Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[O:7][C:8]2[C:13]([C:14](=[O:16])[CH:15]=1)=[CH:12][CH:11]=[C:10]([NH:17]C(=O)C(F)(F)F)[C:9]=2[CH:24]=[CH:25][CH3:26])=[O:5])[CH3:2].[Se](=O)=O.O>O1CCOCC1>[CH2:1]([O:3][C:4]([C:6]1[O:7][C:8]2[C:13]([C:14](=[O:16])[CH:15]=1)=[CH:12][CH:11]=[C:10]1[C:9]=2[CH:24]=[CH:25][CH:26]=[N:17]1)=[O:5])[CH3:2]
Reactant: CC=Cc1c(NC(=O)C(F)(F)F)ccc2c(=O)cc(C(=O)OCC)oc12
Agent: O=[Se]=O
Solvent: O
Solvent: C1COCCO1
Product: CCOC(=O)c1cc(=O)c2ccc3ncccc3c2o1
Reaction time: 8 h
Yield: 74.3 %

Procedure:
To 4-oxo-8-propenyl-7-(2,2,2-trifluoro-acetylamino)-4H-chromene-2-carboxylic acid ethyl ester (3.7 g, 10 mmole) in 100 mL of dioxan was added 4.4 g (40 mmole) of selenium dioxide. The mixture was refluxed under nitrogen for 5 hours. An additional 1.0 g of selenium dioxide was added and reflux continued for 8 hours. After the reaction had cooled, 500 mL of water was added and the mixture was extracted with first 300 mL and then 200 mL of ethyl acetate. The combined organic extracts were washed with water and with saturated brine, dried over sodium sulfate, filtered and evaporated in vacuum to give 2.0 g of the title compound as a yellow solid. An analytically pure sample of yellow solid (m.p. 146-147° C.) was obtained by column chromatography on silica gel with 0-5% ethyl acetate/methylene chloride as eluant.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH:11]([N:13](C(OC(C)(C)C)=O)[CH2:14][C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=2[F:22])[CH2:10][CH:9]1[C:30](O)=[O:31])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:33][CH:34]1[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1>>[CH2:1]([N:8]1[CH2:12][C@@H:11]([NH:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=2[F:22])[CH2:10][C@H:9]1[C:30]([N:37]1[CH2:38][CH2:39][CH:34]([CH3:33])[CH2:35][CH2:36]1)=[O:31])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC1CCNCC1
Reactant: CC(C)(C)OC(=O)N(Cc1ccc(F)cc1F)C1CC(C(=O)O)N(Cc2ccccc2)C1
Product: CC1CCN(C(=O)[C@@H]2C[C@H](NCc3ccc(F)cc3F)CN2Cc2ccccc2)CC1
Yield: 24 %

Procedure:
As described for Example 1f, 1-benzyl-4-[tert-butoxycarbonyl-(2,4-difluoro-benzyl)-amino]-pyrrolidine-2-carboxylic acid (60.0 mg, 0.134 mmol) was converted, using 4-methyl-piperidine instead of 2-piperazin-1-yl-benzonitrile, to the title compound (12.5 mg, 24%) as light yellow oil. MS m/e=428.5 [M+H]+.
Reaction SMILES: C([O:4][C:5]1[C:22]([F:23])=[CH:21][C:8]2[O:9][CH2:10][C:11](=[O:20])[N:12]([CH:13]([CH3:19])[C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:7]=2[CH:6]=1)(=O)C.N1CCOCC1>C1COCC1>[F:23][C:22]1[C:5]([OH:4])=[CH:6][C:7]2[N:12]([CH:13]([CH3:19])[C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:11](=[O:20])[CH2:10][O:9][C:8]=2[CH:21]=1
Reactant: CCOC(=O)C(C)N1C(=O)COc2cc(F)c(OC(C)=O)cc21
Solvent: C1COCCN1
Solvent: C1CCOC1
Product: CCOC(=O)C(C)N1C(=O)COc2cc(F)c(O)cc21
Temperature: 25 °C
Yield: 97.1 %

