Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[OH:10].C([O-])([O-])=O.[K+].[K+].Br[C:18]1[S:19][CH:20]=[CH:21][N:22]=1.O>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[O:10][C:18]1[S:19][CH:20]=[CH:21][N:22]=1
Reactant: Brc1nccs1
Reactant: COc1ccc(O)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(Oc2nccs2)c(Cl)c1
Temperature: 150 °C
Yield: 80.8 %

Procedure:
To a suspension of 2-chloro-4-methoxyphenol (10 g, 63 mmol) and K2CO3 (9.7 g, 69.4 mmol) in N,N-dimethyl formamide (120 mL) was added 2-bromothiazole (11.4 g, 69.4 mmol). The suspension was heated at 150° C. for 4 hours, cooled to ambient temperature, and poured into water (1000 mL). The mixture was extracted with ether (2×300 mL) and the combined ether layers were dried (MgSO4), filtered and concentrated. The resulting black oil was purified by flash chromatography on silica gel eluting with a solvent gradient from 10% to 25% ethyl acetate in hexanes to provide 12.3 g of the title compound (81%) as a light yellow liquid. 1H NMR (300 MHz, DMSO-d6) δ ppm 3.81 (s, 3H) 7.01 (dd, J=9.01, 3.13 Hz, 1H) 7.18-7.21 (m, 1H) 7.23 (t, J=3.13 Hz, 2H) 7.47 (d, J=9.19 Hz, 1H); MS (ESI) m/z 241.9 (M+H)+.
Reaction SMILES: Cl[C:2]1[C:3]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=2.[CH3:23][C@H:24]([NH2:27])[CH2:25][CH3:26]>CS(C)=O.O>[C@@H:24]([NH:27][C:2]1[C:3]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=2)([CH2:25][CH3:26])[CH3:23]
Reactant: CC[C@H](C)N
Reactant: COC(=O)c1ccc2nc(-c3ccc(F)cc3)c(Cl)nc2c1
Solvent: CS(C)=O
Solvent: O
Product: CC[C@H](C)Nc1nc2cc(C(=O)OC)ccc2nc1-c1ccc(F)cc1
Temperature: 90 °C
Reaction time: 8 h
Yield: 62.9 %

Procedure:
To a solution of methyl 3-chloro-2-(4-fluorophenyl)quinoxaline-6-carboxylate (400.0 mg, 1.26 mmol) in DMSO (3 mL) was added (S)-butan-2-amine (200 mg, 2.74 mmol). The resulting solution was stirred overnight at 90° C. and then diluted with water (50 mL), extracted with dichloromethane (5×20 mL), dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was purified by a silica gel column chromatography with 2% ethyl acetate in petroleum ether to afford (S)-methyl 3-(sec-butylamino)-2-(4-fluorophenyl)quinoxaline-6-carboxylate as a yellow solid (280.0 mg, 63%).
Reaction SMILES: [CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[C:17]([C:22]([O:24]C(C)(C)C)=[O:23])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:12][CH:11]=2)[C:7]2[CH:29]=[C:30]([N:33]3[C:37](=[O:38])[CH2:36][N:35]([CH3:39])[C:34]3=[O:40])[CH:31]=[CH:32][C:6]=2[N:5]=1)[CH2:2][CH3:3].FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[C:17]([C:22]([OH:24])=[O:23])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:12][CH:11]=2)[C:7]2[CH:29]=[C:30]([N:33]3[C:37](=[O:38])[CH2:36][N:35]([CH3:39])[C:34]3=[O:40])[CH:31]=[CH:32][C:6]=2[N:5]=1)[CH2:2][CH3:3]
Reactant: CCCc1nc2ccc(N3C(=O)CN(C)C3=O)cc2n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCc1nc2ccc(N3C(=O)CN(C)C3=O)cc2n1Cc1ccc(-c2ccccc2C(=O)O)cc1

