Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: COC1C=CC(C[N:8](CC2C=CC(OC)=CC=2)[C:9]2[N:14]=[C:13]([CH3:15])[N:12]=[C:11]([C:16]3[C:17]([NH:24][C:25]4[CH:26]=[N:27][C:28]([O:31][CH3:32])=[CH:29][CH:30]=4)=[N:18][CH:19]=[C:20]([CH:23]=3)[CH:21]=O)[N:10]=2)=CC=1.C(O)(=O)C.[CH2:48]1[C:51]2([C:55](=[O:56])[NH:54][C:53](=[O:57])[NH:52]2)[CH2:50][NH:49]1>>[NH2:8][C:9]1[N:14]=[C:13]([CH3:15])[N:12]=[C:11]([C:16]2[CH:23]=[C:20]([CH2:21][N:49]3[CH2:48][C:51]4([C:55](=[O:56])[NH:54][C:53](=[O:57])[NH:52]4)[CH2:50]3)[CH:19]=[N:18][C:17]=2[NH:24][C:25]2[CH:26]=[N:27][C:28]([O:31][CH3:32])=[CH:29][CH:30]=2)[N:10]=1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(C=O)cnc3Nc3ccc(OC)nc3)n2)cc1
Reactant: O=C1NC(=O)C2(CNC2)N1
Solvent: CC(=O)O
Product: COc1ccc(Nc2ncc(CN3CC4(C3)NC(=O)NC4=O)cc2-c2nc(C)nc(N)n2)cn1

Procedure:
The title compound was synthesized following an analogous procedure to Example 220 using 5-(4-(bis(4-methoxybenzyl)amino)-6-methyl-1,3,5-triazin-2-yl)-6-(6-methoxypyridin-3-ylamino)nicotinaldehyde (109 mg, 0.189 mmol) and 2,5,7-triazaspiro[3.4]octane-6,8-dione acetate (56.9 mg, 0.283 mmol). 1H NMR (400 MHz, d6-DMSO) δ 11.75 (s, 1H); 10.71 (br. s., 1H); 8.72 (br. s., 1H); 8.60 (s, 1H); 8.54 (d, J=2.54 Hz, 1H); 8.20 (br. s., 1H); 8.16 (dd, J=9.00, 2.74 Hz, 1H); 7.90 (br. s., 1H); 7.75 (br. s., 1H); 6.82 (d, J=8.80 Hz, 1H); 3.84 (s, 3H); 2.44 (s, 3H). m/z (ESI, +ve ion) 463.1 (M+H)+.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][C:5]1[N:13]=[C:12]2[C:8]([N:9]=[CH:10][NH:11]2)=[C:7]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[N:6]=1.CN(C=O)C.[Br:25]Br>>[Br:25][C:10]1[NH:11][C:12]2[C:8]([N:9]=1)=[C:7]([N:14]1[CH2:15][CH2:16][O:17][CH2:18][CH2:19]1)[N:6]=[C:5]([CH2:4][CH2:3][O:2][CH3:1])[N:13]=2
Reactant: BrBr
Reactant: COCCc1nc(N2CCOCC2)c2nc[nH]c2n1
Solvent: CN(C)C=O
Product: COCCc1nc(N2CCOCC2)c2nc(Br)[nH]c2n1
Temperature: 110 °C
Yield: 84.1 %

Procedure:
To a solution of 2-(2-methoxy-ethyl)-6-morpholin-4-yl-9H-purine (0.46 g, 1.7 mmol) in 1 mL of DMF bromine (0.34 g, 1.2 eq) was added dropwise, and a resulted solution was heated at 110° C. for 30 minutes. Solvent was removed in vacuo, a residue was dissolved in dichloromethane, washed with water, brine and dried over MgSO4. Residue was purified by passing through silica gel (eluent dichloromethane:acetone:methanol 3:1:0.25) to afford 8-bromo-2-(2-methoxy-ethyl)-6-morpholin-4-yl-9H-purine (0.42 g, 70%).
Reaction SMILES: [CH:1]1[C:6]([OH:7])=[CH:5][CH:4]=[C:3]([CH3:8])[CH:2]=1.C(CC(=O)C)C(C)=[O:11].CC(C)=O.C(OO)(=O)C>>[CH3:8][C:3]1[CH:4]=[CH:5][C:6]([OH:7])=[C:1]([OH:11])[CH:2]=1
Reactant: Cc1ccc(O)cc1
Reactant: CC(=O)CCC(C)=O
Agent: CC(=O)OO
Solvent: CC(C)=O
Product: Cc1ccc(O)c(O)c1

