Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:10]=1[C:11](=[O:20])[C:12]([CH3:19])=[N:13][NH:14]2.Br[CH:22]([CH2:26][CH2:27][CH3:28])[CH2:23][CH2:24][CH3:25].[H-].[Na+]>CN1CCCC1>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:10]=1[C:11](=[O:20])[C:12]([CH3:19])=[N:13][N:14]2[CH:22]([CH2:26][CH2:27][CH3:28])[CH2:23][CH2:24][CH3:25]
Reactant: CCCC(Br)CCC
Reactant: Cc1ccc(-c2cccc3[nH]nc(C)c(=O)c23)c(C)c1
Agent: CN1CCCC1
Agent: [H-]
Agent: [Na+]
Product: CCCC(CCC)n1nc(C)c(=O)c2c(-c3ccc(C)cc3C)cccc21
Temperature: 25 °C
Reaction time: 1.25 h
Yield: 75 %

Procedure:
To 0.041 g (0.16 mmol) of 5-(2,4-dimethylphenyl)-3-methylcinnolin-4(1H)-one in 0.5 mL of N-methylpyrrolidine was added 0.069 mL of 4-bromoheptane and 0.012 g (0.31 mmol) of sodium hydride (60% dispersion in mineral oil). The mixture was stirred for 75 min. at room temperature and quenched with water. The mixture was extracted with ethyl acetate and the combined organics were washed with water and brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by flash chromatography eluting with a 8% ethyl acetate/hexanes mixture to give 0.042 g (75%) of the title compound as a light green-yellow semisolid.
Reaction SMILES: P(OC1C=CC=CC=1)(OC1C=CC=CC=1)OC1C=CC=CC=1.[NH:23]1[CH:27]=[CH:26][N:25]=[CH:24]1.[Cl:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[C:35]([C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)O>C1(C)C=CC=CC=1>[Cl:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[C:35]([C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1)([C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)[N:23]1[CH:27]=[CH:26][N:25]=[CH:24]1
Reactant: c1c[nH]cn1
Reactant: OC(c1ccccc1)(c1ccccc1)c1ccccc1Cl
Agent: c1ccc(OP(Oc2ccccc2)Oc2ccccc2)cc1
Solvent: Cc1ccccc1
Product: Clc1ccccc1C(c1ccccc1)(c1ccccc1)n1ccnc1
Yield: 81.2 %

Procedure:
A mixture of toluene (20 ml), triphenyl phosphite (2.07 g, 6.7 mmole), imidazole (1.09 g, 16 mmole) and o-chlorophenyldiphenylmethanol (2.95 g, 10 mmole) obtained in Example 1 (B) was refluxed for 4 hours. The reaction mixture was treated in the same manner as in Example 3 to give 2.80 g of 1-(o-chlorophenyldiphenylmethyl)imidazole. Yield, 81%. M.P., 142°-143° C.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]2[C:6]([C:10](=[O:12])[CH3:11])=[CH:7][CH:8]=[CH:9][C:2]1=2.[Br:13]C1C2C=CSC=2C=CC=1.C(OCCCC)=C>[Pd]>[S:1]1[CH:5]=[CH:4][C:3]2[C:6]([C:10](=[O:12])[CH2:11][Br:13])=[CH:7][CH:8]=[CH:9][C:2]1=2
Reactant: CC(=O)c1cccc2sccc12
Reactant: Brc1cccc2sccc12
Agent: [Pd]
Agent: C=COCCCC
Product: O=C(CBr)c1cccc2sccc12

