Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:20][CH2:19][CH2:18][C@H:2]1[C:3]([N:5]([CH3:17])[C@H:6]([C:14](O)=[O:15])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:4].[NH2:28][C@H:29]([C:38]([O:40][C:41]([C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)=[O:42])=[O:39])[CH2:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34]C=1.C1(N=C=NC2CCCCC2)CCCCC1.ON1C(=O)CCC1=O>>[N:1]1([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:20][CH2:19][CH2:18][C@H:2]1[C:3]([N:5]([CH3:17])[C@H:6]([C:14]([NH:28][C@H:29]([C:38]([O:40][C:41]([C:43]1[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=1)=[O:42])=[O:39])[CH2:30][C:31]1[CH:32]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[O:15])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:4]
Reactant: CN(C(=O)[C@@H]1CCCN1C(=O)OC(C)(C)C)[C@@H](Cc1ccccc1)C(=O)O
Reactant: N[C@@H](CCc1ccccc1)C(=O)OC(=O)c1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: O=C1CCC(=O)N1O
Product: CN(C(=O)[C@@H]1CCCN1C(=O)OC(C)(C)C)[C@@H](Cc1ccccc1)C(=O)N[C@@H](Cc1ccccc1)C(=O)OC(=O)c1ccccc1
Yield: 76 %

Procedure:
Condensation of BocProOH (4.30 g.) and HMePheOMe (2.74 g.) by the mixed anhydride method using diphenylphosphinyl chloride gave BocPro-MePheOMe in 77% yield. Demethylation of BocPro-MePheOMe (3.0 g.) using aqueous sodium hydroxide gave BocPro-MePheOH in 83% yield. Condensation of BocPro-MePheOH (1.71 g.) and HPheOBz (2.14 g.) using dicyclohexylcarbodiimide and N-hydroxysuccinimide gave BocPro-MePhe-PheOBz in 76% yield. Debenzylation of BocPro-MePhe-PheOBz (2.0 g.) by hydrogenation with palladium catalyst gave BocPro-MePhe-PheOH in 100% yield.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:10])[CH2:4][C:5]1[CH2:9][CH2:8][CH2:7][CH:6]=1.C([O-])(=[O:13])C.[Na+].C(OO)(=O)C>C(Cl)(Cl)Cl.C(O)(=O)C>[CH3:1][O:2][C:3](=[O:10])[CH2:4][CH:5]1[CH2:9][CH:8]2[O:13][CH:7]2[CH2:6]1
Reactant: CC(=O)[O-]
Reactant: COC(=O)CC1=CCCC1
Agent: CC(=O)OO
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Product: COC(=O)CC1CC2OC2C1
Temperature: 35 °C
Yield: 424.1 %

