Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [ClH:1].Cl.[CH3:3][O:4][C:5]([C@H:7]1[C@@H:13]([C:14]2[CH:19]=[CH:18][C:17]([NH2:20])=[C:16]([I:21])[CH:15]=2)[CH2:12][C@H:11]2[N:22]([CH3:23])[C@@H:8]1[CH2:9][CH2:10]2)=[O:6].N([O-])=O.[Na+].[N-:28]=[N+:29]=[N-].[Na+].Cl>CC(O)=O.O>[ClH:1].[CH3:3][O:4][C:5]([C@H:7]1[C@@H:13]([C:14]2[CH:19]=[CH:18][C:17]([N:20]=[N+:28]=[N-:29])=[C:16]([I:21])[CH:15]=2)[CH2:12][C@H:11]2[N:22]([CH3:23])[C@@H:8]1[CH2:9][CH2:10]2)=[O:6]
Reactant: COC(=O)[C@H]1[C@@H](c2ccc(N)c(I)c2)C[C@@H]2CC[C@H]1N2C
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: COC(=O)[C@H]1[C@@H](c2ccc(N=[N+]=[N-])c(I)c2)C[C@@H]2CC[C@H]1N2C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 72.7 %

Procedure:
To a solution of 3β-[3'-iodo-4'-aminophenyl]tropan-2β-carboxylic acid methyl ester dihydrochloride (1a) (90 mg, 0.1902 retool) in 1 mL of AcOH (3M) was added an aqueous solution of NaNO2 (17.3 mg, 0.2661 mmol, in 0.5 mL of H2O) at 0° C. After 30 min at this temperature NaN3 (19 mg, 0.2754 mmol) in 0.5 mL of H2O was added dropwise to the reaction mixture and stirred for 30 min at 0° C. then 30 min at room temperature. After removal of all solvent by evaporation, the residue was dissolved in CHCl3 and washed with H2O. The organic layer was dried over MgSO4 and concentrated to give an oil which was converted to HCl salt to yield 64 mg (72.7%) of 3β-[3'-iodo-4'-azidophenyl]tropan-2β-carboxylic acid methyl ester hydrochloride (1b) as a yellowish solid: mp 140°-143° C.; [α] 25 -97.4° (c 0.115), MeOh); 1H NMR (250 MHz, CDCl3) δ 1.51-1.73 (m, 3) 2.07-2.16 (m, 2), 2.19 (s, 3, NCH3) 2.47 (m, 1), 2.80-2.93 (m, 2), 3.32 (m, 1, H-5), 3.51 (s, 3, OCH3), 3.54 (m, 1, H-1), 7.01 (d, 1, J-7.7, ArH), 7.28 (dd, 1, J=7.77, J=1, ArH), 7.60 (d, 1, J=1, ArH).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12]Cl)=[CH:8][C:7]=1[CH3:14].[N-:16]=[N+:17]=[N-:18].[Na+].O>CN(C=O)C>[CH3:1][O:2][C:3](=[O:15])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][N:16]=[N+:17]=[N-:18])=[CH:8][C:7]=1[CH3:14]
Reactant: [N-]=[N+]=[N-]
Reactant: COC(=O)CCc1ccc(CCl)cc1C
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)CCc1ccc(CN=[N+]=[N-])cc1C
Reaction time: 8 h
Yield: 90.9 %

