Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:9][O:8][B:7]([OH:10])[C:6]=2[CH:11]=1.[N+:12]([C:15]1[CH:20]=[C:19]([N+:21]([O-:23])=[O:22])[CH:18]=[CH:17][C:16]=1[S:24](Cl)(=[O:26])=[O:25])([O-:14])=[O:13].N1C=CC=CC=1>C(Cl)Cl>[OH:10][B:7]1[C:6]2[CH:11]=[C:2]([NH:1][S:24]([C:16]3[CH:17]=[CH:18][C:19]([N+:21]([O-:23])=[O:22])=[CH:20][C:15]=3[N+:12]([O-:14])=[O:13])(=[O:25])=[O:26])[CH:3]=[CH:4][C:5]=2[CH2:9][O:8]1
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)c([N+](=O)[O-])c1
Reactant: Nc1ccc2c(c1)B(O)OC2
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=[N+]([O-])c1ccc(S(=O)(=O)Nc2ccc3c(c2)B(O)OC3)c([N+](=O)[O-])c1

Procedure:
Using General Procedure 1: 6-amino-3H-benzo[c][1,2]oxaborol-1-ol (4.9 g, 32.6 mmol), 2,4-dinitro-benzenesulfonyl chloride (9.8 g, 36.8 mmol), pyridine (18 mL), methylene chloride (100 ml), 0° C.-rt, 0/N. Purification: precipitation from hot H2O. The title compound was recrystallized from ethyl acetate as a light-orange solid (9.5 g). 1H NMR (400 MHz, DMSO-d6) δ ppm 11.0 (s, 1H), 9.27 (s, 1H), 8.88 (d, Hz, 1H), 8.58 (dd, J=2.2, 8.6 Hz, 1H), 8.17 (d, J=8.6 Hz, 1H), 7.51 (d, Hz, 1H), 7.34 (d, J=8.3 Hz, 1H), (dd, J=1.9, 8.3 Hz, 1H), 4.91 (s, 2H); MS (ESI) m/z=378 (M−1, negative).
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([CH3:11])[N:3]=1.NC1C=CC([N+:19]([O-:21])=[O:20])=C(C)N=1.[N+]([O-])(O)=O>OS(O)(=O)=O>[NH2:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([N+:19]([O-:21])=[O:20])=[C:4]([CH3:11])[N:3]=1
Reactant: Cc1nc(N)ccc1[N+](=O)[O-]
Reactant: Cc1ccc([N+](=O)[O-])c(N)n1
Agent: O=S(=O)(O)O
Solvent: O=[N+]([O-])O
Product: Cc1nc(N)c([N+](=O)[O-])cc1[N+](=O)[O-]
Temperature: 50 °C

Procedure:
8.5 g of this mixture of 2-amino-6-methyl-3-nitropyridine and 2-amino-6-methyl-5-nitropyridine was dissolved in H2SO4 (100 mL) at 0° C. and HNO3 (2.74 mL, d=1.49) was added drop-wise over 10 min. After complete addition, the mixture was warmed to 50° C. for 90 min., cooled, then poured onto 200 g of ice. The residue was collected by filtration and washed with cold H2O (2×50 mL) to give 2-amino-6-methyl-3,5-dinitropyridine as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([F:9])[C:3]=1[NH2:4].Cl[C:11]1[NH:12][C:13]2[CH:19]=[CH:18][CH:17]=[CH:16][C:14]=2[N:15]=1.Cl>C(O)C>[ClH:1].[NH:12]1[C:13]2[CH:19]=[CH:18][CH:17]=[CH:16][C:14]=2[N:15]=[C:11]1[NH:4][C:3]1[C:5]([F:9])=[CH:6][CH:7]=[CH:8][C:2]=1[Cl:1]
Reactant: Nc1c(F)cccc1Cl
Reactant: Clc1nc2ccccc2[nH]1
Agent: Cl
Solvent: CCO
Product: Fc1cccc(Cl)c1Nc1nc2ccccc2[nH]1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 5.5 %

