Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]([NH:4][C:5](=[O:9])[O:6][CH2:7][CH3:8])[CH3:3].[Cl-].[S:11](Cl)[Cl:12]>N1C=CC=CC=1>[Cl:12][S:11][N:4]([CH:2]([CH3:3])[CH3:1])[C:5](=[O:9])[O:6][CH2:7][CH3:8]
Reactant: CCOC(=O)NC(C)C
Reactant: ClSCl
Agent: [Cl-]
Solvent: c1ccncc1
Product: CCOC(=O)N(SCl)C(C)C
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 63.2 %

Procedure:
To a solution of ethyl (1-methylethyl)carbamate (13.1 g, 0.1 mol) in 100 mlmethylene chloride cooled to 0° C. was added sulfur dichloride (11.3g, 0.11 mol) in one portion. While maintaining the temperature of the mixture at 0° C., pyridine (8.7 g, 0.11 mol) was added dropwise over eleven minutes. After complete addition of the pyridine the temperature was allowed to rise to room temperature and stirring was continued for additional 1.5 hours. The mixture was let stand overnight. Methylene chloride was evaporated under vacuum and 100 ml hexane was added. Filteration of the pyridine hydrochloride and evaporation of hexaneresulted in an orange oil which was distilled in a Kugelrohr apparatus to give 12.5 g of the title compound Bp: 64°-80° (bath temperature) at 1.4 mm Hg.
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]([OH:20])=[O:19].[O-2].[Zn+2:22].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O>[C:18]([O-:20])(=[O:19])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]/[CH:10]=[CH:9]\[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH3:1].[Zn+2:22].[C:18]([O-:20])(=[O:19])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]/[CH:10]=[CH:9]\[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH3:1]
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)O
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [O-2]
Agent: [Zn+2]
Solvent: O
Product: CCCCCCCC/C=C\CCCCCCCC(=O)[O-]
Temperature: 60 °C
Reaction time: 0.17 h

Procedure:
A quantity of 35 grams of Pamolyn 100, a high purity oleic acid containing about 90% oleic acid, was added gradually to a stirred slurry of zinc oxide (5.4 grams), citric acid (0.05 gram), Witconate 90 (1.18 grams), and water (60 grams) at 65° C. The mixture was stirred at 55-65° C. for 10 minutes to give a quantitative yield of zinc oleate as indicated by the infrared spectrum of the dried product.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]([C:8]2[C:9]([F:19])=[C:10]([OH:18])[C:11]([CH:14]3[CH2:17][CH2:16][CH2:15]3)=[CH:12][CH:13]=2)=[N:6][CH:7]=1.Cl[C:21]1[N:26]=[C:25]([CH3:27])[CH:24]=[CH:23][N:22]=1.C([O-])([O-])=O.[K+].[K+]>CS(C)=O>[CH:14]1([C:11]2[CH:12]=[CH:13][C:8]([C:5]3[N:6]=[CH:7][C:2]([NH2:1])=[N:3][CH:4]=3)=[C:9]([F:19])[C:10]=2[O:18][C:21]2[N:26]=[C:25]([CH3:27])[CH:24]=[CH:23][N:22]=2)[CH2:15][CH2:16][CH2:17]1
Reactant: Cc1ccnc(Cl)n1
Reactant: Nc1cnc(-c2ccc(C3CCC3)c(O)c2F)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: Cc1ccnc(Oc2c(C3CCC3)ccc(-c3cnc(N)cn3)c2F)n1
Temperature: 100 °C
Yield: 44.5 %

Procedure:
A suspension of 3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenol (25 mg, 0.096 mmol), 2-chloro-4-methylpyrimidine (14 mg, 0.11 mmol), and K2CO3 (27 mg, 0.19 mmol) in DMSO (2 mL) was heated at 100° Celsius for 16 hours. The reaction was then cooled to room temperature, filtered, and the filtrate directly subjected to HPLC purification to give 5-{4-cyclobutyl-2-fluoro-3-[(4-methylpyrimidin-2-yl)oxy]phenyl}pyrazin-2-amine (15 mg, 45%). MS (ESI): mass calcd. for C19H18FN5O, 351.15; m/z found, 352.1 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 8.37-8.33 (m, 1H), 8.26 (d, J=1.9, 2H), 7.81-7.75 (m, 1H), 7.26 (d, J=8.3, 1H), 7.00-6.97 (m, 1H), 3.75-3.63 (m, 1H), 2.52 (d, J=2.0, 3H), 2.27-2.09 (m, 4H), 2.04-1.92 (m, 1H), 1.87-1.76 (m, 1H).
Reaction SMILES: S(O[CH2:12][CH:13]([CH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)(C1C=CC(C)=CC=1)(=O)=O.[I-:26].[Na+]>CC(C)=O>[CH:20]1([CH:13]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:12][I:26])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]1
Reactant: [I-]
Reactant: Cc1ccc(S(=O)(=O)OCC(c2ccccc2)C2CCCCC2)cc1
Agent: [Na+]
Solvent: CC(C)=O
Product: ICC(c1ccccc1)C1CCCCC1

