Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][NH:2][C:3]1[S:4][C:5]([C:10]2[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=2)=[C:6]([CH:8]=O)[N:7]=1.Cl.[I-].C1([P+](C2C=CC=CC=2)(C2C=CC=CC=2)[CH2:25][C:26]2[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=2)C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+].Cl>O1CCCC1.O>[CH3:1][NH:2][C:3]1[S:4][C:5]([C:10]2[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=2)=[C:6]([CH:8]=[CH:25][C:26]2[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=2)[N:7]=1
Reactant: CNc1nc(C=O)c(-c2ccncc2)s1
Reactant: c1ccc([P+](Cc2ccncc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: C1CCOC1
Solvent: O
Product: CNc1nc(C=Cc2ccncc2)c(-c2ccncc2)s1
Yield: 10.8 %

Procedure:
To a solution of 2-methylamino-4-formyl-5-(4-pyridyl)thiazole (1.1 g) in a mixture of tetrahydrofuran (40 ml) and water (40 ml) was added triphenyl (4-pyridylmethyl)phosphonium iodide hydrochloride (7.8 g). The resultant mixture was stirred at ambient temperature for 3 hours, during which time the mixture was maintained at pH 9.5 to 10 with 20% aqueous potassium carbonate. The reaction mixture was adjusted to pH 1.0 with 10% hydrochloric acid and washed with ethyl acetate. The aqueous solution was adjusted to pH 7.0 with 20% aqueous potassium carbonate and extracted with a mixture of ethyl acetate and tetrahydrofuran. The organic extract was dried over magnesium sulfate and evaporated in vacuo. The residue was subjected to column chromatography on silica gel eluting with a mixture of ethyl acetate and tetrahydrofuran (4:1). The fractions containing the desired compound were combined and evaporated in vacuo to give 2-methylamino-4-[2-(4-pyridyl)vinyl]-5-(4-pyridyl)thiazole (0.16 g).
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[C:8]([CH3:17])=[N:9][C:10]([O:15]C)=[C:11]([CH2:13][CH3:14])[CH:12]=2)=[N:5][C:4]([CH3:18])=[N:3]1.[I-].[Na+].Cl[Si](C)(C)C>C(#N)C>[CH3:1][N:2]1[C:6]([C:7]2[CH:12]=[C:11]([CH2:13][CH3:14])[C:10](=[O:15])[NH:9][C:8]=2[CH3:17])=[N:5][C:4]([CH3:18])=[N:3]1
Reactant: CCc1cc(-c2nc(C)nn2C)c(C)nc1OC
Agent: C[Si](C)(C)Cl
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Product: CCc1cc(-c2nc(C)nn2C)c(C)[nH]c1=O
Temperature: 60 °C
Reaction time: 12 h
Yield: 65.5 %