Procedure:
To a solution of ethyl 2-(6-acetoxy-7-fluoro-3-oxo-2H-benzo[b][1,4]oxazin-4(3H)-yl)propanoate (13 g, 40.0 mmol) in THF (100 mL) was added morpholine (10.4 mL, 120 mmol) and the reaction mixture was heated at reflux for 18 h. The reaction mixture was cooled to ambient temperature, filtered and the filtrate was concentrated in vacuo. The residue was purified by column chromatography on silica gel (eluting with 5% EtOAc in petroleum ether) to give ethyl 2-(7-fluoro-6-hydroxy-3-oxo-2H-benzo[b][1,4]oxazin-4(3H)-yl)propanoate (11 g, 80%) as a white solid. 1H NMR (CDCl3, 400 MHz): δ 6.78 (d, J=10.4 Hz, 1H), 6.49 (d, J=8.4 Hz, 1H), 5.20 (m, 2H), 4.57 (q, J=14.8 Hz, 2H), 4.20 (m, 2H), 1.58 (d, J=7.2 Hz, 3H), 1.19 (t, 3H).
Reaction SMILES: [CH3:1][C:2]1[C:3](B2OC(C)(C)C(C)(C)O2)=[C:4]([NH2:8])[CH:5]=[CH:6][CH:7]=1.[C:18]([O:22][C:23](=[O:44])[NH:24][C:25]([C:27]1[S:28][C:29]([S:42][CH3:43])=[C:30]([S:32]([C:35]2[CH:40]=[CH:39][CH:38]=[C:37](Br)[CH:36]=2)(=[O:34])=[O:33])[CH:31]=1)=[NH:26])([CH3:21])([CH3:20])[CH3:19].C([O-])([O-])=O.[Na+].[Na+].C(O)C>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1(C)C=CC=CC=1>[C:18]([O:22][C:23](=[O:44])[NH:24][C:25]([C:27]1[S:28][C:29]([S:42][CH3:43])=[C:30]([S:32]([C:35]2[CH:36]=[C:37]([C:3]3[C:2]([CH3:1])=[CH:7][CH:6]=[CH:5][C:4]=3[NH2:8])[CH:38]=[CH:39][CH:40]=2)(=[O:34])=[O:33])[CH:31]=1)=[NH:26])([CH3:21])([CH3:20])[CH3:19]
Reactant: Cc1cccc(N)c1B1OC(C)(C)C(C)(C)O1
Reactant: CSc1sc(C(=N)NC(=O)OC(C)(C)C)cc1S(=O)(=O)c1cccc(Br)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: CSc1sc(C(=N)NC(=O)OC(C)(C)C)cc1S(=O)(=O)c1cccc(-c2c(C)cccc2N)c1
Yield: 27.6 %

Procedure:
The procedure described in Example 1: step c was followed using 3-methyl-2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenylamine (95 mg. 0.41 mmol, Example 25: step b), {[4-(3-bromo-benzenesulfonyl)-5-methylsulfanyl-thiophen-2-yl]-imino-methyl}-carbamic acid tert-butyl ester (100.7 mg, 0.21 mmol, Example 27: step c), Pd(PPh3)4 (47 mg, 0.04 mmol), aqueous Na2CO3 (2M, 0.8 mL, 1.6 mmol), ethanol (0.8 mL) and toluene (1.6 mL). Purification by preparative SiO2 TLC (33% EtOAc in hexanes) of the residue yielded the title compound (30 mg, 28%) as an off-white solid. ESI-MS (m/z): Calcd. For C24H27N3O4S3: 517.2; found: 517.8.
Reaction SMILES: [Si]([O:18][CH2:19][C@H:20]1[O:24][C@@H:23]([N:25]2[CH:32]=[C:31]([CH3:33])[C:29](=[O:30])[NH:28][C:26]2=[O:27])[C@H:22]([O:34][CH2:35][CH2:36][O:37][CH3:38])[C@@H:21]1[OH:39])(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>>[CH3:38][O:37][CH2:36][CH2:35][O:34][C@@H:22]1[C@H:21]([OH:39])[C@@H:20]([CH2:19][OH:18])[O:24][C@H:23]1[N:25]1[CH:32]=[C:31]([CH3:33])[C:29](=[O:30])[NH:28][C:26]1=[O:27]
Reactant: COCCO[C@@H]1[C@H](O)[C@@H](CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)O[C@H]1n1cc(C)c(=O)[nH]c1=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Product: COCCO[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1n1cc(C)c(=O)[nH]c1=O

