Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O-]S([O-])(=O)=O.[Mg+2].[CH3:7][C:8]1([CH3:15])[O:12][C@H:11]([CH:13]=O)[CH2:10][O:9]1.[CH3:16][O:17][C:18]1[CH:25]=[C:24]([O:26][CH3:27])[CH:23]=[CH:22][C:19]=1[CH2:20][NH2:21]>C(Cl)Cl>[CH3:16][O:17][C:18]1[CH:25]=[C:24]([O:26][CH3:27])[CH:23]=[CH:22][C:19]=1[CH2:20]/[N:21]=[CH:13]/[C@@H:11]1[CH2:10][O:9][C:8]([CH3:7])([CH3:15])[O:12]1
Reactant: COc1ccc(CN)c(OC)c1
Reactant: CC1(C)OC[C@@H](C=O)O1
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: ClCCl
Product: COc1ccc(C/N=C/[C@@H]2COC(C)(C)O2)c(OC)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Prepared according to the procedure described by Hubschwerlen, C. and Schmid, G. Helv. Chim. Acta 1983, 66, 2206-2209 with the addition of MgSO4. To a suspension of (S)-2,2-dimethyl-1,3-dioxolane-4-carbaldehyde (Carbosynth LLC, 346 g, 43% in DCM, 1.143 mol) and MgSO4 (278 g) in DCM (1.5 L) at 0° C. was added 2,4-dimethoxybenzylamine (193 g, 1.154 mol) over 20 min. After stirring at rt for 2 h it was filtered, washing the filter cake with DCM (2×250 mL). The mother liquor was used directly in step 2.
Reaction SMILES: [CH:1]([C:3]1[N:12]=[C:11]2[C:6]([C:7](=[O:16])[C:8]([C:13]([OH:15])=[O:14])=[CH:9][NH:10]2)=[CH:5][CH:4]=1)=[O:2].[C:17](NN)(=O)[CH3:18]>C(O)C>[CH2:17]([N:10]1[C:11]2[C:6](=[CH:5][CH:4]=[C:3]([CH:1]=[O:2])[N:12]=2)[C:7](=[O:16])[C:8]([C:13]([OH:15])=[O:14])=[CH:9]1)[CH3:18]
Reactant: O=Cc1ccc2c(=O)c(C(=O)O)c[nH]c2n1
Reactant: CC(=O)NN
Solvent: CCO
Product: CCn1cc(C(=O)O)c(=O)c2ccc(C=O)nc21
Yield: 118 %

Procedure:
A mixture containing 2 g of 7-formyl-3-carboxy-4-oxo-1, 4-dihydro-1,8-naphthyridine and 0.51 g of acethydrazide and 20 ml of ethanol are stirred and refluxed for 11/2 hours. The mixture was cooled and the solids were filtered and washed with a little ethanol and dried at room temperature. Several washings with hot cellosolve and dimethyl formamide yielded 2 g of 1-ethyl-3-carboxy-4-oxo-1, 4 dihydro-1,8 naphthyridine-7 carboxaldehyde acethydrazone m.p. 300°.
Reaction SMILES: [F:1][C:2]([F:30])([F:29])[C:3]1[CH:4]=[C:5]([C:9]2[CH:10]=[C:11]([CH:25]=[CH:26][C:27]=2[OH:28])[CH2:12][N:13]([CH3:24])[S:14]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)(=[O:16])=[O:15])[CH:6]=[CH:7][CH:8]=1.C([O:35][C:36](=[O:41])[C:37](Br)([CH3:39])[CH3:38])(C)(C)C.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[F:30][C:2]([F:1])([F:29])[C:3]1[CH:4]=[C:5]([C:9]2[CH:10]=[C:11]([CH2:12][N:13]([CH3:24])[S:14]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)(=[O:16])=[O:15])[CH:25]=[CH:26][C:27]=2[O:28][C:37]([CH3:39])([CH3:38])[C:36]([OH:41])=[O:35])[CH:6]=[CH:7][CH:8]=1
Reactant: CN(Cc1ccc(O)c(-c2cccc(C(F)(F)F)c2)c1)S(=O)(=O)c1ccc(F)cc1
Reactant: CC(C)(C)OC(=O)C(C)(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CN(Cc1ccc(OC(C)(C)C(=O)O)c(-c2cccc(C(F)(F)F)c2)c1)S(=O)(=O)c1ccc(F)cc1
Temperature: 80 °C
Reaction time: 16 h
Yield: 4.7 %

