Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][CH:2]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].CS(O[CH2:25][CH:26]1[C:32](=[O:33])[N:31]([CH2:34][C:35]([N:37]([CH:46]([CH3:48])[CH3:47])[C:38]2[CH:43]=[CH:42][C:41]([O:44][CH3:45])=[CH:40][CH:39]=2)=[O:36])[CH:30]=[CH:29][N:28]([C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)[C:27]1=[O:55])(=O)=O>CN(C=O)C>[N:1]1([CH2:25][CH:26]2[C:32](=[O:33])[N:31]([CH2:34][C:35]([N:37]([CH:46]([CH3:47])[CH3:48])[C:38]3[CH:43]=[CH:42][C:41]([O:44][CH3:45])=[CH:40][CH:39]=3)=[O:36])[CH:30]=[CH:29][N:28]([C:49]3[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=3)[C:27]2=[O:55])[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: COc1ccc(N(C(=O)CN2C=CN(c3ccccc3)C(=O)C(COS(C)(=O)=O)C2=O)C(C)C)cc1
Reactant: c1ccc2[nH]cnc2c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(N(C(=O)CN2C=CN(c3ccccc3)C(=O)C(Cn3cnc4ccccc43)C2=O)C(C)C)cc1
Reaction time: 0.17 h

Procedure:
A solution of benzimidazole (9.2 mg) in anhydrous DMF (1.5 mL) under argon was cooled to 0-5° C. Sodium bis(trimethylsilyl)amide (0.6 M in toluene, 129 μL) was added via micropipette followed by (1-{2-[isopropyl(4-methoxyphenyl)amino]-2-oxoethyl}-5,7-dioxo-4-phenyl-4,5,6,7-tetrahydro-1H-1,4-diazepin-6-yl)methyl methanesulfonate (20 mg). After approximately 10 min., the reaction mixture was quenched with several drops of glacial acetic acid and evaporated in vacuo. The residue was partitioned between ethyl acetate and aqueous K2CO3 (5% w/v). The layers were separated and the aqueous layer was back-extracted with ethyl acetate. The combined organic layers were dried over anhydrous MgSO4, filtered and evaporated in vacuo. The residue was purified on a preparative TLC plate (20×20 cm, 500 □M) eluting with 5% methanol in CH2Cl2. The product band was removed, eluted with 4:1 CH2Cl2/methanol, filtered and evaporated in vacuo. The residue was lyophilized from CH3CN/H2O to provide 2-[6-(1H-benzimidazol-1-ylmethyl)-5,7-dioxo-4-phenyl-4,5,6,7-tetrahydro-1H-1,4-diazepin-1-yl]-N-isopropyl-N-(4-methoxyphenyl)acetamide as a white lyophilate (15 mg). 1H NMR (300 MHz, CDCl3) 1.13 (m, 6H), 3.86 (m, 1H), 3.90 (s, 3H), 3.97 (d, J=4 Hz, 2H), 4.90 (m, 1H), 5.07 (m, 2H), 5.90 (d, J=7 Hz, 1H), 5.99 (d, J=7 Hz, 1H), 7.01 (m, 2H), 7.18 (m, 2H), 7.33 (m, 8H), 7.85 (m, 1H), 8.26 (s, 1H).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([CH:9]2[CH2:11][CH2:10]2)[N:3]=1.[OH:12][C:13]1[CH:22]=[C:21]([CH3:23])[C:16]2[NH:17][C:18](=[O:20])[O:19][C:15]=2[CH:14]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[Cl:8][C:6]1[N:5]=[C:4]([CH:9]2[CH2:11][CH2:10]2)[N:3]=[C:2]([O:12][C:13]2[CH:22]=[C:21]([CH3:23])[C:16]3[NH:17][C:18](=[O:20])[O:19][C:15]=3[CH:14]=2)[CH:7]=1
Reactant: Cc1cc(O)cc2oc(=O)[nH]c12
Reactant: Clc1cc(Cl)nc(C2CC2)n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Cc1cc(Oc2cc(Cl)nc(C3CC3)n2)cc2oc(=O)[nH]c12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
0.10 g (0.53 mmol) 4,6-dichloro-2-cyclopropylpyrimidine were added to 95 mg (0.55 mmol) 6-hydroxy-4-methylbenzo[d]oxazol-2(3H)-one and 0.21 g (0.63 mmol) caesium carbonate in 1.5 mL DMF after 15 min and the mixture was stirred overnight at RT. The reaction mixture was purified by preparative HPLC-MS. The fractions containing product were combined and freeze-dried.
Reaction SMILES: FC(F)(F)C(O)=O.[C:8]1([C:14]2[CH:19]=[C:18]([CH:20]3[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]3)[CH:17]=[CH:16][C:15]=2[NH:26][C:27]([C:29]2[NH:30][CH:31]=[C:32]([C:34]#[N:35])[N:33]=2)=[O:28])[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]=1.CCN(CC)CC.Cl.[C:44](Cl)(=[O:51])[C:45]1[CH:50]=[CH:49][CH:48]=[N:47][CH:46]=1.CO>C(Cl)Cl.CCOC(C)=O>[C:8]1([C:14]2[CH:19]=[C:18]([CH:20]3[CH2:21][CH2:22][N:23]([C:44]([C:45]4[CH:46]=[N:47][CH:48]=[CH:49][CH:50]=4)=[O:51])[CH2:24][CH2:25]3)[CH:17]=[CH:16][C:15]=2[NH:26][C:27]([C:29]2[NH:30][CH:31]=[C:32]([C:34]#[N:35])[N:33]=2)=[O:28])[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]=1
Reactant: N#Cc1c[nH]c(C(=O)Nc2ccc(C3CCNCC3)cc2C2=CCCCC2)n1
Reactant: O=C(Cl)c1cccnc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Product: N#Cc1c[nH]c(C(=O)Nc2ccc(C3CCN(C(=O)c4cccnc4)CC3)cc2C2=CCCCC2)n1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 84.6 %