Procedure:
Prepared analogously to Example 1 from tert.-butyl 4'-[(2-n-propyl-6-(1-methyl-imidazolidin-2,4-dion-3-yl)-benzimidazol-1-yl)-methyl]biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.
Reaction SMILES: C[O:2][C:3]1[N:4]=[CH:5][C:6]2[C:11]([CH:12]=1)=[C:10]1[CH:13]=[CH:14][CH:15]=[CH:16][C:9]1=[C:8]1[CH:17]=[CH:18][CH:19]=[CH:20][C:7]=21.Cl.N1C=CC=CC=1>O>[CH:5]1[C:6]2[C:11](=[C:10]3[CH:13]=[CH:14][CH:15]=[CH:16][C:9]3=[C:8]3[CH:17]=[CH:18][CH:19]=[CH:20][C:7]3=2)[CH:12]=[C:3]([OH:2])[N:4]=1
Reactant: COc1cc2c3ccccc3c3ccccc3c2cn1
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Product: Oc1cc2c3ccccc3c3ccccc3c2cn1
Yield: 95.1 %

Procedure:
3-methoxydibenzo[f,h]isoquinoline (1.0 g, 3.9 mmol) and pyridine hydrochloride (4.5 g, 39 mmol) were heated at ca. 220° C. for 1.5 h. The reaction was cooled and water was added. The resulting solids were filtered, wash with water and dried in vacuum to give dibenzo[f,h]isoquinolin-3-ol (0.91 g, 95%).
Reaction SMILES: Br[C:2]1[C:12]2[C:13]3[C:5]([CH2:6][CH2:7][C:8]=3[CH:9]=[CH:10][CH:11]=2)=[CH:4][CH:3]=1.CCCCCC.C([Li])CCC.C([O:28][B:29](OC(C)C)[O:30]C(C)C)(C)C.Cl>C1(C)C=CC=CC=1.CCOCC>[CH2:7]1[C:8]2=[C:13]3[C:12](=[CH:11][CH:10]=[CH:9]2)[C:2]([B:29]([OH:30])[OH:28])=[CH:3][CH:4]=[C:5]3[CH2:6]1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: Brc1ccc2c3c(cccc13)CC2
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: OB(O)c1ccc2c3c(cccc13)CC2
Yield: 45 %

Procedure:
Commercially available 5-bromo acenaphthene in an amount of 11.7 g was dissolved into a mixed solution of dehydrated toluene in an amount 50 milliliter and dehydrated ether in an amount of 50 milliliter, and the resultant solution was cooled down to −40° C. under an atmosphere of argon gas. Thirty five milliliter of 1.6M-normal butyllithium hexane solution was dripped into the resultant solution, followed by elevating the temperature up to −10° C. Two hours later, the resultant solution was cooled down to −70° C. and further, another solution prepared by dissolving triisopropoxyborane in an amount of 35 milliliter into 50 milliliter of ether was dripped into the solution. After stirring the resultant solution for 3 hours at the temperature of −70° C., it was left standing for one night. After the night, the resultant solution was acidified in a dilute hydrochloric acid of 10% by weight and an organic layer was extracted with the use of toluene. Washing with the use of both dilute hydrochloric acid and a saturated sodium chloride solution, the organic layer was dried with anhydrous sodium sulfate, and the organic solvent was distillated by means of an evaporator. Crystallizing the residues with the use of toluene/hexane, 4.5 g of 5-acenaphthene boronic acid was obtained (yield: 45%).
Reaction SMILES: [CH3:1][N:2]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3](=[O:8])[CH2:4][C:5](=[O:7])[CH3:6].[Br:15]Br>C(Cl)(Cl)(Cl)Cl>[Br:15][CH2:6][C:5](=[O:7])[CH2:4][C:3]([N:2]([CH3:1])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:8]
Reactant: CC(=O)CC(=O)N(C)c1ccccc1
Reactant: BrBr
Solvent: ClC(Cl)(Cl)Cl
Product: CN(C(=O)CC(=O)CBr)c1ccccc1
Temperature: 25 °C
Yield: 28 %

