Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([C:8]([CH3:11])([CH3:10])[CH3:9])[CH:5]=[CH:4][C:3]=1[NH2:12].[N+:13]([O-])([O-:15])=[O:14].[K+]>OS(O)(=O)=O>[Br:1][C:2]1[CH:7]=[C:6]([C:8]([CH3:9])([CH3:11])[CH3:10])[C:5]([N+:13]([O-:15])=[O:14])=[CH:4][C:3]=1[NH2:12]
Reactant: O=[N+]([O-])[O-]
Reactant: CC(C)(C)c1ccc(N)c(Br)c1
Agent: O=S(=O)(O)O
Agent: [K+]
Product: CC(C)(C)c1cc(Br)c(N)cc1[N+](=O)[O-]
Temperature: -7.5 °C
Yield: 77.4 %

Procedure:
2-Bromo-4-tert-butyl-phenylamine (160 g, 0.71 mol) was added dropwise to H2SO4 (410 mL) at room temperature to yield a clear solution. This clear solution was then cooled down to −5 to −10° C. A solution of KNO3 (83 g, 0.82 mol) in H2SO4 (410 mL) was added dropwise while the temperature was maintained between −5 to −10° C. Upon completion, the reaction mixture was poured into ice/water and extracted with EtOAc. The combined organic layers. were washed with 5% Na2CO3 and brine, dried over Na2SO4 and concentrated. The residue was purified by a column chromatography (ethyl acetate/petroleum ether 1:10) to give 2-bromo-4-tert-butyl-5-nitro-phenylamine as a yellow solid (150 g, 78%).
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([CH2:9][C:10]([O:12]C(C)(C)C)=[O:11])=[CH:4][C:3]=1[OH:17].[C:18]1([CH3:27])[C:19]([N:24]=[C:25]=S)=[CH:20][CH:21]=[CH:22][CH:23]=1>C(O)C>[CH3:8][C:7]1[C:2]2[N:1]=[C:25]([NH:24][C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=3[CH3:27])[O:17][C:3]=2[CH:4]=[C:5]([CH2:9][C:10]([OH:12])=[O:11])[CH:6]=1
Reactant: Cc1cc(CC(=O)OC(C)(C)C)cc(O)c1N
Reactant: Cc1ccccc1N=C=S
Solvent: CCO
Product: Cc1ccccc1Nc1nc2c(C)cc(CC(=O)O)cc2o1
Reaction time: 7 h
Yield: 69.5 %

Procedure:
A mixture of t-butyl 4-amino-3-hydroxy-5-methyl-phenylacetate (0.38 g, Reference Example 10) in ethanol (10 mL) and o-tolylisothiocyanate (0.24 g) was stirred for 7 hours, then left to stand over night and then evaporated. The residue was dissolved in ethanol (10 mL) and the solution was treated with dicyclohexylcarbodiimide (0.36 g). This mixture was heated at reflux temperature for 2 hours and then evaporated. The residual gum was dissolved in dichloromethane (15 mL) and the solution was treated with trifluoroacetic acid (4.75 mL). After standing at room temperature for 3 hours the mixture was evaporated and the residue was dissolved in diethyl ether. This solution was extracted twice with saturated sodium bicarbonate solution and the pH of the combined aqueous extracts was adjusted to 1-2 by addition of dilute hydrochloric acid. This solution was then extracted with ethyl acetate and the extract was washed with brine, then dried and then evaporated to give the title compound (0.33 g) as a pale yellow solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:15](=[O:16])[C:14]2=[CH:17][C:18]([F:21])=[C:19](Cl)[C:12]3=[C:13]2[N:8]([CH:9]([CH3:23])[CH2:10][C:11]3=[O:22])[CH:7]=1)=[O:5])[CH3:2].[CH3:24][N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1>C(Cl)(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1[C:15](=[O:16])[C:14]2=[CH:17][C:18]([F:21])=[C:19]([N:28]3[CH2:29][CH2:30][N:25]([CH3:24])[CH2:26][CH2:27]3)[C:12]3=[C:13]2[N:8]([CH:9]([CH3:23])[CH2:10][C:11]3=[O:22])[CH:7]=1)=[O:5])[CH3:2]
Reactant: CN1CCNCC1
Reactant: CCOC(=O)c1cn2c3c(c(Cl)c(F)cc3c1=O)C(=O)CC2C
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1cn2c3c(c(N4CCN(C)CC4)c(F)cc3c1=O)C(=O)CC2C
Reaction time: 4 h
Yield: 64.2 %