Procedure:
A solution of 4-cyano-1H-imidazole-2-carboxylic acid (2-cyclohex-1-enyl-4-piperidin-4-yl-phenyl)-amide trifluoroacetic acid salt (as prepared in Example 14, step (b), 75.0 mg, 0.15 mmol) in CH2Cl2 (10 mL) was treated with Et3N (64.1 μL, 0.46 mmol) and cooled to 0° C. The mixture was treated with nicotinoyl chloride hydrochloride (0.030 g, 0.17 mmol) and stirred at 0° C. for 15 min then at room temperature for 17 h. The reaction mixture was adsorbed directly onto silica gel. Silica gel chromatography (10% MeOH in EtOAc) afforded the title compound (61.0 mg, 83%) as a white solid. 1H-NMR (CDCl3; 400 MHz): δ 9.51 (br s, 1H), 8.77 (s, 1H), 8.70-8.66 (m, 1H), 8.32 (d, 1H, J=8.4 Hz), 7.86-7.81 (m, 1H), 7.70 (s, 1H), 7.42-7.37 (m, 1H), 7.17 (d, 1H, J=8.4 Hz), 7.06-7.04 (m, 1H), 5.87-5.82 (m, 1H), 4.98-4.87 (m, 1H), 3.94-3.84 (m, 1H), 3.29-3.18 (m, 1H), 2.98-2.86 (m, 1H), 2.86-2.76 (m, 1H), 2.34-2.20 (m, 4H), 1.94-1.72 (m, 9H). LC-MS (ESI, m/z): Calcd. for C28H28N6O2, 481.2 (M+H). found 481.3.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([CH3:15])([CH3:14])[C:9]([O:11]CC)=O)=[CH:6][N:5]=[C:4]([S:16][CH3:17])[N:3]=1.[C:18]([O:22][C:23](=[O:30])[NH:24][C@H:25]1[CH2:28][C@H:27]([NH2:29])[CH2:26]1)([CH3:21])([CH3:20])[CH3:19].C1(P(C2CCCCC2)C2C(OC)=CC=C(OC)C=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.CC(C)([O-])C.[Na+]>O1CCOCC1.[Pd].[Pd].C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1>[C:18]([O:22][C:23](=[O:30])[NH:24][C@H:25]1[CH2:28][C@H:27]([N:29]2[C:2]3[N:3]=[C:4]([S:16][CH3:17])[N:5]=[CH:6][C:7]=3[C:8]([CH3:14])([CH3:15])[C:9]2=[O:11])[CH2:26]1)([CH3:21])([CH3:19])[CH3:20]
Reactant: CCOC(=O)C(C)(C)c1cnc(SC)nc1Cl
Reactant: CC(C)(C)OC(=O)N[C@H]1C[C@H](N)C1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: COc1ccc(OC)c(P(C2CCCCC2)C2CCCCC2)c1-c1c(C(C)C)cc(C(C)C)cc1C(C)C
Solvent: C1COCCO1
Product: CSc1ncc2c(n1)N([C@H]1C[C@H](NC(=O)OC(C)(C)C)C1)C(=O)C2(C)C
Temperature: 100 °C

