Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[C:9]([OH:10])=[CH:8][CH:7]=[CH:6][N:5]=1.[CH3:11][O:12][CH2:13]Cl.O>O1CCCC1>[Cl:3][C:4]1[C:9]([O:10][CH2:11][O:12][CH3:13])=[CH:8][CH:7]=[CH:6][N:5]=1
Reactant: Oc1cccnc1Cl
Reactant: COCCl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COCOc1cccnc1Cl
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 89 %

Procedure:
Sodium hydride (66%, 633 mg, 17.4 mmol) was added to an ice-cooled solution of 2-chloro-3-hydroxypyridine (2.05 g, 15.8 mmol) in tetrahydrofuran (30 ml) under nitrogen atmosphere, and this reaction mixture was stirred at that temperature for 15 minutes. Chloromethyl methyl ether (1.32 ml, 17.4 mmol) was added, and the resulting reaction mixture was stirred at that temperature for 30 minutes, then at room temperature for another 2 hours. After water was added, the reaction mixture was extracted with ethyl acetate, washed with saturated brine, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound (2.44 g).
Reaction SMILES: C([Mg]Br)C.[Cl:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[CH:12]=[C:11]([SH:16])[CH:10]=[CH:9]2.[O:17]1[CH2:19][C@@H:18]1[C:20]([O:22][CH3:23])=[O:21].[Cl-].[NH4+]>C(OCC)C.C1COCC1>[Cl:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[CH:12]=[C:11]([S:16][CH2:19][C@@H:18]([OH:17])[C:20]([O:22][CH3:23])=[O:21])[CH:10]=[CH:9]2
Reactant: Sc1ccc2cc(Cl)ccc2c1
Reactant: COC(=O)[C@H]1CO1
Agent: CC[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: COC(=O)[C@H](O)CSc1ccc2cc(Cl)ccc2c1
Yield: 77 %

Procedure:
Under argon atmosphere, a 3 M solution of ethylmagnesium bromide in diethyl ether was added dropwise to THF (25 mL) with ice cooling. To this solution, a solution of 6-chloronaphthalene-2-thiol (5.0 g) in THF (50 mL) was added dropwise at 0C, and the mixture was mixed at room temperature for 30 minutes. To this solution, a solution of methyl (2R)-oxirane-2-carboxylate (2.3 mL) in THF (15 mL) was added dropwise, and the reaction solution was mixed at room temperature for 3 hours. To the reaction solution, an aqueous ammonium chloride solution (50 mL) was added, and the mixture was extracted with ethyl acetate (100 mL). The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was recrystallized from hexane/ethyl acetate (3:1) to give the title compound (5.9 g, 77%) as colorless needle-shaped crystals.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH2:11][CH2:12][C:13]([CH3:16])([OH:15])[CH3:14])=[C:4]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)[N:3]=1.CN(C)CCN(C)C.C([Li])CCC.CCCCCC.ClCC[I:45]>C1COCC1>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([I:45])[N:8]2[CH2:11][CH2:12][C:13]([CH3:16])([OH:15])[CH3:14])=[C:4]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)[N:3]=1
Reactant: CC(C)(O)CCn1cnc2c(N3CCOCC3)nc(Cl)nc21
Reactant: ClCCI
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(C)(O)CCn1c(I)nc2c(N3CCOCC3)nc(Cl)nc21
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 78.5 %

