Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([O:13][CH3:14])[C:5]([O:11][CH3:12])=[C:6]([CH:8]([NH2:10])[CH3:9])[CH:7]=1.F[C:16]1[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:17]=1[S:23]([CH3:26])(=[O:25])=[O:24].C(N(CC)C(C)C)(C)C>C(#N)C>[Cl:1][C:2]1[CH:3]=[C:4]([O:13][CH3:14])[C:5]([O:11][CH3:12])=[C:6]([CH:8]([NH:10][C:18]2[CH:19]=[C:20]([F:22])[CH:21]=[CH:16][C:17]=2[S:23]([CH3:26])(=[O:25])=[O:24])[CH3:9])[CH:7]=1
Reactant: CS(=O)(=O)c1ccc(F)cc1F
Reactant: COc1cc(Cl)cc(C(C)N)c1OC
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: COc1cc(Cl)cc(C(C)Nc2cc(F)ccc2S(C)(=O)=O)c1OC
Yield: 30.6 %

Procedure:
A solution of 1-(5-chloro-2,3-dimethoxy-phenyl)-ethyl amine (1.27 g, 5.89 mmol), 2,4-difluoro-1-methanesulfonyl-benzene (1.25 g, 6.48 mmol) and N,N-diisopropylethylamine (2.1 mL, 11.78 mmol) in acetonitrile was stirred at 80° C. for 48 h. The solvent was concentrated in vacuo, the residue was taken up in dichloromethane and washed with water, dried, and concentrated under reduced pressure to the crude compound which was purified by silica gel column (20% ethyl acetate in hexanes) to afford [1-(5-chloro-2,3-dimethoxy-phenyl)-ethyl]-(5-fluoro-2-methanesulfonyl-phenyl)-amine (700 mg, 32%): 1H NMR (400 MHz, CDCl3): δ 7.74 (dd, 1H), 6.82 (m, 2H), 6.73 (dd, 1H), 6.42 (dd, 1H), 6.24 (dd, 1H), 4.82 (m, 1H), 3.95 (s 3 H), 3.88 (s, 3H), 3.27 (3, 3H), 1.58 (s, 3H).
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:5]=[CH:6][CH:7]=[C:8]([OH:10])[CH:9]=1)=[O:3].[C:11]1([CH2:17][O:18][CH2:19][CH2:20][CH2:21]Br)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C)C=O.C(OCC)(=O)C>[C:11]1([CH2:17][O:18][CH2:19][CH2:20][CH2:21][O:10][C:8]2[CH:9]=[C:4]([C:2](=[O:3])[CH3:1])[CH:5]=[CH:6][CH:7]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: BrCCCOCc1ccccc1
Reactant: CC(=O)c1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)c1cccc(OCCCOCc2ccccc2)c1
Reaction time: 24 h

Procedure:
To a solution of 3-hydroxyacetophenone (5.5 g) in dimethylformamide (18 mL) was added 3-bromopropyl phenylmethyl ether (9.25 g) at ambient temperature followed by cesium carbonate (17 g). The suspension was stirred for 24 h and water was added followed by ethyl acetate. The organic layer was separated and the aqueous layer extracted with ethyl acetate. The organic layers were combined and washed twice with 2 N sodium hydroxide, four times with brine, and concentrated in vacuo to an oil to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[N:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.FC1C(C=O)=C(F)C=CC=1NS(C(C)C)(=O)=O.[F:28][C:29]1[C:34]([CH:35]=[O:36])=[C:33]([F:37])[CH:32]=[CH:31][C:30]=1[NH:38][S:39]([C:42]1[S:43][CH:44]=[CH:45][CH:46]=1)(=[O:41])=[O:40]>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:5]([C:35]([C:34]3[C:29]([F:28])=[C:30]([NH:38][S:39]([C:42]4[S:43][CH:44]=[CH:45][CH:46]=4)(=[O:41])=[O:40])[CH:31]=[CH:32][C:33]=3[F:37])=[O:36])=[CH:6][NH:7][C:8]2=[N:9][CH:10]=1
Reactant: Clc1cnc2[nH]ccc2c1
Reactant: O=Cc1c(F)ccc(NS(=O)(=O)c2cccs2)c1F
Agent: CC(C)S(=O)(=O)Nc1ccc(F)c(C=O)c1F
Product: O=C(c1c(F)ccc(NS(=O)(=O)c2cccs2)c1F)c1c[nH]c2ncc(Cl)cc12

