Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][CH:3]([O:20][CH3:21])[CH2:4][O:5][C:6]1[C:7]([CH3:19])=[C:8]([CH:12]=[CH:13][C:14]=1[S:15]([CH3:18])(=[O:17])=[O:16])[C:9]([OH:11])=O.C(Cl)(=O)C(Cl)=O.CN(C=O)C.[OH:33][C:34]1[N:38]([CH3:39])[N:37]=[CH:36][CH:35]=1>C(Cl)(Cl)Cl.C(OCC)(=O)C.C(N(CC)CC)C>[CH3:21][O:20][CH:3]([O:2][CH3:1])[CH2:4][O:5][C:6]1[C:7]([CH3:19])=[C:8]([C:9]([C:35]2[CH:36]=[N:37][N:38]([CH3:39])[C:34]=2[OH:33])=[O:11])[CH:12]=[CH:13][C:14]=1[S:15]([CH3:18])(=[O:17])=[O:16]
Reactant: COC(COc1c(S(C)(=O)=O)ccc(C(=O)O)c1C)OC
Reactant: Cn1nccc1O
Agent: O=C(Cl)C(=O)Cl
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(COc1c(S(C)(=O)=O)ccc(C(=O)c2cnn(C)c2O)c1C)OC
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
3-(2,2-Dimethoxyethoxy)-2-methyl-4-(methylsulfonyl)benzoic acid (390 mg, 1.23 mmol) was dissolved in chloroform (15 mL), and oxalyl chloride (0.5 mL) and DMF in a catalytic amount were added thereto. The reaction mixture was stirred at room temperature for 30 minutes, and the solvent was distilled off under reduced pressure. The residue was dissolved in anhydrous THF (20 mL), and 5-hydroxy-1-methylpyrazole (132 mg, 1.35 mmol), triethylamine (250 mg) and N,N-dimethylaminopyridine (300 mg) were added, followed by reflux with heating for 1 hour. The reaction mixture was allowed to cool to room temperature, and ethyl acetate (200 mL) was added. The mixture was washed twice with a saturated brine. The organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was dissolved in anhydrous acetonitrile (10 mL), and triethylamine (250 mg) and acetone cyanohydrin in a catalytic amount were added, followed by stirring for 12 hours at room temperature. The solvent was distilled off under reduced pressure to obtain crude 5-hydroxy-1-methylpyrazol-4-yl 3-(2,2-dimethoxyethoxy)-2-methyl-4-(methylsulfonyl)phenyl ketone.
Reaction SMILES: [Cl:1][C:2]1[C:12]2[CH2:11][CH2:10][NH:9][CH2:8][CH:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:6]=2[C:5]([Cl:19])=[C:4]([O:20][CH3:21])[C:3]=1[O:22][CH3:23].[OH-].[Na+].[CH3:26]COCC>C(O)=O.C=O>[Cl:1][C:2]1[C:12]2[CH2:11][CH2:10][N:9]([CH3:26])[CH2:8][CH:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:6]=2[C:5]([Cl:19])=[C:4]([O:20][CH3:21])[C:3]=1[O:22][CH3:23]
Reactant: CCOCC
Reactant: COc1c(Cl)c2c(c(Cl)c1OC)C(c1ccccc1)CNCC2
Agent: C=O
Agent: [Na+]
Agent: [OH-]
Solvent: O=CO
Product: COc1c(Cl)c2c(c(Cl)c1OC)C(c1ccccc1)CN(C)CC2

Procedure:
A mixture of 4 g of 6,9-dichloro-7,8-dimethoxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine in 15 ml of formic acid and 10 ml of formaldehyde is refluxed for 18 hours. The mixture is evaporated in vacuo. The residue is treated with 20 ml of 6 N hydrochloric acid. The solution is again evaporated to give a residue which is treated with 20 ml of 10% sodium hydroxide solution then taken into ether. The ethereal extracts are dried and evaporated to give 6,9-dichloro-7,8-dimethoxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C@@H:4]1[CH2:15][CH2:14][C:13]2[S:12][C:11]3[C:6](=[C:7]([O:16][CH:17]4[CH2:22][CH2:21][CH:20]([NH:23][C:24](=O)OC(C)(C)C)[CH2:19][CH2:18]4)[N:8]=[CH:9][N:10]=3)[C:5]1=2.C=O.[CH:33](O)=O>CO>[CH3:33][N:23]([CH3:24])[CH:20]1[CH2:19][CH2:18][CH:17]([O:16][C:7]2[N:8]=[CH:9][N:10]=[C:11]3[C:6]=2[C:5]2[C@H:4]([CH2:3][CH2:2][OH:1])[CH2:15][CH2:14][C:13]=2[S:12]3)[CH2:22][CH2:21]1
