Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]1[C:11](=[O:15])[CH2:12][CH2:13][CH:14]=1)([OH:3])=[O:2].[Br:16]N1C(=O)CCC1=O.C(Cl)(Cl)(Cl)Cl>CO>[Br:16][CH:13]1[CH2:12][C:11](=[O:15])[C:10]([CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][C:1]([OH:3])=[O:2])=[CH:14]1
Reactant: O=C(O)CCCCCCC1=CCCC1=O
Reactant: O=C1CCC(=O)N1Br
Solvent: CO
Solvent: ClC(Cl)(Cl)Cl
Product: O=C(O)CCCCCCC1=CC(Br)CC1=O
Temperature: 5 °C

Procedure:
A stirred mixture of 35.9 g. (0.171 moles) of 2-(6-carboxyhexyl) cyclopent-2-en-1-one [Bagli et al., Tetrahedron Letters, No. 5, 465 (1966)], 35.0 g. (0.197 moles) of N-bromosuccinimide, and 600 ml. of carbon tetrachloride is refluxed for 35 minutes. The mixture is cooled to 5° C. and filtered. The filtrate is washed with cold water, dried over magnesium sulfate, and taken to dryness to give an oil, λmax.MeOH = 225 mμ (8850); νmax. = 1705 (carbonyl groups) and 1625. cm-1 (olefin group).
Reaction SMILES: [CH:1]1([CH2:7][N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][C:15]=3[O:17][CH3:18])[C:10]([C:19]([OH:21])=O)=[CH:9]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(Cl)(=O)C([Cl:25])=O>C1COCC1>[CH:1]1([CH2:7][N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][C:15]=3[O:17][CH3:18])[C:10]([C:19]([Cl:25])=[O:21])=[CH:9]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1cccc2c(C(=O)O)cn(CC3CCCCC3)c12
Reactant: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Product: COc1cccc2c(C(=O)Cl)cn(CC3CCCCC3)c12
Yield: 100.3 %

Procedure:
To a solution of 1-(cyclohexylmethyl)-7-methoxyindole-3-carboxylic acid (2.5 g, 8.8 mmol) in THF (30 ml) was added oxalyl chloride (4.5 g, 35.3 mmol), dropwise with stirring. The mixture was stirred at room temperature for 18 h. The volatile components were evaporated under reduced pressure to afford 1-(cyclohexylmethyl)-7-methoxyindole-3-carbonyl chloride (2.7 g) as a crystalline solid.
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.[C:6]1(=O)[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9][CH2:8][CH2:7]1.CN(C)[CH:19]=[O:20]>>[Cl:3][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9][CH2:8][C:7]=1[CH:19]=[O:20]
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=C1CCCc2ccccc21
Reactant: CN(C)C=O
Product: O=CC1=C(Cl)c2ccccc2CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To N,N-dimethylformamide (2.3 mL) at 0° C. was added phosphorus oxychloride (2.33 mL) dropwise and the solution stirred at ambient temperature for 30 minutes. To this solution was added 3,4-dihydronaphthalen-1(2H)-one (1.46 g) and the mixture heated to 45° C. for 1 hour. The mixture was quenched with ice and extracted with diethyl ether. The combined organic layers were washed with water, saturated sodium bicarbonate, and water, dried over magnesium sulfate, filtered, and concentrated to provide 1.9 g of the title compound as a yellow oil, which was used without further purification. 1H NMR (DMSO-d6) δ 10.28 (s, 1H), 7.81-7.84 (m, 1H), 7.33-7.50 (m, 3H), 2.82-2.87 (m, 2H), 2.54-2.57 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])[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]([F:27])([F:26])[F:25])=[CH:21][CH:22]=4)[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1.[NH+:30]1([CH2:36][B-](F)(F)F)[CH2:35][CH2:34][S:33][CH2:32][CH2:31]1>>[CH3:1][O:2][C:3](=[O:29])[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]([CH2:36][N:30]5[CH2:35][CH2:34][S:33][CH2:32][CH2:31]5)[C:20]([C:24]([F:27])([F:26])[F:25])=[CH:21][CH:22]=4)[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1
Reactant: F[B-](F)(F)C[NH+]1CCSCC1
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c3ccc(C(F)(F)F)c4Br)ccc21
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c3ccc(C(F)(F)F)c4CN3CCSCC3)ccc21

