Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[N:6]2[CH:7]=[CH:8][C:9]([C:11]([F:14])([F:13])[F:12])=[N:10][C:5]2=[N:4][CH:3]=1.CC1(C)COB([C:22]2[CH:23]=[CH:24][C:25]([F:35])=[C:26]([C:28]3[CH:29]=[N:30][CH:31]=[CH:32][C:33]=3[F:34])[CH:27]=2)OC1.FC1C=CC(B2OC(C)(C)C(C)(C)O2)=CC=1C1C(C#N)=CC=CC=1.B1(B2OCC(C)(C)CO2)OCC(C)(C)CO1>[Pd]>[F:35][C:25]1[CH:24]=[CH:23][C:22]([C:2]2[N:6]3[CH:7]=[CH:8][C:9]([C:11]([F:14])([F:13])[F:12])=[N:10][C:5]3=[N:4][CH:3]=2)=[CH:27][C:26]=1[C:28]1[CH:29]=[N:30][CH:31]=[CH:32][C:33]=1[F:34]
Reactant: CC1(C)COB(c2ccc(F)c(-c3cnccc3F)c2)OC1
Reactant: FC(F)(F)c1ccn2c(Br)cnc2n1
Agent: [Pd]
Agent: CC1(C)COB(B2OCC(C)(C)CO2)OC1
Agent: CC1(C)OB(c2ccc(F)c(-c3ccccc3C#N)c2)OC1(C)C
Product: Fc1ccncc1-c1cc(-c2cnc3nc(C(F)(F)F)ccn23)ccc1F
Yield: 36 %

Procedure:
3-Bromo-7-trifluoromethylimidazo[1,2-α]pyrimidine was coupled to 3-[5-(5,5-dimethyl-[1,3,2]dioxaborinan-2-yl)-2-fluorophenyl]-4-fluoropyridine (prepared in an analogous manner to 2′-fluoro-5′-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)biphenyl-2-carbonitrile in Example 1, using bis(neopentyl glycolato)diboron instead of bis(pinacolato)diboron in the final palladium coupling) using the procedure described in Example 65. 3-[4-Fluoro-3-(4-fluoropyridin-3-yl)phenyl]-7-trifluoromethylimidazo[1,2-α]pyrimidine was isolated as a yellow solid in 36% yield after purification on silica gel eluting with dichloromethane on a gradient of diethyl ether (2-15%): δH (400 MHz, DMSO) 7.48-7.55 (2H, m), 7.63 (1H, dd, J 10 and 9), 7.94 (1H, ddd, J 9, 5 and 2), 7.99 (1H, dd, J 7 and 2), 8.33 (1H, s), 8.73 (1H, dd, J 8 and 5.5), 8.85 (1H, d, J 10), 9.38 (1H, d, J 7); m/z (ES+) 377 (M++H).
Reaction SMILES: [C:1]1([CH2:7][CH:8]=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(CCC=O)C=CC=CC=1.[Cl:20][CH2:21][CH2:22][CH2:23]I.ClCCI>>[Cl:20][CH2:21][CH2:22][CH2:23][C:8](=[O:9])[CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=CCc1ccccc1
Reactant: ClCCCI
Agent: ClCCI
Agent: O=CCCc1ccccc1
Product: O=C(CCCCl)Cc1ccccc1

Procedure:
When in the procedure of Example 2 0.10 mole of phenylacetaldehyde is substituted for 3-phenylpropionaldehyde, and 0.10 mole of 1-chloro-3-iodopropane is substituted for 1-chloro-2-iodoethane, 5-chloro-1-phenylpentan-2-one is obtained.
Reaction SMILES: [C:1]([C:3]1[N:8]=[C:7]([C:9]([OH:11])=[O:10])[CH:6]=[CH:5][CH:4]=1)#[N:2].[ClH:12].[H][H]>C(O)C.[Pd]>[ClH:12].[NH2:2][CH2:1][C:3]1[N:8]=[C:7]([C:9]([OH:11])=[O:10])[CH:6]=[CH:5][CH:4]=1
Reactant: [H][H]
Reactant: N#Cc1cccc(C(=O)O)n1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: NCc1cccc(C(=O)O)n1

