Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:18]3=[N:19][CH:20]=[N:21][C:22](Cl)=[C:17]3[CH:16]=[N:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:24][S:25]([C:28]1[CH:34]=[CH:33][C:31]([NH2:32])=[CH:30][CH:29]=1)(=[O:27])=[O:26]>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:18]3=[N:19][CH:20]=[N:21][C:22]([NH:32][C:31]4[CH:30]=[CH:29][C:28]([S:25]([CH3:24])(=[O:27])=[O:26])=[CH:34][CH:33]=4)=[C:17]3[CH:16]=[N:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(n2ncc3c(Cl)ncnc32)CC1
Reactant: CS(=O)(=O)c1ccc(N)cc1
Product: CC(C)(C)OC(=O)N1CCC(n2ncc3c(Nc4ccc(S(C)(=O)=O)cc4)ncnc32)CC1

Procedure:
4-[4-(4-Methanesulfonyl-phenylamino)-pyrazolo[3,4-d]pyrimidin-1-yl]-piperidine-1-carboxylic acid tert-butyl ester was prepared according to General Procedure C by the reaction of 4-(4-chloro-pyrazolo[3,4-d]pyrimidin-1-yl)-piperidine-1-carboxylic acid tert-butyl ester (Intermediate E1) with 4-(methylsulfonyl)aniline (available from Oakwood Products, Inc., West Columbia, S.C., USA). 1H NMR (400 MHz, DMSO-d6) δ 1.43 (s, 9H), 1.90-2.00 (m, 4H), 2.92-3.05 (m, 2H), 3.30 (methyl sulfonyl and water peak), 4.03-4.10 (m, 2H), 4.91-4.95 (m, 1H), 7.92-7.94 (m, 2H), 8.17-8.19 (m, 2H), 8.32 (s, 1H), 8.54 (s, 1H), 10.50 (s, 1H). Mass spectrum MH+=473.
Reaction SMILES: [C:1]([O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(=[O:6])[CH2:2][CH2:3][C:4]#[CH:5].[CH2:15]([SnH:19]([CH2:24][CH2:25][CH2:26][CH3:27])[CH2:20][CH2:21][CH2:22][CH3:23])[CH2:16][CH2:17][CH3:18]>CC(N=NC(C#N)(C)C)(C#N)C>[CH2:24]([Sn:19]([CH2:15][CH2:16][CH2:17][CH3:18])([CH2:20][CH2:21][CH2:22][CH3:23])/[CH:5]=[CH:4]/[CH2:3][CH2:2][C:1]([O:7][CH2:8][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)=[O:6])[CH2:25][CH2:26][CH3:27]
Reactant: C#CCCC(=O)OCc1ccccc1
Reactant: CCCC[SnH](CCCC)CCCC
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Product: CCCC[Sn](/C=C/CCC(=O)OCc1ccccc1)(CCCC)CCCC
Temperature: 25 °C
Yield: 74.3 %

Procedure:
A mixture of Example 510B (8.7017 g, 46.23 mmol), tributyltin hydride (14.5 mL, 54.09 mmol), and AIBN (228 mg, 1.39 mmol) was stirred at 80° C. for 24 hours, cooled to room temperature, and purified by flash column chromatography to provide the desired product (16.4529 g, 74%). 1H NMR (300 MHz, DMSO-d6) δ 7.35 (m, 5H), 5.93 (m, 1H), 5.09 (m, 1H), 5.07 (s, 2H), 2.44 (m, 2H), 2.38 (m, 2H), 1.45 (m, 6H), 1.25 (m, 6H), 0.85 (m, 15H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=O)[O:8][C:6](=[O:7])[C:5]2=[CH:11][CH:12]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3].O.[OH-].[Na+]>O1CCCC1>[Cl:1][C:2]1[CH:12]=[CH:11][C:5]([CH2:6][OH:7])=[C:4]([CH2:9][OH:8])[CH:3]=1
Reactant: O=C1OC(=O)c2cc(Cl)ccc21
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: OCc1ccc(Cl)cc1CO
Temperature: 25 °C
Reaction time: 8 h
Yield: 94.4 %

