Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:53]=[CH:52][C:5]([O:6][CH2:7][C:8]2[N:12]([CH2:13][CH2:14][CH2:15][CH:16]3[CH2:21][CH2:20][CH2:19][N:18](C(OC(C)(C)C)=O)[CH2:17]3)[C:11]3[CH:29]=[CH:30][CH:31]=[C:32]([O:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH:39]4[CH2:44][CH2:43][CH2:42][N:41](C(OC(C)(C)C)=O)[CH2:40]4)[C:10]=3[N:9]=2)=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][CH2:7][C:8]2[N:12]([CH2:13][CH2:14][CH2:15][CH:16]3[CH2:21][CH2:20][CH2:19][NH:18][CH2:17]3)[C:11]3[CH:29]=[CH:30][CH:31]=[C:32]([O:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH:39]4[CH2:44][CH2:43][CH2:42][NH:41][CH2:40]4)[C:10]=3[N:9]=2)=[CH:52][CH:53]=1
Reactant: CC(C)(C)OC(=O)N1CCCC(CCCCCOc2cccc3c2nc(COc2ccc(Cl)cc2)n3CCCC2CCCN(C(=O)OC(C)(C)C)C2)C1
Solvent: O=C(O)C(F)(F)F
Product: Clc1ccc(OCc2nc3c(OCCCCCC4CCCNC4)cccc3n2CCCC2CCCNC2)cc1

Procedure:
The title product is prepared from (RS) 2-(4-chlorophenoxymethyl)-4-[5-[1-(t-butoxycarbonyl)piperidin-3-yl]pentoxy]-1-[3-[1-(t-butoxycarbonyl)piperidin-3-yl]propyl]benzimidazole using a standard trifluoroacetic acid deprotection protocol.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][CH2:5][NH:6][S:7]([CH3:10])(=[O:9])=[O:8].[NH2:11][C:12]1[C:13]([C:17](Cl)=[N:18][OH:19])=[N:14][O:15][N:16]=1>>[NH2:11][C:12]1[C:13]([C:17](=[N:18][OH:19])[NH:2][CH2:3][CH2:4][CH2:5][NH:6][S:7]([CH3:10])(=[O:9])=[O:8])=[N:14][O:15][N:16]=1
Reactant: Nc1nonc1C(Cl)=NO
Reactant: CS(=O)(=O)NCCCN
Agent: Cl
Product: CS(=O)(=O)NCCCNC(=NO)c1nonc1N
Yield: 19 %

Procedure:
The desired compound was prepared according to the procedure of Example 17, step C, using N-(3-aminopropyl)methanesulfonamide hydrochloride and 4-amino-N-hydroxy-1,2,5-oxadiazole-3-carboximidoyl chloride [made according to Example 1, steps A through B] as the starting materials in 19% yield.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[CH3:10][CH:11]1[CH2:16][C:15](=[O:17])[O:14][C:13](=[O:18])[CH2:12]1>C1COCC1>[C:4]([C:3]1[CH:6]=[CH:7][CH:8]=[CH:9][C:2]=1[NH:1][C:15](=[O:17])[CH2:16][CH:11]([CH3:10])[CH2:12][C:13]([OH:18])=[O:14])#[N:5]
Reactant: N#Cc1ccccc1N
Reactant: CC1CC(=O)OC(=O)C1
Solvent: C1CCOC1
Product: CC(CC(=O)O)CC(=O)Nc1ccccc1C#N
Yield: 90.6 %

Procedure:
A solution of 2-aminobenzonitrile (1.181 g, 10 mmol) and 4-methyldihydro-2H-pyran-2,6(3H)-dione (1.281 g, 10 mmol) in THF (20 mL) was stirred at 90° C. for 46 hr. The reaction solution was concentrated to give 5-(2-cyanophenylamino)-3-methyl-5-oxopentanoic acid (2.230 g, 9.06 mmol, 91%) as a white powder.
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][CH:8]1[CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14](Br)[CH:15]=2)[NH:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[CH3:20][N:21](C=O)C>[C-]#N.[Zn+2].[C-]#N.[Pd].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.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>[C:1]([O:5][C:6](=[O:19])[NH:7][CH:8]1[CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:20]#[N:21])[CH:15]=2)[NH:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(C)C=O
Reactant: CC(C)(C)OC(=O)NC1CNc2ccc(Br)cc2C1
Agent: [Pd]
Agent: [C-]#N
Agent: [Zn+2]
Product: CC(C)(C)OC(=O)NC1CNc2ccc(C#N)cc2C1
Temperature: 90 °C
Yield: 67 %

