Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[C:10]([S:11]([OH:14])(=[O:13])=[O:12])=[CH:9][C:8](N)=[C:7]2[C:2]=1[CH:3]=[C:4](S(O)(=O)=O)[CH:5]=[C:6]2O.C1C2C(=CC=CC=2)C=CC=1.O.[S:32](=[O:36])(=[O:35])([OH:34])O.[OH:37][S:38](O)(=[O:40])=[O:39].O=S(=O)=O>>[C:8]1([S:38]([OH:40])(=[O:39])=[O:37])[C:7]2[C:2](=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:1]=[C:10]([S:11]([OH:14])(=[O:13])=[O:12])[C:9]=1[S:32]([OH:34])(=[O:36])=[O:35]
Reactant: O=S(=O)(O)O
Reactant: Nc1cc(S(=O)(=O)O)cc2cc(S(=O)(=O)O)cc(O)c12
Agent: O=S(=O)=O
Solvent: O
Solvent: c1ccc2ccccc2c1
Product: O=S(=O)(O)c1cc2ccccc2c(S(=O)(=O)O)c1S(=O)(=O)O

Procedure:
It is known from FIAT Final Report No. 1016, pages 32 to 39, that H-acid can be prepared as follows: naphthalene is reacted with sulphuric acid monohydrate (=100% strength H2SO4) and 65% strength oleum, a certain temperature programme being maintained and the sulphuric acid monohydrate and oleum being added stepwise, to give a naphthalene-trisulphonic acid isomer mixture which is nitrated with mixed acid. After diluting the mixture with water, driving off the nitrous fumes and removing the sulphuric acid as calcium sulphate, the isomer mixture of the nitronaphthalene-trisulphonic acids is reduced with iron and dissolved iron salts are then precipitated with magnesium oxide and separated off. The acid calcium-sodium salt of T-acid (1-naphthylamine-3,6,8-trisulphonic acid) is precipitated by adding sodium chloride and hydrochloric acid, and is filtered off and repeatedly washed. This salt is introduced into wash water and sodium carbonate is added. The calcium carbonate which has precipitated is then removed on a filter press and the salt solution is concentrated. The concentrated trisodium salt solution of T-acid is reacted with 50% strength sodium hydroxide solution under pressure. Thereafter first sulphuric acid and then water are added and finally the H-acid is isolated as the monosodium salt by filtration, washing and drying.
Reaction SMILES: C[CH2:2][N:3]=[C:4]=NCCCN(C)C.[ClH:12].C(N(C(C)C)CC)(C)C.Cl.CNC.[C:26]1([C:32]#[C:33][C:34]2[CH:35]=[N:36][CH:37]=[C:38]([CH:42]=2)[C:39](O)=[O:40])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>O1CCCC1.C(OCC)(=O)C>[ClH:12].[CH3:2][N:3]([CH3:4])[C:39](=[O:40])[C:38]1[CH:42]=[C:34]([C:33]#[C:32][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:35]=[N:36][CH:37]=1
Reactant: CCN=C=NCCCN(C)C
Reactant: O=C(O)c1cncc(C#Cc2ccccc2)c1
Agent: CNC
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CN(C)C(=O)c1cncc(C#Cc2ccccc2)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Add N-(3-dimethylaminopropyl)-N-ethylcarbodiimide hydrochloride (0.34 g, 1.8 mmol) to a solution of diisopropylethyl amine (0.47 mg, 2.7 mmol), dimethylamine hydrochloride (0.11g, 1.34 mmol) and 5-phenylethynyl-nicotinic acid (0.2 g, 0.9 mmol) in tetrahydrofuran and stir at room temperature for 18 h. Dilute the reaction mixture with ethyl acetate and extract with an aqueous saturated solution of sodium carbonate. Extract the aqueous layer with ethyl acetate. Combine organic layers, dry (magnesium sulfate), filter and concentrate. Purify by silica gel chromatography, eluting with 40:60 to 80:20 ethyl acetate:hexanes, to give the free base of the title compound as a colorless oil. Convert the free base to the hydrochloride salt as described in EXAMPLE 163 to give the title compound (0.18 g, 69%).
Reaction SMILES: Cl[C:2]1[C:7]([NH:8][CH:9]=[O:10])=[C:6]([Cl:11])[N:5]=[C:4]([NH:12][CH:13]=[O:14])[N:3]=1.[NH2:15][O:16][CH2:17][CH2:18][CH2:19][CH2:20][P:21](=[O:28])([O:25][CH2:26][CH3:27])[O:22][CH2:23][CH3:24].C(N(CC)C(C)C)(C)C>COCCOCCOC>[Cl:11][C:6]1[C:7]([NH:8][CH:9]=[O:10])=[C:2]([NH:15][O:16][CH2:17][CH2:18][CH2:19][CH2:20][P:21]([O:22][CH2:23][CH3:24])([O:25][CH2:26][CH3:27])=[O:28])[N:3]=[C:4]([NH:12][CH:13]=[O:14])[N:5]=1
Reactant: CCOP(=O)(CCCCON)OCC
Reactant: O=CNc1nc(Cl)c(NC=O)c(Cl)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: COCCOCCOC
Product: CCOP(=O)(CCCCONc1nc(NC=O)nc(Cl)c1NC=O)OCC
Temperature: 100 °C
Reaction time: 3 h
Yield: 83.7 %