Procedure:
The title compound is prepared from {(S)-6-[(R)-4-bromo-5-trifluoromethyl-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester and (thiomorpholinium-4-ylmethyl)trifluoroborate following a procedure analogous to that described for Intermediate 3. LC (method 1): tR=1.19 min; Mass spectrum (ESI+): m/z=508 [M+H]+.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[C:11]([C:17]#[N:18])[C:12](=[CH:15][CH:16]=2)[C:13]#[N:14])=[N:5]1.[C:19]([C:22]1[CH:26]=[C:25]([C:27](O)=[O:28])[NH:24][N:23]=1)(=[O:21])[CH3:20]>>[C:19]([C:22]1[CH:26]=[C:25]([C:27]([NH:1][CH2:2][CH2:3][N:4]2[CH:8]=[CH:7][C:6]([C:9]3[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[C:11]([C:17]#[N:18])[CH:10]=3)=[N:5]2)=[O:28])[NH:24][N:23]=1)(=[O:21])[CH3:20]
Reactant: CC(=O)c1cc(C(=O)O)[nH]n1
Reactant: N#Cc1ccc(-c2ccn(CCN)n2)cc1C#N
Product: CC(=O)c1cc(C(=O)NCCn2ccc(-c3ccc(C#N)c(C#N)c3)n2)[nH]n1

Procedure:
The title compound was prepared from 4-(1-(2-aminoethyl)-1H-pyrazol-3-yl)-phthalonitrile (50 mg) and 3-acetyl-1H-pyrazole-5-carboxylic acid (34 mg) using the method of Example 34(d). Yield 43 mg. 1H-NMR (400 MHz; d6-DMSO): δ 2.49 (s, 3H), 3.70 (m, 2H), 4.37 (t, 2H), 7.00 (d, 1H), 7.27 (s, 1H), 7.86 (d, 1H), 8.13 (d, 1H), 8.28 (d, 1H), 8.45 (d, 1H), 8.63 (br s, 1H), 14.05 (br s, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:16]([O:18]CC)=O)=[C:7]([C:11](OCC)=[O:12])[NH:8]2)=[CH:4][CH:3]=1.O.[NH2:22][NH2:23]>C(O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[C:16](=[O:18])[N:23]=[N:22][C:11](=[O:12])[C:7]=3[NH:8][C:9]=2[CH:10]=1
Reactant: CCOC(=O)c1[nH]c2cc(Br)ccc2c1C(=O)OCC
Reactant: NN
Solvent: O
Solvent: CCO
Product: O=C1N=NC(=O)c2c1[nH]c1cc(Br)ccc21
Temperature: 25 °C
Yield: 85 %