Procedure:
To a solution of N-(3-(3-trifluoromethylphenyl)-4-hydroxybenzyl)-4-fluoro-N-methylbenzenesulfonamide (36) (50.0 mg, 0.114 mmol, 1 eq) in DMF (3 mL) under argon, was added t-butyl-2-bromo-2-methylpropanoate (66.0 mg, 0.296 mmol, 2.6 eq) and potassium carbonate (31 mg, 0.224 mmol, 2 eq). The mixture was stirred at 80° C. for 16 h, cooled to room temperature and partitioned with saturated sodium bicarbonate and EtOAc. The organic layer was separated, dried (Na2SO4), and concentrated in vacuo. The crude residue was dissolved in TFA/DCM (1 mL/1 mL) and stirred at room temperature for 1 h. Solvent was removed in vacuo and the residue was purified via reversed phase semi-preparative HPLC to afford 2.8 mg of 2-(2-(3-trifluoromethylphenyl)-4-((4-fluoro-N-methylphenylsulfonamido)methyl)phenoxy)-2-methylpropanoic acid (Example 34). 1HNMR (CD3OD, 400 MHz): δ 7.91 (m, 3H), 7.88 (m, 1H), 7.61 (m, 2H), 7.35 (t, 2H), 7.27 (d, 2H), 6.90 (d, 1H), 4.20 (s, 2H), 2.67 (s, 3H), 1.46 (s, 6H). MS (ESI): MH+=526.1. HPLC (Method B) tR=2.53 min.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10]Br)=[CH:4][CH:3]=1.[NH2:12][C:13]1[S:14][C:15]2[CH2:16][CH2:17][NH:18][CH2:19][CH2:20][C:21]=2[N:22]=1>CN(C)C=O>[NH2:12][C:13]1[S:14][C:15]2[CH2:16][CH2:17][N:18]([CH2:10][CH2:9][CH2:8][C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)[CH2:19][CH2:20][C:21]=2[N:22]=1
Reactant: Clc1ccc(CCCBr)cc1
Reactant: Nc1nc2c(s1)CCNCC2
Solvent: CN(C)C=O
Product: Nc1nc2c(s1)CCN(CCCc1ccc(Cl)cc1)CC2
Yield: 37 %

Procedure:
Prepared from 3-(4-chlorophenyl)propyl bromide and 2 equivalents of 2-amino-4,5,7,8-tetrahydro-6H-thiazolo[5,4-d]azepine in anhydrous dimethylformamide. Yield: 37% of theory, Melting point: 153° C.
Reaction SMILES: [F:1][C:2]1[CH:17]=[CH:16][CH:15]=[CH:14][C:3]=1[C:4]([NH:6][C:7]1[C:8](=O)[NH:9][CH:10]=[CH:11][CH:12]=1)=O.C1(C)C(C)=CC=CC=1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:27]>N1C=CC=CC=1>[F:1][C:2]1[CH:17]=[CH:16][CH:15]=[CH:14][C:3]=1[C:4]1[S:27][C:8]2[C:7]([N:6]=1)=[CH:12][CH:11]=[CH:10][N:9]=2
Reactant: O=C(Nc1ccc[nH]c1=O)c1ccccc1F
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Solvent: c1ccncc1
Solvent: Cc1ccccc1C
Product: Fc1ccccc1-c1nc2cccnc2s1

