Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl.[CH:3]([C@:6]1([C:12]([N:14]2[CH2:19][CH2:18][N:17]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[CH:21]=3)[CH2:16][CH2:15]2)=[O:13])[CH2:10][CH2:9][C@@H:8]([NH2:11])[CH2:7]1)([CH3:5])[CH3:4].[CH2:30]([O:32][CH:33]1[C:38](=O)[CH2:37][CH2:36][O:35][CH2:34]1)[CH3:31].C(N(CC)CC)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl.CCOC(C)=O>[CH2:30]([O:32][CH:33]1[CH:38]([NH:11][C@@H:8]2[CH2:9][CH2:10][C@:6]([CH:3]([CH3:5])[CH3:4])([C:12]([N:14]3[CH2:19][CH2:18][N:17]([C:20]4[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:28])([F:29])[F:27])[CH:21]=4)[CH2:16][CH2:15]3)=[O:13])[CH2:7]2)[CH2:37][CH2:36][O:35][CH2:34]1)[CH3:31]
Reactant: CCOC1COCCC1=O
Reactant: CC(C)[C@]1(C(=O)N2CCN(c3cccc(C(F)(F)F)c3)CC2)CC[C@@H](N)C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CCOC1COCCC1N[C@@H]1CC[C@@](C(=O)N2CCN(c3cccc(C(F)(F)F)c3)CC2)(C(C)C)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 102.6 %

Procedure:
To a solution of (1R,3S)-3-isopropyl-3-({4-[3-(trifluoromethyl)phenyl]piperazin-1-yl}carbonyl)cyclopentanamine dihydrochloride (200 mg, 0.438 mmol), 3-ethoxytetrahydro-4H-pyran-4-one (130 mg, 0.88 mmol) and triethylamine (0.18 mL, 1.3 mmol) in methylene chloride (10 mL) was added sodium triacetoxyborohydride (180 mg, 0.88 mmol). After being stirred at room temperature overnight, the reaction mixture was diluted with EtOAc and washed with saturated Na2CO3. The aqueous layer was extracted with EtOAc three times. The combined organic layers were dried (MgSO4), concentrated and purified on silica gel (EtOAc to 1% Et3N/EtOAc to 5% Et3N/EtOAc) affording 230 mg of product. The product was separated by chiral HPLC to give two major isomers: isomer 1 (110 mg) and isomer 2 (77 mg). MS calculated for C27H40F3N3O3: (M+H) 512; found 512.2.
Reaction SMILES: [C:1]([CH:3]([C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][CH:13]=1)[C:8]([OH:10])=O)[CH3:4])#[N:2].C(Cl)(=O)C(Cl)=O.O1CCCC1.[NH2:25][C:26]1[CH:27]=[CH:28][C:29]([O:48][CH3:49])=[C:30]([CH:47]=1)[O:31][C:32]1[CH:33]=[CH:34][C:35]2[N:36]([CH:38]=[C:39]([NH:41][C:42]([CH:44]3[CH2:46][CH2:45]3)=[O:43])[N:40]=2)[N:37]=1>CN(C)C=O.CN1CCCC1=O>[C:1]([CH:3]([C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][CH:13]=1)[C:8]([NH:25][C:26]1[CH:27]=[CH:28][C:29]([O:48][CH3:49])=[C:30]([O:31][C:32]2[CH:33]=[CH:34][C:35]3[N:36]([CH:38]=[C:39]([NH:41][C:42]([CH:44]4[CH2:46][CH2:45]4)=[O:43])[N:40]=3)[N:37]=2)[CH:47]=1)=[O:10])[CH3:4])#[N:2]
Reactant: COc1ccc(N)cc1Oc1ccc2nc(NC(=O)C3CC3)cn2n1
Reactant: CC(C#N)c1cccc(C(=O)O)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN1CCCC1=O
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COc1ccc(NC(=O)c2cccc(C(C)C#N)c2)cc1Oc1ccc2nc(NC(=O)C3CC3)cn2n1
Yield: 56.4 %

