Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(N1CC[N:11]([CH2:14][C:15]2[C:16](=[O:40])[N:17]([CH2:30][CH2:31][CH2:32][C:33]3[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=3)[N:18]=[C:19]([C:21]3[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[C:23]([F:29])[CH:22]=3)[CH:20]=2)CC1)=O)(C)(C)C.FC1C=C(C2C=C(COS(C)(=O)=O)C(=O)N(CCCC3C=CC(F)=CC=3)N=2)C=CC=1OC>>[NH2:11][CH2:14][C:15]1[C:16](=[O:40])[N:17]([CH2:30][CH2:31][CH2:32][C:33]2[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=2)[N:18]=[C:19]([C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[C:23]([F:29])[CH:22]=2)[CH:20]=1
Reactant: COc1ccc(-c2cc(CN3CCN(C(=O)OC(C)(C)C)CC3)c(=O)n(CCCc3ccc(F)cc3)n2)cc1F
Agent: COc1ccc(-c2cc(COS(C)(=O)=O)c(=O)n(CCCc3ccc(F)cc3)n2)cc1F
Product: COc1ccc(-c2cc(CN)c(=O)n(CCCc3ccc(F)cc3)n2)cc1F
Yield: 41.7 %

Procedure:
Following the procedure of Example 24 (1), 6-(3-fluoro-4-methoxyphenyl)-2-[3-(4-fluorophenyl)propyl]-4-methanesulfonyloxymethyl-2H-pyridazin-3-one was reacted to a crude product. Without purification, the crude product was reacted in accordance with the procedure of Example 24 (2) to yield the title compound as a pale yellow crystalline powder (yield: 41.7%).
Reaction SMILES: [S:1]([C:4]1[NH:5][CH:6]=[C:7]([C:12](=[O:28])[C:13]2[CH:18]=[C:17]([C:19]([CH3:22])([CH3:21])[CH3:20])[C:16]([OH:23])=[C:15]([C:24]([CH3:27])([CH3:26])[CH3:25])[CH:14]=2)[C:8]=1[S:9][C:10]#N)[C:2]#N.CI>>[CH3:2][S:1][C:4]1[NH:5][CH:6]=[C:7]([C:12](=[O:28])[C:13]2[CH:18]=[C:17]([C:19]([CH3:21])([CH3:22])[CH3:20])[C:16]([OH:23])=[C:15]([C:24]([CH3:27])([CH3:26])[CH3:25])[CH:14]=2)[C:8]=1[S:9][CH3:10]
Reactant: CC(C)(C)c1cc(C(=O)c2c[nH]c(SC#N)c2SC#N)cc(C(C)(C)C)c1O
Solvent: CI
Product: CSc1[nH]cc(C(=O)c2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)c1SC

Procedure:
For example, using 2,3-dithiocyano-4-(3,5-di-t-butyl-4-hydroxybenzoyl)pyrrole in this general reaction together with two molar equivalents of methyl iodide yields 2,3-dimethylthio-4-(3,5-di-t-butyl-4-hydroxybenzoyl)pyrrole (a compound according to Formula X wherein: m is 0; n is 1; R is H; and Z is H; and X and Y are each SCH3).
Reaction SMILES: [CH2:1]([C:8]1[N:13]=[C:12](I)[C:11]([OH:15])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:16]([C:18]1[CH:32]=[CH:31][C:21]([CH2:22][N:23]2[CH2:26][CH:25]([C:27]([O:29][CH3:30])=[O:28])[CH2:24]2)=[CH:20][C:19]=1[F:33])#[CH:17]>>[CH2:1]([C:8]1[N:13]=[C:12]2[CH:17]=[C:16]([C:18]3[CH:32]=[CH:31][C:21]([CH2:22][N:23]4[CH2:26][CH:25]([C:27]([O:29][CH3:30])=[O:28])[CH2:24]4)=[CH:20][C:19]=3[F:33])[O:15][C:11]2=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C#Cc1ccc(CN2CC(C(=O)OC)C2)cc1F
Reactant: Oc1ccc(Cc2ccccc2)nc1I
Product: COC(=O)C1CN(Cc2ccc(-c3cc4nc(Cc5ccccc5)ccc4o3)c(F)c2)C1