Procedure:
6-Cyano-pyridine-2-carboxylic acid (compound F2) (250 mg, 1.6 mmol) is dissolved in ethanol (100 mL), concentrated hydrochloric acid (1 mL) and Pd/C (150 mg) are added and the mixture is hydrogenated at 3 bar hydrogen pressure for 6 h. The catalyst is filtered of and the crude product is transferred to the next step without any purification.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH:12]([NH:14][CH2:15][CH:16]([C:18]2[CH:23]=[CH:22][C:21]([O:24]CC3C=CC=CC=3)=[C:20]([CH2:32][S:33]([CH3:36])(=[O:35])=[O:34])[CH:19]=2)[OH:17])[CH3:13])=[CH:7][CH:6]=1)([O:3][CH3:4])=[O:2]>C(O)C.[Pd]>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([CH2:11][CH:12]([NH:14][CH2:15][CH:16]([C:18]2[CH:23]=[CH:22][C:21]([OH:24])=[C:20]([CH2:32][S:33]([CH3:36])(=[O:34])=[O:35])[CH:19]=2)[OH:17])[CH3:13])=[CH:9][CH:10]=1)([O:3][CH3:4])=[O:2]
Reactant: COC(=O)c1ccc(CC(C)NCC(O)c2ccc(OCc3ccccc3)c(CS(C)(=O)=O)c2)cc1
Agent: [Pd]
Solvent: CCO
Product: COC(=O)c1ccc(CC(C)NCC(O)c2ccc(O)c(CS(C)(=O)=O)c2)cc1

Procedure:
N-(2-[4-Carbomethoxyphenyl]-1-methylethyl)-2-(4-benzyloxy-3-methylsulphonylmethylphenyl)-2-hydroxyethanamine (2.3 g) was converted to the hydrochloride salt and hydrogenated in ethanol (200 ml) in a Parr hydrogenator at 50 psi and 25° for 2 hours in the presence of 10% palladium on charcoal (0.5 g). The catalyst was removed and the product was isolated as a mixture of diastereoisomers, mp 145°-148° (methanol:ether). τ(d6DMSO) 8.90 (3H, d, J=6 Hz), 7.2 (3H, s), 6.20-7.10 (6H, m), 6.20 (3H, s), 5.70 (2H, s), 5.00 (1H, m), 3.90 (1H, b), 2.40-3.10 (5H, m), 2.08 (2H, d, J=8 Hz), 0.70 (1H, br), -0.10 (1H, br).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[CH3:12]>C1COCC1>[CH3:12][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:2]=1[NH:1][C:6](=[O:7])[CH2:5][CH2:4][CH:3]=[CH2:2])[C:6]([O:8][CH3:9])=[O:7]
Reactant: COC(=O)c1ccc(N)c(C)c1
Solvent: C1CCOC1
Product: C=CCCC(=O)Nc1ccc(C(=O)OC)cc1C

Procedure:
Prepared analogously to Example 46a from methyl 4-amino-3-methyl-benzoate and 4-pentene-1-acid-chloride in THF with TEA.
Reaction SMILES: [O:1]1[C:6]2([CH2:11][CH2:10][NH:9][CH2:8][CH2:7]2)[CH2:5][NH:4][C:3](=[O:12])[CH2:2]1.Br[CH2:14][CH2:15][C:16]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[NH:18][CH:17]=1.O>CN(C)C=O.C(N(CC)CC)C>[NH:18]1[C:19]2[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:16]([CH2:15][CH2:14][N:9]2[CH2:8][CH2:7][C:6]3([O:1][CH2:2][C:3](=[O:12])[NH:4][CH2:5]3)[CH2:11][CH2:10]2)=[CH:17]1
Reactant: O=C1COC2(CCNCC2)CN1
Reactant: BrCCc1c[nH]c2ccccc12
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: O=C1COC2(CCN(CCc3c[nH]c4ccccc34)CC2)CN1
Yield: 42.4 %

