Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:7]=[C:8]([C:14]3[O:15][CH:16]=[C:17]([CH2:19][NH2:20])[N:18]=3)[CH:9]=[CH:10][C:11]=2[O:12][CH3:13])[CH2:3][CH2:2]1.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.[CH3:43][C:44]1[C:45]([C:50](O)=[O:51])=[N:46][CH:47]=[CH:48][CH:49]=1>CC(C)=O.O>[CH:1]1([CH2:4][O:5][C:6]2[CH:7]=[C:8]([C:14]3[O:15][CH:16]=[C:17]([CH2:19][NH:20][C:50](=[O:51])[C:45]4[C:44]([CH3:43])=[CH:49][CH:48]=[CH:47][N:46]=4)[N:18]=3)[CH:9]=[CH:10][C:11]=2[O:12][CH3:13])[CH2:3][CH2:2]1
Reactant: COc1ccc(-c2nc(CN)co2)cc1OCC1CC1
Reactant: Cc1cccnc1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CC(C)=O
Solvent: O
Product: COc1ccc(-c2nc(CNC(=O)c3ncccc3C)co2)cc1OCC1CC1

Procedure:
A 0.2 g quantity of the [2-(3-cyclopropylmethoxy-4-methoxyphenyl)oxazol-4-yl]methylamine obtained in Reference Example 13 was suspended in 4 ml of acetone. To the obtained suspension were added 0.2 g of 1-hydroxybenzotriazole, 0.29 g of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride and 0.14 g of 3-methylpicolinic acid, and the mixture was heated and refluxed for 30 minutes. The reaction mixture was cooled, water was then added thereto, and extraction was performed with ethyl acetate. The organic layer was washed with water twice, and the solvent was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=1:1) to give 0.16 g of white powdery N-[2-(3-cyclopropylmethoxy-4-methoxyphenyl)oxazol-4-ylmethyl]-3-methylpicolinamide.
Reaction SMILES: [OH:1][C@@H:2]([CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:3](O)=[O:4].B.C1COCC1>C1COCC1>[C:7]1([CH2:6][C@H:2]([OH:1])[CH2:3][OH:4])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: O=C(O)[C@@H](O)Cc1ccccc1
Agent: B
Solvent: C1CCOC1
Product: OC[C@@H](O)Cc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.5 %

Procedure:
To a solution of (S)-2-hydroxy-3-phenylpropanoic acid (4.98 g, 30.0 mmol) in 100 mL of anhydrous THF was added slowly BH3.THF complex (90 mL, 1M in THF, 3.0 equiv.) with ice cooling under N2. The solution was stirred overnight at room temperature, and the reaction was quenched with water (Caution, copious H2 evolution). After evaporation of the solvent, the residue was diluted with water and extracted with EtOAc (3×50 mL). The combined organic layers were dried over Na2SO4 and concentrated to afford (S)-3-phenylpropane-1,2-diol (4.13 g, 91%) as a colorless oil. LC-MS (ESI) m/z 153 (M+H+).
Reaction SMILES: [F:1][C:2]([F:45])([F:44])[C:3]1[CH:4]=[C:5]([CH:37]=[C:38]([C:40]([F:43])([F:42])[F:41])[CH:39]=1)[CH2:6][N:7]([CH2:15][C:16]1[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[CH:18][C:17]=1[C:26]1[CH:31]=[C:30]([CH:32]([CH3:34])[CH3:33])[CH:29]=[CH:28][C:27]=1[O:35][CH3:36])[C:8]1[N:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1.[H-].[Na+].Br[CH2:49][CH2:50][CH2:51][C:52]([O:54][CH2:55][CH3:56])=[O:53].O>CN(C)C=O>[F:42][C:40]([F:43])([F:41])[C:38]1[CH:37]=[C:5]([CH:4]=[C:3]([C:2]([F:1])([F:44])[F:45])[CH:39]=1)[CH2:6][N:7]([CH2:15][C:16]1[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[CH:18][C:17]=1[C:26]1[CH:31]=[C:30]([CH:32]([CH3:33])[CH3:34])[CH:29]=[CH:28][C:27]=1[O:35][CH3:36])[C:8]1[N:13]=[CH:12][C:11]([O:14][CH2:49][CH2:50][CH2:51][C:52]([O:54][CH2:55][CH3:56])=[O:53])=[CH:10][CH:9]=1
Reactant: CCOC(=O)CCCBr
Reactant: COc1ccc(C(C)C)cc1-c1ccc(C(F)(F)F)cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ccc(O)cn1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CCCOc1ccc(N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)Cc2cc(C(F)(F)F)ccc2-c2cc(C(C)C)ccc2OC)nc1
Reaction time: 0.08 h

