Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH2:7][C:8]2[N:12]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]4[C:21]([C:26]([O:28]C(C)(C)C)=[O:27])=[CH:22][CH:23]=[CH:24][CH:25]=4)=[CH:16][CH:15]=3)[C:11]3[CH:33]=[C:34]([O:39][CH3:40])[C:35]([O:37][CH3:38])=[CH:36][C:10]=3[N:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.FC(F)(F)C(O)=O>C(Cl)Cl>[CH:1]1([CH2:7][C:8]2[N:12]([CH2:13][C:14]3[CH:15]=[CH:16][C:17]([C:20]4[C:21]([C:26]([OH:28])=[O:27])=[CH:22][CH:23]=[CH:24][CH:25]=4)=[CH:18][CH:19]=3)[C:11]3[CH:33]=[C:34]([O:39][CH3:40])[C:35]([O:37][CH3:38])=[CH:36][C:10]=3[N:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1cc2nc(CC3CCCCC3)n(Cc3ccc(-c4ccccc4C(=O)OC(C)(C)C)cc3)c2cc1OC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cc2nc(CC3CCCCC3)n(Cc3ccc(-c4ccccc4C(=O)O)cc3)c2cc1OC

Procedure:
Prepared in analogous manner to Example 9 from tert.butyl 4'-[(2-cyclohexylmethyl-5,6-dimethoxy-benzimid-azol-1-yl)-methyl]biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:7]([CH:10]([OH:12])[CH3:11])=[CH:6][C:3]=1[C:4]#[N:5].[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[O-][Si]([O-])=O.[Mg+2]>C(Cl)Cl.CCOCC>[C:10]([C:7]1[CH:8]=[CH:9][C:2]([F:1])=[C:3]([CH:6]=1)[C:4]#[N:5])(=[O:12])[CH3:11]
Reactant: CC(O)c1ccc(F)c(C#N)c1
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: O=[Si]([O-])[O-]
Agent: [Mg+2]
Solvent: ClCCl
Solvent: CCOCC
Product: CC(=O)c1ccc(F)c(C#N)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-Fluoro-5-(1-hydroxyethyl)benzonitrile (0.80 g, 4.8 mmol) was dissolved in DCM (50 mL). To this mixture was added pyridinium dichromate (2.73 g, 7.27 mmol) and the mixture was stirred at RT overnight. Florisil (26 g) was added to the reaction mixture which was then diluted with 50 mL of ether and filtered through a pad of Celite. The filtrate was evaporated to dryness and the residue was purified by MPLC through a 120 g Redi-sep column, eluting with 0-100% EtOAc/hexane to yield 5-acetyl-2-fluorobenzonitrile.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][NH:8]2)=[CH:4][C:3]=1[CH2:11][CH2:12][CH3:13].C([BH3-])#N.[Na+]>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][NH:8]2)=[CH:4][C:3]=1[CH2:11][CH2:12][CH3:13]
Reactant: CCCc1cc2cc[nH]c2cc1Cl
Agent: [BH3-]C#N
Agent: [Na+]
Product: CCCc1cc2c(cc1Cl)NCC2
Yield: 92.9 %

Procedure:
6-chloro-5-propylindole (D53) (0.063 g, 0.33 mmol) was treated with sodium cyanoborohydride as in the method of Description 10 to give the title compound (0.06 g, 94%) as a yellow oil.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][OH:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:13]1([CH3:23])[CH:18]=[CH:17][C:16]([S:19](Cl)(=[O:21])=[O:20])=[CH:15][CH:14]=1.O>N1C=CC=CC=1>[S:19]([O:12][CH2:11][CH2:10][CH2:9][NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])([C:16]1[CH:17]=[CH:18][C:13]([CH3:23])=[CH:14][CH:15]=1)(=[O:21])=[O:20]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)(C)OC(=O)NCCCO
Solvent: c1ccncc1
Solvent: O
Product: Cc1ccc(S(=O)(=O)OCCCNC(=O)OC(C)(C)C)cc1
Reaction time: 8 h
Yield: 55 %