Procedure:
A solution of (6-bromo-1,2,3,4-tetrahydroquinolin-3-yl)-carbamic acid tert-butyl ester (250 mg, 0.76 mmol), prepared as described in Example 1B, and zinc cyanide (88 mg, 0.75 mmol) in DMF (2.5 mL) was bubbled with argon for 10 min, then tetrakis-(triphenylphosphine) palladium(0) (65 mg, 0.057 mmol) was added and the solution was deoxygenated. The reaction mixture was then heated at 90° C. for 4 h, cooled to RT, and partitioned between EtOAc and water. The aqueous layer was separated and extracted with EtOAc (2×20 mL). The combined EtOAc extracts were washed with saturated aqueous NaCl, dried Na2SO4) and concentrated. The residue was chromatographed (silica gel) eluting with EtOAc (0 to 60%) in hexanes to give the title compound (140 mg, 67% yield) as a white solid.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[C:13]2[C:8](=[N:9][CH:10]=[C:11]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)[CH:12]=2)[C:7]([OH:22])=[C:6]([C:23]([NH:25][CH2:26][CH2:27][N:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)=[O:24])[C:5]1=[O:34].C(N(C(C)C)CC)(C)C.[CH3:44][S:45](Cl)(=[O:47])=[O:46]>CN(C=O)C>[F:21][C:18]1[CH:17]=[CH:16][C:15]([CH2:14][C:11]2[CH:12]=[C:13]3[C:8]([C:7]([OH:22])=[C:6]([C:23]([NH:25][CH2:26][CH2:27][N:28]4[CH2:29][CH2:30][O:31][CH2:32][CH2:33]4)=[O:24])[C:5](=[O:34])[N:4]3[CH2:3][CH2:2][NH:1][S:45]([CH3:44])(=[O:47])=[O:46])=[N:9][CH:10]=2)=[CH:20][CH:19]=1
Reactant: NCCn1c(=O)c(C(=O)NCCN2CCOCC2)c(O)c2ncc(Cc3ccc(F)cc3)cc21
Reactant: CS(=O)(=O)Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)NCCn1c(=O)c(C(=O)NCCN2CCOCC2)c(O)c2ncc(Cc3ccc(F)cc3)cc21

Procedure:
A solution of 1-(2-aminoethyl)-7-[(4-fluorophenyl)methyl]-4-hydroxy-N-[2-(4-morpholinyl)ethyl]-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxamide (0.025 g, 0.052 mmol) and diisopropyl ethylamine (0.05 mL, 0.29 mmol) in DMF (5 mL) under nitrogen was treated with methanesulfonyl chloride (0.0053 mL, 0.068 mmol) at 40° C. for 1 h then 3½ h at ambient temperature. The reaction was concentrated in vacuo and the resulting residue was triturated with Et2O:MeOH, filtered, washed with 2:1 Et2O:MeOH, and dried in vacuo to provide the title compound as an off-white solid: 1H NMR (300 MHz, DMSO-d6) δ ppm 2.35-2.46 (m, 2 H), 2.90 (s, 3 H), 3.06-3.20 (m, 1 H), 3.21-3.29 (m, 2 H), 3.34-3.45 (m, 2 H), 3.52-3.68 (m, 4 H), 3.72-3.83 (m, 2 H), 3.97-4.02 (m, 1 H), 4.15 (d, J=0.56 Hz, 2 H), 4.30-4.41 (m, 2 H), 7.13 (t, J=8.98 Hz, 2 H), 7.29 (s, 1 H), 7.41 (dd, J=8.84, 5.62 Hz, 2 H), 8.13 (s, 1 H), 8.56 (s, 1 H), 9.83 (br. s., 1 H), 10.32-10.41 (m, 1 H); ES+ MS: 548 (M+H+).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([C:12]2[CH:13]=[N:14][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:16][CH:17]=2)[N:3]=1.[Cl:22][C:23]1[CH:28]=[C:27](B(O)O)[CH:26]=[CH:25][N:24]=1>>[Cl:22][C:23]1[CH:28]=[C:27]([C:2]2[N:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([C:12]3[CH:13]=[N:14][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:16][CH:17]=3)[N:3]=2)[CH:26]=[CH:25][N:24]=1
Reactant: FC(F)(F)c1ccc(-c2cc(C(F)(F)F)nc(Cl)n2)cn1
Reactant: OB(O)c1ccnc(Cl)c1
Product: FC(F)(F)c1ccc(-c2cc(C(F)(F)F)nc(-c3ccnc(Cl)c3)n2)cn1