Procedure:
Synthesized according to Scheme B3 and general procedure G from 6-benzyl-2-iodopyridin-3-ol (0.500 g, 1.61 mmol) and methyl 1-(4-ethynyl-3-fluorobenzyl)azetidine-3-carboxylate (0.477 g, 1.93 mmol). 1H NMR (300 MHz, CDCl3) δ ppm 7.93 (t, J=7.9 Hz, 1H), 7.65 (d, J=8.5 Hz, 1H), 7.37 (d, J=3.1 Hz, 1H), 7.10-7.33 (m, 7H), 7.04 (d, J=8.5 Hz, 1H), 4.27 (s, 2H), 3.72 (s, 3H), 3.65 (s, 2H), 3.48-3.60 (m, 2H), 3.30-3.40 (m, 3H). MS (ESI) m/z: Calculated; 430.2 Observed: 431.1 (M++1).
Reaction SMILES: [C:1]1([C:6]([CH:8]=[CH:9][C:10]([OH:12])=O)=[O:7])[S:5][CH:4]=[CH:3][CH:2]=1.[NH:13]1[CH2:20][CH2:19][CH2:18][C@H:14]1[C:15]([OH:17])=[O:16]>O1CCCC1>[C:1]1([C:6]([CH:8]=[CH:9][C:10]([N:13]2[CH2:20][CH2:19][CH2:18][C@H:14]2[C:15]([OH:17])=[O:16])=[O:12])=[O:7])[S:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)C=CC(=O)c1cccs1
Reactant: O=C(O)[C@@H]1CCCN1
Solvent: C1CCOC1
Product: O=C(C=CC(=O)N1CCC[C@H]1C(=O)O)c1cccs1

Procedure:
As for Example 1, 3-(2-thenoyl)acrylic acid (0.01 mole) is coupled to L-proline (0.01 mole) with N,N'-carbonyldiimidazole (0.011 mole) in tetrahydrofuran to give 1-[3-(2-thenoyl)acryloyl]-L-proline.
Reaction SMILES: C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[O:32]=[C:33]1[N:37]([CH2:38][C:39]([OH:41])=O)[C:36](=[O:42])[C:35]2([CH2:47][CH2:46][CH2:45][CH2:44][CH2:43]2)[N:34]1[C:48]1[CH:53]=[CH:52][C:51]([CH3:54])=[CH:50][CH:49]=1.[C:55]1([CH:61]([NH2:65])[CH2:62][CH2:63][CH3:64])[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=1.Cl>CN1C(=O)CCC1>[O:32]=[C:33]1[N:37]([CH2:38][C:39]([NH:65][CH:61]([C:55]2[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=2)[CH2:62][CH2:63][CH3:64])=[O:41])[C:36](=[O:42])[C:35]2([CH2:47][CH2:46][CH2:45][CH2:44][CH2:43]2)[N:34]1[C:48]1[CH:53]=[CH:52][C:51]([CH3:54])=[CH:50][CH:49]=1
Reactant: Cc1ccc(N2C(=O)N(CC(=O)O)C(=O)C23CCCCC3)cc1
Reactant: CCCC(N)c1ccccc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: CCCC(NC(=O)CN1C(=O)N(c2ccc(C)cc2)C2(CCCCC2)C1=O)c1ccccc1
Reaction time: 0.33 h

