Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=2)[C:9]2[CH:10]=[C:11]3[C:16](=[C:17]([Br:19])[CH:18]=2)[N:15]=[C:14]([OH:20])[CH:13]=[C:12]3[Br:21])=[CH:4][CH:3]=1.[CH3:29]N(C)C=O.C([O-])([O-])=O.[Cs+].[Cs+].CI>O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=2)[C:9]2[CH:10]=[C:11]3[C:16](=[C:17]([Br:19])[CH:18]=2)[N:15]([CH3:29])[C:14](=[O:20])[CH:13]=[C:12]3[Br:21])=[CH:4][CH:3]=1
Reactant: CN(C)C=O
Reactant: Oc1cc(Br)c2cc(C(c3ccc(Cl)cc3)c3ccc(Cl)cc3)cc(Br)c2n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CI
Solvent: O
Product: Cn1c(=O)cc(Br)c2cc(C(c3ccc(Cl)cc3)c3ccc(Cl)cc3)cc(Br)c21
Temperature: 80 °C
Reaction time: 8 h

Procedure:
Into a 25-mL round-bottom flask, was placed 6-[bis(4-chlorophenyl)methyl]-4,8-dibromoquinolin-2-ol (360 mg, 0.67 mmol, 1.00 equip), N,N-dimethylformamide (15 mL), Cs2CO3 (654 mg, 2.01 mmol, 3.00 equip), and CH3I (190 mg, 1.34 mmol, 2.00 equip). The resulting solution was stirred overnight at 80° C. The resulting solution was diluted with water (80 mL). The solids were collected by filtration to yield 6-[bis(4-chlorophenyl)methyl]-4,8-dibromo-1-methyl-1,2-dihydroquinolin-2-one as a yellow solid. LCMS (ES, m/z) 552 [M+H]+
Reaction SMILES: [CH2:1]([C:4]1[CH:5]=[C:6]([OH:11])[C:7](=[CH:9][CH:10]=1)O)[CH2:2][CH3:3].[CH3:12][C:13]([CH3:15])=[O:14].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[CH2:1]([C:4]1[C:5]2[O:14][C:13]([CH3:15])([CH3:12])[O:11][C:6]=2[CH:7]=[CH:9][CH:10]=1)[CH2:2][CH3:3]
Reactant: CC(C)=O
Reactant: CCCc1ccc(O)c(O)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: c1ccccc1
Product: CCCc1cccc2c1OC(C)(C)O2

Procedure:
The same procedures as described in Example 10 were carried out by using a mixture of 7.61 g (50 mM) of 4-n-propylcatechol, 15 ml of acetone, 30 mg of p-toluenesulfonic acid monohydrate and 15 ml of benzene. 5 n-Propyl-2,2-dimethyl-1,3-benzodioxol was obtained in the yield of 9.13 g (47 mM) as colorless transparent liquid having a boiling point of 82°-87° C./3 mmHg.
Reaction SMILES: [O:1]=[C:2]1[O:8][C@H:7]([C@H:9]([CH2:11][OH:12])[OH:10])[C:5]([OH:6])=[C:3]1[OH:4].CO[CH:15](OC)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.CO>CN(C)C=O>[CH2:11]1[O:12][CH:15]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[O:10][C@@H:9]1[C@H:7]1[O:8][C:2](=[O:1])[C:3]([OH:4])=[C:5]1[OH:6]
Reactant: O=C1O[C@H]([C@@H](O)CO)C(O)=C1O
Reactant: COC(OC)c1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: CN(C)C=O
Product: O=C1O[C@H]([C@@H]2COC(c3ccccc3)O2)C(O)=C1O