Procedure:
To a mixture of 3-(2,5-dimethyl-2H-1,2,4-triazol-3-yl)-5-ethyl-6-methoxy-2-methylpyridine (76 mg, 0.309 mmol) and sodium iodide (139 mg, 0.927 mmol) under a nitrogen atmosphere is added anhydrous acetonitrile (5 mL) followed by drop-wise addition of chlorotrimethylsilane (116 μL, 0.924 mmol). The reaction mixture is stirred at 60° C. under nitrogen for 12 hr. LC/MS shows the reaction is incomplete. A further amount of chlorotrimethylsilane (100 μL) is added and the reaction is reheat at 60° C. for 9 hr. The reaction mixture is allowed to cool and then quenched with water (0.7 mL). After stirring for 30 min the mixture is partitioned between water and dichloromethane and the mixture treated with little sodium bisulfite to decolorize. The dichloromethane layer is separated and the aqueous layer is extracted with six further portions of dichloromethane. The combined dichloromethane layer is dried over magnesium sulfate and evaporated. The crude product is purified by flash chromatography on a 5-gram silica gel cartridge by elution with dichloromethane:methanol (1:0, increasing to 19:1). Fractions containing the product are combined, the solvent evaporated and triturated with ether to give 5-(2,5-dimethyl-2H-1,2,4-triazol-3-yl)-3-ethyl-6-methyl-1H-pyridin-2-one (47 mg, 66% yield) as a cream solid. LC/MS: RT: 1.88 min, MS: m/e=233 (M+H); 1H NMR (400 MHz, d6-DMSO, δ, ppm): 11.85 (1H, s), 7.20 (1H, s), 3.61 (3H, s), 2.36 (2H, q), 2.20 (3H, s), 2.07 (3H, s), 1.07 (3H, t).
Reaction SMILES: [ClH:1].[OH:2][NH:3][C:4]([C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[CH2:8][CH2:9][C:10]2=[N:15]O)=[NH:5].Cl.N[N:19]1[CH:23]=[C:22]([CH2:24][CH3:25])[N:21]=[C:20]1[NH2:26]>C(O)(C)C>[ClH:1].[ClH:1].[OH:2][NH:3][C:4]([C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[CH2:8][CH2:9][C:10]2=[N:15][N:19]1[CH:23]=[C:22]([CH2:24][CH3:25])[N:21]=[C:20]1[NH2:26])=[NH:5]
Reactant: N=C(NO)c1cccc2c1CCC2=NO
Reactant: CCc1cn(N)c(N)n1
Agent: Cl
Solvent: CC(C)O
Product: CCc1cn(N=C2CCc3c(C(=N)NO)cccc32)c(N)n1
Temperature: 80 °C
Reaction time: 90 h

Procedure:
3.2 ml of 32% hydrochloric acid (Merck, Darmstadt, Germany; p.a.) are added, with stirring, to a mixture of 3.28 g (0.016 mol) of 4-(N-hydroxyamidino)-2,3-dihydro-1H-inden-1-one oxime, 2.6 g (0.016 mol) of 1,2-diamino-4-ethyl-imidazole hydrochloride and 150 ml of isopropanol, and the reaction mixture is stirred at 80° C. for 90 hours. The reaction mixture is filtered while hot and the filtration product is washed with isopropanol and dried. In that manner there is obtained the title compound, m.p. 245°-246° C., 1H-NMR (DMSO/D2O): δ=8.22 (d, 1H); 7.73 (d, 1H); 7.59 (t, 1H); 7.19 (s, 1H); 3.2 (m, 4H); 2.47 (m, 2H); 1.17 (t, 3H).
Reaction SMILES: [C:1]1([C:7]2([C:13]([O:15][CH3:16])=[O:14])[CH2:12][CH2:11][CH2:10][NH:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:17][N:18]1[CH:22]=[C:21]([S:23](Cl)(=[O:25])=[O:24])[N:20]=[CH:19]1>>[CH3:17][N:18]1[CH:22]=[C:21]([S:23]([N:9]2[CH2:10][CH2:11][CH2:12][C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)([C:13]([O:15][CH3:16])=[O:14])[CH2:8]2)(=[O:25])=[O:24])[N:20]=[CH:19]1
Reactant: Cn1cnc(S(=O)(=O)Cl)c1
Reactant: COC(=O)C1(c2ccccc2)CCCNC1
Product: COC(=O)C1(c2ccccc2)CCCN(S(=O)(=O)c2cn(C)cn2)C1