Procedure:
Into 50 mL of pyridine was dissolved 2.95 g (16.9 mmoles) of 3-tert-butoxycarbonylamino-1-propanol. To the solution, while being cooled in ice under an argon atmosphere, was added dropwise over a period of 40 minutes a solution of 3.36 g (17.7 mmoles) of p-toluenesulfonyl chloride in pyridine. The mixture was left standing overnight at 7° C., then admixed with a small volume of water, and evaporated to dryness. The residue was dissolved in 200 mL of chloroform, washed successively with 5% aqueous potassium hydrogensulfate solution, saturated aqueous sodium hydrogencarbonate solution, and water, then dried over anhydrous sodium sulfate, evaporated to dryness, and subjected to column chromatography using 120 g of silica gel (Wako-Gel®C-200) and a toluene-ethyl acetate (8:1 by volume) mixture as developing solvent. Fraction Nos. 35 to 68 (each 15 mL in volume) were combined and evaporated to dryness to yield 3.06 g (55% yield) of O-tosyl-3-tert-butoxycarbonylamino-1-propanol in colorless oily form.
Reaction SMILES: CCN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.OC(C(F)(F)F)=O.[NH2:39][CH2:40][C:41]([N:43]1[CH2:48][CH2:47][N:46]([C:49](=[O:60])[C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][C:51]=2[C:56]([F:59])([F:58])[F:57])[CH2:45][CH2:44]1)=[O:42].[Li+].[C:62]1([C:68]2[O:72][C:71]([C:73]([O-])=[O:74])=[N:70][N:69]=2)[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=1>CN(C=O)C.O>[O:42]=[C:41]([N:43]1[CH2:44][CH2:45][N:46]([C:49](=[O:60])[C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][C:51]=2[C:56]([F:59])([F:57])[F:58])[CH2:47][CH2:48]1)[CH2:40][NH:39][C:73]([C:71]1[O:72][C:68]([C:62]2[CH:63]=[CH:64][CH:65]=[CH:66][CH:67]=2)=[N:69][N:70]=1)=[O:74]
Reactant: O=C([O-])c1nnc(-c2ccccc2)o1
Reactant: NCC(=O)N1CCN(C(=O)c2ccccc2C(F)(F)F)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(NCC(=O)N1CCN(C(=O)c2ccccc2C(F)(F)F)CC1)c1nnc(-c2ccccc2)o1
Temperature: 25 °C
Yield: 22.8 %

Procedure:
DIPEA (106 mg, 0.142 mL, 0.82 mmol) followed by HOBT (40.8 mg, 0.30 mmol), EDCI.HCl (131.8 mg, 0.69 mmol) and 2-amino-1-[4-(2-trifluoromethyl-benzoyl)-piperazin-1-yl]-ethanone TFA salt (129 mg, 0.3 mmol) were added sequentially to a stirred solution of 5-phenyl-[1,3,4]oxadiazole-2-carboxylic acid lithium salt (52 mg, 0.27 mmol) in DMF (5 mL). The resulting mixture was maintained at room temperature for 6 hrs. Cold water was added and the product was extracted with ethyl acetate. The organic layer was washed with saturated brine solution, dried over sodium sulphate and concentrated. The crude residue was purified by column chromatography (using 60-120 mesh silica gel and 50% EtOAc in hexane as eluent) to afford 30 mg (22.4% yield) of 5-phenyl-[1,3,4]oxadiazole-2-carboxylic acid {2-oxo-2-[4-(2-trifluoromethyl-benzoyl)-piperazin-1-yl]-ethyl}-amide as a white solid, LCMS purity: 87.99%, 1H NMR: (DMSO) δ 9.2 (t, 1H), 8.1 (d, 2H), 7.9-7.72 (dd, 2H), 7.72-7.6 (m, 3H), 7.6-7.5 (t, 1H), 4.3-4.1 (dd, 2H), 3.8-3.5 (m, 4H), 3.3-3.0 (m, 4H).
Reaction SMILES: C([N:8]1[C:12]([NH:13][CH:14]2[CH2:19][CH2:18][CH:17]([O:20][Si:21]([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22])[CH2:16][CH2:15]2)=[CH:11][N:10]=[N:9]1)C1C=CC=CC=1.C([O-])=O.[NH4+].C(O)(=O)C>[C].[Pd].CO>[Si:21]([O:20][CH:17]1[CH2:18][CH2:19][CH:14]([NH:13][C:12]2[NH:8][N:9]=[N:10][CH:11]=2)[CH2:15][CH2:16]1)([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22]
Reactant: CC(C)(C)[Si](C)(C)OC1CCC(Nc2cnnn2Cc2ccccc2)CC1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CC(=O)O
Solvent: CO
Product: CC(C)(C)[Si](C)(C)OC1CCC(Nc2cnn[nH]2)CC1
Temperature: 60 °C
Reaction time: 16 h
Yield: 65.3 %

