Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[CH:4](OCC)[C:5]([C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=1)=O)C.Cl.[NH2:18][NH:19][C:20]([NH2:22])=[O:21]>C(O)C>[F:13][C:10]1[CH:9]=[CH:8][C:7]([C:5]2[CH:4]=[N:22][C:20](=[O:21])[NH:19][N:18]=2)=[CH:12][CH:11]=1
Reactant: NNC(N)=O
Reactant: CCOC(OCC)C(=O)c1ccc(F)cc1
Agent: Cl
Solvent: CCO
Product: O=c1ncc(-c2ccc(F)cc2)n[nH]1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 2,2-diethoxy-1-(4-fluorophenyl)ethanone (5.15 g, 0.0228 mol), semicarbazide hydrochloride (2.6 g, 0.024 mol) in ethanol (50 mL) was stirred at RT overnight, and then heated at 80° C. for 5 h. The mixture was concentrated. The residue was dissolved in acetic acid (50 mL), and heated at 130° C. for 6 h. After cooling, the mixture was concentrated, and the residue was triturated with ethyl ether, filtered, and washed with ether and then hexane. The crystalline solid was collected and dried under high vacuum to the desired product (4.18 g, 96.1%). Analytical LCMS: (M+H)+=192.1.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:6]=[C:7]([CH:17]=[CH:18][C:19]=1[CH2:20][CH3:21])[O:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=O)=[CH:11][CH:10]=1)[CH:2]=[CH2:3].[CH3:22][C:23]1[C:29]([N+:30]([O-:32])=[O:31])=[CH:28][CH:27]=[CH:26][C:24]=1[NH2:25]>>[CH2:1]([O:4][C:5]1[CH:6]=[C:7]([CH:17]=[CH:18][C:19]=1[CH2:20][CH3:21])[O:8][C:9]1[CH:16]=[CH:15][C:12]([CH2:13][NH:25][C:24]2[CH:26]=[CH:27][CH:28]=[C:29]([N+:30]([O-:32])=[O:31])[C:23]=2[CH3:22])=[CH:11][CH:10]=1)[CH:2]=[CH2:3]
Reactant: C=CCOc1cc(Oc2ccc(C=O)cc2)ccc1CC
Reactant: Cc1c(N)cccc1[N+](=O)[O-]
Product: C=CCOc1cc(Oc2ccc(CNc3cccc([N+](=O)[O-])c3C)cc2)ccc1CC

Procedure:
The product from Example 236C and 2-methyl-3-nitroaniline were processed as in Example 6A to provide the titled compound. MS (ESI−) m/z 423 (M−H)−.
Reaction SMILES: [OH:1][CH2:2][C:3]1[N:4]=[CH:5][C:6]2[CH2:7][CH2:8][CH2:9][CH2:10][C:11]=2[CH:12]=1.[Se](=O)=O>O1CCOCC1.ClCCl>[CH:5]1[C:6]2[CH2:7][CH2:8][CH2:9][CH2:10][C:11]=2[CH:12]=[C:3]([CH:2]=[O:1])[N:4]=1
Reactant: OCc1cc2c(cn1)CCCC2
Agent: O=[Se]=O
Solvent: ClCCl
Solvent: C1COCCO1
Product: O=Cc1cc2c(cn1)CCCC2
Temperature: 82.5 °C
Yield: 70.2 %

Procedure:
3-Hydroxymethyl-5,6,7,8-tetrahydroisoquinoline (1.73 g, 10.6 mmole) is dissolved in 30 ml dioxane in a 100 ml one neck round bottom flask under nitrogen. The solution is treated with selenium dioxide (647 mg, 5.8 mmole) and the reaction mixture is warmed to 80-85° C. for 1.5 h. The mixture is cooled to room temperature, is diluted with 30 ml dichloromethane and is filtered through celite. The filter cake is washed well with fresh dichloromethane and the filtrate is concentrated in vacuo to a dark amber oil. The crude material is chromatographed through a 25 g plug of silica gel (230-400 mesh), eluting with 20% acetone/hexane while collecting 50 ml fractions. Fractions 1-3 are combined and concentrated to give 1.20 g (70%) of 5,6,7,8,-tetrahydroisoquinoline-3-carbaldehyde.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[N:10]1[CH2:15][CH2:14][CH2:13][CH2:12][C@H:11]1[C:16]([NH:18][CH2:19][CH2:20][NH:21]C(=O)OCC1C=CC=CC=1)=[O:17]>CO.[Pd]>[NH2:21][CH2:20][CH2:19][NH:18][C:16]([C@@H:11]1[CH2:12][CH2:13][CH2:14][CH2:15][N:10]1[C:2]1[O:1][C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=1)=[O:17]
Reactant: O=C(NCCNC(=O)[C@@H]1CCCCN1c1nc2ccccc2o1)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: NCCNC(=O)[C@@H]1CCCCN1c1nc2ccccc2o1
Reaction time: 3 h
Yield: 90.2 %

