Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]2[C:12](=[C:13]([NH:15][S:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=3)(=[O:18])=[O:17])[CH:14]=1)[NH:11][C:10]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:9]2.Br[CH2:31][CH:32]1[CH2:34][CH2:33]1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>C(OCC)(=O)C.[Cl-].[Na+].O>[CH:32]1([CH2:31][N:15]([S:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)(=[O:17])=[O:18])[C:13]2[CH:14]=[C:6]([O:5][CH2:4][CH2:3][O:2][CH3:1])[CH:7]=[C:8]3[C:12]=2[NH:11][C:10]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:9]3)[CH2:34][CH2:33]1
Reactant: BrCC1CC1
Reactant: CCOC(=O)c1cc2cc(OCCOC)cc(NS(=O)(=O)c3ccccn3)c2[nH]1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cc2cc(OCCOC)cc(N(CC3CC3)S(=O)(=O)c3ccccn3)c2[nH]1
Temperature: 50 °C
Reaction time: 15 h
Yield: 64 %

Procedure:
A mixture of ethyl 5-(2-methoxyethoxy)-7-[(pyridin-2-ylsulfonyl)amino]-1H-indole-2-carboxylate (937 mg), (bromomethyl)cyclopropane (0.22 mL), potassium carbonate (401 mg) and N,N-dimethylformamide (20 mL) was stirred at 50° C. for 15 hr. The reaction mixture was diluted with ethyl acetate and saturated brine. The organic layer was washed with aqueous sodium bicarbonate solution and saturated brine, dried over anhydrous sodium sulfate, and filtered, and the filtrate was concentrated under reduced pressure. The residue was subjected to basic silica gel column chromatography to give the title compound (673 mg, yield 64%) as a pale-yellow amorphous solid from a fraction eluted with ethyl acetate.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][C:4]=1[CH:5]=[CH:6][CH2:7]Cl.[NH2:15][C:16]1[S:17][C:18]2[CH2:19][CH2:20][NH:21][CH2:22][CH2:23][C:24]=2[N:25]=1.CCOCC>C(Cl)(Cl)Cl>[NH2:15][C:16]1[S:17][C:18]2[CH2:19][CH2:20][N:21]([CH2:7][CH:6]=[CH:5][C:4]3[CH:9]=[C:10]([O:13][CH3:14])[CH:11]=[CH:12][C:3]=3[O:2][CH3:1])[CH2:22][CH2:23][C:24]=2[N:25]=1
Reactant: Nc1nc2c(s1)CCNCC2
Reactant: COc1ccc(OC)c(C=CCCl)c1
Solvent: ClC(Cl)Cl
Solvent: CCOCC
Product: COc1ccc(OC)c(C=CCN2CCc3nc(N)sc3CC2)c1
Yield: 4 %

Procedure:
Prepared from 2,5-dimethoxy-cinnamyl chloride (prepared at -b 5° C. for 10 minutes) and 2 equivalents of 2-amino-4,5,7,8-tetrahydro-6H-thiazolo[5,4-d]azepine in chloroform. Yield: 4% of theory, Melting point: 112°-115° C. (ether).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:9]2[N:10]=[N:11][N:12]([CH:14]([CH3:16])[CH3:15])[CH:13]=2)[C:5]([NH2:8])=[N:6][CH:7]=1.[CH3:17][N:18]1[C:26]2[C:21](=[CH:22][C:23](B(O)O)=[CH:24][CH:25]=2)[CH:20]=[CH:19]1.O.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.CCOC(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>[CH:14]([N:12]1[CH:13]=[C:9]([C:4]2[C:5]([NH2:8])=[N:6][CH:7]=[C:2]([C:23]3[CH:22]=[C:21]4[C:26](=[CH:25][CH:24]=3)[N:18]([CH3:17])[CH:19]=[CH:20]4)[CH:3]=2)[N:10]=[N:11]1)([CH3:16])[CH3:15]
Reactant: Cn1ccc2cc(B(O)O)ccc21
Reactant: CC(C)n1cc(-c2cc(Br)cnc2N)nn1
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: [K+]
Solvent: C1COCCO1
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)n1cc(-c2cc(-c3ccc4c(ccn4C)c3)cnc2N)nn1
Temperature: 100 °C
Reaction time: 16 h