Procedure:
A microwave vial containing a mixture of ethyl 2-(4-chloro-2-(methylthio)pyrimidin-5-yl)-2-methylpropanoate (2.08 g, 7.57 mmol), tert-butyl(trans-3-aminocyclobutyl)carbamate (1.551 g, 8.33 mmol), tris(dibenzylideneacetone) dipalladium (0) (0.520 g, 0.568 mmol), dicyclohexyl(2′,4′,6′-triisopropyl-3,6-dimethoxy-[1,1′-biphenyl]-2-yl)phosphine (0.731 g, 1.363 mmol) and sodium tert-butoxide (2.317 ml, 18.93 mmol) in dioxane (15 mL) was purged with argon and capped. The reaction mixture was heated at 100° C. for 3 hours, cooled, and partitioned between water (200 mL) and ethyl actate (200 mL). The organic was isolated and concentrated under reduced pressure. Purification using the ISCO eluting with 0-70% EtOAc/hexane to give the desired product tert-butyl(trans-3-(5,5-dimethyl-2-(methylthio)-6-oxo-5H-pyrrolo[2,3-d]pyrimidin-7(6H)-yl)cyclobutyl)carbamate (0.9 g, 2.378 mmol, 31.4% yield). m/z: 379.2 (M+1).
Reaction SMILES: [CH2:1]1[C:5]2[CH:6]=[CH:7][C:8]([NH:10][CH:11]=O)=[CH:9][C:4]=2[CH2:3][O:2]1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1.O.CCOC(C)=O>[CH3:11][NH:10][C:8]1[CH:7]=[CH:6][C:5]2[CH2:1][O:2][CH2:3][C:4]=2[CH:9]=1
Reactant: O=CNc1ccc2c(c1)COC2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: CNc1ccc2c(c1)COC2
Temperature: 25 °C
Reaction time: 2 h
Yield: 98.3 %

Procedure:
To a solution of N-(1,3-dihydro-2-benzofuran-5-yl)formamide (250 mg, 1.5 mmol) in THF (20 mL) was added LAH (1.9 mL, 2.4 M in THF, 4.6 mmol) at 0° C. The reaction was stirred at r.t. for 2 h. The solution was diluted with water (0.5 mL) and EtOAc (30 mL), dried (Na2SO4), and concentrated to give 220 mg (96%) of the title compound as a yellow oil. [M+H] Calc'd for C9H11NO, 150. Found, 150.
Reaction SMILES: O.[C:2]1([C:8]([CH:10]=O)=[O:9])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:12]([CH:16]=[C:17]([C:19]1[CH:24]=[CH:23][C:22]([CH2:25][CH2:26][NH2:27])=[CH:21][CH:20]=1)[CH3:18])([O:14][CH3:15])=[O:13]>CO.C(Cl)(Cl)Cl>[C:12]([CH:16]=[C:17]([C:19]1[CH:20]=[CH:21][C:22]([CH2:25][CH2:26][NH:27][CH2:10][CH:8]([OH:9])[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:23][CH:24]=1)[CH3:18])([O:14][CH3:15])=[O:13]
Reactant: COC(=O)C=C(C)c1ccc(CCN)cc1
Reactant: O=CC(=O)c1ccccc1
Solvent: CO
Solvent: O
Solvent: ClC(Cl)Cl
Product: COC(=O)C=C(C)c1ccc(CCNCC(O)c2ccccc2)cc1
Yield: 35.3 %

