Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][CH:9]=1.[Cl:18][C:19]1[CH:20]=[C:21](B(O)O)[CH:22]=[CH:23][C:24]=1[O:25][CH3:26]>>[Cl:18][C:19]1[CH:20]=[C:21]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[C:8]2[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][CH:9]=2)[CH:22]=[CH:23][C:24]=1[O:25][CH3:26]
Reactant: CS(=O)(=O)c1ccc(-c2ccccc2Br)cc1
Reactant: COc1ccc(B(O)O)cc1Cl
Product: COc1ccc(-c2ccccc2-c2ccc(S(C)(=O)=O)cc2)cc1Cl
Yield: 68.3 %

Procedure:
Following the general procedure outlined in Synthetic Scheme VI, 4.0 g (13 mmol) of 1-bromo-2-[4-(methylsulfonyl)phenyl]benzene (Example 4, Step 2) was reacted with 2.86 g (15.4 mmol) of 3-chloro-4-methoxyphenylboronic acid (Step 2). Purification by silica gel chromatography (Waters PrepLC500A) with ethyl acetate/hexane (35:65) and subsequent recrystallization from ethyl acetate/hexane gave 3.31 g (69%) of 2-chloro-1-methoxy-4-[2-[4-(methylsulfonyl)phenyl]phenyl]benzene as a colorless solid: mp 161.5-162.3° C.; NMR (CDCl3) δ 3.05 (s, 3H), 3.88 (s, 3H), 6.75 (d, J=9 Hz, 1H), 6.87 (dd, J=1.5, 9 Hz, 1H), 7.17 (d, J=2 Hz, 1H), 7.34 (d, J=9 Hz, 2H), 7.37-7.51 (m, 4H), 7.82 (d, J=8 Hz, 2H). MS (EI): m/e (rel intensity) 372 (100), 243 (24); HRMS Calc'd for C20H17ClO3S: 372.0587. Found: 372.0557. Anal. Calc'd for C20H17ClO3S: C, 64.43; H, 4.60; Cl, 9.51. Found: C, 64.17; H, 4.56; Cl, 9.63.
Reaction SMILES: [K].[Cl:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[C:8]([OH:13])[CH:7]=[CH:6]2.F[C:15]1[CH:16]=[CH:17][C:18]([N+:24]([O-:26])=[O:25])=[C:19]([CH:23]=1)[C:20]([O-:22])=[O:21].Cl>CS(C)=O.O>[Cl:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[C:8]([O:13][C:15]1[CH:16]=[CH:17][C:18]([N+:24]([O-:26])=[O:25])=[C:19]([CH:23]=1)[C:20]([OH:22])=[O:21])[CH:7]=[CH:6]2
Reactant: O=C([O-])c1cc(F)ccc1[N+](=O)[O-]
Reactant: Oc1ccc2cc(Cl)ccc2n1
Agent: Cl
Agent: [K]
Solvent: CS(C)=O
Solvent: O
Product: O=C(O)c1cc(Oc2ccc3cc(Cl)ccc3n2)ccc1[N+](=O)[O-]
Temperature: 100 °C
Reaction time: 16 h

Procedure:
A reactor is charged with 4.34 grams (0.02 mole) of the potassium salt of 6-chloro-2-hydroxyquinoline (Formula II Compound) in 25 milliliters of dimethylsulfoxide. To this mixture is added 4.46 grams (0.02 mole) of the potassium salt of 5-fluoro-2-nitrobenzoate (Formula III Compound). After stirring at about 100° C. for about 16 hours, the reaction mixture is poured into 200 milliliters of water and acidified with concentrated hydrochloric acid. Filtration and air drying affords 5-(6-chloro-2-quinolinoxy)-2-nitrobenzoic acid (Formula IV Compound).
Reaction SMILES: C(O[C:6]([N:8](C(OC(C)(C)C)=O)[C:9](=[O:38])[C:10]1[CH:15]=[C:14]([N:16]2[CH2:20][CH2:19][CH2:18][C:17]2=[O:21])[CH:13]=[CH:12][C:11]=1[C:22]([N:24]1[CH2:29][CH2:28][N:27]([C:30]2[C:35]([CH3:36])=[CH:34][C:33]([CH3:37])=[CH:32][N:31]=2)[CH2:26][CH2:25]1)=[O:23])=O)(C)(C)C.[CH3:46][O:47][CH2:48][CH2:49]NC>>[CH3:36][C:35]1[C:30]([N:27]2[CH2:28][CH2:29][N:24]([C:22]([C:11]3[CH:12]=[CH:13][C:14]([N:16]4[CH2:20][CH2:19][CH2:18][C:17]4=[O:21])=[CH:15][C:10]=3[C:9]([N:8]([CH2:49][CH2:48][O:47][CH3:46])[CH3:6])=[O:38])=[O:23])[CH2:25][CH2:26]2)=[N:31][CH:32]=[C:33]([CH3:37])[CH:34]=1
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(N4CCCC4=O)cc3C(=O)N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)CC2)c(C)c1
Reactant: CNCCOC
Product: COCCN(C)C(=O)c1cc(N2CCCC2=O)ccc1C(=O)N1CCN(c2ncc(C)cc2C)CC1