Procedure:
Using 3-(1-cyanoethyl)benzoic acid (62 mg, 0.35 mmol), oxalyl chloride (38 μL, 0.44 mmol), N,N-dimethylformamide (1 drop), tetrahydrofuran (3.0 mL), N-[6-(5-amino-2-methoxyphenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide (100 mg, 0.30 mmol) and N-methylpyrrolidone (2.0 mL) as starting materials and in the same manner as in Example 335, the title compound (84 mg, 58%) was obtained as a white powder.
Reaction SMILES: [Cl:1][C:2]1[CH:29]=[C:28]([NH2:30])[CH:27]=[CH:26][C:3]=1[C:4]([NH:6][C:7]1[CH:25]=[CH:24][C:10]([C:11]([N:13]2[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=3[CH2:17][CH2:16][CH2:15][CH2:14]2)=[O:12])=[CH:9][CH:8]=1)=[O:5].[C:31](OC(=O)C)(=[O:33])[CH3:32].S(=O)(=O)(O)O.[OH-].[Na+]>C(O)(=O)C>[Cl:1][C:2]1[CH:29]=[C:28]([NH:30][C:31](=[O:33])[CH3:32])[CH:27]=[CH:26][C:3]=1[C:4]([NH:6][C:7]1[CH:25]=[CH:24][C:10]([C:11]([N:13]2[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=3[CH2:17][CH2:16][CH2:15][CH2:14]2)=[O:12])=[CH:9][CH:8]=1)=[O:5]
Reactant: CC(=O)OC(C)=O
Reactant: Nc1ccc(C(=O)Nc2ccc(C(=O)N3CCCCc4ccccc43)cc2)c(Cl)c1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: CC(=O)Nc1ccc(C(=O)Nc2ccc(C(=O)N3CCCCc4ccccc43)cc2)c(Cl)c1

Procedure:
A mixture of 1-[4-(2-chloro-4-aminobenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzazepine (0.55 g), acetic anhydride (15 ml), acetic acid (5 ml) and a drop of sulfuric acid is stirred at room temperature for 1 hour. To the reaction mixture is added aqueous 2N aqueous sodium hydroxide solution and the mixture is extracted with chloroform. The extract is washed with saturated saline solution and dried over magnesium sulfate. The solvent is concentrated and the resulting residue is recrystallized from methanol/diethyl ether to give 1-[4-(2-chloro-4-acetylaminobenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzazepine (0.28 g) as white powder, m.p. 214°-243° C.
Reaction SMILES: [C:1]([O:24][CH2:25][CH2:26][N:27]([CH3:29])[CH3:28])(=[O:23])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=[CH:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22].[I:30][CH3:31]>C(Cl)Cl>[I-:30].[C:1]([O:24][CH2:25][CH2:26][N+:27]([CH3:31])([CH3:29])[CH3:28])(=[O:23])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=[CH:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: CCCCCCCCCC=CC=CC=CC=CC=CC=CC(=O)OCCN(C)C
Reactant: CI
Solvent: ClCCl
Product: CCCCCCCCCC=CC=CC=CC=CC=CC=CC(=O)OCC[N+](C)(C)C
Product: [I-]
Temperature: 25 °C
Reaction time: 3 h
Yield: 96.3 %