Procedure:
A solution of 4-(2-chloro-6-morpholino-9H-purin-9-yl)-2-methylbutan-2-ol (360 mg, 1.1 mmol) and N,N,N′,N′-tetramethylethylenediamine (0.25 mL, 1.7 mmol) in THF (8.1 mL) was cooled to −42° C. and treated with a solution of 2.5M n-butyllithium in hexane (BuLi, 2.0 mL, 5.0 mmol) dropwise over 5 minutes. After 30 minutes at −42° C., 1-chloro-2-iodoethane (0.51 mL, 5.4 mmol) was added and the reaction mixture was slowly warmed to 0° C. over 1 hr. The mixture was quenched with a saturated solution of NH4Cl, and diluted with ethyl acetate. The aqueous layer was extracted into ethyl acetate (3×), and the combined organics were dried over sodium sulfate, filtered, and absorbed onto celite for purification by flash chromatography to afford 4-(2-chloro-8-iodo-6-morpholino-9H-purin-9-yl)-2-methylbutan-2-ol as a white foam (390 mg, 78%). LC/MS (ESI+): m/z 452 (M+H)
Reaction SMILES: C[O:2][C:3]([C:5]1([CH2:11][NH:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:7][CH:6]1[CH:8]([CH3:10])[CH3:9])=[O:4].[Li+].[OH-]>CO.O>[C:16]([O:15][C:13]([NH:12][CH2:11][C:5]1([C:3]([OH:4])=[O:2])[CH2:7][CH:6]1[CH:8]([CH3:9])[CH3:10])=[O:14])([CH3:17])([CH3:19])[CH3:18]
Reactant: COC(=O)C1(CNC(=O)OC(C)(C)C)CC1C(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(C)C1CC1(CNC(=O)OC(C)(C)C)C(=O)O
Temperature: 25 °C
Yield: 87 %

Procedure:
To a solution of 1-(tert-butoxycarbonylamino-methyl)-2-isopropyl-cyclopropanecarboxylic acid methyl ester (10.9 g, 40.2 mmol) in MeOH (320 mL) was added a solution of LiOH (4.2 g, 100 mmol) in water (98 mL). The reaction mixture was heated to reflux for 3 hours and cooled to room temperature. Excess of solvent was removed and the residue was dissolved in water (100 mL). The aqueous solution was washed with ether, acidified to pH=3 with 2N HCl and extracted with EtOAc (2×150 mL). The combined organic phase was washed with brine, dried (Na2SO4) and evaporation of the solvent provided 1-(tert-butoxycarbonylamino-methyl)-2-isopropyl-cyclopropanecarboxylic acid (9.0 g, 87%) as a colorless oil: 1H NMR (300 MHz, CD3OD) δ 0.72 (m, 1H), 0.99 (d, J=6.2 Hz, 3H), 1.06 (d, J=6.2 Hz, 3H), 1.28–1.36 (m, 3H), 1.42 (s, 9H), 3.23 (d, J=14.3 Hz, 1H), 3.54 (d, J=14.3 Hz, 1H); 13C NMR (75 MHz, CD3OD) δ 20.0, 23.0, 23.3, 28.8, 30.2, 37.6, 40.8, 80.2, 158.1, 178.5; MS (APCI) m/z 258 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:23])[C:8]2[CH:9]=[C:10]3[CH:20]=[C:19]([F:21])[C:18](F)=[CH:17][C:11]3=[N:12][C:13]=2[N:14]([CH3:16])[CH:15]=1)=[O:5])[CH3:2].[C:24]1([C@H:30]2[CH2:35][NH:34][CH2:33][CH2:32][NH:31]2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:23])[C:8]2[CH:9]=[C:10]3[CH:20]=[C:19]([F:21])[C:18]([N:34]4[CH2:33][CH2:32][NH:31][C@@H:30]([C:24]5[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=5)[CH2:35]4)=[CH:17][C:11]3=[N:12][C:13]=2[N:14]([CH3:16])[CH:15]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cn(C)c2nc3cc(F)c(F)cc3cc2c1=O
Reactant: c1ccc([C@H]2CNCCN2)cc1
Product: CCOC(=O)c1cn(C)c2nc3cc(N4CCN[C@@H](c5ccccc5)C4)c(F)cc3cc2c1=O
Yield: 73.4 %