Procedure:
To a 250 mL round-bottomed flask equipped with condenser and N2 inlet were added 13.9 g (39.4 mmol) 2-(cyclohexyl)-2-phenylethanol tosylate, 80 mL acetone and 6.49 g (43.3 mmol) sodium iodide. The reaction was refluxed 36 hr, cooled, and evaporated. The residue was taken up in ethyl acetate, washed with water and aqueous sodium bisulfite solution, dried over sodium sulfate, and evaporated to an oil, 12.11 g (98%), which was used directly in the next step.
Reaction SMILES: CN1CCOCC1.[C:8]([O:12][C:13]([NH:15][CH2:16][CH2:17][N:18]([CH2:34][CH2:35][NH:36][C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[C:19]([CH2:21][C@H:22]([NH:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C:23]([OH:25])=O)=[O:20])=[O:14])([CH3:11])([CH3:10])[CH3:9].[NH2:44][C@@H:45]([CH2:65][CH2:66][C:67]1[CH:72]=[CH:71][CH:70]=[CH:69][CH:68]=1)[C:46]([N:48]([CH3:64])[CH2:49][CH2:50][NH:51][C:52]([C:54]1[CH:59]=[CH:58][C:57]([C:60]([F:63])([F:62])[F:61])=[CH:56][CH:55]=1)=[O:53])=[O:47]>C(Cl)Cl>[C:40]([O:39][C:37]([NH:36][CH2:35][CH2:34][N:18]([CH2:17][CH2:16][NH:15][C:13]([O:12][C:8]([CH3:9])([CH3:11])[CH3:10])=[O:14])[C:19]([CH2:21][C@H:22]([NH:26][C:27](=[O:28])[O:29][C:30]([CH3:31])([CH3:33])[CH3:32])[C:23](=[O:25])[NH:44][C@H:45]([C:46](=[O:47])[N:48]([CH3:64])[CH2:49][CH2:50][NH:51][C:52]([C:54]1[CH:55]=[CH:56][C:57]([C:60]([F:62])([F:63])[F:61])=[CH:58][CH:59]=1)=[O:53])[CH2:65][CH2:66][C:67]1[CH:72]=[CH:71][CH:70]=[CH:69][CH:68]=1)=[O:20])=[O:38])([CH3:41])([CH3:43])[CH3:42]
Reactant: CN(CCNC(=O)c1ccc(C(F)(F)F)cc1)C(=O)[C@@H](N)CCc1ccccc1
Reactant: CC(C)(C)OC(=O)NCCN(CCNC(=O)OC(C)(C)C)C(=O)C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CN(CCNC(=O)c1ccc(C(F)(F)F)cc1)C(=O)[C@H](CCc1ccccc1)NC(=O)[C@H](CC(=O)N(CCNC(=O)OC(C)(C)C)CCNC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C
Reaction time: 0.25 h
Yield: 68 %