Procedure:
A solution of 4-chlorophthalic anhydride (24.83 g, 136.01 mmol) in tetrahydrofuran (100 mL) is added dropwise to a mechanically stirred suspension of LAH (8.72 g, 229.78 mmol) in tetrahydrofuran (500 mL). After stirring overnight at room temperature, the excess LAH is decomposed by cautious addition of water (8.5 mL), 10% aqueous NaOH (17 mL) and water (8.5 mL). The reaction is diluted with tetrahydrofuran (300 mL) and the solids are removed by filtration through a celite pad and washed with tetrahydrofuran. The combined filtrate and wash is concentrated in vacuo on a rotary evaporator to afford diol 257 as a colorless liquid (22.16 g) that crystallized on standing. Crystallization is effected in benzene. [O. Farooq, Synthesis, 1035-1036 (1994); R. F. Bird, E. E. Turner, J. Chem. Soc. 5050-5051 (1952); J. Tirouflet, Compt. rend., 238, 2246-2247 (1954)]
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]([CH2:23][C:24]2[CH:29]=[CH:28][C:27]([C:30]([O:32]C)=[O:31])=[CH:26][CH:25]=2)[C:7](=[O:22])[C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][C:11]([Br:21])=[CH:10][CH:9]=2)=[O:4].[OH-].[Na+]>CO.O1CCCC1>[CH3:1][O:2][C:3]([C:5]1[N:6]([CH2:23][C:24]2[CH:25]=[CH:26][C:27]([C:30]([OH:32])=[O:31])=[CH:28][CH:29]=2)[C:7](=[O:22])[C:8]2[C:13]([C:14]=1[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)=[CH:12][C:11]([Br:21])=[CH:10][CH:9]=2)=[O:4]
Reactant: COC(=O)c1ccc(Cn2c(C(=O)OC)c(-c3ccccc3)c3cc(Br)ccc3c2=O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)c1c(-c2ccccc2)c2cc(Br)ccc2c(=O)n1Cc1ccc(C(=O)O)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 66.3 %

Procedure:
To a mixture of 6-bromo-2-(4-methoxycarbonylbenzyl)-1-oxo-4-phenyl-1,2-dihydroisoquinoline-3-carboxylic acid methyl ester (2.00 g) in methanol (10 ml) and tetrahydrofuran (20 ml) was added 8N aqueous sodium hydroxide solution (1 ml) and the mixture was stirred at room temperature for 12 hrs. The solvent was evaporated under reduced pressure and water was added. The mixture was acidified with 1N hydrochloric acid and extracted with ethyl acetate. The extract was washed with saturated brine and dried by adding sodium sulfate. The solvent was evaporated under reduced pressure and the obtained residue was recrystallized from methanol to give the title compound (1.29 g, 65%).
Reaction SMILES: C(OC(N1C[C@@H](C)N2[C@H](CC3C2=NC(C(F)F)=C(CO)C=3)C1)=O)(C)(C)C.[C:27]([O:31][C:32]([N:34]1[CH2:46][C@@H:45]([CH3:47])[N:44]2[C@H:36]([CH2:37][C:38]3[C:43]2=[N:42][C:41]([C@@H:48]([O:50][CH3:51])[CH3:49])=[C:40]([CH:52]=[O:53])[CH:39]=3)[CH2:35]1)=[O:33])([CH3:30])([CH3:29])[CH3:28].[BH4-].[Na+]>>[C:27]([O:31][C:32]([N:34]1[CH2:46][C@@H:45]([CH3:47])[N:44]2[C@H:36]([CH2:37][C:38]3[C:43]2=[N:42][C:41]([C@@H:48]([O:50][CH3:51])[CH3:49])=[C:40]([CH2:52][OH:53])[CH:39]=3)[CH2:35]1)=[O:33])([CH3:30])([CH3:29])[CH3:28]
Reactant: CO[C@@H](C)c1nc2c(cc1C=O)C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@@H](C)N21
Agent: C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]2Cc3cc(CO)c(C(F)F)nc3N21
Agent: [BH4-]
Agent: [Na+]
Product: CO[C@@H](C)c1nc2c(cc1CO)C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@@H](C)N21

