Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][C:18]=1[Cl:19])[O:5][CH:6]1[CH2:11][CH2:10][N:9]([CH2:12][CH2:13][CH2:14][NH2:15])[CH2:8][CH2:7]1.C(=O)([O-])[O-].[K+].[K+].[N:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[C:32]1[S:36][C:35]([S:37](Cl)(=[O:39])=[O:38])=[CH:34][CH:33]=1.O>CC(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][C:18]=1[Cl:19])[O:5][CH:6]1[CH2:7][CH2:8][N:9]([CH2:12][CH2:13][CH2:14][NH:15][S:37]([C:35]2[S:36][C:32]([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][N:26]=3)=[CH:33][CH:34]=2)(=[O:38])=[O:39])[CH2:10][CH2:11]1
Reactant: O=S(=O)(Cl)c1ccc(-c2ccccn2)s1
Reactant: NCCCN1CCC(Oc2ccc(Cl)c(Cl)c2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: O=S(=O)(NCCCN1CCC(Oc2ccc(Cl)c(Cl)c2)CC1)c1ccc(-c2ccccn2)s1
Reaction time: 0.17 h
Yield: 38.9 %

Procedure:
The product of Example 2, Step (b) (0.2 g) was dissolved in acetone (4 ml). Potassium carbonate [0.130 g dissolved in H2O (1 ml)] was then added, followed by 5-pyridin-2-yl-thiophene-2-sulfonyl chloride (0.171 g) and the reaction left to stir for 10 mins. Water was then added and the product extracted with ethyl acetate. The combined organic extracts dried, filtered and concentrated. Purification by reverse phase HPLC {with a gradient eluent system [30% MeCN/NH4OAcaq (0.1%) to 95% MeCN//NH4OAcaq (0.1%)]} gave the title compound as a solid (0.135 g).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[C:4]([O:9][CH2:10][O:11][CH3:12])[CH:3]=1.[CH2:13](N(CC)CC)[CH3:14].C(#N)C.C([Si](C)(C)C)#C>C(OCC)C.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:13]([C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[C:4]([O:9][CH2:10][O:11][CH3:12])[CH:3]=1)#[CH:14]
Reactant: CCN(CC)CC
Reactant: COCOc1cc(I)ccc1C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: C#C[Si](C)(C)C
Solvent: CCOCC
Solvent: CC#N
Product: C#Cc1ccc(C)c(OCOC)c1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
Argon was bubbled into a mixture of the 4-iodo-2-methoxymethoxy-1-methyl-benzene (7.63 g, 27.5 mmol) (from example 18 supra), triethylamine (55 mL) (Aldrich) and acetonitrile (100 mL) in a pressure reactor for 20 minutes at room temperature. Ethynyltrimethylsilane (9.2 mL, 64.5 mmol) (Aldrich), copper(I) iodide (245 mg, 1.28 mmol) (Aldrich) and dichlorobis(triphenylphosphine)palladium(II) (911 mg, 1.29 mmol) (Aldrich) were added. Reactor was capped and mixture heated at 100° C. for 5 hours with magnetic stirring. After cooling to room temperature, mixture was suspended in diethyl ether (250 mL) and water (250 mL) and filtered through Celite®. Layers were separated. Organic layer washed with water (250 mL) and brine (250 mL). Aqueous layers were back washed with ether (250 mL). Organic layers were combined, dried (MgSO4), filtered and concentrated. Residue was dissolved in methanol (50 mL) and potassium carbonate (500 mg) was added. Mixture was stirred at room temperature overnight. After concentrating, residue was partitioned between diethyl ether (2×250 mL) and water (2×250 mL). Organic layers were washed with brine (200 mL), combined, dried (MgSO4), filtered and concentrated. Residue was purified by flash chromatography (Biotage 40 L, hexanes, then hexanes-dichloromethane 9:1 and 3:1 as solvent) to give 4-ethynyl-2-methoxymethoxy-1-methyl-benzene as a brown oil. (Yield 4.65 g, 96.2%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][CH:8]([C:10]([N:12]3[CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14][CH2:13]3)=[O:11])[CH2:7][C:6]=2[CH:25]=1.FC(F)(F)C(O)=O.O.C(=O)(O)[O-].[Na+]>ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][CH:8]([C:10]([N:12]3[CH2:13][CH2:14][NH:15][CH2:16][CH2:17]3)=[O:11])[CH2:7][C:6]=2[CH:25]=1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)C2Cc3cc(Cl)ccc3O2)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(C1Cc2cc(Cl)ccc2O1)N1CCNCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 96.3 %

