Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Li].[C:2]([O:6][C:7](=[O:15])[NH:8][C:9]1[CH:13]=[CH:12][S:11][C:10]=1Br)([CH3:5])([CH3:4])[CH3:3].[CH3:16][Sn:17](Cl)([CH3:19])[CH3:18].[CH2:21]1[CH2:25]OC[CH2:22]1>>[C:2]([O:6][C:7](=[O:15])[NH:8][C:9]1[CH:13]=[CH:12][S:11][C:10]=1[Sn:17]([CH2:19][CH2:22][CH2:21][CH3:25])([CH2:18][CH2:10][CH2:9][CH3:13])[CH2:16][CH2:3][CH2:2][CH3:4])([CH3:5])([CH3:4])[CH3:3]
Reactant: C1CCOC1
Reactant: C[Sn](C)(C)Cl
Reactant: CC(C)(C)OC(=O)Nc1ccsc1Br
Agent: [Li]
Product: CCCC[Sn](CCCC)(CCCC)c1sccc1NC(=O)OC(C)(C)C
Reaction time: 0.75 h

Procedure:
Add n-buthyl lithium (19.8 ml, 1.6 M/hexane) dropwise to a solution 2-Bromothiophen-3-yl-carbamic acid tert-butyl ester (4 g, 14.4 mmol) in anhydrous THF (35 ml) at −78° C. Stir the mixture for 45 minutes and add trimethyltin chloride (3.16 g, 15.8 mmol). Allow the reaction mixture to reach room temperature. Add brine (aprox. 50 mL) and extract with ethyl acetate (2×50 mL). Dry the combined organic layers over magnesium sulfate and concentrate under vacuum yielding 4.9 g of the title compound as colorless oil: 1H NMR (CDCl3, 300 MHZ) δ: 7.49 (d, J=4.8 Hz, 1H), 7.13 (d, J=4.4 Hz, 1H), 1.49 (s, 9H), 0.36 (s, 9H).
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][CH:5]([N:8]2[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[NH:10][C:9]2=[O:17])[CH2:4][CH2:3]1.[N:18]1[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([NH:26][CH:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)=[O:25])[CH:19]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])([O-])=O.[Na+].[Na+]>C(Cl)(Cl)Cl.C(O)(=O)C.ClCCCl>[N:18]1[CH:19]=[C:20]([C:24]([NH:26][CH:27]2[CH2:28][CH2:29][N:30]([C@H:2]3[CH2:7][CH2:6][C@H:5]([N:8]4[C:12]5[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=5[NH:10][C:9]4=[O:17])[CH2:4][CH2:3]3)[CH2:31][CH2:32]2)=[O:25])[CH:21]=[CH:22][CH:23]=1
Reactant: O=C(NC1CCNCC1)c1cccnc1
Reactant: O=C1CCC(n2c(=O)[nH]c3ccccc32)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Solvent: ClCCCl
Product: O=C(NC1CCN([C@H]2CC[C@H](n3c(=O)[nH]c4ccccc43)CC2)CC1)c1cccnc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A mixture of 0.13 g of 1,3-dihydro-1-(4-oxocyclohexyl)-2H-benzimidazol-2-one, 0.12 g of 4-(3-pyridinecarbonylamino)piperidine, 5 mL of 1,2-dichloroethane, 0.04 mL of glacial acetic acid and 0.161 g of sodium triacetoxyborohydride was stirred at room temperature for 48 h. The reaction mixture was poured into 50 mL chloroform and 50 mL saturated aqueous Na2CO3 and the layers separated. The aqueous layer was extracted with 2×25 mL of chloroform and the combined organic layers dried over MgSO4 and concentrated under reduced pressure. Chromatography of the crude product on silica gel, eluting with 10% methanol in choroform gave 0.015 g of 1,3-dihydro-1-{trans-4-[4-(5-pyridinecarbonylamino)piperidin-1-yl]-1-cyclohexyl}-2H-benzimidazol-2-one: 1H NMR (400 MHz, CDCl3) 9.01 (d, J=2 Hz, 1H), 8.75 (dd, J=2 and 4.5 Hz, 1H), 8.40 (br s, 1H), 8.16 (dd, J=2 and 8 Hz, 1H), 7.43 (m, 2H), 7.08 (m, 3H), 6.16 (br m, 1H), 4.47 (m, 1H), 4.12 (m, 2H), 3.1 (br s, 2H), 2.8 (m, 1H), 2.5 (m, 1H), 2.2 (br m, 4H), 1.60 (br m, 8H). The dihydrochloride salt was precipitated from ether: Analysis calculated for C24H29N5O2.2HCl.0.75 CHCl3.1.0 H2O C: 49.54, H: 5.67, N: 11.67 found C: 49.55, H: 5.85, N: 11.88.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([C@H:22]([CH3:30])[CH2:23][CH2:24][CH2:25][CH:26]([CH3:29])[CH:27]=[CH2:28])[C:10]([N:12]1[CH2:16][C@H:15]([OH:17])[CH2:14][C@H:13]1[C:18]([O:20]C)=[O:19])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].CO.[Li+].[OH-]>C1COCC1.O>[C:1]([O:5][C:6]([NH:8][C@@H:9]([C@H:22]([CH3:30])[CH2:23][CH2:24][CH2:25][CH:26]([CH3:29])[CH:27]=[CH2:28])[C:10]([N:12]1[CH2:16][C@H:15]([OH:17])[CH2:14][C@H:13]1[C:18]([OH:20])=[O:19])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C=CC(C)CCC[C@@H](C)[C@H](NC(=O)OC(C)(C)C)C(=O)N1C[C@H](O)C[C@H]1C(=O)OC
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: C=CC(C)CCC[C@@H](C)[C@H](NC(=O)OC(C)(C)C)C(=O)N1C[C@H](O)C[C@H]1C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 77.6 %

