Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2[C:11]([CH2:12][OH:13])=[C:10]([C:14]([F:17])([F:16])[F:15])[O:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:18][O:19][C:20](=[O:28])[C:21]1[CH:26]=[CH:25][C:24](O)=[N: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>C1COCC1>[CH3:18][O:19][C:20](=[O:28])[C:21]1[CH:26]=[CH:25][C:24]([O:13][CH2:12][C:11]2[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[N:8][O:9][C:10]=2[C:14]([F:16])([F:17])[F:15])=[N:23][CH:22]=1
Reactant: OCc1c(-c2ccccc2)noc1C(F)(F)F
Reactant: COC(=O)c1ccc(O)nc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1ccc(OCc2c(-c3ccccc3)noc2C(F)(F)F)nc1
Temperature: 50 °C
Yield: 42.6 %

Procedure:
To a solution of (3-phenyl-5-trifluoromethyl-isoxazol-4-yl)-methanol (100 mg, 0.41 mmol) in THF (5 mL) was added 6-hydroxy-nicotinic acid methyl ester (69.3 mg, 0.45 mmol) and triphenylphosphine (162 mg, 0.62 mmol) at ambient temperature under an argon atmosphere. Then diethyl azodicarboxylate (96 μL, 0.62 mmol) was added and the reaction mixture was heated at 50° C. for 2 h. After cooling to room temperature the mixture was evaporated. Purification by chromatography (SiO2, heptane:ethyl acetate=100:0 to 1:1) afforded the title compound (66 mg, 42%) as all off-whit solid. MS: m/e=379.5 [M+H]+.
Reaction SMILES: Cl.[S:2]1[CH:6]=[CH:5][C:4]([C:7]([CH2:9][NH2:10])=[O:8])=[CH:3]1.C(=O)(O)[O-].[Na+].[Cl:16][C:17]1[CH:25]=[CH:24][C:20]([C:21](Cl)=[O:22])=[CH:19][CH:18]=1>>[Cl:16][C:17]1[CH:25]=[CH:24][C:20]([C:21]([NH:10][CH2:9][C:7]([C:4]2[CH:5]=[CH:6][S:2][CH:3]=2)=[O:8])=[O:22])=[CH:19][CH:18]=1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Reactant: NCC(=O)c1ccsc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: O=C(CNC(=O)c1ccc(Cl)cc1)c1ccsc1
Yield: 94.9 %

Procedure:
19.4 g of N-[(3-thienylcarbonyl)methyl]amine hydrochloride, 36 g of sodium bicarbonate and 21 g of 4-chlorobenzoyl chloride are treated in the same manner as described in Preparation 1-(3). 29 g of N-(4-chlorobenzoyl)-N-[(3-thienylcarbonyl)methyl]amine are thereby obtained.
Reaction SMILES: [CH2:1]=[CH:2][CH2:3][CH2:4][CH2:5][CH3:6].[Cl:7][SiH2:8][Cl:9]>>[CH2:1]([SiH:8]([Cl:9])[Cl:7])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: C=CCCCC
Reactant: Cl[SiH2]Cl
Product: CCCCCC[SiH](Cl)Cl
Temperature: 110 °C
Reaction time: 1 h

