Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [ClH:1].Cl.Cl.[Cl:4][C:5]1[CH:14]=[CH:13][C:12]([Cl:15])=[C:11]2[C:6]=1[CH:7]=[C:8]([C:16]1[C:17]([NH2:33])=[N:18][CH:19]=[C:20]([C:22]3[CH:23]=[N:24][N:25]([CH:27]4[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]4)[CH:26]=3)[CH:21]=1)[N:9]=[CH:10]2.[Cl:34]C1C=C2C(=C(Cl)C=1)C=NC(OS(C(F)(F)F)(=O)=O)=C2>>[ClH:4].[ClH:34].[ClH:1].[Cl:34][C:14]1[CH:5]=[C:6]2[C:11](=[C:12]([Cl:15])[CH:13]=1)[CH:10]=[N:9][C:8]([C:16]1[C:17]([NH2:33])=[N:18][CH:19]=[C:20]([C:22]3[CH:23]=[N:24][N:25]([CH:27]4[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]4)[CH:26]=3)[CH:21]=1)=[CH:7]2
Reactant: O=S(=O)(Oc1cc2cc(Cl)cc(Cl)c2cn1)C(F)(F)F
Reactant: Nc1ncc(-c2cnn(C3CCNCC3)c2)cc1-c1cc2c(Cl)ccc(Cl)c2cn1
Agent: Cl
Product: Nc1ncc(-c2cnn(C3CCNCC3)c2)cc1-c1cc2cc(Cl)cc(Cl)c2cn1

Procedure:
The procedure for the preparation of 3-(5,8-dichloroisoquinolin-3-yl)-5-(1-piperidin-4-yl-1H-pyrazol-4-yl)-pyridin-2-ylamine trihydrochloride was followed, except using trifluoromethanesulfonic acid 6,8-dichloroisoquinolin-3-yl ester in place of trifluoromethanesulfonic acid 5,8-dichloroisoquinolin-3-yl ester. This afforded the title compound as a yellow solid. 1H NMR (400 MHz, DMSO-d6): δ=2.10-2.31 (m, 4H), 3.04-3.18 (m, 2H), 3.33-3.46 (m, 2H), 4.45-4.59 (m, 1H). 8.11 (d, J=1.8 Hz, 1H), 8.14 (s, 1H), 8.22 (d, J=1.3 Hz, 1H), 8.48 (d, J=2.0 Hz, 1H), 8.50 (s, 1H), 8.63 (br. s., 1H), 8.75 (s, 1H), 8.83 (d, J=2.0 Hz, 1H), 8.95 (br. s., 1H), 9.07 (br. s., 1H), 9.65 (s, 1H). MS (ES+): m/z=439.07/441.07/443.06 [MH+]. HPLC: tR=2.00 min (ZQ2, polar—5 min).
Reaction SMILES: CO[C:3]([CH3:5])=[CH2:4].C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.[F:23][C:24]1[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:25]=1[C@H:31]([NH:38][C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[C@@H:32]([OH:37])[C:33]([O:35][CH3:36])=[O:34]>C1C=CC=CC=1>[C:42]([O:41][C:39]([N:38]1[C@@H:31]([C:25]2[CH:26]=[CH:27][C:28]([F:30])=[CH:29][C:24]=2[F:23])[C@H:32]([C:33]([O:35][CH3:36])=[O:34])[O:37][C:3]1([CH3:5])[CH3:4])=[O:40])([CH3:45])([CH3:44])[CH3:43]
Reactant: COC(=O)[C@H](O)[C@@H](NC(=O)OC(C)(C)C)c1ccc(F)cc1F
Reactant: C=C(C)OC
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: c1ccccc1
Product: COC(=O)[C@@H]1OC(C)(C)N(C(=O)OC(C)(C)C)[C@H]1c1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
0.3 ml of isopropenyl methyl ether and 39 mg of pyridinium p-toluenesulfonate were added to a solution of 515 mg of methyl (2R,3S)-3-(2,4-difluorophenyl)-3-tert-butoxycarbonylamino-2-hydroxypropionate dissolved in 30 ml of benzene, and the mixture was stirred at room temperature for 30 minutes. The mixture was further stirred at 90° C. for 30 minutes and then returned to room temperature. 0.3 ml of isopropenyl methyl ether was added to the mixture, and the resulting mixture was stirred at 90° C. for 30 minutes. The mixture was cooled again to room temperature, 0.15 ml of isopropenyl methyl ether was added thereto, and the mixture was stirred at 90° C. for 4 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (solvent; toluene:ethyl acetate=50:1) to obtain 428 mg of methyl (4S,5R)-3-tert-butoxycarbonyl-2,2-dimethyl-4-(2,4-difluorophenyl)-5-oxazolidinecarboxylate.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][CH2:13][O:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][O:20][C:21]2[CH:26]=[CH:25][C:24](/[CH:27]=[CH:28]/[C:29]3[CH:34]=[CH:33][C:32]([N:35](C(OC(C)(C)C)=O)[CH3:36])=[CH:31][CH:30]=3)=[CH:23][CH:22]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>ClCCl>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([O:11][CH2:12][CH2:13][O:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][O:20][C:21]2[CH:26]=[CH:25][C:24](/[CH:27]=[CH:28]/[C:29]3[CH:34]=[CH:33][C:32]([NH:35][CH3:36])=[CH:31][CH:30]=3)=[CH:23][CH:22]=2)(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)OCCOCCOCCOc2ccc(/C=C/c3ccc(N(C)C(=O)OC(C)(C)C)cc3)cc2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CNc1ccc(/C=C/c2ccc(OCCOCCOCCOS(=O)(=O)c3ccc(C)cc3)cc2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 50.2 %

