Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]1[CH:5]=[CH:6][C:7]([NH2:10])=[CH:8][CH:9]=1.C(N(CC)CC)C.Cl.Br[C:20]1[C:21]2[N:22]([CH:27]=[CH:28][N:29]=2)[N:23]=[C:24]([Cl:26])[CH:25]=1>CCO>[Cl:26][C:24]1[CH:25]=[C:20]([NH:10][C:7]2[CH:8]=[CH:9][C:4]([O:3][CH2:2][CH3:1])=[CH:5][CH:6]=2)[C:21]2[N:22]([CH:27]=[CH:28][N:29]=2)[N:23]=1
Reactant: CCOc1ccc(N)cc1
Reactant: Clc1cc(Br)c2nccn2n1
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCOc1ccc(Nc2cc(Cl)nn3ccnc23)cc1
Temperature: 90 °C
Reaction time: 36 h

Procedure:
(1c variation 2) p-Phenetidine (1.0 eq, 0.149 mmol) and triethyamine (33 mg, 0.327 mmol) were added to a mixture of 8-bromo-6-chloroimidazo[1,2-b]pyridazine hydrochloride (40 mg, 0.149 mmol) from 1b in EtOH (1.5 mL). The mixture was heated to 90° C. and stirred for 24-48 hours. The solution was then concentrated in vacuo to give crude 6-chloro-N-(4-ethoxyphenyl)imidazo[1,2-b]pyridazin-8-amine.
Reaction SMILES: [Br:1][C:2]1[C:3]([Cl:38])=[CH:4][C:5]([O:36][CH3:37])=[C:6]([CH:35]=1)[CH2:7][N:8](CC1C=CC(OC)=CC=1OC)[C:9]([CH:11]1[CH2:16][CH2:15][N:14](C(OC(C)(C)C)=O)[CH2:13][CH2:12]1)=[O:10]>C(O)(C(F)(F)F)=O.C(Cl)Cl>[Br:1][C:2]1[C:3]([Cl:38])=[CH:4][C:5]([O:36][CH3:37])=[C:6]([CH:35]=1)[CH2:7][NH:8][C:9]([CH:11]1[CH2:12][CH2:13][NH:14][CH2:15][CH2:16]1)=[O:10]
Reactant: COc1ccc(CN(Cc2cc(Br)c(Cl)cc2OC)C(=O)C2CCN(C(=O)OC(C)(C)C)CC2)c(OC)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cc(Cl)c(Br)cc1CNC(=O)C1CCNCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The crude tert-Butyl 4-((5-bromo-4-chloro-2-methoxybenzyl)(2,4-dimethoxybenzyl)carbamoyl)piperidine-1-carboxylate was dissolved in 50% TFA in DCM (10 mL) and the resulting mixture was stirred at room temperature for 2 h. The mixture was concentrated in vacuo and the residue was partitioned between DCM and saturate NaHCO3 aqueous solution. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated in vacuo to afford the desired product.
Reaction SMILES: O.[CH2:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[OH:11])[CH2:3][CH3:4].[N+:12]([O-])([OH:14])=[O:13]>CCOCC>[CH2:2]([C:5]1[C:6]([OH:11])=[C:7]([N+:12]([O-:14])=[O:13])[CH:8]=[CH:9][CH:10]=1)[CH2:3][CH3:4]
Reactant: O=[N+]([O-])O
Reactant: CCCc1ccccc1O
Solvent: O
Solvent: CCOCC
Product: CCCc1cccc([N+](=O)[O-])c1O
Temperature: 25 °C
Reaction time: 288 h