Procedure:
To a solution of 2-dimethylaminoethyl docosahexaenoate (1.12 g, 2.80 mmol) in CH2Cl2 (10.0 mL) was added iodomethane (0.80 g, 5.60 mmol) dropwise at room temperature. The mixture was stirred at room temperature for 3 hr. The solvent and excess reagent was removed under reduced pressure and the residue was triturated with hexanes. The mixture was centrifuged and the supernatant was removed. The residue was dried under reduced pressure to provide the product, docosahexaenoyl choline iodide (1.46 g, 96%), as an off white solid.
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6]([CH:8]=O)=[CH:5][CH:4]=[CH:3]1.[CH2:10]([O:12][C:13]([C:15]1[NH:16][CH:17]=[CH:18][C:19]=1[NH2:20])=[O:14])[CH3:11].CC(O)=O.[BH3-]C#N.[Na+]>CCO>[CH2:10]([O:12][C:13]([C:15]1[NH:16][CH:17]=[CH:18][C:19]=1[NH:20][CH2:8][C:6]1[NH:7][C:2](=[O:1])[CH:3]=[CH:4][CH:5]=1)=[O:14])[CH3:11]
Reactant: O=Cc1cccc(=O)[nH]1
Reactant: CCOC(=O)c1[nH]ccc1N
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCO
Product: CCOC(=O)c1[nH]ccc1NCc1cccc(=O)[nH]1
Temperature: 25 °C
Reaction time: 1.25 h
Yield: 84.8 %

Procedure:
6-Oxo-1,6-dihydropyridine-2-carbaldehyde (WO 2002/006272) (0.31 g, 2.5 mmol) was dissolved in EtOH (10 mL). 3-Amino-1H-pyrrole-2-carboxylic acid ethyl ester (0.19 g, 1.3 mmol) was added, followed by HOAc (0.14 mL, 2.5 mmol). The mixture was stirred for 75 minutes at r.t. and then NaCNBH3 (0.16 g, 2.5 mmol) was added. The reaction mixture was stirred at r.t. overnight. The solvent was evaporated in vacuo and the crude product was purified by flash column chromatography (CH2Cl2/methanol gradient; 0 to 10% methanol), obtaining 0.288 g (85%) of the title product as an oil that crystallized upon standing.
Reaction SMILES: [O:1]=[C:2]([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=1)[CH2:3][CH2:4][C:5]([OH:7])=O.C(N(CC)CC)C.ClC(OCC(C)C)=O.[CH:33]([N:36]([CH3:54])[C@@H:37]1[CH2:42][CH2:41][C@H:40]([NH2:43])[C@H:39]([CH2:44][S:45]([C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)(=[O:47])=[O:46])[CH2:38]1)([CH3:35])[CH3:34].[OH-].[Na+]>C1COCC1>[CH:33]([N:36]([CH3:54])[C@@H:37]1[CH2:42][CH2:41][C@H:40]([NH:43][C:5](=[O:7])[CH2:4][CH2:3][C:2](=[O:1])[C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)[C@H:39]([CH2:44][S:45]([C:48]2[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=2)(=[O:46])=[O:47])[CH2:38]1)([CH3:35])[CH3:34]
Reactant: CC(C)N(C)[C@@H]1CC[C@H](N)[C@H](CS(=O)(=O)c2ccccc2)C1
Reactant: O=C(O)CCC(=O)c1cccc(C(F)(F)F)c1
Agent: CC(C)COC(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)N(C)[C@@H]1CC[C@H](NC(=O)CCC(=O)c2cccc(C(F)(F)F)c2)[C@H](CS(=O)(=O)c2ccccc2)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 62.3 %

