Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([S:8]([C:11]2[CH:20]=[C:19]3[C:14]([CH2:15][CH2:16][C@H:17]([CH2:21]OS(C)(=O)=O)[O:18]3)=[CH:13][CH:12]=2)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.[C:27]1([C@H:33]([NH2:35])[CH3:34])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>CN1C(=O)CCC1>[C:4]1([S:8]([C:11]2[CH:20]=[C:19]3[C:14]([CH2:15][CH2:16][C@H:17]([CH2:21][NH:35][C@@H:33]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[CH3:34])[O:18]3)=[CH:13][CH:12]=2)(=[O:10])=[O:9])[CH:3]=[CH:2][CH:7]=[CH:6][CH:5]=1
Reactant: C[C@@H](N)c1ccccc1
Reactant: CS(=O)(=O)OC[C@H]1CCc2ccc(S(=O)(=O)c3cccc(F)c3)cc2O1
Solvent: CN1CCCC1=O
Product: C[C@@H](NC[C@H]1CCc2ccc(S(=O)(=O)c3ccccc3)cc2O1)c1ccccc1
Temperature: 110 °C
Reaction time: 18 h

Procedure:
Methanesulfonic acid (R)-7-(3-fluoro-benzenesulfonyl)-chroman-2-ylmethyl ester (1.43 g, 3.7 mmol) and (R)-1-phenyl ethylamine (3 mL) were added to NMP (5 mL), and the reaction mixture was stirred for 18 hours at 110° C. The reaction mixture was cooled to room temperature, quenched by addition of water, and made basic to pH 14 by addition of 1M aqueous NaOH. The mixture was extracted with diethyl ether, and the combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (0-30% EtOAc/hexanes) to give 1.2 g of (R)-(7-benzenesulfonyl-chroman-2-ylmethyl)-((R)-1-phenyl-ethyl)-aminel, MS (M+H)=408.
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[C@H:7]([NH2:22])[CH2:8][CH2:9][CH2:10][N:11]1[C:19](=[O:20])[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]1=[O:21])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[Cl:31][C:32]1[CH:37]=[CH:36][C:35]([C:38]2[CH:43]=[CH:42][C:41]([S:44](Cl)(=[O:46])=[O:45])=[CH:40][CH:39]=2)=[CH:34][CH:33]=1>ClCCl>[C:1]([O:5][C:6](=[O:23])[C@H:7]([NH:22][S:44]([C:41]1[CH:40]=[CH:39][C:38]([C:35]2[CH:36]=[CH:37][C:32]([Cl:31])=[CH:33][CH:34]=2)=[CH:43][CH:42]=1)(=[O:45])=[O:46])[CH2:8][CH2:9][CH2:10][N:11]1[C:12](=[O:21])[C:13]2[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:19]1=[O:20])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=S(=O)(Cl)c1ccc(-c2ccc(Cl)cc2)cc1
Reactant: CC(C)(C)OC(=O)[C@H](N)CCCN1C(=O)c2ccccc2C1=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)[C@@H](CCCN1C(=O)c2ccccc2C1=O)NS(=O)(=O)c1ccc(-c2ccc(Cl)cc2)cc1
Reaction time: 0.5 h
Yield: 52.9 %

