Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CO[N:3]=[C:4]([C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=1)[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.B.O1CCCC1.O>C1COCC1>[NH2:3][CH:4]([C:12]1[CH:13]=[CH:14][C:15]([Cl:18])=[CH:16][CH:17]=1)[CH2:5][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: CON=C(Cc1ccccc1)c1ccc(Cl)cc1
Agent: B
Solvent: O
Solvent: C1CCOC1
Product: NC(Cc1ccccc1)c1ccc(Cl)cc1
Temperature: 25 °C

Procedure:
To a solution of the oxime geometric isomer mixture 9 (2.690 g, 10.36 mmol) in dry THF (50 ml, freshly distilled from sodium benzophenone ketyl) under nitrogen at room temperature was added borane-tetrahydrofuran solution (36.0 ml, 36.0 mmol, 1.0 M solution, Aldrich) by syringe. The resulting very pale orange solution was refluxed for 16 hours, and cooled in an ice bath. Water (80 ml) was added carefully to quench, followed by 20% NaOH (80 ml). The resulting colorless bi-phasic mixture was refluxed overnight with vigorous magnetic stirring. After cooling to room temperature, hexanes (50 ml) were added and the layers separated. The aqueous portion was washed with hexanes (1×30 ml), and the combined organic portions dried over potassium carbonate. Evaporation of the solvent afforded the pure amine as 2.392 g of a clear, pale yellow syrup (99% yield): Rf 0.22 (5% methanol in CHCl3): IR (CDCl3) 3376 (w), 3068 (w), 3031 (w), 2922 (w), 2850 (w), 1602 (m), 1493 (s), 1457 (m), 1409 (w); 1H NMR (CDCl3) δ7.40-21 (m, 7H), 7.19 (d, J=8.6 Hz, 2H), 4.21 (dd, J=8.4, 5.2 Hz, 1H), 2.98 (dd, J=13.2, 5.2 Hz, 1H), 2.81 (dd, J=13.2, 8.6 Hz, 1H), 1.43 (s, 2H); low resolution mass spec. 232 (M-1, 5.0), 230 (m-1, 11), 142 (M-91, 37), 140 (M-91, 100), 91 (28).
Reaction SMILES: [NH2:1][C:2]1[O:6][N:5]=[C:4]([CH3:7])[CH:3]=1.[C:8](Cl)(=[O:16])[O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.O>O1CCCC1.N1C=CC=CC=1>[CH3:7][C:4]1[CH:3]=[C:2]([NH:1][C:8](=[O:16])[O:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[O:6][N:5]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: Cc1cc(N)on1
Solvent: c1ccncc1
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(NC(=O)Oc2ccccc2)on1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 20 %

Procedure:
5-Amino-3-methylisoxazole (1 g) purchased from Aldrich Co. was dissolved in tetrahydrofuran (40 ml) and pyridine (1.5 ml), and after cooling to 0° C. under a nitrogen atmosphere, phenyl chlorocarbonate (1.4 ml) was added and the mixture was stirred at room temperature for 1.5 hours. Water was added, extraction was performed twice with ethyl acetate, and then the organic layers were combined, washed with water and saturated brine in that order, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue was recrystallized from ethyl acetate and n-hexane to obtain the title compound (450 mg, 20% yield).
Reaction SMILES: C([CH:3]([C:9]1[CH:14]=[C:13]([C:15]2[CH:16]=[C:17]3[C:23]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[O:30][CH3:31])=[CH:22][N:21]([S:32]([C:35]4[CH:40]=[CH:39][C:38]([CH3:41])=[CH:37][CH:36]=4)(=[O:34])=[O:33])[C:18]3=[N:19][CH:20]=2)[N:12]=[CH:11][N:10]=1)[C:4]([N:6]([CH3:8])[CH3:7])=[O:5])#N.C(OO)(=[O:44])C.S(=O)(O)[O-].[Na+].C(=O)(O)[O-].[Na+]>O1CCCC1.O>[CH3:31][O:30][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=1[C:23]1[C:17]2[C:18](=[N:19][CH:20]=[C:15]([C:13]3[N:12]=[CH:11][N:10]=[C:9]([C:3](=[O:44])[C:4]([N:6]([CH3:8])[CH3:7])=[O:5])[CH:14]=3)[CH:16]=2)[N:21]([S:32]([C:35]2[CH:36]=[CH:37][C:38]([CH3:41])=[CH:39][CH:40]=2)(=[O:34])=[O:33])[CH:22]=1
Reactant: COc1ccccc1-c1cn(S(=O)(=O)c2ccc(C)cc2)c2ncc(-c3cc(C(C#N)C(=O)N(C)C)ncn3)cc12
Reactant: CC(=O)OO
Agent: O=C([O-])O
Agent: O=S([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccccc1-c1cn(S(=O)(=O)c2ccc(C)cc2)c2ncc(-c3cc(C(=O)C(=O)N(C)C)ncn3)cc12
Temperature: 0 °C
Yield: 64.4 %