Procedure:
L-Ascorbic acid (20 g), α,α-dimethoxytoluene (20 g) and a catalytic quantity (160 mg) of p-toluenesulfonic acid were dissolved in 60 ml of dimethylformamide. The solution was heated at 55°-60° C. for 4 hours. The reactor used for carrying out the reaction was equipped with a reflux-condenser connected to an aspirator, and the methanol formed during the reaction process produces was evaporated out of the reaction mixture. When the reaction was completed, the reaction solution was distilled under reduced pressure to remove the solvent. The resulting syrupy residue was washed with petroleum ether and water, each three times. Then, water and hexane were added to the washed syrup and the mixture was stirred to obtain a crystalline product of 5,6-O-benzylidene-L-ascorbic acid which was then filtrated off and dried to give 21.5 g of white colored crystals of 5,6-O-benzylidene-L-ascorbic acid (72% yield). The product thus obtained was nearly pure substance but was further purified by recrystallization from methanol or benzene. The final pure crystal showed mp. of 166°-168° C.
Reaction SMILES: [C:1]([C:4]1[S:8][C:7]([C:9]([OH:11])=O)=[CH:6][CH:5]=1)(=[O:3])[CH3:2].S(Cl)(Cl)=O.[NH2:16][C:17]1[CH:34]=[CH:33][C:20]([C:21]([C:23]2[CH:31]=[C:30]3[C:26]([CH2:27][C:28](=[O:32])[NH:29]3)=[CH:25][CH:24]=2)=[O:22])=[CH:19][CH:18]=1>C1COCC1>[O:32]=[C:28]1[CH2:27][C:26]2[C:30](=[CH:31][C:23]([C:21]([C:20]3[CH:19]=[CH:18][C:17]([NH:16][C:9]([C:7]4[S:8][C:4]([C:1](=[O:3])[CH3:2])=[CH:5][CH:6]=4)=[O:11])=[CH:34][CH:33]=3)=[O:22])=[CH:24][CH:25]=2)[NH:29]1
Reactant: Nc1ccc(C(=O)c2ccc3c(c2)NC(=O)C3)cc1
Reactant: CC(=O)c1ccc(C(=O)O)s1
Solvent: C1CCOC1
Solvent: O=S(Cl)Cl
Product: CC(=O)c1ccc(C(=O)Nc2ccc(C(=O)c3ccc4c(c3)NC(=O)C4)cc2)s1
Temperature: 79 °C
Reaction time: 2 h
Yield: 99.2 %

Procedure:
A dry 100 mL flask was charged with 5-Acetyl-thiophene-2-carboxylic acid (0.9339 g, 5.49 mmol) and thionyl chloride (6 mL) and allowed to stir at 79° C. for 2 h. The thionyl chloride was then removed by concentration in vacuo. The crude acid chloride was cooled to room temperature, and then dissolved in THF (80 mL). 6-(4-Amino-benzoyl)-1,3-dihydro-indol-2-one (as prepared in Example 15, 1.00 g, 3.97 mmol) was added to the THF solution of the acid chloride, and the mixture was allowed to reflux for 4 h. The reaction mixture was then allowed to cool to room temperature. The room temperature reaction mixture was concentrated in vacuo. The solid residue was suspended in boiling EtOAc. The suspension was allowed to cool to room temperature before filtering to afford the 5-Acetyl-thiophene-2-carboxylic acid [4-(2-oxo-2,3-dihydro-1H-indole-6-carbonyl)-phenyl]-amide as a solid (1.16 g, 3.94 mmol, 99%).
Reaction SMILES: [H-].[Na+].[OH:3][CH2:4][CH2:5][O:6][C:7]1[N:12]=[CH:11][N:10]=[C:9]([NH:13][S:14]([CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)(=[O:16])=[O:15])[C:8]=1[C:25]1[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][CH:26]=1.Cl[C:33]1[N:38]=[CH:37][CH:36]=[CH:35][N:34]=1>C1COCC1>[N:34]1[CH:35]=[CH:36][CH:37]=[N:38][C:33]=1[O:3][CH2:4][CH2:5][O:6][C:7]1[N:12]=[CH:11][N:10]=[C:9]([NH:13][S:14]([CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)(=[O:15])=[O:16])[C:8]=1[C:25]1[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][CH:26]=1
Reactant: Cc1ccc(-c2c(NS(=O)(=O)CCc3ccccc3)ncnc2OCCO)cc1
Reactant: Clc1ncccn1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1ccc(-c2c(NS(=O)(=O)CCc3ccccc3)ncnc2OCCOc2ncccn2)cc1
Temperature: 0 °C
Reaction time: 17 h
Yield: 74.6 %

