Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]([CH2:26][CH3:27])[C:4]1[CH:9]=[C:8]([C:10]2[O:14][N:13]=[C:12]([C:15]3[CH:20]=[C:19]([CH3:21])[C:18]([OH:22])=[C:17]([CH2:23][CH3:24])[CH:16]=3)[N:11]=2)[CH:7]=[C:6]([CH3:25])[N:5]=1)[CH3:2].[CH2:28]([C@H:30]1[O:32][CH2:31]1)Cl>C(O)(C)C.[OH-].[Na+].CC(=O)OCC>[CH2:26]([N:3]([CH2:1][CH3:2])[C:4]1[CH:9]=[C:8]([C:10]2[O:14][N:13]=[C:12]([C:15]3[CH:20]=[C:19]([CH3:21])[C:18]([O:22][CH2:28][C@H:30]4[CH2:31][O:32]4)=[C:17]([CH2:23][CH3:24])[CH:16]=3)[N:11]=2)[CH:7]=[C:6]([CH3:25])[N:5]=1)[CH3:27]
Reactant: ClC[C@@H]1CO1
Reactant: CCc1cc(-c2noc(-c3cc(C)nc(N(CC)CC)c3)n2)cc(C)c1O
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CC(C)O
Product: CCc1cc(-c2noc(-c3cc(C)nc(N(CC)CC)c3)n2)cc(C)c1OC[C@H]1CO1
Reaction time: 24 h
Yield: 74.8 %

Procedure:
To a solution of 4-[5-(2-diethylamino-6-methyl-pyridin-4-yl)-[1,2,4]oxadiazol-3-yl]-2-ethyl-6-methyl-phenol (500 mg, 1.36 mmol) in isopropanol (15 mL) and 3 N aq. NaOH (6 mL), (S)-epichlorohydrine (378 mg, 4.09 mmol) is added. The orange solution is stirred at rt for 24 h before another portion of (S)-epichlorohydrine is added. Stirring is continued for 24 h, the mixture is diluted with EA, washed with sat. aq. NaHCO3-solution, dried over MgSO4, filtered and concentrated. The crude product is purified by CC on silica gel eluting with heptane:EA 4:1 to give diethyl-{4-[3-((R)-3-ethyl-5-methyl-4-oxiranylmethoxy-phenyl)-[1,2,4]oxadiazol-5-yl]-6-methyl-pyridin-2-yl}-amine (430 mg) as a yellow oil; LC-MS: tR=0.96 min; [M+1]+=423.21.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][S:5][C:6]=1[C:7]([Cl:9])=[O:8].[NH2:10][C:11]1[C:20]2[C:15](=[CH:16][C:17]([O:23][CH3:24])=[C:18]([O:21][CH3:22])[CH:19]=2)[N:14]=[C:13]([N:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[N:12]=1>>[ClH:9].[NH2:10][C:11]1[C:20]2[C:15](=[CH:16][C:17]([O:23][CH3:24])=[C:18]([O:21][CH3:22])[CH:19]=2)[N:14]=[C:13]([N:25]2[CH2:30][CH2:29][N:28]([C:7]([C:6]3[S:5][CH:4]=[N:3][C:2]=3[CH3:1])=[O:8])[CH2:27][CH2:26]2)[N:12]=1
Reactant: COc1cc2nc(N3CCNCC3)nc(N)c2cc1OC
Reactant: Cc1ncsc1C(=O)Cl
Product: COc1cc2nc(N3CCN(C(=O)c4scnc4C)CC3)nc(N)c2cc1OC
Product: Cl

Procedure:
The title compound was prepared from 4-methylthiazole-5-carbonyl chloride (1.1 g.) and 4-amino-6,7-dimethyoxy-2-(1-piperazinyl)quinazoline (2.0 g.) following previously described procedures. The product had a m.p. of 293°-295° C. with decomposition.
Reaction SMILES: C[O:2][C:3]([C@@H:5]1[CH2:9][C@H:8]([N:10]([CH3:19])[C:11]([O:13][CH2:14][C:15]([Cl:18])([Cl:17])[Cl:16])=[O:12])[CH2:7][N:6]1[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:4].[OH-].[Na+]>C1COCC1.CO.O>[CH2:20]([N:6]1[CH2:7][CH:8]([N:10]([CH3:19])[C:11]([O:13][CH2:14][C:15]([Cl:18])([Cl:16])[Cl:17])=[O:12])[CH2:9][CH:5]1[C:3]([OH:4])=[O:2])[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: COC(=O)[C@@H]1C[C@H](N(C)C(=O)OCC(Cl)(Cl)Cl)CN1Cc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CN(C(=O)OCC(Cl)(Cl)Cl)C1CC(C(=O)O)N(Cc2ccccc2)C1
Reaction time: 8 h