Procedure:
4,6-Dichloro-2,5-diformamidopyrimidine (0.35 g, 1.5 mmol), diethyl 4-(aminooxy)butylphosphonate (0.216 g, 0.93 mmol) and N,N-diisopropylethylamine (0.521 ml, 3 mmol) were dissolved in diglyme (15 ml) and stirred at 100° C. for 3 hr. The reaction mixture was then allowed to cool, the hydrochloride of N,N-diisopropylethylamine was filtered off and the filtrate was diluted with chloroform (150 ml). The resulting solution was washed with 4% aq. NaHCO3 (1×20 ml) and water (1×20 ml). The combined aqueous layers were extracted with chloroform (4×20 ml) and the combined chloroform solutions were evaporated to dryness. The residue was chromatographed on silica gel (eluted with chloroform-ethanol, 96:4) to yield the title compound (0.330 g, 81%). 1H NMR: δH ((CD3)2SO) 1.22 (6H, t, J=7Hz, (OCH2CH3)2), 1.7 (6H, m, CH2CH2CH 2 P), 3.87 (2H, t, J=5Hz, OCH2), 3.98 (4H, m, (OCH2CH3)2) 8.14 (1H, s, 5-NHCHO), 8.31 (1H, s, 6-NHCHO), 9.24 (1H, br.s, 2-NHCHO), 9.41 (1H, br.s, D2O exchangeable, NHOCH2), 10.81 (2H, br.s, D2O exchangeable, NHCHO, NHCHO).
Reaction SMILES: [N:1]1([C:6]2[CH:18]=[CH:17][C:9]3[O:10][CH2:11][CH2:12][NH:13][CH2:14][CH2:15][O:16][C:8]=3[CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.[CH:19]1([CH2:25][CH:26]=O)[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1.[BH3-]C#N.[Na+]>>[CH:19]1([CH2:25][CH2:26][N:13]2[CH2:12][CH2:11][O:10][C:9]3[CH:17]=[CH:18][C:6]([N:1]4[CH:5]=[CH:4][N:3]=[CH:2]4)=[CH:7][C:8]=3[O:16][CH2:15][CH2:14]2)[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: O=CCC1CCCCC1
Reactant: c1cn(-c2ccc3c(c2)OCCNCCO3)cn1
Agent: [BH3-]C#N
Agent: [Na+]
Product: c1cn(-c2ccc3c(c2)OCCN(CCC2CCCCC2)CCO3)cn1

Procedure:
In a manner similar to example 4, react 9-(1H-imidazol-1-yl)-3,4,5,6-tetrahydro-2H-1,7,4-benzodioxazonine with cyclohexaneacetaldehyde and NaBH3CN to obtain the title compound.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1([C:12]([OH:14])=O)[CH2:11][CH2:10][O:9][CH2:8][CH2:7]1.S(Cl)([Cl:17])=O.CN(C=O)C>C(Cl)Cl>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1([C:12]([Cl:17])=[O:14])[CH2:11][CH2:10][O:9][CH2:8][CH2:7]1
Reactant: O=C(O)C1(c2cccs2)CCOCC1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)C1(c2cccs2)CCOCC1