Procedure:
Zero point eight nine mol of 1-hexene and 0.1 mol % (relative to dichlorosilane) of catalyst NiCl2 (PPh3)2 were introduced into a 500 ml pressure-proof stainless reactor and after closing said reactor, was cooled in a dry ice-methanol bath. After introducing 0.64 mol of dichlorosilane through an introducing pipe, the reactor was sealed and reaction was carried out with stirring in an oil bath at 110° C. for one hour to produce n-hexyldichlorosilane (n-C6H13SiHCl2). After reaction, n-C6H13SiHCl2 having a boiling point of 100°-102° C./100 mmHg and nD20 of 1.4412 was obtained by distillation. The yield was as shown in Table 1 and there was no by-product formed.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]([C:11]2[C:19]3[C:14](=[C:15]([C:20]([F:23])([F:22])[F:21])[CH:16]=[CH:17][CH:18]=3)[NH:13][N:12]=2)=[O:10])[CH:6]=[CH:7][CH:8]=1.[H-].[Na+].I[CH2:27][CH2:28][CH3:29]>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]([C:11]2[C:19]3[C:14](=[C:15]([C:20]([F:23])([F:21])[F:22])[CH:16]=[CH:17][CH:18]=3)[N:13]([CH2:27][CH2:28][CH3:29])[N:12]=2)=[O:10])[CH:6]=[CH:7][CH:8]=1
Reactant: CCCI
Reactant: COc1cccc(C(=O)c2n[nH]c3c(C(F)(F)F)cccc23)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCn1nc(C(=O)c2cccc(OC)c2)c2cccc(C(F)(F)F)c21
Temperature: 50 °C
Reaction time: 24 h
Yield: 85.1 %

Procedure:
To a solution of [3-(methoxy)phenyl](7-trifluoromethyl-1H-indazol-3-yl)methanone (0.27 g, 0.85 mmol) in 5 mL DMF was added in one portion sodium hydride (0.034 g, 0.85 mmol, 60% in oil). After the gas evolution ceased, 1-iodopropane (0.097 mL, 1.0 mmol) was added and the reaction was stirred at ambient to 50° C. for 24 hours. The cool reaction mixture was partitioned with EtOAc and 1 N HCl. The organic phase was washed with brine and dried (Na2SO4). Removal of the solvent in vacuo afforded the crude product which was purified by flash chromatography (silica gel, hexane/EtOAC, 9:1) to give the title compound (0.262 g) as an oil. MS (ESI) m/z 363 ([M+H]+);
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1[CH:11]=[CH:12][C:13]([O:21][CH2:22][C:23]2[CH:24]=[C:25]([CH:33]=[CH:34][CH:35]=2)[O:26][CH2:27][C:28]([O:30]CC)=[O:29])=[N:14][C:15]=1[CH2:16][C:17]([CH3:20])([CH3:19])[CH3:18].[OH-].[Na+].Cl>C1COCC1.CO>[CH3:18][C:17]([CH3:20])([CH3:19])[CH2:16][C:15]1[N:14]=[C:13]([O:21][CH2:22][C:23]2[CH:24]=[C:25]([CH:33]=[CH:34][CH:35]=2)[O:26][CH2:27][C:28]([OH:30])=[O:29])[CH:12]=[CH:11][C:10]=1[C:3]1[CH:4]=[C:5]([O:8][CH3:9])[CH:6]=[CH:7][C:2]=1[F:1]
Reactant: CCOC(=O)COc1cccc(COc2ccc(-c3cc(OC)ccc3F)c(CC(C)(C)C)n2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc(F)c(-c2ccc(OCc3cccc(OCC(=O)O)c3)nc2CC(C)(C)C)c1
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 86.9 %

Procedure:
To a solution of ethyl 2-(3-(((5-(2-fluoro-5-methoxyphenyl)-6-neopentylpyridin-2-yl)oxy)methyl)phenoxy)acetate (77 mg) in THF (3.0 mL) and methanol (3.0 mL) was added 1N aqueous sodium hydroxide solution (1.0 mL), and the mixture was stirred at 50° C. for 30 min. To the reaction mixture was added 1N hydrochloric acid (1.0 mL), and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give the title compound (63 mg) as a colorless oil.
Reaction SMILES: Cl[S:2]([C:5]1[CH:6]=[CH:7][C:8]([O:14][C:15]([F:18])([F:17])[F:16])=[C:9]([CH:13]=1)[C:10]([OH:12])=[O:11])(=[O:4])=[O:3].[CH3:19][NH2:20]>ClCCl.CO>[CH3:19][NH:20][S:2]([C:5]1[CH:6]=[CH:7][C:8]([O:14][C:15]([F:18])([F:17])[F:16])=[C:9]([CH:13]=1)[C:10]([OH:12])=[O:11])(=[O:4])=[O:3]
Reactant: CN
Reactant: O=C(O)c1cc(S(=O)(=O)Cl)ccc1OC(F)(F)F
Solvent: ClCCl
Solvent: CO
Product: CNS(=O)(=O)c1ccc(OC(F)(F)F)c(C(=O)O)c1
Reaction time: 0.03 h

