Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16](O)=[O:17])=[C:11]([N+:19]([O-])=O)[CH:10]=1>C(O)(=O)C.[Fe]>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:10]=[C:11]2[C:12]([CH2:15][C:16](=[O:17])[NH:19]2)=[CH:13][CH:14]=1
Reactant: COc1ccccc1-c1ccc(CC(=O)O)c([N+](=O)[O-])c1
Agent: [Fe]
Solvent: CC(=O)O
Product: COc1ccccc1-c1ccc2c(c1)NC(=O)C2
Temperature: 100 °C
Yield: 66.2 %

Procedure:
Iron powder (5 g) was added in one portion to 9.8 g of 2′-methoxy-3-nitrobiphenyl-4-acetic acid in 50 mL of glacial acetic acid was heated to 100° C. for 3 hours. The reaction mixture was concentrated to dryness, sonicated in ethyl acetate and filtered to remove the insolubles. The filtrate was washed twice with 1 N hydrochloric acid, water, brine, dried over anhydrous sodium sulfate and concentrated. The residue was chromatographed on silica gel in ethyl acetate:hexane 1:2 to give 5.4 g (69% yield based on 5-bromo-2-fluoronitrobenzene) of 6-(2-methoxyphenyl)-2-oxindole as a rose colored solid.
Reaction SMILES: [C:1]1([CH3:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:9]([CH3:17])([CH2:11][CH2:12][C:13](Cl)([CH3:15])[CH3:14])[CH3:10].[Cl-].[Al+3].[Cl-].[Cl-]>O>[CH3:7][C:1]1[CH:6]=[CH:5][C:4]2[C:13]([CH3:15])([CH3:14])[CH2:12][CH2:11][C:9]([CH3:17])([CH3:10])[C:3]=2[CH:2]=1
Reactant: CC(C)(Cl)CCC(C)(C)Cl
Reactant: Cc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Product: Cc1ccc2c(c1)C(C)(C)CCC2(C)C
Temperature: 0 °C
Reaction time: 1 h
Yield: 97.4 %

Procedure:
In a round bottom flask there are introduced 64 ml (600 mmoles) of toluene and 36.6 g (200 mmoles) of 2,5-dichloro-2,5-dimethyl hexane. The reaction mixture is cooled to 0° C. and there are added, by small amounts, 4.1 g (30 mmoles) of aluminum chloride. The reaction mixture is stirred for 1 hour at ambient temperature, poured into water and extracted with CH2Cl2. The organic phase is decanted, dried on magnesium sulfate and evaporated. The resulting oil is purified by distillation. 39.4 g (98%) of 2-methyl-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl naphthalene which boils at 68° C. (under 1 mm of mercury) are obtained.
Reaction SMILES: [Br:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([CH:9]2[CH2:11][O:10]2)=[CH:4][N:3]=1.[NH2:12][CH2:13][CH2:14][OH:15].CCOC(C)=O.C1COCC1>C1COCC1>[Br:1][C:2]1[N:3]=[CH:4][C:5]([CH:9]([OH:10])[CH2:11][NH:12][CH2:13][CH2:14][OH:15])=[CH:6][C:7]=1[CH3:8]
Reactant: Cc1cc(C2CO2)cnc1Br
Reactant: NCCO
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1cc(C(O)CNCCO)cnc1Br
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of (RS)-2-bromo-3-methyl-5-(oxiran-2-yl)pyridine (1.4 g) in THF (6 ml) was added 2-aminoethanol (3.92 ml) and the mixture was stirred at room temperature overnight. The reaction mixture was then poured into EtOAc/THF (1:1) and the mixture was washed with saturated brine. The organic layer was dried over Na2SO4 and concentrated in vacuo to afford (RS)-1-(6-bromo-5-methylpyridin-3-yl)-2-(2-hydroxyethylamino)ethanol (1.76 g) as an off-white solid which was used in the next step without further purification. MS (ISP): 277.0 ([{81Br}M+H]+), 275.0 ([{79Br}M+H]+), 258.9 ([{81Br}M+H—H2O]+), 257.0 ([{79Br}M+H—H2O]+).
