Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:8][C:9]([C:11]1([N:19]([CH:37]=[CH:38][C:39]([O:41][CH2:42][CH3:43])=[O:40])[S:20]([C:23]2[CH:28]=[CH:27][C:26]([O:29][C:30]3[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=3)=[CH:25][CH:24]=2)(=[O:22])=[O:21])[CH2:17][CH:16]2[O:18][CH:13]([CH2:14][CH2:15]2)[CH2:12]1)=[O:10])C1C=CC=CC=1.[H][H]>C(O)C.O>[CH2:42]([O:41][C:39]([CH2:38][CH2:37][N:19]([S:20]([C:23]1[CH:24]=[CH:25][C:26]([O:29][C:30]2[CH:31]=[CH:32][C:33]([F:36])=[CH:34][CH:35]=2)=[CH:27][CH:28]=1)(=[O:22])=[O:21])[C:11]1([C:9]([OH:10])=[O:8])[CH2:17][CH:16]2[O:18][CH:13]([CH2:14][CH2:15]2)[CH2:12]1)=[O:40])[CH3:43]
Reactant: CCOC(=O)C=CN(C1(C(=O)OCc2ccccc2)CC2CCC(C1)O2)S(=O)(=O)c1ccc(Oc2ccc(F)cc2)cc1
Reactant: [H][H]
Solvent: CCO
Solvent: O
Product: CCOC(=O)CCN(C1(C(=O)O)CC2CCC(C1)O2)S(=O)(=O)c1ccc(Oc2ccc(F)cc2)cc1

Procedure:
A solution of (4.4 mmol) of the product of step D in 25 mL of ethanol is treated with 2.5 g of 50% water wet 10% palladium on carbon catalyst and shaken under 53 psi of hydrogen for 48 hours. The catalyst is removed by filtration and washed with ethanol (4×25 mL). The filtrate and washings are combined and concentrated under vacuum to crude product.
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:28])[N:4]([C:20]2[C:25]([F:26])=[CH:24][CH:23]=[CH:22][C:21]=2[F:27])[C:5]([CH3:19])=[C:6](I)[C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[F:17].[CH2:29]([Sn](CCCC)(CCCC)C=C)[CH2:30]CC.C(#N)C.O>C1COCC1.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>[Br:1][C:2]1[C:3](=[O:28])[N:4]([C:20]2[C:25]([F:26])=[CH:24][CH:23]=[CH:22][C:21]=2[F:27])[C:5]([CH3:19])=[C:6]([CH:29]=[CH2:30])[C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[F:17]
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Reactant: Cc1c(I)c(OCc2ccc(F)cc2F)c(Br)c(=O)n1-c1c(F)cccc1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Solvent: C1CCOC1
Solvent: O
Product: C=Cc1c(OCc2ccc(F)cc2F)c(Br)c(=O)n(-c2c(F)cccc2F)c1C
Temperature: 68 °C
Reaction time: 12 h

Procedure:
To a room temperature solution of 3-bromo-4-[(2,4-difluorobenzyl)oxy]-1-(2,6-difluorophenyl)-5-iodo-6-methylpyridin-2(1H)-one (1.00 g, 1.76 mmol) in anhydrous THF (12 mL) was added, sequentially, tributyl(vinyl)tin (1.21 g, 3.81 mmol) and tetrakis(triphenylphosphine)palladium (236 mg, 0.204 mmol) under an argon stream. The reaction vessel was then equipped with a reflux condenser and the reaction system purged with an argon flow. The resulting yellow solution was heated to 68° C. and stirred under a positive pressure of argon for 12.0 hours until complete disappearance of starting material by LCMS analysis. The reaction mixture was concentrated in vacuo and the resulting dark residue was subjected to SiO2 chromatography with ethyl acetate/hexanes (3:7) to furnish a reddish solid. 1H NMR (400 MHz, CDCl3) δ 7.62 (app q, J=7.8 Hz, 1H), 7.45 (app tt, J=8.4, 6.2, 1H), 7.09 (app t, J=8.8 Hz, 2H), 6.90 (app t, J=8.0 Hz, 1H), 6.83 (app dt, J=6.8, 2.5 Hz, 1H), 6.51 (dd, J=17.7, 11.4 Hz, 1H), 5.53 (dd, J=11.4, 1.5 Hz, 1H), 5.41 (dd, J=17.8, 1.5 Hz, 1H), 5.09 (br s, 2H), 2.09 (s, 3H); LC/MS C-18 column, tr=3.20 minutes (5 to 95% acetonitrile/water over 5 minutes at 1 ml/min with detection 254 nm, at 50° C.). ES-MS m/z 468 (M+H). ES-HRMS m/z 468.0210 (M+H calcd for C21H15BrF4NO2 requires 468.0217).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[S:10][CH:9]=[N:8][C:7]=2[C:11]=1[N+:12]([O-])=O.[H][H]>CO.[Pd]>[CH3:1][O:2][C:3]1[C:11]([NH2:12])=[C:7]2[N:8]=[CH:9][S:10][C:6]2=[CH:5][CH:4]=1
Reactant: [H][H]
Reactant: COc1ccc2scnc2c1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Product: COc1ccc2scnc2c1N
Yield: 39.3 %