Procedure:
To sodium hydride (50 mg, 60% in mineral oil) was added THF (25 ml) followed by 2-phenyl-ethanesulfonic acid [6-(2-hydroxy-ethoxy)-5-p-tolyl-pyrimidin-4-yl]-amide (150 mg, Referential Example 1). The mixture was stirred for 1 h at rt before 2-chloro-pyrimidine (86 mg) was added. Stirring was continued for 17 h at 80° C. The solvent was evaporated and diethylether (20 ml) was added to the residue. The precipitate was filtered off and washed with diethylether, dissolved in water (20 ml) and acidified with citric acid and extracted twice with EA (50 ml). The organic phase was washed with water, dried over Na2SO4 and evaporated. The residue is suspended in 2-propanol (15 ml) and stirred at 70° C. for 10 min and cooled to 0° C. before the solid material is collected, washed with 2-propanol (2 ml) and dried under high vacuum to furnish 2-phenyl-ethanesulfonic acid {6-[2-(pyrimidin-2-yloxy)-ethoxy]-5-p-tolyl-pyrimidin-4-yl}-amide (133 mg) as a white powder. LC-MS: tR=4.97 min, [M+1]+=492.34, [M−1]−=490.28.
Reaction SMILES: [F:1][CH:2]([F:25])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12](O)=[O:13])=[C:7]2[N:6]=[C:5]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)[CH:4]=1.[NH2:26][C:27]1[CH:28]=[C:29]([S:33]([NH:36][CH2:37][C:38]2[CH:39]=[N:40][CH:41]=[CH:42][CH:43]=2)(=[O:35])=[O:34])[CH:30]=[CH:31][CH:32]=1>>[N:40]1[CH:41]=[CH:42][CH:43]=[C:38]([CH2:37][NH:36][S:33]([C:29]2[CH:28]=[C:27]([NH:26][C:12]([C:11]3[CH:10]=[N:9][N:8]4[C:3]([CH:2]([F:1])[F:25])=[CH:4][C:5]([C:15]5[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=5)=[N:6][C:7]=34)=[O:13])[CH:32]=[CH:31][CH:30]=2)(=[O:35])=[O:34])[CH:39]=1
Reactant: Nc1cccc(S(=O)(=O)NCc2cccnc2)c1
Reactant: O=C(O)c1cnn2c(C(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Product: O=C(Nc1cccc(S(=O)(=O)NCc2cccnc2)c1)c1cnn2c(C(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12

Procedure:
The title compound was prepared from 7-difluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.1) and 3-amino-N-pyridin-3-ylmethyl-benzenesulfonamide (example B.5) according to general procedure II. Yellow solid. MS (ISP) 603.2 [(M+H+]; mp 256° C.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.Cl[CH2:14][CH2:15][CH2:16][CH2:17][C:18]#[C:19][Si:20]([CH3:23])([CH3:22])[CH3:21]>C1COCC1>[CH:17]1([C:18]#[C:19][Si:20]([CH3:23])([CH3:22])[CH3:21])[CH2:16][CH2:15][CH2:14]1
Reactant: C[Si](C)(C)C#CCCCCCl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: C[Si](C)(C)C#CC1CCC1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 70 %

