Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)(O)[O-].[Na+].[NH2:6][C@H:7]1[CH2:11][CH2:10][N:9]([C:12]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:13])[CH2:8]1.[CH3:22][O:23][C:24](Cl)=[O:25]>O.C(Cl)Cl>[CH3:22][O:23][C:24]([NH:6][C@H:7]1[CH2:11][CH2:10][N:9]([C:12]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:13])[CH2:8]1)=[O:25]
Reactant: N[C@H]1CCN(C(=O)OCc2ccccc2)C1
Reactant: COC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: COC(=O)N[C@H]1CCN(C(=O)OCc2ccccc2)C1
Reaction time: 6 h
Yield: 64 %

Procedure:
Sodium bicarbonate (2.073 g, 24.68 mmol) was dissolved in a mixture of water (20.00 mL) and DCM (20 mL), and phenylmethyl (3S)-3-amino-1-pyrrolidinecarboxylate (2.88 g, 11.22 mmol) was added followed by methylchloroformate (0.953 mL, 12.34 mmol). This mixture was stirred for 6 h. The biphasic mixture was then separated, and the aqueous phase was extracted once with DCM. The combined organics were dried over sodium sulfate, filtered and evaporated. The residual material was then purified via silica gel chromatography (0-100% EtoAc in hexane) yielding phenylmethyl (3S)-3-{[(methyloxy)carbonyl]amino}-1-pyrrolidinecarboxylate (2 g, 64%) as a clear oil. LCMS: (M+H)+: 278.9.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][C:5]1[C:13]2[O:12][CH2:11][CH:10]([C:14]3[CH:19]=[CH:18][C:17]([CH:20]([CH3:22])[CH3:21])=[CH:16][CH:15]=3)[C:9]=2[C:8]([CH3:23])=[C:7]([NH:24][C:25](=[O:32])OCC(Cl)(Cl)Cl)[C:6]=1[CH3:33].[NH2:34][CH2:35][CH2:36][OH:37]>CCCCCC.C(OCC)(=O)C>[OH:37][CH2:36][CH2:35][NH:34][C:25]([NH:24][C:7]1[C:6]([CH3:33])=[C:5]([CH2:4][CH2:3][CH2:2][OH:1])[C:13]2[O:12][CH2:11][CH:10]([C:14]3[CH:15]=[CH:16][C:17]([CH:20]([CH3:22])[CH3:21])=[CH:18][CH:19]=3)[C:9]=2[C:8]=1[CH3:23])=[O:32]
Reactant: NCCO
Reactant: Cc1c(CCCO)c2c(c(C)c1NC(=O)OCC(Cl)(Cl)Cl)C(c1ccc(C(C)C)cc1)CO2
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: Cc1c(CCCO)c2c(c(C)c1NC(=O)NCCO)C(c1ccc(C(C)C)cc1)CO2
Yield: 53 %

Procedure:
Using 2,2,2-trichloroethyl (7-(3-hydroxypropyl)-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl)carbamate obtained in Example 141 and 2-aminoethanol, the title compound was synthesized in the same manner as in Example 143. Yield: 53%. Melting point: 153-154° C. (hexane-ethyl acetate).
Reaction SMILES: C[O:2][C:3](=[O:24])[C@H:4]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[C:14](=[O:23])[N:15]([CH3:22])[C:16](=[O:21])[N:17]([CH3:20])[C:18]=2[CH3:19])=[CH:9][CH:8]=1)[NH2:5].[F:25][C:26]1[CH:34]=[CH:33][CH:32]=[C:31]([F:35])[C:27]=1[C:28](O)=[O:29]>>[F:25][C:26]1[CH:34]=[CH:33][CH:32]=[C:31]([F:35])[C:27]=1[C:28]([NH:5][C@H:4]([C:3]([OH:2])=[O:24])[CH2:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]2[C:14](=[O:23])[N:15]([CH3:22])[C:16](=[O:21])[N:17]([CH3:20])[C:18]=2[CH3:19])=[CH:11][CH:12]=1)=[O:29]
Reactant: COC(=O)[C@@H](N)Cc1ccc(-c2c(C)n(C)c(=O)n(C)c2=O)cc1
Reactant: O=C(O)c1c(F)cccc1F
Product: Cc1c(-c2ccc(C[C@H](NC(=O)c3c(F)cccc3F)C(=O)O)cc2)c(=O)n(C)c(=O)n1C