Procedure:
Using N,N-di-tert-butyloxycarbonyl-2-[4-(3,5-dimethylpyridin-2-yl)piperazine-1-carbonyl]-5-(2-oxopyrrolidin-1-yl)benzamide (150 mg) described in Example 769 and (2-methoxyethyl)(methyl)amine (108 μL) and by the reaction and treatment in the same manner as in Example 770, the title compound (58 mg) was obtained.
Reaction SMILES: CS(O[CH2:6][C@H:7]1[N:14]([S:15]([C:18]2[CH:19]=[CH:20][CH:21]=[C:22]3[C:27]=2[N:26]=[CH:25][CH:24]=[CH:23]3)(=[O:17])=[O:16])[CH2:13][C:12]2[CH:28]=[CH:29][CH:30]=[CH:31][C:11]=2[CH2:10][O:9][CH2:8]1)(=O)=O.CS(C)=O.C([O-])([O-])=O.[Cs+].[Cs+].[NH:42]1[CH:46]=[CH:45][CH:44]=[N:43]1>CC(=O)OCC>[N:42]1([CH2:6][C@H:7]2[N:14]([S:15]([C:18]3[CH:19]=[CH:20][CH:21]=[C:22]4[C:27]=3[N:26]=[CH:25][CH:24]=[CH:23]4)(=[O:16])=[O:17])[CH2:13][C:12]3[CH:28]=[CH:29][CH:30]=[CH:31][C:11]=3[CH2:10][O:9][CH2:8]2)[CH:46]=[CH:45][CH:44]=[N:43]1
Reactant: CS(=O)(=O)OC[C@@H]1COCc2ccccc2CN1S(=O)(=O)c1cccc2cccnc12
Reactant: c1cn[nH]c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: O=S(=O)(c1cccc2cccnc12)N1Cc2ccccc2COC[C@H]1Cn1cccn1
Temperature: 110 °C
Yield: 32.9 %

Procedure:
Compound 17a (100 mg, 0.21 mmol) was added to DMSO (1 mL) and Cs2CO3 (500 mg, 1.5 mmol). 1H-Pyrazole (70 mg, 1.0 mmol) was added in the mixture and sealed in a microwave tube. The mixture was heated to 110° C. for 30 min under microwave irradiation. The reaction mixture was poured into ice/water (50 mL) and extracted with EA (3×50 mL) and washed with brine (2×50 mL) and dried over anhydrous Na2SO4. The residue was purified by CC eluting with PE:EA=3:1 to give compound 17 as white solid (30 mg, 32% yield). 1H-NMR (400 MHz, CD3OD) δ: 8.73 (d, J=1.6 Hz, 1H), 8.33 (d, J=7.2 Hz, 1H), 8.20 (d, 1H), 7.97 (d, 1H), 7.52-7.50 (m, 2H), 7.40-7.38 (m, 2H), 6.80 (d, 1H), 6.70 (t, 1H), 6.14 (s, 1H), 5.10 (m, 1H), 4.92 (d, J=14.4 Hz, 1H), 4.80 (m, 2H), 4.43 (d, J=14.4 Hz, 1H), 4.35 (q, 1H), 4.22 (q, 1H), 3.76 (d, 1H), 3.66 (d, 1H). MS (ESI+) m/z: 435.0 [M+H]+.
Reaction SMILES: [NH:1]1[C:9]2[CH2:8][CH2:7][NH:6][CH2:5][C:4]=2[N:3]=[CH:2]1.[CH:10]1([N:13]=[C:14]=[O:15])[CH2:12][CH2:11]1>O1CCOCC1.C(#N)C>[CH:10]1([NH:13][C:14]([N:6]2[CH2:7][CH2:8][C:9]3[NH:1][CH:2]=[N:3][C:4]=3[CH2:5]2)=[O:15])[CH2:12][CH2:11]1
Reactant: O=C=NC1CC1
Reactant: c1nc2c([nH]1)CCNC2
Solvent: C1COCCO1
Solvent: CC#N
Product: O=C(NC1CC1)N1CCc2[nH]cnc2C1
Yield: 34.3 %

