Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]3[CH:18]=[CH:17][C:16]([S:19][CH3:20])=[CH:15][CH:14]=3)=[CH:11][C:10](N)=[N:9]2)=[CH:4][CH:3]=1.N(OC(C)(C)C)=O>C(#N)C.O1CCOCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:12]([C:13]3[CH:18]=[CH:17][C:16]([S:19][CH3:20])=[CH:15][CH:14]=3)=[CH:11][CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: CSc1ccc(-c2cc(N)nn2-c2ccc(F)cc2)cc1
Agent: CC(C)(C)ON=O
Solvent: C1COCCO1
Solvent: CC#N
Product: CSc1ccc(-c2ccnn2-c2ccc(F)cc2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 49.1 %

Procedure:
A mixture of 1-(4-fluorophenyl)-5-[4-(methylthio)-phenyl]pyrazol-3-amine (3 g), cupric chloride (1.6 g) and t-butyl nitrite (1.14 g) in acetonitrile (50 ml) and dioxane (20 ml) was stirred at ambient temperature for 4 hours. The insoluble was filtered, and to the filtrate were added ethyl acetate and water. The organic layer was separated, washed with dilute hydrochloric acid, dried and concentrated. The oily residue (3.8 g) was purified by column chromatography on silica gel (40 g) eluting with a mixture of toluene and ethyl acetate (10:1) to give a brown oil of 1-(4-fluorophenyl)-5-[4-(methylthio)phenyl]-pyrazole (1.4 g).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[C:7]2[CH:8]=[CH:9][NH:10][C:11]=2[CH:12]=[CH:13][CH:14]=1.[CH3:15][C:16]1[CH:17]=[CH:18][CH:19]=[C:20]2[C:24]=1[NH:23][CH:22]=[C:21]2[C:25]1[CH2:26][CH2:27][NH:28][CH2:29][CH:30]=1.C([O-])([O-])=O.[K+].[K+]>CN(C)C=O>[CH3:15][C:16]1[CH:17]=[CH:18][CH:19]=[C:20]2[C:24]=1[NH:23][CH:22]=[C:21]2[C:25]1[CH2:26][CH2:27][N:28]([CH2:2][CH2:3][CH2:4][O:5][C:6]2[CH:14]=[CH:13][CH:12]=[C:11]3[C:7]=2[CH:8]=[CH:9][NH:10]3)[CH2:29][CH:30]=1
Reactant: ClCCCOc1cccc2[nH]ccc12
Reactant: Cc1cccc2c(C3=CCNCC3)c[nH]c12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cccc2c(C3=CCN(CCCOc4cccc5[nH]ccc45)CC3)c[nH]c12

Procedure:
The title compound was prepared in a fashion similar to that described in Example 99 using 1-chloro-3-(1H-indole-4-oxy)propane (0.499 g, 2.4 mmol) and 7-methyl-3-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indole (0.509 g, 2.4 mmol) in the presence of 2.0 equivalents of K2CO3 (0.593, 4.3 mmol) in dimethylformamide at 90° C. Yield 0.383 g (41%) of a tan powder. mp 166°-169° C. FDMS m/e=405 (M+ of free base).
Reaction SMILES: [C:1]1([CH3:9])[C:2]([CH:7]=O)=[CH:3][CH:4]=[CH:5][CH:6]=1.C1(P(=[CH:29][C:30]([O:32][CH3:33])=[O:31])(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[CH3:9][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]=[CH:29][C:30]([O:32][CH3:33])=[O:31]
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: Cc1ccccc1C=O
Solvent: C1CCOC1
Product: COC(=O)C=Cc1ccccc1C
Yield: 93.8 %

