Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2]([O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[O:12]CC1C=CC=CC=1)(=[O:4])=[O:3].B(F)(F)F.CCOCC.CSC>C(Cl)Cl>[CH3:1][S:2]([O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[OH:12])(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Oc1ccccc1OCc1ccccc1
Agent: FB(F)F
Solvent: CSC
Solvent: CCOCC
Solvent: ClCCl
Product: CS(=O)(=O)Oc1ccccc1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.1 %

Procedure:
2-(Benzyloxy)phenyl methanesulfonate (4.00 g, 14.37 mmol) was dissolved in dry DCM (50 mL) under nitrogen atmosphere. Boron trifluoride diethyl etherate (8.16 g, 57.49 mmol) was added followed by dimethyl sulfide (3.57 g, 57.49 mmol) and the reaction mixture was stirred at rt overnight. The reaction mixture was poured onto ice and the aqueous layer was extracted with DCM. The organic layers were combined, washed with water, dried (Na2SO4), filtered and evaporated to give the title compound (2.49 g, 92%). 1H NMR (500 MHz, CDCl3): δ 3.26 (s, 3H), 6.16 (s, 1H), 6.96 (dt, 1H), 7.09 (dd, 1M), 7.22-7.28 (m, 2H); 13C NMR (125 MHz, CDCl3): δ 37.74, 119.01, 121.65, 123.71, 129.09, 136.99, 148.43; Mass Spectrum: M−H+ 187.
Reaction SMILES: Br[C:2]1[CH:17]=[CH:16][C:5]2[C:6]([C:9]([NH:11][CH2:12][CH:13]3[CH2:15][CH2:14]3)=[O:10])=[N:7][O:8][C:4]=2[CH:3]=1.[CH:18]1([NH:21][C:22](=[O:40])[C:23]2[CH:28]=[C:27](B3OC(C)(C)C(C)(C)O3)[C:26]([CH3:38])=[C:25]([F:39])[CH:24]=2)[CH2:20][CH2:19]1.C(=O)([O-])O.[Na+].C(OCC)(=O)C>C(O)(C)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[CH:18]1([NH:21][C:22]([C:23]2[CH:24]=[C:25]([F:39])[C:26]([CH3:38])=[C:27]([C:2]3[CH:17]=[CH:16][C:5]4[C:6]([C:9]([NH:11][CH2:12][CH:13]5[CH2:15][CH2:14]5)=[O:10])=[N:7][O:8][C:4]=4[CH:3]=3)[CH:28]=2)=[O:40])[CH2:20][CH2:19]1
Reactant: Cc1c(F)cc(C(=O)NC2CC2)cc1B1OC(C)(C)C(C)(C)O1
Reactant: O=C(NCC1CC1)c1noc2cc(Br)ccc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CC(C)O
Product: Cc1c(F)cc(C(=O)NC2CC2)cc1-c1ccc2c(C(=O)NCC3CC3)noc2c1
Yield: 78.3 %

Procedure:
A mixture of 6-bromo-N-(cyclopropylmethyl)-1,2-benzisoxazole-3-carboxamide (Intermediate 56) (0.03 g) N-cyclopropyl-3-fluoro-4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (Intermediate 62) (0.03 g) saturated aqueous sodium hydrogen carbonate (0.25 ml) and tetrakis(triphenylphosphine)palladium(0) (1 mg) in isopropanol (0.5 ml) was stirred at reflux under nitrogen for 4 h. Ethyl acetate (2 ml) and water (2 ml) were added, the phases were separated and the aqueous layer was re-extracted with ethyl acetate. The combined organic extracts were washed with brine, dried using a hydrophobic filter tube and concentrated under a stream of nitrogen. The residue was purified on Varian Bond-Elut SPE cartridge (silica, 1 g) eluting with cyclohexane:ethyl acetate (100:0 to 50:50) to give the title compound as a colourless foam (0.03 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[Cl:11])[C:5](Cl)=[O:6].[C:12]([NH2:21])([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)([CH3:14])[CH3:13].C(N(CC)CC)C>ClCCl.CN(C1C=CN=CC=1)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[Cl:11])[C:5]([NH:21][C:12]([CH3:14])([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH3:13])=[O:6]
Reactant: CC(C)(N)c1ccccc1
Reactant: O=C(Cl)c1ccc(Cl)c(Cl)c1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(NC(=O)c1ccc(Cl)c(Cl)c1)c1ccccc1
Yield: 87.4 %