Procedure:
Benzyl N-[2-([(2S)-1-(1,3-benzoxazol-2-yl)-2-piperidinyl]carbonylamino)ethyl]carbamate (480.6 mg) [see Preparation 4] was dissolved in methanol (20 ml) and 10% palladium on charcoal (48 mg) was added. The reaction mixture was then hydrogenated at 4 atmospheres (60 p.s.i.) at room temperature for 3 hours, after which time the mixture was filtered and the solvent removed under reduced pressure. The product was then azeotroped with dichloromethane to afford (2S)-N2-(2-aminoethyl)-1-(1,3-benzoxazol-2-yl)-2-piperidinecarboxamide (296 mg) as a colourless liquid.
Reaction SMILES: [CH2:1](I)[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH2:10]([NH:17][C:18]1[C:23]([C:24]([N:26]([O:28][CH3:29])[CH3:27])=[O:25])=[CH:22][N:21]=[C:20]2[NH:30][N:31]=[CH:32][C:19]=12)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>CN(C)C=O.O>[CH2:10]([NH:17][C:18]1[C:23]([C:24]([N:26]([O:28][CH3:29])[CH3:27])=[O:25])=[CH:22][N:21]=[C:20]2[N:30]([CH2:1][CH3:2])[N:31]=[CH:32][C:19]=12)[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: CCI
Reactant: CON(C)C(=O)c1cnc2[nH]ncc2c1NCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCn1ncc2c(NCc3ccccc3)c(C(=O)N(C)OC)cnc21
Temperature: 60 °C
Reaction time: 5 h

Procedure:
Ethyl iodide (1.52 gm, 9.63 mmol) and potassium carbonate (2.214 gm, 16.05 mmol) were added to the solution 4-(benzylamino)-N-methoxy-N-methyl-1H-pyrazolo[3,4-b]pyridine-5-carboxamide (1 gm, 3.21 mmol) (example 6a) in dimethylformamide and the reaction mixture was stirred at 60° C. for about 5 hours. It was cooled, diluted with water and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulphate and concentrated under reduced pressure. The crude product was purified over silica gel column.
Reaction SMILES: [C:1]([O:12][CH3:13])(=[O:11])[C:2]1[CH:10]=[C:8]([OH:9])[C:6]([OH:7])=[C:4]([OH:5])[CH:3]=1.CO[CH:16](OC)[C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=1.O>C1(C)C=CC=CC=1.ClCCl.C1(C)C=CC(S(O)(=O)=O)=CC=1>[OH:9][C:8]1[C:6]2[O:7][CH:16]([C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=3)[O:5][C:4]=2[CH:3]=[C:2]([C:1]([O:12][CH3:13])=[O:11])[CH:10]=1
Reactant: COC(=O)c1cc(O)c(O)c(O)c1
Reactant: COc1ccc(C(OC)OC)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: COC(=O)c1cc(O)c2c(c1)OC(c1ccc(OC)cc1)O2
Yield: 52.4 %

