Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]([CH:6]([OH:14])[C:7]1[CH:8]=[N:9][C:10]([CH3:13])=[N:11][CH:12]=1)=[CH2:5].[C:16](OC(=O)C)(=[O:18])[CH3:17].C([O-])(O)=O.[Na+]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH3:1][O:2][C:3](=[O:15])[C:4]([CH:6]([O:14][C:16](=[O:18])[CH3:17])[C:7]1[CH:12]=[N:11][C:10]([CH3:13])=[N:9][CH:8]=1)=[CH2:5]
Reactant: CC(=O)OC(C)=O
Reactant: C=C(C(=O)OC)C(O)c1cnc(C)nc1
Agent: CN(C)c1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: C=C(C(=O)OC)C(OC(C)=O)c1cnc(C)nc1
Temperature: 0 °C
Reaction time: 0.03 h
Yield: 61.1 %

Procedure:
2-[Hydroxy-(2-methyl-pyrimidin-5-yl)-methyl]acrylic acid methyl ester (1.58 g, 7.58 mmol, 1 eq) and 4-DMAP (0.4 eq, 370 mg) were dissolved in 30 ml of dry DCM under argon atmosphere. To the mixture, cooled at 0° C., was added acetic anhydride (1.5 eq, 1.07 ml) dropwise, during 2 minutes. The mixture was warmed-up to room temperature and was stirred overnight (16 hours). The mixture was then poured into 150 ml of NaHCO3 saturated water solution and organic substances were extracted with DCM (3 times, 150 ml of DCM was used in total). The gathered DCM layers were dried, the solvent was evaporated and obtained was 2-[acetoxy-(2-methyl-pyrimidin-5-yl)-methyl]acrylic acid methyl ester (1.16 g, yield=61.1%, purity=90%) in form of orange transparent oil. MS: [M+H]+=251.25 1H NMR (300 MHz; CDCl3) δ/ppm 2.73 (s, 3H), 3.72 (s, 2H), 6.05 (s, 1H), 6.49 (s, 1H), 6.61 (s, 1H) 8.65 (s, 2H)
Reaction SMILES: CN(C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([S:20]([C:23]([F:26])([F:25])[F:24])(=[O:22])=[O:21])[CH:15]=2)[N:8]=1)=O.[F:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[NH:35][NH2:36]>>[F:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[N:35]1[C:5]([C:7]2[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([S:20]([C:23]([F:26])([F:24])[F:25])(=[O:21])=[O:22])[CH:15]=3)[N:8]=2)=[CH:4][CH:3]=[N:36]1
Reactant: CN(C)/C=C/C(=O)c1nn(-c2cccc(S(=O)(=O)C(F)(F)F)c2)ccc1=O
Reactant: NNc1ccccc1F
Product: O=c1ccn(-c2cccc(S(=O)(=O)C(F)(F)F)c2)nc1-c1ccnn1-c1ccccc1F

Procedure:
The product was obtained starting from 3-((E)-3-Dimethylamino-acryloyl)-1-(3-trifluoromethansulfonyl-phenyl)-1H-pyridazin-4-one (A-33) and 2-fluoro-phenylhydrazine according to the method described for example 1. MS: M=465.1 (M+H)+
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH:5]([C:8]2[NH:9][C:10](=[O:18])[C:11]3[C:16]([CH:17]=2)=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH2:4][CH2:3]1.Br[CH2:20][CH2:21][CH2:22][OH:23]>>[OH:23][CH2:22][CH2:21][CH2:20][N:2]1[CH2:7][CH2:6][CH:5]([C:8]2[NH:9][C:10](=[O:18])[C:11]3[C:16]([CH:17]=2)=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH2:4][CH2:3]1
Reactant: O=c1[nH]c(C2CCNCC2)cc2ccccc12
Reactant: OCCCBr
Agent: Cl
Product: O=c1[nH]c(C2CCN(CCCO)CC2)cc2ccccc12
Yield: 25.1 %

