Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[C:2]([C:4]1[C:5]([NH:34][CH2:35][CH2:36][O:37][CH3:38])=[CH:6][C:7]([NH:10][C:11]([N:13]2[C:22]3[C:17](=[CH:18][C:19]([CH:28]4[CH2:33][CH2:32][O:31][CH2:30][CH2:29]4)=[C:20]([CH:23](OC)[O:24]C)[N:21]=3)[CH2:16][CH2:15][CH2:14]2)=[O:12])=[N:8][CH:9]=1)#[N:3].C([O-])(O)=O.[Na+]>C1COCC1.O>[C:2]([C:4]1[C:5]([NH:34][CH2:35][CH2:36][O:37][CH3:38])=[CH:6][C:7]([NH:10][C:11]([N:13]2[C:22]3[C:17](=[CH:18][C:19]([CH:28]4[CH2:29][CH2:30][O:31][CH2:32][CH2:33]4)=[C:20]([CH:23]=[O:24])[N:21]=3)[CH2:16][CH2:15][CH2:14]2)=[O:12])=[N:8][CH:9]=1)#[N:3]
Reactant: COCCNc1cc(NC(=O)N2CCCc3cc(C4CCOCC4)c(C(OC)OC)nc32)ncc1C#N
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COCCNc1cc(NC(=O)N2CCCc3cc(C4CCOCC4)c(C=O)nc32)ncc1C#N

Procedure:
Concentrated hydrochloric acid (0.28 ml) was added to a solution of N-(5-cyano-4-((2-methoxyethyl)amino)pyridin-2-yl)-7-(dimethoxymethyl)-6-(tetrahydro-2H-pyran-4-yl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide (intermediate 310, 640 mg, 0.689 mmol) in THF (6 ml) and water (2 ml) at room temperature. After stirring for 4 h at room temperature saturated aqueous NaHCO3 was added, the mixture extracted with DCM, the organic layers dried over MgSO4 and evaporated. The residue was triturated with EtOAc and then filtered to give the title compound as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][CH:7]2[CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH2:9][N:8]2[CH2:17][CH2:18][CH2:19][NH2:20])=[CH:4][CH:3]=1.[C:23]([C:25]1[CH:26]=[C:27]([N:31]=[C:32]=[O:33])[CH:28]=[CH:29][CH:30]=1)#[N:24]>>[C:23]([C:25]1[CH:26]=[C:27]([NH:31][C:32]([NH:20][CH2:19][CH2:18][CH2:17][N:8]2[CH:7]([CH2:6][C:5]3[CH:21]=[CH:22][C:2]([F:1])=[CH:3][CH:4]=3)[CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH2:9]2)=[O:33])[CH:28]=[CH:29][CH:30]=1)#[N:24]
Reactant: NCCCN1Cc2ccccc2CC1Cc1ccc(F)cc1
Reactant: N#Cc1cccc(N=C=O)c1
Product: N#Cc1cccc(NC(=O)NCCCN2Cc3ccccc3CC2Cc2ccc(F)cc2)c1

Procedure:
The reaction and treatment were carried out in the same manner as in Example 208 using 3-[3-(4-fluorobenzyl)-3,4-dihydroisoquinolin-2(1H)-yl]propanamine obtained in Example 214-b) as a starting material, and using 3-cyanophenyl isocyanate instead of phenyl isocyanate to obtain a title compound as a pale yellow amorphous substance.
Reaction SMILES: C[Si](I)(C)C.[CH3:6][N:7]1[C:13](=[O:14])[CH:12]([NH:15]C(=O)OC)[CH2:11][C:10]2[CH:20]=[CH:21][CH:22]=[CH:23][C:9]=2[CH2:8]1.C(OCC)(=O)C>ClCCl>[NH2:15][CH:12]1[CH2:11][C:10]2[CH:20]=[CH:21][CH:22]=[CH:23][C:9]=2[CH2:8][N:7]([CH3:6])[C:13]1=[O:14]
Reactant: COC(=O)NC1Cc2ccccc2CN(C)C1=O
Agent: C[Si](C)(C)I
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CN1Cc2ccccc2CC(N)C1=O
Temperature: 25 °C
Yield: 56.5 %

