Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH:10]([C:14]([OH:27])([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:9]1)=[O:7])([CH3:4])[CH3:3].[C:28](=O)([O-])[O-:29].[K+].[K+].C(Cl)(=O)OCC>CN(C)C=O>[CH3:4][C:2]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]2[C:28](=[O:29])[O:27][C:14]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH:10]2[CH2:9]1)=[O:7])([CH3:1])[CH3:3]
Reactant: O=C([O-])[O-]
Reactant: CC(C)(C)OC(=O)N1CCNC(C(O)(c2ccccc2)c2ccccc2)C1
Agent: CCOC(=O)Cl
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN2C(=O)OC(c3ccccc3)(c3ccccc3)C2C1
Temperature: 50 °C
Reaction time: 16 h
Yield: 67.3 %

Procedure:
To a solution of (1,1-dimethylethyl)3-(hydroxydiphenylmethyl)-1-piperazine carboxylate (9.6 g, 26 mmol) in N,N-dimethylformamide (180 mL) were added potassium carbonate (20 g, 0.14 mol) and ethyl chlorocarbonate (14 g, 0.26 mol), and the mixture was stirred at 50° C. for 16 hours. To the reaction solution were further added potassium carbonate (20 g, 0.14 mol) and ethyl chlorocarbonate (14 g, 0.26 mol), and the mixture was further stirred at 50° C. for 18 hours. To the reaction solution was added ice water, and the mixture was extracted with ethyl acetate. The extract was washed with water and concentrated under reduced pressure. The residue was purified with silica gel column chromatography (hexane:ethyl acetate=3:1) to obtain the title compound (6.9 g, yield 64%) as a solid.
Reaction SMILES: C([N:4]1[CH2:9][CH2:8][C:7]([C:11](=[O:20])[C:12]2[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=2[F:19])([OH:10])[CH2:6][CH2:5]1)(=O)C>Cl>[F:19][C:13]1[CH:14]=[CH:15][C:16]([F:18])=[CH:17][C:12]=1[C:11]([C:7]1([OH:10])[CH2:8][CH2:9][NH:4][CH2:5][CH2:6]1)=[O:20]
Reactant: CC(=O)N1CCC(O)(C(=O)c2cc(F)ccc2F)CC1
Agent: Cl
Product: O=C(c1cc(F)ccc1F)C1(O)CCNCC1
Temperature: 0 °C
Yield: 91.3 %

Procedure:
A suspension of 5.66 g of 1-acetyl-4-(2,5-difluorobenzoyl)-4-hydroxypiperidine in 10 ml of 6N hydrochloric acid was stirred at reflux, under nitrogen for 3.5 hrs. The reaction mixture was allowed to cool to 0° C. whereupon a solid separated. The solid was collected, washed with ice-cold acetone and dried to give 4.4 g (80%) of product, mp 191°-193° C.
Reaction SMILES: Cl[C:2]([Cl:12])(OC(=O)OC(Cl)(Cl)Cl)Cl.OC[CH:15]1[CH2:21][S:20][CH2:19][C:18](=[CH2:22])[CH2:17][S:16]1.C(N(CC)CC)C>ClCCl>[Cl:12][CH2:2][CH:15]1[CH2:21][S:20][CH2:19][C:18](=[CH2:22])[CH2:17][S:16]1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: C=C1CSCC(CO)SC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=C1CSCC(CCl)SC1
Reaction time: 1 h
Yield: 198.9 %

