Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C@H:3]1[C@H:6]([CH2:7][C@H:8]([OH:20])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[O:5][C:4]1=[O:21])[CH3:2].[CH:22]([NH:24][CH2:25][C:26](O)=[O:27])=[O:23].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1(C)C(C)=CC=CC=1>[CH:22]([NH:24][CH2:25][C:26]([O:20][C@H:8]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH2:7][C@H:6]1[C@H:3]([CH2:1][CH3:2])[C:4](=[O:21])[O:5]1)=[O:27])=[O:23]
Reactant: O=CNCC(=O)O
Reactant: CCCCCCCCCCC[C@@H](O)C[C@@H]1OC(=O)[C@H]1CC
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1C
Product: CCCCCCCCCCC[C@H](C[C@@H]1OC(=O)[C@H]1CC)OC(=O)CNC=O
Yield: 43.5 %

Procedure:
Prepared according to the procedure described in Example 36, above. Hydroxy β-lactone 13f (10 mg, 0.033 mmol), N-formylglycine (12.0 mg, 0.120 mmol), triphenylphosphine (26.6 mg, 0.099 mmol), and 0.5 mL of xylene were combined and the mixture was azeotroped in vacuo for 1.0 h. THF (1.4 mL) was then added followed by DIAD (21.0 μL, 0.108 mmol). After 12 hours the mixture was concentrated in vacuo, and purified by chromatography (SiO2, 10 to 30% EtOAc:hexanes) to afford β-lactone 15i (5.5 mg, 43%).
Reaction SMILES: [CH2:1]([N:5]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[C:29]#[N:30])=[CH:19][CH:18]=1)[C:6](=[O:15])[CH2:7][C:8]([C:11]([O:13]C)=[O:12])([CH3:10])[CH3:9])[CH2:2][CH2:3][CH3:4].C([Sn]([N:44]=[N+:45]=[N-:46])(CCCC)CCCC)CCC.[OH-].[K+]>CC1C=CC=CC=1C>[CH2:1]([N:5]([CH2:16][C:17]1[CH:18]=[CH:19][C:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[C:29]2[NH:46][N:45]=[N:44][N:30]=2)=[CH:21][CH:22]=1)[C:6](=[O:15])[CH2:7][C:8]([C:11]([OH:13])=[O:12])([CH3:9])[CH3:10])[CH2:2][CH2:3][CH3:4]
Reactant: CCCC[Sn](CCCC)(CCCC)N=[N+]=[N-]
Reactant: CCCCN(Cc1ccc(-c2ccccc2C#N)cc1)C(=O)CC(C)(C)C(=O)OC
Agent: [K+]
Agent: [OH-]
Solvent: Cc1ccccc1C
Product: CCCCN(Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1)C(=O)CC(C)(C)C(=O)O

Procedure:
A solution of 4.0 g (9.8 mmol) of 3-methoxycarbonyl-3-methyl-butanoic acid N-butyl-N-(2'-cyanobiphenyl-4-ylmethyl)-amide and 4.3 g (13 mmol) of tributyltin azide in 80 ml of o-xylene is reacted analogously to Example 1 for 24 hours. For hydrolysis, the reaction mixture is stirred with 50 ml of 2N potassium hydroxide solution at from 40 bis 50° for 4 hours. The aqueous phase is separated and acidified with 2N hydrochloric acid, and the oil which separates is extracted with ethyl acetate. Washing of the ethyl acetate solution with water, drying over MgSO4 and concentration by evaporation yield 3-carboxy-3-methyl-butanoic acid N-butyl-N-[2'-(1H-tetrazol-5-yl)biphenyl-4-ylmethyl]-amide in the form of a colourless foam that has an Rf value of 0.25 [toluene/isopropanol/glacial acetic acid (170:30:2)].
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]1[CH:9]=[CH:8][C:7]([C:10]([O:12]CC)=[O:11])=[N:6]1.[OH-].[Na+]>C(O)C.O>[CH3:1][O:2][CH2:3][CH2:4][N:5]1[CH:9]=[CH:8][C:7]([C:10]([OH:12])=[O:11])=[N:6]1
Reactant: CCOC(=O)c1ccn(CCOC)n1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: COCCn1ccc(C(=O)O)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 101.2 %