Procedure:
0.6 ml of trimethylsilyl iodide is added to a solution of 203 mg (0.93 mmol) of product 2 in 10 ml of dichloromethane, and the mixture is then refluxed for 3 hours. After cooling to room temperature and adding 50 ml of ethyl acetate, the organic phase is extracted with 2×25 ml of 1N hydrochloric acid solution. The aqueous phases are combined, cooled and then basified by addition of 5N sodium hydroxide. The basic aqueous phases are then saturated with NaCl, and then extracted with 3×25 ml of ethyl acetate. The organic phases are combined, dried over magnesium sulfate and evaporated under reduced pressure to give an oily residue. This residue is chromatographed on silica gel, eluting with a 90/10 dichloromethane/methanol mixture. 100 mg (57%) of the expected product 3 are obtained in the form of an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[NH2:10][CH2:11][CH2:12][CH2:13]N1C=C(C)N=C1CC1C=CC=CC=1.[BH4-].[Na+]>C(O)C>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][CH2:13][CH2:12][CH2:11][NH2:10])=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(Cl)cc1
Reactant: Cc1cn(CCCN)c(Cc2ccccc2)n1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: NCCCCc1ccc(Cl)cc1

Procedure:
In a similar manner to Example 35, a mixture of 4-chlorobenzaldehyde (5.6 g) and 1-(3-aminopropyl)-2-benzyl-4-methylimidazole (9.2 g) in ethanol (100 ml) was stirred and then reduced with sodium borohydride (1.6 g) to give 3-(2-benzyl-4-methylimidazol-1-yl)-[-(4-chlorobenzyl)propylamine, b.p. 190°-200° C. (0.04 mmHg). Glc and 1H nmr indicated that the product contained 21% of 3-(2-benzyl-5-methylimidazol-1-yl)-N-(4-chlorobenzyl)propylamine.
Reaction SMILES: [CH3:1][NH:2][C:3]1[N:4]=[N:5][C:6]([C:9]([OH:11])=[O:10])=[CH:7][CH:8]=1.Cl.[CH2:13](O)[CH3:14]>>[CH3:1][NH:2][C:3]1[N:4]=[N:5][C:6]([C:9]([O:11][CH2:13][CH3:14])=[O:10])=[CH:7][CH:8]=1
Reactant: CCO
Reactant: CNc1ccc(C(=O)O)nn1
Agent: Cl
Product: CCOC(=O)c1ccc(NC)nn1

Procedure:
A solution of 3-methylaminopyridazine-6-carboxylic acid (0.58 g) in ethanol (50 ml) was saturated with HCl gas, refluxed 48 hours and evaporated. The residue was partitioned between EtOAc and aqueous NaHCO3, separated and the aqueous re-extracted with EtOAc. The organic was dried and evaporated to give title compound (0.61 g). MS(+ve ion chemical ionisation) m/z 182 (MH+, 100%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:10][C:11]2[C:12]([CH3:17])=[N:13][CH:14]=[CH:15][CH:16]=2)[C:5]([C:8]#[N:9])=[N:6][CH:7]=1.[NH:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]1=[S:24].[H-].[Na+].O>CN(C=O)C>[CH3:17][C:12]1[C:11]([O:10][C:4]2[C:5]([C:8]#[N:9])=[N:6][CH:7]=[C:2]([S:24][C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][N:18]=3)[CH:3]=2)=[CH:16][CH:15]=[CH:14][N:13]=1
Reactant: S=c1cccc[nH]1
Reactant: Cc1ncccc1Oc1cc(Br)cnc1C#N
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ncccc1Oc1cc(Sc2ccccn2)cnc1C#N
Temperature: 0 °C
Reaction time: 18 h
Yield: 96.9 %

