Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl.[CH2:3]([NH:5][CH:6]([CH3:27])[CH2:7][N:8]1[CH2:13][CH2:12][C:11]2[C:14]3[CH:22]=[C:21]([O:23][CH3:24])[C:20]([O:25][CH3:26])=[CH:19][C:15]=3[O:16][C:17](=[O:18])[C:10]=2[CH2:9]1)[CH3:4].C([O-])(=O)C.[Na+].[BH4-].[Na+].[CH3:35][CH:36]([CH3:40])[C:37](O)=O>>[CH2:3]([N:5]([CH2:35][CH:36]([CH3:40])[CH3:37])[CH:6]([CH3:27])[CH2:7][N:8]1[CH2:13][CH2:12][C:11]2[C:14]3[CH:22]=[C:21]([O:23][CH3:24])[C:20]([O:25][CH3:26])=[CH:19][C:15]=3[O:16][C:17](=[O:18])[C:10]=2[CH2:9]1)[CH3:4]
Reactant: CCNC(C)CN1CCc2c(c(=O)oc3cc(OC)c(OC)cc23)C1
Reactant: CC(C)C(=O)O
Agent: CC(=O)[O-]
Agent: Cl
Agent: [BH4-]
Product: CCN(CC(C)C)C(C)CN1CCc2c(c(=O)oc3cc(OC)c(OC)cc23)C1

Procedure:
Prepared by the method described in Example 73 from 3-[2-(ethylamino)propyl]-1,2,3,4-tetrahydro-8,9-dimethoxy-5H-[1]benzopyrano[3,4-c]pyridin-5-one dihydrochloride (6.7 g, 0.016 moles), sodium acetate (2.6 g, 0.032 moles), sodium borohydride (3.3 g, 0.087 moles), and 2-methylpropionic acid (28.5 g, 0.32 moles) instead of acetic acid. Several recrystallizations from diisopropyl ether yielded the final product as the free base (1.4 g), mp 108°-111° C.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([F:16])=[C:6]([C@@:8]2([CH3:15])[NH:13][C:12](=[O:14])[CH2:11][O:10][CH2:9]2)[CH:7]=1.C(=[NH:30])(C1C=CC=CC=1)C1C=CC=CC=1.C(P(C(C)(C)C)C1C=CC=CC=1C1C(C(C)C)=CC(C(C)C)=CC=1C(C)C)(C)(C)C.CC(C)([O-])C.[Na+].Cl.C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1.C(OCC)(=O)C.CCCCCCC>[NH2:30][C:2]1[CH:3]=[CH:4][C:5]([F:16])=[C:6]([C@@:8]2([CH3:15])[NH:13][C:12](=[O:14])[CH2:11][O:10][CH2:9]2)[CH:7]=1
Reactant: C[C@@]1(c2cc(Br)ccc2F)COCC(=O)N1
Reactant: N=C(c1ccccc1)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C(C)(C)C)C(C)(C)C)c(C(C)C)c1
Agent: Cl
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: C[C@@]1(c2cc(N)ccc2F)COCC(=O)N1
Temperature: 105 °C
Reaction time: 18 h

Procedure:
A solution of (R)-5-(5-bromo-2-fluoro-phenyl)-5-methyl-morpholin-3-one (building block B) (1.0 g, 3.47 mmol) in toluene (61 ml) was treated with benzophenonimine (1.26 g, 6.94 mmol), tris(dibenzylideneacetone)-dipalladium chloroform complex (108 mg, 0.104 mmol), 2-di-tert-butylphosphino-2′,4′,6′-triisopropylbiphenyl (147 mg, 0.347 mmol) and sodium tert-butoxide (1.0 g, 10.4 mmol). The mixture was heated to 105° C. and stirred at this temperature for 18 hours. Even though following TLC (silica gel; heptane:ethyl acetate=1:1) the reaction was not completed, the mixture was stirred with hydrochloric acid (1M, 50 ml) for 45 minutes. Solid sodium hydrogen carbonate was added until pH 8 was reached and the mixture was extraced with ethyl acetate. The combined organic layers were dried over sodium sulphate and evaporated at reduced pressure. The crude material was purified by flash chromatography on silica gel using a gradient of heptane/ethyl acetate=100:0 to 20:80 as the eluent. The (R)-5-(5-amino-2-fluoro-phenyl)-5-methyl-morpholin-3-one was obtained as a dark red oil (312 mg, 40%); (calculated) C11H13FN2O2 [224.24]; (found) [M+H]+=225.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH:10]([CH3:14])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[C:16]1[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2)CCCCC1>C1(C)C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=2)[CH:10]([CH3:14])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: FC(F)(F)c1ccc(Br)cc1
Reactant: CC1CN(C(=O)OC(C)(C)C)CCN1
Agent: c1ccc(-c2ccccc2P(C2CCCCC2)C2CCCCC2)cc1
Solvent: Cc1ccccc1
Product: CC1CN(C(=O)OC(C)(C)C)CCN1c1ccc(C(F)(F)F)cc1
Temperature: 80 °C
Reaction time: 16 h
Yield: 31 %