Procedure:
To a solution of diisopropylamine (153 g, 1.52 mol) in anhydrous THF (1.0 L) at 0° C., n-butyllithium (2.5 M in hexane, 608 mL, 1.52 mol) was added dropwise. The mixture was stirred for 20 minutes at 0° C. and then cooled to −78° C. To this mixture, a solution of (6-chlorohex-1-yn-1-yl)trimethylsilane (144 g, 0.76 mol) in anhydrous THF (200 mL) was added dropwise. The resulting mixture was allowed to warm to room temperature and stirred for 16 h. The reaction mixture was carefully quenched at room temperature with saturated aqueous NH4Cl (500 mL), and then extracted with pentane (2×200 mL). The combined organic layers were washed with brine (500 mL) and dried over anhydrous Na2SO4. The solvent was evaporated on a rotary evaporator. The residue was distilled at 160-162° C./760 Torr to afford the title compound as a colorless liquid (81 g, yield 70%). 1H NMR (CDCl3, 400 MHz): δ 3.05-3.01 (m, 1H), 2.26-2.20 (m, 2H), 2.17-2.10 (m, 2H), 1.93-1.84 (m, 2H), 0.11 (s, 9H).
Reaction SMILES: Cl.[NH2:2][CH:3]([C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([O:17][CH3:18])[CH:10]=1)[CH2:4][C:5]([O:7][CH3:8])=[O:6].C(N(CC)CC)C.[N+:26]([C:29]1[CH:37]=[CH:36][C:32]([C:33](Cl)=[O:34])=[CH:31][CH:30]=1)([O-:28])=[O:27]>O1CCCC1>[N+:26]([C:29]1[CH:30]=[CH:31][C:32]([C:33]([NH:2][CH:3]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([O:17][CH3:18])[CH:10]=2)[CH2:4][C:5]([O:7][CH3:8])=[O:6])=[O:34])=[CH:36][CH:37]=1)([O-:28])=[O:27]
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Reactant: COC(=O)CC(N)c1ccc(OC)c(OC)c1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)CC(NC(=O)c1ccc([N+](=O)[O-])cc1)c1ccc(OC)c(OC)c1
Reaction time: 0.25 h
Yield: 95.8 %

Procedure:
To an ice bath cooled stirred suspension of methyl 3-amino-3-(3,4-dimethoxyphenyl)propionate hydrochloride(1.38 grams, 5.00 mmol) and triethylamine (1.5 milliliters, 10.8 mmol) in 25 milliliters of tetrahydrofuran was added 4-nitrobenzoyl chloride (0.928 grams, 5.00 mmol) in a single portion. After 15 minutes, the cooling bath was removed and the reaction mixture stirred for 45 minutes. The reaction mixture was then diluted with 50 milliliters of water. The reaction slurry was filtered and the solid washed with water, air-dried, and then dried in vacuo (60 C., <1 mm) to afford 1.86 grams (94%) of the product as a yellow powder: 1H NMR (CDCl3 /TMS, 250 MHz) δ 8.27 (d, J=8.8 Hz, 2 H), 7.98 (d, J=8.8 Hz, 2 H), 7.77 (d, J=8.1 Hz, 1 H, NH), 6.95-6.75 (m, 3 H, Ar), 5.55 (m, 1 H, CH), 3.86 & 3.85 (2 s, 6 H, 2 OCH3), 3.68 (s, 3 H, CO2 CH3), 3.00 (m, 2 H, CH2); 13C NMR (CDCl3 /TMS) δ 172.2, 164.4, 149.6, 1491, 148.7, 139.7, 132.6, 128.2, 123.8, 118.1, 111.2, 109.9, 55.9, 55.8, 52.0, 50.0, 39.3.
Reaction SMILES: [C:1]([O:5][CH:6]([CH3:17])[CH2:7][CH2:8][CH2:9][CH:10]1[O:15][CH:14]([OH:16])[CH2:13][CH2:12][CH2:11]1)([CH3:4])([CH3:3])[CH3:2].[CH:18]([Mg]Cl)=[CH2:19].CCOCC.[Cl-].[NH4+]>O1CCCC1>[OH:16][CH:14]([CH2:13][CH2:12][CH2:11][CH:10]([OH:15])[CH2:9][CH2:8][CH2:7][CH:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])[CH3:17])[CH:18]=[CH2:19]
Reactant: C=C[Mg]Cl
Reactant: CC(CCCC1CCCC(O)O1)OC(C)(C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: C=CC(O)CCCC(O)CCCC(C)OC(C)(C)C