Procedure:
170 μl (0.098 mmol, 0.1 eq.) of N,N-diisopropylethylamine and 204 mg (0.63 mmol, 2 eq.) of TBTU are added to a solution of 100 mg of (2,4-dioxo-1-p-tolyl-1,3-diazaspiro[4.5]dec-3-yl)acetic acid in 30 ml of NMP. The solution is stirred for 20 minutes, and 70 mg (0.47 mmol, 1.5 eq.) of 1-phenylbutylamine (starting material 3) are added. The reaction medium is stirred overnight at room temperature. It is then poured into 1N hydrochloric acid solution and extracted with ethyl acetate. The organic phase is then washed with water, then with 1N sodium hydroxide solution, and then again with water. It is dried over sodium sulfate. The residue is precipitated from dichloromethane and heptane. 2-(2,4-Dioxo-1-p-tolyl-1,3-diazaspiro[4.5]dec-3-yl)-N-(1-phenylbutyl)acetamide is obtained in the form of a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][CH:11]=[C:10]([C:16]([C:18]3[CH:23]=[CH:22][C:21]([NH:24]C(=O)C)=[CH:20][CH:19]=3)=[O:17])[C:9]=2[F:28])[CH:5]=[CH:6][CH:7]=1.Cl>C(O)C>[ClH:1].[NH2:24][C:21]1[CH:22]=[CH:23][C:18]([C:16]([C:10]2[C:9]([F:28])=[C:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=3)[C:13]([O:14][CH3:15])=[CH:12][CH:11]=2)=[O:17])=[CH:19][CH:20]=1
Reactant: COc1ccc(C(=O)c2ccc(NC(C)=O)cc2)c(F)c1-c1cccc(Cl)c1
Agent: Cl
Solvent: CCO
Product: COc1ccc(C(=O)c2ccc(N)cc2)c(F)c1-c1cccc(Cl)c1
Temperature: 25 °C
Yield: 48 %

Procedure:
To a stirred suspension of N-[4-(3′-chloro-2-fluoro-6-methoxy-biphenyl-3-carbonyl)-phenyl]-acetamide synthesized above (1.75 g, 4.44 mmol) in ethanol (40 mL) was added con. HCl (40 mL). The reaction was refluxed for 2 h, cooled to room temperature, filtered, washed with water than hexanes to afford 0.82 g (48%) of (4-amino-phenyl)-(3′-chloro-2-fluoro-6-methoxy-biphenyl-3-yl)-methanone hydrochloride as light yellow solid.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([NH:12][CH2:13][C:14]([NH:16][C@H:17]2[CH2:22][CH2:21][C@@H:20]([N:23]([CH2:27][CH3:28])[CH:24]([CH3:26])[CH3:25])[CH2:19][C@H:18]2[CH2:29][O:30][CH3:31])=[O:15])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:32])[CH:8]=2)[N:3]=1.[CH3:33][NH:34][CH3:35]>O1CCCC1>[Cl:32][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[N:3]=[C:2]([N:34]([CH3:35])[CH3:33])[N:11]=[C:10]2[NH:12][CH2:13][C:14]([NH:16][C@H:17]1[CH2:22][CH2:21][C@@H:20]([N:23]([CH2:27][CH3:28])[CH:24]([CH3:25])[CH3:26])[CH2:19][C@H:18]1[CH2:29][O:30][CH3:31])=[O:15]
Reactant: CNC
Reactant: CCN(C(C)C)[C@@H]1CC[C@H](NC(=O)CNc2nc(Cl)nc3ccc(Cl)cc23)[C@H](COC)C1
Solvent: C1CCOC1
Product: CCN(C(C)C)[C@@H]1CC[C@H](NC(=O)CNc2nc(N(C)C)nc3ccc(Cl)cc23)[C@H](COC)C1

