Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[OH:15])[C:3]#[C:4][Si:5]([CH3:8])([CH3:7])[CH3:6].N1C=CC=CC=1.[O:22](S(C(F)(F)F)(=O)=O)[S:23]([C:26]([F:29])([F:28])[F:27])(=O)=[O:24]>C(Cl)Cl>[CH3:1][CH:2]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[O:15][S:23]([C:26]([F:29])([F:28])[F:27])(=[O:24])=[O:22])[C:3]#[C:4][Si:5]([CH3:8])([CH3:6])[CH3:7]
Reactant: CC(C#C[Si](C)(C)C)c1ccccc1O
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C#C[Si](C)(C)C)c1ccccc1OS(=O)(=O)C(F)(F)F
Temperature: 0 °C

Procedure:
A solution of 20.9 grams (95.7 mmol, 1.0 eq) of phenol 6 in 92.0 mL of CH2Cl2 was stirred in a 250 mL round bottom flask under argon at room temperature. To this colorless solution was then added 580 mg (4.8 mmol, 0.05 eq) of N,N-dimethylaminopyridine followed by 46.0 mL (574 mmol, 6.0 eq) of pyridine. This solution was then cooled to 0° C. in an ice water bath. Once cooled, 19.3 mL (114.8 mmol, 1.2 eq) of Tf2O was carefully added to the cold solution. Once the addition of Tf2O was complete, the ice water bath was removed and the black solution was stirred at room temperature until complete by TLC (7:1 hexane:EtOAc, KMnO4 stain). Upon completion (˜30 minutes), the solution was diluted with Et2O and washed with 1.0 M HCl twice, followed by washings with water and brine. The organic fraction was then dried over MgSO4, concentrated and purified via vacuum distillation yielding 24.88 grams (74% for two steps) of a colorless oil, Rf 0.69 (7:1 hexane:EtOAc). 1H-NMR (500 MHz, CDCl3): 7.76 (dd, J=7.8 Hz, 1.7 Hz, 1H), 7.41 (dt, J=1.2 Hz, 7.6 Hz, 1H), 7.34 (dt, J=1.7 Hz, 7.8 Hz, 1H), 7.29 (dd, J=1.5 Hz, 8.5 Hz, 1H), 4.14 (q, J=7.1 Hz, 1H), 1.52 (d, J=7.1 Hz, 3H), 0.21 (s, 9H). 13C-NMR (500 MHz, CDCl3): 146.66, 135.94, 129.88, 128.92, 128.82, 121.33, 118.73 (q, J=320 Hz), 107.57, 87.12, 27.40, 23.56, 0.21. 19F-NMR (500 MHz, CDCl3): −74.37. IR (cm−1): 2960 (w), 2169 (w), 1757 (w), 1422 (s), 1214 (s), 1142 (s), 886 (s), 844 (s), 761 (m). HRMS (EI) calcd. for C14H17F3O3SSi: 350.0620. found: 350.0619.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]([OH:9])=[O:8].OS(O)(=O)=O.[CH3:15]O>>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]([O:9][CH3:15])=[O:8]
Reactant: CO
Reactant: O=C(O)Cc1cccs1
Agent: O=S(=O)(O)O
Product: COC(=O)Cc1cccs1
Temperature: 25 °C
Yield: 91 %

Procedure:
Thiophene acetic acid (27.3 g, 192 mmol) was treated with a solution of H2SO4 (5.76 mL, 108 mmol) in MeOH (384 mL) at reflux for one hour. The reaction was then cooled to room temperature, concentrated by rotovap, diluted with ether, washed with 5% sodium bicarbonate and brine. The organic phase was then dried with magnesium sulfate and concentrated by rotovap to yield the product as a yellow oil (27.4 g, 176 mmol, 91%), which was used without further purification. The product matches data for commercially available methyl 2-(thiophen-2-yl)acetate (CAS No. 19432-68-9).
Reaction SMILES: [CH3:1][C:2]1[NH:6][C:5]2[CH:7]=[C:8]([C:19]([OH:21])=[O:20])[CH:9]=[C:10]([O:11][CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:4]=2[N:3]=1.S(Cl)(Cl)=O.[CH3:26]O>C(OCC)(=O)C>[CH3:1][C:2]1[NH:6][C:5]2[CH:7]=[C:8]([C:19]([O:21][CH3:26])=[O:20])[CH:9]=[C:10]([O:11][CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:4]=2[N:3]=1
Reactant: Cc1nc2c(OCc3ccccc3)cc(C(=O)O)cc2[nH]1
Reactant: CO
Solvent: CCOC(C)=O
Solvent: O=S(Cl)Cl
Product: COC(=O)c1cc(OCc2ccccc2)c2nc(C)[nH]c2c1
Temperature: 80 °C
Reaction time: 3 h