Procedure:
This was prepared in an identical manner to the compound described in Example 13 using phenylglyoxal monohydrate (1.50 g) and 2-{4-(2-carbomethoxy-1-methylethenyl) phenyl} ethanamine (2.19 g). The title compound (1.18 g) m.p. 120°-125° C. (benzene-hexane) was obtained after chromatography on Kieselgel 60 eluting with 1% methanol-chloroform. τ (CDCl3) 7.5 (3H, d, J=1.5 Hz), 7.5 (2H, m), 7.2 (6H, m), 6.3 (3H, s), 5.29 (1H, dd), 3.87 (1H, q, J=1.5 Hz), 2.85 (2H, d, J=9 Hz), 2.7 (5H, s), 2.6 (2H, d, J=9 Hz).
Reaction SMILES: [C:1]1([C:7]#[C:8][CH:9]=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[NH2:12][OH:13].CCO>O>[C:1]1([C:7]#[C:8][CH:9]=[N:12][OH:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NO
Reactant: O=CC#Cc1ccccc1
Agent: Cl
Solvent: O
Solvent: CCO
Product: ON=CC#Cc1ccccc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 100.2 %

Procedure:
A mixture of phenylpropargylaldehyde (859 mg, 6.6 mmol), hydroxylamine hydrochloride (4.59 g, 66 mmol), EtOH (48 mL) and water (12 mL) was stirred at r.t. for 24 h. The reaction mixture was diluted with H2O, extracted with Et2O-EtOAc, washed with brine and evaporated to dryness in vacuo affording 0.96 g of the title compound (syn:anti 1:1) as a pasty brownish solid.
Reaction SMILES: Cl.[NH:2]1[CH2:5][CH:4]([NH:6][C:7]2[C:12]([F:13])=[CH:11][N:10]=[C:9]([C:14]3[C:22]4[C:17](=[N:18][CH:19]=[C:20]([Cl:23])[CH:21]=4)[N:16]([S:24]([C:27]4[CH:33]=[CH:32][C:30]([CH3:31])=[CH:29][CH:28]=4)(=[O:26])=[O:25])[CH:15]=3)[N:8]=2)[CH2:3]1.CCN(C(C)C)C(C)C.[C:43](=O)([O:52][C@H:53]1[CH2:57][CH2:56][O:55][CH2:54]1)[O:44]N1C(=O)CCC1=O>C1COCC1>[Cl:23][C:20]1[CH:21]=[C:22]2[C:14]([C:9]3[N:8]=[C:7]([NH:6][CH:4]4[CH2:3][N:2]([C:43]([O:52][C@H:53]5[CH2:57][CH2:56][O:55][CH2:54]5)=[O:44])[CH2:5]4)[C:12]([F:13])=[CH:11][N:10]=3)=[CH:15][N:16]([S:24]([C:27]3[CH:33]=[CH:32][C:30]([CH3:31])=[CH:29][CH:28]=3)(=[O:26])=[O:25])[C:17]2=[N:18][CH:19]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3ncc(F)c(NC4CNC4)n3)c3cc(Cl)cnc32)cc1
Reactant: O=C(O[C@H]1CCOC1)ON1C(=O)CCC1=O
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)n2cc(-c3ncc(F)c(NC4CN(C(=O)O[C@H]5CCOC5)C4)n3)c3cc(Cl)cnc32)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A suspension of N-(azetidin-3-yl)-2-(5-chloro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-amine hydrochloride, 6c, (0.06 g, 0.11 mmol) in THF (1 mL) was treated with iPr2NEt (0.30 mL, 1.70 mmol) then solid (S)-2,5-dioxopyrrolidin-1-yl tetrahydrofuran-3-yl carbonate (0.03 g, 0.11 mmol) was added. The resulting mixture was stirred for 2 hours at room temperature and then quenched with 200 μL of morpholine and evaporated to dryness to afford (S)-tetrahydrofuran-3-yl 3-(2-(5-chloro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)azetidine-1-carboxylate, 6d, which was used without purification.
Reaction SMILES: [C:1]([C:4]([S:7]([CH2:10][CH:11]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:12]([O:14]CC1C=CC=CC=1)=[O:13])(=[O:9])=[O:8])([CH3:6])[CH3:5])(=[O:3])[NH2:2]>CO.[Pd]>[C:1]([C:4]([S:7]([CH2:10][CH:11]([CH2:22][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)[C:12]([OH:14])=[O:13])(=[O:9])=[O:8])([CH3:6])[CH3:5])(=[O:3])[NH2:2]
Reactant: CC(C)(C(N)=O)S(=O)(=O)CC(Cc1ccccc1)C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C(N)=O)S(=O)(=O)CC(Cc1ccccc1)C(=O)O
Reaction time: 2 h
Yield: 94.2 %