Procedure:
Ethyl 1-(2-methoxyethyl)-1H-pyrazole-3-carboxylate (Preparation 28, 360 mg, 1.8 mmol) was dissolved in ethanol (6 ml), a solution of sodium hydroxide (90 mg, 2.3 mmol) in water (3 ml) was added and the solution was stirred at room temperature for 3 hours. The ethanol was removed in vacuo and the residue was acidified with 2M HCl (approximately 1.5 ml), the aqueous solution was evaporated to dryness in vacuo and the residue was extracted with a mixture of dichloromethane (15 ml) and 3 drops of methanol. The mixture was filtered to remove the inorganics and the solvent removed in vacuo to give 310 mg of a yellow oil which crystallized on standing.
Reaction SMILES: [C:1]1([S:7]([C:10]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([O:19][CH2:20][CH2:21]OS(C4C=CC(C)=CC=4)(=O)=O)[CH:17]=3)[NH:12][N:11]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:33]1([NH2:36])[CH2:35][CH2:34]1>C1COCC1>[C:1]1([S:7]([C:10]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([O:19][CH2:20][CH2:21][NH:36][CH:33]4[CH2:35][CH2:34]4)[CH:17]=3)[NH:12][N:11]=2)(=[O:8])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NC1CC1
Reactant: Cc1ccc(S(=O)(=O)OCCOc2ccc3[nH]nc(S(=O)(=O)c4ccccc4)c3c2)cc1
Solvent: C1CCOC1
Product: O=S(=O)(c1ccccc1)c1n[nH]c2ccc(OCCNC3CC3)cc12
Temperature: 80 °C
Reaction time: 6 h
Yield: 50 %

Procedure:
A solution of toluene-4-sulfonic acid 2-(3-benzenesulfonyl-1H-indazol-5-yloxy)-ethyl ester (0.336 g, 0.711 mmol) and cyclopropylamine (1.0 mL, 14 mmol) in THF (8 mL) was stirred at 70° C. for 6 hours in a sealed tube. Additional cyclopropylamine (1.0 mL, 14 mmol) was added, and the reaction mixture was stirred for 6 hours at 80° C. in a sealed tube. After cooling somewhat, the reaction mixture was solvent evaporated and partitioned in ethyl acetate and aqueous sodium bicarbonate. The organic phase was then washed with water and brine, dried with anhydrous magnesium sulfate, filtered and concentrated. The residue was purified by flash chromatography using 5% methanol in chloroform. After drying in vacuo at 55° C. temperature for 25 minutes, [2-(3-benzenesulfonyl-1H-indazol-5-yloxy)-ethyl]-cyclopropyl-amine as a light yellow foam (0.127 g, 50.0%) was obtained. This was dissolved in chloroform, and ethereal hydrochloride was added. The mixture was concentrated and dried in vacuo at 75° C. for 16.5 hours to yield the hydrochloride as a buff solid (0.131 g): MP: 184-5° C. dec.; Mass Spectrum (+EI, [M+H]+) m/z 358.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH:10]=[C:11]([C:14]#[N:15])[C:12]#[N:13])=[CH:9][C:4]=2[O:3][CH2:2]1.[C:16]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)(=O)[C:17]1C=CC=CC=1.C([O-])(=O)C.[NH4+:34]>C1(C)C=CC=CC=1>[NH2:13][CH2:12][C:11]1[C:14]([NH2:34])=[N:15][C:16]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[CH:17][C:10]=1[C:8]1[CH:7]=[CH:6][C:5]2[O:1][CH2:2][O:3][C:4]=2[CH:9]=1
Reactant: N#CC(C#N)=Cc1ccc2c(c1)OCO2
Reactant: [NH4+]
Reactant: O=C(c1ccccc1)c1ccccc1
Agent: CC(=O)[O-]
Solvent: Cc1ccccc1
Product: NCc1c(-c2ccc3c(c2)OCO3)cc(-c2ccccc2)nc1N
Temperature: 118 °C
Reaction time: 8 h
Yield: 8.6 %