Procedure:
2-Cyano-2-{6-[3-(2-methoxy-phenyl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-pyrimidin-4-yl}-N,N-dimethyl-acetamide (500 mg, 0.88 mmole) was suspended in tetrahydrofuran (11 mL) and cooled to 0° C. in an ice bath. Peroxy acetic acid (32% in acetic acid, 174 mg, 2.29 mmole) was added and after 10 min, the heterogeneous solution was removed from the ice bath and maintained at ambient temperature for 6 h. Sodium bisulfite (918 mg, 8.83 mmole) in water (10 mL) was added, followed by saturated aqueous sodium bicarbonate (20 mL) and the mixture extracted with ethyl acetate (3×30 mL). The combined organic portions were dried over magnesium sulfate, filtered, and concentrated to dryness. Silica gel chromatography of the crude residue afforded 2-{6-[3-(2-methoxy-phenyl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-pyrimidin-4-yl}-N,N-dimethyl-2-oxo-acetamide (315 mg, 89% yield) as a clear residue. MS: m/z 402.2 (M+H+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:12][NH:11][C:10]3[CH:13]=[CH:14][C:15]([Cl:17])=[CH:16][C:9]=3[CH:8]=[CH:7][C:6]=2[CH:18]=1.N1C=CC=CC=1.[N:25]1([S:31](Cl)(=[O:33])=[O:32])[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1>ClC(Cl)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:12][N:11]([S:31]([N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)(=[O:33])=[O:32])[C:10]3[CH:13]=[CH:14][C:15]([Cl:17])=[CH:16][C:9]=3[CH:8]=[CH:7][C:6]=2[CH:18]=1
Reactant: O=S(=O)(Cl)N1CCOCC1
Reactant: Clc1ccc2c(c1)C=Cc1cc(Br)ccc1CN2
Solvent: c1ccncc1
Solvent: CC(Cl)Cl
Product: O=S(=O)(N1CCOCC1)N1Cc2ccc(Br)cc2C=Cc2cc(Cl)ccc21
Temperature: 100 °C
Reaction time: 4 h
Yield: 75.7 %

Procedure:
A solution of 9-Bromo-2-chloro-5,6-dihydro-dibenzo[b,f]azocine (30 mg, 0.09 mmol) (prepared in a manner analogous to that described for Example 1F) in dichloroethane was treated with pyridine (0.02 mL, 0.27 mmol) and morpholine-4-sulfonyl chloride (22 mg, 0.12 mmol). The reaction mixture was stirred at 100° C. for four hours then concentrated, diluted with MeOH and filtered. The crude product was purified by preparative reversed-phase HPLC to afford Example 338A (32 mg). HPLC Rt=3.89 min. m/z=469 (M+H+)
Reaction SMILES: CC(O[NH:5][CH2:6][Si:7]([CH3:12])(OC)OC)=O.[C:13]([O-:26])(=O)CCCCCCCCCCC.[C:27]([O-:40])(=O)CCCCCCCCCCC.C([Sn+2]CCCC)CCC.[CH3:50][OH:51]>>[N:5]([CH2:6][SiH2:7][CH:12]([O:26][CH3:13])[O:40][CH3:27])=[C:50]=[O:51]
Reactant: CCCCCCCCCCCC(=O)[O-]
Reactant: CO[Si](C)(CNOC(C)=O)OC
Reactant: CO
Agent: CCCC[Sn+2]CCCC
Product: COC(OC)[SiH2]CN=C=O
Temperature: 170 °C