Procedure:
Commercially available 4-oxo-4-(3-trifluoromethylphenyl)butyric acid (45.5 mg, 0.185 mmol) was dissolved in dry THF (3 mL). To the above solution was added triethyl amine (18.7 mg, 0.185 mmol) and isobutyl chloroformate (25.3 mg, 0.185 mmol) at 0° C. The mixture was stirred at 0° C. for 5 min. before the solution of (1R,3R,4S)—N1-isopropyl-N1-methyl-3-(phenylsulfonylmethyl)cyclohexane-1,4-diamine (see 30b) (50 mg, 0.154 mmol) in dry THF (3 mL) was added. The resulting mixture was warmed up to room temperature. The reaction was completed by 0.5 h. The mixture was treated with 1 N NaOH (5 mL) and extracted with CH2Cl2 (10 mL×2) The organic extracts were washed with water, brine and evaporated. The residue was chromatographed on silica gel (4% NH4OH/MeOH/CH2Cl2) to give the product (53 mg). MS found:(M+1)+: 553.32
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([NH2:13])=[C:11]([C:14]([O:16][CH3:17])=[O:15])[N:10]=[N:9]2)=[CH:4][CH:3]=1.[Cl:18][CH2:19][CH2:20][N:21]([CH2:24][CH3:25])[CH2:22][CH3:23]>CN(C)C=O>[ClH:18].[CH2:20]([N:21]([CH2:24][CH3:25])[CH2:22][CH2:23][N:9]1[N:10]=[C:11]([C:14]([O:16][CH3:17])=[O:15])[C:12]([NH:8][C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)=[N:13]1)[CH3:19]
Reactant: CCN(CC)CCCl
Reactant: COC(=O)c1nnn(-c2ccc(F)cc2)c1N
Solvent: CN(C)C=O
Product: CCN(CC)CCn1nc(Nc2ccc(F)cc2)c(C(=O)OC)n1
Product: Cl

Procedure:
A mixture consisting of 4.7 gm (0.02 mol) of methyl 1-(4-fluorophenyl)-5-amino-1H-1,2,3-triazole-4-carboxylate, 70 ml of absolute dimethyl formamide and 8.1 gm (0.06 mol) of 1-chloro-2-diethylamino-ethane was reacted as in Example 1. The reaction mixture was then evaporated in vacuo and the residue was dissolved in 2N hydrochloric acid. The solution was extracted with chloroform, filtered through activated charcoal, dried over sodium sulfate, and the chloroform was distilled off in vacuo. After recrystallization from isopropanol, 1.5 gm (20.2% of theory) of the desired compound were obtained; melting point 179° C.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:6][CH2:5][CH2:4][C@@H:3]1[NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11].C(=O)([O-])[O-].[K+].[K+].Cl[CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24]>C(#N)C>[C:10]([O:9][C:8]([NH:7][C@H:3]1[CH2:4][CH2:5][CH2:6][C@@H:2]1[NH:1][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[O:14])([CH3:11])([CH3:13])[CH3:12]
Reactant: CCOC(=O)CCl
Reactant: CC(C)(C)OC(=O)N[C@H]1CCC[C@@H]1N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)CN[C@H]1CCC[C@@H]1NC(=O)OC(C)(C)C
Temperature: 55 °C

Procedure:
tert-Butyl [(1S,2S)-2-aminocyclopentyl]carbamate (900 mg, 4.49 mmol) (purchased from Sigma Aldrich) was taken up in acetonitrile (13 mL). Potassium carbonate (932 mg, 6.74 mmol) and ethyl chloroacetate (0.577 mL, 5.39 mmol) were added, and the resulting mixture was heated to 55° C. overnight. The resulting mixture was cooled to room temperature and concentrated under reduced pressure. The residue was taken up in EtOAc, washed with water and brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (0-100% EtOAc/hexanes) to afford ethyl N-{(1S,2S)-2-[(tert-butoxycarbonyl)amino]cyclopentyl}glycinate.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][C@H:12]([CH3:14])[NH:11][CH2:10][C@H:9]1[CH3:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.F[C:17]1[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[C:19]([CH3:25])[CH:18]=1.C(N(C(C)C)CC)(C)C.C(OCC)(=O)C>CN1C(=O)N(C)CC1>[CH2:1]([N:8]1[C@H:9]([CH3:15])[CH2:10][N:11]([C:17]2[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[C:19]([CH3:25])[CH:18]=2)[C@@H:12]([CH3:14])[CH2:13]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[C@@H]1CN[C@@H](C)CN1Cc1ccccc1
Reactant: Cc1cc(F)ccc1C#N
Solvent: CN1CCN(C)C1=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(N2C[C@@H](C)N(Cc3ccccc3)C[C@@H]2C)ccc1C#N
Temperature: 210 °C
Reaction time: 48 h
Yield: 25.2 %