Procedure:
A solution of tert-butyl 4-[(5-chloro-2,3-dihydro-1-benzofuran-2-yl)carbonyl]piperazine-1-carboxylate (400 mg, 1.09 mmol) in dichloromethane (5 ml) was treated with trifluoroacetic acid (1 ml). The resulting solution was stirred for 2 h at room temperature and then concentrated under vacuum to give a residue. The crude material was dissolved into water (20 ml) and the pH was adjusted to ˜8 using aqueous sodium bicarbonate. The mixture was extracted with ethyl acetate (3×100 ml). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to afford 1-[(5-chloro-2,3-dihydro-1-benzofuran-2-yl)carbonyl]piperazine as light yellow oil (280 mg, 96%). (ES, m/z): [M+H]+ 267; 1H NMR (300 MHz, CDCl3): δ 7.20 (s, 1H), 7.05-7.11 (m, 1H), 6.70 (d, J=8.4 Hz, 1H), 5.46-5.55 (m, 1H), 3.85-3.95 (m, 3H), 3.53-3.63 (m, 2H), 3.25-3.35 (m, 1H), 2.90-3.05 (m, 4H).
Reaction SMILES: Br[C:2]1[O:6][C:5](/[CH:7]=[CH:8]/[NH:9][C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)=[O:11])=[CH:4][CH:3]=1.[Cl:18][C:19]1[CH:20]=[C:21](B(O)O)[CH:22]=[CH:23][C:24]=1[Cl:25].[O-]P([O-])([O-])=O.[K+].[K+].[K+].O>O1CCOCC1.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[Cl:18][C:19]1[CH:20]=[C:21]([C:2]2[O:6][C:5](/[CH:7]=[CH:8]/[NH:9][C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=3)=[O:11])=[CH:4][CH:3]=2)[CH:22]=[CH:23][C:24]=1[Cl:25]
Reactant: O=C(N/C=C/c1ccc(Br)o1)c1ccccn1
Reactant: OB(O)c1ccc(Cl)c(Cl)c1
Agent: [Pd]
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: O=C(N/C=C/c1ccc(-c2ccc(Cl)c(Cl)c2)o1)c1ccccn1

Procedure:
Pyridine-2-carboxylic acid [(E)-2-(5-bromofuran-2-yl)vinyl]amide (0.014 g, 0.0477 mmol) was dissolved in 1,4-dioxane (4.2 ml) in a microwave reaction vial. 3,4-Dichlorophenylboronic acid (0.0091 g, 0.0477 mmol), potassium phosphate tribasic (0.020 g, 0.0954 mmol), 0.7 ml of water and tetrakis(triphenylphosphine)-palladium(0) (0.005 g, 0.0047 mmol) were added. After removal of oxygen the reaction mixture was irradiated for 10 min at 160° C. Then water (7 ml) was added. The product was extracted into EtOAc (2×15 ml). The organic phase was washed with water, dried over Na2SO4 and evaporated. The crude product was purified by flash chromatography (eluent: heptane-EtOAc 7:3). 1H NMR (400 MHz, CDCl3): 6.26 (1H, d), 6.29 (1H, d), 6.66 (1H, d), 7.45 (1H, distorted d), 7.48-7.52 (2H, m), 7.69-7.76 (2H, m), 7.91 (1H, td), 8.27 (1H, d), 8.61 (1H, dd), 9.88 (1H, d).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([CH:14]=[CH:15][C:16]=1[Cl:17])[CH2:6][N:7]1[CH2:12][CH2:11][CH:10]([NH2:13])[CH2:9][CH2:8]1.Cl[C:19](=[O:26])[CH2:20][CH2:21][C:22]([O:24][CH3:25])=[O:23].C(N(CC)CC)C.C(=O)([O-])O.[Na+]>ClCCl>[Cl:2][C:3]1[CH:4]=[C:5]([CH:14]=[CH:15][C:16]=1[Cl:17])[CH2:6][N:7]1[CH2:8][CH2:9][CH:10]([NH:13][C:19](=[O:26])[CH2:20][CH2:21][C:22]([O:24][CH3:25])=[O:23])[CH2:11][CH2:12]1
Reactant: COC(=O)CCC(=O)Cl
Reactant: NC1CCN(Cc2ccc(Cl)c(Cl)c2)CC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)CCC(=O)NC1CCN(Cc2ccc(Cl)c(Cl)c2)CC1
Reaction time: 2 h
Yield: 67.9 %

