Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH:7]=[CH:6][C:5]([C:8]([OH:10])=O)=[CH:4][C:3]1=[O:11].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.Cl.[CH3:34][O:35][NH:36][CH3:37].CCN(CC)CC>C(Cl)Cl.O>[CH3:34][O:35][N:36]([CH3:37])[C:8]([C:5]1[CH:6]=[CH:7][N:2]([CH3:1])[C:3](=[O:11])[CH:4]=1)=[O:10]
Reactant: Cn1ccc(C(=O)O)cc1=O
Reactant: CNOC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CON(C)C(=O)c1ccn(C)c(=O)c1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 80.2 %

Procedure:
A suspension of 1-methyl-2-oxo-1,2-dihydropyridine-4-carboxylic acid (540 mg, 1.0 eq), EDCI (811 mg, 1.2 eq) and HOBt (572 mg, 1.2 eq) in 20 mL CH2Cl2 was stirred at r.t. for 5 min Then N-methoxymethanamine hydrochloride (413 mg, 1.2 eq) and Et3N (1.1 g, 3.0 eq) were added, and the reaction was stirred at rt overnight. Water was added, and the mixture was extracted with CH2Cl2. The extract was dried, concentrated, and purified by column chromatography to give the desired product (555 mg, 80% yield). 1H NMR (400 MHz, CDCl3) δ 7.32 (d, J=6.8 Hz, 1H), 6.78 (s, 1H), 6.32 (dd, J=6.8 Hz, 1.6 Hz, 1H), 3.61 (s, 3H), 3.57 (s, 3H), 3.32 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[C:3](F)=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[ClH:13]>>[Cl:13][C:3]1[C:2]([Cl:1])=[CH:7][C:6]([C:8]([F:11])([F:10])[F:9])=[CH:5][N:4]=1
Reactant: Cl
Reactant: Fc1ncc(C(F)(F)F)cc1Cl
Product: FC(F)(F)c1cnc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 97.7 %

Procedure:
A 45 milliliter (ml) Teflon®-lined Parr bomb, which was equipped with a pressure gauge, rupture disk and needle valve, was charged with 2 grams (g) of 3-chloro-2-fluoro-5-trifluoromethylpyridine and then pressurized with anhydrous HCl to 200 psig. The bomb was placed in a heated rocker and kept at 110° C. for 20 hours. The maximum pressure was 220 psig. The bomb was removed from the heater and allowed to cool to room temperature, at which time it was placed in an ice bath. The bomb was vented to a caustic scrubber and 2.5 g of a light tan liquid consisting of HF and 84.3% 2,3-dichloro-5-trifluoromethylpyridine (by wt.). This represents a 97.7% yield of 2,3-dichloro-5-trifluoromethylpyridine (by wt.) with 0.4% of 3-chloro-2-fluoro-5-trifluoromethylpyridine remaining. No additional products were observed by analysis with gas chromatography.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([C:13]3[C:14]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[N:15][O:16][C:17]=3[CH3:18])=[N:11][N:12]=2)=[C:4]([O:25][CH3:26])[CH:3]=1.[CH3:27][N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1>>[CH3:26][O:25][C:4]1[CH:3]=[C:2]([N:31]2[CH2:32][CH2:33][N:28]([CH3:27])[CH2:29][CH2:30]2)[CH:7]=[CH:6][C:5]=1[C:8]1[O:9][C:10]([C:13]2[C:14]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[N:15][O:16][C:17]=2[CH3:18])=[N:11][N:12]=1
Reactant: COc1cc(F)ccc1-c1nnc(-c2c(-c3ccccc3)noc2C)o1
Reactant: CN1CCNCC1
Product: COc1cc(N2CCN(C)CC2)ccc1-c1nnc(-c2c(-c3ccccc3)noc2C)o1
Yield: 48 %