Procedure:
A solution of 1.20 g of o-tolualdehyde in 20 ml of anhydrous tetrahydrofuran was added to a suspension of 3.67 g of methyl (triphenylphosphoranylidene)acetate in 20 ml of anhydrous tetrahydrofuran at room temperature, and the mixture was refluxed for 15 hours. The solvent was then distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (40 g). Elution with hexane-ethyl acetate (2:1) gave 1.65 g of methyl 2-methylcinnamate.
Reaction SMILES: [I:1]I.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N1C=CC=CC=1.[C:28]([O:32][C:33]([N:35]1[CH2:44][CH2:43][C:42]2[C:37](=[CH:38][C:39]([CH2:45][CH2:46]O)=[CH:40][CH:41]=2)[CH2:36]1)=[O:34])([CH3:31])([CH3:30])[CH3:29]>C1(C)C=CC=CC=1>[C:28]([O:32][C:33]([N:35]1[CH2:44][CH2:43][C:42]2[C:37](=[CH:38][C:39]([CH2:45][CH2:46][I:1])=[CH:40][CH:41]=2)[CH2:36]1)=[O:34])([CH3:31])([CH3:30])[CH3:29]
Reactant: II
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(CCO)cc2C1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCc2ccc(CCI)cc2C1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To 1.21 g (4.76 mmol) iodine in 50 mL toluene is added 1.59 g (4.76 mmol) polymer bound triphenyl-phosphane. The mixture is stirred 5 min at RT and then 0.80 mL (9.92 mmol) pyridine and 1.10 g (3.97 mmol) 7-(2-hydroxy-ethyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester (preparation 7c) is added. The reaction mixture is stirred 5 h at 90° C., is cooled to RT and is filtered. The filtrate is washed with saturated aqueous sodium thiosulfate-solution, brine and dried over MgSO4. After filtration and evaporation of the solvent, the residue is purified via chromatography (silica gel; PE/EtOAc=9:1).
Reaction SMILES: [C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24]([CH:26]=O)[N:25]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:28]=[C:29]1[N:33]([CH2:34][C:35]([OH:37])=[O:36])[C:32](=[O:38])[CH2:31][S:30]1.[NH:39]1[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]1>C(O)C>[O:28]=[C:29]1[N:33]([CH2:34][C:35]([O-:37])=[O:36])[C:32](=[O:38])[C:31](=[CH:26][C:24]2[N:25]=[C:21]([NH:20][C:1]([C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)([C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[S:22][CH:23]=2)[S:30]1.[NH2+:39]1[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]1
Reactant: C1CCNCC1
Reactant: O=C(O)CN1C(=O)CSC1=O
Reactant: O=Cc1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Solvent: CCO
Product: C1CC[NH2+]CC1
Product: O=C([O-])CN1C(=O)SC(=Cc2csc(NC(c3ccccc3)(c3ccccc3)c3ccccc3)n2)C1=O

Procedure:
Following a procedure similar to that described in Example 17, the desired compound was prepared from 2.3 g of 2-tritylaminothiazole-4-carbaldehyde, 0.9 g of 2,4-dioxothiazolidine-3-acetic acid, 0.9 g of piperidine and 20 ml of ethanol. The resulting product was a pale yellow powder having the following physical properties.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][C:11]1[CH:16]=[CH:15][C:14]([CH:17]=[O:18])=[CH:13][CH:12]=1)[C:5]#[N:6].C(=O)([O-])[O-:20].[K+].[K+].OO>CS(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][C:11]1[CH:16]=[CH:15][C:14]([CH:17]=[O:18])=[CH:13][CH:12]=1)[C:5]([NH2:6])=[O:20]
Reactant: O=C([O-])[O-]
Reactant: N#Cc1ccc(Oc2ccc(C=O)cc2)c(Cl)c1
Agent: OO
Agent: [K+]
Solvent: CS(C)=O
Product: NC(=O)c1ccc(Oc2ccc(C=O)cc2)c(Cl)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 166.5 %