Procedure:
Working under the conditions of Example 25, but starting with 3-ethoxycarbonyl-7,8-difluoro-1-methyl-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine (0.8 g) and (S)-2-phenylpiperazine (0.5 g), (S)-3-ethoxycarbonyl-7-fluoro-1-methyl-4-oxo-8-(3-phenyl-1-piperazinyl)-1,4-dihydrobenzo[b][1,8]naphthyridine (0.85 g) is obtained in the form of a yellow solid, mp. 226° C.
Reaction SMILES: [H-].[Na+].[CH2:3]([N:5]1[CH2:10][CH2:9][CH:8]([OH:11])[CH2:7][CH2:6]1)[CH3:4].Cl[C:13]1[CH:18]=[CH:17][N:16]=[CH:15][C:14]=1[C:19]1[N:27]=[CH:26][C:25]2[NH:24][C:23]3[N:28]=[CH:29][C:30]([C:32]4[CH:33]=[N:34][N:35]([CH3:37])[CH:36]=4)=[CH:31][C:22]=3[C:21]=2[CH:20]=1>CN(C=O)C>[CH2:3]([N:5]1[CH2:10][CH2:9][CH:8]([O:11][C:13]2[CH:18]=[CH:17][N:16]=[CH:15][C:14]=2[C:19]2[N:27]=[CH:26][C:25]3[NH:24][C:23]4[N:28]=[CH:29][C:30]([C:32]5[CH:33]=[N:34][N:35]([CH3:37])[CH:36]=5)=[CH:31][C:22]=4[C:21]=3[CH:20]=2)[CH2:7][CH2:6]1)[CH3:4]
Reactant: Cn1cc(-c2cnc3[nH]c4cnc(-c5cnccc5Cl)cc4c3c2)cn1
Reactant: CCN1CCC(O)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCN1CCC(Oc2ccncc2-c2cc3c(cn2)[nH]c2ncc(-c4cnn(C)c4)cc23)CC1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 13 %

Procedure:
Sodium hydride (60% dispersion in mineral oil, 0.133 g, 3.32 mmol) was added to a solution of 1-ethyl-piperidin-4-ol (0.306 g, 2.37 mmol) in DMF (5 mL) and the reaction mixture was stirred at ambient temperature for 45 minutes. 6-(4-Chloro-pyridin-3-yl)-3-(1-methyl-1H-pyrazol-4-yl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole (0.121 g, 0.474 mmol) was added and the reaction mixture was heated at 80° C. for 5 h. The material was partitioned between water and ethyl acetate. The solid suspended in the aqueous layer was removed by filtration then the aqueous layer was separated, adsorbed onto HM-N and purified by flash chromatography (silica, 12 g column, ISCO, 0-10% (2N ammonia in methanol) in DCM). The resultant residue was triturated with ethyl acetate and cyclohexane to afford the title compound as a yellow solid (28 mg, 13%). 1H NMR (MeOD, 400 MHz): 8.97 (d, J=1.1 Hz, 1H), 8.83-8.80 (m, 2H), 8.73 (s, 1H), 8.60 (d, J=1.1 Hz, 1H); 8.43 (d, J=5.9 Hz, 1H), 8.11 (s, 1H), 7.97 (d, J=0.8 Hz, 1H), 7.28 (d, J=6.0 Hz, 1H), 3.98 (s, 3H), 2.65-2.54 (m, 2H), 2.53-2.43 (m, 2H), 2.39 (q, J=7.3 Hz, 2H), 2.13-2.03 (m, 2H), 1.97-1.86 (m, 2H), 1.02 (t, J=7.2 Hz, 3H). LCMS (Method A): RT=4.0 min, M+H+=454.
Reaction SMILES: [F:1][C:2]1([F:13])[O:6][C:5]2[CH:7]=[CH:8][C:9]([CH2:11]O)=[CH:10][C:4]=2[O:3]1.C(Br)(Br)(Br)[Br:15].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C(Cl)Cl>[Br:15][CH2:11][C:9]1[CH:8]=[CH:7][C:5]2[O:6][C:2]([F:13])([F:1])[O:3][C:4]=2[CH:10]=1
Reactant: BrC(Br)(Br)Br
Reactant: OCc1ccc2c(c1)OC(F)(F)O2
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: FC1(F)Oc2ccc(CBr)cc2O1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
A solution of (2,2-difluorobenzo[d][1,3]dioxol-5-yl)methanol (120 mg; 0.63 mmol) in anh. DCM (5 ml) was treated at rt with CBr4 (211 mg; 0.63 mmol), and with PPh3 (167 mg; 0.63 mmol). The resulting mixture was further stirred at rt, under nitrogen, for 17 h. Concentration to dryness under reduced pressure, and subsequent purification by FC (DCM) afforded 5-(bromomethyl)-2,2-difluorobenzo[d][1,3]dioxole as a pale yellow oil which was directly used for the next reaction.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:6][C:7]1[CH:14]=[CH:13][C:10]([CH2:11][OH:12])=[CH:9][CH:8]=1)[CH:4]=[CH2:5].C[O:16][C:17](=[O:20])[CH2:18]Cl.O>CN(C=O)C>[C:17]([O:20][O:12][CH2:11][C:10]1[CH:13]=[CH:14][C:7]([O:6][CH2:3][CH:4]=[CH2:5])=[CH:8][CH:9]=1)(=[O:16])[CH3:18]
Reactant: C=CCOc1ccc(CO)cc1
Reactant: COC(=O)CCl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: C=CCOc1ccc(COOC(C)=O)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 38.9 %