Procedure:
5′-O-t-Butyldiphenylsilyl-2′-O-(methoxyethyl)-5-methyluridine is treated with TBAF as per the procedure of Example 8 above to give the title compound.
Reaction SMILES: C(OC([NH:11][C@H:12]1[C@H:17]2[CH2:18][C@H:14]([CH:15]=[CH:16]2)[C@H:13]1[C:19]([O:21][CH3:22])=[O:20])=O)C1C=CC=CC=1.[ClH:23]>C(OCC)(=O)C.[Pd].C(OCC)C.O1CCOCC1>[ClH:23].[NH2:11][C@H:12]1[C@H:17]2[CH2:18][C@H:14]([CH2:15][CH2:16]2)[C@H:13]1[C:19]([O:21][CH3:22])=[O:20]
Reactant: COC(=O)[C@H]1[C@@H](NC(=O)OCc2ccccc2)[C@@H]2C=C[C@H]1C2
Agent: [Pd]
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: CCOCC
Product: COC(=O)[C@@H]1[C@H]2CC[C@H](C2)[C@@H]1N
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Methyl (1R,2R,3S,4S)-3-{[(benzyloxy)carbonyl]amino}bicyclo[2.2.1]hept-5-ene-2-carboxylate (1 g, 3.32 mmol) was dissolved in ethyl acetate (15 mL). 5% Palladium on carbon (120 mg) was added. The flask was degassed and backfilled with hydrogen gas via balloon. The mixture was stirred at 25° C. for 16 h. The mixture was passed through a plug of Celite and the filtrate was concentrated in vacuo to afford a thick clear oil. The oil was dissolved in diethyl ether (10 mL) and added dropwise, with vigorous stirring, to a mixture of 4.0M hydrochloric acid solution in 1,4-dioxane (1.8 mL) in diethyl ether (18 mL). The desired product began to precipitate as a white solid. Additional diethyl ether (10 mL) was added and the mixture was stirred for 10 min. The precipitate was collected by vacuum filtration, washed with additional diethyl ether (2×8 mL). The solid was further dried in vacuo for 1 h to afford the desired product, methyl (1S,2R,3S,4R)-3-aminobicyclo[2.2.1]heptane-2-carboxylate hydrochloride (0.64 g, 3.11 mmol, 94%), as a white powder. 1H NMR (400 MHz, DMSO-d6) δ: 1.17-1.27 (3H, m), 1.40-1.61 (2H, m), 1.91 (1H, d, J=10.7 Hz), 2.36 (1H, d, J=4.1 Hz), 2.44 (1H, d, J=3.1 Hz), 2.75 (1H, d, J=7.8 Hz), 3.30-3.38 (1H, m), 3.61 (3H, s), 8.05 (3H, bs). LC-MS (ESI) calcd for C9H15NO2 (free amine) 169.11, found 170.3 [M+H+] (100%), 339.3 [2M+H+] (50%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Br:8])[CH:5]=[CH:4][C:3]=1[CH3:9].C1C(=O)N([Br:17])C(=O)C1.CC(N=NC(C#N)(C)C)(C#N)C.O>C(Cl)(Cl)(Cl)Cl>[Br:8][C:6]1[CH:5]=[CH:4][C:3]([CH2:9][Br:17])=[C:2]([Cl:1])[CH:7]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(Br)cc1Cl
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: O
Solvent: ClC(Cl)(Cl)Cl
Product: Clc1cc(Br)ccc1CBr
Yield: 55.3 %

