Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[CH:5][N:6]=1.C([Li])CCC.[C:12]([Si:16](Cl)([CH3:18])[CH3:17])([CH3:15])([CH3:14])[CH3:13].C(=O)(O)[O-].[Na+]>CCOCC>[Si:16]([C:2]1[S:3][CH:4]=[CH:5][N:6]=1)([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:18])[CH3:17]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: Brc1nccs1
Agent: O=C([O-])O
Agent: [Li]CCCC
Agent: [Na+]
Solvent: CCOCC
Product: CC(C)(C)[Si](C)(C)c1nccs1
Temperature: -70 °C
Reaction time: 1 h
Yield: 65.9 %

Procedure:
A solution of 2-bromothiazole (57.4 g) in ether (70 ml) was added slowly to a solution of n-butyllithium (1.6M solution in hexane, 241 ml) in ether (700 ml) under an atmosphere of argon, maintaining the temperature below -60° C. After stirring for 1 hour at -70° C., a solution of tert-butylchlorodimethylsilane (63.0 g) in ether (70 ml) was added slowly dropwise. The reaction mixture was then allowed to warm to ambient temperature and stirred for 16 hours. Saturated aqueous sodium bicarbonate solution was added, the layers were separated, and the aqueous phase extracted twice with ether. The combined organic phases were dried (MgSO4), concentrated, and the residue was purified by column chromatography, eluting with 25% ethyl acetate/hexane (v/v), and subsequent distillation to give 2-tert-butyldimethylsilylthiazole (Q) (46 g, 58% yield) as an oil (b.p. 88°-96° C. at 10 mm of mercury);
Reaction SMILES: [C:1]([O:5][C:6](=[O:34])[CH:7]([NH:21][C:22]1[C:27]([NH2:28])=[CH:26][N:25]=[C:24]([N:29]([CH2:32][CH3:33])[CH2:30][CH3:31])[N:23]=1)[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][C:16](=[O:20])[N:17]([CH3:19])[CH3:18])=[CH:11][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[F:35][C:36]1[CH:41]=[CH:40][C:39]([S:42](Cl)(=[O:44])=[O:43])=[CH:38][CH:37]=1.CN(C)CCCN>N1C=CC=CC=1>[C:1]([O:5][C:6](=[O:34])[CH:7]([NH:21][C:22]1[C:27]([NH:28][S:42]([C:39]2[CH:40]=[CH:41][C:36]([F:35])=[CH:37][CH:38]=2)(=[O:44])=[O:43])=[CH:26][N:25]=[C:24]([N:29]([CH2:30][CH3:31])[CH2:32][CH3:33])[N:23]=1)[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][C:16](=[O:20])[N:17]([CH3:18])[CH3:19])=[CH:11][CH:10]=1)([CH3:3])([CH3:4])[CH3:2]
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Reactant: CCN(CC)c1ncc(N)c(NC(Cc2ccc(OC(=O)N(C)C)cc2)C(=O)OC(C)(C)C)n1
Agent: CN(C)CCCN
Solvent: c1ccncc1
Product: CCN(CC)c1ncc(NS(=O)(=O)c2ccc(F)cc2)c(NC(Cc2ccc(OC(=O)N(C)C)cc2)C(=O)OC(C)(C)C)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 78.2 %

Procedure:
A pyridine (120 mL) solution of 2-(2-diethylamino-5-aminopyrimidin-4-ylamino)-3-(4-dimethylcarbamoyloxy-phenyl)propionic acid t-butyl ester (32.0 g, 0.067 mol) was cooled to −20° C. with a dry ice/CH3CN bath. The mixture stirred for 30 minutes, and then p-fluorobenzenesulfonyl chloride (13.18 g, 0.067 mol) was added slowly. The reaction was stirred at −20° C. for 4.5 hrs, and then 3-dimethylaminopropyl amine (8.52 mL, 0.067 mol) was added, and then the mixture was allowed to warm to room temperature overnight. The reaction was concentrated in vacuo. The residue was taken up in EtOAc (1 L), and the organic phase was washed with 0.5 M citric acid (3×900 mL), water (1×900 mL), sat. NaHCO3 (3×900 mL), brine (1×900 mL), dried (MgSO4), filtered, and concentrated in vacuo to yield a brown residue. The residue was purified by flash chromatography (50% EtOAc/hexanes on silica gel) to yield 33.04 g (77%) the title compound as a yellow foam. Rf=0.54 (3:2 EtOAc/hexanes on silica gel).
Reaction SMILES: [N+]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N+:10]([O-:12])=[O:11])([O-])=O.[F:13][C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CS(C)=O.O>[F:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][C:9]2[CH:4]=[C:5]([N+:10]([O-:12])=[O:11])[CH:6]=[CH:7][CH:8]=2)=[CH:16][CH:15]=1
Reactant: Oc1ccc(F)cc1
Reactant: O=[N+]([O-])c1ccccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: O
Product: O=[N+]([O-])c1cccc(Oc2ccc(F)cc2)c1
Temperature: 100 °C
Reaction time: 16 h
Yield: 72 %