Procedure:
3-(2-Fluorobenzoylamino)-2-pyridone (2 g.), 60 ml. of xylene and 15 ml. of pyridine were heated until solution was complete. To this solution was added 6.5 grams of phosphorus pentasulfide and the mixture was heated at reflux for 16 hours. The reaction mixture was decanted from a gummy residue while hot, and the solvents were concentrated to dryness. The crystalline residue was recrystallized from ethanol to give 2-(2-fluorophenyl)thiazolo[5,4-b]pyridine, m.p. 119-121° C.
Reaction SMILES: [NH2:1][CH:2]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:3]([OH:5])=[O:4].[OH-].[Na+].[C:14](Cl)(=[O:23])[O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>O>[CH2:16]([O:15][C:14]([NH:1][CH:2]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:3]([OH:5])=[O:4])=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: NC(C(=O)O)c1ccccc1
Reactant: O=C(Cl)OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(NC(C(=O)O)c1ccccc1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 90.5 %

Procedure:
To a solution of 2-amino-2-phenylacetic acid (500 mg, 3.31 mmol) in 2N sodium hydroxide (1.65 ml, 3.31 mmol) stirred at 0° C., benzyl carbonochloridate (512 μl, 3.64 mmol) and 2N sodium hydroxide (1.82 ml, 3.64 mmol) were simultaneously added dropwise from two different syringes. The reaction was stirred at RT for 45 minutes, and a precipitate appeared. Water was added, and the solution was extracted with Et2O. The aqueous phase was acidified with 1N HCl and the desired product was extracted again with Et2O. The combined organic phases were dried over Na2SO4, filtered and evaporated to obtain 2-(benzyloxycarbonylamino)-2-phenylacetic acid (855 mg; 91% yield).
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:10][C:11]1[S:12][C:13]([C:24]2[CH:29]=[CH:28][N:27]=[C:26]([NH2:30])[CH:25]=2)=[C:14]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)[N:15]=1.[C:31](=[O:34])([O-])O.[Na+]>CN(C)C1C=CN=CC=1.CN(C)C(=O)C>[C:1]([NH:10][C:11]1[S:12][C:13]([C:24]2[CH:29]=[CH:28][N:27]=[C:26]([NH:30][C:31](=[O:34])[C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH:25]=2)=[C:14]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)[N:15]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(-c2nc(N)sc2-c2ccnc(N)c2)cc1
Reactant: O=C([O-])O
Reactant: O=C(Cl)c1ccccc1
Agent: CN(C)c1ccncc1
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: COc1ccc(-c2nc(NC(=O)c3ccccc3)sc2-c2ccnc(NC(=O)c3ccccc3)c2)cc1
Temperature: 70 °C
Reaction time: 19 h
Yield: 37 %

Procedure:
Benzoyl chloride (0.59 g, 4.2 mmol) and 4-dimethylaminopyridine (0.05 g, 0.4 mmol) were added to a solution of 4-[2-amino-4-(4-methoxyphenyl)-1,3-thiazol-5-yl]-2-pyridylamine (0.42 g, 1.4 mmol) in N,N-dimethylacetamide (10 mL) and the mixture was stirred at 70° C. for 19 hours. After the reaction mixture was cooled to room temperature, a saturated aqueous solution of sodium hydrogencarbonate (50 mL) was added. The resulting crude crystals were collected by filtration and washed with water. The crude crystals were recrystallized from ethanol to obtain 0.26 g (0.51 mmol, yield 37%) of the title compound.
Reaction SMILES: Cl.[Br:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[CH:5][CH:4]=1.[C:15]([O:19][C:20](=[O:30])[CH:21]([CH2:25][S:26](Cl)(=[O:28])=[O:27])[CH:22]([CH3:24])[CH3:23])([CH3:18])([CH3:17])[CH3:16].C(N(CC)CC)C>ClCCl>[C:15]([O:19][C:20](=[O:30])[CH:21]([CH2:25][S:26]([N:12]1[CH2:13][CH2:14][N:9]([C:6]2[CH:5]=[CH:4][C:3]([Br:2])=[CH:8][CH:7]=2)[CH2:10][CH2:11]1)(=[O:27])=[O:28])[CH:22]([CH3:24])[CH3:23])([CH3:17])([CH3:18])[CH3:16]
Reactant: Brc1ccc(N2CCNCC2)cc1
Reactant: CC(C)C(CS(=O)(=O)Cl)C(=O)OC(C)(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)C(CS(=O)(=O)N1CCN(c2ccc(Br)cc2)CC1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 78.3 %