Procedure:
To a stirred mixture of 100 ml of water, 100 ml of ether and 10.0 g of 2-n-propylphenol was added dropwise 11.0 ml of 61% nitric acid and the reaction was carried out with stirring at room temperature for 12 days. The reaction mixture was extracted with 200 ml of ethyl acetate and dried with anhydrous sodium sulfate. The drying agent was filtered off and the solvent was distilled away under reduced pressure. The residue was purified by subjecting to silica-gel column-chromatography [eluent: chloroform-n-hexane (1 : 1)]to give 3.76 g of 6-n-propyl-2-nitrophenol.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[Cl:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][OH:21]>N1C=CC=CC=1>[C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7]([O:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][Cl:12])(=[O:9])=[O:8])=[CH:3][CH:2]=1
Reactant: OCCCCCCCCCl
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCCCCCCCCCl)cc1

Procedure:
p-Toluenesulphonyl chloride (20.5 g) was added to a mixture of 8-chloro-1-octanol (17.7 g) and pyridine (50 ml) of 0°. After a hour the solution was added to ice and the mixture was extracted with ether. The ethereal solution was washed with dilute hydrochloric acid, dried with magnesium sulfate, and evaporated to yield the title compound as an oil.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.Cl[C:25](=[O:32])[CH2:26][CH2:27][C:28]([O:30][CH3:31])=[O:29]>C(Cl)Cl>[C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[CH2:16][CH2:15][N:14]([C:25](=[O:32])[CH2:26][CH2:27][C:28]([O:30][CH3:31])=[O:29])[CH2:13][CH2:12]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)CCC(=O)Cl
Reactant: CC(C)(C)c1ccccc1N1CCNCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)CCC(=O)N1CCN(c2ccccc2C(C)(C)C)CC1
Temperature: 25 °C
Yield: 73.7 %

Procedure:
To a stirred solution at 0° C. of 1-(2-tert-butylphenyl)piperazine (0.218 g, 1.00 mmol) and triethylamine (0.303 g, 3.00 mmol) in methylene chloride (5.0 mL) was added methyl 4-chloro-4-oxobutanoate (0.171 g, 1.10 mmol) and the resulting reaction mixture was warmed to room temperature. After 2 h the reaction mixture was diluted with methylene chloride (10.0 mL), washed with water (20.0 mL), dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, 50% ethyl acetate/heptanes) to provide methyl 4-(4-(2-tert-butylphenyl)-piperazin-1-yl)-4-oxobutanoate (0.245 g, 74%) as an off-white solid.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([F:11])[CH:8]=[C:7]([F:12])[C:5]=2[N:6]=1.[CH3:13][C:14]1[S:18][C:17]([C:19](Cl)=[O:20])=[CH:16][CH:15]=1>>[F:12][C:7]1[C:5]2[N:6]=[C:2]([NH:1][C:19]([C:17]3[S:18][C:14]([CH3:13])=[CH:15][CH:16]=3)=[O:20])[S:3][C:4]=2[CH:10]=[C:9]([F:11])[CH:8]=1
Reactant: Cc1ccc(C(=O)Cl)s1
Reactant: Nc1nc2c(F)cc(F)cc2s1
Product: Cc1ccc(C(=O)Nc2nc3c(F)cc(F)cc3s2)s1

Procedure:
Using 2-amino-4,6-difluoro-benzothiazole and 5-methyl-thiophene-carboxylicacid chloride the title compound was prepared as a yellow solid (74% yield), MS: m/e=310 (M+).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]1[CH2:12][NH:11][C:10](=[O:13])[CH:9]([N:14]2[C:18](=[O:19])[C:17]3=[CH:20][CH:21]=[CH:22][CH:23]=[C:16]3[C:15]2=[O:24])[CH2:8][S:7]1.Br[CH2:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28]>>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]1[CH2:12][N:11]([CH2:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C:10](=[O:13])[CH:9]([N:14]2[C:18](=[O:19])[C:17]3=[CH:20][CH:21]=[CH:22][CH:23]=[C:16]3[C:15]2=[O:24])[CH2:8][S:7]1
Reactant: O=C1NCC(c2ccco2)SCC1N1C(=O)c2ccccc2C1=O
Reactant: CC(C)(C)OC(=O)CBr
Product: CC(C)(C)OC(=O)CN1CC(c2ccco2)SCC(N2C(=O)c3ccccc3C2=O)C1=O