Procedure:
Sodium hydride (1.20 g; 60% dispersion in oil) was added over a period of 10 minutes to a stirred solution of 4-allyloxybenzyl alcohol (4.60 g) in DHF (20 ml) at 0° C. under an atmosphere of argon. After 0.5 hours, a solution of methylchloroacetate (3.30 g) in DMF (10 ml) was added over a period of 0.25 hours. The reaction mixture was stirred for 40 hours at ambient temperature. Water (300 ml) was added and the mixture extracted with ethyl acetate (3×100 ml). The ethyl acetate extracts were combined, washed with brine (2×100 ml), dried (MgSO4) and evaporated. The residue was purified by flash column chromatography on silica gel using a 9:1 (v/v) mixture of hexane/ethyl acetate to give 4-allyloxyphenylmethyloxy acetate (2.42 g) as a colourless oil; NMR(CDCl3): 3.75(3H,s), 4.07(2H,s), 4.52(4H,m), 5.36(2H,m), 6.10(1H,m), 6.88(2H,m) and 7.28(2H,m); m/z 236(H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]2[N:8]([CH2:12][CH:13]=[CH2:14])[C:9](=[O:11])[NH:10][C:5]2=[CH:4][CH:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].CN1C(=O)CCC1.[CH2:28](I)[C:29]([CH3:32])([CH3:31])[CH3:30]>CCOC(C)=O.C([O-])(O)=O.[Na+]>[Cl:1][C:2]1[N:7]=[C:6]2[N:8]([CH2:12][CH:13]=[CH2:14])[C:9](=[O:11])[N:10]([CH2:28][C:29]([CH3:32])([CH3:31])[CH3:30])[C:5]2=[CH:4][CH:3]=1
Reactant: CC(C)(C)CI
Reactant: C=CCn1c(=O)[nH]c2ccc(Cl)nc21
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: C=CCn1c(=O)n(CC(C)(C)C)c2ccc(Cl)nc21
Temperature: 100 °C

Procedure:
5-Chloro-3-(prop-2-en-1-yl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (71-4, 2.37 g, 11.31 mmol, 1.0 equiv) and Cs2CO3 (18.42 g, 56.6 mmol, 5.0 equiv) were added sequentially to anhydrous NMP (18.6 mL). Neopentyl iodide (2.70 mL, 20.35 mmol, 1.8 equiv) was added dropwise and the resulting mixture was heated to 100° C. for 24 h. Following this duration, the contents were cooled to RT and diluted with EtOAc (50 mL) and saturated aqueous NaHCO3 (50 mL). The layers were separated and the aqueous layer was back-extracted with 3×50 mL EtOAc. The combined organics were dried over Na2SO4, filtered and concentrated to give a brown semi-solid. Purification by normal-phase HPLC provided 5-chloro-1-(2,2-dimethylpropyl)-3-(prop-2-en-1-yl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (71-5) as a white solid. HRMS (M+H)+: observed=280.1207, calculated=280.1211.
Reaction SMILES: C([O:3][C:4](=[O:24])[CH:5]([CH2:17]C1C=CC=CC=1)[CH:6]([C:9]1([C:15]#[N:16])[S:14][CH2:13][CH2:12][CH2:11][S:10]1)[CH2:7][F:8])C.[OH-].[Li+]>C(O)C>[C:15]([C:9]1([CH:6]([CH2:7][F:8])[CH:5]([CH3:17])[C:4]([OH:24])=[O:3])[S:10][CH2:11][CH2:12][CH2:13][S:14]1)#[N:16]
Reactant: CCOC(=O)C(Cc1ccccc1)C(CF)C1(C#N)SCCCS1
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Product: CC(C(=O)O)C(CF)C1(C#N)SCCCS1

