Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16](Br)[CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CC1(C)C(C)(C)OB([C:29]2[CH:38]=[CH:37][C:36]3[C:35]([CH3:40])([CH3:39])[CH2:34][CH2:33][C:32]([CH3:42])([CH3:41])[C:31]=3[CH:30]=2)O1>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:38]3[CH:29]=[CH:30][C:31]4[C:32]([CH3:42])([CH3:41])[CH2:33][CH2:34][C:35]([CH3:40])([CH3:39])[C:36]=4[CH:37]=3)[CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC1(C)CCC(C)(C)c2cc(B3OC(C)(C)C(C)(C)O3)ccc21
Reactant: CC(C)(C)OC(=O)N1CCN(c2cccc(Br)c2)CC1
Product: CC(C)(C)OC(=O)N1CCN(c2cccc(-c3ccc4c(c3)C(C)(C)CCC4(C)C)c2)CC1

Procedure:
The preparation is carried out analogously to FS 102 starting from 4-(3-bromophenyl)piperazine-1-carboxylic acid tert-butyl ester (WO2007/97937) and 4,4,5,5-tetramethyl-2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)-1,3,2-dioxaborolane.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:20]([CH3:22])[CH3:21])[CH:5]=[C:6]2[C:10]=1[NH:9][C:8]1[C:11]([CH2:17][CH2:18][OH:19])([CH2:15][CH3:16])[O:12][CH2:13][CH2:14][C:7]2=1.C(N(CC)CC)C.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.[CH2:52]=[CH:53][C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1>C(#N)C>[CH2:15]([C:11]1([CH2:17][CH2:18][OH:19])[C:8]2[NH:9][C:10]3[C:6]([C:7]=2[CH2:14][CH2:13][O:12]1)=[CH:5][C:4]([CH:20]([CH3:22])[CH3:21])=[CH:3][C:2]=3[CH:52]=[CH:53][C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1)[CH3:16]
Reactant: C=Cc1ccccc1
Reactant: CCC1(CCO)OCCc2c1[nH]c1c(Br)cc(C(C)C)cc21
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCC1(CCO)OCCc2c1[nH]c1c(C=Cc3ccccc3)cc(C(C)C)cc21
Temperature: 90 °C

Procedure:
The title compound is prepared according to the following procedure. To solution of 2-(8-bromo-1-ethyl-6-isopropyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)-ethanol (1.0 mmol) in dried acetonitril (10 mL) at under nitrogen is added triethylamine (1.5 mL), tri-o-tolylphosphine (0.4 mmol), styrene (2.0 mmol), and tri(dibenzylideneacetone)dipalladiumn (0) (0.1 mmol). The reaction mixture is heated at 90° C. (oil bath) overnight. It is quenched with water and extracted with ethyl acetate. Extracts are dried over magnesium sulfate and concentrated under reduced pressure. The chromatography (silica gel) gives the title compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[CH:4]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[O:5][CH2:6][CH:7]=[N:8][NH:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11]>CO.[Ni]>[CH3:1][O:2][C:3](=[O:23])[CH:4]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[O:5][CH2:6][CH2:7][NH:8][NH:9][C:10]([O:12][C:13]([CH3:16])([CH3:14])[CH3:15])=[O:11]
Reactant: COC(=O)C(OCC=NNC(=O)OC(C)(C)C)c1ccccc1
Agent: [Ni]
Solvent: CO
Product: COC(=O)C(OCCNNC(=O)OC(C)(C)C)c1ccccc1
Yield: 95 %