Procedure:
16.89 g (0.05 mole) of 8-chloro-9-fluoro-5-methyl-6,7-dihydro-1,7-dioxo-1H,5H-benzo[ij]quinolizine-2-carboxylic acid ethyl ester was suspended in 300 ml of chloroform, 20.03 g (0.20 mole) of N-methylpiperazine was added thereto, and this mixture was stirred at 40°-50° C. for 4 hours. The resulting reaction solution was concentrated under reduced pressure and the residue thus obtained was purified by silica gel column chromatography [using a chloroform-methanol mixture (with a volume ratio of 10:1) as the developing solvent]. The fraction containing the desired product was evaporated to dryness under reduced pressure and the resulting residue was recrystallized from benzene to obtain 12.89 g (64.2% yield) of 9-fluoro-5-methyl-8-(4-methyl-1-piperazinyl)-6,7-dihydro 1,7-dioxo-1H,5H-benzo[ij]quinolizine-2-carboxylic acid ethyl ester in the form of yellow crystals.
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([O:12][CH3:13])[CH:3]=1.[N+:14]([O-])([O-:16])=[O:15].[K+]>S(=O)(=O)(O)O>[F:1][C:2]1[C:11]([N+:14]([O-:16])=[O:15])=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([O:12][CH3:13])[CH:3]=1
Reactant: O=[N+]([O-])[O-]
Reactant: COC(=O)c1ccc(F)cc1OC
Agent: O=S(=O)(O)O
Agent: [K+]
Product: COC(=O)c1cc([N+](=O)[O-])c(F)cc1OC
Temperature: 12.5 °C
Reaction time: 0.75 h
Yield: 64.3 %

Procedure:
To a solution of methyl 4-fluoro-2-methoxybenzoate (50 g, 271.50 mmol) in sulfuric acid (150 mL) was added a solution of potassium nitrate (35.6 g, 352.48 mmol) in sulfuric acid (30 mL) dropwise with stirring for 45 min at 0-25° C. in an ice/water bath. The reaction was then quenched by the addition of water/ice. The solids were collected by filtration to afford methyl 4-fluoro-2-methoxy-5-nitrobenzoate as a white solid (40.0 g, 64%).
Reaction SMILES: [C:1]([C:3]1[C:7]([CH:8]=C)=[CH:6][N:5]([C:10]2[C:15]([Cl:16])=[CH:14][C:13]([C:17]([F:20])([F:19])[F:18])=[CH:12][C:11]=2[Cl:21])[N:4]=1)#[N:2].C[N+]1([O-])CC[O:26]CC1.CC(C)=O.I([O-])(=O)(=O)=O.[Na+]>C(O)(C)(C)C.O.[Os](=O)(=O)(=O)=O>[C:1]([C:3]1[C:7]([CH:8]=[O:26])=[CH:6][N:5]([C:10]2[C:15]([Cl:16])=[CH:14][C:13]([C:17]([F:20])([F:19])[F:18])=[CH:12][C:11]=2[Cl:21])[N:4]=1)#[N:2]
Reactant: C[N+]1([O-])CCOCC1
Reactant: C=Cc1cn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)nc1C#N
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: CC(C)(C)O
Solvent: CC(C)=O
Solvent: O
Product: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)cc1C=O
Reaction time: 16 h