Procedure:
6-[(3,5-Bis-trifluoromethyl-benzyl)-(5′-isopropyl-2′-methoxy-4-trifluoromethyl-biphenyl-2-ylmethyl)-amino]-pyridin-3-ol (141 mg) is dissolved in N,N-dimethylformamide (1 ml), and thereto is added 60% sodium hydride (10 mg) under ice-cooling and the mixture is stirred for 5 minutes and thereto is added ethyl 4-bromobutyrate (48 μl), and the mixture is stirred at room temperature for 1 hour. To the reaction solution is added water under ice-cooling, and the mixture is extracted with methylene chloride, and the organic layer is concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (hexane:ethyl acetate=19:1→4:1) to give ethyl 4-{6-[(3,5-bis-trifluoromethyl-benzyl)-(5′-isopropyl-2′-methoxy-4-trifluoromethyl-biphenyl-2-ylmethyl)-amino]-pyridin-3-yloxy}-butyrate (154.1 mg). MS (m/z): 757 [M+H]+
Reaction SMILES: [CH3:1][N:2]1[C:6]2=[N:7][C:8]([CH2:20][N:21]3[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]3)=[CH:9][C:10]([C:11]3[CH:16]=[CH:15][C:14]([N+:17]([O-])=O)=[CH:13][CH:12]=3)=[C:5]2[CH:4]=[N:3]1.O.O.Cl[Sn]Cl.N>CCO>[CH3:1][N:2]1[C:6]2=[N:7][C:8]([CH2:20][N:21]3[CH2:22][CH2:23][N:24]([CH3:27])[CH2:25][CH2:26]3)=[CH:9][C:10]([C:11]3[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=3)=[C:5]2[CH:4]=[N:3]1
Reactant: CN1CCN(Cc2cc(-c3ccc([N+](=O)[O-])cc3)c3cnn(C)c3n2)CC1
Agent: Cl[Sn]Cl
Agent: N
Solvent: CCO
Solvent: O
Product: CN1CCN(Cc2cc(-c3ccc(N)cc3)c3cnn(C)c3n2)CC1
Yield: 68.2 %

Procedure:
In analogy to GP3, 1.06 g of 1-methyl-6-(4-methyl-piperazin-1-ylmethyl)-4-(4-nitrophenyl)-1H-pyrazolo[3,4-b]pyridine (Intermediate 17.8; 2.89 mmol, 1 eq.) were dissolved in 15 mL EtOH, treated with 3.26 g SnCl2.2H2O (14.46 mmol, 5 eq.) and stirred at reflux for 2 h. The reaction was poured into conc. NH3, partitioned between CH2Cl2 and water, the aqueous layer was re-extracted, the combined organic layers were dried and concentrated in vacuo to yield 663 mg of the crude aniline (1.97 mmol, 68% yield).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[N:9]([C:13]3[N:22]=[CH:21][C:20]4[N:19]([CH3:23])[C:18](=[O:24])[C@:17]5([CH2:28][CH3:29])[CH2:25][CH2:26][CH2:27][N:16]5[C:15]=4[N:14]=3)[CH:10]=[CH:11][N:12]=2)[CH:5]=[CH:6][CH:7]=1.[NH:30]1[CH:34]=[N:33][CH:32]=[N:31]1.CNC1CCCCC1NC.C([O-])([O-])=O.[Cs+].[Cs+]>CC(N(C)C)=O.C(Cl)Cl.[Cu](I)I>[N:30]1([C:2]2[CH:3]=[C:4]([C:8]3[N:9]([C:13]4[N:22]=[CH:21][C:20]5[N:19]([CH3:23])[C:18](=[O:24])[C@:17]6([CH2:28][CH3:29])[CH2:25][CH2:26][CH2:27][N:16]6[C:15]=5[N:14]=4)[CH:10]=[CH:11][N:12]=3)[CH:5]=[CH:6][CH:7]=2)[CH:34]=[N:33][CH:32]=[N:31]1
Reactant: c1nc[nH]n1
Reactant: CC[C@@]12CCCN1c1nc(-n3ccnc3-c3cccc(Br)c3)ncc1N(C)C2=O
Agent: I[Cu]I
Agent: CNC1CCCCC1NC
Agent: O=C([O-])[O-]
Solvent: CC(=O)N(C)C
Solvent: ClCCl
Product: CC[C@@]12CCCN1c1nc(-n3ccnc3-c3cccc(-n4cncn4)c3)ncc1N(C)C2=O
Yield: 23 %