Procedure:
2-Chloro-6-fluoroaniline (0.48 g) and 2-chlorobenzimidazole (0.5 g) were mixed in a flask and then kept at 170° C. for 30 min. After cooling, the residue was dissolved out of the flask at boiling heat using 1 N HCl and 10% ethanol. The material dissolved out was then stirred at RT for 30 min, then the insoluble material was filtered off with suction and the filtrate was evaporated. The residue was purified by means of preparative HPLC on RP-18 using acetonitrile/water (0.05% TFA). The clean fractions were combined, the acetonitrile was stripped off, the residue was adjusted to pH 10 with potassium carbonate solution, extracted three times with EA, and then the combined phases were dried, filtered, and concentrated. The residue was taken up using HCl/water and freeze-dried. 27 mg of the title compound were obtained.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][CH:6]=[C:7]([CH:20]=1)[C:8]([N:10]=[S@@:11]([CH3:19])(=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9])#[CH:2].[CH3:21][C:22]([C:24]1[CH:29]=[CH:28][C:27](I)=[CH:26][CH:25]=1)=[O:23]>>[C:22]([C:24]1[CH:29]=[CH:28][C:27]([C:2]#[C:1][C:3]2[CH:4]=[N:5][CH:6]=[C:7]([CH:20]=2)[C:8]([N:10]=[S@@:11]([CH3:19])(=[O:18])[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[O:9])=[CH:26][CH:25]=1)(=[O:23])[CH3:21]
Reactant: CC(=O)c1ccc(I)cc1
Reactant: C#Cc1cncc(C(=O)N=[S@@](C)(=O)c2ccccc2)c1
Product: CC(=O)c1ccc(C#Cc2cncc(C(=O)N=[S@@](C)(=O)c3ccccc3)c2)cc1
Yield: 86 %

Procedure:
In a manner similar to that describe in Example 434 a mixture of (S)-5-ethynyl-N-[methyl(oxo)phenyl-λ6-sulfanylidene]nicotinamide and 4-iodoacetophenone were reacted to give the title compound as a light yellow foam (52 mg, 86%).
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12](=[O:57])[C@@H:13]([NH:23][C:24]([C:26]2[CH:30]=[C:29]([O:31][C@H:32]([CH3:50])[C:33]([N:35]3[CH2:39][CH2:38][CH2:37][C@H:36]3[C:40]([O:42]CC3C=CC=CC=3)=[O:41])=[O:34])[N:28]([C:51]3[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=3)[N:27]=2)=[O:25])[CH2:14][CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:8][CH2:7]1)=[O:5])[CH3:2]>C(OCC)(=O)C>[CH2:1]([O:3][C:4]([N:6]1[CH2:7][CH2:8][N:9]([C:12](=[O:57])[C@@H:13]([NH:23][C:24]([C:26]2[CH:30]=[C:29]([O:31][C@H:32]([CH3:50])[C:33]([N:35]3[CH2:39][CH2:38][CH2:37][C@H:36]3[C:40]([OH:42])=[O:41])=[O:34])[N:28]([C:51]3[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=3)[N:27]=2)=[O:25])[CH2:14][CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:10][CH2:11]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CCN(C(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)c2cc(O[C@H](C)C(=O)N3CCC[C@H]3C(=O)OCc3ccccc3)n(-c3ccccc3)n2)CC1
Solvent: CCOC(C)=O
Product: CCOC(=O)N1CCN(C(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)c2cc(O[C@H](C)C(=O)N3CCC[C@H]3C(=O)O)n(-c3ccccc3)n2)CC1
Reaction time: 24 h

