Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[CH:15]=[CH:14][C:13]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=4[F:22])=[N:12][N:11]3[CH:23]=2)=[CH:4][C:3]=1[N+:24]([O-:26])=[O:25].[C:27]([Si:29]([CH3:32])([CH3:31])[CH3:30])#[CH:28].C(N(CC)CC)C>C1COCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[F:22][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[C:13]1[CH:14]=[CH:15][C:10]2[N:11]([CH:23]=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([C:28]#[C:27][Si:29]([CH3:32])([CH3:31])[CH3:30])=[C:3]([N+:24]([O-:26])=[O:25])[CH:4]=3)[N:9]=2)[N:12]=1
Reactant: O=[N+]([O-])c1cc(-c2cn3nc(-c4ccccc4F)ccc3n2)ccc1Br
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C[Si](C)(C)C#Cc1ccc(-c2cn3nc(-c4ccccc4F)ccc3n2)cc1[N+](=O)[O-]
Temperature: 60 °C
Yield: 81.6 %

Procedure:
To a mixture of 2-(4-bromo-3-nitrophenyl)-6-(2-fluorophenyl)imidazo[1,2-b]pyridazine (0.500 g, 1.21 mmol), ethynyltrimethylsilane (2.42 mmol), PdCl2(PPh3)2(0.0242 mmol) in THF (50 mL) containing triethylamine (6.05 mmol) is added CuI (0.0242 mmol). The mixture is degassed with N2 (5 minutes) then heated at 60° C. for 12 hours. The mixture is filtered, followed by washing with EtOAC, filtrate collected, concentrated under reduced pressure and crude product is purified via chromatography using CH2Cl2 to afford the title compound (0.425 g, 81%) as a yellow solid: Rf 0.56 (CH2Cl2); LCMS (m/z)=431.4 [M+H]+, tR=3.86 min.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([NH:16][S:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[C:26]([F:29])([F:28])[F:27])(=[O:19])=[O:18])[CH:12]=[C:13]([CH3:15])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][C:36]([O:38][CH2:39][CH3:40])=[O:37].C([O-])([O-])=O.[K+].[K+]>CN(C)C=O>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([N:16]([S:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[C:26]([F:29])([F:28])[F:27])(=[O:19])=[O:18])[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][C:36]([O:38][CH2:39][CH3:40])=[O:37])[CH:12]=[C:13]([CH3:15])[CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cc(NS(=O)(=O)c2ccccc2C(F)(F)F)cc(OCc2ccccc2)c1
Reactant: CCOC(=O)CCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)CCCCCN(c1cc(C)cc(OCc2ccccc2)c1)S(=O)(=O)c1ccccc1C(F)(F)F
Temperature: 60 °C
Reaction time: 12 h
Yield: 100.3 %