Procedure:
4.5 G. of 6-[4-tertiarybutoxypentyl]-2-tetrahydropyranol produced in Example 120 was dissolved in 200 ml. of tetrahydrofuran and added slowly over a 20 minute period to a solution of 300 ml. of vinyl magnesium chloride in tetrahydrofuran at 0°. After agitation for an additional hour at room temperature, 200 ml. of ether was added which was followed by the addition of 100 ml. of a 20 per cent aqueous solution of ammonium chloride. Extraction with ether yielded a waxy solid, 3,7-dihydroxy-11-tertiarybutoxydodec-1-ene.
Reaction SMILES: Cl.C(OC([N:9]1[CH2:22][CH:12]2[C:13]3[C:14]([C:20]#[N:21])=[C:15]([Cl:19])[S:16][C:17]=3[CH2:18][CH:11]2[CH2:10]1)=O)(C)(C)C>>[Cl:19][C:15]1[S:16][C:17]2[CH2:18][CH:11]3[CH2:10][NH:9][CH2:22][CH:12]3[C:13]=2[C:14]=1[C:20]#[N:21]
Reactant: CC(C)(C)OC(=O)N1CC2Cc3sc(Cl)c(C#N)c3C2C1
Agent: Cl
Product: N#Cc1c(Cl)sc2c1C1CNCC1C2

Procedure:
The title compound was prepared as its HCl salt by the method of Example 1, step b) utilizing the product of step d). 1H NMR (300 MHz, CDCl3, ppm) 2.75-2.82 (m, 1H); 2.92-3.05 (m, 1H); 3.12-3.45 (m, 4H); 3.50-3.62 (m, 1H); 3.82-3.95 (m, 1H); 7.10-7.30 (br s, 2H); MS calculated for C10H9ClN2S+H 225, observed 225.
Reaction SMILES: [CH:1]1([N:4]([CH:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)[S:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)(=[O:7])=[O:6])[CH2:3][CH2:2]1.C(N(CC)CC)C.Cl[CH2:32][C:33]1[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[CH:35][CH:34]=1>CN(C=O)C>[CH:1]1([N:4]([CH:18]2[CH2:23][CH2:22][N:21]([CH2:32][C:33]3[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[CH:35][CH:34]=3)[CH2:20][CH2:19]2)[S:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:15])[F:16])[CH:9]=2)(=[O:6])=[O:7])[CH2:3][CH2:2]1
Reactant: O=S(=O)(c1cccc(C(F)(F)F)c1)N(C1CCNCC1)C1CC1
Reactant: COc1ccc(CCl)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1ccc(CN2CCC(N(C3CC3)S(=O)(=O)c3cccc(C(F)(F)F)c3)CC2)cc1
Temperature: 80 °C
Reaction time: 12 h
Yield: 121.1 %

Procedure:
N-Cyclopropyl-N-piperidin-4-yl-3-trifluoromethyl-benzenesulfonamide (150 mg, 0.43 mmol) was dissolved in DMF (3 mL) and triethylamine (150 μL, 1.07 mmol, 2.5 eq.) added, followed by 1-chloromethyl-4-methoxybenzene (58 mg, 0.43 mmol). The reaction mixture was stirred for 12 hours at 80° C. and then the solvent was evaporated. The residue was purified by flash chromatography to give 244 mg of the title compound 20 as a yellow oil: 1H NMR (CDCl3): δ 8.15-8.10 (m, 1H), 8.07-8.01 (m, 1H), 7.85-7.80 (m, 1H), 7.67-7.62 (m, 1H), 7.23-7.15 (m, 2H), 6.87-6.82 (m, 2H), 3.91-3.76 (m, 4H), 3.42 (s, 2H), 2.93-2.88 (m, 2H), 2.03-1.87 (m, 5H), 1.52-1.43 (m, 2H), 1.01-0.94 (m, 2H), 0.81-0.73 (m, 2H). LC: 100%. MS (EI): m/z 469 (M+H+).
Reaction SMILES: [Li]C(C)(C)C.[CH2:6]([O:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][O:22][CH3:23])=[CH:16][N:15]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[I:24]I>C1COCC1>[CH2:6]([O:13][C:14]1[CH:19]=[C:18]([I:24])[C:17]([O:20][CH2:21][O:22][CH3:23])=[CH:16][N:15]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: COCOc1ccc(OCc2ccccc2)nc1
Reactant: II
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: COCOc1cnc(OCc2ccccc2)cc1I
Reaction time: 0.5 h
Yield: 47.6 %