Procedure:
By the reaction in the same manner as in Example 2a, using 3-(piperidin-4-yl)-2H-isoquinolin-1-one hydrochloride (500 mg) and 3-bromo-1-propanol (315 mg), 3-[1-(3-hydroxypropyl)piperidin-4-yl]-2H-isoquinolin-1-one (136 mg) was obtained.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:17](=[O:18])[C:16]2[C@H:15]3[C:19]([CH3:21])([CH3:20])[C@:12]([CH3:22])([CH2:13][CH2:14]3)[C:11]=2[NH:10]1.Br[CH2:24][C:25]1[CH:34]=[CH:33][C:28]([C:29]([O:31][CH3:32])=[O:30])=[CH:27][CH:26]=1.ClCCl>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C)C=O>[CH3:32][O:31][C:29](=[O:30])[C:28]1[CH:33]=[CH:34][C:25]([CH2:24][N:10]2[C:11]3[C@:12]4([CH3:22])[C:19]([CH3:21])([CH3:20])[C@@H:15]([CH2:14][CH2:13]4)[C:16]=3[C:17](=[O:18])[N:9]2[C:3]2[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=2[F:1])=[CH:26][CH:27]=1
Reactant: CC1(C)[C@H]2CC[C@]1(C)c1[nH]n(-c3ccc(F)cc3F)c(=O)c12
Reactant: COC(=O)c1ccc(CBr)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(Cn2c3c(c(=O)n2-c2ccc(F)cc2F)[C@@H]2CC[C@@]3(C)C2(C)C)cc1
Yield: 48.9 %

Procedure:
A solution of (4R,7S)-2-(2,4-difluoro-phenyl)-7,8,8-trimethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (Intermediate 42; 300 mg, 0.99 mmol), tetrabutylammonium iodide (270 mg, 0.7 mmol) and methyl 4-(bromomethyl)benzoate (1.00 g, 4.37 mmol) in dimethylformamide (10 mL) was heated at 100° C. for 3 h. The reaction mixture was allowed to cool. Dichloromethane (100 mL) was added, and the solution was washed with (5×25 mL), aqueous sodium thiosulfate (25 mL), and brine (25 mL), dried (magnesium sulfate, filtered, and evaporated. The residue was purified using an ISCO 40 g column, eluting with 50-100% ethyl acetate/hexanes. Fractions containing the product were concentrated and then dried under high vacuum at 50° C. give 4-[(4R,7S)-2-(2,4-difluoro-phenyl)-7,8,8-trimethyl-3-oxo-2,3,4,5,6,7-hexahydro-4,7-methano-indazol-1-ylmethyl]-benzoic acid methyl ester (219 mg, 49%) as a pale yellow solid. ES(+)-MS (M+H) 453.
Reaction SMILES: [CH3:1][S:2]([O:5][CH2:6][CH3:7])(=[O:4])=[O:3].C1COCC1.C([Li])CCC.[P:18](Cl)(=[O:25])([O:22][CH2:23][CH3:24])[O:19][CH2:20][CH3:21]>CCCCCC>[CH2:6]([O:5][S:2]([CH2:1][P:18]([O:22][CH2:23][CH3:24])([O:19][CH2:20][CH3:21])=[O:25])(=[O:4])=[O:3])[CH3:7]
Reactant: CCOS(C)(=O)=O
Reactant: CCOP(=O)(Cl)OCC
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCOP(=O)(CS(=O)(=O)OCC)OCC
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
To a solution of methanesulfonic acid, ethyl ester (11.00 mL, 0.1068 mol) in THF (200.0 mL, 2.466 mol) at −78° C. was added 2.500 M of n-butyllithium in hexane (50.00 mL) over 15 minutes and the mixture was stirred for 20 minutes. Phosphorochloridic acid, diethyl ester (10.0 mL, 0.0694 mol) was added to the mixture at −78° C. The mixture was stirred for 3.5 hours, allowing to warm to 0° C. The reaction was quenched with 5M ammonium chloride in water (100 mL) and the mixture was concentrated in vacuo to remove THF. The aqueous was extracted with EtOAc (2×150 mL) and the organics were combined and concentrated in vacuo. The product was purified by flash chromatography (0 to 100% EtOAc/Hexanes) to yield the product as an oil (9.07 g, 50%+10.4 g of a mixed fraction).
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH2:10][CH2:11][CH2:12][N:13]([CH3:33])[CH2:14][CH2:15][C@@:16]1([OH:32])[CH2:25][C:24]([F:27])([F:26])[C:23]2[C:18](=[CH:19][CH:20]=[C:21]([F:28])[CH:22]=2)[C@@H:17]1[CH:29]([CH3:31])[CH3:30].[CH3:34][O:35][CH2:36][C:37](OC1C([2H])([2H])C([2H])([2H])C2C(=CC=C(F)C=2)C1C(C)C)=[O:38]>>[CH3:34][O:35][CH2:36][C:37]([O:32][C@:16]1([CH2:15][CH2:14][N:13]([CH2:12][CH2:11][CH2:10][C:2]2[NH:3][C:4]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[N:1]=2)[CH3:33])[CH2:25][C:24]([F:27])([F:26])[C:23]2[C:18](=[CH:19][CH:20]=[C:21]([F:28])[CH:22]=2)[C@@H:17]1[CH:29]([CH3:31])[CH3:30])=[O:38]
Reactant: CC(C)[C@H]1c2ccc(F)cc2C(F)(F)C[C@]1(O)CCN(C)CCCc1nc2ccccc2[nH]1
Reactant: [2H]C1([2H])c2cc(F)ccc2C(C(C)C)C(OC(=O)COC)C1([2H])[2H]
Product: COCC(=O)O[C@]1(CCN(C)CCCc2nc3ccccc3[nH]2)CC(F)(F)c2cc(F)ccc2[C@@H]1C(C)C