Procedure:
2-Benzo[1,3]dioxol-5-ylmethylene-malononitrile (79 mg, 0.4 mmol), benzophenone (48 mg, 0.4 mmol), ammonium acetate (78 mg, 1.2 mmol), and toluene (4 ml) were placed in a reaction vial and shaken overnight at 118° C. Upon cooling and filtration, the solution was evaporated in a vacuum zentrifuge (45° C.) and the residue was purified by automated, preparative HPLC (YMC CombiPrep C18 column 50×20 mm, solvent gradient 5-95% CH3CN in 0.1% TFA(aq) over 6.0 min, λ=230 nm, flow rate 40 ml/min). The obtained solid (28 mg) was dissolved in THF (1 ml) and added, under an atmosphere of argon, to a cooled (0° C.) suspension of 100 mg of lithium aluminium hydride in 1 ml THF in a reaction vial. The reaction mixture was shaken first for 2 h at r.t. and subsequently for 4 h at 40° C. Upon cooling, water was added carefully and the mixture was filtered. The filtrate was evaporated in a vacuum zentrifuge (45° C.). Purification of the re-dissolved (DMF, 1 ml) residue by automated, preparative HPLC (YMC CombiPrep C18 column 50×20 mm, solvent gradient 5-95% CH3CN in 0.1% TFA(aq) over 6.0 min, λ=230 nm, flow rate 40 ml/min) gave 11 mg (7%) of the title compound, MS: m/e=320.1 (M+H+), as a solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH:7]([O:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][C:20]([OH:22])=O)=[CH:14][CH:13]=1)[CH2:6][CH2:5]2.[CH3:23][S:24]([NH2:27])(=[O:26])=[O:25].Cl.C(N=C=NCCCN(C)C)C.O>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH:7]([O:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][C:20]([NH:27][S:24]([CH3:23])(=[O:26])=[O:25])=[O:22])=[CH:14][CH:13]=1)[CH2:6][CH2:5]2
Reactant: CS(N)(=O)=O
Reactant: O=C(O)CCc1ccc(OC2CCc3cc(Cl)ccc32)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: O
Solvent: ClCCl
Product: CS(=O)(=O)NC(=O)CCc1ccc(OC2CCc3cc(Cl)ccc32)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 26.7 %