Procedure:
To a solution of (2S,4S)-1-benzyl-4-[methyl-(2,2,2-trichloro-ethoxycarbonyl)-amino]-pyrrolidine-2-carboxylic acid methyl ester in THF and methanol is added NaOH in water, and the reaction mixture is stirred overnight, and extracted with EA. The aqueous solution is acidified to ph 5-6 and extracted with EA. The organic phase is washed, dried and concentrated to give 1-benzyl-4-[methyl-(2,2,2-trichloro-ethoxycarbonyl)-amino]-pyrrolidine-2-carboxylic acid (28).
Reaction SMILES: [C:1]([Si:5]([CH3:42])([CH3:41])[O:6][CH:7]([C:17]1[C:18]([CH3:40])=[N:19][O:20][C:21]=1[C:22]1[CH:27]=[CH:26][C:25]([C:28]2[CH:33]=[CH:32][C:31]([C:34]3([C:37]([OH:39])=O)[CH2:36][CH2:35]3)=[CH:30][CH:29]=2)=[CH:24][CH:23]=1)[CH2:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:43][C:44]1[CH:45]=[CH:46][C:47]([S:50]([NH2:53])(=[O:52])=[O:51])=[CH:48][CH:49]=1>>[C:1]([Si:5]([CH3:42])([CH3:41])[O:6][CH:7]([C:17]1[C:18]([CH3:40])=[N:19][O:20][C:21]=1[C:22]1[CH:27]=[CH:26][C:25]([C:28]2[CH:29]=[CH:30][C:31]([C:34]3([C:37]([NH:53][S:50]([C:47]4[CH:48]=[CH:49][C:44]([CH3:43])=[CH:45][CH:46]=4)(=[O:51])=[O:52])=[O:39])[CH2:36][CH2:35]3)=[CH:32][CH:33]=2)=[CH:24][CH:23]=1)[CH2:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccc(S(N)(=O)=O)cc1
Reactant: Cc1noc(-c2ccc(-c3ccc(C4(C(=O)O)CC4)cc3)cc2)c1C(CCCc1ccccc1)O[Si](C)(C)C(C)(C)C
Product: Cc1ccc(S(=O)(=O)NC(=O)C2(c3ccc(-c4ccc(-c5onc(C)c5C(CCCc5ccccc5)O[Si](C)(C)C(C)(C)C)cc4)cc3)CC2)cc1

Procedure:
Prepared according to the procedure described in Example 315 using 1-(4′-{4-[1-(tert-butyl-dimethyl-silanyl oxy)-4-phenyl-butyl]-3-methyl-isoxazol-5-yl}-biphenyl-4-yl)-cyclopropanecarboxylic acid and p-toluenesulfonamide.
Reaction SMILES: [CH3:1][C:2]([C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=1)([CH3:7])[C:3](Cl)=[N:4][NH2:5].[Cl:15][C:16]1[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[C:17]=1[C:18]#[N:19].[Cl-].[Al+3].[Cl-].[Cl-].O.Cl[C:31]1C=CC=CC=1Cl>>[Cl:15][C:16]1[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[C:17]=1[C:18]1[N:5]([CH3:31])[N:4]=[C:3]([C:2]([CH3:7])([CH3:1])[C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=2)[N:19]=1
Reactant: Clc1ccccc1Cl
Reactant: CC(C)(C(Cl)=NN)c1ccc(Cl)cc1
Reactant: N#Cc1c(F)cccc1Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Product: Cn1nc(C(C)(C)c2ccc(Cl)cc2)nc1-c1c(F)cccc1Cl
Temperature: 120 °C