Procedure:
N-[(2,6-difluorophenyl)carbonyl]-4-(1,3,6-trimethyl-2,4-dioxo-5-pyrimidinyl)-L-phenylalanine was prepared from 4-(1,3,6-trimethyl-2,4-dioxo-5-pyrimidinyl)-L-phenylalanine methyl ester and 2,6-difluorobenzoic acid using the general procedures described in example 7 and was obtained as an amorphous white solid. ES-HRMS m/e calcd for C23H21F2N3O5 (M+Na) 480.1483, found 480.1489.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]1[N:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[N:11]=[C:10]([NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[CH:9]=1.[NH2:26][C:27]1[C:28]([C:34](O)=[O:35])=[N:29][C:30]([Br:33])=[CH:31][CH:32]=1.C1C=NC2N(O)N=NC=2C=1.C(Cl)CCl>CN(C=O)C.O>[NH2:26][C:27]1[C:28]([C:34]([NH:1][C:2]2[CH:3]=[N:4][CH:5]=[CH:6][C:7]=2[C:8]2[N:13]=[C:12]([C:14]([F:15])([F:16])[F:17])[N:11]=[C:10]([NH:18][C:19](=[O:25])[O:20][C:21]([CH3:22])([CH3:24])[CH3:23])[CH:9]=2)=[O:35])=[N:29][C:30]([Br:33])=[CH:31][CH:32]=1
Reactant: Nc1ccc(Br)nc1C(=O)O
Reactant: CC(C)(C)OC(=O)Nc1cc(-c2ccncc2N)nc(C(F)(F)F)n1
Agent: On1nnc2cccnc21
Solvent: ClCCCl
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)Nc1cc(-c2ccncc2NC(=O)c2nc(Br)ccc2N)nc(C(F)(F)F)n1
Temperature: 50 °C
Yield: 81 %

Procedure:
A solution of tert-butyl 6-(3-aminopyridin-4-yl)-2-(trifluoro-methyl)pyrimidin-4-ylcarbamate (1.0 equiv.), 3-amino-6-bromopicolinic acid (1.0 equiv.), HOAt (1.0 equiv.), and EDC (1.0 equiv.) in DMF at a concentration of (0.2 M) was stirred for 3 hrs then heated to 50° C. overnight (homogeneous solution). Water was added to the reaction and the precipitate was filtered. The solid was further purified via SiO2 column chromatography eluting with DCM/MeOH (10%) to yield a brown solid as the desired product (81%). LCMS (m/z): 554.1/556.1 (MH+); LC Rt=3.77 min.
Reaction SMILES: [O:1]=[C:2]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH2:3][C:4]([O:6]C)=[O:5].Cl.[Li+].[OH-].[CH:22]1([NH:28][CH:29]2[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]2)[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1>CO>[OH:1][C@H:2]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH2:3][C:4]([O-:6])=[O:5].[CH:29]1([NH2+:28][CH:22]2[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]2)[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34]1
Reactant: C1CCC(NC2CCCCC2)CC1
Reactant: CCCCCCCCCCCC(=O)CC(=O)OC
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: C1CCC([NH2+]C2CCCCC2)CC1
Product: CCCCCCCCCCC[C@@H](O)CC(=O)[O-]
Temperature: 25 °C
Reaction time: 18 h
Yield: 90.8 %