Procedure:
To a solution of N-methyl-3-oxo-N-phenylbutanamide (26.0 g, 0.136 mol) in carbon tetrachloride (200 ml) was added bromine (24.05 g, 0.15 mol) dropwise over 30 min, and the mixture was heated under reflux for 5 min. After allowing to cool to room temperature, the reaction mixture was concentrated in vacuo, triturated with diethyl ether and filtered to afford the title compound as a white solid (10.3 g, 28%).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]2[CH:8]=[N:9][NH:10][C:4]=2[CH:3]=1.Br[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[N:13]=1.CNCCNC.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.[Cu](I)I>[Cl:1][C:2]1[N:7]=[CH:6][C:5]2[CH:8]=[N:9][N:10]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[N:13]=3)[C:4]=2[CH:3]=1
Reactant: Clc1cc2[nH]ncc2cn1
Reactant: Fc1cccc(Br)n1
Agent: I[Cu]I
Agent: CNCCNC
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: Fc1cccc(-n2ncc3cnc(Cl)cc32)n1
Temperature: 100 °C
Reaction time: 20 h
Yield: 55.5 %

Procedure:
A mixture of 6-chloro-1H-pyrazolo[4,3-c]pyridine (13.778 mmol, 2115.9 mg), 2-bromo-6-fluoro-pyridine (15.156 mmol, 2667.3 mg), N,N′-Dimethylethylenediamine (13.778 mmol; 1.215 g; 1.37 mL), Copper iodide (13.778 mmol; 2650.5 mg), and potassium carbonate (15.156 mmol; 2.12 g) in 1,4-Dioxane (10 mL) was purged with Argon, then sealed and stirred at 100° C. for 20 hours. The mixture was cooled to room temperature, and then filtered through Celite. The filtrate was concentrated; the residue was purified on silica and eluted with 0 to 100% Ethyl acetate in Heptane to give 6-Chloro-1-(6-fluoro-2-pyridyl)pyrazolo[4,3-c]pyridine as an off-white solid (1.90 g, 55%) MS (ESI) m/z: 249 [M+H]+
Reaction SMILES: [C:1]1([C:7]#[C:8][C:9]([OH:11])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[CH2:13]CCl.S(=O)(=O)(O)O>CO>[C:1]1([C:7]#[C:8][C:9]([O:11][CH3:13])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: ClCCCl
Reactant: O=C(O)C#Cc1ccccc1
Agent: O=S(=O)(O)O
Solvent: CO
Product: COC(=O)C#Cc1ccccc1

Procedure:
The synthesis method of Example 7-(1) was applied. Phenylpropiolic acid (5.16 g), : 1,2-dichloroethane (40 ml), methanol (5 ml) and concentrated sulfuric acid (0.2 ml) were used as reagents to quantitatively give a colorless transparent liquid.
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH2:5][C@H:4]([N:8]2[C:12]3=[C:13]4[S:19][CH:18]=[CH:17][C:14]4=[N:15][CH:16]=[C:11]3[N:10]=[C:9]2[C@H:20]([OH:22])[CH3:21])[CH2:3]1.C(N(CC)CC)C.Cl[C:31]([O:33][CH2:34][CH3:35])=[O:32]>C(Cl)Cl>[OH:22][C@@H:20]([C:9]1[N:8]([C@H:4]2[CH2:5][CH2:6][CH2:7][N:2]([C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH2:3]2)[C:12]2=[C:13]3[S:19][CH:18]=[CH:17][C:14]3=[N:15][CH:16]=[C:11]2[N:10]=1)[CH3:21]
Reactant: C[C@@H](O)c1nc2cnc3ccsc3c2n1[C@H]1CCCNC1
Reactant: CCOC(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)N1CCC[C@H](n2c([C@@H](C)O)nc3cnc4ccsc4c32)C1
Yield: 34 %