Procedure:
As described for example 26, 2-(4-fluoro-2-methoxy-phenyl)-5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazole (200 mg, 0.57 mmol) was converted using 1-methylpiperazine instead of thiomorpholine to the title compound (SiO2, dichloromethane:(dichloromethane:methanol:ammonia=70:27:3)=92:2 to 80:20, 117 mg, 48%) which was obtained as an off-white solid. MS: m/e=432.4 [M+H]+.
Reaction SMILES: [F:1][C:2]1[C:3]([NH:16][C:17]2[N:22]=[C:21]([NH:23][C:24]3[CH:28]=[C:27]([CH3:29])[NH:26][N:25]=3)[C:20]([C:30]([F:33])([F:32])[F:31])=[CH:19][N:18]=2)=[CH:4][C:5]([CH3:15])=[C:6]([CH:8]2[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]2)[CH:7]=1.[NH:34]1[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>>[F:1][C:2]1[CH:7]=[C:6]([C@H:8]2[CH2:13][CH2:12][C@H:11]([N:34]3[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]3)[CH2:10][CH2:9]2)[C:5]([CH3:15])=[CH:4][C:3]=1[NH:16][C:17]1[N:22]=[C:21]([NH:23][C:24]2[CH:28]=[C:27]([CH3:29])[NH:26][N:25]=2)[C:20]([C:30]([F:33])([F:32])[F:31])=[CH:19][N:18]=1
Reactant: Cc1cc(Nc2nc(Nc3cc(C)c(C4CCC(=O)CC4)cc3F)ncc2C(F)(F)F)n[nH]1
Reactant: C1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Product: Cc1cc(Nc2nc(Nc3cc(C)c([C@H]4CC[C@H](N5CCCCC5)CC4)cc3F)ncc2C(F)(F)F)n[nH]1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 4-(5-fluoro-2-methyl-4-(4-(5-methyl-1H-pyrazol-3-ylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)phenyl)cyclohexanone (30 mg, 0.065 mmol), piperidine (30 μL, 0.174 mmol) and acetic acid (75 μL, 0.13 mmol) was stirred at room temperature for 1 h. Sodium triacetoxyborohydride (27.4 mg, 0.13 mmol) was added to the reaction and the reaction mixture was stirred overnight. The mixture was concentrated and purified by silica chromatography (MeOH/DCM 8:92) to afford N2-(2-fluoro-5-methyl-4-(trans-4-(piperidin-1-yl)cyclohexyl)phenyl)-N4-(5-methyl-1H-pyrazol-3-yl)-5-(trifluoromethyl)pyrimidine-2,4-diamine; Rf: 0.32 (Silica; MeOH/DCM 8:92); ESMS m/z 532.3 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[N:9]=[C:8]([CH3:10])[CH:7]=[CH:6][C:3]=1[CH:4]=O.[C:11]([C:15]1[CH:28]=[CH:27][C:18]([CH2:19][NH:20][C:21](=[O:26])[CH2:22][C:23](=O)[CH3:24])=[CH:17][CH:16]=1)([CH3:14])([CH3:13])[CH3:12].N1CCCCC1>CCO>[C:11]([C:15]1[CH:28]=[CH:27][C:18]([CH2:19][NH:20][C:21]([C:22]2[C:23]([CH3:24])=[N:1][C:2]3[C:3]([CH:4]=2)=[CH:6][CH:7]=[C:8]([CH3:10])[N:9]=3)=[O:26])=[CH:17][CH:16]=1)([CH3:14])([CH3:12])[CH3:13]
Reactant: Cc1ccc(C=O)c(N)n1
Reactant: CC(=O)CC(=O)NCc1ccc(C(C)(C)C)cc1
Solvent: CCO
Solvent: C1CCNCC1
Product: Cc1ccc2cc(C(=O)NCc3ccc(C(C)(C)C)cc3)c(C)nc2n1
Yield: 50.5 %