Procedure:
1-benzo[b]thiophen-4-yl-2-bromo-ethanone was synthesised from 1-benzo[b]thiophen-4-yl-ethanone (available by the palladium coupling of 4-bromobenzo[b]thiophene with 1-vinyloxy-butane) according to the method in Example 10A(a) (6.8 g, 92%) as an orange oil; 1H NMR (CDCl3): 4.6 (2H, s), 7.4 (1H, t, J=7.8 Hz), 7.65 (1H, d, J=5.7 Hz), 7.95 (1H, dd, J=7.8, 0.9 Hz), 8.1 (1H, dt, J=7.8, 0.9 Hz), 8.3 (1H, dd, J=5.7, 0.9 Hz).
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[Cl:16][C:17]1[CH:18]=[C:19]([CH:23]([OH:27])[C:24]([OH:26])=O)[CH:20]=[CH:21][CH:22]=1.[CH3:28][C:29]([CH3:32])([NH2:31])[CH3:30].ON1C2C=CC=CC=2N=N1>CN(C)C=O>[CH3:28][C:29]([NH:31][C:24](=[O:26])[CH:23]([OH:27])[C:19]1[CH:20]=[CH:21][CH:22]=[C:17]([Cl:16])[CH:18]=1)([CH3:32])[CH3:30]
Reactant: O=C(O)C(O)c1cccc(Cl)c1
Reactant: CC(C)(C)N
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CC(C)(C)NC(=O)C(O)c1cccc(Cl)c1

Procedure:
Dicyclohexylcarbodiimide (11.0Sg) was added in portions to a cooled, stirred mixture of 3-chloro-α-hydroxybenzeneacetic acid (10g), 1,1-dimethylethanamine (3.92g, 5.63ml) and 1-hydroxybenzotriazole (7.24g) in dry dimethylformamide (100ml). The mixture was stirred at ambient temperature for 20h., filtered and the filtrate evaporated. The residual oil was taken up in ethyl acetate, filtered, and the filtrate washed sequentially with sodium carbonate solution, hydrochloric acid (2N) and water. The organic layer was dried (MgSO4), filtered, and evaporated to an oil which was chromatographed on silica. Elution with chloroform gave N-[1,1-dimethylethyl]-3-chloro-α-hydroxybenzeneacetamide, 1.71g, as an oil which crystallized on standing, m.p. 93-99° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([Br:17])=[C:4]2[N:11]([OH:12])[C:10]([C:13]([F:16])([F:15])[F:14])=[N:9][C:5]2=[N:6][C:7]=1[Br:8].[CH3:18][N:19]=[C:20]=[O:21].C(N(CC)CC)C>C(OCC)C>[CH3:18][NH:19][C:20]([O:12][N:11]1[C:4]2[C:5](=[N:6][C:7]([Br:8])=[C:2]([Cl:1])[C:3]=2[Br:17])[N:9]=[C:10]1[C:13]([F:14])([F:16])[F:15])=[O:21]
Reactant: CN=C=O
Reactant: On1c(C(F)(F)F)nc2nc(Br)c(Cl)c(Br)c21
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CNC(=O)On1c(C(F)(F)F)nc2nc(Br)c(Cl)c(Br)c21

Procedure:
6-Chloro-5,7-dibromo-1-hydroxy-2-(trifluoromethyl)-1H-imidazo(4,5-b)pyridine (0.9 gram) was mixed with ether (15 milliliters) and methyl isocyanate (2 milliliters) and stirred for fifteen minutes. Triethylamine (0.01 milliliter) was added, and the solution became homogenous. It was permitted to stand for sixteen hours, diluted with 50 milliliters diethyl ether; washed with 0.5N HCl, water, and saturated NaCl; then dried over magnesium sulfate, and evaporated. The resulting 1-(methylcarbamoyloxy)-6 -chloro-5,7 -dibromo-2-(trifluoromethyl)-1H-imidazo(4,5-b)pyridine product was recrystallized from chloroform, m.p., 216° C.
Reaction SMILES: [C:1]([NH:8][C@H:9]([C@@H:17]([O:38][Si](C(C)(C)C)(C)C)[CH2:18][C@@H:19]([NH:27][C:28]([O:30][CH2:31][C:32]1[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=1)=[O:29])[CH2:20][C:21]1[CH:26]=CN=[CH:23][CH:22]=1)[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C[OH:47]>ClCCl>[C:1]([NH:8][C@H:9]([C@@H:17]([OH:38])[CH2:18][C@@H:19]([NH:27][C:28]([O:30][CH2:31][C:32]1[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=1)=[O:29])[CH2:20][C:21]1[CH:22]=[CH:23][O:47][CH:26]=1)[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([O:3][C:4]([CH3:6])([CH3:7])[CH3:5])=[O:2]
Reactant: CO
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@H](C[C@H](Cc1ccncc1)NC(=O)OCc1cccnc1)O[Si](C)(C)C(C)(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@@H](O)C[C@H](Cc1ccoc1)NC(=O)OCc1cccnc1
Yield: 60 %