Procedure:
To a solution of 5-Chlorosulfonyl-2-trifluoromethoxy-benzoic acid (0.15 g) in dichloromethane (1.5 ml) was added a solution of methylamine in methanol (8M, 0.31 mL) and the reaction mixture was stirred for 2 minutes after precipitation was compete. The reaction mixture was then concentrated in vacuo and the residue was dissolved in 1N NaOH (2 mL) and extracted with diethylether. The aqueous phase was then acidified using 3 N hydrochloric acid solution (2 mL) and the solution was extracted with dichloromethane (2×10 mL). The combined organic phases were dried with sodium sulfate and concentrated in vacuo to yield the title compound as a white solid (0.12 g). MS (m/e): 298.0 (M−H, 100%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([NH:8][S:9]([C:12]2[S:16][C:15]3[CH:17]=[CH:18][C:19]([F:21])=[CH:20][C:14]=3[C:13]=2[CH3:22])(=[O:11])=[O:10])=[C:4]([C:23]([F:26])([F:25])[F:24])[CH:3]=1.[N:27]1[CH:32]=[CH:31][CH:30]=[C:29](B(O)O)[CH:28]=1>COCCOC.C(O)C.C(=O)([O-])[O-].[Na+].[Na+].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>[N:27]1[CH:32]=[CH:31][CH:30]=[C:29]([C:2]2[CH:7]=[CH:6][C:5]([NH:8][S:9]([C:12]3[S:16][C:15]4[CH:17]=[CH:18][C:19]([F:21])=[CH:20][C:14]=4[C:13]=3[CH3:22])(=[O:10])=[O:11])=[C:4]([C:23]([F:26])([F:24])[F:25])[CH:3]=2)[CH:28]=1
Reactant: OB(O)c1cccnc1
Reactant: Cc1c(S(=O)(=O)Nc2ccc(Br)cc2C(F)(F)F)sc2ccc(F)cc12
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: COCCOC
Solvent: CCO
Product: Cc1c(S(=O)(=O)Nc2ccc(-c3cccnc3)cc2C(F)(F)F)sc2ccc(F)cc12
Yield: 86.3 %

Procedure:
This compound was prepared in analogy to Example 2 starting from 5-fluoro-3-methyl-benzo[b]thiophene-2-sulfonic acid(4-bromo-2-trifluoromethyl-phenyl)-amide (0.10 g) and 3-pyridineboronic acid (0.052 g) in 1,2-dimethoxyethane (1.5 ml), ethanol (0.32 ml) and 2 M aqueous sodium carbonate solution (0.8 ml) with tetrakis(triphenylphosphine)palladium (0.050 g) to obtain the title compound (0.086 g) as a colorless solid. MS (ISP): 467.0 (M+H)+
Reaction SMILES: [C:1]([C:4]1[C:9]([NH:10][C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([CH:19]([CH3:21])[CH3:20])[N:14]=2)=O)=[C:8]([CH3:22])[C:7]([O:23][CH3:24])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[OH-].[K+].O>N1C=CC=CC=1>[OH:3][C:1]1[C:4]2[C:9](=[C:8]([CH3:22])[C:7]([O:23][CH3:24])=[CH:6][CH:5]=2)[N:10]=[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([CH:19]([CH3:21])[CH3:20])[N:14]=2)[CH:2]=1
Reactant: COc1ccc(C(C)=O)c(NC(=O)c2cccc(C(C)C)n2)c1C
Agent: [K+]
Agent: [OH-]
Solvent: c1ccncc1
Solvent: O
Product: COc1ccc2c(O)cc(-c3cccc(C(C)C)n3)nc2c1C
Temperature: 133 °C
Yield: 94 %