Procedure:
A solution of methyl 3-oxotetradecanoate (19 g, 0.074 mol) in MeOH (100 mL) was degassed by sparging with argon (15 min). [(R)-Ru(Binap)Cl]2·NEt3 catalyst (0.187 g, 0.111 mmol) and 2 N aqueous HCl (0.5 mL) were added and the resulting mixture was hydrogenated at 60 psig and 40-50° C. for 18 h. The reaction was diluted with hexanes (250 mL), filtered through a short column of silica gel, and concentrated. The crude product was dissolved in tetrahydrofuran (THF; 200 mL), treated 2.4 N aqueous LiOH (83 mL, 0.2 mol) and stirred vigorously at room temperature for 4 h. The resulting slurry was partitioned between ether (200 mL) and 1 N aqueous HCl (200 mL) and the layers separated. The aqueous layer was extracted with ether (100 mL) and the combined ethereal extracts were dried (Na2SO4) and concentrated. The crude hydroxy acid was dissolved in hot acetonitrile (250 mL), treated with dicyclohexylamine (DCHA; 17 mL, 0.085 mol) and stirred at 60° C. for 1 h. The product that crystallized upon cooling was collected and recrystallized from acetonitrile (650 mL) to yield 28.6 g (91%) of dicyclohexylammonium (R)-3-hydroxytetradecanoate as a colorless solid: mp 94-95° C.; 1H NMR (CDCl3) δ 0.88 (˜t, 3H, J˜6.5 Hz), 1.05-1.58 (m, 24H), 1.65 (m, 2H), 1.80 (m, 4H), 2.01 (br d, 4H) 2.18 (dd, 1H, J=15.7, 9.4 Hz), 2.36 (dd, 1H, J=15.7, 2.6 Hz), 2.94 (m, 2H), 3.84 (m, 1H)
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][CH2:8][CH2:7][N:6]1[C:10](=[O:32])[NH:11][C:12]1[CH:17]=[CH:16][C:15]([S:18]([N:21]2[CH2:26][CH2:25][CH:24]([CH:27](OC)[O:28]C)[CH2:23][CH2:22]2)(=[O:20])=[O:19])=[CH:14][CH:13]=1)=[O:4].[I-].[Na+].ClC([SiH3])(Cl)Cl>C(#N)C>[CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][CH2:8][CH2:7][N:6]1[C:10](=[O:32])[NH:11][C:12]1[CH:13]=[CH:14][C:15]([S:18]([N:21]2[CH2:26][CH2:25][CH:24]([CH:27]=[O:28])[CH2:23][CH2:22]2)(=[O:20])=[O:19])=[CH:16][CH:17]=1)=[O:4]
Reactant: COC(=O)[C@@H]1CCCN1C(=O)Nc1ccc(S(=O)(=O)N2CCC(C(OC)OC)CC2)cc1
Agent: [I-]
Agent: [Na+]
Agent: [SiH3]C(Cl)(Cl)Cl
Solvent: CC#N
Product: COC(=O)[C@@H]1CCCN1C(=O)Nc1ccc(S(=O)(=O)N2CCC(C=O)CC2)cc1

Procedure:
Under anhydrous conditions, a solution of (2s)-1-[4-(4-dimethoxymethyl-piperidine-1-sulfonyl)-phenylcarbamoyl]-pyrrolidine-2-carboxylic acid methyl ester (0.240 g, 0.5 mmol), sodium iodide (0.192 g, 1.28 mmol), and trichloromethylsilane (0.120 mL, 1.1 mmol) in acetonitrile (2.5 mL) was stirred at ambient temperature for 15 minutes. The reaction mixture was quenched with water and partitioned with methylene chloride. The organic phase was washed with Na2S2O3 dilute solution and dried (Na2SO4). Removal of solvent afforded the crude product which was used directly in the next step without characterization.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:28]=[CH:29][CH:30]=1)[C:5]([NH:7][C:8]1[C:9]([N:18]2[CH2:23][CH2:22][CH:21]([CH2:24][C:25]([OH:27])=O)[CH2:20][CH2:19]2)=[N:10][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:12][CH:13]=1)=[O:6].[C:31]([NH2:35])([CH3:34])([CH3:33])[CH3:32].F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(CC)CC)C>CN(C)C=O.O>[C:31]([NH:35][C:25]([CH2:24][CH:21]1[CH2:20][CH2:19][N:18]([C:9]2[C:8]([NH:7][C:5](=[O:6])[C:4]3[CH:28]=[CH:29][CH:30]=[C:2]([Cl:1])[CH:3]=3)=[CH:13][CH:12]=[C:11]([C:14]([F:15])([F:16])[F:17])[N:10]=2)[CH2:23][CH2:22]1)=[O:27])([CH3:34])([CH3:33])[CH3:32]
Reactant: CC(C)(C)N
Reactant: O=C(O)CC1CCN(c2nc(C(F)(F)F)ccc2NC(=O)c2cccc(Cl)c2)CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)NC(=O)CC1CCN(c2nc(C(F)(F)F)ccc2NC(=O)c2cccc(Cl)c2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 17.8 %