Procedure:
A solution of 3 g of the ethyl ester of Example 22, paragraph 1, in 40 ml of ethanol is treated with 15 ml of a 1 M solution of lithium hydroxide for about 40 hours at 25° C. The mixture is then acidified and extracted well with chloroform. The organic phase is dried and concentrated to afford the title compound.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][C:17]=3[CH3:23])[CH2:12][CH2:11]2)=[O:9])=[CH:4][CH:3]=1.[CH:24]12[CH2:30][CH:27]([CH:28]=[CH:29]1)[C:26](=[O:31])[NH:25]2>>[CH3:23][C:17]1[CH:18]=[C:19]([CH3:22])[CH:20]=[CH:21][C:16]=1[N:13]1[CH2:14][CH2:15][N:10]([C:8]([C:5]2[CH:6]=[CH:7][C:2]([N:25]3[C:26](=[O:31])[CH:27]4[CH2:30][CH:24]3[CH:29]=[CH:28]4)=[CH:3][CH:4]=2)=[O:9])[CH2:11][CH2:12]1
Reactant: O=C1NC2C=CC1C2
Reactant: Cc1ccc(N2CCN(C(=O)c3ccc(Br)cc3)CC2)c(C)c1
Product: Cc1ccc(N2CCN(C(=O)c3ccc(N4C(=O)C5C=CC4C5)cc3)CC2)c(C)c1
Yield: 15.1 %

Procedure:
Using (4-bromophenyl)[4-(2,4-dimethylphenyl)piperazin-1-yl]methanone (747 mg) described in Preparation Example 170 and 2-azabicyclo[2.2.1]hept-5-en-3-one (218 mg) and by the reaction and treatment in the same manner as in Example 1, the title compound (121 mg) was obtained.
Reaction SMILES: [CH2:1]([N:8]([CH2:12][C@@H:13]1[NH:17][C:16](=[O:18])[CH2:15][CH2:14]1)[CH2:9][CH2:10][OH:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:19][S:20](Cl)(=[O:22])=[O:21]>C(O)C.C(Cl)Cl>[CH2:1]([N:8]([CH2:12][C@H:13]1[CH2:14][CH2:15][C:16](=[O:18])[NH:17]1)[CH2:9][CH2:10][O:11][S:20]([CH3:19])(=[O:22])=[O:21])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CC[C@H](CN(CCO)Cc2ccccc2)N1
Reactant: CS(=O)(=O)Cl
Solvent: CCO
Solvent: ClCCl
Product: CS(=O)(=O)OCCN(Cc1ccccc1)C[C@H]1CCC(=O)N1
Temperature: 25 °C
Reaction time: 6 h
Yield: 72.9 %