Procedure:
A suspension of 0.74 g (1.83 mmol) of benzyl rac-α-[[(1-carbamoyl-1-methylethyl)sulfonyl]methyl]hydrocinnamate and 200 mg of palladium/charcoal (5%) in 30 ml of methanol was hydrogenated at room temperature under normal pressure for 2 hours. Subsequently, the catalyst was filtered off and the solution was evaporated under reduced pressure. There was obtained 0.54 g of rac-α-[[(1-carbamoyl-1-methylethyl)sulfonyl]methyl]hydrocinnamic acid as a colourless solid, MS: 314 (M+H)+.
Reaction SMILES: COC1C=CC(C[N:8]2[C:12]3=[N:13][CH:14]=[CH:15][C:16]([O:17][C:18]4[CH:23]=[CH:22][C:21]([NH:24][C:25]([C:27]56[CH2:32][CH:31]5[CH2:30][N:29]([C:33]5[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=5)[C:28]6=[O:40])=[O:26])=[CH:20][C:19]=4[F:41])=[C:11]3[C:10]([N:42]3[CH2:47][CH2:46][CH:45]([N:48]([CH3:50])[CH3:49])[CH2:44][CH2:43]3)=[N:9]2)=CC=1>C(O)(C(F)(F)F)=O>[CH3:49][N:48]([CH3:50])[CH:45]1[CH2:46][CH2:47][N:42]([C:10]2[C:11]3[C:12](=[N:13][CH:14]=[CH:15][C:16]=3[O:17][C:18]3[CH:23]=[CH:22][C:21]([NH:24][C:25]([C:27]45[CH2:32][CH:31]4[CH2:30][N:29]([C:33]4[CH:34]=[CH:35][C:36]([F:39])=[CH:37][CH:38]=4)[C:28]5=[O:40])=[O:26])=[CH:20][C:19]=3[F:41])[NH:8][N:9]=2)[CH2:43][CH2:44]1
Reactant: COc1ccc(Cn2nc(N3CCC(N(C)C)CC3)c3c(Oc4ccc(NC(=O)C56CC5CN(c5ccc(F)cc5)C6=O)cc4F)ccnc32)cc1
Solvent: O=C(O)C(F)(F)F
Product: CN(C)C1CCN(c2n[nH]c3nccc(Oc4ccc(NC(=O)C56CC5CN(c5ccc(F)cc5)C6=O)cc4F)c23)CC1
Yield: 68.9 %

Procedure:
A solution of N-(4-(1-(4-methoxybenzyl)-3-(4-(dimethylamino)piperidin-1-yl)-1H-pyrazolo[3,4-b]pyridin-4-yloxy)-3-fluorophenyl)-3-(4-fluorophenyl)-2-oxo-3-aza-bicyclo[3.1.0]hexane-1-carboxamide (30 mg, 0.042 mmol) was heated in TFA (2 mL) for 4 hours. Excess TFA was evaporated and the residue was purified on a SCX column (7N ammonia in MeOH) to afford the product (17 mg, 68% yield) as a yellow solid. LRMS (APCI pos) m/e 588.2 (M+1). 1H NMR (400 MHz, CDCl3) δ 10.50 (s, 1H), 9.80 (s, 1H), 8.30 (s, 1H), 7.78-7.90 (m, 1H), 7.40-7.60 (m, 2H), 7.00-7.40 (m, 4H), 6.10-6.20 (m, 1H), 4.00-4.20 (m, 4H), 3.70-3.80 (m, 1H), 2.80-3.00 (m, 4H), 2.40 (s, 6H), 1.20-2.10 (m, 5H).
Reaction SMILES: [Cl:1][C:2]1([CH2:8][C:9]([O:11]CC)=[O:10])[NH:6][C:5]([CH3:7])=[CH:4][S:3]1.[OH-].[Na+]>CO>[Cl:1][C:2]1([CH2:8][C:9]([OH:11])=[O:10])[NH:6][C:5]([CH3:7])=[CH:4][S:3]1
Reactant: CCOC(=O)CC1(Cl)NC(C)=CS1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC1=CSC(Cl)(CC(=O)O)N1