Procedure:
200 mg 2-[2-(2-{4-[(E)-2-{4-[(tert-butoxycarbonyl)(methyl)amino]phenyl}-vinyl]phenoxy}ethoxy)ethoxy]ethyl 4-methylbenzenesulfonate (2c) were dissolved in 2.5 mL dichloromethane. 250 μL trifluoroacetic acid were added and the mixture was stirred for 4 h at room temperature. The solvent was removed under reduced pressure. The crude product was dissolved in dichlormethane (5 mL) and washed with sodium carbonate solution (10%, 2×2 mL). The organic layer was dried over sodium sulfate, the solvent was removed under reduced pressure and the residue was purified by flash chromatography (silica, 12-100% ethyl acetate in hexane). 84 mg 2d were obtained as light red solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:10]2[O:20][C:19]3[CH:18]=[C:17]([OH:21])[CH:16]=[C:15]([OH:22])[C:14]=3[C:12](=[O:13])[CH:11]=2)=[CH:7][C:8]=1[OH:9].[H-].[Na+].[CH2:25](Br)[CH:26]=[CH2:27]>CN(C)C=O>[CH2:25]([O:22][C:15]1[C:14]2[C:12](=[O:13])[CH:11]=[C:10]([C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[C:8]([O:9][CH2:4][CH:3]=[CH2:8])[CH:7]=3)[O:20][C:19]=2[CH:18]=[C:17]([O:21][CH2:7][CH:6]=[CH2:5])[CH:16]=1)[CH:26]=[CH2:27]
Reactant: COc1ccc(-c2cc(=O)c3c(O)cc(O)cc3o2)cc1O
Reactant: C=CCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCOc1cc(OCC=C)c2c(=O)cc(-c3ccc(OC)c(OCC=C)c3)oc2c1
Temperature: 40 °C
Reaction time: 22 h

Procedure:
30 g of diosmetin in 300 ml of dimethylformamide are added to a suspension of 11.7 g of sodium hydride in 150 ml of dimethylformamide. The mixture is maintained at 40° C. with stirring until the evolution of gas has ceased. 48 g of allyl bromide are then added and stirring at 40° C. is continued for 22 hours.
Reaction SMILES: [CH2:1]([CH2:13][CH2:14][NH2:15])[CH2:2][CH2:3][CH2:4][NH:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][NH2:12].[C:16]([O:25][CH2:26][CH3:27])(=[O:24])/[CH:17]=[CH:18]\[C:19]([O:21][CH2:22][CH3:23])=[O:20]>>[O:24]=[C:16]([CH2:17][CH:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[NH:15][CH2:14][CH2:13][CH2:1][CH2:2][CH2:3][CH2:4][NH:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][NH:12][CH:17]([C:16]([O:25][CH2:26][CH3:27])=[O:24])[CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[O:25][CH2:26][CH3:27]
Reactant: NCCCCCCNCCCCCCN
Reactant: CCOC(=O)/C=C\C(=O)OCC
Product: CCOC(=O)CC(NCCCCCCNCCCCCCNC(CC(=O)OCC)C(=O)OCC)C(=O)OCC
Yield: 100.7 %