Procedure:
43.46 g (0.31 mol) of cyclopentenylacetic acid methyl ester are dissolved in 80 ml of chloroform. After the addition of 4 g of sodium acetate, 82.51 g of a 40% solution of peracetic acid in acetic acid are added dropwise thereto, with stirring, the temperature being maintained at about 35° C. The reaction mixture is then stirred for a further 5 hours at 35° C. The reaction mixture is extracted with 5% sodium hydrogen carbonate solution and then twice with water. The organic phase is then separated off and dried and residual peroxide is destroyed with sodium sulfite. After distillation of the organic phase there are obtained 32.3 g of 3,4-epoxycyclopentylacetic acid methyl ester (66.5% of theory).
Reaction SMILES: [C:1](Br)(=[O:5])[CH:2]([CH3:4])[CH3:3].Br.Br.[C:9]1([CH2:15][CH2:16][NH:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][NH:24][CH2:25][CH2:26][C:27]2[CH:28]=[C:29]([OH:34])[C:30]([OH:33])=[CH:31][CH:32]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[ClH:35]>FC(F)(F)C(O)=O>[C:9]1([CH2:15][CH2:16][NH:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][NH:24][CH2:25][CH2:26][C:27]2[CH:28]=[C:29]([OH:34])[C:30]([OH:33])=[CH:31][CH:32]=2)[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1.[ClH:35].[ClH:35].[CH3:3][CH:2]([CH3:4])[C:1]([OH:5])=[O:33].[CH3:3][CH:2]([CH3:4])[C:1]([OH:5])=[O:33]
Reactant: CC(C)C(=O)Br
Agent: Br
Agent: Cl
Agent: Oc1ccc(CCNCCCCCCNCCc2ccccc2)cc1O
Solvent: O=C(O)C(F)(F)F
Product: CC(C)C(=O)O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Isobutyryl bromide (12 g) was added to a stirred solution of 4-[2-(6-(2-Phenylethylamino)hexylamino) ethyl]-1,2-benzenediol dihydrobromide (4 g) in trifluoracetic acid (100 ml). The solution was then stirred at room temperature for 24 hours. The excess solvent was evaporated and the residue treated with sodium bicarbonate solution. The basic mixture was thoroughly extracted with chloroform. The organic phase was separated, dried over magnesium sulfate, filtered and evaporated to leave a colorless oil which gave a white precipitate when treated with ethereal HCl. The white precipitate was recrystallised to give the title compound from ethanol as colorless prisms (2.8 g), m.p. 232°-234°.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH:13]=[CH:12][CH:11]=[C:10]2[C:14]#[N:15])=[CH:5][CH:4]=1.[C:16]1(=[O:26])[NH:20][C:19](=[O:21])[C:18]2=[CH:22][CH:23]=[CH:24][CH:25]=[C:17]12.[K]>CN(C=O)C>[C:14]([C:10]1[N:9]([C:6]2[CH:7]=[CH:8][C:3]([CH2:2][N:20]3[C:16](=[O:26])[C:17]4[C:18](=[CH:22][CH:23]=[CH:24][CH:25]=4)[C:19]3=[O:21])=[CH:4][CH:5]=2)[CH:13]=[CH:12][CH:11]=1)#[N:15]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: N#Cc1cccn1-c1ccc(CBr)cc1
Agent: [K]
Solvent: CN(C)C=O
Product: N#Cc1cccn1-c1ccc(CN2C(=O)c3ccccc3C2=O)cc1
Temperature: 70 °C
Reaction time: 10 h

Procedure:
7.0 g (65.1 mmol) 1-(4-(bromomethyl)phenyl)-2-cyanopyrrole (prepared according to P. R. Bovy et al., J. Med Chem. 1993, 36, 101) and 22.0 g (119 mmol) potassium phthalimide were dissolved in 260 ml dry DMF and stirred at 70° C. for 10 h. It was cooled to room temperature, and 600 ml ice-cold water were added. After extraction with ethyl acetate, the organic layer was dried over sodium sulfate, and evaporated in vacuo. The remaining oil solidified upon standing, and it was stirred with t-butylmethylether to give pale yellow crystals of the title compound, which were filtered with suction and dried in vacuo,
Reaction SMILES: C(OC([N:6]1[CH2:27][CH2:26][C:10]2[C:11]3[CH:12]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[C:13]([F:19])([F:18])[CH2:14][C:15]=3[CH:16]=[CH:17][C:9]=2[CH2:8][CH2:7]1)=O)C.Br>C(O)(=O)C>[F:19][C:13]1([F:18])[CH:12]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:11]2[C:10]3[CH2:26][CH2:27][NH:6][CH2:7][CH2:8][C:9]=3[CH:17]=[CH:16][C:15]=2[CH2:14]1
Reactant: CCOC(=O)N1CCc2ccc3c(c2CC1)C(c1ccccc1)C(F)(F)C3
Agent: Br
Solvent: CC(=O)O
Product: FC1(F)Cc2ccc3c(c2C1c1ccccc1)CCNCC3
Temperature: 60 °C
Yield: 92.6 %