Procedure:
A mixture of 0.100 g (0.226 mmol) of [3′-(3-chloro-benzoylamino)-6′-trifluoromethyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl]-acetic acid, 0.050 g (0.68 mmol) tert-butyl amine, 0.094 g (0.296 mmol) of O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate, and 0.094 mL (0.68 mmol) of triethylamine in N,N-dimethylformamide (2 mL) is stirred at room temperature for 2 hours. The mixture is diluted with water and purified using preparative reverse phase HPLC to give 0.020 g (18%) of the title compound (283) as colorless foam. [M+H]+=497.2.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]#[N:13])[CH:7]=1)[CH3:2].Cl.O1CCOCC1>CCO.[Pd]>[CH2:1]([O:3][C:4](=[O:14])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][NH2:13])[CH:7]=1)[CH3:2]
Reactant: CCOC(=O)Cc1cccc(C#N)c1
Agent: [Pd]
Agent: Cl
Solvent: C1COCCO1
Solvent: CCO
Product: CCOC(=O)Cc1cccc(CN)c1
Reaction time: 20 h

Procedure:
A solution of (3-cyano-phenyl)-acetic Acid ethyl ester (6.3 g, 33.29 mmol) in EtOH (50 mL) was added to a mixture of 10% Pd/C (1.26 g) in EtOH (50 mL) under Nitrogen. Additional EtOH (150 mL) was added followed by a solution of HCl in dioxane (4 M, 11.4 mL, 45.6 mmol). The mixture was hydrogenated on a Parr shaker at 45 psi for 20 h and the catalyst was removed by filtration through celite. The solution was concentrated to afford (3-aminomethyl-phenyl)-acetic Acid ethyl ester as the hydrochloride salt (7.31 g). 1H NMR (400 MHz, CD3OD) δ 7.42-7.32 (m, 4H), 4.12 (q, 2H), 4.09 (s, 2H), 3.68 (s, 2H), 1.23 (t, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][C:5](/[C:6](=[N:9]/[H])/[NH:7][OH:8])=[CH:4][CH:3]=1.[O:13]=[C:14]1[C:19]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:18][CH2:17][CH2:16][N:15]1[CH2:32][C:33](O)=O.Cl.C(N=C=NCCCN(C)C)C>ClC(Cl)C>[Cl:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]2[N:9]=[C:33]([CH2:32][N:15]3[CH2:16][CH2:17][CH2:18][C:19]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[C:14]3=[O:13])[O:8][N:7]=2)=[CH:4][CH:3]=1
Reactant: O=C(O)CN1CCCC(c2ccccc2)(c2ccccc2)C1=O
Reactant: [H]/N=C(\NO)c1ccc(Cl)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CC(Cl)Cl
Product: O=C1N(Cc2nc(-c3ccc(Cl)cc3)no2)CCCC1(c1ccccc1)c1ccccc1
Temperature: 85 °C
Reaction time: 8 h