Procedure:
To a solution of 3-(4-Chloromethyl-2-methyl-phenyl)-propionic acid methyl ester (0.52 g, 2.31 mmol) in DMF (7 mL) is added sodium azide (0.25 g, 3.84 mmol). The mixture is stirred overnight. Water is added, and the mixture is extracted with EtOAc. The organics are dried with Na2SO4 and concentrated to yield the title compound (0.49 g, 91%). The material is used without further purification.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][C@@H:3]([CH2:6][OH:7])[CH2:2]1.ClC1N=C2C(N=CN2CC2CCOCC2)=C(Cl)N=1.C(N(CC)CC)C.[CH3:33][S:34](Cl)(=[O:36])=[O:35]>ClCCl>[CH3:33][S:34]([O:7][CH2:6][CH:3]1[CH2:4][CH2:5][O:1][CH2:2]1)(=[O:36])=[O:35]
Reactant: CS(=O)(=O)Cl
Reactant: OC[C@@H]1CCOC1
Agent: Clc1nc(Cl)c2ncn(CC3CCOCC3)c2n1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCC1CCOC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To (3S)-tetrahydro-3-furanylmethanol, Isomer 2 (1.4 g) in dry dichloromethane (40 ml) at 0° C. and under nitrogen, was added triethylamine (3.83 ml) followed by methanesulfonyl chloride (1.39 ml). The reaction was stirred at room temperature overnight. The orange solution was diluted with dichloromethane (50 ml) and washed with saturated aqueous sodium bicarbonate (20 ml). The organic layer was separated, dried through a hydrophobic frit and concentrated in vacuo to yield the title compound as an orange oil (2.6 g).
Reaction SMILES: C(O[C:6](=[O:24])[N:7]([CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=1)[N:8]1[CH:12]=[CH:11][CH:10]=[CH:9]1)(C)(C)C.[CH2:25]([O:27][C:28](=[O:40])[CH:29](C(OCC)=O)[C:30](OCC)=[O:31])[CH3:26]>>[CH2:25]([O:27][C:28]([C:29]1[C:6](=[O:24])[N:7]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:21])([F:22])[F:23])[CH:15]=2)[N:8]2[CH:9]=[CH:10][CH:11]=[C:12]2[C:30]=1[OH:31])=[O:40])[CH3:26]
Reactant: CCOC(=O)C(C(=O)OCC)C(=O)OCC
Reactant: CC(C)(C)OC(=O)N(Cc1cccc(C(F)(F)F)c1)n1cccc1
Product: CCOC(=O)c1c(O)c2cccn2n(Cc2cccc(C(F)(F)F)c2)c1=O

Procedure:
Prepared according to the thermal cyclization condition used in Example 1 step c) from starting materials (3-trifluoromethyl-benzyl)-pyrrol-1-yl-carbamic acid tert-butyl ester (1.0 eq.) and 2-ethoxycarbonyl-malonic acid diethyl ester (3.0 eq.). ESI (m/z): 381 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH3:8])=[CH:6][N:5]=[C:4]([Cl:9])[CH:3]=1.[OH:10][C:11]1[CH:16]=[C:15]([CH3:17])[O:14][C:13](=O)[CH:12]=1.[Cl-].[Li+].CO>ClCCl>[Cl:9][C:4]1[CH:3]=[C:2]([N:1]2[C:15]([CH3:17])=[CH:16][C:11]([OH:10])=[CH:12][C:13]2=[O:14])[C:7]([CH3:8])=[CH:6][N:5]=1
Reactant: Cc1cnc(Cl)cc1N
Reactant: Cc1cc(O)cc(=O)o1
Agent: [Cl-]
Agent: [Li+]
Solvent: ClCCl
Solvent: CO
Product: Cc1cnc(Cl)cc1-n1c(C)cc(O)cc1=O
Temperature: 160 °C
Yield: 6 %

Procedure:
A well-powdered mixture of 4-amino-5-methyl-2-chloropyridine (0.5 g, 3.5 mmol), 4-hydroxy-6-methyl-pyrone (0.665 g, 5.3 mmol), and lithium chloride (0.025 g, 0.6 mmol) was heated at 160° C. for 20 min in a sealed tube. The resulting melt was cooled and the product was isolated by silica gel flash chromatography using 3% methanol in dichloromethane. Appropriate fractions were combined, concentrated under reduced pressure and the resulting solid was triturated with ethyl acetate, cooled and filtered. The solid was washed with ethyl acetate and dried to give 0.053 g of the title compound as a yellow powder. ES-MS: m/z=251 (M+H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]=[O:8])[CH:2]=1.[F:9][C:10]1[CH:15]=[CH:14][C:13]([Mg]Br)=[CH:12][CH:11]=1>O1CCCC1.CCOCC>[F:9][C:10]1[CH:15]=[CH:14][C:13]([CH:7]([C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)[OH:8])=[CH:12][CH:11]=1
Reactant: O=Cc1cccnc1
Reactant: Fc1ccc([Mg]Br)cc1
Solvent: CCOCC
Solvent: C1CCOC1
Product: OC(c1ccc(F)cc1)c1cccnc1
Temperature: 0 °C
Yield: 93 %