Procedure:
5-Bromo-3-(2-methylpyridin-3-yloxy)picolinonitrile (56.9 g, 196 mmol) and pyridine-2(1H)-thione (22.9 g, 206 mmol) were dissolved in DMF (400 mL) and cooled to 0° C. NaH (4.94 g, 206 mmol) was added portionwise and warmed to ambient temperature. The reaction was stirred for 18 hours and then poured into 2.5 L of water and stirred for 30 minutes The solids were filtered to provide 3-(2-methylpyridin-3-yloxy)-5-(pyridin-2-ylthio)picolinonitrile (60.8 g, 190 mmol, 96.8% yield).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][C:16]=2[C:22]([F:25])([F:24])[F:23])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:26]([C:28]1[CH:29]=[C:30]([CH:44]=[CH:45][CH:46]=O)[C:31]([O:34][CH2:35][C:36]2[CH:41]=[CH:40][C:39]([O:42][CH3:43])=[CH:38][CH:37]=2)=[CH:32][CH:33]=1)#[N:27].C(O)(=O)C.[BH3-]C#N.[Na+]>CO>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([NH:21][CH2:46][CH:45]=[CH:44][C:30]3[C:31]([O:34][CH2:35][C:36]4[CH:37]=[CH:38][C:39]([O:42][CH3:43])=[CH:40][CH:41]=4)=[CH:32][CH:33]=[C:28]([C:26]#[N:27])[CH:29]=3)=[CH:17][C:16]=2[C:22]([F:25])([F:23])[F:24])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(N)cc2C(F)(F)F)CC1
Reactant: COc1ccc(COc2ccc(C#N)cc2C=CC=O)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: COc1ccc(COc2ccc(C#N)cc2C=CCNc2ccc(OC3CCN(C(=O)OC(C)(C)C)CC3)c(C(F)(F)F)c2)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 65.7 %

Procedure:
To a mixture of 4-[(N-(t-butoxycarbonyl)piperidin-4-yl)oxy]-3-trifluoromethylbenzenamine (4.9 g) and 3-cyano-6-((4-methoxybenzyl)oxy)-1-(2-formylethenyl)benzene (4 g) in MeOH (80 mL) was added acetic acid (0.73 g). The resulting solution was stirred at ambient temperature for 15 minutes and then NaCNBH3 was added. The resulting solution was stirred at ambient temperature for 1 hour and concentrated. The residue was taken up in 100 mL of aqueous NaHCO3 and extracted with ethyl acetate (3×). The organic layer was dried, concentrated and purified on silica gel column (ethyl acetate/hexane, 3:7) to afford 5.7 g of 4-(N (t-butoxycarbonyl)piperidin-4-yl)oxy-3-trifluoromethyl-N-(3-(6-((4-methoxybenzyl)oxy)-3-cyanophenyl)prop-2-en-1-yl)benzenamine as a yellow oil.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:30]=[CH:29][C:9]([NH:10]/[C:11](=[C:18]2\[C:19](=[O:28])[NH:20][C:21]3[C:26]\2=[CH:25][CH:24]=[C:23]([Cl:27])[CH:22]=3)/[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:8][CH:7]=1)=[O:5])C.[OH-].[Na+].Cl>C(O)C>[C:4]([C:6]1[CH:30]=[CH:29][C:9]([NH:10]/[C:11](=[C:18]2\[C:19](=[O:28])[NH:20][C:21]3[C:26]\2=[CH:25][CH:24]=[C:23]([Cl:27])[CH:22]=3)/[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[CH:8][CH:7]=1)([OH:5])=[O:3]
Reactant: CCOC(=O)c1ccc(N/C(=C2\C(=O)Nc3cc(Cl)ccc32)c2ccccc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C1Nc2cc(Cl)ccc2/C1=C(/Nc1ccc(C(=O)O)cc1)c1ccccc1
Temperature: 80 °C
Reaction time: 3 h