Procedure:
To a solution of 2.640 g 4-[(S)-2-({5-[(R)-2-((S)-2-Benzyloxycarbonyl-pyrrolidin-1-yl)-1-methyl-2-oxo-ethoxy]-1-phenyl-1H-pyrazole-3-carbonyl}-amino)-4-tert-butoxycarbonyl-butyryl]-piperazine-1-carboxylic acid ethyl ester in 50 ml ethyl acetate were added under argon 0.5 g Pd/C (10%) and the suspension was stirred under an atmosphere of hydrogen (1 bar) for 24 h. The suspension was filtered over a plug of Celite® and washed with ethyl acetate. The crude product obtained after evaporation of the solvent was used in the subsequent reaction.
Reaction SMILES: Br[CH2:2][CH:3]1[O:7][CH2:6][CH2:5][O:4]1.[CH2:8]([NH2:14])[CH2:9][CH2:10][CH2:11][CH2:12][CH3:13].[OH-].[Na+]>O>[CH2:8]([NH:14][CH2:2][CH:3]1[O:7][CH2:6][CH2:5][O:4]1)[CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: BrCC1OCCO1
Reactant: CCCCCCN
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCCCCCNCC1OCCO1
Temperature: 100 °C
Reaction time: 0.5 h

Procedure:
2-Bromomethyl-1,3-dioxolane (20 grams) and n-hexylamine (100 ml) were charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. The reaction mixture was heated at a temperature of about 100° C. for a period of about 3 hours. After this time sodium hydroxide (10 grams) dissolved in water (100 ml) was added and the resulting mixture was stirred for a period of about 30 minutes. The reaction mixture was then extracted with ether and the ether solution was separated and dried over magnesium sulfate. The dried solution was filtered and stripped of solvent to yield the desired product N-n-hexyl-N-(1,3-dioxolan-2-ylmethyl)amine as an oil.
Reaction SMILES: CO[C:3]1[C:12]([O:13][CH3:14])=[CH:11][CH:10]=[C:9]2[C:4]=1[CH2:5][CH2:6][CH:7]([NH:15][CH3:16])[CH2:8]2.[CH2:17]([OH:19])C>>[NH2:15][CH2:7][CH2:6][CH2:5][N:15]([CH3:16])[CH:7]1[CH2:6][CH2:5][C:4]2[C:9](=[CH:10][C:11]([O:19][CH3:17])=[C:12]([O:13][CH3:14])[CH:3]=2)[CH2:8]1
Reactant: CNC1CCc2c(ccc(OC)c2OC)C1
Reactant: CCO
Product: COc1cc2c(cc1OC)CC(N(C)CCCN)CC2

Procedure:
Rf value: 0.27 (alumina, eluant: 95 parts by volume of methylene chloride+5 parts by volume of ethanol).
Reaction SMILES: [CH:1]([Cl:4])(Cl)Cl.[C:5]([C:9]1[CH:13]=[C:12](CO)[NH:11][N:10]=1)([CH3:8])([CH3:7])[CH3:6].S(Cl)(Cl)=O>ClCCl>[C:5]([C:9]1[CH:13]=[C:12]([CH2:1][Cl:4])[NH:11][N:10]=1)([CH3:8])([CH3:7])[CH3:6]
Reactant: CC(C)(C)c1cc(CO)[nH]n1
Reactant: ClC(Cl)Cl
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: CC(C)(C)c1cc(CCl)[nH]n1