Procedure:
was prepared using the protocol of Steps 3 and 4 of Scheme 17, substituting 5-pyridin-3-yl-1H-pyrrolo[2,3-b]pyridine 89 with 5-chloro-7-azaindole 80 (see Example 9) and propane-2-sulfonic acid (2,4-difluoro-3-formyl-phenyl)-amide 60 with thiophene-2-sulfonic acid (2,4-difluoro-3-formyl-phenyl)-amide 512 (see Example 21) in Step 3. MS (ESI) [M+H+]+=451.9.
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[C:5]([C:7]#[C:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=2)[N:6]=1.[F:19][C:20]1[CH:21]=[N:22][CH:23]=[C:24](F)[CH:25]=1>>[F:19][C:20]1[CH:21]=[N:22][CH:23]=[C:24]([N:3]2[CH:4]=[C:5]([C:7]#[C:8][C:9]3[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:16])[F:17])[CH:10]=3)[N:6]=[C:2]2[CH3:1])[CH:25]=1
Reactant: Fc1cncc(F)c1
Reactant: Cc1nc(C#Cc2cccc(C(F)(F)F)c2)c[nH]1
Product: Cc1nc(C#Cc2cccc(C(F)(F)F)c2)cn1-c1cncc(F)c1

Procedure:
The title compound, MS: m/e=346.3 (M+), was prepared in accordance with the general method of example 1 from 2-methyl-4-(3-trifluoromethyl-phenylethynyl)-1H-imidazole and 3,5-difluoro-pyridine.
Reaction SMILES: [CH:1]1[CH:2]=[C:3]([CH2:6][NH:7][C:8]2[C:13]([C:14]([OH:16])=O)=[CH:12][C:11]([S:17]([NH2:20])(=[O:19])=[O:18])=[C:10]([Cl:21])[CH:9]=2)[O:4][CH:5]=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[CH2:36]([NH:43][CH2:44][C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>CN(C=O)C>[CH2:44]([N:43]([CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[C:14](=[O:16])[C:13]1[CH:12]=[C:11]([S:17]([NH2:20])(=[O:19])=[O:18])[C:10]([Cl:21])=[CH:9][C:8]=1[NH:7][CH2:6][C:3]1[O:4][CH:5]=[CH:1][CH:2]=1)[C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1
Reactant: NS(=O)(=O)c1cc(C(=O)O)c(NCc2ccco2)cc1Cl
Reactant: c1ccc(CNCc2ccccc2)cc1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: NS(=O)(=O)c1cc(C(=O)N(Cc2ccccc2)Cc2ccccc2)c(NCc2ccco2)cc1Cl

