Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([NH:14]C(OC(C)(C)C)=O)=[CH:11][CH:12]=2)[C:7]([CH3:22])=[CH:6][C:5]1([CH3:24])[CH3:23])(=[O:3])[CH3:2].[Al+3].[Cl-:26].[Cl-].[Cl-]>ClC1C=CC=CC=1>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([NH2:14])=[CH:11][CH:12]=2)[C:7]([C:8]2[CH:13]=[CH:12][C:11]([Cl:26])=[CH:10][CH:9]=2)([CH3:22])[CH2:6][C:5]1([CH3:23])[CH3:24])(=[O:3])[CH3:2]
Reactant: [Cl-]
Reactant: CC(=O)N1c2ccc(NC(=O)OC(C)(C)C)cc2C(C)=CC1(C)C
Agent: [Al+3]
Solvent: Clc1ccccc1
Product: CC(=O)N1c2ccc(N)cc2C(C)(c2ccc(Cl)cc2)CC1(C)C
Reaction time: 1 h

Procedure:
A mixture of 1-acetyl-6-(tert-butoxycarbonyl)amino-1,2-dihydro-2,2,4-trimethylquinoline (25 mg) and AlCl3 (35 mg) in chlorobenzene (2 ml) was stirred for 1 h. The reaction mixture was quenched with water and in addition a solution of 2 M NaOH and ethyl acetate were added. The organic layer was separated, dried over MgSO4 and concentrated in vacuo.
Reaction SMILES: I[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([NH:11][C:12]([CH:14]3[CH2:16][CH2:15]3)=[O:13])[N:10]=2)[N:7]=1.[NH:17]1[C:25]2[CH:24]=[CH:23][CH:22]=[C:21]([OH:26])[C:20]=2[CH:19]=[CH:18]1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[NH:17]1[C:25]2[C:20](=[C:21]([O:26][C:2]3[CH:3]=[CH:4][C:5]4[N:6]([CH:8]=[C:9]([NH:11][C:12]([CH:14]5[CH2:16][CH2:15]5)=[O:13])[N:10]=4)[N:7]=3)[CH:22]=[CH:23][CH:24]=2)[CH:19]=[CH:18]1
Reactant: Oc1cccc2[nH]ccc12
Reactant: O=C(Nc1cn2nc(I)ccc2n1)C1CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(Nc1cn2nc(Oc3cccc4[nH]ccc34)ccc2n1)C1CC1
Yield: 18.3 %

Procedure:
Using N-(6-iodoimidazo[1,2-b]pyridazin-2-yl)cyclopropanecarboxamide (353 mg, 1.08 mmol), 1H-indole-4-ol (241 mg, 1.82 mmol), potassium carbonate (446 mg, 3.23 mmol) and N,N-dimethylformamide (4.0 mL) as starting materials and in the same manner as in Example 95, the title compound (66 mg, 18%) was obtained as a white powder.
Reaction SMILES: [CH3:1][C:2]1[N:11]=[C:10]([N:12]([C:14]2[CH:19]=[CH:18][C:17]([N:20]([CH3:22])[CH3:21])=[CH:16][CH:15]=2)[CH3:13])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([N+:23]([O-])=O)[CH:8]=2)[N:3]=1>C(OCC)(=O)C.CO.[Pd]>[NH2:23][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[N:3]=[C:2]([CH3:1])[N:11]=[C:10]2[N:12]([C:14]1[CH:19]=[CH:18][C:17]([N:20]([CH3:21])[CH3:22])=[CH:16][CH:15]=1)[CH3:13]
Reactant: Cc1nc(N(C)c2ccc(N(C)C)cc2)c2cc([N+](=O)[O-])ccc2n1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: Cc1nc(N(C)c2ccc(N(C)C)cc2)c2cc(N)ccc2n1
Reaction time: 5 h
Yield: 100 %