Procedure:
Cool a solution of 3-chloro-4-(4-formyl-phenoxy)-benzonitrile (1.57 g, 6.10 mmol) in dimethylsulfoxide (50 mL) to 0° C. Add potassium carbonate (0.42 g, 3.05 mmol) followed by 30% aqueous hydrogen peroxide (1.83 mL, 6.10 mmol). Remove the cooling bath and let stir at rt for 3 hrs. Pour into water (100 mL) and after trituration, filter the solid formed to obtain the product (1.40 g, 84%). 1H NMR (DMSO-d6) 9.93 (s, 1H), 8.12 (d, J=1.2 Hz, 1H), 8.10 (bs, 1H), 7.95-7.90 (m, 3H), 7.53 (bs, 1H), 7.34 (d, J=8.6 Hz, 1H), 7.13 (d, J=8.6 Hz, 2H).
Reaction SMILES: [SH:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.CC(C)([O-])C.[K+].Cl[CH2:18][C:19]#[N:20]>O1CCCC1>[C:19]([CH2:18][S:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1)#[N:20]
Reactant: Sc1nc2ccccc2s1
Reactant: N#CCCl
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: N#CCSc1nc2ccccc2s1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
In a 1 liter flask were combined 33.4 g. (0.2 mole) of 2-mercaptobenzothiazole and 22.4 g. (0.2 mole) of potassium t-butoxide with 300 ml. of tetrahydrofuran. The reaction mass was stirred at room temperature for 15 minutes. Chloroacetonitrile, 16 g. (0.2 mole) was added and the resulting mixture was stirred at room temperature for 1 hour. The mixture was then poured into 400 ml. of benzene and was washed with three 250 ml. portions of water. The benzene phase was dried with anhydrous magnesium sulfate. The solvent was evaporated. There was obtained a yield of 37.2 g. of the title compound, m.p. 75°-77° C.
Reaction SMILES: [CH:1]1([CH2:4][NH:5][C:6]([C:8]2[CH:9]=[CH:10][C:11]([CH3:47])=[C:12]([C:14]3[C:15]4[CH:37]=[CH:36][C:35](=[O:38])[N:34]([C:39]5[C:44]([F:45])=[CH:43][CH:42]=[CH:41][C:40]=5[F:46])[C:16]=4[N:17]=[C:18]([NH:20][CH:21]4[CH2:26][CH2:25][N:24](C(OC(C)(C)C)=O)[CH2:23][CH2:22]4)[N:19]=3)[CH:13]=2)=[O:7])[CH2:3][CH2:2]1.C(O)(C(F)(F)F)=O>C1COCC1>[CH:1]1([CH2:4][NH:5][C:6](=[O:7])[C:8]2[CH:9]=[CH:10][C:11]([CH3:47])=[C:12]([C:14]3[C:15]4[CH:37]=[CH:36][C:35](=[O:38])[N:34]([C:39]5[C:40]([F:46])=[CH:41][CH:42]=[CH:43][C:44]=5[F:45])[C:16]=4[N:17]=[C:18]([NH:20][CH:21]4[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]4)[N:19]=3)[CH:13]=2)[CH2:3][CH2:2]1
Reactant: Cc1ccc(C(=O)NCC2CC2)cc1-c1nc(NC2CCN(C(=O)OC(C)(C)C)CC2)nc2c1ccc(=O)n2-c1c(F)cccc1F
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(C(=O)NCC2CC2)cc1-c1nc(NC2CCNCC2)nc2c1ccc(=O)n2-c1c(F)cccc1F
Reaction time: 12 h

Procedure:
To a solution of 1,1-dimethylethyl 4-{[4-(5-{[(cyclopropylmethyl)-amino]carbonyl}-2-methylphenyl)-8-(2,6-difluorophenyl)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl]amino}-1-piperidinecarboxylate in THF (2 mL) was added TFA (3.0 mL). The reaction mixture was stirred for about 12 h and concentrated. The residue was mixed with H2O (5.0 mL) and EtOAc (20.0 mL) and the resultant mixture was basified with 2.5 N NaOH aqueous (hereinafter “aq”) solution. The organic layer was separated and the aqueous layer was extracted with EtOAc (3×15 mL). The combined organic phases were washed with saturated aq. NaCl, dried over Na2SO4, filtered, and concentrated. Purification via a CombiFlash system (DCM:MeOH=10:1) then afforded the title compound: LC-MS m/z 545 (M+H)+, 1.65 min (ret. time).
Reaction SMILES: [NH2:1][C:2]1[O:6][N:5]=[C:4]([CH3:7])[C:3]=1[Br:8].[C:9]1([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:14]=[CH:13][CH:12]=[C:11]([S:15](Cl)(=[O:17])=[O:16])[CH:10]=1>>[Br:8][C:3]1[C:4]([CH3:7])=[N:5][O:6][C:2]=1[NH:1][S:15]([C:11]1[CH:10]=[C:9]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:14]=[CH:13][CH:12]=1)(=[O:17])=[O:16]
Reactant: Cc1noc(N)c1Br
Reactant: O=S(=O)(Cl)c1cccc(-c2ccccc2)c1
Product: Cc1noc(NS(=O)(=O)c2cccc(-c3ccccc3)c2)c1Br
Yield: 22 %