Procedure:
To a solution of 4-[(5-chloro-2,3-dihydro-1H-inden-1-yl)oxy]benzenepropanoic acid (0.3 g, 0.95 mmol) in dichloromethane (10 mL) were added methanesulfonamide (90 mg, 0.95 mmol), N,N-dimethylaminopyridine (0.12 g, 0.95 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.17 mL, 0.95 mmol), and the mixture was stirred at room temperature for 15 hrs. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water, concentrated under reduced pressure to give the title compound (0.10 g, yield 30%).
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[Si]([O:36][CH2:37][CH2:38][O:39][CH2:40][C@H:41]([O:52][C:53]1[N:58]=[CH:57][N:56]=[C:55]2[N:59]([C:62]3[CH:67]=[CH:66][CH:65]=[C:64]([C:68]#[N:69])[C:63]=3[CH3:70])[N:60]=[CH:61][C:54]=12)[C:42]([NH:44][C:45]1[CH:50]=[CH:49][C:48]([CH3:51])=[CH:47][N:46]=1)=[O:43])(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1>C1COCC1>[C:68]([C:64]1[C:63]([CH3:70])=[C:62]([N:59]2[C:55]3=[N:56][CH:57]=[N:58][C:53]([O:52][C@@H:41]([CH2:40][O:39][CH2:38][CH2:37][OH:36])[C:42]([NH:44][C:45]4[CH:50]=[CH:49][C:48]([CH3:51])=[CH:47][N:46]=4)=[O:43])=[C:54]3[CH:61]=[N:60]2)[CH:67]=[CH:66][CH:65]=1)#[N:69]
Reactant: Cc1ccc(NC(=O)[C@H](COCCO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)Oc2ncnc3c2cnn3-c2cccc(C#N)c2C)nc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: Cc1ccc(NC(=O)[C@H](COCCO)Oc2ncnc3c2cnn3-c2cccc(C#N)c2C)nc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Tetrabutylammonium fluoride (1M in THF) (0.440 mL, 0.44 mmol) was added to (2S)-3-(2-(tert-butyldiphenylsilyloxy)ethoxy)-2-(1-(3-cyano-2-methylphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy)-N-(5-methylpyridin-2-yl)propanamide (Intermediate AT6) (313 mg, 0.44 mmol) in THF (2 mL) under nitrogen. The resulting mixture was stirred at ambient temperature for 2 hours. The reaction mixture was quenched with saturated NH4Cl, diluted with DCM and poured onto a phase separator. The organic layer was evaporated to a gum. The crude product was purified by flash silica chromatography, elution gradient 0 to 10% methanol in ethyl acetate to afford the product (59.0 mg, 28.3%, 84% ee). 1H NMR (400 MHz, CDCl3) δ 2.30 (3H, s), 2.40 (3H, s), 3.02 (1H, s), 3.72-3.83 (4H, m), 4.13-4.26 (2H, m), 6.09 (1H, t), 7.45-7.57 (2H, m), 7.63-7.68 (1H, m), 7.76-7.81 (1H, m), 8.03-8.12 (2H, m), 8.43 (1H, s), 8.58 (1H, s), 8.95 (1H, s); m/z (ES+) (M+H)+=474.49; HPLC tR=1.83 min.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][NH:8][C:9]([C:11]2[C:19]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[N:13]3[CH2:20][CH2:21][CH2:22][O:23][C:12]=23)=[O:10])[CH2:3][CH2:2]1.C(N(C(C)C)CC)(C)C.Br[CH2:34][CH2:35][NH:36][S:37]([CH3:40])(=[O:39])=[O:38]>C(#N)C.C(Cl)(Cl)Cl>[CH3:40][S:37]([NH:36][CH2:35][CH2:34][N:1]1[CH2:6][CH2:5][CH:4]([CH2:7][NH:8][C:9]([C:11]2[C:19]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[N:13]3[CH2:20][CH2:21][CH2:22][O:23][C:12]=23)=[O:10])[CH2:3][CH2:2]1)(=[O:39])=[O:38]
Reactant: CS(=O)(=O)NCCBr
Reactant: O=C(NCC1CCNCC1)c1c2n(c3ccccc13)CCCO2
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Solvent: ClC(Cl)Cl
Product: CS(=O)(=O)NCCN1CCC(CNC(=O)c2c3n(c4ccccc24)CCCO3)CC1
Yield: 11.2 %

