Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.N[C@H](C)CSC1SC=CC=1.SC1SC=CC=1.C(O[C@@H]1[C@H](OC(=O)C)[C@@H](COC(=O)C)O[C@H]1N1C=NC2C1=NC(Cl)=NC=2Cl)(=O)C.C([O:50][C@@H:51]1[C@H:55]([O:56]C(=O)C)[C@@H:54]([CH2:60][O:61]C(=O)C)[O:53][C@H:52]1[N:65]1[C:83]2[N:82]=[C:81]([Cl:84])[N:80]=[C:69]([NH:70][C@H:71]([CH3:79])[CH2:72][S:73][C:74]3[S:75][CH:76]=[CH:77][CH:78]=3)[C:68]=2[N:67]=[CH:66]1)(=O)C.C[O-].[Na+]>CO>[Cl:84][C:81]1[N:80]=[C:69]([NH:70][C@H:71]([CH3:79])[CH2:72][S:73][C:74]2[S:75][CH:76]=[CH:77][CH:78]=2)[C:68]2[N:67]=[CH:66][N:65]([C:83]=2[N:82]=1)[C@@H:52]1[O:53][C@H:54]([CH2:60][OH:61])[C@@H:55]([OH:56])[C@H:51]1[OH:50]
Reactant: CC(=O)OC[C@H]1O[C@@H](n2cnc3c(N[C@H](C)CSc4cccs4)nc(Cl)nc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: CC(=O)OC[C@H]1O[C@@H](n2cnc3c(Cl)nc(Cl)nc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: C[C@@H](N)CSc1cccs1
Agent: C[O-]
Solvent: CO
Product: C[C@H](CSc1cccs1)Nc1nc(Cl)nc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Yield: 82 %

Procedure:
The title compound was prepared according to method A as described in Example 1 by reacting 2-[(R)-2-amino-1-propylthio]thiophene hydrochloride [prepared by a Mitsunobu reaction as described in Example 1 using 2-[(R)-N-tert-butyloxycarbonyl]amino-1-propanol (7.53 g, 43 mmol) and 2-mercaptothiophene (5.00 g, 43 mmol) followed by acidic hydrolysis] (0.63 g, 3.0 mmol) with 9-(2,3,5-tri-O-acetyl-β-D-ribofuranosyl)-2,6-dichloro-9H-purine (1.12 g, 2.5 mmol), followed by deacylation of the purified 2',3',5'-tri-O-acetyl-2-chloro-N-[(R)-1-(2-thienyl)thio-2-propyl]adenosine using sodium methoxide in methanol to provide the title 2-chloro-N-[(R)-1-(2-thienyl)thio-2-propyl]adenosine (0.95 g, 82%) as a foam after column chromatography. 1H NMR (DMSO-d6) δ1.26 (3H, d, --CHCH3), 2.95-3.18 (2H, ABX, --CH2 --S--), 3.55 and 3.61 (2H, ABX, H-5'a and H-5'b ), 3.95 (1H, q, H-4), 4.14 (1H, t, H-3'), 4.44 (1H, m, --CH--CH3), 4.54 (1H, t, H-2'), 5.84 (1H, d, H-1'), 7.03 (1H, t, Ar--H), 7.23, 7.61 (2H, 2d, Ar--H), 8.38 (1H, d, --NH), 8.42 (1H, s, H-2). HPLC retention time 19.5 min [gradient elution, 20-80% acetonitrile/water (containing 0.1% TFA)].
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([F:12])[CH:3]=1.[CH3:13][N:14](C)C=O>[C-]#N.[Zn+2].[C-]#N.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Pd]>[C:13]([C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([F:12])[CH:3]=1)#[N:14]
Reactant: COC(=O)c1ccc(Br)cc1F
Reactant: CN(C)C=O
Agent: [Pd]
Agent: [C-]#N
Agent: [Zn+2]
Product: COC(=O)c1ccc(C#N)cc1F
Temperature: 80 °C
Reaction time: 8 h
Yield: 80 %

Procedure:
A solution of methyl 4-bromo-2-fluorobenzoate (10.0 g, 43 mmol), zinc cyanide (10.0 g, 86 mmol) and palladium tetrakis(triphenylphosphine) (2.5 g, 0.64 mmol) in anhydrous N,N-dimethylformamide (100 mL) was purged with nitrogen and the mixture stirred at 80° C. overnight. After cooling, the mixture was partitioned between ethyl acetate and brine and the organic phase washed with water and concentrated. The solid was purified on silica gel using 1:5 ethyl acetate/hexane to afford the title compound (6.1 g, 80%). MS (DCI): m/z 180 (M+H)+.
Reaction SMILES: [BH4-].[Na+].S(=O)(=O)(O)O.[O:8]([C:15]1[CH:23]=[CH:22][C:18]([C:19](O)=[O:20])=[CH:17][CH:16]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[OH-].[Na+]>C(OCC)C.O1CCCC1.C(OCC)(=O)C.CO>[O:8]([C:15]1[CH:16]=[CH:17][C:18]([CH2:19][OH:20])=[CH:22][CH:23]=1)[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: O=C(O)c1ccc(Oc2ccccc2)cc1
Agent: O=S(=O)(O)O
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CO
Product: OCc1ccc(Oc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of sodium borohydride (2.20 g, 58.3 mmol) and concentrated sulfuric acid in diethyl ether (1.6 mL) was added to a solution of 4-phenoxybenzoic acid (5.0 g, 23.3 mmol) in tetrahydrofuran (20 mL) that had been cooled on an ice bath, and the solution was stirred for 4 hours at room temperature. The reaction solution was cooled on an ice bath, methanol was added, then, the solution was allowed to room temperature and stirred for 30 minutes. This reaction solution was cooled again, ethyl acetate and an aqueous solution of 2N sodium hydroxide were added for partitioning, the organic layer was washed with 10% sodium chloride water, dried over anhydrous magnesium sulfate, and the solvent was evaporated to obtain 4-phenoxybenzyl alcohol (4.669, quantitatively) as a colorless solid. This 4-phenoxybenzyl alcohol was used to carry out an analogous reaction to Preparation Example 2, and the title compound (886 mg) was obtained as a pale brown solid.
Reaction SMILES: OC(C)(C)CN1C=C[C:6]([NH:9][C:10](=[O:30])[C@@H:11]([N:16]2[CH2:20][C:19]([O:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[Cl:28])=[CH:18][C:17]2=[O:29])[CH2:12][CH:13]([CH3:15])[CH3:14])=[N:5]1.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.[CH:55]1([C:58]2N=C(N)[S:60][N:59]=2)[CH2:57][CH2:56]1>ClCCl>[CH:55]1([C:58]2[N:5]=[C:6]([NH:9][C:10](=[O:30])[C@@H:11]([N:16]3[CH2:20][C:19]([O:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[Cl:28])=[CH:18][C:17]3=[O:29])[CH2:12][CH:13]([CH3:14])[CH3:15])[S:60][N:59]=2)[CH2:57][CH2:56]1
Reactant: Nc1nc(C2CC2)ns1
Reactant: CC(C)C[C@@H](C(=O)Nc1ccn(CC(C)(C)O)n1)N1CC(Oc2ccccc2Cl)=CC1=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: CC(C)C[C@@H](C(=O)Nc1nc(C2CC2)ns1)N1CC(Oc2ccccc2Cl)=CC1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 32.4 %

Procedure:
To a solution of (S)-2-[4-(2-chloro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid (prepared as in Example 64, 95 mg, 0.29 mmol) in dichloromethane (1.00 mL) was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (62 mg, 0.32 mmol) and 1-hydroxybenzotriazole (41 mg, 0.30 mmol). The resulting solution was stirred for 5 min before 3-cyclopropyl-[1,2,4]thiadiazol-5-ylamine (50 mg, 0.35 mmol) was added and the resulting mixture stirred at 25° C. overnight. The mixture was washed with saturated ammonium chloride (1 mL), evaporated and the crude product purified by HPLC (Gilson semi-prep; Supelcosil ABZ+Plus 12 μM 25 cm×21.2 mm column 20-95% acetonitrile/water gradient) which afforded (S)-2-[4-(2-chloro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid (3-cyclopropyl-[1,2,4]thiadiazol-5-yl)-amide (42 mg, 32%) as a light orange solid: HR-ES-MS m/z calculated for C21H23ClN4O3S [M+H]+ 447.1252, observed 447.1252; 1H NMR (300 MHz, DMSO-d6) ppm 0.84-0.97 (m, 2H), 0.91 (d, J=6.6 Hz, 3H), 0.94 (d, J=6.6 Hz, 3H), 0.97-1.06 (m, 2H), 1.39-1.56 (m, 1H), 1.55-1.75 (m, 1H), 1.76-1.97 (m, 1H), 2.07-2.24 (m, 1H), 4.28 (d, J=18.4 Hz, 1H), 4.51 (d, J=18.4 Hz, 1H), 4.82 (s, 1H), 4.99 (dd, J=11.0, 4.4 Hz, 1H), 7.37 (td, J=8.0, 1.3 Hz, 1H), 7.47 (td, J=8.0, 1.1 Hz, 1H), 7.54 (dd, J=8.0, 1.3 Hz, 1H), 7.66 (dd, J=8.0, 1.1 Hz, 1H), 13.26 (s, 1H).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([N:7]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH3:18])[CH:15]=3)[CH2:10][CH2:9][CH2:8]2)[CH2:3][CH2:2]1.[CH3:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27][CH2:28]Br)=[CH:23][CH:22]=1.C(N(C(C)C)CC)(C)C.O>CN(C=O)C>[CH3:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27][CH2:28][N:1]2[CH2:2][CH2:3][CH:4]([N:7]3[C:16]4[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH3:18])[CH:15]=4)[CH2:10][CH2:9][CH2:8]3)[CH2:5][CH2:6]2)=[CH:23][CH:22]=1
Reactant: COc1ccc2c(c1)N(C1CCNCC1)CCC2
Reactant: COc1ccc(CCBr)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(CCN2CCC(N3CCCc4ccc(OC)cc43)CC2)cc1
Temperature: 25 °C

Procedure:
A solution of 1-(4-piperidinyl)-7-methoxy-1,2,3,4-tetrahydroquinoline (250 mg), 2-(4-methoxyphenyl)ethyl bromide (260 mg) and diisopropylethylamine (270 mg) in DMF (5 ml) was heated at 60° C. for 12 hr under stirring. After the completion of the reaction, the reaction solution was cooled to room temperature and water was added thereto followed by extraction with ethyl acetate. The ethyl acetate layer was washed with brine and dried over magnesium sulfate. After evaporating the solvent, the resulting obtained residue was purified by silica gel column chromatography (toluene/acetone system) to give 1-{1-[2-(4-methoxyphenyl)ethyl]piperidin-4-yl}-7-methoxy-1,2,3,4-tetrahydroquinoline as an oil. This free compound was dissolved in ethyl acetate and 8.5% HCl/ethyl acetate was added thereto. The resulting hydrochloride was recrystallized from ethanol/ether to give the title compound (225 mg) (yield: 53%).
Reaction SMILES: Cl.[NH2:2][CH:3]1[CH2:8][CH2:7][N:6]([CH2:9][CH2:10][N:11]2[C:20]3[C:15](=[N:16][CH:17]=[C:18]([O:21][CH3:22])[CH:19]=3)[CH:14]=[CH:13][C:12]2=[O:23])[CH2:5][CH2:4]1.C[O-].[Na+].CO.[F:29][C:30]1[C:31]([N:38]2[CH2:42][CH2:41][CH2:40][CH2:39]2)=[N:32][CH:33]=[C:34]([CH:37]=1)[CH:35]=O.C([BH3-])#N.[Na+].C(=O)([O-])O.[Na+]>CO.O.C(Cl)(Cl)Cl.C(O)(=O)C>[F:29][C:30]1[CH:37]=[C:34]([CH2:35][NH:2][CH:3]2[CH2:4][CH2:5][N:6]([CH2:9][CH2:10][N:11]3[C:20]4[C:15](=[N:16][CH:17]=[C:18]([O:21][CH3:22])[CH:19]=4)[CH:14]=[CH:13][C:12]3=[O:23])[CH2:7][CH2:8]2)[CH:33]=[N:32][C:31]=1[N:38]1[CH2:42][CH2:41][CH2:40][CH2:39]1
Reactant: O=Cc1cnc(N2CCCC2)c(F)c1
Reactant: COc1cnc2ccc(=O)n(CCN3CCC(N)CC3)c2c1
Agent: C[O-]
Agent: Cl
Agent: O=C([O-])O
Solvent: O
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Product: COc1cnc2ccc(=O)n(CCN3CCC(NCc4cnc(N5CCCC5)c(F)c4)CC3)c2c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 39.1 %

Procedure:
To a suspension of 0.20 g of 1-(2-(4-aminopiperidin-1-yl)ethyl)-7-methoxy-1,5-naphthyridin-2(1H)-one hydrochloride in 2 mL of methanol, 0.28 g of a 28% sodium methoxide/methanol solution, 94 mg of 5-fluoro-6-(pyrrolidin-1-yl)nicotinaldehyde and 28 μL of acetic acid were added. Then, 61 mg of sodium cyanoborohydride was added thereto, and the mixture was stirred at room temperature for 2 hours 20 minutes. To the reaction mixture, chloroform, a saturated aqueous sodium hydrogen carbonate solution and water were added. The organic layer was separated, and the aqueous layer was extracted with chloroform. The organic layer and the extract were combined, the resultant solution was washed with water and a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The resultant residue was purified by basic silica gel column chromatography using gradient elution with chloroform:methanol=95:5 to 9:1, thereto was added diethyl ether, and the solid was filtered off to obtain 91 mg of 1-(2-(4-(((5-fluoro-6-(pyrrolidin-1-yl)pyridin-3-yl)methyl)amino)piperidin-1-yl)ethyl)-7-methoxy-1,5-naphthyridin-2(1H)-one as a slightly yellow solid.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([CH:8]2[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9]2)=[CH:4][CH:3]=1.Br[C:21]1[C:22](=[O:29])[N:23]([CH3:28])[N:24]=[C:25]([Cl:27])[CH:26]=1.C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:27][C:25]1[CH:26]=[C:21]([NH:1][C:2]2[N:7]=[CH:6][C:5]([CH:8]3[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9]3)=[CH:4][CH:3]=2)[C:22](=[O:29])[N:23]([CH3:28])[N:24]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(N)nc2)C1
Reactant: Cn1nc(Cl)cc(Br)c1=O
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: Cn1nc(Cl)cc(Nc2ccc(C3CCN(C(=O)OC(C)(C)C)C3)cn2)c1=O
Temperature: 100 °C
Yield: 50 %

Procedure:
Tert-butyl 3-(6-aminopyridin-3-yl)pyrrolidine-1-carboxylate (422 mg, 1.6 mmol, Eq: 1.00), 4-bromo-6-chloro-2-methylpyridazin-3(2H)-one (430 mg, 1.92 mmol, Eq: 1.20), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (139 mg, 240 μmol, Eq: 0.15), cesium carbonate (1.57 g, 4.81 mmol, Eq: 3) and tris(dibenzylideneacetone)dipalladium(0) (73.4 mg, 80.1 μmol, Eq: 0.05) were combined in dioxane (10 ml). The solution was degassed with Ar for 10 min. The mixture was heated at 100° C. for 18 h. The solution was cooled to room temperature then diluted with 100 ml DCM. The organics washed with water, then dried over MgSO4. The solution was filtered. Concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 40 g, 50% to 100% EtOAC/Hex gradient) to give tert-butyl 3-(6-(6-chloro-2-methyl-3-oxo-2,3-dihydropyridazin-4-ylamino)pyridin-3-yl)pyrrolidine-1-carboxylate (325 mg, 50%) LC/MS-ESI observed [M+H]+ 406.
Reaction SMILES: [C:1]([C:4]1[C:9](=[O:10])[NH:8][C:7](=[O:11])[NH:6][C:5]=1[C:12]([C:14]1[CH:15]=[C:16]([CH:19]=[C:20]([CH3:22])[CH:21]=1)[C:17]#[N:18])=[O:13])([CH3:3])=[CH2:2].[F:23][C:24]1[CH:29]=[C:28]([CH2:30]OS(C)(=O)=O)[CH:27]=[C:26]([NH:36][CH2:37][C:38]2[CH:43]=[CH:42][C:41]([O:44][CH3:45])=[CH:40][CH:39]=2)[N:25]=1.[I-].[Li+].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[F:23][C:24]1[CH:29]=[C:28]([CH2:30][N:6]2[C:5]([C:12]([C:14]3[CH:15]=[C:16]([CH:19]=[C:20]([CH3:22])[CH:21]=3)[C:17]#[N:18])=[O:13])=[C:4]([C:1]([CH3:3])=[CH2:2])[C:9](=[O:10])[NH:8][C:7]2=[O:11])[CH:27]=[C:26]([NH:36][CH2:37][C:38]2[CH:43]=[CH:42][C:41]([O:44][CH3:45])=[CH:40][CH:39]=2)[N:25]=1
Reactant: C=C(C)c1c(C(=O)c2cc(C)cc(C#N)c2)[nH]c(=O)[nH]c1=O
Reactant: COc1ccc(CNc2cc(COS(C)(=O)=O)cc(F)n2)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C=C(C)c1c(C(=O)c2cc(C)cc(C#N)c2)n(Cc2cc(F)nc(NCc3ccc(OC)cc3)c2)c(=O)[nH]c1=O
Temperature: 25 °C
Reaction time: 6 h
Yield: 48.9 %

Procedure:
A solution of 3-(5-isopropenyl-2,6-dioxo-1,2,3,6-tetrahydro-pyrimidine-4-carbonyl)-5-methyl-benzonitrile (0.0375 g, 0.127 mmol), methanesulfonic acid 2-fluoro-6-(4-methoxy-benzylamino)-pyridin-4-ylmethyl ester (0.024 g, 0.072 mmol), lithium iodide (0.0048 g, 0.036 mmol) and potassium carbonate (0.010 g, 0.072 mmol) in DMF (1.0 mL) was stirred at 0° C. for 2 h, then warmed to rt. After 6 h, reaction mixture was diluted with ethyl acetate, washed with water (2×), dried (MgSO4), concentrated and purified by flash column chromatography (silica gel, 10 to 50% ethyl acetate/hexane) to give a yellow solid (0.019 g, 49%). 1H NMR (300 MHz, CD3CN): δ 7.87 (s, 1H), 7.74 (s, 1H), 7.65 (s, 1H), 7.19 (d, J=8.7 Hz, 2H), 6.85 (d, J=8.7 Hz, 2H), 5.89 (s, 1H), 5.84 (s, 1H), 5.66 (br s, 1H), 5.2-4.95 (br s, 1 h), 4.92 (s, 1H), 4.70 (s, 1H), 4.5-4.2 (br s, 1H), 4.20 (d, J=5.7 Hz, 2H), 3.75 (s, 3H), 2.30 (s, 3H), 1.67 (s, 3H). Mass spectrum: 538.1 (M+H)+.
Reaction SMILES: [Si:1]([O:8][C@@H:9]([C@@H:11]1[C@@H:14]([O:15][Si](C)(C)C)[NH:13][C:12]1=[O:20])[CH3:10])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[C:21](O)(=[O:23])[CH3:22].C(OC(=O)C)(=O)C>C(OCC)(=O)C.CN(C)C1C=CN=CC=1>[C:21]([O:15][C@H:14]1[NH:13][C:12](=[O:20])[C@@H:11]1[C@H:9]([O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])[CH3:10])(=[O:23])[CH3:22]
Reactant: C[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]1C(=O)N[C@@H]1O[Si](C)(C)C
Reactant: CC(=O)O
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Solvent: CC(=O)OC(C)=O
Product: CC(=O)O[C@H]1NC(=O)[C@@H]1[C@@H](C)O[Si](C)(C)C(C)(C)C
Temperature: -35 °C
Reaction time: 21 h
Yield: 59 %

Procedure:
After 156 mg of (3R,4R)-3-[(R)-1-tert-butyldimethylsilyloxyethyl]-4-trimethylsilyloxyazetidin-2-one was dissolved in 1.6 ml of ethyl acetate, the mixture was cooled to -35° C. and thereto 0.03 ml (concentration: 1.84% by volume) of acetic acid, 0.5 ml of acetic anhydride and then 30 mg (concentration: 1.36% by weight) of 4-dimethylaminopyridine were added. The mixture was stirred for 21 hours at -35° C. After completion of the reaction and the same treatment as in Example 16, it was analyzed by means of high performance liquid chromatography used in Example 16 to find 83 mg of (3R,4R)-4-acetoxy-3-[(R)-1-tert-butyldimethylsilyloxyethyl]azetidin-2-one (yield: 59%).
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:19])=[C:4]([N:8]2[C:16](=[O:17])[C:15]3[CH:14]=[CH:13][N:12]=[CH:11][C:10]=3[C:9]2=O)[CH:5]=[CH:6][CH:7]=1.[BH4-].[Na+].BrC1C(C)=C(NC(=O)C2C(CO)=CC=NC=2)C=CC=1.BrC1C(C)=C(NC(=O)C2C=CN=CC=2CO)C=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>CO>[Br:1][C:2]1[C:3]([CH3:19])=[C:4]([N:8]2[C:16](=[O:17])[C:15]3[CH:14]=[CH:13][N:12]=[CH:11][C:10]=3[CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1c(Br)cccc1N1C(=O)c2ccncc2C1=O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: Cc1c(Br)cccc1NC(=O)c1ccncc1CO
Agent: Cc1c(Br)cccc1NC(=O)c1cnccc1CO
Solvent: CO
Product: Cc1c(Br)cccc1N1Cc2cnccc2C1=O
Reaction time: 1 h

Procedure:
A suspension of 2-(3-bromo-2-methylphenyl)-1H-pyrrolo[3,4-c]pyridine-1,3(2H)-dione (4.7 g, 14.82 mmol) in methanol (200 mL) was treated with sodium borohydride (2 g, 52.9 mmol) and stirred at A for 1 h. The mixture was concentrated and the residue was treated with NaHCO3 (aq). The mixture was extracted several times with a mixture of DCM and methanol. The combined organic phases were washed with water, dried and concentrated to give a mixture of N-(3-bromo-2-methylphenyl)-4-(hydroxymethyl)-nicotinamide and N-(3-bromo-2-methylphenyl)-3-(hydroxymethyl)isonicotinamide as an off-white solid. Mass spectrum m/z 321, 323 (M+H)+. Without purification, this material was suspended in THF (250 mL) and treated with triphenylphosphine (polymer supported, 3 mmol P/g resin, 18.44 g, 54.8 mmol) and diethyl azodicarboxylate (6.45 g, 37.1 mmol) and the mixture was stirred at A for 4 h. The mixture was filtered and concentrated, and the residue was dissolved in DCM, washed with water, NaHCO3 (aq) and brine, and dried and concentrated. The residue was subjected to column chromatography (eluting with EtOAc) to provide 2-(3-bromo-2-methylphenyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one as a white solid (Intermediate 44-1, 2.7 g, 60%). 1H NMR (400 MHz, chloroform-d) ε9.21 (1H, d, J=0.88 Hz), 8.84 (1H, d, J=5.06 Hz), 7.63 (1H, dd, J=7.70, 1.32 Hz), 7.51 (1H, dd, J=5.06, 0.88 Hz), 7.22 (1H, dt, J=7.70, 1.32 Hz), 7.17 (1H, d, J=7.92 Hz), 4.76 (2H, s), 2.31 (3H, s). Mass spectrum m/z 303, 305 (M+H)+. Also obtained was (Z)-3-bromo-N-(furo[3,4-c]pyridin-1(3H)-ylidene)-2-methylaniline as a white solid (Intermediate 44-2, 760 mg, 17%), which also contained the isomeric (Z)-3-bromo-N-(furo[3,4-c]pyridin-3(1H)-ylidene)-2-methylaniline. 1H NMR (400 MHz, chloroform-d) δ 9.26 (1H, s), 8.80 (1H, d, J=5.06 Hz), 7.42 (1H, dd, J=5.06, 0.88 Hz), 7.31-7.35 (1H, m), 7.02-7.08 (2H, m), 5.39 (2H, s), 2.35 (3H, s). Mass spectrum m/z 303, 305 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[C:7]([C:11]3[CH:12]=[C:13]([O:17][S:18](=[O:25])(=[O:24])[N:19]([CH2:22][CH3:23])[CH2:20][CH3:21])[CH:14]=[N:15][CH:16]=3)[NH:8]2)=[CH:4][CH:3]=1.[CH3:26]N(C=O)C.C(=O)(OC)OC.C(=O)([O-])[O-].[K+].[K+]>C(OCC)(=O)C>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[C:7]([C:11]3[CH:12]=[C:13]([O:17][S:18](=[O:24])(=[O:25])[N:19]([CH2:20][CH3:21])[CH2:22][CH3:23])[CH:14]=[N:15][CH:16]=3)[N:8]2[CH3:26])=[CH:4][CH:3]=1
Reactant: CCN(CC)S(=O)(=O)Oc1cncc(-c2cc3ccc(Cl)cc3[nH]2)c1
Reactant: CN(C)C=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COC(=O)OC
Solvent: CCOC(C)=O
Product: CCN(CC)S(=O)(=O)Oc1cncc(-c2cc3ccc(Cl)cc3n2C)c1
Temperature: 150 °C
Reaction time: 8 h

Procedure:
A flask is charged with diethyl-sulfamic acid 5-(6-chloro-1H-indol-2-yl)-pyridin-3-yl ester (0.175 g, 0.560 mmol) and DMF (5 mL). Dimethyl carbonate (0.116 mL, 1.38 mmol) and potassium carbonate (0.035 g, 0.253 mmol) are added and the reaction is stirred at 150° C. overnight. The reaction mixture is cooled to room temperature, diluted with ethyl acetate and washed with water. The organic layer is dried over sodium sulfate and concentrated in vacuo. The residue is purified by flash chromatography (heptane-ethyl acetate, 3:1) to afford diethyl-sulfamic acid 5-(6-chloro-1-methyl-1H-indol-2-yl)-pyridin-3-yl ester as a yellow solid. MS (ESI) m/z 394.04 (M+H)+
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][CH2:10][CH2:11][S:12]([CH3:15])(=[O:14])=[O:13])[CH:5]=[C:4]([CH3:16])[C:3]=1[C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([CH:23]=[O:24])[CH:18]=1.C(O)C.[OH-].[Na+].[BH4-].[Na+]>O>[CH3:16][C:4]1[CH:5]=[C:6]([O:8][CH2:9][CH2:10][CH2:11][S:12]([CH3:15])(=[O:14])=[O:13])[CH:7]=[C:2]([CH3:1])[C:3]=1[C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([CH2:23][OH:24])[CH:18]=1
Reactant: Cc1cc(OCCCS(C)(=O)=O)cc(C)c1-c1cccc(C=O)c1
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cc1cc(OCCCS(C)(=O)=O)cc(C)c1-c1cccc(CO)c1
Reaction time: 0.17 h
Yield: 94.6 %

Procedure:
To 2′,6′-dimethyl-4′-[3-(methylsulfonyl)propoxy]biphenyl-3-carbaldehyde (50.0 g) was added ethanol (400 mL), and the mixture was stirred for 10 min. To this solution was added dropwise at 25° C. a solution separately prepared by dissolving sodium hydroxide (1.0 g) in water (125 mL) and adding sodium borohydride (3.28 g), and the wall-side of the titration equipment was washed with water (50 mL). The mixture was stirred at 25° C. for 1 hr, activated carbon (10.0 g) was added, and the mixture was stirred for 1 hr. The insoluble material was removed by filtration, and washed with a mixed solution (200 mL) of water.ethanol (1:4). 6M Hydrochloric acid was added to the filtrate at 25° C. to adjust the mixture to pH 3.0. Then, 1 mol/L aqueous sodium hydroxide solution was added to adjust the mixture to pH 7.0. The mixture was concentrated to 200 mL, the attachment on the wall was washed with a mixed solution (50 mL) of water-ethanol (1:4), and the mixture was stirred at 50° C. for 30 min. Water (50 mL) was added dropwise, and the mixture was stirred at 50° C. for 30 min. After stirring at 25° C. for 2 hr, water (450 mL) was added dropwise, and the mixture was stirred at 25° C. for 2 hr. The precipitated solid was collected by filtration, and the solid was washed with water (500 mL) and dried at 60° C. under reduced pressure to give {2′,6′-dimethyl-4′-[3-(methylsulfonyl)propoxy]biphenyl-3-yl}methanol (47.6 g).