Procedure:
In a similar manner to Step 1 of Example 16, 3,4-dichlorobenzoyl chloride (3.00 g, 14.3 mmol) was dissolved in dichloromethane (60 mL), and the solution was treated with cumylamine (2.30 mL, 15.7 mmol), triethylamine (3.00 mL, 21.5 mmol) and DMAP (175 mg, 1.43 mmol), followed by purification by slurry using chloroform to obtain 3,4-dichloro-N-(1-methyl-1-phenylethyl)benzamide (3.85 g, yield 88%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5](/[CH:13]=[CH:14]\[C:15]2[C:20]([O:21][Si](C(C)(C)C)(C)C)=[C:19]([O:29][Si](C(C)(C)C)(C)C)[CH:18]=[CH:17][CH:16]=2)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].C(O)(=O)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O>C1COCC1>[CH3:12][O:11][C:7]1[CH:6]=[C:5](/[CH:13]=[CH:14]\[C:15]2[C:20]([OH:21])=[C:19]([OH:29])[CH:18]=[CH:17][CH:16]=2)[CH:4]=[C:3]([O:2][CH3:1])[C:8]=1[O:9][CH3:10]
Reactant: COc1cc(/C=C\c2cccc(O[Si](C)(C)C(C)(C)C)c2O[Si](C)(C)C(C)(C)C)cc(OC)c1OC
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: COc1cc(/C=C\c2cccc(O)c2O)cc(OC)c1OC
Reaction time: 1 h
Yield: 94.3 %

Procedure:
A solution of 8 (0.106 g, 0.2 mmol) in 2 mL THF was stirred at 0° while adding acetic acid (0.024 g, 0.4 mmol) and tetrabutylammonium fluoride (1M in THF, 0.4 ml, 0.4 mmol). The solution was stirred at 20° for one hour then cooled to 0° and 0.5 mL water added. The mixture was extracted with TBME three times, dried, evaporated and the residue partitioned between 10 mL heptane/10 mL acetonitrile. Evaporation of the acetonitrile layer gave 0.057 g pale yellow gum which was purified by silica chromatography with 7:3 heptane:ethyl acetate to give ZSB-82 as a colourless gum (0.032 g):
Reaction SMILES: O[Li].O.C[O:5][C:6]([C:8]1([C:12]2[CH:49]=[CH:48][CH:47]=[CH:46][C:13]=2[CH2:14][CH2:15][C:16]2[C:21]([C:22]([F:25])([F:24])[F:23])=[CH:20][N:19]=[C:18]([NH:26][C:27]3[CH:32]=[CH:31][C:30]([CH:33]4[CH2:38][CH2:37][N:36]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:35][CH2:34]4)=[CH:29][CH:28]=3)[N:17]=2)[CH2:11][CH2:10][CH2:9]1)=[O:7].O.C(Cl)Cl>C1COCC1>[C:42]([O:41][C:39]([N:36]1[CH2:35][CH2:34][CH:33]([C:30]2[CH:29]=[CH:28][C:27]([NH:26][C:18]3[N:17]=[C:16]([CH2:15][CH2:14][C:13]4[CH:46]=[CH:47][CH:48]=[CH:49][C:12]=4[C:8]4([C:6]([OH:7])=[O:5])[CH2:11][CH2:10][CH2:9]4)[C:21]([C:22]([F:24])([F:23])[F:25])=[CH:20][N:19]=3)=[CH:32][CH:31]=2)[CH2:38][CH2:37]1)=[O:40])([CH3:45])([CH3:43])[CH3:44]
Reactant: COC(=O)C1(c2ccccc2CCc2nc(Nc3ccc(C4CCN(C(=O)OC(C)(C)C)CC4)cc3)ncc2C(F)(F)F)CCC1
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(Nc3ncc(C(F)(F)F)c(CCc4ccccc4C4(C(=O)O)CCC4)n3)cc2)CC1