Procedure:
Compound 104 is prepared from 35d in a manner analogous to that of Example 4 for compound 500.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH:10]([NH:20][C:21]([CH:23]2[CH2:28][CH2:27][CH2:26][NH:25][CH2:24]2)=[O:22])[CH2:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N:29]1[CH:34]=[CH:33][CH:32]=[C:31]([CH2:35][CH2:36][C:37](O)=[O:38])[CH:30]=1.C(N(CC)CC)C.Cl.CN(C)CCCN=C=NCC>C(Cl)Cl>[C:1]1([CH2:7][CH2:8][CH2:9][CH:10]([NH:20][C:21]([CH:23]2[CH2:28][CH2:27][CH2:26][N:25]([C:37](=[O:38])[CH2:36][CH2:35][C:31]3[CH:30]=[N:29][CH:34]=[CH:33][CH:32]=3)[CH2:24]2)=[O:22])[CH2:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)CCc1cccnc1
Reactant: O=C(NC(CCCc1ccccc1)CCCc1ccccc1)C1CCCNC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(NC(CCCc1ccccc1)CCCc1ccccc1)C1CCCN(C(=O)CCc2cccnc2)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 67.6 %

Procedure:
Piperidine-3-carboxylic acid [4-phenyl-1-(3-phenyl-propyl)-butyl]-amide (13) (150 mg; 0.4 mmol) is dissolved in methylene chloride (10 mL) at ambient temperature. 3-Pyridinepropionic acid (60.0 mg; 0.4 mmol), triethylamine (0.111 mL; 0.4 mmol), and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (0.0836 g; 0.4 mmol) are added sequentially. The mixture is stirred for 18 hours at ambient temperature then diluted with methylene chloride (90 mL) and washed successively with water (40 mL), saturated aqueous sodium bicarbonate (40 mL), and saturated brine (25 mL). The organic layer is dried over MgSO4, filtered, and concentrated in vacuo. The residue is purified via silica gel chromatography with gradient elution (1%→20% methanol in methylene chloride) affording the desired product (138.4 mg) as an oil. ESMS: MH+ 512.4 (base).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[C:4]1[CH:9]=[C:8]([C:10]#[N:11])[N:7]=[C:6]([NH:12][C@H:13]([CH2:15][CH3:16])[CH3:14])[CH:5]=1.[N-:18]=[N+:19]=[N-:20].[Na+].Cl.C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3](=[O:17])[C:4]1[CH:9]=[C:8]([C:10]2[N:18]=[N:19][NH:20][N:11]=2)[N:7]=[C:6]([NH:12][C@H:13]([CH2:15][CH3:16])[CH3:14])[CH:5]=1
Reactant: [N-]=[N+]=[N-]
Reactant: CC[C@H](C)Nc1cc(C(=O)OC)cc(C#N)n1
Agent: Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CC[C@H](C)Nc1cc(C(=O)OC)cc(-c2nn[nH]n2)n1
Temperature: 25 °C
Yield: 65.1 %