Procedure:
A stirred suspension of 4-bromophenylpiperazine hydrochloride (2.84 g) and 2-chlorosulfonylmethyl-3-methyl-butyric acid tert-butyl ester (2.77 g) [preparation described in WO-A-98/05635] in dichloromethane (50 ml), cooled in an ice-bath, was treated with triethylamine (2 99 ml). The reaction was then stirred at room temperature for 2 h. The reaction mixture was then evaporated in vacuo, and the residue was dissolved in ethyl acetate (75 ml) and washed with 1% aqueous citric acid (2×50 ml), water (50 ml), saturated sodium bicarbonate (50 ml), saturated brine (50 ml), dried (MgSO4) and concentrated in vacuo to provide the title compound as a pale yellow gum (3.81 g, 79%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]#[N:10])[CH:5]=[C:6]([CH:8]=1)[NH2:7].[Cl:11][C:12]1[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[CH:14][C:13]=1[N:22]=[C:23]=[O:24]>O1CCCC1>[Cl:11][C:12]1[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[CH:14][C:13]=1[NH:22][C:23]([NH:7][C:6]1[CH:8]=[C:2]([F:1])[CH:3]=[C:4]([C:9]#[N:10])[CH:5]=1)=[O:24]
Reactant: O=C=Nc1ccc(C(F)(F)F)cc1Cl
Reactant: N#Cc1cc(N)cc(F)c1
Solvent: C1CCOC1
Product: N#Cc1cc(F)cc(NC(=O)Nc2ccc(C(F)(F)F)cc2Cl)c1
Yield: 84.4 %

Procedure:
A solution of 15 g (110.2 mmol) of 5-fluoro-3-cyanoaniline in 150 ml of tetrahydrofuran is stirred at ambient temperature under an argon atmosphere. Next, 17.5 ml (121.22 mmol) of 2-chloro-4-trifluoromethylphenylisocyanate are added. The reaction medium is heated at reflux for 3 hours then concentrated to dryness using a rotary evaporator. The solid residue obtained is recrystallized at high temperature in 60 ml of ethyl acetate in order to give 33.25 g of 1-(2-chloro-4-trifluoromethylphenyl)-3-(3-cyano-5-fluorophenyl)urea in the form of a white solid.
Reaction SMILES: [N:1]1([C:6]2([C:10]#N)COC2)[CH2:5][CH2:4][CH2:3]C1.[C:12]1(=O)[CH2:15][CH2:14][CH2:13]1.[NH:17]1CCCC[CH2:18]1>>[N:1]1([C:12]2([C:18]#[N:17])[CH2:15][CH2:14][CH2:13]2)[CH2:5][CH2:4][CH2:3][CH2:10][CH2:6]1
Reactant: O=C1CCC1
Reactant: C1CCNCC1
Reactant: N#CC1(N2CCCC2)COC1
Product: N#CC1(N2CCCCC2)CCC1