Procedure:
To a solution of 3-Methyl-piperazine-1-carboxylic acid tert-butyl ester (1.0 g, 5.3 mmol) and of 1-Bromo-4-trifluoromethyl-benzene (1.0 g, 4.4 mmol) in toluene (10 ml) were added sodium-tert butylate (0.6 g, 6.2 mmol), 2-(dicyclohexylphosphino)biphenyl (31 mg, 89 mmol), and tris(dibenzylideneacetone)dipalladium-chloroform complex (23 mg, 22 mmol). The reaction mixture was then stirred for 16 hours at 80° C. After allowing to cool to room temperature the reaction mixture was concentrated in vacuo and purified by column chromatography (SiO2, 70 g, heptane/ethyl acetate 0-30%) to give the title compound as a light brown solid (0.47 g, 31%). MS (m/e): 345.2 (M+H+, 100%).
Reaction SMILES: C([Sn](CCCC)(CCCC)[C:6]1[O:7][CH:8]=[CH:9][CH:10]=1)CCC.[CH3:19][CH:20]([CH3:26])[CH2:21][CH2:22][C:23](Cl)=[O:24]>C1COCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:19][CH:20]([CH3:26])[CH2:21][CH2:22][C:23]([C:6]1[O:7][CH:8]=[CH:9][CH:10]=1)=[O:24]
Reactant: CC(C)CCC(=O)Cl
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccco1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Product: CC(C)CCC(=O)c1ccco1

Procedure:
A solution of 2-tributylstannylfuran (1 mmol), 4-methylvaleroyl chloride (1.1 mmol), and PdCl2(PPh3)2 (0.05 mmol) in THF was stirred at 25° C. for 24 h. Extraction and chromatography gave 2-(4-methylvaleryl)furan.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[S:15][C:14]([CH3:17])([CH3:16])[CH2:13][NH:12][C:11]2[N:18]([CH3:22])[N:19]=[C:20]([CH3:21])[C:10]1=2.[CH2:23]1[O:25][CH:24]1[C:26]([F:29])([F:28])[F:27].[O-]S(C(F)(F)F)(=O)=O.[Yb+3].[O-]S(C(F)(F)F)(=O)=O.[O-]S(C(F)(F)F)(=O)=O.C(=O)(O)[O-].[Na+]>C(#N)C.CN(C=O)C.C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[S:15][C:14]([CH3:17])([CH3:16])[CH2:13][N:12]([CH2:23][CH:24]([OH:25])[C:26]([F:29])([F:28])[F:27])[C:11]2[N:18]([CH3:22])[N:19]=[C:20]([CH3:21])[C:10]1=2
Reactant: Cc1nn(C)c2c1C(c1ccc(Cl)cc1Cl)SC(C)(C)CN2
Reactant: FC(F)(F)C1CO1
Agent: O=C([O-])O
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Na+]
Solvent: CC#N
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1nn(C)c2c1C(c1ccc(Cl)cc1Cl)SC(C)(C)CN2CC(O)C(F)(F)F
Temperature: 50 °C
Reaction time: 72 h
Yield: 57.1 %