Procedure:
To a solution of 1-(3,4-dichlorobenzyl)-4-piperidinamine hydrochloride (3.50 g) in dichloromethane (100 ml) was added methyl 4-chloro-4-oxobutanoate (2.00 g) dropwise. Triethlamine (3.90 g) was added and the reaction stirred under nitrogen for 2 hours. Saturated sodium hydrogen carbonate solution was then added, with the solution being extracted three times with dichloromethane. The pooled organic phase was washed once with water, once with saturated brine and dried over anhydrous magnesium sulfate. After filtration the solvent was removed under reduced pressure to leave methyl 4-{[1-(3,4-dichlorobenzyl)-4-piperidinyl]amino}-4-oxobutanoate (3.00 g).
Reaction SMILES: Br[CH2:2][CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1.[NH:13]1[CH:17]=[CH:16][CH:15]=[N:14]1>O1CCOCC1>[N:13]1([CH2:2][CH2:3][C:4]2[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[NH:6][CH:5]=2)[CH:17]=[CH:16][CH:15]=[N:14]1
Reactant: BrCCc1c[nH]c2ccccc12
Reactant: c1cn[nH]c1
Solvent: C1COCCO1
Product: c1ccc2c(CCn3cccn3)c[nH]c2c1

Procedure:
A solution of 3-(2-bromo-ethyl)-1H-indole (2.24 g, 10 mmol) and pyrazole (1.36 g, 20 mmol) in abs. dioxane (20 ml) was stirred at 80° C. for 16 h. The solvent was then removed i. vac., CHCl3 (100 ml) was added to the residue and the mixture was washed twice with water. The organic phase was dried over Na2SO4 and concentrated i. vac. and the residue which remained was purified by flash chromatography with CHCl3/MeOH (50:1).
Reaction SMILES: [CH:1]1([S:4]([NH:7][C:8](=[O:15])[CH2:9][C:10]([O:12]CC)=[O:11])(=[O:6])=[O:5])[CH2:3][CH2:2]1.O.[OH-].[Li+].Cl>C1COCC1.O>[CH:1]1([S:4]([NH:7][C:8](=[O:15])[CH2:9][C:10]([OH:12])=[O:11])(=[O:6])=[O:5])[CH2:3][CH2:2]1
Reactant: CCOC(=O)CC(=O)NS(=O)(=O)C1CC1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)CC(=O)NS(=O)(=O)C1CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 94.6 %