Reactant: O=CO
Reactant: CC(C)(C)OC(=O)NC1CCC(Oc2ncnc3sc4c(c23)[C@H](CCO)CC4)CC1
Agent: C=O
Solvent: CO
Product: CN(C)C1CCC(Oc2ncnc3sc4c(c23)[C@H](CCO)CC4)CC1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
To a 25-mL round-bottom flask containing a solution of 16.5 (100 mg, 0.23 mmol, 1.00 equiv) in methanol (5 mL) was added HCHO (37%, 1 mL) and HCOOH (5 mL) at room temperature under nitrogen. The resulting solution was stirred overnight at 100° C. and evaporated under reduced pressure. The crude product (80 mg) was purified by preparative HPLC(SHIMADZU) under the following conditions: column: SunFire Prep C18, 19*150 mm 5 um; mobile phase: water (0.05% NH4HCO3) and CH3CN (start at 7.0% CH3CN then ramp up to 63.0% in 13 min); UV detection at 254 and 220 nm. The product-containing fractions were collected and the solvents evaporated to afford Compound I-33 (8 mg) as a colorless oil. An ee of 100% was measured by chiral-SFC analysis. 1H NMR (300 MHz, CDCl3) δ 7.26 (s, 1H), 5.24 (m, 1H), 3.72 (t, 1H), 3.47 (m, 1H), 3.08 (m, 2H), 2.70 (m, 1H), 2.03-2.68 (m, 11H), 1.25-1.81 (m, 9H). MS: m/z 362 (M+H)+.
Reaction SMILES: CS(O[CH2:6][C:7]#[C:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[N:15]=[CH:14][N:13]=[C:12]2[NH:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([F:34])[CH:29]=2)=[C:22]([Cl:35])[CH:21]=1)(=O)=O.CCN(C(C)C)C(C)C.[CH3:45][P:46]([CH3:51])([CH2:48][CH2:49][NH2:50])=[O:47]>ClCCl>[CH3:45][P:46]([CH3:51])([CH2:48][CH2:49][NH:50][CH2:6][C:7]#[C:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[N:15]=[CH:14][N:13]=[C:12]2[NH:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([F:34])[CH:29]=2)=[C:22]([Cl:35])[CH:21]=1)=[O:47]
Reactant: CP(C)(=O)CCN
Reactant: CS(=O)(=O)OCC#Cc1ccc2ncnc(Nc3ccc(OCc4cccc(F)c4)c(Cl)c3)c2c1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CP(C)(=O)CCNCC#Cc1ccc2ncnc(Nc3ccc(OCc4cccc(F)c4)c(Cl)c3)c2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 3-(4-(4-(3-fluorobenzyloxy)-3-chlorophenylamino)quinazolin-6-yl)prop-2-ynyl methanesulfonate (compound 10.2, 319 mg), DIPEA (0.37 mL) in dichloromethane (20 mL) at 0° C. was added 2-(dimethylphosphinoyl)ethanamine (83 mg) and the reaction mixture was stirred at room temperature overnight. The solvent was removed and the residue was purified by flash chromatography, eluting with 20% methanol in dichloromethane to give the desired product as yellow solid. LCMS ESI(+) m/z: 538 (M+1). 1H NMR (300 MHz, CDCl3) δ 9.47 (s, 1H), 8.87 (s, 1H), 8.70 (s, 1H), 7.95 (m, 2H), 7.85 (m, 2H), 7.62 (m, 2H), 7.38 (m, 1H), 6.98 (m, 1H), 5.10 (s, 2H), 4.25 (m, 2H), 3.87 (m, 1H), 3.58 (m, 1H), 2.05 (m, 2H), 1.57 (m, 6H).