Procedure:
Into a 250 ml flask, the product from step (e) (3.75 g, 10.10 mmol) dissolved in acetic acid (50 ml) and HBr (33% in acetic acid, 50 ml) was added. The reaction mixture was heated to 60° C. for 6 hours. The reaction mixture was cooled and the volatiles were evaporated in vacuo. The crude product was dissolved in water (100 ml) and washed with diethyl ether (3×). The aqueous layer was basified with 2M NaOH to pH 10 and then extracted with DCM (3×). The combined DCM extracts were washed with brine, dried over Na2SO4, and solvent evaporated in vacuo to give the title compound as tan oil (2.8 g) which solidified over time. 1H NMR (300 MHz, CDCl3) δ 7.32-7.26 (m, 3H); 7.10-7.07 (m, 2H); 7.02-6.99 (m, 2H); 4.62 (d, J=19.8 Hz, 1H); 3.44-3.35 (m, 2H); 2.99-2.83 (m, 4H); 2.73-2.64 (m, 2H); 2.58-2.45 (m, 2H); 2.33 (bs, 1H); MS: ESI (positive): 300 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[CH2:6]2.[CH:13]([C:15]1[CH:23]=[C:22]2[C:18]([C:19](/[CH:24]=[CH:25]/[C:26]([O:28][CH2:29][CH3:30])=[O:27])=[N:20][NH:21]2)=[CH:17][CH:16]=1)=O>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])/[C:6]/2=[CH:13]/[C:15]1[CH:23]=[C:22]2[C:18]([C:19](/[CH:24]=[CH:25]/[C:26]([O:28][CH2:29][CH3:30])=[O:27])=[N:20][NH:21]2)=[CH:17][CH:16]=1
Reactant: CCOC(=O)/C=C/c1n[nH]c2cc(C=O)ccc12
Reactant: COc1ccc2c(c1)CC(=O)N2
Product: CCOC(=O)/C=C/c1n[nH]c2cc(/C=C3/C(=O)Nc4ccc(OC)cc43)ccc12
Yield: 77 %

Procedure:
The title compound (60 mg, 77%) was synthesized as an orange red solid according to the method described for Example A67 (oil temp 75° C., reflux 2 h) using 5-methoxyoxindole (26.8 mg, 0.2 mmol) and (E)-ethyl 3-(6-formyl-1H-indazol-3-yl)acrylate (48.8 mg, 0.2 mmol). 1H NMR (400 MHz, DMSO-d6) δ 13.80 (brs, 1H, NH), 10.44 (s, 1H, NH), 8.26 (d, J=8.4 Hz, 1H), 7.96 (s, 1H), 7.92 (d, J=16.4 Hz, 1H), 7.77 (s, 1H), 7.56 (d, J=8.4 Hz, 1H), 7.14 (d, 1H), 6.90-6.80 (m, 3H), 4.23 (q, J=7.2 Hz, 2H), 3.58 (s, 3H), 2.29 (t, J=7.2 Hz, 3H); MS ESI 390.3 [M+H]+, calcd for [C22H19N3O4+H]+ 390.1.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]([CH2:18][CH:19]=[CH2:20])[CH2:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[CH:5][C:4]=1[C:21]([F:24])([F:23])[F:22])#[N:2].[CH3:25][C:26]([NH:28][C:29]1[CH:34]=[CH:33][C:32](Br)=[CH:31][CH:30]=1)=[O:27]>>[C:26]([NH:28][C:29]1[CH:34]=[CH:33][C:32]([CH2:20][CH2:19][CH2:18][N:9]([C:6]2[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[C:4]([C:21]([F:23])([F:22])[F:24])[CH:5]=2)[CH2:10][C:11]([O:13][C:14]([CH3:16])([CH3:17])[CH3:15])=[O:12])=[CH:31][CH:30]=1)(=[O:27])[CH3:25]
Reactant: CC(=O)Nc1ccc(Br)cc1
Reactant: C=CCN(CC(=O)OC(C)(C)C)c1ccc(C#N)c(C(F)(F)F)c1
Product: CC(=O)Nc1ccc(CCCN(CC(=O)OC(C)(C)C)c2ccc(C#N)c(C(F)(F)F)c2)cc1