Procedure:
A solution of 3-pyridinecarboxaldehyde (5.32 g, 49.7 mmol) in tetrahydrofuran (100 ml) was cooled to-78° C. and treated dropwise with 25 ml (50 mmol) of a 2 M solution of 4-fluorophenyl magnesium bromide in ether. The reaction mixture was then slowly warmed up to 0° C. over 1 h and then quenched by the addition of saturated aqueous sodium bicarbonate and ethyl acetate. The organic phase was washed with brine, dried (magnesium sulfate) and concentrated under reduced pressure. Filtration of the residue on a short silica gel pad (elution ethyl acetate) followed by distillation in vacuo gave 9.42 g (93%) of the title material as a clear oil which crystallized upon standing. bp 120-130° C./0.2 torr (bulb to bulb distillation, air bath temperature), mp 45-47° C. 1HNMR 400 MHz (CDCl3) δ (ppm): 5.88 (1H, s, CH benzhydryl), 7.05 (2H, m, aromatics), 7.25-7.36 (3H, m, aromatics), 7.73 (1H, d, J=7.9 Hz, aromatic), 8.44 (1H, d, J=5.2 Hz, aromatic), 8.55 (1H, s, aromatic). Anal. Calcd for C12H10FNO: C, 70.92; H, 4.96; N, 6.89. Found: C, 70.61; H, 4.86; N, 6.71.
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]2[C@H:8]3[C@H:17]([CH2:18][CH2:19][C@:3]12[CH3:4])[C@@H:16]1[C:11](=[CH:12][C:13](=[O:20])[CH2:14][CH2:15]1)[CH2:10][CH2:9]3.[CH2:21]([O:27][C:28]1[CH:33]=[CH:32][C:31]([CH2:34][CH2:35][C:36](O)=[O:37])=[CH:30][CH:29]=1)[CH2:22][CH2:23][CH2:24][CH2:25][CH3:26].C1CCC(N=C=NC2CCCCC2)CC1.C(O)(=O)C>N1C=CC=CC=1>[CH2:21]([O:27][C:28]1[CH:29]=[CH:30][C:31]([CH2:34][CH2:35][C:36]([O:1][C@H:2]2[CH2:7][CH2:6][C@H:5]3[C@H:8]4[C@H:17]([CH2:18][CH2:19][C@:3]23[CH3:4])[C@@H:16]2[C:11](=[CH:12][C:13](=[O:20])[CH2:14][CH2:15]2)[CH2:10][CH2:9]4)=[O:37])=[CH:32][CH:33]=1)[CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: CCCCCCOc1ccc(CCC(=O)O)cc1
Reactant: C[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@H]43)[C@@H]1CC[C@@H]2O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CC(=O)O
Solvent: c1ccncc1
Product: CCCCCCOc1ccc(CCC(=O)O[C@H]2CC[C@H]3[C@@H]4CCC5=CC(=O)CC[C@@H]5[C@H]4CC[C@]23C)cc1
Reaction time: 8 h
Yield: 87 %

Procedure:
To a solution of 17β-hydroxyestr-4-en-3-one (5.48 g) and 3-(4-hexyloxyphenyl)propionic acid (5.75 g) in dry pyridine (60 ml) pTSA (0.200 g) and DCC (5.77 g) are added. After 72 h stirring at room temperature acetic acid (2 ml) is added, and the reaction mixture is kept overnight at +4° C. The same work-up procedure as in Example 1 gives 17β-[3-(4-hexyloxyphenyl)-propanoyloxy]estr-4-en-3-one (m. p. 52°-53° C.) in a 87% yield after recrystallization from methanol/water.
Reaction SMILES: [N+:1]([C:4]1[CH:17]=[C:16]([N+:18]([O-:20])=[O:19])[CH:15]=[CH:14][C:5]=1[NH:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)([O-:3])=[O:2].[C:21](=O)([O-])[O-].[K+].[K+].CI>CN(C)C=O>[N+:1]([C:4]1[CH:17]=[C:16]([N+:18]([O-:20])=[O:19])[CH:15]=[CH:14][C:5]=1[NH:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:21])=[CH:9][CH:8]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(Nc2ccc(O)cc2)c([N+](=O)[O-])c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: COc1ccc(Nc2ccc([N+](=O)[O-])cc2[N+](=O)[O-])cc1