Procedure:
5.0 g of 2-chloro-4-bromotoluene are dissolved in 120 ml of CCl4. 4.3 g of NBS and 1.6 g of AIBN are added. The mixture is heated at reflux for 15 hours, water is added, the two phases are separated and then extraction is carried out with CH2Cl2. Purification is carried out by chromatography on a silica column eluted with petroleum ether. 3.8 g of liquid are obtained.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([N:10]2[CH:14]=[CH:13][CH:12]=[CH:11]2)[CH:7]=[CH:6][C:5]=1F)([O-:3])=[O:2].C([NH:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=2)[CH:21]=1)(=O)C>>[N:27]1[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=1[C:22]1[CH:21]=[C:20]([NH:19][C:5]2[CH:6]=[CH:7][C:8]([N:10]3[CH:14]=[CH:13][CH:12]=[CH:11]3)=[CH:9][C:4]=2[N+:1]([O-:3])=[O:2])[CH:25]=[CH:24][CH:23]=1
Reactant: O=[N+]([O-])c1cc(-n2cccc2)ccc1F
Reactant: CC(=O)Nc1cccc(-c2ccccn2)c1
Product: O=[N+]([O-])c1cc(-n2cccc2)ccc1Nc1cccc(-c2ccccn2)c1
Yield: 30 %

Procedure:
N-(3-(2-Pyridyl)phenyl)-2-nitro-4-(1-pyrrolyl)aniline (3e) was prepared analogously from 1a and 2g. Yield: 30%. The product was isolated as an oil.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7](OC2C=C3C(=CC=2)OC(C2C=CC=CC=2)CC3)=[N:8][CH:9]=1)([O-:3])=[O:2].[C:27]1([CH:33]2[CH2:42][CH2:41][C:40]3[C:35](=[CH:36][C:37]([OH:43])=[CH:38][CH:39]=3)[O:34]2)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([O:43][C:37]2[CH:36]=[C:35]3[C:40]([CH2:41][CH2:42][CH:33]([C:27]4[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=4)[O:34]3)=[CH:39][CH:38]=2)=[N:8][CH:9]=1)([O-:3])=[O:2]
Reactant: Oc1ccc2c(c1)OC(c1ccccc1)CC2
Reactant: O=[N+]([O-])c1ccc(Oc2ccc3c(c2)CCC(c2ccccc2)O3)nc1
Product: O=[N+]([O-])c1ccc(Oc2ccc3c(c2)OC(c2ccccc2)CC3)nc1

Procedure:
5-Nitro-2-(2-phenylchroman-7-yloxy)pyridine was prepared as described for 5-nitro-2-(2-phenylchroman-6-yloxy)pyridine in Example 1(b) starting from 115 mg of 2-phenylchroman-7-ol. The product was purified on preparative TLC-plate covered with silica gel using toluene-ethyl acetate (15:1) as an eluant. 1H NMR (400 MHz, d6-DMSO) δ: 9.04 (d, 1H, J 2.8 Hz), 8.60 (dd, 1H, J 9.1, 2.8 Hz), 7.46-7.32 (m, 5H), 7.22 (d, 1H, J 9.1 Hz), 7.20 (d, 1H, J 8.9 Hz), 6.72 (dd, 1H, J 8.9, 2.3 Hz), 6.72 (d, 1H, J 2.3 Hz), 5.16 (dd, 1H, J 10.1, 2.1 Hz), 2.97 (ddd, 1H, J −16.7, 11.3, 5.9 Hz), 2.77 (ddd, 1H, J −16.7, 8.1, 4.5 Hz), 2.20 (m, 1H), 2.02 (m, 1H).
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=2)[C:6](=[C:17](OCC)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:5]1=[O:27])(=O)C.[NH2:28][C:29]([CH2:31][N:32]([CH2:34][C:35]1[CH:41]=[CH:40][C:38]([NH2:39])=[CH:37][CH:36]=1)[CH3:33])=[O:30]>>[NH2:28][C:29]([CH2:31][N:32]([CH2:34][C:35]1[CH:36]=[CH:37][C:38]([NH:39]/[C:17](=[C:6]2\[C:5](=[O:27])[NH:4][C:12]3[C:7]\2=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=3)/[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:40][CH:41]=1)[CH3:33])=[O:30]
Reactant: CN(CC(N)=O)Cc1ccc(N)cc1
Reactant: CCOC(=C1C(=O)N(C(C)=O)c2cc(C(=O)OC)ccc21)c1ccccc1
Product: COC(=O)c1ccc2c(c1)NC(=O)/C2=C(\Nc1ccc(CN(C)CC(N)=O)cc1)c1ccccc1

