Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[O:6][C:5](=[CH:7][C:8](Cl)=[O:9])[C:4](=[O:11])[O:3]1.[CH:13]([O:16][C:17]1[CH:26]=[CH:25][CH:24]=[CH:23][C:18]=1[CH2:19][NH:20][O:21][CH3:22])([CH3:15])[CH3:14]>>[CH3:1][C:2]1([CH3:12])[O:6][C:5](=[CH:7][C:8]([N:20]([CH2:19][C:18]2[CH:23]=[CH:24][CH:25]=[CH:26][C:17]=2[O:16][CH:13]([CH3:15])[CH3:14])[O:21][CH3:22])=[O:9])[C:4](=[O:11])[O:3]1
Reactant: CC1(C)OC(=O)C(=CC(=O)Cl)O1
Reactant: CONCc1ccccc1OC(C)C
Product: CON(Cc1ccccc1OC(C)C)C(=O)C=C1OC(C)(C)OC1=O
Yield: 93 %

Procedure:
Reaction of (2,2-dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-acetyl chloride with N-(2-isopropoxy-benzyl)-O-methyl-hydroxylamine as described in the preparation of compound 1-C gave the title amide as white crystals (93% yield): mp 103° C. (ethyl acetate-hexane). 1HNMR 400 MHz (CDCl3) δ (ppm): 1.34 (6H, d, J=6.0 Hz, CH3), 1.75 (6H, s, CH3), 3.68 (3H, s, OCH3), 4.60 (1H, m, CH), 4.95 (2H, broad s, NCH2), 6.44 (1H, s, CH), 6.89 (2H, m, aromatics), 7.2-7.3 (2H, m, aromatics). Anal. calcd for C18H23NO6: C, 61.88; H, 6.64; N, 4.01. Found: C, 61.22; H, 6.33; N, 3.87.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:29]2[CH2:34][CH2:33][CH2:32][CH2:31][CH:30]=2)=[CH:4][C:5]([O:27][CH3:28])=[C:6]([CH:26]=1)[C:7]([N:9]1[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[CH2:13][N:12]2[C:20]([C:23]([OH:25])=O)=[CH:21][CH:22]=[C:11]2[CH2:10]1)=[O:8].[CH3:35][N:36]([CH3:42])[CH2:37][CH2:38][CH2:39][NH:40][CH3:41].ON1C2C=CC=CC=2N=N1.Cl.C(N=C=N)C.C(N(CC)C(C)C)(C)C>C(OCC)(=O)C>[Cl:1][C:2]1[C:3]([C:29]2[CH2:34][CH2:33][CH2:32][CH2:31][CH:30]=2)=[CH:4][C:5]([O:27][CH3:28])=[C:6]([CH:26]=1)[C:7]([N:9]1[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[CH2:13][N:12]2[C:20]([C:23]([N:40]([CH2:39][CH2:38][CH2:37][N:36]([CH3:42])[CH3:35])[CH3:41])=[O:25])=[CH:21][CH:22]=[C:11]2[CH2:10]1)=[O:8]
Reactant: CNCCCN(C)C
Reactant: COc1cc(C2=CCCCC2)c(Cl)cc1C(=O)N1Cc2ccc(C(=O)O)n2Cc2ccccc21
Agent: CCN=C=N
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: COc1cc(C2=CCCCC2)c(Cl)cc1C(=O)N1Cc2ccc(C(=O)N(C)CCCN(C)C)n2Cc2ccccc21
Temperature: 25 °C
Reaction time: 12 h
Yield: 91.3 %