Procedure:
4-(2-Thienyl)tetrahydropyran-4-carboxylic acid was reacted with thionyl chloride and a catalytic amount of DMF in methylene chloride under heating to obtain 4-(2-thienyl)tetrahydropyran-4-carbonyl chloride. A THF solution of 4-(2-thienyl)tetrahydropyran-4-carbonyl chloride was added dropwise to a THF solution of hydrazine monohydrate and the whole was reacted at 0° C. to obtain 4-(2-thienyl)tetrahydropyran-4-carbohydrazide.
Reaction SMILES: [C:1]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])(=[O:4])[NH:2][NH2:3].[CH3:10][C:11]1[CH:18]=[CH:17][C:14]([CH:15]=O)=[CH:13][CH:12]=1>O.C(O)(C)C.[Pd]>[CH3:10][C:11]1[CH:18]=[CH:17][C:14]([CH2:15][N:2]([C:1]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4])[NH2:3])=[CH:13][CH:12]=1
Reactant: Cc1ccc(C=O)cc1
Reactant: CC(C)(C)OC(=O)NN
Agent: [Pd]
Solvent: CC(C)O
Solvent: O
Product: Cc1ccc(CN(N)C(=O)OC(C)(C)C)cc1
Temperature: 35 °C
Reaction time: 4 h
Yield: 88.1 %

Procedure:
To a 10-gal stainless steel autoclave containing isopropanol (10 L) under nitrogen was charged t-butyl carbazate (1.25 kg, 9.46 mol)followed by isopropanol (2 L). The contents were stirred and heated at 35° C. for 30 min, then 4-methylbenzaldehyde (1.142 kg, 9.51 mol) was added, followed by isopropanol (0.3 L). The contents were heated to 45° C., and a slurry of 5% Pd/C (0.3 kg) in water (0.3 L) and isopropanol (4 L) was added, followed by rinses of isopropanol (2×1 L). The contents were hydrogenated at 40 psig and 45° C. for 4 h, then a second charge of 5% Pd/C (0.3 kg) in water (0.3 L) and isopropanol (4 L) was added, followed by rinses of isopropanol (2×1 L). Hydrogenation was continued at 40 psig and 45° C. for 14 h, at which the reaction was determined to be complete by HPLC. The contents were then cooled to 15° C. and filtered, and the filter cake rinsed with isopropanol (15 L). The filtrate was concentrated in vacuo to afford the title compound (1.97 kg, 88.2%) as a 33.8 wt-% solution in isopropanol.
Reaction SMILES: Cl[C:2]1[NH:6][C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[N:3]=1.[Br:11][C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=1.C(N(CC)CC)C>C(OCC)(=O)C>[Br:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][C:2]2[NH:6][C:5]3[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=3[N:3]=2)=[CH:14][CH:13]=1
Reactant: Oc1ccc(Br)cc1
Reactant: Clc1nc2ccccc2[nH]1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: Brc1ccc(Oc2nc3ccccc3[nH]2)cc1
Temperature: 120 °C
Reaction time: 15 h
Yield: 54.4 %