Procedure:
To a suspension of methyl gallate (10 g, 54.3 mmol) in toluene (25 ml), p-toluensulfonic acid (29 mg) and p-anisaldehyde dimethylacetal (11.56 ml, 67.88 mmol) were added. The reaction was refluxed for 1.5 hours with continuous removal of water. The mixture was diluted with dichloromethane (70 ml) and washed with a saturated aqueous NaHCO3 solution (100 ml) and extracted with ethyl acetate (3×50 ml) The organic layer was washed with water (100 ml), dried over sodium sulphate and concentrated under reduced pressure. The residue was crystallized by n-hexane. The product (8.6 g) was obtained.
Reaction SMILES: C([O:5][C:6]([CH2:8][N:9]([CH2:18][C:19]1[N:24]=[C:23]([C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([C:31]3[CH:36]=[CH:35][CH:34]=[C:33]([CH2:37][N:38]([CH2:47][C:48]([O:50]C(C)(C)C)=[O:49])[CH2:39][C:40]([O:42]C(C)(C)C)=[O:41])[N:32]=3)[N:26]=2)[CH:22]=[CH:21][CH:20]=1)[CH2:10][C:11]([O:13]C(C)(C)C)=[O:12])=[O:7])(C)(C)C>FC(F)(F)C(O)=O>[C:48]([CH2:47][N:38]([CH2:37][C:33]1[N:32]=[C:31]([C:27]2[CH:28]=[CH:29][CH:30]=[C:25]([C:23]3[CH:22]=[CH:21][CH:20]=[C:19]([CH2:18][N:9]([CH2:8][C:6]([OH:7])=[O:5])[CH2:10][C:11]([OH:13])=[O:12])[N:24]=3)[N:26]=2)[CH:36]=[CH:35][CH:34]=1)[CH2:39][C:40]([OH:42])=[O:41])([OH:50])=[O:49]
Reactant: CC(C)(C)OC(=O)CN(CC(=O)OC(C)(C)C)Cc1cccc(-c2cccc(-c3cccc(CN(CC(=O)OC(C)(C)C)CC(=O)OC(C)(C)C)n3)n2)n1
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)CN(CC(=O)O)Cc1cccc(-c2cccc(-c3cccc(CN(CC(=O)O)CC(=O)O)n3)n2)n1

Procedure:
Tetraester (10a) (260 mg, 0.4 mmol) was dissolved in trifluoroacetic acid (3 ml). After two hours the trifluoroacetic acid was evaporated, some diethyl ether was added and the product was filtered.
Reaction SMILES: [CH:1]1([C:7](Cl)=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Br:10][C:11]1[CH:12]=[C:13]([CH:15]=[CH:16][CH:17]=1)[NH2:14]>CN(C1C=CN=CC=1)C.C1COCC1>[Br:10][C:11]1[CH:12]=[C:13]([NH:14][C:7]([CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)=[O:8])[CH:15]=[CH:16][CH:17]=1
Reactant: O=C(Cl)C1CCCCC1
Reactant: Nc1cccc(Br)c1
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Product: O=C(Nc1cccc(Br)c1)C1CCCCC1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
Cyclohexanecarbonyl chloride (0.74 g, 6.97 mmol) was added to a mixture of 3-bromoaniline (1.0 g, 5.8 mmol), TEA (1.07 mL, 7.55 mmol) and DMAP (cat.) in THF with stirring at 0° C. over 10 min. Stirring was continued for another 30 min and quenched with saturated NaHCO3. The product was extracted with ethyl acetate. Combined organic layers were concentrated under reduced pressure to give a residue which was triturated with pentane to give N-(3-bromophenyl)cyclohexanecarboxamide as an off-white solid. Yield (1.3 g, 79%); 1H NMR (400 MHz, DMSO-d6) δ 9.96 (s, 1H), 7.97 (s, 1H), 7.49 (d, J=8.0 Hz, 1H), 7.26-7.18 (m, 2H), 2.33-2.26 (m, 1H), 1.76 (t, J=14.0 Hz, 4H), 1.65 (d, J=10.4 Hz, 1H), 1.43-1.34 (m, 2H), 1.30-1.12 (m, 3H).
Reaction SMILES: [Cl:1][CH:2]([Cl:6])[C:3]([CH3:5])=O.[CH2:7]([SH:11])[CH2:8][CH2:9][SH:10]>>[CH3:5][C:3]1([CH:2]([Cl:6])[Cl:1])[S:11][CH2:7][CH2:8][CH2:9][S:10]1
Reactant: SCCCS
Reactant: CC(=O)C(Cl)Cl
Product: CC1(C(Cl)Cl)SCCCS1