Procedure:
In similar manner to Example 8, furosemide can be reacted with EDC, HOBt and dibenzylamine in DMF to yield N,N-dibenzyl 5-aminosulfonyl-4-chloro-2-[(2-furanylmethyl)amino]benzamide.
Reaction SMILES: S(F)(O)(=O)=O.C[OH:7].CN[C:10]1[C:11](C)=[CH:12][CH:13]=[CH:14][C:15]=1[CH3:16].CN[C:20]1[C:21](C)=[CH:22][CH:23]=[CH:24][CH:25]=1>O>[CH:14]1[C:15]2[CH2:16][C:21]3[C:20](=[CH:25][CH:24]=[CH:23][CH:22]=3)[O:7][C:10]=2[CH:11]=[CH:12][CH:13]=1
Reactant: CNc1c(C)cccc1C
Reactant: CNc1ccccc1C
Reactant: CO
Agent: O=S(=O)(O)F
Solvent: O
Product: c1ccc2c(c1)Cc1ccccc1O2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
In a 500 ml four-neck flask, 41.0 parts of a sulfofluoran compound of the following chemical formula (5), 312 parts of methanol, 6.79 parts of N-methyl-2,6-xylidine and 6.13 parts of N-methyl-o-toluidine were put and refluxed for 30 hours. The reaction solution was filtered at 60° C. to remove insoluble substances therefrom. Then, the solvent was removed under a reduced pressure, until the amount of the reaction solution reached about 70 ml. The reaction solution was poured into 200 parts of 6% hydrochloric acid. Then, 600 parts of water was added thereto and the mixture was stirred at room temperature for 30 minutes. Then, a wet cake was obtained by filtration. The wet cake was suspended in 100 parts of water and stirred at 60° C. for 2 hours. Then, the wet cake was obtained again by filtration, washed with hot water at 60° C. and then dried, thereby obtaining the xanthene-based dye A represented by the following chemical formula (6).
Reaction SMILES: [H-].[Na+].[CH:3]1([NH:6][S:7]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=2)(=[O:9])=[O:8])[CH2:5][CH2:4]1.Br[CH2:22][C:23]([NH2:25])=[O:24].O>CN(C)C=O>[CH:3]1([N:6]([CH2:22][C:23]([NH2:25])=[O:24])[S:7]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:18])[F:19])[CH:12]=2)(=[O:9])=[O:8])[CH2:5][CH2:4]1
Reactant: O=S(=O)(Cc1cccc(C(F)(F)F)c1)NC1CC1
Reactant: NC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: NC(=O)CN(C1CC1)S(=O)(=O)Cc1cccc(C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
0.26 Gram of sodium hydride is added portionwise to a solution containing 2.77 g of N-cyclopropyl-3-trifluoromethylbenzylsulfonamide in 50 ml of dimethylformamide over an ice bath. The mixture is stirred 15 minutes at 0° C. and then 0.0105 moles of bromoacetamide is added dropwise with cooling. The mixture is stirred overnight at room temperature. Water is then added. This will result in the formation of a precipitate and oil. Water is continued to be added until no further precipitate or oil is formed. The mixture is cooled over an ice bath and then filtered. The filter cake is dissolved in hot cyclohexane and then recrystallized affording the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]2[C:6]3[N:21]=[C:20](N)[N:19]=[CH:18][C:7]=3[CH2:8][N:9]=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[F:17])[C:4]=2[CH:3]=1.[OH-:25].[NH4+]>S(=O)(=O)(O)O.O>[Cl:1][C:2]1[CH:24]=[CH:23][C:5]2[C:6]3[N:21]=[C:20]([OH:25])[N:19]=[CH:18][C:7]=3[CH2:8][N:9]=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[F:17])[C:4]=2[CH:3]=1
Reactant: [OH-]
Reactant: Nc1ncc2c(n1)-c1ccc(Cl)cc1C(c1ccccc1F)=NC2
Agent: O=S(=O)(O)O
Agent: [NH4+]
Solvent: O
Product: Oc1ncc2c(n1)-c1ccc(Cl)cc1C(c1ccccc1F)=NC2

Procedure:
A solution of 1.2 g (0.00354 mol) of 9-chloro-7-(2-fluorophenyl)-2-amino-5H-pyrimido[5,4-d][2]benzazepine in 20 ml of concentrated sulfuric acid and 20 ml of water was refluxed for 12 hr, and then cooled. After the addition of ice, the reaction mixture was basified with ammonium hydroxide and extracted with 100 ml of dichloromethane. The solids were collected by filtration and recrystallized from dichloromethane/methanol to give the end product as white prisms, mp 279°-299° dec. The dichloromethane extract was dried, evaporated and the residue crystallized from dichloromethane/methanol to give additional product.
Reaction SMILES: [CH2:1](N(CC)CC)[CH3:2].Cl.C([O:11][C:12](=[O:17])[C@H:13]([CH2:15][SH:16])[NH2:14])C.[Cl:18][C:19]1[C:20]([O:26][C:27]2[CH:38]=[CH:37][C:30]([O:31][CH:32]([CH3:36])[C:33](Cl)=[O:34])=[CH:29][CH:28]=2)=[N:21][CH:22]=[C:23]([Cl:25])[CH:24]=1>C(Cl)(Cl)Cl>[CH2:1]([N:14]([C:33](=[O:34])[CH:32]([O:31][C:30]1[CH:37]=[CH:38][C:27]([O:26][C:20]2[C:19]([Cl:18])=[CH:24][C:23]([Cl:25])=[CH:22][N:21]=2)=[CH:28][CH:29]=1)[CH3:36])[C@H:13]([C:12]([OH:11])=[O:17])[CH2:15][SH:16])[CH3:2]
Reactant: CC(Oc1ccc(Oc2ncc(Cl)cc2Cl)cc1)C(=O)Cl
Reactant: CCOC(=O)[C@@H](N)CS
Reactant: CCN(CC)CC
Agent: Cl
Solvent: ClC(Cl)Cl
Product: CCN(C(=O)C(C)Oc1ccc(Oc2ncc(Cl)cc2Cl)cc1)[C@@H](CS)C(=O)O
Temperature: 0 °C