Procedure:
To a solution of 0.7 g of N-methyl-N-(p-toluenesulfonyl)-(α, α-dimethyl-4-chlorophenylacetohydrazonoyl chloride in 7 ml of o-dichlorobenzene at room temperature, were added 0.33 g of 2-chloro-6-fluorobenzonitrile and 0.28 g of anhydrous aluminium chloride, and the reaction mixture was heated at 120° C. for 30 minutes. After cooling, the reaction mixture was poured into iced water and extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried over magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel chromatography to afford 0.6 g of 5-(2-chloro-6-fluorophenyl)-3-(4-chloro-α,α-dimethylbenzyl)-1-methyl-1H-1,2,4-triazole. m.p.97°-100° C.
Reaction SMILES: [CH2:1]([C:8]([N:25]([CH3:27])[CH3:26])([CH2:23][CH3:24])[C:9]([C:11]1[CH:16]=[CH:15][C:14]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)=[CH:13][CH:12]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:28]([Si:31]([O:36][CH3:37])([O:34][CH3:35])[O:32][CH3:33])[CH:29]=C.[C:38]1(C)C=CC=CC=1>>[CH2:1]([C:8]([N:25]([CH3:27])[CH3:26])([CH2:23][CH3:24])[C:9]([C:11]1[CH:16]=[CH:15][C:14]([N:17]2[CH2:18][CH2:19][O:20][CH2:21][CH2:22]2)=[CH:13][C:12]=1[CH2:29][CH:28]([Si:31]([O:36][CH3:37])([O:34][CH3:35])[O:32][CH3:33])[CH3:38])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1ccccc1
Reactant: C=CC[Si](OC)(OC)OC
Reactant: CCC(Cc1ccccc1)(C(=O)c1ccc(N2CCOCC2)cc1)N(C)C
Product: CCC(Cc1ccccc1)(C(=O)c1ccc(N2CCOCC2)cc1CC(C)[Si](OC)(OC)OC)N(C)C
Reaction time: 8 h
Yield: 4 %

Procedure:
5.49 g (15 mmol) of 2-benzyl-2-dimethylamino-1-(4-morpholinophenyl)-1-butanone, 275 mg (0.3 mmol) of RuH2 (CO) (PPh3)3 and 5 g (30 mmol) of allyltrimethoxysilane were dissolved in 20 ml of toluene and degased with argon. After heating for 5 hours at reflux with stirring, the mixture was left to stand overnight, stirred at reflux for a further 9 hours, and again left to stand at room temperature. 280 mg (0.3 mmol) of RuH2 (CO) (PPh3)3 were added and the mixture was boiled for 9 hours; it was then again left to stand overnight, 260 mg (0.3 mmol) of RuH2 (CO)(PPh3)3 were added, and the whole mixture was boiled again for 9 hours. After the solvent had been distilled off, the product was chromatographed (silica gel, heptane/CH2Cl2 /ethyl acetate) and finally, by means of gel permeation chromatography (Sephadex LH-20, methanol) a pure fraction of 0.33 g (4%) of (11) was obtained as a yellow oil. 1H-NMR (CDCl3): 0.68 ppm (3H, t, Bu-H4, 3 JH,H =7.2 Hz); 0.77 ppm (mc, 2H, Prop-H3); 1.64-1.96 ppm (4H, m, Bu-H3 and Prop-H2); 2.38 ppm (6H, s, N(CH3)2); 2.64 ppm (2H, mc, Prop-H1); 3.16 ppm (2H, mc, CH2 -Ph); 3.24 ppm (4H, mc, morpholine-N --CH2); 3.57 ppm (9H, s, Si(OCH3)3); 3.85 ppm (4H, mc morpholine-O-CH2); 6.61 ppm (1H, dd, Ph-H5, 3 JH5H,6 =8.6 Hz); 6.72 ppm (1H, d, Ph-H3, 4JH3,H5 =2.4 Hz); 7.13-7.25 ppm (5H, m, Ph'-H); 8.38 ppm (1H, d, Ph-H6).
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9](I)=[CH:8][CH:7]=1)=[O:4].[CH2:15]([OH:21])[CH2:16][CH2:17][CH2:18][C:19]#[CH:20]>CN(C=O)C.C([O-])(=O)C.C([N+](CCCC)(CCCC)CCCC)CCC.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[F:1][C:2]([F:14])([F:13])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([C:20]#[C:19][CH2:18][CH2:17][CH2:16][CH2:15][OH:21])=[CH:8][CH:7]=1)=[O:4]
Reactant: C#CCCCCO
Reactant: O=C(Nc1ccc(I)cc1)C(F)(F)F
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CN(C)C=O
Product: O=C(Nc1ccc(C#CCCCCO)cc1)C(F)(F)F
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of Intermediate 32 (2.7 g, 8.5 mmol, prepared according to Melissaris, A. P. and Litt, M. H. J Org Chem 1994, 59, 5818-5821) in DMF (26 mL) was treated successively with tetra-n-butylammonium acetate (3.8 g, 13 mmol) and palladium (II) acetate (57 mg, 0.26 mmol). The mixture was degassed with nitrogen and then treated with 5-hexyn-1-ol (0.93 mL, 8.5 mmol). After four hours of stirring at room temperature, additional quantities of the following reagents were added: tetra-n-butylammonium acetate (1 g), palladium (II) acetate (57 mg), and 5-hexyn-1-ol (1 mL). After stirring overnight at room temperature, the mixture was partitioned between diethyl ether and water. The aqueous phase was extracted four times with diethyl ether. The combined organic extracts were washed twice with water and once with saturated aqueous sodium chloride solution before drying over anhydrous magnesium sulfate, filtration and concentration under reduced pressure to provide the title compound as brown syrup that partially solidified under vacuum. ES/MS calcd. for C14H15F3NO2+: 286.1. Found m/z=286.2 (M+H)+
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C@@H:7]2[CH2:12][CH2:11][CH2:10][C@H:9]([N:13]3C(=O)C4=CC=CC=C4C3=O)[CH2:8]2)[CH:2]=1>CCO>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C@@H:7]2[CH2:12][CH2:11][CH2:10][C@H:9]([NH2:13])[CH2:8]2)[CH:2]=1
Reactant: O=C1c2ccccc2C(=O)N1[C@H]1CCC[C@@H](c2cccnc2)C1
Solvent: CCO
Product: N[C@H]1CCC[C@@H](c2cccnc2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 36904.2 %