Procedure:
This compound was prepared in analogy to example 15, intermediate b) from (4R,9aR)-7-formyl-6-(1-(S)-methoxy-ethyl)-4-methyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2-carboxylic acid tert-butyl ester and sodium borohydride.
Reaction SMILES: C(N(CC)CC)C.Cl.[CH2:9]([C:11]1[CH:20]=[C:19]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][C:26](B(O)O)=[CH:25][CH:24]=2)[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:12]=1)[CH3:10].Br[C:33]1[CH:40]=[CH:39][CH:38]=[CH:37][C:34]=1[C:35]#[N:36]>C(O)CCC.O.[Pd](Cl)Cl>[CH2:9]([C:11]1[CH:20]=[C:19]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][C:26]([C:33]3[C:34]([C:35]#[N:36])=[CH:37][CH:38]=[CH:39][CH:40]=3)=[CH:25][CH:24]=2)[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:12]=1)[CH3:10]
Reactant: N#Cc1ccccc1Br
Reactant: CCc1cc(OCc2ccc(B(O)O)cc2)c2ccccc2n1
Agent: Cl[Pd]Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCCCO
Solvent: O
Product: CCc1cc(OCc2ccc(-c3ccccc3C#N)cc2)c2ccccc2n1
Temperature: 25 °C
Yield: 91.1 %

Procedure:
Triethylamine (13.8 ml) was added to a mixture of 4-[(2-ethylquinolin-4-yloxy)methyl]phenylboronic acid hydrochloride (12.74 g), 2-bromobenzonitrile (5.92 g) and palladium chloride (0.13 g) in butanol (80 ml) and water (40 ml) and the mixture was heated at reflux for 3 hours. The hot reaction mixture was filtered through diatomaceous earth and the filtrate was stirred while allowing to cool to ambient temperature. The mixture was then cooled to 4° C. for 30 minutes. The solid which crystallised was collected by filtration, washed with cold butanol (16 ml) and water (2×16 ml) and then dried at 55° C. to give 4'-[(2-ethylquinolin-4-yloxy)methyl]biphenyl-2-carbonitrile (10.8 g); m.p. 161°-162° C.; NMR (CDCl3): 1.4(t,3H), 2.97(q,2H), 5.35(s,2H), 6.76(s,1H), 7.4-7.6(m,3H), 7.6-7.8(m,6H), 8.0(d,1 H), 8.25(d,1H).
Reaction SMILES: [CH3:1][C:2]([CH3:27])([CH3:26])[C:3]#[C:4][C:5]1[S:9][C:8]([C:10]([OH:12])=[O:11])=[C:7]([N:13]([CH:23]([CH3:25])[CH3:24])[C:14]([C@H:16]2[CH2:21][CH2:20][C:19]([CH3:22])=[CH:18][CH2:17]2)=[O:15])[CH:6]=1.[CH3:28]C(C)(C)C#CC1SC(C(OC)=O)=C(NC(C)C)C=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].CCOC(C)=O>ClC(Cl)C>[CH3:1][C:2]([CH3:26])([CH3:27])[C:3]#[C:4][C:5]1[S:9][C:8]([C:10]([O:12][CH3:28])=[O:11])=[C:7]([N:13]([CH:23]([CH3:24])[CH3:25])[C:14]([C@H:16]2[CH2:21][CH2:20][C:19]([CH3:22])=[CH:18][CH2:17]2)=[O:15])[CH:6]=1
Reactant: CC1=CC[C@@H](C(=O)N(c2cc(C#CC(C)(C)C)sc2C(=O)O)C(C)C)CC1
Reactant: COC(=O)c1sc(C#CC(C)(C)C)cc1NC(C)C
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC(Cl)Cl
Product: COC(=O)c1sc(C#CC(C)(C)C)cc1N(C(=O)[C@@H]1CC=C(C)CC1)C(C)C
Temperature: 90 °C
Reaction time: 16 h
Yield: 50.7 %