Procedure:
Heat a suspension of (S)-2-sec-butylamino-6-cyano-isonicotinic acid methyl ester (932 mg, 4.0 mmol), sodium azide (780 mg, 12 mmol), and triethylamine hydrochloride (1.65 g, 12 mmol) in toluene (13 mL) at 90° C. for 2 days. Cool to room temperature and extract with water (3×30 mL), acidify the combined aqueous layers to about pH=2 using 1 N HCl, extract the desired product with ethyl acetate (4×50 mL), dry (sodium sulfate) and concentrate to give the title compound (720 mg, 65%).
Reaction SMILES: [CH3:1][O:2][C:3]([C@H:5]1[CH2:10][CH2:9][C@H:8]([C:11](=[S:13])[NH2:12])[CH2:7][CH2:6]1)=[O:4].CO[C:16](OC)([N:18]([CH3:20])[CH3:19])[CH3:17]>>[CH3:1][O:2][C:3]([C@H:5]1[CH2:10][CH2:9][C@H:8]([C:11](=[S:13])[N:12]=[C:16]([N:18]([CH3:20])[CH3:19])[CH3:17])[CH2:7][CH2:6]1)=[O:4]
Reactant: COC(=O)[C@H]1CC[C@H](C(N)=S)CC1
Reactant: COC(C)(OC)N(C)C
Product: COC(=O)[C@H]1CC[C@H](C(=S)N=C(C)N(C)C)CC1
Temperature: 25 °C

Procedure:
A mixture of trans-4-thiocarbamoyl-cyclohexanecarboxylic acid methyl ester (0.72 g, 3.6 mmol) and N,N-dimethylacetamide dimethyl acetal (0.95 g, 7.2 mmol) was stirred at room temperature over night. The solvent was evaporated. Flash-chromatography with n-heptane/ethyl acetate as eluent gave the title compound (0.90 g, 93%) as yellow oil. MS m/e: 271 ([M+H]+)
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[C:4]1[CH:9]=[C:8]([S:10]([CH:13]([CH3:15])[CH3:14])(=[O:12])=[O:11])[N:7]=[C:6](Cl)[CH:5]=1.C(N(CC)C(C)C)(C)C.[CH2:27]([NH2:30])[C:28]#[CH:29]>C1COCC1>[CH3:1][O:2][C:3](=[O:17])[C:4]1[CH:5]=[C:6]([NH:30][CH2:27][C:28]#[CH:29])[N:7]=[C:8]([S:10]([CH:13]([CH3:15])[CH3:14])(=[O:12])=[O:11])[CH:9]=1
Reactant: COC(=O)c1cc(Cl)nc(S(=O)(=O)C(C)C)c1
Reactant: C#CCN
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: C#CCNc1cc(C(=O)OC)cc(S(=O)(=O)C(C)C)n1
Temperature: 25 °C
Yield: 19.1 %

Procedure:
Add THF (10 mL), 2-chloro-6-iso-propanesulfonyl-isonicotinic acid methyl ester (0.50 g, 1.80 mmol), N,N-diisopropylethylamine (0.470 mL, 2.70 mmol), and propargylamine (0.740 mL, 10.8 mmol) to a sealed vessel flushed with nitrogen. Heat and stir the reaction at 80° C. overnight. Cool to room temperature, concentrate and purify (silica gel chromatography, eluting with 20:80 to 30:70 ethyl acetate:hexanes) to give the title product (0.102 g, 19%).
Reaction SMILES: [F:1][C:2]([F:38])([F:37])[C:3]1[CH:4]=[C:5]([CH:30]=[C:31]([C:33]([F:36])([F:35])[F:34])[CH:32]=1)[C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14]CCC(=O)C)[CH2:10][C@H:9]1[CH2:20][C:21]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[NH:23][CH:22]=1)=[O:7].[CH:39]([C:41]([CH3:43])=[O:42])=C>C1(C)C=CC=CC=1>[F:35][C:33]([F:36])([F:34])[C:31]1[CH:30]=[C:5]([CH:4]=[C:3]([C:2]([F:38])([F:1])[F:37])[CH:32]=1)[C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:39][C:41](=[O:42])[CH3:43])[CH2:10][C@H:9]1[CH2:20][C:21]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[NH:23][CH:22]=1)=[O:7]
Reactant: CC(=O)CCCN1CCN(C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@H](Cc2c[nH]c3ccccc23)C1
Reactant: C=CC(C)=O
Solvent: Cc1ccccc1
Product: CC(=O)CCN1CCN(C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@H](Cc2c[nH]c3ccccc23)C1