Reaction SMILES: Br[C:2]1[C:7]([CH:8]=[O:9])=[C:6]([F:10])[C:5]([O:11][CH2:12][CH:13]2[CH2:18][CH2:17][CH:16]([CH2:19][CH2:20][CH3:21])[CH2:15][CH2:14]2)=[CH:4][CH:3]=1.[CH2:22]([O:24][C:25]1[CH:30]=[CH:29][C:28](B(O)O)=[C:27]([CH:34]=[O:35])[C:26]=1[F:36])[CH3:23].C(=O)([O-])[O-].[K+].[K+].C1(C)C=CC=CC=1>CCCC[N+](CCCC)(CCCC)CCCC.[Br-].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.O.C(O)C>[CH2:22]([O:24][C:25]1[C:26]([F:36])=[C:27]([CH:34]=[O:35])[C:28]([C:2]2[C:7]([CH:8]=[O:9])=[C:6]([F:10])[C:5]([O:11][CH2:12][CH:13]3[CH2:18][CH2:17][CH:16]([CH2:19][CH2:20][CH3:21])[CH2:15][CH2:14]3)=[CH:4][CH:3]=2)=[CH:29][CH:30]=1)[CH3:23]
Reactant: CCCC1CCC(COc2ccc(Br)c(C=O)c2F)CC1
Reactant: CCOc1ccc(B(O)O)c(C=O)c1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CCO
Solvent: Cc1ccccc1
Product: CCCC1CCC(COc2ccc(-c3ccc(OCC)c(F)c3C=O)c(C=O)c2F)CC1
Yield: 80.3 %

Procedure:
Under a nitrogen atmosphere, a mixture of compound (62) (4.20 g, 11.76 mmol), compound (55) (2.74 g, 12.93 mmol) prepared in Example 1, tetrakis(triphenylphosphine)palladium (0.14 g, 0.121 mmol), potassium carbonate (3.25 g, 23.51 mmol) and TBAB (0.76 g, 2.351 mmol) was refluxed in a toluene (20 mL)-ethanol (10 mL)-water (50 mL) solvent for 5 hours. The reaction mixture was extracted with 20 mL of toluene three times, combined organic layers were washed with water and saturated brine, and then dried over magnesium sulfate, and a solvent was distilled off by an evaporator. The residue was purified by silica gel column chromatography, and thus 4-ethoxy-3,3′-difluoro-4′-((4-propylcyclohexyl)methoxy)-[1,1′-biphenyl]-2,2′-dicarboaldehyde (63) (4.20 g, yield 80.3%) was obtained.
Reaction SMILES: [C:1]([C@@H:5]1[CH2:10][CH2:9][C@H:8]([NH:11][C:12]2[C:17]([Cl:18])=[C:16]([C:19]#[C:20][Si](C)(C)C)[N:15]=[CH:14][N:13]=2)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C(=O)([O-])O.[Na+].O>O1CCCC1.C1(C)C=CC=CC=1>[C:1]([C@@H:5]1[CH2:10][CH2:9][C@H:8]([NH:11][C:12]2[C:17]([Cl:18])=[C:16]([C:19]#[CH:20])[N:15]=[CH:14][N:13]=2)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[C@H]1CC[C@@H](Nc2ncnc(C#C[Si](C)(C)C)c2Cl)CC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])O
Agent: [F-]
Solvent: O
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: C#Cc1ncnc(N[C@H]2CC[C@@H](C(C)(C)C)CC2)c1Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
0.64 g (1.76 mmol) of 4-(cis-4-tert-butylcyclohexylamino)-5-chloro-6-trimethylsilylethynylpyrimidine (Example 27) was dissolved in 20 ml of tetrahydrofuran, and 2 ml of a 1.0M solution of tetrabutylammonium fluoride in tetrahyrofuran were added at 0° C. The mixture was stirred at room temperature for 2 hours, diluted with toluene and exracted by stirring with sodium hydrogen carbonate solution and water. The organic phase was dried and concentrated. Chromatography on silica gel left 0.44 g (86.0% of theory) of a colorless oil which gradually solidified.