Procedure:
To a solution of 3.81 g of (2R,5S)-1-benzyl-2,5-dimethylpiperazine in 20 ml of DMI were added 3.80 g of 4-fluoro-2-methylbenzonitrile and 7.27 g of diisopropylethylamine, followed by 2 days of stirring in a sealed tube at 210° C. After the addition of ethyl acetate to the reaction solution, the mixture was washed with water and the organic layer was dried over anhydrous sodium sulfate. The solvent was removed by evaporation and the resulting residue was purified by silica gel column chromatography to obtain 1.50 g of the title compound as a solid from an eluate eluted with hexane-ethyl acetate (85:15, v/v).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:10]2[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=2)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[CH3:16][O:17][S:18]([O:21]C)(=[O:20])=[O:19]>C(OCC)C>[CH3:16][O:17][S:18]([O-:21])(=[O:20])=[O:19].[CH3:16][N+:13]1[CH:14]=[CH:15][C:10]([C:6]2[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)=[CH:11][CH:12]=1
Reactant: O=[N+]([O-])c1cccc(-c2ccncc2)c1
Reactant: COS(=O)(=O)OC
Solvent: CCOCC
Product: COS(=O)(=O)[O-]
Product: C[n+]1ccc(-c2cccc([N+](=O)[O-])c2)cc1
Temperature: 100 °C

Procedure:
A mixture of 4-(3-nitrophenyl)pyridine (4.0 g; 20 mmol) and dimethylsulphate (10 ml) was heated to 100° C. for five days. The cooled mixture wad diluted with diethyl ether (50 ml) and stirred thoroughly. The mixture was decanted and the oily bottom layer was washed additionally three times with diethyl ether and once with ethanol to leave the crystalline product (2.9 g; 47%).
Reaction SMILES: O.[O:2]=[C:3]1[N:8]([Na])[C:7](=[O:10])[CH:6]=[N:5][NH:4]1.[CH2:11](Br)[CH:12]=[CH2:13]>C(O)CO>[O:2]=[C:3]1[N:8]([CH2:13][CH:12]=[CH2:11])[C:7](=[O:10])[CH:6]=[N:5][NH:4]1
Reactant: C=CCBr
Reactant: O=c1cn[nH]c(=O)n1[Na]
Solvent: OCCO
Solvent: O
Product: C=CCn1c(=O)cn[nH]c1=O
Temperature: 80 °C

Procedure:
A mixture of 6.12 g 3,5-dioxo-4-sodio-2,3,4,5-tetrahydro-1,2,4-triazine monohydrate, 5.81 g allyl bromide and 50 ml ethylene glycol was heated to 80° C. for 4 hours.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([C:13]2[N:14]=[CH:15][N:16]([C:18]3[CH:26]=[CH:25][C:21]([C:22](O)=[O:23])=[CH:20][N:19]=3)[CH:17]=2)=[C:11]([CH3:27])[N:10]=[N:9]1.CN(C(O[N:36]1N=N[C:38]2C=CC=[CH:42][C:37]1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C.C(N)(C)C>CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([C:13]2[N:14]=[CH:15][N:16]([C:18]3[CH:26]=[CH:25][C:21]([C:22]([NH:36][CH:37]([CH3:42])[CH3:38])=[O:23])=[CH:20][N:19]=3)[CH:17]=2)=[C:11]([CH3:27])[N:10]=[N:9]1
Reactant: Cc1nnn(-c2ccccc2F)c1-c1cn(-c2ccc(C(=O)O)cn2)cn1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)N
Solvent: CN(C)C=O
Product: Cc1nnn(-c2ccccc2F)c1-c1cn(-c2ccc(C(=O)NC(C)C)cn2)cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 66.6 %

