Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:3]([N:22]2[CH2:27][CH2:26][CH2:25][C@@H:24]([OH:28])[CH2:23]2)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[N:29]1[CH:34]=[C:33](B(O)O)[CH:32]=[N:31][CH:30]=1>>[OH:28][C@@H:24]1[CH2:25][CH2:26][CH2:27][N:22]([C:3]2[C:2]([C:33]3[CH:34]=[N:29][CH:30]=[N:31][CH:32]=3)=[CH:21][C:6]([C:7]([NH:9][C:10]3[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=3)=[O:8])=[CH:5][N:4]=2)[CH2:23]1
Reactant: OB(O)c1cncnc1
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2CCC[C@@H](O)C2)c(Br)c1
Product: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2CCC[C@@H](O)C2)c(-c2cncnc2)c1

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 118 using (R)-5-bromo-6-(3-hydroxypiperidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 121.1) and pyrimidin-5-ylboronic acid to afford a white solid. UPLC-MS (condition 1) tR=2.21 min, m/z=460.01 [M+H]+, m/z=458.2 [M−H]−; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.21-1.39 (m, 2H) 1.56-1.65 (m, 1H) 1.77-1.86 (m, 1H) 2.63 (dd, J=11.86, 8.44 Hz, 1H) 2.75-2.84 (m, 1H) 3.35-3.38 (m, 1H) 3.43-3.49 (m, 1H) 3.49-3.55 (m, 1H) 4.74 (s, 1H) 7.37 (d, J=8.56 Hz, 2H) 7.83-7.89 (m, 2H) 8.19 (d, J=2.45 Hz, 1H) 8.80 (d, J=2.45 Hz, 2H) 9.08 (s, 1H) 9.21 (s, 1H) 10.30 (s, 1H).
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]([N:12]=[C:13]=[S:14])[CH2:4][CH2:3]1.C(O)C.[CH2:18]([NH2:20])[CH3:19]>C(Cl)Cl>[CH2:18]([NH:20][C:13]([NH:12][CH:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:2](=[O:1])[CH2:3][CH2:4]1)=[S:14])[CH3:19]
Reactant: CCN
Reactant: O=C1CCC(N=C=S)c2ccccc21
Solvent: CCO
Solvent: ClCCl
Product: CCNC(=S)NC1CCC(=O)c2ccccc21
Reaction time: 18 h