Procedure:
10-(5-Chloro-4-cyclohex-1-en-1-yl-2-methoxybenzoyl)-10,11-dihydro-5H-pyrrolo [2,1-c][1,4]benzodiazepine-3-carboxylic acid of Example 1, Step G (0.200 g, 0.419 mmol), (3-dimethylaminopropyl)methylamine (0.074 mL, 0.503 mmol), 1-hydroxy benzotriazole (0.062 g, 0.461 mmol) and 1-[3-dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (0.088 g, 0.461 mmol) were combined in amine-free N,N-dimethylformamide (1.7 mL), followed by addition of N,N-diisopropylethyl amine (0.110 mL, 0.629 mmol). The reaction was stirred at room temperature for 12 hours, then diluted with ethyl acetate and washed with water, saturated aqueous sodium bicarbonate and brine. The combined aqueous washings were saturated with sodium chloride and extracted with ethyl acetate. The combined extracts were dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified by flash column chromatography on silica gel eluting with 10% methanol in chloroform to provide the title compound (0.220 g) as a white powder, m.p. 116-119° C.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:14][C:13]([F:16])([F:15])[CH2:12]2)=[C:7](Cl)[N:6]=1)=[O:4].C(=O)([O-])[O-].[Cs+].[Cs+].[Cl:24][C:25]1[CH:26]=[C:27](B(O)O)[CH:28]=[CH:29][CH:30]=1>O.CN(C=O)C.C(Cl)Cl.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[Cl:24][C:25]1[CH:30]=[C:29]([C:7]2[N:6]=[C:5]([C:3]([OH:2])=[O:4])[CH:10]=[CH:9][C:8]=2[N:11]2[CH2:14][C:13]([F:16])([F:15])[CH2:12]2)[CH:28]=[CH:27][CH:26]=1
Reactant: COC(=O)c1ccc(N2CC(F)(F)C2)c(Cl)n1
Reactant: OB(O)c1cccc(Cl)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Solvent: O
Solvent: ClCCl
Product: O=C(O)c1ccc(N2CC(F)(F)C2)c(-c2cccc(Cl)c2)n1
Temperature: 100 °C
Reaction time: 48 h
Yield: 30 %

Procedure:
6-Chloro-5-(3,3-difluoroazetidin-1-yl)-pyridine-2-carboxylic acid methyl ester (Example 69 a, 0.3 g, 1.15 mmol), 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride methylene chloride complex (CAN 72287-26-4, 47 mg, 0.058 mmol) and cesium carbonate (CAN 534-17-8, 0.56 g, 1.72 mmol) were added to a solution of 3-chlorophenylboronic acid (CAN 63503-60-6, 0.27 g, 1.72 mmol) in water (20 mL) and DMF (10 mL). The mixture was stirred for 48 h at 100° C. The reaction mixture was adjusted to pH=3 and extracted with methylene chloride (3×20 mL). The organic layers were combined, dried over sodium sulfate and concentrated to give the crude product (110 mg, 30%); MS (EI): 325.0 [M+H]+.
Reaction SMILES: [C:1]([C:4]1[N:9]=[C:8]([C:10]2[CH:15]=[CH:14][C:13](B(O)O)=[CH:12][CH:11]=2)[C:7]([CH3:19])=[N:6][C:5]=1[CH3:20])(=[O:3])[NH2:2].[F:21][C:22]1[CH:23]=[C:24]([CH2:37][C:38]([O:40][CH3:41])=[O:39])[CH:25]=[C:26]([F:36])[C:27]=1OS(C(F)(F)F)(=O)=O.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C(#N)CCC.Cl[Pd]Cl.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[C:1]([C:4]1[N:9]=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([C:27]3[C:26]([F:36])=[CH:25][C:24]([CH2:37][C:38]([O:40][CH3:41])=[O:39])=[CH:23][C:22]=3[F:21])=[CH:12][CH:11]=2)[C:7]([CH3:19])=[N:6][C:5]=1[CH3:20])(=[O:3])[NH2:2]
Reactant: COC(=O)Cc1cc(F)c(OS(=O)(=O)C(F)(F)F)c(F)c1
Reactant: Cc1nc(C)c(-c2ccc(B(O)O)cc2)nc1C(N)=O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Solvent: CCCC#N
Product: COC(=O)Cc1cc(F)c(-c2ccc(-c3nc(C(N)=O)c(C)nc3C)cc2)c(F)c1
Temperature: 150 °C
Yield: 25.9 %