Procedure:
A solution of 2-(2,6-dichloroquinazolin-4-ylamino)-N-((1S,2R,4R)-4-(ethyl(isopropyl)amino)-2-(methoxymethyl)cyclohexyl)acetamide (61 mg) in tetrahydrofuran (2 mL) was treaded with dimethylamine (2 M in tetrahydrofuran, 80 μL) and the mixture was heated at reflux overnight. Additional dimethylamine solution (0.825 mL) was added and heating was continued for 3 more days. Concentration under vacuum and purification by reverse phase HPLC and lyophilization provided the bis-trifluoroacetic acid salt of the title product, 2-(6-chloro-2-(dimethylamino)quinazolin-4-ylamino)-N-((1S,2R,4R)-4-(ethyl(isopropyl)amino)-2-(methoxymethyl)cyclohexyl)acetamide, as a white powder (54 mg). MS found: (M+H)+=491.7.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:11]=[CH:12][C:13]2[N:17]=[C:16](Cl)[N:15]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:14]=2[CH:25]=1.[NH:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1>>[CH3:1][O:2][C:3](=[O:26])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:11]=[CH:12][C:13]2[N:17]=[C:16]([N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)[N:15]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:14]=2[CH:25]=1
Reactant: COC(=O)CCCCCOc1ccc2nc(Cl)n(-c3ccccc3)c2c1
Reactant: C1COCCN1
Product: COC(=O)CCCCCOc1ccc2nc(N3CCOCC3)n(-c3ccccc3)c2c1
Temperature: 120 °C
Reaction time: 6 h

Procedure:
657 mg of 6-[[2-chloro-1-phenyl-1H-benzimidazol-6-yl]oxy]hexanoic acid methyl ester was dissolved in 13 ml of morpholine, and the mixture was stirred for 6 hours at 120° C. It was concentrated by evaporation to a very large extent in a vacuum, mixed with water, extracted with ethyl acetate, the organic phase was dried on sodium sulfate and concentrated by evaporation in a vacuum. The residue was purified by column chromatography on silica gel. 271 mg was obtained.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][N:9]=2)[C:4]([NH:11][CH2:12][CH2:13][C:14]2[CH:15]=[CH:16][C:17]([O:21][C:22]3[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[CH:24][N:23]=3)=[C:18]([OH:20])[CH:19]=2)=[N:3][CH:2]=1.I[CH:33]([CH3:35])[CH3:34].C([O-])([O-])=O.[K+].[K+]>CS(C)=O>[CH:33]([O:20][C:18]1[CH:19]=[C:14]([CH2:13][CH2:12][NH:11][C:4]2[C:5]3[C:10](=[N:9][CH:8]=[CH:7][N:6]=3)[N:1]=[CH:2][N:3]=2)[CH:15]=[CH:16][C:17]=1[O:21][C:22]1[CH:27]=[C:26]([C:28]([F:29])([F:30])[F:31])[CH:25]=[CH:24][N:23]=1)([CH3:35])[CH3:34]
Reactant: CC(C)I
Reactant: Oc1cc(CCNc2ncnc3nccnc23)ccc1Oc1cc(C(F)(F)F)ccn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CC(C)Oc1cc(CCNc2ncnc3nccnc23)ccc1Oc1cc(C(F)(F)F)ccn1
Temperature: 50 °C
Yield: 81.4 %

Procedure:
To a solution of 5-[2-(pteridin-4-ylamino)-ethyl]-2-(4-trifluoromethylpyridin-2-yloxy)-phenol (200 mg, 0.47 mmol) in 2 mL of DMSO was added 2-iodopropane (62 mg, 0.5 mmol), and K2CO3 (97 mg, 0.7 mmol). The solution was heated 2 h at 50° C., after which TLC analysis indicated absence of starting material. The mixture was poured onto ice. The product precipitated and was collected by suction filtration, washed with H2O, and air dried, yielding {2-[3-(isopropoxy)-4-(4-trifluoromethylpyridin-2-yloxy)-phenyl]-ethyl}-pteridin-4-ylamine (180 mg; 81% yield) as a light brown solid: ESIMS m/z: 471 ([M+H]+).
Reaction SMILES: [Br:1][C:2]1[O:6][C:5]([C:7]([OH:9])=[O:8])=[CH:4][CH:3]=1.[CH3:10]O>>[CH3:10][O:8][C:7]([C:5]1[O:6][C:2]([Br:1])=[CH:3][CH:4]=1)=[O:9]
Reactant: O=C(O)c1ccc(Br)o1
Reactant: CO
Product: COC(=O)c1ccc(Br)o1