Procedure:
To a solution of 1,2,3,4-tetrahydro-4-oxo-1-naphthyl isothiocyanate (5.0 g) in methylene chloride (100 ml), ethylamine is added via ethanol (15 ml) saturated with ethylamine. After stirring for 18 hours, the mixture is heated at reflux for 2 hours, cooled and evaporated to dryness in vacuo. The residue is triturated with water and the title compound collected and dried; m.p. 134° to 138° C.
Reaction SMILES: [NH2:1][CH:2]([C:6]1[N:7]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:8](=[O:16])[C:9]2[CH:15]=[CH:14][CH:13]=[N:12][C:10]=2[N:11]=1)[CH:3]([CH3:5])[CH3:4].[BH-](O[C:34]([CH3:36])=[O:35])(OC(C)=O)OC(C)=O.[Na+].[C:38]([O:42][C:43](=[O:49])[NH:44][CH2:45][CH2:46][CH:47]=O)([CH3:41])([CH3:40])[CH3:39]>ClCCl>[NH2:44][CH2:45][CH2:46][CH2:47][N:1]([CH:2]([C:6]1[N:7]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:8](=[O:16])[C:9]2[CH:15]=[CH:14][CH:13]=[N:12][C:10]=2[N:11]=1)[CH:3]([CH3:5])[CH3:4])[C:34](=[O:35])[C:36]1[CH:22]=[CH:23][C:18]([CH3:17])=[CH:19][CH:20]=1.[C:38]([O:42][C:43](=[O:49])[NH:44][CH2:45][CH2:46][CH2:47][NH:1][CH:2]([C:6]1[N:7]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:8](=[O:16])[C:9]2[CH:15]=[CH:14][CH:13]=[N:12][C:10]=2[N:11]=1)[CH:3]([CH3:5])[CH3:4])([CH3:41])([CH3:40])[CH3:39]
Reactant: CC(C)C(N)c1nc2ncccc2c(=O)n1Cc1ccccc1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: CC(C)(C)OC(=O)NCCC=O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)C(NCCCNC(=O)OC(C)(C)C)c1nc2ncccc2c(=O)n1Cc1ccccc1
Product: Cc1ccc(C(=O)N(CCCN)C(c2nc3ncccc3c(=O)n2Cc2ccccc2)C(C)C)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a mixture of 2-(1-amino-2-methyl-propyl)-3-benzyl-3-H-pyrido[2,3-d]pyrimidin-4-one (983 mg, 3.188 mmol), Na(OAc)3BH (1.352 g, 6.376 mmol) and dichloromethane (25 mL) was added a solution of t-butyl-N-(3-oxopropyl)-carbamate (714 mg, 3.51 mmol) in dichloromethane (25 mL) dropwise. The reaction mixture was stirred at room temperature for 30 minutes, diluted with 100 mL of dichloromethane, washed with saturated sodium bicarbonate, H2O, brine and dried (Na2SO4). After concentration, the desired product of Formula 108, N-{3-[1-(3-benzyl-4-oxo-3,4-dihydro-pyrido[2,3-d]pyrimidin-2-yl)-2-methyl-proplyamino]-propyl}-carbamic acid tert butyl ester, was obtained as a white solid (1.45 g, 98%).
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[CH:5][NH:4][C:3]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8].[F:12][C:13]([F:32])([F:31])[C:14]1[CH:15]=[CH:16][C:17]2[N:21]=[C:20]([S:22][C:23]3[O:27][C:26]([CH:28]=O)=[CH:25][CH:24]=3)[NH:19][C:18]=2[CH:30]=1.[C:33]1(=[O:40])[CH2:38][CH2:37][CH2:36][C:35](=O)[CH2:34]1>C(O)C>[CH2:10]([O:9][C:7]([C:3]1[NH:4][CH:5]=[C:6]2[CH:28]([C:26]3[O:27][C:23]([S:22][C:20]4[NH:21][C:17]5[CH:16]=[CH:15][C:14]([C:13]([F:32])([F:12])[F:31])=[CH:30][C:18]=5[N:19]=4)=[CH:24][CH:25]=3)[C:38]3[C:33](=[O:40])[CH2:34][CH2:35][CH2:36][C:37]=3[NH:1][C:2]=12)=[O:8])[CH3:11]
Reactant: O=C1CCCC(=O)C1
Reactant: CCOC(=O)c1[nH]ccc1N
Reactant: O=Cc1ccc(Sc2nc3ccc(C(F)(F)F)cc3[nH]2)o1
Solvent: CCO
Product: CCOC(=O)c1[nH]cc2c1NC1=C(C(=O)CCC1)C2c1ccc(Sc2nc3cc(C(F)(F)F)ccc3[nH]2)o1

Procedure:
A mixture of 3-amino-2-ethoxycarbonyl-pyrrole (0.355 g 2.31 mmol), 5-(6-trifluoromethyl-1H-benzimidazol-2-ylsulfanyl)-furan-2-carbaldehyde (0.72 g, 2.31 mmol) and 1,3-cyclohexanedione (0.259 g, 2.31 mmol) in 5 ml ethanol is heated at reflux temperature for 1 hour. The formed insoluble material is filtered off, the filtrate is concentrated under reduced pressure and purified on a silica gel column (120 g) eluted with a mixture of cyclohexane and ethylacetate (7/3, v/v). The fractions containing the expected product are concentrated under reduced pressure and purified via preparative LC/MS method B on a XBridge C18 column (Waters, 30*100 mm) eluted with a 0 to 50% in 12 min. gradient of acetonitrile in 10 mM aqueous ammonium formate pH=9.0 at a 30 ml/min. flow rate to deliver 56 mg of 8-oxo-9-[5-(5-trifluoromethyl-1H-benzimidazol-2-ylsulfanyl)-furan-2-yl]-4,5,6,7,8,9-hexahydro-2H-pyrrolo[3,4-b]quinoline-3-carboxylic acid ethyl ester. Yield=4%.
Reaction SMILES: [I:1][CH2:2][CH2:3][CH2:4][O:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][O:7]1.[C:12]1([P:18]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C1C=CC=CC=1>[I-:1].[O:7]1[CH2:8][CH2:9][CH2:10][CH2:11][CH:6]1[O:5][CH2:4][CH2:3][CH2:2][P+:18]([C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: ICCCOC1CCCCO1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccccc1
Product: [I-]
Product: c1ccc([P+](CCCOC2CCCCO2)(c2ccccc2)c2ccccc2)cc1