Procedure:
A solution of the title H compound, (2R)-amino-5-(1,3-dioxo-1,3-dihydroisoindol-2-yl)pentanoic acid t-butyl ester (1.02 g, 3.19 mmol) and triethylamine (1.34 mL, 9.61 mmol) in 20 mL of dichloromethane is treated with the title 1 compound, 4′-chlorobiphenyl-4-sulfonyl chloride (0.92 g, 3.19 mmol) at 0° C. After stirring at this temperature for 30 min, then at RT for 16 h, the solution is washed with 35 mL of 2M aqueous HCl and the organic solution is washed with brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure. Chomatography on silica gel (eluant; ethyl acetate) affords 0.96 g (53%) of (2R)-(4′-chlorobiphenyl-4-sulfonylamino)-5-(1,3-dioxo-1,3-dihydroisoindol-2-yl)pentanoic acid t-butyl ester as a waxy, white solid: NMR(CDCl3) 1.21 (s, 9H), 1.60-1.68 (br m, 1H), 1.75-1.84 (br m, 3H), 3.68-3.74 (m, 2H), 3.82-3.92 (m, 1H), 5.24 (d, 1H, J=9.2), 7.44 (d, 2H, J=8.6), 7.49 (d, 2H, J=8.6), 7.65 (d, 2H, J=8.5), 7.70-7.74 (m, 2H), 7.83-7.86 (m, 2H), 7.92 (d, 2H, J=8.5); IR 1774, 1712, 1348, 1162; ESI-MS 569 (M++1).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:15])[CH:7]([S:12]([CH3:14])=[O:13])[CH:8]=[N:9]2)=[CH:4][CH:3]=1.S(OC)(O[CH3:20])(=O)=O>[OH-].[K+]>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:15])[C:7]([S:12]([CH3:14])=[O:13])=[CH:8][N:9]2[CH3:20])=[CH:4][CH:3]=1
Reactant: COS(=O)(=O)OC
Reactant: CS(=O)C1C=Nc2cc(Br)ccc2C1=O
Agent: [K+]
Agent: [OH-]
Product: Cn1cc(S(C)=O)c(=O)c2ccc(Br)cc21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
7-Bromo-3-methylsulphinyl-4-quinolone (1.07 g.) was dissolved in aqueous potassium hydroxide (0.3 g. potassium hydroxide in 30 ml. water). Dimethyl sulphate (0.4 ml.) was added and the mixture was stirred at room temperature for 3 hours. More dimethyl sulphate (0.5 ml.) was added and the mixture basified to pH 9.0 by the addition of aqueous KOH (0.4 N). The resulting mixture was stirred overnight. The solid product was collected by filtration and recrystallised from ethanol to give 7-bromo-1-methyl-3-methylsulphinyl-4-quinolone, m.p. 248°-249°.
Reaction SMILES: [F:1][C:2]1[CH:13]=[CH:12][C:5]([O:6][CH2:7][C@@H:8]([OH:11])[C:9]#[CH:10])=[CH:4][CH:3]=1.[N+:14]([C:17]1[CH:18]=[C:19]([CH:23]=[C:24]([N+:26]([O-:28])=[O:27])[CH:25]=1)[C:20](Cl)=[O:21])([O-:16])=[O:15].C(N(CC)CC)C.CN(C1C=CC=CN=1)C>C(Cl)Cl>[F:1][C:2]1[CH:13]=[CH:12][C:5]([O:6][CH2:7][C@@H:8]([O:11][C:20](=[O:21])[C:19]2[CH:18]=[C:17]([N+:14]([O-:16])=[O:15])[CH:25]=[C:24]([N+:26]([O-:28])=[O:27])[CH:23]=2)[C:9]#[CH:10])=[CH:4][CH:3]=1
Reactant: C#C[C@H](O)COc1ccc(F)cc1
Reactant: O=C(Cl)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C#C[C@@H](COc1ccc(F)cc1)OC(=O)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
To a solution of (3S)-4-(4-fluorophenoxy)-3-hydroxy-1-butyne (est. 490 mmol) in methylene chloride (1 L) was added 3,5-dinitrobenzoyl chloride (125 g, 539 mmol) at between −5° C. and 0° C. , followed by slow addition of triethylamine (10.8 mL, 77 mmol) and a catalytic amount of dimethylaminopyridine (DMAP) (20 mg). After the mixture was stirred at ambient temperature for 40 minutes, the reaction mixture was cautiously partitioned between methylene chloride and aqueous NaHCO3. The aqueous layer was extracted with dichloromethane, and the combined organic layers were washed with water and brine, and dried over Na2SO4. The solution was filtered through a pad of silica gel with methylene chloride which gave crude product as a tan solid. Rapid recrystallization from 99:1 mixture of methanol:acetic acid (5 L) gave 101 g of the enantiomerically enriched product, (3S)-4-(4-fluorophenoxy)-3-(3′,5′-dinitrobenzoyl)oxy-1-butyne, a compound of formula (BBa) as fluffy white needles. This material was determined to have greater than 98% ee by analytical HPLC using a Diacel Chiralpak AD® (4.6×250 mm, 60% 2-propanol/hexane, 1 mL/min), which separates the (R) (11.5 min) and the (S) (19.3 min) enantiomers; 1H NMR (CDCl3) δ2.65 (s, 1H), 4.40 (m, 2H), 6.05 (m, 1H), 6.90 (m, 2H), 7.0 (t, 2H), 9.15 (s, 2H), 9.25 (s, 1H) ppm.
Reaction SMILES: F[C:2]1[C:3]([NH:12][C@H:13]2[CH2:17][CH2:16][CH2:15][C@@H:14]2[NH:18][C:19](=[O:31])[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[N:26]2[N:30]=[CH:29][CH:28]=[N:27]2)=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.Cl.N[C@H]1CCC[C@@H]1NC(=O)C1C=CC=CC=1N1N=CC=N1.[Cl:53]C1C(F)=NC=C(C(F)(F)F)C=1>>[Cl:53][C:2]1[C:3]([NH:12][C@H:13]2[CH2:17][CH2:16][CH2:15][C@@H:14]2[NH:18][C:19](=[O:31])[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[N:26]2[N:30]=[CH:29][CH:28]=[N:27]2)=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1
Reactant: Fc1ncc(C(F)(F)F)cc1Cl
Reactant: O=C(N[C@H]1CCC[C@@H]1Nc1ncc(C(F)(F)F)cc1F)c1ccccc1-n1nccn1
Agent: Cl
Agent: N[C@H]1CCC[C@@H]1NC(=O)c1ccccc1-n1nccn1
Product: O=C(N[C@H]1CCC[C@@H]1Nc1ncc(C(F)(F)F)cc1Cl)c1ccccc1-n1nccn1