Procedure:
4-Methyl-cyclohex-3-enecarbonyl chloride (S) (0.71 mmol), methyl 5-(3,3-dimethylbut-1-ynyl)-3-(isopropylamino)thiophene-2-carboxylate (80 mg, 0.29 mmol) and potassium phosphate tribasic (152 mg, 0.71 mmol) were suspended in dichloroethane (0.75 mL), sealed with a cap and heated to 90° C. After 16 h, the reaction mixture was cooled and partitioned between ethyl acetate and water. The organic layer was separated and the aqueous extracted again with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered and concentrated. Flash chromatography (10-35% EtOAc:Hexanes) afforded 59 mg (51% yield) of the desired (S)-methyl 5-(3,3-dimethylbut-1-ynyl)-3-(N-isopropyl-4-methylcyclohex-3-enecarboxamido)thiophene-2-carboxylate as a white foam.
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([O:8][CH2:9][CH2:10][CH2:11][N:12]([CH2:15][CH3:16])[CH2:13][CH3:14])[CH:5]=[CH:4][C:3]=1[N+:17]([O-:19])=[O:18].[CH2:20]([NH2:22])[CH3:21]>C1COCC1>[CH2:20]([NH:22][C:2]1[CH:7]=[C:6]([O:8][CH2:9][CH2:10][CH2:11][N:12]([CH2:15][CH3:16])[CH2:13][CH3:14])[CH:5]=[CH:4][C:3]=1[N+:17]([O-:19])=[O:18])[CH3:21]
Reactant: CCN(CC)CCCOc1ccc([N+](=O)[O-])c(F)c1
Reactant: CCN
Solvent: C1CCOC1
Product: CCNc1cc(OCCCN(CC)CC)ccc1[N+](=O)[O-]
Yield: 88 %

Procedure:
A solution of 2-fluoro-4-(3-diethylamino-1-propoxy)nitrobenzene (2 mmol; preparation described in Example 5) in THF (5 mL) is treated with ethylamine (4 mmol) at rt. After completion of the reaction, the reaction mixture is concentrated in vacuo. The residue is redissolved in EtOAc (10 mL), washed with saturated sodium bicarbonate solution, water, and brine. The organic phase is then dried over sodium sulfate and the solvent is removed in vacuo to afford the product, 2-(ethylamino)-4-(3-diethylamino-1-propoxy)nitrobenzene (520 mg) which was used for further transformation without further purification.
Reaction SMILES: [CH:1]([NH:3][CH2:4][CH:5]1[CH2:10][CH2:9][N:8]([CH:11]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:7][CH2:6]1)=O.[H-].[H-].[H-].[H-].[Li+].[Al+3]>>[CH3:1][NH:3][CH2:4][CH:5]1[CH2:10][CH2:9][N:8]([CH:11]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:7][CH2:6]1
Reactant: O=CNCC1CCN(C(c2ccccc2)c2ccccc2)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: CNCC1CCN(C(c2ccccc2)c2ccccc2)CC1
Yield: 100 %

Procedure:
Step 2): In a similar manner to that of Preparation 1 step 2), 4-(N-formylamino)methyl-1-diphenylmethylpiperidine was reduced by LiAlH4 to give 4-(N-methylamino)methyl-1-diphenylmethylpiperidine; yield 100%.
Reaction SMILES: [NH2:1][C:2]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][N:8]=1)=[O:5].[F:19][C:20]1[CH:28]=[CH:27][C:23]([C:24](Cl)=[O:25])=[CH:22][CH:21]=1.O>C(Cl)Cl.N1C=CC=CC=1>[Cl:18][C:15]1[CH:16]=[CH:17][C:2]([NH:1][C:24](=[O:25])[C:23]2[CH:27]=[CH:28][C:20]([F:19])=[CH:21][CH:22]=2)=[C:3]([CH:14]=1)[C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][N:8]=1)=[O:5]
Reactant: Nc1ccc(Cl)cc1C(=O)Nc1ccc(Cl)cn1
Reactant: O=C(Cl)c1ccc(F)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: O
Product: O=C(Nc1ccc(Cl)cc1C(=O)Nc1ccc(Cl)cn1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.2 %