Procedure:
N-(4-bromo-3-methyl-5-isoxazolyl)-3-biphenylsulfonamide was prepared in the same manner as described in Example 8b from 5-amino-4-bromo-3-methylisoxazole and 3-biphenylsulfonyl chloride in 22% yield. This was purified by HPLC (5% CH3CN to 100% CH3CN over 30 min.) to give a solid., m.p. 78-82° C.
Reaction SMILES: [CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([CH2:27][CH:28]3[CH2:33][CH2:32][O:31][CH2:30][CH2:29]3)[C:14](=O)[CH2:15][CH:16]([CH3:25])[C:17]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=3)=O)=[CH:9][CH:8]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1.C([O-])(=O)C.[NH4+:38]>C(O)(=O)C.C(OCC)(=O)C>[CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([C:14]3[NH:38][C:17]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=4)=[C:16]([CH3:25])[CH:15]=3)[CH2:27][CH:28]3[CH2:33][CH2:32][O:31][CH2:30][CH2:29]3)=[CH:9][CH:8]=2)(=[O:6])=[O:5])[CH2:2][CH2:3]1
Reactant: [NH4+]
Reactant: CC(CC(=O)C(CC1CCOCC1)c1ccc(S(=O)(=O)C2CC2)cc1)C(=O)c1ccccn1
Agent: CC(=O)[O-]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: Cc1cc(C(CC2CCOCC2)c2ccc(S(=O)(=O)C3CC3)cc2)[nH]c1-c1ccccn1
Temperature: 110 °C
Reaction time: 0.5 h
Yield: 81.1 %

Procedure:
To a solution of 5-[4-(cyclopropylsulfonyl)phenyl]-2-methyl-1-(pyridin-2-yl)-6-(tetrahydro-2H-pyran-4-yl)hexane-1,4-dione (180 mg) in acetic acid (5 mL) was added ammonium acetate (472 mg), and the mixture was stirred at 110° C. for 30 min. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate and washed with water. The ethyl acetate layer was washed with saturated aqueous sodium hydrogen carbonate and saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and the title compound (140 mg, yield 81%) was obtained as a colorless amorphous solid from a fraction eluted with ethyl acetate-hexane (2:1, volume ratio). MS: 451 (MH+).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][CH2:7][OH:8])=[CH:4][CH:3]=1.C1C=CN=CC=1.O=S(=O)=O>CS(C)=O.C(Cl)Cl>[OH:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][CH:7]=[O:8])=[CH:4][CH:3]=1
Reactant: OCCc1ccc(O)cc1
Agent: O=S(=O)=O
Solvent: c1ccncc1
Solvent: CS(C)=O
Solvent: ClCCl
Product: O=CCc1ccc(O)cc1
Yield: 49.1 %

Procedure:
4-hydroxyphenylacetaldehyde (15) was synthesized as described in Heterocycles, 2000, 53, 777-784. 4-Hydroxyphenethyl alcohol (Compound 141.0 g, 7.3 mmol, Aldrich) was dissolved in dimethylsulfoxide (8 mL, Aldrich). With stirring, TEA (2.2 mL, 16 mmol, Aldrich) was added slowly. Pyridine-sulfur trioxide (SO3.py) complex (2.5 g, 16 mmol, Aldrich) was completely dissolved in dimethylsulfoxide (9 mL, Aldrich) and this solution was added drop-wise to the alcohol, with vigorous stirring. After stirring for 1 h at room temperature, the reaction was diluted with CH2Cl2, then washed with ice-cold water. The organic layer was dried over Na2SO4, filtered, and concentrated to dryness. Purification using silica gel chromatography with hexane-ethyl acetate as eluent (5:1, then 2:1) yielded 488 mg (49%) of 4-hydroxyphenylacetaldehyde (15).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[C:8]1[S:9][CH:10]=[C:11]([C:13]2[CH:14]=[C:15]([CH:21]=[CH:22][CH:23]=2)[C:16]([O:18]CC)=[O:17])[N:12]=1>[OH-].[Na+]>[CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[C:8]1[S:9][CH:10]=[C:11]([C:13]2[CH:14]=[C:15]([CH:21]=[CH:22][CH:23]=2)[C:16]([OH:18])=[O:17])[N:12]=1
Reactant: CCOC(=O)c1cccc(-c2csc(-c3cnccc3C)n2)c1
Agent: [Na+]
Agent: [OH-]
Product: Cc1ccncc1-c1nc(-c2cccc(C(=O)O)c2)cs1
Yield: 88.8 %