Procedure:
A solution of the hydrobromide salt of 1-oxa-4,9-diazaspiro[5.5]undecan-3-one (15 g) and 3-(2-bromoethyl)indole (13.5 g) in 75 ml of dimethylformamide and 20 ml of triethylamine was stirred at 65° C. for 16 hours. Water was added and the mixture was extracted with methylene chloride. The organic layer was extracted with 5% hydrochloric acid and the aqueous layer was made basic with ammonium hydroxide and extracted with methylene chloride. Evaporation left a residue which was chromatographed on silica gel with 10% methanol-methylene chloride to give 8.0 g of 9-[2-(3-indolyl)ethyl-]-1-oxa-4,9-diazaspiro[5.5] undecan-3-one as the free base, mp 48°-50° C. The free base was dissolved in methanol and acidified with methanolic hydrochloric acid. The precipitate was washed with ether to give 7 g of the hydrochloride salt of 9-[2-(3-indolyl)ethyl]-1-oxa-4,9-diazaspiro[5.5]undecan-3-one, mp 272°-275° C. (dec).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:6]2[NH:7][C:8](=[O:18])[N:9]([CH:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)[CH2:10][CH2:11][C:5]=2[CH:4]=1.[Cl:21][C:22]1[CH:27]=[C:26]([C:28]([C:30]2[CH:40]=[C:39]([CH3:41])[C:33]3[N:34]([CH3:38])[C:35](=[O:37])[O:36][C:32]=3[CH:31]=2)=[O:29])[CH:25]=[C:24](Cl)[N:23]=1>CN1C(=O)CCC1>[Cl:21][C:22]1[N:23]=[C:24]([N:15]2[CH2:14][CH2:13][CH:12]([N:9]3[CH2:10][CH2:11][C:5]4[CH:4]=[C:3]([O:2][CH3:1])[CH:20]=[CH:19][C:6]=4[NH:7][C:8]3=[O:18])[CH2:17][CH2:16]2)[CH:25]=[C:26]([C:28]([C:30]2[CH:40]=[C:39]([CH3:41])[C:33]3[N:34]([CH3:38])[C:35](=[O:37])[O:36][C:32]=3[CH:31]=2)=[O:29])[CH:27]=1
Reactant: Cc1cc(C(=O)c2cc(Cl)nc(Cl)c2)cc2oc(=O)n(C)c12
Reactant: COc1ccc2c(c1)CCN(C1CCNCC1)C(=O)N2
Solvent: CN1CCCC1=O
Product: COc1ccc2c(c1)CCN(C1CCN(c3cc(C(=O)c4cc(C)c5c(c4)oc(=O)n5C)cc(Cl)n3)CC1)C(=O)N2

Procedure:
0.41 g (1.5 mmol) 7-methoxy-3-piperidin-4-yl-1,3,4,5-tetrahydro-benzo[d][1,3]diazepin-2-one and 0.20 g (0.49 mmol) 6-(2,6-dichloro-pyridine-4-carbonyl)-3,4-dimethyl-3H-benzoxazol-2-one were stirred in 3 mL NMP for 3 h at 120° C. The reaction mixture was purified by preparative HPLC. The fractions containing the product were combined and freeze-dried.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH2:8][NH:9][C:10]([C:12]2[NH:21][C:20](=[O:22])[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([C:23]#[N:24])[CH:18]=3)[N:13]=2)=[O:11])[CH:5]=[CH:6][CH:7]=1.[C:25]1([C:31]([C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[N:32]2[CH:36]=[N:35][C:34]([CH2:37][CH2:38][C:39](O)=[O:40])=[N:33]2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1>CN(C=O)C>[C:23]([C:17]1[CH:18]=[C:19]2[C:14](=[CH:15][CH:16]=1)[N:13]=[C:12]([C:10]([NH:9][CH2:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([NH:1][C:39](=[O:40])[CH2:38][CH2:37][C:34]3[N:35]=[CH:36][N:32]([C:31]([C:48]4[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=4)([C:42]4[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=4)[C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[N:33]=3)[CH:3]=1)=[O:11])[NH:21][C:20]2=[O:22])#[N:24]
Reactant: O=C(O)CCc1ncn(C(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reactant: N#Cc1ccc2nc(C(=O)NCc3cccc(N)c3)[nH]c(=O)c2c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: N#Cc1ccc2nc(C(=O)NCc3cccc(NC(=O)CCc4ncn(C(c5ccccc5)(c5ccccc5)c5ccccc5)n4)c3)[nH]c(=O)c2c1
Temperature: 40 °C
Reaction time: 15 h
Yield: 86 %