Procedure:
A mixture of (2-methyl-6-nitroquinazolin-4-yl)-(4-dimethylaminophenyl)-methylamine (214 mg, 0.634 mmol) in 20 mL of ethyl acetate and methanol (1:1) with 5% Palladium on carbon was hydrogenated at 70 psi for 5 h. The reaction mixture was filtered and concentrated. The crude product was purified by chromatography (5% methanol/methylene chloride) to give the title compound (195 mg, 0.634 mmol, 100%). 1H NMR (CDCl3): 7.58 (d, J=8.7, 1H), 7.02 (m, 2H), 6.97 (dd, J=9.0, 2.7, 1H), 6.69 (m, 2H), 6.21 (d, J=2.4, 1H), 3.54 (s, 3H), 3.45 (s, broad, 2H), 2.97 (s, 6H), 2.67 (s, 3H).
Reaction SMILES: [CH:1]1([NH:6][C:7]2[N:12]=[C:11]([C:13]3[C:14]([C:24]4[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=4)=[N:15][N:16]4[C:21]=3[CH:20]=[CH:19][N:18]=[C:17]4SC)[CH:10]=[CH:9][N:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.ClC1C=C(C=CC=1)C(OO)=O.[NH:42]1[CH2:46][CH2:45][CH2:44][CH2:43]1>ClCCl>[CH:1]1([NH:6][C:7]2[N:12]=[C:11]([C:13]3[C:14]([C:24]4[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=4)=[N:15][N:16]4[C:21]=3[CH:20]=[CH:19][N:18]=[C:17]4[N:42]3[CH2:46][CH2:45][CH2:44][CH2:43]3)[CH:10]=[CH:9][N:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C1CCNC1
Reactant: CSc1nccc2c(-c3ccnc(NC4CCCC4)n3)c(-c3ccc(F)cc3)nn12
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: Fc1ccc(-c2nn3c(N4CCCC4)nccc3c2-c2ccnc(NC3CCCC3)n2)cc1
Reaction time: 1 h
Yield: 59 %

Procedure:
To a solution of N-cyclopentyl-4-[2-(4-fluorophenyl)-7-(methylsulfanyl)pyrazolo[1,5-c]pyrimidin-3-yl]pyrimidin-2-amine (24 mg, 0.057 mmol) in dichloromethane (3 mL) was added 3-chloroperoxybenzoic acid (15mg, 0.086 mmol) and the reaction mixture stirred for 1 hour. Pyrrolidine (3 mL) was added and the reaction mixture stirred for 2 hours before being diluted with dichloromethane. The organic phase was washed with saturated sodium bicarbonate, washed with brine, and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with 5% acetone in dichloromethane to yield N-cyclopentyl-4-[2-(4-fluorophenyl)-7-pyrrolidin-1-ylpyrazolo[1,5-c]pyrimidin-3-yl]pyrimidin-2-amine (15 mg, 59%). 1H NMR (CDCl3): δ 8.05 (d, 1H), 7.65 (d, 1H), 7.60 (dd, 2H), 7.43 (d,1H), 7.10 (t, 2H), 6.27 (d, 1H), 5.05 (d, 1H), 4.29 (m, 1H), 4.09 (t, 4H), 1.99 (m, 6H), 1.45–1.78 (m, 6H). MS m/z 444 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[OH:9].[Cl:10][C:11]1[C:12](F)=[CH:13][C:14]2[O:19][CH:18]([C:20]([F:23])([F:22])[F:21])[C:17]([C:24]([O:26]CC)=[O:25])=[CH:16][C:15]=2[CH:29]=1>>[Br:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[O:9][C:12]1[C:11]([Cl:10])=[CH:29][C:15]2[CH:16]=[C:17]([C:24]([OH:26])=[O:25])[CH:18]([C:20]([F:22])([F:23])[F:21])[O:19][C:14]=2[CH:13]=1
Reactant: Oc1ccc(Cl)cc1Br
Reactant: CCOC(=O)C1=Cc2cc(Cl)c(F)cc2OC1C(F)(F)F
Product: O=C(O)C1=Cc2cc(Cl)c(Oc3ccc(Cl)cc3Br)cc2OC1C(F)(F)F