Procedure:
To a solution of 2-amino-5-chloro-N-(5-chloropyridin-2-yl)benzamide (2.82 g, 10 mmol) in methylene chloride (100 mL) and pyridine (3 mL) was added 4-fluorobenzoyl chloride (1.42 mL, 12 mmol) dropwise at 0° C. The reaction mixture was warmed to room temperature and stirred overnight. Water (50 mL) was added; and the mixture was stirred for 30 min before the solids were filtered, washed with saturated sodium bicarbonate (30 mL), water (30 mL), and ether (50 mL), and dried under vacuum to provide the product (3.2 g, 79%) pure enough to use in the next step.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][N:6]=[C:5]([NH:9][NH:10]/[CH:11]=[CH:12]/[C:13]([O:15]CC)=O)[CH:4]=1)#[N:2].CC([O-])(C)C.[K+].Cl>CCO>[OH:15][C:13]1[N:9]([C:5]2[CH:4]=[C:3]([C:1]#[N:2])[CH:8]=[CH:7][N:6]=2)[N:10]=[CH:11][CH:12]=1
Reactant: CCOC(=O)/C=C/NNc1cc(C#N)ccn1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CCO
Product: N#Cc1ccnc(-n2nccc2O)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 31.2 %

Procedure:
To a solution of ethyl (2E)-3-[2-(4-cyanopyridin-2-yl)hydrazinyl]prop-2-enoate (2.0 g, 8.62 mmol) in 30 mL EtOH was added t-BuOK (1.93 g, 17.24 mmol) at 0-5° C. The mixture was stirred for 3 days at rt. The mixture was adjusted to pH=6 with 1 N HCl with cooling. The mixture was extracted with EtOAc (3×100 mL). The organic layers were washed with 200 ml brine, dried over Na2SO4, and concentrated to dryness. The resultant residue was stirred with PE/EtOAc (10/10 mL) for 30 min and filtered to give the title compound (500 mg, 31%) as a red solid. 1H NMR (400 MHz, CDCl3): δ 4.63 (1H, s), 7.12 (1H, dd, J=4.8, 1.2 Hz), 7.16 (1H, s), 8.35 (1H, d, J=4.4 Hz), 8.43 (1H, s). [M+H] Calc'd for C9H6N4O, 187. Found, 187.
Reaction SMILES: Cl.Cl.[C:3]([O:11][CH2:12][CH2:13][NH2:14])(=[O:10])[C:4]1[CH:9]=[CH:8][CH:7]=[N:6][CH:5]=1.ClC1C=C(Cl)C(Cl)=CC=1[CH:24]([F:32])[CH2:25][N:26]([N:30]=[O:31])[C:27](=O)[O-:28].C(Cl)(Cl)Cl.C(OCC)(=O)C>N1C=CC=CC=1>[F:32][CH2:24][CH2:25][N:26]([N:30]=[O:31])[C:27]([NH:14][CH2:13][CH2:12][O:11][C:3]([C:4]1[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=1)=[O:10])=[O:28]
Reactant: O=NN(CC(F)c1cc(Cl)c(Cl)cc1Cl)C(=O)[O-]
Reactant: NCCOC(=O)c1cccnc1
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: O=NN(CCF)C(=O)NCCOC(=O)c1cccnc1