Procedure:
Analogously to (1), 154 g (0.72 mol) of bis(hexamethylene)triamine and 246 g (1.42 mol) of diethyl maleate were used to obtain 400 g of the product as a yellow liquid.
Reaction SMILES: [CH:1]([O:4][C:5](=[O:14])[C:6]1[CH:11]=[C:10]([CH3:12])[N:9]=[C:8](Cl)[CH:7]=1)([CH3:3])[CH3:2].[Br-].[CH2:16]([CH:18]([Zn+])[CH2:19][CH3:20])[CH3:17].C1COCC1>O1CCOCC1>[CH:1]([O:4][C:5](=[O:14])[C:6]1[CH:11]=[C:10]([CH3:12])[N:9]=[C:8]([CH:18]([CH2:19][CH3:20])[CH2:16][CH3:17])[CH:7]=1)([CH3:3])[CH3:2]
Reactant: Cc1cc(C(=O)OC(C)C)cc(Cl)n1
Reactant: CCC([Zn+])CC
Agent: [Br-]
Solvent: C1COCCO1
Solvent: C1CCOC1
Product: CCC(CC)c1cc(C(=O)OC(C)C)cc(C)n1
Temperature: 80 °C
Reaction time: 16 h

Procedure:
A a solution of 2-chloro-6-methyl-isonicotinic acid isopropyl ester (2.0 g, 9.36 mmol) in dioxane (75 mL) is degassed and put under argon before Pd(dppf) (229 mg, 0.281 mmol) is added. At rt, a 0.5 M solution of 1-ethyl-propylzinc bromide in THF (46.8 mL, 23.4 mmol) is added dropwise to the mixture. The mixture is stirred at 80° C. for 16 h before the reaction is quenched by adding ice-cold water (200 mL). A precipitate forms and the mixture is diluted with EA (200 mL) and filtered through celite. The filtrate is transferred into a separatory funnel. The org. phase is collected and the aq. phase is extracted with EA (120 mL). The combined org. extracts are dried over MgSO4, filtered and concentrated. The crude product is purified by CC on silica gel eluting with heptane:EA 9:1 to 4:1 to give 2-(1-ethyl-propyl)-6-methyl-isonicotinic acid isopropyl ester (1.6 g) as a yellow oil; LC-MS: tR=0.79 min, [M+1]+=250.14; 1H NMR (D6-DMSO): δ 0.70 (t, J=7.3 Hz, 6H), 1.33 (d, J=6.3 Hz, 6H), 1.58-1.70 (m, 4H), 2.51 (s, 3H), 2.55-2.63 (m, 1H), 5.15 (hept, J=5.8 Hz), 7.39 (s, 1H), 7.49 (s, 1H).
Reaction SMILES: Cl.[C:2]([C:4]1([NH:7][C:8]([C@@H:10]2[CH2:14][C@@H:13]([S:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[Cl:24])(=[O:17])=[O:16])[CH2:12][NH:11]2)=[O:9])[CH2:6][CH2:5]1)#[N:3].[F:25][C:26]1[CH:34]=[CH:33][C:29]([C:30](O)=[O:31])=[CH:28][CH:27]=1>>[C:2]([C:4]1([NH:7][C:8]([C@@H:10]2[CH2:14][C@@H:13]([S:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[Cl:24])(=[O:17])=[O:16])[CH2:12][N:11]2[C:30](=[O:31])[C:29]2[CH:33]=[CH:34][C:26]([F:25])=[CH:27][CH:28]=2)=[O:9])[CH2:6][CH2:5]1)#[N:3]
Reactant: N#CC1(NC(=O)[C@@H]2C[C@@H](S(=O)(=O)c3ccccc3Cl)CN2)CC1
Reactant: O=C(O)c1ccc(F)cc1
Agent: Cl
Product: N#CC1(NC(=O)[C@@H]2C[C@@H](S(=O)(=O)c3ccccc3Cl)CN2C(=O)c2ccc(F)cc2)CC1