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[CH2:7][N:6]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=3)=[CH:10][CH:9]=2)[C:5](=[O:23])[CH2:4]1.C(N(CC)CC)C.[C:31](Cl)(=[O:33])[CH3:32]>ClCCl>[F:22][C:18]1[CH:17]=[C:16]([CH:21]=[CH:20][CH:19]=1)[CH2:15][O:14][C:11]1[CH:10]=[CH:9][C:8]([N:6]2[C:5](=[O:23])[CH2:4][C@H:3]([NH:2][C:31](=[O:33])[CH3:32])[CH2:7]2)=[CH:13][CH:12]=1
Reactant: CC(=O)Cl
Reactant: N[C@H]1CC(=O)N(c2ccc(OCc3cccc(F)c3)cc2)C1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)N[C@H]1CC(=O)N(c2ccc(OCc3cccc(F)c3)cc2)C1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
A suspension of 11.3 mmol of (S)-4-amino-1-[4-(3-fluoro-benzyloxy)-phenyl]-pyrrolidin-2-one hydrochloride in 86 ml of dichloromethane was treated with 23.8 mmol of triethylamine and cooled to 0° C. To this solution, 12.5 mmol of acetylchloride were added and stirring at 0° C. was continued for 15 min. For the working-up, the reaction mixture was extracted twice with 100 ml of water. The organic layer was separated, dried over sodium sulfate and evaporated under reduced pressure. The crude product was triturated in 100 ml of toluene, then the solid collected on a filter funnel. In a second step, the product was triturated in 200 ml of tert-butylmethylether at RT. Again, the solid product was collected on a filter funnel and dried under high vacuum. There was obtained (S)-N-{1-[4-(3-fluoro-benzyloxy)-phenyl]-5-oxo-pyrrolidin-3-yl}-acetamide as a white solid. MS: m/e=343 (M+H)+; enantiomeric excess: >99.5%.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1F.[CH3:12][S-:13].[Na+]>CN(C=O)C>[Br:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[S:13][CH3:12]
Reactant: C[S-]
Reactant: O=[N+]([O-])c1ccc(F)c(Br)c1
Agent: [Na+]
Solvent: CN(C)C=O
Product: CSc1ccc([N+](=O)[O-])cc1Br
Temperature: 60 °C
Reaction time: 5 h

Procedure:
A solution of 25.7 g (120 mmol) 2-bromo-1-fluoro-4-nitrobenzene in 154 ml DMF is treated with 10.6 g (150 mmol) sodium thiomethylate and stirred for 5 hours at 60° C. The mixture is stirred at room temperature for 18 hours, again treated with 1.0 g sodium thiomethylate and stirred for a further 6 hours at 60° C. After cooling, the mixture is poured into ice-water and extracted with ethyl acetate (3×). The combined organic phases are washed with water, dried (Na2SO4), filtered and concentrated. The residue obtained is chromatographically purified (hexane/ethyl acetate 2:1). 20.4 g (82 mmol, corresponding to 70% of theor.) of the product is obtained.