Procedure:
Triphosgene (0.843 g, 2.84 mmoles) was dissolved in 20 mL of dichloromethane. 2-(Hydroxymethyl)-6-methylene-1,4-dithiepane (1.5 g, 8.52 mmoles) and triethyl amine (1.185 mL, 0.86 g) were dissolved in ca. 5 mL of dichloromethane and added dropwise to the triphosgene solution. After ca. one hour the reaction was largely complete. A little more triphosgene was added and the solution was stirred overnight. The reaction was worked up by evaporation of solvent, addition of water and extraction with ether, The extracts were dried and evaporated and the resulting oil was chromatographed on silica gel to give 1.1 g (67%) of clear oil.
Reaction SMILES: C(O[C:4]([CH:6]1[CH2:11][NH:10][C:9]2[CH:12]=[CH:13][CH:14]=[CH:15][C:8]=2[O:7]1)=[O:5])C.[CH2:16]([NH2:20])[CH2:17][CH2:18][CH3:19]>>[CH2:16]([NH:20][C:4]([CH:6]1[CH2:11][NH:10][C:9]2[CH:12]=[CH:13][CH:14]=[CH:15][C:8]=2[O:7]1)=[O:5])[CH2:17][CH2:18][CH3:19]
Reactant: CCCCN
Reactant: CCOC(=O)C1CNc2ccccc2O1
Product: CCCCNC(=O)C1CNc2ccccc2O1
Temperature: 60 °C
Reaction time: 1 h

Procedure:
A mixture of 600 mg of 2(R,S)-ethoxycarbonyl-3,4-dihydro-2H-1,4-benzoxazine (Example 16)) and 1.2 ml of butylamine is stirred at 60° C. for 1 h. The reaction mixture is concentrated and the residue is purified directly by means of FC over 50 g of silica gel with a 20:1 mixture of methylene chloride and diethyl ether as the mobile phase. 2(R,S)-Butylaminocarbonyl-3,4-dihydro-2H-1,4-benzoxazine is obtained: Rf (20:1-mixture of methylene chloride and diethyl ether)=0.32.
Reaction SMILES: [OH:1][CH:2]1[CH:9]2[CH2:10][C:5]3([C:12]([O:14][CH3:15])=[O:13])[CH2:6][CH:7]([CH2:11][CH:3]1[CH2:4]3)[CH2:8]2.N1C=CC=CC=1.[Cl:22][C:23](Cl)([O:25]C(=O)OC(Cl)(Cl)Cl)Cl>C(Cl)Cl>[Cl:22][C:23]([O:1][CH:2]1[CH:9]2[CH2:10][C:5]3([C:12]([O:14][CH3:15])=[O:13])[CH2:6][CH:7]([CH2:11][CH:3]1[CH2:4]3)[CH2:8]2)=[O:25]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COC(=O)C12CC3CC(C1)C(O)C(C3)C2
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)C12CC3CC(C1)C(OC(=O)Cl)C(C3)C2
Temperature: 25 °C
Reaction time: 3 h
Yield: 272.7 %

Procedure:
A stirred solution of methyl 4-hydroxyadamantane-1-carboxylate (1.01 g, 4.8 mmol) and pyridine (0.38 mL, 4.8 mmol) in CH2Cl2 (25 mL) was cooled in an ice bath and a solution of triphosgene (0.48 g, 1.6 mmol) in CH2Cl2 (10 mL) was added dropwise over 15 min. The ice bath was allowed to melt and the mixture was stirred for 3 h at rt.* The mixture was evaporated to dryness and the residue was triturated with EtOAc (100 mL). The filtrate was concentrated to afford 1-(methoxycarbonyl)-4-adamantyl chloroformate (1.19 g, 91%) as an oil. [* In some experiments the solution of 1-(methoxycarbonyl)-4-adamantyl chloroformate was used directly.]
Reaction SMILES: O[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[NH:12][C:13](=[O:24])[C:14]1[CH:19]=[C:18]([N+:20]([O-:22])=[O:21])[CH:17]=[CH:16][C:15]=1[F:23].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>>[N+:20]([C:18]1[CH:19]=[C:14]([C:13]2[O:24][C:2]3[CH:7]=[CH:6][C:5]([C:8]([F:10])([F:9])[F:11])=[CH:4][C:3]=3[N:12]=2)[C:15]([F:23])=[CH:16][CH:17]=1)([O-:22])=[O:21]
Reactant: O=C(Nc1cc(C(F)(F)F)ccc1O)c1cc([N+](=O)[O-])ccc1F
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Product: O=[N+]([O-])c1ccc(F)c(-c2nc3cc(C(F)(F)F)ccc3o2)c1