Procedure:
730 mg (3.5 mmol) of 5-methoxy-4-nitro-1,3-benzothiazole is solubilized in 50 ml of methanol and 73 mg (10%) of palladium on carbon is added to the reaction mixture which is maintained under stirring under 2.5 bars of hydrogen for 18 hours. The catalyst is filtered out, then the solvent is evaporated off under reduced pressure. 248 mg (yield=40%) of 5-methoxy-1,3-benzothiazol-4-amine is obtained and used in the following stage without other purification.
Reaction SMILES: [CH2:1]([C:7]1[CH:8]=[C:9]([C:19]2[C:20]3[NH:24][C:23]([CH:25]=[C:26]4[N:60]=[C:29]([C:30]([C:42]5[CH:47]=[C:46]([CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH3:53])[CH:45]=[C:44]([CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH3:59])[CH:43]=5)=[C:31]5[NH:41][C:34](=[CH:35][C:36]6[CH:37]=[CH:38][C:39]=2[N:40]=6)[CH:33]=[CH:32]5)[CH:28]=[CH:27]4)=[CH:22][CH:21]=3)[CH:10]=[C:11]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH:12]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[Br:61]N1C(=O)CCC1=O>C(Cl)(Cl)Cl>[CH2:13]([C:11]1[CH:10]=[C:9]([C:19]2[C:20]3[NH:24][C:23]([CH:25]=[C:26]4[N:60]=[C:29]([C:30]([C:42]5[CH:43]=[C:44]([CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH3:59])[CH:45]=[C:46]([CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH3:53])[CH:47]=5)=[C:31]5[NH:41][C:34](=[C:35]([Br:61])[C:36]6[CH:37]=[CH:38][C:39]=2[N:40]=6)[CH:33]=[CH:32]5)[CH:28]=[CH:27]4)=[CH:22][CH:21]=3)[CH:8]=[C:7]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])[CH:12]=1)[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCc1cc(CCCCCC)cc(-c2c3nc(cc4ccc([nH]4)c(-c4cc(CCCCCC)cc(CCCCCC)c4)c4nc(cc5ccc2[nH]5)C=C4)C=C3)c1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)Cl
Product: CCCCCCc1cc(CCCCCC)cc(-c2c3nc(c(Br)c4ccc([nH]4)c(-c4cc(CCCCCC)cc(CCCCCC)c4)c4nc(cc5ccc2[nH]5)C=C4)C=C3)c1
Reaction time: 0.25 h
Yield: 101.7 %