Procedure:
To a mixture of (1R)-1-{1-[(3S)-piperidin-3-yl]-1H-imidazo[4,5-d]thieno[3,2-b]pyridin-2-yl}ethanol hydrochloride (15 mg, 0.044 mmol) and triethylamine (18.5 μL, 0.133 mmol) in methylene chloride (0.3 mL) was added ethyl chloroformate (5.1 μL, 0.0531 mmol). The resulting mixture was stirred until completion then the solvent evaporated. The crude residue was purified using RP-HPLC (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 30 mL/min) to give 5.6 mg (34%) of the desired product. LCMS calculated for C18H23N4O3S (M+H)+: m/z=375.1. Found: 375.0. 1H NMR (300 MHz, CDCl3) δ 9.08 (d, J=1.3 Hz, 1H), 7.69 (dd, J=5.5 and 1.3 Hz, 1H), 7.62 (d, J=5.5 Hz, 1H), 5.21 (d, J=6.7 Hz, 1H), 4.83-4.68 (m, 1H), 4.43-4.23 (m, 2H), 4.15 (q, J=6.9 Hz, 2H), 3.93-3.66 (m, 1H), 3.18-3.01 (m, 1H), 2.76-2.60 (m, 1H), 2.20-2.10 (m, 1H), 2.00 (d, J=13.8 Hz, 1H), 1.79 (d, J=6.4 Hz, 3H), 1.70-1.61 (m, 2H), 1.30-1.16 (m, 3H) ppm.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16]([F:20])[C:17](F)=[CH:18][C:13]=2[NH:12][C:11](=[S:21])[CH2:10][N:9]=1.[H-].[Na+].[CH3:24][O:25][CH2:26][CH2:27][OH:28]>C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16]([F:20])[C:17]([O:28][CH2:27][CH2:26][O:25][CH3:24])=[CH:18][C:13]=2[NH:12][C:11](=[S:21])[CH2:10][N:9]=1
Reactant: Fc1cc2c(cc1F)C(c1ccccc1Cl)=NCC(=S)N2
Reactant: COCCO
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Product: COCCOc1cc2c(cc1F)C(c1ccccc1Cl)=NCC(=S)N2
Temperature: 120 °C

Procedure:
A mixture of 1.0 g (0.0031 mole) of 5-(2-chlorophenyl)-1,3-dihydro-7,8-difluoro-2H-1,4-benzodiazepin-2-thione (IImm), 0.372 g of sodium hydride and 20 mL of 2-methoxyethanol was heated in a microwave vessel at 120° C. for 30 minutes, cooled and then diluted with ethyl acetate. The mixture was washed successively with water and brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was triturated with ethyl acetate to give 0.74 g of 5-(2-chlorophenyl)-1,3-dihydro-7-fluoro-8-methoxyethoxy-2H-1,4-benzodiazepin-2-thione (IIf) as a white solid, which was then used to prepare 5-(2-chlorophenyl)-1,2-dihydro-7-fluoro-8-methoxyethoxy-3-methyl-pyrazolo[3,4-b][1,4]benzodiazepine (IVf) in accordance with Example 58 without further purification.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2[NH:17][C:18]1[CH:19]=[CH:20][C:21]([NH:24][CH:25]2[CH2:29][CH2:28][N:27](C(OC(C)(C)C)=O)[CH2:26]2)=[N:22][CH:23]=1.[Cl:37][C:38]1[CH:43]=[C:42](B2OC(C)(C)C(C)(C)O2)[CH:41]=[C:40]([Cl:53])[C:39]=1[OH:54]>>[CH:14]1([C:12]([C:6]2[CH:7]=[N:8][C:9]3[C:4]([C:5]=2[NH:17][C:18]2[CH:23]=[N:22][C:21]([NH:24][CH:25]4[CH2:29][CH2:28][NH:27][CH2:26]4)=[CH:20][CH:19]=2)=[CH:3][C:2]([C:42]2[CH:43]=[C:38]([Cl:37])[C:39]([OH:54])=[C:40]([Cl:53])[CH:41]=2)=[CH:11][CH:10]=3)=[O:13])[CH2:16][CH2:15]1
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2ccc(Nc3c(C(=O)C4CC4)cnc4ccc(Br)cc34)cn2)C1
Reactant: CC1(C)OB(c2cc(Cl)c(O)c(Cl)c2)OC1(C)C
Product: O=C(c1cnc2ccc(-c3cc(Cl)c(O)c(Cl)c3)cc2c1Nc1ccc(NC2CCNC2)nc1)C1CC1
Yield: 44.7 %