Procedure:
3-Benzyloxy-5-methyl-1-(2-trifluoromethylphenylsulfonylamino)benzene (550 mg, 1.3 mmol), as prepared in the preceding step, ethyl 6-bromohexanoate (290 mg, 1.3 mmol), and K2CO3 (1.0 g) were mixed in N,N-dimethylformamide (10 mL). The mixture was heated to 60° C. and stirred for 12 h. The solid was removed by filtration, and the filtrate was evaporated under high vacuum. The residue was dissolved in ethyl acetate (100 mL), washed with saturated aqueous NaHCO3 (2×50 mL) and brine (2×50 mL), and dried over Na2SO4. The solvent was evaporated in vacuo to give the title compound as a pale red oil (735 mg, 100%) which was directly used for the next step. 1H-NMR (300 MHz, CDCl3) δ 7.85 (d, J=7.7 Hz, 1 H), 7.71 (d, J=7.8 Hz, 1 H), 7.60 (t, J=7.7 Hz, 1 H), 7.47 (t, J=7.7 Hz, 1 H), 7.37 (m, 5 H), 6.71 (s, 1 H), 6.53 (s, 1 H), 6.51 (s, 1 H), 4.95 (s,2H), 4.11 (q, J=7.1 Hz, 2 H),3.66(t,J=7.0 Hz, 2 H), 2.25 (t, J=7.4 Hz, 2 H), 2.23 (s, 3 H), 1.33-1.62 (m, 6 H), 1.24 (t, J=7.1 Hz, 3 H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([F:9])=[CH:4][C:3]=1[N:10]=[C:11]=S.[NH:13]([C:15](=[O:38])[C:16]([NH:18][C:19]1[CH:24]=[CH:23][C:22]([C@H:25]2[CH2:30][CH2:29][C@H:28]([C:31]([CH3:37])([CH3:36])[C:32]([O:34][CH3:35])=[O:33])[CH2:27][CH2:26]2)=[CH:21][CH:20]=1)=[O:17])[NH2:14].CCN=C=NCCCN(C)C>CC(N(C)C)=O.O>[CH3:37][C:31]([C@H:28]1[CH2:27][CH2:26][C@H:25]([C:22]2[CH:21]=[CH:20][C:19]([NH:18][C:16]([C:15]3[O:38][C:11]([NH:10][C:3]4[CH:4]=[C:5]([F:9])[C:6]([F:8])=[CH:7][C:2]=4[F:1])=[N:14][N:13]=3)=[O:17])=[CH:24][CH:23]=2)[CH2:30][CH2:29]1)([CH3:36])[C:32]([O:34][CH3:35])=[O:33]
Reactant: Fc1cc(F)c(N=C=S)cc1F
Reactant: COC(=O)C(C)(C)[C@H]1CC[C@H](c2ccc(NC(=O)C(=O)NN)cc2)CC1
Agent: CCN=C=NCCCN(C)C
Solvent: O
Solvent: CC(=O)N(C)C
Product: COC(=O)C(C)(C)[C@H]1CC[C@H](c2ccc(NC(=O)c3nnc(Nc4cc(F)c(F)cc4F)o3)cc2)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 2,4,5-trifluorophenyl isothiocyanate (183 mg, 0.96 mmol) in DMA (1 mL) was added in one portion to a suspension of methyl 2-[trans-4-(4-{[hydrazino(oxo)acetyl]amino}-phenyl)cyclohexyl]-2-methylpropanoate (Intermediate 105, 290 mg, 0.80 mmol) in DMA (3 mL) and the reaction mixture was stirred at room temperature for 1 h 30 mins. EDCI (230 mg, 1.20 mmol) was added in one portion and the reaction mixture was heated to 90° C. for 10 mins in the microwave. The mixture was then cooled to room temperature, poured into H2O (20 mL) and stirred for 5 mins. The mixture was centrifuged and the aqueous layer decanted off to leave a solid residue. The solid residue was taken up in H2O (5 mL), stirred for 5 mins and then centrifuged and the aqueous layer decanted off to leave a solid residue. H2O (5 mL) was added and the mixture was filtered to give the title compound (398 mg, 96%) as a solid; 1H NMR δ 1.1 (6H, s), 1.12-1.26 (2H, m), 1.36-1.5 (2H, m), 1.57-1.7 (3H, m), 1.78-1.89 (2H, m), 2.39-2.49 (1H, m), 3.6 (3H, s), 7.2 (2H, d), 7.65-7.78 (1H, m), 7.68 (2H, d), 8.12-8.24 (1H, m), 11.0 (1H, s), 11.1 (1H, s); MS m/e MH+ 517.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][C:24]=1[Cl:25])[CH2:5][CH:6](/[CH:10]=[CH:11]/[C:12]1[CH:21]=[CH:20][C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=1)[CH:7]([NH2:9])[CH3:8].[C:26](OCC)(=[O:34])[CH2:27][CH2:28][CH2:29][CH2:30][C:31]([O-:33])=[O:32].Cl.C(N=C=NCCCN(C)C)C>C(Cl)Cl.CN(C)C1C=CN=CC=1.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][C:24]=1[Cl:25])[CH2:5][CH:6](/[CH:10]=[CH:11]/[C:12]1[CH:21]=[CH:20][C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=1)[CH:7]([NH:9][C:26]([CH2:27][CH2:28][CH2:29][CH2:30][C:31]([OH:33])=[O:32])=[O:34])[CH3:8]
Reactant: CCOC(=O)CCCCC(=O)[O-]
Reactant: CC(N)C(/C=C/c1ccc2ccccc2c1)Cc1ccc(Cl)c(Cl)c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(NC(=O)CCCCC(=O)O)C(/C=C/c1ccc2ccccc2c1)Cc1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 52 %