Procedure:
A solution of 3-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)-4-ethenylpyrazole (0.1 g), N-methylmorpholine oxide (0.005 g), osmium tetroxide (5011 of a 2.5% solution in t-butanol) in water (5 ml) and acetone (45 ml) was stirred at room temperature for 16 hours Sodium metaperiodate (0.005 g) was added and stirring continued for 16 hours. The reaction mixture was evaporated and the residue partititoned between ether and aqueous sodium hydrogen carbonate solution. The aqueous layer was separated and extracted with ether. The combined ether extracts were dried (Na2SO4) and evaporated. The residue was purified by column chromatography on silica gel (5 g) eluted with dichloromethane. Combination and evaporation of suitable fractions gave the title compound as a biege solid, m.p. 167.5-168.5° C.
Reaction SMILES: [CH2:1]([O:5][N:6]=[C:7]([C:13]([CH3:15])=[O:14])[C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:2][CH2:3][CH3:4].[Br:16]Br>>[Br:16][CH2:15][C:13](=[O:14])[C:7](=[N:6][O:5][CH2:1][CH2:2][CH2:3][CH3:4])[C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: CCCCON=C(C(C)=O)C(=O)OCC
Reactant: BrBr
Product: CCCCON=C(C(=O)CBr)C(=O)OCC
Yield: 90.3 %

Procedure:
76 g (0.35 mole) of ethyl 2-n-butoxyimino-acetoacetate and 18 ccs (0.35 mole) of bromine react analogously to Example 4, stage 2, to give 93 g of ethyl 4-bromo-2-n-butoxyimino-acetoacetate.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[C:13]([C:18]([F:21])([F:20])[F:19])[CH:14]=[CH:15][CH:16]=3)[N:11]=[CH:10][C:9]=2[C:22]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:23])[CH:5]=[CH:6][CH:7]=1.[Cl:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[CH2:37][C:38](Cl)=[O:39]>>[C:22]([C:9]1[CH:10]=[N:11][C:12]2[C:17]([C:8]=1[C:4]1[CH:3]=[C:2]([NH:1][C:38](=[O:39])[CH2:37][C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=3[Cl:30])[CH:7]=[CH:6][CH:5]=1)=[CH:16][CH:15]=[CH:14][C:13]=2[C:18]([F:21])([F:19])[F:20])(=[O:23])[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: O=C(Cl)Cc1ccccc1Cl
Reactant: Nc1cccc(-c2c(C(=O)c3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Product: O=C(Cc1ccccc1Cl)Nc1cccc(-c2c(C(=O)c3ccccc3)cnc3c(C(F)(F)F)cccc23)c1

Procedure:
The title compound was prepared from [4-(3-amino-phenyl)-8-trifluoromethyl-quinolin-3-yl]-phenyl-methanone and 2-chlorophenyl-acetyl chloride according to the procedure of Example 61. MS (ES) m/z 542.8.
Reaction SMILES: OCC1C=NC=CC=1.C(N(CC)CC)C.[CH3:16][S:17](Cl)(=[O:19])=[O:18].Cl.COC([C@@H]1C[C@@H](O)CN1)=O.[N:32]1[CH:37]=[CH:36][CH:35]=[C:34]([CH2:38][N:39]2[CH2:43][C@H:42]([OH:44])[CH2:41][C@H:40]2[C:45]([O:47][CH3:48])=[O:46])[CH:33]=1>CN(C)C=O.O.C(OCC)(=O)C>[N:32]1[CH:37]=[CH:36][CH:35]=[C:34]([CH2:38][N:39]2[CH2:43][C@H:42]([O:44][S:17]([CH3:16])(=[O:19])=[O:18])[CH2:41][C@H:40]2[C:45]([O:47][CH3:48])=[O:46])[CH:33]=1
Reactant: COC(=O)[C@@H]1C[C@@H](O)CN1Cc1cccnc1
Reactant: CS(=O)(=O)Cl
Agent: COC(=O)[C@@H]1C[C@@H](O)CN1
Agent: Cl
Agent: OCc1cccnc1
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)[C@@H]1C[C@@H](OS(C)(=O)=O)CN1Cc1cccnc1
Temperature: -10 °C
Reaction time: 0.5 h