Procedure:
To a solution of 5-bromo-3-(1-isopropyl-1H-[1,2,3]triazol-4-yl)-pyridin-2-ylamine (200 mg, 0.708 mmol) and N-methylindole-5-boronic acid (124 mg, 0.708 mmol) in 1,4-dioxane (6.0 mL)/water (3.0 mL) was added K2CO3 (293 mg, 2.126 mmol) at room temperature. The reaction mixture was purged with argon for 30 min. Then Pd(PPh3)4 (41 mg, 0.035 mmol) was added and the mixture was allowed to stir at 100° C. for 16 h. The reaction mixture was cooled to RT, diluted with EtOAc (20 mL) and washed with water (20 mL). The organic layer was washed with brine solution (20 mL), dried over anhydrous Na2SO4 and solvent was evaporated under reduced pressure to afford crude compound. Crude compound was purified by column using 100-200 mesh silica gel. The column was eluted with 80% EtOAc in Pet. Ether to afford the title compound as pale yellow solid.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:12])=[C:4]([C:8]([CH3:11])=[CH:9][CH:10]=1)[C:5]([OH:7])=O.[CH3:13][O:14][C:15]1[CH:16]=[C:17]([CH3:25])[CH:18]=[C:19]([O:23][CH3:24])[C:20]=1[O:21][CH3:22].O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.ClCCl>O>[Br:1][C:2]1[CH:10]=[CH:9][C:8]([CH3:11])=[C:4]([C:3]=1[CH3:12])[C:5]([C:16]1[C:17]([CH3:25])=[CH:18][C:19]([O:23][CH3:24])=[C:20]([O:21][CH3:22])[C:15]=1[O:14][CH3:13])=[O:7]
Reactant: COc1cc(C)cc(OC)c1OC
Reactant: Cc1ccc(Br)c(C)c1C(=O)O
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: O
Solvent: ClCCl
Product: COc1cc(C)c(C(=O)c2c(C)ccc(Br)c2C)c(OC)c1OC
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 1B (1.3 g, 5.7 mmol), 3,4,5-trimethoxytoluene (1.0 g; 5.7 mmol), P2O5 (3.5 g) and dichloromethane (20 ml) is stirred at room temperature for 16 hours. Subsequently, water (5 ml) and ice are added and dichloromethane is distilled off and the residue is extracted with toluene. The organic phase is washed with water and concentrated. The residue is recrystallized from petrol ethers/toluene. The solid material is collected by vacuum filtration, washed with cold petrol ethers and dried, yielding white crystals, 1.4 g, mp 859° C.
Reaction SMILES: [C:1]1([CH2:7][C:8]([NH:10][C@@H:11]2[C:38](=[O:39])[N:13]3[C:14]([C:26]([O:28][CH2:29][C:30]4[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=4)=[O:27])=[C:15]([O:18][S:19]([C:22]([F:25])([F:24])[F:23])(=[O:21])=[O:20])[CH2:16][S:17][C@H:12]23)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.ClC1C=CC=C(C(OO)=[O:48])C=1>ClCCl>[O:48]=[S@@:17]1[C@@H:12]2[C@H:11]([NH:10][C:8](=[O:9])[CH2:7][C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[C:38](=[O:39])[N:13]2[C:14]([C:26]([O:28][CH2:29][C:30]2[CH:31]=[CH:32][C:33]([O:36][CH3:37])=[CH:34][CH:35]=2)=[O:27])=[C:15]([O:18][S:19]([C:22]([F:24])([F:25])[F:23])(=[O:21])=[O:20])[CH2:16]1
Reactant: COc1ccc(COC(=O)C2=C(OS(=O)(=O)C(F)(F)F)CS[C@@H]3[C@H](NC(=O)Cc4ccccc4)C(=O)N23)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: COc1ccc(COC(=O)C2=C(OS(=O)(=O)C(F)(F)F)C[S@](=O)[C@@H]3[C@H](NC(=O)Cc4ccccc4)C(=O)N23)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 75.7 %