Procedure:
A solution of N-[(3-aminophenyl)methyl]-6-cyano-4-oxo-3,4-dihydroquinazoline-2-carboxamide obtained in Reference Example 45 (120 mg, 0.376 mmol), 3-[1-(triphenylmethyl)-1H-1,2,4-triazol-3-yl]propanoic acid obtained in Reference Example 25 (152 mg, 0.396 mmol), 1-[3-(dimethylamino)propyl]-3-ethyl-carbodiimide hydrochloride (106 mg, 0.554 mmol) and 1-hydroxybenzotriazole (74.9 mg, 0.554 mmol) in DMF (5 mL) was stirred at 40° C. for 15 hr. The reaction mixture was concentrated under reduced pressure, and water was added to residue. The resulting solid was collected by filtration, washed with water and IPE, and dried to give 6-cyano-4-oxo-N-{[3-({3-[1-(triphenylmethyl)-1H-1,2,4-triazol-3-yl]propanoyl}amino)phenyl]methyl}-3,4-dihydroquinazoline-2-carboxamide as a white powder (232.0 mg, 86%).
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11]([Sn](CCCC)(CCCC)CCCC)[CH:12]=2)[CH2:7]1)=[O:5])[CH3:2].Br[C:29]1[N:30]=[C:31]([N:39]2[CH2:44][CH2:43][N:42]([CH2:45][CH3:46])[CH2:41][CH2:40]2)[C:32]2[C:37]([CH:38]=1)=[CH:36][CH:35]=[CH:34][CH:33]=2>C1(C)C(C)=CC=CC=1.C(OCC)(=O)C.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>[CH2:45]([N:42]1[CH2:41][CH2:40][N:39]([C:31]2[C:32]3[C:37](=[CH:36][CH:35]=[CH:34][CH:33]=3)[CH:38]=[C:29]([C:11]3[CH:12]=[C:13]4[C:8](=[CH:9][CH:10]=3)[CH2:7][CH:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH2:14]4)[N:30]=2)[CH2:44][CH2:43]1)[CH3:46]
Reactant: CCN1CCN(c2nc(Br)cc3ccccc23)CC1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccc2c(c1)CC(C(=O)OCC)C2
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1C
Solvent: CCOC(C)=O
Product: CCOC(=O)C1Cc2ccc(-c3cc4ccccc4c(N4CCN(CC)CC4)n3)cc2C1
Yield: 90.8 %

Procedure:
2-Ethoxycarbonyl -5-(tributyistannyl)indane (3.04 g) and 3-bromo-1-(4-ethylpiperazin-1-yl)isoquinoline (0.87 g) were heated under reflux overnight in the presence of tetrakistriphenylphosphinepalladium(0) (0.12 g) in xylene in nitrogen atmosphere. Af ter cooling, the reaction solution was diluted with ethyl acetate and filtered. The filtrate was extracted with 2N hydrochloric acid, and the resulting aqueous layer was washed with ethyl acetate, adjusted to pH 10 with a 8N aqueous solution of sodium hydroxide, and then extracted with ethyl acetate. The extract was washed with a 10% aqueous solution of sodium carbonate and brine, and dried over magnesium sulfate. The solvent was evaporated, to give 1-(4-ethylpiperazin-1-yl)-3-(2-ethoxycarbonylindan-5-yl)isoquinoline (1.06 g) as a brown viscous oil.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[CH2:5][NH:6][C:7]([C:9]1[C:10](=[O:22])[S:11][C:12]2[C:17]([C:18]=1[OH:19])=[CH:16][C:15]([Cl:20])=[CH:14][C:13]=2Br)=[O:8])[CH3:2].C([Sn](CCCC)(CCCC)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)CCC>CN(C=O)C.C(OCC)(=O)C.O.C1(P([Pd-2](Cl)(Cl)P(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH2:1]([O:3][C:4](=[O:23])[CH2:5][NH:6][C:7]([C:9]1[C:10](=[O:22])[S:11][C:12]2[C:17]([C:18]=1[OH:19])=[CH:16][C:15]([Cl:20])=[CH:14][C:13]=2[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:8])[CH3:2]
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccc1
Reactant: CCOC(=O)CNC(=O)c1c(O)c2cc(Cl)cc(Br)c2sc1=O
Agent: Cl[Pd-2](Cl)([PH](c1ccccc1)(c1ccccc1)c1ccccc1)[PH](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CNC(=O)c1c(O)c2cc(Cl)cc(-c3ccccc3)c2sc1=O
Yield: 83.4 %