Procedure:
LiOH.H2O (41 mg, 0.97 mmol) was added to a solution of tert-butyl 4-(4-((4-(2-(1-(methoxycarbonyl)cyclobutyl)phenethyl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)piperidine-1-carboxylate A55 (31 mg, 0.049 mmol) in THF (5 mL) and H2O (0.5 mL) and the mixture was stirred at 40° C. overnight. Additional LiOH.H2O (400 mg, 9.53 mmol) was added and the mixture was heated at reflux for 12 days. Upon cooling DCM (50 mL) and water (50 mL) were added and the aqueous layer was extracted with EtOAc (2×50 mL). The combined organics were dried (Na2SO4) and the volatiles were removed in vacuo to give the title compound A56 as a yellow oil (30 mg, 98%). LCMS-A: rt 7.586 min, m/z 625 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[C:3]=1[CH:4]=O.[NH2:11][C:12]1[CH:13]=[C:14]([CH:26]=[CH:27][C:28]=1[NH2:29])[C:15]([NH:17][C:18]1[CH:23]=[CH:22][C:21]([CH3:24])=[C:20]([CH3:25])[CH:19]=1)=[O:16].C(S([O-])(=O)=O)(F)(F)F.C(S([O-])(=O)=O)(F)(F)F.C(S([O-])(=O)=O)(F)(F)F.[Yb+3].O>CS(C)=O.CCOC(C)=O>[CH3:25][C:20]1[CH:19]=[C:18]([NH:17][C:15]([C:14]2[CH:26]=[CH:27][C:28]3[N:29]=[C:4]([C:3]4[C:6]([CH3:10])=[CH:7][CH:8]=[CH:9][C:2]=4[Cl:1])[NH:11][C:12]=3[CH:13]=2)=[O:16])[CH:23]=[CH:22][C:21]=1[CH3:24]
Reactant: Cc1cccc(Cl)c1C=O
Reactant: Cc1ccc(NC(=O)c2ccc(N)c(N)c2)cc1C
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Yb+3]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1ccc(NC(=O)c2ccc3nc(-c4c(C)cccc4Cl)[nH]c3c2)cc1C
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 2-chloro-6-methylbenzaldehyde (107 mg) and 3,4-diamino-N-(3,4-dimethylphenyl)-benzamide (Example 5-1, step 6) (160 mg) in DMSO (1.5 mL) was added Yb(OTf)3 (80 mg). The solution was stirred at room temperature for 18 h then an additional 40 mg of Yb(OTf)3 was added the mixture was stirred at 70° C. for 24 h. The mixture was partioned between water and EtOAc. The aqueous layer was extracted with EtOAc. The combined organic layers were dried, filtered and concentrated. The residue was purified by flash chromatography using hexanes/ethyl acetate (5:1) and the product was isolated as a foam. MS (m/z) 390 (M+1), retention time=1.66 min, Method 10.
Reaction SMILES: N1C=CN=C1.[CH3:6][C:7]([Si:10](Cl)([CH3:12])[CH3:11])([CH3:9])[CH3:8].[CH3:14][N:15]([CH3:25])[CH2:16][CH2:17][C@H:18]([OH:24])[C:19]([O:21][CH2:22][CH3:23])=[O:20].O>CN(C=O)C.CCOC(C)=O>[Si:10]([O:24][C@@H:18]([CH2:17][CH2:16][N:15]([CH3:25])[CH3:14])[C:19]([O:21][CH2:22][CH3:23])=[O:20])([C:7]([CH3:9])([CH3:8])[CH3:6])([CH3:12])[CH3:11]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CCOC(=O)[C@@H](O)CCN(C)C
Agent: c1c[nH]cn1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)[C@H](CCN(C)C)O[Si](C)(C)C(C)(C)C
Reaction time: 18 h
Yield: 60.8 %