Procedure:
A solution of p-methoxybenzyl (6R,7R)-7-phenylacetamido-3-(trifluoromethanesulphonyloxy)ceph-3-em-4-carboxylate (1.0 g, 1.7 mmol) in dichloromethane (25 ml) was treated with a solution of m-chloroperbenzoic acid (70%) (0.45, 1.8 mmol) in dichloromethane (15 ml). After stirring at room temperature for 30 min the solvent was evaporated and the residue crystallised from dichloro-methane/hexane to give the title compound (775 mg, 75%); m/z (3-NOBA sodium) 625 (MNa+); νmax (KBr) 1793, 1736, 1649 cm-1 ; δH (CDCl3) 3.47 (1H, dd, J 18.4, 1.4 Hz), 3.63 (1H, d, J 15.6 Hz), 3.66 (1H, d, J 15.6 Hz), 3.81 (3H, s), 3.87 (1H, d, J 18.4 Hz), 4.53 (1H, dd, J 4.8, 1.4 Hz), 5.20 (1H, d, J 11.7 Hz), 5.36 (1H, d, J 11.7 Hz), 6.07 (1H, dd, J 4.9, 9.8 Hz), 6.75 (1H, d, J 9.8 Hz), 6.89 (2H, d, J 8.6 Hz), 7.25-7.36 (7H, m).
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([C:12](CC2C=CC(C3SC=CN=3)=CC=2)([NH2:24])[C:13]2[N:18]=[C:17]([NH:19][CH2:20][C:21]([OH:23])=[O:22])[CH:16]=[CH:15][CH:14]=2)(=[O:11])=[O:10])=[CH:5][CH:4]=1.Cl.N1C=CC=C(S(C(N[CH2:60][C:61]2[CH:66]=[CH:65][C:64]([C:67]3[S:68][CH:69]=[CH:70][N:71]=3)=[CH:63][CH:62]=2)C2N=C(NCC(O)=O)C=CC=2)(=O)=O)C=1>>[F:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([CH:12]([NH:24][CH2:60][C:61]2[CH:62]=[CH:63][C:64]([C:67]3[S:68][CH:69]=[CH:70][N:71]=3)=[CH:65][CH:66]=2)[C:13]2[N:18]=[C:17]([NH:19][CH2:20][C:21]([OH:23])=[O:22])[CH:16]=[CH:15][CH:14]=2)(=[O:11])=[O:10])=[CH:5][CH:4]=1
Reactant: O=C(O)CNc1cccc(C(NCc2ccc(-c3nccs3)cc2)S(=O)(=O)c2cccnc2)n1
Reactant: NC(Cc1ccc(-c2nccs2)cc1)(c1cccc(NCC(=O)O)n1)S(=O)(=O)c1ccc(F)cc1
Agent: Cl
Product: O=C(O)CNc1cccc(C(NCc2ccc(-c3nccs3)cc2)S(=O)(=O)c2ccc(F)cc2)n1
Yield: 95 %