Procedure:
A solution of 3.69 g of 4,5,6,7-tetrahydro-imidazo-[4,5-c]-pyridine and 7.47 g of cyclopropyl isocyanate in 20 ml of dry dioxane is refluxed for 1.5 h. After evaporation to dryness, the residue is dissolved in 44 ml of methanol and treated with 11 ml of 2N sodium hydroxide for 1.5 h at room temperature. After neutralization, the solution is extracted with chloroform. Evaporation of the solvent leaves a residue that is taken up in acetonitrile to give 2.12 g of the title compound, m.p. 215°.
Reaction SMILES: [C:1]([NH:8][C@H:9]([C@H:25]1[O:29][C:28](=[O:30])[CH2:27][CH2:26]1)[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:13][CH:12]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].CN1CCCN(C)C1=O.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH2:50]([O:57][C:58]1[CH:65]=[CH:64][C:61]([CH2:62]I)=[CH:60][CH:59]=1)[C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1>C1COCC1>[C:1]([NH:8][C@H:9]([C@H:25]1[O:29][C:28](=[O:30])[C@H:27]([CH2:62][C:61]2[CH:64]=[CH:65][C:58]([O:57][CH2:50][C:51]3[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=3)=[CH:59][CH:60]=2)[CH2:26]1)[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[CH:13][CH:12]=1)([O:3][C:4]([CH3:6])([CH3:7])[CH3:5])=[O:2]
Reactant: ICc1ccc(OCc2ccccc2)cc1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(OCc2ccccc2)cc1)[C@@H]1CCC(=O)O1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CN1CCCN(C)C1=O
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(OCc2ccccc2)cc1)[C@@H]1C[C@@H](Cc2ccc(OCc3ccccc3)cc2)C(=O)O1

Procedure:
Analogously to Example 21 D) 1)c), 2.47 g (6.0 mmol) of 5(S)-[1(S)-(Boc-amino)-2-(p-benzyloxyphenyl)ethyl]-dihydrofuran-2-(3H)-one (Example 46 c)) dissolved in 12 ml of THF and 1.2 ml of 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone are deprotonated at -70° C. with 11.73 ml of lithium bis(trimethylsilyl)amide 1M in THF and alkylated (60 min) with 1.946 g (6.0 mmol) of p-benzyloxybenzyl iodide (Example 44a)) in 3 ml of THF. Column chromatography (SiO2, hexane/ethyl acetate 4:1) and crystallisation from ethyl acetate/hexane yields the pure title compound: TLC Rf (D)=0.45; tRet (I)=19.9 min; FAB-MS (M+H)+ =608.
Reaction SMILES: [Si]([O:5][S:6]([C:9]([F:12])([F:11])[F:10])(=[O:8])=[O:7])(C)(C)C.[Br-].[Li+:14].CC([N-]C(C)C)C.C1COCC1>C(Cl)Cl>[O:5]([S:6]([C:9]([F:12])([F:11])[F:10])(=[O:8])=[O:7])[Li:14]
Reactant: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Reactant: [Li+]
Agent: CC(C)[N-]C(C)C
Agent: [Br-]
Solvent: C1CCOC1
Solvent: ClCCl
Product: [Li]OS(=O)(=O)C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Me3SiOTf (0.90 ml, 5.0 mmol ) was added at −78° C. to a solution of iminiun bromide 3f (1.83 g, 5.0 mmol) in CH2Cl2 (30 ml). The suspension was warmed to room temperature and stirred for 1 hour. After evaporation of the solvent, a solid residue was obtained. Then to a 1/1 mixture of LDA and iminium triflate (5.0 mmol), 30 ml of THF was added at −78° C. The suspension was warmed to room temperature and stirred for 30 min. After evaporation of the solvent under vacuum, a solid residue containing carbene Cf and LiOTf was obtained. 1H NMR (thf-d8, 25° C.): 7.00-7.20 (m, 3H, Har), 3.34 (m, 1H, CHCH3), 2.85 (sept, 2H, CHCH3, J=6.9), 1.85-1.96 (m, 1H, CH2), 1.29-1.62 (m, 3H, CH2), 1.18 (d, 3H, CHCH3, J=6.9), 1.14 (d, 3H, CHCH3, J=6.9), 1.11 (s, 3H, CH3), 1.04 (s, 3H, CH3), 1.00 (d, 3H, CHCH3, J=6.6), 0.98 (d, 3H, CHCH3, J=6.3), 0.94 (d, 3H, CHCH3, J=6.3). 13C NMR (thf-d8, 25° C.): 322.00 (C), 144.45 (Car), 144.02 (Car), 142.35 (Car), 126.86 (Car), 123.44 (Car), 123.37 (Car), 56.15 (CH), 41.88 (C), 28.39, 28.26, 27.95, 27.12 (CH2), 26.88 (CH2), 26.47, 24.64, 23.91, 22.21, 21.70, 18.34.
Reaction SMILES: C(OC([N:8]1[CH2:11][CH:10]([NH:12][C:13]2[CH:14]=[C:15]3[C:24](=[CH:25][C:26]=2[CH3:27])[O:23][CH2:22][C:21]2[N:16]3[C@H:17]([CH3:29])[C:18](=[O:28])[NH:19][N:20]=2)[CH2:9]1)=O)(C)(C)C.C(Cl)Cl.[C:33]([OH:39])([C:35]([F:38])([F:37])[F:36])=[O:34]>>[F:36][C:35]([F:38])([F:37])[C:33]([OH:39])=[O:34].[NH:8]1[CH2:9][CH:10]([NH:12][C:13]2[CH:14]=[C:15]3[C:24](=[CH:25][C:26]=2[CH3:27])[O:23][CH2:22][C:21]2[N:16]3[C@H:17]([CH3:29])[C:18](=[O:28])[NH:19][N:20]=2)[CH2:11]1
Reactant: Cc1cc2c(cc1NC1CN(C(=O)OC(C)(C)C)C1)N1C(=NNC(=O)[C@H]1C)CO2
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc2c(cc1NC1CNC1)N1C(=NNC(=O)[C@H]1C)CO2
Yield: 93 %