Procedure:
A solution of 3-iodo-1-tetrahydro-2-pyranyloxy propane (20.43 g, 75.63 mmole), and triphenylphosphine (19.84 g, 75.63 mmole) in 150 ml of dry benzene was refluxed under an atmosphere of nitrogen for 24 hours. The solvent was evaporated in vacuo to give a sticky gum. This was rinsed with acetonitrile (80 ml) when a white solid precipitated out. The solid was filtered and dried over phosphorous pentoxide at 60° C. in vacuo for 20 hours to give 32.8 g of the title B compound.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[C:13]1[N:14]=[C:15]2[CH:20]=[C:19]([NH2:21])[CH:18]=[CH:17][N:16]2[CH:22]=1.[N:23]1[CH:28]=[CH:27][CH:26]=[C:25]([CH2:29][C:30](O)=[O:31])[CH:24]=1.C(N(CC)C(C)C)(C)C.[Cl-].[Na+].O.O>CN(C=O)C>[CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:3]=1[C:13]1[N:14]=[C:15]2[CH:20]=[C:19]([NH:21][C:30](=[O:31])[CH2:29][C:25]3[CH:24]=[N:23][CH:28]=[CH:27][CH:26]=3)[CH:18]=[CH:17][N:16]2[CH:22]=1
Reactant: O=C(O)Cc1cccnc1
Reactant: Cc1onc(-c2ccccc2)c1-c1cn2ccc(N)cc2n1
Agent: [Cl-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: Cc1onc(-c2ccccc2)c1-c1cn2ccc(NC(=O)Cc3cccnc3)cc2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 3.6 %

Procedure:
A solution of 2-(5-methyl-3-phenyl-isoxazol-4-yl)-imidazo[1,2-a]pyridin-7-ylamine (92 mg, 0.32 mmol) in DMF (0.2 mL) was added to a solution containing 3-pyridylacetic acid (39.5 mg, 0.29 mmol), N,N,N′,N′-tetramethyl-O-(benzotriazol-1-yl)uranium tetrafluoroborate (101.7 mg, 0.32 mmol), N,N-diisopropyl ethyl amine (247 μL, 1.44 mmol) in DMF (0.3 mL) and the resulting mixture stirred at room temperature overnight and then heated at 110° C. for 6 h. The resulting mixture was then poured into a mixture of brine: water (1:1) and extracted with ethyl acetate. The combined organic layers were then washed with brine, dried over sodium sulphate and evaporated to leave a brown solid. Purification by chromatography (SiO2, dichloromethane:methanol=90:10) afforded the title compound (4.3 mg, 4%) which was obtained as a yellow oil. MS: m/e=410.1 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[N:3]([C@@H:18]2[O:32][C@H:31]([CH2:33][O:34]C(C3C(C)=CC=CC=3)=O)[C@@H:20]([O:21]C(C3C(C)=CC=CC=3)=O)[CH2:19]2)[C:4]2[C:9]([C:10]=1[C:11]1[O:12][CH:13]=[CH:14][CH:15]=1)=[CH:8][C:7]([Cl:16])=[C:6]([Cl:17])[CH:5]=2.C[O-].[Na+].CO.C(Cl)(Cl)Cl>CO.C(Cl)(Cl)Cl>[Cl:1][C:2]1[N:3]([C@@H:18]2[O:32][C@H:31]([CH2:33][OH:34])[C@@H:20]([OH:21])[CH2:19]2)[C:4]2[C:9]([C:10]=1[C:11]1[O:12][CH:13]=[CH:14][CH:15]=1)=[CH:8][C:7]([Cl:16])=[C:6]([Cl:17])[CH:5]=2
Reactant: Cc1ccccc1C(=O)OC[C@H]1O[C@@H](n2c(Cl)c(-c3ccco3)c3cc(Cl)c(Cl)cc32)C[C@@H]1OC(=O)c1ccccc1C
Agent: C[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CO
Product: OC[C@H]1O[C@@H](n2c(Cl)c(-c3ccco3)c3cc(Cl)c(Cl)cc32)C[C@@H]1O
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 75.6 %