Procedure:
To a solution of 6-(4-(1-(2-fluorophenyl)-4-methyl-1H-1,2,3-triazol-5-yl)-1H-imidazol-1-yl)nicotinic acid (46 mg, 0.126 mmol) and TBTU (45 mg, 0.139 mmol) in DMF (2.0 mL) was added DIPEA (110 μL, 0.631 mmol). Then isopropylamine (12 μL, 0.139 mmol) was added and the mixture was stirred at room temperature under Ar for 2 h. The mixture was then evaporated and purification by chromatography (silica, 50 to 100% ethyl acetate in heptane) afforded the title compound (34 mg, 66%) as a white foam. MS: m/e=406.3 [M+H]+.
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][NH:9][S:10]([CH2:13][CH2:14][CH3:15])(=[O:12])=[O:11])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:16][O:17][C:18](=[O:34])[C:19]1[CH:24]=[CH:23][C:22]([CH2:25]Br)=[CH:21][C:20]=1[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[CH3:33]>>[CH3:16][O:17][C:18](=[O:34])[C:19]1[CH:24]=[CH:23][C:22]([CH2:25][N:9]([CH2:8][CH2:7][CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]2)[S:10]([CH2:13][CH2:14][CH3:15])(=[O:12])=[O:11])=[CH:21][C:20]=1[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[CH3:33]
Reactant: CCCS(=O)(=O)NCCC1CCCCC1
Reactant: COC(=O)c1ccc(CBr)cc1-c1ccccc1C
Product: CCCS(=O)(=O)N(CCC1CCCCC1)Cc1ccc(C(=O)OC)c(-c2ccccc2C)c1

Procedure:
The desired product was prepared using the method described in Example 1174B starting with N-(2-cyclohexylethyl)-N-propanesulfonylamine, prepared as in Example 1187A, and 4-bromomethyl-2-(2-methylphenyl)benzoic acid methyl ester, prepared as in Example 1178A-D. m/e (ESI) 472 (MH+)
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[C:6]([CH3:8])[CH:7]=1.[N+:10]([O-])([O-:12])=[O:11].[Na+].Cl>CCOCC.O>[CH3:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[C:6]([CH3:8])[C:7]=1[N+:10]([O-:12])=[O:11]
Reactant: O=[N+]([O-])[O-]
Reactant: Cc1cc(C)cc(O)c1
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Product: Cc1cc(O)cc(C)c1[N+](=O)[O-]
Temperature: 25 °C
Yield: 19.6 %

Procedure:
Formation of compound (b): To a mixture of 3,5-dimethylphenol (a) (25 g, 205 mmol) and NaNO3 (26.1 g, 307mmol) in ether (200 mL) and water (200 mL), at 0° C., 250 mL of conc.HCl solution was added dropwise within 1 hour under stirring. The reaction mixture was kept under stirring overnight and the temperature was allowed to warm to room temperature. The organic phase was separated and the aqueous phase was extracted with ether (3×100 mL). The combined organic phase was washed with 3N HCl (2×100 mL), saturated NaHCO3 solution (3×100 ML) and finally with brine (200 mL), dried over Na2SO4, filtered and concentrated to dryness. The obtained residue was purified by chromatography over silica gel by using ethyl acetate and hexane (2:8) as eluent. The collected fractions were further recrystalized in ether/hexane to afford compound (b), 3,5-dimethyl-4-nitrophenol (6.7g, 19% yield) as a yellow solid. MS: m/e 167
Reaction SMILES: [N:1]1([C:10]2[S:14][C:13]([C:15]([O:17]C)=O)=[C:12]([O:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=3)[CH:11]=2)[C:9]2[CH:8]=[CH:7][N:6]=[CH:5][C:4]=2[N:3]=[CH:2]1.[NH3:31]>CO>[N:1]1([C:10]2[S:14][C:13]([C:15]([NH2:31])=[O:17])=[C:12]([O:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:28])([F:29])[F:30])[CH:22]=3)[CH:11]=2)[C:9]2[CH:8]=[CH:7][N:6]=[CH:5][C:4]=2[N:3]=[CH:2]1
Reactant: N
Reactant: COC(=O)c1sc(-n2cnc3cnccc32)cc1OCc1cccc(C(F)(F)F)c1
Solvent: CO
Product: NC(=O)c1sc(-n2cnc3cnccc32)cc1OCc1cccc(C(F)(F)F)c1