Procedure:
In a further non-limiting embodiment, 1,1-dichloroacetone can be reacted with 1,3-propanedithiol to produce 2-methyl-2-dichloromethyl-1,3-dithiane, as shown below.
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][N: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[C:29](=[O:30])[N:25]([C:22]2[CH:21]=[CH:20][C:19]([O:18][CH2:17][C:16]([F:15])([F:34])[CH:31]([F:33])[F:32])=[CH:24][CH:23]=2)[N:26]=[N:27]1)[CH3:13]
Reactant: C[C@H](O)[C@@]1(c2ccc(F)cc2F)CO1
Reactant: O=c1[nH]nnn1-c1ccc(OCC(F)(F)C(F)F)cc1
Product: C[C@@H](n1nnn(-c2ccc(OCC(F)(F)C(F)F)cc2)c1=O)[C@@]1(c2ccc(F)cc2F)CO1
Yield: 48 %

Procedure:
In the same manner as in Reference Example 5, starting from 1.39 g of (1S)-1-[(2R)-2-(2,4-difluorophenyl)-2-oxiranyl]ethanol and 1.63 g of 1-[4-(2,2,3,3-tetrafluoropropoxy)phenyl]-5(1H, 4H)-tetrazolone, 1.27 g of 1-[(1R,2S)-2-(2,4-difluorophenyl)-2,3-epoxy-1-methylpropyl]-4-[4-(2,2,3,3-tetrafluoropropoxy)phenyl]-5(1H,4H)-tetrazolone was obtained as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.[N+:12]([C:15]1[C:16]([S:21](Cl)(=[O:23])=[O:22])=[N:17][CH:18]=[CH:19][CH:20]=1)([O-:14])=[O:13].N1C=CC=CC=1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[N:10]1[C:11]2[C:6](=[CH:5][CH:4]=[CH:3][C:2]=2[NH:1][S:21]([C:16]2[C:15]([N+:12]([O-:14])=[O:13])=[CH:20][CH:19]=[CH:18][N:17]=2)(=[O:23])=[O:22])[CH:7]=[CH:8][CH:9]=1
Reactant: O=[N+]([O-])c1cccnc1S(=O)(=O)Cl
Reactant: Nc1cccc2cccnc12
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=[N+]([O-])c1cccnc1S(=O)(=O)Nc1cccc2cccnc12
Yield: 42 %