Procedure:
Following the procedure described in Example 42(f), 1.15 g of 2-(2-furyl)-5-oxo-6-phthalimidoperhydro-1,4-thiazepine [prepared as described in step (d) above] was treated with t-butyl bromoacetate, to give 0.86 g of the title compound as crystals, melting at 158°-161° C.
Reaction SMILES: [O:1]1[CH2:3][C@H:2]1[CH2:4][O:5][C:6]1[C:18]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[NH:11][C:10]=2[CH:9]=[CH:8][CH:7]=1.[NH2:19][CH2:20][CH:21]1[CH2:26][CH2:25][N:24]([CH2:27][CH2:28][CH3:29])[CH2:23][CH2:22]1>>[CH:9]1[C:10]2[NH:11][C:12]3[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:18]=2[C:6]([O:5][CH2:4][C@@H:2]([OH:1])[CH2:3][NH:19][CH2:20][CH:21]2[CH2:26][CH2:25][N:24]([CH2:27][CH2:28][CH3:29])[CH2:23][CH2:22]2)=[CH:7][CH:8]=1
Reactant: CCCN1CCC(CN)CC1
Reactant: c1ccc2c(c1)[nH]c1cccc(OC[C@@H]3CO3)c12
Product: CCCN1CCC(CNC[C@H](O)COc2cccc3[nH]c4ccccc4c23)CC1
Yield: 36.7 %

Procedure:
Prepared from 4-[(2S)-oxiranylmethoxy]-9H-carbazole (0.239 g, 1.0 mmol) and 4-aminomethyl-1-propylpiperidine (0.312 g, 2.0 mmol) according to the procedure used for Example 2 to give 0.145 g of the title compound as an off-white solid.
Reaction SMILES: C1(OC)C=CC=CC=1.[C:9]([C:11]1([CH2:17][C:18]([O:20]CCCC)=[O:19])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)#[N:10]>FC(F)(F)C(O)=O>[C:9]([C:11]1([CH2:17][C:18]([OH:20])=[O:19])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)#[N:10]
Reactant: CCCCOC(=O)CC1(C#N)CCCCC1
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: N#CC1(CC(=O)O)CCCCC1