Procedure:
EX-634A) Dinitrobenzene (1.68 g, 10 mmol) and 4-fluorophenol (1.13 g, 10 mmol) were dissolved in anhydrous dimethylsulfoxide (25 mL), and powdered cesium carbonate (8 g, 24.8 mmol) was added. The mixture was stirred and heated to 100° C. using a reflux condenser under a nitrogen atmosphere. After 16 h, the mixture was diluted with water (120 mL), and the aqueous layer was extracted with diethyl ether (4×60 mL). The combined ether layers were washed with 3% HCl, 5% sodium hydroxide, and water, then dried over anhydrous MgSO4. The ether was removed in vacuo, and the recovered oil was purified by flash column chromatography on silica gel eluting with ethyl acetate in hexane (1:25) to give 1.68 g (69%) of the desired 3-(4 -fluorophenoxy)nitrobenzene product as orange crystals, 97% pure by HPLC analysis. MS m/z=234 [M+H+.
Reaction SMILES: [C:1]([C:3]1([OH:12])[C:7]2=[N:8][CH:9]=[CH:10][CH:11]=[C:6]2C[CH2:4]1)#[CH:2].CC1[N:15]=CC(C(=O)C)=NC=1>>[CH3:11][C:10]1[N:15]=[CH:6][C:7]([C:3]([OH:12])([C:1]#[CH:2])[CH3:4])=[N:8][CH:9]=1
Reactant: CC(=O)c1cnc(C)cn1
Reactant: C#CC1(O)CCc2cccnc21
Product: C#CC(C)(O)c1cnc(C)cn1

Procedure:
The title compound was prepared using the method described for the preparation of 7-ethynyl-5H,6H-cyclopenta[b]pyridin-7-ol, by replacing 5,6-dihydro-7H-cyclopenta[b]pyridin-7-one with 1-(5-methylpyrazin-2-yl)ethanone; 1H NMR (500 MHz, CDCl3) delta 1.65 (3H, s), 2.45 (3H, s), 4.32 (1H, s), 8.22 (1H, s), 8.77 (1H, s); LC-MS: m/z=+162.9 (M+H)+.
Reaction SMILES: O.[Na].[N+:3]([CH:6]([CH:9]=O)[CH:7]=O)([O-:5])=[O:4].[NH2:11][C:12]1[N:16]([S:17]([C:20]2[CH:26]=[CH:25][C:23]([CH3:24])=[CH:22][CH:21]=2)(=[O:19])=[O:18])[N:15]=[C:14]([OH:27])[CH:13]=1.FC1(F)C[C@H]1C1C2C(=NC=C(NC(=O)C3C(F)=CC=C(NS(CCC)(=O)=O)C=3F)C=2)NN=1>C(O)(=O)C.O>[N+:3]([C:6]1[CH:7]=[C:13]2[C:14]([OH:27])=[N:15][N:16]([S:17]([C:20]3[CH:26]=[CH:25][C:23]([CH3:24])=[CH:22][CH:21]=3)(=[O:19])=[O:18])[C:12]2=[N:11][CH:9]=1)([O-:5])=[O:4]
Reactant: O=CC(C=O)[N+](=O)[O-]
Reactant: Cc1ccc(S(=O)(=O)n2nc(O)cc2N)cc1
Agent: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)Nc2cnc3[nH]nc([C@@H]4CC4(F)F)c3c2)c1F
Agent: [Na]
Solvent: CC(=O)O
Solvent: O
Product: Cc1ccc(S(=O)(=O)n2nc(O)c3cc([N+](=O)[O-])cnc32)cc1
Temperature: 50 °C
Yield: 63.8 %