Procedure:
To a flask containing 1.00 g (1.25 mmol) of 5,15-bis(3,5-dihexylphenyl)porphyrin and 200 mL of chloroform was added 223 mg (1.25 mmol) of N-bromosuccinimide (NBS). After stirring the reaction mixture for 15 min, TLC (hexanes/methylene chloride, 2:1) indicated that the product was present together with lesser amounts of the starting material and the dibrominated porphyrin. The reaction mixture was concentrated to a viscous oil and this material was chromatographed on silica gel (hexanes/methylene chloride, 4:1/3:1) to give 1.116 g (68% yield) of the desired product. 1H NMR (400 MHz) δ−2.97 (2H, s, —NH), 0.93 (12H, t, J=7 Hz, —CH3), 1.36-1.44 (16H, m, —CH2—), 1.48-1.56 (8H, m, —CH2—), 1.83-1.91 (8H, m, —CH2—), 2.89 (8H, t, J=8 Hz, —CH2—), 7.43 (2H, s, Ar—H), 7.85 (4H, s, Ar—H), 8.99 (2H, d, J=4 Hz, β-H), 9.00 (2H, d, J=4 Hz, β-H), 9.28 (2H, d, J=4 Hz, β-H), 9.73 (2H, d, J=5 Hz, β-H), 10.16 (1H, s, meso-H); MALDI-TOF-MS m/z calcd. for C56H69N4Br 876.5, obsd. 876.4; UV/vis (CH2Cl2) 416, 512, 547, 588, 645 (nm).
Reaction SMILES: [CH:1]([N:4]1[CH:12]=[N:11][C:10]2[C:5]1=[N:6][C:7]([CH:20]1[CH2:25][CH2:24][CH2:23][NH:22][CH2:21]1)=[N:8][C:9]=2[NH:13][C:14]1[CH:15]=[N:16][N:17]([CH3:19])[CH:18]=1)([CH3:3])[CH3:2].C([O-])(O)=O.[Na+].[C:31](Cl)(=[O:34])[CH:32]=[CH2:33]>C(OCC)(=O)C>[CH:1]([N:4]1[CH:12]=[N:11][C:10]2[C:5]1=[N:6][C:7]([CH:20]1[CH2:25][CH2:24][CH2:23][N:22]([C:31](=[O:34])[CH:32]=[CH2:33])[CH2:21]1)=[N:8][C:9]=2[NH:13][C:14]1[CH:15]=[N:16][N:17]([CH3:19])[CH:18]=1)([CH3:3])[CH3:2]
Reactant: C=CC(=O)Cl
Reactant: CC(C)n1cnc2c(Nc3cnn(C)c3)nc(C3CCCNC3)nc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: C=CC(=O)N1CCCC(c2nc(Nc3cnn(C)c3)c3ncn(C(C)C)c3n2)C1
Reaction time: 0.17 h
Yield: 16 %

Procedure:
To 9-isopropyl-N-(1-methyl-1H-pyrazol-4-yl)-2-(piperidin-3-yl)-9H-purin-6-amine from the previous reaction was added sat. aq. NaHCO3 (12 mL) and ethyl acetate (30 mL). The mixture was stirred for 10 min, and acryloyl chloride (148 μL, 1.8 mmol) was added and stirred at ambient temperature for 15 min. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate (30 mL). The combined organics were dried over Na2SO4 and evaporated to give a foamy solid (600 mg) that was subjected to chiral SFC purification to separate the two enantiomers (Chiralcel OJ-H 4.6×250 mm column, 20% EtOH, 140 bar, 3.0 mL/min). Peak 1(+) eluted at 3.18 min. Peak 2 (−) as the title product eluted at 5.03 min) (86.4 mg, ˜98% ee, 16% yield in 3 steps). [α]D22=−76.0° (c 0.14, EtOH). 1H NMR (700 MHz, DMSO-17 mm) δ ppm 9.87 (br. s., 1 H) 8.28 (br. s., 1 H) 7.96-8.13 (m, 1 H) 7.74 (d, J=7.26 Hz, 1 H) 6.76-6.91 (m, 1 H) 5.99-6.17 (m, 1 H) 5.53-5.75 (m, 1 H) 4.69-4.84 (m, 2 H) 4.03-4.30 (m, 2 H) 3.84 (s, 3 H) 2.74-3.02 (m, 2 H) 2.11-2.28 (m, 1 H) 1.75-2.01 (m, 2 H) 1.54 (d, J=2.64 Hz, 7 H). m/z (APCI+) for C20H26N8O 395.1 (M+H)+.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:22]([CH2:23][C:24]#[C:25][CH3:26])[C:21]3[C:20](=[O:27])[NH:19][C:18](=[O:28])[N:17]([CH2:29][C:30]([O:32][CH3:33])=[O:31])[C:16]=3[N:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[F:34][C:35]([F:40])([F:39])[C:36]([OH:38])=[O:37]>>[F:34][C:35]([F:40])([F:39])[C:36]([OH:38])=[O:37].[CH3:33][O:32][C:30](=[O:31])[CH2:29][N:17]1[C:16]2[N:15]=[C:14]([N:11]3[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]3)[N:22]([CH2:23][C:24]#[C:25][CH3:26])[C:21]=2[C:20](=[O:27])[NH:19][C:18]1=[O:28]
Reactant: CC#CCn1c(N2CCN(C(=O)OC(C)(C)C)CC2)nc2c1c(=O)[nH]c(=O)n2CC(=O)OC
Solvent: O=C(O)C(F)(F)F
Product: CC#CCn1c(N2CCNCC2)nc2c1c(=O)[nH]c(=O)n2CC(=O)OC
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
4-[7-(2-Butynyl)-3-methoxycarbonylmethyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]piperazine-1-carboxylic acid tert-butyl ester (13 mg) was dissolved in trifluoroacetic acid (0.5 ml), and the solution was stirred at room temperature for 30 minutes. After the solvent was removed by distillation, a half of the residue was purified by HPLC with a reversed phase system column using water-acetonitrile-trifluoroacetic acid system as elution solvent to give 2.4 mg of the title compound.
Reaction SMILES: [NH:1]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][CH2:4][C:2]1=[O:3].[OH-].[K+].[CH3:14]I>CS(C)=O.C(Cl)(Cl)Cl>[CH3:14][N:1]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][CH2:4][C:2]1=[O:3]
Reactant: CI
Reactant: O=C1CCc2ccccc2N1
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: ClC(Cl)Cl
Product: CN1C(=O)CCc2ccccc21
Temperature: 25 °C
Reaction time: 4.5 h