Procedure:
A reaction flask having an inner volume of 200 ml and provided with a thermometer, a stirrer, a reflux condenser and a dropping funnel was charged with 54.05 g (0.50 mol) of para-cresol and 0.054 g of acetonyl acetone. While the resultant mixture was continuously stirred, 5.59 g (0.025 mol) of an acetone solution of 34.0 percent by weight of peracetic acid was introduced dropwise at a temperature of 80° C over a period of 20 minutes. After termination of the dropwise introduction of the peracetic acid solution, the reaction system was stirred at the same temperature for an additional period of 50 minutes to bring the reaction to completion. Thereafter, the reaction mixture was analyzed for unaltered para-cresol and formed 4-methyl-1,2-dihydroxybenzene by gas chromatography. The results showed the conversion of para-cresol to be 4.19 percent and the selectivity for 4-methyl-1,2-dihydroxybenzene to be 73.6 percent relative to peracetic acid and 88.4 percent relative to para-cresol respectively. From the reaction mixture, acetone, formed acetic acid and para-cresol were recovered by distillation. When the recovered mixture was analyzed for acetonyl acetone by gas chromatography, the recovery ratio of acetonyl acetone was found to be 88 percent.
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([S:11]([CH3:14])(=[O:13])=[O:12])[CH:9]=2)[NH:4][C:3]1=[O:15].Cl[CH2:18][CH2:19][O:20]C1CCCCO1>>[CH3:1][C:2]1([CH3:16])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([S:11]([CH3:14])(=[O:13])=[O:12])[CH:9]=2)[N:4]([CH2:18][CH2:19][OH:20])[C:3]1=[O:15]
Reactant: CC1(C)C(=O)Nc2ccc(S(C)(=O)=O)cc21
Reactant: ClCCOC1CCCCO1
Product: CC1(C)C(=O)N(CCO)c2ccc(S(C)(=O)=O)cc21

Procedure:
Prepared from 3,3-dimethyl-5-methanesulfonyl-1,3-dihydro-2H-indol-2-one and 2-(2-chloroethoxy)tetrahydro-2H-pyran.
Reaction SMILES: Br[CH2:2][C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([Br:12])=[CH:8][C:7]=1[C:13](=O)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[F:20])=[O:4].CO.[NH3:24]>>[Br:12][C:9]1[CH:10]=[CH:11][C:6]2[NH:5][C:3](=[O:4])[CH2:2][N:24]=[C:13]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[F:20])[C:7]=2[CH:8]=1
Reactant: N
Reactant: O=C(CBr)Nc1ccc(Br)cc1C(=O)c1ccccc1F
Solvent: CO
Product: O=C1CN=C(c2ccccc2F)c2cc(Br)ccc2N1
Temperature: 25 °C

Procedure:
The product from Step 1 (21.17 g, 51 mmol) was dissolved in ammonia, 2M in methanol (400 mL, 800 mmol) that was further saturated with anhydrous ammonia. The solution was heated to reflux for 16 hr overnight, and allowed to cool to room temperature. The solution was concentrated and the residue was dissolved in ethyl acetate and water. The ethyl acetate layer was washed twice with water, dried with brine, and concentrated to give a yellow solid. The solid was recrystallized from ethyl acetate/hexane to give a white powder that was washed with hexane and air dried (9.65 g, 56.8%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]([CH2:19][C:20]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH:23]=[CH:22][CH:21]=2)[C:8]2[C:13]([C:14]=1[CH2:15][NH:16][CH3:17])=[CH:12][C:11]([F:18])=[CH:10][CH:9]=2)=[O:5])[CH3:2].[CH3:30][S:31](Cl)(=[O:33])=[O:32]>>[CH2:1]([O:3][C:4]([C:6]1[N:7]([CH2:19][C:20]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH:23]=[CH:22][CH:21]=2)[C:8]2[C:13]([C:14]=1[CH2:15][N:16]([S:31]([CH3:30])(=[O:33])=[O:32])[CH3:17])=[CH:12][C:11]([F:18])=[CH:10][CH:9]=2)=[O:5])[CH3:2]
Reactant: CS(=O)(=O)Cl
Reactant: CCOC(=O)c1c(CNC)c2cc(F)ccc2n1Cc1cccc2ccccc12
Product: CCOC(=O)c1c(CN(C)S(C)(=O)=O)c2cc(F)ccc2n1Cc1cccc2ccccc12