Procedure:
The target was synthesized as in Production Example 1(1), using the raw material methyl 3-phenylpiperidine-3-carboxylate described in literature (Tetrahedron Letters 42 (2001) 1645-1646) and 1-methyl-1H-imidazole-4-sulfonyl chloride.
Reaction SMILES: C([NH:4][CH:5]1[CH2:9][CH2:8][N:7]([C:10]2[N:19]=[C:18]3[C:13]([C:14](=[O:33])[C:15]([C:28]([O:30]CC)=[O:29])=[CH:16][N:17]3[C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=3[F:27])=[CH:12][C:11]=2[F:34])[CH2:6]1)(=O)C.[ClH:35]>>[ClH:35].[NH2:4][CH:5]1[CH2:9][CH2:8][N:7]([C:10]2[N:19]=[C:18]3[C:13]([C:14](=[O:33])[C:15]([C:28]([OH:30])=[O:29])=[CH:16][N:17]3[C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=3[F:27])=[CH:12][C:11]=2[F:34])[CH2:6]1
Reactant: CCOC(=O)c1cn(-c2ccc(F)cc2F)c2nc(N3CCC(NC(C)=O)C3)c(F)cc2c1=O
Agent: Cl
Product: NC1CCN(c2nc3c(cc2F)c(=O)c(C(=O)O)cn3-c2ccc(F)cc2F)C1
Yield: 84 %

Procedure:
In 5 ml of 6N hydrochloric acid was dissolved 500 mg of ethyl 7-(3-acetylamino-1-pyrrolidinyl)-1-(2,4-difluorophenyl)-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylate, and the resulting solution was subjected to reaction under reflux for 4 hours. Subsequently, the crystals thus deposited were collected by filtration and washed with 1 ml of water to obtain 390 mg (yield 84.0%) of 7-(3-amino-1-pyrrolidinyl)-1-(2,4-difluorophenyl)-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid hydrochloride having a melting point of 247°-250° C. (decomp.). The physical properties of this compound were identical with those of the compound obtained in Example 54.
Reaction SMILES: I[Si](C)(C)C.[Br:6][C:7]1[CH:16]=[C:15]2[C:10]([CH2:11][CH:12]([CH3:21])[N:13](C(OC)=O)[CH2:14]2)=[CH:9][CH:8]=1.CO>C(Cl)Cl>[Br:6][C:7]1[CH:16]=[C:15]2[C:10]([CH2:11][CH:12]([CH3:21])[NH:13][CH2:14]2)=[CH:9][CH:8]=1
Reactant: COC(=O)N1Cc2cc(Br)ccc2CC1C
Agent: C[Si](C)(C)I
Solvent: CO
Solvent: ClCCl
Product: CC1Cc2ccc(Br)cc2CN1
Temperature: 50 °C
Reaction time: 2 h

Procedure:
Iodotrimethylsilane (0.982 mL, 0.00690 mol, Aldrich, Cat. No. 195529) was added to a solution of methyl 7-bromo-3-methyl-3,4-dihydroisoquinoline-2(1H)-carboxylate (490 mg, 0.0017 mol) in methylene chloride (10 mL) and the reaction was stirred at 50° C. for 2 h. The reaction was cooled to r.t. and anhydrous methanol (2 mL) was added. The reaction mixture was stirred for additional 5 min, and the volatiles were removed under reduced pressure. The residue was treated with diethyl ether and filtered. The solid was washed with ether, dried under vacuum to provide the desired compound which was directly used in the next step reaction without further purification. LCMS (M+H)+: m/z=226.2.
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH2:12][C:13]([O:15][CH3:16])=[O:14])(=[O:4])=[O:3].[Cl:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22]Cl)=[CH:20][CH:19]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O.ClCCl>[Cl:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22][N:5]([S:2]([CH3:1])(=[O:4])=[O:3])[C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[CH2:12][C:13]([O:15][CH3:16])=[O:14])=[CH:20][CH:19]=1
Reactant: ClCc1ccc(Cl)cc1
Reactant: COC(=O)Cc1ccccc1NS(C)(=O)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: O
Product: COC(=O)Cc1ccccc1N(Cc1ccc(Cl)cc1)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of methyl 2-(methylsulfonylamino)phenylacetate (2.00 kg) in dimethylformamide (10 l), under an atmosphere of nitrogen, is added 4-chlorobenzyl chloride (1.37 kg) all at once, followed by anhydrous potassium carbonate (1.18 kg). The mixture is heated at 75° and stirred for 4 hours, then cooled to room temperature overnight at which time it is poured into water (50 l). The resulting precipitate is dissolved in dichloromethane (4 l). The dichloromethane solution is washed with brine (500 ml), dried over anhydrous magnesium sulfate and filtered. The filtrate is evaporated in vacuo to give a solid which is air-dried overnight and vacuum-dried (0.3 mm Hg) at room temperature to yield methyl 2-[N-(4-chlorophenylmethyl)-methylsulfonylamino]phenylacetate mp 73°-75°.
Reaction SMILES: ClC(OC(Cl)(Cl)Cl)=O.C(O[C:14]([NH:16][C:17]1[C:22]([C:23]([OH:25])=[O:24])=[CH:21][N:20]=[CH:19][CH:18]=1)=[O:15])(C)(C)C>O1CCOCC1>[NH:16]1[C:17]2[CH:18]=[CH:19][N:20]=[CH:21][C:22]=2[C:23](=[O:24])[O:25][C:14]1=[O:15]
Reactant: CC(C)(C)OC(=O)Nc1ccncc1C(=O)O
Agent: O=C(Cl)OC(Cl)(Cl)Cl
Solvent: C1COCCO1
Product: O=c1[nH]c2ccncc2c(=O)o1
Yield: 97.8 %