Procedure:
A solution of 200 mg (1.47 mmol) 2-amino-6-methylnicotinaldehyde, 400 mg (1.62 mmol) N-(4-tert-butylbenzyl)-3-oxobutanamide and 15 (0.15 mmol) piperidine in 3 ml EtOH was refluxed for 36 h. The reaction mixture was concentrated under reduced pressure. Flash chromatography (CH2Cl2/MeOH 20:1) afforded 258 mg (51%) of the title compound as a yellow-brown amorphous solid.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([C:8]2[N:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]3=[N:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([NH2:25])=[CH:21][CH:20]=1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1>[N:10]1[CH:9]=[C:8]([C:4]2[CH:3]=[C:2]([C:23]3[CH:24]=[C:19]([O:18][CH3:17])[CH:20]=[CH:21][C:22]=3[NH2:25])[CH:7]=[CH:6][CH:5]=2)[N:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=12
Reactant: COc1ccc(N)cc1
Reactant: Clc1cccc(-c2cnc3ccccn23)c1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: COc1ccc(N)c(-c2cccc(-c3cnc4ccccn34)c2)c1
Temperature: 110 °C
Yield: 9.9 %

Procedure:
A mixture of 3-(3-Chloro-phenyl)-imidazo[1,2-a]pyridine (183 mg, 0.8 mmol), 4-Methoxy-phenylamine (200 mg, 1.6 mmol) and sodium tertbutoxide (195 mg, 2 mmol) in dry toluene (3 ml) was deoxygenated. 2′-(Dimethylamino)-2-biphenylyl-palladium(II) chloride dinorbornylphosphine complex (45 mg, 0.08 mmol) was added and the reaction mixture deoxygenated again, then heated at 110° C. for 2 h. The mixture was allowed to cool, then partitioned between CH2Cl2 and H2O and separated using a phase separating cartridge. The organic solvent was removed in vacuo and the residue purified by column chromatography, then preparative HPLC to give the desired compound (25 mg).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([F:9])[CH:8]=1)[NH2:5].[C:10](Cl)(=[O:19])[CH:11]=[CH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.N1C(C)=CC=CC=1C.BrC1C=C(NC(=O)/C=C/C2C=CC=CC=2)C=CC=1>>[Br:1][C:2]1[CH:3]=[C:4]([NH:5][C:10](=[O:19])/[CH:11]=[CH:12]/[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:6]=[C:7]([F:9])[CH:8]=1
Reactant: O=C(Cl)C=Cc1ccccc1
Reactant: Nc1cc(F)cc(Br)c1
Agent: O=C(/C=C/c1ccccc1)Nc1cccc(Br)c1
Solvent: Cc1cccc(C)n1
Product: O=C(/C=C/c1ccccc1)Nc1cc(F)cc(Br)c1
Yield: 85 %

Procedure:
The compound was prepared from 3-bromo-5-fluoroaniline (Intermediate 180, 5.3 g, 27.9 mmol) and cinnamoylchloride (5.6 g, 33.5 mmol) in the presence of 2,6-lutidine (5.0 mL, 41.9 mmol) as described for Intermediate 18 to give the product as a colorless solid, 7.6 g (85% yield).
Reaction SMILES: N[C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:4][C:3]=1/[CH:16]=[CH:17]/[C:18]([O:20][CH2:21][CH3:22])=[O:19].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.N([O-])=O.[Na+].[I-:39].[K+]>C(#N)C.O.C(OCC)(=O)C>[CH2:21]([O:20][C:18](=[O:19])[CH:17]=[CH:16][C:3]1[CH:4]=[C:5]([S:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:6]=[CH:7][C:2]=1[I:39])[CH3:22]
Reactant: [I-]
Reactant: CCOC(=O)/C=C/c1cc(SCc2ccccc2)ccc1N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=N[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CC#N
Product: CCOC(=O)C=Cc1cc(SCc2ccccc2)ccc1I
Temperature: 0 °C
Reaction time: 5 h
Yield: 64 %