Procedure:
5-Bromo-furan-2-carboxylic acid (2 g, 10.5 mmol) was esterified with MeOH using Method B to give the title compound.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([I:10])[C:8]=1[I:9])[NH2:5].O.[N:12]([O-])=O.[Na+].Cl[Sn]Cl>Cl>[I:1][C:2]1[CH:3]=[C:4]([NH:5][NH2:12])[CH:6]=[C:7]([I:10])[C:8]=1[I:9]
Reactant: Nc1cc(I)c(I)c(I)c1
Reactant: O=N[O-]
Agent: Cl
Agent: Cl[Sn]Cl
Agent: [Na+]
Solvent: O
Product: NNc1cc(I)c(I)c(I)c1
Temperature: -10 °C
Reaction time: 0.5 h

Procedure:
3,4,5-Triiodoaniline was obtained by the procedure of L. Kalb (L. Kalb et al., Über substituierte Indol-2-carbonsäure-8-propionsäuren and einige jodierte Bensolderivate, Chem. Ber. 59 (1926) 1860-1870). 4 g (8.5 mmol) of 3,4,5-triiodoaniline were stirred with the solution of 2.3 mL of concentrated hydrochloric acid and 2.3 mL of water. The mixture was cooled to about −10° C. and the equivalent quantity of 2.5M solution of NaNO2 was added dropwise with intensive stirring. The reaction mixture was continued stirring for 30 min at −10° C. Next, the cooled solution of 5.75 g (25.5 mmol) of SnCl2. 2H2O in 6 mL of concentrated HCl was added dropwise at −10° C. to the suspension of diazocompound. The reaction mixture was kept at −10° C. for one hour and at 5° C. overnight. The obtained precipitate was filtered off and washed with water to yield 4.7 g of 3,4,5-triiodophenylhydrazine, as a double salt with tin chloride, which was used for following step without additional treatment or purification. 1H-NMR (200 MHz, DMSO-d6), δ, ppm: 10.14 (2H, broad s, NH2), 8.46 (1H, s, NH), 7.5 (2H, s, arom.).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:19](=[O:20])[N:18]([CH3:21])[C:11]3[N:12]=[C:13](NC)[N:14]=[CH:15][C:10]=3[CH:9]=2)=[CH:4][C:3]=1[NH:22][C:23]([NH:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:34])[F:33])[CH:27]=1)=[O:24].[NH2:36][CH:37]([CH3:40])[CH2:38][OH:39]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:19](=[O:20])[N:18]([CH3:21])[C:11]3[N:12]=[C:13]([NH:36][CH:37]([CH3:40])[CH2:38][OH:39])[N:14]=[CH:15][C:10]=3[CH:9]=2)=[CH:4][C:3]=1[NH:22][C:23]([NH:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:33])([F:34])[F:35])[CH:27]=1)=[O:24]
Reactant: CC(N)CO
Reactant: CNc1ncc2cc(-c3ccc(F)c(NC(=O)Nc4cccc(C(F)(F)F)c4)c3)c(=O)n(C)c2n1
Product: CC(CO)Nc1ncc2cc(-c3ccc(F)c(NC(=O)Nc4cccc(C(F)(F)F)c4)c3)c(=O)n(C)c2n1
Yield: 921.8 %