Procedure:
A stirred solution of N-(4-piperidylmethyl) 3,4-dihydro-2H-[1,3]oxazino[3,2-a]indole-10-carboxarnide (E21, 220 mg, 0.70 mmole) in acetonitrile (8 ml) was treated with diisopropylethylamine (0.24 ml, 1.4 mmole) and N-(2-bromoethyl)methanesulphonamide (D14, 160 mg, 0.77 mmole) and the mixture heated under reflux for 2.5 h. The reaction mixture was concentrated in vacuo and the residue chromatographed on silica gel eluting with dichloromethane/methanol/0.88 ammonia solution (200:10:1). The colourless oil obtained was dissolved in chloroform (30 ml) and washed with water (2×20 ml), then dried (Na2SO4) and concentrated in vacuo. The residue was passed through a short plug of basic alumina eluting with ethyl acetate to afford the title compound as a colourless oil (34 mg, 11%). This was converted to its oxalate salt and crystallised from acetone to give a white solid mp 80-85° C.
Reaction SMILES: [CH3:1][CH:2]([CH3:15])[CH2:3][CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[NH:7][C:6]1=[O:14].C(N(CC)CC)C.Cl[C:24](OC1C=CC([N+]([O-])=O)=CC=1)=[O:25].[NH2:36][C@H:37]([C:42]([NH2:44])=[O:43])[C:38]([CH3:41])([CH3:40])[CH3:39]>ClCCl>[NH2:44][C:42]([C@@H:37]([NH:36][C:24]([N:7]1[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[N:5]([CH2:4][CH2:3][CH:2]([CH3:15])[CH3:1])[C:6]1=[O:14])=[O:25])[C:38]([CH3:41])([CH3:40])[CH3:39])=[O:43]
Reactant: CC(C)CCn1c(=O)[nH]c2ccccc21
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: CC(C)(C)[C@H](N)C(N)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)CCn1c(=O)n(C(=O)N[C@H](C(N)=O)C(C)(C)C)c2ccccc21
Temperature: 25 °C
Reaction time: 4 h
Yield: 96.5 %

Procedure:
To a solution of 1-(3-methylbutyl)1,2-dihydro-2H-benzimidazol-2-one (Step 1, 140 mg, 0.69 mmol) in dichloromethane (2.5 mL) were added triethylamine (0.32 mL, 2.3 mmol) and 4-nitrophenyl chloroformate (150 mg, 0.76 mmol) at 0° C. and the mixture was stirred for 4 h at rt. Then to this mixture was added a solution of L-tert-leucinamide (steps 1 and 2 in example 4, 99 mg, 0.76 mmol) in dichloromethane (2 mL) at 0° C. and stirred rt. After 22 h, the reaction was quenched by addition of water (20 mL) and extracted with ethyl acetate (30 mL×2). The combined organic layers were washed with water (20 mL×3), brine (20 mL) and dried over sodium sulfate, filtered and concentrated. The residue was purified by column chromatography on silica gel eluting with hexane/ethyl acetate (3/1-1/1) to afford 240 mg (96%) of the titled compound. The obtained product was further purified by recrystallization from hexane/ethyl acetate to give 220 mg of the title compound.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:9]([CH3:12])([CH3:11])[CH3:10])[C:6]=1[C:7]#[N:8].[CH3:13][N:14]=[C:15]=[O:16].C(N(CC)CC)C>CN(C)C=O>[C:7]([C:6]1[C:5]([C:9]([CH3:12])([CH3:11])[CH3:10])=[CH:4][S:3][C:2]=1[NH:1][C:15]([NH:14][CH3:13])=[O:16])#[N:8]
Reactant: CC(C)(C)c1csc(N)c1C#N
Reactant: CN=C=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CNC(=O)Nc1scc(C(C)(C)C)c1C#N
Reaction time: 8 h

Procedure:
A solution of 4 g 2-amino-3-cyano-4-t-butylthiophene, 1.27 g methyl isocyanate and 3 ml triethylamine in 20 ml dimethylformamide was heated at 130°C. for 3 hours and then allowed to stand at about 25°C. overnight. The dimethylformamide was removed by distillation and the residue was crystallized from ether to give the product, as a tan solid, m.p. 212°-214°C. The infrared spectrum of the product showed cyano absorption at 4.6 microns. Sulfur analysis for the product is tabulated in Table I.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]=[C:7]=[S:8])=[O:5])[CH3:2].[NH2:9][C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][N:11]=1>O1CCOCC1>[Cl:16][C:13]1[CH:14]=[CH:15][C:10]([NH:9][C:7]([NH:6][C:4](=[O:5])[O:3][CH2:1][CH3:2])=[S:8])=[N:11][CH:12]=1
Reactant: CCOC(=O)N=C=S
Reactant: Nc1ccc(Cl)cn1
Solvent: C1COCCO1
Product: CCOC(=O)NC(=S)Nc1ccc(Cl)cn1
Temperature: 25 °C
Reaction time: 14 h
Yield: 72.6 %