Procedure:
(S)-2-(2-(3-bromophenyl)-1H-imidazol-1-yl)-6a-ethyl-5-methyl-6a,7,8,9-tetrahydropyrrolo[2,1-h]pteridin-6(5H)-one (Example 252, 0.118 mmol, 0.050 g) was added to a solution of 1,2,4-triazole (0.593 mmol, 0.041 g), copper iodide (0.007 mmol, 0.001 g), N1,N2-dimethylcyclohexane-1,2-diamine (0.023 mmol, 0.003 g), and Cs2CO3 (0.593 mmol, 0.193 g) in 1 mL of DMA. The reaction mixture was microwaved at 185° C. for 1 h. The reaction mixture was diluted with 15 mL of DCM, washed with 5 mL of water, dried with Na2SO4, filtered and concentrated. The resulting residue was purified by reverse phase HPLC to give the title compound as a white solid (0.012 g, 23%); 1H NMR (400 MHz, CDCl3) δ: 8.83 (s, 1H), 8.12 (m, 2H), 7.95 (s, 1H), 7.90 (m, 1H), 7.69 (s, 1H), 7.60 (m, 3H), 3.37 (m, 4H), 3.20 (m, 1H), 2.35 (m, 1H), 2.26 (m, 3H), 2.00 (m, 2H), 1.77 (m, 1H), 1.62 (m, 1H), 0.78 (t, J=7.4 Hz, 3H); LCMS: 442.3 m/z (M+H)+; ret. Time: 4.722 min (Analytical Method C).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2.[H-].[Na+].[Si:13](Cl)([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14].C(OCC)(=O)C>CN(C)C=O>[Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][N:6]2[Si:13]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: Brc1cccc2[nH]ccc12
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)n1ccc2c(Br)cccc21
Temperature: -10 °C
Reaction time: 0.5 h
Yield: 66.7 %