Procedure:
Imidazole (1.98 g, 29.10 mmol) and TBDMSCl (2.34 g, 15.52 mmol) was added to a stirred solution of ethyl (2S)-4-(dimethylamino)-2-hydroxybutanoate (Step 1) (3.20 g, 19.97 mmol) in DMF (25 mL). The reaction mixture was kept at ambient temperature for 18 hrs. Water and EtOAc were added and the two phases were separated. The aqueous phase was extracted with EtOAc. The organic extracts were combined and washed three times with water, dried over MgSO4 and concentrated in vacuo. The residue was purified with column chromatography (silica gel, eluting with heptane/EtOAc:2/1) to give the title compound as a colourless oil (2.73 g), 1H NMR (300 MHz, DMSO) δ 4.28 (m, 1H), 4.18 (m, 2H), 2.44 (m, 1H), 2.30 (m, 1H), 2.22 (s, 6H), 1.87 (m, 2H), 1.28 (t, 3H), 0.90 (s, 9H), 0.08 (d, 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[C:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[S:11][CH:12]=2)[CH:5]=[CH:6][CH:7]=1.[Br:18]Br.O>C(O)(=O)C>[Br:18][C:12]1[S:11][C:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:9][C:8]=1[C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=1
Reactant: BrBr
Reactant: CCOC(=O)c1cc(-c2cccc(Cl)c2)cs1
Solvent: CC(=O)O
Solvent: O
Product: CCOC(=O)c1cc(-c2cccc(Cl)c2)c(Br)s1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
0.01 ml (0.22 mmol) of bromine is provided in 1 ml of acetic acid, and 58.0 mg (0.22 mmol) of the compound from Example 13A, dissolved in 1 ml of acetic acid, are added dropwise. The mixture is stirred at 60° C. overnight. 0.01 ml (0.22 mmol) of bromine is a subsequently added, and the mixture is stirred at 60° C. for another 24 hours. Water is added to the reaction mixture, and the resulting precipitate is collected by suction filtration, washed with water and dried under high vacuum. 43.0 mg (54% of theory) of the title compound are obtained.
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][N:9]=2)[CH:4]=[CH:3][C:2]1=[O:11].[H-].[Na+].Br[CH2:15][CH:16]1[O:20][CH2:19][CH2:18][O:17]1.O>CN(C)C=O.C(OCC)(=O)C>[O:17]1[CH2:18][CH2:19][O:20][CH:16]1[CH2:15][N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][N:9]=2)[CH:4]=[CH:3][C:2]1=[O:11]
Reactant: BrCC1OCCO1
Reactant: O=c1ccc2cccnc2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=c1ccc2cccnc2n1CC1OCCO1
Temperature: 55 °C
Reaction time: 0.12 h

Procedure:
To a solution of 1.2 g of 1,8-naphthyridin-2(1H)-one in 18 mL of N,N-dimethylformamide, 0.36 g of 60% sodium hydride was added, and the mixture was stirred at 50 to 60° C. for 7 minutes. Thereto was added 0.94 mL of 2-bromomethyl-1,3-dioxolan, and the mixture was stirred at 95 to 105° C. for 3 hours. The reaction mixture was cooled to room temperature, water and ethyl acetate were then added thereto, and the organic layer was separated. The aqueous layer was extracted with ethyl acetate and chloroform. The organic layer and the extract were combined, the resultant solution was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The resultant residue was purified by silica gel column chromatography using an eluent of hexane:ethyl acetate=1:1 to obtain 1.2 g of 1-(1,3-dioxolan-2-ylmethyl)-1,8-naphthyridin-2(1H)-one as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:9])[C:5]([CH3:8])=[N:6][CH:7]=1.[F:10][CH2:11][CH:12](O)[CH2:13][F:14]>>[Br:1][C:2]1[CH:3]=[C:4]([O:9][CH:12]([CH2:13][F:14])[CH2:11][F:10])[C:5]([CH3:8])=[N:6][CH:7]=1
Reactant: Cc1ncc(Br)cc1O
Reactant: OC(CF)CF
Product: Cc1ncc(Br)cc1OC(CF)CF

Procedure:
The title compound was synthesized in a similar manner as described for stage 58.1.2 using 5-bromo-2-methyl-pyridin-3-ol (stage 189.1.2, 2.234 mmol) and 1,3-difluoro-2-propanol (Aldrich, Buchs, Switzerland, 2.68 mmol) to give the title compound as a yellow oil. (HPLC: tR 2.41 min (Method A); M+H=266, 268 MS-ES).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][C:10](=O)[O:11][C:12]=2[CH2:13][CH2:14][C:15]([O:17][CH3:18])=[O:16])=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:22])=O.N1C=CC=CC=1.O>C(#N)C>[Cl:22][C:10]1[O:11][C:12]([CH2:13][CH2:14][C:15]([O:17][CH3:18])=[O:16])=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[N:9]=1
Reactant: COC(=O)CCc1oc(=O)[nH]c1-c1ccc(Cl)cc1
Reactant: O=P(Cl)(Cl)Cl
Solvent: c1ccncc1
Solvent: O
Solvent: CC#N
Product: COC(=O)CCc1oc(Cl)nc1-c1ccc(Cl)cc1
Temperature: 90 °C
Reaction time: 8 h
Yield: 91.7 %