Procedure:
A mixture of 1-benzyl-N-(4-{[tert-butyl(dimethyl)silyl]oxy}cyclohexyl)-1H-1,2,3-triazol-5-amine (11.10 g), 10% palladium-carbon (containing water by 50%, 6.66 g), ammonium formate (9.05 g), acetic acid (22 mL) and methanol (220 mL) was stirred at 60° C. for 16 hr under a nitrogen atmosphere. The reaction mixture was filtered, and the solvent was evaporated. The residue was diluted with saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate-isopropyl alcohol (3:1). The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by basic silica gel chromatography [eluent: hexane/ethyl acetate=70/30→30/70 (volume ratio)] to give the title compound as a colorless oil (5.56 g, 65%).
Reaction SMILES: CS[C:3]1[S:4][CH2:5][CH2:6][CH2:7][N:8]=1.[N+:9]([CH2:12][C:13]([O:15][CH3:16])=[O:14])([O-:11])=[O:10].C(O)(C)C>[Cl-].[Zn+2].[Cl-].CCOCC>[N+:9]([C:12](=[C:3]1[NH:8][CH2:7][CH2:6][CH2:5][S:4]1)[C:13]([O:15][CH3:16])=[O:14])([O-:11])=[O:10]
Reactant: CSC1=NCCCS1
Reactant: COC(=O)C[N+](=O)[O-]
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CCOCC
Solvent: CC(C)O
Product: COC(=O)C(=C1NCCCS1)[N+](=O)[O-]

Procedure:
To a mixture of 221 g of 5,6-dihydro-2-(methylthio)-4H-1,3-thiazine (A. F. McKay et al., J. Am. Chem. Soc., 80, 3339 (1950) and 1 g of zinc chloride at about 100°, 202 g of methyl nitroacetate (S. Zen et al., Kogyo Kagaku Zasshi, 74, 70 (1971)) was added dropwise over a 30-minute period. The resulting mixture was heated for 4 hours at 95°-105°. 200 ml of isopropyl alcohol then was added to the hot mixture, then 400 ml of ether was added. The resulting mixture was filtered to give methyl nitro(tetrahydro-2H-1,3-thiazin-2-ylidene)-acetate (1A), as a pale yellow solid, m.p.: 107°-108° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:10])=[C:6]([CH:9]=1)[C:7]#[N:8].I[CH:12]([CH3:14])[CH3:13].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][CH:12]([CH3:14])[CH3:13])=[C:6]([CH:9]=1)[C:7]#[N:8]
Reactant: N#Cc1cc(Br)ccc1O
Reactant: CC(C)I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)Oc1ccc(Br)cc1C#N
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of 5-bromo-2-hydroxybenzonitrile (25 g) in acetonitrile (150 mL) was added 2-iodopropane (15.14 mL) and potassium carbonate (34.9 g). The reaction mixture was stirred at room temperature for two days. The solvent was removed in vacuo, the residue was dissolved in ethyl acetate (150 mL), washed with water (2*30 mL), the organic phase was dried over sodium sulphate and concentrated to afford 5-bromo-2-[(1-methylethyl)oxy]benzonitrile (D38) (29.8 g) as a white solid without further purification. δH (CDCl3, 400 MHz): 1.39 (6H, d), 4.61 (1H, m), 6.85 (1H, d), 7.58 (1H, dd), 7.64 (1H, d). MS (ES): C10H10BrNO requires 239. found 240.0 (M+H+).
Reaction SMILES: [N+]([C:4]1[CH:5]=[C:6]([C:12]#[N:13])[C:7](=[CH:10][CH:11]=1)[C:8]#[N:9])([O-])=O.[CH3:14][O:15][CH2:16][CH2:17][O:18][CH2:19][CH2:20][O:21][CH2:22][CH2:23][OH:24].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:14][O:15][CH2:16][CH2:17][O:18][CH2:19][CH2:20][O:21][CH2:22][CH2:23][O:24][C:4]1[CH:5]=[C:6]([C:12]#[N:13])[C:7](=[CH:10][CH:11]=1)[C:8]#[N:9]
Reactant: N#Cc1ccc([N+](=O)[O-])cc1C#N
Reactant: COCCOCCOCCO
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COCCOCCOCCOc1ccc(C#N)c(C#N)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 45 %