Reaction SMILES: [C:1]([CH2:3][CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([F:14])[CH:12]=2)/[C:7](=[CH:15]\[C:16]2[CH:21]=[CH:20][C:19]([S:22][CH3:23])=[CH:18][CH:17]=2)/[C:6]=1[CH3:24])#N.[H-].C([Al+]CC(C)C)C(C)C.C[OH:36]>C1(C)C=CC=CC=1>[F:14][C:11]1[CH:12]=[C:13]2[C:8](=[CH:9][CH:10]=1)/[C:7](=[CH:15]\[C:16]1[CH:21]=[CH:20][C:19]([S:22][CH3:23])=[CH:18][CH:17]=1)/[C:6]([CH3:24])=[C:5]2[CH2:4][CH2:3][CH:1]=[O:36]
Reactant: CSc1ccc(/C=C2/C(C)=C(CCC#N)c3cc(F)ccc32)cc1
Reactant: CO
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: Cc1ccccc1
Product: CSc1ccc(/C=C2/C(C)=C(CCC=O)c3cc(F)ccc32)cc1
Temperature: -78 °C
Reaction time: 2 h

Procedure:
To a solution of the nitrile from Step 2 (415 mg, 1.24 mmol) in toluene (4.5 mL) at -78° C. there was added diisobutyl aluminum hydride (1M) in toluene (1.9 mL, 1.9 mmol) and the mixture was stirred at -78° C. for 2 hours; methanol (2 mL) was added and the mixture allowed to warm to room temperature. After partition between ether and water, the residue from evaporation of the organic fraction was chromatographed on silica gel eluting with a 1:2 mixture of ether:hexane to afford the pure title compound as an oil which solidified on standing.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[C:8]([NH:15][C:16]3[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:17]=3[N+:23]([O-])=O)[S:7][C:6]=2[CH:26]=1.[H][H]>[C].[Pd].C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[C:8]([NH:15][C:16]3[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:17]=3[NH2:23])[S:7][C:6]=2[CH:26]=1
Reactant: CCOC(=O)c1c(Nc2cc(F)ccc2[N+](=O)[O-])sc2cc(Br)ccc12
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCOC(=O)c1c(Nc2cc(F)ccc2N)sc2cc(Br)ccc12

Procedure:
In addition, in the same manner as in Starting Material Synthesis Example 19 and using ethyl 6-bromo-2-(5-fluoro-2-nitroanilino)benzo[b]thiophene-3-carboxylate, ethyl acetate, 10% palladium-carbon and hydrogen (60 atm kg/cm2), ethyl 6-bromo-2-(2-amino-5-fluoroanilino)benzo[b]thiophene-3-carboxylate is obtained.
Reaction SMILES: Cl.[F:2][C:3]1[CH:37]=[C:36]([NH:38][C:39]([N:41]2[CH2:45][CH2:44][N:43]([C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=3)[C:42]2=[O:52])=[O:40])[CH:35]=[CH:34][C:4]=1[O:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]2[CH:12]=[C:13]([C:15]3[N:20]=[CH:19][C:18]([CH2:21][N:22]([CH2:30][CH2:31][O:32][CH3:33])C(=O)OC(C)(C)C)=[CH:17][CH:16]=3)[S:14][C:7]=12>C(Cl)Cl>[F:2][C:3]1[CH:37]=[C:36]([NH:38][C:39]([N:41]2[CH2:45][CH2:44][N:43]([C:46]3[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=3)[C:42]2=[O:52])=[O:40])[CH:35]=[CH:34][C:4]=1[O:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]2[CH:12]=[C:13]([C:15]3[CH:16]=[CH:17][C:18]([CH2:21][NH:22][CH2:30][CH2:31][O:32][CH3:33])=[CH:19][N:20]=3)[S:14][C:7]=12
Reactant: COCCN(Cc1ccc(-c2cc3nccc(Oc4ccc(NC(=O)N5CCN(c6ccccc6)C5=O)cc4F)c3s2)nc1)C(=O)OC(C)(C)C
Agent: Cl
Solvent: ClCCl
Product: COCCNCc1ccc(-c2cc3nccc(Oc4ccc(NC(=O)N5CCN(c6ccccc6)C5=O)cc4F)c3s2)nc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 106.1 %

Procedure:
HCl gas was bubbled into a solution of 127 (61 mg, 0.08 mmol) in DCM. The flask was capped and the mixture was stirred at room temperature for 30 min. Formed precipitate was collected by filtration and washed with DCM to afford 128 (52 mg, 84% yield), presumably as a trihydrochloride salt. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 10.59 (s, 1H), 9.34 (br.s, 2H), 8.75 (s, 1H), 8.62 (d, J=5.7 Hz, 1H), 8.43 (s, 11H), 8.38 (d, J=8.5 Hz, 1H), 8.15 (dd, J=8.2, 2.1 Hz, 1H), 7.86 (dd, J=12.9, 2.4 Hz, 1H), 7.62 (d, J=7.6 Hz, 2H), 7.4-7.6 (m, 4H), 7.17 (t, J=7.3 Hz, 1H), 6.81 (d, J=5.5 Hz, 1H), 4.25 (m, 2H), 3.95 (m, 4H), 3.62 (m, 2H), 3.29 (s, 3H), 3.13 (br.s, 2H). MS (m/z): 613.3 (M+H).