Procedure:
The title compound, light yellow liquid, MS: m/e=165.2 [(M+H)+], was prepared in accordance with the general method of intermediate A from cyclobutanone and piperidine.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH:11]=O)=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[CH2:13]([O:15][C:16](=[O:25])[CH:17]([NH:21][C:22](=[O:24])[CH3:23])C(O)=O)[CH3:14].C(OC(=O)C)(=O)C>N1C=CC=CC=1>[CH2:13]([O:15][C:16](=[O:25])[C:17]([NH:21][C:22](=[O:24])[CH3:23])=[CH:11][C:6]1[C:5]2[C:9](=[CH:10][C:2]([CH3:1])=[CH:3][CH:4]=2)[NH:8][CH:7]=1)[CH3:14]
Reactant: CCOC(=O)C(NC(C)=O)C(=O)O
Reactant: Cc1ccc2c(C=O)c[nH]c2c1
Solvent: c1ccncc1
Solvent: CC(=O)OC(C)=O
Product: CCOC(=O)C(=Cc1c[nH]c2cc(C)ccc12)NC(C)=O
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 88.4 %

Procedure:
A 3-l. three-necked flask, equipped with a mechanical stirrer, a thermometer and a dropping funnel with pressure-equalizing arm was charged with 100 g (0.63 mol) of 6-methylindole-3-carboxaldehyde, 119 g (0.63 mol) of acetamidomalonic acid monoethylester and 500 ml of pyridine. The mixture was stirred and kept at 15° with a cold water bath while 175 ml of acetic anhydride was added over 15 minutes. The yellow solution was stirred at room temperature for 3 hours. Then an additional portion of 36 g (0.19 mol) of acetamidomalonic acid monoethyl ester was added and stirring at room temperature was continued for 22 hours before 1 kg of ice was added. The temperature fell to -10° and the product began to precipitate. The suspension was stirred at room temperature for 5 hours and poured into 2 l of water. After 20 minutes, the precipitate was collected by suction filtration, washed with water and dried at 50° in an air oven overnight to afford 159.5 g (89%) of crude product as yellow crystals, m.p. 159°-162° (sinters at 75°).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](/[C:8](/I)=[CH:9]/[CH2:10][O:11][C:12]2[CH:23]=[CH:22][C:15]([O:16][CH2:17][C:18]([O:20][CH3:21])=[O:19])=[C:14]([CH3:24])[CH:13]=2)=[CH:4][CH:3]=1.[S:26]1[C:30]([Sn](CCCC)(CCCC)CCCC)=[CH:29][C:28]2[CH:44]=[CH:45][CH:46]=[CH:47][C:27]1=2.C(P(C(C)(C)C)C(C)(C)C)(C)(C)C.C1CCCCC1>CN(C)C=O>[S:26]1[C:30](/[C:8](/[C:5]2[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=2)=[CH:9]\[CH2:10][O:11][C:12]2[CH:23]=[CH:22][C:15]([O:16][CH2:17][C:18]([O:20][CH3:21])=[O:19])=[C:14]([CH3:24])[CH:13]=2)=[CH:29][C:28]2[CH:44]=[CH:45][CH:46]=[CH:47][C:27]1=2
Reactant: CCCC[Sn](CCCC)(CCCC)c1cc2ccccc2s1
Reactant: COC(=O)COc1ccc(OC/C=C(\I)c2ccc(Br)cc2)cc1C
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Solvent: C1CCCCC1
Solvent: CN(C)C=O
Product: COC(=O)COc1ccc(OC/C=C(/c2ccc(Br)cc2)c2cc3ccccc3s2)cc1C
Temperature: 50 °C
Reaction time: 2 h