Procedure:
2-Chloro-4-methyl-thiazole acetic acid was prepared by hydrolysis of ethyl 2-chloro-4-methyl-thiazole acetate (which was made as described in EP27019), with aqueous sodium hydroxide (1M) in aqueous methanol (1:1), and was used without further purification.
Reaction SMILES: [Br:1][C:2]1[C:3]([OH:13])=[C:4]([C:10](=[O:12])[CH3:11])[CH:5]=[C:6]([F:9])[C:7]=1[CH3:8].[C:14](=O)([O-])[O-].[K+].[K+].CN(C)C=O.CI>O>[Br:1][C:2]1[C:3]([O:13][CH3:14])=[C:4]([C:10](=[O:12])[CH3:11])[CH:5]=[C:6]([F:9])[C:7]=1[CH3:8]
Reactant: CC(=O)c1cc(F)c(C)c(Br)c1O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CI
Product: COc1c(C(C)=O)cc(F)c(C)c1Br
Temperature: 60 °C
Yield: 91.9 %

Procedure:
To a mixture of 1-(3-bromo-5-fluoro-2-hydroxy-4-methylphenyl)ethanone (0.3 g, 1 mmol) and potassium carbonate (0.43 g, 3.1 mmol) was added N,N-dimethylformamide (1 mL) and methyl iodide (0.17 mL, 2.7 mmol) with stirring. The resulting mixture was then heated at 60° C. for 1 hour. The mixture was diluted with water and extracted with ethyl acetate. The combined extracts were washed with brine, dried over sodium sulfate, and evaporated to dryness. The isolated residue was purified on silica gel, eluting with ethyl acetate/hexanes (0 to 20%) to yield 1-(3-Bromo-5-fluoro-2-methoxy-4-methylphenyl)ethanone (0.24 g, 80%). LCMS calculated for C10H11BrFO2 (M+H)+: m/z=261.0, 263.0. Found: 260.9, 262.9. 1H NMR (400 MHz, CDCl3): δ 7.35 (m, 1H), 3.82 (s, 3H), 2.61 (s, 3H), 2.39 (s, 3H).
Reaction SMILES: [CH3:1][N:2]([CH3:10])[C:3]1[CH:8]=[CH:7][C:6](Br)=[CH:5][CH:4]=1.[C:11]([O:16][CH3:17])(=[O:15])[C:12]([CH3:14])=[CH2:13].C1(C(N)C2CCCCC2)CCCCC1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(C)C=CC([B-](C2C=CC(C)=CC=2)(C2C=CC(C)=CC=2)C2C=CC(C)=CC=2)=CC=1.C([PH+](C(C)(C)C)C(C)(C)C)(C)(C)C.O1CCCC1>[CH3:17][O:16][C:11](=[O:15])/[C:12](/[CH3:14])=[CH:13]/[C:6]1[CH:7]=[CH:8][C:3]([N:2]([CH3:10])[CH3:1])=[CH:4][CH:5]=1
Reactant: CN(C)c1ccc(Br)cc1
Reactant: C=C(C)C(=O)OC
Agent: [Pd]
Agent: CC(C)(C)[PH+](C(C)(C)C)C(C)(C)C
Agent: Cc1ccc([B-](c2ccc(C)cc2)(c2ccc(C)cc2)c2ccc(C)cc2)cc1
Solvent: C1CCOC1
Product: COC(=O)/C(C)=C/c1ccc(N(C)C)cc1
Yield: 87 %