Procedure:
The title compound was prepared from 2-bromo-4-chlorophenol and ethyl 6-chloro-7-fluoro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylate (Example 183, Step 2) via a procedure similar to that described in Example 183, Steps 3 and 4: mp 223.6–225.6° C. 1H NMR (acetone-d6/300 MHz) 7.89 (s, 1H), 7.83 (d, 1H, J=2.6 Hz), 7.73 (s,1H), 7.52 (dd, 1H, J=8.7 Hz, 2.4 Hz), 7.25 (d, 1H, J=8.9 Hz), 6.55 (s, 1H), 5.83 (q, 1H, J=7.0 Hz). 19F NMR (acetone-d6/282 MHz) −79.4 (d, J=7.2 Hz). FABLRMS m/z 481 (M−H). ESHRMS m/z,480.8856 (M−H, Calc'd 480.8857). Anal. Calc'd for C17H8BrCl2F3O4: C, 42.18; H, 1.67; Br, 16.51; Cl, 14.65. Found: C, 42.15; H, 1.54; Br, 16.56; Cl, 14.39.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C@@:8]([NH:30][C:31](=[O:42])[NH:32][C@@H:33]2[CH2:38][CH2:37][CH2:36][CH2:35][C@@H:34]2[C:39]([OH:41])=O)([C:16]2[CH:21]=[C:20]([O:22][C:23]([F:28])([F:27])[CH:24]([F:26])[F:25])[CH:19]=[C:18]([F:29])[CH:17]=2)[CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:6][CH:7]=1.[NH2:43][CH2:44][CH2:45][CH2:46][C:47]([O:49][CH3:50])=[O:48].CCN=C=NCCCN(C)C>C(Cl)Cl.CN(C1C=CN=CC=1)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C@@:8]([NH:30][C:31](=[O:42])[NH:32][C@@H:33]2[CH2:38][CH2:37][CH2:36][CH2:35][C@@H:34]2[C:39]([NH:43][CH2:44][CH2:45][CH2:46][C:47]([O:49][CH3:50])=[O:48])=[O:41])([C:16]2[CH:21]=[C:20]([O:22][C:23]([F:28])([F:27])[CH:24]([F:26])[F:25])[CH:19]=[C:18]([F:29])[CH:17]=2)[CH2:9][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)=[N:6][CH:7]=1
Reactant: COC(=O)CCCN
Reactant: O=C(N[C@@H]1CCCC[C@@H]1C(=O)O)N[C@@](Cc1ccccc1)(c1cc(F)cc(OC(F)(F)C(F)F)c1)c1ccc(Cl)cn1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: COC(=O)CCCNC(=O)[C@H]1CCCC[C@H]1NC(=O)N[C@@](Cc1ccccc1)(c1cc(F)cc(OC(F)(F)C(F)F)c1)c1ccc(Cl)cn1
Temperature: 25 °C
Yield: 52.5 %

Procedure:
To a solution of (1S,2R)-2-(3-((S)-1-(5-chloropyridin-2-yl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethyl)ureido)cyclohexanecarboxylic acid (11.6 mg, 0.019 mmol) and methyl 4-aminobutanoate (3.2 mg, 0.027 mmol) in CH2Cl2 (185 μL), was added EDCI (4.6 mg, 0.024 mmol) followed by DMAP (2.9 mg, 0.024 mmol) at room temperature. The reaction mixture was stirred at room temperature until starting material was consumed as indicated by HPLC analysis. The reaction mixture was concentrated to dryness and the resulting residue was taken up in MeOH and purified by preparative HPLC (Phenoma Luna AXIA 10A, C18; mobile phase: MeCN/H2O/TFA) to provide methyl 4-((1S,2R)-2-(3-((S)-1-(5-chloropyridin-2-yl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethyl)ureido)cyclohexanecarboxamido)butanoate as white solid (7.1 mg, 53% yield). LC/MS RT=3.200 min; [M+H] 711.1 (LCMS Method 4), NMR: 500 MHz 1H (CDCl3) 8.19 ppm, 1 H, d, J=2.20 Hz; 7.57 ppm, 1 H, dd, J=8.25, 2.20 Hz; 7.04 ppm, 6 H, m; 6.99 ppm, 2 H, t, J=7.42 Hz; 6.79 ppm, 1 H, d, J=8.25 Hz; 6.52 ppm, 2 H, d, J=7.15 Hz; 6.18 ppm, 1 H, s; 5.78 ppm, 1 H, m; 4.28 ppm, 1 H, d, J=12.65 Hz; 3.87 ppm, 1 H, s; 3.61 ppm, 3 H, m; 3.47 ppm, 2 H, m; 3.40 ppm, 1 H, m; 2.40 ppm, 5 H, m; 1.58 ppm, 9 H, m.
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[C:22]([F:24])[CH:21]=[C:20]([Cl:25])[C:3]=1[O:4][CH:5]1[CH2:10][CH2:9][N:8]([CH2:11][CH2:12][C@H:13]2[CH2:18][CH2:17][C@H:16]([NH2:19])[CH2:15][CH2:14]2)[CH2:7][CH2:6]1.[CH:26]1([C:30](O)=[O:31])[CH2:29][CH2:28][CH2:27]1>>[Cl:1][C:2]1[CH:23]=[C:22]([F:24])[CH:21]=[C:20]([Cl:25])[C:3]=1[O:4][CH:5]1[CH2:10][CH2:9][N:8]([CH2:11][CH2:12][C@H:13]2[CH2:14][CH2:15][C@H:16]([NH:19][C:30]([CH:26]3[CH2:29][CH2:28][CH2:27]3)=[O:31])[CH2:17][CH2:18]2)[CH2:7][CH2:6]1
Reactant: O=C(O)C1CCC1
Reactant: N[C@H]1CC[C@H](CCN2CCC(Oc3c(Cl)cc(F)cc3Cl)CC2)CC1
Product: O=C(N[C@H]1CC[C@H](CCN2CCC(Oc3c(Cl)cc(F)cc3Cl)CC2)CC1)C1CCC1