Procedure:
[(8-Bromo-6-chloro-4-hydroxy-2-oxo-2H-thiochromene-3-carbonyl)-amino]-acetic acid ethyl ester (22(d)) (500 mg, 1.2 mmol) was dissolved in anhydrous DMF (5 mL). To the solution was added Tributyl-phenyl-stannane (467 uL, 1.43 mmol), bis(triphenylphosphino) palladium(II) dichloride (100 mg, 0.12 mmol) and 4A molecular sieves. The reaction was sealed and the solution was heated to 120 C for 45 minutes. The reaction was cooled, diluted with ethyl acetate (25 mL) and water (25 mL). The organic phase was separated, dried over magnesium sulfate and concentrated residue in vacuo. The residue was filtered through silica to provide the title compound (418 mg) which was used directly without further purification.
Reaction SMILES: [H-].[Na+].[I-].[CH3:4][S+](C)C.[C:8]([O:12][C:13]([N:15]1[CH2:21][CH2:20][CH2:19][C@H:16]1[CH:17]=[O:18])=[O:14])([CH3:11])([CH3:10])[CH3:9]>CS(C)=O.C1COCC1>[C:8]([O:12][C:13]([N:15]1[CH2:21][CH2:20][CH2:19][C@H:16]1[CH:17]1[O:18][CH2:4]1)=[O:14])([CH3:11])([CH3:9])[CH3:10]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C=O
Reactant: C[S+](C)C
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1CCC[C@H]1C1CO1
Temperature: 70 °C
Reaction time: 1 h

Procedure:
DMSO (20 ml) was added to sodium hydride (60% NaH, 1.55 g), and the mixture was stirred at 70° C. for 1 hour. The reaction mixture was cooled to room temperature and THF (20 ml) was added. The mixture was cooled to -5° C. , and thereto was dropwise added trimethylsulfonium iodide (7.90 g) in DMSO (30 ml) over 3 minutes. After stirring for 1 minute, t-butoxycarbonyl-L-prolinal (5.13 g) in THF (15 ml) was added quickly, followed by stirring at room temperature for 1 hour. The reaction mixture was poured into ice water (300 ml) and extracted with chloroform. The organic layer was washed with saturated brine, dried over sodium sulfate and concentrated. The residue was purified by silica gel column chromatography (eluate: hexane-ethyl acetate) to give two kinds of diastereomers of (2S)-1-(t-butoxycarbonyl)-2-(1,2-epoxyethyl)pyrrolidine, 3.12 g of its less polar compound and 1.28 g of its more polar compound. (Configuration of the epoxy moiety of the both unidentified.) The less polar compound was used in the following reactions.
Reaction SMILES: [H-].[Na+].OC[CH:5]1[O:9][CH:8]([C:10]2[CH:15]=[CH:14]C=CC=2)[N:7]([CH:16]([CH3:18])C)C1.ClC1C=C(C)C=CN=1>CN(C)C=O>[CH3:5][O:9][C:8]1[CH:10]=[C:15]([CH3:14])[CH:18]=[CH:16][N:7]=1
Reactant: CC(C)N1CC(CO)OC1c1ccccc1
Agent: Cc1ccnc(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc(C)ccn1
Temperature: 40 °C
Reaction time: 1.5 h