Procedure:
A solution of 3,4-dihydrocarbostyril (20 g) in DMSO (100 ml) is added to a suspension of KOH (31.4 g) in DMSO (50 ml). Methyl iodide (39.7 g) in DMSO (25 ml) is added to the reaction mixture and the mixture is stirred under an atmosphere of N2 at RT. After 2 hours a second portion of methyl iodide (20 g) is added and after 3 hours a third portion of methyl iodide (20 g) is added and stirring continued for 4.5 hours. The reaction mixture is diluted with chloroform (200 ml), quenched with sat'd aq. NH4Cl, separated, extracted with chloroform, washed with H2O and dried. The organic extracts are filtered and concentrated in vacuo affording the desired product as an oil.
Reaction SMILES: [F:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][O:7][CH2:8][C@@H:9]2[N:14]3[C:15]4[C:24]5[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=5)[N:18]=[CH:17][C:16]=4[N:25]=[C:13]3[CH2:12][O:11][CH2:10]2)=[CH:4][CH:3]=1.C1C=C(Cl)C=C(C(OO)=[O:36])C=1.C([O-])([O-])=O.[Na+].[Na+]>C(Cl)(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][O:7][CH2:8][C@@H:9]2[N:14]3[C:15]4[C:24]5[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=5)[N+:18]([O-:36])=[CH:17][C:16]=4[N:25]=[C:13]3[CH2:12][O:11][CH2:10]2)=[CH:26][CH:27]=1
Reactant: Fc1ccc(COC[C@H]2COCc3nc4cnc5ccccc5c4n32)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: [O-][n+]1cc2nc3n(c2c2ccccc21)[C@@H](COCc1ccc(F)cc1)COC3
Reaction time: 8 h
Yield: 100 %