Procedure:
A 30-ml four-necked flask was equipped with a stirrer, a thermometer and a reflux condenser. 1.000 g (5 mmol) of 4-dimethylaminobromobenzene, 1.001 g (10 mmol) of methyl methacrylate, 0.011 g (0.012 mmol) of tris(dibenzylideneacetone)dipalladium (0), 1.074 g (5.5 mmol) of dicyclohexylmethylamine and 5 ml of tetrahydrofuran were weighed in the flask, followed by stirring. Further, 0.029 g (0.05 mmol) of tri-tert-butylphosphonium tetra-para-tolylborate obtained in Example B-3 was weighed in air and added into the flask. The flask was purged with argon, followed by stirring at 30° C. for 25 hours. After the completion of the reaction, 5 ml of toluene and 10 ml of saturated sodium chloride solution were added, followed by separation. The organic phase was purified by column chromatography to afford 0.954 g of (E)-3-(4-dimethylaminophenyl)-2-methylacrylic acid methyl ester (yield: 87 mol % based on 4-dimethylaminobromobenzene). The identification of the product was made by 1H-NMR and 13C-NMR.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][CH2:11][C@@H:12]1[CH2:16][CH2:15][N:14]([C:17]2[CH:18]=[N:19][CH:20]=[C:21]([O:23][CH2:24][C@@H:25]3[CH2:29][CH2:28][CH2:27][N:26]3C(OC(C)(C)C)=O)[CH:22]=2)[CH2:13]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl.O>[CH2:1]([O:8][CH2:9][CH2:10][CH2:11][C@@H:12]1[CH2:16][CH2:15][N:14]([C:17]2[CH:18]=[N:19][CH:20]=[C:21]([O:23][CH2:24][C@@H:25]3[CH2:29][CH2:28][CH2:27][NH:26]3)[CH:22]=2)[CH2:13]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1COc1cncc(N2CC[C@@H](CCCOCc3ccccc3)C2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: ClCCl
Product: c1ccc(COCCC[C@@H]2CCN(c3cncc(OC[C@@H]4CCCN4)c3)C2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 70.1 %

Procedure:
To a 25 mL round-bottom flask containing a solution of 3-[3(R)-[3-(benzyloxy)propyl]-1-pyrrolidinyl]-5-[[1-(tert-butoxycarbonyl)-2(S)-pyrrolidinyl]methoxy]pyridine (500 mg, 1.01 mmol) in CH2Cl2/H2O (7.5/0.15 mL) was added CF3COOH (1.5 mL) at 0° C. under N2. The reaction mixture was stirred for 3 h at room temperature. After evaporation under reduced pressure, the crude product (500 mg) was purified by preparative HPLC (column: SunFire Prep C18, 150×19 mm, 5 μm particle size; UV detection at 220 and 254 nm; flow 20 mL/min; mobile phase: A, water with 0.05% CF3COOH; B, methanol; 40-100% of B in A in 8 min, back to 40% in 1 min). The eluate was partially evaporated under reduced pressure (bath 30° C.) to remove CH3OH. The residue was basified with saturated aqueous NaHCO3 solution and extracted with EtOAc. The combined organic layers were washed with brine and dried over Na2SO4. After concentration in vacuo, the free base (280 mg, 70%) was obtained as a light-yellow solid. 1H NMR (CDCl3, 300 MHz) δ 7.65 (s, 1H), 7.61 (s, 1H), 7.37-7.33 (m, 5H), 6.33 (s, 1H), 4.54 (s, 2H), 4.01-3.97 (m, 2H), 3.69-3.59 (m, 1H), 3.53 (t, J=6.3 Hz, 2H), 3.50-3.20 (m, 4H), 3.09-3.06 (m, 2H), 2.90 (t, 1H, J=6.3 Hz), 2.38-2.10 (m, 2H), 2.03-1.83 (m, 3H), 1.79-1.51 (m, 5H). LC-MS (ESI) m/z 396 (M+H+).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=1.Br[CH2:10][C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:12]>>[CH3:8][C:5]1[CH:6]=[CH:7][C:2]([O:1][CH2:10][C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:12])=[CH:3][CH:4]=1
Reactant: Cc1ccc(O)cc1
Reactant: O=C(CBr)c1ccccc1
Product: Cc1ccc(OCC(=O)c2ccccc2)cc1

Procedure:
Using the method of Example 17 and starting with 4-hydroxytoluene and α-bromoacetophenone one obtains α-(4-methylphenoxy)acetophenone.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:14]=[C:13]2[C:9]([C:10]([C:25](O)=[O:26])=[C:11]([CH:22]([CH3:24])[CH3:23])[N:12]2[CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)=[CH:8][CH:7]=1)=[O:5])[CH3:2].C(Cl)CCl.[F:32][C:33]1[CH:34]=[C:35]([CH:38]=[C:39]([F:41])[CH:40]=1)[CH2:36][NH2:37]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[F:32][C:33]1[CH:34]=[C:35]([CH:38]=[C:39]([F:41])[CH:40]=1)[CH2:36][NH:37][C:25]([C:10]1[C:9]2[C:13](=[CH:14][C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])=[CH:7][CH:8]=2)[N:12]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)[C:11]=1[CH:22]([CH3:23])[CH3:24])=[O:26]
Reactant: NCc1cc(F)cc(F)c1
Reactant: CCOC(=O)c1ccc2c(C(=O)O)c(C(C)C)n(Cc3ccccn3)c2c1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: ClCCCl
Product: CCOC(=O)c1ccc2c(C(=O)NCc3cc(F)cc(F)c3)c(C(C)C)n(Cc3ccccn3)c2c1