Procedure:
To a solution of (2S,4R)-methyl 1-((2S,3R)-2-(tert-butoxycarbonylamino)-3,7-dimethylnon-8-enoyl)-4-hydroxypyrrolidine-2-carboxylate (4.3 g, 10 mmol) in THF/water (30 mL, 1:1) was added methanol (10 mL) followed by LiOH (1.3 g, 0.030 moles) at room temperature. The reaction mass was stirred at room temperature overnight. Solvent was evaporated under reduced pressure and the residue was diluted with water (100 mL). The aqueous solution was acidified with aqueous 1.5 N HCl solutions to pH˜3 and extracted with ethyl acetate (100 mL×3). The combined organic layer was dried over anhydrous Na2SO4 and concentrated under reduce pressure to get the desired product (2S,4R)-((2S,3R)-2-(tert-butoxycarbonylamino)-3,7-dimethylnon-8-enoyl)-4-hydroxypyrrolidine-2-carboxylic acid (3.2 g, 78% yield) as a white solid. 1H NMR (400 MHz, CDCl3): δ ppm 5.70-5.61 (m, 1H), 5.14-5.12 (d, J=8.8 Hz, 1H), 4.96-4.88 (m, 2H), 4.82-4.78 (t, J=8.4 Hz, 1H), 4.52 (bs, 1H), 4.27-4.23 (m, 1H), 3.57-3.53 (m, 3H), 2.48-2.42 (m, 1H), 2.33-2.28 (m, 1H), 1.88-1.82 (m, 2H), 1.45-1.42 (s, 9H), 1.29-1.21 (m, 3H), 0.98-0.93 (m, 7H) MS: MS m/z 411.2 (M++1).
Reaction SMILES: [C:1]([O:4][CH2:5][C@@:6]([NH:26]C(=O)C)([CH3:25])[CH2:7][CH2:8][C:9]1[O:10][C:11]([C:14]#[C:15][CH2:16][CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:12][CH:13]=1)(=[O:3])[CH3:2].O1CCCC1.CO.[OH2:37].[OH-:38].[Li+]>O>[C:2]([OH:38])(=[O:37])[C:1]([OH:4])=[O:3].[NH2:26][C@:6]([CH3:25])([CH2:7][CH2:8][C:9]1[O:10][C:11]([C:14]#[C:15][CH2:16][CH2:17][CH2:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[CH:12][CH:13]=1)[CH2:5][OH:4]
Reactant: O
Reactant: CC(=O)N[C@](C)(CCc1ccc(C#CCCCc2ccccc2)o1)COC(C)=O
Reactant: [OH-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CO
Product: C[C@](N)(CO)CCc1ccc(C#CCCCc2ccccc2)o1
Product: O=C(O)C(=O)O
Yield: 149.6 %