Procedure:
(11S)-11-{[(4-Fluorobenzyl)oxy]methyl}-10,11-dihydro-8H-[1,4]oxazino[4′,3′:1,2]imidazo[4,5-c]quinoline (700 mg, 1.93 mmol) was dissolved in 25 mL of CHCl3 and treated with MCPBA (570 mg, 77% max). The reaction was allowed to stir overnight and then 10 mL of aqueous 2% Na2CO3 solution was added and the layers were separated. The aqueous portion was extracted with CHCl3 (3×20 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to afford (11S)-11-{[(4-fluorobenzyl)oxy]methyl}-10,11-dihydro-8H-[1,4]oxazino[4′,3′:1,2]imidazo[4,5-c]quinoline 5-oxide (732 mg) as an orange foam.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[N:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]3=[N:10][C:9]=2[C:17]2[CH:18]=[C:19]([CH:31]=[CH:32][CH:33]=2)[C:20]([NH:22][C:23]2[C:28]([F:29])=[CH:27][CH:26]=[CH:25][C:24]=2[F:30])=[O:21])[CH:5]=[CH:4][N:3]=1.[NH2:34][C:35]1[CH:40]=[CH:39][C:38]([N:41]2[CH2:46][CH2:45][CH:44]([N:47]([CH3:49])[CH3:48])[CH2:43][CH2:42]2)=[CH:37][C:36]=1[O:50][CH3:51].C1(C)C=CC(S(O)(=O)=O)=CC=1>CC(O)C.C(Cl)Cl>[F:30][C:24]1[CH:25]=[CH:26][CH:27]=[C:28]([F:29])[C:23]=1[NH:22][C:20](=[O:21])[C:19]1[CH:31]=[CH:32][CH:33]=[C:17]([C:9]2[N:10]=[C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][N:12]3[C:8]=2[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:34][C:35]3[CH:40]=[CH:39][C:38]([N:41]4[CH2:46][CH2:45][CH:44]([N:47]([CH3:48])[CH3:49])[CH2:43][CH2:42]4)=[CH:37][C:36]=3[O:50][CH3:51])[N:7]=2)[CH:18]=1
Reactant: O=C(Nc1c(F)cccc1F)c1cccc(-c2nc3ccccn3c2-c2ccnc(Cl)n2)c1
Reactant: COc1cc(N2CCC(N(C)C)CC2)ccc1N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)O
Solvent: ClCCl
Product: COc1cc(N2CCC(N(C)C)CC2)ccc1Nc1nccc(-c2c(-c3cccc(C(=O)Nc4c(F)cccc4F)c3)nc3ccccn23)n1
Yield: 77.9 %

Procedure:
3-[3-(2-chloro-4-pyrimidinyl)imidazo[1,2-a]pyridin-2-yl]-N-(2,6-difluorophenyl)-benzamide (Intermediate Example 1) (140 mg, 0.30 mmol), 1-[4-amino-3-(methyloxy)phenyl]-N,N-dimethyl-4-piperidinamine (67 mg, 0.27 mmol) and p-toluenesulfonic acid (140 mg, 0.71 mmol) in iPrOH was heated in the microwave at 180° C. for 13.5 min. The mixture was dissolved in DCM and concentrated onto silica gel. The crude material was purified by flash column chromatography to give the title compound (142 mg, 70%). 1H NMR (400 MHz, DMSO-d6) δ 10.23 (s, 1H), 9.40 (s, 1H), 8.45 (s, 1H), 8.33 (s, 1H), 8.20 (d, J=5.2 Hz, 1H), 8.05 (d, J=8.0 Hz, 1H), 7.81 (d, J=7.6 Hz, 1H), 7.72 (d, J=8.8 Hz, 1H), 7.60 (t, J=7.6 Hz, 1H), 7.48-7.36 (m, 3H), 7.20 (t, J=8.2 Hz, 2H), 6.97 (t, J=6.8 Hz, 1H), 6.67 (m, 1H), 6.49-6.45 (m, 2H), 3.79 (s, 3H), 3.70 (d, J=12.4 Hz, 2H), 2.68-2.63 (m, 2H), 2.18 (s, 7H), 1.84-1.81 (m, 2H), 1.52-1.44 (m, 2H). MS (ESI) m/z=675 [M+H]+.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:5]=[C:4]([CH3:12])[N:3]=1.[C:13]([NH2:17])(=[O:16])[CH2:14][CH3:15]>>[CH3:12][C:4]1[N:3]=[C:2]([NH:17][C:13](=[O:16])[CH2:14][CH3:15])[N:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:5]=1
Reactant: CCC(N)=O
Reactant: COC(=O)c1cc(C)nc(Cl)n1
Product: CCC(=O)Nc1nc(C)cc(C(=O)OC)n1
Yield: 61 %