Procedure:
450 mg of 3-Z-[1-(4-ethoxycarbonyl-anilino)-1-phenyl-methylene]-6-chloro-2-indolinone (educt 1.2) are dissolved in 10 ml of ethanol and 2 ml of 1N sodium hydroxide solution are added. The mixture is stirred for 3 hours at 80° C. After cooling, 2 ml of 1N hydrochloric acid are added and the mixture is stirred for half an hour at ambient temperature. The precipitate formed is suction filtered and washed with ethanol and diethyl ether.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:22])=[C:11]([N:15]4[CH2:20][CH2:19][NH:18][CH:17]([CH3:21])[CH2:16]4)[C:12]=3[CH3:14])[C:7](=[O:23])[C:6]([C:24]([OH:26])=[O:25])=[CH:5]2)[CH2:3][CH2:2]1.[CH:27](O)=[O:28].C(OC(=O)C)(=O)C>O>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:22])=[C:11]([N:15]4[CH2:20][CH2:19][N:18]([CH:27]=[O:28])[CH:17]([CH3:21])[CH2:16]4)[C:12]=3[CH3:14])[C:7](=[O:23])[C:6]([C:24]([OH:26])=[O:25])=[CH:5]2)[CH2:3][CH2:2]1
Reactant: Cc1c(N2CCNC(C)C2)c(F)cc2c(=O)c(C(=O)O)cn(C3CC3)c12
Reactant: O=CO
Solvent: O
Solvent: CC(=O)OC(C)=O
Product: Cc1c(N2CCN(C=O)C(C)C2)c(F)cc2c(=O)c(C(=O)O)cn(C3CC3)c12
Temperature: 80 °C

Procedure:
1-Cyclopropyl-7-(3-methyl-1-piperazinyl)-6-fluoro-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (0.4 g) is added to a mixture of formic acid (1.7 ml) and acetic anhydride (2.2 ml) at 0° C. After the addition, the mixture is heated at 80° C. for 2 hours. To the reaction mixture is added water, and the mixture is extracted with dichloromethane. After removing the solvent by concentration, the resulting residue is recrystallized from methanol to give 1-cyclopropyl-7-(4-formyl-3-methyl-1-piperazinyl)-6-fluoro-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (0.13 g), as white powder, m.p. 236°-239° C.
Reaction SMILES: C([O:8][C:9]([C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:13]([CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[N:12]=1)=O)C1C=CC=CC=1.CC(C[AlH]CC(C)C)C>ClCCl.CCCCCC>[CH2:20]([N:13]1[C:14]2[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:11]([CH2:9][OH:8])=[N:12]1)[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: O=C(OCc1ccccc1)c1nn(Cc2ccccc2)c2ccccc12
Agent: CC(C)C[AlH]CC(C)C
Solvent: CCCCCC
Solvent: ClCCl
Product: OCc1nn(Cc2ccccc2)c2ccccc12
Temperature: 25 °C
Yield: 87.4 %

Procedure:
To a stirring solution of 735 mg (2.15 mmol) of 1-Benzyl-1H-indazole-3-carboxylic acid benzyl ester, prepared as in Intermediate 14, in 15 mL dichloromethane at -78° C. is added dropwise over 5 min a solution of 5.4 mL (5.4 mmol, 2.5 equiv) of a 1.0M solution of DIBAL-H in hexane. The resulting solution is allowed to slowly warm to RT over a 4 h period then quenched by careful addition of 5 mL of H2O. The reaction mixture is poured into 100 mL of EtOAc and extracted with 1N HCl (1×100 mL), dried (MgSO4), and the solvent removed in vacuo. Purification of the crude material by silica gel flash column chromatography using hexane/EtOAc 1/1 as eluent afforded 448 mg of the title compound as a pale yellow solid: 1H NMR (CDCl3, 300 MHz) δ7.80 (d, 1H), 7.40-7.08 (m, 8H), 5.50 (s, 2H), 5.04 (d, 2H), 2.24 (m, 1H); Rf =0.50 in hexane/EtOAc 1/1.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][CH:27]=1)[O:5][C:6]1[C:11]([O:12][CH2:13][CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][N:19]=[CH:18][C:17]=2C(O)=O)=[CH:10][CH:9]=[CH:8][N:7]=1.C1(P([N:42]=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.C(N(CC)CC)C>C(O)(C)(C)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][CH:27]=1)[O:5][C:6]1[C:11]([O:12][CH2:13][CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][N:19]=[CH:18][C:17]=2[NH2:42])=[CH:10][CH:9]=[CH:8][N:7]=1
Reactant: O=C(O)c1cnccc1CCCOc1cccnc1Oc1cccc(Cl)c1
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CC(C)(C)O
Product: Nc1cnccc1CCCOc1cccnc1Oc1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 49.7 %