Procedure:
A solution of 2-aminoethyl nicotinate dihydrochloride (1.5 g, 6.3 mmol) and 2,4,5-trichlorophenyl-N-(2-fluoroethyl)-N-nitrosocarbamate (2.18 g, 6.9 mmol) in 50 mL of pyridine was stirred under nitrogen at room temperature for 24 hours. The reaction was monitored by thin layer chromatography (silica, 1:1 chloroform/ethyl acetate, Rf 0.25). The solvent was removed in vacuo and the residue was chromatographed on a silica gel column by eluting, first with benzene to remove unreacted nitrosocarbamate and trichlorophenol, and then with chloroform to elute the desired product. The compound (1.56 g, 87.4%) melted at 75°-77° C. and was characterized by the structural formula: ##STR155##
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[CH:15]=[CH:14][CH:13]=[C:12]([C:17]([OH:19])=O)[C:11]=3[CH:10]=[N:9]2)=[CH:4][CH:3]=1.Cl.[Br:21][C:22]1[N:27]=[CH:26][C:25]([C@@H:28]([NH2:31])[CH2:29][CH3:30])=[CH:24][CH:23]=1.C(N(CC)CC)C>S(Cl)(Cl)=O.ClCCl.[Cl-].[NH4+]>[Br:21][C:22]1[N:27]=[CH:26][C:25]([C@@H:28]([NH:31][C:17]([C:12]2[C:11]3[CH:10]=[N:9][N:8]([C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=4)[C:16]=3[CH:15]=[CH:14][CH:13]=2)=[O:19])[CH2:29][CH3:30])=[CH:24][CH:23]=1
Reactant: O=C(O)c1cccc2c1cnn2-c1ccc(F)cc1
Reactant: CC[C@H](N)c1ccc(Br)nc1
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: CC[C@H](NC(=O)c1cccc2c1cnn2-c1ccc(F)cc1)c1ccc(Br)nc1
Reaction time: 0.75 h

Procedure:
A suspension of 1-(4-fluoro-phenyl)-1H-indazole-4-carboxylic acid (258 mg, 1.00 mmol) was heated at reflux in thionyl chloride (5 mL) until the solid dissolved. After 45 minutes, the mixture was concentrated to dryness. The yellow residue was diluted with dichloromethane and (S)-1-(6-bromo-pyridin-3-yl)-propylamine hydrochloride (288 mg, 1.00 mmol) was added followed by triethylamine (1.0 mL, 7.2 mmol). After 30 minutes, the reaction was diluted with saturated aqueous ammonium chloride (10 mL) and extracted with ethyl acetate (4×10 mL). The combined organic layers were washed with brine (3×10 mL), dried over magnesium sulfate, filtered and concentrated. The crude material was diluted with dichloromethane and purified by silica gel chromatography eluting with a gradient of 0-100% ethyl acetate in hexanes. The material from the column was triturated with ether to afford 1-(4-fluoro-phenyl)-1H-indazole-4-carboxylic acid [(S)-1-(6-bromo-pyridin-3-yl)-propyl]-amide.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1)#[N:2].[OH:9]F>CC#N>[C:1]([C:3]1[CH:8]=[CH:7][N+:6]([O-:9])=[CH:5][CH:4]=1)#[N:2]
Reactant: N#Cc1ccncc1
Reactant: OF
Solvent: CC#N
Product: N#Cc1cc[n+]([O-])cc1
Yield: 59 %

Procedure:
4-cyanopyridine was reacted with 1 equivalent of HOF.MeCN to yield 59% of 4-cyanopyridine-N-oxide.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@@H:12]([C:13]2[CH:18]=[CH:17][C:16]([C:19]#[C:20][Si](C)(C)C)=[CH:15][CH:14]=2)[C@H:11]([C:25]([O:27][CH3:28])=[O:26])[O:10][C:9]1([CH3:30])[CH3:29])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C-]#N.[K+]>C(O)C.O.[N+]([O-])([O-])=O.[Ag+]>[C:1]([O:5][C:6]([N:8]1[C@@H:12]([C:13]2[CH:14]=[CH:15][C:16]([C:19]#[CH:20])=[CH:17][CH:18]=2)[C@H:11]([C:25]([O:27][CH3:28])=[O:26])[O:10][C:9]1([CH3:30])[CH3:29])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)[C@@H]1OC(C)(C)N(C(=O)OC(C)(C)C)[C@H]1c1ccc(C#C[Si](C)(C)C)cc1
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Agent: [C-]#N
Solvent: CCO
Solvent: O
Product: C#Cc1ccc([C@H]2[C@H](C(=O)OC)OC(C)(C)N2C(=O)OC(C)(C)C)cc1
Temperature: 20 °C
Reaction time: 18 h
Yield: 47.2 %