Procedure:
To a solution of (2R)-1-acetoxy-2-acetylamino-2-methyl-4-[5-(5-phenylpent-1-ynyl)furan-2-yl]butane (0.2710 g, 0.69 mmol) obtained in Example (1a) in a mixed solvent of tetrahydrofuran (1.4 ml) and methanol (1.4 ml) were added successively water (1.4 ml) and lithium hydroxide monohydrate (0.2854 g, 6.80 mmol) with stirring, and the resulting mixture was stirred at 50° C. for 4 hours. After cooling, water was added to the reaction mixture, and the resulting mixture was extracted with dichloromethane. The extract was washed with saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate. After filtration, the solvent was removed in vacuo, and the residue was purified by chromatography on a basic silica gel column (NH type) using a mixed solvent of dichloromethane and methanol (100:1) as the eluent to afford the crude (2R)-2-amino-2-methyl-4-[5-(5-phenylpent-1-ynyl)furan-2-yl]butan-1-ol (0.2072 g).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[Cl:13][C:14]1[C:15]([CH:21]2[CH2:23][CH2:22]2)=[N:16][CH:17]=[C:18]([Cl:20])[N:19]=1.[C:24](=[O:26])=[O:25].Cl>O1CCCC1>[Cl:20][C:18]1[C:17]([C:24]([OH:26])=[O:25])=[N:16][C:15]([CH:21]2[CH2:23][CH2:22]2)=[C:14]([Cl:13])[N:19]=1
Reactant: O=C=O
Reactant: Clc1cnc(C2CC2)c(Cl)n1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: O=C(O)c1nc(C2CC2)c(Cl)nc1Cl
Temperature: -100 °C
Reaction time: 0.17 h
Yield: 97.9 %

Procedure:
Under an argon atmosphere, to a mixture of tetrahydrofuran (6 mL) and diisopropylamine (258 μL) was added dropwise n-butyllithium (1.62 M n-hexane solution, 1.04 mL) under ice-cooling. After cooling to −100° C., a mixture of 3,5-dichloro-2-cyclopropylpyrazine (290 mg) and tetrahydrofuran (2 mL) was added dropwise thereto, followed by stirring for 10 minutes. The obtained reactant was added to dry ice (10 g) and tetrahydrofuran (5 mL), followed by stirring for 30 minutes in a water bath. To the reactant were added 1 M hydrochloric acid and a saturated aqueous ammonium chloride solution, followed by extraction with ethyl acetate. The organic phase was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to obtain 3,5-dichloro-6-cyclopropylpyrazine-2-carboxylic acid (350 mg) as an oily material.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C@H:13]([OH:14])[C@@H:12]([OH:15])[C@H:11]([OH:16])[C@@H:10]([CH2:17][OH:18])[O:9]2)=[CH:4][C:3]=1[CH2:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH2:27][CH3:28])=[CH:22][CH:21]=1.[C:29](Cl)([C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>N1C=CC=CC=1.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C@H:13]([OH:14])[C@@H:12]([OH:15])[C@H:11]([OH:16])[C@@H:10]([CH2:17][O:18][C:29]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)([C:42]3[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=3)[C:36]3[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=3)[O:9]2)=[CH:4][C:3]=1[CH2:19][C:20]1[CH:21]=[CH:22][C:23]([O:26][CH2:27][CH3:28])=[CH:24][CH:25]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCOc1ccc(Cc2cc([C@@H]3O[C@H](CO)[C@@H](O)[C@H](O)[C@H]3O)ccc2Cl)cc1
Solvent: O
Solvent: c1ccncc1
Product: CCOc1ccc(Cc2cc([C@@H]3O[C@H](COC(c4ccccc4)(c4ccccc4)c4ccccc4)[C@@H](O)[C@H](O)[C@H]3O)ccc2Cl)cc1
Yield: 88 %

