Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl-].[Li+].[C:3]([Li])([CH3:6])([CH3:5])[CH3:4].FC(F)(F)S(O[C:14]1[C:15]2[CH:16]=[C:17]([C:26]#[C:27][C:28]3[CH:38]=[CH:37][C:31]([C:32]([O:34][CH2:35][CH3:36])=[O:33])=[CH:30][CH:29]=3)[CH:18]=[CH:19][C:20]=2[C:21]([CH3:25])([CH3:24])[CH2:22][CH:23]=1)(=O)=O>C1COCC1>[CH3:4][C:3]1([CH3:6])[C:14]2[CH:23]=[CH:18][C:17]([C:26]#[C:27][C:28]3[CH:38]=[CH:37][C:31]([C:32]([O:34][CH2:35][CH3:36])=[O:33])=[CH:30][CH:29]=3)=[CH:16][C:15]=2[C:20]([C:21]([CH3:22])([CH3:24])[CH3:25])=[CH:19][CH2:5]1
Reactant: [Li]C(C)(C)C
Reactant: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(OS(=O)(=O)C(F)(F)F)=CCC3(C)C)cc1
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(C(C)(C)C)=CCC3(C)C)cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A mixture of 35.1 mg (0.39 mmol) of cuprous cyanide and 16.6 mg (0.39 mmol) of lithium chloride was flame dried under vacuum, cooled to room temperature and dissolved in 1.5 ml of THF. This solution was cooled to -78° C. and 50.2 mg (0.46 mL, 0.784 mmol) of tert-butyllithium (1.7M solution in pentane) was added forming a clear yellow solution. The reaction mixture was stirred at -78° C. for 15 minutes and then 125.0 mg (0.26 mmol) of ethyl 4-[(5-trifluoromethylsulfonyloxy-7,8-dihydro-8,8-dimethylnaphth-3-yl)ethynyl]benzoate (Compound 66) was added as a solution in 0.5 ml of THF. After 10 minutes the reaction was quenched at -78° C. with 1.5 ml of a 2:1 (v/v) mixture of sat. aqueous NH4Cl and 5% NaOH. The mixture was extracted with EtOAc and the combined organic layers were washed with water and brine. The organic phase was dried over MgSO4, concentrated in vacuo and purified by column chromatography (silica, 5% EtOAc-hexanes) to give a clear yellow oil (7:5 ratio of title compounds). The two compounds were separated by HPLC (partisil 10, 2% EtOAc-hexanes) to give the title compounds as colorless oils.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[N:13]3[C:14]([CH2:17][N:18]4C(=O)C5=CC=CC=C5C4=O)=[CH:15][N:16]=[C:12]3[CH2:11][N:10]=[C:9]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C:8]=2[CH:35]=1)([O-:3])=[O:2].O.NN>C(O)C>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[N:13]3[C:14]([CH2:17][NH2:18])=[CH:15][N:16]=[C:12]3[CH2:11][N:10]=[C:9]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C:8]=2[CH:35]=1)([O-:3])=[O:2]
Reactant: O=C1c2ccccc2C(=O)N1Cc1cnc2n1-c1ccc([N+](=O)[O-])cc1C(c1ccccc1)=NC2
Agent: NN
Solvent: CCO
Solvent: O
Product: NCc1cnc2n1-c1ccc([N+](=O)[O-])cc1C(c1ccccc1)=NC2