Procedure:
tBuLi (27 mL, 46.2 mmol) was added drop wise to a stirring solution of 2-(benzyloxy)-5-(methoxymethoxy)pyridine (5.4 g, 22.06 mmol) in THF (110 mL) at −78° C. The light yellow solution was allowed to stir for 30 min then treated with a solution of iodine (8.4 g, 33.1 mmol) in THF (55 mL) dropwise (the purple color per drop dissipated until after 1.05 equiv was added, then it turned progressively purple). It was allowed to stir for 1 hour and then quenched with H2O and diluted with EtOAc washed with sodium thiosulfate sat. soln and sat NaCl. The organic phase was dried over Na2SO4, filtered and concentrated and was purified on silica gel (Biotage, EtOAc/hexanes gradient, fraction collection at λ=254 nm) to give the expected product 2-(benzyloxy)-4-iodo-5-(methoxymethoxy)pyridine (3.90 g, 10.5 mmol, 48% yield) by LCMS and NMR. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.87 (1H, s), 7.28-7.44 (6H, m), 5.28 (2H, s), 5.21 (2H, s), 3.43 (3H, s). LC-MS retention time: 2.36 min; m/z (MH+): 372. LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Waters SunFire 5u C18 4.6×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 5 ml/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 3 min, a hold time of 1 min, and an analysis time of 4 min where solvent A was 10% acetonitrile/90% H2O/0.1% trifluoroacetic acid and solvent B was 10% H2O/90% acetonitrile/0.1% trifluoroacetic acid. MS data was determined using a Micromass Platform for LC in electrospray mode.
Reaction SMILES: [CH:1]([C:4]1[O:5][CH:6]=[C:7]([CH2:9][NH:10][CH3:11])[N:8]=1)([CH3:3])[CH3:2].[CH3:12][O:13][C:14](=[O:30])[C@H:15]([CH3:29])[NH:16][C:17]([O:19]C1C=CC([N+]([O-])=O)=CC=1)=O>>[CH3:12][O:13][C:14](=[O:30])[C@H:15]([CH3:29])[NH:16][C:17]([N:10]([CH3:11])[CH2:9][C:7]1[N:8]=[C:4]([CH:1]([CH3:2])[CH3:3])[O:5][CH:6]=1)=[O:19]
Reactant: COC(=O)[C@H](C)NC(=O)Oc1ccc([N+](=O)[O-])cc1
Reactant: CNCc1coc(C(C)C)n1
Product: COC(=O)[C@H](C)NC(=O)N(C)Cc1coc(C(C)C)n1
Yield: 66 %

Procedure:
Using the procedure of Example 1S, but replacing 2-isopropyl-4-(((N-methyl)amino)methyl) thiazole with 2-isopropyl-4-(((N-methyl)amino)methyl)-oxazole and replacing N-(((4-nitrophenyl)oxy) carbonyl)-L-valine methyl ester with N-(((4-nitrophenyl)oxy)carbonyl)-L-alanine methyl ester provided the desired compound in 66% yield. 1H NMR (CDCl3) δ 1.32 (d, 6 H), 1.42 (d, 3 H), 2.96 (s, 3 H), 3.05 (m, 1 H), 3.75 (s, 3 H), 4.30 (s, 2 H), 4.47 (m, 1 H), 5.80 (br d, 1 H), 7.46 (s, 1 H). Mass spectrum: (M+H)+ =284.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[NH:6][S:7](=[O:17])(=[O:16])[C:8]2[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=2[C:10]=1[OH:11])=[O:4].[H-].[Na+].[CH2:20]1[O:30][C:29]2[CH:28]=[CH:27][C:24]([CH2:25]Cl)=[CH:23][C:22]=2[O:21]1>CN(C=O)C.C(OCC)(=O)C>[CH3:1][O:2][C:3]([C:5]1[N:6]([CH2:25][C:24]2[CH:27]=[CH:28][C:29]3[O:30][CH2:20][O:21][C:22]=3[CH:23]=2)[S:7](=[O:17])(=[O:16])[C:8]2[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=2[C:10]=1[OH:11])=[O:4]
Reactant: COC(=O)C1=C(O)c2ccccc2S(=O)(=O)N1
Reactant: ClCc1ccc2c(c1)OCO2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)C1=C(O)c2ccccc2S(=O)(=O)N1Cc1ccc2c(c1)OCO2
Reaction time: 0.08 h
Yield: 71.7 %