Procedure:
To a solution of 2.4 mL (2.4 g, 22 mmol) of anisole in 50 mL of trifluoroacetic acid is added 5.00 g (22.4 mmol) of (1-cyanocyclohexyl)acetic acid, 1-butyl ester. The reaction is monitored (TLC) for the loss of starting material and when the reaction is complete it is concentrated under reduced pressure. Water (˜10 mL) is added to the residue and the mixture is adjusted to pH=10-12 with base (NaOH). The basic aqueous layer is extracted with a suitable organic solvent (EtOAc) to remove impurities. The aqueous layer is acidified with acid (HCl) to pH=0-4 and extracted with a suitable solvent (EtOAc). The combined organic extracts of the acidified aqueous layer are dried and concentrated under reduced pressure to afford the product.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][CH2:13][NH:14][CH2:15][CH:16]1[O:25][C:24]2[C:19](=[CH:20][CH:21]=[C:22]3[N:28]=[C:27]([CH3:29])[O:26][C:23]3=2)[O:18][CH2:17]1.C=O.[C:32]([BH3-])#N.[Na+].C(O)(=O)C>CO>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][CH2:13][N:14]([CH3:32])[CH2:15][CH:16]1[CH2:17][O:18][C:19]2[CH:20]=[CH:21][C:22]3[N:28]=[C:27]([CH3:29])[O:26][C:23]=3[C:24]=2[O:25]1
Reactant: Cc1nc2ccc3c(c2o1)OC(CNCCCc1c[nH]c2ccc(F)cc12)CO3
Reactant: [BH3-]C#N
Agent: C=O
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: Cc1nc2ccc3c(c2o1)OC(CN(C)CCCc1c[nH]c2ccc(F)cc12)CO3
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of [3-(5-fluoro-1H-indol-3-yl)-propyl]-(2-methyl-7,8-dihydro-1,6,9-trioxa-3-aza-cyclopenta[a]napthalen-8-ylmethyl)-amine (0.05 g, 0.13 mmol) and formaldehyde (37 wt. % in water, 0.1 g, 1.3 mmol) in methanol (10 mL) was added sodium cyanoborohydride (0.014 g, 0.23 mmol) and acetic acid (0.01 g, 0.26 mmol) at room temperature. The mixture was stirred at room temperature under nitrogen overnight, then quenched with 1N NaOH (5 mL). The mixture was extracted with methylene chloride (3×40 mL). The organic layer was washed with water (3×30 mL), dried over anhydrous sodium sulfate, filtered and the solvent was removed under vacuum. The crude oil was column chromatographed on silica gel (5% methanol-methylene chloride). The product-containing fractions were concentrated in vacuum to give 48 mg of the (S)-enantiomer of the title compound as a brown oil. The dihydrochloride salt was prepared in ethyl acetate as a white solid, m.p. 136-139° C.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][C:7]2[N:10]([CH2:23][CH:24](O)[CH2:25][N:26]3[CH2:31][CH2:30][N:29]([C:32]4[CH:39]=[CH:38][CH:37]=[CH:36][C:33]=4[C:34]#[N:35])[CH2:28][CH2:27]3)[N:11]=[C:12]([C:13]3[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=3)[C:6]=2[CH2:5]1)(=[O:3])[CH3:2].CCN(S(F)(F)[F:47])CC.CO.C(Cl)Cl>C(Cl)Cl>[C:1]([N:4]1[CH2:9][CH2:8][C:7]2[N:10]([CH2:23][CH:24]([F:47])[CH2:25][N:26]3[CH2:31][CH2:30][N:29]([C:32]4[CH:39]=[CH:38][CH:37]=[CH:36][C:33]=4[C:34]#[N:35])[CH2:28][CH2:27]3)[N:11]=[C:12]([C:13]3[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=3)[C:6]=2[CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCc2c(c(-c3ccc(C(F)(F)F)cc3)nn2CC(O)CN2CCN(c3ccccc3C#N)CC2)C1
Reactant: CCN(CC)S(F)(F)F
Solvent: ClCCl
Solvent: CO
Product: CC(=O)N1CCc2c(c(-c3ccc(C(F)(F)F)cc3)nn2CC(F)CN2CCN(c3ccccc3C#N)CC2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 50.1 %

Procedure:
A solution of 2-(4-{3-[5-acetyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperazin-1-yl)-benzonitrile (150 mg, 0.27 mmol) in CH2Cl2 (1 mL) was treated with DAST (Et2NSF3, 7 μL, 0.60 mmol) at −78° C. The reaction mixture was slowly warmed to 25° C. for 1 h and then to 60° C. for an additional 2 h. Preparative TLC (silica, 5% MeOH/CH2Cl2) provided 75 mg (50%) of the title compound as a light yellow powder. TLC (5% MeOH/CH2Cl2): Rf=0.28. MS (electrospray): m/z 555.2 ([M+H]+, C29H30F4N6O requires 554.2). 1H NMR (CDCl3, 400 MHz, a mixture of two rotamers): 7.71 and 7.59 (AB pattern, Jab=8.2 Hz, 2H), 7.66 and 7.62 (AB pattern, Jab=8.4 Hz, 2H), 7.50-7.38 (m, 2H), 6.96-6.92 (m, 2H), 5.01 (dp, J=49.0, 3.0 Hz, 1H), 4.77 and 4.73 (AB pattern, Jab=15.7 Hz, 1.1H), 4.59 (s, 0.9H), 4.41-4.18 (m, 2H), 3.95-3.80 (m, 1H), 3.69 (dd, J=5.5, 5.5 Hz, 1H), 3.18 (m, 4H), 2.83-2.65 (m, 8H), 2.14 (s, 1.6H), 2.10 (s, 1.4H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([OH:15])=[N:11][CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[K+].[CH3:18]I>CS(C)=O>[CH2:1]([O:8][C:9]1[C:10](=[O:15])[N:11]([CH3:18])[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Oc1ncccc1OCc1ccccc1
Reactant: CI
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: Cn1cccc(OCc2ccccc2)c1=O
Yield: 94.4 %