Procedure:
Nitromalonaldehyde sodium salt monohydrate (3.57 g, 22.7 mmol) was added to suspension of 5-amino-1-tosyl-1H-pyrazol-3-ol (5.00 g, 19.7 mmol; see Elgemeie, Galal H., et al. “Novel Synthesis of 5-Amino-1-arylsulfonyl-4-pyrazolin-3-ones as a New Class of N-Sulfonylated Pyrazoles.” J. Chem. Res. (S). Issue 6 (1999): pp. 384-385) in acetic acid (30 mL). The mixture was heated at 50° C. for 4 hours. The partial suspension was allowed to cool and diluted with water. The resulting solid was collected by vacuum filtration and dried under high vacuum to afford 5-nitro-1-tosyl-1H-pyrazolo[3,4-b]pyridin-3-ol (4.21 g, 12.6 mmol, 63.8% yield) as a solid.
Reaction SMILES: [C:1]([C:5]1[C:6]([NH2:15])=[N:7][N:8]2[CH:13]=[C:12]([CH3:14])[CH:11]=[N:10][C:9]=12)([CH3:4])([CH3:3])[CH3:2].[CH:16]1([CH2:21][CH2:22][C:23](Cl)=[O:24])[CH2:20][CH2:19][CH2:18][CH2:17]1>>[C:1]([C:5]1[C:6]([NH:15][C:23](=[O:24])[CH2:22][CH2:21][CH:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)=[N:7][N:8]2[CH:13]=[C:12]([CH3:14])[CH:11]=[N:10][C:9]=12)([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C(Cl)CCC1CCCC1
Reactant: Cc1cnc2c(C(C)(C)C)c(N)nn2c1
Product: Cc1cnc2c(C(C)(C)C)c(NC(=O)CCC3CCCC3)nn2c1

Procedure:
The product from Example 178A and 3-cyclopentylpropionyl chloride were processed using the method analogous to that described in Example 105C to afford the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.04-1.15 (m, 2H), 1.43-1.81 (m, 18H), 2.26-2.30 (m, 5H), 8.38 (d, J=2.0 Hz, 1H), 8.75 (s, 1H), 9.62 (br s, 1H); MS (DCI) m/z 329 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([NH2:8])[N:3]=1.[S:9](=[O:13])(=[O:12])([OH:11])[OH:10].C(O)(=O)[CH:15]([CH2:17][C:18](O)=O)[OH:16]>[Cl-].[Na+].O>[S:9](=[O:11])(=[O:10])([OH:13])[OH:12].[NH2:1][C:2]1[CH:7]=[CH:6][C:5]2[C:4](=[N:8][C:15]([OH:16])=[CH:17][CH:18]=2)[N:3]=1
Reactant: O=C(O)CC(O)C(=O)O
Reactant: Nc1cccc(N)n1
Agent: O=S(=O)(O)O
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Product: Nc1ccc2ccc(O)nc2n1
Temperature: 45 °C
Reaction time: 1 h
Yield: 89 %

Procedure:
2,6-Diaminopyridine (167 g, 1.53 mol) was added in portions to sulfuric acid (1.14 kg, 11.7 mol) at 40° C. The temperature of the solution was maintained at 40-50° C. during the addition with a water bath. When all of the 2,6-diaminopyridine was dissolved, the solution was cooled to 20° C. Malic acid (206 g, 1.53 mol) was added to the solution and the reaction mixture was gradually heated to 110° C. over 90 minutes. The mixture was stirred at 110-120° C. for one hour, cooled to room temperature, and poured slowly into a cold brine solution (167 g NaCl, 1.6 kg ice water). The quenched mixture was stirred at room temperature for one hour and filtered. The material was washed with hexanes (335 mL) and dried at 60° C. under vacuum to yield 2-amino-7-hydroxy-1,8-naphthyridine sulfuric acid salt as a yellow solid: 354 g, 89% yield; MS (DCI) M+1 at 162, 100%; 1H NMR (200 MHz, DMSO-d6) δ 4.32 (br. s, 5H, —OH, —NH2, H2SO4), 6.41 (d, J=9.0 Hz, 1H, C6), 6.56 (d J=9.0 Hz, 1H, C5), 7.85 (d J=6.6 Hz, 1H, C3), 7.91 (d J=6.6 Hz, 1H, C4).
Reaction SMILES: [CH3:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].S(Cl)([Cl:16])=O>>[CH3:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([Cl:16])=[O:5]
Reactant: Cc1c(C(=O)O)cccc1[N+](=O)[O-]
Reactant: O=S(Cl)Cl
Product: Cc1c(C(=O)Cl)cccc1[N+](=O)[O-]