Procedure:
Prepared according to the procedure for N-[(1S,2S)-2-{ [3-fluoro-5-(trifluoromethyl)pyridin-2-yl]amino}cyclopentyl]-2-(2H-1,2,3-triazol-2-yl)benzamide (Example 105) from N-[(1S,2S)-2-amino cyclopentyl]-2-(2H-1,2,3-triazol-2-yl)benzamide hydrochloride (Intermediate 4; 100 mg, 0.33 mmol) and 3-chloro-2-fluoro-5-(trifluoromethyl)pyridine (CAS number 72537-17-8; 71 mg, 0.36 mmol) except this was then further purified using column chromatography (basic silica, 0-100% ethyl acetate/petrol) to afford the title compound.
Reaction SMILES: [Na].[CH2:2]([O:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[OH:13])[CH:3]([CH3:5])[CH3:4].Cl.[CH2:15]([N:17]([CH2:20][CH2:21]Cl)[CH2:18][CH3:19])[CH3:16]>C(O)C>[CH2:2]([O:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[O:13][CH2:16][CH2:15][N:17]([CH2:20][CH3:21])[CH2:18][CH3:19])[CH:3]([CH3:5])[CH3:4]
Reactant: CCN(CC)CCCl
Reactant: CC(C)COc1ccccc1O
Agent: Cl
Agent: [Na]
Solvent: CCO
Product: CCN(CC)CCOc1ccccc1OCC(C)C

Procedure:
The compound was prepared as described in Example 1, using sodium (2.3 g; 100 mole), o-isobutoxyphenol (8.30 g; 50 mmole) and diethylaminoethylchloride hydrochloride (8.6 g; 50 mmole) in 150 ml of ethanol. Yield 9.3 g (70%) of product, boiling at 112° C under a pressure of 0.01 mm Hg, nD25 : 1.4942.
Reaction SMILES: [C:1]1([O:7][CH2:8][CH:9]=[CH2:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:11][SiH:12]([CH3:14])[Cl:13]>[Pt].[H+].[H+].Cl[Pt-2](Cl)(Cl)(Cl)(Cl)Cl>[O:7]([CH2:8][CH2:9][CH2:10][Si:12]([CH3:14])([CH3:11])[Cl:13])[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C=CCOc1ccccc1
Reactant: C[SiH](C)Cl
Agent: Cl[Pt-2](Cl)(Cl)(Cl)(Cl)Cl
Agent: [Pt]
Agent: [H+]
Product: C[Si](C)(Cl)CCCOc1ccccc1
Temperature: 80 °C
Reaction time: 6 h
Yield: 74.2 %