Procedure:
Ethoxycarbonylisothiocyanate (3.37 g) was added to a stirred solution of 2-amino-5-chloropyridine (3.0 g) in dioxane (100 mL). The mixture was stirred at r.t. for 14 h. The solvent was removed in vacuum. The solid was dissolved in dichloromethane and methanol (100:1), filtered and the solvent was removed in vacuum to give a solid that was recrystallized from ethyl acetate to give 4.4 g of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][NH:13][CH2:14][C:15]2[CH:23]=[CH:22][C:18]3[O:19][CH2:20][O:21][C:17]=3[CH:16]=2)[CH:7]=1.[C:25]1([S:31](Cl)(=[O:33])=[O:32])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C(N(CC)CC)C>[CH3:1][O:2][C:3](=[O:24])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][N:13]([S:31]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)(=[O:33])=[O:32])[CH2:14][C:15]2[CH:23]=[CH:22][C:18]3[O:19][CH2:20][O:21][C:17]=3[CH:16]=2)[CH:7]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: COC(=O)CCc1cccc(CNCc2ccc3c(c2)OCO3)c1
Solvent: CCN(CC)CC
Product: COC(=O)CCc1cccc(CN(Cc2ccc3c(c2)OCO3)S(=O)(=O)c2ccccc2)c1

Procedure:
The title compound of Step B was prepared following the method described in Step A of Example 1 from 3-(3-{[(benzo[1,3]dioxol-5-ylmethyl)-amino]-methyl}-phenyl)-propionic acid methyl ester of Step A and benzenesulfonyl chloride using triethylamine in place of N,N-diisopropylethylamine. 1H NMR (400 MHz, CDCl3) δ 7.85 (d, 2H), 7.62-7.50 (m, 3H), 7.13 (m, 1H), 7.03 (m, 1H), 6.88 (m, 1H), 6.78 (s, 1H), 6.62 (d, 1H), 6.54 (s, 1H), 6.46 (d, 1H), 5.90 (s, 2H), 4.28 (s, 2H), 4.21 (s, 2H), 3.67 (s, 3H), 2.81 (t, 2H), 2.50 (t, 2H).
Reaction SMILES: [CH3:1][C:2]1[C:6]2[C:7](=[O:19])[N:8]([CH2:11][CH2:12][N:13]3[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]3)[CH2:9][CH2:10][C:5]=2[NH:4][C:3]=1[CH:20]=O.[Br:22][C:23]1[CH:31]=[CH:30][CH:29]=[C:28]2[C:24]=1[CH2:25][C:26](=[O:32])[NH:27]2>>[Br:22][C:23]1[CH:31]=[CH:30][CH:29]=[C:28]2[C:24]=1[C:25](=[CH:20][C:3]1[NH:4][C:5]3[CH2:10][CH2:9][N:8]([CH2:11][CH2:12][N:13]4[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]4)[C:7](=[O:19])[C:6]=3[C:2]=1[CH3:1])[C:26](=[O:32])[NH:27]2
Reactant: Cc1c(C=O)[nH]c2c1C(=O)N(CCN1CCCCC1)CC2
Reactant: O=C1Cc2c(Br)cccc2N1
Product: Cc1c(C=C2C(=O)Nc3cccc(Br)c32)[nH]c2c1C(=O)N(CCN1CCCCC1)CC2
Yield: 84.9 %