Procedure:
In a similar fashion using route 14 general procedure 27, 8-aminoquinoline (1.3 g, 9.36 mmol), 3-nitro-pyridine-2-sulfonyl chloride 445 (2.7 g, 12.2 mmol), pyridine (2.25 ml, 28.1 mmol), DMAP (cat.) and DCM (100 ml) gave the title compound (1.3 g, 42%) after purification by column chromatography with DCM as the eluent.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[C:8]3[N:9]([CH:32]=[C:33](/[CH:35]=[CH:36]/[C:37]4[CH:46]=[CH:45][C:44]5[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=5)[N:38]=4)[N:34]=3)[C:10]([C:13]3[CH:14]=[CH:15][C:16]([N:19]4[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]4)=[N:17][CH:18]=3)=[CH:11][N:12]=2)[CH2:3][CH2:2]1>CO>[O:1]1[CH2:6][CH2:5][N:4]([C:7]2[C:8]3[N:9]([CH:32]=[C:33]([CH2:35][CH2:36][C:37]4[CH:46]=[CH:45][C:44]5[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=5)[N:38]=4)[N:34]=3)[C:10]([C:13]3[CH:14]=[CH:15][C:16]([N:19]4[CH2:20][CH2:21][N:22]([C:25]([O:27][C:28]([CH3:29])([CH3:30])[CH3:31])=[O:26])[CH2:23][CH2:24]4)=[N:17][CH:18]=3)=[CH:11][N:12]=2)[CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(-c3cnc(N4CCOCC4)c4nc(/C=C/c5ccc6ccccc6n5)cn34)cn2)CC1
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(-c3cnc(N4CCOCC4)c4nc(CCc5ccc6ccccc6n5)cn34)cn2)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of compound 19b (130 mg, 0.210 mmol) in MeOH (50 mL) was evacuated and back flushed with Argon gas three times before Pd/C (10%, 100 mg) was added. The mixture was evacuated and back flushed with H2, and was stirred at rt under H2 (in a balloon) for 3 h. The reaction mixture was filtered through a pad of diatomaceous earth, and the filtrate was concentrated under reduced pressure to leave a brown oil, which was purified by flash column chromatography on silica gel, eluting with EtOAc/heptane (0-100%). Compound 20a was obtained as an off-white solid (69.0 mg, 53% yield). Mass Spectrum (LCMS, ESI pos.): Calcd. for C35H40N8O3: 621.3 (M+H). found: 621.4.
Reaction SMILES: C(O[C@@H](C1C(C)=CC2N=C(N3C=CC=C(C4C=C5C(=CC=4)N(C)N=C5)C3=O)SC=2C=1C1C=CC(Cl)=CC=1)C(O)=O)(C)(C)C.[C:44]([O:48][C@@H:49]([C:54]1[C:79]([CH3:80])=[CH:78][C:57]2[N:58]=[C:59]([N:61]3[CH:66]=[C:65]([C:67]4[CH:68]=[C:69]5[C:73](=[CH:74][CH:75]=4)[N:72]([CH3:76])[N:71]=[CH:70]5)[CH:64]=[CH:63][C:62]3=[O:77])[S:60][C:56]=2[C:55]=1[C:81]1[CH:86]=[CH:85][C:84]([Cl:87])=[CH:83][CH:82]=1)[C:50]([O:52]C)=[O:51])([CH3:47])([CH3:46])[CH3:45]>>[C:44]([O:48][C@@H:49]([C:54]1[C:79]([CH3:80])=[CH:78][C:57]2[N:58]=[C:59]([N:61]3[CH:66]=[C:65]([C:67]4[CH:68]=[C:69]5[C:73](=[CH:74][CH:75]=4)[N:72]([CH3:76])[N:71]=[CH:70]5)[CH:64]=[CH:63][C:62]3=[O:77])[S:60][C:56]=2[C:55]=1[C:81]1[CH:82]=[CH:83][C:84]([Cl:87])=[CH:85][CH:86]=1)[C:50]([OH:52])=[O:51])([CH3:47])([CH3:45])[CH3:46]
Reactant: COC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-n3cc(-c4ccc5c(cnn5C)c4)ccc3=O)sc2c1-c1ccc(Cl)cc1
Agent: Cc1cc2nc(-n3cccc(-c4ccc5c(cnn5C)c4)c3=O)sc2c(-c2ccc(Cl)cc2)c1[C@H](OC(C)(C)C)C(=O)O
Product: Cc1cc2nc(-n3cc(-c4ccc5c(cnn5C)c4)ccc3=O)sc2c(-c2ccc(Cl)cc2)c1[C@H](OC(C)(C)C)C(=O)O

Procedure:
Compound (S)-2-tert-butoxy-2-(7-(4-chlorophenyl)-5-methyl-2-(5-(1-methyl-1H-indazol-5-yl)-2-oxopyridin-1(2H)-yl)benzo[d]thiazol-6-yl)acetic acid was prepared following the procedure used to (S)-2-tert-butoxy-2-(7-(4-chlorophenyl)-5-methyl-2-(3-(1-methyl-1H-indazol-5-yl)-2-oxopyridin-1(2H)-yl)benzo[d]thiazol-6-yl)acetic acid of Example 27, except that (S)-methyl 2-tert-butoxy-2-(7-(4-chlorophenyl)-5-methyl-2-(5-(1-methyl-1H-indazol-5-yl)-2-oxopyridin-1(2H)-yl)benzo[d]thiazol-6-yl)acetate was used instead of (S)-methyl 2-tert-butoxy-2-(7-(4-chlorophenyl)-5-methyl-2-(3-(1-methyl-1H-indazol-5-yl)-2-oxopyridin-1(2H)-yl)benzo[d]thiazol-6-yl)acetate. 1H-NMR: 400 MHz, (CD3OD) δ 9.07 (d, J=2.8 Hz, 1H), 8.04 (s, 1H), 7.97 (s, 1H), 7.93 (dd, J=9.2, 2.4 Hz, 1H), 7.69-7.62 (m, 4H), 7.55-7.51 (m, 3H), 6.72 (d, J=9.6 Hz, 1H), 5.25 (s, 1H), 4.09 (s, 3H), 2.56 (s, 3H), 0.96 (s, 9H); LCMS-ESI+ (m/z): [M+H]+ calcd for C33H30ClN4O4S: 613.17; Found: 613.2.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([N+:9]([O-:11])=[O:10])[C:3]=1[OH:12].[C:13](=O)([O-])[O-].[K+].[K+].CI>CC(C)=O>[F:1][C:2]1[C:3]([O:12][CH3:13])=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: COc1c([N+](=O)[O-])ccc(F)c1F
Yield: 106.7 %