Procedure:
30 mg of (1RS,2RS,3E)-2-(3,4-dichlorobenzyl)-1-methyl-4-(2-naphthyl)-3-butenylamine was dissolved in 1 ml of methylene chloride, and 18 mg of mono-ethyl adipate, 12 mg of 4-dimethylaminopyridine and 19 mg of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride were added thereto. The mixture was stirred at room temperature for 3 hours. The reaction solution was diluted with ethyl acetate, then sequentially washed with 1N hydrochloric acid, a saturated sodium hydrogencarbonate aqueous solution and a saturated sodium chloride aqueous solution, and dried over anhydrous sodium sulfate. The drying agent was separated by filtration, and then the solvent was distilled off under reduced pressure. The residue was dissolved in 1 ml of methanol, and then 0.5 ml of a 2N sodium hydroxide aqueous solution was added thereto. The mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure and then extracted by an addition of ethyl ether and 1N hydrochloric acid. The organic layer was washed with a saturated sodium chloride aqueous solution and then dried over anhydrous magnesium sulfate. The drying agent was separated by filtration, and then the solvent was distilled off under reduced pressure. The residue was subjected to silica gel thin layer chromatography (Kieselgel™ 60F254, Art 5744, manufactured by Merck Co.; chloroform/methanol=10/1) to obtain 21 mg (yield: 51%) of the above-identified compound as colorless oily substance.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH3:13])([CH3:12])[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.[C:14]([C:17]1[S:18][CH:19]=[CH:20][CH:21]=1)(=O)[CH3:15]>C(Cl)Cl>[CH3:12][C:6]1([CH3:13])[C:7](=[O:11])[NH:8][C:9]2[CH:10]=[C:2]3[C:3](=[CH:4][C:5]1=2)[CH:15]=[C:14]([C:17]1[S:18][CH:19]=[CH:20][CH:21]=1)[NH:1]3
Reactant: CC1(C)C(=O)Nc2cc(N)ccc21
Reactant: CC(=O)c1cccs1
Solvent: ClCCl
Product: CC1(C)C(=O)Nc2cc3[nH]c(-c4cccs4)cc3cc21

Procedure:
Analogously to Example 1, 6.8 g. (38 mmole) 6-amino-3,3-dimethylindolin-2-one are diazotised and reduced. Into the solution are added dropwise 10.9 g. (85 mmole) 2-acetylthiophene and the oil which separates out is taken up in methylene chloride, dried and evaporated. As crude product, there are obtained 11.2 g. 2-acetylthiophene-(3,3-dimethyl-2-oxoindoline-6-hydrazone) which is further reacted without purification.
Reaction SMILES: BrCCBr.Br[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[O:12][CH:13]([CH3:15])[CH3:14].[C:16]([N:21]1[CH2:26][CH2:25][C:24](=[O:27])[CH2:23][CH2:22]1)([O:18][CH2:19][CH3:20])=[O:17].Cl>CCOCC>[C:16]([N:21]1[CH2:22][CH2:23][C:24]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[O:12][CH:13]([CH3:15])[CH3:14])([OH:27])[CH2:25][CH2:26]1)([O:18][CH2:19][CH3:20])=[O:17]
Reactant: CCOC(=O)N1CCC(=O)CC1
Reactant: CC(C)Oc1ccccc1Br
Agent: Cl
Solvent: BrCCBr
Solvent: CCOCC
Product: CCOC(=O)N1CCC(O)(c2ccccc2OC(C)C)CC1
Temperature: 22 °C
Reaction time: 2 h
Yield: 91.7 %