Procedure:
A reactor connected with a fractionating column and a condenser was charged with 100 g (0.52 mol) of the obtained methyl(N-dimethoxymethylsilylmethyl)carbamate and 13 mg (0.002 mmol) of dibutyltin dilaurate, and the pressure in the system was reduced to 45 mmHg. The mixture was heated to 170° C. While the degradation reaction product methanol was separated and collected, (isocyanatomethyl)dimethoxymethylsilane (OCN—CH2—SiCH3(OCH3)2) was synthesized over 5 hours. The resultant was purified by distillation under reduced pressure to obtain (isocyanatomethyl)dimethoxymethylsilane (yield: 50 g).
Reaction SMILES: [C:1]1(C([O-])=O)[CH:6]=[CH:5]C=[CH:3][CH:2]=1.[NH2:10][C@@H:11]([C:13]([OH:15])=[O:14])[CH3:12].C(N)(C)C.P([O-])([O-])([O-])=O>>[CH:1]1[CH:6]=[CH:5][C:12]([C@@H:11]([NH2:10])[C:13]([OH:15])=[O:14])=[CH:3][CH:2]=1
Reactant: C[C@@H](N)C(=O)O
Reactant: O=C([O-])c1ccccc1
Agent: O=P([O-])([O-])[O-]
Solvent: CC(C)N
Product: N[C@@H](C(=O)O)c1ccccc1

Procedure:
D-phenylglycine was produced with a conversion of 98% by conducting reactions using 50 mL of a mixture of 0.3 M phenylformate, 20 mM D-alanine, 0.45 M isopropylamine, 0.5 mM PLP, 50 mM phosphate pH 8, 35 U/mL DATA and 30 U/mL ARmutTA. 2.02 g of pure D-phenylglycine was obtained through purification based on solubility.
Reaction SMILES: [NH2:1][CH:2]([P:4](=[O:11])([O:8][CH2:9][CH3:10])[O:5][CH2:6][CH3:7])[CH3:3].[CH:12](CC(OC(=O)CC=O)=O)=[O:13]>>[CH:12]([NH:1][CH:2]([P:4](=[O:11])([O:5][CH2:6][CH3:7])[O:8][CH2:9][CH3:10])[CH3:3])=[O:13]
Reactant: O=CCC(=O)OC(=O)CC=O
Reactant: CCOP(=O)(OCC)C(C)N
Product: CCOP(=O)(OCC)C(C)NC=O
Temperature: 120 °C

Procedure:
A mixture of 3.6 g of diethyl α-aminoethyl-phosphonate prepared by the process of Chalmers et al, J.A.C.S., Vol 75 (1953), p. 5278 and 2 g of formylacetic acid anhydride stood overnight at room temperature and was then heated at 120° C. under a pressure of 0.5 to 1 mm Hg for 15 to 20 minutes. The residue was distilled to obtain pure diethyl 1-(N-formylamino)-ethyl-phosphonate with a boiling point of 148°~150° at 0.5 mm Hg which was used as is for the next step.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([OH:6])=[CH:4][C:3]=1[OH:9].[CH3:10][O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH2:18][C:19]([OH:21])=O.P(Cl)(Cl)(Cl)(Cl)Cl.[CH3:28]N(C=O)C>>[Cl:1][C:2]1[CH:8]=[C:7]2[C:5](=[CH:4][C:3]=1[OH:9])[O:6][CH:28]=[C:18]([C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[O:11][CH3:10])[C:19]2=[O:21]
Reactant: Oc1ccc(Cl)c(O)c1
Reactant: CN(C)C=O
Reactant: COc1ccccc1CC(=O)O
Agent: ClP(Cl)(Cl)(Cl)Cl
Product: COc1ccccc1-c1coc2cc(O)c(Cl)cc2c1=O