Procedure:
In the manner given in Example 28, 8-nitro-1-(phthalimidomethyl)-6-phenyl-4H-imidazo[1,2-a][1,4]-benzodiazepine is reacted at room temperature with hydrazine hydrate, dissolved in ethanol to give 8-nitro-1-(aminomethyl)-6-phenyl-4H-imidazo[1,2-a][1,4]benzodiazepine.
Reaction SMILES: [NH2:1][C:2]1[C:7]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.C[Si](C)(C)[N-][Si](C)(C)C.[Li+].[CH2:26](I)[CH2:27][CH2:28][CH3:29]>O1CCCC1>[CH2:9]([O:8][C:7]1[C:2]([NH:1][CH2:26][CH2:27][CH2:28][CH3:29])=[N:3][CH:4]=[CH:5][CH:6]=1)[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: Nc1ncccc1OCc1ccccc1
Reactant: CCCCI
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCCCNc1ncccc1OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To 2-amino-3-benzyloxypyridine (2.50 g, 12.5 mmol) dissolved in tetrahydrofuran (10 mL) and cooled to 0° C. was slowly added a solution of 1N lithium hexamethyldisilazide in tetrahydrofuran (12.5 mL, 12.5 mmol). The ice bath was removed and the solution stirred for 30 minutes. The bath was replaced and n-butyl iodide (2.30 g, 1.4 mL, 12.5 mmol) was added to the solution. After the addition was complete, the bath was removed and the solution stirred at ambient temperature overnight. The reaction mixture was evaporated in vacuo and the residue dissolved in ethyl acetate (25 mL). The solution was washed with water (25 mL) and brine (25 mL), dried and concentrated in vacuo. Purification by flash chromatography on silica gel eluting with 10% ethyl acetate in hexane afforded the desired product as an offwhite solid (2.75 g, 86% yield). 1H NMR (CDCl3, 300 MHz) δ 0.95 (t, J=7 Hz, 3 H), 1.42 (sextet, J=7 Hz, 2H), 1.60 (m, 2H), 3.44 (dt, J=7 Hz, 1 Hz, 2H), 4.92 (bt, 1H), 5.06 (s, 2H), 6.45 (dd, J=8 Hz, 6 Hz 1H), 6.86 (dd, J=8 Hz, 1 Hz, 1H), 7.37 (m, 5H), 7.73 (dd, J=6 Hz, 1 Hz, 1H). MS (DCl/NH3) m/e 257 (M+H)+.
Reaction SMILES: Cl.Cl.[Br:3][C:4]1[CH:9]=[C:8]([NH:10][CH3:11])[C:7]([NH2:12])=[CH:6][CH:5]=1.[S:13](N)(N)(=[O:15])=[O:14]>N1C=CC=CC=1.C(Cl)Cl>[Br:3][C:4]1[CH:5]=[CH:6][C:7]2[NH:12][S:13](=[O:15])(=[O:14])[N:10]([CH3:11])[C:8]=2[CH:9]=1
Reactant: NS(N)(=O)=O
Reactant: CNc1cc(Br)ccc1N
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CN1c2cc(Br)ccc2NS1(=O)=O

Procedure:
A mixture of 5-bromo-N1-methylbenzene-1,2-diamine dihydrochloride (800.0 mg, 3.00 mmol) and sulfamide (560 mg, 5.80 mmol) in pyridine (10 mL) was heated at reflux for 2 h. Pyridine was removed under reduced pressure and the residue obtained was dissolved in DCM (20 mL) and washed with 1N HCl (20 mL). The DCM layer was separated, dried over Na2SO4, filtered, and concentrated to obtain 6-bromo-1-methyl-1,3-dihydrobenzo[c][1,2,5]thiadiazole 2,2-dioxide. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 7.98 (d, J=2.0 Hz, 1H), 7.93 (dd, J=8.8, 2.3 Hz, 1H), 7.46 (d, 1H), 3.41 (s, 3H).
Reaction SMILES: Cl[CH:2]1[NH:7][C:6]([NH2:8])=[N:5][CH:4]=[C:3]1[N+:9]([O-:11])=[O:10].[H-].[Na+].[NH:14]1[C:22]2[C:17](=[CH:18][CH:19]=[C:20]([C:23]#[N:24])[CH:21]=2)[CH:16]=[N:15]1>CN(C=O)C>[NH2:8][C:6]1[NH:7][CH:2]([N:14]2[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([C:23]#[N:24])[CH:21]=3)[CH:16]=[N:15]2)[C:3]([N+:9]([O-:11])=[O:10])=[CH:4][N:5]=1
Reactant: N#Cc1ccc2cn[nH]c2c1
Reactant: NC1=NC=C([N+](=O)[O-])C(Cl)N1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#Cc1ccc2cnn(C3NC(N)=NC=C3[N+](=O)[O-])c2c1
Reaction time: 18 h