Procedure:
1.43 g of 4-(2,4-dinitroanilino)phenol, 500 mg of potassium carbonate and 0.32 ml of methyl iodide were stirred in 5 ml of N,N-dimethylformamide for 2 days at 20° C. The mixture was poured onto water, extracted three times with ethyl acetate, the extracts were dried on sodium sulfate, concentrated by evaporation in a vacuum, and the residue was chromatographed on silica gel.
Reaction SMILES: C1(S[CH2:8][N:9]2[C:13](=[O:14])[CH:12]([CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[N:11]([CH3:22])[S:10]2(=O)=O)C=CC=CC=1.C(Cl)[Cl:26]>>[Cl:26][CH2:8][N:9]1[C:13](=[O:14])[CH:12]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:11]([CH3:22])[S:10]1
Reactant: CN1C(Cc2ccccc2)C(=O)N(CSc2ccccc2)S1(=O)=O
Reactant: ClCCl
Product: CN1SN(CCl)C(=O)C1Cc1ccccc1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 92.4 %

Procedure:
To a solution of 2-phenylthiomethyl-4-phenylmethyl-5-methyl-1,2,5-thiadiazolidin-3-one 1,1-dioxide (11.78 g, 33.05 mmol) in 200 ml of methylene chloride was added in one portion under nitrogen sulfuryl chloride (3.15 ml, 39.66 mmol) and the mixture was stirred for 3.5 hours at room temperature. The mixture was concentrated in vacuo and the residue was triturated in hexane and purified by flash chromatography (20% ethyl acetate in hexane) to afford 8.82 g (92.4%) of 2-chloromethyl-4-phenylmethyl-5-methyl-1,2,5-thiadiazolidin-3-one (Formula II: R1 =H; R2 =CH2Ph; R3 =CH3 ; X'=Cl) as an oil.
Reaction SMILES: N(C1C(C(OCC)=O)=CN=C2N(CC3OC=CC=3)N=CC=12)N.C(N1C2=NC=C(C(OCC)=O)C(NN)=C2C=N1)C.[CH2:41]([N:47]1[C:51]2[N:52]=[CH:53][C:54]3[C:55](=[O:63])[NH:56][C:57]4[N:58]([N:60]=[CH:61][N:62]=4)[C:59]=3[C:50]=2[CH:49]=[N:48]1)[C:42]1[O:46][CH:45]=[CH:44][CH:43]=1.[C:64]1(O)[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=1>C(O)C>[CH2:41]([N:47]1[C:51]2[N:52]=[CH:53][C:54]3[C:55]([O:63][C:64]4[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=4)=[N:56][C:57]4[N:58]([N:60]=[CH:61][N:62]=4)[C:59]=3[C:50]=2[CH:49]=[N:48]1)[C:42]1[O:46][CH:45]=[CH:44][CH:43]=1
Reactant: O=c1[nH]c2ncnn2c2c1cnc1c2cnn1Cc1ccco1
Reactant: Oc1ccccc1
Agent: CCOC(=O)c1cnc2c(cnn2CC)c1NN
Agent: CCOC(=O)c1cnc2c(cnn2Cc2ccco2)c1NN
Solvent: CCO
Product: c1ccc(Oc2nc3ncnn3c3c2cnc2c3cnn2Cc2ccco2)cc1