Procedure:
Synthesized according to Example 84B from 1,1-dimethylethyl N-[4-cyano-3-(trifluoromethyl)phenyl]-N-2-propen-1-ylglycinate and 4-bromoacetanilide: MS (APCI) m/z 498 ([M+Na]+), 420 ({[M+H]—C4H8}+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([OH:13])=[N:8][CH:7]=[CH:6]2.I[C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1.N1CCC[C@H]1C(O)=O.C(=O)([O-])[O-].[K+].[K+]>[Cu]I.O.CS(C)=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[N:8]([C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1)[CH:7]=[CH:6]2
Reactant: COc1ccc(I)cc1
Reactant: COc1ccc2c(O)nccc2c1
Agent: [Cu]I
Agent: O=C(O)[C@@H]1CCCN1
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CS(C)=O
Product: COc1ccc(-n2ccc3cc(OC)ccc3c2=O)cc1
Temperature: 130 °C
Yield: 90.3 %

Procedure:
6-Methoxyisoquinoline-1-ol (2.00 g, 11.42 mmol), 4-iodoanisole (4.01 g, 17.13 mmol), copper (1) iodide (0.44 g, 2.28 mmol). L-proline (0.53 g, 4.57 mmol) and anhydrous potassium carbonate (3.16 g, 22.84 mmol) were placed in a dry 250 mL three-necked round-bottomed flask fitted with a stirring bar and reflux condenser. The reaction flask was vacuumed and refilled with dry argon. 50 mL of anhydrous methyl sulfoxide was added via syringe. The reaction mixture was stirred and heated to 130° C. for 20 hours. 50 mL of water was added to quench the reaction, and yellow solid precipitated out. The pale-yellow solid was filtered, washed with water (2×20 mL) and dried in air. This pale-yellow solid was purified by flash column chromatography (silica gel, ethyl acetate) to give a pale-yellow solid product, 2.90 g, 90.3% yield. MS: 282.2 [M+H]+. 1H NMR (DMSO-d6, 300 MHz): δ 8.14 (d, 1H, J=8.7 Hz), 7.39-7.34 (m, 3H), 7.19 (d, 1H, J=2.4 Hz), 7.13-7.03 (m, 3H), 6.62 (dd, 1H, J=7.5 Hz), 3.89 (s, 3H), 3.81 (s, 3H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[C:11]([F:14])([F:13])[F:12].[CH2:15]([OH:18])[CH:16]=[CH2:17].C(N(CC)CC)C>CN(C=O)C.[Cl-].C([N+](CCCC)(CCCC)CCCC)CCC.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([CH2:17][CH2:16][CH:15]=[O:18])=[C:3]([C:11]([F:14])([F:13])[F:12])[CH:4]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccc(Br)c(C(F)(F)F)c1
Reactant: C=CCO
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=CCCc1ccc([N+](=O)[O-])cc1C(F)(F)F
Temperature: 90 °C
Reaction time: 0.5 h
Yield: 68.8 %

Procedure:
4-Bromo-3-(trifluoromethyl)nitrobenzene (2700 mg, 10 mmol) was dissolved in DMF (15 mL), and allyl alcohol (1750 mg, 30 mmol), tetrabutylammonium chloride (2780 mg, 10 mmol), palladium acetate (120 mg, 5 mol %), and triethylamine (3 mL, 21 mmol) were added thereto. The resulting mixture was stirred under argon atmosphere at 90° C. for 0.5 hours. The reaction solution was partitioned between water and ethyl acetate. The organic layer was washed with saturated brine and concentrated under reduced pressure. The residue was purified by silica-gel column chromatography (n-hexane:ethyl acetate=4:1) to give 3-(4-nitro-2-(trifluoromethyl)phenyl)propionaldehyde (1700 mg, 69%) as a light-yellow oil.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([CH2:20][CH3:21])=[C:6]([CH:8]2[C:13](=[O:14])[C:12]([CH3:16])([CH3:15])[O:11][C:10]([CH3:18])([CH3:17])[C:9]2=[O:19])[CH:7]=1.N1CCC[C@H]1C(O)=[O:25].[OH-].[Na+].Cl>[Cu]I>[CH2:20]([C:5]1[CH:4]=[CH:3][C:2]([OH:25])=[CH:7][C:6]=1[CH:8]1[C:13](=[O:14])[C:12]([CH3:16])([CH3:15])[O:11][C:10]([CH3:18])([CH3:17])[C:9]1=[O:19])[CH3:21]
Reactant: CCc1ccc(Br)cc1C1C(=O)C(C)(C)OC(C)(C)C1=O
Reactant: O=C(O)[C@@H]1CCCN1
Agent: [Cu]I
Agent: Cl
Agent: [Na+]
Product: CCc1ccc(O)cc1C1C(=O)C(C)(C)OC(C)(C)C1=O
Temperature: 200 °C