Procedure:
Trichloromethyl chloroformate (9 mL, 75 mmol) was added slowly to a solution of 4-tert-butoxycarbonylamino-nicotinic acid (118) (16.2 g, 68 mmol) in dioxane and refluxed for 4 h under nitrogen atmosphere. The solution was cooled and the solvent was removed under vacuum. The residue was recrystallized by ether to yield 10.92 g (98%) of 1H-pyrido[4,3-d][1,3]oxazine-2,4-dione (119) as white solids. MP: 243° C.; 1H-NMR (DMSO-d6): ), δ 7.32 (d, J=6.0 Hz, 1H), 8.71 (d, J=6.0 Hz, 1H), 9.11 (s, 1H); EIMS m/z 165 (M+1).
Reaction SMILES: C1CCN(C(CNCC2C=CC3OCOC=3C=2)=S)CC1.Br[CH2:22][C:23]1[CH:28]=[CH:27][C:26]([CH2:29][CH2:30][N:31]2[CH:36]=[CH:35][C:34]([O:37][C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)=[CH:33][C:32]2=[O:44])=[CH:25][CH:24]=1.[OH:45][CH:46]1[CH2:51][CH2:50][NH:49][CH2:48][CH2:47]1>>[OH:45][CH:46]1[CH2:51][CH2:50][N:49]([CH2:22][C:23]2[CH:28]=[CH:27][C:26]([CH2:29][CH2:30][N:31]3[CH:36]=[CH:35][C:34]([O:37][C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=4)=[CH:33][C:32]3=[O:44])=[CH:25][CH:24]=2)[CH2:48][CH2:47]1
Reactant: OC1CCNCC1
Reactant: O=c1cc(Oc2ccccc2)ccn1CCc1ccc(CBr)cc1
Agent: S=C(CNCc1ccc2c(c1)OCO2)N1CCCCC1
Product: O=c1cc(Oc2ccccc2)ccn1CCc1ccc(CN2CCC(O)CC2)cc1

Procedure:
1-{2-[4-(4-Hydroxy-piperidin-1-ylmethyl)-phenyl]-ethyl}-4-phenoxy-1H-pyridin-2-one is prepared as example 16.2c from 100 mg (0.26 mmol) 1-[2-(4-bromomethyl-phenyl)-ethyl]-4-phenoxy-1H-pyridin-2-one (example 16.2b) and 105 mg (1.04 mmol) 4-hydroxy-piperidine.
Reaction SMILES: Cl[C:2]1[C:7]([CH:8]=O)=[CH:6][CH:5]=[CH:4][N:3]=1.O.[NH2:11][NH2:12]>O.CCOC(C)=O>[NH:11]1[C:2]2=[N:3][CH:4]=[CH:5][CH:6]=[C:7]2[CH:8]=[N:12]1
Reactant: NN
Reactant: O=Cc1cccnc1Cl
Solvent: O
Solvent: CCOC(C)=O
Product: c1cnc2[nH]ncc2c1
Temperature: 25 °C