Procedure:
According to the synthesis of example 1 the title compound was prepared from Trans(4-{2-[4-(2,6-dichloro-4-fluoro-phenoxy)-piperidin-1-yl]-ethyl}-cyclohexyl)-amine and cyclobutanecarboxylic acid. Preparative HPLC on reversed phase eluting with acetonitrile/water yielded the title compound. MS (m/e): 471.0 (M+H+).
Reaction SMILES: O=[C:2]([CH2:10][CH2:11][C:12](=O)[C:13]1[CH:18]=[CH:17][C:16]([N:19]2[CH2:23][CH2:22][O:21][C:20]2=[O:24])=[CH:15][CH:14]=1)[CH2:3][CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].[NH2:26][C:27]1[CH:35]=[CH:34][C:30]([C:31]([NH2:33])=[O:32])=[CH:29][C:28]=1[CH3:36]>CCO.C(S([O-])(=O)=O)(F)(F)F.C(S([O-])(=O)=O)(F)(F)F.[Zn+2]>[C:31]([C:30]1[CH:34]=[CH:35][C:27]([N:26]2[C:12]([C:13]3[CH:18]=[CH:17][C:16]([N:19]4[CH2:23][CH2:22][O:21][C:20]4=[O:24])=[CH:15][CH:14]=3)=[CH:11][CH:10]=[C:2]2[CH2:3][CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6])=[C:28]([CH3:36])[CH:29]=1)(=[O:32])[NH2:33]
Reactant: Cc1cc(C(N)=O)ccc1N
Reactant: CCOC(=O)CCC(=O)CCC(=O)c1ccc(N2CCOC2=O)cc1
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Zn+2]
Solvent: CCO
Product: CCOC(=O)CCc1ccc(-c2ccc(N3CCOC3=O)cc2)n1-c1ccc(C(N)=O)cc1C
Temperature: 120 °C
Yield: 38.8 %