Procedure:
A mixture of 2-chloro-1H-benzimidazole (5.6 g), 4-bromophenol (9.87 g) and triethylamine (19.89 ml) was stirred at 120° C. for 15 hr, and ethyl acetate was added. The reaction mixture was washed with 1 M aqueous sodium hydroxide solution and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. A solid precipitated from the residue was collected by filtration to give the title compound (5.77 g).
Reaction SMILES: CC([O:5][C:6](=[O:46])[C@H:7]([CH2:20][NH:21][C:22]1[C:27]([CH2:28][CH3:29])=[C:26]([N:30]2[CH2:35][CH2:34][CH:33]([C:36]3[N:45]=[C:44]4[C:39]([CH2:40][CH2:41][CH2:42][NH:43]4)=[CH:38][CH:37]=3)[CH2:32][CH2:31]2)[N:25]=[CH:24][N:23]=1)[NH:8][S:9]([C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1)(=[O:11])=[O:10])(C)C.FC(F)(F)C(O)=O.ClCCl.CO.O.C(O)(=O)C.C1(C)C=CC=CC=1>ClCCl>[CH2:28]([C:27]1[C:22]([NH:21][CH2:20][C@@H:7]([C:6]([OH:46])=[O:5])[NH:8][S:9]([C:12]2[CH:13]=[CH:14][C:15]([O:18][CH3:19])=[CH:16][CH:17]=2)(=[O:10])=[O:11])=[N:23][CH:24]=[N:25][C:26]=1[N:30]1[CH2:35][CH2:34][CH:33]([C:36]2[N:45]=[C:44]3[C:39]([CH2:40][CH2:41][CH2:42][NH:43]3)=[CH:38][CH:37]=2)[CH2:32][CH2:31]1)[CH3:29]
Reactant: CCc1c(NC[C@H](NS(=O)(=O)c2ccc(OC)cc2)C(=O)OC(C)(C)C)ncnc1N1CCC(c2ccc3c(n2)NCCC3)CC1
Solvent: Cc1ccccc1
Solvent: ClCCl
Solvent: CC(=O)O
Product: CCc1c(NC[C@H](NS(=O)(=O)c2ccc(OC)cc2)C(=O)O)ncnc1N1CCC(c2ccc3c(n2)NCCC3)CC1
Yield: 85 %

Procedure:
55.8 mg (0.086 mmoles) of (1,1-dimethylethyl)3-[[5-ethyl-6-[4-(1,2,3,4-tetrahydro-1,8-naphthyridin-7-yl)-1-piperidinyl]-4-pyrimidinyl]amino]-N-(4-methoxy-benzenesulphonyl)alaninate in 5 ml of dichloromethane with 0.5 ml of trifluoroacetic acid is stirred at ambient temperature until the starting product disappears according to TLC (silicagel, eluent: CH2Cl2-MeOH-H2O—AcOH 85-15-2-2). Toluene is added and the reaction mixture is evaporated to dryness under reduced pressure (2 kPa). The residue is solubilized in the minimum amount of dichloromethane with a little methanol then poured into diisopropyl ether. The precipitate is filtered. 59.8 mg (Yield=85% expressed as ditrifluoroacetate) of expected product is obtained.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C:8]([N:10]2[CH2:14][CH2:13][C@@H:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[C:21]([F:24])([F:23])[F:22])[CH2:11]2)=[O:9])[CH:5]=[CH:4][CH:3]=1.[NH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1.CC(C)([O-])C.[Na+].[Cl-].[NH4+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>[N:25]1([C:2]2[N:7]=[C:6]([C:8]([N:10]3[CH2:14][CH2:13][C@@H:12]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=4[C:21]([F:24])([F:23])[F:22])[CH2:11]3)=[O:9])[CH:5]=[CH:4][CH:3]=2)[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1
Reactant: C1CCNCC1
Reactant: O=C(c1cccc(Br)n1)N1CC[C@@H](c2ccccc2C(F)(F)F)C1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: Cc1ccccc1
Product: O=C(c1cccc(N2CCCCC2)n1)N1CC[C@@H](c2ccccc2C(F)(F)F)C1
Temperature: 100 °C
Reaction time: 3 h
Yield: 64.4 %

Procedure:
(S)-(6-Bromopyridin-2-yl)(3-(2-(trifluoromethyl)phenyl)pyrrolidin-1-yl)methanone (60 mg, 0.150 mmol), piperidine (15 mg, 0.180 mmol), Pd2(dba)3 (3 mg, 0.003 mmol), xantphos (5 mg, 0.009 mmol), and sodium-tert-butoxide (22 mg, 0.225 mmol) were suspended in toluene (3 ml), and then stirred at 100° C. under nitrogen stream for 3 hours. A saturated aqueous ammonium chloride solution (15 ml) was added to the resulting reaction liquid, followed by extraction with MC (15 ml×2). The organic layer was dried over anhydrous magnesium sulfate, followed by filtration and concentration, and then the residue thus obtained was subjected to MPLC (50% EtOAc/Hexanes), to obtain 39 mg of pale yellow oil (64%). MS (ESI): 404 [M+H]+
Reaction SMILES: C[Si](N[Si](C)(C)C)(C)C.[Li]CCCC.[Br:15][C:16]1[CH:17]=[C:18]([CH:24]=[CH:25][CH:26]=1)[C:19]([O:21]CC)=O.[C:27]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])(=[O:29])[CH3:28]>CC(OC)(C)C>[C:31]([O:30][C:27](=[O:29])[CH2:28][C:19]([C:18]1[CH:24]=[CH:25][CH:26]=[C:16]([Br:15])[CH:17]=1)=[O:21])([CH3:34])([CH3:33])[CH3:32]
Reactant: CCOC(=O)c1cccc(Br)c1
Reactant: CC(=O)OC(C)(C)C
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: [Li]CCCC
Solvent: COC(C)(C)C
Product: CC(C)(C)OC(=O)CC(=O)c1cccc(Br)c1