Reaction SMILES: [CH2:1]([N:3]1[CH2:7][CH2:6][CH2:5][C@@H:4]1[C:8]([N:10]([CH2:12][C:13]1[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=1[S:20]([NH:23][C:24]1[C:33]([C:34]([O:36]C)=[O:35])=[C:32]2[C:27]([CH:28]3[CH2:38][CH:29]3[CH2:30][O:31]2)=[CH:26][CH:25]=1)(=[O:22])=[O:21])[CH3:11])=[O:9])[CH3:2].O.[OH-].[Li+]>O1CCOCC1.O>[CH2:1]([N:3]1[CH2:7][CH2:6][CH2:5][C@@H:4]1[C:8]([N:10]([CH2:12][C:13]1[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=1[S:20]([NH:23][C:24]1[C:33]([C:34]([OH:36])=[O:35])=[C:32]2[C:27]([CH:28]3[CH2:38][CH:29]3[CH2:30][O:31]2)=[CH:26][CH:25]=1)(=[O:22])=[O:21])[CH3:11])=[O:9])[CH3:2]
Reactant: CCN1CCC[C@@H]1C(=O)N(C)Cc1cc(F)ccc1S(=O)(=O)Nc1ccc2c(c1C(=O)OC)OCC1CC21
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CCN1CCC[C@@H]1C(=O)N(C)Cc1cc(F)ccc1S(=O)(=O)Nc1ccc2c(c1C(=O)O)OCC1CC21
Temperature: 100 °C
Yield: 30.7 %

Procedure:
A mixture of methyl (1aRS,7bSR)-5-(2-{N—[((R)-1-ethylpyrrolidine-2-yl)carbonyl]-N-methyl-aminomethyl}-4-fluorobenzenesulfonylamino)-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylate (Intermediate 155, 0.177 g) and lithium hydroxide monohydrate (0.136 g) in dioxane (5 mL) and water (2 mL) was stirred and heated at 100° C. for 19.5 hours. After cooling, the mixture was evaporated to dryness and the residue was acidified by addition of aqueous citric acid solution (10%). The resultant solid was collected by filtration, washed with water and dried under vacuum at 40° C. The solid was purified by preparative HPLC (C18) eluting with a mixture of methanol and water, containing 0.1% formic acid, with a gradient of 10-98% to give (1aRS,7bSR)-5-(2-{N—[((R)-1-ethylpyrrolidine-2-yl)carbonyl]-N-methylaminomethyl}-4-fluoro-benzenesulfonylamino)-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylic acid (0.053 g) as a white solid.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([N:13](CC2C=CC(OC)=CC=2)[C:14]2[CH:15]=[C:16]([CH:27]=[CH:28][CH:29]=2)[C:17]([N:19]([CH3:26])[CH:20]2[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21]2)=[O:18])[C:5]2[N:6]([C:8]([C:11]#[N:12])=[CH:9][N:10]=2)[N:7]=1.[CH3:39][O:40][C:41]1[CH:42]=[C:43]([CH:45]=[C:46]([N:48]2[C:52]([CH3:53])=[N:51][N:50]=[N:49]2)[CH:47]=1)[NH2:44].CO>O>[C:11]([C:8]1[N:6]2[N:7]=[C:2]([NH:44][C:43]3[CH:45]=[C:46]([N:48]4[C:52]([CH3:53])=[N:51][N:50]=[N:49]4)[CH:47]=[C:41]([O:40][CH3:39])[CH:42]=3)[CH:3]=[C:4]([NH:13][C:14]3[CH:15]=[C:16]([CH:27]=[CH:28][CH:29]=3)[C:17]([N:19]([CH3:26])[CH:20]3[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21]3)=[O:18])[C:5]2=[N:10][CH:9]=1)#[N:12]