Procedure:
20 g (0.114 mole) of 2,3-difluoro-6-nitrophenol (VI) were dissolved in 700 ml of acetone. 18.9 g (0.137 mole) of potassium carbonate and 34.1 g (0.24 mole) of methyl iodide were added to the solution, and the mixture was heated under reflux for 20 hours, whilst stirring. The solvent was then removed from the mixture by evaporation under reduced pressure, and the residue was extracted with ethyl acetate. The ethyl acetate extract was washed with water and dried, and the solvent was removed by evaporation under reduced pressure to give 23.0 g of 3,4-difluoro-2-methoxy-1-nitrobenzene (VII) as a yellow oil [Step (B1)].
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:24])[C:6]([C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=2)=[CH:7][C:8]2[CH:16]=[CH:15][C:11]([C:12](O)=[O:13])=[CH:10][CH:9]=2)[CH2:3][CH2:2]1.CN(C=O)C.[CH:30]1[CH:31]=[CH:32][C:33]2[N:38](O)N=[N:36][C:34]=2[CH:35]=1.C1(N)C=CC=CC=1N>O>[NH2:38][C:33]1[CH:32]=[CH:31][CH:30]=[CH:35][C:34]=1[NH:36][C:12](=[O:13])[C:11]1[CH:10]=[CH:9][C:8]([CH:7]=[C:6]([C:17]2[CH:18]=[CH:19][C:20]([CH3:23])=[CH:21][CH:22]=2)[C:5]([NH:4][CH:1]2[CH2:2][CH2:3]2)=[O:24])=[CH:16][CH:15]=1
Reactant: Cc1ccc(C(=Cc2ccc(C(=O)O)cc2)C(=O)NC2CC2)cc1
Reactant: On1nnc2ccccc21
Agent: Nc1ccccc1N
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(C(=Cc2ccc(C(=O)Nc3ccccc3N)cc2)C(=O)NC2CC2)cc1
Reaction time: 4 h
Yield: 45 %