Procedure:
By substituting 4-hydrazino-1-furfurylpyrazolo-[3,4-b]pyridine-5-carboxylic acid, ethyl ester for the 1-ethyl-4-hydrazino-1H-pyrazolo[3,4-b]pyridine-5-carboxylic acid, ethyl ester in Example 1 a, 8-furfuryl-4H-pyrazolo-[4',3':5,6]pyrido[3,4-e][1,2,4]triazolo[1,5-a]pyrimidin-5(8H)-one is obtained. This compound is now processed as in Example 1 b and then as in Example 4, substituting phenol for the ethanol to obtain 8-furfuryl-5-phenyloxy-8H-pyrazolo[4',3':5,6]pyrido[3,4-e][1,2,4]triazolo-[1,5-a]pyrimidine.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[C:5]2[S:10][C:9]([CH2:11][N:12]3[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]3)=[CH:8][C:6]=2[N:7]=1.[N:25]1[CH:30]=[C:29](B(O)O)[CH:28]=[N:27][CH:26]=1>>[CH3:18][N:15]1[CH2:16][CH2:17][N:12]([CH2:11][C:9]2[S:10][C:5]3[C:4]([N:19]4[CH2:24][CH2:23][O:22][CH2:21][CH2:20]4)=[N:3][C:2]([C:29]4[CH:30]=[N:25][CH:26]=[N:27][CH:28]=4)=[N:7][C:6]=3[CH:8]=2)[CH2:13][CH2:14]1
Reactant: OB(O)c1cncnc1
Reactant: CN1CCN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CC1
Product: CN1CCN(Cc2cc3nc(-c4cncnc4)nc(N4CCOCC4)c3s2)CC1

Procedure:
2-Chloro-6-(4-methyl-piperazin-1-ylmethyl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidine, prepared via General Procedure B-3, was reacted with pyrimidine-5-boronic acid in General Procedure A. Purification on silica yielded 164. (400 MHz CDCl3): 2.31 (3H, s, CH3), 2.50 (4H, b, CH2), 2.61 (4H, b, CH2), 3.85 (2H, s, CH2), 3.88-3.91 (4H, m, CH2), 4.06-4.08 (4H, m, CH2), 7.33 (1H, s, ar), 9.27 (1H, s, ar), 9.67 (2H, s, ar). MH+=412.27
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[O:12])[O:10][C:8](=O)[C:7]2=[CH:13][CH:14]=1)([O-:3])=[O:2].[NH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]([OH:23])=[O:22]>>[N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[O:12])[N:15]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]([OH:23])=[O:22])[C:8](=[O:10])[C:7]2=[CH:13][CH:14]=1)([O-:3])=[O:2]
Reactant: NCCCCCC(=O)O
Reactant: O=C1OC(=O)c2cc([N+](=O)[O-])ccc21
Product: O=C(O)CCCCCN1C(=O)c2ccc([N+](=O)[O-])cc2C1=O
Yield: 98 %

Procedure:
4-nitrophthalic anhydride (0.25 g, 0.0013 mol) and 6-aminohexanoic acid (0.177 g, 0.0013 mol) were refluxed as above overnight. The clear solution was purified as per 120 to yield 0.39 g (97%) 144 as very pale dull orange crystals: mp=140° C.; Rf0.86 (A): Rf0.85 (B): Rf0.75 (D): IR (cm−1): 2875-3125 (OH), 3064 (C═CH), 1775 (C═O), 1706 (bs, C═O), 1624 (C═C), 1544 (N═O), 1437 (C═C), 1398 (C—O), 1348 (N═O), 1069 (C—O), 722 (C═CH); MS m/z (rel intensity) 277 (100), 251 (11), 191 (124).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=[O:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:15]([Mg]Br)=[CH2:16].C1COCC1>C(OCC)C>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][C:11]([CH:15]=[CH2:16])([OH:14])[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: C=C[Mg]Br
Solvent: CCOCC
Solvent: C1CCOC1
Product: C=CC1(O)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
4-Oxo-piperidine-1-carboxylic acid tert-butyl ester (2.5 g, 12.5 mmol) was dissolved in 25 ml of diethylether and cooled to 0° C. A 1M solution of vinylmagnesiumbromide in THF (16.3 ml, 16.31 mmol) was added dropwise at 0° C. After 90 min stirring at 0° C., the reaction mixture was quenched with NH4Cl solution and extracted with ethyl acetate. The organic layer was washed with brine, dried over Na2 SO4 and evaporated. The crude product was further purified by flash chromatography (silicagel, cyclohexane/ethylacetate 4:1).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=2)[CH:11]=1)[C:6]([OH:8])=O)#[N:2].[NH2:19][C:20]1[C:21]([F:28])=[C:22]([OH:27])[CH:23]=[CH:24][C:25]=1[F:26].C([O-])(O)=O.[Na+]>O=S(Cl)Cl.C1COCC1>[C:1]([C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=2)[CH:11]=1)[C:6]([NH:19][C:20]1[C:25]([F:26])=[CH:24][CH:23]=[C:22]([OH:27])[C:21]=1[F:28])=[O:8])#[N:2]
Reactant: Nc1c(F)ccc(O)c1F
Reactant: N#Cc1cc(C(=O)O)cc(-c2cccc(F)c2)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O=S(Cl)Cl
Product: N#Cc1cc(C(=O)Nc2c(F)ccc(O)c2F)cc(-c2cccc(F)c2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 67.9 %