Procedure:
To 4-(2,4-dichlorophenyl)-1,3,6,6-tetramethyl-7,8-dihydro-4H-pyrazolo[3,4-e][1,4]thiazepine (0.1 g, 0.28 mmol, Ex. D.4), dissolved in dry acetonitrile/DMF (4:1, 5 mL), was added 3,3,3-trifluoro-1,2-propenoxide (0.5 mL, 5.45 mmol) and ytterbium triflate (0.05 g, 0.4 mmol). The reaction mixture was stirred, for about 72 h, at about 50° C. After cooling to rt, 5% aqueous sodium bicarbonate (25 mL) and ethyl acetate (25 mL) were added. The layers were separated and the organic layer was washed with water (25 mL), dried (MgSO4), filtered and concentrated in vacuo. The resulting residue was purified by column chromatography (SiO2, ethyl acetate/methanol/acetic acid (8:2:0.1) followed by ethyl acetate/methanol/acetic acid (5:5:0.1)), to afford crude product which was purified by prep-HPLC (Table 2, Method c) to yield 3-[4-(2,4-dichlorophenyl)-1,3,6,6-tetramethyl-4,7-dihydropyrazolo[3,4-e][1,4]thiazepin-8-yl]-1,1,1-trifluoro-propan-2-ol (0.077 g, 0.16 mmol, 58%), as a white solid: LC-MS (Table 1, Method a) Rt=2.71 min, m/z 468 (M+H)+; 1H NMR (400 MHz, CDCl3, diastereomer mixture, ratio A:B=54:46) δ ppm 1.04 (3 H, s) 1.38 (3 H, s) 1.87 (3 H, s) 3.43 (1 H, dd, J=14.7, 6.1 Hz) 3.65-3.75 (1 H, m) 4.07 (3 H, s) 4.11-4.28 (2 H, m) 4.41-4.50 (1 H, m) 5.22 (1 H, s) 7.30 (1 H, dd, J=8.3, 2.2 Hz) 7.46 (1 H, d, J=2.2 Hz) 7.50 (1 H, d, J=8.3 Hz) 8.93 (1H, t, J=4.8 Hz) (Isomer A); 1H NMR (400 MHz, CDCl3) δ ppm 1.01 (3 H, s) 1.36 (3 H, s) 1.90 (3 H, s) 3.37 (1 H, dd, J=14.6, 7.1 Hz) 3.65-3.75 (1 H, m) 3.98 (3 H, s) 4.11-4.28 (2 H, m) 4.50-4.60 (1 H, m) 5.17 (1 H, s) 7.29 (1 H, dd, J=8.3, 2.2 Hz) 7.44 (1 H, d, J=2.2 Hz) 7559 (1 H, d, J=8.3 Hz) 8.83 (1 H, t, J=4.8 Hz) (Isomer B).
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C@@H:6]([CH2:12][CH2:13]Cl)[C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:4].[CH3:15][P:16](OCC)(=[O:20])[O:17][CH2:18][CH3:19]>>[CH3:1][O:2][C:3]([NH:5][C@@H:6]([CH2:12][CH2:13][P:16]([O:17][CH2:18][CH3:19])([CH3:15])=[O:20])[C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:4]
Reactant: CCOP(C)(=O)OCC
Reactant: CCOC(=O)[C@H](CCCl)NC(=O)OC
Product: CCOC(=O)[C@H](CCP(C)(=O)OCC)NC(=O)OC