Reaction SMILES: [NH2:1][C@H:2]([C:15]([OH:17])=[O:16])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:6][CH:5]=1.[NH2:18][C@H:19]([C:44](O)=[O:45])[CH2:20][CH2:21][CH2:22][NH:23][C:24](=[NH:43])[NH:25][S:26]([C:29]1[C:41]([CH3:42])=[C:40]2[C:34]([O:35][C:36]([CH2:39]2)([CH3:38])[CH3:37])=[C:32]([CH3:33])[C:30]=1[CH3:31])(=[O:28])=[O:27]>CN(C=O)C>[NH2:18][C@H:19]([C:44]([NH:1][C@H:2]([C:15]([OH:17])=[O:16])[CH2:3][C:4]1[CH:5]=[CH:6][C:7]([O:10][C:11]([CH3:14])([CH3:12])[CH3:13])=[CH:8][CH:9]=1)=[O:45])[CH2:20][CH2:21][CH2:22][NH:23][C:24](=[NH:43])[NH:25][S:26]([C:29]1[C:41]([CH3:42])=[C:40]2[C:34]([O:35][C:36]([CH2:39]2)([CH3:38])[CH3:37])=[C:32]([CH3:33])[C:30]=1[CH3:31])(=[O:27])=[O:28]
Reactant: Cc1c(C)c(S(=O)(=O)NC(=N)NCCC[C@H](N)C(=O)O)c(C)c2c1OC(C)(C)C2
Reactant: CC(C)(C)Oc1ccc(C[C@H](N)C(=O)O)cc1
Solvent: CN(C)C=O
Product: Cc1c(C)c(S(=O)(=O)NC(=N)NCCC[C@H](N)C(=O)N[C@@H](Cc2ccc(OC(C)(C)C)cc2)C(=O)O)c(C)c2c1OC(C)(C)C2

Procedure:
Commercially available Rink Amide MBHA resin (1 g, 0.45 mmol) was measured and placed in a reaction vessel and swollen with DMF. By a manual solid phase synthesis operation, Tyr(But), Arg(Pbf) were successively condensed, and Fmoc was removed. The resin was washed with DMF, MeOH, and dried to give H-Arg(Pbf)-Tyr(But)-Rink Amide MBHA resin (1.162 g). From the obtained resin, 65.6 mg, 0.025 mmol was measured and placed in a reaction vessel. Gln(Trt), Lys(Mtt) were introduced thereto by manual solid phase synthesis process to give Fmoc-Lys(Mtt)-Gln(Trt)-Arg(Pbf)-Tyr(But)-Rink Amide MBHA resin (SEQ ID NO:175) (Mtt: methyltrityl). The obtained resin was washed with toluene, then TFA-TIS-TFE-toluene (1:5:47:47) was added and the mixture was shaken in the reaction vessel for 10 min. The processing was repeated until the solution was no longer colored with free trityl group to remove Mtt group. The resin was neutralized with 5% DIEA/toluene solution, suspended in toluene:TFE (4:1), N,N-bis-Boc-1-guanylpyrazole (31.0 mg, 0.1 mmol) was added, and the mixture was adjusted to pH 10 with DIEA, and treated overnight at room temperature. After removal of Fmoc from the obtained Fmoc-Har(Boc2)-Gln(Trt)-Arg(Pbf)-Tyr(But)-Rink Amide MBHA resin (SEQ ID NO:157), the resin was treated with Fmoc-Ambz(4)-Arg(Pbf)-Ala-Tyr(But)-Ile-Asn (Trt)-Leu-Ile-Thr (γMe,MePro)-OH (28.4 mg, 0.015 mmol) obtained in Example 3, PyAOP (27.1 mg, 0.05 mmol), 0.5 M HOAt/DMF (0.2 mL, 0.1 mmol), DIEA (34.8 μL, 0.2 mmol) at room temperature overnight. The obtained resin (92.0 mg) was treated with TFA:thioanisole:m-cresol:H2O:EDT:TIS (80:5:5:5:2.5:2.5) (0.6 mL) for 90 min, and diethyl ether was added to the reaction solution to allow precipitation of a white powder. An operation to remove ether by decantation after centrifugation was repeated twice to remove acid and scavenger. The residue was extracted with aqueous acetic acid solution, and purified by preparative HPLC using Daisopak-SP100-5-ODS-P 2×25 cm to give 2.2 mg of a white powder.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17](Br)=[CH:16][C:15]=2[CH:21]2[CH2:26][CH2:25][C:24]([CH3:28])([CH3:27])[CH2:23][CH2:22]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:29][C@H:30]1[O:35][C@@H:34]([CH3:36])[CH2:33][NH:32][CH2:31]1.CC(C)([O-])C.[Na+].F[B-](F)(F)F.C([PH+](C(C)(C)C)C(C)(C)C)(C)(C)C>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(C)C(C)=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([N:32]3[CH2:31][C@H:30]([CH3:29])[O:35][C@H:34]([CH3:36])[CH2:33]3)=[CH:16][C:15]=2[CH:21]2[CH2:26][CH2:25][C:24]([CH3:28])([CH3:27])[CH2:23][CH2:22]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC1(C)CCC(c2cc(Br)ccc2N2CCN(C(=O)OC(C)(C)C)CC2)CC1