Procedure:
Using the procedure of Example 4G but replacing (2S,3S,5S)-2-(Boc-amino)-5-(N-((3-pyridinyl)methoxy-carbonyl)amino)-1-phenyl-6-(4-pyridinyl)-3-(tert-butyl-dimethylsilyloxy)hexane with the resultant compound of Example 5D provided, after silica gel chromatography using 5% methanol in dichloromethane, 334.5 mg (60%) of the desired compound as a white solid.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Br:8])[CH:7]=1.[CH3:9][O:10][C:11]1[CH:16]=[CH:15][C:14](B(O)O)=[CH:13][CH:12]=1.C([O-])([O-])=O.[Na+].[Na+]>CC#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>[Br:8][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([C:14]2[CH:15]=[CH:16][C:11]([O:10][CH3:9])=[CH:12][CH:13]=2)[CH:7]=1
Reactant: Brc1cncc(Br)c1
Reactant: COc1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: COc1ccc(-c2cncc(Br)c2)cc1

Procedure:
To a solution of 3,5-dibromopyridine (Sigma-Aldrich, St. Louis, USA) (1 eq, 8.4 mmol, 2 g) and 4-methoxy-phenylboronic acid (Sigma-Aldrich, St. Louis, USA) (1 eq, 8.4 mmol, 1.30 g) in MeCN (12 ml), Na2CO3 (2 eq, 16.7 mmol, 1.79 g) and Pd(PPh3)4 (0.04 eq, 0.334 mmol, 398 mg) are added. The mixture is heated using microwave radiation at 140° C. for 10 min. The solvents are evaporated, the residue is taken up in aqueous NaOH solution (1 M) and extracted with DCM. The organic layer is washed with brine, dried over MgSO4, filtered, and concentrated in vacuo. Purification by column chromatography (hexane/EtOAc) yields the title compound; [M+H]+=264/266.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:15]([N+:16]([O-:18])=[O:17])=[CH:14][C:6]2[N:7]([CH3:13])[C:8](=[O:12])[CH2:9][NH:10][CH2:11][C:5]=2[CH:4]=1.[CH:19]1([CH2:22]Br)[CH2:21][CH2:20]1.[I-].[Na+].C(N(CC)C(C)C)(C)C.CN(C)C=O>>[CH:19]1([CH2:22][N:10]2[CH2:11][C:5]3[CH:4]=[C:3]([O:2][CH3:1])[C:15]([N+:16]([O-:18])=[O:17])=[CH:14][C:6]=3[N:7]([CH3:13])[C:8](=[O:12])[CH2:9]2)[CH2:21][CH2:20]1
Reactant: COc1cc2c(cc1[N+](=O)[O-])N(C)C(=O)CNC2
Reactant: BrCC1CC1
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc2c(cc1[N+](=O)[O-])N(C)C(=O)CN(CC1CC1)C2

Procedure:
A mixture of 7-Methoxy-1-methyl-8-nitro-1,3,4,5-tetrahydro-benzo[e][1,4]diazepin-2-one (0.50 g, 0.0020 mol), [B] Cyclopropylmethyl bromide (0.55 mL, 0.0057 mol), Sodium iodide (0.003 g, 0.00002 mol) and N,N-Diisopropylethylamine (0.87 mL, 0.0050 mol) in N,N-Dimethylformamide (4 mL, 0.05 mol) was reacted in an analogous manner to example 743-C to give 4-Cyclopropylmethyl-7-methoxy-1-methyl-8-nitro-1,3,4,5-tetrahydro-benzo[e][1,4]diazepin-2-one as a red oil. (0.56 g, 92%). LCMS (m/e) 306 (M+1); 1H-NMR (DMSO, 400 MHz) δ 7.92 (s, 1H), 7.44 (s, 1H), 3.95 (s, 3H), 3.66 (s, 2H), 3.26 (s, 2H), 3.13 (s, 2H), 2.89 (s, 1H), 2.73 s, 1H), 2.44-2.42 (d, 2H, J=6.57 Hz), 1.30-1.20 (br, 1H), 0.95-0.87 (br, 2H), 0.50 (d, 2H, J=7.83 Hz), 0.18-0.16 (d, 2H, J=4.80 Hz).
Reaction SMILES: [CH3:1][S:2][C:3]1[N:8]=[C:7]([NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:6]([C:16]([OH:18])=O)=[CH:5][N:4]=1.C(N(CC)CC)C.N1C(F)=NC(F)=NC=1[F:28]>C(Cl)Cl>[CH3:1][S:2][C:3]1[N:8]=[C:7]([NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:6]([C:16]([F:28])=[O:18])=[CH:5][N:4]=1
Reactant: Fc1nc(F)nc(F)n1
Reactant: CSc1ncc(C(=O)O)c(Nc2ccccc2)n1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CSc1ncc(C(=O)F)c(Nc2ccccc2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 103.4 %