Procedure:
2.6 g (11.6 mmol) of ethyl (S)-2-(methoxycarbonylamino)-4-chlorobutanoate and 6.3 g (46.4 mmol) of diethyl methanephosphonate are stirred for 15 h at 140° C. The excess diethyl methanephosphonate is then removed at 90° C. under a high vacuum. The crude product thus obtained is produced as a colorless oil and shows no further impurities in 1H-NMR; yield: 2.8 g (82%),
Reaction SMILES: CO.[C:3]([O:7][C:8](=[O:26])[NH:9][C:10]1[CH:15]=[C:14]([C:16]#[C:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[O:24][CH3:25])[CH:13]=[CH:12][N:11]=1)([CH3:6])([CH3:5])[CH3:4]>C(OCC)(=O)C.[Pd]>[C:3]([O:7][C:8](=[O:26])[NH:9][C:10]1[CH:15]=[C:14]([CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[O:24][CH3:25])[CH:13]=[CH:12][N:11]=1)([CH3:6])([CH3:5])[CH3:4]
Reactant: COc1ccccc1C#Cc1ccnc(NC(=O)OC(C)(C)C)c1
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: COc1ccccc1CCc1ccnc(NC(=O)OC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Methanol (10 mL) and Pd/C (100 mg) are added to a solution of [4-(2-methoxy-phenylethynyl)-pyridin-2-yl]-carbamic acid tert-butyl ester (146 mg, 0.450 mmol) in ethyl acetate (10 mL). The mixture is evacuated and purged with H2 (three times), and stirred at the room temperature under an atmosphere of H2 for 2 hours. The mixture is evacuated and purged with Argon, and filtered through a pad of diatomaceous earth. The filtrate is concentrated to give the crude product, which is used in the next step without purification.
Reaction SMILES: [H-].[Na+].[OH:3][C@H:4]([C@@H:10]([OH:16])[C:11]([N:13]([CH3:15])[CH3:14])=[O:12])[C:5]([N:7]([CH3:9])[CH3:8])=[O:6].I[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]>CCCCC.CN(C=O)C>[CH2:18]([O:16][C@H:10]([C@@H:4]([O:3][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH3:18])[C:5]([N:7]([CH3:9])[CH3:8])=[O:6])[C:11]([N:13]([CH3:15])[CH3:14])=[O:12])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]
Reactant: CCCCCCCCCCCCI
Reactant: CN(C)C(=O)[C@H](O)[C@@H](O)C(=O)N(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CCCCC
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCO[C@@H](C(=O)N(C)C)[C@@H](OCCCCCCCCCCCC)C(=O)N(C)C
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 24.4 %

Procedure:
Sodium hydride (3.60 g, 60%, 90.0 mmol) was washed with pentane (3×) before DMF (150 ml) and (+)-(2R,3R)-2,3-dihydroxy-N,N,N′,N′-tetramethylsuccinamide (9.2 g, 45.0 mmol, origin: Aldrich) were added. The reaction mixture was left stirring at room temperature for 90 min, then a solution of 1-iodododecane (28.0 g, 94.5 mmol) in DMF (50 ml) was added. The reaction was left stirring for another 2 h at room temperature and then heated at 80° C. overnight. After cooling to room temperature, the reaction mixture was extracted with ether (4×), washed with water (2×), dried (Na2SO4), and concentrated. Column chromatography (SiO2, dichloromethane/acetone 3:1) gave 5.93 g (28%) of a pale-yellow solid.
Reaction SMILES: S(Cl)(Cl)=O.[C:5]([CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]1[CH:19]=[CH:18][C:17]([C:20]([OH:22])=O)=[CH:16][CH:15]=1)#[N:6].[N:23]1[CH:28]=[CH:27][CH:26]=[C:25]([CH2:29][NH:30][C:31]([C:33]2[N:42]3[C:36]([CH2:37][NH:38][C:39]4[CH:46]=[CH:45][CH:44]=[CH:43][C:40]=4[CH2:41]3)=[CH:35][CH:34]=2)=[O:32])[CH:24]=1.CN(C)C=O>O1CCOCC1>[C:5]([CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]1[CH:15]=[CH:16][C:17]([C:20]([N:38]2[C:39]3[CH:46]=[CH:45][CH:44]=[CH:43][C:40]=3[CH2:41][N:42]3[C:33]([C:31]([NH:30][CH2:29][C:25]4[CH:24]=[N:23][CH:28]=[CH:27][CH:26]=4)=[O:32])=[CH:34][CH:35]=[C:36]3[CH2:37]2)=[O:22])=[CH:18][CH:19]=1)#[N:6]
Reactant: N#CCc1ccccc1-c1ccc(C(=O)O)cc1
Reactant: O=C(NCc1cccnc1)c1ccc2n1Cc1ccccc1NC2
Solvent: C1COCCO1
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: N#CCc1ccccc1-c1ccc(C(=O)N2Cc3ccc(C(=O)NCc4cccnc4)n3Cc3ccccc32)cc1