Procedure:
5-Fluoro-3-methylaminomethyl-1-naphthalen-1-ylmethyl-1H-indole-2-carboxylic acid ethyl ester (from Example 86.1.) was reacted with methanesulfonyl chloride as described in Example 77.1. to give 5-fluoro-3-[(methanesulfonyl-methyl-amino)-methyl]-1-naphthalen-1-ylmethyl-1H-indole-2-carboxylic acid ethyl ester which was hydrolyzed as described in the general procedure B (Exp. 2.2) to give the title compound as a colorless solid. MS: 439.4 ([M−H]−).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[C:3]=1[CH2:4]Cl.[N-:11]=[N+:12]=[N-:13].[Na+]>CS(C)=O>[N:11]([CH2:4][C:3]1[C:2]([F:1])=[CH:9][CH:8]=[CH:7][C:6]=1[F:10])=[N+:12]=[N-:13]
Reactant: [N-]=[N+]=[N-]
Reactant: Fc1cccc(F)c1CCl
Agent: [Na+]
Solvent: CS(C)=O
Product: [N-]=[N+]=NCc1c(F)cccc1F

Procedure:
2,6-difluorobenzylchloride of formula II and sodium azide are reacted in the presence of DMSO to obtain 2-(azidomethyl)-1,3-difluorobenzene of formula III, which is then treated with 2-propiolic acid to give a carboxylic acid intermediate which on further reaction with methanol in the presence of sulfuric acid yields methyl 1-(2,6-difluorobenzyl)-1H-1,2,3-triazole-4-carboxylate intermediate of formula IV. This intermediate is then isolated and further reacted with methanolic ammonia to yield rufinamide of formula I.
Reaction SMILES: [OH:1][C:2]1[C:10]([NH2:11])=[C:9]2[C:5]([CH:6]=[N:7][NH:8]2)=[CH:4][CH:3]=1.[CH:12]([O-])([O-])OCC>>[NH:8]1[C:9]2[C:10]3[N:11]=[CH:12][O:1][C:2]=3[CH:3]=[CH:4][C:5]=2[CH:6]=[N:7]1
Reactant: CCOC([O-])[O-]
Reactant: Nc1c(O)ccc2cn[nH]c12
Product: c1nc2c(ccc3cn[nH]c32)o1

Procedure:
A 0.40 g of 6-hydroxy-7-aminoindazole was mixed with 10 ml of ethyl orthoformate and heated under reflux for 2 hours. After cooling of the reaction solution, the solvent was evaporated under a reduced pressure and the residue was purified by a silica gel column chromatography to give 0.31 g of 1H-pyrazolo[3,4-e]benzoxazole.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]([CH3:23])[C:13](=[O:22])[N:14]([C:15]4[C:16]([CH3:21])=[N:17][N:18]([CH3:20])[CH:19]=4)[C:5]=3[C:4]=2[CH:3]=1.CC1(C)C(C)(C)OB([C:32]2[CH:33]=[N:34][C:35]([NH2:38])=[N:36][CH:37]=2)O1>>[NH2:38][C:35]1[N:36]=[CH:37][C:32]([C:2]2[CH:11]=[CH:10][C:9]3[N:8]=[CH:7][C:6]4[N:12]([CH3:23])[C:13](=[O:22])[N:14]([C:15]5[C:16]([CH3:21])=[N:17][N:18]([CH3:20])[CH:19]=5)[C:5]=4[C:4]=3[CH:3]=2)=[CH:33][N:34]=1
Reactant: CC1(C)OB(c2cnc(N)nc2)OC1(C)C
Reactant: Cc1nn(C)cc1-n1c(=O)n(C)c2cnc3ccc(Br)cc3c21
Product: Cc1nn(C)cc1-n1c(=O)n(C)c2cnc3ccc(-c4cnc(N)nc4)cc3c21