Procedure:
A mixture of cis-N-[3-(3-pyridyl)cyclohexyl]phtalimide (1.64 g, 5.35 mmol) and hydrazinemonohydorate (0.52 mL, 10.7 mmol) in EtOH (25 mL) was stirred at room temperature for 2 h. The reaction mixture was filtered followed by the removal of solvent. The crude product was purified by column chromatography (NH, EtOAc) to yield cis-3-(3-pyridyl)cyclohexylamine (348 g, 37%) as colorless oil.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]1[CH2:12][C@H:11]([C:13]([OH:15])=O)[C:10]1([CH3:17])[CH3:16])=[O:7])([CH3:4])([CH3:3])[CH3:2].C1C=CC2N(O)N=NC=2C=1.Cl.[NH2:29][C@@H:30]([CH:35]([CH3:37])[CH3:36])[C:31]([O:33][CH3:34])=[O:32].CCN(CC)CC>C(Cl)Cl>[C:1]([O:5][C:6]([NH:8][C@@H:9]1[CH2:12][C@H:11]([C:13]([NH:29][C@@H:30]([CH:35]([CH3:37])[CH3:36])[C:31]([O:33][CH3:34])=[O:32])=[O:15])[C:10]1([CH3:17])[CH3:16])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N[C@@H]1C[C@H](C(=O)O)C1(C)C
Reactant: COC(=O)[C@@H](N)C(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)[C@@H](NC(=O)[C@H]1C[C@@H](NC(=O)OC(C)(C)C)C1(C)C)C(C)C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 85.9 %