Procedure:
Reaction and post-treatment were carried out in the same manner as in Example 2-(c) except for using (6-{(4-fluorobenzenesulfonyl)[4-(thiazol-2-yl)benzyl]-aminomethyl}pyridin-2-ylamino)acetic acid hydrochloride (148 mg, 0.248 mmol) obtained in Example 4-(b) in place of (6-{(pyridin-3-ylsulfonyl)[4-(thiazol-2-yl)-benzyl]aminomethyl}pyridin-2-ylamino)acetic acid hydrochloride to afford the title compound (122 mg) as a pale brown solid. (Yield: 95%)
Reaction SMILES: [F:1][C:2]([F:49])([F:48])[C:3]1[CH:4]=[C:5]([CH:41]=[C:42]([C:44]([F:47])([F:46])[F:45])[CH:43]=1)[CH2:6][N:7]([CH2:19][C:20]1[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[CH:22][C:21]=1[N:30]([CH2:39][CH3:40])[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][C:36]([OH:38])=[O:37])[C:8]1[N:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][O:17][CH3:18])=[CH:10][N:9]=1.[OH-].[Na+:51]>C(O)C>[Na+:51].[F:49][C:2]([F:1])([F:48])[C:3]1[CH:4]=[C:5]([CH:41]=[C:42]([C:44]([F:45])([F:46])[F:47])[CH:43]=1)[CH2:6][N:7]([CH2:19][C:20]1[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[CH:22][C:21]=1[N:30]([CH2:39][CH3:40])[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][C:36]([O-:38])=[O:37])[C:8]1[N:9]=[CH:10][C:11]([O:14][CH2:15][CH2:16][O:17][CH3:18])=[CH:12][N:13]=1
Reactant: CCN(CCCCCC(=O)O)c1ccc(C(F)(F)F)cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ncc(OCCOC)cn1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCN(CCCCCC(=O)[O-])c1ccc(C(F)(F)F)cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ncc(OCCOC)cn1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
6-{[2-({(3,5-Bis-trifluoromethyl-benzyl)-[5-(2-methoxy-ethoxy)-pyrimidin-2-yl]-amino}-methyl)-4-trifluoromethyl-phenyl]-ethyl-amino}-hexanoic acid (105 mg) is dissolved in ethanol (1 ml), and thereto is added a 2M-aqueous sodium hydroxide solution (74 μl), and the mixture is stirred at room temperature for 5 minutes. The reaction solution is concentrated under reduced pressure to give 6-{[2-({(3,5-bis-trifluoromethyl-benzyl)-[5-(2-methoxy-ethoxy)-pyrimidin-2-yl]-amino}-methyl)-4-trifluoromethyl-phenyl]-ethyl-amino}-hexanoic acid sodium salt (102 mg). MS (m/z): 709 [M−Na]−
Reaction SMILES: [N:1]1([C:10]([C@@H:12]([C@H:22]([CH2:35][OH:36])[O:23][CH2:24][P:25]([O:31][CH:32]([CH3:34])[CH3:33])([O:27][CH:28]([CH3:30])[CH3:29])=[O:26])[O:13]C(=O)C2C=CC=CC=2)=[O:11])[CH:9]=[C:7]([CH3:8])[C:5](=[O:6])[NH:4][C:2]1=[O:3].N>CO>[N:1]1([C:10]([C@@H:12]([C@H:22]([CH2:35][OH:36])[O:23][CH2:24][P:25]([O:31][CH:32]([CH3:34])[CH3:33])([O:27][CH:28]([CH3:30])[CH3:29])=[O:26])[OH:13])=[O:11])[CH:9]=[C:7]([CH3:8])[C:5](=[O:6])[NH:4][C:2]1=[O:3]
Reactant: Cc1cn(C(=O)[C@H](OC(=O)c2ccccc2)[C@H](CO)OCP(=O)(OC(C)C)OC(C)C)c(=O)[nH]c1=O
Agent: N
Solvent: CO
Product: Cc1cn(C(=O)[C@H](O)[C@H](CO)OCP(=O)(OC(C)C)OC(C)C)c(=O)[nH]c1=O
Yield: 70.6 %

Procedure:
A solution of 12 (715 mg, 1.7 mmol) in MeOH saturated with ammonia (100 mL) was stirred at room temperature overnight. The mixture was concentrated, and the residue was purified by column chromatography (CH2Cl2:MeOH=10:1) to give compound 16 (515 mg, 1.2 mmol) as a white powder in 71% yield which was characterized as follows:
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[C:7]([O:14][CH3:15])[C:6]=1[O:16][CH3:17].C([O-])([O-])=O.[K+].[K+].[CH3:24][N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1.N1CCNCC1>CC#N>[CH3:17][O:16][C:6]1[C:7]([O:14][CH3:15])=[CH:8][C:9]([N+:11]([O-:13])=[O:12])=[CH:10][C:5]=1[O:4][CH2:3][CH2:2][N:28]1[CH2:29][CH2:30][N:25]([CH3:24])[CH2:26][CH2:27]1
Reactant: COc1cc([N+](=O)[O-])cc(OCCCl)c1OC
Reactant: CN1CCNCC1
Agent: C1CNCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1cc([N+](=O)[O-])cc(OCCN2CCN(C)CC2)c1OC