Procedure:
The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate A) and 5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrimidin-2-ylamine (Combi-Blocks, San Diego, USA) to give the title compound as a white solid. (HPLC: tR 2.04 min (Method A); M+H=387 MS-ES; 1H-NMR (d6-DMSO, 400 MHz) 8.93 (s, 1H), 8.37 (s, 2H), 8.14-8.12 (m, 1H), 8.07-8.03 (m, 1H), 7.90-7.86 (m, 1H), 7.41-7.38 (m, 1H), 6.93 (s, br, 2H), 3.91 (s, 3H), 3.57 (s, 3H), 1.95 (s, 3H))
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:19]=[C:20]([CH:24]2[CH2:26][CH2:25]2)[C:21]=1[O:22]C)[C:6]([N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[S:10](=[O:18])(=[O:17])[CH2:9]1)=[O:7])#[N:2].[Cl-].[Li+].Cl>CN(C)C=O>[C:1]([C:3]1[CH:4]=[C:5]([CH:19]=[C:20]([CH:24]2[CH2:26][CH2:25]2)[C:21]=1[OH:22])[C:6]([N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[S:10](=[O:18])(=[O:17])[CH2:9]1)=[O:7])#[N:2]
Reactant: COc1c(C#N)cc(C(=O)N2CS(=O)(=O)c3ccccc32)cc1C1CC1
Agent: Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: N#Cc1cc(C(=O)N2CS(=O)(=O)c3ccccc32)cc(C2CC2)c1O
Temperature: 100 °C
Reaction time: 23 h
Yield: 84.2 %

Procedure:
3-(3-cyano-5-cyclopropyl-4-methoxybenzoyl)-1,1-dioxo-2,3-dihydro-1,3-benzothiazole (142 mg) was dissolved in N,N-dimethylformamide (2 mL), and lithium chloride (163 mg) was added to the solution, and then the mixture was stirred at 100° C. for 23 hours. To the reaction solution, 1N hydrochloric acid was added, and then the mixture was extracted with ethyl acetate. The organic layer was washed with 1N hydrochloric acid and saturated brine, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the obtained residue was crystallized from n-hexane-ethyl acetate to obtain the title compound (115 mg) as a colorless crystal.
Reaction SMILES: Cl[CH:2]([O:4][C:5](=[O:32])[N:6]([C:29](=[O:31])[CH3:30])[CH2:7][C@@H:8]1[O:12][C:11](=[O:13])[N:10]([C:14]2[CH:19]=[CH:18][C:17]([CH:20]3[CH2:25][CH2:24][S:23](=[O:27])(=[O:26])[CH2:22][CH2:21]3)=[C:16]([F:28])[CH:15]=2)[CH2:9]1)[CH3:3].[C:33]([O-:41])(=[O:40])[C:34]1[CH:39]=[CH:38][N:37]=[CH:36][CH:35]=1.[Cs+].O>C(#N)C>[C:29]([N:6]([CH2:7][C@@H:8]1[O:12][C:11](=[O:13])[N:10]([C:14]2[CH:19]=[CH:18][C:17]([CH:20]3[CH2:25][CH2:24][S:23](=[O:27])(=[O:26])[CH2:22][CH2:21]3)=[C:16]([F:28])[CH:15]=2)[CH2:9]1)[C:5]([O:4][CH:2]([O:41][C:33](=[O:40])[C:34]1[CH:39]=[CH:38][N:37]=[CH:36][CH:35]=1)[CH3:3])=[O:32])(=[O:31])[CH3:30]
Reactant: CC(=O)N(C[C@H]1CN(c2ccc(C3CCS(=O)(=O)CC3)c(F)c2)C(=O)O1)C(=O)OC(C)Cl
Reactant: O=C([O-])c1ccncc1
Agent: [Cs+]
Solvent: O
Solvent: CC#N
Product: CC(=O)N(C[C@H]1CN(c2ccc(C3CCS(=O)(=O)CC3)c(F)c2)C(=O)O1)C(=O)OC(C)OC(=O)c1ccncc1
Temperature: 25 °C
Yield: 83 %