Procedure:
A solution of 4-bromo-1H-indole (36 g) in dimethylformamide (80 mL) was treated with a suspension of NaH (60% in mineraloil, 6.9 g) in dimethylformamide (200 mL) at 20° C. After stirring for 30 min the mixture was cooled to −10° C. an treated portionwise with t-butyldimethylsilyl chloride (38 g) followed by stirring for 1 h at room temperature. Standard work-up with ethyl acetate gave and oil which was purified by flash chromatography giving 4-bromo-1-(t-butyldimethylsilyl)-1H-indole (38 g) as a crystalline material.
Reaction SMILES: [CH3:1][N:2]1[CH2:15][CH2:14][C:5]2[NH:6][C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.N1CCC[C@H]1C(O)=O.P([O-])([O-])([O-])=O.[K+].[K+].[K+].Br[CH:33]=[C:34]([C:36]1[CH:41]=[CH:40][C:39]([F:42])=[C:38]([F:43])[CH:37]=1)[CH3:35]>CN(C=O)C.[Cu]I>[F:43][C:38]1[CH:37]=[C:36](/[C:34](/[CH3:35])=[CH:33]/[N:6]2[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]3[CH2:3][N:2]([CH3:1])[CH2:15][CH2:14][C:5]2=3)[CH:41]=[CH:40][C:39]=1[F:42]
Reactant: CC(=CBr)c1ccc(F)c(F)c1
Reactant: Cc1ccc2[nH]c3c(c2c1)CN(C)CC3
Agent: [Cu]I
Agent: O=C(O)[C@@H]1CCCN1
Agent: O=P([O-])([O-])[O-]
Solvent: CN(C)C=O
Product: C/C(=C\n1c2c(c3cc(C)ccc31)CN(C)CC2)c1ccc(F)c(F)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
2,8-Dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (72 mg, 0.36 mmol) was dissolved in DMF (5 mL). Copper (I) iodide (7 mg, 0.036 mmol), L-proline (8 mg, 0.072 mmol) and potassium phosphate (153 mg, 0.72 mmol) were added and the reaction mixture was stirred for 10 min. at RT. 4-(1-Bromoprop-1-en-2-yl)-1,2-difluorobenzene (100 mg, 0.43 mmol) was added dropwise and the reaction mixture was purged with nitrogen. The reaction mixture was heated overnight at 80° C. (prolonged heating in some cases was required). DMF was evaporated under reduced pressure, the residue was diluted with water and the solid was filtered. The solid material was purified by silica gel chromatography (100-200 mesh). Yield: 110 mg. 1H NMR (DMSO-d6, oxalate salt) δ (ppm): 7.80 (m, 1H), 7.50 (d, 2H), 7.30 (s, 1H), 7.20 (s, 1H), 7.10 (d, 1H), 7.0 (d, 1H), 4.36 (m, 2H), 3.60 (m, 2H), 3.0 (m, 2H), 2.90 (s, 3H), 2.40 (s, 3H), 1.90 (s, 3H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][N:12]=[C:13]=[O:14])=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:15][C:16]1[C:17](=[O:23])[NH:18][C:19](=[O:22])[NH:20][CH:21]=1>CN(C)C(=O)C.C(OCC)(=O)C>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][NH:12][C:13]([N:20]1[CH:21]=[C:16]([F:15])[C:17](=[O:23])[NH:18][C:19]1=[O:22])=[O:14])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCCCN=C=O
Reactant: O=c1[nH]cc(F)c(=O)[nH]1
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NCCCNC(=O)n1cc(F)c(=O)[nH]c1=O
Reaction time: 3 h

Procedure:
To the above solution of 3-t-butoxycarbonylaminopropyl isocyanate was added a solution of 5-fluorouracil (2.60 g.) in N,N-dimethylacetamide (20 ml.) at 80° C. and stirred for further 3 hours at the same temperature. The resultant mixture was diluted with ethyl acetate (200 ml.), washed with water (each 30 ml., 3 times), dried over magnesium sulfate, treated with activated charcoal, filtered and evaporated in vacuo. The residue was recrystallized from ethyl acetate to give 1-[N-(3-t-butoxycarbonylaminopropyl)carbamoyl]-5-fluorouracil.
Reaction SMILES: C(N(C(C)C)CC)(C)C.[N:10]1[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][NH:18][CH2:19][CH2:20][C:21]2[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=2)=[CH:12][CH:11]=1.[C:27]([C:30]1[CH:31]=[CH:32][C:33]2[NH:39][CH:38]([CH2:40][C:41]([O:43][CH3:44])=[O:42])[C:37](=[O:45])[N:36]([CH3:46])[CH2:35][C:34]=2[CH:47]=1)(O)=[O:28].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.O.C([O-])(O)=O.[Na+]>CN(C=O)C>[N:10]1[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][N:18]([CH2:19][CH2:20][C:21]2[CH:22]=[CH:23][N:24]=[CH:25][CH:26]=2)[C:27]([C:30]2[CH:31]=[CH:32][C:33]3[NH:39][CH:38]([CH2:40][C:41]([O:43][CH3:44])=[O:42])[C:37](=[O:45])[N:36]([CH3:46])[CH2:35][C:34]=3[CH:47]=2)=[O:28])=[CH:12][CH:11]=1
Reactant: COC(=O)CC1Nc2ccc(C(=O)O)cc2CN(C)C1=O
Reactant: c1cc(CCNCCc2ccncc2)ccn1
Agent: O=C([O-])O
Agent: On1nnc2ccccc21
Agent: [Na+]
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)CC1Nc2ccc(C(=O)N(CCc3ccncc3)CCc3ccncc3)cc2CN(C)C1=O
Temperature: 25 °C
Reaction time: 19.5 h
Yield: 93 %