Procedure:
A mixture of 2-methyl-4-[(phenylmethyl)oxy]-1H-benzimidazole-6-carboxylic acid (10.0 g, 35.4 mmol, STEP 4 in Example 1), and thionyl chloride (5.2 mL, 7.1 mmol) in methanol (300 mL) was stirred at 80° C. for 3 hours. The mixture was diluted with ethyl acetate, and washed with saturated ammonium chloride aqueous solution. The organic layer was dried over magnesium sulfate, and concentrated in vacuum. The residue was diluted with methanol, filtered to remove the precipitate, and the filtrate was concentrated in vacuum. The resulted solid was washed with dichloromethane to give the title compound as a brown solid (29.8 g, crude), which was used in the next step without further purification. MS (ESI) m/z: 297 (M+H)+, 295 (M−H)−.
Reaction SMILES: [Li][CH3:2].[CH3:3][O:4][C:5]1[CH:16]=[CH:15][C:8]([CH2:9][C@@H:10]([CH2:13][CH3:14])[CH:11]=O)=[C:7]([CH:17]=[CH2:18])[CH:6]=1>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1>[CH2:11]([C@@H:10]([CH:13]=[CH2:14])[CH2:9][C:8]1[CH:15]=[CH:16][C:5]([O:4][CH3:3])=[CH:6][C:7]=1[CH:17]=[CH2:18])[CH3:2]
Reactant: [Li]C
Reactant: C=Cc1cc(OC)ccc1C[C@H](C=O)CC
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: C1CCOC1
Product: C=Cc1cc(OC)ccc1C[C@H](C=C)CC
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
MeLi (32 mL, 51 mmol, 1.6 M in diethyl ether) is added to a suspension of methyltriphenylphosphonium bromide (27.8 g, 77.8 mmol) in THF (100 mL) at 0° C. The mixture is stirred at 0° C. for 30 min. Then a solution of (R)-2-(4-Methoxy-2-vinylbenzyl)-butyraldehyde (6.12 g) in THF (50 mL) is added. The mixture is stirred at 0° C. for 1 h. The mixture is partitioned between EtOAc and aq. NH4Cl. The organic extract is dried with MgSO4, concentrated and purified to give the title compound as an oil: 1H NMR (CDCl3) δ 0.85 (t, J=7.3 Hz, 3H), 1.23-1.28 (m, 1H), 1.42-1.47 (m, 1H), 2.09-2.14 (m, 1H), 2.56-2.69 (m, 2H), 3.81 (s, 3H), 4.85 (d, J=17 Hz, 1H), 4.93 (dd, J=2, 10 Hz, 1H), 5.27 (dd, J=1, 11 Hz, 1H), 5.50-5.65 (m, 2H), 6.74 (dd, J=3, 8 Hz, 1H), 6.94 (dd, J=11, 17 Hz, 1H), 6.99 (d, J=8 Hz, 1H), 7.02 (d, J=3 Hz, 1H).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4]Br.[CH2:6]([O:13][C:14]1[CH:23]=[C:22]2[C:17]([C:18](=[S:24])[NH:19][CH:20]=[N:21]2)=[CH:16][CH:15]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[CH2:6]([O:13][C:14]1[CH:23]=[C:22]2[C:17]([C:18]([S:24][CH2:4][CH2:3][O:2][CH3:1])=[N:19][CH:20]=[N:21]2)=[CH:16][CH:15]=1)[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: S=c1[nH]cnc2cc(OCc3ccccc3)ccc12
Reactant: COCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COCCSc1ncnc2cc(OCc3ccccc3)ccc12
Reaction time: 4 h
Yield: 87.5 %