Procedure:
(2S,4R)-4-(2-chloro-benzenesulfonyl)-pyrrolidine-2-carboxylic acid (1-cyano-cyclopropyl)-amide hydrochloride from experiment K4 was coupled with 4-fluoro benzoic acid in analogy to experiment A1 to give (2S,4R)-4-(2-chloro-benzenesulfonyl)-1-(4-fluoro-benzoyl)-pyrrolidine-2-carboxylic acid (1-cyano-cyclopropyl)-amide as an amorphous white solid. MS: 476.0 [M+H]+.
Reaction SMILES: C1N=CN([C:6](N2C=NC=C2)=[O:7])C=1.[NH2:13][C:14]1[CH:15]=[C:16]([CH:24]2[C:29]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[C:28]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[NH:27][C:26](=[O:42])[NH:25]2)[CH:17]=[C:18]([O:21][CH2:22][CH3:23])[C:19]=1[OH:20].O>C1COCC1>[CH2:22]([O:21][C:18]1[C:19]2[O:20][C:6](=[O:7])[NH:13][C:14]=2[CH:15]=[C:16]([CH:24]2[C:29]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[C:28]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[NH:27][C:26](=[O:42])[NH:25]2)[CH:17]=1)[CH3:23]
Reactant: CCOc1cc(C2NC(=O)NC(c3ccccc3)=C2c2ccccc2)cc(N)c1O
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: O
Solvent: C1CCOC1
Product: CCOc1cc(C2NC(=O)NC(c3ccccc3)=C2c2ccccc2)cc2[nH]c(=O)oc12
Yield: 26.8 %

Procedure:
To a solution of CDI (243 mg, 1.50 mmol) in THF (3 mL) was added 4-(3-amino-5-ethoxy-4-hydroxyphenyl)-5,6-diphenyl-3,4-dihydropyrimidin-2(1H)-one (386 mg, 0.96 mmol) and the resultant mixture was heated to reflux for 1.0 h. The reaction mixture was added water (10 mL) and filtered. The filtered mass was washed with methanol (3 mL) and dried to afford Compound 72 as a yellow solid (110 mg, 30%). 1H NMR (DMSO-d6 500 MHz): δ 11.56 (s, 1H), 8.69 (s, 1H), 7.49 (s, 1H), 7.21 (s, 3H), 7.20 (s, 2H), 6.99-7.04 (m, 3H), 6.81 (d, J=6.0 Hz, 2H), 6.74 (d, J=6.0 Hz, 2H), 5.12 (s, 1H), 4.11 (q, J=6.8 Hz, 2H), 1.31 (t, J=7.0 Hz, 3H); MS (ESI): m/z 428.1 [M+1]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1.C(NC(C)C)(C)C.C[Si](C[Li])(C)C.C([O:25][B:26](OC(C)C)[O:27]C(C)C)(C)C.[OH-].[Na+]>C1COCC1>[CH3:1][O:2][C:3]1[C:8]([B:26]([OH:27])[OH:25])=[CH:7][CH:6]=[CH:5][N:4]=1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: COc1ccccn1
Agent: [Li]C[Si](C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: COc1ncccc1B(O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 68.4 %