Procedure:
To a stirred solution of diethyl 6-bromoindole-2,3-dicarboxylate (0.5 g, 1.47 mM) in ethanol (4 mL) was added hydrazine hydrate (2.2 mL, 44 mM). The solution was heated to reflux for 90 minutes and then cooled to room temperature. The resulting solid was filtered and then suspended in glacial acetic acid (5 mL). After heating this mixture to reflux for several minutes and cooling to room temperature, the solid was filtered off and dried under vacuum. This afforded the titled compound as a white solid (0.35 g, 85%), mp 260° C. NMR (d6 -DMSO): 11.81 (br s, 2H), 8.04 (dd, J1 =1.0 Hz, J2 =8 Hz), 7.76 (s, 1H), 7.46 (d, J=8 Hz), 3.36 (br s, 1H). MS(CI): 280 (M+1).
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([OH:12])=[O:11])=[CH:4][CH:3]=1.CO.[N+](=[CH:17][Si](C)(C)C)=[N-]>C1(C)C=CC=CC=1>[I:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][C:10]([O:12][CH3:17])=[O:11])=[CH:6][CH:7]=1
Reactant: O=C(O)CCc1ccc(I)cc1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Solvent: Cc1ccccc1
Product: COC(=O)CCc1ccc(I)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 3-(4-iodophenyl)propanoic acid (commercially available) in toluene and methanol (9:1, 0.2 M) 0° C. was added (diazomethyl)trimethylsilane (1 N solution in Et2O, 2 eq). After stirring at room temperature overnight the reaction mixture was concentrated under vacuum and the resulting crude residue was purified by chromatography (silica gel, 20-50% EtOAc in hexanes) to afford methyl 3-(4-iodophenyl)propanoate.
Reaction SMILES: F[C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[CH3:12][NH2:13]>CCO.O>[Cl:8][C:7]1[CH:6]=[CH:5][CH:4]=[C:3]([N+:9]([O-:11])=[O:10])[C:2]=1[NH:13][CH3:12]
Reactant: CN
Reactant: O=[N+]([O-])c1cccc(Cl)c1F
Solvent: CCO
Solvent: O
Product: CNc1c(Cl)cccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 90 %

Procedure:
2-Fluoro-3-chloronitrobenzene (3.0 g, 17 mmol) was dissolved in EtOH (6 mL) and Methylamine 40% in Water (6 mL) was added dropwise at 0° C. and mixture was warmed up to RT overnight Mixture went to a dark orange precipitate within 10 min The solid was isolated by filtration, rinsed with water (2*10 mL) and dried in a desiccators under vacuum to afford 3 g of 2-chloro-N-methyl-6-nitrobenzenamine (Yield: 90%) as an orange crystalline solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14]O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH:16]1[CH:20]=[N:19][N:18]=[N:17]1>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][N:17]2[N:18]=[N:19][CH:20]=[N:16]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: c1nnn[nH]1
Reactant: CC(C)(C)OC(=O)N1CCC(CO)CC1
Product: CC(C)(C)OC(=O)N1CCC(Cn2ncnn2)CC1