Procedure:
Triethylamine is added to a stirred mixture of L-cysteine ethyl ester hydrochloride (2.71 g, 14.66 mmol) in chloroform under nitrogen. After the reaction mixture is cooled to 0° C., a solution of 2-{p-[(3,5-dichloro-2-pyridyl)oxy]phenoxy}propionyl chloride (5.08 g, 1 4.66 mmol) in chloroform (30 mL) is added dropwise with stirring. The reaction mixture is then stirred overnight at room temperature, concentrated in vacuo and filtered to obtain a semi-solid. Chromatography of the semi-solid using silica gel and eluting with methylene chloride followed by 2% to 5% ethyl acetate in methylene chloride gives the title product as a white solid, mp 89°-91° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:8]([NH:14][C:15]([C@@H:17]2[CH2:22][CH2:21][CH2:20][N:19]([C:23](=[O:39])[CH2:24][CH2:25][CH:26]3[CH2:31][CH2:30][N:29]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:28][CH2:27]3)[CH2:18]2)=[O:16])[CH2:9][C:10]([O:12][CH3:13])=[O:11])[CH:5]=[N:6][CH:7]=1.[OH:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=1B(O)O.[F-].[K+]>C1(C)C=CC=CC=1.C(O)C.O.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>[OH:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=1[C:2]1[CH:3]=[C:4]([CH:8]([NH:14][C:15]([C@@H:17]2[CH2:22][CH2:21][CH2:20][N:19]([C:23](=[O:39])[CH2:24][CH2:25][CH:26]3[CH2:27][CH2:28][N:29]([C:32]([O:34][C:35]([CH3:36])([CH3:38])[CH3:37])=[O:33])[CH2:30][CH2:31]3)[CH2:18]2)=[O:16])[CH2:9][C:10]([O:12][CH3:13])=[O:11])[CH:5]=[N:6][CH:7]=1
Reactant: COC(=O)CC(NC(=O)[C@@H]1CCCN(C(=O)CCC2CCN(C(=O)OC(C)(C)C)CC2)C1)c1cncc(Br)c1
Reactant: OB(O)c1ccccc1O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [F-]
Agent: [K+]
Solvent: CCO
Solvent: O
Solvent: Cc1ccccc1
Product: COC(=O)CC(NC(=O)[C@@H]1CCCN(C(=O)CCC2CCN(C(=O)OC(C)(C)C)CC2)C1)c1cncc(-c2ccccc2O)c1
Temperature: 100 °C
Reaction time: 20 h
Yield: 58.4 %