Procedure:
A mixture of 2-methoxypyridine (23.2 g) and diisopropylamine (1.35 mL) in THF (223 mL) was added to (trimethylsilylmethyl)lithium (218 mL, 13.8 weight percent in hexanes) at −20° C. The lithiation was 84% complete after 7 hours. Tri-isopropylborate (40.8 g) was added at −20° C. over 40 minutes. The mixture was stirred overnight at ambient temperature. 5 percent NaOH (aq, 225 mL) was added. The aqueous layer was removed and brought to pH 5 by adding 10% HCl (aq). The resulting white precipitate was isolated by filtration. After drying, 22.23 g of 2-methoxypyridine-3-boronic acid was obtained (68% yield).
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([C:10]1[N:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:13]2[CH:21]=[CH:22][C:23]([CH3:25])=[CH:24][C:12]=2[N:11]=1)[CH3:9])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:25][C:23]1[CH:22]=[CH:21][C:13]2[N:14]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:10]([C@@H:8]([NH2:7])[CH3:9])=[N:11][C:12]=2[CH:24]=1
Reactant: Cc1ccc2c(c1)nc([C@H](C)NC(=O)OC(C)(C)C)n2-c1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1ccc2c(c1)nc([C@H](C)N)n2-c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 94.8 %

Procedure:
To a solution of [(S)-1-(5-methyl-1-phenyl-1H-benzoimidazol-2-yl)ethyl]carbamic acid tertbutyl ester (912 mg, 2.59 mmol) in DCM (10 mL) was added TFA (5 mL) and the mixture was stirred at RT for 2 h. Volatiles were removed under reduced pressure and the resulting residue was dissolved in DCM (40 mL) and washed with a saturated solution of NaHCO3 (50 mL). The two phase system was stirred for 10 min, then the organic layer was dried (Na2SO4) and concentrated in vacuo affording (S)-1-(5-Methyl-1-phenyl-1H-benzoimidazol-2-yl)ethylamine (617 mg, 95%). LCMS: RT 2.10 and 2.23 min [M−NH2] 252.0.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]#[CH:10].[Cl:11][C:12]1[CH:19]=[C:18]([CH3:20])[CH:17]=[CH:16][C:13]=1[CH2:14][SH:15].[Na]>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1/[CH:9]=[CH:10]\[CH:14]([S:15][CH:14](/[CH:10]=[CH:9]\[C:3]1[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=1[Cl:1])[C:13]1[CH:16]=[CH:17][C:18]([CH3:20])=[CH:19][C:12]=1[Cl:11])[C:13]1[CH:16]=[CH:17][C:18]([CH3:20])=[CH:19][C:12]=1[Cl:11]
Reactant: C#Cc1ccc(Cl)cc1Cl
Reactant: Cc1ccc(CS)c(Cl)c1
Agent: [Na]
Product: Cc1ccc(C(/C=C\c2ccc(Cl)cc2Cl)SC(/C=C\c2ccc(Cl)cc2Cl)c2ccc(C)cc2Cl)c(Cl)c1

Procedure:
A solution of 2,4-dichlorophenylacetylene (0.02 mol), 2-chloro-4-methylbenzyl mercaptan (0.02 mol) and metallic sodium (0.02 g atom) is subjected to the General Procedure to form (Z)-2,4-dichlorostyryl-2-chloro-4-methylbenzylsulfide. The title compound is obtained following oxidation of the sulfide, according to the General Procedure.
Reaction SMILES: Br[C:2]1[C:6]([Cl:7])=[N:5][S:4][N:3]=1.[C:8]1(B(O)O)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[F-].[K+]>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:7][C:6]1[C:2]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:3][S:4][N:5]=1
Reactant: OB(O)c1ccccc1
Reactant: Clc1nsnc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [F-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: Clc1nsnc1-c1ccccc1
Reaction time: 26 h
Yield: 91.5 %