Procedure:
A solution of 2-chloropyridine-3-carbaldehyde (20 g, 141 mmol) and hydrazine monohydrate (60% in water, 113 g, 2.1 mol) in 140 mL water was heated at 100° C. for 72 hours. The reaction mixture was cooled to room temperature and diluted with 200 mL of EtOAc. The aqueous layer was separated and extracted with EtOAc (3×). The combined organics were dried over MgSO4, filtered and concentrated in vacuo to give a light orange solid which was crystallized from hexanes to give the title compound as an off-white solid. 1H NMR (400 MHz, CH3CN-d3): δ 11.56 (s, 1H); 8.51 (dd, J=4.52, 1.56 Hz, 1H); 8.17 (dd, J=8.05, 1.58 Hz, 1H); 8.05 (s, 1H); 7.17 (dd, J=8.05, 4.51 Hz, 1H).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:4]=[C:5]([CH:39]=[CH:40][CH:41]=1)[C:6]([NH:8][C:9]1[S:10][C:11]2[CH2:38][CH2:37][CH2:36][CH2:35][C:12]=2[C:13]=1[C:14]([NH:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][CH2:24][C:25]2[CH:34]=[CH:33][C:28]([C:29]([O:31][CH3:32])=[O:30])=[CH:27][CH:26]=2)=[CH:19][CH:18]=1)=[O:15])=[O:7].[CH:42]([NH:45][CH2:46][CH2:47][NH:48][CH:49]([CH3:51])[CH3:50])([CH3:44])[CH3:43]>>[CH:42]([N:45]([CH2:2][C:3]1[CH:4]=[C:5]([CH:39]=[CH:40][CH:41]=1)[C:6]([NH:8][C:9]1[S:10][C:11]2[CH2:38][CH2:37][CH2:36][CH2:35][C:12]=2[C:13]=1[C:14]([NH:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][CH2:24][C:25]2[CH:34]=[CH:33][C:28]([C:29]([O:31][CH3:32])=[O:30])=[CH:27][CH:26]=2)=[CH:19][CH:18]=1)=[O:15])=[O:7])[CH2:46][CH2:47][NH:48][CH:49]([CH3:51])[CH3:50])([CH3:44])[CH3:43]
Reactant: CC(C)NCCNC(C)C
Reactant: COC(=O)c1ccc(CCc2ccc(NC(=O)c3c(NC(=O)c4cccc(CCl)c4)sc4c3CCCC4)cc2)cc1
Product: COC(=O)c1ccc(CCc2ccc(NC(=O)c3c(NC(=O)c4cccc(CN(CCNC(C)C)C(C)C)c4)sc4c3CCCC4)cc2)cc1

Procedure:
By using 250 mg of methyl 4-[2-(4-{[(2-{[3-(chloromethyl)benzoyl]amino}-4,5,6,7-tetrahydro-1-benzothiophen-3-yl)carbonyl]amino}phenyl)ethyl]benzoate and 0.25 mL of N,N′-diisopropylethylenediamine as starting materials, the reaction similar to Preparation Example 9 was performed, thereby obtaining 220 mg of methyl 4-[2-(4-{[(2-{[3-({isopropyl[2-(isopropylamino)ethyl]amino}methyl)benzoyl]amino}-4,5,6,7-tetrahydro-1-benzothiophen-3-yl)carbonyl]amino}phenyl)ethyl]benzoate.
Reaction SMILES: [C:1]([C:4]1[N:5]=[C:6]([NH:19][C:20](=[O:29])[C:21]2[C:26]([F:27])=[CH:25][CH:24]=[CH:23][C:22]=2[F:28])[S:7][C:8]=1[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=1)(=[O:3])[CH3:2].[Br-:30].[Br-].[Br-].C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1>C1COCC1>[Br:30][CH2:2][C:1]([C:4]1[N:5]=[C:6]([NH:19][C:20](=[O:29])[C:21]2[C:26]([F:27])=[CH:25][CH:24]=[CH:23][C:22]=2[F:28])[S:7][C:8]=1[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:16])([F:17])[F:18])[CH:10]=1)=[O:3]
Reactant: CC(=O)c1nc(NC(=O)c2c(F)cccc2F)sc1-c1cccc(C(F)(F)F)c1
Reactant: [Br-]
Agent: C[N+](C)(C)c1ccccc1
Solvent: C1CCOC1
Product: O=C(CBr)c1nc(NC(=O)c2c(F)cccc2F)sc1-c1cccc(C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 76.8 %