Procedure:
To a solution of 1.4 g of methyl (4S,5R)-3-tert-butoxycarbonyl-2,2-dimethyl-4-(4-trimethylsilylethynylphenyl)-5-oxazolidinecarboxylate in 20 cm3 of ethanol is added dropwise, with stirring and at a temperature in the region of 20° C., a solution of 1.7 g of silver nitrate in a mixture of 2 cm3 of distilled water and 1 cm3 of ethanol. The reaction mixture is subsequently stirred for 2 hours at a temperature in the region of 20° C., followed by dropwise addition of a solution of 2.93 g of potassium cyanide in 3 cm3 of distilled water. Stirring is continued at a temperature in the region of 20° C. for 18 hours and the mixture is extracted with 3 times 50 cm3 of ethyl acetate. The organic phases are combined, washed with 3 times 5 cm3 of distilled water, dried over magnesium sulphate, filtered and then concentrated to dryness under reduced pressure (2.7 kPa) at 40° C. 0.55 g of methyl (4S,5R)-3-tert-butoxycarbonyl-2,2-dimethyl-4-(4-ethynylphenyl)-5-oxazolidinecarboxylate is thus obtained, in the form of a brown oil which is converted to the corresponding acid under the conditions described in Example 2.
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[C:6]([C:15]([OH:17])=O)[C:7]3[CH:12]=[N:11][N:10]([CH2:13][CH3:14])[C:8]=3[N:9]=2)[CH2:3][CH2:2]1.[NH2:18][CH2:19][C:20]1[C:21](=[O:28])[NH:22][C:23]([CH3:27])=[CH:24][C:25]=1[CH3:26].ON1C2N=CC=CC=2N=N1.C(Cl)CCl.CN1CCOCC1>CS(C)=O>[CH:1]1([C:4]2[CH:5]=[C:6]([C:15]([NH:18][CH2:19][C:20]3[C:21](=[O:28])[NH:22][C:23]([CH3:27])=[CH:24][C:25]=3[CH3:26])=[O:17])[C:7]3[CH:12]=[N:11][N:10]([CH2:13][CH3:14])[C:8]=3[N:9]=2)[CH2:2][CH2:3]1
Reactant: CCn1ncc2c(C(=O)O)cc(C3CC3)nc21
Reactant: Cc1cc(C)c(CN)c(=O)[nH]1
Agent: On1nnc2cccnc21
Solvent: CN1CCOCC1
Solvent: CS(C)=O
Solvent: ClCCCl
Product: CCn1ncc2c(C(=O)NCc3c(C)cc(C)[nH]c3=O)cc(C3CC3)nc21

Procedure:
The title compound was prepared in the same manner as described for intermediate 56 using 6-cyclopropyl-1-ethyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid (91 mg, 0.394 mmol), 3-(aminomethyl)-4,6-dimethyl-2(1H)-pyridinone (75 mg, 0.493 mmol), 1-hydroxy-7-azabenzotriazole (107 mg, 0.788 mmol), DMSO (10 mL), EDC (151 mg, 0.788 mmol), and N-methylmorpholine (0.173 mL, 1.577 mmol). The final product was collected as 0.090 g (63%). LCMS E-S (M+H)=366.3 1H NMR (400 MHz, DMSO-d6) δ ppm 1.07 (d, J=6.32 Hz, 4H), 1.39 (t, J=7.20 Hz, 3H), 2.13 (s, 3H), 2.19-2.32 (m, 4H), 4.36 (d, J=4.80 Hz, 2H), 4.42 (q, J=7.07 Hz, 2H), 5.90 (s, 1H), 7.43 (s, 1H), 8.21 (s, 1H), 8.75 (t, J=4.67 Hz, 1H), 11.57 (br. s., 1H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1F.[NH2:12][NH2:13]>C(O)(C)C>[F:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1[NH:12][NH2:13]
Reactant: NN
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1
Solvent: CC(C)O
Product: NNc1ccc([N+](=O)[O-])cc1F