Procedure:
A mixture of 4-nitrophthalonitrile (1.73 g, 10 mmol), triethylene glycol monomethyl ether (1.52 g, 10 mmol) and dried potassium carbonate (2.76 g, 20 mmol) in anhydrous DMF (15 mL) was stirred overnight at ambient temperature under argon. The solvents were removed in vacuo, and the crude product was purified by column chromatography on silica gel using dichloromethane/methanol mixture (97:3) as an eluent to give the product in 45% yield. [1H NMR (δ, ppm, CDCl3): 7.70 (d, 1H, J=8.7 Hz), 7.31 (d, 1H, J=2.5 Hz), 7.23 (dd, 1H, J=8.7 Hz, J=2.5 Hz), 4.22 (m, 2H), 3.88 (m, 2H), 3.6-3.75 (m, 6H), 3.53 (m, 2H), 3.37 (s, 3H).]
Reaction SMILES: [O:1]=[C:2]1[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:12]3[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=3)[CH:8]=2)[N:3]1[CH2:22][C:23]1[CH:24]=[C:25]([CH:31]=[CH:32][CH:33]=1)[C:26]([O:28]CC)=[O:27].[OH-].[K+].CO>CN(C)C=O>[O:1]=[C:2]1[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:12]3[CH:13]=[CH:14][C:15]([C:18]([F:20])([F:19])[F:21])=[CH:16][CH:17]=3)[CH:8]=2)[N:3]1[CH2:22][C:23]1[CH:24]=[C:25]([CH:31]=[CH:32][CH:33]=1)[C:26]([OH:28])=[O:27]
Reactant: CCOC(=O)c1cccc(CN2C(=O)CCc3cc(-c4ccc(C(F)(F)F)cc4)ccc32)c1
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CO
Product: O=C(O)c1cccc(CN2C(=O)CCc3cc(-c4ccc(C(F)(F)F)cc4)ccc32)c1
Temperature: 25 °C
Reaction time: 17 h
Yield: 60 %