Procedure:
To a stirred solution of (1S,3R)-3-(tert-butoxycarbonylamino)-2,2-dimethylcyclobutanecarboxylic acid (0.350 g, 1.44 mmol) in DCM (5 ml) EDCI (0.331 g, 1.73 mmol) and HOBt (0.234 g, 1.73 mmol) were added at about 0° C. After 10 minutes, (S)-methyl 2-amino-3-methylbutanoate hydrochloride (0.720, 8.64 mmol) and Et3N (1.2 ml, 6.17 mmol) in DCM (5 ml) were added drop wise and the reaction mass was allowed to stir at room temperature for about 16 hours. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with DCM and washed with water and saturated NaHCO3 solution, then washed with aqueous 1N HCl, then washed with water and saturated brine, and the organic layer was concentrated under reduced pressure, the resulting crude was purified by silica gel column (100-200 mesh, elution 70% EtOAC in hexane) to afford the title compound as a solid. Wt: 0.440 g; Yield: 85.9%; 1H NMR (300 MHz, CDCl3): δ 5.62 (d, 1H, J=8.4 Hz), 4.77 (d, 111, J=8.4 Hz), 4.70-4.60 (m, 1H), 4.89-4.71 (m, 1H), 3.72 (s, 3H), 2.46-2.21 (m, 2H), 2.18-1.99 (m, 1H), 1.70-1.50 (m, 1H), 1.42 (s, 9H), 1.31 (s, 3H), 0.94-0.90 (s, 9H); Mass: The related mass peak was not observed; IR (KBr, cm−1): 3345, 3314, 2960, 1753, 1690, 1664, 1529, 1456, 1366, 1271, 1172, 1049, 1028, 986, 873.
Reaction SMILES: [F:1][C:2]1[CH:28]=[CH:27][CH:26]=[CH:25][C:3]=1[C:4](=[O:24])[CH2:5][CH2:6][NH:7][C:8]1[C:16]2[C:11](=[CH:12][C:13]([Cl:18])=[CH:14][C:15]=2[Cl:17])[NH:10][C:9]=1[C:19]([O:21]CC)=[O:20].[OH-].[Li+].O1CCCC1.O>C(OCC)(=O)C>[F:1][C:2]1[CH:28]=[CH:27][CH:26]=[CH:25][C:3]=1[C:4](=[O:24])[CH2:5][CH2:6][NH:7][C:8]1[C:16]2[C:11](=[CH:12][C:13]([Cl:18])=[CH:14][C:15]=2[Cl:17])[NH:10][C:9]=1[C:19]([OH:21])=[O:20]
Reactant: CCOC(=O)c1[nH]c2cc(Cl)cc(Cl)c2c1NCCC(=O)c1ccccc1F
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C(CCNc1c(C(=O)O)[nH]c2cc(Cl)cc(Cl)c12)c1ccccc1F
Temperature: 25 °C
Reaction time: 24 h
Yield: 82.6 %

Procedure:
Mix 3-[(o-fluorophenacyl)methylamino]-2-carbethoxy-4,6-dichloroindole (600 mg, 1.47 mmol), lithium hydroxide (184 mg, 4.4 mmol), tetrahydrofuran (10 mL) and water (10 mL). Stir for 24 hours at room temperature. Dilute with ethyl acetate (40 mL). Acidify while stirring and separate the layers. Dry the organic phase over magnesium sulfate, filter and concentrate in vacuo. Recrystallize the residue (ethyl acetate/hexane) to yield the title compound as a white powder (480 mg, 86%).
Reaction SMILES: Cl.[CH3:2][NH:3][CH3:4].[CH:5]([C:7]1[N:8]=[C:9]([NH:12][C:13]([C:15]2[C:16]3[N:17]=[CH:18][CH:19]=[N:20][C:21]=3[C:22]([C:25]3[C:30]([F:31])=[C:29]([O:32][CH3:33])[CH:28]=[C:27]([O:34][CH3:35])[C:26]=3[F:36])=[CH:23][CH:24]=2)=[O:14])[NH:10][CH:11]=1)=O>C(Cl)Cl.CO>[CH3:2][N:3]([CH2:5][C:7]1[N:8]=[C:9]([NH:12][C:13]([C:15]2[C:16]3[N:17]=[CH:18][CH:19]=[N:20][C:21]=3[C:22]([C:25]3[C:30]([F:31])=[C:29]([O:32][CH3:33])[CH:28]=[C:27]([O:34][CH3:35])[C:26]=3[F:36])=[CH:23][CH:24]=2)=[O:14])[NH:10][CH:11]=1)[CH3:4]
Reactant: COc1cc(OC)c(F)c(-c2ccc(C(=O)Nc3nc(C=O)c[nH]3)c3nccnc23)c1F
Reactant: CNC
Agent: Cl
Solvent: CO
Solvent: ClCCl
Product: COc1cc(OC)c(F)c(-c2ccc(C(=O)Nc3nc(CN(C)C)c[nH]3)c3nccnc23)c1F