Procedure:
tert-Butyl 2-(2-(2-methoxy-2-oxo-1-phenylethoxy)ethylidene)hydrazinecarboxylate (4.7 g, 14.6 mmol) in MeOH (175 mL) was hydrogenated at 3.5 bar and 30° C. for 20 hours in a Parr bottle in the presence of Raney-nickel (4.69 g, 37.2 mmol). The reaction mixture was filtered and washed with MeOH. The solvent was evaporated to give the title compound as brown oil (4.5 g, 95%) that was used crude for the next reaction.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][N:17]=1)[C:5]([NH:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:6].[F:18][C:19]1[CH:27]=[CH:26][CH:25]=[CH:24][C:20]=1[C:21](Cl)=[O:22]>CN(C)C1C=CN=CC=1.N1C=CC=CC=1.ClCCl>[CH2:8]([NH:7][C:5](=[O:6])[C:4]1[CH:15]=[CH:16][N:17]=[C:2]([NH:1][C:21](=[O:22])[C:20]2[CH:24]=[CH:25][CH:26]=[CH:27][C:19]=2[F:18])[CH:3]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=C(Cl)c1ccccc1F
Reactant: Nc1cc(C(=O)NCc2ccccc2)ccn1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(NCc1ccccc1)c1ccnc(NC(=O)c2ccccc2F)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 45.5 %

Procedure:
To a solution of 2-amino-N-benzylisonicotinamide (0.10 g, 0.44 mmol) and 4-dimethylaminopyridine (0.01 g, 0.08 mmol) in pyridine (3.0 mL) was added 2-fluorobenzoyl chloride (0.07 g, 0.44 mmol). The resulting solution was stirred at ambient temperature for 16 hours, diluted with dichloromethane (25 mL), washed with water (2×25 mL) and brine (10 mL). The organic solution was dried over anhydrous sodium sulphate, filtered and concentrated in vacuo. The residue was purified by column chromatography eluting with 45% ethyl acetate in hexanes to give N-benzyl-2-(2-fluorobenzamido)isonicotinamide as a colorless solid (0.07 g, 44%): mp 175-176° C. (hexanes/ethyl acetate); 1H NMR (300 MHz, CDCl3) δ 9.21 (d, J=13.7 Hz, 1H), 8.64 (s, 1H), 8.46-8.42 (m, 1H), 8.12-8.06 (m, 1H), 7.64-7.48 (m, 2H), 7.35-7.16 (m, 7H), 6.68 (s, 1H), 4.65 (d, J=5.7 Hz, 2H); 13C NMR (CDCl3, 75 MHz) δ 165.2, 162.1, 161.9, 158.8, 151.7, 148.8, 144.1, 137.5, 134.5, 134.4, 131.9, 128.8, 127.7, 125.1, 120.7, 118.8, 116.6, 116.3, 111.0, 44.2; MS (ES+) m/z 350.6 (M+1).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[CH2:5][NH:6][CH2:7][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH3:2].[C:15](Cl)(=[O:20])[CH2:16][CH2:17][CH:18]=[CH2:19].CCN(CC)CC>C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:14])[CH2:5][N:6]([C:15](=[O:20])[CH2:16][CH2:17][CH:18]=[CH2:19])[CH2:7][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH3:2]
Reactant: CCOC(=O)CCNCC(=O)OCC
Reactant: C=CCCC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=CCCC(=O)N(CCC(=O)OCC)CC(=O)OCC
Reaction time: 18 h

Procedure:
To the product of Step A, 1-a, (5.10 g, 25.1 mmol) in CH2Cl2 (50 mL) was added pent-4-enoyl chloride (2.83 mL, 25.1 mmol, 98% purity) and NEt3 (4.20 mL, 30.1 mmol) at 5° C. The reaction stirred about 18 hours and was then diluted with CH2Cl2, washed with aq Na2CO3 (2 M) and brine, dried (Na2SO4), filtered and concentrated to afford the product, 1-b.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([S:9][CH:10]([CH3:12])[CH3:11])[N:4]=1.C([O:15][C:16](=[O:27])[CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([OH:25])=[C:21]([Cl:26])[CH:20]=1)C>>[Cl:26][C:21]1[CH:20]=[C:19]([CH2:18][CH2:17][C:16]([OH:27])=[O:15])[CH:24]=[CH:23][C:22]=1[O:25][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([S:9][CH:10]([CH3:12])[CH3:11])[N:4]=1
Reactant: CCOC(=O)CCc1ccc(O)c(Cl)c1
Reactant: CC(C)Sc1cccc(CCl)n1
Product: CC(C)Sc1cccc(COc2ccc(CCC(=O)O)cc2Cl)n1
Yield: 51.9 %