Procedure:
To a solution of ethyl 3-((2-oxo-6-(4-(trifluoromethyl)phenyl)-3,4-dihydroquinolin-1(2H)-yl)methyl)benzoate (45 mg, 0.10 mmol) (PT-094) in N,N-dimethylformamide (2.0 mL) was added 1N potassium hydroxide in methanol (10 mL, 10 mmol). The reaction mixture was stirred at room temperature for 17 hours, and then the solvent was removed under reduced pressure. Water (5.0 mL) was added, and the pH was adjusted to 4-5. The mixture was extracted with ethyl acetate (3×20 mL), and the combined organic phase was washed with 30% ammonium chloride (20 mL), brine (20 mL), dried over magnesium sulfate, and the solvent removed under reduced pressure. The residue was subjected to reverse phase HPLC with a gradient of acetonitrile/water (2% to 98%) to afford 3-((2-oxo-6-(4-(trifluoromethyl)phenyl)-3,4-dihydroquinolin-1(2H)-yl)methyl)benzoic acid (26 mg, 0.06 mmol, 60%) (PT-095). LCMS mz 426.0 M+H), 448.0 (M+Na). 1H NMR (400 MHz; CDCl3) δ 8.06 (bs, 2H); 7.65 (m, 4H); 7.47 (m, 3H); 7.36 (m, 1H); 6.92 (d, J=8.6 Hz, 1H); 5.28 (s, 2H); 3.08 (m, 2H), 2.86 (m, 2H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([N+:18]([O-:20])=[O:19])[CH:5]=[C:6]([CH3:17])[C:7]=1[O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=1.[F:21][C:22]1[CH:30]=[CH:29][C:25]([C:26](Cl)=[O:27])=[CH:24][CH:23]=1>C(Cl)Cl.[Cl-].[Cl-].[Cl-].[Ti+3]>[F:21][C:22]1[CH:30]=[CH:29][C:25]([C:26]([C:11]2[CH:10]=[C:9]([O:8][C:7]3[C:6]([CH3:17])=[CH:5][C:4]([N+:18]([O-:20])=[O:19])=[CH:3][C:2]=3[CH3:1])[CH:14]=[CH:13][C:12]=2[O:15][CH3:16])=[O:27])=[CH:24][CH:23]=1
Reactant: COc1ccc(Oc2c(C)cc([N+](=O)[O-])cc2C)cc1
Reactant: O=C(Cl)c1ccc(F)cc1
Agent: [Ti+3]
Agent: [Cl-]
Solvent: ClCCl
Product: COc1ccc(Oc2c(C)cc([N+](=O)[O-])cc2C)cc1C(=O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 192 h

Procedure:
To a solution of 4.5 g (16.5 mmol) of 3,5-dimethyl-4-(4'-methoxyphenoxy)nitrobenzene and 6.63 g (41.8 mmol) of p-fluorobenzoyl chloride in 100 ml methylene chloride is added 15.8 g (83.3 mmol) of titanium trichloride. The reaction mixture is stirred for 8 days at room temperature, then poured into ice water (300 ml) and stirred 2 hours. The organic layer is separated, washed with 5% aqueous sodium carbonate, water, dried (CaSO4) and evaporated. The residue is triturated with ether-petroleum ether and recrystallized from methanol to give (4-fluorophenyl)[2-methoxy-5-(2,6-dimethyl-4-nitrophenoxy)phenyl]-methanone, m.p. 167°-168°.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[CH2:13][N:14]([S:17]([CH3:20])(=[O:19])=[O:18])[CH2:15][CH2:16][C:11]=3[N:10]([CH2:21][CH:22]3[CH2:24][O:23]3)[N:9]=2)=[CH:4][CH:3]=1.[Cl:25][C:26]1[CH:27]=[CH:28][C:29]2[NH:33][C:32](=[O:34])[N:31]([CH:35]3[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]3)[C:30]=2[CH:41]=1>CCO>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[CH2:13][N:14]([S:17]([CH3:20])(=[O:19])=[O:18])[CH2:15][CH2:16][C:11]=3[N:10]([CH2:21][CH:22]([OH:23])[CH2:24][N:38]3[CH2:37][CH2:36][CH:35]([N:31]4[C:30]5[CH:41]=[C:26]([Cl:25])[CH:27]=[CH:28][C:29]=5[NH:33][C:32]4=[O:34])[CH2:40][CH2:39]3)[N:9]=2)=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)N1CCc2c(c(-c3ccc(Br)cc3)nn2CC2CO2)C1
Reactant: O=c1[nH]c2ccc(Cl)cc2n1C1CCNCC1
Solvent: CCO
Product: CS(=O)(=O)N1CCc2c(c(-c3ccc(Br)cc3)nn2CC(O)CN2CCC(n3c(=O)[nH]c4ccc(Cl)cc43)CC2)C1
Yield: 61.7 %