Procedure:
A mixture of ethyl 3-(cyclopropanesulfonamido)-3-oxopropanoate (0.48 g, 2.04 mmol) and lithium hydroxide monohydrate (0.17 g, 4.08 mmol) in THF (5 mL) and water (3 mL) was stirred at rt overnight. The pH of the reaction solution was adjusted to ˜6 by using 1N HCl and extracted with EtOAc (3×). Aq. layer was then saturated using ammonium sulfate and extracted with EtOAc (3×), dried (MgSO4), and concentrated to give 3-(cyclopropanesulfonamido)-3-oxopropanoic acid (0.4 g, 1.93 mmol, 95% yield) as a light brown solid. LCMS Anal. Calc'd for C6H9NO5S 207.02. found [M+H] 207.9.
Reaction SMILES: [F:1][C:2]1[C:10]([C:11]([F:14])([F:13])[F:12])=[N:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH:15]12[CH:23]([N:24]3[CH2:27][C:26]([CH2:50][C:51]#[N:52])([N:28]4[CH:32]=[C:31]([C:33]5[C:34]6[CH:41]=[CH:40][N:39](COCC[Si](C)(C)C)[C:35]=6[N:36]=[CH:37][N:38]=5)[CH:30]=[N:29]4)[CH2:25]3)[CH:19]([CH2:20][NH:21][CH2:22]1)[CH2:18][O:17][CH2:16]2.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C=O)C>[F:1][C:2]1[C:10]([C:11]([F:14])([F:13])[F:12])=[N:9][CH:8]=[CH:7][C:3]=1[C:4]([N:21]1[CH2:20][CH:19]2[CH:23]([N:24]3[CH2:25][C:26]([CH2:50][C:51]#[N:52])([N:28]4[CH:32]=[C:31]([C:33]5[C:34]6[CH:41]=[CH:40][NH:39][C:35]=6[N:36]=[CH:37][N:38]=5)[CH:30]=[N:29]4)[CH2:27]3)[CH:15]([CH2:16][O:17][CH2:18]2)[CH2:22]1)=[O:6]
Reactant: O=C(O)c1ccnc(C(F)(F)F)c1F
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C4(CC#N)CN(C5C6CNCC5COC6)C4)c3)ncnc21
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: N#CCC1(n2cc(-c3ncnc4[nH]ccc34)cn2)CN(C2C3COCC2CN(C(=O)c2ccnc(C(F)(F)F)c2F)C3)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 35.1 %

Procedure:
To a mixture of 3-fluoro-2-(trifluoromethyl)isonicotinic acid (50.0 mg, 0.239 mmol) and {1-(3-oxa-7-azabicyclo[3.3.1]non-9-yl)-3-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile (128 mg, 0.239 mmol) in DMF (2 mL) were added triethylamine (0.100 mL, 0.717 mmol) and benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (127 mg, 0.287 mmol). The mixture was stirred at room temperature for 2 hours. Direct purification with prep-LCMS (pH=10) afforded 50 mg (30% yield) of the desired product. LCMS found: 696.3 (M+1)+.
Reaction SMILES: C[O:2][C:3](=[O:17])[C:4]1[CH:9]=[C:8]([Cl:10])[C:7]([NH2:11])=[CH:6][C:5]=1[O:12][CH2:13][CH2:14][O:15][CH3:16].[OH-].[Na+].O>C(O)C>[NH2:11][C:7]1[C:8]([Cl:10])=[CH:9][C:4]([C:3]([OH:17])=[O:2])=[C:5]([O:12][CH2:13][CH2:14][O:15][CH3:16])[CH:6]=1
Reactant: COCCOc1cc(N)c(Cl)cc1C(=O)OC
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: COCCOc1cc(N)c(Cl)cc1C(=O)O
Yield: 78 %