Procedure:
To a solution of 6-chloro-5-nitro-1,6-dihydropyrimidin-2-amine (538.5 mg, 60% purity, 2.00 mmol) in DMF (10 mL) was added NaH (60% oil suspension, 172 mg, 4.30 mmol) at 0° C. Mixture was stirred at RT for 10 min before addition of 1H-indazole-6-carbonitrile (410 mg, 2.87 mmol). Stirring was continued at RT for 18 hr. The reaction mixture was quenched with water (25 mL) cooled in an ice bath and extracted with EtOAc (3×20 mL). Insoluble solid formed during extraction was separated out. Combined EtOAc extract was washed with water (20 mL), dried over Na2SO4, filtered and concentrated in vacuo. A portion (70 mg) of the crude product was purified by reverse phase preparative HPLC to give the title compound: 1H NMR (250 MHz, DMSO) δ 7.79 (1 H, dd, J=8.22, 1.07 Hz), 8.14 (1H, d, J=8.22 Hz), 8.20 (1H, br. s.), 8.33 (1H, br. s.), 8.65 (1H, s), 8.91 (1H, s), 9.03 (1H, s); LC-MS: m/z=+281.95 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:10]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([Si:18]([CH3:21])([CH3:20])[CH3:19])=[CH:14][C:13]=2[F:22])=[N:9][C:8](Cl)=[CH:7][N:6]=1)=[O:4].C(OCC)(=O)C.CO.[CH3:32][N:33](C)C=O>[C-]#N.[Zn+2].[C-]#N.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>[CH3:1][O:2][C:3]([C:5]1[C:10]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([Si:18]([CH3:21])([CH3:20])[CH3:19])=[CH:14][C:13]=2[F:22])=[N:9][C:8]([C:32]#[N:33])=[CH:7][N:6]=1)=[O:4]
Reactant: COC(=O)c1ncc(Cl)nc1Nc1ccc([Si](C)(C)C)cc1F
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: CO
Solvent: CCOC(C)=O
Product: COC(=O)c1ncc(C#N)nc1Nc1ccc([Si](C)(C)C)cc1F
Yield: 99.8 %

Procedure:
A degassed suspension of 5-chloro-3-(2-fluoro-4-trimethylsilanyl-phenylamino)-pyrazine-2-carboxylic acid methyl ester (1.35 g, 3.82 mmol), zinc (II) cyanide (492.8 mg, 4.2 mmol, 1.1 eq.), and Pd(PPh3)4 (551.0 mg, 0.48 mmol, 0.12 eq.) in anhydrous dimethylformamide (30 mL) was subjected to microwave irradiation at 150° C. for 18 minutes. The reaction mixture was poured into ethyl acetate and then filtered through a pad of Celite®. The pad was rinsed well with ethyl acetate (2×). The combined filtrates were washed with 50% brine (2×) and brine (1×), dried (Na2SO4), filtered and concentrated in vacuo. The crude residue was purified by column chromotagraphy (Si-PPC, gradient 0 to 30% ethyl acetate in hexane) to give a brown oil. Trituration with MeOH afforded the desired compound as an orange solid (1.31 g, 99.8%). 1H NMR (CDCl3, 400 MHz) δ ppm 10.56 (s, 1H), 8.36 (s, 1H), 8.29 (t, J=7.82 Hz, 1H), 7.37-7.27 (m, 2H), 4.10 (s, 3H), 0.29 (s, 9H); LCMS (method D1): RT=1.28 min, [M+H]+=345.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([CH2:14][N:15]([CH3:27])[C:16](=[O:26])[CH2:17][NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[CH:9]=2)=[CH:4][CH:3]=1.N1C=CC=CC=1.[CH3:34][N:35]([CH3:39])[C:36](Cl)=[O:37]>C(Cl)Cl>[CH3:34][N:35]([CH3:39])[C:36]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([CH2:14][N:15]([CH3:27])[C:16](=[O:26])[CH2:17][NH:18][C:19](=[O:25])[O:20][C:21]([CH3:23])([CH3:24])[CH3:22])[CH:9]=2)=[CH:4][CH:3]=1)=[O:37]
Reactant: CN(Cc1cccc(-c2ccc(N)cc2)c1)C(=O)CNC(=O)OC(C)(C)C
Reactant: CN(C)C(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CN(C)C(=O)Nc1ccc(-c2cccc(CN(C)C(=O)CNC(=O)OC(C)(C)C)c2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.3 %