Procedure:
To a solution containing 2.88 g (11.02 mmol) of the product prepared in step 20.2 and 2.1 mL (15.0 mmol) of triethylamine in 55 mL of CH2Cl2 are added 1.40 mL (16.53 mmol) of cyanuric fluoride. The mixture is stirred at room temperature overnight and washed twice with 50 mL of ice-cold aqueous NaHCO3 solution. The organic phase is washed with 75 mL of ice-cold water and dried over MgSO4. The solvent is then evaporated off under reduced pressure. 3.0 g of the expected product are obtained in the form of a yellow solid. The yield is quantitative.
Reaction SMILES: [S:1]1[C:13]2[C:12]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=3[NH:6][C:5]=2[C:4](=[O:14])[CH:3]=[CH:2]1.F[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[N+:22]([O-:24])=[O:23]>>[N+:22]([C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[N:6]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=2[C:13]2[S:1][CH:2]=[CH:3][C:4](=[O:14])[C:5]1=2)([O-:24])=[O:23]
Reactant: O=c1ccsc2c1[nH]c1ccccc12
Reactant: O=[N+]([O-])c1ccccc1F
Product: O=c1ccsc2c3ccccc3n(-c3ccccc3[N+](=O)[O-])c12
Temperature: 95 °C
Reaction time: 40 h

Procedure:
By the same method as described in Example 7, 8.9 g of thiopyrano [3,2-b]indol-4(5H)-one is alkylated with o-fluoronitrobenzene, except the reaction is stirred for 40 hours at 95° C. The yield of product is 9.2 g, mp 207°-208° C after recrystallization from ether-hexane.
Reaction SMILES: Cl[CH2:2][C:3]1[NH:4][C:5](=[O:12])[C:6]2[S:11][CH:10]=[CH:9][C:7]=2[N:8]=1.[Cl:13][C:14]1[C:15]([O:37][CH3:38])=[CH:16][C:17]([O:35][CH3:36])=[C:18]([CH2:20][CH2:21][C:22]2([CH:30]3[CH2:34][CH2:33][CH2:32][CH2:31]3)[O:27][C:26](=[O:28])[CH2:25][C:24](=[O:29])[CH2:23]2)[CH:19]=1>>[Cl:13][C:14]1[C:15]([O:37][CH3:38])=[CH:16][C:17]([O:35][CH3:36])=[C:18]([CH2:20][CH2:21][C:22]2([CH:30]3[CH2:34][CH2:33][CH2:32][CH2:31]3)[O:27][C:26](=[O:28])[C:25]([CH2:2][C:3]3[NH:4][C:5](=[O:12])[C:6]4[S:11][CH:10]=[CH:9][C:7]=4[N:8]=3)=[C:24]([OH:29])[CH2:23]2)[CH:19]=1
Reactant: O=c1[nH]c(CCl)nc2ccsc12
Reactant: COc1cc(OC)c(CCC2(C3CCCC3)CC(=O)CC(=O)O2)cc1Cl
Product: COc1cc(OC)c(CCC2(C3CCCC3)CC(O)=C(Cc3nc4ccsc4c(=O)[nH]3)C(=O)O2)cc1Cl
Yield: 20 %