Procedure:
2-Bromoethyl methyl ether (3.2 ml, 33 mmol) was added dropwise to a solution of 7-benzyloxy-3,4-dihydroquinazolin-4-thione (7.4 g, 28 mmol), (prepared as described for the starting material in Example 8), in DMF (275 ml) containing potassium carbonate (4.6 g, 33 mmol). After stirring for 4 hours, water was added and the precipitate was collected by filtration, washed with water, and dried under vacuum to give 7-benzyloxy4-(2-methoxyethylsulphanyl)quinazoline (8 g, 89%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.Br[C:10]1[CH:15]=[CH:14][C:13]([C:16](=[O:18])[CH3:17])=[CH:12][CH:11]=1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:10]2[CH:15]=[CH:14][C:13]([C:16](=[O:18])[CH3:17])=[CH:12][CH:11]=2)=[CH:4][CH:3]=1
Reactant: CC(=O)c1ccc(Br)cc1
Reactant: Oc1ccc(F)cc1
Product: CC(=O)c1ccc(Oc2ccc(F)cc2)cc1

Procedure:
The starting material was prepared as follows. An Ullmann reaction using p-fluorophenol and p-bromoacetophenone gave 4'-(4-fluorophenoxy)acetophenone, m.p. 65°-67°C. This was subjected to the Willgerodt reaction using morpholine and sulfur, followed by hydrolysis, to give crude 4-(4-fluorophenoxy)phenylacetic acid, which was esterified and gave ethyl 4-(4-fluorophenoxy)phenylacetate, b.p. 139°-142°C./0.3 mm. This ester was treated conventionally with diethyl carbonate and sodium ethoxide, and then with dimethyl sulfate, to yield the required ethyl 2-[4-(4-fluorophenoxy)phenyl]-2-methylmalonate, b.p. 174°-182°C./0.7 mm.
Reaction SMILES: CC1(C)[O:9][C:8](=[O:10])[C:5]2([CH2:7][CH2:6]2)[C:4](=[O:11])O1.[CH2:13]([C:15]1[CH:16]=[C:17]([CH:19]=[CH:20][CH:21]=1)[NH2:18])[CH3:14]>C(O)C>[CH2:13]([C:15]1[CH:16]=[C:17]([N:18]2[CH2:6][CH2:7][CH:5]([C:8]([OH:9])=[O:10])[C:4]2=[O:11])[CH:19]=[CH:20][CH:21]=1)[CH3:14]
Reactant: CC1(C)OC(=O)C2(CC2)C(=O)O1
Reactant: CCc1cccc(N)c1
Solvent: CCO
Product: CCc1cccc(N2CCC(C(=O)O)C2=O)c1
Yield: 35 %

Procedure:
A mixture of 6,6-dimethyl-5,7-dioxaspiro[2.5]octane-4,8-dione (0.500 g; 2.94 mmol) and 3-ethylaniline (1.1 mL; 8.82 mmol) in ethanol (3 mL) was irradiated in a microwave oven for 3 minutes at 100° C. The mixture was concentrated under reduced pressure and the residue was dissolved in a solution of sodium hydroxide 6N, washed with dichloromethane, acidified with a solution of hydrochloric acid 6N to pH=2, extracted with ethyl acetate dried and concentrated under reduced pressure to yield 0.240 g (35%) of a yellow oil which was used in the next step without further purification.
Reaction SMILES: FC(F)(F)S(O[CH2:7][C:8]([F:25])([F:24])[C:9]([F:23])([F:22])[C:10]([F:21])([F:20])[C:11]([F:19])([F:18])[C:12]([F:17])([F:16])[CH:13]([F:15])[F:14])(=O)=O.C(=O)([O-])[O-].[K+].[K+].[C:34](#[N:38])[CH2:35][C:36]#[N:37].O>CS(C)=O>[F:24][C:8]([F:25])([C:9]([F:22])([F:23])[C:10]([F:20])([F:21])[C:11]([F:18])([F:19])[C:12]([F:16])([F:17])[CH:13]([F:14])[F:15])[CH2:7][CH:35]([C:34]#[N:38])[C:36]#[N:37]
Reactant: O=S(=O)(OCC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)F)C(F)(F)F
Reactant: N#CCC#N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: N#CC(C#N)CC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)F
Temperature: 25 °C
Reaction time: 3 h
Yield: 16.7 %