Procedure:
Following general procedure D, tert-butyl 3-(5-(6-bromo-3-(cyclopropanecarbonyl)quinoline-4-ylamino)pyridin-2-ylamino)pyrrolidine-1-carboxylate (100 mg, 0.18 mmol) was reacted with 2,6-dichloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (78 mg, 0.27 mmol) to obtain the protected intermediate which was subjected to general procedure A-2 to afford the desired product (43 mg, 45% over 2 steps) as a yellow-orange solid: 1H NMR (500 MHz, MeOD+TFA-d) δ 9.40 (br s, 1H), 8.26-8.07 (m, 3H), 8.00 (d, J=8.9 Hz, 1H), 7.57 (dd, J=8.9, 2.7 Hz, 1H), 7.34 (s, 2H), 6.85-6.77 (m, 1H), 4.65-4.56 (m, 1H), 3.66-3.49 (m, 2H), 3.44-3.30 (m, 2H), 2.86 (br s, 1H), 2.47-2.36 (m, 1H), 2.18-2.07 (m, 1H), 1.27-1.15 (m, 4H). ESI MS m/z 534 [C28H25Cl2N5O2+H]+; HPLC>99.0% (AUC), tR=10.64 min.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([NH:8][CH:9]2[CH2:11][CH2:10]2)[N:5]2[N:12]=[CH:13][C:14]([CH:15]=[O:16])=[C:4]2[N:3]=1.[N-:17]=[N+:18]=[N-:19].[Na+].O>CN(C)C=O>[N:17]([C:2]1[CH:7]=[C:6]([NH:8][CH:9]2[CH2:11][CH2:10]2)[N:5]2[N:12]=[CH:13][C:14]([CH:15]=[O:16])=[C:4]2[N:3]=1)=[N+:18]=[N-:19]
Reactant: O=Cc1cnn2c(NC3CC3)cc(Cl)nc12
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: [N-]=[N+]=Nc1cc(NC2CC2)n2ncc(C=O)c2n1
Temperature: 80 °C
Yield: 71.9 %

Procedure:
To 5-chloro-7-(cyclopropylamino) pyrazolo[1,5-a]pyrimidine-3-carbaldehyde (4.0 g, 16.87 mmol) in dimethylformamide was added sodium azide (1.56 g, 23.9 mmol) and the reaction mixture was heated at 80° C. for 8 hrs. Cooled the reaction mixture, added water and white precipitate filtered and dried to yield 5-azido-7-(cyclopropylamino) pyrazolo[1,5-a]pyrimidine-3-carbaldehyde (2.95 g, 75% yield). LCMS (M+1=244)
Reaction SMILES: [N:1]([C@H:4]1[CH2:9][CH2:8][O:7][C@@H:6]([CH:10]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:5]1)=[N+]=[N-]>[Pd]>[CH:10]([C@H:6]1[CH2:5][C@@H:4]([NH2:1])[CH2:9][CH2:8][O:7]1)([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: [N-]=[N+]=N[C@H]1CCO[C@@H](C(c2ccccc2)c2ccccc2)C1
Agent: [Pd]
Product: N[C@H]1CCO[C@@H](C(c2ccccc2)c2ccccc2)C1
Yield: 100.7 %