Procedure:
A solution of (Z)-4-chloro-N-hydroxybenzimidamide (0.121 g, 0.711 mmol), 2-(2-oxo-3,3-diphenylpiperidin-1-yl)acetic acid (0.200 g, 0.646 mmol; Example 68E) and N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (0.161 g, 0.840 mmol) were stirred together in dichloroethane (0.5 mL) at room temperature for 2 hours. The reaction was then heated to 85° C. and stirred overnight. The reaction was cooled, loaded onto a SF15-12 column (Analogix®) and the product eluted using a gradient of 5% ethyl acetate/hexanes to 50% ethyl acetate over 20 minutes (Flow=30 mL/minute) to provide the title compound. 1H NMR (300 MHz, CDCl3) δ 8.09-8.02 (m, 2H), 7.52-7.45 (m, 2H), 7.33-7.25 (m, 10H), 4.91 (s, 2H), 3.62 (t, J=6.5, 2H), 2.73-2.67 (m, 2H), 1.98-1.85 (m, 2H); MS (ESI+) m/z 444.0 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([CH3:38])[C:5]2=[C:6]([CH2:8][C@H:9]([C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:24]=3[C:30]3[CH:35]=[CH:34][CH:33]=[C:32]([O:36][CH3:37])[N:31]=3)[NH:10]/[C:11]/2=[N:12]\[O:13][CH:14]([CH2:20][CH2:21][OH:22])[C:15]([N:17]([CH3:19])[CH3:18])=[O:16])[N:7]=1.[H-].[Na+].S(OC)(O[CH3:45])(=O)=O>C1COCC1>[NH2:1][C:2]1[N:3]=[C:4]([CH3:38])[C:5]2=[C:6]([CH2:8][C@H:9]([C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:24]=3[C:30]3[CH:35]=[CH:34][CH:33]=[C:32]([O:36][CH3:37])[N:31]=3)[NH:10]/[C:11]/2=[N:12]\[O:13][CH:14]([CH2:20][CH2:21][O:22][CH3:45])[C:15]([N:17]([CH3:18])[CH3:19])=[O:16])[N:7]=1
Reactant: COS(=O)(=O)OC
Reactant: COc1cccc(-c2cc(F)ccc2[C@H]2Cc3nc(N)nc(C)c3/C(=N/OC(CCO)C(=O)N(C)C)N2)n1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCCC(O/N=C1\N[C@@H](c2ccc(F)cc2-c2cccc(OC)n2)Cc2nc(N)nc(C)c21)C(=O)N(C)C
Reaction time: 0.25 h
Yield: 22.3 %