Procedure:
A solution of the ester (2.75 g, 0.0106 mole) in 95% ethanol (20 ml) was treated with 50% sodium hydroxide (10 ml) and water (10 ml), and refluxed for one hour. The ethanol was removed in vacuo and replaced with water, and the aqueous solution was extracted with ether (20 ml) and adjusted to pH~4 with concentrated hydrochloric acid (16 ml). A solid soon precipitated, and this was filtered, washed with water, air dried, and recrystallized from ethyl acetate (2 crops) to afford 2.03 g (78%) of the title compound as fine pale tan needles; mp 119°-120° C.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[NH2:6].C[Si](CCOCCl)(C)C.[CH3:16][O:17][C:18]1[CH:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:21]=[CH:20][C:19]=1[C:28]1[C:37]2[C:32](=[CH:33][C:34]([S:38](Cl)(=[O:40])=[O:39])=[CH:35][CH:36]=2)[CH:31]=[N:30][N:29]=1.CN1C=CN=C1>CC#N>[CH3:16][O:17][C:18]1[CH:23]=[C:22]([C:24]([F:25])([F:26])[F:27])[CH:21]=[CH:20][C:19]=1[C:28]1[C:37]2[C:32](=[CH:33][C:34]([S:38]([NH:6][C:2]3[S:1][CH:5]=[CH:4][N:3]=3)(=[O:40])=[O:39])=[CH:35][CH:36]=2)[CH:31]=[N:30][N:29]=1
Reactant: COc1cc(C(F)(F)F)ccc1-c1nncc2cc(S(=O)(=O)Cl)ccc12
Reactant: Nc1nccs1
Agent: C[Si](C)(C)CCOCCl
Agent: Cn1ccnc1
Solvent: CC#N
Product: COc1cc(C(F)(F)F)ccc1-c1nncc2cc(S(=O)(=O)Nc3nccs3)ccc12
Reaction time: 1 h

Procedure:
A solution of thiazol-2-amine (0.027 g, 0.273 mmol) in 3 mL of MeCN was treated with SEM-Cl (0.048 ml, 0.273 mmol), and the reaction mixture was allowed to stir for one hour. LC/MS showed mostly product, so 1-(2-methoxy-4-(trifluoromethyl)phenyl)phthalazine-6-sulfonyl chloride (Intermediate BBBB; 0.100 g, 0.248 mmol) was added as a solution in 3 mL of MeCN, followed by 1-methylimidazole (0.049 ml, 0.497 mmol). After stirring at room temperature for an additional hour, LC/MS showed mostly desired product. The reaction mixture was concentrated then dissolved in 4N HCl in dioxanes (1.862 ml, 7.45 mmol), and the reaction mixture was heated to 110° C. for 3 hours. The reaction mixture was concentrated and was purified by reverse phase column chromatography [C18 50 g, 10 to 100% (0.1% NH4OH in MeOH)/(0.1% NH4OH in water)] to yield 1-(2-methoxy-4-(trifluoromethyl)phenyl)-n-(thiazol-2-yl)phthalazine-6-sulfonamide. 1H NMR (acetonitrile-d3) δ ppm: 9.70 (s, 1H), 8.63 (s, 1H), 8.20 (d, J=8.7 Hz, 1H), 7.71 (d, J=8.7 Hz, 1H), 7.62 (d, J=7.7 Hz, 1H), 7.45-7.53 (m, 2H), 7.02 (d, J=4.7 Hz, 1H), 6.65 (d, J=4.7 Hz, 1H), 3.75 (s, 3H). m/z (ESI) 467.0 (M+H)+
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][CH:26]=[CH:25][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]([NH:15][CH2:16][CH:17]([OH:24])[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=O)=[CH:9][CH:8]=1)=[O:5].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.S(=O)(=O)(O)[O-].[Na+]>CN(C=O)C.C(OCC)(=O)C>[Cl:1][C:2]1[CH:28]=[CH:27][CH:26]=[CH:25][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[O:24][C:17]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)=[CH:16][N:15]=2)=[CH:9][CH:8]=1)=[O:5]
Reactant: O=C(NCC(O)c1ccccc1)c1ccc(NC(=O)c2ccccc2Cl)cc1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C(Nc1ccc(-c2ncc(-c3ccccc3)o2)cc1)c1ccccc1Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 168.1 %