Procedure:
To a mixture of 3-bromo-4-chloro-1,2,5-thiadiazole (0.2 g, 1 mmol), phenylboronic acid (0.135 g, 1.1 mol) in toluene (5 ml) is added a 1M aqueous solution of KF (3 cc, 3 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.055 g, 0.05 mmol, 5%mol) and the biphasic mixture is refluxed with vigorous stirring for 26 hours. The organic layer is decanted off and the aqueous layer is extracted with toluene (2×10 ml). After drying over magnesium sulfate and concentration under vacuum, the oily material is purified by flash chromatography on silica gel eluting with hexane/ethyl acetate (99/1) to afford 0.18 g (95%) of 3-chloro-4-phenyl-1,2,5-thiadiazole as a colorless oil, which crystallizes on standing (melting point 33° C.).
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:16])[CH3:15])[C:11](Cl)=[CH:10][C:9]=1[NH2:18])([CH3:4])([CH3:3])[CH3:2].CC1(C)[O:26][C:25]([C:27]2[CH:28]=[C:29]([CH:32]=[CH:33][CH:34]=2)[C:30]#[N:31])=[CH:24][C:23](=[O:35])O1>>[C:1]([O:5][C:6](=[O:19])[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:16])[CH3:15])[C:11]([C:24]#[C:25][C:27]2[CH:28]=[CH:29][CH:32]=[CH:33][CH:34]=2)=[CH:10][C:9]=1[NH:18][C:23](=[O:35])[CH2:24][C:25]([C:27]1[CH:34]=[CH:33][CH:32]=[C:29]([C:30]#[N:31])[CH:28]=1)=[O:26])([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(C)c1cc(NC(=O)OC(C)(C)C)c(N)cc1Cl
Reactant: CC1(C)OC(=O)C=C(c2cccc(C#N)c2)O1
Product: CN(C)c1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(C#N)c2)cc1C#Cc1ccccc1

Procedure:
The title compound was prepared from (2-amino-4-chloro-5-dimethylamino-phenyl)-carbamic acid tert.-butyl ester (Example J2) and 3-(2,2-dimethyl-6-oxo-6H-[1,3]dioxin-4-yl)-benzonitrile (Example L1) according to the general procedure M. Obtained as an orange solid (108 mg).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][S:5]([CH3:8])(=[O:7])=[O:6].[CH3:9][NH:10][CH3:11]>CCOCC>[CH3:8][S:5]([CH2:4][CH2:3][CH2:2][N:10]([CH3:11])[CH3:9])(=[O:7])=[O:6]
Reactant: CNC
Reactant: CS(=O)(=O)CCCBr
Solvent: CCOCC
Product: CN(C)CCCS(C)(=O)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 101.7 %

Procedure:
1-Bromo-3-methanesulfonylpropane (500 mg, 2.5 mmol) was suspended in a dimethylamine solution (2 M in THF; 10 mL, 20 mmol) and stirred at RT, resulting in a crystalline solid. The reaction was left to stand overnight and the reaction mixture was then diluted with Et2O (10 mL) and filtered. The filtrate was concentrated in vacuo resulting in an orange oily solid which was redissolved in Et2O (10 mL), filtered and concentrated in vacuo to give the title compound as an orange oil (420 mg).
Reaction SMILES: [OH:1][CH:2]1[CH2:5][N:4]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[CH2:3]1.CCN(C(C)C)C(C)C.[Cl:22][C:23](Cl)([O:25]C(=O)OC(Cl)(Cl)Cl)Cl>C1COCC1>[Cl:22][C:23]([O:1][CH:2]1[CH2:3][N:4]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[CH2:5]1)=[O:25]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CC(C)(C)OC(=O)N1CC(O)C1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CC(OC(=O)Cl)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 55 %

Procedure:
To a stirred solution of 3-hydroxy-1-Boc azetidine (21; 350 mg, 2.023 mmol) and DIPEA (1.3 ml, 7.080 mmol) in THF (5 ml) at 0° C. was slowly added triphosgene (898 mg, 3.034 mmol). The resulting mixture was stirred for 2 hr at RT. After completion of the reaction, the reaction mixture was filtered and washed with fresh THF to get rid of inorganic salts. The filtrate was concentrated under reduced pressure to get crude product 61 in 55% yield. The crude product, thus obtained, was immediately used for the next reaction.
Reaction SMILES: [CH3:1][NH2:2].[NH2:3][C:4]1[C:5]([F:30])=[CH:6][C:7]([F:29])=[C:8]([N:10]2[C:19]3[C:14](=[CH:15][C:16]([CH3:24])=[C:17](F)[C:18]=3[N+:20]([O-:22])=[O:21])[C:13](=[O:25])[C:12]([C:26]([OH:28])=[O:27])=[CH:11]2)[CH:9]=1>CS(C)=O.N1C=CC=CC=1>[NH2:3][C:4]1[C:5]([F:30])=[CH:6][C:7]([F:29])=[C:8]([N:10]2[C:19]3[C:14](=[CH:15][C:16]([CH3:24])=[C:17]([NH:2][CH3:1])[C:18]=3[N+:20]([O-:22])=[O:21])[C:13](=[O:25])[C:12]([C:26]([OH:28])=[O:27])=[CH:11]2)[CH:9]=1
Reactant: CN
Reactant: Cc1cc2c(=O)c(C(=O)O)cn(-c3cc(N)c(F)cc3F)c2c([N+](=O)[O-])c1F
Solvent: c1ccncc1
Solvent: CS(C)=O
Product: CNc1c(C)cc2c(=O)c(C(=O)O)cn(-c3cc(N)c(F)cc3F)c2c1[N+](=O)[O-]
Temperature: 40 °C
Reaction time: 8 h