Procedure:
Following General Procedure E, 6-(ethoxycarbonyl)-2-isopropyl-1-(pyridin-2-ylmethyl)-1H-indole-3-carboxylic acid (Compound 40, 80 mg, 0.22 mmol) in CH2Cl2 (5 ml) was added EDC (84 mg, 0.42 mmol) and DMAP (40 mg, 0.32 mmol), followed by 3,5-difluorobenzyl amine (47 mg, 0.32mmol). The crude material was purified by chromatography on silica gel (0→40% EtOAc-hexanes) to yield the title compound as an off white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[C:12]([CH2:13][NH2:14])=[CH:11][C:10]([C:15]([F:18])([F:17])[F:16])=[N:9]2)[CH:5]=[CH:6][CH:7]=1.CCN(CC)CC.[F:26][C:27]1[CH:28]=[C:29]([NH:35][C:36](=O)[O:37]C2C=CC=CC=2)[CH:30]=[CH:31][C:32]=1[CH2:33][OH:34]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[C:12]([CH2:13][NH:14][C:36]([NH:35][C:29]3[CH:30]=[CH:31][C:32]([CH2:33][OH:34])=[C:27]([F:26])[CH:28]=3)=[O:37])=[CH:11][C:10]([C:15]([F:16])([F:17])[F:18])=[N:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: NCc1cc(C(F)(F)F)nn1-c1cccc(Cl)c1
Reactant: O=C(Nc1ccc(CO)c(F)c1)Oc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(NCc1cc(C(F)(F)F)nn1-c1cccc(Cl)c1)Nc1ccc(CO)c(F)c1
Reaction time: 16 h
Yield: 57.2 %

Procedure:
To a stirred solution of (1-(3-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methanamine (100 mg, 0.316 mmol, 1.0 eq.) in DCM (2.0 mL) was added Et3N (0.07 mL, 0.632 mmol, 3.0 eq) followed by phenyl 3-fluoro-4-(hydroxymethyl)phenylcarbamate (82.4 mg, 0.316 mmol, 1.0 eq.) at RT and stirred for 16 h. After completion of the reaction, a solid precipitate was filtered and washed with DCM (2 mL) followed by n-pentane (5 mL) and dried to get 1-((1-(3-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methyl)-3-(3-fluoro-4-(hydroxymethyl)phenyl)urea (compound A59) (80 mg; 47%, white solid; TLC system: EtOAc/PE (3:2); Rf: 0.2).
Reaction SMILES: N(OC(C)(C)C)=O.[CH3:8][O:9][C:10]([C:12]1[CH:17]=[C:16](N)[CH:15]=[C:14]([O:19][CH3:20])[N:13]=1)=[O:11].[ClH:21]>C(#N)C.[Cu](Cl)Cl>[CH3:8][O:9][C:10]([C:12]1[CH:17]=[C:16]([Cl:21])[CH:15]=[C:14]([O:19][CH3:20])[N:13]=1)=[O:11]
Reactant: Cl
Reactant: COC(=O)c1cc(N)cc(OC)n1
Agent: Cl[Cu]Cl
Agent: CC(C)(C)ON=O
Solvent: CC#N
Product: COC(=O)c1cc(Cl)cc(OC)n1
Temperature: 80 °C
Reaction time: 1 h

Procedure:
To a mixture of 1.25 mL (10.5 mmol) tert-butyl nitrite and 1.42 g (10.5 mmol) copper(II)chloride in 40 mL acetonitrile was added a solution of 1.20 g (6.59 mmol) 4-amino-6-methoxy-pyridine-2-carboxylic acid methyl ester in 10 mL acetonitrile dropwise at 40° C. This mixture was stirred at 80° C. for 1 h, then poured into ice water, acidified with 4 M aqueous HCl and extracted with EtOAc. The combined organic phases were dried over sodium sulfate, filtered and concentrated in vacuo. The crude material was purified by flash chromatography (PE/EtOAc=3/1→2/1).