Procedure:
under an N2 atmosphere, 2-chloro-N-(4-(((2-hydroxy-2-phenylethyl)amino)carbonyl)phenyl)benzamide (0.578 g, 1.46 mmol) was dissolved in DMF (7.00 ml). Dess-Martin periodinane (0.745 g, 1.76 mmol) was added and the reaction was stirred at room temperature for 3 hours. The reaction was diluted with ethyl acetate and a saturated aqueous solution of sodium bisulfate. The layers were separated and the organic layer was washed with water and brine. The organic layer was dried (Na2SO4), filtered and concentrated in vacuo. The residue was triturated with ethyl acetate and hexanes. The resulting solid was collected by filtration. The solid was suspended in pyridine (8.00 ml) and POCl3 (4.00 ml). The reaction was heated to 70° C. for 3 hours. The reaction was poured into a cooled 5% NaHCO3 solution and stirred vigorously for 15 minutes. The mixture was then extracted with ethyl acetate. The organic layer was dried (Na2SO4), filtered and concentrated in vacuo. The crude residue was purified by column chromatography eluting with 25% to 50% ethyl acetate in hexanes. The resulting solid was triturated with ethyl acetate/hexanes and collected by filtration to afford 2-chloro-N-(4-(5-phenyloxazol-2-yl)phenyl)benzamide (0.920 g, 16.8%). ESI m/z=375.0 (M+H+).
Reaction SMILES: [Br:1][CH:2]1[CH2:38][C@@H:37]([CH3:39])[CH2:36][O:35][C@@:3]21[C@@H:7]([CH3:8])[C@@H:6]1[C@:9]3([CH3:34])[C@@H:22]([CH2:23][C@@H:5]1[O:4]2)[C@H:21]1[C@@H:12]([C@:13]2([CH3:25])[C@@H:18]([CH2:19][CH2:20]1)[CH2:17][C@@H:16]([OH:24])[CH2:15][CH2:14]2)[C@@H:11]([OH:26])[C@@H:10]3[O:27]C(=O)C(Cl)(Cl)Cl.[OH-].[Na+]>O.C(O)C>[Br:1][CH:2]1[CH2:38][C@@H:37]([CH3:39])[CH2:36][O:35][C@@:3]21[C@@H:7]([CH3:8])[C@@H:6]1[C@:9]3([CH3:34])[C@@H:22]([CH2:23][C@@H:5]1[O:4]2)[C@H:21]1[C@@H:12]([C@:13]2([CH3:25])[C@@H:18]([CH2:19][CH2:20]1)[CH2:17][C@@H:16]([OH:24])[CH2:15][CH2:14]2)[C@@H:11]([OH:26])[C@@H:10]3[OH:27]
Reactant: C[C@H]1CO[C@@]2(O[C@H]3C[C@H]4[C@@H]5CC[C@H]6C[C@@H](O)CC[C@]6(C)[C@H]5[C@@H](O)[C@H](OC(=O)C(Cl)(Cl)Cl)[C@]4(C)[C@H]3[C@@H]2C)C(Br)C1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: C[C@H]1CO[C@@]2(O[C@H]3C[C@H]4[C@@H]5CC[C@H]6C[C@@H](O)CC[C@]6(C)[C@H]5[C@@H](O)[C@H](O)[C@]4(C)[C@H]3[C@@H]2C)C(Br)C1

Procedure:
Using the procedure described in J. Chem. Soc., 1956, 4330, (3β,5α,11β,12α,25R)-23-bromo-12-(trichloroacetoxy)spirostan-3,11-diol was saponifled with sodium hydroxide in water and ethanol to give the title compound.
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[NH:13][C:12]2[C:7](=[N:8][CH:9]=[CH:10][CH:11]=2)[C:6]=1[S:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:4].[CH3:21]OS(OC)(=O)=O>CN(C=O)C>[CH3:1][NH:2][C:3]([C:5]1[N:13]([CH3:21])[C:12]2[C:7](=[N:8][CH:9]=[CH:10][CH:11]=2)[C:6]=1[S:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:4]
Reactant: CNC(=O)c1[nH]c2cccnc2c1Sc1ccccc1
Reactant: COS(=O)(=O)OC
Solvent: CN(C)C=O
Product: CNC(=O)c1c(Sc2ccccc2)c2ncccc2n1C