Procedure:
A mixture of 4-(5-bromo-2-ethylphenyl)-2,2,6,6-tetramethylpyran-3,5-dione (1.0 g, 2.8 mmol), copper(I) iodide (108 mg, 0.57 mmol) and L-proline (33 mg, 0.28 mmol) in an aqueous solution of sodium hydroxide (8.8 ml of a 1N solution) is heated at 200° C. for 2 hours under microwave irradiation. The mixture is cooled to room temperature, poured into 2M aqueous hydrochloric acid and extracted with ethyl acetate. The organic extract is washed with brine, dried over anhydrous magnesium sulfate, filtered and the filtrate is evaporated under reduced pressure. The solvent is evaporated under reduced pressure and the residue is purified by column chromatography on silica gel to give 4-(2-ethyl-5-hydroxyphenyl)-2,2,6,6-tetramethylpyran-3,5-dione.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][CH2:11][CH:12]2[CH2:17][CH2:16][CH2:15][NH:14][CH2:13]2)=[CH:2]1.[OH-].[Na+].[CH:20]([Cl:23])(Cl)Cl>[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1.O>[Cl:23][C:20]1[CH:2]=[N:1][C:9]2[C:4]([C:3]=1[CH2:10][CH2:11][CH:12]1[CH2:17][CH2:16][CH2:15][NH:14][CH2:13]1)=[CH:5][CH:6]=[CH:7][CH:8]=2
Reactant: ClC(Cl)Cl
Reactant: c1ccc2c(CCC3CCCNC3)c[nH]c2c1
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Product: Clc1cnc2ccccc2c1CCC1CCCNC1

Procedure:
The operation is as in Example 1, but starting from 3.8 g of 3-[2-(3-indolyl)-ethyl]-piperidine and 0.075 g of benzyltriethylammonium chloride in 40 ml of chloroform, and 5 g of sodium hydroxide in 10 ml of water. 1.3 g of 3-chloro-4-[2-(3-piperidyl)-ethyl]-quinoline are finally obtained in the form of the dihydrated monohydrochloride melting at 75° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13](=[O:21])[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[NH2:20])=[CH:8][CH:7]=1)[CH3:2].Cl[C:24](Cl)([O:26]C(=O)OC(Cl)(Cl)Cl)Cl.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:22])[CH2:5][C:6]1[CH:7]=[CH:8][C:9]([N:12]2[C:13](=[O:21])[C:14]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[NH:20][C:24]2=[O:26])=[CH:10][CH:11]=1)[CH3:2]
Reactant: CCOC(=O)Cc1ccc(NC(=O)c2ccccc2N)cc1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOC(=O)Cc1ccc(-n2c(=O)[nH]c3ccccc3c2=O)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of [4-(2-amino-benzoylamino)-phenyl]-acetic acid ethyl ester (14.2 g, 47 mmol) and triphosgene (0.5 eq, 7.03 g, 23.5 mmol) in DCM (200 ml) is treated with DIPEA (2 eq, 16.5 ml, 94 mmol) dropwise via dropping funnel while stirring at RT. After 1 hour, the reaction mixture is diluted with DCM and washed with saturated aqueous NaHCO3. The separated organic layer is washed with distilled water (2×), dried over MgSO4, filtered and the solvent removed in vacuo. The title compound is obtained as pure white solid.
Reaction SMILES: N[C@@H](C(C)C)C(C1C=CC=CC=1)(C1C=CC=CC=1)O.B.O1CCCC1.[CH:26]1(/[CH:32]=[C:33](/[N:40]2[CH:44]=[N:43][CH:42]=[N:41]2)\[C:34](=[O:39])[C:35]([CH3:38])([CH3:37])[CH3:36])[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1.Cl>ClCCCl>[CH:26]1(/[CH:32]=[C:33](/[N:40]2[CH:44]=[N:43][CH:42]=[N:41]2)\[CH:34]([OH:39])[C:35]([CH3:38])([CH3:37])[CH3:36])[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31]1
Reactant: CC(C)(C)C(=O)/C(=C\C1CCCCC1)n1cncn1
Agent: B
Agent: CC(C)[C@H](N)C(O)(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: ClCCCl
Solvent: C1CCOC1
Product: CC(C)(C)C(O)/C(=C\C1CCCCC1)n1cncn1
Reaction time: 24 h