Procedure:
To a solution of 3-(benzyloxy)pyridin-2-ol (25 g, 123.00 mmol) and potassium hydroxide (10 g, 178.22 mmol, 1.45 equiv) in dimethylsulfoxide (250 mL) maintained under nitrogen atmosphere was added methyl iodide (27 g, 190.14 mmol) dropwise with stirring. The resulting solution was stirred overnight at room temperature then concentrated under vacuum. The residue was diluted with water (500 mL) then extracted with dichloromethane (2×400 mL). The combined organic layer was washed with water (3×500 mL), dried over anhydrous sodium sulfate and concentrated under vacuum to give the title compound (25 g, 93%) as a light brown oil: 1H NMR (400 MHz, DMSO) delta 7.44-7.32 (m, 5H), 7.29-7.27 (m, 1H), 6.91-6.88 (m, 1H), 6.12-6.09 (m, 1H), 5.02 (s, 2H), 3.44 (s, 3H).
Reaction SMILES: Cl.[OH:2][CH2:3][CH:4]1[CH:7]2[C:8]3[C:13]([CH2:14][CH2:15][N:6]2[CH2:5]1)=[CH:12][C:11]([O:16][CH3:17])=[C:10]([O:18][CH3:19])[CH:9]=3.[C:20]([Cl:28])(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[ClH:28].[C:20]([O:2][CH2:3][CH:4]1[CH:7]2[C:8]3[C:13]([CH2:14][CH2:15][N:6]2[CH2:5]1)=[CH:12][C:11]([O:16][CH3:17])=[C:10]([O:18][CH3:19])[CH:9]=3)(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: COc1cc2c(cc1OC)C1C(CO)CN1CC2
Reactant: O=C(Cl)c1ccccc1
Agent: Cl
Product: COc1cc2c(cc1OC)C1C(COC(=O)c3ccccc3)CN1CC2

Procedure:
0.01 mole (1,85 g) of 1-(hydroxymethyl)-7,8-dimethoxy-1,4,5,9b-tetrahydro-2H-azeto[2,1-a]isoquinoline hydrochloride is acylated with benzoyl chloride following the conventional Schotten-Baumann acylation method.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[CH2:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9](=[O:16])[NH:8][N:7]=1.[C:20]([CH2:23][C:24]1([C:29](O)=[O:30])[CH2:28][CH2:27][CH2:26][CH2:25]1)(O)=[O:21]>CO>[O:16]=[C:9]1[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:6]([CH2:5][C:4]2[CH:3]=[C:2]([N:1]3[C:20](=[O:21])[CH2:23][C:24]4([CH2:28][CH2:27][CH2:26][CH2:25]4)[C:29]3=[O:30])[CH:19]=[CH:18][CH:17]=2)=[N:7][NH:8]1
Reactant: Nc1cccc(Cc2n[nH]c(=O)c3ccccc23)c1
Reactant: O=C(O)CC1(C(=O)O)CCCC1
Solvent: CO
Product: O=C1CC2(CCCC2)C(=O)N1c1cccc(Cc2n[nH]c(=O)c3ccccc23)c1
Temperature: 200 °C