Procedure:
By the reaction in the same manner as in Example 77 using ethyl 3-[2-(4-methylpyridin-3-yl)-1,3-thiazol-4-yl]benzoate (6.50 g) and 1N NaOH (80 ml), the title compound (5.27 g) was obtained as a colorless powder.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:23]=[CH:22][CH:21]=[CH:20][C:4]=1[O:5][CH:6]([CH:14]1[O:19][CH2:18][CH2:17][NH:16][CH2:15]1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[Cl:13].[BH4-].[Na+].[C:26]([O-])(O)=O.[Na+].[C:31](O)(=O)[CH3:32]>CC(C)=O.O>[CH:31]([N:16]1[CH2:17][CH2:18][O:19][CH:14]([CH:6]([O:5][C:4]2[CH:20]=[CH:21][CH:22]=[CH:23][C:3]=2[O:2][CH3:1])[C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[Cl:13])[CH2:15]1)([CH3:32])[CH3:26]
Reactant: O=C([O-])O
Reactant: CC(=O)O
Reactant: COc1ccccc1OC(c1ccccc1Cl)C1CNCCO1
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: COc1ccccc1OC(c1ccccc1Cl)C1CN(C(C)C)CCO1
Temperature: 0 °C
Reaction time: 30 h
Yield: 82.3 %

Procedure:
To a well stirred mixture of 2-[α-(2-methoxy-phenoxy)-2-chloro-benzyl]-morpholine (2 g) in glacial acetic acid (5.2 ml), acetone (12 ml) and water (8 ml), NaBH4 (6.024 g) was added over 1 hour maintaining the temperature near 0° C. Then more acetone (12 ml) and NaBH4 (3 g) were added; the temperature was allowed to rise to room temperature and after 30 hours the reaction mixture was poured into a solution of NaHCO3 in water, then extracted with diethyl ether. The ethereal extracts were washed with water, dried over Na2SO4 and evaporated to dryness to give 4-isopropyl-2-[α-(2-methoxy-phenoxy)-2-chloro-benzyl]-morpholine (1.85 g; yield 82.3%) .HCl m.p. 200°-240° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([C:11](O)=O)[CH3:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:14][C:15]1[C:20]([Cl:21])=[CH:19][CH:18]=[CH:17][C:16]=1[SH:22]>O1CCCC1>[C:1]([O:5][C:6]([NH:8][C@@H:9]([C:11]1[S:22][C:16]2[CH:17]=[CH:18][CH:19]=[C:20]([Cl:21])[C:15]=2[N:14]=1)[CH3:10])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Nc1c(S)cccc1Cl
Reactant: C[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Solvent: C1CCOC1
Product: C[C@@H](NC(=O)OC(C)(C)C)c1nc2c(Cl)cccc2s1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 52 %

Procedure:
18.4 g of N,N'-carbonyldiimidazole was gradually added to a solution containing 20.5 g of N-tert-butoxycarbonyl-D-alanine dissolved in 200 mL of tetrahydrofuran, and the reaction mixture was stirred for 30 minutes at room temperature. 16.5 g of 2-amino-3-chlorothiophenol was added to the reaction mixture, and the whole mixture was refluxed for 3 hours. After completion of the reaction, the resulting mixture was poured into ice-cold water. The organic layer was extracted with ethyl acetate, washed using water, and then dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel, thus yielding 16.8 g of (R)-N-tert-butoxycarbonyl-1-(4-chloro-2-benzothiazolyl)ethylamine (melting point: 95°~96° C.). Furthermore, a hydrogen chloride gas was bubbled into a solution containing 10 g of the crystals obtained above dissolved in 50 mL of methylene chloride, for 3 hours at room temperature. After completion of the reaction, the reaction mixture was extracted with water, and was made basic using a saturated aqueous solution of sodium bicarbonate. The solution was extracted with ethyl acetate, washed with water, and then dried over anhydrous magnesium sulfate, followed by concentration under reduced pressure. The residue was purified by column chromatography on silica gel to afford 5.7 g (yield 84%) of the desired product.
Reaction SMILES: [ClH:1].CC([N:6]([C:10]1([C:16]([NH:18][C@@H:19]([CH2:33][CH:34]([CH3:36])[CH3:35])/[CH:20]=[CH:21]/[C:22]([N:24]2[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH2:26][CH2:25]2)=[O:23])=[O:17])[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1)C(=O)[O-])(C)C>C(O)(C)C>[ClH:1].[NH2:6][C:10]1([C:16]([NH:18][C@@H:19]([CH2:33][CH:34]([CH3:36])[CH3:35])/[CH:20]=[CH:21]/[C:22]([N:24]2[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH2:26][CH2:25]2)=[O:23])=[O:17])[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1
Reactant: CC(C)C[C@@H](/C=C/C(=O)N1CCc2ccccc21)NC(=O)C1(N(C(=O)[O-])C(C)(C)C)CCOCC1
Agent: Cl
Solvent: CC(C)O
Product: CC(C)C[C@@H](/C=C/C(=O)N1CCc2ccccc21)NC(=O)C1(N)CCOCC1
Temperature: 65 °C
Reaction time: 0.75 h
Yield: 59.9 %