Procedure:
In a nitrogen atmosphere, a solution of 0.230 g (0.90 mmole) of (S)-2-amino-1,1-diphenyl-3-methylbutan-1-ol in 2.5 ml of 1,2-dichloroethane was added dropwise at -78° C. to a solution comprising 1.29 ml (0.90 mmole) of 0.70M borane-tetrahydrofuran solution and 1 ml of 1,2-dichloroethane, and the temperature of the mixture was raised from -78° C. to room temperature over about 2 hours. Thereafter, a solution of 0.157 g (0.6 mmole, E/Z=99.9/0.1) of (E)-1-cyclohexyl-4,4-dimethyl-2-(1,2,4-triazol-1-yl)-1-penten-3-one in 2.5 ml of 1,2-dichloroethane was added dropwise to this solution, and stirring was carried out for 24 hours. The reaction product was decomposed with addition of 6 ml of 10% hydrochloric acid to the solution, and after removing (S)-2-amino-1,1-diphenyl-3-methylbutan-1-ol hydrochloride by filtration, the organic layer was washed with water and concentrated under reduced pressure to obtain crude (-)-(E)-1-cyclohexyl-4,4-dimethyl-2-(1,2,4-triazol-1-yl)-1-penten-3-ol.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1)=[O:5])[CH3:2].C(N(CC)CC)C.Br[CH2:20][C:21]([O:23][CH3:24])=[O:22]>ClCCl>[CH2:1]([O:3][C:4]([N:6]1[CH2:7][CH2:8][N:9]([CH2:20][C:21]([O:23][CH3:24])=[O:22])[CH2:10][CH2:11]1)=[O:5])[CH3:2]
Reactant: COC(=O)CBr
Reactant: CCOC(=O)N1CCNCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)N1CCN(CC(=O)OC)CC1
Reaction time: 0.21 h
Yield: 100 %

Procedure:
To a solution of 1-ethoxycarbonylpiperazine (20 g) and triethylamine (14.1 g) in dichloromethane (200 ml) at 0° C. was added gradually with stirring over 10-15 minutes, methyl bromoacetate (20.3 g). On completion of the addition the reaction mixture was stirred at room temperature for 2 hours, washed with water and brine, dried (MgSO4) and evaporated to yield 1-ethoxycarbonyl-4-methoxycarbonylmethylpiperazine (29.1 g) as a colourless oil: NMR (CDCl3) δ1.28 (3H, t), 2.56 (4H, m), 3.25 (2H, s), 3.52 (4H, m), 3.72 (3H, s), 4.14 (2H, q); m/Z 231 (M+H)+.
Reaction SMILES: [N+]([C:4]([CH3:15])=[CH:5][C:6]1[CH:7]=[CH:8][C:9]2[N:10]([CH:12]=[CH:13][N:14]=2)[CH:11]=1)([O-])=O.Cl.[OH2:17]>CCO>[N:14]1[CH:13]=[CH:12][N:10]2[CH:11]=[C:6]([CH2:5][C:4](=[O:17])[CH3:15])[CH:7]=[CH:8][C:9]=12
Reactant: O
Reactant: CC(=Cc1ccc2nccn2c1)[N+](=O)[O-]
Agent: Cl
Solvent: CCO
Product: CC(=O)Cc1ccc2nccn2c1