Procedure:
2,5,6-Trichloro-3-(2-furyl)-1-(3,5-di-O-toluoyl-2-deoxy-β-D-ribofuranosyl)indole (4.76, 142 mg, 0.22 mmol) was suspended in dry MeOH (10 mL) to which was added sodium methoxide (30 mg, 0.56 mmol). The suspension was stirred at room temperature for 45 min, until the solids were completely dissolved. The solvent was then removed under vacuum, and the residue suspended in brine (50 mL). The aqueous suspension was extracted with EtOAc (2×50 mL), and the combined organic extracts were dried over MgSO4, filtered and evaporated to yield a clear oil. The oil was dissolved in CHCl3 (1 mL) and subjected to column chromatography (40×350 mm) on silica gel with 10% MeOH/CHCl3. Fractions containing product were pooled and evaporated to yield a pale yellow solid which was recrystallized from 10% MeOH/CHCl3 and hexane to yield 67 mg (75%) of 4.78 as a white crystalline solid: mp 140-141 C; Rf 0.5 (10% MeOH/CHCl3); 1H-NMR (500 MHz, DMSO-d6): δ 8.46 (s, 1H), 8.14 (s, 1H), 7.86 (s, 1H), 6.88 (d, 1H), 6.68 (s, 1H), 6.47 (dd, 1H), 5.42 (d, 1H, D2O exch.), 5.23 (s, 1H, D2O exch.), 4.45 (d, 1H), 3.89 (d, 1H), 3.73 (s, 2H), 2.55 (m, 1H), 2.13 (m, 1H). 13C-NMR (125 MHz, DMSO-d6): δ 146.54, 142.25, 132.30, 125.61, 124.39, 124.09, 122.64, 120.75, 114.98, 111.51, 106.91, 104.87, 87.25, 85.04, 69.98, 60.91, 38.97. HRMS (EI) m/z calcd. for C17H14Cl3NO4 400.9988, found 400.9986. Anal calcd for C17H14Cl3NO4·¼H2O: C, 50.15; H, 3.59; N, 3.44. Found: C, 50.17; H, 3.65; N, 3.43.
Reaction SMILES: C(OC1N=NC(C#CC2C=CC(C(F)(F)F)=CN=2)=CC=1OCC1C=CC=CC=1)C1C=CC=CC=1.[CH2:35]([O:42][C:43]1[N:44]=[N:45][C:46]([C:57]#[CH:58])=[CH:47][C:48]=1[O:49][CH2:50][C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.[F:59][CH:60]([F:69])[O:61][C:62]1[CH:67]=[CH:66][C:65](I)=[CH:64][CH:63]=1>>[CH2:35]([O:42][C:43]1[N:44]=[N:45][C:46]([C:57]#[C:58][C:65]2[CH:66]=[CH:67][C:62]([O:61][CH:60]([F:69])[F:59])=[CH:63][CH:64]=2)=[CH:47][C:48]=1[O:49][CH2:50][C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1)[C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1
Reactant: FC(F)Oc1ccc(I)cc1
Reactant: C#Cc1cc(OCc2ccccc2)c(OCc2ccccc2)nn1
Agent: FC(F)(F)c1ccc(C#Cc2cc(OCc3ccccc3)c(OCc3ccccc3)nn2)nc1
Product: FC(F)Oc1ccc(C#Cc2cc(OCc3ccccc3)c(OCc3ccccc3)nn2)cc1
Yield: 58 %