Procedure:
A solution of CDMT (0.22 g, 1.26 mmol) in DCM (30 mL) was cooled to 0° C. before adding N-methylmorpholine (0.3 mL, 2.62 mmol). After 15 min, (2S)-3-[bis(2-{[(tert-butoxy)carbonyl]amino}ethyl)carbamoyl]-2-{[(tert-butoxy)carbonyl]amino}propanoic acid CXXIV (0.62 g, 1.20 mmol) was added and the solution was stirred for additional 40 min. After that time, (2S)-2-amino-N-methyl-4-phenyl-N-(2-{[4-(trifluoromethyl)phenyl]formamido}ethyl)butanamide CXXIII (0.56 g, 1.26 mmol) was added and the mixture stirred at r.t. overnight. The mixture was washed with 1 M HCl (5×), 1 M K2CO3 (5×), brine and dried over MgSO4. The solvent was evaporated under vacuum and the residue was purified on a silica gel column (50:1 DCM/methanol) to give tert-butyl N-[(1S)-2-[bis(2-{[(tert-butoxy)carbonyl]amino}ethyl)carbamoyl]-1-{[(1S)-1-[methyl(2-{[4-(trifluoromethyl)phenyl]formamido}ethyl)carbamoyl]-3-phenylpropyl]carbamoyl}ethyl]carbamate as yellow solid (0.78 g, 0.86 mmol, 68% yield). ESIMS found for C44H64F3N7O10 m/z 908 (M+H).
Reaction SMILES: [C:1]([NH:4][C:5]1[C:6]([Cl:22])=[C:7]([N+:19]([O-])=O)[CH:8]=[CH:9][C:10]=1[S:11][C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=1)(=[O:3])[CH3:2].O.C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C.[Zn]>[C:1]([NH:4][C:5]1[C:6]([Cl:22])=[C:7]([CH:8]=[CH:9][C:10]=1[S:11][C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=1)[NH2:19])(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1c(Sc2ccc(F)cc2)ccc([N+](=O)[O-])c1Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Agent: [Zn]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)Nc1c(Sc2ccc(F)cc2)ccc(N)c1Cl
Temperature: 100 °C
Reaction time: 8 h
Yield: 95.4 %

Procedure:
A mixture of 3-acetamido-2-chloro-4-(4-fluorophenylsulphanyl)nitrobenzene (Method 15) (0.1 g), ferric chloride hexahydrate (0.238 g) and zinc dust (0.192 g in DMF (1 ml) and water (1 ml) was stirred and heated (oil bath 100° C.) for 1 hour then cooled. Water (15 ml) was added and the mixture was basified to pH 11 with saturated aqueous sodium carbonate solution (3 ml) then extracted with DCM (3×15 ml). The extracts were washed with brine then dried. Volatile material was removed by evaporation and the residue was left under high vacuum (2 mm Hg) overnight to give the title compound (0.087 g) as a solid. NMR: 1.95 (s, 3H), 5.72 (brs, 2H), 6.73 (d, 1H), 7.05-7.20 (m, 5H), 9.54 (brs, 1H); m/z: 309.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[CH2:7][S:8][C@@H:9]2[CH:16]([NH:17][C:18](=[O:55])[C:19]([C:30]3[N:31]=[C:32]([NH:35]C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[S:33][CH:34]=3)=[N:20][O:21][C:22]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[O:23])[C:15](=[O:56])[N:10]2[C:11]=1[C:12]([OH:14])=[O:13])(=[O:3])[CH3:2].C(NCC)C>C(O)=O>[C:1]([O:4][CH2:5][C:6]1[CH2:7][S:8][C@@H:9]2[CH:16]([NH:17][C:18](=[O:55])[C:19]([C:30]3[N:31]=[C:32]([NH2:35])[S:33][CH:34]=3)=[N:20][O:21][C:22]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[O:23])[C:15](=[O:56])[N:10]2[C:11]=1[C:12]([OH:14])=[O:13])(=[O:3])[CH3:2]
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)C(NC(=O)C(=NOC(=O)c3ccccc3)c3csc(NC(c4ccccc4)(c4ccccc4)c4ccccc4)n3)[C@H]2SC1
Solvent: CCNCC
Solvent: O=CO
Product: CC(=O)OCC1=C(C(=O)O)N2C(=O)C(NC(=O)C(=NOC(=O)c3ccccc3)c3csc(N)n3)[C@H]2SC1
Temperature: 45 °C
Reaction time: 0.17 h

Procedure:
A mixture of 0.27 g of the product of Step A and 2 ml of 50% aqueous formic acid was stirred at 45° C. for 10 minutes and was thn evaporated to dryness. The residue was triturated with ether and 1.55 g of raw product were recovered which was dissolved in 0.5 ml of methanol. 5 ml of ether were added thereto to recover 0.14 g of the syn isomer of 3-acetoxymethyl-7-[2-(2-amino-4-thiazolyl-2-(phenylcarbonyloxyimino)-acetamido]-ceph-3-eme-4-carboxylic acid.
Reaction SMILES: F[C:2](F)(F)C(O)=O.[N:8]1([C:15]2[CH:20]=[C:19]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=3)[N:18]=[C:17]([C:31]#[N:32])[N:16]=2)[CH2:14][CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1.C=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CO>[CH3:2][N:11]1[CH2:12][CH2:13][CH2:14][N:8]([C:15]2[CH:20]=[C:19]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:28])([F:29])[F:30])[CH:22]=3)[N:18]=[C:17]([C:31]#[N:32])[N:16]=2)[CH2:9][CH2:10]1
Reactant: N#Cc1nc(-c2cccc(C(F)(F)F)c2)cc(N2CCCNCC2)n1
Reactant: O=C(O)C(F)(F)F
Agent: C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CO
Product: CN1CCCN(c2cc(-c3cccc(C(F)(F)F)c3)nc(C#N)n2)CC1
Reaction time: 2 h