Procedure:
4.8 g of sodium hydride dispersion (55% strength) are cautiously added in portions to a solution of 27.5 g of 5-hydroxymethyl-3-isopropyl-2-phenyl-oxazolidine in 100 ml of dimethylformamide at 20°-40° C. and after foaming has ceased the mixture is stirred for a further 1-2 hours at 40° C. 12.7 g of 2-chloro-4-methyl-pyridine are then added and the reaction mixture is stirred for 2 hours at 80° C. After evaporating off the solvent in vacuo, the evaporation residue is taken up in ether and the ether solution is washed with water, dried over magnesium sulphate and evaporated in vacuo. Crude 2-[3'-isopropyl]-2'-phenyl-oxazolidinyl-(5')]-methoxy-4-methyl-pyridine is thus obtained.
Reaction SMILES: [CH3:1][S:2]([CH:5]([CH2:15][C:16]#[C:17][C@@H:18]([OH:24])[CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13])(=[O:4])=[O:3].[H][H]>[Pt].C(OCC)(=O)C.C1CCCCC1>[CH3:1][S:2]([CH:5]([CH2:15][CH2:16][CH2:17][C@@H:18]([OH:24])[CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13])(=[O:3])=[O:4]
Reactant: CCCCC[C@H](O)C#CCC(CCCCCCC(=O)O)S(C)(=O)=O
Reactant: [H][H]
Agent: [Pt]
Solvent: CCOC(C)=O
Solvent: C1CCCCC1
Product: CCCCC[C@H](O)CCCC(CCCCCCC(=O)O)S(C)(=O)=O

Procedure:
8-Methylsulfonyl-12(S)-hydroxy-10-heptadecynoic acid (36.0 g., 0.10 mole) and 5% platinum-on-charcoal catalyst (4.0 g.) are placed in a mixture of ethyl acetate (100 ml.) and cyclohexane (200 ml.) and hydrogenated in a Parr apparatus with an initial hydrogen pressure of 45 pounds per square inch. The uptake of the required 0.2 mole of hydrogen is complete in 20 minutes. The catalyst is removed by filtration and the solvents evaporated to leave the product as a residual oil weighing 33.5 g. It is purified by chromatography on silica gel with benzene-dioxane-acetic acid elution. The title compound is obtained as a nearly colorless viscous oil.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][NH:8][CH2:9]2)=[CH:4][CH:3]=1.B(O)O>>[N:8]1[CH:9]=[CH:10][CH:5]=[C:6]([C:2]2[CH:11]=[C:10]3[C:5]([CH2:6][CH2:7][NH:8][CH2:9]3)=[CH:4][CH:3]=2)[CH:7]=1
Reactant: Brc1ccc2c(c1)CNCC2
Agent: OBO
Product: c1cncc(-c2ccc3c(c2)CNCC3)c1

Procedure:
In close analogy to the procedure described above, 7-Bromo-1,2,3,4-tetrahydro-isoquinoline is reacted with the corresponding boronic acid to provide the title compound.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:12][N:11]([C:13]([C:15]3[CH:16]=[CH:17][C:18]([CH3:40])=[C:19]([C:21]4[N:22]=[C:23]([CH:27]5[CH2:32][CH2:31][N:30](C(OC(C)(C)C)=O)[CH2:29][CH2:28]5)[NH:24][C:25]=4[CH3:26])[CH:20]=3)=[O:14])[CH2:10]2)=[CH:5][CH:4]=1)#[N:2].FC(F)(F)C(O)=O>C(Cl)Cl>[CH3:40][C:18]1[CH:17]=[CH:16][C:15]([C:13]([N:11]2[CH2:12][CH:9]([C:6]3[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:8][CH:7]=3)[CH2:10]2)=[O:14])=[CH:20][C:19]=1[C:21]1[NH:22][C:23]([CH:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)=[N:24][C:25]=1[CH3:26]
Reactant: Cc1ccc(C(=O)N2CC(c3ccc(C#N)cc3)C2)cc1-c1nc(C2CCN(C(=O)OC(C)(C)C)CC2)[nH]c1C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(C(=O)N2CC(c3ccc(C#N)cc3)C2)cc1-c1[nH]c(C2CCNCC2)nc1C
Reaction time: 1.5 h