Procedure:
Cis-4-azido-2-diphenylmethyltetrahydropyran 5a (0.23 g, 0.78 mmol) was hydrogenated (60 psi) in the presence of 10% Pd—C (0.02 g, 10% wt) for 4 hr. The reaction mixture was filtered through a short bed of celite, and removal of the solvent afforded 0.21 g (quantitative yield) of product. This product was pure enough to continue to the next reaction step.
Reaction SMILES: [CH3:1][C:2]1([CH3:8])[CH2:6][C:5](=[O:7])[CH:4]=[CH:3]1.[C:9]([O:16][CH3:17])(=[O:15])[CH2:10][C:11]([O:13][CH3:14])=[O:12]>CC(O)(C)C>[CH3:14][O:13][C:11]([CH:10]([C:9]([O:16][CH3:17])=[O:15])[CH:3]1[C:2]([CH3:8])([CH3:1])[CH2:6][C:5](=[O:7])[CH2:4]1)=[O:12]
Reactant: COC(=O)CC(=O)OC
Reactant: CC1(C)C=CC(=O)C1
Solvent: CC(C)(C)O
Product: COC(=O)C(C(=O)OC)C1CC(=O)CC1(C)C
Temperature: 40 °C
Reaction time: 48 h
Yield: 58.2 %

Procedure:
Under an atmosphere of argon, 12.3 mg (0.02 mmol, SIC=50) of Ru[(S,S)-Tsdpen] (1,2,3,4,5-pentamethylbenzene), 122 μL (1.0 mmol) of 4,4-dimethyl-2-cyclopentenone, 114 μL (1.0 mmol) of dimethyl malonate, and 1 mL of 2-methyl-2-propanol were placed in a 20 mL Schlenk tube and stirred at 40° C. for 48 hours. This solution was purified by flash column chromatography (hexane/acetone=90/10, SiO2) to give 141 mg (58% yield) of the title compound. After they were converted into an ethylene ketal derivative by the same procedure as in Example 3, the optical purity was measured by HPLC (CHIRALCEL OD manufactured by Daicel Chemical Industries, Ltd., hexane; 2-propanol=97:3, flow rate 0.5 mL/min, detection at 210 nm) and it was found to be 99% ee.
Reaction SMILES: [N:1]1[S:5][N:4]=[C:3]2[C:6]([C:10]([OH:12])=O)=[CH:7][CH:8]=[CH:9][C:2]=12.C(Cl)(=O)C(Cl)=O.Cl.[CH3:20][NH:21][O:22][CH3:23].C(N(CC)CC)C>C1C=CC=CC=1.C(Cl)(Cl)Cl.CN(C=O)C.C(Cl)Cl>[CH3:23][O:22][N:21]([CH3:20])[C:10]([C:6]1[C:3]2=[N:4][S:5][N:1]=[C:2]2[CH:9]=[CH:8][CH:7]=1)=[O:12]
Reactant: CNOC
Reactant: O=C(O)c1cccc2nsnc12
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: c1ccccc1
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: CON(C)C(=O)c1cccc2nsnc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 89.7 %