Procedure:
A mixture of 20 mL of thionyl chloride and 0.243 g (0.001 mol) of 2′-(cyanomethyl)-1,1′-biphenyl-4-carboxylic acid of Step A was heated under reflux for 1 hour. The excess thionyl chloride was removed in vacuo. To the residue was added 35 mL of dry 1,4-dioxane, 0.318 g (0.001 mol) of N-(pyridin-3-ylmethyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide and 0.122 g (0.001 mol) of N,N-dimethylformamide. The reaction was heated under reflux for three hours, cooled and evaporated to dryness. The residue was collected, washed with water and triturated with ether to give 0.62 g. of a tan solid, m.p. 105-108° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@@:9]2([CH3:56])[N:18]([CH2:19]/[CH:20]=[CH:21]/[C:22]3[CH:23]=[C:24]4[C:45](=[CH:46][CH:47]=3)[CH2:44][C:26]3([C:34]5[C:29](=[N:30][CH:31]=[CH:32][CH:33]=5)[N:28](COCC[Si](C)(C)C)[C:27]3=[O:43])[CH2:25]4)[C:17](=[O:48])[C:12]3([CH2:16][CH2:15][CH2:14][CH2:13]3)[N:11](C(OC(C)(C)C)=O)[CH2:10]2)[CH:5]=[C:6]([F:8])[CH:7]=1.C(O)(C(F)(F)F)=O.[OH-].[Na+].C(N)CN>C(Cl)Cl>[F:8][C:6]1[CH:5]=[C:4]([C@@:9]2([CH3:56])[N:18]([CH2:19]/[CH:20]=[CH:21]/[C:22]3[CH:23]=[C:24]4[C:45](=[CH:46][CH:47]=3)[CH2:44][C:26]3([C:34]5[C:29](=[N:30][CH:31]=[CH:32][CH:33]=5)[NH:28][C:27]3=[O:43])[CH2:25]4)[C:17](=[O:48])[C:12]3([CH2:13][CH2:14][CH2:15][CH2:16]3)[NH:11][CH2:10]2)[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: CC(C)(C)OC(=O)N1C[C@@](C)(c2cc(F)cc(F)c2)N(C/C=C/c2ccc3c(c2)CC2(C3)C(=O)N(COCC[Si](C)(C)C)c3ncccc32)C(=O)C12CCCC2
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: NCCN
Solvent: ClCCl
Product: C[C@@]1(c2cc(F)cc(F)c2)CNC2(CCCC2)C(=O)N1C/C=C/c1ccc2c(c1)CC1(C2)C(=O)Nc2ncccc21
Reaction time: 24 h

Procedure:
tert-Butyl (8R)-8-(3,5-difluorophenyl)-8-methyl-10-oxo-9-[(2E)-3-(2′-oxo-1′-{[2-(trimethylsilyl)ethoxy]methyl}-1,1′,2′,3-tetrahydrospiro[indene-2,3′-pyrrolo[2,3-b]pyridin]-5-yl)prop-2-en-1-yl]-6,9-diazaspiro[4.5]decane-6-carboxylate from Step A above (0.2276 g, 0.290 mmol) was dissolved in DCM (5 mL). To this solution was added 1 mL of TFA. The reaction was stirred for 24 hours, then concentrated in vacuo. The residue was dissolved in MeOH (5 mL) and to this solution was added 1N NaOH (2.90 ml, 2.90 mmol), and ethylenediamine (0.078 ml, 1.160 mmol). The reaction was stirred for ½ hour at RT, then concentrated in vacuo. The residue was partitioned between ethyl acetate and water. The layers were separated, then the aqueous layer was washed 3×20 mL with ethyl acetate. The combined organic layers were washed with brine. Dried over Magnesium sulfate, filtered and concentrated in vacuo to yield the title compound. Diastereomer separation was accomplished using a Chiralcel OJ column, eluting with CO2:MeOH—70:30. Two peaks were isolated. Peak 1 MS: m/z=555 (M+1) HRMS: m/z=555.2569 (M+1); calculated m/z=555.2566 (M+1) for C33H32F2N4O2, and Peak 2 MS: m/z=555 (M+1)HRMS: m/z=555.2569 (M+1); calculated m/z=555.2566 (M+1) for C33H33F2N4O2.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].O1CCCC1.[C:12]1([NH:18][C:19]2[N:27]=[CH:26][CH:25]=[CH:24][C:20]=2[C:21](O)=[O:22])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[OH-].[Na+]>C(OCC)(=O)C>[C:12]1([NH:18][C:19]2[C:20]([CH2:21][OH:22])=[CH:24][CH:25]=[CH:26][N:27]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C(O)c1cccnc1Nc1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: OCc1cccnc1Nc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 108.7 %