Procedure:
Prepared as described for 3,4-bis(benzyloxy)-6-{[5-(trifluoromethyl)pyridin-2-yl]ethynyl}pyridazine (Intermediate 6) from 3,4-bis(benzyloxy)-6-ethynylpyridazine (Intermediate 5) and 1-(difluoromethoxy)-4-iodobenzene in 58% yield.
Reaction SMILES: [S:1]1[CH2:6][CH2:5][CH:4]([OH:7])[CH2:3][CH2:2]1.[CH3:8][C:9]1[CH:14]=[CH:13][C:12]([S:15](Cl)(=[O:17])=[O:16])=[CH:11][CH:10]=1.O>N1C=CC=CC=1>[CH3:8][C:9]1[CH:14]=[CH:13][C:12]([S:15]([O:7][CH:4]2[CH2:5][CH2:6][S:1][CH2:2][CH2:3]2)(=[O:17])=[O:16])=[CH:11][CH:10]=1
Reactant: OC1CCSCC1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Solvent: O
Product: Cc1ccc(S(=O)(=O)OC2CCSCC2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 142 %

Procedure:
To a solution of 4.1 g (0.015 mole) of tetrahydro-4H-thiopyran-4-ol in 40 mL of pyridine, cooled in an ice bath, was added 2.90 g (0.15 mole) of 4-methylphenylsulfonyl chloride, and the reaction mixture was stirred at room temperature for 16 hours. The mixture was poured into a mixture of ice and water, and the whole extracted with diethyl ether. The organic phase was washed with water then with a 10% aqueous solution of sodium hydroxide, dried, and concentrated to give 5.8 g of product as an oil.
Reaction SMILES: O[C:2]1[CH:7]=[CH:6][C:5]2[CH:8]3[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH:9]3[O:21][C:4]=2[CH:3]=1.C(N1CC=CC(O)C1)(OC(C)(C)C)=[O:23].BrC1C=C(OC)C=CC=1O>>[OH:23][C:7]1[CH:2]=[CH:3][C:4]2[O:21][CH:9]3[CH2:10][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:12][CH2:13][CH:8]3[C:5]=2[CH:6]=1
Reactant: CC(C)(C)OC(=O)N1CCC2c3ccc(O)cc3OC2C1
Reactant: CC(C)(C)OC(=O)N1CC=CC(O)C1
Agent: COc1ccc(O)c(Br)c1
Product: CC(C)(C)OC(=O)N1CCC2c3cc(O)ccc3OC2C1

Procedure:
Tert-butyl 6-hydroxy-3,4,4a,9a-tetrahydro[1]benzofuro[2,3-c]pyridine-2(1H)-carboxylate was synthesized as described for tert-butyl 7-hydroxy-3,4,4a,9a-tetrahydro[1]benzofuro[2,3-c]pyridine-2(1H)-carboxylate starting N-boc-3-hydroxy-1,2,3,6-tetrahydropyridine and 2-bromo-4-methoxyphenol.
Reaction SMILES: [C:1]([O:5][C:6](=[O:12])[NH:7][C@@H:8]([CH3:11])[CH2:9][OH:10])([CH3:4])([CH3:3])[CH3:2].[C:13](Cl)(=[O:18])[C:14]([CH3:17])([CH3:16])[CH3:15].CCN(CC)CC.O>C(Cl)Cl>[C:13]([O:10][CH2:9][C@@H:8]([NH:7][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:12])[CH3:11])(=[O:18])[C:14]([CH3:17])([CH3:16])[CH3:15]
Reactant: C[C@@H](CO)NC(=O)OC(C)(C)C
Reactant: CC(C)(C)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: C[C@@H](COC(=O)C(C)(C)C)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of the commercially available tert-butyl[(1S)-2-hydroxy-1-methylethyl]carbamate (1.0 eq.) in DCM (0.19M), pivaloyl chloride (1.1 eq.) and Et3N (1.1 eq.) were added. The reaction mixture was stirred at RT for 48 h, then water was added and the organic phase was separated and washed with 10% aqueous citric acid. The residue was purified by column chromatography on silica gel eluting with 92:8 PE/EtOAc.
Reaction SMILES: C1C[O:4][CH2:3]C1.C(N1C=CN=C1)(N1C=CN=C1)=O.[Cl:18][C:19]1[C:28]([NH2:29])=[C:27]([NH:30][C@@H:31]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH3:32])[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[N:20]=1.O>N1C=CC=CC=1>[Cl:18][C:19]1[C:28]2[N:29]=[C:3]([OH:4])[N:30]([C@@H:31]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[CH3:32])[C:27]=2[C:26]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[N:20]=1
Reactant: C[C@@H](Nc1c(N)c(Cl)nc2ccccc12)c1ccccc1
Reactant: C1CCOC1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: c1ccncc1
Solvent: O
Product: C[C@H](c1ccccc1)n1c(O)nc2c(Cl)nc3ccccc3c21
Temperature: 90 °C
Reaction time: 8 h