Procedure:
3-Cyano-5-(3-fluorophenyl)benzoic acid (500 mg, 2.1 mmol, 1 eq) was dissolved in SOCl2 (15 mL) and heated at reflux overnight. The excess SOCl2 was removed under reduced pressure and the residue that remained dissolved in THF (10 mL) and added dropwise to a mixture of 3-amino-2,4-difluorophenol (280 mg, 2 mmol, 0.95 eq) and NaHCO3 (880 mg, 10.5 mmol, 5 eq) in THF (40 mL). The reaction was stirred at room temperature for 3 h, then filtered and the filtrate concentrated in vacuo. The residue was purified by column chromatography (petroleum ether: EtOAc, 10:1) to give the title compound as a white solid (500 mg, 64%).
Reaction SMILES: Cl.[S:2]1[C:10]2[CH2:9][CH2:8][NH:7][CH2:6][C:5]=2[CH:4]=[CH:3]1.Br[CH:12]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[Cl:22])[C:13]([OH:15])=[O:14].[OH-].[K+].Cl>O.CO>[Cl:22][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[CH:12]([N:7]1[CH2:8][CH2:9][C:10]2[S:2][CH:3]=[CH:4][C:5]=2[CH2:6]1)[C:13]([OH:15])=[O:14]
Reactant: O=C(O)C(Br)c1ccccc1Cl
Reactant: c1cc2c(s1)CCNC2
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)C(c1ccccc1Cl)N1CCc2sccc2C1
Temperature: 40 °C
Yield: 93.3 %

Procedure:
50.0 g of 4,5,6,7-tetrahydrothieno[3,2-c]pyridine hydrochloride and 74.6 g of α-bromo-(2-chlorophenyl)acetic acid were successively added to a mixture of 275 ml of water and 75 ml of methanol, and the resulting solution was cooled to below 10° C. while stirring. 63.9 g of 85.0% KOH dissolved in 142 ml of water was slowly added to the above solution while maintaining the temperature at below 15° C. The resulting transparent solution was heated to 40° C. and stirred at that temperature for 3 hrs. The pH of the reaction solution was adjusted to 3.5 with 6N—HCl, cooled to room temperature and stirred for 2 hrs. Then, the reaction mixture was further cooled to below 5° C. and stirred for 2 hrs. The precipitated crystals were filtered, washed sequentially with 150 ml of water and 100 ml of n-hexane, and dried at 40° C. to obtain 81.7 g of the title compound (yield: 88%) as a white-yellow monohydrate.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[CH2:3][C@H:4]([OH:32])[C@@H:5]([NH:19][C:20]([C@@H:22]([NH:27][C:28](=[O:31])[O:29][CH3:30])[C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)=[CH:9][CH:8]=1.[CH3:40][O:41][C:42]([NH:44][C@@H:45]([C:49]([CH3:52])([CH3:51])[CH3:50])[C:46](O)=[O:47])=[O:43].CCOP(ON1N=NC2C=CC=CC=2C1=O)(OCC)=O.C(N(CC)C(C)C)(C)C>C1COCC1>[CH3:30][O:29][C:28](=[O:31])[NH:27][C@@H:22]([C:23]([CH3:25])([CH3:26])[CH3:24])[C:20](=[O:21])[NH:19][C@@H:5]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)=[CH:9][CH:8]=1)[C@@H:4]([OH:32])[CH2:3][C@H:2]([CH2:33][C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)[NH:1][C:46](=[O:47])[C@H:45]([C:49]([CH3:51])([CH3:50])[CH3:52])[NH:44][C:42](=[O:43])[O:41][CH3:40]
Reactant: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccc(-c2ccccn2)cc1)[C@@H](O)C[C@@H](N)Cc1ccccc1)C(C)(C)C
Reactant: COC(=O)N[C@H](C(=O)O)C(C)(C)C
Agent: CCOP(=O)(OCC)On1nnc2ccccc2c1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccccc1)C[C@H](O)[C@H](Cc1ccc(-c2ccccn2)cc1)NC(=O)[C@@H](NC(=O)OC)C(C)(C)C)C(C)(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 45.3 %