Procedure:
Under a nitrogen gas stream, 2.41 g (63.4 mmol) of lithium aluminum hydride was added to tetrahydrofuran (80 mL) under ice cooling, and a tetrahydrofuran (30 mL) solution of 6.79 g (31.7 mmol) of 2-(phenylamino)nicotinic acid was added dropwise to the above solution. The resulting mixture was stirred for 2 hours at room temperature. Ethyl acetate was added to the reaction mixture, and 25 mL of a 10% aqueous solution of sodium hydroxide was further added thereto. Insoluble materials were filtered off. The filtrate was concentrated, and the residue thus obtained was dissolved in ethyl acetate, dried, filtered, and concentrated. Thus, 6.9 g of the title compound was obtained as a yellow viscous product (yield: quantitative).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][CH3:9])[C:5]([N+:10]([O-:12])=[O:11])=[C:4]([NH2:13])[CH:3]=1.[Cl:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+].C1(C)C=CC=CC=1>ClCCl.C(OCC)(=O)C.O.C(O)C>[Cl:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[C:2]1[N:7]=[C:6]([O:8][CH3:9])[C:5]([N+:10]([O-:12])=[O:11])=[C:4]([NH2:13])[CH:3]=1
Reactant: COc1nc(Cl)cc(N)c1[N+](=O)[O-]
Reactant: OB(O)c1ccccc1Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: O
Product: COc1nc(-c2ccccc2Cl)cc(N)c1[N+](=O)[O-]
Temperature: 69 °C
Reaction time: 17 h

Procedure:
A 5 L, four neck round bottom flask equipped with mechanical stirrer, water condenser with nitrogen inlet, thermocouple, and stopper was charged with 6-chloro-2-methoxy-3-nitro-4-pyridinamine (125.30 g, 0.615 mol), 2-chlorophenylboronic acid (116.36 g, 0.744 mol), sodium carbonate (164.97 g, 1.54 mol), toluene (1.80 L), water (0.8 L), and ethanol (0.625 L) and the resulting mixture stirred to achieve a red slurry. The slurry was heated to a mild reflux for 15 min to degas solution and then the temperature was lowered to 60° C. The resulting mixture was treated with (1,1′-bis-(di-tert-butylphosphino)ferrocenepalladium(II) chloride (40.8 g, 61 mmol) and the temperature increased to 69° C., generating a mild reflux. The temperature to 60° C. and stirring was continued for 17 h. The resulting mixture was diluted into water (2 L) and ethyl acetate (1 L), then filtered through CELITE, washing with ethyl acetate (1 L). The layers of filtrate were partitioned and the aqueous further extracted with ethyl acetate (3×500 mL). The combined organics were dried (MgSO4) and concentrated to yield a dark oil. The dark oil was dissolved in dichloromethane and slurried with silica gel (325 g). The slurry was loaded onto a BIOTAGE 150M (2.5 kg silica) and eluted with dichloromethane (3 L) and ethyl acetate-dichloromethane 1:19 (9 L). Fractions of suitable purity were concentrated, lastly from heptane (500 mL) to yield the title compound as a residue. The residue (282 g) was triturated with MTBE (0.50 L), heated in water bath at 40° C. for 30 min, transferred to a mechanically stirred 5 L round bottom flask then diluted with heptane (2 L). The resulting slurry was stirred for 1 h at room temperature and the solids collected by filtration. The filter cake washed with MTBE-heptane (1:9, 500 mL) and heptane (500 mL), then dried in vacuum oven at 50° C. for 45 min to yield 6-(2-chlorophenyl)-2-methoxy-3-nitropyridin-4-amine as a yellow solid. 1H NMR (400 MHz, CHLOROFORM-d) δ 3.62 (s, 1H), 4.07 (s, 3H), 6.14 (br. s., 2H), 6.69 (s, 1H), 7.30-7.40 (m, 2H), 7.42-7.52 (m, 1H), 7.59-7.66 (m, 1H)
Reaction SMILES: [C:1](Cl)(=[O:4])[CH2:2][CH3:3].C(N(CC)CC)C.[F:13][C:14]1[CH:19]=[C:18]([N+:20]([O-:22])=[O:21])[CH:17]=[CH:16][C:15]=1[N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1.O>CN(C)C1C=CN=CC=1.O1CCCC1>[F:13][C:14]1[CH:19]=[C:18]([N+:20]([O-:22])=[O:21])[CH:17]=[CH:16][C:15]=1[N:23]1[CH2:28][CH2:27][N:26]([C:1](=[O:4])[CH2:2][CH3:3])[CH2:25][CH2:24]1
Reactant: CCC(=O)Cl
Reactant: O=[N+]([O-])c1ccc(N2CCNCC2)c(F)c1
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(CC)CC
Product: CCC(=O)N1CCN(c2ccc([N+](=O)[O-])cc2F)CC1
Temperature: 25 °C
Reaction time: 6 h
Yield: 53 %