Procedure:
To a chloroform (20 mL)-dichloromethane (10 mL) mixed solution of [3-(tert-butyl)-1H-pyrazol-5-yl]methanol (617 mg, 4.00 mmol), thionyl chloride (577 μL, 8.01 mmol) was added at room temperature and the resultant solution was stirred at room temperature for 1 day. After completion of the reaction, the reaction solution was concentrated under reduced pressure to obtain a crude product (931 mg) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:38]2[CH:43]=[CH:42][C:41]([Cl:44])=[CH:40][CH:39]=2)[N:9]2[CH2:12][C:11](=[C:13]([S:34]([CH3:37])(=[O:36])=[O:35])[C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([C:20](OC4C(F)=C(F)C(F)=C(F)C=4F)=[O:21])[CH:15]=3)[CH2:10]2)=[CH:4][CH:3]=1.[NH2:45][N:46]1[CH2:51][CH2:50][CH2:49][CH2:48][CH2:47]1>CN(C)C=O.C(OCC)(=O)C>[Cl:44][C:41]1[CH:42]=[CH:43][C:38]([CH:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[N:9]2[CH2:12][C:11](=[C:13]([S:34]([CH3:37])(=[O:35])=[O:36])[C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([C:20](=[O:21])[NH:45][N:46]4[CH2:51][CH2:50][CH2:49][CH2:48][CH2:47]4)[CH:15]=3)[CH2:10]2)=[CH:39][CH:40]=1
Reactant: NN1CCCCC1
Reactant: CS(=O)(=O)C(=C1CN(C(c2ccc(Cl)cc2)c2ccc(Cl)cc2)C1)c1cccc(C(=O)Oc2c(F)c(F)c(F)c(F)c2F)c1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CS(=O)(=O)C(=C1CN(C(c2ccc(Cl)cc2)c2ccc(Cl)cc2)C1)c1cccc(C(=O)NN2CCCCC2)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of 0.45 g of 1-[bis(4-chlorophenyl)methyl]-3-{(methylsulfonyl)[3-(pentafluorophenoxycarbonyl)phenyl]methylene}azetidine, 0.07 cm3 of 1-aminopiperidine in 4 cm3 of dimethylformamide is stirred for 18 hours at room temperature. The mixture is taken up in 30 cm3 of ethyl acetate. The organic phase is washed with 3 times 50 cm3 of water, dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure (2.7 kPa). 0.2 g of 1-[bis-(4-chlorophenyl)methyl]-3-{(methylsulfonyl)[3-(N-piperidylcarbamoyl)phenyl]methylene}azetidine is obtained melting at 175° C. [NMR spectrum in DMSO-d6, T=300K, δ in ppm (400 MHz): 1.40 (2H, m, CH2), 1.60 (4H, m, 2CH2), 2.85 (4H, m, 2NCH2), 3.00 (3H, s, SCH3), 3.80 (2H, s, NCH2), 4.20 (2H, s, NCH2), 4.80 (1H, s, NCH), between 7.45 and 7.60 (10H, m, 10CH arom.), 7.75 (2H, m, 2CH arom.), 9.45 (1H, s, NH)].
Reaction SMILES: C(N(CC)CC)C.Cl.[NH2:9][CH:10]([C:28]1[CH:33]=[CH:32][C:31]([Br:34])=[CH:30][C:29]=1[S:35][CH3:36])[C:11]1[C:12](=[O:27])[CH2:13][CH2:14][C:15]=1[NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[CH:18]=1.[C:37](N1C=CN=C1)(N1C=CN=C1)=[O:38]>C(#N)C>[Br:34][C:31]1[CH:32]=[CH:33][C:28]([CH:10]2[NH:9][C:37](=[O:38])[N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:25])([F:26])[F:24])[CH:18]=3)[C:15]3[CH2:14][CH2:13][C:12](=[O:27])[C:11]2=3)=[C:29]([S:35][CH3:36])[CH:30]=1
Reactant: CSc1cc(Br)ccc1C(N)C1=C(Nc2cccc(C(F)(F)F)c2)CCC1=O
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CSc1cc(Br)ccc1C1NC(=O)N(c2cccc(C(F)(F)F)c2)C2=C1C(=O)CC2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Triethylamine (250 μL, 1.81 mmol) is added to a mixture of 2-(amino(4-bromo-2-(methyl-thio)phenyl)methyl)-3-(3-(trifluoromethyl)phenyl amino)cyclopent-2-enone hydrochloride (intermediate 20.5, 4.08 g, 7.23 mmol based on 90% purity) and 1,1′-carbonyldiimidazole (1.46 g, 9.04 mmol) in acetonitrile (54 mL), and the mixture is stirred at room temperature for 1 h. All volatiles are removed under reduced pressure, and the residue is treated with water. The precipitate is filtered and purified by flash chromatography on silica (gradient dichloromethane to dichloromethane/methanol 95:5). Yield: 3.04 g; ESI mass spectrum: [(79Br)-M+H]+=497, [(81Br)-M+H]+=499; Retention time HPLC: 0.65 min (X011_S03).
Reaction SMILES: Br[C:2]1[CH:25]=[CH:24][C:5]2[C:6]3[N:7]=[C:8]([C:14]4[N:15]([CH2:19][C:20]([F:23])([F:22])[F:21])[N:16]=[CH:17][N:18]=4)[S:9][C:10]=3[CH2:11][CH2:12][O:13][C:4]=2[CH:3]=1.CC1(C)C(C)(C)OB([C:34]2[CH:35]=[N:36][N:37]([CH2:39][C@@H:40]([OH:42])[CH3:41])[CH:38]=2)O1>>[F:21][C:20]([F:23])([F:22])[CH2:19][N:15]1[C:14]([C:8]2[S:9][C:10]3[CH2:11][CH2:12][O:13][C:4]4[CH:3]=[C:2]([C:34]5[CH:35]=[N:36][N:37]([CH2:39][C@@H:40]([OH:42])[CH3:41])[CH:38]=5)[CH:25]=[CH:24][C:5]=4[C:6]=3[N:7]=2)=[N:18][CH:17]=[N:16]1
Reactant: C[C@H](O)Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: FC(F)(F)Cn1ncnc1-c1nc2c(s1)CCOc1cc(Br)ccc1-2
Product: C[C@H](O)Cn1cc(-c2ccc3c(c2)OCCc2sc(-c4ncnn4CC(F)(F)F)nc2-3)cn1