Procedure:
This compounds was synthesised in the same manner as described above. 4-Chlororesorcinol (1.74 g, 12.0 mmol), 2-methoxyphenylacetic acid (2.0 g, 12.0 mmol), BF3Et2O (10 ml), PCl5 (3.76 g, 18.1 mmol), DMF (20 ml and 10 ml). The pale brown solid precipitate was taken directly onto the next stage without further purification.
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@@H:10]([CH2:13][C:14]([OH:16])=O)[CH2:9]1)=[O:7])([CH3:4])[CH3:3].C(O)C.O.[NH2:21][NH2:22]>C(OCC)C.CN(C)C1C=CN=CC=1>[NH:21]([C:14](=[O:16])[CH2:13][C@@H:10]1[CH2:11][CH2:12][N:8]([C:6]([O:5][C:2]([CH3:4])([CH3:3])[CH3:1])=[O:7])[CH2:9]1)[NH2:22]
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](CC(=O)O)C1
Reactant: NN
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: CCO
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N1CC[C@@H](CC(=O)NN)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.6 %

Procedure:
A solution of ((3S)-1-{[(1,1-dimethylethyl)oxy]carbonyl}-3-pyrrolidinyl)acetic acid (5 g, 21.81 mmol) in diethyl ether (50 mL) was treated with N,N-dimethyl-4-pyridinamine (2.181 mmol), N-[3-(dimethylamino)propyl]-N-ethylcarbodiimide(HCl) (23.99 mmol), and ethanol (48.0 mmol) and was stirred at room temperature overnight. Analysis by LCMS indicated that all starting material had converted to the desired methyl ester. The reaction contents were diluted with ether (100 mL) and washed with saturated aq NaHSO4 solution, water, and brine. The organic phase was dried over magnesium sulfate, filtered and concentrated to dryness in vacuo. The resulting clear oil was dissolved in ethanol (25 mL), treated with hydrazine monohydrate (436 mmol), and was stirred overnight at 80° C. LCMS analysis indicated complete conversion of the intermediate. The reaction solution was concentrated to dryness in vacuo to afford the title compound as a clear oil (4.65 grams, 88% yield). No further purification was utilized. MS(ES)+ m/e 244.2 [M+H]+.
Reaction SMILES: [C:1](=[O:29])([O:3][CH2:4][C:5]1[N:6]([CH2:22][C:23]2[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=2)[C:7]([S:13][C:14]2[CH:19]=[C:18]([Cl:20])[CH:17]=[C:16]([Cl:21])[CH:15]=2)=[C:8]([CH:10]([CH3:12])[CH3:11])[N:9]=1)[NH2:2].[CH2:30]([NH:34][CH2:35][CH2:36][CH2:37][CH3:38])[CH2:31][CH2:32][CH3:33].[CH2:39]=O>C(OCC)(=O)C>[CH2:30]([N:34]([CH2:39][NH:2][C:1](=[O:29])[O:3][CH2:4][C:5]1[N:6]([CH2:22][C:23]2[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=2)[C:7]([S:13][C:14]2[CH:15]=[C:16]([Cl:21])[CH:17]=[C:18]([Cl:20])[CH:19]=2)=[C:8]([CH:10]([CH3:12])[CH3:11])[N:9]=1)[CH2:35][CH2:36][CH2:37][CH3:38])[CH2:31][CH2:32][CH3:33]
Reactant: CCCCNCCCC
Reactant: CC(C)c1nc(COC(N)=O)n(Cc2ccncc2)c1Sc1cc(Cl)cc(Cl)c1
Reactant: C=O
Solvent: CCOC(C)=O
Product: CCCCN(CCCC)CNC(=O)OCc1nc(C(C)C)c(Sc2cc(Cl)cc(Cl)c2)n1Cc1ccncc1
Temperature: 25 °C
Yield: 56.4 %