Procedure:
A stirred solution of 25.0 mg (0.061 mmol) of 3-(4-bromo-phenyl)-5-methanesulfonyl-1-oxiranylmethyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine and 19.0 mg (0.073 mmol) of 6-chloro-1-piperidin-4-yl-1,3-dihydro-benzoimidazol-2-one in EtOH (0.5 mL) was heated to 80° C. in a sealed vessel for 16 h. The reaction was cooled and the solvent was removed under reduced pressure. The crude product was purified by column chromatography (silica, 0-5% MeOH/CH2Cl2) to afford 0.025 g (63%) of the title compound. TLC (silica, 5% MeOH/CH2Cl2): Rf=0.4. MS (electrospray): m/z calculated for C28H32BrClN6O4S [M++H] 663.11, observed 663.0. 1H NMR (400 MHz, CDCl3): 10.2 (s, 1H), 7.52 and 7.46 (A and B of AA′BB′, J=8.6 Hz, 4H), 7.15 (br d, J=1.5 Hz, 1H), 7.04-6.95 (m, 2H), 4.52 and 4.49 (A and B of AB quartet, Jab=14.5 Hz, 2H), 4.33-4.14 (m, 3H), 4.07-3.97 (m, 1H), 3.74-3.58 (m, 2H), 3.17-2.89 (m, 4H), 2.86 (s, 3H), 2.57-2.30 (m, 5H), 2.20 (t, J=11.1 Hz, 1H), 1.87-1.73 (m, 2H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:16][C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[C:9]=2[CH3:17])=[CH:4][CH:3]=1.C([Li])CCC.[C:23](=[O:25])=[O:24]>C1COCC1>[C:23]([C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:16][C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[C:9]=2[CH3:17])=[CH:4][CH:3]=1)([OH:25])=[O:24]
Reactant: Cc1c(-c2ccc(Br)cc2)[nH]c2ncccc12
Reactant: O=C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1c(-c2ccc(C(=O)O)cc2)[nH]c2ncccc12

Procedure:
2-(p-Bromophenyl)-3-methyl-pyrrolo-[2,3 -b]pyridine (1 g, 3.5 mmol) was dissolved in 200 ml dry THF, deaerated and cooled to -78° C. n-Butyllithium (5.19 ml, 8.4 mmol) was added dropwise and the mixture was allowed to reach room temperature CO2 (g) was bubbled through the solution for 10 min.
Reaction SMILES: [Br:1][C:2]1[CH:12]=[C:11]([Br:13])[CH:10]=[C:9]([Br:14])[C:3]=1[O:4][CH2:5][C:6](=O)[CH3:7].C([O-])(=O)C.[NH4+].C([BH3-])#[N:21].[Na+]>CO>[CH3:7][CH:6]([NH2:21])[CH2:5][O:4][C:3]1[C:2]([Br:1])=[CH:12][C:11]([Br:13])=[CH:10][C:9]=1[Br:14]
Reactant: [BH3-]C#N
Reactant: CC(=O)COc1c(Br)cc(Br)cc1Br
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Product: CC(N)COc1c(Br)cc(Br)cc1Br
Temperature: 0 °C
Reaction time: 8 h
Yield: 31.7 %

Procedure:
To a solution of 1 g 1-(2,4,6-tribromo-phenoxy)-propan-2-one (2.6 mmol) in 20 ml methanol is added 2.9 g ammonium acetate (39 mmol). The mixture is cooled to 0° C. and 0.81 g sodiumcyanoborohydride (13 mmol) is added. The reaction mixture is stirred overnight at ambient temperature. The completion of the reaction is confirmed by TLC. The reaction mixture is concentrated and the remaining residue is dissolved with 1.5 N HCl and washed with diethylether. The aqueous layer is neutralised and extracted with ethylacetate. The ethylacetate layer is dried over anhydrous sodium sulphate and the solvent removed. 0.32 g 1-methyl-2-(2,4,6-tribromo-phenoxy)-ethylamine (32%) is obtained.
Reaction SMILES: Cl[CH2:2][C:3]([O:5]C)=[O:4].[Br:7][C:8]1[C:9]([OH:17])=[C:10]([CH:13]=[C:14]([F:16])[CH:15]=1)[CH:11]=O.C(=O)([O-])[O-].[K+].[K+].[OH-].[K+]>O1CCCC1.O>[Br:7][C:8]1[C:9]2[O:17][C:2]([C:3]([OH:5])=[O:4])=[CH:11][C:10]=2[CH:13]=[C:14]([F:16])[CH:15]=1
Reactant: O=Cc1cc(F)cc(Br)c1O
Reactant: COC(=O)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1cc2cc(F)cc(Br)c2o1
Temperature: 130 °C
Reaction time: 18 h
Yield: 62.3 %