Procedure:
To a solution of (R)-(−)-5-((benzyl(2-hydroxyethyl)amino)methyl)pyrrolidin-2-one (2.4 g, 9.67 mmol) in ethanol-free CHCl3 (80 ml), TEA (1.95 g, 19.34 mmol) and methansulfonyl chloride (2.21 g, 19.34 mmol) were added at 0° C. The mixture was allowed to warm to room temperature and left stirring for 6 hours, then it was diluted with DCM (80 ml) and washed with a saturated solution of NaHCO3. After drying (Na2SO4) and removal of the solvent, the crude was purified by flash chromatography (DCM/abs EtOH/Petroleum Ether/33% NH4OH/Et2O 300/180/900/9.9/360 respectively) to afford the title compound (2.3 g, 73% yield).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]([N:10]=[S:11]([CH2:21][CH2:22][CH2:23][CH2:24][C:25]([O:27][CH3:28])=[O:26])([CH2:13][CH2:14][CH2:15][CH2:16][C:17]([O:19][CH3:20])=[O:18])=[O:12])=[O:9])=[CH:4][C:3]=1I.[C:30]([C:32]1[CH:38]=[CH:37][C:35]([NH2:36])=[CH:34][CH:33]=1)#[CH:31].C(N(CC)CC)C>CN(C=O)C.CCOC(C)=O.[Cu]I>[NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]([N:10]=[S:11]([CH2:21][CH2:22][CH2:23][CH2:24][C:25]([O:27][CH3:28])=[O:26])([CH2:13][CH2:14][CH2:15][CH2:16][C:17]([O:19][CH3:20])=[O:18])=[O:12])=[O:9])=[CH:4][C:3]=1[C:31]#[C:30][C:32]1[CH:38]=[CH:37][C:35]([NH2:36])=[CH:34][CH:33]=1
Reactant: COC(=O)CCCCS(=O)(CCCCC(=O)OC)=NC(=O)c1cnc(N)c(I)c1
Reactant: C#Cc1ccc(N)cc1
Agent: [Cu]I
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)CCCCS(=O)(CCCCC(=O)OC)=NC(=O)c1cnc(N)c(C#Cc2ccc(N)cc2)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 95.9 %

Procedure:
To the degassed mixture of dimethyl 5,5′-{N-[(6-amino-5-iodopyridin-3-yl)carbonyl]sulfonimidoyl}dipentanoate (234 mg, 0.434 mmol, 1.0 equiv.), 4-ethynylaniline (76.3 mg, 0.651 mmol, 1.5 equiv.), and triethylamine (0.242 mL, 1.736 mmol, 4.0 equiv.) in anhydrous DMF (2 mL) under nitrogen atmosphere was added CuI (16.5 mg, 0.087 mmol, 0.2 equiv.) and PdCl2(Ph3P)2 (30.5 mg, 0.043 mmol, 0.1 equiv.). The reaction mixture was stirred at room temperature for 15 minutes. The reaction was then diluted with EtOAc, washed with sat. aq. NaHCO3, aq. NH4Cl, and brine, and lastly dried with anhydrous Na2SO4. The solution was decanted, concentrated, and the oily residue was subject to a gradient column chromatography (from EtOAc-Hex 1:3 to EtOAc) yielding dimethyl 5,5′-[N-({6-amino-5-[(4-aminophenyl)ethynyl]pyridin-3-yl}carbonyl)sulfonimidoyl]dipentanoate as brown oil (220 mg).
Reaction SMILES: [CH:1]1([NH:4][S:5](Cl)(=[O:7])=[O:6])[CH2:3][CH2:2]1.[C@H:9]1([NH:18][C:19]2[CH:28]=[CH:27][C:26]3[C:21](=[CH:22][CH:23]=[C:24]([NH2:29])[CH:25]=3)[N:20]=2)[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:11][CH2:10]1>>[CH:1]1([NH:4][S:5]([NH:29][C:24]2[CH:25]=[C:26]3[C:21](=[CH:22][CH:23]=2)[N:20]=[C:19]([NH:18][C@H:9]2[C:17]4[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=4)[CH2:11][CH2:10]2)[CH:28]=[CH:27]3)(=[O:7])=[O:6])[CH2:3][CH2:2]1
Reactant: Nc1ccc2nc(N[C@@H]3CCc4ccccc43)ccc2c1
Reactant: O=S(=O)(Cl)NC1CC1
Product: O=S(=O)(Nc1ccc2nc(N[C@@H]3CCc4ccccc43)ccc2c1)NC1CC1

Procedure:
The title compound was prepared in accordance with the general method described in example 66 from cyclopropylsulfamoylchloride and (R)—N2-indan-1-yl-quinoline-2,6-diamine; MS: m/e=395.6 (M+H+).
Reaction SMILES: [Mg].[OH:2][C:3]([CH2:9][C:10]([O:12][CH3:13])=[O:11])=[CH:4][C:5]([O:7][CH3:8])=[O:6].C1COCC1.[C:19](Cl)(=[O:23])[CH:20]([CH3:22])[CH3:21].Cl>C1(C)C=CC=CC=1>[C:19]([CH:9]([C:3](=[O:2])[CH2:4][C:5]([O:7][CH3:8])=[O:6])[C:10]([O:12][CH3:13])=[O:11])(=[O:23])[CH:20]([CH3:22])[CH3:21]
Reactant: COC(=O)C=C(O)CC(=O)OC
Reactant: CC(C)C(=O)Cl
Agent: Cl
Agent: [Mg]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: COC(=O)CC(=O)C(C(=O)OC)C(=O)C(C)C
Temperature: 25 °C
Reaction time: 18 h
Yield: 167.9 %