Procedure:
Prepared from 1-acetyl-3-(1-ethoxy-1-phenylmethylene)-6-methoxycarbonyl-2-indolinone and 4-((N-aminocarbonylmethyl-N-methyl-amino)-methyl)-aniline Rf value: 0.5 (silica gel, methylene chloride/methanol=9:1) C27H26N4O4
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:6][N:5]=[C:4]2[NH:14][N:15]=[C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:3]=12.[F:23][CH2:24][CH2:25]O>>[Cl:1][C:2]1[C:7]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)=[N:6][N:5]=[C:4]2[N:14]([CH2:25][CH2:24][F:23])[N:15]=[C:16]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:3]=12
Reactant: OCCF
Reactant: Clc1c(-c2ccccc2)nnc2[nH]nc(-c3ccccc3)c12
Product: FCCn1nc(-c2ccccc2)c2c(Cl)c(-c3ccccc3)nnc21

Procedure:
Compound IIl was synthesized from 4-chloro-3,5-diphenyl-1H-pyrazolo[3,4-c]pyridazine and 2-fluoroethanol following the general procedure for the Mitsunobu reaction as described above.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([NH:8][NH2:9])[N:5]=[C:4]([S:10][CH3:11])[N:3]=1.[CH:12](OCC)(OCC)OCC>>[Cl:1][C:2]1[N:3]=[C:4]([S:10][CH3:11])[N:5]2[CH:12]=[N:9][N:8]=[C:6]2[CH:7]=1
Reactant: CSc1nc(Cl)cc(NN)n1
Reactant: CCOC(OCC)OCC
Product: CSc1nc(Cl)cc2nncn12

Procedure:
A mixture of 7.0 g (0.037 mole) of 4-chloro-6-hydrazino-2-methylthiopyrimidine and 100 ml of triethyl orthoformate was heated at reflux for 48 hours. Cooling provided a precipitate which was isolated by filtration, and then recrystallized from an ethanol-heptane mixture, with treatment with decolorizing charcoal. The product was red crystals of 7-chloro-5-methylthio-1,2,4-triazolo[4,3-c]pyrimidine, m.p. 164°-165° C.
Reaction SMILES: [H-].[Na+].[CH:3](=[C:9]1[CH2:14][CH2:13][CH:12]([OH:15])[CH2:11][CH2:10]1)[CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].Cl[C:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[N:20]=[CH:19][N:18]=1.C(O)(C)C>C1COCC1.[NH4+].[Cl-].CCOCC>[CH:3](=[C:9]1[CH2:14][CH2:13][CH:12]([O:15][C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[N:20]=[CH:19][N:18]=2)[CH2:11][CH2:10]1)[CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCC=C1CCC(O)CC1
Reactant: Clc1ncnc2ccccc12
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CC(C)O
Solvent: CCOCC
Product: CCCCCC=C1CCC(Oc2ncnc3ccccc23)CC1