Procedure:
To a mixture of (2S,3R,4R,5S,6R)-2-[4-chloro-3-(4-ethoxy-benzyl)-phenyl]-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol (7.0 g, 17.1 mmole) (prepared according to procedure as described in J. Med. Chem. 2008; 51 (5); 1145-1149), trityl chloride (5.2 g, 18.8 mmole) in pyridine (50 mL) was added at room temperature and refluxed for 18 hrs. The excess pyridine was evaporated; reaction mixture was diluted with water (250 mL) and washed with 1N dil. HCl (50 mL) extracted with dichloromethane (2×200 mL). The crude product obtained after the removal of solvent was purified using silica gel column chromatography (0.5% methanol in DCM) to furnish 9.8 g of (2S,3R,4R,5S,6R)-2-[4-Chloro-3-(4-ethoxy-benzyl)-phenyl]-6-trityloxymethyl-tetrahydro-pyran-3,4,5-triol.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[C:7]([Cl:24])[CH:8]=[C:9]2[C:14]=1[NH:13][CH:12]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([NH2:21])[CH:16]=1)[C:11]([CH3:23])([CH3:22])[CH2:10]2)=[O:4].Cl>CO.O1CCCC1.[OH-].[Na+].O>[NH2:21][C:17]1[CH:16]=[C:15]([CH:12]2[C:11]([CH3:23])([CH3:22])[CH2:10][C:9]3[C:14](=[C:5]([C:3]([OH:4])=[O:2])[CH:6]=[C:7]([Cl:24])[CH:8]=3)[NH:13]2)[CH:20]=[CH:19][CH:18]=1
Reactant: COC(=O)c1cc(Cl)cc2c1NC(c1cccc(N)c1)C(C)(C)C2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CC1(C)Cc2cc(Cl)cc(C(=O)O)c2NC1c1cccc(N)c1
Temperature: 60 °C
Reaction time: 12 h
Yield: 98.6 %

Procedure:
A mixture of 2-(3-amino-phenyl)-6-chloro-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-8-carboxylic acid methyl ester (0.8 g, 2.3 mmol) in methanol (50 mL) and tetrahydrofuran (100 mL), 30% sodium hydroxide in water (20 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 (2×100 mL), washed with water, dried over anhydrous sodium sulfate and then concentrated in vacuo to afford 2-(3-amino-phenyl)-6-chloro-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-8-carboxylic acid (0.75 g, 65%) as a brown solid which was used for next step without further purification: LC/MS m/e calcd for C18H19ClN2O2 (M+H)+: 331.82, observed: 331.1.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]([P:15]([O:20][CH2:21][CH3:22])([O:17][CH2:18][CH3:19])=[O:16])([F:14])[F:13])[CH:8]=[C:7]([CH2:23]P(=O)(OCC)OCC)[CH:6]=[CH:5]2.[CH:32]([C:34]1[CH:35]=[C:36]([CH:41]=[CH:42][CH:43]=1)[C:37]([O:39][CH3:40])=[O:38])=O.CC(C)([O-])C.[K+]>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]([P:15]([O:17][CH2:18][CH3:19])([O:20][CH2:21][CH3:22])=[O:16])([F:14])[F:13])[CH:8]=[C:7](/[CH:23]=[CH:32]/[C:34]1[CH:35]=[C:36]([CH:41]=[CH:42][CH:43]=1)[C:37]([O:39][CH3:40])=[O:38])[CH:6]=[CH:5]2
Reactant: CCOP(=O)(Cc1ccc2cc(Br)c(C(F)(F)P(=O)(OCC)OCC)cc2c1)OCC
Reactant: COC(=O)c1cccc(C=O)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCOP(=O)(OCC)C(F)(F)c1cc2cc(/C=C/c3cccc(C(=O)OC)c3)ccc2cc1Br
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of diethyl {6-bromo-7-[(diethoxyphosphoryl)(difluoro)methyl]-2-naphthyl}methylphosphonate (190 mg), and methyl 3-formylbenzoate (60 mg) in degassed THF (5 mL) at −78° C. was added potassium tert-butoxide (0.35 mL of a 1M solution in THF) and the reaction mixture was stirred for 1 h at 0° C. The mixture was quenched with a saturated solution of NH4Cl, extracted with EtOAc, dried over Na2SO4 and evaporated to dryness. The residue was purified by flash chromatography eluting with 25% EtOAc/hexanes to afford the titled product.
Reaction SMILES: Cl.[N:2]1([C:8]([NH2:10])=[O:9])[CH2:7][CH2:6][O:5][CH2:4][CH2:3]1.[NH2:11][CH:12]1[CH2:20][C:19]2[C:14](=[CH:15][CH:16]=[C:17]([C:21]([OH:23])=[O:22])[CH:18]=2)[CH2:13]1.C(N(CC)CC)C.Cl[C:32]1[C:33]2[C:40]([CH3:41])=[CH:39][S:38][C:34]=2[N:35]=[CH:36][N:37]=1>C(O)C>[N:2]1([C:8]([NH2:10])=[O:9])[CH2:7][CH2:6][O:5][CH2:4][CH2:3]1.[CH3:41][C:40]1[C:33]2[C:32]([NH:11][CH:12]3[CH2:20][C:19]4[C:14](=[CH:15][CH:16]=[C:17]([C:21]([OH:23])=[O:22])[CH:18]=4)[CH2:13]3)=[N:37][CH:36]=[N:35][C:34]=2[S:38][CH:39]=1
Reactant: NC1Cc2ccc(C(=O)O)cc2C1
Reactant: Cc1csc2ncnc(Cl)c12
Agent: Cl
Agent: NC(=O)N1CCOCC1
Solvent: CCN(CC)CC
Solvent: CCO
Product: Cc1csc2ncnc(NC3Cc4ccc(C(=O)O)cc4C3)c12
Yield: 63 %