Reactant: COc1cc(N)cc(-n2nnnc2C)c1
Reactant: COc1ccc(CN(c2cccc(C(=O)N(C)C3CCN(C)C3)c2)c2cc(Cl)nn3c(C#N)cnc23)cc1
Solvent: O
Solvent: CO
Product: COc1cc(Nc2cc(Nc3cccc(C(=O)N(C)C4CCN(C)C4)c3)c3ncc(C#N)n3n2)cc(-n2nnnc2C)c1

Procedure:
Example 254 was prepared from 254A and 3-methoxy-5-(5-methyl-1H-tetrazol-1-yl)aniline by utilizing the procedure as described in Example 6. HPLC: Rt=1.53 min. (PHENOMENEX® Luna 5 micron C18 4.6×30 mm, 0 to 100 B in 2 min. with 1 min. hold time, flow rate=5 mL/min., detection at 254 nm, Solvent A: 10% methanol/90% water/0.1% TFA; Solvent B: 10% water/90% methanol/0.1% TFA). MS (ES): m/z=579.13 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]2[N:5]([N:15]=[CH:16][C:17]=2[C:18]#[C:19][C:20]2[CH:25]=[CH:24][N:23]=[C:22]([NH2:26])[CH:21]=2)[CH:6]=[C:7]([C:9]2[CH:10]=[N:11][N:12]([CH3:14])[CH:13]=2)[CH:8]=1.[CH3:27][O:28][C:29]1[CH:30]=[C:31]([S:35](Cl)(=[O:37])=[O:36])[CH:32]=[CH:33][CH:34]=1>N1C=CC=CC=1>[CH3:27][O:28][C:29]1[CH:30]=[C:31]([S:35]([NH:26][C:22]2[CH:21]=[C:20]([C:19]#[C:18][C:17]3[CH:16]=[N:15][N:5]4[CH:6]=[C:7]([C:9]5[CH:10]=[N:11][N:12]([CH3:14])[CH:13]=5)[CH:8]=[C:3]([O:2][CH3:1])[C:4]=34)[CH:25]=[CH:24][N:23]=2)(=[O:37])=[O:36])[CH:32]=[CH:33][CH:34]=1
Reactant: COc1cc(-c2cnn(C)c2)cn2ncc(C#Cc3ccnc(N)c3)c12
Reactant: COc1cccc(S(=O)(=O)Cl)c1
Solvent: c1ccncc1
Product: COc1cccc(S(=O)(=O)Nc2cc(C#Cc3cnn4cc(-c5cnn(C)c5)cc(OC)c34)ccn2)c1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of 4-{[4-methoxy-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-3-yl]ethynyl}pyridin-2-amine (24 mg, 0.070 mmol) in pyridine (1400 μl), was added 3-methoxybenzenesulfonyl chloride (29 μl, 0.203 mmol). The reaction mixture was stirred for 72 hours at room temperature. The precipitated solid was filtered and the solid washed with 10 mL of dichloromethane. The solid was dried in vacuo to afford 3-methoxy-N-(4-{[4-methoxy-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-3-yl]ethynyl}pyridin-2-yl)benzenesulfonamide an off-white solid. 1H NMR (500 MHz, DMSO-d6) δ 8.75 (s, 1H); 8.34 (s, 1H); 8.26 (s, 1H); 8.06 (s, 1H); 7.99 (bs, 2H); 7.49-7.42 (m, 2H); 7.38 (s, 1H); 7.16-7.15 (m, 2H); 7.11 (s, 1H); 6.85 (bs, 1H); 4.07 (s, 3H); 3.87 (s, 3H); 3.79 (s, 3H). LRMS (ESI) calculated for C26H22N6O3S [M+H]+, 515.1; found 515.1.