Procedure:
The title compound was prepared as described in Example B(53), using 2-(chloromethyl)thieno[3,2-d]-pyrimidine-4(3H)-one (Example B(56), Step 1) in place of 5-(chloromethyl)-1,3-dimethyl-1H-1,2,4-triazole, and using 6-[2-(5-chloro-2,4-dimethoxyphenyl)ethyl]-6-cyclopentyldihydro-2H-pyran-2,4(3H)-dione in place of 6-[2-(3-chloro-4-methoxyphenyl)ethyl]-6-cyclopentyldihydro-2H-pyran-2,4(3H)-dione. Yield: 20%. 1H NMR (300 MHz, DMSO-d6) δ 1.24-1.67 (m, 8H), 1.90 (m, 1H), 2.04 (m, 1H), 2.32 (m, 1H), 2.40-2.54 (m, 3H, overlap with DMSO-d5), 2.71 (d, J=18 Hz, 1H), 3.52 (ABQ pattern, J=15 Hz, 2H, overlap with H2O), 3.69 (s, 3H), 3.80 (s, 3H), 6.65 (s, 1H), 6.71 (d, J=5.4 Hz, 1H), 7.05 (s, 1H), 7.96 (d, J=5.4 Hz, 1H), 10.88 (br s, 1H), 12.26 (br s, 1H). LC-MS (APCI) calcd for C27H29ClN2O6S: 544.14; found (M+H+) 544.9 m/z.
Reaction SMILES: [N:1]1([C:10]2[O:11][C:12]3[CH:18]=[C:17]([CH2:19][C:20]([O:22]C)=[O:21])[CH:16]=[CH:15][C:13]=3[N:14]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[OH-].[Na+]>C1COCC1.CO>[N:1]1([C:10]2[O:11][C:12]3[CH:18]=[C:17]([CH2:19][C:20]([OH:22])=[O:21])[CH:16]=[CH:15][C:13]=3[N:14]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1
Reactant: COC(=O)Cc1ccc2nc(N3CCc4ccccc43)oc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)Cc1ccc2nc(N3CCc4ccccc43)oc2c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 84.3 %

Procedure:
To methyl (2-(1-indolinyl)-6-benzoxazolyl)acetate (200 mg, 0.649 mmol) were added THF/methanol (6/3 ml) and 1N NaOH (3 ml). The resulting mixture was stirred at room temperature for 1.5 hours. The reaction mixture was distilled under reduced pressure to remove the solvent. To the residue was added 1N HCl to acidify the residue therewith. The crystals thus precipitated were collected by filtration under reduced pressure, washed with water and dried under reduced pressure to give (2-(1-indolinyl)-6-benzoxazolyl)acetic acid (161 mg, 84%) as a brown solid.
Reaction SMILES: Cl[C:2]1[C:7]2[C:8](=[O:22])[C:9]3[CH:10]=[C:11]([C:16]4[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=4)[CH:12]=[CH:13][C:14]=3[O:15][C:6]=2[CH:5]=[CH:4][N:3]=1.C([O-])(=[O:25])C.[NH4+]>C(O)(=O)C>[N:18]1[CH:19]=[CH:20][CH:21]=[C:16]([C:11]2[CH:12]=[CH:13][C:14]3[O:15][C:6]4[CH:5]=[CH:4][NH:3][C:2](=[O:25])[C:7]=4[C:8](=[O:22])[C:9]=3[CH:10]=2)[CH:17]=1
Reactant: O=c1c2cc(-c3cccnc3)ccc2oc2ccnc(Cl)c12
Reactant: CC(=O)[O-]
Agent: [NH4+]
Solvent: CC(=O)O
Product: O=c1[nH]ccc2oc3ccc(-c4cccnc4)cc3c(=O)c12
Temperature: 65 °C
Reaction time: 20 h

