S(=O)(=O)Nc2nccs2)cc1F
Yield: 84.5 %

Procedure:
A solution of the 3-fluoro-4-{[(1S*,2R*)-2-(1-methyl-1H-pyrazol-5-yl)cyclopentyl]oxy}benzenesulfonamide (0.07 g, 0.21 mmol) prepared in Example 16c, 2-bromothiazole (0.07 g, 0.41 mmol), copper iodide (0.01 g, 0.04 mmol), trans-N,N′-dimethylcyclohexane-1,2-diamine (0.01 g, 0.09 mmol) and cesium carbonate (0.20 g, 0.62 mmol) in DMF (2.0 mL) was stirred at 120° C. for 20 hours under the nitrogen atmosphere. After allowing to cool, the reaction solution was vacuum concentrated, and the residue was purified with HPLC to yield the title compound (75 mg, 86%) as a colorless solid.
Reaction SMILES: CON(C)[C:4](=[O:18])[C:5]1[CH:10]=[C:9]([CH:11]2[O:15][CH2:14][CH2:13][O:12]2)[CH:8]=[CH:7][C:6]=1[O:16][CH3:17].[CH3:20][Mg]I.CCOCC.[Cl-].[NH4+]>O1CCCC1>[O:15]1[CH2:14][CH2:13][O:12][CH:11]1[C:9]1[CH:8]=[CH:7][C:6]([O:16][CH3:17])=[C:5]([C:4](=[O:18])[CH3:20])[CH:10]=1
Reactant: C[Mg]I
Reactant: COc1ccc(C2OCCO2)cc1C(=O)N(C)OC
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: COc1ccc(C2OCCO2)cc1C(C)=O
Yield: 79 %

Procedure:
N-Methoxy-N-methyl-5-(1,3-dioxolan-2-yl)-2-methoxybenzamide (6.60 g, 24.7 mmol) and dehydrated tetrahydrofuran (200 mL) were mixed, and under an atmosphere of argon, the mixture was cooled using dry ice-acetone bath, and 3.0 mol/L solution of methyl magnesium iodide in ether (24.7 mL, 74.1 mmol) was added dropwise slowly under stirring. After completion of the dropwise addition, the mixture was stirred for 1.5 hours under cooling with ice. A saturated aqueous solution of ammonium chloride (200 mL) was added dropwise thereto under cooling with ice and stirring. After separated the organic layer, the aqueous layerwas extracted with ethyl acetate. Respective organic layers were combined, washed with water and saturated brine in sequence, then dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel chromatography (eluate n-hexane:ethyl acetate=4:1 v/v) to obtain 4.31 g (79%) of the title compound as colorless crystals.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[C:7]([C:9]1[CH:10]=[C:11]([CH:15]([CH2:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]#[N:29])=[CH:24][CH:23]=2)[CH2:16][C:17]([OH:19])=O)[CH:12]=[CH:13][CH:14]=1)#[N:8].[CH3:30][NH2:31].Cl>C(Cl)Cl.O.C(OCC)(=O)C>[C:28]([C:25]1[CH:24]=[CH:23][C:22]([CH2:21][CH2:20][CH:15]([C:11]2[CH:12]=[CH:13][CH:14]=[C:9]([C:7]#[N:8])[CH:10]=2)[CH2:16][C:17]([NH:31][CH3:30])=[O:19])=[CH:27][CH:26]=1)#[N:29]
Reactant: N#Cc1ccc(CCC(CC(=O)O)c2cccc(C#N)c2)cc1
Reactant: CN
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: O
Product: CNC(=O)CC(CCc1ccc(C#N)cc1)c1cccc(C#N)c1
Reaction time: 2 h
Yield: 46 %

Procedure:
Part A. Oxalyl chloride was added to a solution of 3-(3-cyanophenyl)-5-(4-cyanophenyl)pentanoic acid (0.25 gm, 0.82 mmol) in 10 mLs methylene chloride under a nitrogen atmosphere at ambient temperature. The reaction was stirred for 2 hrs and was concentrated in vacuo to give a semi solid residue. The residue was taken up in 5 mLs methylene chloride and 40% methyl amine in water (5 mLs) was added. The reaction was stirred vigorously for 2 hrs and then was partioned between 1N HCl and ethyl acetate. The organic layer was washed with water, brine dried over magnesium sulfate and concentrated to give the crude product as a semisolid. The residue was purified by flash chromatography on silica gel (100 mLs) eluting methylene chloride:ethyl acetate (v:v, 80:20) to give 4-(cyano)-beta-(3-cyanophenyl)-N-methylbenzenepentanamide as a semisolid 0.120 gm (46%) MS 335(M+NH4) 1H NMR (CDCl3): 7.6-7.4(m, 6H), 7.17(d, 2H), 5.3(m, 1H), 3.27(m, 1H), 2.67(d, 2H), 2.55-2.35(m, 4H), 2.07(m, 1H), 1.95(m, 1H).
Reaction SMILES: C([O:8][C:9](=[O:42])[CH2:10][CH2:11][C@H:12]([NH:24][C:25](=[O:41])[C@@H:26]([NH:31][C:32](=[O:40])[C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([CH3:39])[CH:34]=1)[CH2:27][CH:28]([CH3:30])[CH3:29])[CH2:13][N:14]1[C:22]2[C:17](=[CH:18][C:19]([F:23])=[CH:20][CH:21]=2)[CH2:16][CH2:15]1)C1C=CC=CC=1.[H][H]>[Pd].CO>[F:23][C:19]1[CH:18]=[C:17]2[C:22](=[CH:21][CH:20]=1)[N:14]([CH2:13][C@@H:12]([NH:24][C:25](=[O:41])[C@@H:26]([NH:31][C:32](=[O:40])[C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([CH3:39])[CH:34]=1)[CH2:27][CH:28]([CH3:30])[CH3:29])[CH2:11][CH2:10][C:9]([OH:42])=[O:8])[CH2:15][CH2:16]2
Reactant: Cc1cccc(C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(=O)OCc2ccccc2)CN2CCc3cc(F)ccc32)c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: Cc1cccc(C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(=O)O)CN2CCc3cc(F)ccc32)c1
Reaction time: 8 h

Procedure:
The title compound of Example 42 (200 mg, 0.348 mmol) and 10% Pd/C were treated with MeOH (2 mL) and the atmosphere in the reaction was switched to hydrogen. After stirring overnight, the atmosphere in the reaction was switched back to nitrogen and the reaction was filtered through celite. Removal of solvent and drying afforded a white solid (168 mg, 94); HPLC-MS calcd. for C27H34FN3O4 (M+H+) 484.3, found 484.4.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8].[Cl-]>CO>[NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][C@H:2]1[C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8]
Reactant: CC(C)(C)OC(=O)c1cnccn1
Agent: [Cl-]
Solvent: CO
Product: CC(C)(C)OC(=O)[C@@H]1CNCCN1

Procedure:
Analogously to Example 4, 0.52 g (2.85 mmol) of tert-butyl pyrazinecarboxylate (prepared according to Example 2), 25.3 mg (54 μmol) of bicyclo[2.2.1 ]hepta-2,5-dienerhodium(I) chloride dimer and 61.5 mg (113.3 μmol) of 1-[1(R)-(di-tert-butylphosphino)ethyl]-2(S)- (diphenylphosphino)ferrocene were hydrogenated for 20 hours in 10 ml of methanol at 70° C. and 50 bar. A conversion of 67 percent was determined by NMR. The ee value was determined by hydrolyzing the ester (see Example 8).