Procedure:
Diisopropylethylamine (0.35 g, 2.7 mmole) was added in one portion to a stirred mixture of bis [2-(4-pyridyl)ethyl]amine (0.37 g, 1.65 mmole), methyl (±)-7-carboxy-4-methyl-3-oxo-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine-2-acetate (0.44 g, 1.50 mmole), EDC (0.34 g, 1.8 mmole), and HOBT . H2O (0.24 g, 1.8 mmole) in DMF (8 mL) at 0° C. under argon, and the reaction was allowed to warm to RT. After 19.5 h, the reaction was poured into a mixture of ice water (100 g) and 5% NaHCO3 (10 mL) and extracted with CH2Cl2 (2×100 mL). The combined organic layers were washed with 5% NaHCO3 (50 mL), dried (MgSO4), and concentrated. Chromatography on silica gel (7% MeOH/CH2Cl2) gave the title compound (0.7 g, 88%). MS (ES) m/e 502.4 (M+H)+. c) (±)-7-[[Bis[2-(4-pyridinyl)ethyl]amino]carbonyl]-4-methyl-3-oxo-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine-2-acetic acid
Reaction SMILES: [Cl:1][C:2]1[CH:33]=[CH:32][C:5]([C:6]([N:8]2[CH2:12][CH2:11][C@@H:10]([NH:13][C:14]3[N:19]=[CH:18][C:17](/[CH:20]=[CH:21]/[C:22]([NH:24][O:25]C4CCCCO4)=[O:23])=[CH:16][CH:15]=3)[CH2:9]2)=[O:7])=[CH:4][CH:3]=1.CO.Cl>CO.CCOC(C)=O>[ClH:1].[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([N:8]2[CH2:12][CH2:11][C@@H:10]([NH:13][C:14]3[N:19]=[CH:18][C:17](/[CH:20]=[CH:21]/[C:22]([NH:24][OH:25])=[O:23])=[CH:16][CH:15]=3)[CH2:9]2)=[O:7])=[CH:32][CH:33]=1
Reactant: O=C(/C=C/c1ccc(N[C@@H]2CCN(C(=O)c3ccc(Cl)cc3)C2)nc1)NOC1CCCCO1
Agent: Cl
Solvent: CO
Solvent: CCOC(C)=O
Product: O=C(/C=C/c1ccc(N[C@@H]2CCN(C(=O)c3ccc(Cl)cc3)C2)nc1)NO
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 138.9 %

Procedure:
To a solution of (2E)-3-(6-{[(3R)-1-(4-chlorobenzoyl)-3-pyrrolidinyl]amino}-3-pyridyl)-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide (1.89 g) in MeOH (32 mL) was added hydrogen chloride methanol reagent 10 (8.0 mL, Tokyo Kasei), and the mixture was stirred at ambient temperature for 0.5 hour. The reaction mixture was diluted with AcOEt and the precipitate was collected with filtration to give (2E)-3-(6-{[(3R)-1-(4-chlorobenzoyl)-3-pyrrolidinyl]amino}-3-pyridyl)-N-hydroxyacrylamide hydrochloride (1.18 g) as colorless powder.
Reaction SMILES: [C:1]([CH2:3][C:4](=O)[C:5]([O:7][CH2:8][CH3:9])=[O:6])#[N:2].[F:11][C:12]1[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=1[CH2:14][NH:15][NH2:16]>O1CCOCC1>[NH2:2][C:1]1[N:15]([CH2:14][C:13]2[CH:17]=[CH:18][CH:19]=[CH:20][C:12]=2[F:11])[N:16]=[C:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH:3]=1
Reactant: CCOC(=O)C(=O)CC#N
Reactant: NNCc1ccccc1F
Solvent: C1COCCO1
Product: CCOC(=O)c1cc(N)n(Cc2ccccc2F)n1