Procedure:
To a solution of 6-isopropylpyridine-2-carboxylic acid (6-acetyl-3-methoxy-2-methyl-phenyl)amide (107, 0.70 g, 2.14 mmol) in pyridine (5 mL) were added 2.5 equivalents of freshly grounded KOH along with water (50 μL). The mixture was heated by microwave irradiation at 133° C. for 55 min, then 80-85% of the pyridine was evaporated under reduced pressure. The residue was poured on ice and neutralized with acetic acid. The precipitate was filtered off, then dried to give 0.62 g (95%) of the title compound 108 (1.8 g, 95%): m/z=309 (M+H)+.
Reaction SMILES: [C:1]([CH2:8][N:9]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16][N:15]([CH2:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C(N(CC)CC)C.[N+:36]([C:39]1[CH:46]=[CH:45][C:42]([CH2:43]Br)=[CH:41][CH:40]=1)([O-:38])=[O:37]>C(Cl)(Cl)Cl>[C:22]([CH2:21][N:15]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10][N:9]([CH2:8][C:1]([O:3][C:4]([CH3:6])([CH3:5])[CH3:7])=[O:2])[CH2:20][CH2:19][N:18]([CH2:43][C:42]2[CH:45]=[CH:46][C:39]([N+:36]([O-:38])=[O:37])=[CH:40][CH:41]=2)[CH2:17][CH2:16]1)([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23]
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Reactant: CC(C)(C)OC(=O)CN1CCNCCN(CC(=O)OC(C)(C)C)CCNCC1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)CN1CCNCCN(CC(=O)OC(C)(C)C)CCN(Cc2ccc([N+](=O)[O-])cc2)CC1
Temperature: 25 °C
Reaction time: 10 h
Yield: 80 %

Procedure:
To a solution of compound (20) (1.85 g, 4.62 mmol) in dry CHCl3 (50 ml) were added triethylamine (1.93 ml, 1.40 g, 13.86 mmol) and 4-nitrobenzylbromide (0.99 g, 4.62 mmol). After stirring the mixture at an ambient temperature for 10 hours, the solvent was removed under reduced pressure, and the residue was purified via alumina (basic) column chromatography. Extraction with ethyl acetate/methanol (10:2) gave a solidified clear oily compound (21) (1.98 g, 80% yield).
Reaction SMILES: C([O:5][C:6](=[O:72])[C@H:7]([CH2:63][CH2:64][C:65]([O:67]C(C)(C)C)=[O:66])[NH:8][S:9]([C:12]1[CH:17]=[CH:16][C:15]([NH:18][C:19](=[O:62])[CH2:20][CH2:21][S:22][CH2:23][CH:24]([O:44][C:45](=[O:61])[CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH3:60])[CH2:25][O:26][C:27](=[O:43])[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])=[CH:14][CH:13]=1)(=[O:11])=[O:10])(C)(C)C>FC(F)(F)C(O)=O>[C:45]([O:44][CH:24]([CH2:25][O:26][C:27](=[O:43])[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])[CH2:23][S:22][CH2:21][CH2:20][C:19]([NH:18][C:15]1[CH:14]=[CH:13][C:12]([S:9]([NH:8][C@H:7]([C:6]([OH:72])=[O:5])[CH2:63][CH2:64][C:65]([OH:67])=[O:66])(=[O:10])=[O:11])=[CH:17][CH:16]=1)=[O:62])(=[O:61])[CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH3:60]
Reactant: CCCCCCCCCCCCCCCC(=O)OCC(CSCCC(=O)Nc1ccc(S(=O)(=O)N[C@@H](CCC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)cc1)OC(=O)CCCCCCCCCCCCCCC
Solvent: O=C(O)C(F)(F)F
Product: CCCCCCCCCCCCCCCC(=O)OCC(CSCCC(=O)Nc1ccc(S(=O)(=O)N[C@@H](CCC(=O)O)C(=O)O)cc1)OC(=O)CCCCCCCCCCCCCCC
Temperature: 25 °C
Reaction time: 4 h
Yield: 100 %