Procedure:
2-(3-Chlorophenoxy)-3-[3-(3-carboxypyridin-4-yl)propoxy]-pyridine (0.50 g, 1.3 mmol) obtained in Example 24 is dissolved in tert-butanol (20 ml), and thereto are added diphenylphosphoryl azide (0.42 ml, 2.0 mmol) and triethylamine (0.27 ml, 2.0 mmol), and the mixture is heated under reflux for 8 hours. The reaction is quenched with a saturated brine (50 ml), and the reaction solution is extracted with ethyl acetate (50 ml×2). The organic layer is washed with a saturated brine (30 ml×2), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue is dissolved in methylene chloride (10 ml), and thereto is added trifluoroacetic acid (5 ml), and the mixture is stirred at 25° C. for 30 minutes. The reaction solution is concentrated under reduced pressure, and to the residue is added a saturated aqueous sodium hydrogen carbonate solution (50 ml), and the mixture is extracted with ethyl acetate (50 ml×2). The organic layer is washed with a saturated brine (30 ml×2), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue is purified by silica gel column chromatography (eluent; chloroform/methanol), and further recrystallized from diethyl ether to give the title compound (0.23 g) as colorless crystals, m.p. 140-142° C.
Reaction SMILES: [CH3:1][C:2]1[O:8][CH:7]=[C:6]([OH:9])[C:4](=[O:5])[CH:3]=1.C(N(CC)CC)C.[O:17]1[CH:21]=[CH:20][CH:19]=[C:18]1[C:22](Cl)=[O:23]>C1COCC1>[O:17]1[CH:21]=[CH:20][CH:19]=[C:18]1[C:22]([O:9][C:6]1[C:4](=[O:5])[CH:3]=[C:2]([CH3:1])[O:8][CH:7]=1)=[O:23]
Reactant: Cc1cc(=O)c(O)co1
Reactant: O=C(Cl)c1ccco1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1cc(=O)c(OC(=O)c2ccco2)co1
Temperature: 0 °C
Reaction time: 8 h
Yield: 69.9 %

Procedure:
Allomaltol (1.256 g, 10 mmol) was dissolved in 40 mL of anhydrous THF. The mixture was cooled to 0° C. Triethylamine (1.8 mL, 13 mmol) was added. Furan-2-carbonyl chloride (1.500 g, 11 mmol) was added dropwise. Cold bath was removed and the mixture was stirred at room temperature overnight. The reaction was extracted with EtOAc. The organic phase was washed with brine 2 times then dried over Na2SO4 and concentrated. The crude product was purified with flash chromatography using EtOAc/hexanes to give the desired product as a brown solid (1.539 g, 70%). MP (136° C.). 1H NMR (CDCl3) δ (ppm): 2.30 (s, 3H), 6.29 (s, 1H), 6.55 (m, 1H), 7.37 (m, 1H), 7.64 (m, 1H), 7.94, (s, 1H). 13C NMR (CDCl3) δ (ppm): 19.8, 112.6, 115.4, 120.8, 140.5, 143.0, 147.9, 148.4, 155.4, 166.5, 172.1.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([OH:24])[C:8]=2[C:12]2[C:13]([OH:23])=[CH:14][CH:15]=[C:16]3[C:21]=2[CH:20]=[CH:19][C:18](Br)=[CH:17]3)[CH:3]=1.[Cl-].O.NN.[C:29]1(B(O)O)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>O.C1COCC1>[C:29]1([C:18]2[CH:19]=[CH:20][C:21]3[C:16](=[CH:15][CH:14]=[C:13]([OH:23])[C:12]=3[C:8]3[C:7]([OH:24])=[CH:6][CH:5]=[C:4]4[C:9]=3[CH:10]=[CH:11][C:2]([C:2]3[CH:11]=[CH:10][CH:9]=[CH:4][CH:3]=3)=[CH:3]4)[CH:17]=2)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: OB(O)c1ccccc1
Reactant: Oc1ccc2cc(Br)ccc2c1-c1c(O)ccc2cc(Br)ccc12
Agent: NN
Agent: [Cl-]
Solvent: O
Solvent: C1CCOC1
Product: Oc1ccc2cc(-c3ccccc3)ccc2c1-c1c(O)ccc2cc(-c3ccccc3)ccc12