Procedure:
A resealable tube was charged with 1-chloro-8-(pyridin-3-yl)-10H-chromeno[3,2-c]pyridin-10-one (0.500 g, 1.620 mmol) and acetic acid (12.5 mL). Ammonium acetate (1.248 g, 16.20 mmol) was added, the system was purged with argon, and the tube was sealed. The mixture stirred at 65° C. for 20 h. The reaction mixture was filtered and washed with water. The filter cake was concentrated down from heptanes to afford 8-(pyridin-3-yl)-1H-chromeno[3,2-c]pyridine-1,10(2H)-dione as an off-white solid. MS m/z=291.0 [M+H]+. Calcd for C17H10N2O3: 290.07.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:8])[C:4]([CH2:6]Br)=[CH2:5].[CH3:9][NH:10][CH3:11].C1COCC1.C([O-])([O-])=O.[K+].[K+]>CC#N>[CH3:1][O:2][C:3](=[O:8])[C:4]([CH2:6][N:10]([CH3:11])[CH3:9])=[CH2:5]
Reactant: C=C(CBr)C(=O)OC
Reactant: CNC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: C1CCOC1
Product: C=C(CN(C)C)C(=O)OC
Reaction time: 8 h

Procedure:
To a stirred solution of 2-bromomethyl-acrylic acid methyl ester (1 g, 5.59 mmol) in dry CH3CN (20 ml) was added 2M solution of dimethylamine in THF (3.07 ml, 6.14 mmol) followed by K2CO3 (0.93 g, 6.7 mmol). The reaction mixture was stirred overnight, filtered and washed with CH2Cl2. The filtrate was concentrated. The crude product was used in next reaction without further purification.
Reaction SMILES: Br[C:2]1[O:6][C:5]([N:7]2[CH2:11][C@:10]3([CH:16]4[CH2:17][CH2:18][N:13]([CH2:14][CH2:15]4)[CH2:12]3)[O:9][C:8]2=[O:19])=[CH:4][CH:3]=1.[N:20]1[CH:25]=[CH:24][CH:23]=[C:22](B(O)O)[CH:21]=1>>[N:20]1[CH:25]=[CH:24][CH:23]=[C:22]([C:2]2[O:6][C:5]([N:7]3[CH2:11][C@:10]4([CH:16]5[CH2:17][CH2:18][N:13]([CH2:14][CH2:15]5)[CH2:12]4)[O:9][C:8]3=[O:19])=[CH:4][CH:3]=2)[CH:21]=1
Reactant: OB(O)c1cccnc1
Reactant: O=C1O[C@]2(CN3CCC2CC3)CN1c1ccc(Br)o1
Product: O=C1O[C@]2(CN3CCC2CC3)CN1c1ccc(-c2cccnc2)o1

Procedure:
The title compound was prepared by a method analogous to that described in Example 12 from (R)-3′-(5-bromofuran-2-yl)spiro[1-azabicyclo[2.2.2]octan-3,5′-oxazolidin]-2′-one and pyridine-3-boronic acid. The title compound (206 mg) was obtained as a pale solid, m/z 326 (MH+).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[C:8](F)[C:5]([C:6]#[N:7])=[CH:4][N:3]=1.[O:11]1[CH2:15][CH2:14][C@H:13]([OH:16])[CH2:12]1>>[NH2:1][C:2]1[CH:9]=[C:8]([O:16][C@H:13]2[CH2:14][CH2:15][O:11][CH2:12]2)[C:5]([C:6]#[N:7])=[CH:4][N:3]=1
Reactant: N#Cc1cnc(N)cc1F
Reactant: O[C@H]1CCOC1
Product: N#Cc1cnc(N)cc1O[C@H]1CCOC1

Procedure:
From intermediate 21 and (S)-tetrahydrofuran-3-ol, reacted in an analogous manner to the preparation of intermediate 47. (UPLC-MS 3) tR 0.48 min; ESI-MS 206.1 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C@@H:7]([CH3:12])[CH2:6][C@H:5]2[NH:13][C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=1.C(N(CC)CC)C.[CH:28]1([C:34](Cl)=[O:35])[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1.[Cl-].[NH4+]>ClCCl>[CH:28]1([C:34]([N:8]2[C:9]3[C:4](=[CH:3][C:2]([F:1])=[CH:11][CH:10]=3)[C@H:5]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=3)[CH2:6][C@@H:7]2[CH3:12])=[O:35])[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1
Reactant: O=C(Cl)C1CCCCC1
Reactant: C[C@H]1C[C@@H](Nc2ccc(F)cc2)c2cc(F)ccc2N1
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@H]1C[C@@H](Nc2ccc(F)cc2)c2cc(F)ccc2N1C(=O)C1CCCCC1
Reaction time: 16 h
Yield: 17 %