Procedure:
A solution of 3-(4(R),7-dimethyl-3-oxo-2,3,4,10-tetrahydro-9-oxa-1,2,4a-triaza-phenanthren-6-ylamino)-azetidine-1-carboxylic acid tert-butyl ester ((Enantiomer 1, SFC (Table 1, Method 8), Rt=3.090 min, 0.250 g, 0.62 mmol) in TFA (4 mL) and DCM (24 mL) was stirred at 25° C. for 3 h. The solvent was removed in vacuo to give 6-(azetidin-3-ylamino)-4(R),7-dimethyl-2,10-dihydro-9-oxa-1,2,4a-triaza-phenanthren-3-one trifluoroacetic acid (Example #54-1, Enantiomer 1, SFC (Table 1, Method 9), Rt=4.110 min, 0.240 g, 93%) as yellow solid. LC/MS (Table 1, Method 5) Rt=2.048 min.; MS m/z: 302 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[NH:9][CH2:10][C@@H:11]([NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:12][CH2:13][CH2:14][CH3:15].C(N(CC)CC)C.[C:31](Cl)(=[O:33])[CH3:32]>ClCCl>[C:20]([O:19][C:17]([NH:16][C@@H:11]([CH2:12][CH2:13][CH2:14][CH3:15])[CH2:10][N:9]([C:3]1[CH:4]=[CH:5][CH:6]=[C:7]([CH3:8])[C:2]=1[CH3:1])[C:31](=[O:33])[CH3:32])=[O:18])([CH3:22])([CH3:21])[CH3:23]
Reactant: CC(=O)Cl
Reactant: CCCC[C@@H](CNc1cccc(C)c1C)NC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCC[C@@H](CN(C(C)=O)c1cccc(C)c1C)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of the product of Step H (500 mg, 1.56 mmol) and triethylamine (0.240 mL, 1.72 mmol) in 10 mL of dichloromethane at 0° C. was added acetyl chloride (0.122 mL, 1.72 mmol). After 20 min, the solution was warmed to room temperature, then stirred another 2 hours. The reaction was poured into CH2Cl2, washed with 10% citric acid and brine, dried (Na2SO4), filtered, and concentrated in vacuo to provide the titled product.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][S:5][CH:6]=1.[O:7]1[C:11]2[CH:12]=[CH:13][C:14]([CH2:16][C:17](N(OC)C)=[O:18])=[CH:15][C:10]=2[O:9][CH2:8]1.[Cl-].[NH4+]>CCCCCC.O1CCCC1>[O:7]1[C:11]2[CH:12]=[CH:13][C:14]([CH2:16][C:17]([C:4]3[S:5][CH:6]=[C:2]([CH3:1])[N:3]=3)=[O:18])=[CH:15][C:10]=2[O:9][CH2:8]1
Reactant: CON(C)C(=O)Cc1ccc2c(c1)OCO2
Reactant: Cc1cscn1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: Cc1csc(C(=O)Cc2ccc3c(c2)OCO3)n1
Reaction time: 0.5 h
Yield: 91.5 %