Procedure:
To a mixture of methyl 4-(4-chlorophenyl)-2-oxo-4-oxazoline-5-propionate (823.7 g) and phosphorus oxychloride (1090 mL) was added pyridine (235.5 mL) and the mixture was stirred at 90° C. for 8 h and allowed to stand overnight at room temperature. A solution obtained by diluting the obtained mixture with acetonitrile (2471 mL) was added dropwise to water (8237 mL) at not higher than 35° C. Then water (4119 mL) was added and the precipitated crystals were collected by filtration to give the title compound (805.4 g, yield: 91.7%).
Reaction SMILES: [C:1]([Si:5]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)Cl)([CH3:4])([CH3:3])[CH3:2].[CH3:19][O:20][C:21]([C:23]1[S:24][C:25]([CH2:36][OH:37])=[CH:26][C:27]=1[NH:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])=[O:22].C(N(CC)C(C)C)(C)C.[Cl-].[NH4+]>ClCCl.CN(C)C1C=CN=CC=1>[CH3:19][O:20][C:21]([C:23]1[S:24][C:25]([CH2:36][O:37][Si:5]([C:1]([CH3:4])([CH3:3])[CH3:2])([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[CH:26][C:27]=1[NH:28][C:29]([O:31][C:32]([CH3:33])([CH3:35])[CH3:34])=[O:30])=[O:22]
Reactant: COC(=O)c1sc(CO)cc1NC(=O)OC(C)(C)C
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: CN(C)c1ccncc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1sc(CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)cc1NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 6 h

Procedure:
tert-Butyldiphenylchlorosilane (1.7 g) dissolved in dichloromethane (5 mL) was added dropwise over the course of 10 min to a mixture of 3-tert-butoxycarbonylamino-5-hydroxymethylthiophene-2-carboxylic acid methyl ester (1.4 g), 4-dimethylaminopyridine (30.2 mg), N,N-diisopropylethylamine (1.3 mL) in dichloromethane (30 mL). The reaction mixture was then stirred at room temperature for 6 h. The mixture was mixed with dichloromethane and saturated ammonium chloride solution. The organic phase was washed with water, dried over sodium sulfate and concentrated. The product with the molecular weight of 525.74 (C28H35NO5SSi) was obtained in this way; MS (ESI): 426 (M-Boc+H+).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][C:5]([N:8]2[CH2:13][CH2:12][NH:11][C@@H:10]([CH3:14])[CH2:9]2)=[C:4]2[CH:15]=[N:16][CH:17]=[CH:18][C:3]=12.[C:19](Cl)(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(N(CC)CC)C.C(=O)(O)[O-].[Na+].[OH-].[Na+]>ClCCl>[Cl:1][C:2]1[N:7]=[N:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:19]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[O:26])[C@@H:10]([CH3:14])[CH2:9]2)=[C:4]2[CH:15]=[N:16][CH:17]=[CH:18][C:3]=12
Reactant: C[C@H]1CN(c2nnc(Cl)c3ccncc23)CCN1
Reactant: O=C(Cl)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@H]1CN(c2nnc(Cl)c3ccncc23)CCN1C(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 79.3 %

Procedure:
To (S)-1-chloro-4-(3-methylpiperazin-1-yl)pyrido[3,4-d]pyridazine 4 (0.190 g, 0.720 mmol) in dichloromethane (3 ml) was added benzoyl chloride (0.0920 ml, 0.792 mmol) and triethylamine (0.220 ml, 1.58 mmol). The reaction was stirred at 25° C. After 2 h, the reaction contents were poured into saturated sodium bicarbonate (6 mL). The aqueous layer was brought to pH 11 with 5 N NaOH and extracted with 10% methanol in dichloromethane (3×15 mL). Silica gel chromatography (gradient elution 30 to 60% EtOAc in hexanes with 2.5% TEA additive) afforded 210 mg of (S)-(4-(1-chloropyrido[3,4-d]pyridazin-4-yl)-2-methylpiperazin-1-yl)(phenyl)methanone 5. 1H NMR (CDCl3) δ 9.55 (s, 1H), 9.08 (d, J=5.9 Hz, 1H), 8.00 (d, J=5.1 Hz, 1H) 7.41-7.51 (m, 5H) 4.70 (m, 1H), 4.02 (app d, J=11.7 Hz, 1H), 3.86 (app d, J=12.1 Hz, 1H) 3.62-3.72 (m, 1H), 3.47 (dd, J=13.1, 3.3 Hz, 1H), 3.30 (td, J=12.6, 3.3 Hz, 1H), 1.61 (bs, 1H), 1.57 (d, J=6.3 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:12](Cl)=[O:13])=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[NH2:15][C:16]1[CH:17]=[CH:18][C:19]([C:22]([O:24][CH3:25])=[O:23])=[N:20][CH:21]=1.N1C=CC=CC=1.O>ClCCl>[Cl:1][C:2]1[C:3]([C:12]([NH:15][C:16]2[CH:17]=[CH:18][C:19]([C:22]([O:24][CH3:25])=[O:23])=[N:20][CH:21]=2)=[O:13])=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2
Reactant: COC(=O)c1ccc(N)cn1
Reactant: O=C(Cl)c1nc2ccccc2nc1Cl
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: O
Product: COC(=O)c1ccc(NC(=O)c2nc3ccccc3nc2Cl)cn1
Temperature: 25 °C
Yield: 81.4 %