Procedure:
88 mg of cis-6-fluoro-4-[(4-fluorophenyl)amino]-2-methyl-1,2,3,4-tetrahydroquinoline was dissolved in 3 mL of dichloromethane, and 117 mg of triethylamine and 168 mg of cyclohexanecarbonyl chloride were added to the solution under ice cooling. The mixture was stirred for 16 hours under ice cooling. After completion of the reaction, a saturated aqueous solution of ammonium chloride was added to the reaction liquid, and the mixture was extracted with dichloromethane. Subsequently, the extraction product was dehydrated over anhydrous magnesium sulfate, and then was concentrated under reduced pressure. The resulting residue was subjected to recrystallization using chloroform, and thus 21 mg (17%) of the title compound was obtained as a colorless flake-shaped crystal.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[C:6]([CH:10]=1)[C:7]([OH:9])=O.[CH3:19][O:20][C:21](=[O:38])[C@@H:22]([NH2:37])[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[OH:36])=[CH:26][CH:25]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>>[CH3:19][O:20][C:21](=[O:38])[C@@H:22]([NH:37][C:7](=[O:9])[C:6]1[CH:10]=[C:2]([Br:1])[CH:3]=[CH:4][C:5]=1[O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[OH:36])=[CH:26][CH:25]=1
Reactant: COC(=O)[C@@H](N)Cc1ccc(-c2ccccc2O)cc1
Reactant: CCCCCCCOc1ccc(Br)cc1C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CCCCCCCOc1ccc(Br)cc1C(=O)N[C@@H](Cc1ccc(-c2ccccc2O)cc1)C(=O)OC
Yield: 47.7 %

Procedure:
5-Bromo-2-heptyloxy-benzoic acid (0.231 g, 0.738 mmol) and the (2S)-amino-3-(2′-hydroxy-biphenyl-4-yl)-propionic acid methyl ester (0.200 g, 0.738 mmol) were then combined as per general procedure A with HBTU (0.335 g, 0.885 mmol) and diisopropylethylamine (0.285 g, 2.21 mmol) to yield the (2S)-(5-bromo-2-heptyloxy-benzoylamino)-3-(2′-hydroxy-biphenyl-4-yl)-propionic acid methyl ester (0.200 g, 50%).
Reaction SMILES: FC1C=C(CC(N[C@H](C(O)=O)C(C)C)=O)C=C(F)C=1.[F:20][C:21]1[CH:22]=[C:23]([CH2:28][C:29]([NH:31][C@H:32]([C:37]([O:39]C)=[O:38])[CH2:33][CH:34]([CH3:36])[CH3:35])=[O:30])[CH:24]=[C:25]([F:27])[CH:26]=1>>[F:20][C:21]1[CH:22]=[C:23]([CH2:28][C:29]([NH:31][C@H:32]([C:37]([OH:39])=[O:38])[CH2:33][CH:34]([CH3:36])[CH3:35])=[O:30])[CH:24]=[C:25]([F:27])[CH:26]=1
Reactant: COC(=O)[C@H](CC(C)C)NC(=O)Cc1cc(F)cc(F)c1
Agent: CC(C)[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)O
Product: CC(C)C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)O
Yield: 80.9 %

Procedure:
A method similar to that used for the preparation of (107b) was used except that methyl N-[(3,5-difluorophenyl)acetyl]-L-leucinate (108a) (280 mg) was used instead of methyl N-[(3,5-difluorophenyl)acetyl]-L-valinate to afford the desired product (216 mg). 1H NMR (300 MHz, CDCl3) δ 0.83 (d, 3, J=6 Hz), 0.89 (d, 3H, J=6 Hz), 1.51 (m, 3H), 3.52 (s, 2H), 4.22 (m, 1H), 7.07 (m, 3H), 8.41 (d, 1H, J=8 Hz), 12.54 (s, 1H).
Reaction SMILES: [Mg].Br[C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[CH:4]=1.[CH3:11][N:12]([CH2:14][CH:15]1[C:24](=[O:25])[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[S:17][CH2:16]1)[CH3:13].[Cl-].[NH4+]>O1CCCC1>[CH3:13][N:12]([CH2:14][CH:15]1[C:24]([C:3]2[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[CH:4]=2)([OH:25])[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[S:17][CH2:16]1)[CH3:11]
Reactant: COc1cccc(Br)c1
Reactant: CN(C)CC1CSc2ccccc2C1=O
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: C1CCOC1
Product: COc1cccc(C2(O)c3ccccc3SCC2CN(C)C)c1
Temperature: 20 °C
Reaction time: 6 h