Procedure:
130 mg (4.3 mmol) of 80% NaH are added to a solution of 0.7 g (3.5 mmol) of 4-hexylidenecyclohexanol in 20 ml of absolute THF, and the mixture is refluxed for 1 hour until deproteination is complete. 0.6 g (3.6 mmol) of 4-chloroquinazoline is subsequently added to the reaction solution at boiling point, and the mixture is refluxed for 3 hours. For working up, 2 ml of isopropanol are added. After cooling, the mixture is taken up in aqueous NH4Cl/ether and the organic phase is dried over MgSO4. Concentration of the solvent gives 1.1 g (crude product which is purified by flash chromatography (silica gel/petroleum ether:ethyl acetate=2:1)).
Reaction SMILES: [Br:1][C:2]1[N:7]=[CH:6][C:5]([CH:8]=O)=[CH:4][CH:3]=1.[CH3:10][O:11][CH2:12][CH2:13][NH2:14].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[NH4+].[Cl-]>C(Cl)Cl.O>[Br:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][NH:14][CH2:13][CH2:12][O:11][CH3:10])=[CH:4][CH:3]=1
Reactant: COCCN
Reactant: O=Cc1ccc(Br)nc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: ClCCl
Product: COCCNCc1ccc(Br)nc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 44.9 %

Procedure:
To a solution of 6-bromopyridine-3-carbaldehyde (5 g, 26.9 mmol) in DCM (40 mL), was added 2-methoxyethylamine (2.80 mL, 32.3 mmol). After 10 min, sodium triacetoxyborohydride (7.98 g, 37.6 mmol) was added to the mixture and it was stirred at rt for 17 h. DCM (100 mL water (50 mL and NH4Cl (50 mL) were added to the reaction mixture. The organic phase was collected and the aqueous layer was extracted with DCM (3×100 mL). The combined organic solutions were washed with brine and concentrated under reduce pressure. The residue was purified by flash column chromatography, eluent 98/2 to 95/5 DCM/MeOH, to afford title 143 (2.958 g, 45% yield) as a brown oil. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.31 (dd, J=2.6, 0.6 Hz, 1H), 7.70 (dd, J=8.2, 2.6 Hz, 1H), 7.58 (d, J=8.4 Hz, 1H), 3.69 (s, 2H), 3.37 (t, J=5.8 Hz, 2H), 3.22 (s, 3H), 2.60 (t, J=5.8 Hz, 2H). MS (m/z): 245.1 (M+H).
Reaction SMILES: [S:1]([CH2:5][CH2:6][OH:7])([O-:4])(=[O:3])=[O:2].[Na+].[C:9]12([C:19](O)=[O:20])[CH2:18][CH:13]3[CH2:14][CH:15]([CH2:17][CH:11]([CH2:12]3)[CH2:10]1)[CH2:16]2.FC(F)(F)C(OC(=O)C(F)(F)F)=O.[Cl-].[C:36]1([S+:42]([C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)[C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.C(=O)(O)[O-].[Na+]>FC(F)(F)C(O)=O.C(Cl)Cl.O>[C:9]12([C:19]([O:7][CH2:6][CH2:5][S:1]([O-:4])(=[O:3])=[O:2])=[O:20])[CH2:16][CH:15]3[CH2:14][CH:13]([CH2:12][CH:11]([CH2:17]3)[CH2:10]1)[CH2:18]2.[C:49]1([S+:42]([C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=2)[C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[CH:50]=[CH:51][CH:52]=[CH:53][CH:54]=1
Reactant: O=S(=O)([O-])CCO
Reactant: O=C(O)C12CC3CC(CC(C3)C1)C2
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Product: O=C(OCCS(=O)(=O)[O-])C12CC3CC(CC(C3)C1)C2
Temperature: 25 °C
Reaction time: 2 h
Yield: 62 %