Procedure:
A mixture of 12.15 g (0.03 mol) of product of Step A in 50 ml of toluene was refluxed using a Dean-Stark trap for 1 hour. The resulting clear solution was cooled to room temperature and 50 ml of anhydrous THF were added. To this solution 6.4 g (6.3 ml, 0.06 mol) of isobutyryl chloride was added and stirred for 18 hours. Crude was poured into 3.7% HCl, extracted with EtOAc, the EtOAc layer was washed again with 3.7% HCl and saturated NaCl. Organic layer was dried (MgSO4) and removed in vacuo affording 12.3 g of crude dimethyl 2-(isobutyryl)-3-oxo-1,5-pentanedioate. The crude was purified by HPLC using 10% EtOAc/cyclohexane as eluting solvent affording 8.87 g (61%) of this intermediate as a light yellow oil; nD25 1.4783.
Reaction SMILES: [CH:1]([C:3]1[S:7][C:6]([B:8]([OH:10])[OH:9])=[CH:5][CH:4]=1)=[O:2].[BH4-].[Na+]>C(O)(C)C>[OH:2][CH2:1][C:3]1[S:7][C:6]([B:8]([OH:10])[OH:9])=[CH:5][CH:4]=1
Reactant: O=Cc1ccc(B(O)O)s1
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(C)O
Product: OCc1ccc(B(O)O)s1
Temperature: 0 °C

Procedure:
A suspension of 5-formylthiophen-2-ylboronic acid 185 (1.096 g, 7.03 mmol) in isopropanol (10 mL), stirred at 0° C., was treated with solid sodium borohydride (0.336 g, 8.88 mmol) added portion-wise at 0° C. then stirred for 75 min. The reaction was quenched with acetone and concentrated to give compound 186 (used directly in Step 2).
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:22])([F:21])[CH2:17]2)[C:8]2[C:9](=[N:11][N:12]([CH2:14][CH3:15])[N:13]=2)[N:10]=1)([CH3:4])([CH3:3])[CH3:2].C(C1N=C(N2CCC(F)(F)C2)C2N=NNC=2N=1)(C)(C)C.Br[CH2:44][C:45]1C=C[CH:48]=[C:47]([Cl:51])[CH:46]=1>>[C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:21])([F:22])[CH2:17]2)[C:8]2[C:9](=[N:11][N:12]([CH2:14][C:15]3[CH:44]=[CH:45][CH:46]=[C:47]([Cl:51])[CH:48]=3)[N:13]=2)[N:10]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: Clc1cccc(CBr)c1
Reactant: CCn1nc2nc(C(C)(C)C)nc(N3CCC(F)(F)C3)c2n1
Agent: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn[nH]c2n1
Product: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn(Cc3cccc(Cl)c3)nc2n1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-7-(3,3-difluoro-pyrrolidin-1-yl)-2-ethyl-2H-[1,2,3]triazolo[4,5-d]pyrimidine (example 3, step b), the title compound was prepared from 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and 1-(bromomethyl)-3-chlorobenzene and isolated as white solid (4.8 mg, 29%). MS (m/e): 407.4 (MH+).
Reaction SMILES: [CH3:1][C:2]([C@H:4]1[C@@H:8]2[C@@H:9]3[C@@:22]([CH3:25])([CH2:23][CH2:24][C@@:7]2([CH2:31][OH:32])[CH2:6][CH2:5]1)[C@@:21]1([CH3:26])[C@@H:12]([C@:13]2([CH3:30])[C@@H:18]([CH2:19][CH2:20]1)[C:17]([CH3:28])([CH3:27])[C@@H:16]([OH:29])[CH2:15][CH2:14]2)[CH2:11][CH2:10]3)=[CH2:3].CC(C)=[O:35].OS(O)(=O)=O.O=[Cr](=O)=O>CC(C)=O.C1C=CC=CC=1.CO>[CH3:3][C:2]([C@H:4]1[C@@H:8]2[C@@H:9]3[C@@:22]([CH3:25])([CH2:23][CH2:24][C@@:7]2([C:31]([OH:35])=[O:32])[CH2:6][CH2:5]1)[C@@:21]1([CH3:26])[C@@H:12]([C@:13]2([CH3:30])[C@@H:18]([CH2:19][CH2:20]1)[C:17]([CH3:28])([CH3:27])[C:16](=[O:29])[CH2:15][CH2:14]2)[CH2:11][CH2:10]3)=[CH2:1]
Reactant: C=C(C)[C@@H]1CC[C@]2(CO)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC[C@H](O)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Reactant: CC(C)=O
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: CO
Solvent: c1ccccc1
Product: C=C(C)[C@@H]1CC[C@]2(C(=O)O)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CCC(=O)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Reaction time: 5 h