Procedure:
THF (100 mL) and 1,1′-carbonyldiimidazole (8.1 g, 50.5 mmol) were sequentially added to a solution of 2-chloro-N4-[(1R)-1-phenylethyl]quinoline-3,4-diamine (10.0 g, 33.6 mmol) in pyridine (100 mL), and the reaction was heated at 90° C. overnight. An analysis by LC/MS indicated the presence of starting material, and additional 1,1′-carbonyldiimidazole (6 equivalents) was added in portions as heating at 90° C. was continued for a second day. The reaction was cooled to approximately 0° C., and water (300 mL) was added. The mixture was stirred overnight. A precipitate was present and was isolated by filtration and washed with water and diethyl ether to provide 6.67 g of 4-chloro-1-[(1R)-1-phenylethyl]-1H-imidazo[4,5-c]quinolin-2-ol. A small portion of the product was triturated with hot acetonitrile, isolated by filtration, washed with cold acetonitrile and diethyl ether, and dried under vacuum to provide a white solid with the following analytical data, mp 227-229° C.
Reaction SMILES: Cl[C:2]1[C:7]([CH2:8][C:9]2[CH:28]=[CH:27][C:12]3/[C:13](=[C:23](/[CH3:26])\[C:24]#[N:25])/[C:14]4[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:15]=4[O:16][CH2:17][C:11]=3[CH:10]=2)=[C:6]([CH2:29][CH2:30][CH3:31])[N:5]=[C:4]([CH3:32])[N:3]=1.[NH:33]1[CH2:36][CH2:35][CH2:34]1>C(O)C>[N:33]1([C:2]2[C:7]([CH2:8][C:9]3[CH:28]=[CH:27][C:12]4/[C:13](=[C:23](/[CH3:26])\[C:24]#[N:25])/[C:14]5[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:15]=5[O:16][CH2:17][C:11]=4[CH:10]=3)=[C:6]([CH2:29][CH2:30][CH3:31])[N:5]=[C:4]([CH3:32])[N:3]=2)[CH2:36][CH2:35][CH2:34]1
Reactant: C1CNC1
Reactant: CCCc1nc(C)nc(Cl)c1Cc1ccc2c(c1)COc1cc(F)ccc1/C2=C(\C)C#N
Solvent: CCO
Product: CCCc1nc(C)nc(N2CCC2)c1Cc1ccc2c(c1)COc1cc(F)ccc1/C2=C(\C)C#N
Temperature: 50 °C
Yield: 14.1 %

Procedure:
[step 4] (E)-2-{8-[(4-chloro-2-methyl-6-propylpyrimidin-5-yl)methyl]-3-fluorodibenzo[b,e]oxepin-11(6H)-ylidene}propanenitrile (140 mg, 3.13 mmol) obtained in step 3 was dissolved in ethanol (3 mL), azetidine (0.148 mL, 2.19 mmol) was added, and the mixture was stirred with heating at 50° C. for 2 hr. The mixture was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=1/2 v/v) to give the title compound (145 mg, 99%).
Reaction SMILES: CN(C)C=O.C(=O)([O-])[O-].[K+].[K+].I[C:13]1[C:18]([O:19][C:20]2[C:29]3[C:24](=[CH:25][C:26]([O:32][CH3:33])=[C:27]([O:30][CH3:31])[CH:28]=3)[N:23]=[CH:22][CH:21]=2)=[CH:17][CH:16]=[C:15]([CH3:34])[N:14]=1.B(O)(O)[C:36]1[CH:41]=[CH:40][CH:39]=[C:38]([C:42]([NH2:44])=[O:43])[CH:37]=1>O>[CH3:31][O:30][C:27]1[CH:28]=[C:29]2[C:24](=[CH:25][C:26]=1[O:32][CH3:33])[N:23]=[CH:22][CH:21]=[C:20]2[O:19][C:18]1[C:13]([C:36]2[CH:37]=[C:38]([CH:39]=[CH:40][CH:41]=2)[C:42]([NH2:44])=[O:43])=[N:14][C:15]([CH3:34])=[CH:16][CH:17]=1
Reactant: COc1cc2nccc(Oc3ccc(C)nc3I)c2cc1OC
Reactant: NC(=O)c1cccc(B(O)O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc2nccc(Oc3ccc(C)nc3-c3cccc(C(N)=O)c3)c2cc1OC
Temperature: 70 °C
Reaction time: 5 h
Yield: 99.6 %