Procedure:
14.6 g of 2,2,3,3,4,4,5,5,6,6,7,7-dodecafluoroheptyl trifluoromethanesulfonate was dissolved in 20 ml of dimethyl sulfoxide, and 5.5 g of potassium carbonate was added. 2.6 g of malononitrile dissolved in 10 ml of dimethyl sulfoxide was added dropwise thereto, and the mixture was stirred at room temperature for 3 hours. The reaction mixture was poured to water and then extracted with diethyl ether. The organic layer was washed successively with water and aqueous saturated sodium chloride, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 2.0 g of 2-(2,2,3,3,4,4,5,5,6,6,7,7-dodecafluoroheptyl)malononitrile.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:14](=[O:15])[CH:13]=[C:12]([O:16]C)[CH:11]=[N:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.[OH-].[K+]>C(O)C.O>[Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:14](=[O:15])[CH:13]=[C:12]([OH:16])[CH:11]=[N:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: COc1cnn(-c2cc(Cl)cc(Cl)c2)c(=O)c1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=c1cc(O)cnn1-c1cc(Cl)cc(Cl)c1

Procedure:
2-(3,5-Dichlorophenyl)-5-methoxypyridazin-3-one (0.25 g, 0.92 mmoles) was suspended in ethanol (40 ml) and potassium hydroxide (0.12 g, 1.8 mmoles) was added in water (5 ml). Refluxed overnight with stirring to give a yellow solution. Evaporated to dryness and added 2M hydrochloric acid. Extracted with ethyl acetate (×2) and washed with water and dried over anhydrous magnesium sulphate. Filtered and evaporated to give a yellow solid. Triturated with dichloromethane to give a pale yellow solid. (0.1 g, 42%)
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][NH:9][CH2:10][C:11]1[CH:12]=[C:13]([C:17]2[CH:22]=[CH:21][C:20]([CH2:23][CH:24]3[S:28][C:27](=[O:29])[NH:26][C:25]3=[O:30])=[CH:19][CH:18]=2)[CH:14]=[CH:15][CH:16]=1.[CH2:31]([O:33][C:34]1[CH:42]=[CH:41][C:37]([C:38](Cl)=[O:39])=[CH:36][CH:35]=1)[CH3:32]>>[O:29]=[C:27]1[NH:26][C:25](=[O:30])[CH:24]([CH2:23][C:20]2[CH:19]=[CH:18][C:17]([C:13]3[CH:14]=[CH:15][CH:16]=[C:11]([CH2:10][N:9]([CH3:8])[C:38](=[O:39])[C:37]4[CH:41]=[CH:42][C:34]([O:33][CH2:31][CH3:32])=[CH:35][CH:36]=4)[CH:12]=3)=[CH:22][CH:21]=2)[S:28]1
Reactant: CNCc1cccc(-c2ccc(CC3SC(=O)NC3=O)cc2)c1
Reactant: CCOc1ccc(C(=O)Cl)cc1
Solvent: O=C(O)C(F)(F)F
Product: CCOc1ccc(C(=O)N(C)Cc2cccc(-c3ccc(CC4SC(=O)NC4=O)cc3)c2)cc1