Procedure:
To a solution of (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(1H-indol-3-ylmethyl)-4-(4-pentanon-1-yl)piperazine (1.37 g) in toluene (15 mL) was added drop-wise methyl vinyl ketone (0.3 g). After 2.5 h at room temperature the solution was concentrated to afford crude (2R)-1-[3,5-bis(trifluoromethyl)-benzoyl]-2-(1H-indol-3-ylmethyl)-4-(3-butanon-1-yl)piperazine which was used as such. Rf 0.55 (CH2Cl2/MeOH 95/5).
Reaction SMILES: CO[C:3](=[O:32])[CH:4]([C:15]1[N:19]2[CH:20]=[C:21]([CH3:24])[CH:22]=[CH:23][C:18]2=[N:17][C:16]=1[C:25]1[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][CH:26]=1)[CH2:5][CH2:6][CH2:7][NH:8]S(C(C)(C)C)=O.Cl>CO.CO.CCOC(C)=O>[CH3:24][C:21]1[CH:22]=[CH:23][C:18]2[N:19]([C:15]([CH:4]3[CH2:5][CH2:6][CH2:7][NH:8][C:3]3=[O:32])=[C:16]([C:25]3[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][CH:26]=3)[N:17]=2)[CH:20]=1
Reactant: COC(=O)C(CCCNS(=O)C(C)(C)C)c1c(-c2ccc(C)cc2)nc2ccc(C)cn12
Agent: Cl
Solvent: CO
Solvent: CCOC(C)=O
Product: Cc1ccc(-c2nc3ccc(C)cn3c2C2CCCNC2=O)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 76.8 %

Procedure:
To a magnetically stirred solution of (+/−)-5-(2-methyl-propane-2-sulfinylamino)-2-(6-methyl-2-p-tolyl-imidazo[1,2-a]pyridin-3-yl)-pentanoic acid methyl ester 44b (0.039 g, 0.0824 mmol) in methanol (3 mL) at room temperature under Ar atmosphere was 5N HCl (1.71 mL). The reaction mixture was stirred for 3 h at room temperature, then concentrated in vacuo. The reaction mixture was treated with 10% aq NaOH solution until basic. After 30 min, water (30 mL) was added, and the aqueous phase was extracted with EtOAc (2×50 mL). The combined organic layers were dried (MgSO4), and concentrated in vacuo to the crude product. The pure product was obtained by column chromatography over silica gel (EtOAc, then 4:96 MeOH/EtOAc as eluent) which gave the title compound (0.0202 g, 77%) as a white solid. 1H NMR (400 MHz, CDCl3) 1.92 (m, 1H), 2.04 (m, 2H), 2.16 (m, 1H), 2.32 (s, 3H), 2.39 (s, 3H), 3.50 (m, 2H), 4.28 (dd, J=6.2, 12.4 Hz, 1H), 6.37 (s, 1H), 7.00 (d, J=10.2 Hz, 1H), 7.24 (d, J=8.0 Hz, 2H), 7.56 (m, 3H). Mass spectrum (m/e) 320 (M+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8](=[O:10])[CH3:9])=[N:6][CH:7]=1.[BH4-].[Na+].O.Cl>C(O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([OH:10])[CH3:9])=[N:6][CH:7]=1
Reactant: CC(=O)c1ccc(Br)cn1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CC(O)c1ccc(Br)cn1
Reaction time: 2 h
Yield: 59.4 %