Procedure:
Prepared by the method of Example 15b), from N-(2-hydroxy-5-trifluoromethylphenyl)-2-fluoro-5-nitrobenzamide (667 g, 2.3 mmol) and p-toluenesulfonic acid monohydrate (961 g, 5.1 mmol) the subtitle compound was obtained (349 mg, 56%). 1H NMR (DMSO) δ 8.95(m, 1H), 8.56(m, 1H), 8.36(s, 1H), 8.12(d, 1H), 7.84(m, 2H).
Reaction SMILES: CS(C)=O.O1CCCC1.[F:10][C:11]1[CH:12]=[CH:13][C:14]([CH2:17][O:18][C:19]2[CH:24]=[CH:23][C:22](/[CH:25]=[CH:26]/[N+:27]([O-:29])=[O:28])=[C:21]([F:30])[CH:20]=2)=[N:15][CH:16]=1.[BH4-].[Na+]>O.C(O)(=O)C>[F:10][C:11]1[CH:12]=[CH:13][C:14]([CH2:17][O:18][C:19]2[CH:24]=[CH:23][C:22]([CH2:25][CH2:26][N+:27]([O-:29])=[O:28])=[C:21]([F:30])[CH:20]=2)=[N:15][CH:16]=1
Reactant: O=[N+]([O-])/C=C/c1ccc(OCc2ccc(F)cn2)cc1F
Agent: [BH4-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: O=[N+]([O-])CCc1ccc(OCc2ccc(F)cn2)cc1F
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 34.4 %

Procedure:
To a dimethyl sulfoxide (20.0 mL)-tetrahydrofuran (5.00 mL) solution of 5-fluoro-2-(3-fluoro-4-((E)-2-nitro-vinyl)-phenoxymethyl)-pyridine (1.00 g, 3.42 mmol) described in Manufacturing Example 96-1-2 and acetic acid (1.00 mL) was added sodium borohydride (207 mg, 5.47 mmol) at room temperature while cooling appropriately under nitrogen atmosphere, which was stirred for 10 minutes at room temperature. Water was then added dropwise at room temperature while cooling appropriately. The reaction mixture was extracted with ethyl acetate, and the organic layer was washed with water and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure, and the residue was crystallized with an ethyl acetate:heptane system and filtered to obtain the title compound (346 mg, 34.4%).
Reaction SMILES: ClC1C=C(C(F)(F)F)C=C(Cl)C=1C1N(C)N=C(SC)C=1.[Cl:21][C:22]1[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[C:24]([Cl:32])[C:23]=1[C:33]1[N:37]([CH3:38])[N:36]=[C:35]([S:39]([CH3:41])=[O:40])[CH:34]=1.ClC1C=CC=C(C(OO)=[O:50])C=1.S([O-])([O-])=O.[Na+].[Na+]>C(Cl)(Cl)Cl>[Cl:32][C:24]1[CH:25]=[C:26]([C:28]([F:31])([F:29])[F:30])[CH:27]=[C:22]([Cl:21])[C:23]=1[C:33]1[N:37]([CH3:38])[N:36]=[C:35]([S:39]([CH3:41])(=[O:50])=[O:40])[CH:34]=1
Reactant: Cn1nc(S(C)=O)cc1-c1c(Cl)cc(C(F)(F)F)cc1Cl
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: CSc1cc(-c2c(Cl)cc(C(F)(F)F)cc2Cl)n(C)n1
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: Cn1nc(S(C)(=O)=O)cc1-c1c(Cl)cc(C(F)(F)F)cc1Cl
Reaction time: 8 h