Procedure:
In 25 ml of water and 25 ml of EtOH, 1.14 g of 6-(2-nitro-1-propenyl)imidazo[1,2-a]pyridine was heated to 80° C. together with 100 mg of ferrous chloride. With stirring, 2.5 ml of conc. hydrochloric acid was added at a refluxing rate and the mixture was stirred of 1 hour. Upon heating, insoluble matter was removed by filtration. After the insoluble matter was thoroughly washed with ethanol, the solvent was removed by distillation under reduced pressure. An aqueous sodium bicarbonate solution was added to the residue and the mixture was extracted with chloroform. After washing with water and drying over magnesium sulfate, chloroform was removed by distillation under reduced pressure. The residue was purified by column chromatography to obtain 500 mg of 1-(imidazo[1,2-a]pyridin-6-yl)-2-propanone.
Reaction SMILES: C1(C[N:8]2[CH2:13][CH:12]3[C:10]([C:14]4[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][N:15]=4)([CH2:11]3)[CH2:9]2)C=CC=CC=1.Cl>C(O)C.[Pd]>[F:23][C:20]([F:21])([F:22])[C:17]1[CH:18]=[CH:19][C:14]([C:10]23[CH2:11][CH:12]2[CH2:13][NH:8][CH2:9]3)=[N:15][CH:16]=1
Reactant: FC(F)(F)c1ccc(C23CC2CN(Cc2ccccc2)C3)nc1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: FC(F)(F)c1ccc(C23CNCC2C3)nc1
Yield: 81 %

Procedure:
3-(Phenylmethyl)-1-[5-(trifluoromethyl)-2-pyridinyl]-3-azabicyclo[3.1.0]hexane was dissolved in ethanol (15 mL), hydrochloric acid (3M, 0.76 mL) was added followed, in inert atmosphere, by Pd/C 10% w/w (120 mg). After 20 h under a hydrogen atmosphere (1 atm) the mixture was filtered. Solvent was removed under reduced pressure. A saturated solution of sodium bicarbonate was added (10 mL) and the mixture extracted with diethyl ether (2×10 mL) to provide the title compound (0.14 g, 81%) after evaporation of volatiles.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:47]=[CH:48][CH:49]=1)[CH2:5][N:6]1[C:10]([CH3:11])=[C:9]([C:12]2[C:20]3[C:15](=[N:16][CH:17]=[C:18]([C:21]4[C:22]([O:34][CH3:35])=[C:23]([NH:29][S:30]([CH3:33])(=[O:32])=[O:31])[C:24]([O:27][CH3:28])=[CH:25][CH:26]=4)[CH:19]=3)[N:14](S(C3C=CC(C)=CC=3)(=O)=O)[CH:13]=2)[C:8]([CH3:46])=[N:7]1.[OH-].[Li+]>C1COCC1.CO.O>[F:1][C:2]1[CH:3]=[C:4]([CH:47]=[CH:48][CH:49]=1)[CH2:5][N:6]1[C:10]([CH3:11])=[C:9]([C:12]2[C:20]3[C:15](=[N:16][CH:17]=[C:18]([C:21]4[C:22]([O:34][CH3:35])=[C:23]([NH:29][S:30]([CH3:33])(=[O:32])=[O:31])[C:24]([O:27][CH3:28])=[CH:25][CH:26]=4)[CH:19]=3)[NH:14][CH:13]=2)[C:8]([CH3:46])=[N:7]1
Reactant: COc1ccc(-c2cnc3c(c2)c(-c2c(C)nn(Cc4cccc(F)c4)c2C)cn3S(=O)(=O)c2ccc(C)cc2)c(OC)c1NS(C)(=O)=O
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(-c2cnc3[nH]cc(-c4c(C)nn(Cc5cccc(F)c5)c4C)c3c2)c(OC)c1NS(C)(=O)=O
Yield: 25.5 %