Procedure:
By a similar manner to Reference Example 29, 1-tert-butoxycarbonyl-piperidin-4-methanol (2.15 g, 10.0 mmol) was reacted with 1H-tetrazole (2.10 g, 30 mmol) to give 1tert-butoxycarbonyl-4-(2H-tetrazol-2-ylmethyl)piperidine as pale yellow oily substance (1.35 g, 50%) and 1-tert-1butoxycarbonyl-4-(1H-tetrazol-1-ylmethyl)piperidine as pale yellow solid substance (1.23 g, 46%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:19]2[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:20]=2[O:26][CH3:27])=[C:4]2[CH:10]=[C:9]([C:11]3[CH2:12][CH2:13][N:14]([CH2:17]C)[CH2:15][CH:16]=3)[NH:8][C:5]2=[N:6][CH:7]=1.C([N:30]([CH2:33]C)CC)C.CNC(=O)[O:38]N1C(=O)CCC1=O.O>CN(C)C=O>[Cl:1][C:2]1[C:3]([C:19]2[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:20]=2[O:26][CH3:27])=[C:4]2[CH:10]=[C:9]([C:11]3[CH2:12][CH2:13][N:14]([C:17]([NH:30][CH3:33])=[O:38])[CH2:15][CH:16]=3)[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: CCN(CC)CC
Reactant: CNC(=O)ON1C(=O)CCC1=O
Reactant: CCN1CC=C(c2cc3c(-c4cc(F)ccc4OC)c(Cl)cnc3[nH]2)CC1
Solvent: O
Solvent: CN(C)C=O
Product: CNC(=O)N1CC=C(c2cc3c(-c4cc(F)ccc4OC)c(Cl)cnc3[nH]2)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of Example 229F (0.049 g, 0.137 mmol) and triethylamine (0.057 mL, 0.411 mmol) in N,N-dimethylformamide (1.4 mL) was treated with 2,5-dioxopyrrolidin-1-yl methylcarbamate (0.035 g, 0.205 mmol) and the mixture was stirred at room temperature for 16 hours. The mixture was poured into water and the solid was filtered and dried under vacuum to afford the title compound. 1H NMR (500 MHz, DMSO-d6) δ 2.32-2.43 (m, 2H), 2.58 (d, J=4.3 Hz, 3H), 3.46 (t, J=5.7 Hz, 2H), 3.70 (s, 3H), 3.96-4.03 (m, 2H), 6.01-6.08 (m, 1H), 6.40-6.47 (m, 1H), 6.47-6.55 (m, 1H), 7.14 (dd, J=8.6, 3.1 Hz, 1H), 7.20 (dd, J=9.2, 4.5 Hz, 1H), 7.26-7.39 (m, 1H), 8.24 (s, 1H), 12.03 (bs, 1H). MS (ESI+) m/z 415.1 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:11]=[CH:12][C:13](OS(C(F)(F)F)(=O)=O)=[C:14](OS(C(F)(F)F)(=O)=O)[CH:15]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[P:32]([O-:39])([O:36][CH2:37][CH3:38])[O:33][CH2:34][CH3:35].CN1[CH2:46][CH2:45][O:44]CC1>C(#N)C.CCOC(C)=O.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH2:34]([O:33][P:32]([C:13]1[CH:12]=[CH:11][C:10]([CH2:9][NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])=[CH:15][C:14]=1[P:32]([O:44][CH2:45][CH3:46])([O:33][CH2:34][CH3:35])=[O:36])(=[O:39])[O:36][CH2:37][CH3:38])[CH3:35]
Reactant: CCOP([O-])OCC
Reactant: CN1CCOCC1
Reactant: CC(C)(C)OC(=O)NCc1ccc(OS(=O)(=O)C(F)(F)F)c(OS(=O)(=O)C(F)(F)F)c1
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CCOP(=O)(OCC)c1ccc(CNC(=O)OC(C)(C)C)cc1P(=O)(OCC)OCC
Temperature: 90 °C
Yield: 41.7 %

Procedure:
Trifluoro-methanesulfonic acid 5-(tert-butoxycarbonylamino-methyl)-2-trifluoromethanesulfonyloxy-phenyl ester (5 g, 10.0 mmol), diethyl phosphite (2.8 mL, 20.3 mmol), N-methylmorpholine (2.7 mL, 25.1 mmol) and tetrakis(triphenylphosphine)-palladium(0) (1.2 g) were dissolved in anhydrous acetonitrile (100 mL) and heated in a sealed tube at 90° C. for 48 h. After cooling, the mixture was diluted with EtOAc (200 mL) and washed with water, 1 N HCl and brine. The organic layer was dried over magnesium sulfate, concentrated, and purified by silica gel chromatography (5% MeOH/CHCl3) to yield the product as a colorless oil (2.0 g, 42%). 1H NMR (300 Mhz, CDCl3) δ 1.35 (m, 12 H), 3.79 (bs, 2 H), 3.96 (m, 8H), 7.45 (m, 1H), 7.91 (m, 2H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:13][S:14]([C:17]2[S:18][CH:19]=[CH:20][CH:21]=2)(=[O:16])=[O:15])[C:5]2[C:10]([C:11]=1[OH:12])=[CH:9][CH:8]=[CH:7][CH:6]=2.[I:22]I>>[I:22][C:2]1[CH:3]=[C:4]([NH:13][S:14]([C:17]2[S:18][CH:19]=[CH:20][CH:21]=2)(=[O:16])=[O:15])[C:5]2[C:10]([C:11]=1[OH:12])=[CH:9][CH:8]=[CH:7][CH:6]=2
Reactant: II
Reactant: O=S(=O)(Nc1cc(Br)c(O)c2ccccc12)c1cccs1
Product: O=S(=O)(Nc1cc(I)c(O)c2ccccc12)c1cccs1
Yield: 100 %