Procedure:
In 125 g of trifluoroacetic acid were dissolved 14.8 g (0.10 mole) of sodium isethionate and 18.0 g (0.10 mole) of 1-adamantanecarboxylic acid. To this solution, 32.0 g (0.15 mole) of trifluoroacetic anhydride was added dropwise, followed by stirring for 2 hours at room temperature. Then 430 g (0.15 mole) of an aqueous solution of triphenylsulfonium chloride prepared in Synthesis Example 1-1, 800 g of water, and 1,500 g of methylene chloride were added, followed by stirring for 1 hour at room temperature. At the end of stirring, the organic layer was taken out, aqueous sodium bicarbonate was added dropwise until the pH of the aqueous layer ceased to be acidic, and the organic layer was then taken out. The organic layer was washed with water and concentrated in vacuum. Methyl isobutyl ketone was added to the concentrate, which was concentrated in vacuum again while distilling off the residual water. Diisopropyl ether was added to the residue for recrystallization. The crystals were collected and dried, obtaining the target compound, triphenylsulfonium 2-(adamantane-1-carbonyloxy)ethanesulfonate. White crystals, 34.1 g, yield 62%. The compound, designated PAG-1, has the following structure.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:12]([C:14]3[CH:21]=[C:20]([Cl:22])[C:17]([C:18]#[N:19])=[C:16]([CH:23]4[CH2:26][NH:25][CH2:24]4)[C:15]=3[O:27][CH3:28])[CH3:13])[N:9]=[C:10]([CH3:11])[C:3]=12.C(N(CC)CC)C.Cl[C:37]([O:39][CH3:40])=[O:38]>ClCCl.CO>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:12]([C:14]3[C:15]([O:27][CH3:28])=[C:16]([CH:23]4[CH2:24][N:25]([C:37]([O:39][CH3:40])=[O:38])[CH2:26]4)[C:17]([C:18]#[N:19])=[C:20]([Cl:22])[CH:21]=3)[CH3:13])[N:9]=[C:10]([CH3:11])[C:3]=12
Reactant: COc1c(C(C)n2nc(C)c3c(N)ncnc32)cc(Cl)c(C#N)c1C1CNC1
Reactant: COC(=O)Cl
Solvent: CCN(CC)CC
Solvent: CO
Solvent: ClCCl
Product: COC(=O)N1CC(c2c(C#N)c(Cl)cc(C(C)n3nc(C)c4c(N)ncnc43)c2OC)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 52.6 %

Procedure:
A solution of 4-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-2-azetidin-3-yl-6-chloro-3-methoxybenzonitrile (chiral intermediate from Example 261) (20 mg, 0.05 mmol) in dichloromethane (1 mL) was treated with triethylamine (20 μL, 0.14 mmol) followed by methyl chloroformate (4.7 μL, 0.06 mmol) and stirred at room temperature for 1 h. The reaction mixture was diluted with methanol and purified by preparative LCMS (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 60 mL/min) to give the desired product (12 mg, 52%). The product was isolated as a single enantiomer. 1H NMR (300 MHz, DMSO-d6) δ 8.11 (s, 1H), 7.51 (s, 1H), 7.34 (br s, 2H), 6.25 (q, J=7.0 Hz, 1H), 4.53-4.38 (m, 1H), 4.36-4.17 (m, 4H), 3.71 (s, 3H), 3.55 (s, 3H), 2.55 (s, 3H), 1.73 (d, J=7.1 Hz, 3H). LCMS for C21H23ClN7O3 (M+H)+: m/z=456.2; Found: 456.1.
Reaction SMILES: CO[C:3]1[C:9](=[O:10])[NH:8][C:7]2[CH:11]=[CH:12][CH:13]=[CH:14][C:6]=2[C:5](=[O:15])[CH:4]=1.[CH2:16]([CH2:18][NH2:19])[OH:17]>CO>[OH:17][CH2:16][CH2:18][NH:19][C:3]1[C:9](=[O:10])[NH:8][C:7]2[CH:11]=[CH:12][CH:13]=[CH:14][C:6]=2[C:5](=[O:15])[CH:4]=1
Reactant: COc1cc(=O)c2ccccc2[nH]c1=O
Reactant: NCCO
Solvent: CO
Product: O=c1[nH]c2ccccc2c(=O)cc1NCCO
Temperature: 25 °C
Yield: 63 %