Procedure:
The title compound is prepared in 61% yield (0.73 g, a yellow solid) from methyl 2-chloro-6-methylpyrimidine-4-carboxylate (1.0 g, 5.4 mmol) and propionamide by the similar manner in Step-1 of Carboxylic acid-4.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[N:8]([C:9]([C:11]2[N:12]=[C:13]([CH3:23])[S:14][C:15]=2[C:16]2[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=2)=[O:10])[CH2:7][C@H:6]2[C@@H:4]1[CH2:5]2.[CH3:24][O:25][C:26]1[CH:27]=[C:28]([CH:32]=[C:33]([O:35][CH3:36])[CH:34]=1)[C:29](O)=[O:30]>>[CH3:36][O:35][C:33]1[CH:32]=[C:28]([CH:27]=[C:26]([O:25][CH3:24])[CH:34]=1)[C:29]([NH:1][CH2:2][C@H:3]1[N:8]([C:9]([C:11]2[N:12]=[C:13]([CH3:23])[S:14][C:15]=2[C:16]2[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=2)=[O:10])[CH2:7][C@H:6]2[C@@H:4]1[CH2:5]2)=[O:30]
Reactant: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CN)c1
Reactant: COc1cc(OC)cc(C(=O)O)c1
Product: COc1cc(OC)cc(C(=O)NC[C@@H]2[C@H]3C[C@H]3CN2C(=O)c2nc(C)sc2-c2cccc(C)c2)c1

Procedure:
prepared by reaction of ((1S,2S,5R)-2-Aminomethyl-3-aza-bicyclo[3.1.0]hex-3-yl)-(2-methyl-5-m-tolyl-thiazol-4-yl)-methanone with 3,5-Dimethoxy-benzoic acid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[CH:10][N:11]([CH3:23])[C:12]=2[C:13]2[S:22][C:16]3[N:17]=[CH:18][N:19]=[C:20]([NH2:21])[C:15]=3[CH:14]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:24][N:25](C=O)C>[C-]#N.[Zn+2].[C-]#N.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>[NH2:21][C:20]1[C:15]2[CH:14]=[C:13]([C:12]3[N:11]([CH3:23])[CH:10]=[N:9][C:8]=3[C:4]3[CH:3]=[C:2]([CH:7]=[CH:6][CH:5]=3)[C:24]#[N:25])[S:22][C:16]=2[N:17]=[CH:18][N:19]=1
Reactant: Cn1cnc(-c2cccc(Br)c2)c1-c1cc2c(N)ncnc2s1
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: Cn1cnc(-c2cccc(C#N)c2)c1-c1cc2c(N)ncnc2s1
Temperature: 80 °C
Yield: 16 %

Procedure:
6-[4-(3-Bromophenyl)-1-methyl-1H-imidazol-5-yl]thieno[2,3-d]pyrimidin-4-amine (Example 50) (192 mg) was stirred with zinc cyanide (118 mg) and tetrakis(triphenylphosphine)palladium (116 mg) in DMF (7 mL), degassed, then heated under an inert atmosphere at 80° C. for 20 hours. The solvent was evaporated and the residue was purified by flash chromatography on silica using 0-100% EtOAc in DCM then 0-20% MeOH in DCM as eluent. Further purification by preparative RPBPLC using an MeCN/water/formic acid gradient gave the title compound as a solid (28 mg, 16%);
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.[C:13]([O:18][CH2:19][CH3:20])(=[O:17])[CH:14]([CH3:16])[CH3:15].[Br:21][CH2:22][CH2:23][CH2:24]Br.[NH4+].[Cl-]>C1COCC1>[Br:21][CH2:22][CH2:23][CH2:24][C:14]([CH3:16])([CH3:15])[C:13]([O:18][CH2:19][CH3:20])=[O:17]
Reactant: CCOC(=O)C(C)C
Reactant: BrCCCBr
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CCOC(=O)C(C)(C)CCCBr
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 73 %