Procedure:
To a suspension of 4-(3-(cyclopropylamino)-2-(4-methylphenyl)-3-oxoprop-1-en-1-yl)benzoic acid (0.2 g, 0.6 mmol, prepared according to the procedure described in Example 99, step I-III) in DMF (3 mL) EDCl (0.23 g, 1.1 mmol), HOBt (0.08 g, 5 mmol), o-phenylenediamine (0.08 g, 0.7 mmol), were added followed by TEA (0.23 mL, 15 mmol). The reaction mixture was stirred for 4 hours after which the mixture was added to cold water (100 mL) and kept 0° C. for 1 hour to obtain a pale yellow solid. The solid was filtered and washed with water (50 mL) dried under vacuum to afford the title compound (0.110 g, 45% yield). 1H NMR (DMSO-d6) δ (ppm): 0.51 (2H, m, —CH2), 0.63-0.65 (2H, m, —CH2), 2.33 (3H, s, —CH3), 2.67-2.75 (1H, m, —CH), 4.87 (2H, s, —NH2), 6.55-6.58 (1H, m, Ar—H), 6.74-6.76 (1H, m, Ar—H), 6.93-6.97 (1H, m, Ar—H), 7.04 (2H, d, Ar—H), 7.11 (3H, m, Ar—H), 7.19 (2H, m, Ar—H), 7.25 (1H, s, ═CH), 7.76-7.78 (3H, m, Ar—H and —NH), 9.57 (1H, s, —NH), MS m/z: 412.2 (M++1).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][C:17]=1[OH:18])[O:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]([C:12]([NH2:14])=[O:13])[CH:7]=1.[Cl:19][C:20]1[CH:33]=[CH:32][C:31]([N:34]=[C:35]=S)=[CH:30][C:21]=1[O:22][CH2:23][C@@H:24]1[CH2:28][CH2:27][CH2:26][N:25]1[CH3:29]>CC#N.CN(C=O)C>[Cl:19][C:20]1[CH:33]=[CH:32][C:31]([NH:34][C:35]2[O:18][C:17]3[CH:16]=[CH:15][C:4]([O:5][C:6]4[CH:11]=[CH:10][N:9]=[C:8]([C:12]([NH2:14])=[O:13])[CH:7]=4)=[CH:3][C:2]=3[N:1]=2)=[CH:30][C:21]=1[O:22][CH2:23][C@@H:24]1[CH2:28][CH2:27][CH2:26][N:25]1[CH3:29]
Reactant: CN1CCC[C@H]1COc1cc(N=C=S)ccc1Cl
Reactant: NC(=O)c1cc(Oc2ccc(O)c(N)c2)ccn1
Solvent: CN(C)C=O
Solvent: CC#N
Product: CN1CCC[C@H]1COc1cc(Nc2nc3cc(Oc4ccnc(C(N)=O)c4)ccc3o2)ccc1Cl

Procedure:
To a stirring RT solution of 4-(3-amino-4-hydroxy-phenoxy)-pyridine-2-carboxylic acid amide (Step d, 217 mg, 0.884 mmol) in CH3CN (30 ml) and DMF (3 mL) was added (2S)-2-(2-chloro-5-isothiocyanato-phenoxymethyl)-1-methyl-pyrrolidine (208 mg, 0.737 mmol). The following day, the CH3CN was evaporated off, and the crude mix was diluted into 1N NaOH and EtOAc. The layers were separated. The aqueous layer was extracted 3× with EtOAc, and the combined organic layers were washed once with 1N NaOH and once with brine. The organic layer was then dried over Na2SO4, filtered and concentrated in vacuo. The crude residue was purified by silica gel chromatography to yield the title compound. (MH+)=494.2; Calc'd 493.15 for C25H24ClN5O4.
Reaction SMILES: C([Li])CCC.[Cl:6][C:7]1[C:8]2[CH2:15][C:14](=[O:16])[NH:13][C:9]=2[N:10]=[CH:11][N:12]=1.CN(C)CCN(C)C.Br[CH2:26][C:27]1[CH:32]=[CH:31][C:30]([N+:33]([O-:35])=[O:34])=[CH:29][C:28]=1[CH2:36]Br>C1COCC1>[Cl:6][C:7]1[C:8]2[C:15]3([CH2:36][C:28]4[C:27](=[CH:32][CH:31]=[C:30]([N+:33]([O-:35])=[O:34])[CH:29]=4)[CH2:26]3)[C:14](=[O:16])[NH:13][C:9]=2[N:10]=[CH:11][N:12]=1
Reactant: O=[N+]([O-])c1ccc(CBr)c(CBr)c1
Reactant: O=C1Cc2c(Cl)ncnc2N1
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=C1Nc2ncnc(Cl)c2C12Cc1ccc([N+](=O)[O-])cc1C2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Butyllithium (2.5 M in hexanes, 0.29 ml, 0.74 mmol) was added to a stirred solution of 4-chloro-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one from Step B (50 mg, 0.295 mmol) at −78° C. in THF (30 mL). After complete addition of butyllithium, N,N,N′,N′-tetramethylethane-1,2-diamine (0.31 mL, 0.77 mmol) was added. After 1 h at −78° C., 1,2-bis(bromomethyl)-4-nitrobenzene (91 mg, 0.295 mmol, described in Intermediate 2) was added and the reaction warmed to ambient temperature. After 8 h, the reaction was quenched with H2O and the mixture was partitioned between EtOAc and H2O. The aqueous solution was extracted with EtOAc (3×20 mL). The combined organic extracts were washed with brine (100 mL), dried over Na2SO4, filtered, and concentrated in vacuo to give the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([F:10])[CH:9]=1)[C:5]#[N:6].Br.Br[CH:13]([C:15]1[CH:16]=[C:17]([C:32]([N:34]([CH3:36])[CH3:35])=[O:33])[CH:18]=[C:19]2[C:24]=1[O:23][C:22]([N:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1)=[CH:21][C:20]2=[O:31])[CH3:14]>>[C:5]([C:4]1[CH:3]=[C:2]([NH:1][CH:13]([C:15]2[CH:16]=[C:17]([C:32]([N:34]([CH3:36])[CH3:35])=[O:33])[CH:18]=[C:19]3[C:24]=2[O:23][C:22]([N:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)=[CH:21][C:20]3=[O:31])[CH3:14])[CH:9]=[C:8]([F:10])[CH:7]=1)#[N:6]
Reactant: CC(Br)c1cc(C(=O)N(C)C)cc2c(=O)cc(N3CCOCC3)oc12
Reactant: N#Cc1cc(N)cc(F)c1
Agent: Br
Product: CC(Nc1cc(F)cc(C#N)c1)c1cc(C(=O)N(C)C)cc2c(=O)cc(N3CCOCC3)oc12
Yield: 56 %