Procedure:
The title compound was prepared in analogy to the procedure described in Example 180 but using dimethylamine hydrochloride (1.5 equiv) instead of N,N,N′-trimethylethylenediamine and 8-(2,6-difluoro-3,5-dimethoxy-phenyl)-quinoxaline-5-carboxylic acid (4-formyl-1H-imidazol-2-yl)-amide (Example 7). Title compound: ES-MS: 469 [M+H]+; tR=3.14 min (System 1); TLC: Rf=0.22 (DCM/MeOH/NH3aq, 91.5:7.5:1).
Reaction SMILES: [F:1][C:2]1[CH:25]=[CH:24][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([C:13]3[N:18]=[C:17]([C:19]([OH:21])=[O:20])[CH:16]=[C:15]([CH:22]=[CH2:23])[N:14]=3)=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.[CH:26]1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.CO>ClCCl>[F:1][C:2]1[CH:25]=[CH:24][C:5]([O:6][C:7]2[CH:8]=[CH:9][C:10]([C:13]3[N:18]=[C:17]([C:19]([O:21][CH3:26])=[O:20])[CH:16]=[C:15]([CH:22]=[CH2:23])[N:14]=3)=[CH:11][CH:12]=2)=[CH:4][CH:3]=1
Reactant: C=Cc1cc(C(=O)O)nc(-c2ccc(Oc3ccc(F)cc3)cc2)n1
Reactant: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CO
Solvent: ClCCl
Product: C=Cc1cc(C(=O)OC)nc(-c2ccc(Oc3ccc(F)cc3)cc2)n1
Yield: 93.7 %

Procedure:
2-(4-(4-fluorophenoxy)phenyl)-6-vinylpyrimidine-4-carboxylic acid (23) (580 mg, 1.73 mmol), HOBt (279.5 mg, 2.07 mmol), and EDC (395.4 mg, 2.07 mmol) in dry dichloromethane were stirred for 20 minutes at room temperature and MeOH (3.46 mL, 86.5 mmol) was added thereto. After the reaction was complete, the solvent was removed in vacuo. The residue was dissolved in dichloromethane which was then washed with H2O. The organic layer was dried over anhydrous MgSO4 and concentrated to give oily residue. The resulting oil was purified by Combiflash (50% EtOAc in Hexanes) to give methyl 2-(4-(4-fluorophenoxy)phenyl)-6-vinylpyrimidine-4-carboxylate (24) (568 mg, 94% yield). 1H NMR (400 MHz, CD3OD): 8.45 (2H, d, J=8.5 Hz), 7.74 (1H, s), 6.90-7.01 (6H, m), 6.77-6.86 (1H, dd, J=11, 18 Hz), 6.60 (1H, d, J=17 Hz), 5.7 (1H, d, J=10.5 Hz), 3.98 (3H, s); LC/MS: m/z=351[M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH3:12])=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6](O)=[O:7].C1C=CC2N(O)N=[N:19]C=2C=1.N>C(Cl)Cl.CN(C=O)C>[CH3:1][O:2][C:3]1[C:4]([CH3:12])=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([NH2:19])=[O:7]
Reactant: On1nnc2ccccc21
Reactant: COc1cccc(C(=O)O)c1C
Agent: N
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1cccc(C(N)=O)c1C
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 58.5 %