Procedure:
In an atmosphere of nitrogen, 3-hydroxymethylpyridine (35.95 g, 0.329 mol) was dissolved in N,N-dimethylformamide (250 ml) followed by cooling to -15°~-20° C. Then, triethylamine (36.65 g, 0.329 mol) was added thereto and methanesulfonyl chloride (41.45 g, 0.362 mol) was added dropwise to the mixture at 0°~-10° C. After completion of the dropwise addition, the mixture was stirred at -10° C. for 30 minutes. To this mixture were added (2S,4R)-2-methoxycarbonyl-4-hydroxypyrrolidine hydrochloride (50 g, 0.275 mol) and triethylamine (100 g, 0.988 mol) followed by warming to 65° C. The mixture was stirred at 65° C. for 1 hour to provide a reaction mixture containing (2S,4R)-1-(3-pyridylmethyl)-2-methoxycarbonyl-4-hydroxypyrrolidine. This reaction mixture was cooled to -20° C. and triethylamine (66.8 g, 0.66 mol) was added thereto. Then, methanesulfonyl chloride (75.6 g, 0.66 mol) was added thereto dropwise at -20°~-15° C. The mixture was stirred at -20°~-25° C. for 1 hour, after which it was poured into ethyl acetate (1 l)-water (1 l) and extracted. After phase separation, the aqueous layer was extracted with ethyl acetate (500 ml) twice. The ethyl acetate layer was combined and washed with a saturated aqueous sodium chloride solution (125 ml). The ethyl acetate layer was concentrated to dryness under reduced pressure to provide (2S,4R)-1-(3-pyridylmethyl)-2-methoxycarbonyl-4-methylsulfonyloxypyrrolidine (84.65 g) as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[CH:13]=[CH:14][CH:15]=[C:16]3[C:21]=2[N:20]=[C:19]([Cl:22])[CH:18]=[CH:17]3)(=[O:10])=[O:9])=[C:4]([N+:23]([O-])=O)[CH:3]=1.Cl[Sn]Cl>CCO>[NH2:23][C:4]1[CH:3]=[C:2]([Cl:1])[CH:7]=[CH:6][C:5]=1[S:8]([NH:11][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:21]=1[N:20]=[C:19]([Cl:22])[CH:18]=[CH:17]2)(=[O:9])=[O:10]
Reactant: O=[N+]([O-])c1cc(Cl)ccc1S(=O)(=O)Nc1cccc2ccc(Cl)nc12
Agent: Cl[Sn]Cl
Solvent: CCO
Product: Nc1cc(Cl)ccc1S(=O)(=O)Nc1cccc2ccc(Cl)nc12
Yield: 47.4 %

Procedure:
In a similar fashion using route 1 general procedure 4, 4-chloro-N-(2-chloro-quinolin-8-yl)-2-nitro-benzenesulfonamide (Intermediate 258) (0.36 g, 0.63 mmol), SnCl2 (0.36 g, 1.88 mmol) and EtOH (10 ml) at 90° C. for 4 h gave the title compound (0.11 g, 46%) after purification by column chromatography with DCM/MeOH (99.5:0.5) as the eluent.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:9]#[N:10])[C:5](=[O:8])[NH:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:18][C:19]([O:21][CH3:22])=[O:20].CN(C=O)C>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]([C:9]#[N:10])[C:5](=[O:8])[N:6]([CH2:18][C:19]([O:21][CH3:22])=[O:20])[CH:7]=1
Reactant: N#Cc1cc(Br)c[nH]c1=O
Reactant: COC(=O)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COC(=O)Cn1cc(Br)cc(C#N)c1=O
Temperature: 80 °C
Reaction time: 3.5 h
Yield: 74.8 %