Procedure:
From the reaction of 3,4-difluoronitrobenzene with hydrazine in isopropyl alcohol at an elevated temperature (e.g. 75°-85° C.) there is produced 2-fluoro-4-nitrophenylhydrazine. The latter is then treated with acetone and sulfuric acid in tetrahydrofuran to yield N'-(2-fluoro-4-nitrophenyl)-dimethylketone hydrazone. The latter is then treated with potassium cyanate in aqueous acetic acid to produce 1-(2-fluoro-4-nitrophenyl)-5,5-dimethyl-1,2,4-triazolidin-3-one. The latter is then reacted with pyruvic acid and sulfuric acid in 1,4-dioxane to form 2-(2-fluoro-4-nitrophenyl-1,2,4-triazine-3,4(2H,4H)-dione. The latter is then reacted first with sodium hydride in dimethylformamide followed by methyl iodide to yield 2-(2-fluoro-4-nitrophenyl)-4-methyl-1,2,4-triazine-3,5(2H,4H)-dione. The latter is treated with iron powder in acetic acid to yield 2-(4-amino-2-fluorophenyl)-4-methyl-1,2,4-triazine-3,5(2H,4H)-dione. The latter dione is treated first with sodium nitrite in acetone and hydrochloric acid, then with methyl acrylate, and lastly with copper (I) chloride to form methyl 2-chloro-3-[5-fluoro-4-[4-methyl-1,2,4-triazine-3,5(2H,4H)-dione-1-yl]phenyl]propionate. The latter is then nitrated by treatment with a mixture of nitric acid and sulfuric acid to form methyl 2-chloro-3-[5-fluoro-4-[4-methyl-1,2,4-triazine-3,5(2H,4H)-dione-1-yl]-2-nitrophenyl]propionate. The latter is dissolved in acetic acid and added to a hot suspension of iron powder in acetic acid, then heated at an elevated temperature (e.g. 80°-90° C.) for about one hour to form 1-(3-chloro-6-fluoro-3,4-dihydroquinolin-2(1H)-one-7-yl)-4-methyl-1,2,4-triazine-3,5,(2H,4H)-dione. The latter is dehydrohalogenated with triethylamine in tetrahydroduran to yield 1-[6-fluoroquinolin-2(1H)-one-7-yl]-4-methyl-1,2,4-triazine-3,5(2H,4H)-dione. The latter is dissolved in dimethylformamide and treated first with potassium carbonate followed by propargyl chloride to yield 1-[6-fluoro-1-[2-propynyl]quinolin-2(1H)-one-7-yl]-4-methyl-1,2,4-triazine-3,5(2H,4H)-dione.
Reaction SMILES: [CH3:1][N:2]([CH3:17])[C:3]([C:5]1[CH:6]=[C:7]([N+:14]([O-:16])=[O:15])[CH:8]=[C:9]([CH3:13])[C:10]=1[O:11][CH3:12])=O.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:19].O.CCOCC>C1C=CC=CC=1>[CH3:1][N:2]([CH3:17])[C:3]([C:5]1[CH:6]=[C:7]([N+:14]([O-:16])=[O:15])[CH:8]=[C:9]([CH3:13])[C:10]=1[O:11][CH3:12])=[S:19]
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: COc1c(C)cc([N+](=O)[O-])cc1C(=O)N(C)C
Solvent: c1ccccc1
Solvent: CCOCC
Solvent: O
Product: COc1c(C)cc([N+](=O)[O-])cc1C(=S)N(C)C
Yield: 85.2 %

Procedure:
To a solution of 3-dimethylcarbamoyl-4-methoxy-5-methylnitrobenzene (1.10 g) in benzene (11 ml) is added phosphorus pentasulfide (3.08 g), and the resultant mixture is refluxed for 1 hour. After sooling, the reaction mixture is mixed with icy water and shaken with ether. The organic layer is washed with water, dried over Glauber's salt and concentrated under reduced pressure to remove the solvent. The residue is chromatographed on a column of silica gel, which is eluted with benzene, methylene chloride and then methylene chloride/2% methanol in order. The eluted fractions are concentrated under reduced pressure and the residue is washed with isopropyl ether to give 3-dimethylthiocarbamoyl-4-methoxy-5-methyl-nitrobenzene (1.0 g) as crystals melting at 138°-139° C.