Procedure:
Following the procedure for 114, 8-Bromo-2-[2-(2,2,2-trifluoro-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene was reacted with (S)-1-[4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrazol-1-yl]-propan-2-ol to give 381. MS(ESI+) 477.1
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9](=O)[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][CH:3]=1.[C:16]1([NH:22]N)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(O)C.Cl>S(=O)(=O)(O)O.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[NH:22][C:9]=2[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][CH:3]=1
Reactant: NNc1ccccc1
Reactant: CCOC(=O)C(=O)Cc1ccc(Cl)cc1
Agent: Cl
Agent: O=S(=O)(O)O
Solvent: CCO
Solvent: O
Product: CCOC(=O)c1[nH]c2ccccc2c1-c1ccc(Cl)cc1
Temperature: 120 °C
Yield: 11.9 %

Procedure:
A mixture of Example 52A (4.75 g, 21.0 mmol) and phenyl hydrazine (2.07 mL, 21.0 mmol) was treated with concentrated sulfuric acid (5 drops), heated to 120° C. for 15 minutes, cooled to room temperature, treated with ethanol (25 mL), treated with bubbling HCl gas for 2 minutes, and heated to reflux for 1 hour. The mixture was poured into water (30 mL) and extracted with diethyl ether. The combined extracts were washed with water and brine, dried (MgSO4), filtered, and concentrated. The concentrate was recrystallized from ethanol to provide 750 mg (12%) of the desired product.
Reaction SMILES: O=[C:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[S:4](=[O:12])(=[O:11])[NH:3]1.O.[NH2:14][NH2:15]>C(O)CCC>[NH:14]([CH:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[S:4](=[O:12])(=[O:11])[NH:3]1)[NH2:15]
Reactant: NN
Reactant: O=C1NS(=O)(=O)c2ccccc21
Solvent: CCCCO
Solvent: O
Product: NNC1NS(=O)(=O)c2ccccc21
Yield: 91.1 %