Procedure:
was prepared according to the procedure for 4b except using I2 solid. The reaction afforded title compound 129.4 mg (100%) as a brown solid, m.p.: 134-136° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:7]2[C:12]([C:13]=1[OH:14])=[CH:11][CH:10]=[CH:9][CH:8]=2)=[O:4].[CH3:21][O:22]C1C=CC(NC2C=CC=CC=2C(O)=O)=CC=1.C1(NC2C=CC=CC=2C(O)=O)C=CC=CC=1>>[CH3:1][O:2][C:3]([C:5]1[N:6]([C:15]2[CH:20]=[CH:19][C:18]([O:22][CH3:21])=[CH:17][CH:16]=2)[C:7]2[C:12]([C:13]=1[OH:14])=[CH:11][CH:10]=[CH:9][CH:8]=2)=[O:4]
Reactant: COc1ccc(Nc2ccccc2C(=O)O)cc1
Reactant: COC(=O)c1c(O)c2ccccc2n1-c1ccccc1
Agent: O=C(O)c1ccccc1Nc1ccccc1
Product: COC(=O)c1c(O)c2ccccc2n1-c1ccc(OC)cc1

Procedure:
Prepared in a manner analogous to the multi-step procedure described [P. Friedlander and K. Kunz, Chem. Ber., 55, 1597 (1922)] for the preparation of 3-hydroxy-1-phenyl-1H-indole-2-carboxylic acid methyl ester, with 2-(4-methoxyphenylamino)benzoic acid substituted for 2-(phenylamino)benzoic acid in the first step of the synthetic sequence. The final indole product was recrystallized from 2-propanol to yield analytically pure product, mp 153°-155° C.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[CH2:7])=[CH:4][CH:3]=1.[CH3:10][O:11][C:12]([CH3:14])=[CH2:13].C1(C)C=CC(S(O)(=O)=O)=CC=1.N1C=CC=CC=1>C(OCC)C.O1CCOCC1>[CH:6]([C:5]1[CH:8]=[CH:9][C:2]([O:1][C:12]([O:11][CH3:10])([CH3:14])[CH3:13])=[CH:3][CH:4]=1)=[CH2:7]
Reactant: C=Cc1ccc(O)cc1
Reactant: C=C(C)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccncc1
Solvent: C1COCCO1
Solvent: CCOCC
Product: C=Cc1ccc(OC(C)(C)OC)cc1
Temperature: 10 °C
Reaction time: 20 h

Procedure:
72.1 g (600 mmol) of 4-hydroxystyrene are dissolved in a mixture of 300 ml of diethyl ether and 150 ml of dioxane under a nitrogen atmosphere in a 1500 ml sulfonation flask. 216.3 g (3000 mmol) of 2-methoxypropene are added, and the mixture is cooled to 10° C. 1,48 g (7.8 mmol) of p-toluenesulfonic acid in 28.5 g (360 mmol) of pyridine are then added dropwise in the course of 20 minutes, and the mixture is stirred at room temperature for 20 hours. The reaction mixture is washed three times with 300 ml of 0.2N NaOH and three times with 300 ml of demineralized water. The organic phase is dried using magnesium sulfate, filtered through 1 cm of Ambefiyst A27 and evaporated in a rotary evaporator. Further drying of the resultant residue under a high vacuum leaves 99.2 g (82% of theory) of the desired product in the form of a yellow oil.
Reaction SMILES: Br[CH2:2][C:3]1[CH:11]=[C:10]([O:12][CH3:13])[C:9]([N+:14]([O-:16])=[O:15])=[CH:8][C:4]=1[C:5]([O-])=[O:6].C[CH2:18][N:19](CC)CC.CN.CCO.Cl>CO.CCOC(C)=O>[CH3:13][O:12][C:10]1[CH:11]=[C:3]2[C:4](=[CH:8][C:9]=1[N+:14]([O-:16])=[O:15])[C:5](=[O:6])[N:19]([CH3:18])[CH2:2]2
Reactant: CCN(CC)CC
Reactant: COc1cc(CBr)c(C(=O)[O-])cc1[N+](=O)[O-]
Agent: CN
Agent: Cl
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: CO
Product: COc1cc2c(cc1[N+](=O)[O-])C(=O)N(C)C2
Temperature: 70 °C