Procedure:
To a solution of 3-methoxy-2,5-dioxo-2,5-dihydro-1H-benz[b]azepine (1.0 g) in methanol (20 mL) was added ethanolamine (0.36 g). The mixture was heated to reflux until a precipitate formed. The reaction mixture was cooled to room temperature, filtered, and the resulting solid was recrystallized from ethanol to give the title compound (0.72 g); mp 207° C.; NMR: 5.91 (s,1); MS(EI): m/z=232(M). Analysis for C12H12N2O3.0.2 H2O: Calculated: C, 61.11; H, 5.30; N, 11.88; Found: C, 61.13; H, 5.20; N, 11.72.
Reaction SMILES: [C:1]1([CH:7]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[N:8]2[CH2:13][CH2:12][N:11]([CH2:14][C:15]3[CH:16]=[C:17]([NH2:26])[C:18]([NH:21][CH2:22][CH2:23][O:24][CH3:25])=[CH:19][CH:20]=3)[CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:33]OC(OC)OC>C(O)(=O)C>[C:27]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:8]2[CH2:13][CH2:12][N:11]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]4[N:21]([CH2:22][CH2:23][O:24][CH3:25])[CH:33]=[N:26][C:17]=4[CH:16]=3)[CH2:10][CH2:9]2)[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: COC(OC)OC
Reactant: COCCNc1ccc(CN2CCN(C(c3ccccc3)c3ccccc3)CC2)cc1N
Solvent: CC(=O)O
Product: COCCn1cnc2cc(CN3CCN(C(c4ccccc4)c4ccccc4)CC3)ccc21
Yield: 70 %

Procedure:
A solution of 2.8 parts of 4-[4-(diphenylmethyl)-1-piperazinylmethyl]-N1 -(2-methoxyethyl)-1,2-benzenediamine, 20 parts of trimethoxymethane and 0.39 parts of acetic acid is stirred and refluxed for 1.50 hours. The reaction mixture is evaporated and the residue is dissolved in a diluted hydrochloric acid solution. The free base is liberated in the conventional manner with ammonium hydroxide and extracted with dichloromethane. The extract is dried, filtered and evaporated. The residue is washed with 2,2'-oxybispropane and dried, yielding 2 parts (70%) of 5-[4-(diphenylmethyl)-1-piperazinylmethyl]-1-(2-methoxyethyl)-1H-benzimidazole; mp. 161.7° C.
Reaction SMILES: [C:1]1([C@@H:7]2[CH2:9][C@H:8]2[CH2:10][NH:11][OH:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:13][CH2:14][C:15](Cl)=[O:16].C(N(CC)CC)C.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[Cl:13][CH2:14][C:15]([N:11]([OH:12])[CH2:10][C@@H:8]1[CH2:9][C@H:7]1[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)=[O:16]
Reactant: ONC[C@@H]1C[C@H]1c1ccccc1
Reactant: O=C(Cl)CCl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(CCl)N(O)C[C@@H]1C[C@H]1c1ccccc1
Reaction time: 5 h
Yield: 41.8 %

Procedure:
To a stirred solution of N-[(trans-2-phenylcyclopropyl)methyl]-N-hydroxylamine (3.26 g, 20 mM) in methylene chloride (50 ml) was added chloroacetyl chloride (4.52 g, 40 mM) and triethylamine (4.04 g, 40 ml) at room temperature. After stirring for 5 hours, it was poured into saturated aqueous sodium bicarbonate. The whole was extracted with chloroform (2×100 ml). The extracts were washed with water and brine, then were added and evaporated in vacuo. Chromatographic purification (eluent chloroform:ethanol=15:1) of the residue provided 2 g (41.8% yield) of the desired product as a pale yellow oil.
Reaction SMILES: [F:1][C:2]1[C:3]([CH3:9])=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].[Cl:10][CH2:11][C:12](Cl)=[O:13]>>[Cl:10][CH2:11][C:12]([NH:5][C:4]1[CH:6]=[CH:7][CH:8]=[C:2]([F:1])[C:3]=1[CH3:9])=[O:13]
Reactant: Cc1c(N)cccc1F
Reactant: O=C(Cl)CCl
Product: Cc1c(F)cccc1NC(=O)CCl

Procedure:
The subtitle compound was prepared from 3-fluoro-2-methylaniline (0.232 g) and chloroacetyl chloride (0.164 ml) by the method of Example 33 step (iii) as a beige solid. Yield: 0.3 g