Procedure:
In a manner similar to that of Example 37(e), by reacting 1 g (2.2 mmol) of 5-(3′-methylaminomethyl-biphenyl-4-ylmethyl)thiazolidine-2,4-dione trifluoro-acetate with 460 mg (2.5 mmol) of 4-ethoxybenzoyl chloride, and after purification, 960 mg (88%) of N-[4′-(2,4-dioxothiazolidin-5-ylmethyl)biphenyl-3-ylmethyl]-4-ethoxy-N-methylbenzamide are obtained in the form of a white solid with a melting point of 182° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]2[CH2:15][CH2:14][C@:13]([CH2:23][CH2:24][CH2:25][NH:26][S:27]([CH3:30])(=[O:29])=[O:28])([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[O:12][C:11]2=[O:31])[CH3:9])=[CH:4][CH:3]=1.[CH3:32][O:33][C:34]1[N:39]=[CH:38][C:37](B(O)O)=[CH:36][CH:35]=1>>[F:22][C:19]1[CH:20]=[CH:21][C:16]([C@:13]2([CH2:23][CH2:24][CH2:25][NH:26][S:27]([CH3:30])(=[O:29])=[O:28])[O:12][C:11](=[O:31])[N:10]([C@H:8]([C:5]3[CH:6]=[CH:7][C:2]([C:37]4[CH:38]=[N:39][C:34]([O:33][CH3:32])=[CH:35][CH:36]=4)=[CH:3][CH:4]=3)[CH3:9])[CH2:15][CH2:14]2)=[CH:17][CH:18]=1
Reactant: C[C@@H](c1ccc(Br)cc1)N1CC[C@](CCCNS(C)(=O)=O)(c2ccc(F)cc2)OC1=O
Reactant: COc1ccc(B(O)O)cn1
Product: COc1ccc(-c2ccc([C@H](C)N3CC[C@](CCCNS(C)(=O)=O)(c4ccc(F)cc4)OC3=O)cc2)cn1

Procedure:
The title compound was prepared from N-(3-((R)-3-((S)-1-(4-bromophenyl)ethyl)-6-(4-fluorophenyl)-2-oxo-1,3-oxazinan-6-yl)propyl)methanesulfonamide and 6-methoxypyridine-3-boronic acid following a procedure analogous to that described in Example 75 Step 1. LC-MS Method 2 tR=1.327 min, m/z=542.1; 1H NMR (CD3OD) 1.33 (m, 1H), 1.58 (d, 3H), 1.66 (m, 1H), 1.98 (m, 2H), 2.20-2.39 (m, 2H), 2.47 (m, 1H), 2.87 (s, 3H), 2.99 (m, 2H), 3.15 (m, 1H), 3.96 (s, 3H), 5.60 (m, 1H), 6.87 (d, 1H), 7.12 (m, 4H), 7.36 (m, 4H), 7.87 (d, 1H), 8.29 (s, 1H).
Reaction SMILES: [CH2:1]([O:4][C:5]([O:7][CH2:8][C:9]([OH:11])=O)=[O:6])[CH:2]=[CH2:3].C(Cl)(=O)C([Cl:15])=O.CN(C)C=O>O1CCCC1>[CH2:1]([O:4][C:5]([O:7][CH2:8][C:9]([Cl:15])=[O:11])=[O:6])[CH:2]=[CH2:3]
Reactant: C=CCOC(=O)OCC(=O)O
Reactant: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: C=CCOC(=O)OCC(=O)Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 90.1 %