Procedure:
To a solution of 0.2 g of 5-(2,6-dichloro-4-trifluoromethylphenyl)-1-methyl-3-methylsulfenylpyrazole (compound 40) in 20 ml of anhydrous chloroform was slowly added 0.3 g of 70% m-chloroperbenzoic acid at room temperature, followed by stirring overnight. The reaction mixture was poured into 10% aqueous sodium sulfite solution, and the organic layer was separated off, washed with 5% aqueous sodium hydroxide solution and brine and dried over anhydrous magnesium sulfate. The solvent was thereafter distilled of under reduced pressure to give 0.3 g of the desired compound in the form of white crystals (quantitative crude yield).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[CH2:14][CH2:13][S:12](=[O:16])(=[O:15])[CH2:11][CH2:10]1.[N+:17]([O-])([OH:19])=[O:18].O>C(O)(=O)C>[F:8][C:4]1[CH:5]=[C:6]([N+:17]([O-:19])=[O:18])[CH:7]=[C:2]([F:1])[C:3]=1[N:9]1[CH2:10][CH2:11][S:12](=[O:16])(=[O:15])[CH2:13][CH2:14]1
Reactant: O=S1(=O)CCN(c2c(F)cccc2F)CC1
Reactant: O=[N+]([O-])O
Solvent: CC(=O)O
Solvent: O
Product: O=[N+]([O-])c1cc(F)c(N2CCS(=O)(=O)CC2)c(F)c1
Reaction time: 18 h

Procedure:
To a suspension of 4-(2,6-difluorophenyl)thiomorpholine 1,1-dioxide (Step 1, 300 g, 1.21 mol) in 3 L of acetic acid, nitric acid (255 mL, ca. 6 mol, fuming, 90%) is added over 30 minutes at ambient temperature. A yellow precipitate forms within minutes and increases over time. The reaction is kept at room temperature for 18 h and is then poured into 6 L of water. After stirring for 2 h, the yellow suspension is filtered. The precipitate is washed with water (1.5 L×3) and ethanol (0.5 L×2) and dried at 50° C. overnight to give the title compound, 1H NMR (DMSO-d6) δ 8.05 (m, 2H), 3.69 (m, 4H), 3.26 (m, 4H).
Reaction SMILES: [H-].[Na+].[CH:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][C:4]=1[OH:13].Cl.Cl[CH2:16][CH2:17][C:18]1[N:19]=[CH:20][NH:21][CH:22]=1>CN(C)C=O.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][C:4]=1[O:13][CH2:16][CH2:17][C:18]1[N:19]=[CH:20][NH:21][CH:22]=1
Reactant: ClCCc1c[nH]cn1
Reactant: Oc1ccc2ccccc2c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [H-]
Solvent: CN(C)C=O
Product: c1ccc2cc(OCCc3c[nH]cn3)ccc2c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
240 mg (60% in oil, 6 mmol) of sodium hydride are added to a solution of 1.73 g (12 mmol) of 2-naphthol in 10 ml of dimethylformamide. The mixture is stirred at room temperature for 3 hours under nitrogen. 200 mg (1.2 mmol) of 4-(2-chloroethyl)-1H-imidazole hydrochloride and tetrabutylammonium iodide (catalytic amount) are added and the mixture is heated at 100° C. for 3 days and then the solvent is evaporated under reduced pressure. The excess 2-naphthol is extracted with diethyl ether under acidic conditions (dilute hydrochloric acid). The aqueous solution is basified with potassium carbonate and the product is extracted with diethyl ether. The ethereal extracts are concentrated and the residue obtained is crystallized from a methanol/water (1/2) mixture, M.p.: 157°-158° C.
Reaction SMILES: I[C:2]1[C:10]2[C:9]([NH2:11])=[N:8][CH:7]=[N:6][C:5]=2[N:4]([C@H:12]2[CH2:17][CH2:16][C@@H:15]([N:18]3[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]3)[CH2:14][CH2:13]2)[CH:3]=1.[F:25][C:26]1[CH:31]=[C:30](B2OC(C)(C)C(C)(C)O2)[CH:29]=[CH:28][C:27]=1[NH:41][C:42]1[O:43][C:44]2[CH:50]=[CH:49][CH:48]=[CH:47][C:45]=2[N:46]=1.O.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O.[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>[NH2:11][C:9]1[C:10]2[C:2]([C:30]3[CH:29]=[CH:28][C:27]([NH:41][C:42]4[O:43][C:44]5[CH:50]=[CH:49][CH:48]=[CH:47][C:45]=5[N:46]=4)=[C:26]([F:25])[CH:31]=3)=[CH:3][N:4]([C@H:12]3[CH2:17][CH2:16][C@@H:15]([N:18]4[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]4)[CH2:14][CH2:13]3)[C:5]=2[N:6]=[CH:7][N:8]=1
Reactant: CC1(C)OB(c2ccc(Nc3nc4ccccc4o3)c(F)c2)OC1(C)C
Reactant: CN1CCN([C@H]2CC[C@@H](n3cc(I)c4c(N)ncnc43)CC2)CC1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: CN1CCN([C@H]2CC[C@@H](n3cc(-c4ccc(Nc5nc6ccccc6o5)c(F)c4)c4c(N)ncnc43)CC2)CC1
Temperature: 80 °C
Reaction time: 21 h
Yield: 27.7 %