Procedure:
A solution of the product from Example 23S (0.025 g, 0.047 mmol) in THF (0.5 mL) was treated with the product from Example 1F (0.010g, 0.053 mmol), DEPBT (0.020 g, 0.067 mmol), and N,N-diisopropylethylamine (0.040 mL, 0.229 mmol), stirred at 25° C. for 16 hours, and partitioned between ethyl acetate and 10% Na2CO3 solution. The organic phase was washed with additional 10% Na2CO3 solution and brine, dried over MgSO4, filtered and concentrated. The residue was chromatographed on silica gel eluting with 0-100% ethyl acetate/dichloromethane to give the title compound (0.015 g, 45% yield). 1H NMR (300 MHz, DMSO-d6), δ ppm 0.77 (s, 9 H), 0.83 (s, 9 H), 1.48 (m, 2 H), 2.74 (m, 3 H), 3.50 (s, 3 H), 3.54 (s, 3 H), 3.64 (m, 1 H), 3.79 (d, J=9.19 Hz, 1 H), 3.93 (d, J=956 Hz, 1 H), 4.09 (m, 2 H), 4.85 (d, J=5.88 Hz, 1 H), 6.60 (d, J=9.93 Hz, 1 H), 6.75 (d, J=9.93 Hz, 1 H), 7.11 (m, 5 H), 7.31 (m, 3 H), 7.59 (d, J=9.19 Hz, 1 H), 7.74 (d, J=8.82 Hz, 1 H), 7.86 (m, 4 H), 8.63 (d, J=4.41 Hz, 1 H).
Reaction SMILES: ClC1C=C(N/C=C2\C(=O)NC(=O)C3C\2=CC=CC=3)C=CC=1SC1N(C)C=CN=1.CO/[CH:31]=[C:32]1/[C:33](=[O:46])[NH:34][C:35](=[O:45])[C:36]2[C:41]/1=[CH:40][C:39]([N+:42]([O-:44])=[O:43])=[CH:38][CH:37]=2.[N:47]1([CH2:53][C:54]2[CH:59]=[CH:58][C:57]([NH2:60])=[CH:56][CH:55]=2)[CH2:52][CH2:51][CH2:50][CH2:49][CH2:48]1>>[CH2:50]1[CH2:51][CH2:52][N:47]([CH2:53][C:54]2[CH:55]=[CH:56][C:57]([NH:60]/[CH:31]=[C:32]3/[C:41]4[CH:40]=[C:39]([N+:42]([O-:44])=[O:43])[CH:38]=[CH:37][C:36]=4[C:35]([NH:34][C:33]/3=[O:46])=[O:45])=[CH:58][CH:59]=2)[CH2:48][CH2:49]1
Reactant: CO/C=C1/C(=O)NC(=O)c2ccc([N+](=O)[O-])cc21
Reactant: Nc1ccc(CN2CCCCC2)cc1
Agent: Cn1ccnc1Sc1ccc(N/C=C2\C(=O)NC(=O)c3ccccc32)cc1Cl
Product: O=C1NC(=O)c2ccc([N+](=O)[O-])cc2/C1=C/Nc1ccc(CN2CCCCC2)cc1
Yield: 73.3 %