Procedure:
To 400.0 mg (0.66 mmol) tert-butyl 4-{3-[(3R)-3-{[1-(5-bromopyridin-3-yl)-3-methoxy-3-oxopropyl]carbamoyl}piperidin-1-yl]-3-oxopropyl}piperidine-1-carboxylate in 16 ml toluene were added 15.17 mg (0.01 mmol) tetrakis(triphenylphosphine)palladium(0), 108.6 mg (0.79 mmol) (2-hydroxyphenyl)boronic acid in 4.0 ml ethanol and 118.3 mg (2.04 mmol) potassium fluoride in 4.0 ml water. The mixture was stirred at 100° C. for 20 hours, diluted with water and extracted with ethyl acetate. The organic phase was dried over sodium sulfate and concentrated in vacuum. Chromatography over 10 g silica gel (dichloromethane/ethanol 100/0-95/5-90/10) gave 240 mg (59%) tert-butyl 4-{3-[(3R)-3-({1-[5-(2-hydroxyphenyl)pyridin-3-yl]-3-methoxy-3-oxopropyl}carbamoyl)piperidin-1-yl]-3-oxopropyl}piperidine-1-carboxylate.
Reaction SMILES: [CH:1]1([C:4]2C(OC3C=CC(C4C=CC=CC=4C4N=NN(C(OC(=O)C(C)(C)C)C(C)C)N=4)=CC=3)=C(C(O)=O)C3C(=CC=CC=3)N=2)[CH2:3][CH2:2]1.[CH:46]1([C:49]2[C:58]([O:59][C:60]3[CH:65]=[CH:64][C:63]([C:66]4[CH:71]=[CH:70][CH:69]=[CH:68][C:67]=4[C:72]4[N:73]=[N:74][N:75]([C:77]([C:90]5[CH:95]=[CH:94][CH:93]=[CH:92][CH:91]=5)([C:84]5[CH:89]=[CH:88][CH:87]=[CH:86][CH:85]=5)[C:78]5[CH:83]=[CH:82][CH:81]=[CH:80][CH:79]=5)[N:76]=4)=[CH:62][CH:61]=3)=[C:57]([C:96]([OH:98])=[O:97])[C:56]3[C:51](=[CH:52][CH:53]=[CH:54][CH:55]=3)[N:50]=2)[CH2:48][CH2:47]1.[C:99](=[O:102])([O-:101])[O-:100].[K+].[K+]>CN(C)C=O.C(OCC)(=O)C>[CH:46]1([C:49]2[C:58]([O:59][C:60]3[CH:61]=[CH:62][C:63]([C:66]4[CH:71]=[CH:70][CH:69]=[CH:68][C:67]=4[C:72]4[N:73]=[N:74][N:75]([C:77]([C:90]5[CH:91]=[CH:92][CH:93]=[CH:94][CH:95]=5)([C:78]5[CH:83]=[CH:82][CH:81]=[CH:80][CH:79]=5)[C:84]5[CH:85]=[CH:86][CH:87]=[CH:88][CH:89]=5)[N:76]=4)=[CH:64][CH:65]=3)=[C:57]([C:96]([O:98][CH2:4][C:1]3[O:102][C:99](=[O:101])[O:100][C:2]=3[CH3:3])=[O:97])[C:56]3[C:51](=[CH:52][CH:53]=[CH:54][CH:55]=3)[N:50]=2)[CH2:47][CH2:48]1
Reactant: O=C(O)c1c(Oc2ccc(-c3ccccc3-c3nnn(C(c4ccccc4)(c4ccccc4)c4ccccc4)n3)cc2)c(C2CC2)nc2ccccc12
Reactant: CC(C)C(OC(=O)C(C)(C)C)n1nnc(-c2ccccc2-c2ccc(Oc3c(C4CC4)nc4ccccc4c3C(=O)O)cc2)n1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1oc(=O)oc1COC(=O)c1c(Oc2ccc(-c3ccccc3-c3nnn(C(c4ccccc4)(c4ccccc4)c4ccccc4)n3)cc2)c(C2CC2)nc2ccccc12
Temperature: 25 °C
Reaction time: 21 h