Procedure:
To a solution of ethyl 4,7-dioxo-7-(4-(2-oxooxazolidin-3-yl)phenyl)heptanoate (158 mg, 0.43 mmol) and 4-amino-3-methylbenzamide (130 mg, 0.68 mmol) in EtOH (1 mL) was added Zn(OTf)2 (313 mg, 0.86 mmoL). The mixture was heated to 120° C. under microwave for 2 h. After evaporation under reduced pressure, the crude product was purified by silica gel column chromatography (DCM:MeOH=20:1) to afford the titled compound as a yellow solid (77 mg, yield 39%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([OH:12])=O)[CH:5]=[C:6]([F:8])[CH:7]=1.[NH2:13][C@H:14]([C:16]([C:18]1([NH2:39])[N:24]=[C:23]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[Cl:31])[C:22]2[CH:32]=[C:33]([Cl:36])[CH:34]=[CH:35][C:21]=2[N:20]([CH3:37])[C:19]1=[O:38])=[O:17])[CH3:15]>>[F:8][C:6]1[CH:5]=[C:4]([CH2:9][C:10]([NH:13][C@H:14]([C:16]([C:18]2([NH2:39])[N:24]=[C:23]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[Cl:31])[C:22]3[CH:32]=[C:33]([Cl:36])[CH:34]=[CH:35][C:21]=3[N:20]([CH3:37])[C:19]2=[O:38])=[O:17])[CH3:15])=[O:12])[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: O=C(O)Cc1cc(F)cc(F)c1
Reactant: C[C@H](N)C(=O)C1(N)N=C(c2ccccc2Cl)c2cc(Cl)ccc2N(C)C1=O
Product: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)C1(N)N=C(c2ccccc2Cl)c2cc(Cl)ccc2N(C)C1=O

Procedure:
Following General Procedure D above using 3,5-difluorophenylacetic acid (Oakwood Products, Inc.) and 3-(L-alaninyl)-amino-7-chloro-2,3-dihydro-1-methyl-5-(2-chlorophenyl)-1H-1,4-benzodiazepin-2-one (Example 8-F), the title compound was prepared as a white solid.
Reaction SMILES: C([SiH2][O:6][C:7](C)(C)[C:8]1[CH:23]=[CH:22][C:11]([C:12]([C:14]2[CH:15]=[N:16][CH:17]=[C:18]([CH:21]=2)[C:19]#[N:20])=[O:13])=[CH:10][CH:9]=1)(C)(C)C.C(=O)(O)[O-].[Na+]>Cl.O1CCCC1>[OH:6][CH2:7][C:8]1[CH:9]=[CH:10][C:11]([C:12]([C:14]2[CH:15]=[N:16][CH:17]=[C:18]([CH:21]=2)[C:19]#[N:20])=[O:13])=[CH:22][CH:23]=1
Reactant: CC(C)(C)[SiH2]OC(C)(C)c1ccc(C(=O)c2cncc(C#N)c2)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: N#Cc1cncc(C(=O)c2ccc(CO)cc2)c1
Reaction time: 1 h
Yield: 94.1 %

Procedure:
Dissolve 5-[4-(tert-butyl-dimethyl-silanyloxymethyl)-benzoyl]-nicotinonitrile (510 mg, 1.45 mmol) in 10% aqueous hydrochloric acid (10 mL) and tetrahydrofuran (50 mL) and stir. After 1 hour, add saturated aqueous sodium bicarbonate (50 mL) and extract with ethyl acetate. Combine organic layers, dry over sodium sulfate, filter and concentrate under reduced pressure to yield the title compound as a white solid (325 mg, 94%): 1H NMR (DMSO-d6) δ 4.64 (d, 2H), 5.44 (t, 1H), 7.53 (d, 2H), 7.80 (d, 2H), 8.59 (t, 1H), 9.09 (d, 1H), 9.27 (d, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][N:5]([CH3:23])[C:6]=1[N:7]1[CH2:13][CH2:12][CH:11]([O:14][CH3:15])[CH:10]([NH:16][C:17](=[O:22])[C:18]([F:21])([F:20])[F:19])[CH2:9][CH2:8]1.CCN(C(C)C)C(C)C.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.[C:66]([O:70][C:71]([NH:73][C:74]1[S:78][C:77]([C:79]2[C:84]([F:85])=[CH:83][CH:82]=[CH:81][C:80]=2[F:86])=[N:76][C:75]=1[C:87](O)=[O:88])=[O:72])([CH3:69])([CH3:68])[CH3:67]>C(Cl)Cl>[F:86][C:80]1[CH:81]=[CH:82][CH:83]=[C:84]([F:85])[C:79]=1[C:77]1[S:78][C:74]([NH:73][C:71](=[O:72])[O:70][C:66]([CH3:68])([CH3:67])[CH3:69])=[C:75]([C:87](=[O:88])[NH:1][C:2]2[CH:3]=[N:4][N:5]([CH3:23])[C:6]=2[N:7]2[CH2:8][CH2:9][CH:10]([NH:16][C:17](=[O:22])[C:18]([F:21])([F:20])[F:19])[CH:11]([O:14][CH3:15])[CH2:12][CH2:13]2)[N:76]=1
Reactant: COC1CCN(c2c(N)cnn2C)CCC1NC(=O)C(F)(F)F
Reactant: CC(C)(C)OC(=O)Nc1sc(-c2c(F)cccc2F)nc1C(=O)O
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC1CCN(c2c(NC(=O)c3nc(-c4c(F)cccc4F)sc3NC(=O)OC(C)(C)C)cnn2C)CCC1NC(=O)C(F)(F)F
Temperature: 25 °C
Reaction time: 18 h
Yield: 86.7 %