Procedure:
A solution of 2-(allyloxycarbonyloxy)acetic acid (3.03 g, 18.9 mmol) obtained from Example 39-(3) in tetrahydrofuran (30 ml) was cooled to 0° C., and to the solution were added oxalyl chloride (2.64 g, 20.8 mmol) and N,N-dimethylformamide (30 μl). The mixture was warmed to room temperature. After the mixture was stirred for 30 minutes, the solvent was distilled off under reduced pressure, and the resulting residue was purified using simple distillation under reduced pressure to give the title compound (3.04 g, yield 90%) as a colorless oil.
Reaction SMILES: Cl.Cl.Cl.[S:4]1[C:12]2[CH:11]=[CH:10][N:9]=[C:8]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[CH:6]=[CH:5]1.C[O:29][C:30](=O)[CH2:31][C@H:32]1[CH2:37][CH2:36][C@H:35]([OH:38])[CH2:34][CH2:33]1>>[OH:38][C@H:35]1[CH2:36][CH2:37][C@H:32]([CH2:31][C:30]([NH:27][C@H:24]2[CH2:25][CH2:26][C@H:21]([CH2:20][CH2:19][N:16]3[CH2:17][CH2:18][N:13]([C:8]4[C:7]5[CH:6]=[CH:5][S:4][C:12]=5[CH:11]=[CH:10][N:9]=4)[CH2:14][CH2:15]3)[CH2:22][CH2:23]2)=[O:29])[CH2:33][CH2:34]1
Reactant: COC(=O)C[C@H]1CC[C@H](O)CC1
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3nccc4sccc34)CC2)CC1
Agent: Cl
Product: O=C(C[C@H]1CC[C@H](O)CC1)N[C@H]1CC[C@H](CCN2CCN(c3nccc4sccc34)CC2)CC1

Procedure:
The title compound was prepared in analogy to example 2 starting from trans-4-[2-(4-thieno[3,2-c]pyridin-4-yl-piperazin-1-yl)-ethyl]-cyclohexylamine trihydrochloride (intermediate B) (1150 mg, 0.33 mmol) and trans-(4-hydroxy-cyclohexyl)-acetic acid methyl ester [CAS-Nr. 1124174-16-8, WO 2010/031735] (68 mg, 0.39 mmol). Purification by flash chromatography on silica gel (CH2Cl2/MeOH 95:5). White crystals (83 mg, 52%), MS (ISP) m/z=485.4 [(M+H)+].
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:15]=[CH:14][C:6]2[NH:7]C(=O)[NH:9][S:10](=[O:12])(=[O:11])[C:5]=2[CH:4]=1.[OH-].[Na+]>S(=O)(=O)(O)O>[NH2:7][C:6]1[CH:14]=[CH:15][C:3]([O:2][CH3:1])=[CH:4][C:5]=1[S:10]([NH2:9])(=[O:11])=[O:12]
Reactant: COc1ccc2c(c1)S(=O)(=O)NC(=O)N2
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: COc1ccc(N)c(S(N)(=O)=O)c1
Yield: 61 %

Procedure:
A solution of 7-methoxy-1,1-dioxo-1,4-dihydro-2H-1λ6-benzo[1,2,4]thiadiazin-3-one (Example 2a, 15 g, 65.7 mmol) in a 50% aqueous sulfuric acid solution (140 mL) was heated at 130° C. for 6 h. The solution was then poured over ice and neutralized at 0° C. with the addition of saturated aqueous sodium hydroxide solution. The mixture was then extracted with ethyl acetate. The organic phase was washed with brine, and dried over magnesium sulfate, filtered and dried in vacuo to afford the desired product, 2-amino-5-methoxy-benzenesulfonamide (8.1 g, 40.1 mmol, 61% yield) as a brown solid. See procedure described in Girard, Y., et al., J. Chem. Soc. Perkin Trans 1, 1043-1047 (1979). 1H NMR (400 MHz, DMSO-d6): δ 3.65 (s, 3H), 5.40 (s, 2H), 6.73 (d, 1H, J=8.8 Hz), 6.90 (dd, 1H, J1=8.8 Hz, J2=2.8 Hz), 7.07 (d, 1H, J=2.8 Hz), 7.19 (s, 2H).
Reaction SMILES: [F:1][C:2]1[C:9]([CH:10]=O)=[CH:8][CH:7]=[C:6]([I:12])[C:3]=1[C:4]#[N:5].[CH:13]([NH2:16])([CH3:15])[CH3:14].C([BH3-])#N.[Na+].[OH-].[Na+]>CO.CC(O)=O>[F:1][C:2]1[C:9]([CH2:10][NH:16][CH:13]([CH3:15])[CH3:14])=[CH:8][CH:7]=[C:6]([I:12])[C:3]=1[C:4]#[N:5]
Reactant: N#Cc1c(I)ccc(C=O)c1F
Reactant: CC(C)N
Agent: [BH3-]C#N
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CO
Product: CC(C)NCc1ccc(I)c(C#N)c1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 32.5 %