Procedure:
To a solution of cis-5-iodo-7-[4-(4-methylpiperazino)cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine (0.100 g, 0.227 mmol) in ethylene glycol dimethyl ether (3 mL) and water (1.5 mL) under nitrogen was added N2-[2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-1,3-benzoxazol-2-amine (0.100 g, 0.283 mmol, 1.25 equiv.), tetrakis(triphenylphosphine) palladium (0) (0.013 mg, 0.011 mmol, 0.05 equiv), and sodium carbonate monohydrate (0.070 mg, 0.568 mmol, 2.5 equiv). The solution was stirred at 80° C. for 21 hours. The resulting yellow mixture was concentrated in vacuo to give a yellow oil. Purification by preparative HPLC (25 to 100% CH3CN in 0.1 N aqueous ammonium acetate over 20 minutes at 21 mL/min. using a 8μ Hypersil HS C18, 250×21 mm column, tr=6.4-8.5 min.) afforded cis-N2-(4-{4-amino-7-[4-(4-methylpiperazino)cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin-5-yl}-2-fluorophenyl)-1,3-benzoxazol-2-amine as a cream solid (34 mg, 28%). RP-HPLC (25 to 100% CH3CN in 0.1 N aqueous ammonium acetate over 10 min at 1 mL/min using a Hypersil HS C18, 250×4.6 mm column) tr=7.167 min., 98%; and m/z 540.8(MH+).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[S:10][CH:9]=[CH:8][C:6]=2[N:7]=1.[CH2:12]([OH:14])[CH3:13].[OH-].[Na+]>O>[Cl:1][C:2]1[N:3]=[C:4]([O:14][CH2:12][CH3:13])[C:5]2[S:10][CH:9]=[CH:8][C:6]=2[N:7]=1
Reactant: CCO
Reactant: Clc1nc(Cl)c2sccc2n1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCOc1nc(Cl)nc2ccsc12
Temperature: 25 °C

Procedure:
A mixture of 2,4-dichlorothieno[3,2-d]pyrimidine (0.1 g), ethanol (5 mL), water (0.5 mL) and sodium hydroxide (0.04 g) was stirred at room temperature. The precipitated solids were collected by filtration and washed with diethyl ether to obtain 2-chloro-4-ethoxythieno[3,2-d]pyrimidine (0.07 g).
Reaction SMILES: [Cl:1][C:2]1[C:3]([Cl:15])=[C:4]([Cl:14])[C:5]([Cl:13])=[C:6]2[C:11](=[O:12])[O:10][C:8](=[O:9])[C:7]=12.[CH2:16]([N:18]([CH2:26][CH3:27])[C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH3:25])[CH:20]=1)[CH3:17].[Cl-].[Al+3].[Cl-].[Cl-]>ClC1C=CC=CC=1Cl>[CH3:25][C:21]1[CH:20]=[C:19]([N:18]([CH2:16][CH3:17])[CH2:26][CH3:27])[CH:24]=[CH:23][C:22]=1[C:11]([C:6]1[C:5]([Cl:13])=[C:4]([Cl:14])[C:3]([Cl:15])=[C:2]([Cl:1])[C:7]=1[C:8]([OH:10])=[O:9])=[O:12]
Reactant: O=C1OC(=O)c2c(Cl)c(Cl)c(Cl)c(Cl)c21
Reactant: CCN(CC)c1cccc(C)c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: Clc1ccccc1Cl
Product: CCN(CC)c1ccc(C(=O)c2c(Cl)c(Cl)c(Cl)c(Cl)c2C(=O)O)c(C)c1
Temperature: 0 °C
Yield: 77.3 %