Procedure:
A solution of (4-(6,7-bis(palmitoyloxy)-4-thiaheptanoylamino)benzenesulfonyl)glutamic acid di-t-butyl ester as obtained in Example 19 (213 mg) in trifluoroacetic acid (5 ml) was stirred at room temperature for 4 hours and then concentrated to yield the title compound (190 mg, yield 100% ) as a colorless crystal.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]12[CH2:13][CH:8]3[CH2:9][CH:10]([CH2:12][CH:6]([C:7]3=[O:14])[CH2:5]1)[CH2:11]2.[CH3:15]I.[Cl-].[Na+]>CN(C)C=O>[CH3:15][O:3][C:4]12[CH2:13][CH:8]3[CH2:9][CH:10]([CH2:12][CH:6]([C:7]3=[O:14])[CH2:5]1)[CH2:11]2
Reactant: O=C1C2CC3CC1CC(O)(C3)C2
Reactant: CI
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC12CC3CC(C1)C(=O)C(C3)C2
Temperature: 50 °C
Reaction time: 8 h

Procedure:
55% sodium hydride (40 mg, 0.917 mmol) in N,N-dimethylformamide (1 mL) was mixed with 5-hydroxy-2-adamantanone (100 mg, 0.602 mmol) and methyl iodide (750 μL, 12 mmol) at 0° C. and stirred at 50° C. for 8 hours. After completion of the reaction, the reaction solution was mixed with saturated aqueous sodium chloride and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and evaporated under reduced pressure. The resulting crude reaction product containing the desired product was used for the next step.
Reaction SMILES: CS([O:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([Br:13])=[C:9]([F:14])[CH:8]=1)(=O)=O.N1C(C)=CC=C[C:16]=1C>CO.CCOCC>[Br:13][C:10]1[CH:11]=[CH:12][C:7]([CH2:6][O:5][CH3:16])=[CH:8][C:9]=1[F:14]
Reactant: Cc1cccc(C)n1
Reactant: CS(=O)(=O)OCc1ccc(Br)c(F)c1
Solvent: CCOCC
Solvent: CO
Product: COCc1ccc(Br)c(F)c1

Procedure:
A solution of 4-bromo-3-fluorobenzyl methanesulfonate (Intermediate 18, 286 mg; 1.01 mmol) and 2,6-lutidine (234 μL; 2.0 mmol) in methanol (4 mL) was stirred for 16 hours at RT. Additional aliquots of 2,6-lutidine (234 μL; 2.0 mmol each) were added once a day for a total of three days, during which stirring was continued at RT. The mixture was taken up in Et2O, washed with water, HCl (0.1N in water) and brine. The organic phase was dried over MgSO4, filtered and concentrated with moderate vacuum and without heating affording the title compound in a mixture with ethyl ether.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[O:10])[O:8][C:6](=O)[C:5]2=[CH:11][C:12]=1[Cl:13].[C:14]([CH:19]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O:16][CH2:17][CH3:18])=[O:15]>C(Cl)(Cl)Cl>[CH2:17]([O:16][C:14]([CH:19]=[C:6]1[C:5]2[C:4](=[CH:3][C:2]([Cl:1])=[C:12]([Cl:13])[CH:11]=2)[C:9](=[O:10])[O:8]1)=[O:15])[CH3:18]
Reactant: O=C1OC(=O)c2cc(Cl)c(Cl)cc21
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClC(Cl)Cl
Product: CCOC(=O)C=C1OC(=O)c2cc(Cl)c(Cl)cc21
Yield: 70.8 %