Procedure:
To the title A compound of Example 17, 2-cyclopropyl-3-[[2'-[2-(triphenylmethyl)-2H-tetrazol-5-yl][1,1'-biphenyl]-4-yl]oxy]-4-quinolinecarboxylic acid (1.32 g, 1.91 mmol, 1 eq.), and the title B compound (1.84 g, 9.54 mmol, 5 eq.) in dimethylformamide (3.8 mL, 0.5M), potassium carbonate (0.66 g, 4.77 mmol, 2.5 eq.) was added. The mixture was stirred at room temperature for 21 hours, diluted with ethyl acetate and filtered. The filtrate was washed with ammonium chloride/water and saturated sodium chloride, dried (magnesium sulfate), filtered and concentrated to afford the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][C@@H:9]1[CH2:14][OH:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].[N+:16]([C:19]1[CH:26]=[CH:25][CH:24]=[C:23]([N+]([O-])=O)[C:20]=1[C:21]#[N:22])([O-:18])=[O:17].[H-].[Na+]>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][C@@H:9]1[CH2:14][O:15][C:23]1[CH:24]=[CH:25][CH:26]=[C:19]([N+:16]([O-:18])=[O:17])[C:20]=1[C:21]#[N:22])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: N#Cc1c([N+](=O)[O-])cccc1[N+](=O)[O-]
Reactant: CC(C)(C)OC(=O)N1CCCC[C@@H]1CO
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCCC[C@@H]1COc1cccc([N+](=O)[O-])c1C#N
Temperature: 25 °C
Reaction time: 18 h
Yield: 90.6 %

Procedure:
To a solution of (R)-tert-butyl-2-(hydroxymethyl)piperidine-1-carboxylate (Example 15f, 7.10 g, 33.0 mmol) and 2,6-dinitrobenzonitrile (6.37 g, 33.0 mmol) in THF (142 mL) cooled to -78° C., was added NaH (60% dispersion in oil, 1.45 g, 36.3 mmol). The reaction was allowed to warm to room temperature and stirring was continued for 18 hours. Upon completion, the reaction was cooled to 0° C. and quenched with water. The mixture was extracted with ethyl acetate, and the organic extracts were combined and dried over anhydrous Na2SO4, filtered, and concentrated. The residue was recrystallized from ethyl acetate/hexanes to afford (R)-tert-butyl-2-((2-cyano-3-nitrophenoxy)methyl)piperidine-1-carboxylate (10.8 g, 91%) as a yellow solid. MS 282 (MH+-boc).
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[CH:6][C:7](C(OC)=O)=[CH:8][CH:9]=2)[N:4](S(C(F)(F)F)(=O)=O)[N:3]=1.[C:22]([O-])([O-:24])=[O:23].[K+].[K+]>CO.O.CCOC(C)=O>[CH3:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:22]([OH:24])=[O:23])[CH:9]=2)[NH:4][N:3]=1
Reactant: COC(=O)c1ccc2c(C)nn(S(=O)(=O)C(F)(F)F)c2c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1n[nH]c2ccc(C(=O)O)cc12
Temperature: 25 °C
Yield: 80.3 %

Procedure:
To a solution of methyl 3-methyl-1-[(trifluoromethyl)sulfonyl]-1H-indazole-6-carboxylate (590 mg, 1.83 mmol) in methanol/water (3:1, 72 mL) was added K2CO3 (1.01 g, 7.31 mmol) and the mixture was heated at reflux for 2 hours. The reaction was cooled to room temperature and the methanol was removed under reduced pressure. The aqueous solution was acidified to pH 3-3.5 with KHSO4. The solid was isolated by filtration, dissolved in EtOAc and washed with water. The organic layer was dried over Na2SO4, filtered and concentrated to provide the title compound (259 mg, 80%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]1([C@@H:12](O)[CH3:13])[CH2:11][O:10]1.[F:15][C:16]([F:34])([CH:31]([F:33])[F:32])[CH2:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]2[C:29](=[O:30])[NH:28][CH:27]=[N:26]2)=[CH:21][CH:20]=1>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]1([O:10][CH2:11]1)[C@H:12]([N:28]1[CH:27]=[N:26][N:25]([C:22]2[CH:21]=[CH:20][C:19]([O:18][CH2:17][C:16]([F:34])([F:15])[CH:31]([F:33])[F:32])=[CH:24][CH:23]=2)[C:29]1=[O:30])[CH3:13]
Reactant: O=c1[nH]cnn1-c1ccc(OCC(F)(F)C(F)F)cc1
Reactant: C[C@H](O)[C@@]1(c2ccc(F)cc2F)CO1
Product: C[C@@H](n1cnn(-c2ccc(OCC(F)(F)C(F)F)cc2)c1=O)[C@@]1(c2ccc(F)cc2F)CO1
Yield: 46.1 %