Procedure:
A suspension of benzo[1,2,5]thiadiazole-4-carboxylic acid (Intermediate L1) (1.8 g, 9.99 mmol) (commercially available from Maybridge) in benzene (100 mL) was treated with oxalyl chloride (5.1 mL of a 2 M CH2Cl2 solution) and DMF (catalytic amount) at rt for 1 h. The solvent was removed under vacuum and re-suspended in benzene. The mixture was decanted into a flask and concentrated under vacuum. The acid chloride intermediate was dissolved in chloroform (10 mL) and added to a solution of N,O-dimethylhydroxylamine-HCl (1.47 g, 15 mmol) (commercially available from Aldrich) and triethylamine (4 mL, 30 mmol) in chloroform (90 mL) at 0° C. The mixture was stirred at rt for 2 h. The mixture was subjected to a standard aqueous work-up. All solvent was removed under vacuum and the residue was purified by chromatography on silica gel with 50% EtOAc:hexane to give benzo[1,2,5]thiadiazole-4-carboxylic acid methoxy-methyl-amide (Intermediate L2) 2 g (90% over two steps).
Reaction SMILES: F[C:2]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:3]=1[NH2:4].[CH3:12][NH2:13].C1COCC1.C(=O)([O-])[O-].[K+].[K+]>CN1CCCC1=O>[CH3:12][NH:13][C:2]1[C:3]([NH2:4])=[CH:5][C:6]([N+:9]([O-:11])=[O:10])=[CH:7][CH:8]=1
Reactant: CN
Reactant: Nc1cc([N+](=O)[O-])ccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CN1CCCC1=O
Product: CNc1ccc([N+](=O)[O-])cc1N
Temperature: 120 °C

Procedure:
In a 350 mL pressure flask, 2-fluoro-5-nitroaniline (10 g, 0.064 mol), methylamine as a 2M solution in THF (65 mL, 0.13 mol) and potassium carbonate (18 g, 0.13 mol) in 1-Methyl-2-pyrrolidinone (80 mL) were combined. The flask was sealed and heated to 120 degrees C. overnight. The reaction was monitored by TLC. When reaction was judged to be complete based upon consumption of 2-fluoro-5-nitroaniline, it was cooled to room temperature and poured into 2-3 times the total reaction volume of water. When a precipitate was formed, it was filtered and dried. The product was carried on without purification. 1H NMR (300 MHz, d6DMSO) δ 7.54 (dd, J=8.79, 2.64 Hz, 1H), 7.39 (d, J=2.64 Hz, 1H), 6.41 (d, J=8.79 Hz, 1H), 6.11 (d, J=4.39 Hz, 1H), 5.07 (s, 2H), 2.83 (d, J=4.83 Hz, 3H).
Reaction SMILES: [C:1]([C:3]1[C:8]([CH:9]2[CH2:11][CH2:10]2)=[CH:7][CH:6]=[CH:5][C:4]=1[NH:12][S:13]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)(=[O:15])=[O:14])#[N:2].[N:22]([Si](C)(C)C)=[N+:23]=[N-:24].C([Sn](=O)CCCC)CCC.Cl>ClCCCl>[CH:9]1([C:8]2[C:3]([C:1]3[NH:24][N:23]=[N:22][N:2]=3)=[C:4]([NH:12][S:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)(=[O:14])=[O:15])[CH:5]=[CH:6][CH:7]=2)[CH2:10][CH2:11]1
Reactant: N#Cc1c(NS(=O)(=O)c2ccccc2)cccc1C1CC1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Agent: CCCC[Sn](=O)CCCC
Agent: Cl
Solvent: ClCCCl
Product: O=S(=O)(Nc1cccc(C2CC2)c1-c1nnn[nH]1)c1ccccc1
Temperature: 140 °C
Yield: 65.5 %

Procedure:
N-(2-Cyano-3-cyclopropylphenyl)-benzenesulfonamide (Intermediate 9, 0.052 g), azidotrimethyl-silane (0.087 g) and dibutyltin oxide (0.038 g) were suspended in 1,2-dichloroethane (3 mL). The mixture was heated by microwave irradiation at 140° C. for 45 minutes. Six further aliquots of azidotrimethylsilane (0.174 g) were added and after each addition the mixture was heated by microwave irradiation at 140° C. for 60 minutes. The reaction mixture was acidified to pH 1 using 1N hydrochloric acid, and then extracted with ethyl acetate. The combined organic extracts were dried with magnesium sulfate, filtered and the filtrate was evaporated under vacuum. The residue was triturated with a mixture of pentane and cyclohexane and the solid was collected by filtration, to give the title compound as a white solid (0.039 g).
Reaction SMILES: B(F)(F)F.C[CH2:6][O:7]CC.[Cl:10][C:11]1[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:12]=1[C:18]1([CH2:21][CH3:22])[O:20][CH2:19]1>CO>[Cl:10][C:11]1[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:12]=1[C:18]([O:20][CH3:19])([CH2:21][CH3:22])[CH2:6][OH:7]
Reactant: CCOCC
Reactant: CCC1(c2ccc(Cl)cc2Cl)CO1
Agent: FB(F)F
Solvent: CO
Product: CCC(CO)(OC)c1ccc(Cl)cc1Cl
Reaction time: 16 h
Yield: 71.5 %