Procedure:
A mixture of 1-(2-chloroethoxy)-2,3-dimethoxy-5-nitrobenzene (1.382 g, 5.28 mmol), K2CO3 (1.83 g, 13.2 mmol), and N-methylpiperazine (1.76 mL, 15.85 mmol) was stirred and heated under N2 in CH3CN (20 mL) under reflux overnight. The next day 0.80 g K2CO3 and 0.66 mL piperazine were added (1.1 eq.) and heated for 3 h more when HPLC showed that the reaction was complete. The solids were filtered and washed well with CH3CN and the filtrate was evaporated at 80° C. to remove excess amine. The resulting red oil was dissolved in CH2Cl2 and washed with water. The aqueous layer was washed with CH2Cl2. The combined organic layers were dried and evaporated giving 2,3-dimethoxy-1-(2-(4-methylpiperazin-1-yl)ethoxy)-5-nitrobenzene.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[C:11](Cl)=[N:12][C:13]([Cl:15])=[N:14][C:5]=3[C:4]=2[CH:3]=1.[CH3:17][CH2:18][O-:19].[Na+]>C(O)C>[Br:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[C:11]([O:19][CH2:18][CH3:17])=[N:12][C:13]([Cl:15])=[N:14][C:5]=3[C:4]=2[CH:3]=1
Reactant: CC[O-]
Reactant: Clc1nc(Cl)c2[nH]c3ccc(Br)cc3c2n1
Agent: [Na+]
Solvent: CCO
Product: CCOc1nc(Cl)nc2c1[nH]c1ccc(Br)cc12
Temperature: 25 °C
Yield: 97.1 %

Procedure:
930 mg (2.9 mmol) 8-bromo-2,4-dichloro-5H-pyrimido[5,4-b]indole was suspended in 20 ml ethanol and mixed with 592 mg (8.7 mmol) sodium ethylate. The mixture was refluxed for 8 h. Having cooled down to room temperature, the solvent was concentrated and water was added. The resulting precipitate was sucked off and washed with water. 920 mg (97%) 8-bromo-2-chloro-4-ethoxy-5H-pyrimido[5,4-b]indole was obtained. ESI-MS [m/z]: 324, 326 [M−H]−
Reaction SMILES: C(OC([NH:11][C@H:12]([C:16](O)=[O:17])[CH:13]([CH3:15])[CH3:14])=O)C1C=CC=CC=1.[NH2:19][C@@H:20]([CH2:54][OH:55])[C@@H:21]([OH:53])[C@@H:22]([OH:52])[C@H:23]([OH:51])[C:24]([NH:26][C@H:27]([C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)[CH2:28][C:29]([O:31]C(C1C=CC=CC=1)C1C=CC=CC=1)=[O:30])=[O:25].C(N(CC)CC)C>CN(C)C=O.CO.[Pd]>[OH:51][C@@H:23]([C@H:22]([OH:52])[C@H:21]([OH:53])[C@@H:20]([NH:19][C:16](=[O:17])[C@H:12]([CH:13]([CH3:15])[CH3:14])[NH2:11])[CH2:54][OH:55])[C:24]([NH:26][C@H:27]([C:45]1[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=1)[CH2:28][C:29]([OH:31])=[O:30])=[O:25]
Reactant: N[C@@H](CO)[C@@H](O)[C@@H](O)[C@H](O)C(=O)N[C@@H](CC(=O)OC(c1ccccc1)c1ccccc1)c1ccccc1
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: [Pd]
Solvent: CO
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)[C@H](N)C(=O)N[C@@H](CO)[C@@H](O)[C@@H](O)[C@H](O)C(=O)N[C@@H](CC(=O)O)c1ccccc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 152.8 %