Procedure:
2-Chloromethyl-6-isopropylsulfanyl-pyridine (41 mg, 0.20 mmol) obtained in Step C of Preparation Example 16 and 3-(3-chloro-4-hydroxy-phenyl)-propionic acid ethyl ester (51 mg, 0.22 mmol) obtained in Step C of Preparation Example 42 were used to react sequentially in the same manner as in Steps A and B of Example 1 to obtain the title compound (38 mg, 59%).
Reaction SMILES: [CH:1]1([NH:5][C:6]([C:8]2[CH:17]=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[N:13][CH:14]=3)[N:9]=2)=[O:7])[CH2:4][CH2:3][CH2:2]1.Br[CH2:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21].[BH4-].[Na+]>CC#N>[CH:1]1([NH:5][C:6]([C:8]2[CH:17]=[CH:16][C:15]3[CH2:14][N:13]([CH2:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:12][CH2:11][C:10]=3[N:9]=2)=[O:7])[CH2:4][CH2:3][CH2:2]1
Reactant: O=C(NC1CCC1)c1ccc2cnccc2n1
Reactant: CC(C)(C)OC(=O)CBr
Agent: [BH4-]
Agent: [Na+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)CN1CCc2nc(C(=O)NC3CCC3)ccc2C1

Procedure:
A mixture of N-cyclobutyl-1,6-naphthyridine-2-carboxamide (227 mg, 1 mmol), tert-butyl bromoacetate (234 mg, 1.2 mmol) in CH3CN (15 mL) is refluxed overnight. Solvent is removed in vacuo and the residue is dissolve in MeOH (20 mL). To the solution is added NaBH4 (181 mg, 4.8 mmol) and the mixture is refluxed for 4 hr. The solvent is removed in vacuo and the residue is partitioned between water (20 mL) and EtOAc (20 mL). The layers are separated and the aqueous layer is extracted with EtOAc (20 ml). The combined extracts are washed with brine (10 mL), dried and evaporated. The residue is purified by flash column to give the title compound as a light yellow oil. MS (M+1): 346.2.
Reaction SMILES: [H-].[Li+].[CH3:3][O:4][C:5]([C:7]1[C:12]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([Br:20])=[CH:16][C:15]=2[F:21])=[C:11]([F:22])[C:10](=[O:23])[NH:9][CH:8]=1)=[O:6].Br.Br[CH2:26][C:27]1[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=1>CN(C=O)C>[CH3:3][O:4][C:5]([C:7]1[C:12]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([Br:20])=[CH:16][C:15]=2[F:21])=[C:11]([F:22])[C:10](=[O:23])[N:9]([CH2:26][C:27]2[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=2)[CH:8]=1)=[O:6]
Reactant: COC(=O)c1c[nH]c(=O)c(F)c1Nc1ccc(Br)cc1F
Reactant: BrCc1cccnc1
Agent: Br