Procedure:
To a solution of 2-((Z)—((R)-2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-ylidene)aminooxy)-4-hydroxy-N,N-dimethylbutanamide (0.03 mmol, 16 mg) in THF (2 mL) was added 50% NaH (0.034 mmol, 1.65 mg) at 0° C. under N2 atmosphere. The reaction mixture was stirred for 15 minutes and dimethyl sulphate (4.08 μL, 0.043 mmol) was added. The reaction mixture was stirred at r.t. for 3 h. Quenched with MeOH (1 mL) and purified by LCMS to afford the title compound 2-((Z)—((R)-2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-ylidene)aminooxy)-4-methoxy-N,N-dimethylbutanamide (95, 3.6 mg, 25%) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ 1.81-2.06 (m, 2H) 2.47 (s, 3H) 2.70-2.80 (m, 1H) 2.83 (d, J=10.61 Hz, 3H) 3.05 (d, J=7.58 Hz, 3H) 3.07-3.17 (m, 1H) 3.20 (d, J=4.80 Hz, 3H) 3.31-3.39 (m, 2H) 3.40-3.49 (m, 2H) 3.87 (d, J=3.79 Hz, 3H) 4.80-4.93 (m, 1H) 5.06-5.22 (m, 1H) 6.83-6.90 (m, 1H) 7.20 (d, J=8.84 Hz, 1H) 7.23-7.32 (m, 2H) 7.44 (ddd, J=14.34, 8.91, 5.81 Hz, 1H) 7.85 (td, J=7.83, 3.28 Hz, 1H). MS (ES) [M+H] calculated for C27H33FN7O4, 538.58. found 538.40.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][N:11]1[C:15]2[CH:16]=[CH:17][C:18]3[C:23]([C:14]=2[S:13][C:12]1=O)=[CH:22][CH:21]=[CH:20][CH:19]=3.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:34])=CC=1>C1(C)C=CC=CC=1>[CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][N:11]1[C:15]2[CH:16]=[CH:17][C:18]3[C:23]([C:14]=2[S:13][C:12]1=[S:34])=[CH:22][CH:21]=[CH:20][CH:19]=3
Reactant: COCCOCCOCCn1c(=O)sc2c3ccccc3ccc21
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Product: COCCOCCOCCn1c(=S)sc2c3ccccc3ccc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1.7 g of 3-methoxyethoxyethoxyethylnaphtho[2,1-d]thiazoline-2-on, 2.4 g of Lawesson's reagent and 10 ml of toluene were fed into a 50 ml short-neck flask provided with a reflux condenser. The resultant mixture was heated under reflux and stirring for 2 hours. After cooling to room temperature followed by purification by column chromatography (hexane:ethyl acetate=3:1), the intended compound was obtained.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:18]3=[N:19][CH:20]=[N:21][C:22](Cl)=[C:17]3[CH:16]=[N:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:24][C:25]1[C:30](N)=[CH:29][CH:28]=[C:27]([N:32]2[CH:36]=[N:35][CH:34]=[N:33]2)[N:26]=1.C(=O)([O-])[O-:38].[K+].[K+].ClCCl>CN(C)C=O.O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:18]3=[N:19][CH:20]=[N:21][C:22]([O:38][C:30]4[C:25]([CH3:24])=[N:26][C:27]([N:32]5[CH:36]=[N:35][CH:34]=[N:33]5)=[CH:28][CH:29]=4)=[C:17]3[CH:16]=[N:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(n2ncc3c(Cl)ncnc32)CC1
Reactant: O=C([O-])[O-]
Reactant: Cc1nc(-n2cncn2)ccc1N
Agent: [K+]
Solvent: O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1nc(-n2cncn2)ccc1Oc1ncnc2c1cnn2C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 160 °C
Yield: 67 %

Procedure:
A mixture of 4-(4-chloro-pyrazolo[3,4-d]pyrimidin-1-yl)-piperidine-1-carboxylic acid tert-butyl ester (Intermediate 19; 100 mg, 0.30 mmol), 2-methyl-6-[1,2,4]triazol-1-yl-pyridin-3-ol (Intermediate 7; 68 mg, 0.385 mmol), and potassium carbonate (53 mg, 0.385 mmol) in dimethylformamide (3 mL) was heated in the microwave oven at 160° C. for 10 min. Dichloromethane and water were added, and the aqueous layer was extracted three times with dichloromethane. The dichloromethane layers were combined, evaporated, and purified by preparative C18 HPLC, eluting with 10-100% acetonitrile/water. Samples containing the product were extracted three times with dichloromethane and the solvent was evaporated to give 4-[4-(2-methyl-6-[1,2,4]triazol-1-yl-pyridin-3-yloxy)pyrazolo[3,4-d]pyrimidin-1-yl]-piperidine-1-carboxylic acid tert-butyl ester (96 mg, 68%) as a white powder. 1H NMR (300 MHz, CDCl3) δ 1.49 (s, 9H), 1.95-2.04 (m, 2H), 2.20-2.35 (m, 2H), 2.90-3.05 (m, 2H), 4.25-4.40 (m, 2H), 4.90-5.02 (m, 1H), 7.69 (d, 1H, J=8.5 Hz), 7.86 (d, 1H, J=8.8 Hz), 8.12 (s, 1H), 8.17 (s, 1H), 8.47 (s, 1H), 9.20 (s, 1H). Mass spectrum (ES) MH+=478. HRMS Calcd. for C23H28N9O3 (MH+): 478.2310. Found: 478.2307.
Reaction SMILES: [CH2:1]1[C@H:13]2[N:4]([CH2:5][C:6]3[CH:7]=[CH:8][CH:9]=[CH:10][C:11]=3[CH2:12]2)[C:3](=[S:14])[S:2]1.[CH2:15]([I:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(OC(C)C)(C)C>C(Cl)Cl>[I-:22].[CH2:15]([S:14][C:3]1[S:2][CH2:1][C@@H:13]2[CH2:12][C:11]3[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=3[CH2:5][N+:4]=12)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: ICc1ccccc1
Reactant: S=C1SC[C@@H]2Cc3ccccc3CN12
Solvent: CC(C)OC(C)C
Solvent: ClCCl
Product: [I-]
Product: c1ccc(CSC2=[N+]3Cc4ccccc4C[C@H]3CS2)cc1
Yield: 89.3 %