Procedure:
To a suspended solution of Mg chips (10.07 g, 0.414 mol) in anhydrous ether (150 mL) at 22° C. under argon was added ca. 0.15 mL of 1,2-dibromoethane. Then 43.7 g (0.200 mol) of XIV in 200 mL of ether was added dropwise. After 50% of the aryl halide was added, the reaction began to reflux vigorously. The flask was cooled in an ice bath. After the refluxing had subsided somewhat, the ice bath was removed and the remaining aryl halide was added over a 1.5 h period. The resultant Grignard reagent was cooled in a dry ice/ether bath for 2 h and then treated with 34.0 mL (0.221 mol) of 98% 1-carbethoxy-4-piperidone. Upon complete addition of ketone, the reaction mixture was allowed to warm to 22° C. and stirred for 2 h. The reaction was then quenched with cold aqueous ammonium chloride which resulted in an emulsion. Addition of 1M aqueous HCl solution separated the two layers. The aqueous phase was extracted with additional ether and the combined organic solution was washed with 10% aqueous sodium bisulfite, 1.0M HCl, saturated NaHCO3, and dried (K2CO3). Filtration concentration yielded 56.36 g of XV as a yellow viscous oil which was carried on without further purification The structure of this oil was supported by 1H NMR.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=O.Cl.[C:13]1([C:19]2([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH:27]3[CH:23]([CH2:24][NH:25][CH2:26]3)[C:22](=[O:28])[CH2:21][CH2:20]2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(N(CC)CC)C>ClCCl>[C:29]1([C:19]2([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH:27]3[CH:23]([CH2:24][N:25]([C:9](=[O:11])[CH2:8][C:3]4[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=4[OH:1])[CH2:26]3)[C:22](=[O:28])[CH2:21][CH2:20]2)[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: O=C1CCC(c2ccccc2)(c2ccccc2)C2CNCC12
Reactant: O=C(O)Cc1ccccc1O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C1CCC(c2ccccc2)(c2ccccc2)C2CN(C(=O)Cc3ccccc3O)CC12
Reaction time: 0.5 h
Yield: 27.6 %

Procedure:
N,N'-Carbonyldiimidazole (1.14 g) is added to a solution of 2-hydroxyphenylacetic acid (1.06 g) in dry dichloromethane (30 cc), cooled to +5° C. The mixture is stirred for 30 minutes at +5° C. and a solution of (3aRS,7aRS)-7,7-diphenyl-4-perhydroisoindolone hydrochloride (2.23 g) and triethylamine (1.96 cc) in dichloromethane (20 cc) is then added. The reaction mixture is stirred at 20° C. for 16 hours, then washed with water (2×100 cc), dried over magnesium sulphate and filtered and the filtrate is concentrated to dryness under reduced pressure (2.7 kPa). The residue is chromatographed on a silica gel column (0.2-0.063 mm, diameter 4 cm, height 40 cm), eluting under a nitrogen pressure of 0.7 bar with a mixture of cyclohexane and ethyl acetate (70/30 by volume) and collecting 125 cc fractions. Fractions 4 to 11 are combined and concentrated to dryness under reduced pressure (2.7 kPa). The residue is crystallized from a mixture of acetonitrile (15 cc) and isopropyl ether (30 cc). The crystals are drained, washed with isopropyl ether and dried. (3aRS,7aRS)-7,7-diphenyl-2-[(2-hydroxyphenyl)acetyl]-4-perhydroisoindolone (0.8 g) is obtained in the form of white crystals melting at 232° C.
Reaction SMILES: [C:1]([C:9]1[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=1[C:11]([OH:13])=O)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:18]([O:22][C:23](=[O:29])[C@@H:24]1[CH2:28][CH2:27][CH2:26][NH:25]1)([CH3:21])([CH3:20])[CH3:19].O.ON1C2C=CC=CC=2N=N1.C1CCC(N=C=NC2CCCCC2)CC1>C(Cl)Cl>[CH3:21][C:18]([O:22][C:23](=[O:29])[C@@H:24]1[CH2:28][CH2:27][CH2:26][N:25]1[C:11](=[O:13])[C:10]1[CH:14]=[CH:15][CH:16]=[CH:17][C:9]=1[C:1](=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)([CH3:19])[CH3:20]
Reactant: CC(C)(C)OC(=O)[C@@H]1CCCN1
Reactant: O=C(O)c1ccccc1C(=O)c1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)OC(=O)[C@@H]1CCCN1C(=O)c1ccccc1C(=O)c1ccccc1