Procedure:
To a solution of (E)-ethyl 3-(2-amino-5-(benzylthio)phenyl)acrylate (150 g, 479 mmol, 1.0 equiv) in acetonitrile (2.0 L) was added para-toluenesulfonic acid monohydrate (273.16 g, 1437 mmol, 3.0 equiv, Spectrochem). The reaction mixture was cooled to 0° C. and a solution of sodium nitrite (66.03 g, 958 mmol, 2.0 equiv, Spectrochem) and potassium iodide (185.7 g, 1198 mmol, 2.5 equiv, Spectrochem) in water (450 mL) was added drop wise keeping temperature below 5° C. The reaction mixture was stirred at 0° C. for 5 h. The mixture was then diluted with ethyl acetate (5.0 L) and quenched with 2M aqueous sodium hyposulfite solution (5.0 L). The layers were separated and the organic layer was washed with saturated aqueous sodium bicarbonate solution (3.0 L). The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure to obtain the crude material which was purified by column chromatography (silica gel; mesh size 60-120, elution 0-5% ethyl acetate in hexane) to yield ethyl-3-(5-(benzylthio)-2-iodophenyl)acrylate (130 g, 64%) as light brown solid. TLC solvent system: 20% ethyl acetate in hexane. Product's Rf: 0.6. MS (ESI, positive ion) m/z; 425.0 (M+1)
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]([O:15][CH3:16])=[CH:13][C:12]([C:17]([N:19]2[CH2:24][CH2:23][N:22]([C:25]3[N:30]=[CH:29][CH:28]=[CH:27][N:26]=3)[CH2:21][CH2:20]2)=[O:18])=[C:11]([N+:31]([O-])=O)[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.O.Cl[Sn]Cl>CO>[NH2:31][C:11]1[CH:10]=[C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:14]([O:15][CH3:16])=[CH:13][C:12]=1[C:17]([N:19]1[CH2:20][CH2:21][N:22]([C:25]2[N:26]=[CH:27][CH:28]=[CH:29][N:30]=2)[CH2:23][CH2:24]1)=[O:18]
Reactant: COc1cc(C(=O)N2CCN(c3ncccn3)CC2)c([N+](=O)[O-])cc1OCc1ccccc1
Agent: Cl[Sn]Cl
Solvent: CO
Solvent: O
Product: COc1cc(C(=O)N2CCN(c3ncccn3)CC2)c(N)cc1OCc1ccccc1
Yield: 90.2 %

Procedure:
[4-(Benzyloxy)-5-methoxy-2-nitrophenyl][4-(2-pyrimidinyl)piperazino-]methanone (7c) (500 mg, 1.11 mmol) was dissolved in methanol (10 mL), SnCl2.2H2O (751 mg, 3.3 mmol) was added and refluxed until the TLC indicated the completion of the reaction. The methanol was evaporated by vacuum and the aqueous layer was then adjusted to pH 8 with 10% NaHCO3 solution and extracted with ethyl acetate (2×30 mL). The combined organic phase was dried over Na2SO4 and evaporated under vacuum to afford the crude This was further purified by column chromatography using ethyl acetate:hexane (6:4) as a solvent system to obtain the pure product (8c) (420 mg, 90% yield). 1H NMR (CDCl3) δ 3.10-3.25 (m, 4H), 3.60-3.80 (m, 4H), 3.95 (s, 3H), 5.20 (s, 2H), 6.20 (s, br), 6.45-6.55 (t, 1H) 6.75 (s, 1H), 7.30-7.55 (m, 5H), 7.80 (s, 1H); FABMS: 419 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]2[CH:8]=[C:9]([N:13]3[C:17]4[CH:18]=[CH:19][C:20]([C:22](=[O:24])[CH3:23])=[CH:21][C:16]=4[N:15]=[CH:14]3)[CH:10]=[CH:11][CH:12]=2)=[N:4][CH:3]=1.[BH4-].[Na+]>CO.O>[Cl:1][C:2]1[S:6][C:5]([C:7]2[CH:8]=[C:9]([N:13]3[C:17]4[CH:18]=[CH:19][C:20]([CH:22]([OH:24])[CH3:23])=[CH:21][C:16]=4[N:15]=[CH:14]3)[CH:10]=[CH:11][CH:12]=2)=[N:4][CH:3]=1
Reactant: CC(=O)c1ccc2c(c1)ncn2-c1cccc(-c2ncc(Cl)s2)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CC(O)c1ccc2c(c1)ncn2-c1cccc(-c2ncc(Cl)s2)c1
Yield: 78.1 %