Procedure:
A solution of 4-(6-carbamoyl-3,5-dimethylpyrazin-2-yl)phenylboronic acid (243 mg, 0.90 mmol), methyl 2-(3,5-difluoro-4-(trifluoromethylsulfonyloxy)phenyl)acetate (Intermediate 24-2; 300 mg, 0.90 mmol) and tripotassium phosphate (286 mg, 1.35 mmol) in butyronitrile (2 mL) was put under vacuum and refilled with nitrogen before addition of (1,1′-bis(diphenylphosphino)ferrocene)-dichloropalladium(II) (DCM adduct) (59.1 mg, 0.07 mmol). The reaction mixture was heated in the microwave at 150° C. for 6 hours. The reaction mixture was concentrated and diluted with DCM (25 mL), and washed with water (2×25 mL). The organic layer was dried by passing through a phase seperating cartridge and evaporated to afford crude product. The crude product was purified by flash Silica chromatography {CombiFlash Companion—Presearch Ltd}, column size=12 g, flow rate=30 mL/min, elution gradient 0 to 50% EtOAc in isohexane. Pure fractions were evaporated to dryness to afford methyl 2-(4′-(6-carbamoyl-3,5-dimethylpyrazin-2-yl)-2,6-difluorobiphenyl-4-yl)acetate (96 mg, 26.0%) as a slightly coloured (purple tinge) solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([C:22]([F:28])([F:27])[C:23]([F:26])([F:25])[F:24])=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([C:13](=[S:21])[N:14]([CH3:20])[CH2:15][C:16]([O:18]C)=[O:17])=[CH:8][CH:7]=[CH:6]2.COCCO.[OH-].[Na+].Cl>C(OCC)(=O)C.CCCCCC>[CH3:1][O:2][C:3]1[C:4]([C:22]([F:28])([F:27])[C:23]([F:24])([F:25])[F:26])=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([C:13](=[S:21])[N:14]([CH3:20])[CH2:15][C:16]([OH:18])=[O:17])=[CH:8][CH:7]=[CH:6]2
Reactant: COC(=O)CN(C)C(=S)c1cccc2c(C(F)(F)C(F)(F)F)c(OC)ccc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: COCCO
Product: COc1ccc2c(C(=S)N(C)CC(=O)O)cccc2c1C(F)(F)C(F)(F)F
Temperature: 0 °C
Yield: 18 %

Procedure:
The N-[[6-methoxy-5-(pentafluoroethyl)-1-naphthalenyl]thioxomethyl]-N-methylglycine, methyl ester (2.3 g, 5.46 mmol), 2-methoxyethanol (50 ml) and 2N aqueous sodium hydroxide (5.46 ml) were mixed at 0° C. and the mixture stirred at room temperature for 3 hours (until disappearance of the ester spot in t.l.c. with ethyl acetate/hexane 1:1). The mixture was cooled to 0° C., neutralized to pH 8 with 1N aqueous hydrochloric acid, evaporated, the residue triturated with water, the neutral material extracted with ethyl acetate and the aqueous layer acidified with 1N aqueous hydrochloric acid to pH3. The product was extracted with ethyl acetate, the extract washed with water, dried over anhydrous MgSO4 and evaporated. The residue was purified by crystallization from chloroform/hexane to obtain 700 mg of the first crop and an additional 568 mg of the crude material from the mother liquor. Recrystallization of the first crop afforded 400 mg of the pure N-[[6-methoxy-5-(pentafluoroethyl)-1-naphthalenyl]thioxomethyl]-N-methylglycine. The recrystallization of mother liquor gave further 291 mg. mp. 164°-165° C. Anal. Calcd: C, 50.13% H, 3.46% N, 3.44% Found: C, 49.42%, H, 3.58% N, 3.40%. nmr (DMSO): δ2.95 (s, 3H, N--CH3); δ3.97 (s, 3H, OCH3); δ4.9 (q, 2H, CH2); δ7.1-8.4 (m, 5H, Har). ir (nujol): 1700, 1723, 1750 cm-1 uv, λmax(ε): 338 (3990), 269 (13,000), 227 (45,400) ms: m/e 407 (M+), 363, 319.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[C:9](O)(=[O:27])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C(C)=CC=CC=1.O>[OH:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][C:9](=[O:27])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])=[CH:3][CH:4]=1
Reactant: CCCCCCCCCCCCCCCCCC(=O)O
Reactant: Nc1ccc(O)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1C
Product: CCCCCCCCCCCCCCCCCC(=O)Nc1ccc(O)cc1
Temperature: 110 °C