Procedure:
Methyl chloroacetate (7.6 mL, 86.8 mmol) was added to a mixture of 3-bromo-5-fluoro-2-hydroxy-benzaldehyde (9.5 g, 43.4 mmol), tetra-N-butyl-ammonium iodide (1.6 g, 4.34 mmol) and anhydrous potassium carbonate (24 g, 174 mmol). The reaction mixture was heated at 130° C. for 4 h, cooled to 0° C., diluted with tetrahydrofuran (100 mL) and then potassium hydroxide (17 g, 303 mmol) in water (100 mL). The mixture was stirred at rt for 18 h and then, concentrated under reduced pressure. The residue was acidified with HCl and extracted with ethyl acetate. The combined organic extracts were dried (Na2SO4), filtered and concentrated under reduced pressure. The crude compound was purified by flash chromatography (SiO2; toluene/EtOAc, 40/1) to give 7.0 g (63%) of the product.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:11]=2)[C:6](=[C:18](OCC)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:5]1=[O:28])(=O)C.[CH3:29][N:30]([CH3:46])[CH2:31][CH2:32][CH2:33][N:34]([S:42]([CH3:45])(=[O:44])=[O:43])[C:35]1[CH:40]=[CH:39][C:38]([NH2:41])=[CH:37][CH:36]=1>>[CH3:46][N:30]([CH3:29])[CH2:31][CH2:32][CH2:33][N:34]([C:35]1[CH:40]=[CH:39][C:38]([NH:41]/[C:18](=[C:6]2\[C:5](=[O:28])[NH:4][C:12]3[C:7]\2=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:11]=3)/[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:37][CH:36]=1)[S:42]([CH3:45])(=[O:44])=[O:43]
Reactant: CN(C)CCCN(c1ccc(N)cc1)S(C)(=O)=O
Reactant: CCOC(=O)c1ccc2c(c1)N(C(C)=O)C(=O)C2=C(OCC)c1ccccc1
Product: CCOC(=O)c1ccc2c(c1)NC(=O)/C2=C(\Nc1ccc(N(CCCN(C)C)S(C)(=O)=O)cc1)c1ccccc1

Procedure:
Prepared from 1-acetyl-3-(1-ethoxy-1-phenylmethylene)-6-ethoxycarbonyl-2-indolinone and N-(3-dimethylamino-propyl)-N-methylsulphonyl-p-phenylenediamine Rf value: 0.6 (silica gel, methylene chloride/ethanol/ammonia=5:2:0.01) C30H34N4O5S
Reaction SMILES: Cl.O1CCOCC1.[F:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[C:23]3[C:18](=[CH:19][CH:20]=[C:21]([NH:24][C:25]([C:27]4([N:53]([CH:55]=[O:56])[CH3:54])[CH2:31][CH2:30][N:29]([CH2:32][C:33](=[O:52])[N:34]5[CH2:39][CH:38]=[C:37]([C:40]6[CH:45]=[CH:44][C:43]([C:46]7[N:51]=[CH:50][CH:49]=[CH:48][N:47]=7)=[CH:42][CH:41]=6)[CH2:36][CH2:35]5)[CH2:28]4)=[O:26])[CH:22]=3)[N:17](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[N:16]=2)=[CH:11][CH:10]=1>C(Cl)Cl>[F:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[C:23]3[C:18](=[CH:19][CH:20]=[C:21]([NH:24][C:25]([C:27]4([N:53]([CH:55]=[O:56])[CH3:54])[CH2:31][CH2:30][N:29]([CH2:32][C:33](=[O:52])[N:34]5[CH2:35][CH:36]=[C:37]([C:40]6[CH:45]=[CH:44][C:43]([C:46]7[N:47]=[CH:48][CH:49]=[CH:50][N:51]=7)=[CH:42][CH:41]=6)[CH2:38][CH2:39]5)[CH2:28]4)=[O:26])[CH:22]=3)[NH:17][N:16]=2)=[CH:11][CH:10]=1
Reactant: CN(C=O)C1(C(=O)Nc2ccc3c(c2)c(-c2ccc(F)cc2)nn3C(c2ccccc2)(c2ccccc2)c2ccccc2)CCN(CC(=O)N2CC=C(c3ccc(-c4ncccn4)cc3)CC2)C1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: CN(C=O)C1(C(=O)Nc2ccc3[nH]nc(-c4ccc(F)cc4)c3c2)CCN(CC(=O)N2CC=C(c3ccc(-c4ncccn4)cc3)CC2)C1
Reaction time: 2 h
Yield: 85.2 %