Procedure:
36.6 g (0.2 mol) of 3-keto-2H,3H-1,2-benzisothiazole 1,1-dioxide and 20 g of hydrazine hydrate in 200 ml of n-butanol are boiled under reflux for about 35 hours. The yellow solution is then evaporated down in vacuo, and the residue is stirred with 50 ml of acetic acid. The crystal slurry is filtered under suction, and the crude product which is obtained in this manner and has a melting point of 249° C. can be recrystallized from water. 36.3 g (91% of theory) of 3-hydrazino-2H,3H-1,2-benzisothiazole 1,1-dioxide of melting point 263° C. are obtained.
Reaction SMILES: [C:1]1([C:7]2[S:8][CH:9]=[C:10]([C:12]3[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=3[C:14]([OH:16])=O)[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl-].[NH2:22][C:23](=[O:32])[CH:24]([OH:31])[CH:25]([NH3+:30])[CH2:26][CH2:27][CH2:28][CH3:29]>>[NH2:22][C:23](=[O:32])[CH:24]([OH:31])[CH:25]([NH:30][C:14](=[O:16])[C:13]1[CH:17]=[CH:18][CH:19]=[CH:20][C:12]=1[C:10]1[N:11]=[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[S:8][CH:9]=1)[CH2:26][CH2:27][CH2:28][CH3:29]
Reactant: O=C(O)c1ccccc1-c1csc(-c2ccccc2)n1
Reactant: CCCCC([NH3+])C(O)C(N)=O
Agent: [Cl-]
Product: CCCCC(NC(=O)c1ccccc1-c1csc(-c2ccccc2)n1)C(O)C(N)=O
Yield: 87.7 %

Procedure:
Coupling of 2-(2-phenylthiazol-4-yl)benzoic acid (200 mg, 0.711 mmol) and 1-amino-2-hydroxy-1-oxoheptan-3-aminium chloride (145 mg, 0.737 mmol) in an analogous manner as described for example 1.2 afforded 264 mg of the title compound as white solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([N+:17]([O-:19])=[O:18])=[C:11]([CH:14]=[CH:15][CH:16]=1)[NH:12][CH3:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C)C1C=CC=CC=1.[CH3:29][O:30][CH2:31][C:32](Cl)=[O:33]>C(OCC)(=O)C>[CH2:1]([O:8][C:9]1[C:10]([N+:17]([O-:19])=[O:18])=[C:11]([CH:14]=[CH:15][CH:16]=1)[N:12]([C:32](=[O:33])[CH2:31][O:30][CH3:29])[CH3:13])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CNc1cccc(OCc2ccccc2)c1[N+](=O)[O-]
Reactant: COCC(=O)Cl
Solvent: CN(C)c1ccccc1
Solvent: CCOC(C)=O
Product: COCC(=O)N(C)c1cccc(OCc2ccccc2)c1[N+](=O)[O-]
Temperature: 90 °C
Reaction time: 2.5 h

Procedure:
To a mixture of 3-benzyloxy-2-nitro-N-methylaniline (400 mg) and N,N-dimethylaniline (1 ml) was added methoxyacetyl chloride (310 μl) under nitrogen atmosphere, and the mixture was stirred for 2.5 hours at 90° C. After cooling, ethyl acetate was added to the reaction mixture, and the mixture was washed with water and brine, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by silica gel column chromatography (ethyl acetate:n-hexane=2:1, v/v) to give 3-benzyloxy-2-nitro-N-methoxyacetyl-N-methylaniline (474.2 mg).
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([C:15]([OH:17])=O)=[N:8][C:9]=2[O:10][CH2:11][CH:12]2[CH2:14][CH2:13]2)[CH2:3][CH2:2]1.[CH3:18][C:19]([NH2:29])([CH3:28])[CH2:20][CH2:21][N:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1>>[CH3:28][C:19]([NH:29][C:15]([C:7]1[CH:6]=[CH:5][C:4]([CH:1]2[CH2:2][CH2:3]2)=[C:9]([O:10][CH2:11][CH:12]2[CH2:13][CH2:14]2)[N:8]=1)=[O:17])([CH3:18])[CH2:20][CH2:21][N:22]1[CH2:23][CH2:24][O:25][CH2:26][CH2:27]1
Reactant: CC(C)(N)CCN1CCOCC1
Reactant: O=C(O)c1ccc(C2CC2)c(OCC2CC2)n1
Product: CC(C)(CCN1CCOCC1)NC(=O)c1ccc(C2CC2)c(OCC2CC2)n1