Procedure:
The title compound was prepared from 2-chloro-4-trifluoromethyl-6-(6-trifluoromethyl-pyridin-3-yl)-pyrimidine (example A.2) (2.0 g, 6.1 mmol) and commercially available 2-chloro-pyridine-4-boronic acid (1.06 g, 6.74 mmol) according to the general procedure IIb. Obtained as a light brown solid (0.94 g, 38%). MS (ISN) 405.2 [(M−H)−]; mp 148.5° C.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][P:6]([CH2:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])([O:8][CH2:9][CH3:10])=[O:7])[CH3:4].Br[CH:20]([C:22]1[CH:31]=[CH:30][C:25]([C:26]([O:28][CH3:29])=[O:27])=[CH:24][CH:23]=1)[CH3:21]>CN(C=O)C>[C:15]([O:14][C:12](=[O:13])[CH:11]([P:6]([O:5][CH2:3][CH3:4])([O:8][CH2:9][CH3:10])=[O:7])[CH:20]([C:22]1[CH:31]=[CH:30][C:25]([C:26]([O:28][CH3:29])=[O:27])=[CH:24][CH:23]=1)[CH3:21])([CH3:16])([CH3:18])[CH3:17]
Reactant: CCOP(=O)(CC(=O)OC(C)(C)C)OCC
Reactant: COC(=O)c1ccc(C(C)Br)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOP(=O)(OCC)C(C(=O)OC(C)(C)C)C(C)c1ccc(C(=O)OC)cc1
Temperature: 0 °C
Reaction time: 5 h

Procedure:
Sodium hydride (60% dispersion in mineral oil, 2.98 g, 74.7 mmol) was added portionwise to a solution of tert-butyl 2-(diethoxyphosphoryl)acetate (12.6 g, 49.8 mmol) in anhydrous DMF (150 mL) at 23° C. over 20 min. The reaction mixture was cooled to 0° C., and then a solution of methyl 4-(1-bromoethyl)benzoate (12.1 g, 49.8 mmol) in anhydrous DMF (100 mL) was added dropwise over 15 min. The resulting mixture was stirred at room temperature for 5 h, then concentrated under reduced pressure. The residue was partitioned between ethyl acetate and water (2×). The combined organic layers were washed with brine and dried over anhydrous sodium sulfate, and concentrated. The residue was purified by flash chromatography on silica gel eluting with 25% ethyl acetate in petrolum ethers to give the title compound. MS: m/z=829.4 (2M+1).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][N:5]([C:11]([O:13][C@H:14]1[CH2:31][N:30]3[C@H:16]([C:17](=[O:51])[NH:18][C@:19]4([C:42](=[O:50])[NH:43][S:44]([CH:47]5[CH2:49][CH2:48]5)(=[O:46])=[O:45])[CH2:41][C@H:20]4[CH:21]=[CH:22][CH2:23][O:24][CH2:25][CH2:26][CH2:27][C@H:28]([NH:33][C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[C:29]3=[O:32])[CH2:15]1)=[O:12])[CH2:6]2.[H][H].O.S([O-])(O)(=O)=O.[K+]>C(OCC)(=O)C>[F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][N:5]([C:11]([O:13][C@H:14]1[CH2:31][N:30]3[C@H:16]([C:17](=[O:51])[NH:18][C@:19]4([C:42](=[O:50])[NH:43][S:44]([CH:47]5[CH2:49][CH2:48]5)(=[O:45])=[O:46])[CH2:41][C@H:20]4[CH2:21][CH2:22][CH2:23][O:24][CH2:25][CH2:26][CH2:27][C@H:28]([NH:33][C:34]([O:36][C:37]([CH3:39])([CH3:40])[CH3:38])=[O:35])[C:29]3=[O:32])[CH2:15]1)=[O:12])[CH2:6]2
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCOCC=C[C@@H]2C[C@@]2(C(=O)NS(=O)(=O)C2CC2)NC(=O)[C@@H]2C[C@@H](OC(=O)N3Cc4cccc(F)c4C3)CN2C1=O
Reactant: [H][H]
Agent: CC(C)(C)OC(=O)N[C@H]1CCCOC/C=C\[C@@H]2C[C@@]2(C(=O)NS(=O)(=O)C2CC2)NC(=O)[C@@H]2C[C@@H](OC(=O)N3Cc4cccc(F)c4C3)CN2C1=O
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N[C@H]1CCCOCCC[C@@H]2C[C@@]2(C(=O)NS(=O)(=O)C2CC2)NC(=O)[C@@H]2C[C@@H](OC(=O)N3Cc4cccc(F)c4C3)CN2C1=O
Reaction time: 16 h
Yield: 49.8 %