Procedure:
A solution of concentrated aq. HCl (0.22 mL, 2.64 mmol) was added to a solution of 1,1-dimethylethyl[4-({[(1S,2E)-4-(2,3-dihydro-1H-indol-1-yl)-1-(2-methylpropyl)-4-oxo-2-buten-1-yl]amino}carbonyl)tetrahydro-2H-pyran-4-yl]carbamate (251 mg, 0.517 mmol) in isopropanol (2.5 mL). The reaction flask was fitted with an air condenser, and the reaction mixture was heated to 65° C. (bath temp). After 1 h 45 min, the solvent was evaporated under reduced pressure at 60° C. Water (5 mL) was added to the residue, and the mixture was concentrated under reduced pressure at 65° C. Water (2 mL) was added to the residue, and the mixture was lyophilized, giving 130.6 mg (60%) of the title compound. LC-MS m/z 386 (M+H)+, 0.79 (ret time). 1H NMR (400 MHz, METHANOL-d4) δ ppm 8.15 (d, J=7.03 Hz, 1H); 7.25 (d, J=7.03 Hz, 1H); 7.18 (t, J=7.65 Hz, 1H); 7.06 (t, J=7.91 Hz, 1H); 6.81 (dd, J=15.18, 6.40 Hz, 1H); 6.49 (br. s., 1H); 4.73-4.85 (m, 2H); 4.21 (t, J=8.28 Hz, 2H); 3.91-3.97 (m, 2H); 3.70-3.77 (m, 2H); 3.25-3.21 (m, 2H); 2.35-2.48 (m, 2H); 1.82 (d, J=14.31 Hz, 2H); 1.63-1.71 (m, 2H); 1.50-1.57 (m, 1H); 0.98 (dd, J=11.92, 6.40 Hz, 6H).
Reaction SMILES: [CH2:1]([O:3][C@H:4]1[CH2:11][C@:7]2([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[F:18])[NH:8][O:9][CH2:10][C@@H:6]2[CH2:5]1)[CH3:2].C(=O)(O)[O-].[Na+].C(OCC)(=O)C>C(O)(=O)C.[Zn]>[NH2:8][C@@:7]1([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[F:18])[CH2:11][C@H:4]([O:3][CH2:1][CH3:2])[CH2:5][C@H:6]1[CH2:10][OH:9]
Reactant: CCO[C@@H]1C[C@H]2CON[C@@]2(c2ccccc2F)C1
Agent: O=C([O-])O
Agent: [Na+]
Agent: [Zn]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CCO[C@@H]1C[C@@H](CO)[C@](N)(c2ccccc2F)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.2 %

Procedure:
Zinc (3.68 g) was added to a solution of (3aR*,5R*,6aS*)-5-ethoxy-6a-(2-fluorophenyl)hexahydrocyclopenta[c]isoxazole (540 mg) in acetic acid (15 mL), and the mixture was stirred at room temperature for two hours. A saturated sodium bicarbonate solution and ethyl acetate were added to the reaction solution, and zinc was removed by filtration. The filtrate was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate. The drying agent was removed by filtration and the filtrate was concentrated under reduced pressure to obtain the title compound (540 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[N:13]([CH3:17])[C:12](=[O:18])[CH2:11]3)[CH:5]=[N:6][CH:7]=1.C(N(C(C)C)CC)(C)C.[CH3:28][S:29](Cl)(=[O:31])=[O:30].[OH-].[Na+].Cl>ClCCl.O>[CH3:17][N:13]1[C:14]2[C:10](=[CH:9][C:8]([C:4]3[CH:3]=[C:2]([NH:1][S:29]([CH3:28])(=[O:31])=[O:30])[CH:7]=[N:6][CH:5]=3)=[CH:16][CH:15]=2)[CH2:11][C:12]1=[O:18]
Reactant: CN1C(=O)Cc2cc(-c3cncc(N)c3)ccc21
Reactant: CS(=O)(=O)Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CN1C(=O)Cc2cc(-c3cncc(NS(C)(=O)=O)c3)ccc21
Temperature: -10 °C
Reaction time: 0.17 h