Procedure:
A 3-liter flask was charged with 218 grams (2 moles) of 4-aminophenol, 538 grams (1.9 moles) of stearic acid, 20 grams of p-toluenesulfonic acid, 300 ml of xylene and swept with nitrogen. The flask was fitted with a Dean-Stark trap for water removal and the contents heated with stirring to 220° C. with water and xylene removal for 2 hours. Twenty-eight milliliters of water were removed. The contents of the flask were cooled to 110° C. and poured into a polyethylene container, which was stripped of volatiles at 125-130° C. at 29 inches of Hg vacuum to give 737 grams of a waxy solid with an infrared spectroscopic spectra showing phenolic and amide functional groups.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][N+:3]=1[O-:9].C([Mg]Cl)(C)C.[Li+].[Cl-].Br[C:18]1[C:23]([F:24])=[CH:22][CH:21]=[C:20]([CH3:25])[N:19]=1>C1COCC1.[Cl-].[Cl-].[Zn+2].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>[F:24][C:23]1[C:18]([C:2]2[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][N+:3]=2[O-:9])=[N:19][C:20]([CH3:25])=[CH:21][CH:22]=1
Reactant: Cc1ccc(F)c(Br)n1
Reactant: Cc1ccc(Br)[n+]([O-])c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Solvent: C1CCOC1
Product: Cc1ccc(-c2nc(C)ccc2F)[n+]([O-])c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 187.2 %

Procedure:
To a cooled solution (−40 to −45° C.) of 2-bromo-5-methylpyridine 1-oxide (12 g, 63.8 mmol) in dry THF (250 mL) was added a solution of i-PrMgCl.LiCl (127 mL, 165.8 mmol, 1.3M) in THF and the reaction mixture was stirred for 1 hour at −40° C. Dry ZnCl2 (1 g, 127. mmol) was added and the reaction was warmed to room temperature and stirred for 1 hour. 2-Bromo-3-fluoro-6-methylpyridine (2 g, 127. mmol) and Pd(PPh3)4 (5. g, 4.4 mmol) were added and the reaction mixture was refluxed for 20 hours. The mixture was cooled 0° C. and stirred for 1 hour to afford a solid. The solid was collected by filtration and then dissolved in dichloromethane and washed with a saturated solution of ethylenediaminetetraacetic acid and saturated K2CO3 successively. The organic layers were separated, dried, and concentrated to give a residue which was purified by flash silica chromatography eluted with dichloromethane/MeOH (50:1) to give 2-(3-fluoro-6-methylpyridin-2-yl)-5-methylpyridine 1-oxide (4.3 g; 30.1%). 1HNMR (CDCL3): δ ppm 8.22 (s, 1H), 7.47-7.42 (m, 2H), 7.30-7.27 (m, 1H), 7.20-7.28 (m, 1H), 2.61 (s, 3H), 2.38 (s, 3H). MS [M+H] found 219.0.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5](I)[CH:4]=[N:3]1.[C:8]1([C:14]#[CH:15])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(NC(C)C)(C)C.C(OCC)(=O)C.[Cu](I)I.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:1][N:2]1[CH:6]=[C:5]([C:15]#[C:14][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:4]=[N:3]1
Reactant: Cn1cc(I)cn1
Reactant: C#Cc1ccccc1
Agent: Cl[Pd]Cl
Agent: I[Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC(C)NC(C)C
Solvent: CCOC(C)=O
Product: Cn1cc(C#Cc2ccccc2)cn1
Reaction time: 3 h