Procedure:
To a solution of 1-(5-bromopyridin-2-yl)ethanone (5 g, 25 mmol) in anhydrous ethanol (100 mL) was added sodium borohydride (2.85 g, 75 mmol) at room temperature. After 2 hours, water (10 mL) was added to quench the reaction at 0° C. and then saturated hydrochloric acid aqueous (10 mL) was added the mixture to adjust pH to 7. The mixture was extracted with ethyl acetate (50 mL). The crude product was purified by column chromatography (petroleum ether/ethyl acetate=1:1) to give 1-(5-bromopyridin-2-yl)ethanol (3 g, 60%).
Reaction SMILES: [C:1]([CH:5]1[N:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:11][CH:10]2[N:6]1[CH2:7][CH2:8][CH2:9]2)(OC)=[O:2].[Cl-].[Mg+2].[Cl-].[CH3:22][Mg]Br.[Cl-].[NH4+]>C1COCC1.CCOCC>[C:1]([CH:5]1[N:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:11][CH:10]2[N:6]1[CH2:7][CH2:8][CH2:9]2)(=[O:2])[CH3:22]
Reactant: COC(=O)C1N(c2ccccc2)CC2CCCN21
Reactant: C[Mg]Br
Agent: [Cl-]
Agent: [Mg+2]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(=O)C1N(c2ccccc2)CC2CCCN21
Temperature: -70 °C
Reaction time: 0.25 h
Yield: 72 %

Procedure:
In 7 ml of THF, was dissolved 295 mg of 2-carbomethoxy-3-phenyl-1,3-diazabicyclo[3,3,0]octane. After addition of 138 mg of anhydrous magnesium chloride, the mixture was refluxed for 10 minutes. To the mixture cooled to -70° C., was added dropwise an ether solution of 1.36 equivalents of methylmagnesium bromide. After having been stirred for 15 minutes at -70° C., the reaction mixture was admixed with saturated aqueous ammonium chloride solution and ether and brought to room temperature. The mixture was extracted with ether and the ether layer was dried. The ether layer was freed from the solvent by distillation in vacuo and the residue was purified by alumina column chromatography to obtain 199 mg (72%) of 2-acetyl-3-phenyl-1,3-diazabicyclo[3,3,0]octane. NMR peaks: δ (ppm)=1.5-2.2 (4H, multiplet), 1.9 (3H, singlet), 2.4-3.3 (3H, multiplet), 3.5-3.9 (2H, multiplet), 4.1 (1H, singlet), 6.1-7.1 (5H, multiplet).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].[C:13]([NH:20][CH:21]1[CH2:26][CH2:25][CH2:24][NH:23][CH2:22]1)([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14]>>[CH3:9][O:8][C:5]1[CH:6]=[CH:7][C:2]([N:23]2[CH2:24][CH2:25][CH2:26][CH:21]([NH:20][C:13](=[O:14])[O:15][C:16]([CH3:18])([CH3:17])[CH3:19])[CH2:22]2)=[C:3]([N+:10]([O-:12])=[O:11])[CH:4]=1
Reactant: CC(C)(C)OC(=O)NC1CCCNC1
Reactant: COc1ccc(Cl)c([N+](=O)[O-])c1
Product: COc1ccc(N2CCCC(NC(=O)OC(C)(C)C)C2)c([N+](=O)[O-])c1
Yield: 50 %

Procedure:
Method 1 was followed using 4-chloro-3-nitroanisole (1.0 eq), 3-(N-Boc-amino) piperidine (1.2 eq), and TEA (2.0 eq) at 60° C. for 72 hours yielding tert-butyl 1-(4-methoxy-2-nitrophenyl)piperidin-3-ylcarbamate (50%). LCMS (m/z): 352.1 (MH+); LC Rt=3.27 min.
Reaction SMILES: F[C:2]1[N:7]=[C:6]([N:8]2[C:12]([N:13]3[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]3)=[N:11][N:10]=[N:9]2)[CH:5]=[CH:4][CH:3]=1.O.[OH-].[Li+].S(=O)(=O)(O)[O-:30].[Na+]>O1CCCC1.O>[OH:30][C:2]1[N:7]=[C:6]([N:8]2[C:12]([N:13]3[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]3)=[N:11][N:10]=[N:9]2)[CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2nnnn2-c2cccc(F)n2)CC1
Reactant: O=S(=O)([O-])O
Agent: [Li+]
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(c2nnnn2-c2cccc(O)n2)CC1
Temperature: 25 °C
Reaction time: 264 h