Procedure:
A solution of 3-chloroquinoxaline-2-carbonyl chloride (3.5 g, 15.45 mmol) in dichloromethane (32.3 mL) was added dropwise to a mixture of methyl 5-aminopyridine-2-carboxylate (2.35 g, 15.45 mmol), pyridine (3.75 mL, 46.35 mmol) and dichloromethane (48.38 mL) at 0° C. The mixture was stirred and allowed to warm up to room temperature overnight. To the reaction, water (40 mL) was added and the product precipitated. The solid was isolated by filtration, washed with water (1×40 mL) and hexanes (2×50 mL) to yield methyl 5-[(3-chloroquinoxaline-2-carbonyl)amino]pyridine-2-carboxylate (4.31 g, 81%) as a cream colored solid. 1H NMR (400 MHz, DMSO-d6) δ 11.61 (s, 1H), 9.00 (d, J=2.5 Hz, 1H), 8.46 (dd, J=8.6, 2.6 Hz, 1H), 8.36-8.26 (m, 1H), 8.24-8.12 (m, 2H), 8.12-7.95 (m, 2H), 3.89 (s, 3H) ppm. ESI-MS m/z calc. 342.05, found 343.4 (M+1)+; Retention time: 1.25 minutes (3 minutes run).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:11]([CH3:14])([CH3:13])[OH:12])[CH:5]=[C:6]([O:9][CH3:10])[C:7]=1[OH:8].[Cl:15][C:16]1[N:21]=[C:20](Cl)[N:19]=[C:18]([CH3:23])[N:17]=1>[OH-].[Na+].O.C(#N)C>[Br:1][C:2]1[CH:3]=[C:4]([C:11]([CH3:14])([CH3:13])[OH:12])[CH:5]=[C:6]([O:9][CH3:10])[C:7]=1[O:8][C:20]1[N:21]=[C:16]([Cl:15])[N:17]=[C:18]([CH3:23])[N:19]=1
Reactant: Cc1nc(Cl)nc(Cl)n1
Reactant: COc1cc(C(C)(C)O)cc(Br)c1O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC#N
Product: COc1cc(C(C)(C)O)cc(Br)c1Oc1nc(C)nc(Cl)n1
Reaction time: 1 h