Agent: [H-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: COC(=O)c1cn(Cc2cccnc2)c(=O)c(F)c1Nc1ccc(Br)cc1F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Lithium hydride (14 mg, 1.64 mmol) was added to a stirred solution of 4-(4-bromo-2-fluorophenylamino)-5-fluoro-6-oxo-1,6-dihydropyridine-3-carboxylic acid methyl ester (0.190 g, 0.529 mmol) in DMF (5 mL) at 0° C. After stirring for 30 minutes, 3-bromomethyl-pyridine hydrobromide (0.14 g, 0.53 mmol) was added. The reaction mixture was warmed to room temperature and stirred for 16 hours. After quenching with ice water, the reaction mixture was extracted with ethyl acetate. The combined organic extracts were dried (MgSO4) and concentrated under reduced pressure. Purification by flash column chromatography (1% MeOH in methylene chloride) yielded 4-(4-bromo-2-fluorophenylamino)-5-fluoro-6-oxo-1-pyridin-3-ylmethyl-1,6-dihydropyridine-3-carboxylic acid methyl ester. The methyl ester was dissolved in 4:1 THF:MeOH (5 mL) and 1 M LiOH solution (1.1 mL) was added. After 1 hour, the reaction mixture was acidified to pH 1 with 10% aqueous HCl solution and extracted with ethyl acetate. The combined organic extracts were washed with brine, dried (MgSO4) and concentrated under reduced pressure. Trituration with diethyl ether gave 0.160 g (69% two step yield) clean desired product. MS APCI (−) m/z 434, 436 (M−, Br pattern) detected; 1H NMR (400 mHz, DMSO-d6) δ 9.40 (bs, 1H), 8.65 (s, 1H), 8.61 (s, 1H), 8.51 (d, 1H), 7.74 (d, 1H), 7.58 (d, 1H), 7.39 (m, 1H), 7.34 (s, 1H), 7.16 (m, 1H), 0.525 (s, 1H).
Reaction SMILES: [CH:1]([C:4]1[C:5]2[CH:6]=[C:7]([CH3:28])[C:8]([NH:16][C:17]3[CH:27]=[CH:26][C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:19][CH:18]=3)=[CH:9][C:10]=2[C:11]([CH3:15])([CH3:14])[CH2:12][CH:13]=1)([CH3:3])[CH3:2].[CH2:29]=O>>[CH3:29][N:16]([C:8]1[C:7]([CH3:28])=[CH:6][C:5]2[C:4]([CH:1]([CH3:3])[CH3:2])=[CH:13][CH2:12][C:11]([CH3:14])([CH3:15])[C:10]=2[CH:9]=1)[C:17]1[CH:18]=[CH:19][C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:26][CH:27]=1
Reactant: CCOC(=O)c1ccc(Nc2cc3c(cc2C)C(C(C)C)=CCC3(C)C)cc1
Reactant: C=O
Product: CCOC(=O)c1ccc(N(C)c2cc3c(cc2C)C(C(C)C)=CCC3(C)C)cc1
Yield: 98.2 %

Procedure:
Following General Procedure D, ethyl 4-(5-isopropyl-3,8,8-trimethyl-7,8-dihydronaphthalen-2-ylamino)benzoate (Compound 48, 0.10 g, 0.26 mmol) was reacted with an aqueous solution of formaldehyde 37% (0.20 mL, 2.6 mmol) to give 0.10 g (100%) of the title compound as a clear oil.
Reaction SMILES: [CH3:1][CH:2]([OH:4])[CH3:3].C(N(CC)CC)C.[CH2:12]([S:14](Cl)(=[O:16])=[O:15])[CH3:13]>ClCCl>[CH:2]([O:4][S:14]([CH2:12][CH3:13])(=[O:16])=[O:15])([CH3:3])[CH3:1]
Reactant: CC(C)O
Reactant: CCS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCS(=O)(=O)OC(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 76.2 %