Procedure:
To a solution of 5-(5-amino-pyridin-3-yl)-1-methyl-1,3-dihydro-indol-2-one, prepared as described in Example 3, (35 mg, 0.146 mmol), in dichloromethane (2.0 mL) was added diisopropylethylamine (75 pt, 0.44 mmol). The reaction was cooled to −10° C. and methanesulfonyl chloride (22 μL, 0.28 mmol) was added. After 15 minutes the reaction was quenched with saturated aqueous sodium bicarbonate and diluted with dichloromethane. The layers were separated and the organic layer was dried over sodium sulfate, filtered and concentrated. The resulting residue was dissolved in methanol (5 mL) and treated with 2 M aqueous sodium hydroxide (0.5 mL, 1 mmol) and permitted to stir at room temperature for 10 minutes. The reaction was then diluted with dichloromethane and water and the pH of the solution was brought to ca. 7 via the careful addition of 1M aqueous HCl. The layers were separated and the aqueous layer was extracted four additional times with dichloromethane and one time with ethyl acetate. The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated. The resulting residue was purified by silica gel flash chromatography (ethanol-dichloromethane, 0 to 7%) to furnish N-[5-(1-methyl-2-oxo-2,3-dihydro-1H-indol-5-yl)-pyridin-3-yl]-methanesulfonamide; HRMS: (ES+) m/z 318.0912 (M+H)+; 1H NMR (400 MHz, CDCl3) δ ppm 3.11 (s, 3H), 3.28 (s, 3H), 3.62 (s, 2H), 6.94 (d, J=8.1 Hz, 1H), 7.50 (s, 1H), 7.51-7.59 (m, 1H), 7.91 (s, 1H), 8.41 (d, J=2.5 Hz, 1H), 8.67 (d, J=1.8 Hz, 1H).
Reaction SMILES: Cl.[NH2:2][OH:3].C(=O)([O-])O.[Na+].[NH2:9][C:10]1[N:15]=[C:14]([NH2:16])[C:13]([O:17][C:18]2[C:19]([CH:28]([CH3:30])[CH3:29])=[CH:20][C:21]([O:26][CH3:27])=[C:22]([CH:25]=2)[C:23]#[N:24])=[CH:12][N:11]=1>C(O)C.O>[NH2:9][C:10]1[N:15]=[C:14]([NH2:16])[C:13]([O:17][C:18]2[C:19]([CH:28]([CH3:30])[CH3:29])=[CH:20][C:21]([O:26][CH3:27])=[C:22]([CH:25]=2)[C:23]([NH:2][OH:3])=[NH:24])=[CH:12][N:11]=1
Reactant: NO
Reactant: COc1cc(C(C)C)c(Oc2cnc(N)nc2N)cc1C#N
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: COc1cc(C(C)C)c(Oc2cnc(N)nc2N)cc1C(=N)NO
Yield: 82.8 %

Procedure:
The benzamidination carried out in this step follows the procedure reported by Meyer et al., Synthesis 2003, 6, pp. 899-905. To a stirred mixture of hydroxylamine hydrochloride (0.099 g, 1.43 mmol) and sodium hydrogen carbonate (0.119 g, 1.42 mmol) in ethanol (1.4 ml) and water (0.3 ml) was added 5-(2,4-diamino-pyrimidin-5-yloxy)-4-isopropyl-2-methoxy-benzonitrile (0.385 g, 1.29 mmol) and the mixture heated at reflux for 5 hours. A second portion of hydroxylamine hydrochloride (0.049 g, 0.71 mmol) and sodium hydrogen carbonate (0.060 g, 0.71 mmol) was added. After a further 2 hours the mixture was cooled, concentrated in vacuo, then diluted with water (10 ml) and extracted with ethyl acetate. The combined organic extracts were washed with brine then dried (MgSO4), filtered and concentrated in vacuo to yield 5-(2,4-diamino-pyrimidin-5-yloxy)-N-hydroxy-4-isopropyl-2-methoxy-benzamidine (355 mg) as a yellow foam. This material was used directly without further purification.