Procedure:
3-amino-5-fluorobenzonitrile (0.111 g, 0.82 mmol) was reacted with 8-(1-bromoethyl)-N,N-dimethyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide hydrobromide (0.1 g, 0.20 mmol) using an analogous procedure to the one described in Example 3.03 to give 8-(1-(3-cyano-5-fluorophenylamino)ethyl)-N,N-dimethyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide (0.052 g, 55%) as a white solid. Mass Spectrum: M+H+ 465.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[NH:10]1[CH2:14][CH2:13][CH2:12][CH2:11]1>>[N:10]1([C:2]2[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=2[C:4]#[N:5])[CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: C1CCNC1
Reactant: N#Cc1ccccc1F
Product: N#Cc1ccccc1N1CCCC1

Procedure:
According to a similar manner to that in Reference Example 12, the title compound was synthesized from 2-fluorobenzonitrile and pyrrolidine.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][S:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N+:12]=2[O-:17])=[O:10])=[CH:4][C:3]=1[N+:18]([O-:20])=[O:19].C(OO)(=[O:23])C.S(=O)(=O)(O)[O-].[Na+].O>C(O)(=O)C>[N+:18]([C:3]1[CH:4]=[C:5]([CH2:8][S:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N+:12]=2[O-:17])(=[O:23])=[O:10])[CH:6]=[CH:7][C:2]=1[Cl:1])([O-:20])=[O:19]
Reactant: CC(=O)OO
Reactant: O=[N+]([O-])c1cc(CS(=O)c2cccc[n+]2[O-])ccc1Cl
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: O=[N+]([O-])c1cc(CS(=O)(=O)c2cccc[n+]2[O-])ccc1Cl
Temperature: 70 °C

Procedure:
To a mixture of 14.0 g (0.0426 mole) of 2-[[(4-chloro-3-nitrophenyl) methyl]sulfinyl]-pyridine-N-oxide in 35 ml of acetic acid was added 10.1 g of peracetic acid (40% in acetic acid) dropwise over one hour. The temperature of the reaction mixture rose to 27° C. before a water bath was placed on the flask to hold the temperature at 25° C. After addition, the mixture was heated to 70° C. for five hours. The mixture was cooled, and 20 ml additional acetic acid and solid sodium bisulfate and water were added to destroy the excess peracetic acid. The aqueous mixture was neutralized with potassium carbonate and chilled in an ice bath to precipitate an almost white solid. This solid was filtered off, washed with water, dried under vacuum overnight, and had a melting point of 162-164° C. Infrared and NMR spectra were both consistent with the proposed structure. The product was recrystallized from ethanol to give needle-like white crystals having a melting point of 168-170° C. C,H,N calculated for C12H9ClN2O5S: C=43.85%; H=2.76%; N=8.52%. Found: C=43.27% H=2.65%; N=8.21%.