Procedure:
The compound of the formula (II) is obtainable in a multi-stage synthesis from the sodium salts of ethyl cyanopyruvate, which is known from the literature (Borsche and Manteuffel, Liebigs. Ann. Chem. 1934, 512, 97). By reaction thereof with 2-fluorobenzylhydrazine with heating and under a protective gas atmosphere in an inert solvent such as dioxane, ethyl 5-amino-1-(2-fluorobenzyl)pyrazole-3-carboxylate is obtained, which cyclizes by means of reaction with dimethylaminoacrolein in the acidic medium under a protective gas atmosphere and with heating to give the corresponding pyridine derivative. This pyridine derivative, ethyl 1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridine-3-carboxylate, is converted by means of a multi-stage sequence, consisting of conversion of the ester into the corresponding amide using ammonia, dehydration using a dehydrating agent such as trifluoroacetic anhydride to give the corresponding nitrite derivative, reaction of the nitrile derivative with sodium ethoxide and final reaction with ammonium chloride, into the compound of the formula (II).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:11]=[CH:12][C:13](=[O:16])[NH:14][CH:15]=2)=[CH:6][CH:5]=1)([OH:3])=[O:2].Cl.[CH3:18]O>>[CH3:18][O:2][C:1]([C:4]1[CH:5]=[CH:6][C:7]([C:10]2[N:11]=[CH:12][C:13](=[O:16])[NH:14][CH:15]=2)=[CH:8][CH:9]=1)=[O:3]
Reactant: O=C(O)c1ccc(-c2c[nH]c(=O)cn2)cc1
Reactant: CO
Agent: Cl
Product: COC(=O)c1ccc(-c2c[nH]c(=O)cn2)cc1

Procedure:
A mixture of 5-(4-carboxyphenyl)pyrazin-2(1H)-one (1.2 g) and anhydrous methanol was stirred with heating under reflux while a gentle steam of dry hydrogen chloride gas was passed through the solution. After two hours the solvent was evaporated under reduced pressure and the residue was purified by elution from a silica gel column with chloroform/methanol mixtures followed by crystallisation from methanol. This afforded the title compound as a crystalline solid (0.8 g); m.p. 240°-242° C.
Reaction SMILES: C(=O)([O-])[O-:2].[Na+].[Na+].[CH2:7]([OH:16])/[CH:8]=[CH:9]/[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(OO)(=O)C.S([O-])([O-])=O.[Na+].[Na+]>O.C(Cl)Cl>[O:2]1[CH:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:8]1[CH2:7][OH:16]
Reactant: OC/C=C/c1ccccc1
Reactant: O=C([O-])[O-]
Agent: CC(=O)OO
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: OCC1OC1c1ccccc1
Temperature: 17.5 °C
Reaction time: 2.5 h