Procedure:
reacting said 2-methyl-3-nitrobenzoic acid in refluxing thionyl chloride to form 2-methyl-3-nitrobenzoyl chloride,
Reaction SMILES: [O:1]=[C:2]1[C:6]2([CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]2)[CH2:5][CH2:4][N:3]1[C:19]1[CH2:20][O:21][C:22](=[O:24])[CH:23]=1.C1C(=O)N([Cl:32])C(=O)C1>C(Cl)(Cl)Cl>[Cl:32][C:23]1[C:22](=[O:24])[O:21][CH2:20][C:19]=1[N:3]1[CH2:4][CH2:5][C:6]2([CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:17])([CH3:18])[CH3:16])=[O:13])[CH2:8][CH2:7]2)[C:2]1=[O:1]
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CCN(C1=CC(=O)OC1)C2=O
Reactant: O=C1CCC(=O)N1Cl
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)N1CCC2(CC1)CCN(C1=C(Cl)C(=O)OC1)C2=O
Temperature: 60 °C

Procedure:
To a solution of tert-butyl 1-oxo-2-(5-oxo-2,5-dihydrofuran-3-yl)-2,8-diazaspiro[4.5]decane-8-carboxylate (I-16, Step A) (2.1 g, 6.2 mmol) in chloroform (50 mL) was added NCS (1.00 g, 7.49 mmol) at rt and the resulting solution was heated at 60° C. overnight. After removing the volatiles the residue was purified on silica gel column using EtOAc/hexane as eluting solvents to give the title compound. LC/MS: (M+1)+: 371.11, 372.99.
Reaction SMILES: CS(O[CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:15]2[N:24]=[CH:23][C:22]3[CH2:21][C@@H:20]([C:25]4[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=4)[C:19]4[CH:32]=[CH:33][CH:34]=[CH:35][C:18]=4[C:17]=3[N:16]=2)=[CH:10][CH:9]=1)(=O)=O.[NH:36]1[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]1>C(N(CC)CC)C>[F:31][C:28]1[CH:27]=[CH:26][C:25]([C@H:20]2[C:19]3[CH:32]=[CH:33][CH:34]=[CH:35][C:18]=3[C:17]3[N:16]=[C:15]([NH:14][C:11]4[CH:12]=[CH:13][C:8]([CH2:7][CH2:6][N:36]5[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]5)=[CH:9][CH:10]=4)[N:24]=[CH:23][C:22]=3[CH2:21]2)=[CH:30][CH:29]=1
Reactant: CS(=O)(=O)OCCc1ccc(Nc2ncc3c(n2)-c2ccccc2[C@H](c2ccc(F)cc2)C3)cc1
Reactant: C1CCNCC1
Solvent: CCN(CC)CC
Product: Fc1ccc([C@@H]2Cc3cnc(Nc4ccc(CCN5CCCCC5)cc4)nc3-c3ccccc32)cc1

Procedure:
This was synthesized by using (S)-4-(6-(4-fluorophenyl)-5,6-dihydrobenzo[h]quinazolin-2-ylamino)phenethyl methanesulfonate, piperidine and triethylamine as described in general procedure 2 to afford the desired product. M.p.=185-188° C. 1H NMR (CDCl3) 400 MHz δ 12.19 (brs, 1H), 10.89 (brs, 1H), 8.36 (brs, 1H), 8.01 (brs, 1H), 7.69 (d, J=6.6 Hz, 2H), 7.58-7.59 (m, 2H), 7.35 (d, J=6.2 Hz, 2H), 7.26 (d, J=2.7 Hz, 1H, 7.11-7.12 (m, 1H), 7.01-7.11 (m, 3H), 4.14 (s, 1H), 3.63 (d, J=10.5 Hz), 3.31-3.33 (m, 3H), 3.12-3.17 (m, 3H), 2.74 (d, J=11.2 Hz, 2H), 2.36 (d, J=12.1 Hz, 2H), 2.09 (s, 1H), 1.92-1.95 (m, 3H), 1.43-1.46 (m, 1H). LCMS m/e 479 [M+H].
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([O:13][C:14]2[CH:15]=[C:16]([CH:20]=[CH:21][CH:22]=2)[C:17]([OH:19])=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:23][C:24]1[CH:25]=[C:26]([NH:31][C:32](=[O:45])[C:33]2[CH:38]=[CH:37][CH:36]=[C:35]([N:39]([CH2:41][CH2:42][O:43][CH3:44])[CH3:40])[CH:34]=2)[CH:27]=[CH:28][C:29]=1[CH3:30]>>[CH3:44][O:43][CH2:42][CH2:41][N:39]([C:35]1[CH:34]=[C:33]([CH:38]=[CH:37][CH:36]=1)[C:32]([NH:31][C:26]1[CH:27]=[CH:28][C:29]([CH3:30])=[C:24]([NH:23][C:17](=[O:19])[C:16]2[CH:20]=[CH:21][CH:22]=[C:14]([O:13][CH:10]3[CH2:11][CH2:12][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:9]3)[CH:15]=2)[CH:25]=1)=[O:45])[CH3:40]
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2cccc(C(=O)O)c2)C1
Reactant: COCCN(C)c1cccc(C(=O)Nc2ccc(C)c(N)c2)c1
Product: COCCN(C)c1cccc(C(=O)Nc2ccc(C)c(NC(=O)c3cccc(OC4CCN(C(=O)OC(C)(C)C)C4)c3)c2)c1
Yield: 59 %