Procedure:
Acetyl-{3-[4-(1,1-dioxo-hexahydro-1λ6-thiopyran-4-yl)-3-fluoro-phenyl]-2-oxo-oxazolidin-5(R)-ylmethyl}-carbamic acid 1-chloro-ethyl ester (11) (0.40 g, 0.81 mmol) and cesium isonicotinate (0.42 g, 1.64 mmol) in acetonitrile (20 mL) are heated to reflux overnight. After cooling to RT, water is added and the reaction mixture is extracted with EtOAc and then with dichloromethane. The organic phases are washed separately with brine and then the organic layers are combined, dried over MgSO4, filtered, and conc in vacuo. The isolated residue is subjected to silica gel flash chromatography, eluting with MeOH/CH2Cl2 gradient (0-5% MeOH over 1 hour and 20 minutes) to afford the title compound. Isolated yield: 83%. 1H NMR (400 MHz, DMSO-d6): δ 8.78-8.74 (m, 2H), 7.85 (dd, 1H), 7.79 (dd, 1H), 7.40-7.35 (m, 1H), 7.31 (t, 1H), 7.21-7.17 (m, 1H), 7.01-6.94 (m, 1H), 4.79-4.72 (m, 1H), 4.12-4.00 (m, 2H), 3.91-3.84 (m, 1H), 3.78-3.73 (m, 1H), 3.36-3.26 (m, partially obscured by water, 2H), 3.17-3.11 (m, 1H), 3.07-3.03 (m, 2H), 2.40 (d, 3H), 2.15-2.04 (m, 2H), 2.00-1.97 (m, 2H) 1.59 (dd, 3H).
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[C@H:2]([C:10]([N:12]1[CH2:19][CH2:18][CH2:17][C@H:13]1[C:14]([OH:16])=[O:15])=[O:11])[CH2:3][S:4][CH2:5][NH:6][C:7]([CH3:9])=[O:8].[ClH:27].CC(O)=O>CN(C=O)C>[NH2:1][C@H:2]([C:10]([N:12]1[CH2:19][CH2:18][CH2:17][C@H:13]1[C:14]([OH:16])=[O:15])=[O:11])[CH2:3][S:4][CH2:5][NH:6][C:7]([CH3:9])=[O:8].[ClH:27]
Reactant: CC(=O)NCSC[C@H](NC(=O)OC(C)(C)C)C(=O)N1CCC[C@H]1C(=O)O
Agent: Cl
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: CC(=O)NCSC[C@H](N)C(=O)N1CCC[C@H]1C(=O)O

Procedure:
BocCys(Acm)ONp is prepared from BocCys(Acm)OH (Novabiochem, Laufalingen, CH) and p-nitrophenol by reaction with N,N'-dicyclohexylcarbodiimide (DCC) in ethyl acetate and used without purification for the preparation of Boc-Cys(Acm)-Pro-OH (XII) by reacting it with H-Pro-OH in DMF/etyl acetate/HCl at 0° C. while keeping pH neutral by addition of Et3N. Yield 81%. Purity>95% (TLC). Boc-Asn-Cys(Acm)-Pro-OH (XIII) is obtained by deblocking XII in HCl/HOAc at room temperature, dissolving the thus obtained raw H-Cys(Acm)-Pro-OH.HCl in DMF and neutralizing it with Et3N, and adding Boc-Asn-ONp (Novabiochem, Laufelingen, CH) at -5° C. while keeping pH neutral. XIII is isolated in 81% yield. [a]D20 =-77.1° (1 g/100 ml DMF). The tetrapeptide derivative X is prepared from XIII and Boc-Gln-ONp (Novabiochem, Laufelingen, CH) in a way corresponding to the preparation of XIII from XII and Boc-Asn-ONp. Yield 78.5%; [a]D20 =-89.7° (1 g/100 ml H2O).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]([C:11]1[N:15]([CH2:16][CH2:17][CH2:18]O)[C:14]2[C:20]([N:24]([CH2:27][CH3:28])[CH2:25][CH3:26])=[CH:21][CH:22]=[CH:23][C:13]=2[N:12]=1)=[O:10].[Br:29]C(Br)(Br)Br.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(#N)C.C(OCC)(=O)C>[Br:29][CH2:18][CH2:17][CH2:16][N:15]1[C:14]2[C:20]([N:24]([CH2:27][CH3:28])[CH2:25][CH3:26])=[CH:21][CH:22]=[CH:23][C:13]=2[N:12]=[C:11]1[C:9]([C:3]1[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=1[Cl:1])=[O:10]
Reactant: CCN(CC)c1cccc2nc(C(=O)c3ccc(Cl)cc3Cl)n(CCCO)c12
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CCN(CC)c1cccc2nc(C(=O)c3ccc(Cl)cc3Cl)n(CCCBr)c12
Reaction time: 0.25 h
Yield: 87.6 %