Procedure:
4-[1,4]Diazepan-1-yl-6-(3-trifluoromethyl-phenyl)-pyrimidine-2-carbonitrile trifluoroacetic acid salt (Example 13; 30 mg) and formaldehyde (6 mg, 37% wt aqueous) were stirred at room temperature in methanol (500 μl) for ten minutes. Sodium triacetoxyborohydride (17 mg) was added to the reaction and stirring continued for two hours. Solvent was evaporated under reduced pressure to yield crude product. Purification by flash chromatography on silica yielded product 4-(4-methyl-[1,4]diazepan-1-yl)-6-(3-trifluoromethyl-phenyl)-pyrimidine-2-carbonitrile (10 mg).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([S:9](Cl)(=[O:11])=[O:10])[CH:5]=[C:6]([F:8])[CH:7]=1.[NH2:13][C:14]1[C:15]([O:29][C:30]2[CH:35]=[CH:34][C:33]([C:36]#[N:37])=[CH:32][CH:31]=2)=[N:16][C:17]([O:20][C:21]2[CH:26]=[CH:25][C:24]([C:27]#[N:28])=[CH:23][CH:22]=2)=[CH:18][CH:19]=1>>[C:36]([C:33]1[CH:34]=[CH:35][C:30]([O:29][C:15]2[C:14]([NH:13][S:9]([C:4]3[CH:3]=[C:2]([F:1])[CH:7]=[C:6]([F:8])[CH:5]=3)(=[O:11])=[O:10])=[CH:19][CH:18]=[C:17]([O:20][C:21]3[CH:26]=[CH:25][C:24]([C:27]#[N:28])=[CH:23][CH:22]=3)[N:16]=2)=[CH:31][CH:32]=1)#[N:37]
Reactant: N#Cc1ccc(Oc2ccc(N)c(Oc3ccc(C#N)cc3)n2)cc1
Reactant: O=S(=O)(Cl)c1cc(F)cc(F)c1
Product: N#Cc1ccc(Oc2ccc(NS(=O)(=O)c3cc(F)cc(F)c3)c(Oc3ccc(C#N)cc3)n2)cc1
Yield: 75.9 %

Procedure:
3,5-difluorobenzene sulfonyl chloride (0.5 g, 2.35 mmol) was added to a stirred solution of 3-amino-2,6-bis(4-cyano phenoxy)pyridine (0.77 g, 2.35 mmol) using the reagents and reaction conditions described in Example 1(c) to afford 0.9 g of the required product. 1H NMR (DMSO-d6): δ 6.82 (1H, d), 6.95 (1H, d), 7.11 (2H, d), 7.24 (3H, m), 7.34 (2H, d), 7.80 (7H, m).
Reaction SMILES: [CH2:1]([C:5]1[N:6]=[C:7]([CH2:11][C:12]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=2[F:21])=[O:13])[NH:8][C:9]=1[CH3:10])[CH2:2][CH2:3][CH3:4].[C:22](O)(=[O:25])[C:23]#[CH:24].N1(C(N2C=CN=C2)=O)C=CN=C1>>[CH2:1]([C:5]1[NH:6][C:7]2[N:8]([C:9]=1[CH3:10])[C:22](=[O:25])[CH:23]=[CH:24][C:11]=2[C:12](=[O:13])[C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=1[F:21])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(CC(=O)c2ccc(F)cc2F)[nH]c1C
Reactant: C#CC(=O)O
Agent: O=C(n1ccnc1)n1ccnc1
Product: CCCCc1[nH]c2c(C(=O)c3ccc(F)cc3F)ccc(=O)n2c1C