Procedure:
4 mg of platinum in the form of hexachloroplatinic acid are added to 88.5 g (0.66 mol) of allyl phenyl ether under a nitrogen atmosphere and the mixture is heated to 80° C. 125 g of dimethylchlorosilane are metered into the mixture over a period of 2 hours, the liquid-phase temperature falling to below 50° C. The mixture is stirred for a further 6 hours under gentle reflux. Fractional distillation gives a total of 112 g of 3-phenoxypropyldimethylchlorosilane. The product has an acid number of 248 (theoretically 244).
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:11])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6].[As](=O)(O)(O)O.O[CH2:18][CH:19]([CH2:21]O)O.S(=O)(=O)(O)O>O.C(Cl)(Cl)Cl>[CH3:11][C:3]1[C:4]([C:5]([OH:7])=[O:6])=[CH:8][CH:9]=[C:10]2[C:2]=1[N:1]=[CH:21][CH:19]=[CH:18]2
Reactant: Cc1c(N)cccc1C(=O)O
Reactant: OCC(O)CO
Agent: O=S(=O)(O)O
Agent: O=[As](O)(O)O
Solvent: ClC(Cl)Cl
Solvent: O
Product: Cc1c(C(=O)O)ccc2cccnc12
Temperature: 25 °C
Yield: 52.1 %

Procedure:
A mixture of 3-amino-2-methylbenzoic acid (Intermediate M1) (6.06 g, 39.6 mmol) (commercially available from Aldrich) and arsenic acid (H5AS3O10) 7.43 g (commercially available from VWR/ALFA) in glycerol (5.8 mL, 79.2 mmol), and sulfuric acid (9 mL) was heated to 160° C. for 5 h. The mixture was cooled to rt, diluted with water and filtered through a bed of diatomaceous earth. The pH was adjusted to pH 6-7 with 2 M NaOH. The aqueous layer was exhaustively extracted with CHCl3:MeOH (3:1). The organic fractions were pooled and evaporated under vacuum to give a solid. This solid was titurated with CHCl3, and collected on a glass frit. The solid material was washed with hexanes and dried under high vacuum to give a pure solid, 8-methylquinoline-7-carboxylic acid (intermediate M2) 3.86 g (51%).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](S(C)=O)[C:5]([C:11]#[N:12])=[C:4]([N:13]2[CH:17]=[CH:16][CH:15]=[N:14]2)[N:3]=1.[CH3:18][C:19]1[CH:26]=[CH:25][CH:24]=[CH:23][C:20]=1[CH2:21][NH2:22].C1CCN2C(=NCCC2)CC1>COCCOC>[NH2:1][C:2]1[N:7]=[C:6]([NH:22][CH2:21][C:20]2[CH:23]=[CH:24][CH:25]=[CH:26][C:19]=2[CH3:18])[C:5]([C:11]#[N:12])=[C:4]([N:13]2[CH:17]=[CH:16][CH:15]=[N:14]2)[N:3]=1
Reactant: Cc1ccccc1CN
Reactant: CS(=O)c1nc(N)nc(-n2cccn2)c1C#N
Solvent: COCCOC
Solvent: C1CCC2=NCCCN2CC1
Product: Cc1ccccc1CNc1nc(N)nc(-n2cccn2)c1C#N

Procedure:
From 2-amino-4-methanesulfinyl-6-pyrazol-1-yl-pyrimidine-5-carbonitrile, 2-methyl-benzylamine and DBU in DME. ES-MS m/e (%): 328 (M+Na+, 35), 306 (M+H+, 100).
Reaction SMILES: Cl[C:2]1([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[O:19][CH3:20])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([Cl:11])[CH:9]=2)[NH:4][C:3]1=[O:12].[CH3:21][N:22]([CH3:35])[C:23](=[O:34])[C@@H:24]([NH:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=1)[CH3:25]>>[Cl:11][C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][CH:7]=1)[NH:4][C:3](=[O:12])[C:2]2([N:26]([CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=1)[C@@H:24]([CH3:25])[C:23]([N:22]([CH3:35])[CH3:21])=[O:34])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[O:19][CH3:20]
Reactant: COc1ccccc1C1(Cl)C(=O)Nc2ccc(Cl)cc21
Reactant: C[C@H](NCc1ccccn1)C(=O)N(C)C
Product: COc1ccccc1C1(N(Cc2ccccn2)[C@@H](C)C(=O)N(C)C)C(=O)Nc2ccc(Cl)cc21