Procedure:
A suspension of the above prepared 5-(3,5-dichlorophenylthio)-4-isopropyl-1-(4-pyridylmethyl)-1H-imidazol-2-ylmethyl carbamate (111) (219 mg, 0.5 mmol), di-n-butylamine (85 mg, 0.5 mmol) and paraformaldehyde (17.5 mg, 0.583 mmol) in ethyl acetate (3mL) was heated under reflux in an atmosphere of nitrogen for 5 days. After cooling down at room temperature, the reaction mixture was concentrated under reduced pressure. The residue was dissolved in a small amount of ether, and hexane was added thereto. The precipitated insoluble material was filtered off, and the filtrate was cooled at -50° C. The purified precipitate was collected to give the compound 112 (167 mg, 66%) as oil. 1H-NMR (CDCl3): δH 0.88 (6H, t, J 6.9 Hz, 2 x CH3), 1.31 (6 H, d, J 6.9 Hz, (CH3)2CH), 1.20-1.42 (8 H, m, 2 x --CH2 --), 2.34 (4 H, t, J 7.8 Hz, 2 x --CH2 --), 3.17 (1 H, sep, J 6.9 Hz, (CH3)2CH), 4.06 (2 H, d, J 6.0 Hz, NCH2NH), 4.82 (1 H, t, J 6.0 Hz, NCH2NH), 5.18 (2 H, s, CH2O), 5.24 (2 H, 8, NCH2), 6.68 (2 H, d, J 1.5 Hz, arom 2- and 6-H), 6.79 (2 H, d-like, 4-pyridyl 2- and 6-H), 7.03 (1 H, t, J 1.5 Hz, arom 4-H), 8.42 (2 H, d-like, 4-pyridyl 3- and 5-H). Elementary analysis (C29H39N5O2SCl2) Calcd. : C, 58.78% H, 6.63% N, 11.82% S, 5.41% Cl, 11.96% Found: C, 58.72% H, 6.76% N, 11.63% S, 5.59% Cl, 11.63% hydrochloride of 112 Elementary analysis (for C29H39N6O2SCl5 3HCl 1.5H2O) Calcd. : C, 47.78% H, 6.22. N, 9.61% S, 4.40% Cl, 24.31% Found: C, 47.95% H, 6.01% N, 9.77% S, 4.63% Cl, 23.93%
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:14]([O:16][CH3:17])=[O:15])=[CH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[C:7]([O:12][CH3:13])[CH:6]=2.CO[CH:20](OC)[N:21]([CH3:23])[CH3:22]>>[CH3:20][N:21](/[CH:23]=[N:1]/[C:2]1[C:3]([C:14]([O:16][CH3:17])=[O:15])=[CH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[C:7]([O:12][CH3:13])[CH:6]=2)[CH3:22]
Reactant: COC(=O)c1cc2cc(OC)ccc2cc1N
Reactant: COC(OC)N(C)C
Product: COC(=O)c1cc2cc(OC)ccc2cc1/N=C/N(C)C
Temperature: 25 °C

Procedure:
A suspension of 1.2 g (5.2 mmol) of methyl 3-amino-7-methoxy-2-naphthoate in 30 mL of dimethylformamide dimethylacetal is refluxed for 2.5 hours. The mixture is cooled to room temperature. The resulting precipitate is collected by filtration and washed with ether. After drying in vacuo, this yields 1.28 g (85.9%) of methyl 3-{[(E)-(dimethylamino)methylidene]amino}-7-methoxy-2-naphthoate as a light yellow solid, mp 160-162° C.
Reaction SMILES: Cl.ClC[C:4]1[CH:12]=[CH:11][C:7]([C:8](Cl)=[O:9])=[C:6]([NH:13][C:14]2[C:23]3[C:18](=[C:19]([C:24]([F:27])([F:26])[F:25])[CH:20]=[CH:21][CH:22]=3)[N:17]=[CH:16][CH:15]=2)[CH:5]=1.[Cl:28]C1C2C(=C(C(F)(F)F)C=CC=2)N=CC=1.NC1C=C(Cl)C=CC=1C(O)=O.S(Cl)(Cl)=O.[NH2:58][CH:59]1[CH2:64][CH2:63][CH2:62][N:61]([CH2:65][CH2:66][CH2:67][CH3:68])[CH2:60]1>>[CH2:65]([N:61]1[CH2:62][CH2:63][CH2:64][CH:59]([NH:58][C:8](=[O:9])[C:7]2[CH:11]=[CH:12][C:4]([Cl:28])=[CH:5][C:6]=2[NH:13][C:14]2[C:23]3[C:18](=[C:19]([C:24]([F:27])([F:26])[F:25])[CH:20]=[CH:21][CH:22]=3)[N:17]=[CH:16][CH:15]=2)[CH2:60]1)[CH2:66][CH2:67][CH3:68]
Reactant: CCCCN1CCCC(N)C1
Reactant: O=C(Cl)c1ccc(CCl)cc1Nc1ccnc2c(C(F)(F)F)cccc12
Reactant: FC(F)(F)c1cccc2c(Cl)ccnc12
Agent: Cl
Agent: Nc1cc(Cl)ccc1C(=O)O
Solvent: O=S(Cl)Cl
Product: CCCCN1CCCC(NC(=O)c2ccc(Cl)cc2Nc2ccnc3c(C(F)(F)F)cccc23)C1