Procedure:
To a 0° C. solution of diisopropylamine (14.35 mL, 0.102 mol) in 70 mL of THF was added n-BuLi (68 mL, 0.102 mol). The mixture was stirred at 0˜5° C. for 30 min. After the mixture was cooled to −78° C., ethyl isobutyrate (13.7 mL, 0.102 mol, 1 eq.) was added drop wise and stirring was maintained at −78° C. for 1 h. 1,3-Dibromopropane (1.01 equiv, 10.5 mL) was added drop wise at −78° C. and stirring was maintained at −78° C. for 1 h. Reaction was then warmed up to 23° C. over 2 hrs. Reaction mixture was added to an aqueous NH4Cl solution and extracted with EtOAc. The organic layer was washed with 1N HCl and brine, dried over MgSO4, filtered and concentrated down to give 23 g of crude product. The residue was purified by silica gel chromatography (5% to 30% EtOAc in hexanes) to provide 17.4 g (73% yield) of ethyl 5-bromo-2,2-dimethylpentanoate 90.
Reaction SMILES: Br[C:2]1[C:3]([F:16])=[C:4]([CH:13]=[CH:14][CH:15]=1)[O:5][CH:6]1[CH2:11][CH2:10][N:9]([CH3:12])[CH2:8][CH2:7]1.[C:17](=[NH:30])([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1>[C:17](=[N:30][C:2]1[CH:15]=[CH:14][CH:13]=[C:4]([O:5][CH:6]2[CH2:11][CH2:10][N:9]([CH3:12])[CH2:8][CH2:7]2)[C:3]=1[F:16])([C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CN1CCC(Oc2cccc(Br)c2F)CC1
Reactant: N=C(c1ccccc1)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: Cc1ccccc1
Product: CN1CCC(Oc2cccc(N=C(c3ccccc3)c3ccccc3)c2F)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Heat a mixture of 4-(3-bromo-2-fluoro-phenoxy)-1-methyl-piperidine (preparation 18 or 19, 1.60 g), benzhydrylideneamine (1.21 g), tris(dibenzylidineacetone)-dipalladium(0) (0.11 g), racemic-2,2′-bis(diphenylphosphino)-1,1′binaphthyl (0.138 g) and sodium t-butoxide (0.75 g) in toluene (100 mL) and reflux. After 3 hr., cool to room temperature, load on a SCX column (10 g), wash with methanol, elute the product with 2 M NH3 in methanol. Evaporate the NH3-methanol solution and purify on a 35 g silica gel column eluting with dichloromethane-2M NH3 in methanol, gradient to give benzhydrylidene-[2-fluoro-3-(1-methyl-piperidin-4-yloxy)-phenyl]-amine. Dissolve the amine in THF and add 1N HCl. After 10 min., basify with NH4OH and partition between ethyl acetate and saturated aqueous NaCl, dry over sodium sulfate, evaporate and purify on a 35 g silica gel column eluting with: dichloromethane-2M NH3 in methanol, gradient) to give the title compound (1.19 g): mass spectrum (electric spray) m/z=225 (M+1); 1H NMR (CDCl3): 6.78 (m, 1H), 6.38 (m, 2H), 4.25 (m, 1H), 3.73 (br s, 2H), 2.69 (m, 2H), 2.27 (s, 3H), 2.26 (m, 2H), 1.97 (m, 2H), 1.87 (m, 2H).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([CH2:7][N:8]2[C:16]3[C:11](=[CH:12][C:13]([C:17]([OH:19])=O)=[CH:14][CH:15]=3)[C:10]([C:20]([CH:22]3[C:24]([CH3:26])([CH3:25])[C:23]3([CH3:28])[CH3:27])=[O:21])=[CH:9]2)[CH2:3][CH2:2]1.[C:29](N1C=CN=C1)([N:31]1C=CN=[CH:32]1)=O.CNC>CCOC(C)=O.C1COCC1>[CH3:29][N:31]([CH3:32])[C:17]([C:13]1[CH:12]=[C:11]2[C:16](=[CH:15][CH:14]=1)[N:8]([CH2:7][CH:4]1[CH2:5][CH2:6][O:1][CH2:2][CH2:3]1)[CH:9]=[C:10]2[C:20]([CH:22]1[C:24]([CH3:25])([CH3:26])[C:23]1([CH3:28])[CH3:27])=[O:21])=[O:19]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CC1(C)C(C(=O)c2cn(CC3CCOCC3)c3ccc(C(=O)O)cc23)C1(C)C
Agent: CNC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CN(C)C(=O)c1ccc2c(c1)c(C(=O)C1C(C)(C)C1(C)C)cn2CC1CCOCC1
Yield: 35 %