Procedure:
Starting off with Betulin (10 g) in acetone (300 mL), add freshly prepared Jones Reagent added dropwise at 0° C. Stir for 5 hours, quench with methanol (100 mL), then stir for 5 minutes and add H2O (200 mL). Remove organic solvent under vacuum, and then separate the precipitate by filtration. Wash precipitate on the filter with cooled water, and dry to obtain crude material. This dry material is to be dissolved in 30 mL benzene. The solution is then filtered through a layer of aluminum oxide and the eluate is treated with an aqueous 10% KOH solution until complete precipitation. The precipitate is then separated by filtration, washed with 10 mL cooled benzene, and dried to obtain white solid. The salt is dissolved in 30 mL methanol and the solution is poured into 100 mL 15% aqueous HCL solution. The betulonic acid (2.7 g) is obtained after the precipitate is filtered, washed with water, and dried.
Reaction SMILES: ClC1C(=O)C(C#N)=C(C#N)C(=[O:9])C=1Cl.O.[CH3:16][C:17]1[CH:33]=[CH:32][C:31]2[C:19](=[CH:20][C:21]3[S:25][C:24]4[CH:26]=[CH:27][CH:28]=[CH:29][C:23]=4[C:22]=3[CH:30]=2)[CH:18]=1>C(Cl)(Cl)Cl>[CH:29]1[C:23]2[C:22]3[CH:30]=[C:31]4[C:19](=[CH:20][C:21]=3[S:25][C:24]=2[CH:26]=[CH:27][CH:28]=1)[CH:18]=[C:17]([CH:16]=[O:9])[CH:33]=[CH:32]4
Reactant: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Reactant: Cc1ccc2cc3c(cc2c1)sc1ccccc13
Solvent: O
Solvent: ClC(Cl)Cl
Product: O=Cc1ccc2cc3c(cc2c1)sc1ccccc13
Yield: 22.8 %

Procedure:
To a RB flask equipped with magentic stirring bar, reflux condenser and N2 inlet line with bubbler was added 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) (Aldrich, 38.6 g, 0.119 mol), H2O (100 mL) and CHCl3 (1500 mL). After refluxing the mixture for 15 min, 8-methylbenzo[b]-naphtho-[2,3-d]thiophene (Cambridge Chemicals, Inc., 21.0 g, 89.6 mmol) was added to the flask. After refluxing the mixture for 5 h an additional portion of DDQ (19.3 g, 85 mmol) was added. The mixture was then refluxed overnight, cooled and the deep red solution filtered. The solvent was then removed by rotary evaporation and the residual H2O removed by azeotropic distillation with several portions of PhCH3. The material was then dissolved in PhCH3 (500 mL) and applied to a 40×10 cm column of SiO2 and eluted with additional PhCH3 as the solvent. The appropriate fractions were combined and the solvent removed to give 7.12 g of crude material. This was crystallized (PhCH3), filtered and dried to give 5.35 g (22.7% yield) of benzo[b]naphtho[2,3-d]thiophene-8-carbaldehyde, mp 182°-185°, (C, H, S).