Procedure:
To a solution of 2-propanol (2.4 mL, 32 mmol) in dichloromethane (50 were added triethylamine (3.5 ml, 25 mmol) and ethanesulfonyl chloride (2.0 mL, 21 mmol), and the mixture was stirred at room temperature for 3 hours. The reaction mixture was washed successively with 1N hydrochloric acid, saturated aqueous sodium hydrogen carbonate and saturated brine, and dried over sodium sulfate. The drying agent was filtered off, and the filtrate was concentrated under reduced pressure to give the title compound (2.4 g, 16 mmol, 75%).
Reaction SMILES: [CH3:1][N:2]([S:15]([C:18]1[S:19][CH:20]=[CH:21][CH:22]=1)(=[O:17])=[O:16])[C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12](=[S:14])[NH2:13])=[CH:8]2.Cl[CH2:24][C:25](=O)[CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28].CN(C)C(=O)C>O>[CH3:1][N:2]([S:15]([C:18]1[S:19][CH:20]=[CH:21][CH:22]=1)(=[O:17])=[O:16])[C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12]1[S:14][CH:24]=[C:25]([CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])[N:13]=1)=[CH:8]2
Reactant: CN(c1cccc2cc(C(N)=S)[nH]c12)S(=O)(=O)c1cccs1
Reactant: CCOC(=O)CC(=O)CCl
Solvent: O
Solvent: CC(=O)N(C)C
Product: CCOC(=O)Cc1csc(-c2cc3cccc(N(C)S(=O)(=O)c4cccs4)c3[nH]2)n1
Temperature: 80 °C
Reaction time: 3 h
Yield: 72.3 %

Procedure:
A mixture of 7-[methyl(2-thienylsulfonyl)amino]-1H-indole-2-carbothioamide (0.40 g), ethyl 4-chloro-3-oxobutyrate (0.55 g) and N,N-dimethylacetamide (6 mL) was stirred at 80° C. for 3 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The obtained residue was subjected to silica gel column chromatography and the title compound (0.38 g, yield 75%) was obtained as colorless crystals from a fraction eluted with ethyl acetate-hexane (2:3, volume ratio). melting point 117-118° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:19]=[CH:20][C:21]=1[O:22][CH3:23])[C:6]([C@H:8]1[CH2:12][CH2:11][CH2:10][N:9]1[C:13](=[O:18])[C:14]([F:17])([F:16])[F:15])=O.C([SiH](CC)CC)C.C(=O)([O-])[O-].[K+].[K+]>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:19]=[CH:20][C:21]=1[O:22][CH3:23])[CH2:6][C@H:8]1[CH2:12][CH2:11][CH2:10][N:9]1[C:13](=[O:18])[C:14]([F:17])([F:15])[F:16]
Reactant: COc1ccc(C(=O)[C@H]2CCCN2C(=O)C(F)(F)F)cc1OC
Agent: CC[SiH](CC)CC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: COc1ccc(C[C@H]2CCCN2C(=O)C(F)(F)F)cc1OC
Temperature: 25 °C
Reaction time: 72 h
Yield: 67.2 %

Procedure:
(R)-2-(3,4-dimethoxybenzoyl)-1-trifluoroacetylpyrrolidine (4.9 g, 0.015 mol) was dissolved in 50 mL dry CH2Cl2 in a 500 mL round-bottom flask. To the solution was added triethylsilane (20 g, 0.172 mol) and BF3 ·Et2O (50 mL). The reaction mixture was stirred at room temperature for 3 days, after which time a saturated aqueous solution of potassium carbonate was added cautiously in a dropwise manner. When no more gas was evolved, 100 mL CH2Cl2 was added. The mixture was then shaken. The triphasic mixture was filtered through a glass fritted funnel, and the organic layer separated and dried with MgSO4. Removal of the solvent in vacuo yielded 3.2 g of (R)-2-(3,4-dimethoxybenzyl)-1-trifluoroacetylpyrrolidine (68% yield), as an oil which could be used without further purification.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[Cl:8].[CH3:9][P:10]([O:14]CC)[O:11]CC.Cl>>[Cl:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[P:10]([CH3:9])(=[O:11])[OH:14]
Reactant: CCOP(C)OCC
Reactant: Clc1ccccc1I
Agent: Cl
Product: CP(=O)(O)c1ccccc1Cl