Procedure:
(2R,6S,13aS,14aR,16aS,Z)-6-(tert-butoxycarbonylamino)-14a-(cyclopropylsulfonylcarbamoyl)-5,16-dioxo-2,3,5,6,7,8,9,11,13a,14,14a,15,16,16a-tetradecahydro-1H-cyclopropa(e)pyrrolo[2,1-i][1,7,10]oxadiazacyclopentadecin-2-yl 4-fluoroisoindoline-2-carboxylate (0.022 g, 0.030 mmol) and Rh/Al (5%) (0.0062 g, 0.0030 mmol) in Ethyl acetate (5 mL) was charged with 1 atmosphere of hydrogen and stirred for 16 hrs. Water (3 mL) and saturated potassium hydrogen sulfate (3 mL) was added and stirred for 10 minutes. The organic phase was separated and aqueous phase extracted with ethyl acetate (10 mL), washed with brine and dried over sodium sulfate. After removal of solvent, the residue was purified by chromatography (Hexane:Ethyl acetate=1:2) to give (2R,6S,13aR,14aR,16aS)-6-(tert-butoxycarbonylamino)-14a-(cyclopropylsulfonylcarbamoyl)-5,16-dioxohexadecahydro-1H-cyclopropa(e)pyrrolo[2,1-i][1,7,10]oxadiazacyclopentadecin-2-yl 4-fluoroisoindoline-2-carboxylate as white solid (0.011 g, 50%). MS: Calcd.: 735; Found: [M+H]+ 736. 1H NMR (400 MHz, CD2Cl2) δ9.69 (s, 1H), 7.18 (m, 1H), 6.84-7.15 (m, 2H), 5.24 (m, 1H), 5.04 (m, 1H), 4.65 & 4.61 (s, 4H), 4.15 (m, 2H), 3.70 (m, 1H), 3.44 (m, 2H), 3.34 (m, 1H), 3.28 (m, 1H), 2.84 (m, 1H), 2.52 (m, 1H), 2.35 (m, 1H), 1.86 (m, 2H), 0.97-1.56 (m, 22H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:39]=[CH:40][C:41]=1[O:42][CH3:43])[C:6]([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]([N:18]2[C:27]3[C:22](=[CH:23][C:24]([O:28][CH2:29][CH2:30][CH2:31][CH2:32][C:33]([O:35]CC)=[O:34])=[CH:25][CH:26]=3)[CH2:21][CH2:20][CH2:19]2)[CH2:10][CH:9]1[CH3:38])=[O:7].C(O)C.O.[OH-].[Li+].Cl>C1COCC1.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:39]=[CH:40][C:41]=1[O:42][CH3:43])[C:6]([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]([N:18]2[C:27]3[C:22](=[CH:23][C:24]([O:28][CH2:29][CH2:30][CH2:31][CH2:32][C:33]([OH:35])=[O:34])=[CH:25][CH:26]=3)[CH2:21][CH2:20][CH2:19]2)[CH2:10][CH:9]1[CH3:38])=[O:7]
Reactant: CCOC(=O)CCCCOc1ccc2c(c1)CCCN2C1CC(C)N(C(=O)c2ccc(OC)c(OC)c2)c2ccccc21
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Solvent: C1CCOC1
Product: COc1ccc(C(=O)N2c3ccccc3C(N3CCCc4cc(OCCCCC(=O)O)ccc43)CC2C)cc1OC
Temperature: 25 °C
Reaction time: 3 h
Yield: 34.7 %