Procedure:
To a solution of Intermediate 54, N-(1-(4-amino-1-methyl-1H-pyrazol-5-yl)-5-methoxyazepan-4-yl)-2,2,2-trifluoroacetamide (150 mg, 0.45 mmol) in DCM (20 mL) was added DIPEA (1.0 mL), PyBOP (580 mg, 1.12 mmol) and 5-(tert-butoxycarbonylamino)-2-(2,6-difluorophenyl)-thiazole-4-carboxylic acid (159 mg, 0.45 mmol) and the mixture was stirred at room temperature for 18 hr. The mixture was diluted with DCM (100 mL) and washed with water (20 mL). The organic layer was separated, dried over MgSO4 and the solvent removed under reduced pressure. Purification via silica gel column chromatography (70-80% EtOAc/isohexane) gave tert-butyl 2-(2,6-difluorophenyl)-4-(5-(4-methoxy-5-(2,2,2-trifluoroacetamido)azepan-1-yl)-1-methyl-1H-pyrazol-4-ylcarbamoyl)thiazol-5-ylcarbamate as an off-white solid (260 mg, 0.39 mmol) which was stirred with HCl in 1,4-dioxane (4 M, 4.8 mL, 19.3 mmol) in MeOH (5 mL) at room temperature for 3 days. The solvent was removed under reduced pressure and the resulting solid was dissolved in MeOH/water (10 mL/10 mL) and to this was added K2CO3 (267 mg, 19.3 mmol). The reaction mixture was heated at 65° C. for 3 hr. The MeOH was removed under reduced pressure and the aqueous residue was diluted with water (5 mL) and extracted with 5% MeOH in DCM (2×75 mL). The organic layers were combined, dried over MgSO4 and concentrated under reduced pressure to give 217 as a beige solid (144 mg, 67% over 3 steps). 1H NMR (400 MHz, CDCl3) δ 8.62 (s, 1H), 7.84 (s, 1H), 7.38-7.28 (m, 1H), 7.02 (t, J=8.8 Hz, 2H), 6.15 (s, 2H), 3.72 (s, 3H), 3.37 (s, 3H), 3.36-3.25 (m, 2H), 3.22-3.08 (m, 3H), 3.07-2.99 (m, 1H), 2.17-2.10 (m, 1H), 2.02-1.93 (m, 1H), 1.88-1.65 (m, 2H). Alkyl NH2 not observed. LCMS (ES+) m/z 478 (M+1).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([N:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH:22]2[C:27](=[O:36])[NH:28][C:29]2[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=2)[C:5]2[N:11]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([OH:18])=[C:14]([O:19][CH3:20])[CH:13]=3)[CH:9]=[CH:8][C:6]=2[N:7]=1.C(=O)([O-])[O-].[K+].[K+].I[CH:44]([CH3:46])[CH3:45]>CC(C)=O>[NH2:1][C:2]1[N:3]=[C:4]([N:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH:22]2[C:27](=[O:36])[NH:28][C:29]2[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=2)[C:5]2[N:11]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([O:18][CH:44]([CH3:46])[CH3:45])=[C:14]([O:19][CH3:20])[CH:13]=3)[CH:9]=[CH:8][C:6]=2[N:7]=1
Reactant: CC(C)I
Reactant: COc1cc(-c2ccc3nc(N)nc(N4CCNCC4C(=O)Nc4ccc(F)cc4)c3n2)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COc1cc(-c2ccc3nc(N)nc(N4CCNCC4C(=O)Nc4ccc(F)cc4)c3n2)ccc1OC(C)C
Reaction time: 24 h
Yield: 39.2 %