Procedure:
A stirred mixture of 4-(3-aminobenzyl)-2H-phthalazin-1-one (0.1 g, 0.4 mmol; prepared in a manner similar to that described in Example 1) and 1-(carboxymethyl)cyclopentanecarboxylic acid (0.0685 g, 0.4 mmol) was heated at 200° C. for 2.5 hours then it was allowed to cool to ambient temperature. Methanol (1 ml) was added and the mixture was heated under reflux for 5 minutes. No solid precipitated, so the mixture was concentrated in vacuo and the residue was triturated with water (5 ml). The resulting solid was collected by filtration and dried in vacuo to give 2-[3-(4-oxo-3,4-dihydrophthalazin-1-ylmethyl)phenyl]-2-azaspiro[4.4]nonane-1,3-dione (0.108 g) as a brown solid, m/z (M+H)+. 388, 89.1% purity.
Reaction SMILES: [CH:1]1[C:6]2[C:7](=[O:16])[NH:8][C:9]3[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=3[O:11][C:5]=2[CH:4]=[CH:3][CH:2]=1.[H-].[Na+].Br[CH2:20][CH2:21][CH3:22]>CN(C)C=O>[CH2:20]([N:8]1[C:7](=[O:16])[C:6]2[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=2[O:11][C:10]2[CH:12]=[CH:13][CH:14]=[CH:15][C:9]1=2)[CH2:21][CH3:22]
Reactant: CCCBr
Reactant: O=C1Nc2ccccc2Oc2ccccc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCN1C(=O)c2ccccc2Oc2ccccc21
Reaction time: 1 h
Yield: 86.2 %

Procedure:
To a solution of 3.0 grams of 10H-dibenz[b,f][1,4]oxazepin-11-one in 50 ml of dry dimethylformamide was added 0.82 grams of a 50% dispersion of sodium hydride in mineral oil. The resulting mixture was stirred for one hour and 3.7 grams of 1-bromopropane was then added slowly. The reaction mixture was stirred for 3 hours and the excess sodium hydride decomposed by the addition of ice. After further dilution with water the product was extracted with ether, dried (anhydrous sodium sulfate) and concentrated. The resulting oil was purified on a silica gel column (ethyl acetate/hexane, 1:4) to provide 3.1 grams (87% of theory) of 10-propyl-10H-dibenz[b,f][1.4]oxazepin-11-one as a colorless oil.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([NH:11][C:12](=[O:19])[C:13]3[CH:18]=[CH:17][CH:16]=[N:15][CH:14]=3)[N:10]=[C:6]2[CH:5]=[C:4]([C:20]([F:23])([F:22])[F:21])[CH:3]=1.[CH:24]1([CH2:30][NH2:31])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1>>[CH:24]1([CH2:30][NH:31][C:2]2[N:7]3[N:8]=[C:9]([NH:11][C:12](=[O:19])[C:13]4[CH:18]=[CH:17][CH:16]=[N:15][CH:14]=4)[N:10]=[C:6]3[CH:5]=[C:4]([C:20]([F:23])([F:22])[F:21])[CH:3]=2)[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: O=C(Nc1nc2cc(C(F)(F)F)cc(Cl)n2n1)c1cccnc1
Reactant: NCC1CCCCC1
Product: O=C(Nc1nc2cc(C(F)(F)F)cc(NCC3CCCCC3)n2n1)c1cccnc1

Procedure:
The title compound was prepared following procedure described for example 76 but starting from N-[5-chloro-7-(trifluoromethyl)[1,2,4]triazolo[1,5-a]pyridin-2-yl]nicotinamide ((B7), 50 mg; 0.14 mmol; 1.0 eq.) and cyclohexanemethylamine (500 μl) as a white powder (27 mg; 44%). HPLC, Rt: 4.11 min. (purity 99.8%). LC/MS, M+(ESI): 419.4, M−(ESI): 417.4.
Reaction SMILES: C(OC([N:11]1[CH2:15][C@H:14]([OH:16])[CH2:13][C@H:12]1[CH2:17][C:18]#[N:19])=O)C1C=CC=CC=1.[H][H]>C(O)C.[C].[Pd]>[C:18]([CH2:17][C@@H:12]1[CH2:13][C@@H:14]([OH:16])[CH2:15][NH:11]1)#[N:19]
Reactant: [H][H]
Reactant: N#CC[C@@H]1C[C@@H](O)CN1C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: N#CC[C@@H]1C[C@@H](O)CN1