Procedure:
The title compound was synthesized in analogy to Example 1, using 5-cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid (Example 42 a) and 1,1-dimethyl-3-morpholin-4-yl-propylamine (Example 35 d) as starting materials, MS (EI): m/e=388.3 [M+H]+.
Reaction SMILES: CC[O-].[Na+].[F:5][C:6]([F:23])([F:22])[C:7]([CH:9]([CH2:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:10]([O:12]CC)=O)=O.Cl.[C:25]([NH2:28])(=[NH:27])[CH3:26].CCCCCC>CCO>[CH3:26][C:25]1[NH:28][C:10](=[O:12])[C:9]([CH2:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])=[C:7]([C:6]([F:5])([F:22])[F:23])[N:27]=1
Reactant: CC(=N)N
Reactant: CCOC(=O)CCC(C(=O)OCC)C(=O)C(F)(F)F
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCCCCC
Solvent: CCO
Product: CCOC(=O)CCc1c(C(F)(F)F)nc(C)[nH]c1=O
Yield: 24.1 %

Procedure:
To a solution of NaOEt (0.026 mol) in EtOH (prepared from 0.60 g of Na and 30 mL of EtOH) was added diethyl trifluoroacetylglutarate (3.70 g, 0.013 mol) and acetamidine hydrochloride (1.23 g, 0.013 mol). The reaction mixture was heated under reflux for 18 h , concentrated, and taken up in water. The mixture was acidified to pH 4 with 2N HCl and extracted with CH2Cl2. The extracts were dried (MgSO4) and concentrated to give a yellow solid. Trituration with hexane gave 0.87 g of product as a white solid.
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][NH:5][C@H:4]([C:7]([OH:9])=[O:8])[CH2:3]1.[C:10]1([CH3:20])[CH:15]=[CH:14][C:13]([S:16](Cl)(=[O:18])=[O:17])=[CH:12][CH:11]=1>[OH-].[Na+].CCOCC>[OH:1][CH:2]1[CH2:6][N:5]([S:16]([C:13]2[CH:14]=[CH:15][C:10]([CH3:20])=[CH:11][CH:12]=2)(=[O:18])=[O:17])[C@@H:4]([C:7]([OH:9])=[O:8])[CH2:3]1
Reactant: O=C(O)[C@@H]1C[C@@H](O)CN1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Product: Cc1ccc(S(=O)(=O)N2CC(O)C[C@@H]2C(=O)O)cc1
Temperature: 5 °C
Reaction time: 6 h
Yield: 93.1 %

Procedure:
A stirred solution of 52.45 g (0.40 mole) of trans-4-hydroxy-L-proline in 500 ml of sodium hydroxide is treated with 85.79 g (0.45 mole) of p-toluenesulfonyl chloride in 500 ml of ether at room temperature. Stirring is continued for 6 hours, the layers are separated and the aqueous phase is cooled to 5° C. in an ice-bath. The mixture is then acidified while cooling with 30 ml of concentrated hydrochloric acid to pH 2 and the precipitated white solid is collected, washed with 150 ml of cold water, and dried in vacuo yielding 106.2 g of material, melting point 139°-143° C. Crystallization from 300 ml of ethyl acetate yields 98.6 g of the title compound, melting point 142°-145° C.
Reaction SMILES: Cl[S:2]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][CH:6]=1)(=[O:4])=[O:3].[CH3:14][O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1>>[CH3:14][O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][S:2]([C:5]2[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][CH:6]=2)(=[O:4])=[O:3])=[CH:18][CH:17]=1
Reactant: O=C(O)c1ccc(S(=O)(=O)Cl)cc1
Reactant: COc1ccc(N)cc1
Product: COc1ccc(NS(=O)(=O)c2ccc(C(=O)O)cc2)cc1

Procedure:
4-(chlorosulfonyl)benzoic acid (573 mg, 2.60 mmol) was treated with 4-methoxyaniline (800 mg, 6.5 mmol) using method A to give 4-(N-(4-methoxyphenyl)sulfamoyl)benzoic acid as an off white solid. Yield: 528 mg (66%). 1H-NMR: 10.05 (s, 1H), 6.96 (d, J=8.5 Hz, 2H), 6.80 (d, J=8.5 Hz, 2H), 6.96 (d, J=9.0 Hz, 2H), 6.80 (d, J=9.0 Hz, 2H), 3.67 (s, 3H).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C@@H:3]([OH:5])[CH3:4].F[C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[CH:11][CH:10]=1>>[F:1][C:2]([F:7])([F:6])[C@H:3]([CH3:4])[O:5][C:9]1[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][CH:10]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: C[C@H](O)C(F)(F)F
Product: C[C@H](Oc1ccc(N)cc1)C(F)(F)F