Procedure:
To a solution of 1-{1-[3-(5-chloro-thiazol-2-yl)-phenyl]-1H-benzoimidazol-5-yl}-ethanone (6.3 g, 17.8 mmol) in methanol (75 ml) was added sodium borohydride (0.91 g, 23.9 mmol) and the resultant mixture was stirred at room temperature in a nitrogen atmosphere for 7 days. The reaction mixture was diluted with four volumes of water and extracted with ethyl acetate. The organic extract was washed with brine, dried over magnesium sulphate and evaporated in vacuo to leave the desired product (4.95 g, 78%). LC-ESI-HRMS of [M+H]+ shows 356.0635 Da. Calc. 356.062436 Da. dev. 3 ppm.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:9]2[C:16](=[S:17])[N:15]([C:18]3[CH:19]=[C:20]([C:26]([F:29])([F:28])[F:27])[C:21]([C:24]#[N:25])=[N:22][CH:23]=3)[C:14](=[O:30])[C:10]32[CH2:13][CH2:12][CH2:11]3)[CH:5]=[CH:6][C:7]=1[OH:8].[CH2:31](O)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[CH2:31]([O:8][C:7]1[CH:6]=[CH:5][C:4]([N:9]2[C:16](=[S:17])[N:15]([C:18]3[CH:19]=[C:20]([C:26]([F:29])([F:27])[F:28])[C:21]([C:24]#[N:25])=[N:22][CH:23]=3)[C:14](=[O:30])[C:10]32[CH2:11][CH2:12][CH2:13]3)=[CH:3][C:2]=1[F:1])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: N#Cc1ncc(N2C(=O)C3(CCC3)N(c3ccc(O)c(F)c3)C2=S)cc1C(F)(F)F
Reactant: OCc1ccccc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Solvent: C1CCOC1
Product: N#Cc1ncc(N2C(=O)C3(CCC3)N(c3ccc(OCc4ccccc4)c(F)c3)C2=S)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A mixture of 5-(5-(3-fluoro-4-hydroxyphenyl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-7-yl)-3-(trifluoromethyl)picolinonitrile (Example 1, 100 mg, 0.23 mmol), benzyl alcohol (35 μL, 0.30 mmol) triphenylphosphine (79 mg, 0.30 mmol), and diisopropyl azodicarboxylate (60 μL, 0.30 mmol) in THF (5 mL) was stirred at room temperature for 2 days then heated to 60° C. overnight. The reaction mixture was absorbed on silica gel and purified by column chromatography on silica gel eluting with 0 to 50% EtOAc/Hexanes to afford impure desired product. The solid was triturated in MeOH, filtered, and dried to afford 36 mg of 5-(5-(4-(benzyloxy)-3-fluorophenyl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-7-yl)-3-(trifluoromethyl)picolinonitrile as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 9.21 (d, 1H), 8.75 (d, 1H), 7.53-7.36 (m, 7H), 7.23 (d, 1H), 5.28 (s, 2H), 2.66-2.60 (m, 2H), 2.53-2.43 (m, 2H), 2.02-1.92 (m, 1H), 1.61-1.55 (m, 1H).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[C:8]([CH2:10][N:11]2[CH:15]=[CH:14][N:13]=[CH:12]2)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[C:16]1([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:21]=[CH:20][C:19]([CH2:22]I)=[CH:18][CH:17]=1>>[C:16]1([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:17]=[CH:18][C:19]([CH2:22][O:1][C:2]2[CH:9]=[C:8]([CH2:10][N:11]3[CH:15]=[CH:14][N:13]=[CH:12]3)[CH:7]=[CH:6][C:3]=2[C:4]#[N:5])=[CH:20][CH:21]=1
Reactant: N#Cc1ccc(Cn2ccnc2)cc1O
Reactant: ICc1ccc(-c2ccccc2)cc1
Product: N#Cc1ccc(Cn2ccnc2)cc1OCc1ccc(-c2ccccc2)cc1