Procedure:
6.78 g (30mmol) of o-benzoylbenzoic acid, 5.13 g (30 mmol) of L-proline t-butyl ester, 4.05 g (30 mmol) of 1-hydroxybenzotriazole hydrate and 6.18 g (30 mmol) of DCC in 100 ml methylene chloride were reacted in the manner described in Example 25 for the coupling of o-benzoylbenzoic acid with L-proline t-butyl ester. A standard work-up as described in Example 25 afforded a viscous gum which was purified by flash chromatography on silica gel with 40:1/methylene chloride:methanol as eluant to give an amorphous solid. The isolated yield of the title compound was 8.6 g (76%). TLC (90:10/CH2Cl2 :MeOH): Rf =0.80. 1H NMR (CDCl3) δ: 7.30-7.80(m,9H,); 4.06-4.38(m,1H); 3.36-3.65(m,2H); 1.78-2.32(m,4H); 1.32(s),1.43(s,9H). I.R. (KBr): 1595, 1627, 1661, 1733 cm-1. Low Resolution Mass Spectrum: 380 (p+1). Standard Combustion Analysis Calculated: C,72.80; H,6.64; N,3.69. Found: C,72.37; H,6.59; N,3.76.
Reaction SMILES: C(OC(=O)[NH:7][CH:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[C:24]([C:26](=[O:40])[NH:27][CH2:28][C:29]4[C:30](=[O:39])[NH:31][C:32]([CH3:38])=[CH:33][C:34]=4[CH:35]([CH3:37])[CH3:36])[C:23]([CH3:41])=[C:22]([N:42]([CH2:49][CH3:50])[CH:43]4[CH2:48][CH2:47][O:46][CH2:45][CH2:44]4)[CH:21]=3)=[CH:16][N:15]=2)[CH2:10][CH2:9]1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:7][CH:8]1[CH2:9][CH2:10][N:11]([C:14]2[N:15]=[CH:16][C:17]([C:20]3[CH:21]=[C:22]([N:42]([CH2:49][CH3:50])[CH:43]4[CH2:44][CH2:45][O:46][CH2:47][CH2:48]4)[C:23]([CH3:41])=[C:24]([CH:25]=3)[C:26]([NH:27][CH2:28][C:29]3[C:30](=[O:39])[NH:31][C:32]([CH3:38])=[CH:33][C:34]=3[CH:35]([CH3:37])[CH3:36])=[O:40])=[CH:18][CH:19]=2)[CH2:12][CH2:13]1
Reactant: CCN(c1cc(-c2ccc(N3CCC(NC(=O)OC(C)(C)C)CC3)nc2)cc(C(=O)NCc2c(C(C)C)cc(C)[nH]c2=O)c1C)C1CCOCC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCN(c1cc(-c2ccc(N3CCC(N)CC3)nc2)cc(C(=O)NCc2c(C(C)C)cc(C)[nH]c2=O)c1C)C1CCOCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 98.4 %