Procedure:
Sodium carbonate (224 g) and trans-cinnamyl alcohol (200.0 g) were mixed with 2 L of methylene chloride, a slow nitrogen sweep was maintained through the vapor space of the flask and the mixture was cooled to 15-20° C. with a cold water bath. Peracetic acid solution (35%, 381.2 mL) was added over a 3 hour period, maintaining the internal temperature below 25° C. After the peracetic acid addition was complete, the mixture was stirred for 2-3 hours until complete, as shown by HPLC analysis. The mixture was cooled to 10° C. with an ice bath, and a solution of sodium sulfite (160 g) in 1200 ml water was added slowly over 90 minutes, keeping the temperature below 30° C. The phases were separated and the aqueous phase was extracted with methylene chloride (200 mL) to give a solution of the title compound.
Reaction SMILES: [CH3:1][O-:2].[Na+].[Na].[NH2:5][CH:6]1[CH:10]([CH3:11])[CH2:9][N:8]([C:12]2[C:21](F)=[C:20]3[C:15]([C:16](=[O:29])[C:17]([C:26]([OH:28])=[O:27])=[CH:18][N:19]3[CH:23]3[CH2:25][CH2:24]3)=[CH:14][C:13]=2[F:30])[CH2:7]1>CO>[NH2:5][CH:6]1[CH:10]([CH3:11])[CH2:9][N:8]([C:12]2[C:21]([O:2][CH3:1])=[C:20]3[C:15]([C:16](=[O:29])[C:17]([C:26]([OH:28])=[O:27])=[CH:18][N:19]3[CH:23]3[CH2:24][CH2:25]3)=[CH:14][C:13]=2[F:30])[CH2:7]1
Reactant: CC1CN(c2c(F)cc3c(=O)c(C(=O)O)cn(C4CC4)c3c2F)CC1N
Reactant: C[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CO
Product: COc1c(N2CC(C)C(N)C2)c(F)cc2c(=O)c(C(=O)O)cn(C3CC3)c12
Reaction time: 86 h

Procedure:
To a solution of sodium methoxide prepare from sodium (50 mg) and absolute methanol (3 ml) was added 7-(3-amino-4-methyl-1-pyrrolidinyl)-1-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid (80 mg) and the mixture in sealed tube was stirred for 86 hours at 140° to 150° C. and then concentrated. Small amount of water was added to the residue, and the solution was adjusted pH 7 with acetic acid and concentrated. The resulting residue was purified by silica gel column chromatography eluting with chloroform-methanol-concentrated aqueous ammonia (20:6:1) and recrystallized from a solution of dichloromethanemethanol (1:1) to give the title compound (9 mg) as pale yellow prisms, mp 191.5°-193.5° C.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[N:7]1[S:8][N:9]=[C:10]2[CH:15]=[C:14]([C:16](OC)=[O:17])[CH:13]=[CH:12][C:11]=12.C(C(C(C([O-])=O)O)O)([O-])=O.[Na+].[K+]>C(OCC)C.C(OCC)(=O)C>[N:7]1[S:8][N:9]=[C:10]2[CH:15]=[C:14]([CH2:16][OH:17])[CH:13]=[CH:12][C:11]=12
Reactant: COC(=O)c1ccc2nsnc2c1
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: OCc1ccc2nsnc2c1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 46.3 %

Procedure:
To a suspension of lithium aluminum hydride (215 mg, 5.7 mmol) in diethyl ether (15 mL) at 0° C. was added methyl 2,1,3-benzothiadiazole-5-carboxylate (1.0 g, 5.2 mmol) in one portion. The reaction mixture was allowed to stir at 0° C. for 10 min, then at room temperature for 24 h. Ethyl acetate (30 mL) was added very slowly dropwise at 0° C. The reaction mixture was then added slowly to an aqueous solution of potassium sodium tartrate (30% w/v; 100 mL) and stirred for 2 h. The reaction mixture was diluted with 100 mL of ethyl acetate and the layers were separated. The aqueous layer was re-extracted with ethyl acetate (1×100 mL). The combined organic layers were dried (MgSO4), filtered and evaporated under reduced pressure. The crude product was purified by flash chromatography (silica gel, 25% ethyl acetate in petroleum ether) to give 2,1,3-benzothiadiazole-5-methanol (400 mg, 47% yield) as an orange solid.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([N:18]3[CH2:22][CH2:21][CH2:20][CH:19]3[CH2:23][O:24][CH3:25])[CH:13]=2)[C:5]2[N:10]=[CH:9][S:8][C:6]=2[N:7]=1.CC1(C)C(C)(C)OB([C:34]2[CH:35]=[C:36]([CH:41]=[CH:42][CH:43]=2)[C:37]([O:39][CH3:40])=[O:38])O1.C([O-])([O-])=O.[Na+].[Na+]>O.O1CCOCC1.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>[CH3:25][O:24][CH2:23][CH:19]1[CH2:20][CH2:21][CH2:22][N:18]1[C:14]1[CH:13]=[C:12]([NH:11][C:4]2[C:5]3[N:10]=[CH:9][S:8][C:6]=3[N:7]=[C:2]([C:34]3[CH:35]=[C:36]([CH:41]=[CH:42][CH:43]=3)[C:37]([O:39][CH3:40])=[O:38])[N:3]=2)[CH:17]=[CH:16][CH:15]=1
Reactant: COCC1CCCN1c1cccc(Nc2nc(Cl)nc3scnc23)c1
Reactant: COC(=O)c1cccc(B2OC(C)(C)C(C)(C)O2)c1
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: C1COCCO1
Product: COCC1CCCN1c1cccc(Nc2nc(-c3cccc(C(=O)OC)c3)nc3scnc23)c1
Yield: 59.5 %