Procedure:
To a solution of 1-methyl-4-iodopyrazole (208 g, 1 mol) and phenylacetylene (112 g, 1.1 mol) in diisopropylamine (2 l) are added, under nitrogen, copperiodide (2 g), triphenylphosphine (0.1 g) and bis-(triphenylphosphine) palladiumdichloride (0.5 g). The mixture is kept during 3 hours at ca. +35° C. and then heated for 1 hour at +90° C. The cooled reaction mixture is diluted with ethyl acetate and filtrated. Concentration of the filtrate and distillation yields the title compound: b.p. 116°-118° C./0.3 mbar, m.p. 70°-72° C.
Reaction SMILES: COC1C=C(C=CC=1OC)C[N:7]1[C:13](=[O:14])[C@@H:12]2[C@H:8]1[CH2:9][CH2:10][N:11]2[C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16].P([O-])([O-])(O)=O.[K+].[K+].[K]>C(#N)C.O>[O:14]=[C:13]1[C@@H:12]2[C@@H:8]([CH2:9][CH2:10][N:11]2[C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:16])[NH:7]1
Reactant: COc1ccc(CN2C(=O)[C@@H]3[C@H]2CCN3C(=O)OCc2ccccc2)cc1OC
Agent: O=P([O-])([O-])O
Agent: [K+]
Agent: [K]
Solvent: CC#N
Solvent: O
Product: O=C1N[C@@H]2CCN(C(=O)OCc3ccccc3)[C@H]12
Temperature: 100 °C
Reaction time: 2.5 h

Procedure:
135 g (0.34 mol) of benzyl (1S,5R)-6-(3,4-dimethoxy- benzyl)-7-oxo-2,6-diazabicyclo[3.2.0]heptane-2-carboxylate were placed in 1.5 liters of acetonitrile. Thereto there was added a solution of 77 g (0.44 mol) of dipotassium hydrogen phosphate and 128 g (0.47 mol) of potassium peroxodisulphate in 660 ml of water and the mixture was heated to 100° C. The reaction time amounted to 2.5 hours. During this time the pH value of the mixture becomes acidic. This pH was held at about 5 by the portionwise addition of further dipotasium hydrogen phosphate. After completion of the reaction the acetonitrile was removed on a rotary evaporator and the aqueous residue was extracted with 3×250 ml of methylene chloride. The combined organic phases were washed once each time with 500 ml of 3% sodium hydrogen carbonate solution and 750 ml of saturated, aqueous sodium chloride solution and subsequently dried over magnesium sulphate. After concentration there was obtained a brown oil which was purified by chromatography [silica gel, 0.063-0.2 mm particle size, elution with 1) ethyl acetate:hexane =2:1; 2) ethyl acetate].
Reaction SMILES: CS(O[CH2:6][CH2:7][C:8]1[O:9][C:10]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([N:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)=[O:24])=[CH:19][N:18]=3)=[CH:13][C:11]=2[CH:12]=1)(=O)=O.[CH:31]([NH:34][CH3:35])([CH3:33])[CH3:32]>>[CH:31]([N:34]([CH3:35])[CH2:6][CH2:7][C:8]1[O:9][C:10]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([N:25]4[CH2:26][CH2:27][O:28][CH2:29][CH2:30]4)=[O:24])=[CH:19][N:18]=3)=[CH:13][C:11]=2[CH:12]=1)([CH3:33])[CH3:32]
Reactant: CS(=O)(=O)OCCc1cc2cc(-c3ccc(C(=O)N4CCOCC4)cn3)ccc2o1
Reactant: CNC(C)C
Product: CC(C)N(C)CCc1cc2cc(-c3ccc(C(=O)N4CCOCC4)cn3)ccc2o1