Procedure:
A mixture of tetrachlorophthalic anhydride (21.4 g.), N,N-diethyl-m-toluidine (41 g.), aluminum chloride (30 g.) and o-dichlorobenzene (90 ml.) was heated (75°-95° C.) during one to two hours, then diluted with ice-water. The o-dichlorobenzene layer was separated and steam distilled. The residue was heated with dilute sulfuric acid. The mixture was poured onto ice and made alkaline. The resulting oil was heated in concentrated sulfuric acid. Dilution with water and purification of the product with toluene and hexane afforded 2-(2-methyl-4-(diethylamino)benzoyl)-3,4,5,6-tetrachlorobenzoic acid (IV: Y2 =CH3, Y'4 =(CH3CH2)2N, Z4 =Z"5 =Z"6 =Z7 =Cl) (26 g., m.p. 117° C. with sublimation).
Reaction SMILES: [F:1][C:2]1([F:27])[CH2:4][CH:3]1[CH2:5][N:6]1[C:10]2[CH:11]=[CH:12][C:13](B3OC(C)(C)C(C)(C)O3)=[CH:14][C:9]=2[N:8]([CH3:24])[S:7]1(=[O:26])=[O:25].Cl[C:29]1[N:34]=[C:33]([C:35]([O:37][CH2:38][CH3:39])=[O:36])[CH:32]=[CH:31][C:30]=1[CH3:40].P([O-])([O-])([O-])=O.[K+].[K+].[K+].COC1C=CC=C(OC)C=1C1C=CC=CC=1P(C1CCCCC1)C1CCCCC1>C1COCC1.O.CCOC(C)=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[F:1][C:2]1([F:27])[CH2:4][CH:3]1[CH2:5][N:6]1[C:10]2[CH:11]=[CH:12][C:13]([C:29]3[N:34]=[C:33]([C:35]([O:37][CH2:38][CH3:39])=[O:36])[CH:32]=[CH:31][C:30]=3[CH3:40])=[CH:14][C:9]=2[N:8]([CH3:24])[S:7]1(=[O:25])=[O:26]
Reactant: CN1c2cc(B3OC(C)(C)C(C)(C)O3)ccc2N(CC2CC2(F)F)S1(=O)=O
Reactant: CCOC(=O)c1ccc(C)c(Cl)n1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1ccc(C)c(-c2ccc3c(c2)N(C)S(=O)(=O)N3CC2CC2(F)F)n1
Temperature: 75 °C