Procedure:
To a stirred suspension of (2,4-dichlorophenyl)[7-(diethylamino)-1-(3-hydroxypropyl)-1H-benzimidazol-2-yl]methanone (404 mg, 0.961 mmol) and tetrabromomethane (637 mg, 1.92 mmol) in acetonitrile was added triphenylphosphine (504 mg, 1.92 mmol). After 15 min, the reaction mixture was diluted with ethyl acetate, washed with aqueous sodium hydrogen carbonate and brine, dried over sodium sulfate, filtrated, and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with a 0-30% ethyl acetate/n-hexane gradient mixture to afford the desired product as yellow solid (407 mg, 0.842 mmol), 88%).
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8](=[O:12])[NH:9]2)=[N:4][CH:3]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].Br[CH2:22][CH:23]([O:27][CH2:28][CH3:29])[O:24][CH2:25][CH3:26].COC1CCCC1.Cl>CS(C)=O.O>[CH2:25]([O:24][CH:23]([O:27][CH2:28][CH3:29])[CH2:22][N:9]1[C:10]2[C:5](=[N:4][CH:3]=[C:2]([F:1])[CH:11]=2)[CH:6]=[CH:7][C:8]1=[O:12])[CH3:26]
Reactant: O=c1ccc2ncc(F)cc2[nH]1
Reactant: CCOC(CBr)OCC
Agent: Cl
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: COC1CCCC1
Solvent: O
Product: CCOC(Cn1c(=O)ccc2ncc(F)cc21)OCC
Yield: 60.7 %

Procedure:
To a suspension of 3.00 g of 7-fluoro-1,5-naphthyridin-2(1H)-one and 5.04 g of potassium phosphate in 12 mL of dimethyl sulfoxide, 4.68 g of 2-bromo-1,1-diethoxyethane was added at room temperature, and the resultant mixture was stirred for 4.5 hours at 94° C. The reaction mixture was cooled, and 21 mL of water and 12 mL of cyclopentyl methyl ether were added thereto. The mixture was adjusted to pH 5.8 with 12 mol/L hydrochloric acid, subsequently the insoluble matter was filtered out, and the filter residue was washed twice with 3 mL of cyclopentyl methyl ether. The organic layers of the obtained filtrate and the wash liquid were separated, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give 3.11 g of 1-(2,2-diethoxyethyl)-7-fluoro-1,5-naphthyridin-2(1H)-one as a light yellow oily substance.
Reaction SMILES: [ClH:1].[N+:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH2:11][CH:12]1[NH:18][C:17](=[NH:19])[CH2:16][CH2:15][CH2:14][CH2:13]1)([O-])=O.[H][H]>C(O)C.[Rh]>[ClH:1].[ClH:1].[NH:19]=[C:17]1[NH:18][CH:12]([CH2:11][CH:6]2[CH2:7][CH2:8][CH2:9][CH2:10][CH:5]2[NH2:2])[CH2:13][CH2:14][CH2:15][CH2:16]1
Reactant: N=C1CCCCC(Cc2ccccc2[N+](=O)[O-])N1
Reactant: [H][H]
Agent: [Rh]
Agent: Cl
Solvent: CCO
Product: N=C1CCCCC(CC2CCCCC2N)N1
Temperature: 60 °C
Yield: 48.9 %