Procedure:
Following the procedure described in Example 2, Step E but using 2-hydroxy-4-imidazol-1-ylmethyl-benzonitrile (as described in Step F) and biphenyl-4-ylmethyl iodide as starting materials, the title compound was obtained as a solid.
Reaction SMILES: [CH3:1][N:2]([CH3:6])[CH2:3][CH2:4][NH2:5].[Cl:7][C:8]1[S:12][C:11]([S:13](Cl)(=[O:15])=[O:14])=[CH:10][CH:9]=1.C(N(CC)CC)C>C1COCC1>[CH3:1][N:2]([CH3:6])[CH2:3][CH2:4][NH:5][S:13]([C:11]1[S:12][C:8]([Cl:7])=[CH:9][CH:10]=1)(=[O:15])=[O:14]
Reactant: O=S(=O)(Cl)c1ccc(Cl)s1
Reactant: CN(C)CCN
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CN(C)CCNS(=O)(=O)c1ccc(Cl)s1
Temperature: 25 °C
Reaction time: 16 h
Yield: 99.3 %

Procedure:
To a stirred solution of 2-dimethylamino-ethylamine (1.61 g, 13.8 mmol) in THF (20 mL) was added at 0° C. (ice water bath) commercially available 5-chloro-thiophene-2-sulfonyl chloride (1.0 g, 4.61 mmol) and triethylamine (0.71 mL, 5.07 mmol). The reaction mixture was stirred at room temperature for 16 h and evaporated. The crude product was further purified by flash chromatography (ethyl acetate/MeOH) to yield the title compound (1.23 g, 99%) as a light yellow oil. MS (ISP) 269.0 [(M+H)+].
Reaction SMILES: [C:1]([N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[O:7][C:6]1=[O:14])(=[O:4])[CH2:2][CH3:3].[CH:15](=[O:21])[CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]>>[CH3:3][C@H:2]([C@@H:15]([OH:21])[CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[C:1]([N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[O:7][C:6]1=[O:14])=[O:4]
Reactant: CCC(=O)n1c(=O)oc2ccccc21
Reactant: CCCCCC=O
Product: CCCCC[C@H](O)[C@@H](C)C(=O)n1c(=O)oc2ccccc21

Procedure:
Was prepared according to the method of paragraph C by reaction of N-propionyl-2-benzoxazolinone with hexanal.
Reaction SMILES: C[O:2][C:3](=[O:41])[CH2:4][O:5][C:6]1[CH:37]=[CH:36][C:9]2[C:10](=[O:35])[CH2:11][C:12]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]3[CH:27]=[CH:26][C:25]([C:28](=[O:30])[CH3:29])=[C:24]([OH:31])[C:23]=3[CH2:32][CH2:33][CH3:34])([CH3:14])[O:13][C:8]=2[C:7]=1[CH2:38][CH2:39][CH3:40].[OH-].[Na+].O.Cl>CO>[C:28]([C:25]1[CH:26]=[CH:27][C:22]([O:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][C:12]2([CH3:14])[CH2:11][C:10](=[O:35])[C:9]3[CH:36]=[CH:37][C:6]([O:5][CH2:4][C:3]([OH:41])=[O:2])=[C:7]([CH2:38][CH2:39][CH3:40])[C:8]=3[O:13]2)=[C:23]([CH2:32][CH2:33][CH3:34])[C:24]=1[OH:31])(=[O:30])[CH3:29]
Reactant: CCCc1c(OCCCCCCC2(C)CC(=O)c3ccc(OCC(=O)OC)c(CCC)c3O2)ccc(C(C)=O)c1O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCCc1c(OCCCCCCC2(C)CC(=O)c3ccc(OCC(=O)O)c(CCC)c3O2)ccc(C(C)=O)c1O
Yield: 96.9 %