Procedure:
Into a solution of Compound 84 (132 mg, 0.33 mmol) in THF (10 mL) at 0° C. was added phenyltrimethylammonium tribromide (125 mg, 0.33 mmol). The mixture was stirred at 0° C. for 1 hour, quenched by ice addition, extracted with methylene chloride. The combined extracted was dried (Na2SO4), filtered and concentrated. The residue was purified on silica (eluted with methylene chloride) to give Compound 85 (128 mg, 85%) as a white solid.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([CH3:9])=[CH:5][C:4]=1[C:10](=[O:23])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]([O:21][CH3:22])=[O:20].B(Br)(Br)Br.O>C(Cl)Cl>[OH:2][C:3]1[CH:8]=[CH:7][C:6]([CH3:9])=[CH:5][C:4]=1[C:10](=[O:23])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]([O:21][CH3:22])=[O:20]
Reactant: COC(=O)CCCCCCCCC(=O)c1cc(C)ccc1OC
Agent: BrB(Br)Br
Solvent: O
Solvent: ClCCl
Product: COC(=O)CCCCCCCCC(=O)c1cc(C)ccc1O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 35.7 %

Procedure:
Methyl 10-(2-methoxy-5-methyl-phenyl)-10-oxo-decanoate (1.6 g) was dissolved in methylene chloride (30 ml), 1 M boron tribromide (7.5 ml) was added to the solution at −78° C., and the mixture was stirred at room temperature for 30 min. Water was added to the reaction solution, and the mixture was extracted with chloroform, and the chloroform layer was then washed with water and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by column chromatography using acetone-hexane to give methyl 10-(2-hydroxy-5-methyl-phenyl)-10-oxo-decanoate (546 mg, yield 34%).
Reaction SMILES: [CH2:1]([OH:4])[CH:2]=[CH2:3].[C:5]1(=[O:11])[O:10][C:8](=[O:9])[CH:7]=[CH:6]1.Cl>C(Cl)(Cl)Cl>[CH2:1]([O:4][C:5](=[O:11])/[CH:6]=[CH:7]\[C:8]([OH:10])=[O:9])[CH:2]=[CH2:3]
Reactant: O=C1C=CC(=O)O1
Reactant: C=CCO
Agent: Cl
Solvent: ClC(Cl)Cl
Product: C=CCOC(=O)/C=C\C(=O)O
Yield: 85 %

Procedure:
1.8 ml allyl alcohol (26 mmol, 1.3 eq.) were added to a 2 g solution of maleic anhydride (20 mmol) in chloroform. The reaction mixture was stirred at reflux for 5 h. The resulting solution was treated with 1N HCl and was extracted with chloroform. The organic extracts were washed with a saturated sodium chloride solution, dried on anhydrous magnesium sulfate and filtered. The solvent was evaporated at reduced pressure, and the residue obtained was identified as intermediate VI in the form of an oil (95% purity, 85% yield).
Reaction SMILES: [CH2:1](Br)[CH:2]1[O:6][CH2:5][CH2:4][CH2:3]1.[NH:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1.[I-].[Na+].O1CCCC1>C(OCC)C>[CH2:1]([N:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1)[CH:2]1[O:6][CH2:5][CH2:4][CH2:3]1
Reactant: BrCC1CCCO1
Reactant: C1COCCN1
Agent: [I-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: C1COC(CN2CCOCC2)C1
Yield: 92 %