Procedure:
Using 2-aminoindan-5-carboxylic acid morpholinamide hydrochloride (750 mg, 2.7 mmol), ethanol (23 ml), triethylamine (1.1 ml, 8.2 mmol), and 4-chloro-5-methylthieno[2,3-d]pyrimidine (500 mg, 2.7 mmol), a similar procedure to b) in Production Example 208 was carried out. The product obtained was purified by silica gel chromatography (methylene chloride:methanol=95:5) to yield a fraction, which was then washed with ether to obtain the title compound (680 mg, 1.7 mmol) having the following physical properties:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:12]2[C:16]([C:17]3[CH:22]=[CH:21][C:20]([C:23]4[O:24][CH:25]=[CH:26][CH:27]=4)=[CH:19][CH:18]=3)=[CH:15][C:14]([C:28](O)=[O:29])=[N:13]2)[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].O.C(OCC)(=O)C>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([N:12]2[C:16]([C:17]3[CH:18]=[CH:19][C:20]([C:23]4[O:24][CH:25]=[CH:26][CH:27]=4)=[CH:21][CH:22]=3)=[CH:15][C:14]([CH2:28][OH:29])=[N:13]2)[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:9])=[O:10]
Reactant: CS(=O)(=O)c1ccc(-n2nc(C(=O)O)cc2-c2ccc(-c3ccco3)cc2)cc1F
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CS(=O)(=O)c1ccc(-n2nc(CO)cc2-c2ccc(-c3ccco3)cc2)cc1F
Temperature: 25 °C
Reaction time: 3 h
Yield: 52.6 %

Procedure:
To a solution of 1-[3-fluoro-4-(methylsulfonyl)phenyl]-5-[4-(2-furyl)phenyl]-1H-pyrazole-3-carboxylic acid (0.1 g, 0.235 mmol) in THF (2 mL) at 0° C. was added dropwise 1M borane-THF complex (0.7 mL). The mixture was stirred at room temperature for 3 hours. The solution was added water (1 mL) and ethyl acetate (20 mL), and the mixture was washed with 1N HCl, saturated NaHCO3, and brine, dried over MgSO4, filtered, and concentrated in vacuo. The crude mixture was purified by flash chromatography eluting with hexane/ethyl acetate (1/1) to give the title compound (0.051 g, 52.6% yield).
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[C:12]2[C:7]([CH:8]=[CH:9][N+:10]([O-])=[CH:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].P(Cl)(Cl)([Cl:17])=O.C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1>[Cl:17][C:11]1[C:12]2[C:7](=[CH:6][CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:13]=2)[CH:8]=[CH:9][N:10]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=[N+]([O-])c1ccc2cc[n+]([O-])cc2c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: O=[N+]([O-])c1ccc2ccnc(Cl)c2c1
Temperature: 90 °C
Yield: 14 %

Procedure:
To a suspension of 7-nitroisoquinoline N-oxide obtained in Preparation Example 1-5, Step 3 in toluene (185 ml) was added phosphorus oxychloride (3.5 ml, 37 mmol), and the mixture was stirred under heating at 90° C. for 2 hr. The reaction mixture was cooled to room temperature and the reaction mixture was poured into an aqueous sodium hydrogencarbonate solution. The aqueous layer was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:acetone=30:1) to give 1-chloro-7-nitroisoquinoline (540 mg, 14%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH2:9])[CH:5]=[CH:6][C:7]=1[CH3:8].[C:10]1(B(O)O)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C([O-])([O-])=O.[Na+].[Na+].C(O)C>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1(C)C=CC=CC=1>[CH3:8][C:7]1[C:2]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:3][C:4]([NH2:9])=[CH:5][CH:6]=1
Reactant: Cc1ccc(N)cc1Br
Reactant: OB(O)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: Cc1ccc(N)cc1-c1ccccc1
Temperature: 25 °C
Yield: 47.1 %