Procedure:
Using an analogous procedure to that described in the first paragraph of Example 25, 3-(1-tert-butoxycarbonylpyrrolidin-3-yloxy)benzoic acid was reacted with N-(3-amino-4-methylphenyl)-3-[N-(2-methoxyethyl)-N-methylamino]benzamide to give N-(5-{3-[N-(2-methoxyethyl)-N-methylamino]benzamido}-2-methylphenyl)-3-(1-tert-butoxycarbonylpyrrolidin-3-yloxy)benzamide in 59% yield; NMR Spectrum: (DMSOd6) 1.39 (s, 9H), 2.08 (m, 2H), 2.18 (s, 3H), 2.96 (s, 3H), 3.22 (s, 3H),3.25 (m, 2H), 3.52 (m, 6H), 5.07 (s, 1H), 6.87 (d, 1H), 7.2 (m, 5H), 7.43 (t, 1H), 7.55 (m, 3H), 7.79 (s, 1H), 9.86 (s, 1H), 10.06 (s, 1H); Mass Spectrum: M−C3H7+ 547.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:21]2[C:13](=[CH:14][C:15]3[CH2:16][O:17][CH2:18][C:19]=3[CH:20]=2)[C@@H:12]([NH:22][CH2:23][C:24]2[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:27]=[C:26]([C:34]([F:37])([F:36])[F:35])[CH:25]=2)[CH2:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:38]([N:41](C(C)C)CC)(C)C.N#CBr>O1CCCC1.C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[C:21]2[C:13](=[CH:14][C:15]3[CH2:16][O:17][CH2:18][C:19]=3[CH:20]=2)[C@@H:12]([N:22]([CH2:23][C:24]2[CH:25]=[C:26]([C:34]([F:36])([F:37])[F:35])[CH:27]=[C:28]([C:30]([F:32])([F:31])[F:33])[CH:29]=2)[C:38]#[N:41])[CH2:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H](NCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2cc3c(cc21)COC3
Reactant: CCN(C(C)C)C(C)C
Agent: N#CBr
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC[C@H](N(C#N)Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2cc3c(cc21)COC3
Temperature: 65 °C
Reaction time: 8 h

Procedure:
To a solution of (S)-9-(3,5-bis-trifluoromethyl-benzylamino)-1,3,6,7,8,9-hexahydro-2-oxa-5-aza-cyclohepta[f]indene-5-carboxylic acid tert-butyl ester (1.75 mmol) in tetrahydrofuran (7 mL) and diisopropyl ethylamine (5.25 mmol), add cyanogenbromide (5.25 mmol) and heat to 65° C. After stirring overnight, cool to room temperature and dilute with ethyl acetate (10 mL). Wash the organic portion with water (10 mL), followed by brine (10 mL). Dry the organic portion over sodium sulfate, filter, and remove solvent under vacuum. Chromatograph the product over silica gel, eluting with ethyl acetate/hexane (5-35%) to afford the title compound as an oil. MS (ES+): 554.2 (M−H).
Reaction SMILES: Cl.[F:2][C:3]1[C:13]([F:14])=[C:7]([C:8]([O:10]CC)=O)[C:6]([NH2:15])=[CH:5][CH:4]=1.[C:16]([C:18]([O:20][CH2:21][CH3:22])=[O:19])#[N:17]>Cl.C(O)(=O)C>[F:14][C:13]1[C:3]([F:2])=[CH:4][CH:5]=[C:6]2[C:7]=1[C:8](=[O:10])[NH:17][C:16]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[N:15]2
Reactant: CCOC(=O)C#N
Reactant: CCOC(=O)c1c(N)ccc(F)c1F
Agent: Cl
Solvent: CC(=O)O
Product: CCOC(=O)c1nc2ccc(F)c(F)c2c(=O)[nH]1
Temperature: 80 °C
Yield: 81.7 %