Procedure:
A solution of Example 220A (1.00 g, 3.6 mmol) in MeOH (15 mL) was treated with isopropylamine (0.31 mL, 3.6 mmol) and sodium cyanoborohydride (227 mg, 3.6 mmol), and the mixture was stirred overnight at rt. HOAc (1 mL) was added and the reaction was stirred for 5 h, then treated with 1N NaOH and extracted with EtOAc. The extracts were washed with brine, dried (MgSO4) and concentrated. The residue was purified by flash chromatography on silica gel eluting with 8% MeOH/CH2Cl2 to give the desired product (372 mg). MS (ESI(+)) m/e 318.9 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([NH:7][C:8]2[CH:18]=[C:17]([O:19][C:20]3[C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[CH:23]=[CH:22][CH:21]=3)[C:11]([C:12]([O:14]CC)=[O:13])=[CH:10][N:9]=2)[S:5][CH:6]=1.O.[OH-].[Li+]>C1COCC1.O>[CH3:1][C:2]1[N:3]=[C:4]([NH:7][C:8]2[CH:18]=[C:17]([O:19][C:20]3[C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[CH:23]=[CH:22][CH:21]=3)[C:11]([C:12]([OH:14])=[O:13])=[CH:10][N:9]=2)[S:5][CH:6]=1
Reactant: CCOC(=O)c1cnc(Nc2nc(C)cs2)cc1Oc1cccc2ccccc12
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1csc(Nc2cc(Oc3cccc4ccccc34)c(C(=O)O)cn2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 65.4 %

Procedure:
Ethyl 6-(4-methylthiazol-2-ylamino)-4-(naphthalen-1-yloxy)nicotinate (1.00 g, 2.47 mmol) was dissolved in THF (5 mL). A solution of lithium hydroxide hydrate (0.207 g, 4.93 mmol) in water (1 mL) was added, and the reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated, 2M HCl was added to adjust the pH to 3. The reaction mixture was filtered to obtain the desired product (0.61 g, 65.5% yield) as a white solid. 1H NMR (d6-DMSO) δ 10.85 (bs, 1H), 8.76 (s, 1H), 8.06 (d, 1H), 7.88-7.93 (m, 2H), 7.55-7.65 (m, 3H), 7.35 (d, 1H), 6.58 (s, 1H), 6.32 (s, 1H), 2.14 (s, 3H).
Reaction SMILES: [CH2:1]([CH:6]1[O:11][C:10]2[CH:12]=[CH:13][C:14]([CH:16]=[CH:17][CH3:18])=[CH:15][C:9]=2[CH2:8][O:7]1)[CH2:2][CH2:3][CH2:4][CH3:5].[H][H]>C(O)C.[Pd]>[CH2:1]([CH:6]1[O:11][C:10]2[CH:12]=[CH:13][C:14]([CH2:16][CH2:17][CH3:18])=[CH:15][C:9]=2[CH2:8][O:7]1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: [H][H]
Reactant: CC=Cc1ccc2c(c1)COC(CCCCC)O2
Agent: [Pd]
Solvent: CCO
Product: CCCCCC1OCc2cc(CCC)ccc2O1

Procedure:
2.5 g of crude 2-pentyl-6-propenyl-1,3-benzodioxan are dissolved in 75 ml of ethanol and hydrogenated with 0.25 g of palladium/carbon (5% by weight) at room temperature until the hydrogen uptake comes to a standstill. The mixture is filtered and concentrated. The crude product is purified by chromatography on a column of 32 g of basic aluminium oxide with hexane/ether (9:1). Pure 2-pentyl-6-propyl-1,3-benzodioxan is obtained as a colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([N+:10]([O-:12])=[O:11])[CH:9]=1)[C:5]#[N:6].O.S(=O)(=O)(O)[OH:15].N>C(O)(C(F)(F)F)=O>[F:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([N+:10]([O-:12])=[O:11])[CH:9]=1)[C:5]([NH2:6])=[O:15]
Reactant: O=S(=O)(O)O
Reactant: N#Cc1cc(F)cc([N+](=O)[O-])c1
Agent: N
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: NC(=O)c1cc(F)cc([N+](=O)[O-])c1
Temperature: 70 °C
Reaction time: 24 h
Yield: 36 %