Procedure:
To a dried flask was added 3-bromo-4-methyl-phenylamine (1 g, 5.37 mmol), phenyl boronic acid (2.62 g, 21.5 mmol), aqueous Na2CO3 (2M, 21.5 mL, 43 mmol), ethanol (21.5 mL), and toluene (43 mL). The flask was sparged with Ar, and Pd(PPh3)4 (1.55 g, 1.34 mmol) was added. The reaction mixture was stirred and heated at 80° for 18 hrs, then cooled to room temperature. The solvent was removed in vacuo and the residue was dissolved in ethyl acetate. The organic layer was washed with water and brine, then dried over MgSO4. The solvent was removed in vacuo and the residue was purified via column chromatography (SiO2, 5% DCM/hexane) to afford a yellow oil (463 mg, 47%). This was directly used in the next step.
Reaction SMILES: [C:1]([NH:8][C@H:9]([C@H:17]1[O:21][C:20](=[O:22])[C@H:19]([CH2:23][C:24]2[CH:29]=[CH:28][C:27]([O:30][CH2:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)=[CH:26][CH:25]=2)[CH2:18]1)[CH2:10][CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[Li+].[OH-:39]>COCCOC>[C:1]([NH:8][C@@H:9]([CH2:10][CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)[C@@H:17]([OH:39])[CH2:18][C@@H:19]([CH2:23][C:24]1[CH:25]=[CH:26][C:27]([O:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[CH:28][CH:29]=1)[C:20]([OH:21])=[O:22])([O:3][C:4]([CH3:6])([CH3:5])[CH3:7])=[O:2]
Reactant: CC(C)(C)OC(=O)N[C@@H](CC1CCCCC1)[C@@H]1C[C@@H](Cc2ccc(OCc3ccccc3)cc2)C(=O)O1
Reactant: [OH-]
Agent: [Li+]
Solvent: COCCOC
Product: CC(C)(C)OC(=O)N[C@@H](CC1CCCCC1)[C@@H](O)C[C@@H](Cc1ccc(OCc2ccccc2)cc1)C(=O)O

Procedure:
Analogously to Example 1 h), 2.4 g (4.728 mmol) of 5(S)-[1(S)-(Boc-amino)-2-cyclohexylethyl]-3(R)-(4-benzyloxy-benzyl)-dihydrofuran-2-(3H)-one in 10 ml of 1,2-dimethoxyethane are reacted with 9.45 ml of 1M LiOH solution to give the title compound. The title compound is purified by crystallisation from hexane. TLC Rf (E)=0.33; tRet (III)=18 min; FAB-MS (M+H+)=526.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:10]2[N:11]=[CH:12][N:13]=[C:14](Cl)[C:9]=2[NH:8][CH:7]=1)=[O:5])[CH3:2].[CH:16]1([CH2:19][O:20][C:21]2[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=2B2OC(C)(C)C(C)(C)O2)[CH2:18][CH2:17]1>>[CH2:1]([O:3][C:4]([C:6]1[C:10]2[N:11]=[CH:12][N:13]=[C:14]([C:22]3[CH:23]=[CH:24][C:25]([F:27])=[CH:26][C:21]=3[O:20][CH2:19][CH:16]3[CH2:17][CH2:18]3)[C:9]=2[NH:8][CH:7]=1)=[O:5])[CH3:2]
Reactant: CC1(C)OB(c2ccc(F)cc2OCC2CC2)OC1(C)C
Reactant: CCOC(=O)c1c[nH]c2c(Cl)ncnc12
Product: CCOC(=O)c1c[nH]c2c(-c3ccc(F)cc3OCC3CC3)ncnc12