Reactant: C[C@@H]1CNC[C@H](C)O1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: Cc1ccccc1C
Product: C[C@@H]1CN(c2ccc(N3CCN(C(=O)OC(C)(C)C)CC3)c(C3CCC(C)(C)CC3)c2)C[C@H](C)O1
Temperature: 100 °C
Reaction time: 2 h
Yield: 86.1 %

Procedure:
A mixture of the 4-[4-bromo-2-(4,4-dimethylcyclohexyl)phenyl]piperazine-1-carboxylic acid t-butyl ester (700 mg, 1.55 mmol) produced in Example (3e), cis-2,6-dimethylmorpholine (268 mg, 2.33 mmol), sodium t-butoxide (372 mg, 3.88 mmol), palladium(II) acetate (35 mg, 0.155 mmol), tri-t-butylphosphonium tetrafluoroborate (135 mg, 0.465 mmol) and xylene (7 mL) was stirred for 2 hours at an external temperature of 100° C. under a nitrogen atmosphere. The reaction mixture was air-cooled to room temperature, and then the insoluble matters were filtered off, water was added to the obtained filtrate and extraction was performed with ethyl acetate. The separated organic layer was washed with water and brine in that order and then dried over anhydrous sodium sulfate. The desiccant was filtered off and the filtrate was concentrated under reduced pressure. The resultant residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give 648 mg of the title compound as yellow crystals.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]([CH2:11][CH2:12][O:13][C:14]2[CH:19]=[CH:18][C:17]([CH2:20][CH:21]([O:26][CH2:27][CH3:28])[C:22]([O:24][CH3:25])=[O:23])=[CH:16][CH:15]=2)[CH2:3][CH2:2]1.[CH:29]([N-]C(C)C)(C)C.[Li+].CI.Cl>O1CCCC1.O>[CH3:29][C:21]([O:26][CH2:27][CH3:28])([CH2:20][C:17]1[CH:16]=[CH:15][C:14]([O:13][CH2:12][CH2:11][N:4]2[C:5]3[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=3[O:1][CH2:2][CH2:3]2)=[CH:19][CH:18]=1)[C:22]([O:24][CH3:25])=[O:23]
Reactant: CC(C)[N-]C(C)C
Reactant: CCOC(Cc1ccc(OCCN2CCOc3ccccc32)cc1)C(=O)OC
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Solvent: CI
Product: CCOC(C)(Cc1ccc(OCCN2CCOc3ccccc32)cc1)C(=O)OC
Temperature: -78 °C
Reaction time: 1 h
Yield: 80 %

Procedure:
To a solution of methyl 3-[4-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-ethoxypropanoate (0.6 g, 1.5 mmol) obtained in example 2 in dry tetrahydrofuran (5 mL) was added lithium diisopropyl amide (5.25 μL, 0.5 mL solution in THF/hexane) at −78° C. After stirring for 1 h at −78° C., methyl iodide (0.75 mL) was added and the reaction mixture was allowed to warm to room temperature (ca 25° C.) and stirred for further 20 h at the same temperature. Water (20 mL) was added, acidified with 1 N hydrochloric acid and extracted with ethyl acetate (2×25 mL). The combined ethyl acetate layer was washed with water (25 mL), brine (25 mL), dried (Na2SO4), filtered and the solvent was evaporated under reduced pressure to afford the title compound (0.5 g, 80%) as an oil.