Procedure:
(S)-1,5,10,10a-Tetrahydrothiazolo[3,4-b]-isoquinoline-3-thione (8.8 g) is dissolved in methylene chloride (100 cc), and benzyl iodide (9.5 g) is added. After 48 hours at a temperature of about 20° C., diisopropyl ether (200 cc) is added. The resulting precipitate is filtered off, washed with diisopropyl ether and dried at 20° C. under reduced pressure (1 mm Hg; 0.13 kPa). (S)-3-Benzylthio-1,5,10,10a-tetrahydrothiazolo[3,4-b]isoquinolinium iodide (15.6 g) is thus obtained.
Reaction SMILES: [CH3:1][N:2]([CH3:17])[C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([CH:13]([NH:15][CH3:16])[CH3:14])=[CH:8][CH:7]=[CH:6]2.[F:18][C:19]([F:36])([F:35])[C:20]1[CH:25]=[CH:24][C:23]([C:26]2[CH:31]=[CH:30][C:29]([C:32]([Cl:34])=[O:33])=[CH:28][CH:27]=2)=[CH:22][CH:21]=1>C(Cl)Cl>[ClH:34].[CH3:17][N:2]([CH3:1])[C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([CH:13]([N:15]([CH3:16])[C:32]([C:29]1[CH:30]=[CH:31][C:26]([C:23]3[CH:24]=[CH:25][C:20]([C:19]([F:36])([F:35])[F:18])=[CH:21][CH:22]=3)=[CH:27][CH:28]=1)=[O:33])[CH3:14])=[CH:8][CH:7]=[CH:6]2
Reactant: CNC(C)c1cccc2cc(N(C)C)ccc12
Reactant: O=C(Cl)c1ccc(-c2ccc(C(F)(F)F)cc2)cc1
Solvent: ClCCl
Product: CC(c1cccc2cc(N(C)C)ccc12)N(C)C(=O)c1ccc(-c2ccc(C(F)(F)F)cc2)cc1
Product: Cl
Yield: 69 %

Procedure:
A solution of (6-dimethylamino-methyl-naphthalen-1-ylmethyl)-methyl-amine, 9, (14.25 g, 62.50 mmol), and 4′-trifluoromethyl-biphenyl-4-carbonyl chloride (17.81 g, 62.50 mmol) in CH2Cl2 (500 mL) is stirred at room temperature for 1 hr. The white solid which forms is collected by filtration and rinsed twice with CH2Cl2 (100 mL) to afford 22.0 g (69% yield) of the desired product as a white solid. 1H NMR (300 MHz, CD3OD): δ 8.37 (d, J=8.4 Hz, 1H), 8.15-7.56 (m, 13H), 5.31 (s, 2H), 5.31 and 5.14 (2×s, 2H, two rotamers), 3.17 and 2.93 (2×s, 9H, two rotamers). 13C NMR (75 MHz, CDCl3): δ 172.0, 165.5, 143.9, 141.4, 135.8, 134.1, 132.4, 132.1, 130.0, 129.0, 128.7, 127.7, 127.6, 127.4, 126.7, 126.6, 125.2, 123.9, 117.1, 61.1, 53.3, 42.1, 36.6. 19F NMR (282 MHz, CD3OD): δ 99.1. Mass Spec.: Calcd.: 477.5106; found HRMS: 477.5113; Formula: C29H27F3N2O+H, found LRMS: 477.27 (M+1).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4](SC)[N:3]=1.[CH2:17]([NH2:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(O)C>[NH2:1][C:2]1[N:3]=[C:4]([NH:24][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:5]([C:13]#[N:14])=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[N:7]=1
Reactant: CSc1nc(N)nc(-c2ccco2)c1C#N
Reactant: NCc1ccccc1
Solvent: CCO
Product: N#Cc1c(NCc2ccccc2)nc(N)nc1-c1ccco1