Procedure:
Using the procedure described for (4Z)-4-[({3-chloro-4-[(1-methyl-1H-imidazol-2-yl)thio]phenyl}amino)methylene]isoquinoline-1,3(2H,4H)-dione, 115 mg (0.46 mmol) of (4E)-4-(methoxy)methylene-6-nitroisoquinoline-1,3(2H,4H)-dione is reacted with 93 mg (0.49 mmol) of 4-piperidin-1-ylmethyl-phenylamine to give 137 mg (73%) of brown solid, mp 225-235 (dec); MS (ES−) m/z 405.2 (M−H)−1.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[CH:7][C:8]([S:15]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([O:25][C:26](=[O:28])[CH3:27])[CH:20]=2)(=[O:17])=[O:16])=[C:9]2[C:14]=1[N:13]=[CH:12][CH:11]=[CH:10]2)(=[O:3])[CH3:2].ClC1C=CC=C(C(OO)=[O:37])C=1>>[C:1]([NH:4][C:5]1[CH:6]=[CH:7][C:8]([S:15]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([O:25][C:26](=[O:28])[CH3:27])[CH:20]=2)(=[O:17])=[O:16])=[C:9]2[C:14]=1[N+:13]([O-:37])=[CH:12][CH:11]=[CH:10]2)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1ccc(S(=O)(=O)Cc2cccc(OC(C)=O)c2)c2cccnc12
Reactant: O=C(OO)c1cccc(Cl)c1
Product: CC(=O)Nc1ccc(S(=O)(=O)Cc2cccc(OC(C)=O)c2)c2ccc[n+]([O-])c12
Temperature: 25 °C
Reaction time: 72 h

Procedure:
8-Acetamido-5-(m-acetoxybenzylsulfonyl)quinoline (3.98 g, 10 mmole) was dissolved in 30 ml of dichlomethane and treated with m-chloroperbenzoic acid (2.03 g). The solution was stirred for 3 days at room temperature. Some m-chlorobenzoic acid which separated was filtered off and the filtrate concentrated to a syrup. On boiling with 40 ml 2-propanol a pale yellow solid was induced to crystallize. After chilling in an ice bath, the solid was filtered off, washed with 2-propanol and ether, and dried to yield 3.8 g (92 percent). The structure was confirmed by NMR.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([S:12](=[O:25])(=[O:24])[NH:13][C:14]2[CH:15]=[CH:16][C:17]3[CH2:21][O:20][B:19]([OH:22])[C:18]=3[CH:23]=2)=[C:6]([CH2:8][C:9]([OH:11])=O)[CH:7]=1.[CH:26]1([NH2:31])[CH2:30][CH2:29][CH2:28][CH2:27]1.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.O>CN(C=O)C>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([S:12](=[O:25])(=[O:24])[NH:13][C:14]2[CH:15]=[CH:16][C:17]3[CH2:21][O:20][B:19]([OH:22])[C:18]=3[CH:23]=2)=[C:6]([CH2:8][C:9]([NH:31][CH:26]2[CH2:30][CH2:29][CH2:28][CH2:27]2)=[O:11])[CH:7]=1
Reactant: NC1CCCC1
Reactant: Nc1ccc(S(=O)(=O)Nc2ccc3c(c2)B(O)OC3)c(CC(=O)O)c1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: O
Solvent: CN(C)C=O
Product: Nc1ccc(S(=O)(=O)Nc2ccc3c(c2)B(O)OC3)c(CC(=O)NC2CCCC2)c1
Reaction time: 16 h
Yield: 6.3 %

Procedure:
To a stirred solution of 2-(5-amino-2-(N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)sulfamoyl)phenyl)acetic acid (360 mg, 1 mmol) and cyclopentylamine (0.6 mL, 6 mmol) in 10 mL of DMF was added PyBOP (780 mg, 1.5 mmol) and TEA (0.5 mL, 3.56 mmol). The reaction mixture was stirred for 16 hours. After water was added, the reaction mixture was extracted with ethyl acetate and washed with water, 1N HCl and brine. The organic layer was dried over Na2SO4 and concentrated. The crude residue was purified by prep HPLC (SunFire Prep C18 OBD 5 uM 30×50 mm column) to give the desired product as a white powder (27 mg, yield 6%). MS calcd for (C20H24BN3O5S): 429.2. MS found (ESI negative): (M−H)−=428.2. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 9.89 (s, 1H), 9.17 (bs, 1H), 8.02 (d, J=7.2 Hz, 1H), 7.44 (m, 2H), 7.22 (d, J=8 Hz, 1H), 7.11 (d, J=8 Hz, 1H), 6.46 (s, 1H), 6.35 (d, J=8 Hz, 1H), 5.94 (bs, 2H), 4.87 (s, 2H), 4.02 (q, J=6.4 Hz, 1H), 3.77 (s, 2H), 1.81 (m, 2H), 1.64 (m, 2H), 1.51 (m, 2H), 1.39 (m, 2H).