Procedure:
12.0 g (25.7 mmol) of (±)-6,6′-dibromo[1,1′]binaphthalinyl-2,2′-diol, 11.5 g (41 mmol) of sodium metaborate octahydrate and 800 mg of bistriphenylphosphinepalladium(II) chloride are initially introduced in 100 ml of water and 20 ml of THF, 0.13 ml of hydrazine hydrate is added, and a solution of 7.0 g (57 mmol) of benzeneboronic acid in 80 ml of THF is added dropwise. The batch is subsequently heated under reflux overnight, added to water and extracted three times with MTB ether. The combined org. phases are washed with water and dried over sodium sulfate. The solvent is removed in vacuo, and the residue is filtered through silica gel with toluene/ethyl acetate (19:1) and evaporated, and the product is recrystallized once each from toluene/cyclohexane (1:1) and isopropanol, giving (±)-6,6′-diphenyl[1,1′]binaphthalinyl-2,2′-diol as colorless crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[O:10][C@@H:9]2[CH2:11][OH:12])=[CH:4][C:3]=1[F:13].[Na].[H-].[Al+3].[H-].[H-]>COCCOC.CCOCC>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([OH:10])[CH2:9][CH2:11][OH:12])=[CH:4][C:3]=1[F:13]
Reactant: OC[C@H]1O[C@@H]1c1ccc(Cl)c(F)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Na]
Solvent: COCCOC
Solvent: CCOCC
Product: OCC[C@H](O)c1ccc(Cl)c(F)c1
Temperature: 0 °C
Reaction time: 3 h
Yield: 98.5 %

Procedure:
((2R,3R)-3-(4-Chloro-3-fluorophenyl)oxiran-2-yl)methanol (10.55 g, 52.07 mmol) was dissolved in 1,2-dimethoxyethane (150 mL) and cooled to 0° C. Sodium bis (2-methohyethoxy) aluminum hydride (“Red-Al”) (17.46 mL, 57.28 mmol) was added dropwise. The mixture was agitated for 3 hours at room temperature, diluted with ether (250 mL) and quenched with HCl solution (20 mL, 6M HCl+60 mL water). After agitating for 30 minutes, the aqueous phase was separated and extracted twice with ethyl acetate. The combined organics were washed with brine, dried with MgSO4, and evaporated to give (S)-1-(4-chloro-3-fluorophenyl)propane-1,3-diol (10.5 g, 51.31 mmol, 98.55% yield) as thick oil.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C@H:12]([C:35]([OH:37])=[O:36])[CH2:13][CH2:14][CH2:15][CH2:16][NH:17][C:18]([O:20]CC2C3C=CC=CC=3C3C2=CC=CC=3)=O)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[C:38]([NH:46][C@H:47](C(O)=O)[CH2:48][C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1)(=[O:45])[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1>>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([N:11]([C@H:12]([C:35]([OH:37])=[O:36])[CH2:13][CH2:14][CH2:15][CH2:16][NH:17][C:18]([C@@H:47]([NH:46][C:38]([C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=2)=[O:45])[CH2:48][C:49]2[CH:50]=[CH:51][CH:52]=[CH:53][CH:54]=2)=[O:20])[CH2:1][CH:2]([CH3:7])[CH3:3])(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)N[C@@H](CCCCNC(=O)OCC2c3ccccc3-c3ccccc32)C(=O)O)cc1
Reactant: O=C(N[C@@H](Cc1ccccc1)C(=O)O)c1ccccc1
Product: Cc1ccc(S(=O)(=O)N(CC(C)C)[C@@H](CCCCNC(=O)[C@H](Cc2ccccc2)NC(=O)c2ccccc2)C(=O)O)cc1