Procedure:
Treat 3-phenylsulfanyl-1H-pyrrolo[3,2-b]pyridine-2-carboxylic acid methylamide Ia-33 (1.0 equiv) in DMF with dimethylsulfate (1.5 equiv) as described in General Synthetic Procedure V to provide Ia-29 as an ivory colored solid, MS Obs 298.09 (M+1).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:12]2[C:13]([F:28])=[CH:14][C:15]([N+:25]([O-])=O)=[C:16]([CH:24]=2)[O:17][CH2:18][C:19]([O:21]CC)=O)=[N:4][N:5]([CH3:11])[C:6]=1[C:7]([F:10])([F:9])[F:8]>C(O)(=O)C.[Fe]>[Cl:1][C:2]1[C:3]([C:12]2[C:13]([F:28])=[CH:14][C:15]3[NH:25][C:19](=[O:21])[CH2:18][O:17][C:16]=3[CH:24]=2)=[N:4][N:5]([CH3:11])[C:6]=1[C:7]([F:10])([F:8])[F:9]
Reactant: CCOC(=O)COc1cc(-c2nn(C)c(C(F)(F)F)c2Cl)c(F)cc1[N+](=O)[O-]
Agent: [Fe]
Solvent: CC(=O)O
Product: Cn1nc(-c2cc3c(cc2F)NC(=O)CO3)c(Cl)c1C(F)(F)F
Temperature: 80 °C
Reaction time: 0.83 h
Yield: 50.8 %

Procedure:
A solution of 2.3 g (5.4 mmole) (5-(4-chloro-1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl)-4-fluoro-2-nitrophenoxy)acetic acid, ethyl ester in 50 mL acetic acid was heated to 80° C. under a nitrogen atmosphere. The heat and nitrogen were removed and 0.9 g (16.2 mmole) iron powder was added in 3 portions over 5 minutes. The solution was stirred at 80° C. for an additional 50 minutes. The solution was cooled and filtered through Celite®. The filtrate was diluted with 100 mL water and extracted three times with ethyl acetate. The ethyl acetate extracts were washed with a saturated NaHCO3 solution, dried over anhydrous MgSO4 and concentrated in vacuo. The residue was recrystallized from methylcyclohexane/ethyl acetate to give 0.96 g (50%) of 7-(4-chloro-1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl)-6-fluoro-2H-1,4-benzoxazin-3(4H)-one as a white solid, mp 242° C.
Reaction SMILES: [CH:1]([C:4]1[CH:10]=[C:9](C(C)C)[CH:8]=[CH:7][C:5]=1[NH2:6])([CH3:3])[CH3:2].C(C1C=CC(C(C)C)=CC=1N)(C)C>>[CH:1]([C:4]1[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=1[NH2:6])([CH3:3])[CH3:2]
Reactant: CC(C)c1ccc(N)c(C(C)C)c1
Agent: CC(C)c1ccc(C(C)C)c(N)c1
Product: CC(C)c1ccccc1N