Procedure:
A suspension of 2-amino-4-[(N-4-fluoro-phenyl-carbamoyl)-piperazin-1-yl]-6-(4-hydroxy-3-methoxy-phenyl)-pyrido[3,2-d]pyrimidine (96 μmole), anhydrous potassium carbonate (0.22 mmole) and 2-iodopropane (0.96 mmole) in acetone (7 ml) was refluxed under a nitrogen atmosphere for 20 hours. Then, another aliquot of 2-iodopropane was added and the reaction was continued for another 24 hours. Upon cooling, the reaction mixture was partitioned between ethyl acetate and brine and the aqueous layer was extracted several times with ethyl acetate. The combined organic layers were dried over MgSO4, filtered and evaporated under reduced pressure. Purification of the crude residue by silica gel flash chromatography, using 10% methanol in CH2Cl2 as mobile phase, afforded the pure title compound (20 mg, yield 39%) which was characterized by its mass spectrum as follows: MS (m/z): 532 ([M+H]+, 100).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[C:13]([O:15]CC2C=CC=CC=2)[C:12]([Cl:23])=[CH:11][C:10]=1[C:24]1[C:28]([C:29]2[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=2)=[C:27]([Br:37])[NH:26][N:25]=1)C1C=CC=CC=1.B(Cl)(Cl)Cl.C([O-])(O)=O.[Na+]>ClCCl>[Br:37][C:27]1[NH:26][N:25]=[C:24]([C:10]2[CH:11]=[C:12]([Cl:23])[C:13]([OH:15])=[CH:14][C:9]=2[OH:8])[C:28]=1[C:29]1[CH:30]=[CH:31][C:32]([O:35][CH3:36])=[CH:33][CH:34]=1
Reactant: COc1ccc(-c2c(-c3cc(Cl)c(OCc4ccccc4)cc3OCc3ccccc3)n[nH]c2Br)cc1
Agent: ClB(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COc1ccc(-c2c(-c3cc(Cl)c(O)cc3O)n[nH]c2Br)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
3-(2,4-Bis-benzyloxy-5-chloro-phenyl)-5-bromo-4-(4-methoxy-phenyl)-1H-pyrazole (1 eq) was dissolved in anhydrous dichloromethane, and under a nitrogen atmosphere, was cooled to 0° C. 1M boron trichloride in dichloromethane (8 eq) was added drop wise and the solution was stirred at 0° C. for 30 minutes. The solution was added drop wise to sat. NaHCO3(aq), and extracted into dichloromethane. The organic phase was washed with brine, dried over MgSO4, filtered and concentrated in vacuo, to give a white solid. This was purified by preparative LC/MS to give 4-[5-bromo-4-(4-methoxy-phenyl)-1H-pyrazol-3-yl]-6-chloro-benzene-1,3-diol (Example 179) as a white solid.
Reaction SMILES: [CH2:1]([Mg]Br)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].Br[C:10]1[CH:14]=[CH:13][S:12][CH:11]=1>>[CH2:1]([C:10]1[CH:14]=[CH:13][S:12][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: Brc1ccsc1
Reactant: CCCCCC[Mg]Br
Product: CCCCCCc1ccsc1

Procedure:
In the presence of 0.0012 eq. of [1,3-bis(diphenylphosphine)propane]dichloronickel (II) (Ni(dppp)Cl2) catalyst, 1.3 eq. of hexylmagnesium bromide (Hexyl-MgBr) is added to 3-bromothiophene monomer to obtain 3-hexylthiophene, and then 2 eq. of N-bromosuccimide (NBS) is further added thereto to obtain 2,5-dibromo-3-hexylthiophene monomer.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]3[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=3)=[C:11]([C:19]([O:21]C)=O)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[NH3:23]>CO>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]3[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=3)=[C:11]([C:19]([NH2:23])=[O:21])[CH:10]=[N:9]2)=[CH:4][CH:3]=1
Reactant: N
Reactant: COC(=O)c1cnn(-c2ccc(F)cc2)c1-c1ccncc1
Solvent: CO
Product: NC(=O)c1cnn(-c2ccc(F)cc2)c1-c1ccncc1
Temperature: 80 °C
Yield: 15 %