Reaction SMILES: [OH:1][CH:2]([CH3:13])[CH2:3][N:4]([CH2:9][CH:10]([OH:12])[CH3:11])[CH2:5][CH:6](O)[CH3:7].S(=O)(=O)(O)O>>[OH:1][CH:2]([CH3:13])[CH2:3][N:4]1[CH2:9][CH:10]([CH3:11])[O:12][CH:6]([CH3:7])[CH2:5]1
Reactant: CC(O)CN(CC(C)O)CC(C)O
Agent: O=S(=O)(O)O
Product: CC(O)CN1CC(C)OC(C)C1
Reaction time: 1 h

Procedure:
3 g of tris-(2-hydroxypropyl)amine and 1 g of SnO2 doped with sulfuric acid were heated in a manner similar to that described in Example 3 for a period of 1 h at 250° C. There were obtained, in addition to 50 wt % of educt, 30 wt % of N-(2-hydroxypropyl)-2,6-dimethylmorpholine.
Reaction SMILES: [CH:1]([N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([C:14]([OH:16])=O)=[C:6]1[CH3:17])([CH2:3][CH3:4])[CH3:2].C1C=C2N=NN(O)C2=CC=1.N.C(N(CC)CC)C.[NH2:36][CH2:37][C:38]1[C:39]([OH:46])=[N:40][C:41]([CH3:45])=[CH:42][C:43]=1[CH3:44]>ClCCl>[CH:1]([N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([C:14]([NH:36][CH2:37][C:38]2[C:39]([OH:46])=[N:40][C:41]([CH3:45])=[CH:42][C:43]=2[CH3:44])=[O:16])=[C:6]1[CH3:17])([CH2:3][CH3:4])[CH3:2]
Reactant: CCC(C)n1c(C)c(C(=O)O)c2ccccc21
Reactant: Cc1cc(C)c(CN)c(O)n1
Agent: N
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCC(C)n1c(C)c(C(=O)NCc2c(C)cc(C)nc2O)c2ccccc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 37.1 %

Procedure:
A mixture of 1-sec-butyl-2-methyl-1H-indole-3-carboxylic acid (97 mg, 0.42 mmol), 1-ethyl-3-(3-dimethyllaminopropyl)carbodiimide hydrochloride (121 mg, 0.63 mmol), N-hydroxybenzotrizole (85 mg, 0.63 mmol) and triethylamine (127.26 mg, 1.26 mmol) in dichloromethane (30 mL) was stirred for 30 minutes at room temperature. Then to the mixture, 3-(aminomethyl)-4,6-dimethylpyridin-2-ol (63.8 mg, 0.42 mmol) was added. The resulting mixture was stirred at room temperature for 12 hours. Then the mixture was washed with water (20 mL×3). The organic layer was concentrated to give a residue which was purified by column chromatography (silica gel, dichloromethane/methanol=20:1) to give 1-sec-butyl-N-((2-hydroxy-4,6-dimethylpyridin-3-yl)methyl)-2-methyl-1H-indole-3-carboxamide (57 mg, 30%). LRMS (M+H+) m/z: calcd 365.2. found 365. HPLC purity (214 nm): 99%. 1H.NMR (300 MHz, CD3OD): δ 7.72-7.69 (m, 1H), 7.53 (d, J=7.2 Hz, 1H), 7.11-7.06 (m, 2H), 6.10 (s, 1H), 4.53-4.51 (m, 3H), 2.62 (s, 3H), 2.41 (s, 3H), 2.24 (s, 3H), 1.95-1.93 (m, 2H), 1.59 (d, J=6.9 Hz, 3H), 0.72 (t, J=7.5 Hz, 3H).