Procedure:
tert-butyl(1-(5-(3-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-5-(((4-isopropyl-6-methyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)carbamoyl)-4-methylphenyl)pyridin-2-yl)piperidin-4-yl)carbamate (0.31 g, 0.44 mmol) was taken in DCM (5 mL) and TFA (1 mL) was added to it and stirred at rt for 2 h. After completion of reaction, solvent was removed under reduced pressure and saturated NaHCO3 solution was added to it. Extraction was carried out using 10% MeOH/DCM; the combined organic layers were washed with water and brine; dried over anhydrous Na2SO4; filtered and concentrated under reduced pressure to give the title compound (0.26 g, 98.11%)
Reaction SMILES: [C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([S:20][C:21]3[C:30]4[C:25](=[CH:26][C:27]([O:33][CH2:34][CH2:35]Cl)=[C:28]([O:31][CH3:32])[CH:29]=4)[N:24]=[CH:23][N:22]=3)[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:37][S:38]([N:41]1[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]1)(=[O:40])=[O:39].C(N(C(C)C)CC)(C)C>CN(C=O)C.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([S:20][C:21]3[C:30]4[C:25](=[CH:26][C:27]([O:33][CH2:34][CH2:35][N:44]5[CH2:45][CH2:46][N:41]([S:38]([CH3:37])(=[O:40])=[O:39])[CH2:42][CH2:43]5)=[C:28]([O:31][CH3:32])[CH:29]=4)[N:24]=[CH:23][N:22]=3)[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CS(=O)(=O)N1CCNCC1
Reactant: COc1cc2c(Sc3cccc(NC(=O)Nc4cc(C(C)(C)C)on4)c3)ncnc2cc1OCCCl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc2c(Sc3cccc(NC(=O)Nc4cc(C(C)(C)C)on4)c3)ncnc2cc1OCCN1CCN(S(C)(=O)=O)CC1
Temperature: 60 °C
Yield: 16.8 %

Procedure:
To a solution of 1-(5-tert-butyl-isoxazol-3-yl)-3-{3-[7-(2-chloro-ethoxy)-6-methoxy-quinazolin-4-ylsulfanyl]-phenyl}-urea from Example 79A (225 mg, 0.426 mmol) in DMF (3 mL) was added 1-methane sulfonyl pyperazine (139.9 mg, 0.852 mmol) followed by diisopropyl ethylamine (0.222 mL, 1.278 mmol) and tetrabutyl ammonium iodide (157.35 mg, 0.426 mmol). The reaction mixture was heated at 60° C. for 3 days. Formation of the product was determined by LCMS. The crude reaction mixture was purified by preparative HPLC (phenomenex phenylhexyl reverse phase column eluted with gradient of solvent A=0.05% HOAc/H2O and solvent B=0.05% HOAc/CH3CN) to afford 1-(5-tert-butylisoxazol-3-yl)-3-(3-(6-methoxy-7-(2-(4-(methylsulfonyl)piperazin-1-yl)ethoxy)quinazolin-4-ylthio)phenyl)urea (47 mg, 17%) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 9.60 (s, 1H), 9.05 (s, 1H), 8.65 (s, 1H), 7.85 (s, 1H), 7.62-7.25 (m, 5H), 6.45 (s, 1H), 4.30 (m, 2H), 3.15 (m, 4H), 2.85 (m, 5H), 2.60 (m, 4H), 1.25 (s, 9H); LC-MS (ESI) m/z 656 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([C:16]([O:18][CH3:19])=[O:17])=[N:11][C:12]([OH:15])=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:20](Br)[CH3:21].C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[CH2:1]([O:8][C:9]1[C:10]([C:16]([O:18][CH3:19])=[O:17])=[N:11][C:12]([O:15][CH2:20][CH3:21])=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1nc(O)ccc1OCc1ccccc1
Reactant: CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOc1ccc(OCc2ccccc2)c(C(=O)OC)n1