Procedure:
Ethyl 5-[[1-[1-(3,4-dimethoxybenzoyl)-2-methyl-1,2,3,4-tetrahydro-4-quinolinyl]-1,2,3,4-tetrahydro-6-quinolinyl]oxy]pentanoate (100 mg, 0.17 mmol) prepared in Example 94 was dissolved in THF (3 ml), ethanol (2 ml) and water (2 ml), to which lithium hydroxide monohydrate (21 mg, 0.51 mmol) was then added and stirred at room temperature for 3 hours. The reaction mixture was neutralized with 1N hydrochloric acid and then extracted with ethyl acetate. After the organic layer was dried and concentrated, the residue was applied to silica gel column chromatography (developing solvent: ethyl acetate/hexane=4/1) to give the titled compound (33 mg, yield: 35%) as a colorless oil. (cis:trans=1:1.5)
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[C:3]=1[CH:4]=[O:5].[CH3:11][Si:12]([C:15]#[CH:16])([CH3:14])[CH3:13].C(N(CC)CC)C>CN(C)C=O.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:10][C:6]1[CH:7]=[CH:8][CH:9]=[C:2]([C:16]#[C:15][Si:12]([CH3:14])([CH3:13])[CH3:11])[C:3]=1[CH:4]=[O:5]
Reactant: C#C[Si](C)(C)C
Reactant: O=Cc1c(F)cccc1Br
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: C[Si](C)(C)C#Cc1cccc(F)c1C=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.6 %

Procedure:
To a solution of 2-bromo-6-fluorobenzaldehyde (Description 39; 10.0 g, 49.3 mmol) and (trimethylsilyl) acetylene (13.94 ml, 98.6 mmol) in anhydrous N,N-dimethylformamide (250 ml) under an atmosphere of nitrogen was added triethylamine (10.25 ml, 73.95 mmol), copper (I) iodide (0.94 g, 4.93 mmol) and Pd(PPh3)2Cl2 (1.73 g, 2.47 mmol). The mixture was degassed and stirred at room temperature overnight. The mixture was poured into water (600 ml) and extracted with ethyl acetate (3×200 ml). The combined organic layers were washed with water (3×300 ml), brine (200 ml) then dried over Na2SO4 and evaporated. The residue was purified by column chromatography on silica gel eluting with 5% Et2O in iso-hexanes to give the title compound (10.38 g, 95%).
Reaction SMILES: [CH2:1]([N:5]1[CH2:9][C:8](=[O:10])[NH:7][C:6]1=[O:11])[CH2:2][CH2:3][CH3:4].C([N-]C(C)C)(C)C.[Li+].[CH2:20]([C:24]1[N:25]([CH2:31][C:32]2[CH:41]=[CH:40][C:35]([C:36]([O:38][CH3:39])=[O:37])=[CH:34][CH:33]=2)[C:26]([CH:29]=[O:30])=[CH:27][N:28]=1)[CH2:21][CH2:22][CH3:23].[Cl-].[NH4+]>C1COCC1>[CH2:20]([C:24]1[N:25]([CH2:31][C:32]2[CH:33]=[CH:34][C:35]([C:36]([O:38][CH3:39])=[O:37])=[CH:40][CH:41]=2)[C:26]([CH:29]([CH:9]2[C:8](=[O:10])[NH:7][C:6](=[O:11])[N:5]2[CH2:1][CH2:2][CH2:3][CH3:4])[OH:30])=[CH:27][N:28]=1)[CH2:21][CH2:22][CH3:23]
Reactant: CCCCN1CC(=O)NC1=O
Reactant: CCCCc1ncc(C=O)n1Cc1ccc(C(=O)OC)cc1
Agent: CC(C)[N-]C(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCCCc1ncc(C(O)C2C(=O)NC(=O)N2CCCC)n1Cc1ccc(C(=O)OC)cc1
Temperature: -78 °C
Reaction time: 0.33 h