Procedure:
Prepared from hexamethyldisilizane (16.5 mL, 79 mmol) and n-BuLi (48.4 mL, 77 mmol) in TBME (40 mL), then commercially available ethyl 3-bromobenzoate (7.55 g, 33 mmol) and tert-butyl acetate (4.86 mL, 36 mmol) in TBME (80 mL) according to the general procedure III. Obtained as a light yellow oil (9.934 g, 101%; 95% purity).
Reaction SMILES: [Si]([O:8][C@H:9]1[CH2:13][N:12]([C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=2)=[O:15])[C@H:11]([CH2:27][S:28][CH:29]([F:31])[F:30])[CH2:10]1)(C(C)(C)C)(C)C.Cl>CO>[F:31][CH:29]([F:30])[S:28][CH2:27][C@@H:11]1[CH2:10][C@@H:9]([OH:8])[CH2:13][N:12]1[C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=1)=[O:15]
Reactant: CC(C)(C)[Si](C)(C)O[C@@H]1C[C@@H](CSC(F)F)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Agent: Cl
Solvent: CO
Product: O=C(OCc1ccc([N+](=O)[O-])cc1)N1C[C@H](O)C[C@H]1CSC(F)F
Reaction time: 1 h
Yield: 99.6 %

Procedure:
To a solution of (2S,4R)-4-t-butyldimethylsilyloxy-2-(difluoromethyl)thiomethyl-1-(4-nitrobenzyloxycarbonyl)pyrrolidine (1.36 g) in methanol (30 ml) was added conc. hydrochloric acid (0.47 ml) at ambient temperature and the mixture was stirred at the same temperature for 1 hour. The reaction mixture was concentrated under reduced pressure. The resulting residue was dissolved in ethyl acetate (50 ml). The solution was washed in turn with saturated aqueous sodium hydrogen carbonate and saturated aqueous sodium chloride dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give (2S,4R)-2-(difluoromethyl)thiomethyl-4-hydroxy-1-(4-nitrobenzyloxycarbonyl)pyrrolidine (1.03 g).
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:11]1[C:40]([CH3:41])=[C:39]([CH3:42])[C:38]2=[N:43][C:35]3=[CH:36][N:37]2[C:12]=1[N:13]1[CH2:49][CH2:48][C:16]([CH3:50])([O:17][CH2:18][CH2:19][CH2:20][CH2:21][C@H:22]([CH3:47])[O:23][C:24]2[CH:25]=[C:26]([F:46])[C:27]([F:45])=[CH:28][C:29]=2[C:30]2[CH:44]=[C:34]3[CH:33]=[CH:32][CH:31]=2)[CH2:15][CH2:14]1)[C:7]([O:9]C)=[O:8])([CH3:4])([CH3:3])[CH3:2].C(O[C@@H](C1C(C)=CC2=NC3=C(Cl)N2C=1N1CCC(C)(OCCCC[C@H](C)OC2C=CC(C)=CC=2C2C=C3C=CC=2)CC1)C(O)=O)(C)(C)C>>[C:1]([O:5][C@@H:6]([C:11]1[C:40]([CH3:41])=[C:39]([CH3:42])[C:38]2=[N:43][C:35]3=[CH:36][N:37]2[C:12]=1[N:13]1[CH2:14][CH2:15][C:16]([CH3:50])([O:17][CH2:18][CH2:19][CH2:20][CH2:21][C@H:22]([CH3:47])[O:23][C:24]2[CH:25]=[C:26]([F:46])[C:27]([F:45])=[CH:28][C:29]=2[C:30]2[CH:44]=[C:34]3[CH:33]=[CH:32][CH:31]=2)[CH2:48][CH2:49]1)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)[C@@H](OC(C)(C)C)c1c(C)c(C)c2nc3cn2c1N1CCC(C)(CC1)OCCCC[C@H](C)Oc1cc(F)c(F)cc1-c1cccc-3c1
Agent: Cc1ccc2c(c1)-c1cccc(c1)-c1nc3cc(C)c([C@H](OC(C)(C)C)C(=O)O)c(n3c1Cl)N1CCC(C)(CC1)OCCCC[C@H](C)O2
Product: Cc1c([C@H](OC(C)(C)C)C(=O)O)c2n3cc(nc3c1C)-c1cccc(c1)-c1cc(F)c(F)cc1O[C@@H](C)CCCCOC1(C)CCN2CC1
Yield: 52.5 %