Procedure:
To crude 2-(bromomethyl)-4-methoxy-5-nitrobenzoate (<4 mmol) in methanol (36 mL) was added Et3N (0.68 mL, 4.8 mmol) and methylamine in EtOH (0.6 mL, ˜8 M in EtOH, 4.8 mmol). The mixture was heated to 70° C. for 5 h. and then EtOAc (30 mL) and 2M HCl(aq) (30 mL) was added. The layers were separated and the aqueous layer was extracted with EtOAc (2×30 mL). The combined organic fractions were passed through a hydrophobic frit and the solvent was removed in vacuo. Purification of the residue via silica gel column chromatography (0-100% EtOAc in iso-hexane then EtOAc-10% MeOH in DCM) gave impure 5-methoxy-2-methyl-6-nitroisoindolin-1-one (487 mg) as a brown solid. The crude material was used directly in the next reaction without any further purification.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:28])=[C:4]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:26][CH3:27])=[C:16]([CH2:19][NH:20][C@@H:21]([CH3:25])[CH2:22][O:23][CH3:24])[CH:17]=3)[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1.CC[O:31][C:32]([C@@H:34](OS(C(F)(F)F)(=O)=O)[CH3:35])=[O:33]>>[Cl:1][C:2]1[C:3]([F:28])=[C:4]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:26][CH3:27])=[C:16]([CH2:19][N:20]([C@@H:21]([CH3:25])[CH2:22][O:23][CH3:24])[C@@H:34]([C:32]([OH:33])=[O:31])[CH3:35])[CH:17]=3)[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: COC[C@H](C)NCc1cc2c(Nc3cccc(Cl)c3F)ncnc2cc1OC
Reactant: CCOC(=O)[C@H](C)OS(=O)(=O)C(F)(F)F
Product: COC[C@H](C)N(Cc1cc2c(Nc3cccc(Cl)c3F)ncnc2cc1OC)[C@H](C)C(=O)O

Procedure:
N-(3-Chloro-2-fluorophenyl)-7-methoxy-6-({[(1S)-2-methoxy-1-methylethyl]amino}methyl)quinazolin-4-amine was coupled with ethyl O-trifluoromethanesulfonyl-L-lactate and hydrolysed using analogous methods to those described for the equivalent steps in Example 46 to give N-({4-[(3-chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-yl}methyl)-N-[(1S)-2-methoxy-1-methylethyl]-D-alanine; 1H NMR Spectrum: (DMSO-d6) 1.08 (d, 3H); 1.32 (d, 3H); 3.04 (m, 1H); 3.14 (s, 3H); 3.22 (dd, 1H); 3.43 (dd, 1H); 3.69 (q, 1H); 3.96 (m, 4H); 4.05 (d, 1H); 7.19 (s, 1H); 7.29 (t, 1H); 7.49 (t, 1H); 7.60 (t, 1H); 8.43 (m, 2H); 9.64 (brs, 1H); 12.01 (brs, 1H); Mass Spectrum: (M+H)+ 477.
Reaction SMILES: [OH-:1].[K+].[NH2:3][CH2:4][C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[CH:7][CH:6]=1>CC(O)(C)C>[NH2:10][CH2:9][C:8]1[CH:11]=[CH:12][C:5]([C:4]([NH2:3])=[O:1])=[CH:6][CH:7]=1
Reactant: N#Cc1ccc(CN)cc1
Reactant: [OH-]
Agent: [K+]
Solvent: CC(C)(C)O
Product: NCc1ccc(C(N)=O)cc1
Temperature: 25 °C
Yield: 66.6 %