Procedure:
Methyl (Z)-[4-[3-(4-bromophenyl)-3-iodoallyloxy]-2-methylphenoxy]acetate (760 mg, 1.47 mmol) and (benzo[b]thiophen-2-yl)-tributyltin (0.72 g, 1.7 mmol) were dissolved in anhydrous N,N-dimethylformamide (20 mL) and the solution was degassed. 0.15 M solution of tri-t-butylphosphine in cyclohexane (1.2 mL, 0.18 mmol) and tris(dibenzylidenacetone)dipalladium chloroform complex (46 mg, 0.044 mmol) were added; the reaction solution was degassed again and then stirred under inert atmosphere at 50° C. for 2 h. The reaction mixture was diluted with ethyl acetate (50 mL) and extracted with 10% aqueous solution of potassium fluoride (50 mL), water (2×50 mL) and brine (2×30 mL). The organic layer was dried with anhydrous magnesium sulfate and evaporated in vacuo. The residue was purified by column chromatography (silica gel Fluka 60, hexanes/ethyl acetate 95:5-90:10) yielding methyl (Z)-[4-[3-(benzo[b]thiophen-2-yl)-3-(4-bromophenyl)allyloxy]-2-methylphenoxy]acetate.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[N:3]=1.[CH3:18][C:19]1[CH:20]=[C:21]([CH:23]=[C:24]([CH3:26])[CH:25]=1)[NH2:22]>>[CH3:18][C:19]1[CH:20]=[C:21]([CH:23]=[C:24]([CH3:26])[CH:25]=1)[NH:22][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[N:3]=1
Reactant: FC(F)(F)c1cc(Cl)nc(-c2cccnc2)n1
Reactant: Cc1cc(C)cc(N)c1
Product: Cc1cc(C)cc(Nc2cc(C(F)(F)F)nc(-c3cccnc3)n2)c1

Procedure:
The title compound was prepared from a mixture of 4-chloro-2-(3-pyridinyl)-6-(trifluoromethyl)pyrimidine (50 mg, 0.193 mmol) and 3,5-dimethylaniline (36 μl, 0.290 mmol) similar to Example 117 and isolated as a yellow solid (26 mg, 39%). 1H NMR (CDCl3): 9.66-9.64 (m, 1H), 8.73 (s, 1H), 8.72-8.69 (m, 1H), 7.44-7.40 (m, 1H), 7.30 (s, 1H), 7.04 (s, 2H), 6.93 (s, 1H), 6.90 (s, 1H), 2.38 (s, 3H), 2.37 (s, 3H).
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH2:5][CH2:4][C@H:3]1[C:7]([NH:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([N+:16]([O-])=O)[CH:11]=1)=[O:8]>CO.[Pd]>[NH2:16][C:12]1[CH:11]=[C:10]([NH:9][C:7]([C@@H:3]2[CH2:4][CH2:5][CH2:6][N:2]2[CH3:1])=[O:8])[CH:15]=[CH:14][CH:13]=1
Reactant: CN1CCC[C@H]1C(=O)Nc1cccc([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CO
Product: CN1CCC[C@H]1C(=O)Nc1cccc(N)c1
Reaction time: 3 h

Procedure:
To a solution of (S)-1-methyl-N-(3-nitrophenyl)pyrrolidine-2-carboxamide (crude from step 1) in MeOH (5 ml) was added Pd/C (50 mg), charged with H2 (1 atm), after stirring for 3 h, Pd/C was filtered off and the filtrate was concentrated to give (S)—N-(3-aminophenyl)-1-methylpyrrolidine-2-carboxamide (350 mg).
Reaction SMILES: [C:1]([N:9]([CH2:24][CH2:25][CH:26]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH2:10][CH2:11][NH:12][C:13]([C:15]1[C:16]2[CH2:17][CH2:18][NH:19][C:20]=2[CH:21]=[CH:22][CH:23]=1)=[O:14])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N=P1(N(CC)CC)N(C)CCCN1C)(C)(C)C.Br[CH2:58][C:59]([O:61][CH2:62][CH3:63])=[O:60]>CN(C=O)C.CCOC(C)=O>[C:1]([N:9]([CH2:24][CH2:25][CH:26]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1)[CH2:10][CH2:11][NH:12][C:13]([C:15]1[CH:23]=[CH:22][CH:21]=[C:20]2[C:16]=1[CH2:17][CH2:18][N:19]2[CH2:58][C:59]([O:61][CH2:62][CH3:63])=[O:60])=[O:14])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)CBr
Reactant: O=C(NCCN(CCC(c1ccccc1)c1ccccc1)C(=O)c1ccccc1)c1cccc2c1CCN2
Agent: CCN(CC)P1(=NC(C)(C)C)N(C)CCCN1C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)CN1CCc2c(C(=O)NCCN(CCC(c3ccccc3)c3ccccc3)C(=O)c3ccccc3)cccc21
Temperature: 25 °C
Reaction time: 40 h