Procedure:
A solution of 4,5-dichlorophthalic anhydride (10.0 g) and (carbethoxymethylene)triphenylphosphorane (16.0 g) in chloroform (450 ml) was refluxed for 16 hours. Evaporation of chloroform and chromatography of the residue over silica gel gave the product (9.34 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][CH:6]=[C:5]2[S:13]([N:16]1[CH2:22][CH2:21][CH2:20][N:19]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:18][CH2:17]1)(=[O:15])=[O:14].CS(O[CH2:35][C:36]1([CH2:39][O:40][Si:41]([C:44]([CH3:47])([CH3:46])[CH3:45])([CH3:43])[CH3:42])[CH2:38][CH2:37]1)(=O)=O.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.O>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7]([CH2:35][C:36]1([CH2:39][O:40][Si:41]([C:44]([CH3:47])([CH3:46])[CH3:45])([CH3:43])[CH3:42])[CH2:37][CH2:38]1)[CH:6]=[C:5]2[S:13]([N:16]1[CH2:22][CH2:21][CH2:20][N:19]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:18][CH2:17]1)(=[O:14])=[O:15]
Reactant: CC(C)(C)[Si](C)(C)OCC1(COS(C)(=O)=O)CC1
Reactant: CC(C)(C)OC(=O)N1CCCN(S(=O)(=O)c2c[nH]c(=O)c3ccc(Br)cc23)CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCCN(S(=O)(=O)c2cn(CC3(CO[Si](C)(C)C(C)(C)C)CC3)c(=O)c3ccc(Br)cc23)CC1
Temperature: 25 °C

Procedure:
tert-Butyl 4-[(6-bromo-1-oxo-1,2-dihydroisoquinolin-4-yl)sulfonyl]-1,4-diazepane-1-carboxylate (Example 46b, 0.40 g), [1-({[tert-butyl(dimethyl)silyl]oxy}methyl)cyclopropyl]methyl methanesulfonate (0.24 g) and cesium carbonate (0.536 g) were stirred together in DMF (20 mL) at 110° C. for 72 h under nitrogen, cooled to room temperature, diluted with water (100 mL) and extracted into ethyl acetate (3×20 mL). The combined organics were washed with saturated brine (3×20 mL), dried (MgSO4) filtered and evaporated, and the residue was purified (SiO2 chromatography, elution with 10% ethyl acetate in DCM) to give (tert-butyl 4-[(6-bromo-2-{[1-({[tert-butyl(dimethyl)silyl]oxy}methyl)cyclopropyl]methyl}-1-oxo-1,2-dihydroisoquinolin-4-yl)sulfonyl]-1,4-diazepane-1-carboxylate) as a solid. This was dissolved in DMF (10 mL), treated with N-cyclopropyl-3-fluoro-4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (0.089 g), potassium carbonate (0.077 g) and Pd-118 (0.006 g) and the resulting mixture was stirred at 70° C. under nitrogen for 1 h. After being cooled to room temperature, it was diluted with saturated brine and extracted into ethyl acetate (3×30 mL). The combined extracts were washed with brine (3×30 mL), dried (MgSO4) filtered and evaporated. The residue was dissolved in THF (20 mL), treated with 4 M HCl in dioxane (3 mL), stirred at room temperature for 3 h, evaporated and purified by preparative HPLC (Waters Xbridge column using a 95-5% gradient of aqueous 0.2% ammonia in acetonitrile as eluent) to give the title compound (0.019 g) as a solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([NH:15][C:16]2[N:21]=[C:20]([N:22]3[CH2:27][C@@H:26]([NH:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:25][C@@H:24]([NH:36][C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:23]3)[N:19]=[C:18]([N:44]3[CH2:49][C@@H:48]([NH:50][C:51]([O:53][C:54]([CH3:57])([CH3:56])[CH3:55])=[O:52])[CH2:47][C@@H:46]([NH:58][C:59]([O:61][C:62]([CH3:65])([CH3:64])[CH3:63])=[O:60])[CH2:45]3)[N:17]=2)[CH:12]=[CH:11][C:10]=1[NH2:66])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:67][C:68]1[CH:79]=[CH:78][C:71]2[C:72](=O)[O:73]C(=O)[O:75][C:70]=2[CH:69]=1>CN1C(=O)CCC1.CCOC(C)=O>[CH2:1]([O:8][C:9]1[CH:14]=[C:13]([NH:15][C:16]2[N:21]=[C:20]([N:22]3[CH2:27][C@@H:26]([NH:28][C:29]([O:31][C:32]([CH3:33])([CH3:34])[CH3:35])=[O:30])[CH2:25][C@@H:24]([NH:36][C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:23]3)[N:19]=[C:18]([N:44]3[CH2:45][C@@H:46]([NH:58][C:59]([O:61][C:62]([CH3:65])([CH3:64])[CH3:63])=[O:60])[CH2:47][C@@H:48]([NH:50][C:51]([O:53][C:54]([CH3:57])([CH3:56])[CH3:55])=[O:52])[CH2:49]3)[N:17]=2)[CH:12]=[CH:11][C:10]=1[NH:66][C:72](=[O:73])[C:71]1[CH:78]=[CH:79][C:68]([Cl:67])=[CH:69][C:70]=1[OH:75])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=c1oc(=O)c2ccc(Cl)cc2o1
Reactant: CC(C)(C)OC(=O)N[C@@H]1C[C@H](NC(=O)OC(C)(C)C)CN(c2nc(Nc3ccc(N)c(OCc4ccccc4)c3)nc(N3C[C@H](NC(=O)OC(C)(C)C)C[C@H](NC(=O)OC(C)(C)C)C3)n2)C1
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: CC(C)(C)OC(=O)N[C@@H]1C[C@H](NC(=O)OC(C)(C)C)CN(c2nc(Nc3ccc(NC(=O)c4ccc(Cl)cc4O)c(OCc4ccccc4)c3)nc(N3C[C@H](NC(=O)OC(C)(C)C)C[C@H](NC(=O)OC(C)(C)C)C3)n2)C1
Temperature: 80 °C
Yield: 60 %