Procedure:
To 5-bromo-3-cyano-2(1H)-pyridinone (1.4 g, 7.0 mmol) and potassium carbonate (1.9 g, 1.3 mL, 14.1 mmol), THF (26.4 mL) and methyl chloroacetate (1.53 g, 1.2 mL, 14.1 mmol) were added. The reaction was stirred at 80° C. The starting material didn't dissolve well in THF. After 3.5 hours, mainly staring material was observed. DMF (18 mL) was added and the starting material went into solution. The reaction was heated at 80° C. for 45 minutes. The desired mass was observed by LCMS. The reaction was filtered using ethyl acetate and the solvent was evaporated under reduced pressure. The crude product was separated by column chromatography on silica gel (0-100% ethyl acetate in hexane) to yield methyl 2-(5-bromo-3-cyano-2-oxopyridin-1(2H)-yl)acetate as a yellow solid (1.42 g, 74%). ESI-MS m/z calc. 271.07. found 271.3 (M+1)+. Retention time 0.59 minutes.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])/[C:5]/2=[CH:14]\[NH:15][CH2:16][C:17]1[CH:22]=[C:21]([OH:23])[CH:20]=[C:19]([OH:24])[CH:18]=1.I[CH2:26][CH2:27][CH3:28].C([O-])([O-])=O.[K+].[K+]>CN(C)C=O>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])[C:5]2=[CH:14][NH:15][CH2:16][C:17]1[CH:18]=[C:19]([O:24][CH2:26][CH2:27][CH3:28])[CH:20]=[C:21]([OH:23])[CH:22]=1
Reactant: O=C1NC(=O)c2ccc(Br)cc2/C1=C/NCc1cc(O)cc(O)c1
Reactant: CCCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCOc1cc(O)cc(CNC=C2C(=O)NC(=O)c3ccc(Br)cc32)c1
Temperature: 100 °C
Yield: 34.4 %

Procedure:
(4Z)-6-bromo-4-{[(3,5-dihydroxybenzyl)amino]methylene}isoquinoline-1,3(2H,4H)-dione (50 mg, 0.128 mmol) is dissolved in 1 mL N,N-dimethylformamide (DMF) (1 mL). To the resulting solution is added 1-iodo-propane (25 μL, 0.256 mmol) and K2CO3 (53 mg, 0.384 mmol). The reaction mixture is heated at 100° C. for 2 hours. The solid is filtered and purified by HPLC eluting with 20% CH3CN/H2O to 100% CH3CN over 30 minutes to give 19 mg (34%) of the title compound as a tan powder. MS (ESI) m/z 431.1(M+H)+
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=O)[C:10]1[CH:15]=[CH:14][N:13]=[C:12]([NH:16][C:17](=[O:24])[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:11]=1.P(Cl)(Cl)(Cl)=O>C1(C)C=CC=CC=1>[NH:8]1[C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[N:1]=[C:9]1[C:10]1[CH:15]=[CH:14][N:13]=[C:12]([NH:16][C:17](=[O:24])[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:11]=1
Reactant: Nc1ccccc1NC(=O)c1ccnc(NC(=O)c2ccccc2)c1
Solvent: Cc1ccccc1
Solvent: O=P(Cl)(Cl)Cl
Product: O=C(Nc1cc(-c2nc3ccccc3[nH]2)ccn1)c1ccccc1
Temperature: 25 °C
Yield: 12 %