Procedure:
After dissolving 4.8 grams of o-iodochlorobenzene in 10 ml. of diethyl methylphosphonite, the resulting solution is irradiated for 3 hours. After concentration under reduced pressure and vacuum distillation, a colorless oil is produced having a boiling point from 96°-100° C. (0.05- 0.1 mm. Hg.). The product is combined with 25 ml. of 12M HCl, and the mixture is refluxed for 2 hours. The solution is concentrated to leave a thick oil which crystallizes upon trituration with ether. Upon recrystallization from acetone-ether, 0.5 grams of the solid is collected having a melting point of 97°-98° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH2:8][CH3:9])[N:5]=[C:4]2[N:10]([CH3:21])[N:11]=[C:12]([C:13]3[O:14][C:15]([N+:18]([O-:20])=[O:19])=[CH:16][CH:17]=3)[C:3]=12.ClC1N=C[N:26]=C2N(C)N=C(C3OC([N+]([O-])=O)=CC=3)C=12>>[NH2:26][C:2]1[N:7]=[C:6]([CH2:8][CH3:9])[N:5]=[C:4]2[N:10]([CH3:21])[N:11]=[C:12]([C:13]3[O:14][C:15]([N+:18]([O-:20])=[O:19])=[CH:16][CH:17]=3)[C:3]=12
Reactant: Cn1nc(-c2ccc([N+](=O)[O-])o2)c2c(Cl)ncnc21
Reactant: CCc1nc(Cl)c2c(-c3ccc([N+](=O)[O-])o3)nn(C)c2n1
Product: CCc1nc(N)c2c(-c3ccc([N+](=O)[O-])o3)nn(C)c2n1

Procedure:
The procedure described in Example 3b was repeated using 4-chloro-6-ethyl-1-methyl-3-(5-nitro-2-furyl)-1H-pyrazolo[3,4-d]pyrimidine as starting material instead of 4-chloro-1-methyl-3-(5-nitro-2-furyl)-1H-pyrazolo[3,4-d] pyrimidine, the reaction conditions being the same. The crystalline product was recrystallised from dimethyl formamide to give 4-amino-6-ethyl-1-methyl-3-(5-nitro-2-furyl)-1H-pyrazolo[3,4-d]pyrimidine, having decomposition point 294° C.
Reaction SMILES: [OH-].[K+].O.C([O:6][C:7]([C:9](C(OCC)=O)([CH2:24][CH3:25])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([CH:17]([CH3:23])[C:18]([O:20]CC)=[O:19])=[CH:13][CH:12]=1)=[O:8])C>C(O)C>[C:7]([CH:9]([CH2:24][CH3:25])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([CH:17]([CH3:23])[C:18]([OH:20])=[O:19])=[CH:13][CH:12]=1)([OH:8])=[O:6]
Reactant: CCOC(=O)C(C)c1ccc(CC(CC)(C(=O)OCC)C(=O)OCC)cc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCC(Cc1ccc(C(C)C(=O)O)cc1)C(=O)O

Procedure:
To a mixture of 14g. of potassium hydroxide, 100 ml. of water and 10 ml. of ethanol was added 14g. of ethyl 2-[4-(2,2-diethoxycarbonylbutyl)phenyl]propionate and the mixture was refluxed for 6 hours. The reaction mixture was treated with the same procedure as in Example 1 (2) to give 11.1g. of a pale yellow oil. The oil was heated at 160° - 170° C. for 3 hours and subjected to vacuum distillation to give 7.2g. of the desired product boiling at 230° C./0.05 mmHg. as a colorless oil.
Reaction SMILES: [CH3:1][CH:2]1[C:8](=[O:9])[N:7]2[CH:3]1[CH2:4][C:5]([Cl:20])=[C:6]2[C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11].C([N-]C(C)C)(C)C.[Li+].[CH:29](=[O:31])[CH3:30]>C1COCC1>[OH:31][CH:29]([C:2]1([CH3:1])[C:8](=[O:9])[N:7]2[CH:3]1[CH2:4][C:5]([Cl:20])=[C:6]2[C:10]([O:12][CH2:13][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)=[O:11])[CH3:30]
Reactant: CC1C(=O)N2C(C(=O)OCc3ccccc3)=C(Cl)CC12
Reactant: CC=O
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(O)C1(C)C(=O)N2C(C(=O)OCc3ccccc3)=C(Cl)CC21