Procedure:
To a solution of (2R,4R)-1-benzyloxycarbonyl-2-cyanomethyl-4-hydroxypyrrolidine (5.94 g) in ethanol (60 ml), 10% palladium-carbon (600 mg) was added, and the resultant mixture was stirred at room temperature for 1.5 hours under an atmospheric pressure of hydrogen, followed by filtration. The filtrate was combined with 10% palladiumcarbon (600 mg) and stirred under the same condition as above. This operation was repeated three times. After removal of the catalyst by filtration, the solvent was removed by distillation to give (2R,4R)-2-cyanomethyl-4-hydroxypyrrolidine.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:14]([F:17])([F:16])[F:15])[N:5]=[C:4]([NH2:18])[C:3]=1[N+:19]([O-:21])=[O:20].C([O-])([O-])=O.[K+].[K+].[NH:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1>CN(C=O)C.O>[N:28]1([C:2]2[CH:7]=[C:6]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[C:14]([F:17])([F:16])[F:15])[N:5]=[C:4]([NH2:18])[C:3]=2[N+:19]([O-:21])=[O:20])[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1
Reactant: Nc1nc(-c2ccccc2C(F)(F)F)cc(Cl)c1[N+](=O)[O-]
Reactant: C1COCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Nc1nc(-c2ccccc2C(F)(F)F)cc(N2CCOCC2)c1[N+](=O)[O-]
Temperature: 80 °C
Reaction time: 8 h

Procedure:
To a solution of 4-chloro-3-nitro-6-(2-trifluoromethyl-phenyl)-pyridin-2-ylamine (900 mg, 2.83 mmol, prepared as described in the Example 1) in DMF (5 mL), K2CO3 (1.90 g, 14.0 mmol) was added followed by addition of morpholine (0.240 mL, 2.80 mmol). The resulting mixture was stirred at 80° C. overnight. The resulting mixture was diluted with water (20 mL) and extracted with EtOAc (3×10 mL). The organic layers were combined, dried (MgSO4) and concentrated. The resulting residue was purified on silica 0:100-50:50 EtOAc/hexanes to yield 4-morpholin-4-yl-3-nitro-6-(2-trifluoromethyl-phenyl)-pyridin-2-ylamine. Mass Spectrum (LCMS, ESI pos.) Calculated For Mass Spectrum (LCMS, ESI pos.) Calculated For C16H15F3N4O3: 369.1 (M+H), Measured: 369.1.
Reaction SMILES: [CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([CH:10]([CH3:15])[C:11]([O:13][CH3:14])=[O:12])=[CH:4][C:3]=2[O:2]1.Cl[Sn](Cl)(Cl)Cl.[C:21](Cl)(=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl>[C:21]([C:6]1[CH:7]=[C:8]2[O:9][CH2:1][O:2][C:3]2=[CH:4][C:5]=1[CH:10]([CH3:15])[C:11]([O:13][CH3:14])=[O:12])(=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: COC(=O)C(C)c1ccc2c(c1)OCO2
Reactant: O=C(Cl)c1ccccc1
Agent: Cl[Sn](Cl)(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: COC(=O)C(C)c1cc2c(cc1C(=O)c1ccccc1)OCO2
Temperature: 25 °C
Yield: 23 %