Procedure:
3-Methoxy-2-methylbenzoic acid (5.0 g, 30 mmol) in CH2Cl2 (90 ml) and DMF (90 ml) was treated with HOBt (4.06 g, 30 mmol) and WSCDI (5.75 g, 30 mmol) and the resulting mixture stirred at RT for 20 min. After cooling to 0° C. ammonia (2H in EtOH, 30 ml, 60 mmol) was added and the mixture stirred for a further 2 h. The mixture was filtered, the solvent was removed from the filtrate. The crude material was taken up in CH2Cl2 and washed with water and brine and dried (Na2SO4), which gave a white solid (2.9 g) on isolation.
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]2[CH2:6][N:7]3[CH:14]=[CH:13][CH:12]=[C:8]3[C:9](=[O:11])[NH:10][C:4]=2[CH:3]=1.[Cl-:17].[Cl-].[Cl-].[Al+3].[OH-].[NH4+]>C(Cl)Cl>[Cl:17][C:13]1[CH:12]=[C:8]2[N:7]([CH:14]=1)[CH2:6][C:5]1[CH:15]=[CH:16][C:2]([Cl:1])=[CH:3][C:4]=1[NH:10][C:9]2=[O:11]
Reactant: O=C1Nc2cc(Cl)ccc2Cn2cccc21
Reactant: [Cl-]
Agent: [Al+3]
Agent: [NH4+]
Agent: [OH-]
Solvent: ClCCl
Product: O=C1Nc2cc(Cl)ccc2Cn2cc(Cl)cc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 2.33 g of 8-chloro-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-11-one in 50 mL of methylene chloride is added 5.33 g of aluminum trichloride. The reaction is stirred for 1 hour at room temperature and 0.77 mL (1.2 g) of methanesulfonyl chgloride is added. Stirring is then continued at room temperature overnight. The reaction mixture is basified with 10% ammonium hydroxide and the resulting solid collected by filtration. The solid is dissolved in methylene chloride, the solution is washed with water, dried over magnesium sulfate and evaporated to dryness to yield 2,8-dichloro-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]-benzodiazepin-11-one, which is used without further purification.
Reaction SMILES: [OH:1][CH2:2][C:3]1[NH:4][C:5]2[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=2[N:7]=1>C(O)C.O=[Mn]=O>[N:4]1[C:5]2[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=2[NH:7][C:3]=1[CH:2]=[O:1]
Reactant: OCc1nc2ccccc2[nH]1
Agent: O=[Mn]=O
Solvent: CCO
Product: O=Cc1nc2ccccc2[nH]1
Reaction time: 48 h

Procedure:
A mixture of 2-Hydroxymethyl-benzimidazole (11.9 g) and MnO2 (59.5 g) in ethanol (250 mL) was vigorously stirred for 2 days. The reaction was concentrated in vacuo, hot dimethylformamide was added and the mixture was filtered through celite. After removal of the solvent in vacuo the tan solid was triturated with ethanol to afford 2-Benzimidazolecarboxaldehyde as a tan powder.
Reaction SMILES: CN(C)C=O.[NH2:6][C:7]1[N:12]=[C:11]([N:13]2[C:22]3[C:17](=[CH:18][C:19]([F:25])=[C:20](F)[C:21]=3[Cl:23])[C:16](=[O:26])[C:15]([C:27]([OH:29])=[O:28])=[CH:14]2)[C:10]([Cl:30])=[CH:9][C:8]=1[F:31].Cl.Cl.[CH3:34][NH:35][CH:36]1[CH2:39][NH:38][CH2:37]1.CN1CCCC1=O>C(O)C>[NH2:6][C:7]1[N:12]=[C:11]([N:13]2[C:22]3[C:17](=[CH:18][C:19]([F:25])=[C:20]([N:38]4[CH2:39][CH:36]([NH:35][CH3:34])[CH2:37]4)[C:21]=3[Cl:23])[C:16](=[O:26])[C:15]([C:27]([OH:29])=[O:28])=[CH:14]2)[C:10]([Cl:30])=[CH:9][C:8]=1[F:31]
Reactant: Nc1nc(-n2cc(C(=O)O)c(=O)c3cc(F)c(F)c(Cl)c32)c(Cl)cc1F
Reactant: CNC1CNC1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CN1CCCC1=O
Solvent: CCO
Product: CNC1CN(c2c(F)cc3c(=O)c(C(=O)O)cn(-c4nc(N)c(F)cc4Cl)c3c2Cl)C1
Temperature: 85 °C
Reaction time: 0.5 h
Yield: 81.8 %