Reaction SMILES: C([O:5][NH:6][C:7]([C:9]1([N:22]([S:30]([C:33]2[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[CH:35][CH:34]=2)(=[O:32])=[O:31])[CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:14][CH2:13][N:12]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:11][CH2:10]1)=[O:8])(C)(C)C.C(O)C>ClC(Cl)C>[OH:5][NH:6][C:7]([C:9]1([N:22]([S:30]([C:33]2[CH:34]=[CH:35][C:36]([O:39][CH3:40])=[CH:37][CH:38]=2)(=[O:32])=[O:31])[CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:14][CH2:13][N:12]([CH2:15][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:11][CH2:10]1)=[O:8]
Reactant: COc1ccc(S(=O)(=O)N(Cc2ccccc2)C2(C(=O)NOC(C)(C)C)CCN(Cc3ccccc3)CC2)cc1
Solvent: CC(Cl)Cl
Solvent: CCO
Product: COc1ccc(S(=O)(=O)N(Cc2ccccc2)C2(C(=O)NO)CCN(Cc3ccccc3)CC2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4-[N-t-Butyloxycarbamoyl]-4-[[4-methoxybenzenesulfonyl](benzyl)amino]-1-[benzyl]piperidine is dissolved in dichloroethane (60 mL) and ethanol (1.0 mL) in a glass sealed tube. Hydrochloric acid gas (from a lecture bottle) is bubbled through the solution for 30 minutes at -10° C. The tube is sealed, gradually warmed to room temperature, and stirred overnight. At this point, hydrochloric acid gas is again bubbled through the reaction mixture as done previously and stirred at room temperature for an additional 24 hours. The reaction mixture is reduced to 1/3 volume in vacuo and triturated with diethyl ether. The solid is filtered off and dried in vacuo to provide 4-[N-hydroxy-carbamoyl]-4-[[4-methoxybenzenesulfonyl](benzyl)amino]- 1-[benzyl]-piperidine, m.p. 135.5°-142° C.
Reaction SMILES: [N:1]#N.[CH3:3][C:4]1([C:9]2[CH:10]=[C:11]([CH2:14][N:15]3C=[C:18]([N+:20]([O-])=O)[CH:17]=[N:16]3)[S:12][CH:13]=2)[O:8][CH2:7][CH2:6][O:5]1.[NH4+].[Cl-]>CCO.O.[Fe]>[CH3:3][C:4]1([C:9]2[CH:10]=[C:11]([CH2:14][N:15]3[N:1]=[C:18]([NH2:20])[CH:17]=[N:16]3)[S:12][CH:13]=2)[O:8][CH2:7][CH2:6][O:5]1
Reactant: N#N
Reactant: CC1(c2csc(Cn3cc([N+](=O)[O-])cn3)c2)OCCO1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: CC1(c2csc(Cn3ncc(N)n3)c2)OCCO1
Temperature: 75 °C
Reaction time: 1 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a mixture of 1-[4-(2-methyl-[1,3]dioxolan-2-yl)-thiophen-2-ylmethyl]-4-nitro-1H-pyrazole (115 mg, 0.39 mmol), iron powder (65 mg, 1.16 mmol) and NH4Cl (106 mg, 1.97 mmol) in a mixture of EtOH (3.0 mL) and water (1.5 mL) was stirred at 75° C. for 60 min. The reaction mixture was filtered while hot and concentrated under reduced pressure. The filtrated was dried over Na2SO4, filtered, and the solvents were removed under reduced pressure to give the title compound as a yellow oil: TLC: rf (EA)=0.63. LC-MS-conditions 02: tR=0.76 min; [M+H]+=267.09.
Reaction SMILES: O[C:2]1([C:8]2([C:12]#[N:13])[CH2:11][CH2:10][CH2:9]2)[CH2:7][CH2:6][O:5][CH2:4][CH2:3]1.O=P(Cl)(Cl)Cl>N1C=CC=CC=1>[O:5]1[CH2:4][CH:3]=[C:2]([C:8]2([C:12]#[N:13])[CH2:11][CH2:10][CH2:9]2)[CH2:7][CH2:6]1
Reactant: N#CC1(C2(O)CCOCC2)CCC1
Solvent: O=P(Cl)(Cl)Cl
Solvent: c1ccncc1
Product: N#CC1(C2=CCOCC2)CCC1
Temperature: 25 °C
Yield: 78 %

Procedure:
To a solution of Example 239A (0.4 g, 2.2 mmol) in pyridine (5 mL) was added POCl3 (2 mL, 22 mmol) at room temperature. and the mixture was refluxed overnight. The reaction mixture was cooled to room temperature and carefully quenched with cold water. The resulting mixture was extracted with EtOAc (2×30 mL). The combined organic phases were washed with brine (10 mL), dried over Na2SO4, filtered and concentrated to obtain a dehydration product 1-(3,6-dihydro-2H-pyran-4-yl)cyclobutanecarbonitrile (0.28 g). This crude material was dissolved in EtOH, followed by the addition of Pd/C. The solution was hydrogenated at room temperature overnight, filtered, and concentrated to obtain the title compound (0.24 g), which was used in the next step without further purification.