Procedure:
The title compound was prepared under the same conditions as described in Example 25 with 3-methyl-4-oxo-5-(2-piperidin-1-yl-ethyl)-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine-2-carbaldehyde and 4-bromo-1,3-dihydro-indol-2-one prepared according to US20030225127) as starting materials to give 2-(4-bromo-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-3-methyl-5-(2-piperidin-1-yl-ethyl)-1,5,6,7-tetrahydro-pyrrolo[3,2-c]pyridin-4-one (58 mg, 84.9%) as a yellow solid.
Reaction SMILES: [K+].[Br:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([C:19]2[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=2)[O:10][CH:11]([CH2:15][CH:16]([CH3:18])[CH3:17])[C:12]([O-])=[O:13])=[CH:5][CH:4]=1.Cl.[NH2:26][CH2:27][C:28]#[N:29]>>[Br:2][C:3]1[CH:4]=[CH:5][C:6]([CH:9]([C:19]2[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=2)[O:10][CH:11]([CH2:15][CH:16]([CH3:18])[CH3:17])[C:12]([NH:29][CH2:28][C:27]#[N:26])=[O:13])=[CH:7][CH:8]=1
Reactant: CC(C)CC(OC(c1ccncc1)c1ccc(Br)cc1)C(=O)[O-]
Reactant: N#CCN
Agent: Cl
Agent: [K+]
Product: CC(C)CC(OC(c1ccncc1)c1ccc(Br)cc1)C(=O)NCC#N

Procedure:
Using the same protocol as described in example 17, step 3, 2-[(4-bromophenyl)(pyridin-4-yl)methoxy]-4-methylpentanoic acid potassium salt from step 3 (312 mg, 0.75 mmol) was coupled with aminoacetonitrile HCl Salt. The crude residue obtained was chromatographed on silica gel using 10% MeOH in dichloromethane to afford the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[C:5]#[N:6].C([CH2:12][C:13](Br)([CH3:17])[C:14]([O-:16])=[O:15])C.C(=O)([O-])[O-].[K+].[K+].[C:25](#N)[CH3:26]>>[CH2:25]([O:16][C:14](=[O:15])[C:13]([O:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:4]([C:5]#[N:6])[CH:3]=1)([CH3:12])[CH3:17])[CH3:26]
Reactant: CCCC(C)(Br)C(=O)[O-]
Reactant: CC#N
Reactant: N#Cc1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCOC(=O)C(C)(C)Oc1cccc(C#N)c1
Temperature: 80 °C
Reaction time: 16 h