Procedure:
Powdered potassium hydroxide (340 mg, 6 mmol) was added in one portion to a stirred solution of 4-(aminomethyl)benzonitrile (200 mg, 1.5 mmol) in 2-methyl-2-propanol (20 ml) at reflux under nitrogen. The reaction was heated at reflux for 30 minutes and cooled to room temperature. The mixture was concentrated under reduced pressure and the crude product was purified by flash chromatography on silica gel eluting with dichloromethane:methanol:ammonia (95:5:0.5, by volume) to provide the title compound (150 mg) as a white solid.
Reaction SMILES: F[C:2](F)(F)[C:3]1[N:4]=[C:5]([C:8]2[C:12]([CH:13]=[CH:14][C:15]3[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=3)=[CH:11][NH:10][N:9]=2)[NH:6][CH:7]=1.[OH-].[NH4+:24]>>[N:17]1[CH:18]=[CH:19][CH:20]=[C:15]([CH:14]=[CH:13][C:12]2[C:8]([C:5]3[NH:6][CH:7]=[C:3]([C:2]#[N:24])[N:4]=3)=[N:9][NH:10][CH:11]=2)[CH:16]=1
Reactant: FC(F)(F)c1c[nH]c(-c2n[nH]cc2C=Cc2cccnc2)n1
Reactant: [NH4+]
Agent: [OH-]
Product: N#Cc1c[nH]c(-c2n[nH]cc2C=Cc2cccnc2)n1
Temperature: 60 °C
Reaction time: 3 h

Procedure:
A mixture of 3-{2-[3-(4-trifluoromethyl-1H-imidazol-2-yl)-1H-pyrazol-4-yl]-vinyl}-pyridine Compound 2 (50 mg, 0.164 mmole) and 5% aqueous ammonium hydroxide (20 mL) was stirred at 60° C. for 3 h until all of the starting material disappeared. After the solvent was removed in vacuo, the residue was dissolved in methanol and neutralized with several drops of 2M aqueous HCl to pH˜7. The solvent was evaporated and the crude compound was diluted with ethyl acetate and washed with water. The organic extracts were dried over MgSO4, filtered, and evaporated in vacuo. The product was purified by flash chromatography with 10% methanol/dichloromethane to give 2-[4-(2-pyridin-3-yl-vinyl)-1H-pyrazol-3-yl]-1H-imidazole-4-carbonitrile Compound 3 as a white solid (21.5 mg, 50%). 1H NMR (300 MHz, MeOD) δ 7.10 (d, J=16.5 Hz, 1H), 7.44 (dd, J=5, 7.8 Hz, 1H), 7.82 (d, J=14 Hz, 1H), 7.92 (s, 1H), 8.09 (d, J=7.7 Hz 1H), 8.18 (s, 1H), 8.37 (dd, J=1.5, 5 Hz, 1H), 8.63 (d, J=2 Hz, 1H); MS (ESI) m/z: 263.7 (M+H+).
Reaction SMILES: [OH:1][C@H:2]1[C@@H:6]([OH:7])[CH2:5][N:4]([C:8](=[O:29])[CH2:9][C:10]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C@@H:3]1[C:30]([N:32]1[CH2:36][CH2:35][CH2:34][C@@H:33]1[C:37]([NH:39][CH2:40][C@H:41]1[CH2:46][CH2:45][CH2:44][NH:43][CH2:42]1)=[O:38])=[O:31].[CH2:47](I)[CH3:48]>>[CH2:47]([N:43]1[CH2:44][CH2:45][CH2:46][C@H:41]([CH2:40][NH:39][C:37]([C@H:33]2[CH2:34][CH2:35][CH2:36][N:32]2[C:30]([C@@H:3]2[C@@H:2]([OH:1])[C@@H:6]([OH:7])[CH2:5][N:4]2[C:8](=[O:29])[CH2:9][C:10]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)=[O:31])=[O:38])[CH2:42]1)[CH3:48]
Reactant: O=C(NC[C@H]1CCCNC1)[C@H]1CCCN1C(=O)[C@@H]1[C@@H](O)[C@@H](O)CN1C(=O)CC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCI
Product: CCN1CCC[C@H](CNC(=O)[C@H]2CCCN2C(=O)[C@@H]2[C@@H](O)[C@@H](O)CN2C(=O)CC(c2ccccc2)(c2ccccc2)c2ccccc2)C1