Procedure:
A mixture of 165 g of tetrahydrofurfuryl bromide, 348 g of morpholine, 5 g of sodium iodide and 500 g of tetrahydrofuran was heated under reflux for 50 hours. After cooling, diethyl ether was added to the reaction solution, which was filtered, concentrated in vacuum and purified by vacuum distillation, whereby 158 g of 4-tetrahydrofurfuryl-morpholine, designated [B-44], was obtained (boiling point 64° C./15 Pa, yield: 92%).
Reaction SMILES: [F:1][C:2]1[C:7](B(O)O)=[CH:6][CH:5]=[CH:4][N:3]=1.C(=O)([O-])[O-].[Na+].[Na+].Br[C:18]1[C:19]([F:46])=[CH:20][C:21]([F:45])=[C:22]([C@:24]23[CH2:33][CH2:32][CH2:31][CH2:30][C@H:29]2[CH2:28][S:27][C:26]([NH:34]C(=O)OCC2C=CC=CC=2)=[N:25]3)[CH:23]=1.I[Si](C)(C)C.C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1.C(Cl)(Cl)Cl.C(OCC)(=O)C.S([O-])([O-])(=O)=S.[Na+].[Na+].C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C(O)(C)C>[F:45][C:21]1[CH:20]=[C:19]([F:46])[C:18]([C:7]2[C:2]([F:1])=[N:3][CH:4]=[CH:5][CH:6]=2)=[CH:23][C:22]=1[C@:24]12[CH2:33][CH2:32][CH2:31][CH2:30][C@H:29]1[CH2:28][S:27][C:26]([NH2:34])=[N:25]2
Reactant: OB(O)c1cccnc1F
Reactant: O=C(NC1=N[C@@]2(c3cc(Br)c(F)cc3F)CCCC[C@H]2CS1)OCc1ccccc1
Agent: [Pd]
Agent: C[Si](C)(C)I
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Solvent: ClC(Cl)Cl
Solvent: CCOC(C)=O
Product: NC1=N[C@@]2(c3cc(-c4cccnc4F)c(F)cc3F)CCCC[C@H]2CS1
Temperature: 85 °C
Reaction time: 9.5 h
Yield: 7.5 %