Procedure:
Starting from 4-chloro-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid ethyl ester and 2-(2-cyclopropylmethoxy-4-fluoro-phenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (example A38) the title compound is obtained as colorless solid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]([C:9](C)(C)[C:10]([O:12]CC)=O)=O)[CH:2]=1.[C:17]1([NH:23][NH2:24])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH2:9][C:10](=[O:12])[N:23]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[N:24]=2)[CH:2]=1
Reactant: CCOC(=O)C(C)(C)C(=O)c1cccnc1
Reactant: NNc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: O=C1CC(c2cccnc2)=NN1c1ccccc1
Yield: 93 %

Procedure:
A mixture of 1.5 g (6.8 mmol) of ethyl α-(3-pyridylcarbonyl)isobutyrate and 0.88 g (12 mmol) of phenyl hydrazine was dissolved in 50 ml of toluene, and the solution was dehydrated and heated under reflux in the presence of p-toluenesulfonic acid monohydrate (catalytic amount) for 18 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane/ethyl acetate=3/2 (v/v)) to give 1.5 g of the object compound as white crystals (yield 83%).
Reaction SMILES: [C:1]([C:4]1[S:8][C:7]([N:9]2[CH2:13][CH2:12][N:11]([CH2:14][CH:15]3[CH2:17][CH2:16]3)[C:10]2=[O:18])=[N:6][C:5]=1[CH3:19])(=O)[CH3:2].CO[C:22](OC)([N:24](C)C)[CH3:23].O.[NH2:30]N>CN(C)C(=O)C>[CH:15]1([CH2:14][N:11]2[CH2:12][CH2:13][N:9]([C:7]3[S:8][C:4]([C:1]4[CH:2]=[C:22]([CH3:23])[NH:24][N:30]=4)=[C:5]([CH3:19])[N:6]=3)[C:10]2=[O:18])[CH2:17][CH2:16]1
Reactant: CC(=O)c1sc(N2CCN(CC3CC3)C2=O)nc1C
Reactant: COC(C)(OC)N(C)C
Reactant: NN
Solvent: O
Solvent: CC(=O)N(C)C
Product: Cc1cc(-c2sc(N3CCN(CC4CC4)C3=O)nc2C)n[nH]1
Temperature: 110 °C
Yield: 71 %

Procedure:
To a solution of 1-(5-acetyl-4-methylthiazol-2-yl)-3-(cyclopropylmethyl)-imidazolidin-2-one (0.28 g, 1.00 mmol) in N,N-dimethylacetamide (10 mL) was added N,N-dimethylacetamide dimethyl acetal (1.4 mL, 8.60 mmol). The reaction mixture was heated for 20 hours at 110° C., followed by the addition of hydrazine monohydrate (2.0 mL, 41.12 mmol). The reaction mixture was heated for another 10 minutes at 110° C. and concentrated in vacuo. The residue was washed with water and triturated with ethyl acetate and the title compound was obtained as a white solid in 71% yield (0.23 g): mp 231-233° C. (ethyl acetate); 1H NMR (300 MHz, DMSO-d6) δ 12.5 (s, 1H), 6.15 (s, 1H), 3.98-3.92 (m, 2H), 3.62-3.57 (m, 2H), 3.05 (d, J=7.2 Hz, 2H), 2.33 (s, 3H), 2.21 (s, 3H), 0.95-0.84 (m, 1H), 0.49-0.43 (m, 2H), 0.21-0.17 (m, 2H); 13C NMR (75 MHz, DMSO-d6) δ 155.8, 155.5, 144.4, 142.1, 139.9, 129.0, 102.5, 48.2, 42.5, 42.3, 16.9, 10.8, 9.3, 3.6; MS (ES+) m/z 318.2 (M+1).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][C:6]=1[N+:12]([O-:14])=[O:13])(=[O:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH3:21][S:22][CH2:23]Cl>CC(C)=O>[C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:21][S:22][CH3:23])=[CH:7][C:6]=1[N+:12]([O-:14])=[O:13])(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1ccc(O)cc1[N+](=O)[O-]
Reactant: CSCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CSCOc1ccc(NC(C)=O)c([N+](=O)[O-])c1

Procedure:
6 G. of 1-acetamido-4-hydroxy-2-nitrobenzene is added to 200 ml. acetone containing 25 g. potassium carbonate and 6 ml. chloromethyl methyl sulfide. The mixture is heated at reflux for four hours and is filtered. The acetone is evaporated leaving 1-acetamido-4-methylthiomethoxy-2-nitrobenzene as a gum. This is purified by column chromatography.