Procedure:
tert-Butyl (2-{[(4′-aminobiphenyl-3-yl)methyl](methyl)amino}-2-oxoethyl)carbamate (200 mg) and pyridine (64 mg) were dissolved in methylene chloride (6 ml), followed by ice-cooling. Dimethylcarbamoylchloride (64 mg) was added thereto, followed by warming to room temperature and stirring for 1 hour. The reaction mixture was subjected to liquid separation with CHCl3 and water. The organic layer was separated, and then the aqueous layer was extracted with CHCl3 again. These organic layers were combined and dried over sodium sulfate, and the solvent was evaporated. The obtained residue was purified by silica gel column chromatography (2% MeOH/CHCl3) to obtain tert-butyl {2-[({4′-[(dimethylcarbamoyl)amino]biphenyl-3-yl}methyl)(methyl)amino]-2-oxoethyl}carbamate (220 mg) as a colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([CH:13]=[CH:14][CH:15]=[O:16])[S:11][CH:12]=2)=[CH:4][CH:3]=1.[BH4-].[Na+].O>C(O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[C:10]([CH:13]=[CH:14][CH2:15][OH:16])[S:11][CH:12]=2)=[CH:6][CH:7]=1
Reactant: O=CC=Cc1nc(-c2ccc(F)cc2)cs1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: OCC=Cc1nc(-c2ccc(F)cc2)cs1

Procedure:
692 mg (2.97 mmol) of 3-(4-(4-fluorophenyl)thiazol-2-yl)propenal and 224.5 mg (5.93 mmol) of sodium borohydride were stirred in 50 ml of ethanol at room temperature for 3 h. Water was added, and the mixture was concentrated. The residue was taken up with water and ethyl acetate. The organic phase was separated and evaporated. The residue was purified by preparative HPLC (RP18, acetonitrile/water containing 0.1% TFA). Yield: 280 mg (40%).
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][C:5]#[C:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1.[F:13][C:14]1[CH:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[CH:16][CH:15]=1>>[F:13][C:14]1[CH:19]=[CH:18][C:17]([S:20]([N:2]([CH3:1])[CH2:3][CH2:4][C:5]#[C:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=2)(=[O:22])=[O:21])=[CH:16][CH:15]=1
Reactant: CNCCC#Cc1ccccn1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Product: CN(CCC#Cc1ccccn1)S(=O)(=O)c1ccc(F)cc1
Yield: 16.2 %

Procedure:
The title compound was prepared in accordance with the general method of Example 199(D), from N-methyl-4-(pyridin-2-yl)but-3-yn-1-amine (100 mg, 0.62 mmol) and 4-fluorobenzene-1-sulfonyl chloride (121 mg, 0.62 mmol). The crude residue was purified over silicagel chromatography prepacked 10 g silicagel column, DCM/MeOH: 98/2 as eluent) to afford 32 mg of 4-fluoro-N-methyl-N-(4-(pyridine-2-yl)but-3-ynyl)benzenesulfonamide as a yellow oil (Yield: 16%).
Reaction SMILES: [Br:1]Br.[CH2:3]([C:5]1[CH:9]=[C:8]([CH2:10][CH3:11])[N:7]([C:12]2[C:17]([CH3:18])=[CH:16][C:15]([CH3:19])=[CH:14][C:13]=2[CH3:20])[N:6]=1)[CH3:4]>C(O)(=O)C>[Br:1][C:9]1[C:5]([CH2:3][CH3:4])=[N:6][N:7]([C:12]2[C:17]([CH3:18])=[CH:16][C:15]([CH3:19])=[CH:14][C:13]=2[CH3:20])[C:8]=1[CH2:10][CH3:11]
Reactant: CCc1cc(CC)n(-c2c(C)cc(C)cc2C)n1
Reactant: BrBr
Solvent: CC(=O)O
Product: CCc1nn(-c2c(C)cc(C)cc2C)c(CC)c1Br
Reaction time: 1 h