Procedure:
In a similar manner as described for example 33, 27.5 mg of methyl 5-(1H-imidazo[4,5-c]pyridin-1-yl)-3-{[3-(trifluoromethyl)benzyl]oxy}thiophene-2-carboxylate and 5 ml of a saturated solution of ammonia in methanol yield the title compound.
Reaction SMILES: C(O)=O.[C:4](OC(=O)C)(=O)C.[NH2:11][C:12]1[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][CH:13]=1>C(Cl)Cl>[C:16]([C:15]1[CH:18]=[CH:19][C:12]([NH:11][CH3:4])=[CH:13][CH:14]=1)#[N:17]
Reactant: N#Cc1ccc(N)cc1
Reactant: CC(=O)OC(C)=O
Solvent: O=CO
Solvent: ClCCl
Product: CNc1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of formic acid 30 mL and acetic anhydride 30 mL stirred at room temperature for 1 h was added a solution of 4-aminobenzonitrile 2.36 g (20.0 mmol) in CH2Cl2 150 mL dropwise at 0° C. The reaction mixture was stirred at room temperature for 4 h (EMI-mass: 146 [M]+). After concentration, the crude intermediate was dissolved in THF 50 mL, and was added BH3 in Me2S 15 mL. The reaction mixture was then stirred for 5 h under reflux. The crude product was extracted with EtOAc, washed with water, sat. Na2CO3 aqueous solution and dried on anhydrous MgSO4. After removal of solvents, 4-cyano-N-methylaniline was obtained in 80% purity based on GC/MS (EMI-mass: 132 [M]+). A mixture of crude 4-cyano-N-methylaniline 0.40 g (ca. 2 mmol) and 4-chloro-2-methylquinazoline 0.357 g (2.0 mmol) with NaOAc 0.2 g (2.3 mmol) in THF 20 mL and H2O 12 mL was stirred at 23° C. for 4 days. After removing solvents, the crude product was purified with preparative HPLC to give the titled compound in 1% yield (10 mg). 1H NMR (CD3OD, 400 MHz): δ 7.94 (d, 2H, J=8.8 Hz), 7.91-7.86 (m, 1H), 7.76-7.73 (m, 1H), 7.65 (d, 2H, J=8.8 Hz), 7.34-7.30 (m, 1H), 6.99-6.96 (m, 1H), 3.87 (s, 3H), 2.81 (s, 3H). m/e: 275.1420 (M+1).
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH:8]=O)=[C:6]([NH:10][C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[N:16]([CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[CH:22]=2)[N:15]=[CH:14]3)[N:5]=[CH:4][N:3]=1.[CH3:28][NH:29][NH2:30].[CH3:31]C(O)C>O>[CH3:28][N:29]([CH3:31])[N:30]=[CH:8][C:7]1[C:6]([NH:10][C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[N:16]([CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[CH:22]=2)[N:15]=[CH:14]3)=[N:5][CH:4]=[N:3][C:2]=1[NH2:1]
Reactant: Nc1ncnc(Nc2ccc3c(cnn3Cc3cccc(F)c3)c2)c1C=O
Reactant: CC(C)O
Reactant: CNN
Solvent: O
Product: CN(C)N=Cc1c(N)ncnc1Nc1ccc2c(cnn2Cc2cccc(F)c2)c1
Temperature: 95 °C
Reaction time: 3 h
Yield: 94 %