Procedure:
10.64 g of boron trifluoride-etherate, dissolved in 30 ml of methanol, are added dropwise at 4°-6° C. to a solution of 16.25 g (75 mmoles) of 2-(2,4-dichlorophenyl)-1,2-epoxybutane of purity 95%, in 30 ml of methanol. The clear solution is then allowed to reach room temperature (20° C.) in a water bath and, after 16 hours, is worked up by extraction with water and chloroform. The chloroform solution is washed with NaHCO3 and dried with Na2SO4, and the solvent is removed on a rotary evaporator. This gives 19 g of crude product, which is purified by chromatography, using silica gel and a mixture of 4 parts of petroleum ether and one part of ethyl acetate. Removing the solvent at 60° C. in vacuo (20 mbar) gives 13.35 g (75.2%) of pure product in the form of a colourless oil. 60 MHz-1H-NMR (DCCl3): δ=7.1-7.6 ppm (m, 3H, aromatic); 3.7-4.6 ppm (m, --CH2OH); 3.28 ppm (s, OCH3); 1.6-2.3 ppm (m, CH2CH3, OH); 0.67 ppm (t, CH2CH3).
Reaction SMILES: [CH3:1][CH:2]([C:4]1[N:8]([CH2:9][CH2:10][C@@H:11]([OH:19])[CH2:12][C@@H:13]([OH:18])[CH2:14][C:15]([OH:17])=O)[C:7]([C:20]2[CH:21]=[CH:22][C:23]([F:26])=[CH:24][CH:25]=2)=[C:6]([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:5]=1[C:33](NC1C=CC=CC=1)=[O:34])[CH3:3].[OH-:42].[Na+].Cl>C1COCC1.O>[F:26][C:23]1[CH:24]=[CH:25][C:20]([C:7]2[N:8]([CH2:9][CH2:10][C@@H:11]3[CH2:12][C@@H:13]([OH:18])[CH2:14][C:15](=[O:17])[O:19]3)[C:4]([CH:2]([CH3:3])[CH3:1])=[C:5]([C:33]([OH:34])=[O:42])[C:6]=2[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[CH:21][CH:22]=1
Reactant: CC(C)c1c(C(=O)Nc2ccccc2)c(-c2ccccc2)c(-c2ccc(F)cc2)n1CC[C@@H](O)C[C@@H](O)CC(=O)O
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)c1c(C(=O)O)c(-c2ccccc2)c(-c2ccc(F)cc2)n1CC[C@@H]1C[C@@H](O)CC(=O)O1

Procedure:
A solution of atorvastatin (prepared as described in U.S. Pat. Nos. 5,397,792 and 5,446,054) (1 mmol) and NaOH (10 mmol) in THF (30 mL) and water (10 mL) is maintained at 50° C. The progress of the reaction is monitored by tlc. When the reaction is complete, the solution is acidified with dilute HCl and extracted with CH2Cl2. The extract is then dried and evaporated. The residue is dissolved in toluene (50 mL) and the solution is heated at reflux until tlc monitoring shows that formation of the lactone moiety is complete. The solvent is removed under reduced pressure and compound 18 is purified by chromatography.