Procedure:
Ethyl 5,6-difluoroanthranilate hydrochloride (2.50 g, 10.5 mmol) was suspended in 1N hydrogen chloride-acetic acid solution (50 mL), ethyl cyanoformate (1.14 g, 11.6 mmol) was added thereto, and the mixture was stirred under heating at 80° C. for 3 hr. The reaction mixture allowed to cool to room temperature, and concentrated under reduced pressure. The residue was suspended in ethanol, and the insoluble material was collected by filtration to give the title compound as a white powder (2.18 g, 82%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([NH:11][CH2:12][CH2:13][N:14]([CH3:16])[CH3:15])=[O:10])=[CH:4][C:3]=1[C:17]1[CH2:22][CH2:21][C:20]([CH3:24])([CH3:23])[CH2:19][CH:18]=1.[C:25]([C:27]1[N:28]=[C:29]([C:40]([O-])=[O:41])[N:30]([CH2:32][O:33][CH2:34][CH2:35][Si:36]([CH3:39])([CH3:38])[CH3:37])[CH:31]=1)#[N:26].[K+]>>[CH3:15][N:14]([CH3:16])[CH2:13][CH2:12][NH:11][C:9]([CH2:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][C:40]([C:29]2[N:30]([CH2:32][O:33][CH2:34][CH2:35][Si:36]([CH3:39])([CH3:38])[CH3:37])[CH:31]=[C:27]([C:25]#[N:26])[N:28]=2)=[O:41])=[C:3]([C:17]2[CH2:22][CH2:21][C:20]([CH3:24])([CH3:23])[CH2:19][CH:18]=2)[CH:4]=1)=[O:10]
Reactant: CN(C)CCNC(=O)Cc1ccc(N)c(C2=CCC(C)(C)CC2)c1
Reactant: C[Si](C)(C)CCOCn1cc(C#N)nc1C(=O)[O-]
Agent: [K+]
Product: CN(C)CCNC(=O)Cc1ccc(NC(=O)c2nc(C#N)cn2COCC[Si](C)(C)C)c(C2=CCC(C)(C)CC2)c1

Procedure:
The title compound was prepared from 2-[4-amino-3-(4,4-dimethyl-cyclohex-1-enyl)-phenyl]-N-(2-dimethylamino-ethyl)-acetamide (as prepared in the previous step) and potassium 4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylate (as prepared in Example 1, step (d)) according to the procedure in Example 1, step (f). Mass spectrum (ESI, m/z): Calcd. for C31H46N6O3Si, 579.3 (M+H). found 579.3.
Reaction SMILES: C[N:2](C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[CH:15]=2)[N:8]=1)=O.[N:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:26]([NH:33]N)=[CH:25][CH:24]=1>>[CH3:21][O:20][C:16]1[CH:15]=[C:14]([N:9]2[CH:10]=[CH:11][C:12](=[O:13])[C:7]([C:5]3[N:33]([C:26]4[C:27]5[C:32](=[CH:31][CH:30]=[CH:29][CH:28]=5)[N:23]=[CH:24][CH:25]=4)[N:2]=[CH:3][CH:4]=3)=[N:8]2)[CH:19]=[CH:18][CH:17]=1
Reactant: COc1cccc(-n2ccc(=O)c(C(=O)/C=C/N(C)C)n2)c1
Reactant: NNc1ccnc2ccccc12
Product: COc1cccc(-n2ccc(=O)c(-c3ccnn3-c3ccnc4ccccc34)n2)c1