Procedure:
To a solution of N-benzyloxycarbonyl-L-valine (460 mg) and diphenylmethyl (S)-3-[(2S,3R,4R,5S)-5-amino-2,3,4,6-tetrahydroxyhexanoyl]amino-3-phenylpropionate (500 mg) in dimethylformamide (50 ml) were added diethyl cyanophosophonate (298 mg) and triethylamine (0.191 ml) and the whole was stirred at room temperature for 15 hours. Aftert concentration under reduced pressure, to the residue was added 0.1N hydrochloric acid (50 ml) and the whole was extracted with ethyl acetate (100 ml). The organic layer was washed with saturated aqueous sodium hydrogencarbonate solution and saturated brine respectively and dried over anhydrous sodium sulfate. Removal of the organic solvent gave a residue, which was dissolved in methanol (20 ml) and stirred at room temperature with 10% palladium on activated carbon (150 mg) under hydrogen atmosphere for 1 hour. After filtration, the filtrate was concentrated under reduced pressure to give a residue, which was passed through a column of DIAION HP-20SS (Mitsubishi kasei corporation), followed by elution with water-acetonitrile. The effective fractions were combined and concentrated under reduced pressure. The residue was recrystallized from methanol-ethyl acetate to afford the title compound (663 mg).
Reaction SMILES: P([O-])([O-])([O-])=O.[K+].[K+].[K+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.[CH3:51][O:52][C:53]1[CH:62]=[C:61]2[C:56]([C:57]([O:63][C:64]3[CH:69]=[CH:68][C:67]([NH2:70])=[CH:66][CH:65]=3)=[CH:58][CH:59]=[N:60]2)=[N:55][CH:54]=1.Cl[C:72]1[N:73]=[N:74][CH:75]=[C:76]([O:78][CH3:79])[CH:77]=1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(C)C=CC=CC=1>[CH3:79][O:78][C:76]1[CH:77]=[C:72]([NH:70][C:67]2[CH:68]=[CH:69][C:64]([O:63][C:57]3[C:56]4[C:61](=[CH:62][C:53]([O:52][CH3:51])=[CH:54][N:55]=4)[N:60]=[CH:59][CH:58]=3)=[CH:65][CH:66]=2)[N:73]=[N:74][CH:75]=1
Reactant: COc1cnnc(Cl)c1
Reactant: COc1cnc2c(Oc3ccc(N)cc3)ccnc2c1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: COc1cnnc(Nc2ccc(Oc3ccnc4cc(OC)cnc34)cc2)c1
Temperature: 100 °C

Procedure:
A pyrex reaction tube was charged with potassium phosphate (88 mg, 415 μmol), Pd2dba3 (16 mg, 17 mmol), Xantphos (22 mg, 38 mmol), 4-(7-methoxy-1,5-naphthyridin-4-yloxy)benzenamine (92 mg, 346 μmol), 3-chloro-5-methoxypyridazine (50 mg, 346 μmol), and toluene (1 mL). The tube was purged with argon, sealed, and the mixture was heated at 100° C. for 4 h. LCMS showed complete conversion to desired product. The mixture was then concentrated and purified by silica gel chromatography using 0 to 60% (90/10/1 DCM/MeOH/ammonium hydroxide) in DCM. MS: M+H+=376.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C@H:10]([CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:11]([OH:13])=O)[CH3:9])=[O:7])([CH3:4])([CH3:3])[CH3:2].O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.Cl.[C:45]([O:48][C:49]([CH3:53])([CH3:52])[CH2:50][NH2:51])(=[O:47])[CH3:46].C(N(C(C)C)C(C)C)C>CN(C)C=O.C(OCC)(=O)C>[C:45]([O:48][C:49]([CH3:53])([CH3:52])[CH2:50][NH:51][C:11](=[O:13])[C@H:10]([N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH3:9])[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)(=[O:47])[CH3:46]
Reactant: CN(C(=O)OC(C)(C)C)[C@H](Cc1ccccc1)C(=O)O
Reactant: CC(=O)OC(C)(C)CN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: CC(=O)OC(C)(C)CNC(=O)[C@@H](Cc1ccccc1)N(C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 80.4 %