Procedure:
A solution of 6.4 g (0.04 mol) of bromine in 20 mL of glacial acetic acid was added dropwise to a stirred solution of 9.00 g (37 mmol) of 3,5-diethyl-1-(2,4,6-trimethylphenyl)pyrazole in 100 mL of glacial acetic acid. After 1 hour at room temperature, the acetic acid was evaporated under reduced pressure and the residues were dissolved in ethyl acetate. This solution was washed with saturated sodium bicarbonate to remove residual acetic acid, dried with brine and magnesium sulfate, and was concentrated on the rotovap. The product was a tan solid (10.26 g, purification. 1H-NMR(CDCl3):0.92 (3H, t, J=7), 1.15 (3H, t, J=7), 1.86 (6H, s), 2.24 (3H, s), 2.32 (2H, q, J=7), 2.60 (2H, q, J=7), 6.82 (2H, s).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:4][CH:3]=1.Br[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30].C(=O)([O-])[O-].[K+].[K+].CN(C)P(N(C)C)(N(C)C)=O>O>[CH2:30]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:6][CH:7]=1)[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH3:15]
Reactant: CCOC(=O)Cc1ccc(N)cc1
Reactant: CCCCCCCCCCCCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: O
Product: CCCCCCCCCCCCCCCCNc1ccc(CC(=O)OCC)cc1

Procedure:
A solution of 8.2 g. of p-aminophenylacetic acid, 150 ml. of absolute ethanol, and 3 ml. of boron trifluoride etherate is heated to reflux for 15 hrs. The solution is concentrated to ca. 50 ml. by distillation of the solvent and then evaporated to dryness in vacuo. The residue is dissolved in ethyl ether, washed with aqueous sodium bicarbonate, dried and evaporated to yield ethyl p-aminophenylacetate. A mixture of 5.0 g. of this amine, 9.4 g. of 1-bromohexadecane, 4.2 g. of anhydrous potassium carbonate and 40 ml. of hexamethylphosphoramide is heated to 80° C. for 7 hours. The mixture is then cooled, diluted with water and extracted with ethyl ether. The ether extracts are washed with water, dried and evaporated. The residue is recrystallized from a mixture of chloroform and hexane, yielding ethyl (4-hexadecylaminophenyl)acetate.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[C:4]([O:14][CH2:15][C:16]([F:19])([F:18])[F:17])[CH:3]=1.Cl[CH2:21][CH2:22][CH2:23][N:24]1[C:29](=[O:30])[CH:28]=[CH:27][N:26]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[C:25]1=[O:39]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([CH2:21][CH2:22][CH2:23][N:24]3[C:29](=[O:30])[CH:28]=[CH:27][N:26]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:36])([CH3:38])[CH3:37])[C:25]3=[O:39])[CH2:10][CH2:9]2)=[C:4]([O:14][CH2:15][C:16]([F:18])([F:17])[F:19])[CH:3]=1
Reactant: C[Si](C)(C)CCOCn1ccc(=O)n(CCCCl)c1=O
Reactant: Fc1ccc(N2CCNCC2)c(OCC(F)(F)F)c1
Product: C[Si](C)(C)CCOCn1ccc(=O)n(CCCN2CCN(c3ccc(F)cc3OCC(F)(F)F)CC2)c1=O