Procedure:
Added 4M HCl/dioxane (2 ml) to a solution of 3-(Formyl-methyl-amino)-1-{2-oxo-2-[4-(4-pyrimidin-2-yl-phenyl)-3,6-dihydro-2H-pyridin-1-yl]-ethyl}-pyrrolidine-3-carboxylic acid [3-(4-fluoro-phenyl)-1trityl-indazol-5-yl]-amide (7T) (89 mg, 0.098 mmol) in MeCl2 (2 ml) at room temperature, then stirred for 2 hours. The solvent was evaporated and the residue extracted with MeCl2 (50 ml), H2O (25 ml) and 3M NaOH (2 ml). The organic layer was separated, dried over MgSO4, filtered and solvent evaporated yielding a solid. Hexanes (2×50 ml) was added and the supernatant decanted. The residual solid was dried yielding 8T as a white solid (55 mg, 84%) LCMS (MH 659) Retention time=2.98 minutes.
Reaction SMILES: C(OC(N1CCC(NC(C2SC=CC=2NC2C=CN=C3NC=CC=23)=O)C1)=O)(C)(C)C.[CH2:31]([NH:38][CH2:39][CH2:40][NH2:41])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.[NH:42]1[C:46]2=[N:47][CH:48]=[CH:49][C:50]([NH:51][C:52]3[S:53][CH:54]=[CH:55][C:56]=3[C:57](O)=[O:58])=[C:45]2[CH:44]=[CH:43]1>>[CH2:31]([NH:38][CH2:39][CH2:40][NH:41][C:57]([C:56]1[CH:55]=[CH:54][S:53][C:52]=1[NH:51][C:50]1[CH:49]=[CH:48][N:47]=[C:46]2[NH:42][CH:43]=[CH:44][C:45]=12)=[O:58])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: NCCNCc1ccccc1
Reactant: O=C(O)c1ccsc1Nc1ccnc2[nH]ccc12
Agent: CC(C)(C)OC(=O)N1CCC(NC(=O)c2sccc2Nc2ccnc3[nH]ccc23)C1
Product: O=C(NCCNCc1ccccc1)c1ccsc1Nc1ccnc2[nH]ccc12

Procedure:
This compound was prepared in an analogous manner as 3-{[3-(1H-Pyrrolo[2,3-b]pyridin-4-ylamino)-thiophene-2-carbonyl]-amino}-pyrrolidine-1-carboxylic acid tert-butyl ester using N-benzylethylenediamine instead of 1-BOC-3-aminopyrrolidine and 2-(1H-Pyrrolo[2,3-b]pyridin-4-ylamino)-thiophene-3-carboxylic acid instead of 3-(1H-Pyrrolo[2,3-b]pyridin-4-ylamino)-thiophene-2-carboxylic acid. LCMS (ESI) 392 (M+H) 1H NMR (400 MHz, DMSO-d6) δ ppm 11.95 (1H, br. s.) 11.66 (1H, br. s.) 8.27 (1H, t, J=5.73 Hz) 8.15 (1H, d, J=5.52 Hz) 7.48 (1H, d, J=5.86 Hz) 7.25-7.39 (6H, m) 7.15-7.24 (1H, m) 6.98 (1H, d, J=5.47 Hz) 6.92 (1H, d, J=0.10 Hz) 6.46 (1H, dd, J=3.42, 1.76 Hz) 3.73 (2H, s) 3.41 (2H, q, J=6.44 Hz) 2.68 (2H, t, J=6.56 Hz)