Procedure:
A mixture of crude 4-amino-6-[1-(3-fluoro-benzyl)-1H-indazol-5-ylamino]-pyrimidine-5-carbaldehyde (14.2 mg, 0.039 mmol) and methylhydrazine (5.4 mg, 0.118 mmol) in i-PrOH (1.5 mL) was stirred at 95° C. for 3 h, then diluted with water. The yellow precipitate was extracted with ethyl acetate (35 mL) and the organic extracts were evaporated. The residue was purified by flash column chromatography on silica gel (EtOAc then to 5% MeOH/EtOAc) to give the desired product (14.3 mg, 94%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].[C:9]([O:13][C:14]([NH:16][CH:17]([CH2:20][C:21]#CC)[CH:18]=O)=[O:15])([CH3:12])([CH3:11])[CH3:10].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].CCOC(C)=O>ClC(Cl)C>[C:9]([O:13][C:14]([NH:16][CH:17]([CH2:20][CH2:21][NH:5][C:4]1[CH:6]=[CH:7][CH:8]=[C:2]([Cl:1])[CH:3]=1)[CH3:18])=[O:15])([CH3:12])([CH3:11])[CH3:10]
Reactant: CC#CCC(C=O)NC(=O)OC(C)(C)C
Reactant: Nc1cccc(Cl)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(Cl)Cl
Product: CC(CCNc1cccc(Cl)c1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a 0° C. solution of 3-chloroaniline (4.33 mL, 40.9 mmol), the product from Step F (ca. 41 mmol), and crushed 4 Å molecular sieves (10 g) in dichloroethane (100 mL) under nitrogen was added sodium triacetoxyborohydride (12.9 g, 61.5 mmol). The reaction was stirred for one hour, then warmed to room temperature. After 3 hours, the solution was poured into EtOAc and washed with water, sat. NaHCO3 soln. and brine. The solution was dried over sodium sulfate and concentrated in vacuo to provide the crude product.
Reaction SMILES: [NH:1]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C@H:2]([C:4](N[C@@H](C(OC)=O)CCC(=O)O)=[O:5])[CH3:3].N(C(OCC1C=CC=CC=1)=O)[C@H](C(N[C@@H](C(OCC1C=CC=CC=1)=O)CC(O[N:37]1[C:42](=[O:43])[CH2:41][CH2:40][C:38]1=[O:39])C(=O)O)=O)C.ClC1C=CC(S(ON2C3C=C(Cl)C=CC=3N=N2)(=O)=[O:72])=CC=1>C(Cl)Cl>[NH:1]([C:17]([O:19][C:20]([CH3:21])([CH3:22])[CH3:23])=[O:18])[C@@H:2]([C:4]([O:5][N:37]1[C:42](=[O:43])[CH2:41][CH2:40][C:38]1=[O:39])=[O:72])[CH3:3]
Reactant: C[C@H](NC(=O)OCc1ccccc1)C(=O)N[C@H](CC(ON1C(=O)CCC1=O)C(=O)O)C(=O)OCc1ccccc1
Reactant: O=S(=O)(On1nnc2ccc(Cl)cc21)c1ccc(Cl)cc1
Reactant: COC(=O)[C@@H](CCC(=O)O)NC(=O)[C@H](C)NC(=O)OC(C)(C)C
Solvent: ClCCl
Product: C[C@@H](NC(=O)OC(C)(C)C)C(=O)ON1C(=O)CCC1=O
Temperature: 25 °C
Reaction time: 48 h
Yield: 188.3 %

Procedure:
To a mixture of Boc-L-Ala-D-Glu(OH)OMe (1)(1.33 g), L-Lys(ε-Boc)-GlyOEt (2)(2.02 g) and 1-(4-chlorobenzenesulfonyloxy)-6-chlorobenzotriazole (1.38 g) in methylene chloride (50 ml) was added N-methylmorphorine (0.808 g) at 0° C. and the mixture was stirred for 30 minutes at the same temperature and for 2 days at room temperature. The reaction mixture was washed successively with 5% aqueous sodium bicarbonate, water, 5% hydrochloride acid and water, dried over magnesium sulfate and evaporated to give a crystalline mass, which was washed with ether to give Boc-L-Ala-γ-D-Glu(α-OMe)-L-Lys(ε-Boc)-GlyOEt (3)(1.96 g).