Procedure:
2-Benzyloxy-N4-(4,6-bis-((3R,5S)-3,5-bis-(tert-butoxycarbonylamino)-piperidin-1-yl)-[1,3,5]triazin-2-yl)-benzene-1,4-diamine (83) (0.16 g, 0.174 mmol) and 7-chloro-benzo[1,3]dioxine-2,4-dione (91) (0.2 g, 1.0 mmol) were combined and dissolved in NMP (8 mL). The mixture was heated to 80° C. for 16 h. LC-MS indicated complete reaction at this point. The mixture was diluted with EtOAc (30 mL), washed with water (2×15 mL), saturated aqueous NaHCO3 (2×15 mL) and brine (2×15 mL) via extraction, dried over MgSO4 and concentrated to give a brown oil. Purification by flash chromatography on silica gel using a gradient of hexane and EtOAc (15–100% EtOAc in hexane) gave the desired product (92) as a yellow powder upon concentration (0.111 g, 0.103 mmol, 60% yield). LC-MS (ESI): (exact mass: 1073.51) m/e=1074.6 [M+1]+ (100%).
Reaction SMILES: C([O:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:8][N:7]=1)(=O)C.[OH-].[Na+].O1CCCC1>CO>[C:12]1([C:9]2[CH:10]=[CH:11][C:6]([CH2:5][OH:4])=[N:7][CH:8]=2)[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: CC(=O)OCc1ccc(-c2ccccc2)cn1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: OCc1ccc(-c2ccccc2)cn1
Yield: 94.7 %