Procedure:
4-Chloromethyl-2-(8-trifluoromethyl-4-quinolylamino)benzoyl chloride hydrochloride prepared by reaction of 4-chloro-8-trifluoromethylquinoline with 2-amino-4-chlorobenzoic acid and treatment of the reaction product with thionyl chloride, is reacted with 3-amino-1-butylpiperidine to form the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[C:18]([O:20][CH2:21][CH:22]=[C:23]([Cl:25])[Cl:24])[CH:17]=[C:16]([Cl:26])[C:3]=1[O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][O:10][CH2:11][C:12](=[N:14][OH:15])[CH3:13].C(N(CC)CC)C.[CH2:34]([N:36]([CH2:40][CH3:41])[C:37](Cl)=[O:38])[CH3:35].Cl>O1CCCC1>[CH2:34]([N:36]([CH2:40][CH3:41])[C:37]([O:15][N:14]=[C:12]([CH2:11][O:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][O:4][C:3]1[C:2]([Cl:1])=[CH:19][C:18]([O:20][CH2:21][CH:22]=[C:23]([Cl:25])[Cl:24])=[CH:17][C:16]=1[Cl:26])[CH3:13])=[O:38])[CH3:35]
Reactant: CCN(CC)C(=O)Cl
Reactant: CC(COCCCCCOc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl)=NO
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCN(CC)C(=O)ON=C(C)COCCCCCOc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl

Procedure:
First, 0.45 g of 5-(2,6-dichloro-4-(3,3-dichloro-2-propenyloxy)phenoxy)pentyloxyacetone oxime, 0.12 g of triethylamine, and 10 ml of tetrahydrofuran are placed in a reaction vessel, to which 0.16 g of N,N-diethylcarbamoyl chloride is slowly added dropwise with stirring under ice cooling. After completion of the addition, the reaction mixture is further stirred at room temperature for 30 minutes, poured into diluted hydrochloric acid, and extracted twice with diethyl ether. The diethyl ether layers are combined, washed with water, dried over anhydrous magnesium sulfate, and concentrated to give a crude product. This crude product is subjected to silica gel chromatography, which affords 5-(2,6-dichloro-4-(3,3-dichloro-2-propenyloxy)phenoxy)pentyloxyacetone O-(N,N-diethylcarbamoyl)oxime.
Reaction SMILES: [H-].[Na+].[CH:3]1([NH:9][C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][N:11]=2)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.[CH3:19]I>CN(C)C=O>[CH:3]1([N:9]([C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][N:11]=2)[CH3:19])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]1
Reactant: CI
Reactant: O=[N+]([O-])c1ccc(NC2CCCCC2)nc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(c1ccc([N+](=O)[O-])cn1)C1CCCCC1
Temperature: 22 °C
Reaction time: 0.5 h