Procedure:
To a solution of N-{2-[benzoyl(3,3-diphenylpropyl)amino]ethyl}-4-indolinecarboxamide (77.0 mg) and 2-(tert-butylimino)-2-diethylamino-1,3-dimethylperhydro-1,3,2-diazaphosphorine (106 μL) in DMF (2.3 mL) was added ethyl bromoacetate (39 μL) and the mixture was stirred at ambient temperature for 40 hours. The resulting mixture was diluted with EtOAc (20 mL), washed successively with 1M HCl aqueous solution, saturated NaHCO3 aqueous solution and brine, dried over anhydrous MgSO4, filtered and evaporated in vacuo. The residue was purified by silica gel column chromatography (chloroform: MeOH=99:1) to afford ethyl {4-[({2-[benzoyl(3,3-diphenylpropyl)amino]ethyl}amino)-carbonyl]-2,3-dihydro-1H-indol-1-yl}acetate (87 mg) as an yellow syrup.
Reaction SMILES: [C:1]([CH2:3][C:4]([OH:6])=O)#[N:2].[C:7]([CH2:9][C:10]1([N:14]2[CH:18]=[C:17]([C:19]3[CH:24]=[N:23][N:22]4[C:25]([C:28]5[CH:29]=[C:30]([NH:34][C:35]([NH:37][CH2:38][C:39]([F:42])([F:41])[F:40])=[O:36])[CH:31]=[CH:32][CH:33]=5)=[CH:26][N:27]=[C:21]4[CH:20]=3)[CH:16]=[N:15]2)[CH2:13][NH:12][CH2:11]1)#[N:8].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)CC)C>CN(C)C=O>[C:1]([CH2:3][C:4]([N:12]1[CH2:13][C:10]([N:14]2[CH:18]=[C:17]([C:19]3[CH:24]=[N:23][N:22]4[C:25]([C:28]5[CH:29]=[C:30]([NH:34][C:35]([NH:37][CH2:38][C:39]([F:42])([F:41])[F:40])=[O:36])[CH:31]=[CH:32][CH:33]=5)=[CH:26][N:27]=[C:21]4[CH:20]=3)[CH:16]=[N:15]2)([CH2:9][C:7]#[N:8])[CH2:11]1)=[O:6])#[N:2]
Reactant: N#CCC1(n2cc(-c3cnn4c(-c5cccc(NC(=O)NCC(F)(F)F)c5)cnc4c3)cn2)CNC1
Reactant: N#CCC(=O)O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: N#CCC(=O)N1CC(CC#N)(n2cc(-c3cnn4c(-c5cccc(NC(=O)NCC(F)(F)F)c5)cnc4c3)cn2)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Cyanoacetic acid (3.1 mg, 0.036 mmol) was added to a mixture of N-[3-(7-{1-[3-(cyanomethyl)azetidin-3-yl]-1H-pyrazol-4-yl}imidazo[1,2-b]pyridazin-3-yl)phenyl]-N′-(2,2,2-trifluoroethyl)urea (11.9 mg, 0.0241 mmol) and benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (16 mg, 0.036 mmol) in N,N-dimethylformamide (0.6 mL), followed by triethylamine (10. μL, 0.072 mmol). The reaction mixture was stirred at r.t. for 1 h. The mixture was purified by RP-HPLC (pH=10) to afford the desired product. LCMS (M+H)+: m/z=563.2.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[F:11])[C:5]([OH:7])=O.[CH2:12]([O:14][C:15](=[O:24])[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([NH2:23])[CH:18]=1)[CH3:13]>>[CH2:12]([O:14][C:15](=[O:24])[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([NH:23][C:5](=[O:7])[C:4]2[CH:8]=[CH:9][C:10]([F:11])=[C:2]([Br:1])[CH:3]=2)[CH:18]=1)[CH3:13]
Reactant: O=C(O)c1ccc(F)c(Br)c1
Reactant: CCOC(=O)Cc1cccc(N)c1
Product: CCOC(=O)Cc1cccc(NC(=O)c2ccc(F)c(Br)c2)c1