Procedure:
To a suspension of 1-Butyl-2,4-imidazolidinedione (0.600 g, 4.17 mmol) in THF (15ml) at -78° C. is added lithium diisopropylamide (2.1 equiv.). After stirring for 20 minutes a solution of methyl 4-[(2-butyl-5-formyl-1H-imidazol-1-yl)methyl]benzoate (1.250 g, 4.17 mmol) in THF (10 mL) is added dropwise over 10 minutes to form an orange solution. This solution is stirred for a further 20 minutes at -78° C. and is then added to aqueous ammonium chloride. This mixture is evaporated in vacuo and then extracted into ethyl acetate. After washing with water and then brine the solution is dried over Na2SO4. Evaporation in vacuo and chromatography, eluant 5% methanol in chloroform, affords the required product. Recrystallized from ethyl acetate containing traces of methanol.
Reaction SMILES: F[C:2]1[N:26]=[CH:25][CH:24]=[CH:23][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]([CH3:22])([CH:15]2[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]2)[CH3:14])=[CH:9][CH:8]=1)=[O:5].[F:27][C:28]1[CH:35]=[CH:34][C:31]([CH2:32][NH2:33])=[CH:30][CH:29]=1.C([O-])(O)=O.[Na+]>N1C=CC=CC=1>[F:27][C:28]1[CH:35]=[CH:34][C:31]([CH2:32][NH:33][C:2]2[N:26]=[CH:25][CH:24]=[CH:23][C:3]=2[C:4]([NH:6][C:7]2[CH:12]=[CH:11][C:10]([C:13]([CH3:22])([CH:15]3[CH2:16][CH2:17][N:18]([CH3:21])[CH2:19][CH2:20]3)[CH3:14])=[CH:9][CH:8]=2)=[O:5])=[CH:30][CH:29]=1
Reactant: NCc1ccc(F)cc1
Reactant: CN1CCC(C(C)(C)c2ccc(NC(=O)c3cccnc3F)cc2)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Product: CN1CCC(C(C)(C)c2ccc(NC(=O)c3cccnc3NCc3ccc(F)cc3)cc2)CC1
Temperature: 105 °C

Procedure:
A solution of 2-fluoro-N-{4-[1-methyl-1-(1-methyl-piperidin-4-yl)-ethyl]-phenyl}-nicotinamide (355 mg) and 4-fluorobenzylamine (250 mg) in pyridine (10 mL) was suspended with NaHCO3 (1 g). The mixture was heated to 105° C. overnight. Solids were removed by filtration and the filtrate was concentrated in vacuo. The residue was purified on prep. TLC plates (silica, EtOAc:TEA=10:1) to provide the desired product. MS (ES+): 461 (M+1)+, Calc'd for C28H33FN4O-460.59.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH2:8][S:9]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)(=[O:11])=[O:10])=[CH:6][CH:5]=[CH:4][N:3]=1.[Si:19]([O:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31]O)([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20].C(C=P(CCCC)(CCCC)CCCC)#N>C1(C)C=CC=CC=1>[Si:19]([O:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH:8]([C:7]1[C:2]([Cl:1])=[N:3][CH:4]=[CH:5][CH:6]=1)[S:9]([C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=1)(=[O:11])=[O:10])([C:22]([CH3:23])([CH3:24])[CH3:25])([CH3:20])[CH3:21]
Reactant: O=S(=O)(Cc1cccnc1Cl)c1ccc(Cl)cc1
Reactant: CC(C)(C)[Si](C)(C)OCCCCCO
Agent: CCCCP(=CC#N)(CCCC)CCCC
Solvent: Cc1ccccc1
Product: CC(C)(C)[Si](C)(C)OCCCCCC(c1cccnc1Cl)S(=O)(=O)c1ccc(Cl)cc1
Temperature: 25 °C