Procedure:
The product was obtained starting from 3-((E)-3-Dimethylamino-acryloyl)-1-(3-methoxy-phenyl)-1H-pyridazin-4-one (A-5) and quinolin-4-yl-hydrazine according to the method described for example 91. MS: M=396.0 (M+H)+
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1)#[N:2].[CH:9]([C:12]1[CH:18]=[CH:17][C:15]([NH2:16])=[CH:14][CH:13]=1)([CH3:11])[CH3:10].[K+].[Br-]>>[CH:9]([C:12]1[CH:18]=[CH:17][C:15]([NH:16][C:1]([C:3]2[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=2)=[NH:2])=[CH:14][CH:13]=1)([CH3:11])[CH3:10]
Reactant: N#Cc1ccncc1
Reactant: CC(C)c1ccc(N)cc1
Agent: [Br-]
Agent: [K+]
Product: CC(C)c1ccc(NC(=N)c2ccncc2)cc1
Yield: 90.4 %

Procedure:
The title compound was prepared from 4-cyanopyridine (7.7 g, 74 mmol) and 4-isopropylaniline (10 g, 74 mmol) by following the procedure described in preparation 10 (16 g, yield 90.4%, mp 131-134 C, purity 96.43% by HPLC). 1H-NMR (DMSO): δ 1.20-1.22 (d, 6H), 2.82-2.87 (m, 1H), 6.54 (bs, 2H, D2O exchangeable), 6.8-6.82 (d, 2H), 7.18-7.2 (d, 2H), 7.89-7.9 (d, 2H), 8.65-8.67 (d, 2H). IR (KBr) cm−1: 3452, 3299, 3163, 2955, 1647, 1597. MS m/z:240.2 (M+).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C@@:9]3([CH3:14])[C:11]([CH3:13])([CH3:12])[C@H:6]([CH2:7][CH2:8]3)[C:5]=2[C:4](=[O:15])[NH:3]1.[CH3:16][O:17][C:18]([C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1)=[O:19]>ClCCl.N1C=CC=CC=1.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH3:16][O:17][C:18](=[O:19])[C:20]1[CH:25]=[CH:24][C:23]([N:3]2[C:4](=[O:15])[C:5]3[C@@H:6]4[C:11]([CH3:12])([CH3:13])[C@@:9]([CH3:14])([CH2:8][CH2:7]4)[C:10]=3[N:2]2[CH3:1])=[CH:22][CH:21]=1
Reactant: COC(=O)c1ccc(B(O)O)cc1
Reactant: Cn1[nH]c(=O)c2c1[C@]1(C)CC[C@H]2C1(C)C
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)c1ccc(-n2c(=O)c3c(n2C)[C@]2(C)CC[C@H]3C2(C)C)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 29.5 %

Procedure:
A mixture of (4S,7R)-1,7,8,8-tetramethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (Intermediate 19; 100 mg, 0.48 mmol), 4-methoxycarbonyl-phenyl-boronic acid (180 mg, 0.97 mmol), and copper(II) acetate (133 mg, 0.73 mmol) in dichloromethane (1 mL) and pyridine (0.8 mL) was stirred at room temperature for 2 days. The reaction mixture was evaporated and purified using an Analogix Intelliflash 280 system (Analogix, Inc., Burlington, Wis.) with an Isco 12 g column, eluting with 10-60% ethyl acetate/hexanes to give 4-((4S,7R)-1,7,8,8-tetramethyl-3-oxo-1,3,4,5,6,7-hexahydro-4,7-methano-indazol-2-yl)-benzoic acid methyl ester (48.2 mg, 29%) as an off-white solid. ES(+)-MS (M+H) 341.
Reaction SMILES: C(OC([N:8]1[CH:13]([CH3:14])[CH2:12][N:11]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]3[CH:27]=[CH:26][N:25]=[C:24](Cl)[N:23]=3)[CH:17]=2)[CH2:10][CH:9]1[CH3:29])=O)(C)(C)C.[NH2:30][CH2:31][CH2:32][C:33]1[CH:38]=[CH:37][C:36]([OH:39])=[C:35]([Cl:40])[CH:34]=1>>[Cl:40][C:35]1[CH:34]=[C:33]([CH2:32][CH2:31][NH:30][C:24]2[N:23]=[C:22]([C:18]3[CH:19]=[CH:20][CH:21]=[C:16]([CH2:15][N:11]4[CH2:10][CH:9]([CH3:29])[NH:8][CH:13]([CH3:14])[CH2:12]4)[CH:17]=3)[CH:27]=[CH:26][N:25]=2)[CH:38]=[CH:37][C:36]=1[OH:39]
Reactant: NCCc1ccc(O)c(Cl)c1
Reactant: CC1CN(Cc2cccc(-c3ccnc(Cl)n3)c2)CC(C)N1C(=O)OC(C)(C)C
Product: CC1CN(Cc2cccc(-c3ccnc(NCCc4ccc(O)c(Cl)c4)n3)c2)CC(C)N1