Procedure:
Part C″: To a solution of tert-butyl 4-(1-(6-fluoropyridin-2-yl)-1H-tetrazol-5-yl)piperazine-1-carboxylate (0.349 g, 1.00 mmol) in 20 mL of tetrahydrofuran at 25° C. was added a solution of lithium hydroxide monohydrate (0.084 g, 2.00 mmol) in 5 mL of water, and the resulting mixture was stirred at 25° C. for 11 days. The reaction mixture was diluted with water, the pH of the solution was adjusted to ˜pH 6 employing aqueous sodium bisulfate solution, and the mixture was extracted with ethyl acetate. The combined extracts were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated. Column chromatography on silica gel (elution: 0-50% diethyl ether/methylene chloride) to afford tert-butyl 4-(1-(6-hydroxypyridin-2-yl)-1H-tetrazol-5-yl)piperazine-1-carboxylate (0.090 g); Mass Spec.: m/e: 348.24 (M+H)+ [calc'd: 348.18]; 1H NMR (300 MHz, CDCl3) δ 7.84 (m, 1H), 7.21 (m, 1H), 6.89 (m, 1H), 3.52 (m, 4H), 3.32 (m, 4H), 1.45 (s, 9H).
Reaction SMILES: Cl.[CH2:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][CH2:4][N:3]1[CH2:12][C:13]([OH:15])=O.[NH2:16][C@@H:17]([CH2:35][O:36][CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[C:18]([NH:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][C:28]2[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=2)=[CH:23][CH:22]=1)=[O:19]>>[CH2:37]([O:36][CH2:35][C@H:17]([NH:16][C:13](=[O:15])[CH2:12][N:3]1[CH2:4][CH2:5][C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH2:2]1)[C:18]([NH:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][C:28]2[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=2)=[CH:23][CH:22]=1)=[O:19])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1
Reactant: O=C(O)CN1CCc2ccccc2C1
Reactant: N[C@@H](COCc1ccccc1)C(=O)Nc1ccc(Oc2ccc(F)cc2)cc1
Agent: Cl
Product: O=C(CN1CCc2ccccc2C1)N[C@@H](COCc1ccccc1)C(=O)Nc1ccc(Oc2ccc(F)cc2)cc1
Yield: 35.2 %

Procedure:
Proceeding as in Example 1, but substituting 2-(3,4-dihydroisoquinolin-2(1H)-yl)acetic acid hydrochloride and (S)-2-amino-3-(benzyloxy)-N-(4-(4-fluorophenoxy)phenyl)propanamide, gave Compound 221, (S)-3-(benzyloxy)-2-(2-(3,4-dihydroisoquinolin-2(1H)-yl)acetamido)-N-(4-(4-fluorophenoxy)phenyl)propanamide (15.6 mg, 35.2%); Major isomer: 1H-NMR (400 MHz, DMSO-D6): σ 10.20 (s, 1H), 8.03 (d, 1H), 7.60 (d, 2H), 7.22-7.26 (m, 5H), 7.19-7.21 (m, 2H), 7.12-7.15 (m, 3H), 6.98-7.04 (m, 5H), 4.73 (m, 1H), 4.50 (s, 2H), 3.71-3.79 (m, 2H), 3.70 (s, 2H), 3.18 (s, 2H), 2.83-2.86 (m, 2H), 2.71-2.81 (m, 2H). MS (EI) for C33H32FN3O4: 554.6 (MH+).
Reaction SMILES: CCN(C(C)C)C(C)C.F[C:11]1[C:16]([N+:17]([O-:19])=[O:18])=[CH:15][C:14]([NH:20][C:21]2[N:26]=[C:25]([C:27]3[CH:28]=[N:29][N:30]4[CH2:35][CH2:34][CH2:33][CH2:32][C:31]=34)[CH:24]=[CH:23][N:22]=2)=[C:13]([O:36][CH3:37])[CH:12]=1.[CH3:38][N:39]1[CH2:43][C@@H:42]2[NH:44][CH2:45][CH2:46][C@@H:41]2[CH2:40]1>FC(F)(F)CO>[CH3:38][N:39]1[CH2:40][C@@H:41]2[C@@H:42]([N:44]([C:11]3[C:16]([N+:17]([O-:19])=[O:18])=[CH:15][C:14]([NH:20][C:21]4[N:26]=[C:25]([C:27]5[CH:28]=[N:29][N:30]6[CH2:35][CH2:34][CH2:33][CH2:32][C:31]=56)[CH:24]=[CH:23][N:22]=4)=[C:13]([O:36][CH3:37])[CH:12]=3)[CH2:45][CH2:46]2)[CH2:43]1
Reactant: COc1cc(F)c([N+](=O)[O-])cc1Nc1nccc(-c2cnn3c2CCCC3)n1
Reactant: CN1C[C@H]2CCN[C@H]2C1
Solvent: OCC(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(N2CC[C@@H]3CN(C)C[C@@H]32)c([N+](=O)[O-])cc1Nc1nccc(-c2cnn3c2CCCC3)n1
Temperature: 140 °C
Yield: 60.9 %