Procedure:
The product from Example 44E and isopropyl(methyl)amine were processed as described in Example 1D to provide the titled compound. 1H NMR (300 MHz, CD3OD) δ8.70 (m, 1H), 8.24 (d, J=1.8 Hz, 1H), 7.96 (m, 3H), 7.59 (d, J=8.7 Hz, 1H), 6.85 (s, 1H), 3.3-3.8 (m, 13H), 2.88 (s, 3H), 1.40 (d, 6.3 Hz, 3H), 1.36 (d, 6.3 Hz, 3H); MS (DCI) m/z 408 (M+H)+;
Reaction SMILES: Cl.[CH3:2][O:3][C:4]([C@@H:6]1[CH2:10][CH2:9][CH2:8][C@@H:7]1[NH2:11])=[O:5].[F:12][C:13]1[CH:20]=[CH:19][C:16]([CH:17]=O)=[CH:15][C:14]=1[Cl:21].C(O)(=O)C.[BH4-].[Na+]>CO>[CH3:2][O:3][C:4]([C@@H:6]1[CH2:10][CH2:9][CH2:8][C@@H:7]1[NH:11][CH2:17][C:16]1[CH:19]=[CH:20][C:13]([F:12])=[C:14]([Cl:21])[CH:15]=1)=[O:5]
Reactant: O=Cc1ccc(F)c(Cl)c1
Reactant: COC(=O)[C@@H]1CCC[C@@H]1N
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: COC(=O)[C@@H]1CCC[C@@H]1NCc1ccc(F)c(Cl)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
(1R,2S)-2-Amino-cyclopentanecarboxylic acid methyl ester hydrochloride (prepared as described in Example 11a, 0.2 g, 1.27 mmol) was dissolved in methanol (5.5 mL), followed by addition of 4-fluoro-3-chlorobenzaldehyde (0.201 g, 1.27 mmol) and stirred at 25° C. for 10 min. After this time, 5.2 M acetic acid (0.245 mL) was added, stirred at 25° C. for 5 min before placing in an ice-bath. Once at 0° C., sodium borohydride (0.203 mg, 3.2 mmol) was added portionwise after which time the mixture was allowed to warm to 25° C. and continued to stir for 17 h. The reaction mixture was quenched by pouring into saturated aqueous sodium bicarbonate solution (200 mL) and extracted with ethyl acetate (200 mL). The organic layer was concentrated in vacuo and purified by flash column chromatography (Teledyne Isco RediSep Flash Column; 0-80% ethyl acetate in hexanes) to afford the desired product, (1R,2S)-2-(3-chloro-4-fluoro-benzylamino)-cyclopentanecarboxylic acid methyl ester (256 mg, 0.898 mmol, 70% as a yellow oil, containing residual ethyl acetate. 1H NMR (400 MHz, CDCl3) δ: 1.55-1.97 (m, 6H), 2.86 (dd, 1H, J1=14.2 Hz, J2=7.0 Hz), 3.19 (dd, 1H, J1=13.1 Hz, J2=6.9 Hz), 3.62 (s, 3H), 3.64 (d, 2H, J=6.2 Hz), 6.96 (t, 1H, J=8.5 Hz), 7.04-7.08 (m, 1H), 7.26-7.28 (m, 1H). LC-MS (ESI) calcd for C14H17ClFNO2 285.09, found 286.0 [M+H+].
Reaction SMILES: C(Br)C1C=CC=CC=1.[CH2:9]([O:16][C:17]1[CH:18]=[CH:19][C:20]([C:23]([O:25][CH3:26])=[O:24])=[N:21][CH:22]=1)C1C=CC=CC=1>>[CH3:9][O:16][C:17]1[CH:18]=[CH:19][C:20]([C:23]([O:25][CH3:26])=[O:24])=[N:21][CH:22]=1
Reactant: COC(=O)c1ccc(OCc2ccccc2)cn1
Agent: BrCc1ccccc1
Product: COC(=O)c1ccc(OC)cn1