Procedure:
3-bromo-4-hydroxy-5-methoxy-a,a-dimethylbenzenemethanol (1.16 g) was dissolved in 10% NaOH (1.78 g) and 5 mL of water. The solvent was stripped under reduced pressure. The salt was taken up in 50 mL acetonitrile and cooled to 0°-5° C. 2,4-dichloro-6-methyl-1,3,5-triazine (0.61g) was added and the mixture was stirred at 0°-5° C. for 1 hour. The solvent was removed under reduced pressure and the residue was extracted with methylene chloride. The extracts were combined and stripped under reduced pressure to yield 3-bromo-4-[[4-chloro-6-methyl-1,3,5-triazin-2-yl]oxy]-5-methoxy-a,a-dimethylbenzenemethanol.
Reaction SMILES: [CH2:1]([O:3][P:4]([O-:8])[O:5]CC)[CH3:2].[C:9]([BH2:11])#[N:10].[Si](I)(C)(C)C.CCOC(C)=O>CC#N>[CH2:1]([O:3][P:4]([O-:8])[O-:5])[CH3:2].[C:9]([BH2:11])#[N:10]
Reactant: CCOP([O-])OCC
Agent: BC#N
Agent: C[Si](C)(C)I
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CCOP([O-])[O-]
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
Diethylphosphite-cyanoborane (7a) (1.15 g) and Me3SiI (4 equivalents) were taken in anhydrous CH3CN and were heated at reflux in the dark for 2 days. The solvent and excess Me3SiI were removed under reduced pressure. The residue was taken in CH2Cl2 /water (1:1, v/v, 50 ml) and was stirred at room temperature for 1.5 hours. The aqueous layer was separated and washed with CH2Cl2 until the organic layer was colorless. The water was evaporated at room temperature by passing a stream of air over the solution. The residue was taken in EtOAc and filtered to remove a solid. The filtrate was dried and the solvent was removed under reduced pressure to give an oil. Often, the EtOAc solution became dark colored, which could not be removed by treatment with charcoal. To remove this color, the EtOAc was removed and the whole work-up was repeated. The yield of light yellow oil was 0.49 g, 50.72%.
Reaction SMILES: [C:1]([NH:5][C:6](=[O:8])[OH:7])([CH3:4])([CH3:3])[CH3:2].[CH:9]1([S:12]([NH2:15])(=[O:14])=[O:13])[CH2:11][CH2:10]1.C([Li])CCC.[CH3:21][O:22][CH2:23]Cl.Cl>C1COCC1>[C:1]([NH:5][C:6](=[O:7])[OH:8])([CH3:4])([CH3:3])[CH3:2].[CH3:21][O:22][CH2:23][C:9]1([S:12]([NH2:15])(=[O:14])=[O:13])[CH2:11][CH2:10]1
Reactant: COCCl
Reactant: NS(=O)(=O)C1CC1
Agent: CC(C)(C)NC(=O)O
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COCC1(S(N)(=O)=O)CC1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a solution of cyclopropylsulfonylamine tert-butyl carbamate (1.0 g, 4.5 mmol) dissolved in THF (30 mL) cooled to −78° C., was added n-butyl lithium (6.4 mL, 10.2 mmol, 1.6M in hexane) and the reaction mixture was stirred for 1 hour. To this solution was added a neat solution of chloromethyl methyl ether (0.40 mL, 5.24 mmol), and the mixture was slowly allowed to warm to room temperature overnight. The solution pH was adjusted to 3 using 1N aqueous HCl and was then extracted with ethyl acetate (4×50 mL portions). The combined extracts were dried (MgSO4), filtered, and concentrated to afford 1-methoxymethylcyclopropylsulfonylamine tert-butylcarbamate, as a waxy solid (1.20 g, 100%) which was taken directly into the next reaction without further purification: 1H NMR (CDCl3) δ 1.03 (m, 2H), 1.52 (s, 9H), 1.66 (m, 2H), 3.38 (s, 3H), 3.68 (s, 2H), 7.54 (s, 1H); 13C NMR (CDCl3) δ 11.37, 28.29, 40.38, 58.94, 73.43, 83.61, 149.57.
Reaction SMILES: [CH2:1]([NH:5][CH2:6][C:7]1[S:8][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([S:18]([CH3:21])(=[O:20])=[O:19])[CH:13]=2)=[CH:10][CH:11]=1)[CH:2]([CH3:4])[CH3:3].[CH:22]1([CH2:28][S:29](Cl)(=[O:31])=[O:30])[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1>ClCCl>[CH:22]1([CH2:28][S:29]([N:5]([CH2:1][CH:2]([CH3:4])[CH3:3])[CH2:6][C:7]2[S:8][C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([S:18]([CH3:21])(=[O:20])=[O:19])[CH:13]=3)=[CH:10][CH:11]=2)(=[O:31])=[O:30])[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: CC(C)CNCc1ccc(-c2cccc(S(C)(=O)=O)c2)s1
Reactant: O=S(=O)(Cl)CC1CCCCC1
Solvent: ClCCl
Product: CC(C)CN(Cc1ccc(-c2cccc(S(C)(=O)=O)c2)s1)S(=O)(=O)CC1CCCCC1

Procedure:
In analogy to example 25, isobutyl-[5-(3-methanesulfonyl-phenyl)-thiophen-2-ylmethyl]-amine (example 15, step 2) was reacted with cyclohexyl-methane-sulfonylchloride and dimethylketene-methyltrimethylsilylacetal in dichloromethane to give C-cyclohexyl-N-isobutyl-N-[5-(3-methanesulfonyl-phenyl)-thiophen-2-ylmethyl]-methanesulfonamide as an off-white solid. MS: 500.9 ([M+NH4]+)