Procedure:
Benzyl 6-methyl-3-chloro-1-azabicyclo[3.2.0]hept-2-en-7-one-2-carboxylate is converted to its enolate derivative with lithium diisopropylamide in anhydrous THF at -78° as described in the previous example. To this solution is added 10 equivalents of acetaldehyde. Workup as described in example 16 yields benzyl 6-(1-hydroxyethyl)-6-methyl-3-chloro-1-azabicyclo[3.2.0]hept-2-en-7-one-2-carboxylate.
Reaction SMILES: [O:1]([CH2:8][CH2:9][NH2:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:11][C:12]1[C:17](Cl)=[N:16][CH:15]=[CH:14][N:13]=1.C([O-])([O-])=O.[K+].[K+]>C(#N)C.CCOCC>[Cl:11][C:12]1[C:17]([NH:10][CH2:9][CH2:8][O:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[N:16][CH:15]=[CH:14][N:13]=1
Reactant: Clc1nccnc1Cl
Reactant: NCCOc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOCC
Product: Clc1nccnc1NCCOc1ccccc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 49 %

Procedure:
A mixture of 2-phenoxyethylamine (2.65 g, 19.3 mmol), 2,3-dichloropyrazine (2.88 g, 19.3 mmol) and K2CO3 (2.67 g, 19.3 mmol) in acetonitrile (8 mL) was stirred in a sealed tube for 12 h at room temperature, and for a further 9.5 h at 80° C. The reaction mixture was diluted with ether, filtered, and concentrated. The residue was purified by chromatography on silica gel using n-hexane/EtOAc (7:3) as eluent to give 2.36 g (49%) of the title compound as a yellowish oil that solidified on standing: mp 51-53° C.; HRMS m/z calcd for C12H12ClN3O (M)+ 249.0669. found 249.0659. Anal. (C12H12ClN3O) C, H, N
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[C:4]([CH2:9][S:10]([CH3:13])(=[O:12])=[O:11])[N:3]=1.C(N(CC)CC)C.[CH3:21][C@H:22]1[CH2:27][O:26][CH2:25][CH2:24][NH:23]1>ClCCl>[Cl:1][C:2]1[N:7]=[C:6]([N:23]2[CH2:24][CH2:25][O:26][CH2:27][C@@H:22]2[CH3:21])[CH:5]=[C:4]([CH2:9][S:10]([CH3:13])(=[O:12])=[O:11])[N:3]=1
Reactant: C[C@H]1COCCN1
Reactant: CS(=O)(=O)Cc1cc(Cl)nc(Cl)n1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@H]1COCCN1c1cc(CS(C)(=O)=O)nc(Cl)n1
Temperature: -5 °C