Procedure:
A mixture 1-(tetrahydro-2H-pyran-4-ylmethyl)-3-[(2,2,3,3-tetramethylcyclopropyl)carbonyl]-1H-indole-5-carboxylic acid (0.10 g, 0.26 mmol, the minor product of Example 114B), 1,1′-carbonyldimidazole (55 mg, 0.34 mmol) and dimethylamine (2 M solution in THF, 0.17 mL, 0.34 mmol) in 4 mL of EtOAc and 3 mL of THF was processed as described in Example 93 to provide the title compound (38 mg, 0.093 mmol, 35% yield). 1H NMR (DMSO-d6, 300 MHz) δ ppm 1.25 (s, 6H), 1.27 (s, 6H), 1.29-1.48 (m, 4H), 2.03-2.18 (m, 1H), 2.20 (s, 1H), 2.97 (s, 6H), 3.23 (dt, J=11.3, 2.9 Hz, 2H), 3.78-3.89 (m, 2H), 4.17 (d, J=7.1 Hz, 2H), 7.27 (dd, J=8.5, 1.7 Hz, 1H), 7.66 (d, J=9.2 Hz, 1H), 8.27 (d, J=1.4 Hz, 1H), 8.37 (s, 1H); MS (DCI/NH3) m/z 411 (M+H)+; Anal. Calculated for C25H34N2O3.0.2H2O: C, 72.50; H, 8.37; N, 6.76. Found: C, 72.51; H, 8.29; N, 6.66.
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=2)[C:12]#[N:13])[C:4]1=[O:17].[Cl:18][C:19]1[S:23][C:22]([C:24]2[S:25][C:26]([S:29](Cl)(=[O:31])=[O:30])=[CH:27][CH:28]=2)=[CH:21][CH:20]=1>>[C:12]([C:11]1[CH:10]=[C:9]([CH:16]=[CH:15][CH:14]=1)[CH2:8][N:5]1[CH2:6][CH2:7][C@H:3]([NH:2][S:29]([C:26]2[S:25][C:24]([C:22]3[S:23][C:19]([Cl:18])=[CH:20][CH:21]=3)=[CH:28][CH:27]=2)(=[O:30])=[O:31])[C:4]1=[O:17])#[N:13]
Reactant: O=S(=O)(Cl)c1ccc(-c2ccc(Cl)s2)s1
Reactant: N#Cc1cccc(CN2CC[C@H](N)C2=O)c1
Agent: Cl
Product: N#Cc1cccc(CN2CC[C@H](NS(=O)(=O)c3ccc(-c4ccc(Cl)s4)s3)C2=O)c1

Procedure:
The title compound is prepared from 3-(3-(S)-amino-2-oxo-pyrrolidin-1-ylmethyl)-benzonitrile hydrochloride as described in EXAMPLE 1, Part E using 5'-chloro-[2,2']bithiophenyl-5-sulfonyl chloride in place of benzo[b]thiophene-2-sulfonyl chloride. The crude product is triturated with EtOAc/CH2Cl2 to yield a beige solid.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]([OH:9])=O)[N:4]=[CH:3]1.[NH2:10][C@@H:11]([CH3:28])[CH2:12][N:13]1[CH:17]=[CH:16][C:15]([C:18]2[CH:25]=[C:24]([F:26])[C:21]([C:22]#[N:23])=[C:20]([Cl:27])[CH:19]=2)=[N:14]1>>[Cl:27][C:20]1[CH:19]=[C:18]([C:15]2[CH:16]=[CH:17][N:13]([CH2:12][C@@H:11]([NH:10][C:7]([C:5]3[N:4]=[CH:3][N:2]([CH3:1])[CH:6]=3)=[O:9])[CH3:28])[N:14]=2)[CH:25]=[C:24]([F:26])[C:21]=1[C:22]#[N:23]
Reactant: C[C@H](N)Cn1ccc(-c2cc(F)c(C#N)c(Cl)c2)n1
Reactant: Cn1cnc(C(=O)O)c1
Product: C[C@@H](Cn1ccc(-c2cc(F)c(C#N)c(Cl)c2)n1)NC(=O)c1cn(C)cn1

Procedure:
The title compound was prepared using the method of Example 247 starting from 1-methyl-1H-imidazole-4-carboxylic acid and (S)-4-[1-(2-aminopropyl)-1H-pyrazol-3-yl]-2-chloro-6-fluorobenzonitrile (which can be prepared according to Example 34(c)). The crude product was purified by flash chromatography on silica gel by using CH2Cl2-MeOH as a gradient eluent (100:0-99:1). The resulting product was triturated in diethyl ether at RT to afford the title product. 1H NMR (400 MHz, DMSO-d6): 1.21 (31-1, d), 3.74 (3H, s), 4.26 (1H, distorted dd), 4.42 (1H, distorted dd), 4.56 (1H, m), 6.60 (1H, d), 7.43 (1H, d), 7.49 (1H, d), 7.50 (1H, d), 7.75 (1H, dd), 7.87 (1H, m), 7.97 (1H, d).