Procedure:
1-[(2,2-difluorocyclopropyl)methyl]-3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide (12-1) (100 mg, 0.25 mmol, 1 eq), ethyl 6-chloro-5-methylpyridine-2-carboxylate (26-4) (75 mg, 0.38 mmol, 1.5 eq), tripotassium phosphate (106 mg, 0.50 mmol, 2.0 eq), S-Phos (10 mg, 0.025 mmol, 0.1 eq), and palladium(II) acetate (2.8 mg, 0.012 mmol, 0.05 eq) were combined in THF (1 mL) and water (0.2 mL). The resulting mixture was heated at 75° C. for 14 hours. The reaction mixture was allowed to cool to room temperature. The mixture was then diluted with EtOAc (10 mL), washed with water (1 mL) and brine (1 mL), dried over MgSO4, filtered and concentrated. The crude residue was purified by flash chromatography (12 g SiO2, 0-80% EtOAc in hexanes) to afford ethyl 6-{1-[(2,2-difluorocyclopropyl)methyl]-3-methyl-2,2-dioxido-1,3-dihydro-2,1,3-benzothiadiazol-5-yl}-5-methylpyridine-2-carboxylate (26-5). HRMS m/z (M+H) 438.1291 found, 438.1294 required.
Reaction SMILES: [CH2:1]([N:9]1[C:13](=[O:14])[CH:12]=[CH:11][S:10]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[H-].[Al+3].[Li+].[H-].[H-].[H-].[C:21]1([CH2:27][C:28](Cl)=[O:29])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>O1CCCC1>[CH2:1]([NH:9][C:13](=[O:14])/[CH:12]=[CH:11]\[S:10][C:28](=[O:29])[CH2:27][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCCn1sccc1=O
Reactant: O=C(Cl)Cc1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCCCCCCCNC(=O)/C=C\SC(=O)Cc1ccccc1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a cooled (-78° C.), stirred solution of 2.0 g (0.0094 mol) of 2-octyl-4-isothiazolin-3-one in 50 ml of anhydrous tetrahydrofuran under nitrogen was added dropwise 2.82 ml (0.0028 mol) of a 1.0M solution of lithium aluminum hydride in tetrahydrofuran over a 20 min. period. After the addition the mixture was stirred at -78° C. for 1 hr. Over a 15 min period 1.24 ml (0.0094 mol) of phenylacetyl chloride was added. After this addition the mixture was allowed to warm to room temperature. After 12 hr the reaction mixture was a white solid suspended in an orange solution. The mixture was filtered and the filtrate was diluted with ethyl acetate and washed once with aqueous saturated sodium bicarbonate solution. The organic layer was set aside and the aqueous layer was extracted three times with ethyl acetate. The combined organic layers were washed once with water, with brine, and dried over anhydrous magnesium sulfate. Filtration and removal of solvents gave N-octyl-cis-3 -(phenylacetylthio)acrylamide as an oil which crystallized upon standing to give 3.0 g (96% yield) of a white solid whose NMR is reported in Table 2.
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:7][O:6][CH2:5][CH2:4][N:3]1[C:8]1[N:16]=[C:15]2[C:11]([N:12]=[CH:13][NH:14]2)=[C:10]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][C@H:18]2[CH3:23])[N:9]=1.[O:24]1[CH:29]=[CH:28][CH2:27][CH2:26][CH2:25]1.FC(F)(F)C(OC(=O)C(F)(F)F)=O.FC(F)(F)C(O)=O.C([O-])([O-])=O.[Na+].[Na+]>CCOC(C)=O>[CH3:1][C@@H:2]1[CH2:7][O:6][CH2:5][CH2:4][N:3]1[C:8]1[N:16]=[C:15]2[C:11]([N:12]=[CH:13][N:14]2[CH:25]2[CH2:26][CH2:27][CH2:28][CH2:29][O:24]2)=[C:10]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][C@H:18]2[CH3:23])[N:9]=1
Reactant: C[C@@H]1COCCN1c1nc(N2CCOC[C@H]2C)c2nc[nH]c2n1
Reactant: C1=COCCC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Product: C[C@@H]1COCCN1c1nc(N2CCOC[C@H]2C)c2ncn(C3CCCCO3)c2n1
Temperature: 70 °C
Reaction time: 6 h
Yield: 78.9 %

Procedure:
2,6-Bis-((R)-3-methyl-morpholin-4-yl)-9H-purine (600 mg, 1.89 mmol) was dissolved in EtOAc (25 mL) under argon. After addition of 3,4-dihydro-2H-pyrane (172 μl, 1.89 mmol), trifluoro acetic acid anhydride (27 μl, 188 μmol), and trifluoro acetic acid (319 μl, 4.15 mmol), the reaction mixture was heated to 70° C. After 6 hours, 3,4-dihydro-2H-pyrane (1.44 mL, 15.7 mmol) was added. The reaction was then stirred for 22 hours at 70° C. and then cooled to room temperature. 500 mg of solid Na2CO3 was added and stirring continued for 10 minutes. The reaction mixture was diluted with EtOAc, the organic layer was separated, dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue, which was purified by column chromatography (40 g SiO2, heptane/EtOAc in a gradient from 9/1 to 2/3) to give the product as a foam (600 mg, 79%).
Reaction SMILES: [F:1][C:2]1[C:7]([S:8]([CH3:11])(=[O:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[N:12]1[CH2:17][CH2:16][N:15](C(OC)=O)[CH2:14][CH2:13]1>C(O)C.Cl>[F:1][C:2]1[C:7]([S:8]([CH3:11])(=[O:9])=[O:10])=[CH:6][CH:5]=[CH:4][C:3]=1[N:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1
Reactant: COC(=O)N1CCN(c2cccc(S(C)(=O)=O)c2F)CC1
Agent: Cl
Solvent: CCO
Product: CS(=O)(=O)c1cccc(N2CCNCC2)c1F