Procedure:
The title compound was prepared by a method similar to Example 77, using (2R)-1-{(2S,3R,4S)-3,4-dihydroxy-1-(3,3,3-triphenylpropanoyl)pyrrolidin-2-yl}carbonyl-N-((3S)-3-piperidyl-methyl)pyrrolidine-2-carboxamide and ethyl iodide. The compound was obtained as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[O:9][C:10]1[CH:15]=[CH:14][N:13]=[C:12]2[CH:16]=[C:17]([C:19]3[CH2:20][CH2:21][N:22]([CH3:25])[CH2:23][CH:24]=3)[S:18][C:11]=12)[NH2:5].[CH3:26][O:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[NH:34][C:35](=[O:40])[CH2:36][C:37](O)=[O:38].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C.CCOC(C)=O>[F:1][C:2]1[CH:3]=[C:4]([NH:5][C:37](=[O:38])[CH2:36][C:35]([NH:34][C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=2[O:27][CH3:26])=[O:40])[CH:6]=[CH:7][C:8]=1[O:9][C:10]1[CH:15]=[CH:14][N:13]=[C:12]2[CH:16]=[C:17]([C:19]3[CH2:20][CH2:21][N:22]([CH3:25])[CH2:23][CH:24]=3)[S:18][C:11]=12
Reactant: COc1ccccc1NC(=O)CC(=O)O
Reactant: CN1CC=C(c2cc3nccc(Oc4ccc(N)cc4F)c3s2)CC1
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: COc1ccccc1NC(=O)CC(=O)Nc1ccc(Oc2ccnc3cc(C4=CCN(C)CC4)sc23)c(F)c1
Reaction time: 6 h
Yield: 50909.1 %

Procedure:
A solution of 3-fluoro-4-(2-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)thieno[3,2-b]pyridin-7-yloxy)aniline (230) (50 mg, 0.110 mmol), 3-(2-methoxyphenylamino)-3-oxopropanoic acid 27 (34 mg, 0.165 mmol) (scheme 8), EDC (25 mg, 0.165 mmol) and HOBt (22 mg, 0.165 mmol) in DMF (1.1 mL) was stirred overnight at room temperature. More 27 (34 mg, 0.165 mmol) and EDC (25 mg, 0.165 mmol) were added and the mixture stirred for a further 6 h. The mixture was diluted with EtOAc, extracted with water, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was re-dissolved in MeOH and purified by preparative HPLC (gradient 40% to 95% MeOH in water, 45 min) followed by flash chromatography (MeOH/CHCl3/NH4Cl 1:9:0.1) giving title compound 224 (19 mg, 0,056 mmol, 51% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 10.61 (s, 1H), 9.64 (s, 1H), 8.45 (d, J=5.5 Hz, 1H), 8.07 (dd, J=8.8 Hz, J=1.4 Hz, 1H), 7.86 (dd, J=2.3 Hz, J=13.1 Hz, 1H), 7.49-7.41 (m, 3H), 7.11-7.05 (m, 2H), 6.92 (m, 1H), 6.61 (dd, J=0.8 Hz, J=5.5 Hz, 1H), 6.43 (m, 1H), 3.86 (s, 3H), 3.64 (s, 2H), 3.33 (m, 2H), 2.52-2.50 (m, 2H), 2.49 (m, 2H), 2.36-2.33 (m, 5H). MS (m/z): 547.42 (100% yield).