Procedure:
Pyridine (500 mg) and a 40% aqueous solution (300 mg) of methylamine were added to 1-(5-amino-2,4-difluorophenyl)-7-fluoro-6-methyl-8-nitro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (70 mg), and the mixture was heated and stirred overnight at 40° C. Dimethyl sulfoxide (10 drops) was added to the reaction mixture, followed by stirring at 40° C. for 5 hours. The solvent and the like were distilled off under reduced pressure, and ethanol (0.5 ml) was added to the residue. Solids deposited were collected by filtration aid washed with ethanol and diethyl ether to obtain the title compound (53 mg) as a yellow powder.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[C:11](=O)[CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14].[NH2:19][CH2:20][CH2:21][NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26].C(O)(=O)C>C(O)C>[C:25]([O:24][C:23]([NH:22][CH2:21][CH2:20][NH:19]/[C:11](/[C:4]1[CH:5]=[CH:6][C:7]([O:9][CH3:10])=[CH:8][C:3]=1[O:2][CH3:1])=[CH:12]\[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[O:29])([CH3:28])([CH3:27])[CH3:26]
Reactant: CC(C)(C)OC(=O)NCCN
Reactant: CCOC(=O)CC(=O)c1ccc(OC)cc1OC
Solvent: CCO
Solvent: CC(=O)O
Product: CCOC(=O)/C=C(\NCCNC(=O)OC(C)(C)C)c1ccc(OC)cc1OC

Procedure:
A solution of ethyl 3-(2,4-dimethoxyphenyl)-3-oxopropanoate (41.91 g, 166 mmol), tert-butyl 2-aminoethylcarbamate (54.7 g, 342 mmol), and acetic acid (16.14 g, 269 mmol) in ethanol (180 mL) was heated at reflux for 5.3 h. After removal of most of the solvent by rotary evaporation, the resulting oil was partitioned between EtOAc (ca. 300 mL) and 10% (w/v) aq. ammonium chloride. The EtOAc layer was separated and then washed with water, 10% (w/v) aq. ammonium chloride (3 mL), and brine (10 mL). The EtOAc layer was washed with sat. aq. sodium bicarbonate, brine (6 mL) was added, and the emulsion was allowed to settle. The EtOAc layer was finally washed with brine and dried over sodium sulfate. Evaporation of the EtOAc layer's volatile components afforded a viscous, amber taffy (62.3 g, 95%). This crude product was used without further purification.
Reaction SMILES: C(OC(=O)C(CS(N1CCN(C2C=CC(Br)=CC=2)CC1)(=O)=O)C(C)C)(C)(C)C.[F:29][C:30]1[CH:35]=[CH:34][C:33]([C:36]2[CH:37]=[CH:38][C:39]([O:42][CH:43]3[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]3)=[N:40][CH:41]=2)=[CH:32][CH:31]=1.[CH2:49]([C@@H:56]1[CH2:60][O:59][C:58](=[O:61])[N:57]1[C:62](=[O:72])[C@H:63]([CH2:67][S:68](Cl)(=[O:70])=[O:69])[CH:64]([CH3:66])[CH3:65])[C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1>>[CH2:49]([C@@H:56]1[CH2:60][O:59][C:58](=[O:61])[N:57]1[C:62](=[O:72])[C@H:63]([CH2:67][S:68]([N:46]1[CH2:47][CH2:48][CH:43]([O:42][C:39]2[CH:38]=[CH:37][C:36]([C:33]3[CH:32]=[CH:31][C:30]([F:29])=[CH:35][CH:34]=3)=[CH:41][N:40]=2)[CH2:44][CH2:45]1)(=[O:70])=[O:69])[CH:64]([CH3:66])[CH3:65])[C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1
Reactant: CC(C)[C@@H](CS(=O)(=O)Cl)C(=O)N1C(=O)OC[C@H]1Cc1ccccc1
Reactant: Fc1ccc(-c2ccc(OC3CCNCC3)nc2)cc1
Agent: CC(C)C(CS(=O)(=O)N1CCN(c2ccc(Br)cc2)CC1)C(=O)OC(C)(C)C
Product: CC(C)[C@@H](CS(=O)(=O)N1CCC(Oc2ccc(-c3ccc(F)cc3)cn2)CC1)C(=O)N1C(=O)OC[C@H]1Cc1ccccc1
Yield: 75.3 %