Procedure:
Sodium hydride (60% dispersion in mineral oil, 0.38 g, 9.48 mmol) was washed 3x with hexanes then a solution of 2-cyclohexylamino-5-nitropyridine (1.88 g, 8.5 mmol) dissolved in dimethylformamide (20 mL) was added. After stirring for 30 minutes at 22° C., the reaction mixture was cooled to 0° C. and methyl iodide (0.55 mL, 8.9 mmol) was added. The solution was stirred for 1.5 hours at 0° C. followed by quenching with saturated aqueous NH4Cl. The reaction mixture was diluted with ethyl acetate and extracted 5x with water (200 mL), saturated NaCl, dried over Na2SO4 and concentrated in vacuo oil was chromatographed on SiO2 using 2:1 hexanes/ethyl acetate as eluent.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.[CH3:9][O-:10].[Na+]>CO.CCCCCC>[Cl:1][C:2]1[N:7]=[C:6]([O:10][CH3:9])[CH:5]=[CH:4][N:3]=1
Reactant: Clc1ccnc(Cl)n1
Reactant: C[O-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: CO
Product: COc1ccnc(Cl)n1
Temperature: 25 °C
Reaction time: 14 h
Yield: 50 %

Procedure:
To a solution of 2,4-dichloro pyrimidine (20 gm) in methanol (200 ml) was added sodium methoxide (8.7 gm) at 0 to 5° C. The resulting mixture was stirred for 14 hours at room temperature and then concentrated under reduced pressure to obtain a residual mass. The residual mass obtained was extracted with ethyl acetate and water. The combined organic layers were washed with water and sodium chloride solution, and then concentrated under vacuum to obtain a crude solid. The crude solid obtained was dissolved in hexane (40 ml) at 0 to 5° C. and stirred for 1 hour. The solid obtained was collected by filtration and then dried to obtain 9.7 gm of 2-chloro-4-methoxypyrimidine.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[CH:12]1[S:18][CH2:17][CH2:16][NH:15][C:14]2[N:19]([CH3:28])[N:20]=[C:21]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=3)[C:13]1=2)[C:5](OC)=[O:6].[NH2:29][C:30]1[C:31]([CH3:36])=[N:32][CH:33]=[CH:34][CH:35]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+]>C1COCC1>[CH3:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[CH:12]1[S:18][CH2:17][CH2:16][NH:15][C:14]2[N:19]([CH3:28])[N:20]=[C:21]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=3)[C:13]1=2)[C:5]([NH:29][C:30]1[C:31]([CH3:36])=[N:32][CH:33]=[CH:34][CH:35]=1)=[O:6]
Reactant: Cc1ncccc1N
Reactant: COC(=O)c1ccc(C2SCCNc3c2c(-c2ccccn2)nn3C)c(C)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1cc(C(=O)Nc2cccnc2C)ccc1C1SCCNc2c1c(-c1ccccn1)nn2C
Reaction time: 0.5 h
Yield: 41.2 %

Procedure:
To a mixture of methyl 3-methyl-4-[1-methyl-3-(2-pyridyl)-4,6,7,8-tetrahydropyrazolo[3,4-e][1,4]thiazepin-4-yl]benzoate (0.20 g, 0.51 mmol) and 3-amino-2-methylpyridine (0.066 g, 0.61 mmol) in anhydrous THF (20 mL), was added lithium bis(trimethylsilyl)amide solution (1.01 mL, 1 M in THF, 1.01 mmol), at about −60° C. The resulting mixture was stirred for about 30 min, during which time the temperature was allowed to rise from about −60° C. to about 0° C., and then quenched by the addition of water (20 mL), while keeping the temperature below 0° C. The resulting mixture was extracted with ethyl acetate (60 mL). The organic layer was washed with brine (20 mL), dried (MgSO4), filtered and concentrated in vacuo. The resulting residue was purified by column chromatography (SiO2, ethyl acetate) to afford 3-methyl-N-(2-methyl-3-pyridyl)-4-[1-methyl-3-(2-pyridyl)-4,6,7,8-tetrahydropyrazolo[3,4-e][1,4]thiazepin-4-yl]benzamide (0.10 g, 0.21 mmol, 42%) as a beige foam: LC-MS (Table 1, Method a) Rt=1.85 min, m/z 471 (M+H)+; 1H-NMR (CDCl3, Bruker 400 MHz) δ 2.56 (3H, s) 2.72 (3H, s) 2.67-2.75 (1H, m) 2.87 (1H, ddd, J=15.0, 9.3, 2.6 Hz) 3.29 (1H, ddd, J=13.3, 9.3, 2.5 Hz) 3.65 (1H, ddd, J=13.3, 6.2, 2.3 Hz) 3.85 (3H, s) 3.87 (1H, br s) 6.76 (1H, s) 7.08 (1H, ddd, J=7.4, 4.9, 1.1 Hz) 7.20 (1H, dd, J=8.1, 4.7 Hz) 7.35 (1H, t, J=8.0 Hz) 7.55 (1H, dd, J=8.0, 2.0 Hz) 7.60 (1H, td, J=7.8, 1.8 Hz) 7.62 (1H, d, J=1.8 Hz) 7.69 (1H, br s) 7.84 (1H, dt, J=8.0, 1.0 Hz) 8.30 (1H, dd, J=4.8, 1.6 Hz) 8.35 (1H, dd, J=8.1, 1.4 Hz) 8.47 (1H, ddd, J=4.8, 1.7, 0.8 Hz).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([C:13]([OH:15])=O)[CH:10]([CH3:12])[OH:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.C(Cl)(=O)OCC.[NH2:29][C:30]1[S:31][CH:32]=[N:33][N:34]=1>O1CCCC1>[C:1]([O:5][C:6]([NH:8][CH:9]([C:13]([NH:29][C:30]1[S:31][CH:32]=[N:33][N:34]=1)=[O:15])[CH:10]([CH3:12])[OH:11])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(O)C(NC(=O)OC(C)(C)C)C(=O)O
Reactant: Nc1nncs1
Agent: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(O)C(NC(=O)OC(C)(C)C)C(=O)Nc1nncs1
Reaction time: 2 h
Yield: 79.1 %