Procedure:
substituting 1-[4-fluoro-2-(2,2,2-trifluoroethoxy)phenyl]piperazine and 3-(3-chloropropyl)-1-[2-(trimethylsilyl)ethoxymethyl]-2,4(1H,3H)-pyrimidinedione gave 3-(3-{4-[4-fluoro-2-(2,2,2-trifluoroethoxy)phenyl]piperazin-1-yl}propyl)-1-[2-(trimethylsilyl)ethoxymethyl]-2,4(1H,3H)-pyrimidinedione;
Reaction SMILES: [C:1]([C:4]1[C:12]2[N:11]=[C:10]([C:13]3[CH:18]=[CH:17][C:16]([CH:19]4[CH2:23][CH2:22][CH2:21][N:20]4C(OC(C)(C)C)=O)=[CH:15][C:14]=3[F:31])[NH:9][C:8]=2[CH:7]=[CH:6][CH:5]=1)(=[O:3])[NH2:2].C(O)(C(F)(F)F)=O>ClCCl>[F:31][C:14]1[CH:15]=[C:16]([CH:19]2[CH2:23][CH2:22][CH2:21][NH:20]2)[CH:17]=[CH:18][C:13]=1[C:10]1[NH:9][C:8]2[CH:7]=[CH:6][CH:5]=[C:4]([C:1]([NH2:2])=[O:3])[C:12]=2[N:11]=1
Reactant: CC(C)(C)OC(=O)N1CCCC1c1ccc(-c2nc3c(C(N)=O)cccc3[nH]2)c(F)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NC(=O)c1cccc2[nH]c(-c3ccc(C4CCCN4)cc3F)nc12
Reaction time: 1 h

Procedure:
A solution of EXAMPLE 50E (1.5 g) in dichloromethane (50 mL) was treated with TFA (10 mL), stirred for 1 hour and concentrated. The concentrate was purified by HPLC (Zorbax, C-18, 250×2.54 column, mobile phase A: 0.1% TFA in water; B: 0.1% TFA in CH3CN, 0-100% gradient). 1H NMR (CD3OD) δ 2.21-2.36 (m, 3H), 2.54-2.63 (m, 1H), 3.47-3.59 (m, 2H), 4.76 (dd, J=9.51, 7.06 Hz, 1H), 7.43 (t, J=7.83 Hz, 1H), 7.50-7.55 (m, 2H), 7.84 (d, J=7.36 Hz, 1H), 7.98 (d, J=7.67 Hz, 1H), 8.42 (t, J=8.13 Hz, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([I:11])[CH:10]=1)[C:5]([OH:7])=[O:6].Cl.CN(C)CCCN=C=NCC.[C:24](O)([CH3:27])([CH3:26])[CH3:25]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:24]([O:6][C:5](=[O:7])[C:4]1[CH:8]=[C:9]([I:11])[CH:10]=[C:2]([Br:1])[CH:3]=1)([CH3:27])([CH3:26])[CH3:25]
Reactant: CC(C)(C)O
Reactant: O=C(O)c1cc(Br)cc(I)c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)c1cc(Br)cc(I)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 86.3 %

Procedure:
To a solution of 3-bromo-5-iodo-benzoic acid (D7) (50 g, 153 mmol, 1 equiv) in CH2Cl2 (500 ml) was added 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride (30.8 g, 160 mmol, 1.05 equiv), DMAP (14 g, 114 mmol, 0.75 equiv) and tert-butanol (90 ml, 917 mmol, 6 equiv). The resulting mixture was stirred at room temperature for 48 h. DMAP (4.67 g, 38 mmol, 0.25 equiv) was then added and the solution was stirred for another 24 h then concentrated in vacuo. The residue was dissolved in AcOEt and washed sequentially with 2N aqueous HCl solution, 1N aqueous NaOH solution and brine, dried over MgSO4 and concentrated in vacuo to give 3-bromo-5-iodo-benzoic acid tert-butyl ester (D8b) (50.6 g, 86%) as a brown solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:16]([O:17][CH3:18])=[CH:15][CH:14]=[C:13]([C:19]2[CH:27]=[CH:26][CH:25]=[C:24]3[C:20]=2[CH2:21][CH2:22][C:23]3=[O:28])[C:4]=1[O:5][CH2:6][C:7]([CH3:12])([CH3:11])[C:8](O)=[O:9].COC1C(OC)=CC=C(C2C=CC=C3C=2CCC3=O)C=1OC[C:35](C)(C)[C:36]([NH:38]C)=O>>[CH3:1][O:2][C:3]1[C:16]([O:17][CH3:18])=[CH:15][CH:14]=[C:13]([C:19]2[CH:27]=[CH:26][CH:25]=[C:24]3[C:20]=2[CH2:21][CH2:22][C:23]3=[O:28])[C:4]=1[O:5][CH2:6][C:7]([CH3:12])([CH3:11])[C:8]([NH:38][CH2:36][CH3:35])=[O:9]
Reactant: COc1ccc(-c2cccc3c2CCC3=O)c(OCC(C)(C)C(=O)O)c1OC
Reactant: CNC(=O)C(C)(C)COc1c(-c2cccc3c2CCC3=O)ccc(OC)c1OC
Product: CCNC(=O)C(C)(C)COc1c(-c2cccc3c2CCC3=O)ccc(OC)c1OC