Procedure:
To a solution of N-(2-aminophenyl)-2-benzamidoisonicotinamide (0.18 g, 0.53 mmol) in toluene (10 mL) was added phosphorus oxychloride (0.14 mL, 1.57 mmol) at ambient temperature. The resulting solution was refluxed for 5 hours, cooled to ambient temperature and concentrated in vacuo. The residue was taken up in 1 M aqueous sodium hydroxide solution (50 mL) and extracted with dichloromethane (2×50 mL). The combined organic layers were dried over anhydrous sodium sulphate, filtered and concentrated in vacuo to dryness. The residue was purified by column chromatography eluting with 20-100% ethyl acetate in hexanes to give N-(4-(1H-benzo[d]imidazol-2-yl)pyridin-2-yl)benzamide as a pale yellow solid (0.02 g, 9%): mp 145-146° C.; 1H NMR (300 MHz, DMSO-d6) δ 11.03 (s, 1H), 9.01 (s, 1H), 8.59 (d, J=5.2 Hz, 1H), 8.12-8.07 (m, 2H), 7.91 (dd, J=5.2, 1.4 Hz, 1H), 7.69 (dd, J=6.0, 3.2 Hz, 2H), 7.66-7.51 (m, 4H), 7.30 (dd, J=6.0, 3.2 Hz, 2H); MS (ES+) m/z 315.5 (M+1).
Reaction SMILES: Cl[C:2]1[C:11]2[CH2:10][N:9]([CH3:12])[C:8](=[O:13])[NH:7][C:6]=2[N:5]=[CH:4][CH:3]=1.[NH2:14][C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:22](=[O:30])[C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[CH:24]=2)=[CH:17][C:16]=1[F:31].Cl>CN1C(=O)CCC1>[F:29][C:25]1[CH:24]=[C:23]([CH:28]=[CH:27][CH:26]=1)[C:22]([NH:21][C:18]1[CH:19]=[CH:20][C:15]([NH:14][C:2]2[C:11]3[CH2:10][N:9]([CH3:12])[C:8](=[O:13])[NH:7][C:6]=3[N:5]=[CH:4][CH:3]=2)=[C:16]([F:31])[CH:17]=1)=[O:30]
Reactant: Nc1ccc(NC(=O)c2cccc(F)c2)cc1F
Reactant: CN1Cc2c(Cl)ccnc2NC1=O
Agent: Cl
Solvent: CN1CCCC1=O
Product: CN1Cc2c(Nc3ccc(NC(=O)c4cccc(F)c4)cc3F)ccnc2NC1=O
Temperature: 170 °C
Reaction time: 1 h
Yield: 20.8 %

Procedure:
19 (40.0 mg, 0.20 mmol), N-(4-amino-3-fluorophenyl)-3-fluorobenzamide (50.2 mg, 0.20 mmol), and HCl (51.0 μl, 0.18 mol) were suspended in NMP (1 mL), and stirred for 1 h at 170° C. in a microwave. The resulting mixture was purified by HPLC to provide 20 (17 mg, 20% yield) as a solid. LC-MS (M+H=410, obsd.=410).
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]#[C:5][C:6]1[S:10][C:9]([C:11]2[S:12][CH:13]=[CH:14][CH:15]=2)=[CH:8][CH:7]=1.[C:16](Cl)(=O)[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31]>N1C=CC=CC=1>[CH2:31]([O:1][CH2:2][CH2:3][C:4]#[C:5][C:6]1[S:10][C:9]([C:11]2[S:12][CH:13]=[CH:14][CH:15]=2)=[CH:8][CH:7]=1)[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH3:16]
Reactant: CCCCCCCCCCCCCCCC(=O)Cl
Reactant: OCCC#Cc1ccc(-c2cccs2)s1
Solvent: c1ccncc1
Product: CCCCCCCCCCCCCCCCOCCC#Cc1ccc(-c2cccs2)s1
Reaction time: 8 h