Procedure:
If the procedure described above is used, but replacing the 2,4-diisopropylaniline by the same amount of 2,5-diisopropylaniline or by 99 parts of 2-isopropylaniline, perylenetetracarboxylic acid N,N'-bis-(2',5'-diisopropylanilide) and N,N'-bis-(2'-isopropylanilide), respectively, are obtained in very good yield.
Reaction SMILES: Cl.[C:2]([O:6][C:7](=[O:25])[C@@H:8]([NH2:24])[CH2:9][NH:10][C:11]([C:13]1[S:14][C:15]([CH2:18][CH2:19][C:20]([O:22][CH3:23])=[O:21])=[CH:16][CH:17]=1)=[O:12])([CH3:5])([CH3:4])[CH3:3].C(N(CC)CC)C.[C:33]([C:37]1[CH:42]=[CH:41][C:40]([S:43](Cl)(=[O:45])=[O:44])=[CH:39][CH:38]=1)([CH3:36])([CH3:35])[CH3:34]>ClCCl>[C:2]([O:6][C:7](=[O:25])[C@@H:8]([NH:24][S:43]([C:40]1[CH:41]=[CH:42][C:37]([C:33]([CH3:36])([CH3:35])[CH3:34])=[CH:38][CH:39]=1)(=[O:45])=[O:44])[CH2:9][NH:10][C:11]([C:13]1[S:14][C:15]([CH2:18][CH2:19][C:20]([O:22][CH3:23])=[O:21])=[CH:16][CH:17]=1)=[O:12])([CH3:5])([CH3:3])[CH3:4]
Reactant: COC(=O)CCc1ccc(C(=O)NC[C@H](N)C(=O)OC(C)(C)C)s1
Reactant: CC(C)(C)c1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)CCc1ccc(C(=O)NC[C@H](NS(=O)(=O)c2ccc(C(C)(C)C)cc2)C(=O)OC(C)(C)C)s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 51.6 %

Procedure:
A solution of 0.395 g (1 mmol) of (2S)-2-amino-3-((5-(2-methoxycarbonyl-ethyl)-thiophene-2-carbonyl)-amino)-propionic acid tert-butyl ester hydrochloride (example 15, step a) and triethylamine (0.15 ml, 1.1 mmol) in dichloromethane (10 ml) was cooled to 0° C. in an ice bath and a solution of 0.255 g (1.1 mmol) of 4-tert-butylphenylsulfonyl chloride in dichloromethane (5 ml) was added. Then the reaction mixture was stirred at room temperature overnight. After removal of the solvent in vacuo the residue was absorbed onto silica gel and chromatographed with ethyl acetate/cyclohexane (1/1) to yield 0.285 g (52%) of the title compound as a white amorphous solid.
Reaction SMILES: C(S[C:9]1[S:10][C:11]([CH2:14][N:15]2[C:20](=[N:21][N+:22]([O-:24])=[O:23])[N:19]([CH3:25])[CH2:18][O:17][CH2:16]2)=[CH:12][N:13]=1)C1C=CC=CC=1.[Cl:26]CCl.[O-]Cl.[Na+]>Cl>[Cl:26][C:9]1[S:10][C:11]([CH2:14][N:15]2[C:20](=[N:21][N+:22]([O-:24])=[O:23])[N:19]([CH3:25])[CH2:18][O:17][CH2:16]2)=[CH:12][N:13]=1
Reactant: CN1COCN(Cc2cnc(SCc3ccccc3)s2)C1=N[N+](=O)[O-]
Reactant: ClCCl
Agent: Cl
Agent: [Na+]
Agent: [O-]Cl
Product: CN1COCN(Cc2cnc(Cl)s2)C1=N[N+](=O)[O-]
Temperature: 0 °C

Procedure:
2 g of 3-(2-benzylthiothiazol-5-ylmethyl)-5-methyl-4-nitroimino-perhydro-1,3,5-oxadiazine are dissolved in a mixture of 10 ml of 4N aqueous hydrochloric acid, 20 g of ice and 30 ml of dichloromethane, and 30 g of Javelle water are added dropwise with stirring to the solution. After stirring for a further 30 minutes, the organic phase is separated off, the aqueous phase is extracted repeatedly with a little dichloromethane, and the combined organic phases are subsequently dried with sodium sulphate and evaporated under reduced pressure. The oily residue is dissolved in tetrahydrofuran and precipitated with hexane, whereby the product deposits on the walls of the vessel as a sticky material. The solvent is decanted, the residue is redissolved in tetrahydrofuran, and the solution is slowly concentrated, yielding 0.84 g of the title compound in the form of a semi-crystalline resin. A sample of this resin is purified by chromatography [silica gel; dichloromethane/methanol (95:5)], yielding crystals melting at 132 to 135°.