Procedure:
To a solution of tert-butyl 4-(4-(5-(3-(4-cyanophenyl)azetidine-1-carbonyl)-2-methylphenyl)-5-methyl-1H-imidazol-2-yl)piperidine-1-carboxylate (compound 182.3, 475 mg, 0.88 mmol) in 20 mL CH2Cl2, was added trifluoroacetic acid (4 mL). The reaction stirred for 1.5 hours and concentrated under reduced pressure, neutralized with 10 mL Na2CO3 (1M) and lyophilized to afford 4-(1-(4-methyl-3-(4-methyl-2-(piperidin-4-yl)-1H-imidazol-5-yl)benzoyl)azetidin-3-yl)benzonitrile. The mixture of 4-(1-(4-methyl-3-(4-methyl-2-(piperidin-4-yl)-1H-imidazol-5-yl)benzoyl)azetidin-3-yl)benzonitrile (135 mg, 0.31 mmol), formic acid (300 μL, 6.76 mmol), formaldehyde (37% in water, 300 μL, 3.41 mmol) and water (1.5 mL) was heated to reflux for 10 hours. The reaction was diluted with saturated NaHCO3 until pH 9 and extracted with CH2Cl2 (3×20 mL). The residue was purified by preparative TLC with 10% methanol and 1% ammonium hydroxide in dichloromethane and lyophilized to give 43 mg (30% two steps) of the title compound as a white solid. m/z (ES+) 540 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](F)[CH:5]=[CH:4][C:3]=1[C:9]([F:12])([F:11])[F:10].C[Si](C)(C)CC[OH:17].[H-].[Na+]>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[C:6]([OH:17])[CH:5]=[CH:4][C:3]=1[C:9]([F:12])([F:11])[F:10]
Reactant: Fc1ccc(C(F)(F)F)c(Cl)c1
Reactant: C[Si](C)(C)CCO
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Oc1ccc(C(F)(F)F)c(Cl)c1
Temperature: 0 °C
Reaction time: 16 h
Yield: 71.9 %

Procedure:
To a stirred solution of 2-chloro-4-fluorobenzotrifluoride (500 mg, 2.52 mmol) in anhydrous N,N-dimethylformamide (10 mL) was added 2-(trimethylsilyl)ethanol (0.40 mL, 2.77 mmol) and the reaction mixture was cooled to 0° C. Sodium hydride (302 mg, 60% w/w dispersion in oil, 7.55 mmol) was then added portionwise. After 5 minutes a thick white suspension had formed. The reaction mixture was warmed to room temperature slowly and then stirred for a further 16 hours. The reaction mixture was then quenched with ice water (50 mL) and washed with diethyl ether (50 mL). The aqueous extracts were acidified with aqueous 2 M hydrogen chloride solution and extracted with diethyl ether (2×50 mL). The organic extracts were dried over anhydrous magnesium sulphate and evaporated in vacuo for 16 hours to afford the title compound as a yellow oil (356 mg, 72%).
Reaction SMILES: I[C:2]1[N:20]([S:21]([C:24]2[CH:30]=[CH:29][C:27]([CH3:28])=[CH:26][CH:25]=2)(=[O:23])=[O:22])[C:5]2=[N:6][CH:7]=[CH:8][C:9]([C:10]3[S:14][C:13]([C:15]4([OH:19])[CH2:18][CH2:17][CH2:16]4)=[N:12][CH:11]=3)=[C:4]2[CH:3]=1.[F:31][C:32]1[CH:33]=[C:34]2[C:38](=[CH:39][CH:40]=1)[N:37]([CH3:41])[CH:36]=[C:35]2B1OC(C)(C)C(C)(C)O1.C(=O)(O)[O-]>CN(C)C=O.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[F:31][C:32]1[CH:33]=[C:34]2[C:38](=[CH:39][CH:40]=1)[N:37]([CH3:41])[CH:36]=[C:35]2[C:2]1[N:20]([S:21]([C:24]2[CH:25]=[CH:26][C:27]([CH3:28])=[CH:29][CH:30]=2)(=[O:22])=[O:23])[C:5]2=[N:6][CH:7]=[CH:8][C:9]([C:10]3[S:14][C:13]([C:15]4([OH:19])[CH2:16][CH2:17][CH2:18]4)=[N:12][CH:11]=3)=[C:4]2[CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)n2c(I)cc3c(-c4cnc(C5(O)CCC5)s4)ccnc32)cc1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)c2cc(F)ccc21
Agent: Cl[Pd]Cl
Agent: O=C([O-])O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)n2c(-c3cn(C)c4ccc(F)cc34)cc3c(-c4cnc(C5(O)CCC5)s4)ccnc32)cc1
Temperature: 70 °C