Procedure:
5-(4-Hydroxy-1-butynyl)-2,2'-bithiophene (0.6 g) was dissolved in pyridine (10 ml). Palmitoyl chloride (1 ml) was added at room temperature, stirred for few minutes and kept overnight. The reaction mixture was treated as in example 21, and 1.2 g of light yellowish crystals were then obtained and the melting point thereof was 68°-69° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:12]([F:15])([F:14])[F:13])=[CH:4][C:5]([N+:9]([O-])=O)=[C:6]([NH2:8])[CH:7]=1.O.O.[Sn](Cl)Cl.C([O-])(O)=O.[Na+]>CCOC(C)=O.CCO>[Cl:1][C:2]1[CH:7]=[C:6]([NH2:8])[C:5]([NH2:9])=[CH:4][C:3]=1[C:12]([F:13])([F:14])[F:15]
Reactant: Nc1cc(Cl)c(C(F)(F)F)cc1[N+](=O)[O-]
Agent: Cl[Sn]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCO
Product: Nc1cc(Cl)c(C(F)(F)F)cc1N
Temperature: 70 °C
Reaction time: 1 h

Procedure:
To a solution of 5-chloro-2-nitro-4-(trifluoromethyl)phenylamine (2 g, 8.3 mmol, Oakwood) in EtOAc (26 mL) and EtOH (13 mL) was added tin (II) chloride dihydrate (13.1 g, 45 mmol, Aldrich). The reaction mixture was stirred at 70° C. for 1 h. The light-yellow reaction solution was poured to crushed ice (50 mL) and carefully neutralized using saturated aqueous solution of NaHCO3. The resulting suspension was extracted with EtOAc (3×60 mL). The combined organic extracts were dried over MgSO4, filtered and the filtrate evaporatedcon in vacuo to give the title compound as white solid, which was used in the next step without additional purification. MS (ESI, pos. ion) m/z: 211.4 (M+1).
Reaction SMILES: [C:1]([NH:5][NH2:6])([CH3:4])([CH3:3])[CH3:2].C(Cl)Cl.S([O-])([O-])(=O)=O.[Na+].[Na+].Cl[CH2:18][C:19](=O)[CH3:20]>CCCCC>[C:1]([N:5]=[N:6][C:19]([CH3:20])=[CH2:18])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)NN
Reactant: CC(=O)CCl
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCCCC
Product: C=C(C)N=NC(C)(C)C
Reaction time: 0.75 h

Procedure:
To a solution of 6.75 g. (0.077 m.) tert.-butylhydrazine in 50 ml. of methylene chloride containing 2 g. of anhydrous sodium sulfate, was added 3.0 g. (0.0326 m.) chloroacetone. The addition was carried out dropwise holding the reaction temperature below 10° C. with an ice bath. The reaction was stirred an additional 45 minutes and filtered. The filtrate was washed with cold water (10° C.), dried over anhydrous sodium sulfate, filtered and the methylene chloride evaporated off using a rotating evaporator and a 20° C. water bath. A yellow oil containing some solids suspended in it was obtained. The crude material was slurried in cold pentane and filtered. The pentane was then evaporated off from the filtrate on the rotating evaporator. The yield was 1.9 g. (47%) of a yellow oil. The infra-red spectrum was consistent with the structure of the proposed compound. 2-tert.-butylazopropene is a thermally unstable compound and evolves nitrogen at room temperature and is therefore a very low temperature blowing agent.
Reaction SMILES: [CH2:1]([Li])[CH2:2][CH2:3][CH3:4].C([Mg]Br)C.[O:10]([C:17]1[CH:18]=[C:19]([CH:26]=[CH:27][CH:28]=1)[CH:20]=[C:21]1[CH2:25][CH2:24][N:23]=[CH:22]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>CCCCCC.C1COCC1>[CH2:1]([CH:22]1[C:21](=[CH:20][C:19]2[CH:26]=[CH:27][CH:28]=[C:17]([O:10][C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH:18]=2)[CH2:25][CH2:24][NH:23]1)[CH2:2][CH2:3][CH3:4]
Reactant: C1=NCCC1=Cc1cccc(Oc2ccccc2)c1
Reactant: [Li]CCCC
Agent: CC[Mg]Br
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCCCC1NCCC1=Cc1cccc(Oc2ccccc2)c1
Yield: 44 %