Procedure:
A solution of 1.1 g of the ester product from Example 5 and 0.966 g of sodium hydroxide, in 36 ml of methanol and 9 ml of water was stirred at room temperature for 5.5 hours then poured into 60 ml of cold 1N hydrochloric acid and 150 ml of water. The mixture was extracted 3 times with ether. The combined ether extracts were washed with 3 portions of saturated aqueous sodium bicarbonate. Each bicarbonate wash was back-extracted with ether. The bicarbonate washes were combined and acidified to pH 1 with 3N hydrochloric acid. The acidic mixture was extracted 3 times with ethyl acetate. The ethyl acetate extracts were combined, washed with water and brine, dried (magnesium sulfate), filtered and concentrated in vacuo to yield 1.04 g of a yellow solid. This material was recrystallized from acetonitrile giving 0.82 g (76.6%) of rac.-[[2-[6-(4-acetyl-3-hydroxy-2-propylphenoxy)hexyl]-3,4-dihydro-2-methyl-4-oxo-8-propyl-2H-1-benzopyran-7-yl]oxy]acetic acid as a colorless solid, m.p. 120.5°-125.0° C.
Reaction SMILES: [CH3:1][S:2]([OH:5])(=[O:4])=[O:3].C([NH:13][C:14]1[CH:19]=[CH:18][C:17]([N+:20]([O-])=O)=[CH:16][C:15]=1[S:23]([NH2:26])(=[O:25])=[O:24])C1C=CC=CC=1.O1CCCC1.[H][H]>[Pd].C(O)C.O>[CH3:1][S:2]([OH:5])(=[O:4])=[O:3].[NH2:13][C:14]1[CH:19]=[CH:18][C:17]([NH2:20])=[CH:16][C:15]=1[S:23]([NH2:26])(=[O:24])=[O:25]
Reactant: NS(=O)(=O)c1cc([N+](=O)[O-])ccc1NCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Agent: CS(=O)(=O)O
Solvent: O
Solvent: C1CCOC1
Solvent: CCO
Product: Nc1ccc(N)c(S(N)(=O)=O)c1
Temperature: 23 °C
Reaction time: 22 h
Yield: 92.7 %

Procedure:
Methanesulfonic acid (465 mL, 7.16 mol) was added slowly to a solution of 2-benzylamino-5-nitro-benzenesulfonamide (2.20 kg, 7.16 mol) and tetrahydrofuran (11.0 L). The resulting solution was added to a mixture of 10% palladium on carbon (220 g of 50% water wet catalyst) and water (1.1 L) in a hydrogenation reactor. The mixture was further diluted with absolute ethanol (21.0 L) and was then hydrogenated with 55 psi hydrogen at 50° C. for 21 h. Additional 10% palladium on carbon (55 g of 50% water wet catalyst) was added, and hydrogenation at 55 psi and 50° C. was continued for 22 h. The resulting suspension was diluted with water (1.1 L) and the suspension was then filtered through a pad of Celite. The filtrate was partially concentrated in vacuo and was then diluted with acetonitrile (15.4 L). The solution was again partially concentrated in vacuo and diluted with acetonitrile (15.4 L). The resulting suspension was partially concentrated in vacuo and was allowed to stir at 23° C. for 2 h. The suspension was filtered and the solid was then washed with acetonitrile (3 L). The solid was further dried in vacuo at 45° C. to afford the desired product, 2,5-diamino-benzenesulfonamide methanesulfonate (1.88 kg, 6.64 mol, 93%), as a purple solid. 1H NMR (400 MHz, DMSO-d6) δ: 2.34 (3H, s), 6.05 (2H, b), 6.87 (1H, d, J=8.6 Hz), 7.20 (1H, dd, J1=8.6 Hz, J2=2.3 Hz), 7.38 (2H, s), 7.53 (1H, d, J=2.3 Hz), 9.62 (3H, b). LC-MS (ESI) calcd for C6H9NO2S 187.04, found 187.9 [M+H+].
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5]([S:8]([N:11](C2C=CC=CC=2)[C:12](=[O:14])[O-])(=[O:10])=[O:9])=[CH:6][CH:7]=1.[NH2:21][C:22]1[N:27]=[C:26]([O:28][CH3:29])[N:25]=[C:24]([CH3:30])[N:23]=1>O1CCOCC1>[Cl:1][C:2]1[N:3]=[N:4][C:5]([S:8]([NH:11][C:12]([NH:21][C:22]2[N:27]=[C:26]([O:28][CH3:29])[N:25]=[C:24]([CH3:30])[N:23]=2)=[O:14])(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: COc1nc(C)nc(N)n1
Reactant: O=C([O-])N(c1ccccc1)S(=O)(=O)c1ccc(Cl)nn1
Solvent: C1COCCO1
Product: COc1nc(C)nc(NC(=O)NS(=O)(=O)c2ccc(Cl)nn2)n1
Yield: 43.3 %