Procedure:
From 3-[2,3-Dimethoxy-6-(1-oxo-indan-4-yl)-phenoxy]-2,2-dimethyl-propionic acid (Compound 199) and 2-Methylamine solution following the procedure for the preparation of Compound 200. Purification by column chromatography (silica gel, 0-50% ethyl acetate in pet ether) afforded the title compound as a solid.
Reaction SMILES: [C:1]1([N:7]2[C:19](=[O:20])[C:10]3=[CH:11][NH:12][C:13]4[CH:14]=[CH:15][CH:16]=[CH:17][C:18]=4[C:9]3=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[F:22]C1C=CC=CC=1NN>>[F:22][C:6]1[CH:5]=[CH:4][CH:3]=[CH:2][C:1]=1[N:7]1[C:19](=[O:20])[C:10]2=[CH:11][NH:12][C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:18]=3[C:9]2=[N:8]1
Reactant: NNc1ccccc1F
Reactant: O=c1c2c[nH]c3ccccc3c-2nn1-c1ccccc1
Agent: Cl
Product: O=c1c2c[nH]c3ccccc3c-2nn1-c1ccccc1F

Procedure:
The title compound was prepared following the procedure described in Step 3 for the synthesis of 4a, using 2-fluorophenyl hydrazine hydrochloride instead of phenyl hydrazine hydrochloride. 1H NMR (DMSO-d6) δ (ppm): 7.13-7.46 (3H, m), 7.48-7.62 (2H, m), 7.67 (1H, dd, J=6.87, 1.37 Hz), 7.73 (1H, d, J=8.24 Hz), 8.11 (1H, dd, J=8.24, 1.09 Hz), 8.70 (1H, d, J=6.31 Hz). m/z 280.3 (MH+).
Reaction SMILES: [NH2:1][C:2]1[CH:28]=[CH:27][C:5]([O:6][C:7]2[C:16]3[C:11](=[CH:12][C:13]([O:19][CH2:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)=[C:14]([C:17]#[N:18])[CH:15]=3)[N:10]=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.[F:29][C:30]1[CH:35]=[CH:34][C:33]([N:36]=[C:37]=[O:38])=[CH:32][CH:31]=1>C1(C)C=CC=CC=1.C(#N)C>[CH2:20]([O:19][C:13]1[CH:12]=[C:11]2[C:16]([C:7]([O:6][C:5]3[CH:4]=[CH:3][C:2]([NH:1][C:37]([NH:36][C:33]4[CH:34]=[CH:35][C:30]([F:29])=[CH:31][CH:32]=4)=[O:38])=[CH:28][CH:27]=3)=[CH:8][CH:9]=[N:10]2)=[CH:15][C:14]=1[C:17]#[N:18])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: N#Cc1cc2c(Oc3ccc(N)cc3)ccnc2cc1OCc1ccccc1
Reactant: O=C=Nc1ccc(F)cc1
Solvent: Cc1ccccc1
Solvent: CC#N
Product: N#Cc1cc2c(Oc3ccc(NC(=O)Nc4ccc(F)cc4)cc3)ccnc2cc1OCc1ccccc1
Temperature: 120 °C
Yield: 91.5 %