Procedure:
In a similar manner as Example 62 except for using 18 ml of a solution of 1.6M n-butyllithium in hexane instead of 10 ml of the solution of 3N ethyl magnesiumbromide in THF for reacting with 3-(m-phenoxybenzylidene)-1-pyrroline, 3.2 g (yield 44%) of 2-n-butyl-3-(m-phenoxybenzylidene)-pyrrolidine was obtained.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH2:9][CH2:10][O:11][CH2:12][C:13]([NH:15][C:16]([C:18]1[C:23](Cl)=[N:22][CH:21]=[CH:20][N:19]=1)=[O:17])=[NH:14].CC([O-])(C)C.[K+].O.Cl>CS(C)=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH2:9][CH2:10][O:11][CH2:12][C:13]1[NH:15][C:16](=[O:17])[C:18]2[C:23](=[N:22][CH:21]=[CH:20][N:19]=2)[N:14]=1
Reactant: N=C(COCCc1cc(F)ccc1F)NC(=O)c1nccnc1Cl
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: O=c1[nH]c(COCCc2cc(F)ccc2F)nc2nccnc12
Temperature: 45 °C
Yield: 23.5 %

Procedure:
Crude 3-chloro-pyrazine-2-carboxylic acid{2-[2-(2,5-difluoro-phenyl)-ethoxy]-1-imino-ethyl}-amide (190 mg) was dissolved in DMSO (1 ml). KOtBu (60 mg, 0.536 mmol) was added and the mixture was heated to 45° C. for 2.5 h. Then water was added, the pH was adjusted to 6 by addition of 0.1 N HCl and the resulting mixture was extracted three times with CH2Cl2. The combined extracts were washed with water (three times) and brine, dried (Na2SO4) and evaporated. The resulting orange brown solid was triturated with Et2O. The remaining solid was filtered off, washed with a small amount of Et2O and dried to give the title compound as a light brown solid (40 mg, 23%). MS: m/e=319.1 [M+H+].
Reaction SMILES: F[C:2]1(F)[CH2:7][CH2:6][N:5]([C:8]2[N:13]=[CH:12][N:11]=[C:10]([NH:14][C:15]3[CH:16]=[C:17]([CH2:21][S:22]([NH2:25])(=[O:24])=[O:23])[CH:18]=[CH:19][CH:20]=3)[N:9]=2)[CH2:4][CH2:3]1.ClC1N=CN=C(NC2C=C(CS(N)(=O)=O)C=CC=2)N=1.Cl.[CH3:47][O:48][CH2:49]C1CCCCN1>>[CH3:47][O:48][CH2:49][CH:6]1[CH2:7][CH2:2][CH2:3][CH2:4][N:5]1[C:8]1[N:13]=[CH:12][N:11]=[C:10]([NH:14][C:15]2[CH:16]=[C:17]([CH2:21][S:22]([NH2:25])(=[O:24])=[O:23])[CH:18]=[CH:19][CH:20]=2)[N:9]=1
Reactant: COCC1CCCCN1
Reactant: NS(=O)(=O)Cc1cccc(Nc2ncnc(N3CCC(F)(F)CC3)n2)c1
Agent: Cl
Agent: NS(=O)(=O)Cc1cccc(Nc2ncnc(Cl)n2)c1
Product: COCC1CCCCN1c1ncnc(Nc2cccc(CS(N)(=O)=O)c2)n1

Procedure:
B4 was prepared following the procedure reported for B2 using A1 and rac-2-methoxymethylpiperidine hydrochloride. The title compound was purified by thick-layer chromatography (silica gel, chloroform/MeOH 19:1) and obtained as a white crystalline solid; yield: 235 mg (67%). MS (ES) C17H24N6O3S requires: 392. found: 393 (M+H)+.