Procedure:
Under N2 atmosphere, 5-chloro-N-(3-(2-(methoxymethyl)pyrrolidin-1-yl)phenyl)thiazolo[5,4-d]pyrimidin-7-amine (200 mg, 0.53 mmol), methyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (153 mg, 0.58 mmol), Pd(PPh3)4 (40 mg, 0.035 mmol) and Na2CO3 (112 mg, 1.06 mmol) in 5 mL of water was added in 30 mL of 1,4-dioxane. The mixture was stirred at reflux for 18 hours. The solvent was removed under reduce pressure and the residue was purified by silica gel chromatography, eluting with petroleum ether and ethyl acetate (3:1) to give methyl 3-(7-(3-(2-(methoxymethyl)pyrrolidin-1-yl)phenylamino)thiazolo[5,4-d]pyrimidin-5-yl)benzoate (150 mg, 59%) as a yellow sold. 1H NMR (300 MHz, CDCl3): δ 9.13 (s, 1H), 8.82 (s, 1H), 8.68 (d, 1H, J=7.8 Hz), 8.14 (d, 1H, J=7.8 Hz), 8.06 (s, 1H), 7.54 (t, 1H, J=7.8 Hz), 7.35 (s, 1H), 7.28 (t, 1H, J=7.2 Hz), 7.16 (d, 1H, J=7.8 Hz), 6.49 (d, 1H, J=7.5 Hz), 3.96 (brs, 4H), 3.57-3.50 (brs, 2H), 3.32 (s, 3H), 3.25-3.19 (m, 2H), 2.11-2.02 (m, 5H). LC-MS: 476 [M+H]+, tR=1.93 min. HPLC: 98.15% at 214 nm, 97.85% at 254 nm, tR=5.24 min.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]([N:12]2[CH:16]=[N:15][N:14]=[N:13]2)=[CH:8][C:3]=1[C:4]([O:6]C)=[O:5].O.[OH-].[Li+]>O1CCCC1.O.C(OCC)C>[CH3:1][C:2]1[CH:11]=[CH:10][C:9]([N:12]2[CH:16]=[N:15][N:14]=[N:13]2)=[CH:8][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: COC(=O)c1cc(-n2cnnn2)ccc1C
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOCC
Product: Cc1ccc(-n2cnnn2)cc1C(=O)O
Reaction time: 2 h

Procedure:
Combine methyl 2-methyl-5-(1H-tetrazol-1-yl)benzoate (5.2 g, 23.9 mmol) and lithium hydroxide hydrate (2.0 g, 47.7 mmol) in tetrahydrofuran/water (50 mL/50 mL). Heat to reflux. After 2 hours, dilute with diethyl ether and separate the layers. Extract the aqueous layer three times with diethyl ether. Extract the combined diethyl ether layers three times with a 1M sodium hydroxide solution (20 mL). Combine the aqueous layers, acidify with a 1M aqueous hydrochloric acid solution (pH about 1) to give a solid. Collect the solid by filtration and recrystallize form water to give the title compound.