Procedure:
The corresponding Grignard reagent was prepared from 0.73 g magnesium turnings and 5.61 g 1-bromo-3-methoxy-benzene in 20 ml of dry tetrahydrofuran, with gentle boiling. A solution of 4.43 g (RS)-3-dimethylaminomethyl-thiochroman-4-one in 10 ml dry tetrahydrofuran was added drop-wise thereto at +5 to 10° C. The batch was subsequently stirred for 6 hours at 20° C. and was then decomposed with 10 ml of a saturated ammonium chloride solution. The batch was extracted three times with diethyl ether, and the combined extracts were washed with a saturated sodium chloride solution and dried over sodium sulphate. The crude product which remained after evaporating off the volatile constituents was purified by column chromatography using ethyl acetate as the elutant, whereupon 3.68 g (55.8% theoretical) of the title compound was obtained.
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11](=[O:19])OC2C=CC=CC=2)[N:7]([CH:20]([CH3:22])[CH3:21])[N:6]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)C(C)C)(C)C.[CH3:32][O:33][C:34]1[CH:35]=[C:36]2[C:41](=[CH:42][C:43]=1[O:44][CH3:45])[N:40]=[CH:39][N:38]=[C:37]2[O:46][C:47]1[CH:48]=[C:49]([CH:51]=[CH:52][CH:53]=1)[NH2:50]>C1COCC1>[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:50][C:49]2[CH:51]=[CH:52][CH:53]=[C:47]([O:46][C:37]3[C:36]4[C:41](=[CH:42][C:43]([O:44][CH3:45])=[C:34]([O:33][CH3:32])[CH:35]=4)[N:40]=[CH:39][N:38]=3)[CH:48]=2)=[O:19])[N:7]([CH:20]([CH3:21])[CH3:22])[N:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)n1nc(C(C)(C)C)cc1NC(=O)Oc1ccccc1
Reactant: COc1cc2ncnc(Oc3cccc(N)c3)c2cc1OC
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc2ncnc(Oc3cccc(NC(=O)Nc4cc(C(C)(C)C)nn4C(C)C)c3)c2cc1OC
Temperature: 25 °C
Yield: 39.6 %

Procedure:
A stirred solution of phenyl 3-tert-butyl-1-isopropyl-1H-pyrazol-5-ylcarbamate (150 mg, 0.50 mmol), N,N-Diisopropylethylamine (80 mg, 0.62 mmol) and 3-(6,7-dimethoxyquinazolin-4-yloxy)aniline (prepared as described in Example 113A) (92 mg, 0.31 mmol) in THF (1.0 mL) was heated at 60° C. for 15 h. After cooling to rt, the reaction solution was partitioned between dichloromethane and a saturated aqueous solution of sodium carbonate. The organic phase was separated and concentrated under reduced pressure. The crude product was purified via silica gel column chromatography (eluting with a gradient of 40:1 to 20:1 dichloromethane: methanol) then reverse-phase preparative HPLC to afford 1-(3-tert-butyl-1-isopropyl-1H-pyrazol-5-yl)-3-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)urea (62 mg, 40%) as a colorless solid. 1H NMR (400 MHz, DMSO-d6) δ9.08 (s, 1H), 8.57 (s, 1H), 8.43 (s, 1H), 7.55-7.59 (m, 2H), 7.37-7.40 (m, 2H), 7.24 (m, 1H), 6.93 (m, 1H), 6.00 (s, 1H), 4.35 (m, 1H), 4.00 (s, 3H), 3.99 (s, 3H), 1.34 (d, J=6.4 Hz, 6H), 1.24 (s, 9H); LC-MS (ESI) m/z 505 (M+H)+.