Procedure:
The product of Example 270 (0.262 g, 0.9 mmol) was dissolved in ethanol, treated with 5% Rhodium on Carbon under 60 psi of Hydrogen and warmed to 60° C. to give the title product (66 mg, 0.22 mmol).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH2:7][C:6]([CH3:11])=[C:5]2[CH2:12][C:13]([OH:15])=[O:14].[CH3:16][O:17][C:18]1[CH:19]=[C:20]([CH:23]=[C:24]([O:28][CH3:29])[C:25]=1[O:26][CH3:27])[CH:21]=O.C[O-].[Na+].Cl>CO>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)/[C:7](=[CH:21]\[C:20]1[CH:23]=[C:24]([O:28][CH3:29])[C:25]([O:26][CH3:27])=[C:18]([O:17][CH3:16])[CH:19]=1)/[C:6]([CH3:11])=[C:5]2[CH2:12][C:13]([OH:15])=[O:14]
Reactant: COc1cc(C=O)cc(OC)c1OC
Reactant: CC1=C(CC(=O)O)c2cc(F)ccc2C1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: COc1cc(/C=C2/C(C)=C(CC(=O)O)c3cc(F)ccc32)cc(OC)c1OC
Temperature: 0 °C
Reaction time: 6 h

Procedure:
5-fluoro-2-methyl-3-indenyl-acetic acid (15 g, 0.072 mol), 3,4,5-trimethoxybenzaldehyde (17.85 g, 0.091 mol) and sodium methoxide (13.0 g, 0.24 mol) are heated in methanol (200 ml) at 60° C. under nitrogen with stirring for 6 hours. After cooling, the reaction mixture is poured into 750 ml of ice-water, and is acidified with 2.5 N hydrochloric acid. The collected solid is triturated with a little ether to produce (Z)-5-fluoro-2-methyl-1-(3,4,5-trimethoxybenzylidene)-3-indenyl-acetic acid (m.p. 166-169° C.). (R=H, R1 =H, R2 =F, R3 =H, R4 =H, R5 =OCH3, R6 =OCH3, R7 =OCH3, R8 =CH3, o=1, M=OH).
Reaction SMILES: [CH2:1]([NH2:5])[CH2:2][CH2:3][CH3:4].[C:6]1(C2C=CC=CC=2)[CH:11]=[CH:10][C:9]([CH2:12][C@H:13]([NH:23][C:24]([N:26]([CH:32]([CH2:41][C:42]([O:44][CH2:45][CH3:46])=[O:43])[CH2:33][S:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH2:27][CH2:28][CH:29]([CH3:31])[CH3:30])=[O:25])[C:14](OC2C=CC=CC=2)=[O:15])=[CH:8][CH:7]=1>O1CCCC1>[C:6]1([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH:7]=[CH:8][C:9]([CH2:12][C@H:13]([NH:23][C:24]([N:26]([CH:32]([CH2:41][C:42]([O:44][CH2:45][CH3:46])=[O:43])[CH2:33][S:34][C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)[CH2:27][CH2:28][CH:29]([CH3:30])[CH3:31])=[O:25])[C:14]([NH:5][CH2:1][CH2:2][CH2:3][CH3:4])=[O:15])=[CH:10][CH:11]=1
Reactant: CCOC(=O)CC(CSc1ccccc1)N(CCC(C)C)C(=O)N[C@@H](Cc1ccc(-c2ccccc2)cc1)C(=O)Oc1ccccc1
Reactant: CCCCN
Solvent: C1CCOC1
Product: CCCCNC(=O)[C@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)N(CCC(C)C)C(CSc1ccccc1)CC(=O)OCC
Yield: 90 %

Procedure:
n-Butylamine (0.35 ml) is added to a solution of phenyl (2S)-3-(4-biphenylyl)-2-[3-[(1RS)-1-(ethoxycarbonylmethyl)-2-(phenylthio)ethyl]-3-isoamylureido]propionate (Compound No. 1-80, 464 mg) in tetrahydrofuran (7 ml), and the mixture is stirred at room temperature for 1.5 hours. The reaction mixture is concentrated under reduced pressure, water is added to the concentrate, and the whole is extracted with ethyl acetate. The organic layer is washed with water and saturated brine successively, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting oily matter is purified by silica gel column chromatography to give 402 mg (90%) of the titled compound (Compound No. 38-1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[C:5]([F:11])=[CH:4][C:3]=1[OH:12].C(=O)([O-])[O-].[K+].[K+].Br[CH2:20][CH3:21].ICC>C(#N)C>[CH2:20]([O:12][C:3]1[CH:4]=[C:5]([F:11])[C:6]([N+:8]([O-:10])=[O:9])=[CH:7][C:2]=1[F:1])[CH3:21]
Reactant: CCBr
Reactant: O=[N+]([O-])c1cc(F)c(O)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCI
Product: CCOc1cc(F)c([N+](=O)[O-])cc1F
Temperature: 70 °C
Reaction time: 3.5 h
Yield: 88.2 %