Procedure:
Dissolved in tetrahyrofuran were 6.6 g of t-butyoxycarbonyl-DL-threonine and 3.1 g of triethylamine, to which was added dropwise 3.3 g of ethyl chlorocarbonate at 0° C. After stirring for two hours, 3.1 g of 2-amino-1,3,4-thiadiazole was added, and stirred at room temperature for further 20 hours. The reaction solution was concentrated under a reduced pressure, water was added to the residue, and the precipitates were collected by filtration to obtain 7.2 g (Yield 80%) of 2-(t-butoxycarbonyl-DL-threonyl)amino-1,3,4-thiadiazole as white crystals having a melting point of from 165° to 172° C. (dec.).
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]([C:16]1[CH:21]=[C:20]([N:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)[CH:19]=[C:18]([CH3:28])[CH:17]=1)[C:10]([CH3:30])([CH3:29])[CH2:9]2)=[O:5])C.O.[OH-].[Li+].O.Cl>CO.O1CCCC1>[CH3:29][C:10]1([CH3:30])[CH2:9][C:8]2[C:13](=[CH:14][CH:15]=[C:6]([C:4]([OH:5])=[O:3])[CH:7]=2)[NH:12][CH:11]1[C:16]1[CH:21]=[C:20]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[CH:19]=[C:18]([CH3:28])[CH:17]=1
Reactant: CCOC(=O)c1ccc2c(c1)CC(C)(C)C(c1cc(C)cc(N3CCOCC3)c1)N2
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: Cc1cc(C2Nc3ccc(C(=O)O)cc3CC2(C)C)cc(N2CCOCC2)c1
Temperature: 60 °C
Reaction time: 12 h
Yield: 40.4 %

Procedure:
A mixture of 3,3-dimethyl-2-(3-methyl-5-morpholin-4-yl-phenyl)-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (0.52 g, 1.3 mmol), lithium hydroxide hydrate (0.54 g, 13 mmol), water (1 mL) in methanol (2 mL) and tetrahydrofuran (10 mL) was stirred at 60° C. for 12 h. The mixture was neutralized with a 3 N aqueous hydrochloric acid solution and extracted with ethyl acetate (2×50 mL), washed with water, dried over anhydrous sodium sulfate and then concentrated in vacuo to afford an oil residue. Purification by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% formic acid in water) afforded 3,3-dimethyl-2-(3-methyl-5-morpholin-4-yl-phenyl)-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (200 mg, 31%) as a white solid: LC/MS m/e calcd for C23H28N2O3 (M+H)+: 381.5, observed: 381.2.