Procedure:
To 4-hydroxy-1,1-dioxo-1,2-dihydro-1λ6 -benzo[e][1,2]thiazine-3-carboxylic acid methyl ester (1.48 g, 5.84 mmol) in DMF (10 mL) was added sodium hydride (0.257 g, 60%, 6.4 mmol) and the mixture stirred for 5 minutes. 3,4-methylenedioxybenzyl chloride (2.2 g, 50 wt. % in dichloromethane, 6.4 mmol) was added and the mixture stirred at room temperature for 18 hours. Diluted with ethyl acetate (100 mL), washed with water (2×80 mL), brine (80 mL), dried over magnesium sulfate, removed solvent in vacuo, and crystallized from ethyl acetate/heptane to give the title compound (1.63 g, 72%);
Reaction SMILES: [NH2:1][NH:2][C:3]([NH2:5])=[S:4].[CH3:6][N:7]1[C:11]([CH:12]=O)=[CH:10][N:9]=[C:8]1[N+:14]([O-:16])=[O:15]>O.CO>[CH3:6][N:7]1[C:11]([CH:12]=[N:1][NH:2][C:3]([NH2:5])=[S:4])=[CH:10][N:9]=[C:8]1[N+:14]([O-:16])=[O:15]
Reactant: NNC(N)=S
Reactant: Cn1c(C=O)cnc1[N+](=O)[O-]
Solvent: O
Solvent: CO
Product: Cn1c(C=NNC(N)=S)cnc1[N+](=O)[O-]

Procedure:
A solution of 1.42 g. of thiosemicarbazide in water is added to a solution of 1.8 g. of 1-methyl-2-nitro-5-imidazolecarboxaldehyde in methanol. The solid which precipitates is recovered on the filter. Yield: 2.2 g., m.p. 282°-287° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]3[CH:18]=[C:19]([C:23](O)=[O:24])[O:20][C:21]=3[CH3:22])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.[S:26]([C:30]1[CH:35]=[CH:34][C:33]([O:36]C(=O)C)=[CH:32][CH:31]=1)(=[O:29])(=[O:28])[NH2:27].C[O-].[Na+]>CO.O>[OH:36][C:33]1[CH:34]=[CH:35][C:30]([S:26]([NH:27][C:23]([C:19]2[O:20][C:21]([CH3:22])=[C:17]([CH2:16][O:15][C:12]3[CH:11]=[CH:10][C:9]([C:6]4[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=4)=[CH:14][CH:13]=3)[CH:18]=2)=[O:24])(=[O:28])=[O:29])=[CH:31][CH:32]=1
Reactant: COc1ccc(-c2ccc(OCc3cc(C(=O)O)oc3C)cc2)cc1
Reactant: CC(=O)Oc1ccc(S(N)(=O)=O)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COc1ccc(-c2ccc(OCc3cc(C(=O)NS(=O)(=O)c4ccc(O)cc4)oc3C)cc2)cc1
Yield: 20.6 %