Procedure:
Propionyl chloride (0.620 g, 4.88 mmol), triethylamine (0.747 ml, 5.32 mmol) and 4-dimethylaminopyridine (0.0542 g, 0.444 mmol) were added to a solution of 1-(2-fluoro-4-nitrophenyl)piperazine (compound of Reference Example 52; 1.00 g, 4.44 mmol) in anhydrous tetrahydrofuran (9 ml) under ice cooling, and the mixture was stirred at room temperature for 6 hours. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The residue obtained by evaporation of the solvent under reduced pressure was purified by column chromatography on silica gel (n-hexane:ethyl acetate=1:1) to give the title compound (0.662 g, 53%) as a yellow solid.
Reaction SMILES: [S:1]([OH:5])([OH:4])(=[O:3])=[O:2].[NH2:6][C@H:7]([C:12]([OH:14])=[O:13])[CH2:8][CH2:9][S:10][CH3:11].S(O)(O)(=O)=O.[CH2:20]([S:27]SCC[C@H](N)C(O)=O)C[C@H](N)C(O)=O.S([O-])([O-])(=O)=O>>[NH2:6][C@H:7]([C:12]([OH:14])=[O:13])[CH2:8][CH2:9][S:10][CH3:11].[S:1]([O-:5])([O-:4])(=[O:3])=[O:2].[CH3:20][SH2+:27].[CH3:9][SH2+:10]
Reactant: N[C@@H](CCSSCC[C@H](N)C(=O)O)C(=O)O
Reactant: O=S(=O)(O)O
Agent: CSCC[C@H](N)C(=O)O
Agent: O=S(=O)([O-])[O-]
Product: C[SH2+]

Procedure:
The analysis of the above-mentioned reaction solution 1 by liquid chromatography showed that 2.6 g (0.01 mole) of L-methionine sulfate, 112.5 g (0.31 mole) of L-homocystine sulfate, 12.4 g (0.03 mole) of mesohomocystine sulfate and 52.7 g (0.17 mole) of L-methionine-S-methylsulfonium sulfate were produced. The conversion rate was 99%, and the selection rate was 61%.
Reaction SMILES: [NH2:1][CH:2]([C:6]([NH2:8])=[O:7])[C:3]([NH2:5])=[O:4].[CH:9](O)=[O:10].C(OCC)(OCC)OCC.[ClH:22]>O.CC(O)C>[OH2:4].[OH2:10].[ClH:22].[OH:4][C:3]1[NH:5][CH:9]=[N:1][C:2]=1[C:6]([NH2:8])=[O:7]
Reactant: NC(=O)C(N)C(N)=O
Reactant: O=CO
Agent: Cl
Solvent: CC(C)O
Solvent: CCOC(OCC)OCC
Solvent: O
Product: NC(=O)c1nc[nH]c1O
Temperature: 81 °C
Reaction time: 0.55 h