Procedure:
Using similar reaction conditions as described in step-iii of example-1, N-(3-(3-(1-(3-fluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-2,6-dimethoxy phenyl)methanesulfonamide (40 mg, 0.05 mmol) was hydrolyzed by lithium hydroxide (23.8 mg, 0.5 mmol), THF/Methanol/water (12/4/4 ml) to afford 7 mg (25.9% yield) of the titled compound. 1H NMR (CD3OD, 400 MHz): δ 8.5 (b, 1H), 8.181-8.177 (d, 1H), 7.525 (s, 1H), 7.356-7.334 (m, 2H), 6.991-6.957 (m, 3H), 6.9-6.85 (m, 1H), 5.363 (s, 2H), 3.930 (s, 3H), 3.499 (s, 3H), 3.184 (s, 1H), 2.231-2.204 (d, 6H). MS: m/z=550.0 (M+1); HPLC: 94.463% in method A.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([C:11]2[CH:12]=[N:13][C:14]([O:17][CH3:18])=[CH:15][CH:16]=2)=[O:10])=[C:4]([Cl:19])[CH:3]=1.I[CH3:21]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:21])[C:9]([C:11]2[CH:12]=[N:13][C:14]([O:17][CH3:18])=[CH:15][CH:16]=2)=[O:10])=[C:4]([Cl:19])[CH:3]=1
Reactant: COc1ccc(C(=O)Cc2ccc(Br)cc2Cl)cn1
Reactant: CI
Product: COc1ccc(C(=O)C(C)c2ccc(Br)cc2Cl)cn1

Procedure:
In analogy to Example 1, steps 4 and 5, 2-(4-bromo-2-chloro-phenyl)-1-(6-methoxy-pyridin-3-yl)-ethanone was alkylated with iodomethane to give 2-(4-bromo-2-chloro-phenyl)-1-(6-methoxy-pyridin-3-yl)-propan-1-one which was further converted to the title compound. Colorless Oil. MS (m/e)=424.0 [M+H+].
Reaction SMILES: [CH3:1][C:2]([CH3:11])([CH2:6][O:7][C:8](=[O:10])[CH3:9])[C:3](O)=[O:4].C(Cl)(=O)C([Cl:15])=O>C1C=CC=CC=1>[CH3:1][C:2]([CH3:11])([CH2:6][O:7][C:8](=[O:10])[CH3:9])[C:3]([Cl:15])=[O:4]
Reactant: CC(=O)OCC(C)(C)C(=O)O
Reactant: O=C(Cl)C(=O)Cl
Solvent: c1ccccc1
Product: CC(=O)OCC(C)(C)C(=O)Cl
Temperature: 0 °C
Reaction time: 3 h

Procedure:
The product of Step A, 2,2-dimethyl-3-acetyloxypropionic acid (11.76 g, 80 mmol) was dissolved in benzene (100 mL), the reaction solution was cooled 0° C., oxalyl chloride (15.0 g, 120 mmol) was slowly added dropwise. After 3 h, the solvent was removed in vacuo, and distilled in vacuo to give the title compound.
Reaction SMILES: [F:1][C:2]1[C:3]([NH:22][C:23]2[CH:28]=[CH:27][C:26]([I:29])=[CH:25][C:24]=2[F:30])=[C:4]([CH:12]=[C:13](/[CH:16]=[N:17]/[O:18][CH:19]([CH3:21])[CH3:20])[C:14]=1[F:15])[C:5]([NH:7][O:8][CH2:9][CH2:10][OH:11])=[O:6].ClC(Cl)C(O)=O>>[F:1][C:2]1[C:3]([NH:22][C:23]2[CH:28]=[CH:27][C:26]([I:29])=[CH:25][C:24]=2[F:30])=[C:4]([CH:12]=[C:13]([CH2:16][NH:17][O:18][CH:19]([CH3:21])[CH3:20])[C:14]=1[F:15])[C:5]([NH:7][O:8][CH2:9][CH2:10][OH:11])=[O:6]
Reactant: CC(C)O/N=C/c1cc(C(=O)NOCCO)c(Nc2ccc(I)cc2F)c(F)c1F
Agent: O=C(O)C(Cl)Cl
Product: CC(C)ONCc1cc(C(=O)NOCCO)c(Nc2ccc(I)cc2F)c(F)c1F
Yield: 89 %

Procedure:
The title compound was obtained by a procedure similar to that in Step C of Example 9. Namely, (E)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-(isopropoxyimino-methyl)-benzamide was reduced with borane-pyridine complex in the presence of dichloroacetic acid to give 3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-(isopropoxyamino-methyl)-benzamide (65.0 mg, 89% in 2 steps).