Procedure:
The title compound was prepared from solid phase bound Nα-isobutyl-N(-(4-methylbenzenesulfonyl)-Nε-(9-fluorenylmethoxycarbonyl)-L-lysine as described in general procedure Bb using Nα-benzoyl-L-phenylalanine (321 mg, 1.2 mmol). The final product was purified by preparative HPLC to yield 44 mg (58%) of the desired material.
Reaction SMILES: P(Cl)(Cl)(Cl)(Cl)[Cl:2].[CH2:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[NH:15][C:16](=O)[CH3:17])[CH3:8]>C1C=CC=CC=1>[Cl:2][C:16](=[N:15][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[CH2:7][CH3:8])[CH3:17]
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: CCc1ccccc1NC(C)=O
Solvent: c1ccccc1
Product: CCc1ccccc1N=C(C)Cl
Temperature: 25 °C
Yield: 83.7 %

Procedure:
Phosphorus pentachloride (8.97 g, 43 mmol) was dissolved in 100 mL of benzene. Under a gentle argon purge, N-(2-ethylphenyl)acetamide (Amide I) (6.52 g, 40 mmol) was added slowly with stirring at room temperature. The yellow solution was refluxed for 2 hours. Benzene was removed in vacuo, yielding a brown oil. The oil was distilled under reduced pressure (45-50° C., 0.10 Torr) affording 6.08 g (84%) of a clear oil. 1H NMR (400 MHz, C6D6): 7.07 (t, 2H), 6.99 (t, 1H), 6.80 (d, 1H), 2.50 (q, 2H), 2.08 (s, 3H), 1.11 (t, 3H).
Reaction SMILES: [Mg].Cl[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[O:10][CH:11]([CH3:13])[CH3:12].II.[CH2:16]([N:23]1[CH2:28][CH2:27][O:26][CH:25]([C:29]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[O:30])[CH2:24]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>O1CCCC1>[CH2:16]([N:23]1[CH2:28][CH2:27][O:26][CH:25]([C:29]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)([OH:30])[CH2:3][C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[O:10][CH:11]([CH3:13])[CH3:12])[CH2:24]1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: CC(C)Oc1ccccc1CCl
Reactant: O=C(c1ccccc1)C1CN(Cc2ccccc2)CCO1
Agent: II
Agent: [Mg]
Solvent: C1CCOC1
Product: CC(C)Oc1ccccc1CC(O)(c1ccccc1)C1CN(Cc2ccccc2)CCO1
Temperature: 8 °C
Yield: 163 %