Procedure:
In the same manner as in Reference Example 5, starting from 0.975 g of (1S)-[(2R)-(2,4-difluorophenyl)-2-oxiranyl]ethanol and 1.13 g of 2-[4-(2,2,3,3-tetrafluoropropoxy)phenyl]-3(2H,4H)-1,2,4-triazolone, 0.847 g of 4-[(1R,2S)-2-(2,4-difluorophenyl)-2,3-epoxy-1-methylpropyl]-2-[4-(2,2,3,3-tetrafluoropropoxy)phenyl]-3(2H, 4H)-1,2,4-triazolone was obtained as colorless prisms.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][OH:8])=[CH:3][CH:2]=1.[H-].[Na+].Cl[C:12]1[N:17]=[CH:16][C:15]([C:18]2[CH:19]=[C:20]([CH:35]=[CH:36][CH:37]=2)[CH2:21][N:22]([CH3:34])[C:23](=[O:33])[CH2:24][NH:25][C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[CH:14][N:13]=1.O>CN(C=O)C>[C:28]([O:27][C:26](=[O:32])[NH:25][CH2:24][C:23]([N:22]([CH3:34])[CH2:21][C:20]1[CH:35]=[CH:36][CH:37]=[C:18]([C:15]2[CH:16]=[N:17][C:12]([O:8][CH2:7][C:4]3[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=3)=[N:13][CH:14]=2)[CH:19]=1)=[O:33])([CH3:31])([CH3:30])[CH3:29]
Reactant: CN(Cc1cccc(-c2cnc(Cl)nc2)c1)C(=O)CNC(=O)OC(C)(C)C
Reactant: OCc1ccncc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CN(Cc1cccc(-c2cnc(OCc3ccncc3)nc2)c1)C(=O)CNC(=O)OC(C)(C)C
Reaction time: 0.5 h
Yield: 99.9 %

Procedure:
Pyridin-4-ylmethanol (112 mg) was dissolved in DMF (4 ml), and NaH (45 mg) was added thereto under ice-cooling. After stirring at the same temperature for 30 minutes, tert-butyl (2-{[3-(2-chloropyrimidin-5-yl)benzyl](methyl)amino}-2-oxoethyl)carbamate (200 mg) was added thereto, followed by stirring at room temperature for 2 hours. To the reaction mixture was added water, followed by extraction with EtOAc. The organic layer was dried over MgSO4 and evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (0% to 7% MeOH/CHCl3) to obtain tert-butyl[2-(methyl{3-[2-(pyridin-4-ylmethoxy)pyrimidin-5-yl]benzyl}amino)-2-oxoethyl]carbamate (237 mg).
Reaction SMILES: [CH2:1]([N:8]1[CH2:24][CH2:23][C:11]2([NH:20][C:19](=[O:21])[C:18]3[C:13](=[CH:14][CH:15]=[C:16](Br)[CH:17]=3)[NH:12]2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:25]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])(=[O:28])[CH:26]=[CH2:27].COC(=O)/C=C/C1C=C2C(=CC=1)OC1(CCN(C(OC(C)(C)C)=O)CC1)CC2=O>>[C:30]([O:29][C:25](=[O:28])/[CH:26]=[CH:27]/[C:16]1[CH:17]=[C:18]2[C:13](=[CH:14][CH:15]=1)[NH:12][C:11]1([CH2:23][CH2:24][N:8]([CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH2:9][CH2:10]1)[NH:20][C:19]2=[O:21])([CH3:33])([CH3:32])[CH3:31]
Reactant: O=C1NC2(CCN(Cc3ccccc3)CC2)Nc2ccc(Br)cc21
Reactant: C=CC(=O)OC(C)(C)C
Agent: COC(=O)/C=C/c1ccc2c(c1)C(=O)CC1(CCN(C(=O)OC(C)(C)C)CC1)O2
Product: CC(C)(C)OC(=O)/C=C/c1ccc2c(c1)C(=O)NC1(CCN(Cc3ccccc3)CC1)N2