Procedure:
DIPEA (0.583 mL, 3.35 mmol) was added to a suspension of N-(4-fluoro-2-methoxy-5-nitrophenyl)-4-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyrimidin-2-amine (Intermediate 127, 515 mg, 1.34 mmol) and (3aR,6aR)-5-methyl-2,3,3a,4,6,6a-hexahydro-1H-pyrrolo[3,4-b]pyrrole (Intermediate 37, 186 mg, 1.47 mmol) in 2,2,2-trifluoroethanol (5 mL) and the mixture was heated in a microwave at 140° C. for 1 h. After cooling, the mixture was part-purified by ion exchange chromatography, using an SCX column, eluting with 7M methanolic ammonia, and then concentrated in vacuo onto silica. Purification by FCC, eluting with 0-5% 7N methanolic ammonia in CH2Cl2 gave the title compound (400 mg, 61%) as an orange/red foam; 1H NMR (CDCl3): 1.87 (1H, dd), 1.90-1.98 (2H, m), 2.03-2.14 (3H, m), 2.20 (3H, s), 2.28 (1H, dd), 2.45 (2H, ddd), 2.60-2.67 (1H, m), 2.97-3.07 (1H, m), 3.18-3.34 (3H, m), 3.48-3.58 (1H, m), 3.96 (3H, s), 4.20 (2H, t), 4.40 (1H, ddd), 6.43 (1H, s), 6.86 (1H, d), 7.35 (1H, s), 7.95 (1H, s), 8.30 (1H, d), 8.92 (1H, s); m/z: ES+ MH+ 491.15.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([F:8])=[N:6][CH:7]=1.C([Li])CCC.CN(CCN(C)C)C.[CH2:22]1[O:32][C:25]2([CH2:30][CH2:29][C:28](=[O:31])[CH2:27][CH2:26]2)[O:24][CH2:23]1>CCOCC.C1COCC1>[F:8][C:5]1[N:6]=[CH:7][C:2]([C:28]2([OH:31])[CH2:29][CH2:30][C:25]3([O:32][CH2:22][CH2:23][O:24]3)[CH2:26][CH2:27]2)=[CH:3][CH:4]=1
Reactant: Fc1ccc(Br)cn1
Reactant: O=C1CCC2(CC1)OCCO2
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: C1CCOC1
Product: OC1(c2ccc(F)nc2)CCC2(CC1)OCCO2
Temperature: -78 °C
Reaction time: 1 h
Yield: 71.8 %

Procedure:
A solution of 5-bromo-2-fluoropyridine (2 g, 0.011 mol) in 50 mL of dry ether under nitrogen was cooled to −78° C. n-butyllithium (7.5 mL, 0.011 mol, 1.6 M solution in hexane) and TMEDA (2.5 g, 0.022 mol) were added dropwise. The orange solution was stirred for an additional 1 h at −78° C. and then treated dropwise over 10 min with a solution of 1,4-cyclohexanedione monoethylene ketal (1.8 g, 0.011 mol) in 20 mL of dry THF. The reaction mixture was stirred for 1 h, allowed to warm to 20° C. and poured into ice water (400 mL). The organic layer was separated, and the aqueous layer was extracted twice with EtOAc (20 mL×2). The combined organic extracts were dried over MgSO4 and evaporated to give 2 g of white solid. Chromatography on silica gel afforded 1.7 g (67% yield) of white crystals: MS: 254 (M+1)+.