Procedure:
2,4-Dichloro-6-(methylsulfonylmethyl)pyrimidine (30 g, 0.13 mol) was dissolved in dichloromethane and stirred (under nitrogen) at −5° C. Triethylamine (17.4 mL, 0.13 mol) was added to give a clear brown solution. (3S)-3-Methylmorpholine was dissolved in dichloromethane and added dropwise keeping the reaction below −5° C. The cooling bath was then removed and the mixture stirred for 1 hour. The reaction mixture was heated at reflux for 2 hours, then the reaction mixture was washed with water, dried then evaporated. The crude material was purified by preparative HPLC to give the desired material as a solid (19.3 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:33][C:34]([CH3:45])([CH3:44])[C:35]([NH:37][S:38]([CH:41]2[CH2:43][CH2:42]2)(=[O:40])=[O:39])=[O:36])=[C:6]([CH:8]2[CH2:13][C:12](=O)[NH:11][CH:10]([C:15]3[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:16]=3[CH3:22])[C:9]32[C:30]2[C:25](=[CH:26][C:27]([Cl:31])=[CH:28][CH:29]=2)[NH:24][C:23]3=[O:32])[CH:7]=1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:47]>C1COCC1.C1(C)C=CC=CC=1>[Cl:31][C:27]1[CH:26]=[C:25]2[NH:24][C:23](=[O:32])[C:9]3([CH:8]([C:6]4[CH:7]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=4[O:33][C:34]([CH3:45])([CH3:44])[C:35]([NH:37][S:38]([CH:41]4[CH2:42][CH2:43]4)(=[O:39])=[O:40])=[O:36])[CH2:13][C:12](=[S:47])[NH:11][CH:10]3[C:15]3[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:16]=3[CH3:22])[C:30]2=[CH:29][CH:28]=1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: Cc1ccc(F)cc1C1NC(=O)CC(c2cc(Cl)ccc2OC(C)(C)C(=O)NS(=O)(=O)C2CC2)C12C(=O)Nc1cc(Cl)ccc12
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: Cc1ccc(F)cc1C1NC(=S)CC(c2cc(Cl)ccc2OC(C)(C)C(=O)NS(=O)(=O)C2CC2)C12C(=O)Nc1cc(Cl)ccc12
Temperature: 50 °C
Yield: 88.5 %

Procedure:
A mixture of chiral (2′S, 3S, 4′R)-4′-[5-chloro-2-(2-cyclopropanesulfonylamino-1,1-dimethyl-2-oxo-ethoxy)-phenyl]-6-chloro-2′-(5-fluoro-2-methyl-phenyl)-spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (12 mg, 0.018 mmol) and P2S5 (12 mg, 0.054 mmol) in THF (1 mL) was heated at 50° C. for 2 h, and then diluted with toluene (10 mL). The mixture was concentrated in vacuo and the residue was washed with DCM twice. The DCM layers were combined and concentrated. The residue was purified by flash chromatography to give the title compound as white solid (11 mg).
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([O:12][C:13]1[N:21]=[C:20]2[C:16]([N:17]=[C:18]([O:22][CH3:23])[NH:19]2)=[C:15]([NH2:24])[N:14]=1)[CH2:9][CH2:10][CH3:11].C(=O)([O-])[O-].[K+].[K+].Br[CH2:32][CH:33]1[CH2:38][CH2:37][CH2:36][O:35][CH2:34]1>CN(C)C=O>[CH2:8]([O:12][C:13]1[N:21]=[C:20]2[C:16]([N:17]=[C:18]([O:22][CH3:23])[N:19]2[CH2:32][CH:33]2[CH2:38][CH2:37][CH2:36][O:35][CH2:34]2)=[C:15]([NH2:24])[N:14]=1)[CH2:9][CH2:10][CH3:11]
Reactant: BrCC1CCCOC1
Reactant: CCCCOc1nc(N)c2nc(OC)[nH]c2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Product: CCCCOc1nc(N)c2nc(OC)n(CC3CCCOC3)c2n1
Temperature: 25 °C
Yield: 55.2 %

Procedure:
2-Butoxy-8-methoxy-9H-purin-6-amine trifluoroacetate salt (0.2 g) in dry N,N-dimethylformamide (5 mL) was heated at 60° C. with anhydrous potassium carbonate (0.315 g) for 1 hour and allowed to cool to room temperature before adding 3-(bromomethyl)tetrahydro-2H-pyran (0.112 g). The reaction mixture was heated at 50° C., overnight. The reaction mixture was quenched with water (20 mL) and extracted into ethyl acetate (3 times, 75 mL combined volume). The organic phase was separated, combined and passed through a hydrophobic frit to dry. The organic phase was evaporated under reduced pressure to give a yellow oil which was purified by C18 reverse phase chromatography using water (containing 0.1% formic acid)-acetonitrile (containing 0.05% formic acid) as eluant (20-60%) to afford the title compound as a white solid (105.4 mg).