Procedure:
Intermediate 142 was coupled with 4-(2-amino-ethyl)-2-chloro-phenol following procedure F. The resulting product was deprotected following procedure G2. LC-MS showed the product had the expected M+H+ of 452. 1H NMR (Varian 300 MHz, CD3OD, shifts relative to the solvent peak at 3.3 ppm) δ 8.63 (s, 1H) 8.35 (d, 2H)) 7.93 (d, 1H) 7.74 (d, 1H) 7.62 (d, 1H) 7.17 (s, 1H) 7.07 (d, 1H) 6.74 (d, 1H) 4.60 (s, 2H) 3.60-3.70 (m, 6H) 3.35 (t, 2H) 2.92 (t, 2H) 1.44 (d, 6H).
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:13]=[C:12]2[C:7]([CH:8]=[CH:9][CH:10]=[C:11]2[CH2:14][CH2:15][NH2:16])=[CH:6][CH:5]=1.C(=O)([O-])[O-].[K+].[K+].Cl.[NH:24]1[CH:28]=[C:27]([CH2:29][C:30](Cl)=[O:31])[N:26]=[CH:25]1>C(Cl)(Cl)Cl.O>[CH3:2][O:3][C:4]1[CH:13]=[C:12]2[C:7]([CH:8]=[CH:9][CH:10]=[C:11]2[CH2:14][CH2:15][NH:16][C:30](=[O:31])[CH2:29][C:27]2[N:26]=[CH:25][NH:24][CH:28]=2)=[CH:6][CH:5]=1
Reactant: COc1ccc2cccc(CCN)c2c1
Reactant: O=C(Cl)Cc1c[nH]cn1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: O
Product: COc1ccc2cccc(CCNC(=O)Cc3c[nH]cn3)c2c1
Temperature: 25 °C

Procedure:
0.01 mol of 2-(7-methoxynaphth-1-yl)ethylamine hydrochloride is dissolved in 60 ml of a chloroform/water mixture, and 0.025 mol of potassium carbonate is added under magnetic agitation. The mixture is cooled, and 0.012 mol of 4-imidazoleacetyl chloride hydrochloride is added dropwise. The agitation is maintained for 30 minutes at room temperature and the chloroform phase is evaporated to dryness. The residue is then recrystallized.
Reaction SMILES: [C:1]([CH:3]([CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[C:11]=1[Cl:17])[C:4]([O:6]CC)=[O:5])#[N:2].C(=O)([O-])[O-].[Na+].[Na+]>CO.O>[C:1]([CH:3]([CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[C:11]=1[Cl:17])[C:4]([OH:6])=[O:5])#[N:2]
Reactant: CCOC(=O)C(C#N)Cc1cccc(Cl)c1Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: N#CC(Cc1cccc(Cl)c1Cl)C(=O)O
Temperature: 65 °C
Reaction time: 8 h
Yield: 98.2 %

Procedure:
To a solution of ethyl 2-cyano-3-(2,3-dichlorophenyl)propanoate (1.02 g, 3.63 mmol) in methanol/water (15 mL/15 mL) was added sodium carbonate (1.54 g, 14.5 mmol). The mixture was stirred at 65° C. overnight. After cooled to room temperature, the mixture was concentrated under vacuo to remove MeOH, the resulting mixture was then acidified with 4 N hydrochloric acid. This solution was extracted with ethyl acetate (50 mL×3). The combined organic layers were washed with water and brine, dried over sodium sulphate, concentrated under reduced pressure to give the titled product (0.87 g, 98%) as a white solid; LC/MS: MS (ES+) m/e 244 (MH+); 1H NMR (300 MHz, CDCl3) δ ppm 3.21 (dd, J=10.2, 13.8 Hz, 1H), 3.59 (dd, J=5.4, 13.8 Hz, 1H), 3.87-3.92 (dd, J=5.4, 10.2 Hz, 1H), 4.74 (s, br, 1H), 7.18-7.32 (m, 2H), 7.44 (dd, J=1.8, 7.8 Hz, 1H).