Procedure:
To a solution of methyl 2-(3,4-methylenedioxyphenyl)propionate (1.04 g, 5 mmol) in CH2Cl2 (30 mL) at 0° C. was added SnCl4 (1M solution in CH2Cl2, 9 mL, 9 mmol). Then a solution of benzoyl chloride (1 mL) in CH2Cl2 (10 mL) was added dropwise and the mixture obtained was warmed to 25° C. for 20 h with stirring. The reaction mixture was poured into a separatory funnel containing Na2CO3 solution (sat. 50 mL) and some ice. The organic layer was separated and the aqueous was extracted with CH2Cl2 (3×50 mL). The combined extracts were washed with water (50 mL), NaHCO3 (sat. 40 mL) and brine (50 mL) and dried over Na2SO4. The pure product (360 mg, 23%) was obtained by chromatography on silica gel (hexane/ethyl acetate=4:1). 1H NMR (CDCl3) 7.80-7.45 (m, 5H), 6.96 (s, 1H), 6.79 (s, 1H), 6.03 (s, 2H) 3.70 (m, 1H), 3.58 (s, 3H), 1.47 (d, J=7.4, 3H).
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([F:11])=[CH:4][C:3]=1[NH2:12].O.O.[C:15](O)(=[O:19])[C:16](O)=[O:17]>Cl>[F:11][C:5]1[CH:4]=[C:3]2[C:2]([NH:1][C:15](=[O:19])[C:16](=[O:17])[NH:12]2)=[C:7]([N+:8]([O-:10])=[O:9])[CH:6]=1
Reactant: O=C(O)C(=O)O
Reactant: Nc1cc(F)cc([N+](=O)[O-])c1N
Agent: Cl
Solvent: O
Product: O=c1[nH]c2cc(F)cc([N+](=O)[O-])c2[nH]c1=O
Temperature: 25 °C
Yield: 43.5 %

Procedure:
A mixture of 1,2-diamino-4-fluoro-6-nitrobenzene (80 mg, 0.46 mmole) and oxalic acid dihydrate (70 mg, 0.56 mmole, used as received) in 4N HCl (4 mL) was refluxed at 120°-5° C. for 3 h, then cooled to room temperature. The mixture was centrifuged and the supernatant was removed. The yellow solid was washed by cold water (2×2 mL), collected by filtration, and dried in vacuo for 2 h, affording 45 mg of crude 7-fluoro-5-nitro-1,4-dihydro-2,3-quinoxalinedione (42%) as a yellow powder. The crude product was taken up in 1N NaOH (1 mL) and filtered. The filtrate was acidified to pH=3, affording 35 mg of 7-fluoro-5-nitro-1,4-dihydro-2,3-quinoxalinedione (33%), mp: 333°-335° C. (dec.), IR (KBr, cm-1): 3427, 3328, 3104, 3072, 1716, 1545. 1H NMR (DMSO-d6): δ12.418 (s, 1H), 11.149 (s, 1H), 7.819 (dd, J1 =2.4 Hz, J2 =9.0 Hz, 1H), 7.297 (dd, J1 =2.4 Hz, J2 =9.0 Hz, 1H); HRMS: calcd for C8H4FN3O4 (M+) m/z: 225.0185; found: 225.0188.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[C:7]([OH:12])[CH:6]=1)[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH:20](Br)([CH3:22])[CH3:21]>CN(C=O)C>[CH2:1]([O:3][C:4](=[O:13])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH:20]([CH3:22])[CH3:21])=[C:7]([OH:12])[CH:6]=1)[CH3:2]
Reactant: CCOC(=O)c1ccc(O)c(O)c1
Reactant: CC(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(OC(C)C)c(O)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
5 g (27.5 mmol) of 3,4-Dihydroxy-benzoic acid ethyl ester was dissolved in 110 ml of DMF and treated at 0° C. with 3.8 g (27.5 mmol) of potassium carbonate and 3.38 g (27.5 mmol) of isopropyl bromide. The solution was stirred for 16 h at RT, then a further 1.014 g (8.3 mmol) of isopropyl bromide was added. The reaction solution was heated at 50° C. for 3 h. The solvent was removed under reduced pressure, the residue was taken-up in ethyl acetate and the solution was washed three times with water and twice with saturated aqueous sodium chloride. The organic phase was dried with magnesium sulphate, filtered and the solvent was removed under reduced pressure. The residue was chromatographed on silica gel eluting with n-heptane/ethyl acetate (5/1).