Procedure:
5.0 g (42.0 mmol) of 3-hydroxybenzonitrile and 16.25 ml=21.29 g (109 mmol) of ethyl-bromoisobutyrate were dissolved in 70 ml acetonitrile; then, 17.40 g (126 mmol) of potassium carbonate were added and the reaction mixture stirred for 16 hours at 80° C. (reflux). It was then cooled down to ambient temperature and the solvent was evaporated. The residue was partitioned between water and ether and extracted twice with ether; the organic phases were washed with water, dried (MgSO4) and evaporated. The crude product was purified by flash chromatography (SiO2, heptane/AcOEt) to finally give 9.10 g of the title compound as colorless oil.
Reaction SMILES: C([O:5][C:6]([C@:8]1([C:20](=[O:25])[N:21]([O:23][CH3:24])[CH3:22])[C@@H:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C@H:9]1[CH2:17][O:18][CH3:19])=[O:7])(C)(C)C>FC(F)(F)C(O)=O.ClCCl>[CH3:19][O:18][CH2:17][C@@H:9]1[C@H:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C@@:8]1([C:20](=[O:25])[N:21]([O:23][CH3:24])[CH3:22])[C:6]([OH:7])=[O:5]
Reactant: COC[C@@H]1[C@H](c2ccccc2)[C@]1(C(=O)OC(C)(C)C)C(=O)N(C)OC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC[C@@H]1[C@H](c2ccccc2)[C@]1(C(=O)O)C(=O)N(C)OC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
(1R*,2R*,3R*)-2-methoxymethyl-1-(methoxy-methyl-carbamoyl)-3-phenyl-cyclopropanecarboxylic acid t-butyl ester (30 mg, 0.086 mmol) was dissolved in 1 mL of trifluoroacetic acid and 1 mL of dichloromethane. After stirring at room temperature for 2 hours, the reaction mixture was concentrated and azeotroped with toluene. The product was dried under high vacuum before use.
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[CH3:13][C:14]([CH3:51])([CH3:50])[CH2:15][O:16][C:17]1[N:22]=[CH:21][C:20]([N:23]2[C:28](=[O:29])[C:27]([CH2:30][C:31]3[CH:36]=[CH:35][C:34]([C:37]4[C:38]([C:43]#[N:44])=[CH:39][CH:40]=[CH:41][CH:42]=4)=[CH:33][CH:32]=3)=[C:26]([CH2:45][CH2:46][CH3:47])[N:25]=[C:24]2[CH2:48][CH3:49])=[CH:19][CH:18]=1>C(OCC)(=O)C>[CH3:51][C:14]([CH3:50])([CH3:13])[CH2:15][O:16][C:17]1[N:22]=[CH:21][C:20]([N:23]2[C:28](=[O:29])[C:27]([CH2:30][C:31]3[CH:36]=[CH:35][C:34]([C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=4[C:43]4[NH:3][C:4](=[O:7])[O:5][N:44]=4)=[CH:33][CH:32]=3)=[C:26]([CH2:45][CH2:46][CH3:47])[N:25]=[C:24]2[CH2:48][CH3:49])=[CH:19][CH:18]=1
Reactant: O=C([O-])O
Reactant: [NH3+]O
Reactant: CCCc1nc(CC)n(-c2ccc(OCC(C)(C)C)nc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CCCc1nc(CC)n(-c2ccc(OCC(C)(C)C)nc2)c(=O)c1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 59.9 %

Procedure:
A mixture of hydroxylammonium chloride (0.12 g), sodium hydrogen carbonate (0.19 g) and dimethyl sulfoxide (5 mL) was stirred at 40° C. for 30 min, 4′-({1-[6-(2,2-dimethylpropoxy)pyridin-3-yl]-2-ethyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl}methyl)biphenyl-2-carbonitrile (0.12 g) was added, and the mixture was stirred at 90° C. for 12 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was dissolved in tetrahydrofuran (3 mL) N,N′-carbonyldiimidazole (0.06 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.05 mL) were added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous potassium hydrogen sulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as a colorless amorphous solid (0.08 g, 62%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[OH:12])[C:5]([O:7][CH3:8])=[O:6].C([O-])([O-])=O.[K+].[K+].I[CH:20]([CH3:22])[CH3:21]>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[O:12][CH:20]([CH3:22])[CH3:21])[C:5]([O:7][CH3:8])=[O:6]
Reactant: CC(C)I
Reactant: COC(=O)c1ccc(O)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(OC(C)C)c(F)c1
Temperature: 60 °C

Procedure:
To methyl 3-fluoro-4-hydroxy-benzoate (2.00 g, 11.8 mmol) in DMF (12.5 mL) was added K2CO3 (6.50 g, 47.0 mmol) followed by 2-iodopropane (2.35 mL, 23.5 mmol). The mixture was heated at 60° C. for 1.5 h. The mixture was filtered using EtOAc and the filtrate was evaporated under reduced pressure. The residue was dissolved in EtOAc and was washed with water and brine. The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure to give methyl 3-fluoro-4-isopropoxybenzoate. ESI-MS m/z calc 212.1. found 213.3 (M+1)+. Retention time: 1.70 minutes (3 min run).