Reaction SMILES: C(OC[N:9]1[CH:13]=[C:12]([CH2:14][CH2:15][CH2:16][C:17](=[O:25])[NH:18][CH:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)[N:11]=[N:10]1)(=O)C(C)(C)C.[Cl:26][C:27]1[CH:32]=[C:31]([Cl:33])[CH:30]=[CH:29][C:28]=1[CH2:34][CH2:35][C:36](O)=[O:37]>>[Cl:26][C:27]1[CH:32]=[C:31]([Cl:33])[CH:30]=[CH:29][C:28]=1[CH2:34][CH2:35][C:36]([N:22]1[CH2:21][CH2:20][CH:19]([NH:18][C:17](=[O:25])[CH2:16][CH2:15][CH2:14][C:12]2[N:11]=[N:10][NH:9][CH:13]=2)[CH2:24][CH2:23]1)=[O:37]
Reactant: CC(C)(C)C(=O)OCn1cc(CCCC(=O)NC2CCNCC2)nn1
Reactant: O=C(O)CCc1ccc(Cl)cc1Cl
Product: O=C(CCCc1c[nH]nn1)NC1CCN(C(=O)CCc2ccc(Cl)cc2Cl)CC1

Procedure:
The title compound was prepared from (4-(4-oxo-4-(piperidin-4-ylamino)butyl)-1H-1,2,3-triazol-1-yl)methyl pivalate (Example 37, step 5) (200 mg, 0.516 mmol) and commercially available 3-(2,4-dichlorophenyl)propanoic acid (Fisher) (113 mg, 0.516 mmol) analogously to Example 38, steps 1 and 2;
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:12][CH:11]([CH3:13])[C:10]([NH:14][CH:15]=[O:16])=[N:9]2)=[CH:4][CH:3]=1.[C:17](OC(=O)C)(=O)C>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:12][CH:11]([CH3:13])[C:10]([NH:14][C:15](=[O:16])[CH3:17])=[N:9]2)=[CH:6][CH:7]=1
Reactant: CC1CN(c2ccc(Cl)cc2)N=C1NC=O
Reactant: CC(=O)OC(C)=O
Product: CC(=O)NC1=NN(c2ccc(Cl)cc2)CC1C
Reaction time: 0.25 h

Procedure:
A 9.0 g. amount of 3-amino-1-(p-chlorophenyl)-4-methyl-2-pyrazoline (prepared as described in Example 23) is dissolved in 54.0 ml. of acetic anhydride. The warm solution is allowed to stand for 16 hours at room temperature with some solid separation. The solid is collected by filtration and is dissolved in methanol. Then 1 N potassium hydroxide in methanol is added to make basic. After 15 minutes at room temperature, the solvent is removed in vacuo and water is added to separate a solid. The solid is collected and recrystallized from dichloromethane-hexane to give 6.5 g. of the desired product as white crystals, m.p. 172°-173° C.