Procedure:
A 2.6M solution of n-butylithium in hexane (34 ml) was dropped into a solution of 4-methylthiazole (8.0 g) of tetrahydrofuran (150 ml) at −70° C. and the mixture was stirred for 30 minutes. Further, a solution of 2-benzo(1,3)dioxol-5-yl-N-methoxy-N-methylacetamide (20.0 g) in tetrahydrofuran (20 ml) was dropped therein and the mixture was stirred for 1 hour. This solution, to which a saturated aqueous solution of ammonium chloride was added, was extracted with ethyl acetate, and after the organic layer was dried over anhydrous magnesium sulfate, the solvent was evaporated. The resultant residue was purified by silica gel flash column chromatography using a mixed solvent of ethyl acetate and hexane to yield 2-benzo(1,3)dioxol-5-yl-1-(4-methylthiazol-2-yl)ethanone (19.3 g).
Reaction SMILES: C1(CCO)CC1.OC1C=CC(C=O)=CC=1.[OH:16][C@@H:17]1[CH2:22][CH2:21][C@H:20]([C:23]([N:25]([O:27][CH3:28])[CH3:26])=[O:24])[CH2:19][CH2:18]1.[Cl:29][C:30]1[CH:35]=[CH:34][C:33](O)=[CH:32][CH:31]=1>>[Cl:29][C:30]1[CH:35]=[CH:34][C:33]([O:16][C@H:17]2[CH2:22][CH2:21][C@H:20]([C:23]([N:25]([O:27][CH3:28])[CH3:26])=[O:24])[CH2:19][CH2:18]2)=[CH:32][CH:31]=1
Reactant: CON(C)C(=O)[C@H]1CC[C@@H](O)CC1
Reactant: Oc1ccc(Cl)cc1
Agent: O=Cc1ccc(O)cc1
Agent: OCCC1CC1
Product: CON(C)C(=O)[C@H]1CC[C@H](Oc2ccc(Cl)cc2)CC1

Procedure:
Instead of 2-cyclopropylethanol and 4-hydroxybenzaldehyde, the compound (850 mg) obtained in step (1) above and p-chlorophenol (700 mg) were respectively used and treated by the same technique as in Reference Example 11-1 to give trans-4-(4-chlorophenoxy)-N-methoxy-N-methylcyclohexanecarboxamide as a colorless solid (458 mg).
Reaction SMILES: [C:1]([C:4]1[C:5]([F:13])=[C:6](N)[C:7]([O:10][CH3:11])=[CH:8][CH:9]=1)(=[O:3])[CH3:2].[CH3:14][C:15](C1C=CC(OC)=CC=1F)=[O:16].C(O)CO.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[F:13][C:5]1[CH:6]=[C:7]([O:10][CH3:11])[CH:8]=[CH:9][C:4]=1[C:1]1([CH3:2])[O:16][CH2:15][CH2:14][O:3]1
Reactant: COc1ccc(C(C)=O)c(F)c1N
Reactant: COc1ccc(C(C)=O)c(F)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: OCCO
Product: COc1ccc(C2(C)OCCO2)c(F)c1