Procedure:
A mixture of 5-phenyl-2-pyridylmethyl acetate (3.68 g), a 1N aqueous sodium hydroxide solution (30 ml), tetrahydrofuran (30 ml) and methanol (300 ml) was stirred at room temperature for 3 hours, which was concentrated. The residue was dissolved in ethyl acetate, and then the solution was washed with water, then with saturated aqueous sodium chloride solution, dried (MgSO4), and concentrated. The residual colorless crystals were collected by filtration to obtain 5-phenyl-2-pyridylmethanol (2.84 g, yield 95%). This was recrystallized from ethyl acetate-hexane. Melting point: 86–87° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[C:9]([F:29])=[C:10](F)[C:11]3[C:21](=[O:22])[C:20]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:19][N:13]4[C@@H:14]([CH3:18])[CH2:15][O:16][C:17]=2[C:12]=34)[CH:5]=[C:4]([CH3:30])[N:3]=1.[CH2:31]([SH:38])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.[H-].[Na+]>O1CCCC1.C([O-])(=O)C.[Na+]>[CH2:31]([S:38][C:10]1[C:11]2[C:21](=[O:22])[C:20]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:19][N:13]3[C@@H:14]([CH3:18])[CH2:15][O:16][C:17]([C:12]=23)=[C:8]([C:6]2[CH:7]=[C:2]([CH3:1])[N:3]=[C:4]([CH3:30])[CH:5]=2)[C:9]=1[F:29])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: CCOC(=O)c1cn2c3c(c(-c4cc(C)nc(C)c4)c(F)c(F)c3c1=O)OC[C@@H]2C
Reactant: SCc1ccccc1
Agent: CC(=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)c1cn2c3c(c(-c4cc(C)nc(C)c4)c(F)c(SCc4ccccc4)c3c1=O)OC[C@@H]2C
Reaction time: 1 h

Procedure:
To a suspension of 2.78 g ethyl (S)-10-(2,6-dimethyl-4-pyridinyl)-8,9-difluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido[1,2,3-de][1,4]benzoxazine-6-carboxylate in 67 ml tetrahydrofuran cooled in an ice-bath was added 0.79 ml benzyl mercaptan, followed by 0.34 g sodium hydride (60% in oil, washed with hexane before use) portionwise, and the mixture was stirred for one hour. An additional 0.079 ml benzyl mercaptan was added and stirring continued at room temperature for 3 hours. The reaction mixture was diluted with saturated sodium acetate solution and extracted with ethyl acetate. The extract was washed with water, dried (sodium sulfate) and concentrated. The residue was crystallized from isopropyl acetate to give 1.98 g ethyl (S)-8-(benzylthio)-10-(2,6-dimethyl-4-pyridinyl)-9-fluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido[1,2,3-de][1,4]benzoxazine-6-carboxylate, yellow solid, m.p. 175°-178° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]=[N:7][C:8]([Cl:12])=[CH:9][C:10]=1Cl)=[O:4].[CH3:13][N:14]1[CH:18]=[CH:17][C:16]([NH2:19])=[N:15]1>CN1CCCC1=O>[CH3:1][O:2][C:3]([C:5]1[N:6]=[N:7][C:8]([Cl:12])=[CH:9][C:10]=1[NH:19][C:16]1[CH:17]=[CH:18][N:14]([CH3:13])[N:15]=1)=[O:4]
Reactant: Cn1ccc(N)n1
Reactant: COC(=O)c1nnc(Cl)cc1Cl
Solvent: CN1CCCC1=O
Product: COC(=O)c1nnc(Cl)cc1Nc1ccn(C)n1
Temperature: 110 °C
Yield: 32.2 %

Procedure:
4,6-Dichloro-pyridazine-3-carboxylic acid methyl ester (165 mg, 0.8 mmol) and 1-methyl-1H-pyrazol-3-amine (81 mg, 0.837 mmol) were dissolved in of N-methylpyrrolidinone (3.2 mL). The reaction was heated at 110° C. for 2 h, then cooled and concentrated in vacuo. The residue was diluted with water and then extracted with ethyl acetate. The combined organic extracts were washed with brine, dried (sodium sulfate), filtered and concentrated in vacuo. Purification by chromatography (silica, 10 to 70% ethyl acetate in hexanes) gave 6-chloro-4-(1-methyl-1H-pyrazol-3-ylamino)-pyridazine-3-carboxylic acid methyl ester (69 mg, 32%) as a light brown solid. 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 10.09 (br. s., 1H) 8.24 (s, 1H) 7.34 (d, J=2.3 Hz, 1H) 6.02 (d, J=2.3 Hz, 1H) 4.08 (s, 3H) 3.91 (s, 3H); LCMS (EI/CI) m/z: 268 [M+H].