Procedure:
3-Bromo-4-fluorobenzoic acid (123 mg, 0.56 mmol) was coupled with ethyl ester (6) (100 mg, 0.56 mmol) following Method C to give the title compound.
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][N:38]1[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]1.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:41]5[CH2:42][CH2:43][N:38]([CH3:37])[CH2:39][CH2:40]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: CN1CCNCC1
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(C)CC1
Temperature: 60 °C
Yield: 8.3 %

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 N-methyl piperazine (0.141 mL, 1.278 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 24 h. Formation of the product was determined by LCMS. The crude reaction mixture was purified by preparative HPLC (using 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-methylpiperazin-1-yl)ethoxy)quinazolin-4-ylthio)phenyl)urea (21 mg, 8.3%) 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), 7.60-7.25 (m, 5H), 6.45 (s, 1H), 4.35 (m, 2H), 4.00 (m, 3H), 2.80-2.25 (m, 10H), 2.15 (s, 3H), 1.25 (s, 9H); LC-MS (ESI) m/z 592 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:27])[NH:5][CH:6]1[CH2:15][CH2:14][C:13]2[C:8](=[CH:9][C:10]([CH2:16][CH2:17]O)=[CH:11][CH:12]=2)[CH:7]1[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[CH:21]=1)[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:48]>C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:27])[NH:5][CH:6]1[CH2:15][CH2:14][C:13]2[C:8](=[CH:9][C:10]([CH2:16][CH2:17][Br:48])=[CH:11][CH:12]=2)[CH:7]1[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[CH:21]=1)[CH3:2]
Reactant: BrC(Br)(Br)Br
Reactant: CCOC(=O)NC1CCc2ccc(CCO)cc2C1Cc1cccc(Cl)c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCOC(=O)NC1CCc2ccc(CCBr)cc2C1Cc1cccc(Cl)c1
Reaction time: 1 h
Yield: 43 %

Procedure:
To a solution of [1-(3-chloro-benzyl)-7-(2-hydroxy-ethyl)-1,2,3,4-tetrahydro-naphthalen-2-yl]-carbamic acid ethyl ester (554 mg, 1.428 mmol) in 15 ml dry CH2Cl2 cooled to 0° C. was added triphenylphosphine (562 mg, 2.142 mmol) and carbon tetrabromide (0.208 ml, 2.142 mmol). The mixture was stirred for 1 h, after which solvents were evaporated. The residue was purified by chromatography to obtain 277 mg of product as a white solid.
Reaction SMILES: [NH2:1][C:2]1[N:3]=C(SC)[S:5][C:6]=1[C:7]#[N:8].ClC1C=CC=C(C(OO)=[O:19])C=1.[CH3:22][S:23]([CH3:25])=[O:24].C(=O)(O)[O-].[Na+]>ClCCl>[NH2:1][C:2]1[N:3]=[C:22]([S:23]([CH3:25])(=[O:19])=[O:24])[S:5][C:6]=1[C:7]#[N:8]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSc1nc(N)c(C#N)s1
Reactant: CS(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CS(=O)(=O)c1nc(N)c(C#N)s1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
2.7 g (15.77 mmol) of 4-amino-2-(methylthio)-1,3-thiazole-5-carbonitrile were dissolved in 200 ml of dichloromethane, and 11.97 g (34.7 mmol) of 3-chloroperbenzoic acid were added. The mixture was stirred at RT for 30 min, 6 ml of DMSO and then saturated aqueous sodium bicarbonate solution were then added and the mixture was extracted three times with dichloromethane. The organic phase was dried over magnesium sulfate giving, after removal of the solvent, 2.22 g (46% of theory) of the product as an oil which was used without further purifications.