Procedure:
To 300 mg of N,N-dimethylformamide were added 103 mg of 1-(6-amino-3-chloro-5-fluoropyridin-2-yl)-8-chloro-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid, 85 mg of 3-methylaminoazetidine dihydrochloride, and 150 mg of N-methylpyrrolidone, and the mixture was stirred at 85° C. for 30 minutes. After adding 0.3 ml of ethanol, the mixture was allowed to cool, and the precipitate was collected by filtration and washed with ethanol and diisopropylether successively to obtain 98 mg of the title compound as a colorless powder.
Reaction SMILES: [OH-:1].[Na+].[CH2:3]([C:10]1[C:15](=[O:16])[N:14]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19](C(OC)=O)[C:18]=2C)[C:13]2[N:28]=[CH:29][CH:30]=[CH:31][C:12]=2[N:11]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Cl.[O:33]1[CH2:38][CH2:37]OCC1>CO>[CH2:3]([C:10]1[C:15](=[O:16])[N:14]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([CH2:37][C:38]([OH:33])=[O:1])[CH:18]=2)[C:13]2[N:28]=[CH:29][CH:30]=[CH:31][C:12]=2[N:11]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: COC(=O)c1cccc(-n2c(=O)c(Cc3ccccc3)nc3cccnc32)c1C
Reactant: C1COCCO1
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: O=C(O)Cc1cccc(-n2c(=O)c(Cc3ccccc3)nc3cccnc32)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1N aqueous solution of sodium hydroxide (2 ml) was added to a solution of 2-benzyl-4-(3-methoxycarbonyl-methylphenyl)-3-oxo-3,4-dihydropyrido[2,3-b]pyrazine (213 mg) in methanol (4 ml) and 1,4-dioxane (2 ml). After stirred at room temperature for 1 hour, the mixture was acidified with dilute hydrochloric acid and extracted with ethyl acetate. The organic phase was washed with water and brine, dried over magnesium sulfate and concentrated to give 2-benzyl-4-(3-carboxymethylphenyl)-3-oxo-3,4-dihydropyrido[2,3-b]pyrazine (163 mg) as powder.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH3:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[CH:20]=[CH:19][C:18]([C:21]([OH:23])=O)=[CH:17][C:16]=1[CH3:24].O[N:26]=[C:27]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[O:35][C:36]([F:39])([F:38])[F:37])[NH2:28].CCN(C(C)C)C(C)C>>[CH3:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[CH:20]=[CH:19][C:18]([C:21]2[O:23][N:28]=[C:27]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[O:35][C:36]([F:37])([F:38])[F:39])[N:26]=2)=[CH:17][C:16]=1[CH3:24]
Reactant: COc1ccccc1-c1ccc(C(=O)O)cc1C
Reactant: NC(=NO)c1ccccc1OC(F)(F)F
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccccc1-c1ccc(-c2nc(-c3ccccc3OC(F)(F)F)no2)cc1C

Procedure:
Oxalyl chloride (126 μL; 1.49 mmol; 3 eq.), Intermediate 26 (120 mg; 0.5 mmol; 1 eq.), Intermediate 2 (109 mg; 0.5 mmol, 1 eq.) and DIEA (256 μL; 1.49 mmol; 3 eq.) were reacted according to general procedure 2. Purification by column chromatography (c-hexane/ethyl acetate, 95/5) afforded the title compound as a yellow oil.
Reaction SMILES: C([NH:4][N:5]1[CH2:10][C:9]([CH3:11])=[N:8][NH:7][C:6]1=[O:12])(=O)C.Cl.O.[OH-].[Na+]>CO>[NH2:4][N:5]1[CH2:10][C:9]([CH3:11])=[N:8][NH:7][C:6]1=[O:12]
Reactant: CC(=O)NN1CC(C)=NNC1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC1=NNC(=O)N(N)C1
Temperature: 5 °C

Procedure:
85 g of 4-acetylamino-6-methyl-3-oxo-2,3,4,5-tetrahydro-1,2,4-triazine in 250 ml of methanol are stirred together with 63 ml of hydrochloric acid (37%) for 4 hours at 50° C. After cooling to 5° C., 250 ml of icecold water and 125 ml of sodium hydroxide solution (50%) are added. The solvent is removed by evaporation in vacuo. The residue is taken up in 100 ml of ethanol, and the solvent is removed again in vacuo. The residue is taken up in 1200 ml of acetonitrile, undissolved salt precipitates are removed by filtration, the filtrate is concentrated to a small volume, the residue is caused to crystallize by adding 100 ml of acetic acid ethyl ester at 0° C., and the colorless crystals are filtered off and dried yielding 60.4 g (92% of the theoretical amount) of the title compound having a melting point of 118°-120° C.