Procedure:
To a stirred ambient solution of 1-(5-(2-iodo-1-tosyl-1H-pyrrolo[2,3-b]pyridin-4-yl)thiazol-2-yl)cyclobutanol (Example 107C) (150 mg, 0.272 mmol) and 5-fluoro-1-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole (Example 107A) (112 mg, 0.408 mmol) in N,N-dimethylformamide (2.04 mL) was added saturated aqueous bicarbonate solution (680 μL) followed by bis(triphenylphosphine) palladium dichloride (13.37 mg, 0.019 mmol). The mixture was heated to 70° C. for 3 hours and was quenched by the addition of water and dichloromethane. The layers were separated, and the aqueous layer was extracted with additional dichloromethane. The combined organics were dried with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to give crude product. The residue was purified by flash chromatography on silica gel, eluting with a gradient of 0 to 100% ethyl acetate in hexane, to give the title compound LCMS APCI(+) m/z 602.99 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]([C:14]([OH:16])=O)[CH:11]=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[CH2:17]([O:19][C:20](=[O:30])[CH2:21][O:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([NH2:29])[CH:24]=1)[CH3:18]>>[CH2:17]([O:19][C:20](=[O:30])[CH2:21][O:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([NH:29][C:14]([C:12]2[CH:11]=[CH:10][CH:9]=[C:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[N:13]=2)=[O:16])[CH:24]=1)[CH3:18]
Reactant: CCOC(=O)COc1cccc(N)c1
Reactant: O=C(O)c1cccc(-c2ccc(F)cc2)n1
Product: CCOC(=O)COc1cccc(NC(=O)c2cccc(-c3ccc(F)cc3)n2)c1

Procedure:
Carboxylic acid (152) (50 mg, 0.23 mmol) was coupled to aniline (64) (45 mg, 0.23 mmol) using Method C to give the title compound.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[N:10]([C:14]1[N:19]=[CH:18][C:17]([CH2:20][O:21][CH:22]3[CH2:27][CH2:26][N:25]([C:28]#[N:29])[CH2:24][CH2:23]3)=[CH:16][CH:15]=1)[CH:9]=[CH:8]2)(=[O:4])=[O:3].[OH:30][NH:31][C:32](=N)[CH3:33]>>[CH3:33][C:32]1[N:29]=[C:28]([N:25]2[CH2:24][CH2:23][CH:22]([O:21][CH2:20][C:17]3[CH:18]=[N:19][C:14]([N:10]4[C:11]5[C:7](=[CH:6][C:5]([S:2]([CH3:1])(=[O:3])=[O:4])=[CH:13][CH:12]=5)[CH:8]=[CH:9]4)=[CH:15][CH:16]=3)[CH2:27][CH2:26]2)[O:30][N:31]=1
Reactant: CC(=N)NO
Reactant: CS(=O)(=O)c1ccc2c(ccn2-c2ccc(COC3CCN(C#N)CC3)cn2)c1
Product: Cc1noc(N2CCC(OCc3ccc(-n4ccc5cc(S(C)(=O)=O)ccc54)nc3)CC2)n1

Procedure:
The title compound was prepared by following the similar procedure as described in Example-4 using 4-((6-(5-(methylsulfonyl)-1H-indol-1-yl)pyridin-3-yl)methoxy)piperidine-1-carbonitrile (intermediate 38) and N-hydroxyacetimidamide (0.014 g, 8%).