Procedure:
A toluene (5 ml) solution of the 2-chloro-3-(4-chlorophenylsulfonylmethyl)pyridine (200 mg, 0.662 mmol) obtained in Example 98, 5-(tert-butyldimethylsilyloxy)pentanol (288 mg, 1.32 mmol) and cyanomethylenetri-n-butylphosphorane (318 mg, 1.32 mmol) was heated under reflux for 22 hours under an argon atmosphere. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The residue was subjected to flash chromatography on a silica gel column, and the fraction obtained from the 15% ethyl acetate/hexane eluate was concentrated under reduced pressure, whereby the title compound (307 mg, 92%) was obtained as a colorless oil.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:26]=[CH:25][C:8]2[N:9]=[C:10]([NH:12][C:13]([C:15]34[CH2:24][CH:19]5[CH2:20][CH:21]([CH2:23][CH:17]([CH2:18]5)[CH2:16]3)[CH2:22]4)=[O:14])[S:11][C:7]=2[CH:6]=1)(=[O:4])=[O:3].[H-].[Na+].[CH3:29][O:30][CH2:31][CH2:32]Br>>[CH3:1][S:2]([C:5]1[CH:26]=[CH:25][C:8]2[N:9]([CH2:32][CH2:31][O:30][CH3:29])[C:10](=[N:12][C:13]([C:15]34[CH2:22][CH:21]5[CH2:20][CH:19]([CH2:18][CH:17]([CH2:23]5)[CH2:16]3)[CH2:24]4)=[O:14])[S:11][C:7]=2[CH:6]=1)(=[O:3])=[O:4]
Reactant: CS(=O)(=O)c1ccc2nc(NC(=O)C34CC5CC(CC(C5)C3)C4)sc2c1
Reactant: COCCBr
Agent: [H-]
Agent: [Na+]
Product: COCCn1c(=NC(=O)C23CC4CC(CC(C4)C2)C3)sc2cc(S(C)(=O)=O)ccc21

Procedure:
The product from Example 62A, sodium hydride (60% solution in mineral oil) and 2-bromoethyl methyl ether were processed as described for Example 17B to afford the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.61-1.80 (m, 6H), 1.87-1.94 (m, 6H), 1.99-2.07 (m, 3H), 3.24 (s, 3H), 3.26 (s, 3H), 3.78 (t, J=5.4 Hz, 2H), 4.63 (t, J=5.3 Hz, 2H), 7.82-7.91 (m, 1H), 7.93-8.03 (m, 1H), 8.46 (d, J=1.7 Hz, 1H); MS (ESI+) m/z 449 (M+H)+; Anal. Calculated for C22H28N2O4S2: C, 58.90; H, 6.29; N, 6.24. Found: C, 58.86; H, 6.30; N, 6.25.
Reaction SMILES: [CH2:1]([O:5][C:6]1[C:11]2[C:12]([OH:15])=[N:13][O:14][C:10]=2[CH:9]=[CH:8][CH:7]=1)[CH:2]([CH3:4])[CH3:3].O[CH2:17][CH:18]1[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]1.OCCC1CCN(C(OC(C)(C)C)=O)CC1>>[CH2:1]([O:5][C:6]1[C:11]2[C:12]([O:15][CH2:17][CH:18]3[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:28])([CH3:30])[CH3:29])=[O:25])[CH2:20][CH2:19]3)=[N:13][O:14][C:10]=2[CH:9]=[CH:8][CH:7]=1)[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(CO)CC1
Reactant: CC(C)COc1cccc2onc(O)c12
Agent: CC(C)(C)OC(=O)N1CCC(CCO)CC1
Product: CC(C)COc1cccc2onc(OCC3CCN(C(=O)OC(C)(C)C)CC3)c12

Procedure:
The title compound was prepared according to the procedure described in Step 2 of EXAMPLE 7 using 4-isobutoxy-1,2-benzisoxazol-3-ol (EXAMPLE 8, Step 2) and tert-butyl 4-(hydroxymethyl)piperidine-1-carboxylate instead of 4-(benzyloxy)-1,2-benzisoxazol-3-ol and tert-butyl 4-(2-hydroxyethyl)piperidine-1-carboxylate.
Reaction SMILES: [C:1]1([C@H:7]([NH:10][C:11]([C:13]2[CH:14]=[CH:15][N:16]3[CH2:21][CH2:20][O:19][CH2:18][C:17]=23)=[O:12])[CH2:8][CH3:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:22]N1C(=O)CCC1=O.[OH-].[Na+].O>ClCCl>[C:1]1([C@H:7]([NH:10][C:11]([C:13]2[CH:14]=[C:15]([Br:22])[N:16]3[CH2:21][CH2:20][O:19][CH2:18][C:17]=23)=[O:12])[CH2:8][CH3:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC[C@@H](NC(=O)c1ccn2c1COCC2)c1ccccc1
Reactant: O=C1CCC(=O)N1Br
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: CC[C@@H](NC(=O)c1cc(Br)n2c1COCC2)c1ccccc1
Temperature: -78 °C
Reaction time: 1.83 h
Yield: 93.3 %