Procedure:
N,N-Dimethylformamide (1 ml) and a 2 M aqueous potassium carbonate solution (1 ml) were added to 4-(2-iodo-6-methyl-pyridin-3-yloxy)-6,7-dimethoxy-quinoline (compound 116) (50 mg), tetrakistriphenylphosphine palladium (14 mg), and (3-aminocarbonyl)phenylboronic acid (58 mg) under an argon atmosphere, and the mixture was stirred at 70° C. for 5 hr. The reaction solution was cooled to room temperature, water was then added thereto, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using chloroform-methanol to give the title compound (49 mg, yield 100%).
Reaction SMILES: C[O:2][C:3](=O)[CH:4]([C:8](=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH:5]1[CH2:7][CH2:6]1.Cl.[NH2:18]O.C[O-].[Na+]>>[CH:5]1([C:4]2[C:3]([OH:2])=[N:18][O:15][C:8]=2[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:7][CH2:6]1
Reactant: COC(=O)C(C(=O)c1ccccc1)C1CC1
Reactant: NO
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Product: Oc1noc(-c2ccccc2)c1C1CC1
Yield: 38.6 %

Procedure:
2-Benzoyl-2-cyclopropylacetic acid methyl ester (0.9 g), hydroxylamine hydrochloride (0.6 g) and sodium methoxide (28% methanol solution, 4.0 ml) were subjected to reaction and post-treatment in a similar manner to that described in Reference example 8(b) to obtain the title compound (0.32 g, 39%) as colorless crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[CH:9][S:10][C:3]=12.[Li]CCCC.Br[C:17]1[CH:18]=[CH:19][C:20]([CH:23]2[O:28][CH2:27][CH2:26][CH2:25][O:24]2)=[N:21][CH:22]=1>C1COCC1.[Cl-].[Cl-].[Zn+2]>[O:24]1[CH2:25][CH2:26][CH2:27][O:28][CH:23]1[C:20]1[N:21]=[CH:22][C:17]([C:9]2[S:10][C:3]3[C:4](=[N:5][CH:6]=[CH:7][C:2]=3[Cl:1])[CH:8]=2)=[CH:18][CH:19]=1
Reactant: Brc1ccc(C2OCCCO2)nc1
Reactant: Clc1ccnc2ccsc12
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [Zn+2]
Solvent: C1CCOC1
Product: Clc1ccnc2cc(-c3ccc(C4OCCCO4)nc3)sc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 58.8 %

Procedure:
To a stirred solution of 7-chlorothieno[3,2-b]pyridine (12.08 g, 71.2 mmol) in THF (138 mL) at −15° C. was added n-BuLi (30.7 mL, 77.0 mmol). After 30 min, a solution of ZnCl2 0.5 M in THF (142 mL, 71.2 mmol) was added at −15° C. and the reaction mixture was allowed to warm to RT over 45 min. A solution of palladium tetrakistriphenylphosphine (1.266 g, 1.096 mmol) and bromide 278 (13.37 g, 54.8 mmol) in THF (18.5 mL) was added and the mixture was heated to reflux for 2 h then concentrated. The residue was diluted with water and ammonium hydroxide and extracted with DCM. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was triturated with MTBE to afford the title compound 279 (10.70 g, 32.2 mmol, 59% yield) as light brown solid. MS (m/z): 333.33 (M+H).
Reaction SMILES: Cl.Cl.[NH2:3][C:4]([C:16]1[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[C:18]([F:24])[CH:17]=1)([C:6]1[N:7]([C:11]#CC2CC2)[CH:8]=[N:9][CH:10]=1)[CH3:5].[CH3:25][O:26][C:27]1[CH:28]=[C:29]([S:33]([NH:36][CH2:37][CH2:38][C:39]([OH:41])=O)(=[O:35])=[O:34])[CH:30]=[CH:31][CH:32]=1.CN([P+](ON1N=NC2C=[CH:57][CH:58]=[CH:59][C:54]1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F.ON1C2N=CC=CC=2N=N1.CN1CCOCC1>CN(C=O)C>[C:20]([C:19]1[CH:22]=[CH:23][C:16]([C:4]([NH:3][C:39](=[O:41])[CH2:38][CH2:37][NH:36][S:33]([C:29]2[CH:30]=[CH:31][CH:32]=[C:27]([O:26][CH3:25])[CH:28]=2)(=[O:34])=[O:35])([C:6]2[N:7]([CH3:11])[CH:8]=[N:9][CH:10]=2)[C:5]#[C:57][CH:58]2[CH2:54][CH2:59]2)=[CH:17][C:18]=1[F:24])#[N:21]
Reactant: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Reactant: COc1cccc(S(=O)(=O)NCCC(=O)O)c1
Reactant: CC(N)(c1ccc(C#N)c(F)c1)c1cncn1C#CC1CC1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: COc1cccc(S(=O)(=O)NCCC(=O)NC(C#CC2CC2)(c2ccc(C#N)c(F)c2)c2cncn2C)c1
Reaction time: 18 h