Procedure:
With 789 mg of 3,5-dichloro-3-(2-methoxyphenyl)-1,3-dihydro-2H-indol-2-one and the compound obtained in Step 253-2 (2.56 mmol, crude form) as starting materials, respectively 821 mg (Isomer A, colorless amorphous) and 406 mg (Isomer B, colorless amorphous) of two species of diastereoisomers of the title compound were obtained by a similar method to Step 4-2.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([F:9])=[C:4]([F:10])[C:3]=1[CH3:11].C([Li])CCC.[C:17](=[O:19])=[O:18].Cl>CCCCCC.C(OCC)C>[F:1][C:2]1[C:7]([F:8])=[C:6]([C:17]([OH:19])=[O:18])[C:5]([F:9])=[C:4]([F:10])[C:3]=1[CH3:11]
Reactant: Cc1c(F)c(F)cc(F)c1F
Reactant: O=C=O
Agent: Cl
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CCCCCC
Product: Cc1c(F)c(F)c(C(=O)O)c(F)c1F
Temperature: -70 °C
Reaction time: 1 h

Procedure:
The product of step (a) above (4.3 g) was mixed with diethyl ether (30 ml), the mixture cooled to -70° C., and maintained at this temperature whilst a solution of n-butyllithium in n-hexane (1.6 M, 16.4 ml) was slowly added. The mixture was stirred for a period of 1 hour during which time a fine white precipitate was formed. Dry carbon dioxide gas was then passed into the mixture for 30 minutes whilst the temperature was maintained within the range -70° to -40° C., and continued to be passed in thereafter whilst the mixture was allowed to warm to the ambient temperature. After acidifying with dilute hydrochloric acid (6 N, 40 ml) the organic phase was separated, washed with water and dried over anhydrous magnesium sulphate. After evaporation of the solvents under reduced pressure the residual solid was recrystallised from toluene to yield 2,3,5,6-tetrafluoro-4-toluic acid, m.p. 170° C. identified by infra red and nuclear magnetic resonance spectroscopy.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:11][C:10]([C:12]([OH:14])=[O:13])=[CH:9][C:8]=2[CH:15]=1)([O-:3])=[O:2].[CH3:16]N(C=O)C.C(Cl)(C(Cl)=O)=O.N1C=CC=CC=1>C(Cl)Cl>[CH3:16][O:13][C:12]([C:10]1[O:11][C:7]2[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:15][C:8]=2[CH:9]=1)=[O:14]
Reactant: O=C(O)c1cc2cc([N+](=O)[O-])ccc2o1
Reactant: CN(C)C=O
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)c1cc2cc([N+](=O)[O-])ccc2o1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a suspension of 5-nitro-2-benzofurancarboxylic acid (5 g, 24.15 mmol) in CH2Cl2 (250 mL) at 0° C. was added DMF (0.100 mL) followed by (COCl)2 (2M in CH2Cl2, 36.23 mL, 72.46 mL) over a period of 10 min. The reaction was stirred at 0° C. for 1 h and then at room temperature for 30 min. The reaction solvent was removed under a reduced pressure, dried under high vacuum and again suspended in CH2Cl2 (250 mL). The solution was cooled to 0° C., were added pyridine (4.8 mL, 48.03 mmol) followed by McOH (10 mL, excess) and stirred overnight. The extractive work-up with CH2Cl2 gave the expected 2-methoxycarbonyl-5-nitrobenzofuran (R926609). 1H NMR (CDCl3): δ 8.66 (d, 1H, J=2.4 Hz), 8.36 (dd, 1H, J=2.4 and 9.6 Hz), 7.71 (d, 1H, J=9.3 Hz), 7.65 (s, 1H), 4.01 (s, 3H); LCMS: ret. time: 26.94 min.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([O:10][C:11]2[CH:16]=[CH:15][C:14]([CH:17]=[CH:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:13][CH:12]=2)=[N:8][CH:9]=1)([O-])=O.[Cl-].[NH4+].C(O)(=O)C>CO.[Zn]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([O:10][C:11]2[CH:16]=[CH:15][C:14]([CH:17]=[CH:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:13][CH:12]=2)=[N:8][CH:9]=1
Reactant: CCOC(=O)C=Cc1ccc(Oc2ccc([N+](=O)[O-])cn2)cc1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CC(=O)O
Solvent: CO
Product: CCOC(=O)C=Cc1ccc(Oc2ccc(N)cn2)cc1
Reaction time: 2.5 h