Reaction SMILES: Cl[O-].[Na+].[CH2:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13](=[O:15])C)[CH:11]=2)[CH2:6][CH2:5]1.C([O-])(O)=[O:17].[Na+]>>[CH2:6]1[C:7]2[C:12](=[CH:11][C:10]([C:13]([OH:15])=[O:17])=[CH:9][CH:8]=2)[CH2:4][CH2:5]1
Reactant: O=C([O-])O
Reactant: CC(=O)c1ccc2c(c1)CCC2
Agent: [Na+]
Agent: [O-]Cl
Product: O=C(O)c1ccc2c(c1)CCC2
Temperature: 55 °C
Reaction time: 2 h
Yield: 99 %

Procedure:
To a stirred aqueous sodium hypochlorite solution (2230 ml, 1.80 mmol, 6%) at 55° C. was added 1-(2,3-dihydro-1H-inden-6-yl)ethanone (120.0 g, 0.75 mol) and the mixture was stirred at 55° C. for 2 h. After cooling to room temperature, saturated NaHCO3 solution was added until the solution became clear. The produced precipitate was filtered, washed several times with water and dried to afford the desired product (120.0 g, 99%). 1H NMR (CDCl3, 300 MHz) δ 2.07-2.17 (m, 2H), 2.96 (t, J=7.5 Hz, 4H), 7.30 (d, J=7.8, 1H,), 7.91 (d, J=7.8, 1H), 7.96 (s, 1H).
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.C([O:11][CH:12]=[C:13]([C:19](OCC)=O)[C:14]([O:16][CH2:17][CH3:18])=[O:15])C.C(O)C.C1(OC2C=CC=CC=2)C=CC=CC=1>C(OCC)C>[F:1][C:2]1[CH:8]=[C:7]2[C:5](=[CH:4][CH:3]=1)[N:6]=[CH:19][C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[C:12]2[OH:11]
Reactant: Nc1ccc(F)cc1
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Solvent: CCO
Solvent: CCOCC
Solvent: c1ccc(Oc2ccccc2)cc1
Product: CCOC(=O)c1cnc2ccc(F)cc2c1O
Temperature: 140 °C
Yield: 68.9 %

Procedure:
A mixture of 66.6 g (0.6 mole) of 4-fluoroaniline and 129.79 g (0.6 mole) of diethyl ethoxymethylenemalonate was prepared under a nitrogen atmosphere and heated to 140° C. The ethanol generated was allowed to vaporize during a reaction time of about one hour. To the mixture was added 500 ml of diphenyl ether. The mixture was stirred and heated to its reflux temperature, and maintained at reflux for 15 minutes. The mixture was then cooled, and diethyl ether was added. The product was separated by filtration, washed with diethyl ether and air dried to provide 97.3 g (69% yield) of ethyl 6-fluor-4-hydroxyquinoline-3-carboxylate.