Reaction SMILES: B(Br)(Br)Br.[CH:5]1([C:12]2[N:16]=[C:15]([CH:17]=[CH:18][C:19]3[CH:24]=[CH:23][C:22]([O:25]C)=[C:21]([O:27]C)[CH:20]=3)[O:14][N:13]=2)[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1>ClCCl>[CH:5]1([C:12]2[N:16]=[C:15]([CH:17]=[CH:18][C:19]3[CH:20]=[C:21]([OH:27])[C:22]([OH:25])=[CH:23][CH:24]=3)[O:14][N:13]=2)[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1
Reactant: COc1ccc(C=Cc2nc(C3CCCCCC3)no2)cc1OC
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Oc1ccc(C=Cc2nc(C3CCCCCC3)no2)cc1O
Reaction time: 0.62 h

Procedure:
To a cooled solution of 1 mL of 1M boron tribromide (10.5 mmol) in 2 mL dichloromethane, 1.5 g (4.5 mmol) of 3-cycloheptyl-5-[2-(3,4-dimethoxy-phenyl)-vinyl]-[1,2,4]oxadiazole (compound of Example 57) dissolved in 15 mL of dichloromethane was added over a period of 15-20 min at −45° C. to −40° C. The reaction mixture was stirred at −45° C. to −40° C. for 30-45 min and allowed to attain a temperature of 25° C. to 30° C. slowly, over a period of 1 h. The reaction mixture was further stirred at 25° C. to 30° C. for 4-5 h. After completion of the reaction, the reaction mixture was quenched with 10 mL of chilled 5% sodium bicarbonate solution, below 20° C. (pH: 8-9). 10 mL of ethyl acetate was added to the reaction mixture to dissolve the solid and stirred for 10-15 min. The organic layer was separated and the aqueous layer was washed with 10 mL of 10% sodium chloride solution. The organic layer was collected and distilled to obtain a crude residue, which was purified by column chromatography (silica gel, chloroform-methanol) to yield the title compound.
Reaction SMILES: Br[C:2]1[CH:16]=[CH:15][C:5]([CH2:6][O:7][Si:8]([C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:10])[CH3:9])=[CH:4][CH:3]=1.[CH2:17]([C:19]1[N:29]([CH2:30][C:31]2[CH:32]=[C:33]([CH:36]=[CH:37][CH:38]=2)[CH:34]=[O:35])[C:22]2=[N:23][C:24]([CH3:28])=[CH:25][C:26]([CH3:27])=[C:21]2[N:20]=1)[CH3:18].[Cl-].[NH4+]>C1COCC1.C(OCC)(=O)C>[Si:8]([O:7][CH2:6][C:5]1[CH:15]=[CH:16][C:2]([CH:34]([C:33]2[CH:36]=[CH:37][CH:38]=[C:31]([CH2:30][N:29]3[C:22]4=[N:23][C:24]([CH3:28])=[CH:25][C:26]([CH3:27])=[C:21]4[N:20]=[C:19]3[CH2:17][CH3:18])[CH:32]=2)[OH:35])=[CH:3][CH:4]=1)([C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:10])[CH3:9]
Reactant: CC(C)(C)[Si](C)(C)OCc1ccc(Br)cc1
Reactant: CCc1nc2c(C)cc(C)nc2n1Cc1cccc(C=O)c1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCc1nc2c(C)cc(C)nc2n1Cc1cccc(C(O)c2ccc(CO[Si](C)(C)C(C)(C)C)cc2)c1
Temperature: -78 °C
Reaction time: 0.08 h
Yield: 65.8 %

Procedure:
4-Bromobenzyloxy-tert-butyldimethylsilane (1.23 g, 4.08 mmol) obtained in Step 1 was dissolved in THF (30 mL) and the flask was filled with argon. The reaction mixture was cooled to −78° C., and a 1.57 mol/L n-butyl lithium-hexane solution (2.60 mL, 4.09 mmol) was added thereto, followed by stirring at same temperature for 5 minutes. A solution of 3-(2-ethyl-5,7-dimethylimidazo[4,5-b]pyridin-3-ylmethyl)benzaldehyde (0.800 g, 2.72 mmol) obtained in Step 2 in THF (5 mL) was dropped into the mixture for 15 minutes, followed by stirring at −78° C. for 1 hour. The reaction mixture was added with a saturated aqueous ammonium chloride solution to terminate the reaction, and diluted with ethyl acetate. The organic layer was separated from the aqueous layer, and washed with water and saturated brine. The organic layer was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=3:2) to obtain [4-(tert-butyldimethylsilyloxymethyl)phenyl][3-(2-ethyl-5,7-dimethylimidazo[4,5-b]pyridin-3-ylmethyl)phenyl]methanol (0.923 g, yield 66%).