Procedure:
Using a procedure analogous to Example A1, 1-(4-chloro-3-(trifluoromethyl)phenyl)-3-(2-fluoro-5-(8-methyl-2-(methylthio)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)phenyl)urea from Example 67 (55 mg, 0.100 mmol) and 2-amino-1-propanol (249 mg, 3.31 mmol) were combined to provide 1-(2-fluoro-5-(2-(1-hydroxypropan-2-ylamino)-8-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)phenyl)-3-(3-(trifluoromethyl)phenyl)urea (489 mg, 22% yield). 1H NMR (300 MHz, DMSO-d4), δ 1.15 (s, 3H), 3.37-3.56 (m, 4 H), 3.90-4.15 (m, 1 H), 4.69 (s, 1 H), 7.22-7.55 (m, 6 H), 7.84 (s, 1 H), 8.02 (s, 1 H), 8.36-8.38 (m, 1 H), 8.63 (br. s, 2 H), 9.38 (s, 1 H), OH missing; MS (ESI) m/z: 531.2 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:17][C:18]2[C:23]([C:24]#[N:25])=[CH:22][N:21]=[C:20]3[S:26][C:27]4[CH2:28][NH:29][CH2:30][CH2:31][C:32]=4[C:19]=23)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=1.Cl.[CH3:34][N:35]([CH:42]([CH3:44])[CH3:43])[CH2:36]/[CH:37]=[CH:38]/[C:39](O)=[O:40].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([NH:17][C:18]2[C:23]([C:24]#[N:25])=[CH:22][N:21]=[C:20]3[S:26][C:27]4[CH2:28][N:29]([C:39](=[O:40])/[CH:38]=[CH:37]/[CH2:36][N:35]([CH3:34])[CH:42]([CH3:44])[CH3:43])[CH2:30][CH2:31][C:32]=4[C:19]=23)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=1
Reactant: N#Cc1cnc2sc3c(c2c1Nc1ccc(OCc2cccc(F)c2)c(Cl)c1)CCNC3
Reactant: CC(C)N(C)C/C=C/C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)N(C)C/C=C/C(=O)N1CCc2c(sc3ncc(C#N)c(Nc4ccc(OCc5cccc(F)c5)c(Cl)c4)c23)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 61.3 %

Procedure:
A solution of 4-({3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}amino)-5,6,7,8-tetrahydrothieno[2,3-b:5,4-c′]dipyridine-3-carbonitrile from Example 90A (80 mg, 0.17 mmol) and (2E)-4-[methyl(1-methylethyl)amino]but-2-enoic acid hydrochloride from Example 2A (47 mg, 0.24 mmol) in DMF (2 mL) was treated with DIPEA (89 mg, 0.69 mmol) and TBTU (83 mg, 0.26 mmol). The mixture was stirred at rt overnight and then directly purified by preparative HPLC to yield 63 mg (61%) of the title compound.
Reaction SMILES: C([O:3][C:4]([CH2:6][C@H:7]1[CH2:12][CH2:11][CH2:10][CH2:9][C@H:8]1[N:13]1[C:18](=[O:19])[CH:17]=[CH:16][C:15]([C:20]2[C:21]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[N:22][N:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=23)=[N:14]1)=[O:5])C.[OH-].[Na+]>O1CCOCC1>[C:4]([CH2:6][C@H:7]1[CH2:12][CH2:11][CH2:10][CH2:9][C@H:8]1[N:13]1[C:18](=[O:19])[CH:17]=[CH:16][C:15]([C:20]2[C:21]([C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)=[N:22][N:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=23)=[N:14]1)([OH:5])=[O:3]
Reactant: CCOC(=O)C[C@H]1CCCC[C@H]1n1nc(-c2c(-c3ccccc3)nn3ccccc23)ccc1=O
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: O=C(O)C[C@H]1CCCC[C@H]1n1nc(-c2c(-c3ccccc3)nn3ccccc23)ccc1=O
Temperature: 70 °C
Reaction time: 4 h
Yield: 84.8 %