Procedure:
A solution of methyl 1-(4-fluorophenyl)-5-(4-pyridinyl)-1H-pyrazole-4-carboxylate (0.9 g, 0.003 mol) in 10 mL of methanol in a sealed tube treated with excess liquid ammonia at low temperature. Then the reaction mixture was heated at 80° C. for 48 hours. Solvent was removed and the residue was triturated with ethyl acetate to give 0.13 g of product as a yellow solid (15% yield), mp 215-216° C.; Anal. Calcd. For C15H11FN4O: C, 63.38; H, 3.93; N, 19.85. Found: C, 63.21; H, 3.98; N, 19.37.
Reaction SMILES: [CH3:1][C:2]([O:7][Si:8]([CH2:13][CH3:14])([CH2:11][CH3:12])[CH2:9][CH3:10])([CH3:6])[C:3](=[O:5])[CH3:4].C(N(CC)CC)C.C(Cl)Cl.[Br:25]N1C(=O)CCC1=O>>[Br:25][CH2:4][C:3](=[O:5])[C:2]([CH3:1])([O:7][Si:8]([CH2:13][CH3:14])([CH2:11][CH3:12])[CH2:9][CH3:10])[CH3:6]
Reactant: CC[Si](CC)(CC)OC(C)(C)C(C)=O
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC[Si](CC)(CC)OC(C)(C)C(=O)CBr
Reaction time: 0.25 h
Yield: 50 %

Procedure:
To a stirred solution of 13 (2.40 g; 10.4 mmol) and triethylamine (2.92 ml; 2.12 g; 21.0 mmol) in methylene dichloride (50 ml) triethylsilyl trifluoromethanesulfonate (2.37 ml; 2.75 g; 10.4 mmol) was added dropwise at 0° C. After 15 min. N-bromosuccinimide (2.05 g; 11.5 mmol) was added and a cooling bath was removed. After 30 min. saturated aqueous solution of NH4Cl (10 ml) and water (50 ml) was added and the mixture was extracted with methylene dichloride (3×100 ml). Organic phase was dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by column chromatography (hexane—5% ethyl acetate/hexane) to give 1.55 g (5.25 mmol; 50% yield) of 14. 1H NMR (400 MHz, CDCl3) δ 0.64 (6H, q, J=7.9 Hz), 0.97 (9H, t, J=7.9 Hz), 1.41 (6H, s), 4.44 (2H, s); 13C NMR (101 MHz, CDCl3) δ 6.5, 7.0, 27.8, 33.6, 80.4, 206.2; MS (EI) m/z 294 and 296 ([M−Et]+, 24 and 23), 187 (45), 173 (100); exact mass calculated for C9H18O2BrSi ([M−Et]+) 265.0254. found 265.0247.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]([C:6]([C:8]2[C:9](C)=[C:10]([CH:13]=[CH:14][CH:15]=2)C#N)=[O:7])=[CH:4][CH:3]=1.[C:19]([OH:22])(=[O:21])[CH3:20].S(=O)(=O)(O)O>O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([C:8]2[C:9]([CH3:10])=[C:20]([CH:13]=[CH:14][CH:15]=2)[C:19]([OH:22])=[O:21])=[O:7])=[CH:17][CH:18]=1
Reactant: CC(=O)O
Reactant: Cc1c(C#N)cccc1C(=O)c1ccc(Cl)cc1
Agent: O=S(=O)(O)O
Solvent: O
Product: Cc1c(C(=O)O)cccc1C(=O)c1ccc(Cl)cc1
Temperature: 80 °C

Procedure:
A mixture of 28 g of 3-p-chlorobenzoyl-2-methyl-benzonitrile, 210 cc of glacial acetic acid, 210 cc of water and 210 cc of concentrated sulfuric acid was refluxed overnight and after cooling to 80° C., the reaction mixture was added to a water-ice mixture. The mixture was vacuum filtered and the resulting precipitate was washed with water until the wash waters were neutral and then dried under reduced pressure to obtain 29.9 g of 3-p-chlorobenzoyl-2-methyl-benzoic acid melting at 205° C. The product was soluble in ethanol and chloroform and slightly soluble in ethyl ether. After crystallization from methanol for analysis, the product melted at 206° C.