Procedure:
To a solution of 2,5-difluoro-4-nitro-phenol (4.86 g, 28.2 mmol) in acetonitrile (50 mL), potassium carbonate (4.7 g, 34 mmol) and bromoethane (4.21 mL, 56.4 mmol) were added. After stirring at 70° C. for 3.5 hours, iodoethane (2.73, 33.8 mmol) was added and mixture was stirred at 80° C. After 20 hours, mixture was concentrated and extracted with methylene chloride and 2M NaOH solution. Organic phases were dried over magnesium sulfate, filtered, and concentrated to give 1-ethoxy-2,5-difluoro-4-nitro-benzene as a yellow solid (5.05 g, 88%). 1HNMR (CDCl3, 400 MHz) δ 7.92-7.88 (m, 1H), 6.82-6.78 (m, 1H), 4.21-4.16 (q, 1H), 4.13-4.07 (q, J=7.0 Hz, 2H), 1.54-1.51 (t, J=7.0 Hz, 3H).
Reaction SMILES: [CH2:1]([N:3]1[C:8]2[N:9]=[C:10]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([N:20]4[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]4)=[CH:16][CH:15]=3)[N:11]=[CH:12][C:7]=2[CH:6]=[C:5](B(O)O)[C:4]1=[O:30])[CH3:2].Br[C:32]1[S:36][C:35]([C:37]2[S:38][CH:39]=[CH:40][CH:41]=2)=[CH:34][CH:33]=1.C(=O)([O-])[O-].[Na+].[Na+]>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.C(COC)OC.O>[S:36]1[C:32]([C:5]2[C:4](=[O:30])[N:3]([CH2:1][CH3:2])[C:8]3[N:9]=[C:10]([NH:13][C:14]4[CH:19]=[CH:18][C:17]([N:20]5[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]5)=[CH:16][CH:15]=4)[N:11]=[CH:12][C:7]=3[CH:6]=2)=[CH:33][CH:34]=[C:35]1[C:37]1[S:38][CH:39]=[CH:40][CH:41]=1
Reactant: CCn1c(=O)c(B(O)O)cc2cnc(Nc3ccc(N4CCN(C)CC4)cc3)nc21
Reactant: Brc1ccc(-c2cccs2)s1
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: O
Solvent: COCCOC
Product: CCn1c(=O)c(-c2ccc(-c3cccs3)s2)cc2cnc(Nc3ccc(N4CCN(C)CC4)cc3)nc21
Yield: 33.5 %

Procedure:
8-Ethyl-2-[4-(4-methyl-piperazin-1-yl)-phenylamino]-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidine-6-boronic acid (21, 71 mg, 0.17 mmol), 5-bromo-2,2′-bithiophene (47 mg, 0.19 mmol), sodium carbonate (55 mg, 0.52 mmol) and Pd(PPh3)4 (20 mg, 0.02 mmol) were mixed under argon in a degassed mixture of dimethoxyethane:water (10:1, 3 mL). The resulting suspension was irradiated for 60 min at 120° C. in a microwave reactor. After completion, the reaction mixture was evaporated and the residue was purified by column chromatography using dichloromethane:methanol (100:5) as eluent. The crude product was triturated with ethyl acetate (10 mL) and collected by filtration. The title compound (30 mg, 0.057 mmol, 33%) was obtained as a yellow solid. ESMS m/z 529 (M+H)+; 1H NMR (400 MHz, DMSO-d6) δ ppm 9.99 (br. s., 1H) 8.81 (s, 1H) 8.45 (s, 1H) 7.72 (d, J=3.8 Hz, 1H) 7.66 (br. s., 2H) 7.51 (dd, J=5.1, 0.9 Hz, 1H) 7.31-7.37 (m, 2H) 7.11 (dd, J=5.0, 3.8 Hz, 1H) 6.95 (d, J=9.0 Hz, 2H) 4.42 (q, J=7.0 Hz, 2H) 3.04-3.17 (m, 4H) 2.42-2.48 (m, 4H) 2.23 (s, 3H) 1.31 (t, J=7.0 Hz, 3H).