Procedure:
5.0 g (19 mmol) of methyl 3-benzyloxy-6-hydroxypicolinate, 2.1 g (19 mmol) of ethyl bromide and 2.9 g (21 mmol) of potassium carbonate were added to 100 ml of DMF, and the resultant mixture was reacted at 80° C. for 5 hours. After the reaction, the reaction content was poured into water, and was extracted with ethyl acetate, washed with water, dried and concentrated. The residue thus obtained was purified by column chromatography to obtain an aimed compound.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:15]([C:26]2[C:31](Cl)=[N:30][CH:29]=[CH:28][N:27]=2)[NH:16][C:17](=O)[CH2:18][CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OC1C=C(C(NC(C2CCC2)=O)C2C(Cl)=NC=C[N:49]=2)C=CC=1)C1C=CC=CC=1>>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:15]2[N:16]=[C:17]([CH2:18][CH:19]3[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]3)[N:27]3[CH:28]=[CH:29][N:30]=[C:31]([NH2:49])[C:26]=23)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(CC1CCCCC1)NC(c1cccc(OCc2ccccc2)c1)c1nccnc1Cl
Reactant: O=C(NC(c1cccc(OCc2ccccc2)c1)c1nccnc1Cl)C1CCC1
Product: Nc1nccn2c(CC3CCCCC3)nc(-c3cccc(OCc4ccccc4)c3)c12

Procedure:
N-[(3-Benzyloxyphenyl)-(3-chloropyrazin-2-yl)-methyl]-2-cyclohexyl-acetamide: Prepared according to the procedures for Cyclobutanecarboxylic Acid [(3-benzyloxy-phenyl)-(3-chloro-pyrazin-2-yl)-methyl]Amide, White solid, 1H NMR (CDCl3, 400 MHz) δ 0.88-0.97 (m, 2H), 1.09-1.29 (m, 3H), 1.63-1.82 (m, 6H), 2.11 (d, 1H, J=7.2 Hz), 5.02 (s, 2H), 6.55 (d, 1H, J=7.6 Hz), 6.86-6.94 (m, 3H), 7.03 (d, 1H, J=7.6 Hz), 7.19-7.25 (m, 1H), 7.30-7.40 (m, 6H), 8.32 (d, 1H, J=2.0 Hz), 8.49 (d, 1H, J=2.0 Hz).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19](Br)[C:20]([C:24]#[N:25])=[CH:21][CH:22]=4)[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1.[Br-].[C:29]([C:31]1[CH:32]=[C:33]([CH:36]=[CH:37][CH:38]=1)[CH2:34][Zn+])#[N:30]>>[CH3:1][O:2][C:3](=[O:27])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19]([CH2:34][C:33]5[CH:36]=[CH:37][CH:38]=[C:31]([C:29]#[N:30])[CH:32]=5)[C:20]([C:24]#[N:25])=[CH:21][CH:22]=4)[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c3ccc(C#N)c4Br)ccc21
Reactant: N#Cc1cccc(C[Zn+])c1
Agent: [Br-]
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c3ccc(C#N)c4Cc3cccc(C#N)c3)ccc21

Procedure:
The title compound is prepared from {(S)-6-[(R)-4-bromo-5-cyano-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester and 3-cyano-benzylzinc bromide following a procedure analogous to that described in Step 6 of Intermediate 1. LC (method 4): tR=1.18 min; Mass spectrum (ESI+): m/z=487 [M+Na]+.
Reaction SMILES: [C:1]1([C@H:7]2[CH2:12][C@@H:11]([OH:13])[CH2:10][CH2:9][O:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CCN(C(C)C)C(C)C.[CH3:23][S:24](Cl)(=[O:26])=[O:25]>C(Cl)Cl>[CH3:23][S:24]([O:13][C@H:11]1[CH2:10][CH2:9][O:8][C@@H:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:12]1)(=[O:26])=[O:25]
Reactant: O[C@H]1CCO[C@@H](c2ccccc2)C1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)O[C@H]1CCO[C@@H](c2ccccc2)C1
Yield: 62.6 %