Procedure:
Preparation according to preparation 29: methyl 4-[2-fluoro-3-(methylsulfonyl)phenyl]piperazine-1-carboxylate (1.0 g, 3.16 mmol) in ethanol (8 ml), hydrochloric acid (6 M, 20 ml). Yield: 0.34 g. MS m/z (rel. intensity, 70 eV) 258 (M+, 17), 215 (13), 216 (bp), 209 (6), 137 (9).
Reaction SMILES: C[O:2][C:3]([C@@H:5]1[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][C@@H:6]1[N:13]([CH2:34][C:35]1[CH:40]=[CH:39][C:38]([F:41])=[CH:37][CH:36]=1)[C:14](=[O:33])[CH2:15][C:16]1[NH:21][C:20]2[CH:22]=[CH:23][C:24]([NH:26][S:27]([CH3:30])(=[O:29])=[O:28])=[CH:25][C:19]=2[S:18](=[O:32])(=[O:31])[N:17]=1)=O.[O-]CC.[Na+].Cl>C(O)C>[F:41][C:38]1[CH:39]=[CH:40][C:35]([CH2:34][N:13]2[C:14](=[O:33])[C:15]([C:16]3[NH:21][C:20]4[CH:22]=[CH:23][C:24]([NH:26][S:27]([CH3:30])(=[O:29])=[O:28])=[CH:25][C:19]=4[S:18](=[O:32])(=[O:31])[N:17]=3)=[C:3]([OH:2])[CH:5]3[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH:6]23)=[CH:36][CH:37]=1
Reactant: COC(=O)[C@@H]1CCCCCC[C@@H]1N(Cc1ccc(F)cc1)C(=O)CC1=NS(=O)(=O)c2cc(NS(C)(=O)=O)ccc2N1
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CS(=O)(=O)Nc1ccc2c(c1)S(=O)(=O)N=C(C1=C(O)C3CCCCCCC3N(Cc3ccc(F)cc3)C1=O)N2
Temperature: 60 °C
Reaction time: 4 h
Yield: 30.6 %

Procedure:
cis-2-{(4-Fluoro-benzyl)-[2-(7-methanesulfonylamino-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)-acetyl]-amino}-cyclooctanecarboxylic acid methyl ester (0.241 g, 0.396 mmol) was dissolved in ethanol (4 mL), a 21% w/w solution of sodium ethoxide in ethanol (0.739 mL, 1.98 mmol) was added. The mixture was stirred at 60° C. for 4 h and allowed to cool to 25° C. The mixture was poured into a 0.5 M aqueous hydrochloric acid solution (100 mL). The product started to precipitate and was collected by vacuum filtration. The precipitate was washed with water and dried under high vacuum to afford the pure product N-{3-[1-(4-fluoro-benzyl)-4-hydroxy-2-oxo-1,2,4a,5,6,7,8,9,10,10a-decahydro-cycloocta[b]pyridin-3-yl]-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-7-yl}-methanesulfonamide (0.07 g, 0.121 mmol, 31%), as a light yellow solid. 1H NMR (400 MHz, DMSO-d6) δ: 1.24-1.83 (12H, m), 3.04 (3H, s), 3.73-3.58 (2H, m), 4.21-4.46 (1H, m),4.99 (1H, d, J=16 Hz), 7.18 (2H, t, J=8 Hz), 7.47-7.53 (6H, m), 10.08 (1H, s). LC-MS (ESI) calcd for C26H29FN4O6S2 576.15, found 577.5 [M+H+].