Procedure:
The following compound was prepared using benzyl bromide according to the procedure above for compound 206: Methyl 5-benzyloxypyridine-2-carboxylate (compound 207)
Reaction SMILES: [CH3:1][NH:2][CH3:3].C([N:7]1[C:15]2[C:10](=[CH:11][C:12]([Br:20])=[C:13]([S:16](Cl)(=[O:18])=[O:17])[CH:14]=2)[CH2:9][CH2:8]1)(=O)C>>[CH3:1][N:2]([CH3:3])[S:16]([C:13]1[CH:14]=[C:15]2[C:10]([CH2:9][CH2:8][NH:7]2)=[CH:11][C:12]=1[Br:20])(=[O:18])=[O:17]
Reactant: CC(=O)N1CCc2cc(Br)c(S(=O)(=O)Cl)cc21
Reactant: CNC
Product: CN(C)S(=O)(=O)c1cc2c(cc1Br)CCN2

Procedure:
Starting with dimethylamine and 1-acetyl-5-bromo-2,3-dihydro-1H-indole-6-sulfonyl chloride, the title compound was prepared by using similar methods to those described for Preparation 27.1H NMR (DMSO-d6): 7.40 (1H, s), 7.01 (1H, s), 3.51 (2H, t), 3.01 (2H, t), 2.77 (6H, s).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:15]3[C:14]([CH2:16][O:17][CH3:18])=[N:13][N:12]([CH:19]4[CH2:21][CH2:20]4)[C:11]=3[C:10](=[O:22])[NH:9]2)=[CH:4][CH:3]=1.Br[C:24]1[CH:25]=[C:26]([CH3:34])[C:27]2[N:28]([C:30]([CH3:33])=[N:31][N:32]=2)[CH:29]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:15]3[C:14]([CH2:16][O:17][CH3:18])=[N:13][N:12]([CH:19]4[CH2:20][CH2:21]4)[C:11]=3[C:10](=[O:22])[N:9]2[C:24]2[CH:25]=[C:26]([CH3:34])[C:27]3[N:28]([C:30]([CH3:33])=[N:31][N:32]=3)[CH:29]=2)=[CH:4][CH:3]=1
Reactant: COCc1nn(C2CC2)c2c1C(c1ccc(Cl)cc1)NC2=O
Reactant: Cc1cc(Br)cn2c(C)nnc12
Product: COCc1nn(C2CC2)c2c1C(c1ccc(Cl)cc1)N(c1cc(C)c3nnc(C)n3c1)C2=O
Temperature: 110 °C
Reaction time: 16 h

Procedure:
The title compound was prepared using an analogous procedure to that described in Example 23 using 4-(4-chlorophenyl)-1-cyclopropyl-3-(methoxymethyl)-4,5-dihydropyrrolo[3,4-c]pyrazol-6(1H)-one (Step 130.4) and 6-bromo-3,8-dimethyl-[1,2,4]triazolo[4,3-a]pyridine (Step 130.6). The reaction mixture was stirred for 16 h at 110° C. After purification by silica gel column chromatography (CH2Cl2/MeOH 1-5.5%), the resulting residue was purified by SFC (column: PPU, 25 cm, Ø 3 cm, 5 μm, 100 Å; gradient: 12% B for 1 min, 12-17% B in 6 min, 17-50% B in 1 min, 50% B for 1.5 min, 50%-12% B in 1 min, 12% B for 0.5 min; A: scCO2, B: MeOH; flow: 100 mL/min) to provide the title compound (151 mg) as a colorless solid. tR: 0.94 min (LC-MS 2); ESI-MS: 463.1 [M+H]+ (LC-MS 2); Rf=0.37 (CH2Cl2/MeOH 9:1); 1H NMR (400 MHz, DMSO-d6) δ ppm 1.03-1.11 (m, 2H) 1.23-1.31 (m, 2H) 2.42 (s, 3H) 2.61 (s, 3H) 3.06 (s, 3H) 3.84-3.92 (m, 1H) 3.99 (d, J=12.12 Hz, 1H) 4.23 (d, J=12.51 Hz, 1H) 6.46 (s, 1H) 7.28-7.35 (m, 4H) 7.37 (br. s, 1H) 8.48 (br. s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:10](=[CH:11][CH:12]=1)[C:8](=[O:9])[O:7][C:6]([C:13]([OH:15])=[O:14])=[C:5]2[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.S(=O)(=O)(O)O.[CH3:27]O>>[CH3:27][O:14][C:13]([C:6]1[O:7][C:8]([C:10]2[C:4]([C:5]=1[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)=[CH:3][C:2]([Cl:1])=[CH:12][CH:11]=2)=[O:9])=[O:15]
Reactant: CO
Reactant: O=C(O)c1oc(=O)c2ccc(Cl)cc2c1-c1ccccc1
Agent: O=S(=O)(O)O
Product: COC(=O)c1oc(=O)c2ccc(Cl)cc2c1-c1ccccc1