Procedure:
To a solution of ethyl 3-[4-(5-nitropyridin-2-yloxy)phenyl]acrylate (2.02 g, 6.43 mmol) in methanol (100 mL) were added zinc (6.3 g, 96.3 mmol) and ammonium chloride (710 mg, 13.27 mmol). The resulting reaction solution was stirred for 2.5 hours under reflux, then acetic acid (5 mL) was added, and stirred for 20 minutes under reflux. Insoluble matter was filtered off through Celite, after which the filtrate was concentrated under reduced pressure. To the residue was added 5% potassium hydrogensulfate (150 mL), the mixture was extracted with dichloromethane, and the dichloromethane layer was washed with a saturated sodium bicarbonate solution and brine. The dichloromethane layer was dried over anhydrous magnesium sulfate, and evaporated, to thereby yield 1.78 g of the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][N:3]=1.N12CCN(CC1)CC2.[Cl:16][C:17]1[C:18]([F:28])=[CH:19][C:20]([F:27])=[C:21]([S:23](Cl)(=[O:25])=[O:24])[CH:22]=1>C(#N)C>[Cl:16][C:17]1[C:18]([F:28])=[CH:19][C:20]([F:27])=[C:21]([S:23]([NH:1][C:2]2[CH:7]=[CH:6][N:5]=[CH:4][N:3]=2)(=[O:25])=[O:24])[CH:22]=1
Reactant: O=S(=O)(Cl)c1cc(Cl)c(F)cc1F
Reactant: Nc1ccncn1
Agent: C1CN2CCN1CC2
Solvent: CC#N
Product: O=S(=O)(Nc1ccncn1)c1cc(Cl)c(F)cc1F
Reaction time: 72 h
Yield: 4.6 %

Procedure:
A mixture of 4-aminopyrimidine (1.30 g, 13.7 mmol) and 1,4-diazabicyclo[2.2.2]octane (1.54 g, 13.7 mmol) were added concurrently to a solution of 5-chloro-2,4-difluorobenzenesulfonyl chloride (3.4 g, 14 mmol) in anhydrous acetonitrile (63 mL). The reaction mixture immediately turned yellow and a precipitate formed. The reaction mixture was stirred under argon. After 72 hours, the reaction mixture was filtered and the filtrate was concentrated in vacuo to give a residue. The residue was partitioned between 1M hydrochloric acid and ethyl acetate. The organic phase was separated, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was partially purified by automated flash column chromatography using an 80 g silica gel ISCO™ column using hexanes to 1% v/v acetic acid in ethyl acetate gradient elution. The product was purified a second time by reverse phase HPLC to give the title compound (193 mg, 5%) as a white solid.
Reaction SMILES: [OH:1][C:2]([CH3:35])([CH3:34])[CH2:3][C@@:4]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16](B3OC(C)(C)C(C)(C)O3)=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1.Br[C:37]1[N:38]=[C:39]([N:42]2[CH:47]=[CH:46][CH:45]=[CH:44][C:43]2=[O:48])[S:40][CH:41]=1>>[OH:1][C:2]([CH3:34])([CH3:35])[CH2:3][C@@:4]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:14]=[CH:15][C:16]([C:37]3[N:38]=[C:39]([N:42]4[CH:47]=[CH:46][CH:45]=[CH:44][C:43]4=[O:48])[S:40][CH:41]=3)=[CH:17][CH:18]=2)[CH3:12])[CH2:6][CH2:5]1
Reactant: C[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Reactant: O=c1ccccn1-c1nc(Br)cs1
Product: C[C@@H](c1ccc(-c2csc(-n3ccccc3=O)n2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O

Procedure:
The title compound was prepared from (S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-{(S)-1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]ethyl}-1,3-oxazinan-2-one and 1-(4-bromothiazol-2-yl)pyridin-2(1H)-one following a procedure analogous to that described in Example 31. LC (method 5): tR=1.73 min; Mass spectrum (ESI+): m/z=472, 530 [M+H]+; 1H NMR (CDCl3) δ 1.10 (s, 3H), 1.20 (s, 3H), 1.57 (d, 3H), 2.20-2.30 (m, 4H), 2.39 (m, 1H), 2.91 (m, 1H), 5.72 (q, 1H), 6.52 (t, 1H), 6.83 (d, 1H), 7.05 (d, 2H), 7.20-7.40 (m, 6H), 7.50 (m, 1H), 7.70 (d, 2H), 8.98 (d, 1H).
Reaction SMILES: [Li]CCCC.C(NC(C)C)(C)C.[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][C:22]([O:24][CH3:25])=[O:23])=[CH:16][CH:15]=1.Br[CH2:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29]>C1COCC1>[Cl:13][C:14]1[CH:15]=[CH:16][C:17]([CH2:20][CH:21]([CH2:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[C:22]([O:24][CH3:25])=[O:23])=[CH:18][CH:19]=1
Reactant: COC(=O)CCc1ccc(Cl)cc1
Reactant: CC(C)(C)OC(=O)CBr
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: COC(=O)C(CC(=O)OC(C)(C)C)Cc1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 81.4 %