Procedure:
Starting material 3-acetyl-2-fluoro-6-methoxyphenyl-amine, was prepared in following manner: A mixture of 2-Fluoro-4-methoxyacetophenone (5 g)(Fluorochem), ethylene glycol (4 ml), and p-toluensulfonic acid (50 mg) in toluene was refluxed 10 hours to give 5.7 g of 2-(2-fluoro-4-methoxyphenyl)-2-methyl-1,3-dioxolane. This was converted to 2-fluoro-6-methoxy-3-(2-methyl-1,3-dioxol-2-yl)-benzaldehyde according to Example 362 of WO 93/03022. This compound was converted to 2-fluoro-6-methoxy-3-(2-methyl-1,3-dioxol-2-yl)-cinnamic acid ethylester according to the methods described in Example 353 of WO 93/03022. 2-Fluoro-6-methoxy-3-(2-methyl-1,3-dioxol-2-yl)cinnamic acid ethylester was then treated with KOH in dioxane and water to yield 2-fluoro-6-methoxy-3-(2-methyl-1,3-dioxol-2-yl)cinnamic acid. Hydrolysis with aqueous HCl in dioxane gave 3-acetyl-2-fluoro-6-methoxycinnamic acid. N-(3-Acetyl-2-fluoro-6-methoxyphenyl)-N′-(5-chloropyrid-2-yl)-urea was then prepared in a manner analogous to the method in Example 7. 1H NMR (250 MHz, CDCl3) δ 9.18 (br s, 1H), 8.97 (br s, 1H), 7.85 (d, 1H), 7.83 (t, 1H), 7.51 (dd, 1H), 6.83 (d, 1H), 6.70 (d, 1H), 3.82 (s, 3H), 3.57 (q, 2H), 3.08-2.92 (m, 2H), 2.51 (d, 3H).
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:8]([OH:10])=[O:9])=[N:4][CH:5]=[CH:6][CH:7]=1>CCO.O.O=[Pt]=O>[CH3:1][C@H:2]1[CH2:7][CH2:6][CH2:5][NH:4][C@H:3]1[C:8]([OH:10])=[O:9]
Reactant: Cc1cccnc1C(=O)O
Agent: O=[Pt]=O
Solvent: O
Solvent: CCO
Product: C[C@H]1CCCN[C@H]1C(=O)O
Reaction time: 18 h

Procedure:
3-Methylpicolinic acid (10 g, 72.9 mmol) in EtOH (80 mL) and water (80 mL) was treated with PtO2 (4 g) and placed under a H2 atmosphere (60 psi). The mixture was shaken vigorously for 18 h, and then the PtO2 was degassed via vacuum for 30 min. The mixture was filtered through a Celite pad, which was washed with EtOH (3 50 mL) and H2O (3 80 mL). The solution was concentrated to afford (+/−) cis-3-methylpiperidine-2-carboxylic acid, which was used without further purification.
Reaction SMILES: BrC1C=CC=CC=1.[Li].O1CCCCC1[O:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH2:24][CH3:25])=[C:18]([O:26][CH3:27])[CH:17]=1.CN(C)[CH:30]=[O:31]>CCOCC>[OH:15][C:16]1[C:17]([CH:30]=[O:31])=[C:18]([O:26][CH3:27])[C:19]([O:22][CH2:23][CH2:24][CH3:25])=[CH:20][CH:21]=1
Reactant: CCCOc1ccc(OC2CCCCO2)cc1OC
Reactant: CN(C)C=O
Agent: [Li]
Solvent: Brc1ccccc1
Solvent: CCOCC
Product: CCCOc1ccc(O)c(C=O)c1OC
Temperature: 25 °C

Procedure:
1 ml of bromobenzene (11.88 ml) was added to a mixture of lithium chips (1.63 g) and anhydrous ether (90 ml) under nitrogen. When the reaction had commenced the remainder of the bromobenzene was added dropwise to the stirred mixture at such a rate as to cause gentle refluxing. After the addition was complete the mixture was stirred and refluxed (1 hr) and then cooled to room temperature. 3-Methoxy-4-n-propoxyphenol tetrahydropyranyl ether (30.03 g, 0.113 M) was added dropwise to the stirred mixture and then stirred at room temperature (3 days). A solution of anhydrous dimethyl formamide (8.5 ml) in anhydrous ether (8.5 ml) was added dropwise to the stirred mixture at such a rate as to cause gentle refluxing, and then stirred for an extra hour. The reaction mixture was poured into 2 N sulphuric acid/ice (200 ml) and extracted with ethyl acetate. The combined extracts were washed with water, dried (sodium sulphate) and evaporated. The residue was dissolved in 95% ethanol (175 ml) and 2 N hydrochloric acid (210 ml) was added. After stirring at room temperature (2 hr) the mixture was diluted with water (500 ml) and extracted with ethyl acetate/ether (1:1). The combined extracts were extracted with 2 N sodium hydroxide solution, the combined aqueous phases acidified with concentrated hydrochloric acid and extracted with ethyl acetate. The combined extracts were washed with water, dried (sodium sulphate) and evaporated. The residue was chromatographed on silica (MFC) eluting with chloroform-methanol (98:2) to give 6-hydroxy-2-methoxy-3-n-propoxybenzaldahyde as an oil.
Reaction SMILES: [H-].[Na+].[I-].[CH3:4][S+](C)C.[CH3:8][CH:9]([C:11]1[CH:16]=[CH:15][C:14]([C:17](=[CH2:21])[C:18](=[O:20])[CH3:19])=[CH:13][CH:12]=1)[CH3:10]>CN(C)C=O>[CH3:10][CH:9]([C:11]1[CH:12]=[CH:13][C:14]([C:17]2([C:18](=[O:20])[CH3:19])[CH2:4][CH2:21]2)=[CH:15][CH:16]=1)[CH3:8]
Reactant: C=C(C(C)=O)c1ccc(C(C)C)cc1
Reactant: C[S+](C)C
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)C1(c2ccc(C(C)C)cc2)CC1
Temperature: 0 °C
Yield: 44.7 %