Procedure:
To a solution of 6-chloro-4-phenylisocoumarin-3-carboxylic acid (9 g) in methanol (200 ml) was added sulfuric acid (20 ml) and the mixture was refluxed for 2 hrs. The reaction mixture was concentrated, and the residue was neutralized with aqueous sodium hydrogen carbonate and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over sodium sulfate and concentrated. The residue was crystallized from isopropyl ether to give the title compound (8.7 g) as colorless crystals.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:6]=1[CH2:13][N:14]([CH:54]1[CH2:56][CH:55]1[C:57]1[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=1)[C:15]1[C:16]2[N:27]=[N:26][N:25]([CH:28]3[CH:32]([OH:33])[CH:31]([OH:34])[CH:30]([CH2:35][O:36][Si:37]([C:50]([CH3:53])([CH3:52])[CH3:51])([C:44]4[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=4)[C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=4)[CH2:29]3)[C:17]=2[N:18]=[C:19]([S:21][CH2:22][CH2:23][CH3:24])[N:20]=1.[CH3:63]I.[Cl-].[NH4+]>CN(C=O)C>[CH3:3][O:4][C:5]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:6]=1[CH2:13][N:14]([CH:54]1[CH2:56][CH:55]1[C:57]1[CH:58]=[CH:59][CH:60]=[CH:61][CH:62]=1)[C:15]1[C:16]2[N:27]=[N:26][N:25]([CH:28]3[CH:32]([OH:33])[CH:31]([O:34][CH3:63])[CH:30]([CH2:35][O:36][Si:37]([C:50]([CH3:52])([CH3:53])[CH3:51])([C:38]4[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=4)[C:44]4[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=4)[CH2:29]3)[C:17]=2[N:18]=[C:19]([S:21][CH2:22][CH2:23][CH3:24])[N:20]=1
Reactant: CCCSc1nc(N(Cc2ccc(OC)cc2OC)C2CC2c2ccccc2)c2nnn(C3CC(CO[Si](c4ccccc4)(c4ccccc4)C(C)(C)C)C(O)C3O)c2n1
Reactant: CI
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: CCCSc1nc(N(Cc2ccc(OC)cc2OC)C2CC2c2ccccc2)c2nnn(C3CC(CO[Si](c4ccccc4)(c4ccccc4)C(C)(C)C)C(OC)C3O)c2n1
Reaction time: 4 h

Procedure:
Sodium hydride (65.3 mg) was added to a solution of the diol from step (b) (1.23 g) and methyl iodide (0.13 ml) in DMF (4 ml) and the mixture was stirred for 4 h. Ammonium chloride solution was added and the mixture was extracted with ethyl acetate. The organic extracts were dried, concentrated and purified (SiO2, petrol:acetone 4:1 and petrol:ethyl acetate 2:1 as eluants) to give the subtitle compound (676 mg) as a 1:2.5 mixture with the regioisomeric [1R-[1α,2α,3β,5β(1R*,2S*)]]-3-[7-[N-(2,4-dimethoxyphenylmethyl)-(2-phenylcyclopropyl)amino]]-5-propylthio-3H-1,2,3-triazolo[4,5d]pyrimidin-3-yl]-5-[[[(1,1-dimethylethyl)diphenylsilyl]oxy]methyl]-2-methoxycyclopentanol compound.