Procedure:
BuLi (5.2 mL, 1.6M in hexanes) was added to a 0° C. solution of diisopropylamine (0.91 g, 9.0 mmol) in THF (40 mL). The reaction mixture was then stirred at 0° C. for 30 minutes, and then cooled to −78° C. A solution of methyl 3-(4-chlorophenyl)propanoate (1.5 g, 7.5 mmol) in THF (8 mL) was added slowly, and the reaction mixture was stirred at −78° C. for 40 minutes. A solution tert-butyl 2-bromoacetate (4.4 g, 22.7 mmol) in THF (5 mL) was then added. The reaction was then stirred for 30 minutes at −78° C. and then warmed to room temperature and stirred overnight. The reaction was then quenched with saturated NH4Cl and concentrated to remove THF. The reaction was then extracted with EtOAc, and the combined extracts were dried (Na2SO4), filtered, concentrated, and dried in vacuo to give 4-tert-butyl 1-methyl 2-(4-chlorobenzyl)succinate (1.91 g, 81%) as an oil.
Reaction SMILES: [N:1]1([CH2:6][N:7]2[CH:11]=[N:10][CH:9]=[N:8]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C([Li])CCC.[CH:17]1([C:23]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[O:24])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1.O>O1CCCC1>[CH:25]1([C:23]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)([C:11]2[N:7]([CH2:6][N:1]3[CH2:2][CH2:3][CH2:4][CH2:5]3)[N:8]=[CH:9][N:10]=2)[OH:24])[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30]1
Reactant: O=C(c1ccccc1)C1CCCCC1
Reactant: c1ncn(CN2CCCC2)n1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: OC(c1ccccc1)(c1ncnn1CN1CCCC1)C1CCCCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
1-(pyrrolidin-1-ylmethyl)-1H-1,2,4-triazole (Preparation 16, 12.0 g, 78.84 mmol) was dissolved in tetrahydrofuran (120 mL) and the solution cooled to −78° C. n-Butyl lithium (2.5M in hexanes, 34.7 ml, 86.7 mmol) was then added dropwise over 30 mins. After warming to room temperature and stirring for 1 hour the reaction mixture was cooled to −78° C. and a solution of cyclohexyl(phenyl)methanone (16.3 g, 86.7 mmol) in tetrahydrofuran (30 mL) added dropwise. After warming to room temperature over 18 hr, water (100 ml) was added and the solvent removed in vacuo. The residue was partitioned with ethyl acetate (200 ml), the aqueous phase separated and re-extracted with ethyl acetate (2×200 ml). The combined organic layers were dried over magnesium sulphate, filtered and the solvent removed in vacuo to furnish the title compound as a yellow oil, in 100% yield, 27.28 g.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.C([O:18][B:19](OC(C)C)[O:20]C(C)C)(C)C.C([Li])CCC.CCCCCC.[Cl-].[NH4+]>C1COCC1>[N:8]1([C:5]2[CH:6]=[CH:7][C:2]([B:19]([OH:20])[OH:18])=[CH:3][CH:4]=2)[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: Ic1ccc(N2CCCCCC2)cc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: OB(O)c1ccc(N2CCCCCC2)cc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 35.7 %

Procedure:
Under an argon atmosphere, 1-(4-iodophenyl)azepane (200 mg) and triisopropylborate (162 mg) were dissolved in THF (2 ml), followed by cooling to −78° C. A 1.59 M butyl lithium/hexane solution (0.5 ml) was added thereto, followed by elevating the temperature to 0° C. over 1 hour, and further stirring at the same temperature for 1 hour. To the reaction mixture was added a saturated aqueous ammonium chloride solution, followed by extraction with EtOAc. The organic layer was dried over Na2SO4 and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (CHCl3/MeOH) to obtain (4-azepan-1-ylphenyl)boronic acid (52 mg).