Procedure:
(E)-3-{1-Benzyl-3′,4′-dihydro-4′-oxo-spiro[piperidine-4,2′(1′H)-quinazoline]-6′-yl}-acrylic acid tert-butyl ester was synthesized starting from 1-benzyl-6′-bromo-3′,4′-dihydro-spiro[piperidine-4,2′(1′H)-quinazoline]-4′-one (600 mg, 1.55 mmol) and tert-butyl acrylate according to the procedure described for Intermediate 1, Step B, giving 486 mg of the product.
Reaction SMILES: Cl.[CH3:2][N:3]1[C:8]([NH:9][CH2:10][CH2:11][NH:12][CH2:13][CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=2)=[CH:7][C:6](=[O:25])[N:5]([CH3:26])[C:4]1=[O:27].[C:28](=[O:31])([O-])[O-].[K+].[K+]>O>[CH3:2][N:3]1[C:8]([NH:9][CH2:10][CH2:11][N:12]([CH2:13][CH2:14][CH2:15][C:16]2[CH:17]=[CH:18][C:19]([N+:22]([O-:24])=[O:23])=[CH:20][CH:21]=2)[CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:31][CH3:28])=[CH:18][CH:17]=2)=[CH:7][C:6](=[O:25])[N:5]([CH3:26])[C:4]1=[O:27]
Reactant: O=C([O-])[O-]
Reactant: Cn1c(NCCNCCCc2ccc([N+](=O)[O-])cc2)cc(=O)n(C)c1=O
Agent: Cl
Agent: [K+]
Solvent: O
Product: COc1ccc(CN(CCCc2ccc([N+](=O)[O-])cc2)CCNc2cc(=O)n(C)c(=O)n2C)cc1

Procedure:
1.4 g of 1,3-dimethyl-6-{2-[3-(4-nitrophenyl)propylamino]ethylamino}-2,4(1H,3H)-pyrimidinedione hydrochloride (Compound e) were dissolved in 5 ml of water, followed by the addition of potassium carbonate to render the solution alkaline. The solution was then extracted with chloroform. The thus-obtained chloroform solution was concentrated to dryness, followed by the addition of 0.6 g of p-methoxybenzyl bromide, 3 ml of triethylamine and 20 ml of isopropanol. The resultant mixture was heated for 8 hours under reflux. The solvent was distilled off under reduced pressure and the residue was directly subjected to chromatographic purification on a silica gel (eluent: chloroform/methanol=40/1, by volume), thereby obtaining 0.55 g of 1,3-dimethyl-6-{2-[N-(4-methoxybenzyl)-3-(4-nitrophenyl)propylamino]ethylamino}-2,4(1H,3H)-pyrimidinedione.
Reaction SMILES: [CH2:1]([C:4]1[O:5][CH:6]=[CH:7][CH:8]=1)[CH2:2][CH3:3].[Li]CCCC.[CH2:14]1[O:16][CH2:15]1>C1COCC1>[CH2:1]([C:4]1[O:5][C:6]([CH2:14][CH2:15][OH:16])=[CH:7][CH:8]=1)[CH2:2][CH3:3]
Reactant: CCCc1ccco1
Reactant: C1CO1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCc1ccc(CCO)o1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 91 %

Procedure:
To a solution of 2-propylfuran (3.00 g, 31.2 mmol) in THF (31 mL) at −78° C. was added n-BuLi (15.0 mL, 2.5 M, 37.4 mmol) dropwise over 10 min. The reaction was warmed to rt and stirred for 3.5 h. After cooling to 0° C., ethylene oxide (2.33 mL, 46.8 mmol) was added, the reaction was warmed to rt and stirring was continued for 19 h. The reaction was then cooled to 0° C. and quenched with sat. NH4Cl (20 mL), followed by extraction with Et2O (2×50 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated to give 4.38 g (91%) of compound 501A as a bright orange oil. This material was used without further purification. HPLC: 94% at 2.91 min (retention time) (YMC Combiscreen ODS-A column, 4.6×50 mm, eluting with 10-90% aqueous methanol containing 0.2% phosphoric acid over 4 min, 4 mL/min, monitoring at 220 nm). MS (ES): m/z 137.13 [M−H2O+H]+.