Procedure:
Solid magnesium turnings (4.6 g, 48 equiv.) under nitrogen atmosphere at room temperature were stirred vigorously with a magnetic stirring bar overnight. The magnesium was then covered with dry tetrahydrofuran. A cold bath was then applied followed by dropwise addition of 1-chloromethyl-2-isopropoxy-benzene (3.0 g, 4 equiv. prepared as described above) in tetrahydrofuran (40 mL). During slow addition of the electrophile no exotherm was observed so on completion of addition 3 crystals of Iodine were added to promote initiation of the reaction. After this addition the reaction temperature was allowed to spike to 50° C. then cooled rapidly to 8° C. before being left to warm to room temperature for one hour. The resulting black suspension was cooled down to −10° C. and a solution of (4-Benzyl-morpholin-2-yl)-phenyl-methanone (1.2 g, 1 equiv.) in tetrahydrofuran (10 mL) was then added dropwise. The reaction mixture was left to warm to room temperature over thirty minutes and then quenched by addition of aqueous saturated solution of NaHCO3 (50 mL) prior to filtration through Celite. The aqueous solution was extracted with diethyl ether, the organic phase dried with MgSO4, evaporated in vacuo to give 3 g of a yellow amorphous solid. The compound was taken without further purification in the next step. LCMS (6 minutes method) [M+H]+=432 @ Rt 3.25 min. major peak.
Reaction SMILES: [N:1]1([CH2:6][C:7]2[CH:8]=[C:9]3[C:14](=[CH:15][CH:16]=2)[NH:13][C:12](=O)[CH:11]=[C:10]3[CH3:18])[CH:5]=[CH:4][N:3]=[CH:2]1.P(Cl)(Cl)([Cl:21])=O>>[Cl:21][C:12]1[CH:11]=[C:10]([CH3:18])[C:9]2[C:14](=[CH:15][CH:16]=[C:7]([CH2:6][N:1]3[CH:5]=[CH:4][N:3]=[CH:2]3)[CH:8]=2)[N:13]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1cc(=O)[nH]c2ccc(Cn3ccnc3)cc12
Product: Cc1cc(Cl)nc2ccc(Cn3ccnc3)cc12
Yield: 12.5 %

Procedure:
A solution of 13 parts of 6-(1H-imidazol-1-ylmethyl)-4-methyl-2(1H)-quinolinone in 55 parts of phosphoryl chloride was stirred for 1 hour at room temperature. After evaporation, the residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (95:5 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from a mixture of acetonitrile and 2,2'-oxybispropane. The product was filtered off and dried, yielding 1.75 parts (12.5%) of 2-chloro-6-(1H-imidazol-1-ylmethyl)-4-methylquinoline; mp. 120.6° C. (compound 24).
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[C:9]2[N:10]=[C:11]([C:13]3[NH:22][C:16]4[CH2:17][CH2:18][NH:19][CH2:20][CH2:21][C:15]=4[N:14]=3)[S:12][C:8]=2[C:7]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)=[CH:6][CH:5]=1.C(N(C(C)C)C(C)C)C.[C:38](Cl)(=[O:43])[C:39]([CH3:42])([CH3:41])[CH3:40]>O1CCCC1>[CH3:2][O:3][C:4]1[C:9]2[N:10]=[C:11]([C:13]3[NH:22][C:16]4[CH2:17][CH2:18][N:19]([C:38](=[O:43])[C:39]([CH3:42])([CH3:41])[CH3:40])[CH2:20][CH2:21][C:15]=4[N:14]=3)[S:12][C:8]=2[C:7]([N:23]2[CH2:24][CH2:25][O:26][CH2:27][CH2:28]2)=[CH:6][CH:5]=1
Reactant: CC(C)(C)C(=O)Cl
Reactant: COc1ccc(N2CCOCC2)c2sc(-c3nc4c([nH]3)CCNCC4)nc12
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COc1ccc(N2CCOCC2)c2sc(-c3nc4c([nH]3)CCN(C(=O)C(C)(C)C)CC4)nc12
Yield: 105.6 %

Procedure:
To a suspension of 0.04 g 2-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-1,4,5,6,7,8-hexahydro-imidazo[4,5-d]azepine hydrochloride in 3.4 ml tetrahydrofurane were added at 0–4° C. 0.07 ml N-ethyldiisopropylamine and 0.014 g pivaloyl chloride. The mixture was refluxed for 17 hours, silicagel was added and the solvent was distilled off. The residue was transferred to a column prefilled with silicagel and was chromatographed with dichloromethane/methanol 96:4 to yield 0.047 g (88%) 1-[2-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-4,5,7,8-tetrahydro-1H-imidazo[4,5-d]azepin-6-yl]-2,2-dimethyl-propan-1-one as yellow solid; MS (ISP): m/e=470 (M+H+).