Procedure:
Prepared in 52.5% yield from methyl(2S)-2-(tert-butoxy)-2-[(22S)-17,18-difluoro-4,5,22,28-tetramethyl-21,27-dioxa-1,7,34-triazahexacyclo[26.2.2.16,9.110,14.02,7.015,20]tetratriaconta-2,4,6(34),8,10(33),11,13,15(20),16,18-decaen-3-yl]acetate following the procedure for (2S)-2-(tert-butoxy)-2-[(22S)-8-chloro-4,17,22,28-tetramethyl-21,27-dioxa-1,7,34-triazahexacyclo[26.2.2.16,9.110,14.02,7.015,20]tetratriaconta-2,4,6(34),8,10(33),11,13,15(20),16,18-decaen-3-yl]acetic acid. 1H NMR (500 MHz, DMSO-d6) δ 8.17 (d, J=7.7 Hz, 1H), 8.09 (s, 1H), 8.00 (s, 1H), 7.53 (t, J=7.7 Hz, 1H), 7.48-7.42 (m, 1H), 7.38-7.29 (m, 2H), 6.01 (br. s., 1H), 4.67 (br. s., 1H), 3.84 (t, J=11.0 Hz, 1H), 3.64 (t, J=11.6 Hz, 1H), 3.49-3.41 (m, 2H), 3.12 (d, J=7.7 Hz, 1H), 2.64 (d, J=9.2 Hz, 1H), 2.51 (s, 3H), 2.31 (s, 3H), 1.93-1.47 (m, 10H), 1.20 (s, 3H), 1.17 (s, 9H), 1.10 (d, J=5.9 Hz, 3H); LCMS (ESI, M): 675.3.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([C:25](=[O:30])[C:26]([F:29])([F:28])[F:27])[CH2:23][CH2:22][C:21]([C:31]([NH:33][C:34]4[CH:39]=[CH:38][C:37]([CH:40]([OH:47])[C:41]5[CH:46]=[CH:45][CH:44]=[CH:43][N:42]=5)=[C:36]([O:48][CH2:49][C:50]([F:53])([F:52])[F:51])[CH:35]=4)=[O:32])=[CH:20][C:19]=3[CH:54]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].ClC1C=CC=C(C(OO)=[O:63])C=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>ClCCl>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([C:25](=[O:30])[C:26]([F:27])([F:29])[F:28])[CH2:23][CH2:22][C:21]([C:31]([NH:33][C:34]4[CH:39]=[CH:38][C:37]([CH:40]([OH:47])[C:41]5[CH:46]=[CH:45][CH:44]=[CH:43][N+:42]=5[O-:63])=[C:36]([O:48][CH2:49][C:50]([F:53])([F:51])[F:52])[CH:35]=4)=[O:32])=[CH:20][C:19]=3[CH:54]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(C(O)c4ccccn4)c(OCC(F)(F)F)c2)CCN3C(=O)C(F)(F)F)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(C(O)c4cccc[n+]4[O-])c(OCC(F)(F)F)c2)CCN3C(=O)C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.9 %