Procedure:
From 2-amino-4-(2-furyl)-6-(methylthio)-5-pyrimidinecarbonitrile and benzylamine in ethanol. EI-MS m/e (%): 291 (M+, 100), 290 ([M—H]+, 36), 106 (64), 91 (48).
Reaction SMILES: [NH2:1][CH2:2][C:3]([OH:5])=[O:4].[C:6](Cl)(=[O:13])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[OH-].[Na+]>O.CCOCC>[C:6]([NH:1][CH2:2][C:3]([OH:5])=[O:4])(=[O:13])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: NCC(=O)O
Reactant: CCCCCCC(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOCC
Product: CCCCCCC(=O)NCC(=O)O
Yield: 72.4 %

Procedure:
Glycine (1.5 g, 20 mmol) and heptanoyl chloride (22 mmol) were reacted in the presence of NaOH (40 mmol) in a mixture of water and ether using the method described in Example 5. The crude product was recrystallized from EtOAc (30 ml) to give title compound (2.71 g, 72%), m.p. 98°-100° C.
Reaction SMILES: [C:1]([C:3]1[C:8]([F:9])=[CH:7][CH:6]=[CH:5][N:4]=1)#[N:2].[ClH:10]>C(O)C.[Pd]>[ClH:10].[ClH:10].[NH2:2][CH2:1][C:3]1[C:8]([F:9])=[CH:7][CH:6]=[CH:5][N:4]=1
Reactant: N#Cc1ncccc1F
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: NCc1ncccc1F
Yield: 90 %

Procedure:
Dissolve 2-cyano-3-fluoropyridine (300 mg, 2.457 mmol) in absolute ethanol (12 mL). Add 10% Pd/C (93 mg) and concentrated HCl (0.614 mL, 7.37 mmol). Hydrogenate at 40 psi overnight. Filter through Celite® and concentrate in vacuo to give the title compound as a solid (440 mg, 90%). MS (ES+) M/z: 127 (M+H)+.
Reaction SMILES: C(OC([NH:11][CH2:12][CH2:13][CH:14]([P:16]([CH3:21])(=[O:20])[O:17]CC)[OH:15])=O)C1C=CC=CC=1.[ClH:22]>>[ClH:22].[NH2:11][CH2:12][CH2:13][CH:14]([P:16]([CH3:21])(=[O:17])[OH:20])[OH:15]
Reactant: CCOP(C)(=O)C(O)CCNC(=O)OCc1ccccc1
Agent: Cl
Product: CP(=O)(O)C(O)CCN
Temperature: 25 °C

Procedure:
A solution of 4.0 g of ethyl P-(3-benzyloxycarbonylamino- 1-hydroxypropyl)-P-methyl-phosphinate in 50 ml of 5.0M aqueous hydrochloric acid is heated to reflux for 20 hours under an inert gas atmosphere. Then, the reaction mixture is cooled to room temperature and washed twice with 100 ml each of dichloromethane and once with diethyl ether. The aqueous layer is evaporated to dryness at 50° under reduced pressure. The oily residue is then co-evaporated 5 times with 50 ml each of water and of absolute ethanol. The remaining white solid is dried under reduced pressure at 80° and then re-crystallised to afford P-(3-amino-1-hydroxy-propyl)-P-methyl-phosphinic acid hydrochloride of m.p. 115°-116.5°. This can be converted into the free compound by dissolving in ethanol and treating with propylene oxide yielding, after filtration and drying, P-(3-amino-1-hydroxy-propyl)-P-methyl-phosphinic acid of m.p. 125°-126.5°.