Procedure:
(2R)-2-(N-(tert-Butoxycarbonyl)-N-methylamino)-3-phenylpropionic acid (391 mg, 1.4 mmol) was dissolved in N,N-dimethylformamide (6 ml). 1-Hydroxybenzotriazole hydrate (189 mg, 1.4 mmol) and N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride were added. The reaction mixture was stirred for 10 min at room temperature. 2-Amino-1,1-dimethylethyl acetate hydrochloride (237 mg, 1.4 mmol) was added as a solid. Ethyldiisopropylamine (0.53 ml, 3.1 mmol) was added. The reaction mixture was stirred for 20 h at room temperature. It was diluted with ethyl acetate (200 ml) and washed with 1N hydrochloric acid. The aqueous phase was extracted with ethyl acetate (2×50 ml). The combined organic layers were washed with saturated sodium hydrogen carbonate solution (100 ml) and dried over magnesium sulfate. The solvent was removed in vacuo. The crude product was purified by flash chromatography on silica (80 g), using ethyl acetate/heptane (1:1) as eluent, to give 442 mg of 2-((2R)-2-(N-(tert-butoxycarbonyl)-N-methylamino)-3-phenylpropionylamino)-1,1-dimethylethyl acetate.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10](=[O:17])[C:11]([Cl:16])=[C:12]([CH3:15])[NH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:18](=O)([O-])[O-].[K+].[K+].IC.C(OCC)(=O)C>CN(C=O)C.O>[CH2:1]([O:8][C:9]1[C:10](=[O:17])[C:11]([Cl:16])=[C:12]([CH3:15])[N:13]([CH3:18])[CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1[nH]cc(OCc2ccccc2)c(=O)c1Cl
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CI
Solvent: O
Product: Cc1c(Cl)c(=O)c(OCc2ccccc2)cn1C
Temperature: 25 °C
Yield: 63.2 %

Procedure:
5-(Benzyloxy)-3-chloro-2-methylpyridin-4(1H)-one (3.00 g, 12.0 mmol) was suspended in 25 mL of DMF. Potassium carbonate (3.30 g, 24.0 mmol) was added followed by the addition of iodomethane (1.53 mL, 24.0 mmol). The progress of the reaction was monitored by TLC (30% ethyl acetate in hexanes). Upon completion, the reaction was allowed to stir at room temperature. Water was added and a white precipitate formed. The solid was collected by suction filtration, allowed to air dry and then further dried under vacuum. Thus, 5-(benzyloxy)-3-chloro-1,2-dimethylpyridin-4(1H)-one (2.00 g) was obtained. Yield=63%; 1H NMR (MeOD-D4, 90 MHz,) δ (ppm): 7.61 (s, 1H), 7.27-7.46 (m, 5H), 5.21 (s, 2H), 3.75 (s, 3H) and 2.54 (s, 3H).
Reaction SMILES: C([C:5]1[CH:6]=[CH:7][C:8]([NH:14][CH:15]=[O:16])=[C:9]([N+:11]([O-:13])=[O:12])[CH:10]=1)CCC.[CH:17]([O:20][C:21]([NH:23]C1C=CC(N)=C([N+]([O-])=O)C=1)=[O:22])([CH3:19])[CH3:18].C(C1C=CC(N)=C([N+]([O-])=O)C=1)CCC>>[CH:15]([NH:14][C:8]1[CH:7]=[CH:6][C:5]([NH:23][C:21]([O:20][CH:17]([CH3:19])[CH3:18])=[O:22])=[CH:10][C:9]=1[N+:11]([O-:13])=[O:12])=[O:16]
Reactant: CCCCc1ccc(NC=O)c([N+](=O)[O-])c1
Reactant: CC(C)OC(=O)Nc1ccc(N)c([N+](=O)[O-])c1
Agent: CCCCc1ccc(N)c([N+](=O)[O-])c1
Product: CC(C)OC(=O)Nc1ccc(NC=O)c([N+](=O)[O-])c1