Procedure:
7-[4-(2-butoxyethoxy)phenyl]-N-[4-[hydroxy(pyridin-2-yl)methyl]-3-(2,2,2-trifluoroethoxy)phenyl]-1-trifluoroacetyl-2,3-dihydro-1H-1-benzazepine-4-carboxamide (1.5 g) was dissolved in dichloromethane (150 ml), and to the solution was added 3-chloroperbenzoic acid (0.75 g) under ice-cooling and the mixture, was stirred overnight at room temperature. An aqueous solution of sodium thiosulfate was added to the mixture, and the mixture was concentrated and extracted with ethyl acetate. The organic layer was washed with sodium bicarbonate solution, water and saturated brine, and dried over anhydrous magnesium sulfate, and then, the solvent was distilled off. The residue was purified by silica gel column chromatography (elution solvent: ethyl acetate/hexane), to give 7-[4-(2-butoxyethoxy)phenyl]-N-[4-[hydroxy(1-oxidopyridin-2-yl)methyl]-3-(2,2,2-trifluoroethoxy)phenyl]-1-trifluoroacetyl-2,3-dihydro-1H-1-benzazepine-4-carboxamide (1.5 g) as colorless crystals.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)=[CH:6][CH:5]=1)([O-])=O.C(O)(=O)C>[Zn].C(O)C>[O:14]1[CH2:13][CH2:12][N:11]([CH2:10][C:7]2[CH:8]=[CH:9][C:4]([NH2:1])=[CH:5][CH:6]=2)[CH2:16][CH2:15]1
Reactant: O=[N+]([O-])c1ccc(CN2CCOCC2)cc1
Agent: [Zn]
Solvent: CC(=O)O
Solvent: CCO
Product: Nc1ccc(CN2CCOCC2)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of (i) (205 mg, 0.92 mmol) in 50:50 acetic acid:ethanol (10 mL) was treated with zinc dust (370 mg, 5.53 mmol) then stirred at RT under N2 for 4 hr. The mixture was concentrated under vacuum and the residue suspended in EtOAc (20 mL). The solution was filtered to remove undissolved zinc, and then washed with water (50 mL). The aqueous layer was neutralised then extracted with EtOAc (3×20 mL). The organic extracts were combined and concentrated to give (ii). Sample was used in subsequent reactions without further purification. 1H NMR (400 MHz, CDCl3) δ 8.20-8.15 (m, 2H), 7.55-7.50 (m, 2H), 3.76-3.70 (m, 4H), 3.59 (s, 2H), 2.49-2.42 (m, 4H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]1([NH2:12])[CH2:11][CH2:10]1.[Br:13][C:14]1[CH:15]=[CH:16][C:17]2[N:18]([CH:20]=[C:21]([C:23](OCC)=[O:24])[N:22]=2)[CH:19]=1>>[Br:13][C:14]1[CH:15]=[CH:16][C:17]2[N:18]([CH:20]=[C:21]([C:23]([NH:12][C:9]3([C:3]4[CH:4]=[C:5]([F:8])[CH:6]=[CH:7][C:2]=4[F:1])[CH2:10][CH2:11]3)=[O:24])[N:22]=2)[CH:19]=1
Reactant: CCOC(=O)c1cn2cc(Br)ccc2n1
Reactant: NC1(c2cc(F)ccc2F)CC1
Product: O=C(NC1(c2cc(F)ccc2F)CC1)c1cn2cc(Br)ccc2n1

Procedure:
The title compound was prepared by essentially following the same procedures described for Intermediate I, using 1-(2,5-difluorophenyl)cyclopropanamine and ethyl 6-bromoimidazo[1,2-a]pyridine-2-carboxylate as starting materials.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:22]C(=O)C(F)(F)F)[CH:5]=[CH:6][C:7]=1[S:8](=[O:21])(=[O:20])[NH:9][C:10]1[CH:11]=[CH:12][C:13]2[CH2:17][O:16][B:15]([OH:18])[C:14]=2[CH:19]=1>N.CO>[NH2:22][C:4]1[CH:5]=[CH:6][C:7]([S:8]([NH:9][C:10]2[CH:11]=[CH:12][C:13]3[CH2:17][O:16][B:15]([OH:18])[C:14]=3[CH:19]=2)(=[O:20])=[O:21])=[C:2]([Br:1])[CH:3]=1
Reactant: O=C(Nc1ccc(S(=O)(=O)Nc2ccc3c(c2)B(O)OC3)c(Br)c1)C(F)(F)F
Agent: N
Solvent: CO
Product: Nc1ccc(S(=O)(=O)Nc2ccc3c(c2)B(O)OC3)c(Br)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 68.8 %