Procedure:
Prepared according to the method for the preparation of 2-[4-(4-bromophenyl)-piperazine-1-sulfonylmethyl]-3-methyl-butyric acid tert-butyl ester, from 5-(4-fluorophenyl)-2-(piperidin-4-yloxy)pyridine (0.52 g) and 4-(R)-Benzyl-3-(2-(R)-chlorosulfonylmethyl-3-methylbutyryl)oxazolidin-2-one (0.57 g) to yield the title compound as an off-white solid (0.70 g, 58%).
Reaction SMILES: [CH2:1]([N:7]1[CH2:12][CH2:11][C:10]([CH3:21])([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([CH:19]=O)[CH:14]=2)[CH:9]([CH3:22])[CH2:8]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].Cl.[NH2:24][OH:25]>N1C=CC=CC=1.C(O)C>[CH2:1]([N:7]1[CH2:12][CH2:11][C:10]([CH3:21])([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([CH:19]=[N:24][OH:25])[CH:14]=2)[CH:9]([CH3:22])[CH2:8]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCN1CCC(C)(c2cccc(C=O)c2)C(C)C1
Reactant: NO
Agent: Cl
Solvent: CCO
Solvent: c1ccncc1
Product: CCCCCCN1CCC(C)(c2cccc(C=NO)c2)C(C)C1
Yield: 21.1 %

Procedure:
A solution of 1-hexyl-3,4-dimethyl-4-(3-formylphenyl)piperidine (Example 28, 80 mg, 0.27 mmol) in a mixture of pyridine (1 mL) and ethanol (1 mL) was treated with hydroxylamine hydrochloride (22 mg, 0.32 mmol) and the resulting mixture was heated at reflux for 18 hours. The solvent was evaporated in vacuo and the residual orange oil was purified by column chromatography on silica gel (10 g) eluted with a gradient of dichloromethane:methanol:0.880 ammonia (98:1:1 to 94:5:1). This gave the title compound as an oil (18 mg).
Reaction SMILES: [OH-].[Na+].[N+:3]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[OH:12])([O-:5])=[O:4].Cl[CH2:14][CH:15]=[CH2:16].CS(C)=O>O>[CH2:16]([O:12][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=1[N+:3]([O-:5])=[O:4])[CH:15]=[CH2:14]
Reactant: O=[N+]([O-])c1ccccc1O
Reactant: C=CCCl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: C=CCOc1ccccc1[N+](=O)[O-]
Reaction time: 18 h

Procedure:
A solution of 64 g of sodium hydroxide in 75 ml of water was added drop-by-drop (over 15 minutes) to a stirred mixture of 209.6 g of 2-nitrophenol, 115.5 g of 3-chloropropene and 500 ml of dimethyl sulfoxide (DMSO), at room temperature. The mixture was stirred at 85°-90° C. for 18 hours and then mixed with 3 liters of water. The resulting mixture was extracted with methylene chloride, the extract was washed with ice water, dried (MgSO4) and the solvent was evaporated, to give 1-(2-propen-1-yloxy)-2-nitrobenzene (1A), as an amber syrup.