Reaction SMILES: C=[C:2]1[CH2:7][CH2:6][O:5][CH2:4][CH:3]1[CH2:8][CH2:9][CH2:10][CH:11]=C>C(Cl)Cl>[CH2:4]1[CH:3]2[C:2](=[CH:11][CH2:10][CH2:9][CH2:8]2)[CH2:7][CH2:6][O:5]1
Reactant: C=CCCCC1COCCC1=C
Solvent: ClCCl
Product: C1=C2CCOCC2CCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 4-methylidene-3-(pent-4-en-1-yl)tetrahydro-2H-pyran (0.198 g, 1.19 mmol) in CH2Cl2 (20 mL) was degassed (3×N2/pump). Zhan-Ib (0.044 g, 0.060 mmol) was added, the reaction was degassed again, and stirred at rt for 1 hr. The resulting mixture was concentrated and purified by silica gel chromatography to provide the title compound. 1H NMR (500 MHz, CDCl3) δ 5.47 (s, 1H), 3.90-4.10 (m, 2H), 3.26-3.35 (m, 1H), 2.94 (t, 1H, J=11.0 Hz), 2.24-2.40 (m, 2H), 1.74-2.07 (m, 3H), 1.65-1.76 (m, 2H), 1.38-1.49 (m, 1H), 0.96-1.07 (m, 1H).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[CH:6][C:5]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)=[CH:4][N:3]=1.[NH3:17]>CS(C)=O>[NH2:17][C:2]1[C:7]([C:8]#[N:9])=[CH:6][C:5]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)=[CH:4][N:3]=1
Reactant: N
Reactant: N#Cc1cc(-c2ccc(Cl)cc2)cnc1Cl
Solvent: CS(C)=O
Product: N#Cc1cc(-c2ccc(Cl)cc2)cnc1N
Temperature: 0 °C
Reaction time: 60 h

Procedure:
A solution of 2-chloro-5-(4-chlorophenyl)-3-pyridinecarbonitrile (2.0 grams) in 30 ml DMSO was heated in an oil bath at 80°-90° C. and then treated with gaseous NH3 for 21/2 hours. The reaction mixture was allowed to stand at room temperature for about 60 hours and then additional starting material (4 g) in 35 ml DMSO was added. The mixture was then treated with NH3 at 80°-90° C. for about 28 hours and poured into ice water. The tan solid precipitate which formed was filtered and used without further purification, yield 5.5 grams, m.p. 202°-204° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:13]3[N:14]([CH2:17][C@H:18]4[CH2:23][CH2:22][C@H:21]([CH3:24])[CH2:20][CH2:19]4)[CH:15]=[N:16][C:12]=3[CH:11]=[C:10]([C:25]#[N:26])[N:9]=2)[CH:5]=[N:6][CH:7]=1.[Cl-].[Li+].CC1(C)CCCC(C)(C)N1[Mg]Cl.[CH3:41][O:42][CH2:43][C:44](=[O:46])[CH3:45]>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:13]3[N:14]([CH2:17][C@H:18]4[CH2:23][CH2:22][C@H:21]([CH3:24])[CH2:20][CH2:19]4)[C:15]([C:44]([OH:46])([CH3:45])[CH2:43][O:42][CH3:41])=[N:16][C:12]=3[CH:11]=[C:10]([C:25]#[N:26])[N:9]=2)[CH:5]=[N:6][CH:7]=1
Reactant: C[C@H]1CC[C@H](Cn2cnc3cc(C#N)nc(-c4cncc(Cl)c4)c32)CC1
Reactant: COCC(C)=O
Agent: CC1(C)CCCC(C)(C)N1[Mg]Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COCC(C)(O)c1nc2cc(C#N)nc(-c3cncc(Cl)c3)c2n1C[C@H]1CC[C@H](C)CC1
Temperature: -78 °C
Reaction time: 2 h

Procedure:
4-(5-chloropyridin-3-yl)-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridine-6-carbonitrile (Preparative Example 3.1, Step 2) (350 mg, 0.95 mmol) was dissolved in THF (10 mL) and cooled to −78° C. 2,2,6,6-tetramethylpiperidinylmagnesium chloride lithium chloride complex (Aldrich, 1M in THF/toluene) (2.0 mL, 2.0 mmol) was added slowly to the solution at −78° C. The reaction was stirred at −78° C. for 2 hours. Then methoxyacetone (168 mg, 2.0 mmol) was added into the reaction mixture at −78° C. The reaction was allowed to warm to room temperature and stirred for 8 hours under a nitrogen atmosphere. The reaction was quenched with saturated NH4Cl solution (5 mL) at −78° C. and extracted with EtOAc (2×10 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified on a silica gel column (0 to 100% EtOAc/hexanes) to afford 4-(5-chloropyridin-3-yl)-2-(2-hydroxy-1-methoxypropan-2-yl)-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridine-6-carbonitrile. MS APCI calcd. for C24H28ClN5O2 [M+H]+ 454. found 454.