Procedure:
Under the nitrogen atmosphere, 5.00 g of 2-aminomalonamide and 20 mg of formic acid were added to 80 mL of 2-propanol. After heating to 81° C., 17.7 mL of triethyl orthoformate was added to the mixture over 14 minutes. Subsequently, the reaction mixture was stirred for 6 hours and 33 minutes at 83° C. Subsequently, after cooling to 58° C., the reaction mixture was added dropwise with 5 mL of water followed by 4 mL of conc. hydrochloric acid. After cooling the mixture to 20° C., the crystal was collected by filtration and then washed with 20 mL of acetone to give 8.05 g of 5-hydroxy-1H-imidazole-4-carboxamide hydrochloric acid salt dihydrate as a yellow crystal.
Reaction SMILES: [CH2:1]([C:3]1[N:13]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][NH:22][CH3:23])=[CH:16][CH:15]=2)[C:6]2=[N:7][C:8]([CH3:12])=[CH:9][C:10]([CH3:11])=[C:5]2[N:4]=1)[CH3:2].[C:24]1([CH3:36])[CH:29]=[CH:28][C:27]([S:30]([N:33]=[C:34]=[O:35])(=[O:32])=[O:31])=[CH:26][CH:25]=1>ClCCl.C(N(CC)CC)C>[CH2:1]([C:3]1[N:13]([C:14]2[CH:15]=[CH:16][C:17]([CH2:20][CH2:21][N:22]([CH3:23])[C:34]([NH:33][S:30]([C:27]3[CH:26]=[CH:25][C:24]([CH3:36])=[CH:29][CH:28]=3)(=[O:31])=[O:32])=[O:35])=[CH:18][CH:19]=2)[C:6]2=[N:7][C:8]([CH3:12])=[CH:9][C:10]([CH3:11])=[C:5]2[N:4]=1)[CH3:2]
Reactant: Cc1ccc(S(=O)(=O)N=C=O)cc1
Reactant: CCc1nc2c(C)cc(C)nc2n1-c1ccc(CCNC)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCc1nc2c(C)cc(C)nc2n1-c1ccc(CCN(C)C(=O)NS(=O)(=O)c2ccc(C)cc2)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 41.6 %

Procedure:
To a solution of N-{2-[4-(2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)phenyl]ethyl}-N-methylamine (step 1, 523 mg, 1.7 mmol) in dichloromethane (10 mL) and triethylamine (2 mL) was added p-toluenesulfonyl isocyanate (400 mg, 2.0 mmol). The resulting reaction mixture was stirred at room temperature for 6 h. After removal of solvent, the residue was purified by flash column chromatography on silica gel eluting with dichloromethane/methanol (10:1) to afford 358 mg (42%) of the title compound as white solids: 1H-NMR (CDCl3) δ 7.93 (2H, d, J=8.3 Hz), 7.31 (2H, d, J=8.4 Hz), 7.24 (2H, d, J=8.3 Hz), 7.14 (2H, d, J=8.4 Hz), 6.92 (1H, s), 3.66–3.49 (2H, m), 3.51 (3H, s), 2.93–2.70 (4H, m), 2.65 (3H, s), 2.50 (3H, s), 2.38 (3H, s), 1.24 (3H, t, J=7.2 Hz).
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]([NH:9][CH3:10])=[S:8])[N:5]=[C:4]([N:11]=[CH:12][N:13]([CH3:15])[CH3:14])[N:3]=1.[C:16](OC(OCC)OCC)(=O)C>>[CH3:15][N:13]([CH:12]=[N:11][C:4]1[N:3]=[C:2]2[N:1]=[CH:10][N:9]([CH3:16])[C:7](=[S:8])[N:6]2[N:5]=1)[CH3:14]
Reactant: CCOC(OCC)OC(C)=O
Reactant: CNC(=S)n1nc(N=CN(C)C)nc1N
Product: CN(C)C=Nc1nc2ncn(C)c(=S)n2n1
Yield: 56 %

Procedure:
The synthesis method of Example 55 was applied. The compound (486 mg) obtained in Example 33 and diethoxymethyl acetate (5 ml) were used as reagents. The mixture was reacted at 95° C. for 2 hours to give 282 mg of pale-brown crystals (yield 56%).