Procedure:
A solution of cis-2-phenyltetrahydro-2H-pyran-4-ol (1 g) in DCM (20 mL) was cooled in an ice-salt water bath and treated with DIEA (2.2 g) and methanesulfonyl chloride (0.7 g) for 2 hours. The mixture was diluted with DCM (50 mL) and washed with water and brine. The organic layer was dried and concentrated. Preparative TLC provided 0.9 g of cis-2-phenyl-tetrahydro-2H-pyran-4-yl methanesulfonate.
Reaction SMILES: CON(C)[C:4]([C:6]1[N:7]=[CH:8][N:9]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]3[C:18]([F:23])=[N:19][CH:20]=[CH:21][CH:22]=3)[CH:12]=2)[CH:10]=1)=[O:5].[S:25]1[CH:29]=[CH:28][N:27]=[CH:26]1>>[F:23][C:18]1[C:17]([C:13]2[CH:12]=[C:11]([N:9]3[CH:10]=[C:6]([C:4]([C:26]4[S:25][CH:29]=[CH:28][N:27]=4)=[O:5])[N:7]=[CH:8]3)[CH:16]=[CH:15][CH:14]=2)=[CH:22][CH:21]=[CH:20][N:19]=1
Reactant: CON(C)C(=O)c1cn(-c2cccc(-c3cccnc3F)c2)cn1
Reactant: c1cscn1
Product: O=C(c1cn(-c2cccc(-c3cccnc3F)c2)cn1)c1nccs1

Procedure:
This compound is prepared by method C using compound 12i and thiazole
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:18])[C:7]([C:13](OCC)=[O:14])=[CH:8][N:9]2[CH3:12])=[CH:4][CH:3]=1.[NH3:19]>>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:18])[C:7]([C:13]([NH2:19])=[O:14])=[CH:8][N:9]2[CH3:12])=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1cn(C)c2cc(Cl)ccc2c1=O
Reactant: N
Product: Cn1cc(C(N)=O)c(=O)c2ccc(Cl)cc21
Reaction time: 21 h

Procedure:
A mixture of ethyl 7-chloro-1-methyl-4-oxo-1,4-dihydroquinoline-3-carboxylate (5.0 g) and aqueous ammonia (specific gravity 0.88, 100 ml) was stirred and heated on a steam bath for 3.5 hours. More aqueous ammonia (100 ml) was added and heating was continued for a further 21 hours. The mixture was cooled in ice. The solid product was collected by filtration and dried to give the novel compound 7-chloro-1-methyl-4-oxo-1,4-dihydroquinoline-3-carboxamide, m.p. >240°.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9]N.[NH:11]1[CH2:16][CH2:15][C:14](=O)[CH2:13][CH2:12]1.Cl>C(O)C>[CH3:1][S:2][C:3]1[C:4]2[NH:9][C:14]3[CH2:15][CH2:16][NH:11][CH2:12][C:13]=3[C:5]=2[CH:6]=[CH:7][CH:8]=1
Reactant: O=C1CCNCC1
Reactant: CSc1ccccc1NN
Agent: Cl
Solvent: CCO
Product: CSc1cccc2c3c([nH]c12)CCNC3
Temperature: 25 °C
Reaction time: 4 h

Procedure:
The 2-(methylthio)phenyl hydrazine (5.32 g, 30.0 mmol) and 4-piperidone (4.07 g, 30.0 mmol) were partially dissolved in the ethanol (75 mL) and heated initially to reflux for 1 h. A heavy precipitate formed from the almost clear solution. The reaction was then treated with the conc hydrochloric acid (2.5 mL) and diluted with further ethanol (25 mL) to assist stirring and heating continued for a further 4 h. After cooling to RT overnight the solid was filtered washing isopropanol (25 mL). Obtained 7.70 g