Procedure:
4-(4′-Methoxy-biphenyl-4-yloxymethyl)-5-methyl-furan-2-carboxylic acid (4) (50 mg) was reacted with acetic acid 4-sulphamoyl-phenyl ester (64 mg) in an analogous manner to that described in Example 2A. The acetic ester intermediate was hydrolysed with sodium methoxide (80 mg) in a mixture of methanol (10 mL) and water (1 mL) for 1 hour. The solution was concentrated in vacuo then partitioned between dichloromethane (10 mL) and water (10 mL). The organic layer was washed with brine (10 mL)r dried, filtered and concentrated in vacuo. The crude product was purified by preparative HPLC (starting at 30% acetonitrile and increasing at a rate of 1% per minute up to 98% acetonitrile) to give compound 13 as a white solid (15 mg). LC/MS System C: Rt=3.50 mins, m/z (ES−)=492 (M− for C26H23N2O7S).
Reaction SMILES: Cl.[CH2:2]([O:4][C:5]([C:7]1([NH2:13])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1)=[O:6])[CH3:3].[O:14]1[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[CH:16]=[C:15]1[C:23](O)=[O:24]>>[CH2:2]([O:4][C:5]([C:7]1([NH:13][C:23]([C:15]2[O:14][C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=3[CH:16]=2)=[O:24])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1)=[O:6])[CH3:3]
Reactant: O=C(O)c1cc2ccccc2o1
Reactant: CCOC(=O)C1(N)CCCCC1
Agent: Cl
Product: CCOC(=O)C1(NC(=O)c2cc3ccccc3o2)CCCCC1
Yield: 80.3 %

Procedure:
3.11 g (15 mmol) of 1-aminocyclohexanecarboxylic acid ethyl ester hydrochloride was used instead of 1-aminocyclohexanecarboxylic acid methyl ester hydrochloride and 2.43 g (15 mmol) of benzofuran-2-carboxylic acid was used instead of 3-furancarboxylic acid in the process according to Reference example 15 to obtain 3.80 g (80%) of the title compound.
Reaction SMILES: NC(=NO)[C:3]1[CH:18]=[CH:17][C:6]([CH2:7][O:8][CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])=[CH:5][CH:4]=1.[C:21](C1C=C(C=CC=1)CO)#[N:22]>>[C:21]([C:18]1[CH:17]=[C:6]([CH:5]=[CH:4][CH:3]=1)[CH2:7][O:8][CH2:9][C:10]([O:12][C:13]([CH3:14])([CH3:15])[CH3:16])=[O:11])#[N:22]
Reactant: N#Cc1cccc(CO)c1
Reactant: CC(C)(C)OC(=O)COCc1ccc(C(N)=NO)cc1
Product: CC(C)(C)OC(=O)COCc1cccc(C#N)c1

Procedure:
The title compound was prepared following the procedure described for Intermediate 15 Step 1, but starting from 3-cyanobenzyl alcohol. It was obtained as a colorless oil (4.4 g, 78%). HPLC (Method A) Rt 4.55 min (Purity: 98.3%).
Reaction SMILES: O=[C:2]1[C:5](=[O:6])[C:4]([O-:7])=[C:3]1[CH:8]=[C:9]1[C:17]([CH3:19])([CH3:18])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]1[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25]([OH:27])=[O:26].[CH2:28]([NH+:30]([CH2:33][CH3:34])[CH2:31][CH3:32])[CH3:29].[C:35](#[N:39])[CH2:36][C:37]#[N:38]>C(O)C>[C:37]([C:36]([C:35]#[N:39])=[C:2]1[C:5](=[O:6])[C:4]([O-:7])=[C:3]1[CH:8]=[C:9]1[C:17]([CH3:19])([CH3:18])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]1[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25]([OH:27])=[O:26])#[N:38].[CH2:28]([NH+:30]([CH2:33][CH3:34])[CH2:31][CH3:32])[CH3:29]
Reactant: CC1(C)C(=Cc2c([O-])c(=O)c2=O)N(CCCCCC(=O)O)c2ccccc21
Reactant: N#CCC#N
Agent: CC[NH+](CC)CC
Solvent: CCO
Product: CC1(C)C(=CC2=C([O-])C(=O)C2=C(C#N)C#N)N(CCCCCC(=O)O)c2ccccc21
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
A mixture of 1.2 g (2.82 mmol) of 11, 190 mg (2.87 mmol) of malononitrile and 0.4 ml (2.85 mmol) of TEA in 15 ml of ethanol was stirred at room temperature for 2.5 h. Then solvent was removed by a rotary evaporator. Product 12 was used in next synthesis without further purification.