Procedure:
474 mg of sodium hydride (55% in paraffin oil) is introduced into 20 ml of dimethylformamide under nitrogen at 0° C., and 1.29 g of trimethylsulfonium iodide is added. After 30 minutes at this temperature, 930 mg of ketone 46 is added in drops to 4 ml of dimethylformamide. It is stirred for 1 more hour at 0° C., then quenched with sodium chloride solution, extracted with ethyl acetate, dried on sodium sulfate and concentrated by evaporation. After chromatography on silica gel with ethyl acetate/hexane, 447 mg of title compound 47 is obtained as a colorless oil.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[CH:8]=[C:9]3[C:14](=[CH:15][CH:16]=2)[N:13]=[CH:12][CH:11]=[CH:10]3)=[N:5][N:4]=[C:3]1[S:17][CH2:18][CH2:19][CH2:20][CH:21]=O.[CH2:23]([S:25]([C:28]1[CH:38]=[CH:37][C:31]2[CH2:32][CH2:33][NH:34][CH2:35][CH2:36][C:30]=2[CH:29]=1)(=[O:27])=[O:26])[CH3:24].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[CH2:23]([S:25]([C:28]1[CH:38]=[CH:37][C:31]2[CH2:32][CH2:33][N:34]([CH2:21][CH2:20][CH2:19][CH2:18][S:17][C:3]3[N:2]([CH3:1])[C:6]([C:7]4[CH:8]=[C:9]5[C:14](=[CH:15][CH:16]=4)[N:13]=[CH:12][CH:11]=[CH:10]5)=[N:5][N:4]=3)[CH2:35][CH2:36][C:30]=2[CH:29]=1)(=[O:26])=[O:27])[CH3:24]
Reactant: Cn1c(SCCCC=O)nnc1-c1ccc2ncccc2c1
Reactant: CCS(=O)(=O)c1ccc2c(c1)CCNCC2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CCS(=O)(=O)c1ccc2c(c1)CCN(CCCCSc1nnc(-c3ccc4ncccc4c3)n1C)CC2
Reaction time: 8 h
Yield: 20.4 %

Procedure:
4-(4-Methyl-5-quinolin-6-yl-4H-[1,2,4]triazol-3-ylsulfanyl)-butyraldehyde (0.1 g, 0.32 mmol) and 7-Ethanesulfonyl-2,3,4,5-tetrahydro-1H-benzo[d]azepine (0.11 g, 0.45 mmol) were stirred at room temperature in dichloromethane (4 ml) for 20 min. Sodium triacetoxyborohydride (71 mg, 0.34 mmol) was then added and the mixture stirred overnight. The mixture was diluted with dichloromethane (50 ml) and washed with saturated sodium bicarbonate solution (30 ml). The aqueous was extracted with further dichloromethane (50 ml) and the combined organic portions were dried (Na2SO4), filtered and evaporated to give a yellow oil. Purification by silica gel chromatography (eluent 10% MeOH:EtOAc) which gave the title compound as a colourless oil (35 mg, 21%).
Reaction SMILES: C([NH:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12](Cl)[CH:13]=2)[N:8]=[C:7]([NH:16][CH2:17][C:18]2[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=2[O:25][CH3:26])[CH:6]=1)C=C.[CH2:27]([NH2:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[CH2:27]([NH:34][C:12]1[CH:13]=[C:14]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([NH:16][CH2:17][C:18]1[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=1[O:25][CH3:26])[CH:6]=[C:5]2[NH2:4])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: C=CCNc1cc(NCc2cc(F)ccc2OC)nc2ccc(Cl)cc12
Reactant: NCc1ccccc1
Product: COc1ccc(F)cc1CNc1cc(N)c2cc(NCc3ccccc3)ccc2n1