Procedure:
A mixture of cis-3-[2-(2-ethoxycarbonylmethyl-cyclohexyl)-3-oxo-2,3-dihydropyridazin-6-yl]-2-phenylpyrazolo[1,5-a]pyridine (89.7 mg), 1N aqueous sodium hydroxide (1 ml), and dioxane (4 ml) was stirred at room temperature for 5 hours and at 70° C. for 4 hours. Dioxane was removed in vacuo. The remaining aqueous solution was diluted with water and extracted with ethyl acetate (10 ml). The aqueous layer was acidified with 1N hydrochloric acid and extracted with dichloromethane (10 ml x 2). The combined extracts were washed with brine (10 ml), dried over anhydrous magnesium sulfate, and evaporated in vacuo to give colorless crystals of cis-3-[2-(2-carboxymethylcyclohexyl)-3-oxo-2,3-dihydropyridazin-6-yl]-2-phenylpyrazolo[1,5-a]pyridine (71.4 mg).
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([Br:12])=[CH:4][CH:3]=1.[CH:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1B(O)O)=[O:14].C(=O)([O-])[O-].[Na+].[Na+]>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.C(COC)OC>[Br:12][C:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:2]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[CH:13]=[O:14])=[CH:3][CH:4]=1
Reactant: O=Cc1ccccc1B(O)O
Reactant: Brc1ccc(Br)c2ccccc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: O=Cc1ccccc1-c1ccc(Br)c2ccccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 67 %

Procedure:
A flask was charged with 230 g of 1,4-dibromonaphthalene, 121 g of 2-formylphenylboronic acid, and 18.5 g of tetrakis(triphenylphosphine)palladium(0) in an argon atmosphere. After the addition of 2.4 L of dimethoxyethane (DME) and 1.2 L of a 2 M sodium carbonate aqueous solution, the mixture was heat refluxed with stirring for 8 hours. The mixture was then cooled to room temperature. After removing the aqueous phase, the organic phase was washed with water and a saturated sodium chloride solution, and dried over magnesium sulfate. After removing magnesium sulfate by filtration, the organic phase was concentrated. The residue was purified by silica gel column chromatography to obtain 170 g of the target 1-bromo-4-(2-formylphenyl)naphthalene (yield: 67%).
Reaction SMILES: [C:1]1([CH3:17])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][S:8]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)(=[O:10])=[O:9].C([Li])CCC.[CH3:23][O:24][C:25]1[CH:26]=[C:27]([CH:30]=[C:31]2[O:35][CH2:34][O:33][C:32]=12)[CH:28]=[O:29].[Cl-].[NH4+]>O1CCCC1>[OH:29][CH:28]([C:27]1[CH:26]=[C:25]([O:24][CH3:23])[C:32]2[O:33][CH2:34][O:35][C:31]=2[CH:30]=1)[C:16]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[S:8]([NH:7][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=1[CH3:17])(=[O:9])=[O:10]
Reactant: COc1cc(C=O)cc2c1OCO2
Reactant: Cc1ccccc1NS(=O)(=O)c1ccccc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: COc1cc(C(O)c2ccccc2S(=O)(=O)Nc2ccccc2C)cc2c1OCO2
Temperature: -72 °C
Reaction time: 3 h

Procedure:
To tetrahydrofuran (200 mL) was added N-o-tolyl-benzenesulfonamide (4.95 g, 20 mmol). After cooling to −72° C., a solution of n-butyllithium (1.6 M, 25 mL in hexane) was added, and the mixture was stirred for 3 hours at −72° C. A solution of 3-methoxy-4,5-methylenedioxybenzaldehyde (3.60 g, 20 mmol) in tetrahydrofuran (70 mL) was added, and the mixture was stirred and warmed to 0° C. over 1.5 hours. The mixture was poured into 200-mL saturated ammonium chloride solution, and the organic phase was decanted. The solvent was evaporated in vacuo and the residue was suspended in ethyl ether, washed with saturated sodium bicarbonate and brine solutions. The solution was dried over anhydrous magnesium sulfate, filtered, and evaporated to give a syrup which was chromatographed on 500 g silica gel eluted with a mixture of ethyl acetate and hexane (35:65). The appropriate fractions were concentrated in vacuo and crystallized giving a solid, 4.15 g, 48.6%o yield, mp 155-158° C. NMR spectra and elemental analysis were consistent with the structure.
Reaction SMILES: I[C:2]1[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[C:15]1(B(O)O)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(=O)([O-])[O-].[Na+].[Na+]>O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[F:12][C:11]([F:14])([F:13])[C:9]1[CH:10]=[C:2]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:3]([C:4]([OH:6])=[O:5])=[CH:7][CH:8]=1
Reactant: O=C(O)c1ccc(C(F)(F)F)cc1I
Reactant: OB(O)c1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: O
Product: O=C(O)c1ccc(C(F)(F)F)cc1-c1ccccc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 89.1 %