Procedure:
To a solution of 3-fluoro-5-nitrobenzonitrile (1.0 g, 6.02 mmoL) in TFA (8 mL) was added water (1 mL) and conc. sulfuric acid (2 mL). The reaction mixture was heated to 70° C. and stirred for 24 h. Then the reaction mixture was cooled to 0° C. and liquid ammonia solution was added. The solidified solid was filtered through Celite® (diatomaceous earth) and washed with water to obtain 3-fluoro-5-nitrobenzamide (0.400 g, 36%) as an off white solid. Observed mass (M−1): 183.02.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:31]=[CH:30][C:6]([CH2:7][S:8][C@@H:9]2[CH2:13][N:12]([C:14]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=3)=[O:15])[C@H:11]([C:27](O)=[O:28])[CH2:10]2)=[CH:5][CH:4]=1.[OH:32][CH2:33][CH2:34][N:35]1[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1>C(#N)C>[OH:32][CH2:33][CH2:34][N:35]1[CH2:40][CH2:39][N:38]([C:27]([C@@H:11]2[CH2:10][C@H:9]([S:8][CH2:7][C:6]3[CH:30]=[CH:31][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)[CH2:13][N:12]2[C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=2)=[O:15])=[O:28])[CH2:37][CH2:36]1
Reactant: OCCN1CCNCC1
Reactant: COc1ccc(CS[C@H]2C[C@@H](C(=O)O)N(C(=O)OCc3ccc([N+](=O)[O-])cc3)C2)cc1
Solvent: CC#N
Product: COc1ccc(CS[C@H]2C[C@@H](C(=O)N3CCN(CCO)CC3)N(C(=O)OCc3ccc([N+](=O)[O-])cc3)C2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 91.4 %

Procedure:
10.9 g of N,N'-carbonyldiimidazole were added to a solution of 25.0 g of (2S,4S)-4-(4-methoxybenzylthio)-1-(4-nitrobenzyloxycarbonyl)-2-pyrrolidinecarboxylic acid in 200 ml of anhydrous acetonirile, and the resulting mixture was stirred at room temperature for 1 hour. At the end of this time, a solution of 10.9 g of 1-(2-hydroxyethyl)piperazine in 50 ml of anhydrous acetonitrile was added to the mixture, which was then stirred at room temperature for 45 minutes. The reaction mixture was then concentrated by evaporation under reduced pressure, and the resulting residue was diluted with 800 ml of ethyl acetate and then washed, three times with 200 ml of water, and then once with 150 ml of an aqueous solution of sodium chloride. The ethyl acetate layer was concentrated by evaporation under reduced pressure to a volume of 100 ml, and the crystals which precipitated were collected by filtration, to give 28.6 g of the title compound as colorless crystals, melting at 140°-141 ° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[N:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[C:12]([CH2:19][OH:20])=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1.[C:21]1(O)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[N:14]=[C:13]([C:15]([F:17])([F:18])[F:16])[C:12]([CH2:19][O:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: OCc1cnc(Nc2cccc(Cl)c2)nc1C(F)(F)F
Reactant: Oc1ccccc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: FC(F)(F)c1nc(Nc2cccc(Cl)c2)ncc1COc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of {2-[(3-chlorophenyl)amino]-4-(trifluoromethyl)pyrimidin-5-yl}methanol (200 mg), phenol (70 μL), triphenyl phosphine (190 mg) and dichloromethane (4 mL) was added diethyl azodicarboxylate (330 pt), and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated and the obtained residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate). The obtained pale yellow solid was washed with ethanol-water to obtain N-(3-chlorophenyl)-5-(phenoxymethyl)-4-(trifluoromethyl)pyrimidin-2-amine (55 mg) as a white solid.