Procedure:
(+)-4-[1-Amino-1-(3-(cyclopropylethynyl)-3H-imidazol-4-yl)-ethyl]-2-fluoro-benzonitrile bishydrochloride (0.120 g, 0.408 mmol), 3-(3-methoxy-benzenesulfonylamino)-propionic acid (Example 7, Step B) (0.1273 g, 0.49 mmol), Bop reagent (0.186 g, 0.49 mmol), 1-hydroxy-7-aza-benzotriazole (HOAT) (0.067 g, 0.49 mmol) and N-methyl morpholine(0.134 mL, 1.22 mmol) were dissolved in DMF (5.0 mL) and stirred for 18 h. The reaction mixture was concentrated in vacuo, partitioned between EtOAc and saturated NaHCO3 solution, the organic layer separated, washed with H2O, brine, and dried (MgSO4). Filtration and concentration in vacuo gave the title compound after chromatography on an ISCO Combiflash eluting with 2-5% MeOH/CH2Cl2 with NH4OH. MS (M+1) 536.
Reaction SMILES: [O:1]1CCO[CH:2]1[CH2:6][CH2:7][C@H:8]1[CH2:13][CH2:12][C@H:11]([C@H:14]2[CH2:19][CH2:18][C@H:17]([C:20]#[N:21])[CH2:16][CH2:15]2)[CH2:10][CH2:9]1.C(O)(=O)C.O1CCOCC1>O>[C:20]([C@H:17]1[CH2:16][CH2:15][C@H:14]([C@H:11]2[CH2:12][CH2:13][C@H:8]([CH2:7][CH2:6][CH:2]=[O:1])[CH2:9][CH2:10]2)[CH2:19][CH2:18]1)#[N:21]
Reactant: N#C[C@H]1CC[C@H]([C@H]2CC[C@H](CCC3OCCO3)CC2)CC1
Solvent: CC(=O)O
Solvent: C1COCCO1
Solvent: O
Product: N#C[C@H]1CC[C@H]([C@H]2CC[C@H](CCC=O)CC2)CC1
Temperature: 100 °C
Reaction time: 1 h

Procedure:
3.0 g of crude trans-4-[trans-4-[2-(I.3-dioxolan-2-yl)ethyl]cyclohexyl)cyclohexanecarbonitrile were suspended in 50 ml of water, 25 ml of glacial acetic acid and 10 ml of dioxan while gassing with argon and stirred at 100° C. for 1 hour. Thereafter, the reaction solution was treated with 100 ml of water. The aqueous phase was separated and extracted three times with 100 ml of diethyl ether each time. The organic phases were washed with 100 ml of dilute sodium hydrogen carbonate solution and with 100 ml of water, dried over magnesium sulfate, filtered and concentrated. Recrystallization of the yellow crystals obtained (2.25 g) from 60 ml of hexane gave 1.98 g of 3-[trans-4-(trans-4-cyanocyclohexyl)cyclohexyl]-propionaldehyde as colorless crystals.