Procedure:
N-(3-bromo-4-(N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)sulfamoyl)phenyl)-2,2,2-trifluoroacetamide (200 mg) was dissolved in 7N NH3 in methanol and stirred at rt overnight. Evaporated to remove the solvent and purified by prep-HPLC to give 4-amino-2-bromo-N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)benzenesulfonamide (110 mg). 1H NMR (400 MHz, DMSO-d6) δ (ppm): 10.06 (s, 1H), 9.10 (brs, 1H), 7.65 (d, J=8.8 Hz, 1H), 7.44 (d, J=2.0 Hz, 1H), 7.21 (d, J=8.4 Hz, 1H), 7.17 (dd, J=2.0, 8.4 Hz, 1H), 6.79 (d, J=2.0 Hz, 1H), 6.48 (dd, J=2.0, 8.4 Hz, 1H), 4.84 (s, 2H). MS (ESI) m/z=381 (M−1).
Reaction SMILES: I[C:2]1[C:7]([CH3:8])=[CH:6][N:5]=[C:4]([O:9][CH3:10])[C:3]=1[CH3:11].C(=O)([O-])[O-].[Cs+].[Cs+].[F:18][C:19]1[CH:24]=[C:23](B2OC(C)(C)C(C)(C)O2)[CH:22]=[CH:21][C:20]=1[C:34]1[N:38]([C@H:39]2[CH2:43][CH2:42][O:41][CH2:40]2)[N:37]=[CH:36][C:35]=1[C:44]([O:46][CH2:47][CH3:48])=[O:45].COC1C=C(OC)C=CC=1CN1C2C=C(B(O)O)C=CC=2C2N(C3CCOCC3)N=CC=2C1=O>O1CCOCC1.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>[F:18][C:19]1[CH:24]=[C:23]([C:2]2[C:7]([CH3:8])=[CH:6][N:5]=[C:4]([O:9][CH3:10])[C:3]=2[CH3:11])[CH:22]=[CH:21][C:20]=1[C:34]1[N:38]([C@H:39]2[CH2:43][CH2:42][O:41][CH2:40]2)[N:37]=[CH:36][C:35]=1[C:44]([O:46][CH2:47][CH3:48])=[O:45]
Reactant: CCOC(=O)c1cnn([C@H]2CCOC2)c1-c1ccc(B2OC(C)(C)C(C)(C)O2)cc1F
Reactant: COc1ncc(C)c(I)c1C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: COc1ccc(Cn2c(=O)c3cnn(C4CCOCC4)c3c3ccc(B(O)O)cc32)c(OC)c1
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: CCOC(=O)c1cnn([C@H]2CCOC2)c1-c1ccc(-c2c(C)cnc(OC)c2C)cc1F

Procedure:
Water (170 mL), 4-iodo-2-methoxy-3,5-dimethylpyridine obtained in Preparation Example 29(3) (35.6 g), Pd(PPh3)4 (6.52 g) and cesium carbonate (110 g) were added to a solution of ethyl 5-[2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-1-[(S)-tetrahydrofuran-3-yl]-1H-pyrazole-4-carboxylate obtained in Preparation Example 6 (51.9 g) in 1,4-dioxane (500 mL), and the reaction mixture was reacted at 110° C. for six hours. The reaction mixture was returned to room temperature, and the organic layer was then separated. The organic layer was concentrated under reduced pressure. The aqueous layer, ethyl acetate (700 m) and water (100 mL) were added to the resulting residue, and the organic layer was separated. The aqueous layer was re-extracted with ethyl acetate (50 mL). The combined organic layers were sequentially washed with water and brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by NH silica gel column chromatography (ethyl acetate/n-heptane, 5% to 14%). The product was then purified again by NH silica gel column chromatography (ethyl acetate/n-heptane, 2% to 10%) to give the title compound (435 g).