Procedure:
A mixture of 2-iodo-4-trifluoromethyl-benzoic acid (CAS: 54507-44-7) (300 mg, 0.949 mmol) phenylboronic acid (239 mg, 1.898 mmol), sodium carbonate (302 mg, 2.847 mmol) and palladium (II) acetate (10.7 mg, 0.0475 mmol) in 4.5 ml water was stirred at room temperature for 48 hours. The mixture was filtered and the filtrate was acidified with HC137%. The mixture was stirred at room temperature for 30 minutes. The solid was filtered, washed with water and dried in vacuo to provide 225 mg (89%) of the title compound as a brown solid. MS (m/e): 264.9 (M+H+).
Reaction SMILES: C(=O)([O-])O.[Na+].[F:6][C:7]([F:18])([F:17])[C:8]1[CH:9]=[C:10](B(O)O)[CH:11]=[CH:12][CH:13]=1.I[C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=1>O1CCOCC1.Cl.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[F:6][C:7]([F:18])([F:17])[C:8]1[CH:9]=[C:10]([C:20]2[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=2)[CH:11]=[CH:12][CH:13]=1
Reactant: Oc1ccc(I)cc1
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Agent: [Pd]
Agent: Cl
Agent: O=C([O-])O
Solvent: C1COCCO1
Product: Oc1ccc(-c2cccc(C(F)(F)F)c2)cc1
Temperature: 100 °C
Yield: 30.4 %

Procedure:
An aqueous solution of sodium hydrogen carbonate (6.9 g in 18 mL water, 82 mmol) was added to a stirred solution of 3-trifluoromethylbenzeneboronic acid (7.77 g, 41 mmol) and 4-iodophenol (6.0 g, 30 mmol) in 1,4-dioxane (90 mL). The reaction mixture was degassed, then tetrakis(triphenylphosphine) palladium (0) (1.58 g, 1.36 mmol) was added and the reaction mixture heated at 100° C. for 18 hours. The mixture was diluted with a 2M aqueous solution of HCl and extracted with ethyl acetate (50 mL). The organic layer was separated, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (5%-40% ethyl acetate in heptane gradient elution) to afford the title compound (2.17 g, 30%) as an oil.
Reaction SMILES: Cl.C[O:3][C:4]1[C:5]([S:21](=[O:24])(=[O:23])[NH2:22])=[CH:6][C:7]2[CH2:13][CH2:12][NH:11][CH2:10][CH:9]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:8]=2[CH:20]=1.[BrH:25]>>[BrH:25].[OH:3][C:4]1[C:5]([S:21](=[O:23])(=[O:24])[NH2:22])=[CH:6][C:7]2[CH2:13][CH2:12][NH:11][CH2:10][CH:9]([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:8]=2[CH:20]=1
Reactant: COc1cc2c(cc1S(N)(=O)=O)CCNCC2c1ccccc1
Agent: Br
Agent: Cl
Product: NS(=O)(=O)c1cc2c(cc1O)C(c1ccccc1)CNCC2

Procedure:
The sulfamoyl compound (3.7 g, 0.01 m) is suspended in 3N hydrochloric acid, heated to reflux for 16 hours and concentrated in vacuo to give 8-methoxy-1-phenyl-7-sulfamoyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride. 8-Methoxy-1-phenyl-7-sulfamoyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride (3.7 g, 0.01 m) is dissolved in 48% hydrobromic acid (20 ml), refluxed for 2 hours and concentrated in vacuo to afford 8-hydroxy-1-phenyl-7-sulfamoyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrobromide.