Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]([CH2:4][CH2:5][CH2:6][CH2:7][N:8]1[C:20]2[C:19]3[N:21]([CH3:28])[C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][C:27]=4[C:18]=3[C:17]3[C:29](=[O:33])[NH:30][C:31](=[O:32])[C:16]=3[C:15]=2[C:14]2[C:9]1=[CH:10][CH:11]=[CH:12][CH:13]=2)=[N+]=[N-]>O1CCCC1.C(O)C.[Pd]>[NH2:1][CH2:4][CH2:5][CH2:6][CH2:7][N:8]1[C:20]2[C:19]3[N:21]([CH3:28])[C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][C:27]=4[C:18]=3[C:17]3[C:29](=[O:33])[NH:30][C:31](=[O:32])[C:16]=3[C:15]=2[C:14]2[C:9]1=[CH:10][CH:11]=[CH:12][CH:13]=2
Reactant: Cn1c2ccccc2c2c3c(c4c5ccccc5n(CCCCN=[N+]=[N-])c4c21)C(=O)NC3=O
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: Cn1c2ccccc2c2c3c(c4c5ccccc5n(CCCCN)c4c21)C(=O)NC3=O
Reaction time: 48 h

Procedure:
300 mg (0.1 mmol) 12-(4-Azidobutyl)-6,7,12,13-tetrahydro-13-methyl-5,7-dioxo-5H-indolo[2,3-a]-pyrrolo[3,4-c]carbazole (see Example 1w) in 40 ml tetrahydrofuran/ethanol (1:1 v/v) are hydrogenated in the presence of 300 mg 5% palladium on active carbon at 25° C. and 50 bar pressure for 48 hours in an autoclave. After filtration of the solution, the solvent is distilled off and the residue is crystallised from ethanol. 12-(4-Aminobutyl)-6,7,12,13-tetrahydro-13-methyl-5,7-dioxo-5H-indolo[2,3-a]pyrrolo[3,4-c]carbazole is obtained in the form of yellow crystals; m.p.10 220-223° C.
Reaction SMILES: [NH2:1][C:2]1[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:5][N:4]([CH3:12])[N:3]=1.C[Si](C)(C)[N-][Si](C)(C)C.[Na+].O1C[CH2:26][CH2:25][CH2:24]1.C(Br)C=C>CN1CCCN(C)C1=O.O>[CH2:26]([NH:1][C:2]1[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:5][N:4]([CH3:12])[N:3]=1)[CH:25]=[CH2:24]
Reactant: C1CCOC1
Reactant: CCOC(=O)c1cn(C)nc1N
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: CN1CCCN(C)C1=O
Solvent: O
Solvent: C=CCBr
Product: C=CCNc1nn(C)cc1C(=O)OCC
Temperature: -40 °C
Reaction time: 0.13 h
Yield: 34 %

Procedure:
Ethyl 3-amino-1-methylpyrazole-4-carboxylate, prepared by the method of Schmidt et al., Helvetica Chim. Acta. 42 349 (1959), (12.5 g, 7.40 mmol) was dissolved in 80 mL of 1,3-dimethyl-3,4,5,6-tetrahydro2(1H)-pyrimidinone (DMPU) and cooled to -40° C. A 1M solution of sodium hexamethyldisilazide in tetrahydrofuran (80 mL, 8.0 mmol) was added dropwise. After 8 minutes at -35° C., the reaction was cooled to -40° C. and 13.16 g (10.8 mmol) of allyl bromide was added dropwise. The reaction mixture was allowed to warm to 10° C. over 90 minutes. Water was added and the mixture was extracted with ether. The combined organic extracts were washed with water (3×), dried over sodium sulfate and concentrated in vacuo to afford a mixture of mono- and di-allyl products plus 10% unreacted starting material. Separation by column chromatography on silica gel eluting with 30% ethyl acetate in hexane afforded 5.26 g (34%) of the title compound as a colorless oil.
Reaction SMILES: C(OC([NH:8][C@H:9]([C:15]([OH:17])=[O:16])[CH2:10][Si:11]([CH3:14])([CH3:13])[CH3:12])=O)(C)(C)C.[CH3:18][Si]([Cl:22])(C)C>CO>[ClH:22].[CH3:18][O:17][C:15](=[O:16])[C@H:9]([CH2:10][Si:11]([CH3:12])([CH3:13])[CH3:14])[NH2:8]
Reactant: CC(C)(C)OC(=O)N[C@@H](C[Si](C)(C)C)C(=O)O
Reactant: C[Si](C)(C)Cl
Solvent: CO
Product: COC(=O)[C@@H](N)C[Si](C)(C)C
Product: Cl
Temperature: 0 °C

Procedure:
The compound of Example 6A (300 mg) is dissolved in methanol (3 ml) and cooled to 0° C. Trimethylsilyl chloride (590 mg, 4.7 eq.) is added dropwise in the course of 30 min. and the mixture is warmed to RT overnight. The volatile components are removed on a Rotavapor and subsequently under high vacuum. The target compound (224 mg, 92% of th.) is obtained.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:18]2[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:11]=[C:10]([NH2:19])[C:9]=2[N:8]=[CH:7]1.[CH3:20][N:21]([CH3:36])[C:22]1[CH:31]=[CH:30][CH:29]=[C:28]2[C:23]=1[CH:24]=[CH:25][CH:26]=[C:27]2[S:32](Cl)(=[O:34])=[O:33]>N1C=CC=CC=1>[NH2:19][C:10]1[C:9]2[N:8]=[CH:7][N:6]([CH2:5][CH2:4][CH2:3][CH2:2][NH:1][S:32]([C:27]3[C:28]4[C:23](=[C:22]([N:21]([CH3:36])[CH3:20])[CH:31]=[CH:30][CH:29]=4)[CH:24]=[CH:25][CH:26]=3)(=[O:34])=[O:33])[C:18]=2[C:17]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N:11]=1
Reactant: NCCCCn1cnc2c(N)nc3ccccc3c21
Reactant: CN(C)c1cccc2c(S(=O)(=O)Cl)cccc12
Solvent: c1ccncc1
Product: CN(C)c1cccc2c(S(=O)(=O)NCCCCn3cnc4c(N)nc5ccccc5c43)cccc12
Temperature: 60 °C

Procedure:
A suspension of 1-(4-aminobutyl)-1H-imidazo[4,5-c]quinolin-4-amine (0.5 g, 2.0 mmol) in pyridine (250 mL) was warmed to 60° C. to dissolve the amine. The solution was allowed to cool to about 30° C. and then 5-dimethylamino-1-naphthalenesulfonyl chloride (0.5 g, 1.8 mmol) was slowly added. After 1 hour 0.3 g of 5-dimethylamino-1-naphthalenesulfonyl chloride was added. The reaction mixture was warmed to 60° C. and maintained at that temperature overnight. The reaction mixture was concentrated under vacuum. The residue was recrystallized from propyl acetate to provide N1-[4-(4-amino-1H-imidazo[4,5-c]quinolin-1-yl)butyl]-5-(dimethylamino)-1-naphthalenesulfonamide as a solid, m.p. 200-201° C.
Reaction SMILES: [N:1]([C@:4]1([C:43]([O:45]CC(=O)C2C=CC=CC=2)=[O:44])[C@@H:8]([CH2:9][CH2:10][CH2:11][B:12]2[O:16][C:15]([CH3:18])([CH3:17])[C:14]([CH3:20])([CH3:19])[O:13]2)[CH2:7][N:6]([C:21](=[O:42])[C@H:22]([CH2:31][C:32]2[CH:37]=[CH:36][C:35]([C:38]([F:41])([F:40])[F:39])=[CH:34][CH:33]=2)[NH:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:5]1)=[N+]=[N-]>C(O)(=O)C.[Zn]>[NH2:1][C@:4]1([C:43]([OH:45])=[O:44])[C@@H:8]([CH2:9][CH2:10][CH2:11][B:12]2[O:16][C:15]([CH3:18])([CH3:17])[C:14]([CH3:19])([CH3:20])[O:13]2)[CH2:7][N:6]([C:21](=[O:42])[C@H:22]([CH2:31][C:32]2[CH:33]=[CH:34][C:35]([C:38]([F:41])([F:39])[F:40])=[CH:36][CH:37]=2)[NH:23][C:24]([O:26][C:27]([CH3:28])([CH3:29])[CH3:30])=[O:25])[CH2:5]1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(C(F)(F)F)cc1)C(=O)N1C[C@H](CCCB2OC(C)(C)C(C)(C)O2)[C@](N=[N+]=[N-])(C(=O)OCC(=O)c2ccccc2)C1
Agent: [Zn]
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(C(F)(F)F)cc1)C(=O)N1C[C@H](CCCB2OC(C)(C)C(C)(C)O2)[C@](N)(C(=O)O)C1
Temperature: 25 °C
Reaction time: 1.25 h

Procedure:
A stirred solution of 2-oxo-2-phenylethyl (3R,4S)-3-azido-1-[N-(tert-butoxycarbonyl)-4-(trifluoromethyl)phenylalanyl]-4-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)propyl]pyrrolidine-3-carboxylate (Step 1) in acetic acid (9 mL) was treated with zinc (201 mg, 3.08 mmol, 10 equiv), and the heterogeneous mixture was stirred at room temperature. After 1.25 h, the reaction was filtered, the filter pad was washed with acetic acid and ethyl acetate, and the filtrate was concentrated and dried under reduced pressure to give the crude (3R,4S)-3-amino-1-[N-(tert-butoxycarbonyl)-4-(trifluoromethyl)phenylalanyl]-4-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)propyl]pyrrolidine-3-carboxylic acid (242 mg) as a clear film which was used without further purification. LC-MS ESI+ MS found for C29H43BF3N3O7 m/z 614.3 (M+H); ESI− MS m/z 612.3 (M−H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([OH:13])[CH:7]=[CH:6]2.C1(=O)O[CH2:17][CH2:16][O:15]1>CO.C(Cl)(Cl)Cl.CCCCCC>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([O:13][CH2:17][CH2:16][OH:15])[CH:7]=[CH:6]2
Reactant: COc1ccc2cc(O)ccc2c1
Reactant: O=C1OCCO1
Solvent: CO
Solvent: CCCCCC
Solvent: ClC(Cl)Cl
Product: COc1ccc2cc(OCCO)ccc2c1

Procedure:
*Prepared from 6-methoxy-2-naphthol and ethylene carbonat according to the procedure of Example 134, step 1, in WO 00/76984. The reaction mixture was refluxed for 2 h. Pure 2-(6-methoxy-naphthalen-2-yloxy)ethanol was obtained by recrystallization from MeOH/CHCl3/n-hexane.
Reaction SMILES: [CH:1]1([C:4]2[NH:8][N:7]=[C:6]([NH:9][C:10]3[CH:15]=[C:14](F)[CH:13]=[CH:12][C:11]=3[N+:17]([O-:19])=[O:18])[CH:5]=2)[CH2:3][CH2:2]1.[F:20][C:21]1[CH:26]=[CH:25][C:24]([C@@H:27]([NH2:29])[CH3:28])=[CH:23][CH:22]=1.CCN(C(C)C)C(C)C>CCCCO>[CH:1]1([C:4]2[NH:8][N:7]=[C:6]([NH:9][C:10]3[CH:15]=[C:14]([NH:29][C@H:27]([C:24]4[CH:25]=[CH:26][C:21]([F:20])=[CH:22][CH:23]=4)[CH3:28])[CH:13]=[CH:12][C:11]=3[N+:17]([O-:19])=[O:18])[CH:5]=2)[CH2:3][CH2:2]1
Reactant: O=[N+]([O-])c1ccc(F)cc1Nc1cc(C2CC2)[nH]n1
Reactant: C[C@H](N)c1ccc(F)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: C[C@H](Nc1ccc([N+](=O)[O-])c(Nc2cc(C3CC3)[nH]n2)c1)c1ccc(F)cc1
Temperature: 230 °C
Yield: 96.7 %

Procedure:
A mixture of 5-cyclopropyl-N-(5-fluoro-2-nitrophenyl)-1H-pyrazol-3-amine (Method 82; 0.27 g, 1.03 mmol), (S)-1-(4-fluoro-phenyl)-ethylamine (0.72 g, 5.15 mmol), and DIEA (0.27 ml, 1.54 mmol) in n-BuOH (5 ml) was heated in a sealed tube at 230° C. for 23 hours. The solvent was removed under reduced pressure and the residue was purified by column chromatography (hexane:EtOAc=1:2) to give the title compound as a yellow solid (0.38 g, 97%). NMR (400 MHz) 12.25 (s, 1H), 10.14 (s, 1H), 7.87 (d, J=9.6 Hz, 1H), 7.76 (d, J=6.4 Hz, 1H), 7.36 (m, 2H), 7.15 (m, 2H), 6.68 (s, 1H), 6.22 (d, J=8.4 Hz, 1H), 5.60 (br, 1H), 4.57 (m, 1H), 1.87 (m, 1H), 1.44 (d, J=6.8 Hz, 3H), 0.98 (m, 2H), 0.70 (m 2H). MS: Calcd.: 381; Found: [M+H]+ 382.
Reaction SMILES: [NH:1]1[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Br[CH2:9][CH2:10][CH2:11][N:12]1[C:20](=[O:21])[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]1=[O:22].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[N:1]1([CH2:9][CH2:10][CH2:11][N:12]2[C:20](=[O:21])[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13]2=[O:22])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C1CCCNCC1
Reactant: O=C1c2ccccc2C(=O)N1CCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=C1c2ccccc2C(=O)N1CCCN1CCCCCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The mixture of Azepane (2.3 mL), 2-(3-bromopropyl)isoindoline-1,3-dione (5.4 g) and potassium carbonate (5.5 g) in acetone (50 mL) was stirred at room temperature overnight. The solid was filtered and the filtrate was concentrated to provide 2-(3-(azepan-1-yl)propyl)isoindoline-1,3-dione, used without purification.
Reaction SMILES: [C:1]1([C:7]2([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[NH:11][C:10](=[O:12])[NH:9][C:8]2=[O:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Na].BrCCCCC(OC)=O>>[CH:17]1[CH:18]=[CH:19][C:14]([C:7]2([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[NH:11][C:10]([OH:12])=[N:9][C:8]2=[O:13])=[CH:15][CH:16]=1
Reactant: O=C1NC(=O)C(c2ccccc2)(c2ccccc2)N1
Agent: COC(=O)CCCCBr
Agent: [Na]
Product: O=C1N=C(O)NC1(c1ccccc1)c1ccccc1

Procedure:
Following the method of Cook et al, Res. Comm. Chem. Path. Pharm. 5:767(1973), sodium diphenylhydantoin is reacted with methyl 5-bromovalerate followed by acid hydrolysis to yield the following: ##STR15##
Reaction SMILES: C(N(CC)CC)C.[Si:8]([O:15][CH2:16][C@@H:17]([C:19]1[CH:24]=[CH:23][C:22]([F:25])=[C:21]([Cl:26])[CH:20]=1)[OH:18])([C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:10])[CH3:9].[CH3:27][S:28](Cl)(=[O:30])=[O:29]>C(Cl)Cl>[CH3:27][S:28]([O:18][C@H:17]([C:19]1[CH:24]=[CH:23][C:22]([F:25])=[C:21]([Cl:26])[CH:20]=1)[CH2:16][O:15][Si:8]([C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:10])[CH3:9])(=[O:30])=[O:29]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)[Si](C)(C)OC[C@H](O)c1ccc(F)c(Cl)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OC[C@H](OS(C)(=O)=O)c1ccc(F)c(Cl)c1
Reaction time: 1 h
Yield: 98.7 %

Procedure:
Triethylamine (0.480 mL, 3.44 mmol) was added to (R)-2-(tert-butyldimethylsilyloxy)-1-(3-chloro-4-fluorophenyl)ethanol (0.70 g, 2.30 mmol) in DCM (10 mL) cooled in ice, and then methanesulfonyl chloride (0.213 mL, 2.76 mmol) was added. After 1 hour, the reaction mixture was diluted with DCM, washed with aqueous NaHCO3, dried over MgSO4, filtered, and evaporated to yield (R)-2-(tert-butyldimethylsilyloxy)-1-(3-chloro-4-fluorophenyl)ethyl methanesulfonate (0.87 g, 2.27 mmol, 98.9% yield) as an oil. 1H NMR (400 MHz, CDCl3) δ 7.47-7.44 (m, 1H), 7.29-7.24 (m, 1H), 7.16 (t, 1H), 5.51-5.47 (m, 1H), 3.94-3.89 (m, 1H), 3.81-3.76 (m, 1H), 2.97 (s, 3H), 0.88 (s, 9H), 0.04 (d, 6H).
Reaction SMILES: Br[CH2:2][CH2:3][C@H:4]([NH:10][O:11][Si](C(C)(C)C)(C)C)[C:5]([O:7][CH2:8][CH3:9])=[O:6].CCCC[N+](CCCC)(CCCC)CCCC.O.O.O.[F-]>C1COCC1>[O:11]1[CH2:2][CH2:3][C@@H:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[NH:10]1
Reactant: CCOC(=O)[C@H](CCBr)NO[Si](C)(C)C(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)[C@@H]1CCON1
Temperature: 25 °C
Reaction time: 1 h
Yield: 91.6 %

Procedure:
To a solution of ethyl (2S)-4-bromo-2-({[tert-butyl(dimethyl)silyl]oxy}amino)butanoate (870 mg, 2.556 mmol) in THF (25 mL) was added tetrabutylammoniumfluoride trihydrate (887 mg, 2.812 mmol) and the mixture was stirred at rt for 1 h. The solvents were evaporated and the residue was purified by flash chromatography (DCM/EtOAc 9:1, then 4:1) to give ethyl (3S)-isoxazolidine-3-carboxylate (340 mg, 91%) as an oil.
Reaction SMILES: CC(C)([O-])C.[K+].[Si:7]([O:14][C@@H:15]1[C@H:19]([CH2:20][O:21][Si:22]([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23])[CH2:18][C@@H:17]([O:29][C:30]2[CH:35]=[CH:34][N:33]=[C:32](Cl)[CH:31]=2)[CH2:16]1)([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:9])[CH3:8].[Cl:37][C:38]1[CH:39]=[C:40]2[C:44](=[CH:45][CH:46]=1)[C@@H:43]([NH2:47])[CH2:42][C:41]2([CH3:49])[CH3:48].CCOC(C)=O>COCCOC>[Si:22]([O:21][C@@H:20]1[C@H:19]([CH2:15][O:14][Si:7]([C:10]([CH3:12])([CH3:11])[CH3:13])([CH3:9])[CH3:8])[CH2:18][C@@H:17]([O:29][C:30]2[CH:35]=[CH:34][N:33]=[C:32]([NH:47][C@@H:43]3[C:44]4[C:40](=[CH:39][C:38]([Cl:37])=[CH:46][CH:45]=4)[C:41]([CH3:49])([CH3:48])[CH2:42]3)[CH:31]=2)[CH2:16]1)([C:25]([CH3:27])([CH3:28])[CH3:26])([CH3:24])[CH3:23]
Reactant: CC(C)(C)[Si](C)(C)OC[C@@H]1C[C@@H](Oc2ccnc(Cl)c2)C[C@@H]1O[Si](C)(C)C(C)(C)C
Reactant: CC1(C)C[C@H](N)c2ccc(Cl)cc21
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: CC1(C)C[C@H](Nc2cc(O[C@@H]3C[C@@H](CO[Si](C)(C)C(C)(C)C)[C@@H](O[Si](C)(C)C(C)(C)C)C3)ccn2)c2ccc(Cl)cc21
Reaction time: 8 h
Yield: 17.7 %

Procedure:
To a mixture of [1,3-bis(2,6-diisopropylphenyl)imidazolidin-2-yl](chloro)[(2,3-●)-(1Z)-1-phenylprop-1-ene-2,3-diyl]palladium(2+) (3.4 mg, 0.0000052 mol) and potassium tert-butoxide (32.0 mg, 0.000286 mol) under an atmosphere of argon was added 4-{[(1R,3S,4S)-3-{[tert-butyl(dimethyl)silyl]oxy}-4-({[tert-butyl(dimethyl)silyl]oxy}methyl)-cyclopentyl]oxy}-2-chloropyridine (0.1226 g, 0.0002596 mol) in 1.00 ml DME, followed by (1S)-5-chloro-3,3-dimethylindan-1-amine (0.048 g, 0.00025 mol) in 1 ml DME. The mixture was stirred overnight, and the solution was poured into 50 ml EtOAc, washed with 10 ml water and concentrated. The residue was purified by preparative plate chromatography (70% EtOAc/hexanes) to afford the title compound (28.0 mg, 18.0%).
Reaction SMILES: [Cl:1][CH2:2][C:3]([C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=1[F:22])([OH:14])[CH:4]([O:6][Si](C(C)(C)C)(C)C)[CH3:5].Cl.O.C(OCC)(=O)C>CO>[Cl:1][CH2:2][C:3]([C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=1[F:22])([OH:14])[CH:4]([OH:6])[CH3:5]
Reactant: CC(O[Si](C)(C)C(C)(C)C)C(O)(CCl)c1ccc(F)cc1F
Agent: Cl
Solvent: CO
Solvent: CCOC(C)=O
Solvent: O
Product: CC(O)C(O)(CCl)c1ccc(F)cc1F
Reaction time: 18 h
Yield: 75 %

Procedure:
To a solution of 0.45 g (1.28 mmol) of 1-chloro-2-(2,4-difluorophenyl)-3-(tert-butyldimethylsilyloxy)butan-2-ol ((2R,3S)/(2S,3S)=92/8) in 5 mL of methanol was added 0.25 mL of concentrated hydrochloric acid at room temperature. After the completion of the dropwise addition, stirring was performed at room temperature for 18 hours. Then, 10 mL of water was added to stop the reaction, and extraction was performed with ethyl acetate (20 mL). The resulting organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain a crude product as a colorless oil. A quantitative analysis was performed by HPLC (under the same HPLC measurement conditions as those in Example 6). Thereby, the title compound was obtained in a yield of 75% ((2R,3S)/(2S,3S)=91/9). 1H-NMR (400 MHz, CDCl3) (2R,3S) δ: 0.98 (d, 3H, J=6.6 Hz), 2.48 (brs, 1H), 3.20 (s, 1H), 4.11-4.23 (m, 3H), 6.77-6.80 (m, 1H), 6.91-6.93 (m, 1H), 7.69-7.71 (m, 1H); (2S,3S) δ: 1.93 (dd, 3H, J=6.3, 1.2 Hz), 2.25 (d, 1H, J=5.2 Hz), 3.15 (s, 1H), 3.97 (d, J=11.0 Hz), 4.06 (q, 1H, J=6.3 Hz), 4.35 (d, J=11.2 Hz), 6.75-6.82 (m, 1H), 6.91-6.93 (m, 1H), 7.69-7.71 (m, 1H).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][C@H:3]1[O:15][CH3:16].[Cl:17][C:18]1[N:19]=[C:20]([C:26](O)=[O:27])[NH:21][C:22]=1[CH2:23][CH2:24][CH3:25].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>>[Cl:17][C:18]1[N:19]=[C:20]([C:26]([NH:1][C@H:2]2[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:12])([CH3:13])[CH3:14])=[O:9])[CH2:4][C@H:3]2[O:15][CH3:16])=[O:27])[NH:21][C:22]=1[CH2:23][CH2:24][CH3:25]
Reactant: CCCc1[nH]c(C(=O)O)nc1Cl
Reactant: CO[C@@H]1CN(C(=O)OC(C)(C)C)CC[C@@H]1N
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Product: CCCc1[nH]c(C(=O)N[C@H]2CCN(C(=O)OC(C)(C)C)C[C@H]2OC)nc1Cl

Procedure:
The same operation as in Example (1g) was performed using tert-butyl cis(±)-4-amino-3-methoxypiperidine-1-carboxylate obtained by the method described in Example (1e) (0.39 g, 1.69 mmol), 4-chloro-5-propyl-1H-imidazole-2-carboxylic acid obtained in Example (46d) (0.16 g, 0.85 mmol), WSC hydrochloride (0.50 g, 2.58 mmol) and HOBT (0.12 g, 0.87 mmol), to obtain 0.32 g of the title compound as a white foamy substance (94%).
Reaction SMILES: [F:1][C:2]1[CH:8]=[C:7]([CH:9]2[CH2:11][CH2:10]2)[CH:6]=[CH:5][C:3]=1[NH2:4].[CH3:12][O:13][C:14]([C:16]1[CH:17]=[CH:18][C:19]2[N:20]([CH:23]=[N:24][CH:25]=2)[C:21]=1Cl)=[O:15].C[Si]([N-][Si](C)(C)C)(C)C.[Li+]>C1COCC1>[CH3:12][O:13][C:14]([C:16]1[CH:17]=[CH:18][C:19]2[N:20]([CH:23]=[N:24][CH:25]=2)[C:21]=1[NH:4][C:3]1[CH:5]=[CH:6][C:7]([CH:9]2[CH2:11][CH2:10]2)=[CH:8][C:2]=1[F:1])=[O:15]
Reactant: COC(=O)c1ccc2cncn2c1Cl
Reactant: Nc1ccc(C2CC2)cc1F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)c1ccc2cncn2c1Nc1ccc(C2CC2)cc1F
Temperature: -70 °C
Reaction time: 1 h
Yield: 74.3 %

Procedure:
To a solution of 2-fluoro-4-cyclopropyl aniline (395 mg, 2.61 mmol) and 5-chloro-imidazo[1,5-a]pyridine-6-carboxylic acid methyl ester (500 mg, 2.37 mmol) in THF under nitrogen at −70° C. (20 mL) was added lithium bis(trimethylsilyl)amide (4.98 mL, 1M solution, 4.98 mmol) dropwise. After stirring for 1 hour at −70° C. the reaction mixture was allowed to warm and then quenched with saturated aqueous ammonium chloride. The mixture was extracted with ethyl acetate (150 mL), the organic extract dried (Na2SO4), filtered and concentrated in vacuo. The resultant residue was subjected to flash chromatography (Si-PPC, gradient 0-50% ethyl acetate in cyclohexane) to yield the title compound (573 mg, 60%). LCMS (Method B): RT=3.60 min, MA-H+=326.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8](=[O:15])[N:9]2[CH2:12][CH:13]=C)=[CH:4][CH:3]=1.I([O-])(=O)(=O)=[O:17].[Na+].C(Cl)Cl>O1CCOCC1.O.O=[Os](=O)(=O)=O>[F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8](=[O:15])[N:9]2[CH2:12][CH:13]=[O:17])=[CH:4][CH:3]=1
Reactant: C=CCn1c(=O)ccc2ccc(F)cc21
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: C1COCCO1
Solvent: O
Product: O=CCn1c(=O)ccc2ccc(F)cc21
Temperature: 25 °C
Yield: 54.4 %

Procedure:
A solution of 7-fluoro-1-(2-propen-1-yl)-2(1H)-quinolinone (0.909 g, 4.48 mmol) in 1,4-dioxane (50 ml) and water (30 ml) at 0° C. was treated with sodium periodate (2.20 g, 10.30 mmol) and OsO4 (4% in water, 5 ml). The reaction was warmed to rt and stirred at rt for 1 h before an extra 30 ml of water was added, after another 1 h more sodium periodate (2.20 g, 10.30 mmol) was added and after a further 2 h more sodium periodate (4.20 g, 19.70 mmol) was added. The reaction was then stirred at rt for 0.5 h before evaporation, treatment with water and extraction with DCM (×3). The combined organics were dried and evaporated to give the desired product (0.50 g, 88%). This material contained approximately 10% of the isomeric (5-fluoro-2-oxo-1(2H)-quinolinyl)acetaldehyde.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH:5]2[C:12](=[O:18])[C:13]1[S:17][CH:16]=[CH:15][CH:14]=1.[C:19](=[O:25])=[N:20]S(Cl)(=O)=O.C(#N)C.ClS(NC=O)(=O)=O>CS(C)=O>[Cl:1][C:2]1[N:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:19]([NH2:20])=[O:25])[C:6](=[O:11])[CH:5]2[C:12](=[O:18])[C:13]1[S:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C1Nc2ccc(Cl)nc2C1C(=O)c1cccs1
Reactant: O=C=NS(=O)(=O)Cl
Agent: O=CNS(=O)(=O)Cl
Solvent: CC#N
Solvent: CS(C)=O
Product: NC(=O)N1C(=O)C(C(=O)c2cccs2)c2nc(Cl)ccc21

Procedure:
The title compound was prepared from 5-chloro-3-(2-thenoyl)-4-azaoxindole (Example 1B), according to the procedure of Example 2C, using 5-chloro-3-(2-thenoyl)-4-azaoxindole (500 mg, 1.79 mmol), N-chlorosulfonyl isocyanate (0.18 mL, 2.15 mmol), and acetonitrile (15 mL). The crude N-chlorosulfonyl carboxamide was hydrolyzed by stirring in DMSO (1.5 mL) for 1 hour in a flask open to the air. The product was precipitated by addition of water and the precipitate was collected by filtration, and recrystallized from acetic acid. Yield: 36 mg (6%). MS m/e (relative percent) 323 (7), 321 (17), 280 (9), 278 (24), 196 (22), 194 (62), 170 (25), 168 (100). Exact mass calc'd for C13H8ClN3O3 S: 320.9975; found: 320.9977. IR (KBr disc) 1724, 1623, 1570, 1512, 1415 cm-1. M.p. 222°-224° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@H:8]2[CH2:12][CH2:11][CH2:10][N:9]2[C:13]2[CH:18]=[CH:17][N:16]3[N:19]=[CH:20][C:21]([NH2:22])=[C:15]3[N:14]=2)[CH:5]=[CH:6][CH:7]=1.[C:23](O)(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[N:26][CH:25]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CCOC(C)=O.CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]([C@H:8]2[CH2:12][CH2:11][CH2:10][N:9]2[C:13]2[CH:18]=[CH:17][N:16]3[N:19]=[CH:20][C:21]([NH:22][C:23](=[O:30])[C:24]4[CH:29]=[CH:28][CH:27]=[N:26][CH:25]=4)=[C:15]3[N:14]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Nc1cnn2ccc(N3CCC[C@@H]3c3cccc(F)c3)nc12
Reactant: O=C(O)c1cccnc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C(Nc1cnn2ccc(N3CCC[C@@H]3c3cccc(F)c3)nc12)c1cccnc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 74.5 %

Procedure:
To a mixture of (R)-5-(2-(3-fluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-amine (Example 6, Step A; 30 mg, 0.1 mmol), nicotinic acid (25 mg, 0.2 mmol), and HATU (77 mg, 0.2 mmol) was added 0.7 mL DMF to make a solution. After cooling in an ice bath for 10 minutes, DIEA (0.053 mL, 0.3 mmol) was added to the reaction drop-wise. The reaction was allowed to warm up to ambient temperature and stirred for 3 hours. The reaction mixture was diluted with EtOAc (15 mL), washed with water and brine (5 mL each), concentrated, and purified by reverse-phase column chromatography, eluting with 5 to 57% acetonitrile/water to yield the final product as a yellowish solid (30 mg, 74% yield). MS (apci) m/z=403.2 (M+H).