Procedure:
Isopropyl alcohol (1 mL), 2-fluoro-3-pyridineboronic acid (49.8 mg), a 1 N sodium carbonate solution (354 μL) and bis(tri-tert-butylphosphine)palladium (0) (3.61 mg) were added to a solution of benzyl (±)-[(4aR*,8aS)-8a-(5-bromo-2,4-difluorophenyl)-4a,5,6,7,8,8a-hexahydro-4H-benzo[d][1,3]thiazin-2-yl]carbamate (35 mg) in toluene (2 mL). After replacement with nitrogen, the mixture was stirred at 85° C. for 9.5 hours. The reaction solution was cooled to room temperature, and the solvent was evaporated under reduced pressure. The residue was purified by NH-silica gel column chromatography to obtain an intermediate. The resulting intermediate was dissolved in chloroform (2 mL). Iodotrimethylsilane (30 μL) was added, followed by stirring for 14 hours. The reaction solution was returned to room temperature, and a sodium bicarbonate solution was added to the reaction mixture. The mixture was diluted with ethyl acetate and sodium thiosulfate was added, followed by stirring for 30 minutes. The reaction mixture was extracted with ethyl acetate when it became transparent. The organic layer was washed with brine. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was sequentially purified by NH-pTLC and pTLC to obtain the title compound (2.0 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:8](=O)([O:39]C1C=CC([N+]([O-])=O)=CC=1)[O:9][C@@H:10]1[CH2:14][C@H:13]([C:15]2[N:19]3[C:20]4[CH:26]=[CH:25][N:24]([S:27]([C:30]5[CH:36]=[CH:35][C:33]([CH3:34])=[CH:32][CH:31]=5)(=[O:29])=[O:28])[C:21]=4[N:22]=[CH:23][C:18]3=[N:17][N:16]=2)[C@H:12]([CH2:37][CH3:38])[CH2:11]1>CN(C1C=CN=CC=1)C.O1CCOCC1>[C:2]1([NH:1][C:8](=[O:39])[O:9][C@@H:10]2[CH2:14][C@H:13]([C:15]3[N:19]4[C:20]5[CH:26]=[CH:25][N:24]([S:27]([C:30]6[CH:31]=[CH:32][C:33]([CH3:34])=[CH:35][CH:36]=6)(=[O:29])=[O:28])[C:21]=5[N:22]=[CH:23][C:18]4=[N:17][N:16]=3)[C@H:12]([CH2:37][CH3:38])[CH2:11]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ccccc1
Reactant: CC[C@@H]1C[C@H](OC(=O)Oc2ccc([N+](=O)[O-])cc2)C[C@@H]1c1nnc2cnc3c(ccn3S(=O)(=O)c3ccc(C)cc3)n12
Agent: CN(C)c1ccncc1
Solvent: C1COCCO1
Product: CC[C@@H]1C[C@H](OC(=O)Nc2ccccc2)C[C@@H]1c1nnc2cnc3c(ccn3S(=O)(=O)c3ccc(C)cc3)n12
Reaction time: 2 h
Yield: 63.7 %

Procedure:
To aniline (0.063 g, 0.677 mmol) and DMAP (0.033 g, 0.271 mmol) in 1,4-dioxane (1 mL) at about 40° C. was added a solution of (1S,3R,4S)-3-ethyl-4-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyl 4-nitrophenyl carbonate (0.080 g, 0.135 mmol, prepared from Example #42 Step N) in 1,4-dioxane (1 mL). After about 2 h, the solvent was removed and the residue was purified by silica gel chromatography (12 g) eluting with 0-40% EtOAc in DCM to give (1S,3R,4S)-3-ethyl-4-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyl phenylcarbamate (0.0468 g, 63%): LC/MS (Table 1, Method b) Rt=2.58 min; MS m/z: 545 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[N:11]=[CH:10][C:9]2[C:8](SC)=[N:7][CH:6]=[N:5][C:4]=2[CH:3]=1.[NH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH3:21])[CH:16]=1>>[NH2:1][C:2]1[N:11]=[CH:10][C:9]2[C:8]([NH:14][C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([CH3:21])[CH:16]=3)=[N:7][CH:6]=[N:5][C:4]=2[CH:3]=1
Reactant: Cc1cccc(N)c1
Reactant: CSc1ncnc2cc(N)ncc12
Product: Cc1cccc(Nc2ncnc3cc(N)ncc23)c1
Temperature: 155 °C
Reaction time: 0.5 h
Yield: 66.9 %

Procedure:
A mixture of 7-amino-4-methylthiopyrido[4,3-d]pyrimidine (217 mg, 1.13 mmol) and m-toluidine (1.50 g, 14.0 mmol) is stirred at 155° C. for 30 min. The resulting product is chromatographed over silica gel (5% MeOH/CH2Cl2) to give 7-amino-4-(3-methylanilino)pyrido[4,3-d]pyrimidine (190 mg, 67%) as a pale yellow solid. 1H NMR (DMSO) δ 9.81 (1H, brs), 9.34 (1H, s), 8.38 (1H, s), 7.60 (2H, s), 7.26 (1H, dd, J=8.5, 7.6 Hz), 6.95 (1H, d, J=7.4 Hz), 6.63 (2H, brs), 6.44 (1H, s), 2.33 (3H, s).