Procedure:
In a similar manner to that described above for the preparation of 5-n-butyl-2-formamido-1-nitrobenzene but substituting an equimolecular quantity of 4-isopropoxycarbonylamino-2-nitroaniline for the 4-n-butyl-2-nitroaniline, there was obtained 2-formamido-5-isopropoxycarbonylamino-1-nitrobenzene, m.p. 168°-170° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[C:23]([C:26]4[O:27][C:28]([CH:31]5OCC[O:32]5)=[CH:29][CH:30]=4)[CH:24]=3)[N:19]=[CH:18][N:17]=2)=[CH:11][C:10]=1[C:36]([F:39])([F:38])[F:37])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.O>C1COCC1>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[C:23]([C:26]4[O:27][C:28]([CH:31]=[O:32])=[CH:29][CH:30]=4)[CH:24]=3)[N:19]=[CH:18][N:17]=2)=[CH:11][C:10]=1[C:36]([F:39])([F:37])[F:38])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: FC(F)(F)c1cc(Nc2ncnc3ccc(-c4ccc(C5OCCO5)o4)cc23)ccc1OCc1ccccc1
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: O=Cc1ccc(-c2ccc3ncnc(Nc4ccc(OCc5ccccc5)c(C(F)(F)F)c4)c3c2)o1
Reaction time: 0.5 h
Yield: 84 %

Procedure:
Prepared according to Procedure C using (4-Benzyloxy-3-trifluoromethylphenyl)-(6-(5-(1,3-dioxolan-2-yl)-furan-2-yl)-quinazolin-4-yl)-amine (470 mg, 0.88 mmol) solution in THF (5 ml) followed by the addition of 2N HCl (20 ml) at room temperature. The resulting mixture was stirred for 30 minutes. Water was added (15 ml) then filtered. The yellow solid was washed with water and small amount of ether and dried in vacuo (0.39 g, 84% yield). ESI-MS m/z 490 (M+H)+.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[C:9]([NH2:27])[C:10]([F:26])=[C:11]([N:15]4[CH2:22][C:21](=[N:23][O:24][CH3:25])[C:17]5([CH2:20][NH:19][CH2:18]5)[CH2:16]4)[C:12]=3[F:14])[C:7](=[O:28])[C:6]([C:29]([OH:31])=[O:30])=[CH:5]2)[CH2:3][CH2:2]1.[CH2:32](O)C.C([BH3-])#N.[Na+]>C(O)(=O)C>[CH:1]1([N:4]2[C:13]3[C:8](=[C:9]([NH2:27])[C:10]([F:26])=[C:11]([N:15]4[CH2:22][C:21](=[N:23][O:24][CH3:25])[C:17]5([CH2:18][N:19]([CH3:32])[CH2:20]5)[CH2:16]4)[C:12]=3[F:14])[C:7](=[O:28])[C:6]([C:29]([OH:31])=[O:30])=[CH:5]2)[CH2:2][CH2:3]1
Reactant: CCO
Reactant: CON=C1CN(c2c(F)c(N)c3c(=O)c(C(=O)O)cn(C4CC4)c3c2F)CC12CNC2
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Product: CON=C1CN(c2c(F)c(N)c3c(=O)c(C(=O)O)cn(C4CC4)c3c2F)CC12CN(C)C2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 90.4 %

Procedure:
1-Cyclopropyl-5-amino-6,8-difluoro-7-[8-(methoxyimino)-2,6-diazaspiro[3,4]oct-6-yl]-4-oxo-1,4-dihydro-3-quinolinecarboxylic acid was added to 10 ml of ethanol, and thereto 0.2 ml of acetic acid was dropped and 44 mg of p-formaldehyde was added. It was stirred at room temperature for 30 minutes and thereto 91 mg of sodium cyanoborohydride was added. It was stirred at room temperature for 2 hours. The resulting precipitate was filtered to give 280 mg of the titled compound(yield 90.4%).