Procedure:
To a solution of 3,4-dihydro-1H-pyrrolo[2,1-c][1,4]oxazine-8-carboxylic acid ((R)-1-phenyl-propyl)-amide (9a) (2.50 g, 8.79 mmol) in dry dichloromethane (245 ml) at −78° C. was added N-bromo-succinimide (1.565 g, 8.79 mmol) in several portions (over 2 min) and the mixture was stirred for 110 min at −78° C., then aqueous 0.1 M sodium hydroxide was added, water was added, and the mixture was extracted 3 times with dichloromethane, the combined organic layers were dried over sodium sulfate, and evaporated to give 2.98 g (93%) of 6-bromo-3,4-dihydro-1H-pyrrolo[2,1-c][1,4]oxazine-8-carboxylic acid ((R)-1-phenyl-propyl)-amide. LC/MS (method 4): Rt=1.27 min; m/z=363.07 (M+H+).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[C:7]1[N:8]=[CH:9][S:10][C:11]=1[NH2:12].Cl.[CH:14]1[C:23]2[C:18](=[C:19]([CH2:24][C:25](O)=[O:26])[CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][N:15]=1>>[CH:14]1[C:23]2[C:18](=[C:19]([CH2:24][C:25]([NH:12][C:11]3[S:10][CH:9]=[N:8][C:7]=3[C:2]3[CH:3]=[N:4][CH:5]=[CH:6][N:1]=3)=[O:26])[CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][N:15]=1
Reactant: Nc1scnc1-c1cnccn1
Reactant: O=C(O)Cc1cccc2cnccc12
Agent: Cl
Product: O=C(Cc1cccc2cnccc12)Nc1scnc1-c1cnccn1

Procedure:
The crude 4-(pyrazin-2-yl)thiazol-5-amine was coupled with 2-(isoquinolin-5-yl)acetic acid hydrochloride using procedure A and was purified by HPLC purified to afford desired material as a white trifluoroacetic acid salt (107 mg). Method [8]: rt=3.71 min; 1H NMR (CDCl3) δ12.16 (s, 1H), 9.80 (s, 1H), 9.48 (d, J=1.2 Hz, 1H), 8.64 (d, J=6.4 Hz, 1H), 8.47 (s, 1H), 8.45 (d, J=2.7 Hz, 1H), 8.39 (d, J=8.5 Hz, 1H), 8.31 (d, J=6.5 Hz, 1H), 8.15 (d, J=7.2 Hz, 1H), 8.10-7.98 (m, 2H), 4.45 (s, 2H); MH+ 348.0.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[C:11]([OH:13])[CH:12]=1)[O:9][C:8]([CH3:15])([CH3:14])[CH2:7][C:6]2([CH3:17])[CH3:16])#[CH:2].[CH3:18][O:19][C:20](=[O:30])[CH2:21][C:22]1[CH:27]=[CH:26][C:25](I)=[CH:24][C:23]=1[F:29].C(N(CC)CC)C.C(OCC)(=O)C>CCCCCC.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:18][O:19][C:20](=[O:30])[CH2:21][C:22]1[CH:27]=[CH:26][C:25]([C:2]#[C:1][C:3]2[CH:4]=[C:5]3[C:10](=[C:11]([OH:13])[CH:12]=2)[O:9][C:8]([CH3:15])([CH3:14])[CH2:7][C:6]3([CH3:17])[CH3:16])=[CH:24][C:23]=1[F:29]
Reactant: C#Cc1cc(O)c2c(c1)C(C)(C)CC(C)(C)O2
Reactant: COC(=O)Cc1ccc(I)cc1F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: COC(=O)Cc1ccc(C#Cc2cc(O)c3c(c2)C(C)(C)CC(C)(C)O3)cc1F

Procedure:
Following General Procedure B and using 6-ethynyl-8-hydroxy-2,2,4,4-tetramethyl-chroman (Intermediate 19, 0.05 g, 0.22 mmol), 2-fluoro-4-iodo phenyl acetic acid methyl ester (0.096 g, 0.33 mmol), triethyl amine (3 mL), copper(I)iodide (0.020 g, 0.1 mmol) and dichlorobis(triphenylphosphine)palladium(II) (0.07 g, 0.1 mmol) followed by flash column chromatography over silica gel (230-400 mesh), and preparative normal phase HPLC using 10% ethyl acetate in hexane as the mobile phase, the title compound was obtained (0.037 g, 43%).