Procedure:
A mixture of 14.2 g of N-(3-chloropyridazine-6-sulfonyl)phenylcarbamate and 6.3 g of 2-amino-4-methoxy-6-methyl-1,3,5-triazine are refluxed for 1 hour in 120 ml of absolute dioxan. When the reaction is complete, the mixture is concentrated in vacuo and the residue is taken up in a saturated aqueous solution of sodium bicarbonate and the insoluble constituents are extracted with methylene chloride. The aqueous phase is acidified with dilute hydrochloric acid and extracted with methylene chloride. The methylene chloride solution is dried over sodium sulfate and concentrated, affording 7 g of the compound of the above formula with a melting point of 135° C.
Reaction SMILES: C[O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH:8]([C:16]3[CH:21]=[CH:20][C:19]([O:22]C)=[CH:18][CH:17]=3)[CH:9]3[CH2:15][CH2:14][CH2:13][CH:10]32)=[C:5]([CH2:24]O)[CH:4]=1.B(Br)(Br)[Br:27].C(Cl)Cl.Cl>C(OCC)(=O)C.O>[Br:27][CH2:24][C:5]1[CH:4]=[C:3]([OH:2])[CH:12]=[C:11]2[C:6]=1[CH2:7][CH:8]([C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=1)[CH:9]1[CH2:15][CH2:14][CH2:13][CH:10]12
Reactant: BrB(Br)Br
Reactant: COc1ccc(C2Cc3c(CO)cc(OC)cc3C3CCCC23)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: O
Product: Oc1ccc(C2Cc3c(CBr)cc(O)cc3C3CCCC23)cc1
Yield: 83.3 %

Procedure:
Combine [8-Methoxy-4-(4-methoxy-phenyl)-2,3,3a,4,5,9b-hexahydro-1H-cyclopenta[a]naphthalen-6-yl]-methanol (0.025 g, 0.074 mmol), boron tribromide (0.11 g, 0.44 mmol), and methylene chloride (1.5 ml) and stir 3 hours. Add water, ethyl acetate and 1N HCl. Rinse organic layer with water, dry over anhydrous sodium sulfate and remove solvent to yield the titled compound (0.023 g, 84%). 1H NMR (DMSO-d6) 9.18(s, 1H), 9.14 (s, 1H), 7.1 (d, J=7.9 Hz, 2H), 6.7 (d, J=7.9 Hz, 2H), 6.62 (s, 1H), 6.56 (s, 1H), 4.68 (d, J=10.1 Hz, 1H), 4.58 (d, J=9.6 Hz, 1H), 3.4 (m, 1H presumed), 2.95 (m, 1H), 2.8 (m, 2H), 2.45(m, 1H) 2.1 (m, 1H), 1.6-1.1 (m, 5H). MS m/z 371 (M−2).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:17]=[C:16]([CH2:18]O)[O:15][N:14]=1.S(Cl)([Cl:22])=O>>[Cl:22][CH2:18][C:16]1[O:15][N:14]=[C:13]([O:12][CH2:11][C:2]2[CH:3]=[CH:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[N:1]=2)[CH:17]=1
Reactant: OCc1cc(OCc2ccc3ccccc3n2)no1
Reactant: O=S(Cl)Cl
Product: ClCc1cc(OCc2ccc3ccccc3n2)no1
Temperature: 25 °C
Reaction time: 1 h
Yield: 98 %

Procedure:
A mixture of 3-(2-quinolylmethoxy)-5-isoxazolylmethanol (1.54 g) and thionyl chloride (5 ml) was stirred at room temperature for 1 hr. The reaction mixture was concentrated under reduced pressure and saturated aqueous sodium hydrogen carbonate was added to the residue. The mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated to give 2-(5-chloromethyl-3-isoxazolyloxymethyl)quinoline (1.61 g, yield 98%) as colorless crystals. The crystals were recrystallized from ethyl acetate-hexane. melting point: 126–127° C.