Procedure:
The title compound, MS: m/e=403.5 (M+H+), was prepared in accordance with the general method of example 44 from N4-allyl-6-chloro-N2-(5-fluoro-2-methoxy-benzyl)-quinoline-2,4-diamine and benzylamine
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]2[NH:15][N:14]=[C:13]([CH3:16])[C:8]=2[C:9](Cl)=[N:10][CH:11]=1)=[O:5])C.[CH2:17]([NH:19][CH2:20][CH3:21])[CH3:18]>>[CH2:17]([N:19]([CH2:20][CH3:21])[C:9]1[C:8]2[C:13]([CH3:16])=[N:14][NH:15][C:7]=2[C:6]([C:4]([OH:3])=[O:5])=[CH:11][N:10]=1)[CH3:18]
Reactant: CCNCC
Reactant: CCOC(=O)c1cnc(Cl)c2c(C)n[nH]c12
Product: CCN(CC)c1ncc(C(=O)O)c2[nH]nc(C)c12

Procedure:
2.4 g. of 4-chloro-3-methyl-1H-pyrazolo[4,3-c]pyridine-7-carboxylic acid ethyl ester is refluxed with 20 ml. of diethylamine for 24 hours. The excess diethylamine is removed by distillation and the residue treated with 20 ml. of water. 4-Diethylamino-3-methyl-1H-pyrazolo[4,3-c]pyridine-7-carboxylic acid ethyl ester precipitates and is recrystallized from ethyl acetate. Yield 2.1 g. (76%), m.p. 85°-88°. Hydrolysis of this product with aqueous sodium hydroxide yields 4-diethylamino-3-methyl-1H-pyrazolo[4,3-c]pyridine-7-carboxylic acid.
Reaction SMILES: Cl.Cl.Cl.[F:4][C:5]1[CH:6]=[C:7]([C:12]2[N:13]=[C:14]([CH:24]3[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]3)[N:15]([CH2:17][CH2:18][N:19]3[CH2:23][CH2:22][CH2:21][CH2:20]3)[CH:16]=2)[CH:8]=[CH:9][C:10]=1[F:11].Cl[C:31]1[C:32]2[CH2:39][C:38](=[O:40])[NH:37][C:33]=2[N:34]=[CH:35][N:36]=1.CCN(C(C)C)C(C)C>CC(O)C>[F:4][C:5]1[CH:6]=[C:7]([C:12]2[N:13]=[C:14]([CH:24]3[CH2:25][CH2:26][N:27]([C:31]4[C:32]5[CH2:39][C:38](=[O:40])[NH:37][C:33]=5[N:34]=[CH:35][N:36]=4)[CH2:28][CH2:29]3)[N:15]([CH2:17][CH2:18][N:19]3[CH2:20][CH2:21][CH2:22][CH2:23]3)[CH:16]=2)[CH:8]=[CH:9][C:10]=1[F:11]
Reactant: O=C1Cc2c(Cl)ncnc2N1
Reactant: Fc1ccc(-c2cn(CCN3CCCC3)c(C3CCNCC3)n2)cc1F
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: O=C1Cc2c(ncnc2N2CCC(c3nc(-c4ccc(F)c(F)c4)cn3CCN3CCCC3)CC2)N1
Yield: 15.6 %

Procedure:
Combine 4-(4-(3,4-difluoro-phenyl)-1-(2-pyrrolidin-1-yl-ethyl)-1H-imidazol-2-yl)-piperidine tris hydrochloride (0.3 g; 0.00065 mol), 4-chloro-5,7-dihydro-pyrrolo[2,3-d]pyrimidin-6-one (0.15 g; 0.00083 mol), DIPEA, (1.00 mL, 0.0057 mol) into IPA (9 mL) and heat in a microwave at 80° C. for 1 h; cool and concentrate. Quench with saturated sodium bicarbonate solution and extract with EA. Evaporate the EA and purify by column chromatography using 0-10% MeOH/DCM as eluent to give the title compound (0.05 g; 15.67%). MS (ES+): m/z=494 (M+1).