Procedure:
This material was made in analogy to example 142, step 1 from (S)-1,1,1-trifluoro-2-propanol [CAS 17628-73-8] and 1-fluoro-4-nitro-benzene [CAS 350-46-9]. MS (m/e): 206.1 (MH+).
Reaction SMILES: [F:1][C:2]([F:8])([F:7])[C:3]1([NH2:6])[CH2:5][CH2:4]1.C(N(C(C)C)CC)(C)C.[C:18]1(=[O:24])[O:23][C:21](=[O:22])[CH2:20][CH2:19]1>O1CCOCC1>[O:24]=[C:18]([NH:6][C:3]1([C:2]([F:8])([F:7])[F:1])[CH2:5][CH2:4]1)[CH2:19][CH2:20][C:21]([OH:23])=[O:22]
Reactant: NC1(C(F)(F)F)CC1
Reactant: O=C1CCC(=O)O1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: O=C(O)CCC(=O)NC1(C(F)(F)F)CC1
Temperature: 10 °C
Reaction time: 0.33 h

Procedure:
Slowly, 800.7 mg (4.96 mmol) of 1-(trifluoromethyl)cyclopropanamine and 0.85 ml (4.96 mmol) of diisopropylethylamine were added to a solution of 496 mg (4.96 mmol) of succinic anhydride in 10 ml of dioxane, with ice-cooling (10° C.). Stirring was continued for 20 min at room temperature, and the mixture was allowed to stand overnight at this temperature. Again, stirring was continued for 20 min at 80° C., the mixture was allowed to cool to room temperature, and the solution was concentrated. Repeatedly, the solution was washed alternately with ethyl acetate and with water. The combined organic phases were dried and concentrated. This gave 815.8 mg (73% of theory) of the desired compound.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([OH:8])[C:5]([NH2:9])=[C:4]([NH2:10])[N:3]=1.[F:11][C:12]1[CH:19]=[CH:18][C:15]([CH:16]=O)=[CH:14][CH:13]=1>>[NH2:1][C:2]1[N:3]=[C:4]2[C:5]([N:9]=[C:16]([C:15]3[CH:18]=[CH:19][C:12]([F:11])=[CH:13][CH:14]=3)[NH:10]2)=[C:6]([OH:8])[N:7]=1
Reactant: O=Cc1ccc(F)cc1
Reactant: Nc1nc(N)c(N)c(O)n1
Product: Nc1nc(O)c2nc(-c3ccc(F)cc3)[nH]c2n1
Yield: 60 %

Procedure:
This compound was synthesized from commercially available 2,5,6-triamino-4-hydroxypyrimidine (40 mmol) and 4-fluorobenzaldehyde (40 mmol), yielding the title compound in 60% yield.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:8]([C:9]([OH:11])=O)[C:7]([NH2:13])=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH:14]([NH2:16])=O>>[N+:1]([C:4]1[CH:12]=[C:8]2[C:7](=[CH:6][CH:5]=1)[N:13]=[CH:14][NH:16][C:9]2=[O:11])([O-:3])=[O:2]
Reactant: Nc1ccc([N+](=O)[O-])cc1C(=O)O
Reactant: NC=O
Product: O=c1[nH]cnc2ccc([N+](=O)[O-])cc12

Procedure:
A mixture of 5-nitroanthranilic acid (2 g, 14.6 mmol) and formamide (2.9 ml, 72 mmol) is irradiated at 150 C in a microwave (power: 60 W) until TLC shows completion of reaction (20 minutes). After cooling, the reaction mixture is rinsed with ethyl acetate and evaporated under reduced pressure. The crude is purified by flash chromatography (silica gel; ethyl acetate/hexanes) to give the above product.