Procedure:
4-(4-Aminophenoxy)-7-(benzyloxy)-6-cyanoquinoline (7.776 g, 21.2 mmol) was dissolved in a toluene (400 ml) and acetonitrile (200 ml) mixed solvent, and then 4-fluorophenyl isocyanate (3.68 ml, 31.7 mmol) was added and the mixture was heated to reflux at 120° C. for 1 hour. The reaction solution was concentrated under reduced pressure, the residue was suspended in tetrahydrofuran (150 ml), and then hexane (150 ml) was added, sonication was performed, and the precipitated crystals were filtered out and dried under reduced pressure to obtain N-(4-(7-(benzyloxy)-6-cyano-4-quinolyl)oxyphenyl)-N′-(4-fluorophenyl)urea (9.81 g, 19.4 mmol, 91.9%) as light brown crystals. These were dissolved in trifluoroacetic acid (100 ml) and thioanisole (9.13 ml, 77.7 mmol) under a nitrogen atmosphere, and the solution was stirred at 60° C. for 12 hours. The reaction solution was concentrated under reduced pressure, and after adding tetrahydrofuran (50 ml) and then 1N aqueous sodium hydroxide (150 ml) and water (150 ml) to the residue, the mixture was stirred and the precipitated crystals were filtered out and washed with water, diethyl ether and ethyl acetate and dried at 70° C. to obtain the title compound (3.646 g, 8.36 mmol, 43.0%) as yellow crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.[CH2:12]=[O:13].C1(C)C=CC=CC=1>CCOCC>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:12][OH:13])[C:6](=[O:11])[CH2:5]2
Reactant: O=C1Cc2cc(Cl)ccc2N1
Reactant: C=O
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: O=C1Cc2cc(Cl)ccc2N1CO
Temperature: 25 °C

Procedure:
In an high pressure autoclave, 5-chloro-1,3-dihydro-indol-2-one (5 g, 0.029 mol), paraformaldehyde (1.07 g) and toluene (60 ml) are heated up to 120° C. for 4 h. The mixture is cooled down to room temperature, diluted with ether and filtrated to give 5-chloro-1-hydroxymethyl-1,3-dihydro-indol-2-one a22 as white crystals (4.03 g, 70%). 1H NMR δH (250 MHz, C2D6SO): 3.61 (2H, s); 5.04 (2H, d); 6.26 (1H, t); 7.08 (1H, d); 7.29-7.34 (2H, m).
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([Cl:12])[C:3]=1[C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][CH:22]=1)[N:19]=[C:18]([NH:23][C@@H:24]1[CH2:28][O:27][CH2:26][C@@H:25]1[NH:29]C(=O)OC(C)(C)C)[N:17]=[CH:16]2.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:12][C:4]1[C:5]([O:10][CH3:11])=[CH:6][C:7]([O:8][CH3:9])=[C:2]([Cl:1])[C:3]=1[C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][CH:22]=1)[N:19]=[C:18]([NH:23][C@H:24]1[C@@H:25]([NH2:29])[CH2:26][O:27][CH2:28]1)[N:17]=[CH:16]2
Reactant: COc1cc(OC)c(Cl)c(-c2ccc3nc(N[C@@H]4COC[C@@H]4NC(=O)OC(C)(C)C)ncc3c2)c1Cl
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(OC)c(Cl)c(-c2ccc3nc(N[C@@H]4COC[C@@H]4N)ncc3c2)c1Cl

Procedure:
A solution of tert-butyl ((3R,4S)-4-((6-(2,6-dichloro-3,5-dimethoxyphenyl)quinazolin-2-yl)amino)tetrahydrofuran-3-yl)carbamate (1.097 g, 2.049 mmol) in DCM (15 mL, 0.137 M) and TFA (11.7 g, 102 mmol) was stirred about 40 minutes at room temperature. The excess solvents were removed under reduced pressure. The yellow oil was dissolved into DCM (˜60 mL) and washed with aqueous 1N NaOH (˜30 mL). The aqueous layer was then diluted with brine (˜15 mL) and extracted with fresh DCM (3×30 mL). The combined organic layers were dried over sodium sulfate, filtered, concentrated down, and dried to yield (3S,4R)—N3-(6-(2,6-dichloro-3,5-dimethoxyphenyl)quinazolin-2-yl)tetrahydrofuran-3,4-diamine as a very light yellow foam (0.879 g, 99%).