Procedure:
The compounds are prepared as described in example 10 with 200 mg (0.68 mmol) of 2-(4-Butyl-5-methyl-1H-imidazol-2-yl)-1-(2,4-difluorophenyl)ethanone (example XXI), 72 mg (1.03 mmol) of propiolic acid and 200 mg (1.23 mmol) of 1-(1H-imidazol-1yl-carbonyl)-1H-imidazole. The following compounds are obtained:
Reaction SMILES: Cl.[NH2:2][OH:3].[CH3:4][N:5]1[C:10](=[O:11])[CH:9]=[CH:8][C:7]([C:12](=O)[CH2:13][C@H:14]([C:22]2[CH:27]=[CH:26][C:25]([CH2:28][C:29]([OH:31])=[O:30])=[CH:24][CH:23]=2)[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH3:21])=[CH:6]1.C(=O)([O-])O.[Na+]>>[OH:3]/[N:2]=[C:12](/[C:7]1[CH:8]=[CH:9][C:10](=[O:11])[N:5]([CH3:4])[CH:6]=1)\[CH2:13][C@H:14]([C:22]1[CH:23]=[CH:24][C:25]([CH2:28][C:29]([OH:31])=[O:30])=[CH:26][CH:27]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[CH3:21]
Reactant: NO
Reactant: Cc1ccccc1[C@H](CC(=O)c1ccc(=O)n(C)c1)c1ccc(CC(=O)O)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1ccccc1[C@H](C/C(=N\O)c1ccc(=O)n(C)c1)c1ccc(CC(=O)O)cc1

Procedure:
In analogy to example 1, step 2, from and (R)-2-(4-(3-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-3-oxo-1-o-tolylpropyl)phenyl)acetic acid hydroxylamine hydrochloride in the presence of sodium hydrogencarbonate was prepared the title compound as an off-white solid, MS (ESI+): m/z=405.4 [M+H]+.
Reaction SMILES: [I:1][C:2]1[C:3](=[O:21])[C:4]2[C:9]([O:10][C:11]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[C:8]1[NH:18][N:19]=[CH:20][C:7]1=[CH:6][CH:5]=2.[H-].[Na+].I[CH3:25]>CN(C=O)C>[I:1][C:2]1[C:3](=[O:21])[C:4]2[CH:5]=[CH:6][C:7]3[C:8](=[N:18][N:19]([CH3:25])[CH:20]=3)[C:9]=2[O:10][C:11]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=c1c(I)c(-c2ccccc2)oc2c1ccc1cn[nH]c12
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1cc2ccc3c(=O)c(I)c(-c4ccccc4)oc3c2n1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 19.1 %

Procedure:
To a solution of 7-iodo-8-phenyl-1H-9-oxa-1,2-diaza-cyclopenta[a]naphthalen-6-one (100 mg, 0.26 mmol) in DMF (5 mL) was added sodium hydride (60% dispersion in oil, 30 mg, 0.77 mmol) and the reaction stirred at RT. After 5 min, iodomethane (0.06 mL, 0.90 mmol) was added and the reaction stirred at RT for 6 h. The reaction was quenched by addition of water (3 mL) and extracted with EtOAc (×2). The combined organic extracts were washed with brine, dried (Na2SO4), filtered and concentrated in vacuo. The resultant residue was subjected to flash chromatography (SiO2, gradient 0 to 100% EtOAc in cyclohexane) to afford the title compound (20 mg, 20%). LCMS (Method B) RT=3.70 min, [M+H]+=403. 7-iodo-1-methyl-8-phenyl-1H-9-oxa-1,2-diaza-cyclopenta[a]naphthalen-6-one was also isolated.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8]CC2C=CC(OC)=CC=2)[C:5]([C:18]([O:20][CH3:21])=[O:19])=[CH:4][CH:3]=1.C1(OC)C=CC=CC=1>FC(F)(F)C(O)=O>[NH2:8][C:6]1[C:5]([C:18]([O:20][CH3:21])=[O:19])=[CH:4][CH:3]=[C:2]([Cl:1])[N:7]=1
Reactant: COC(=O)c1ccc(Cl)nc1NCc1ccc(OC)cc1
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1ccc(Cl)nc1N
Temperature: 25 °C
Reaction time: 2 h
Yield: 98 %

Procedure:
To a solution of methyl 6-chloro-2-[(4-methoxybenzyl)amino]pyridine-3-carboxylate (1.0 g) in trifluoroacetic acid (5 ml) was added anisole (0.5 ml), and the mixture was stirred at room temperature for 2 hr. The reaction mixture was concentrated under reduced pressure, and the residue was subjected to azeotropic distillation with toluene. The obtained oil residue was diluted with ethyl acetate (80 ml), and the mixture was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (596 mg).
Reaction SMILES: [CH:1]1([C:4]2[N:13]=[CH:12][C:11]3[C:10](=[O:14])[N:9](COCC[Si](C)(C)C)[CH:8]=[N:7][C:6]=3[CH:5]=2)[CH2:3][CH2:2]1.FC(F)(F)C(O)=O.[OH-].[K+]>ClCCl>[CH:1]1([C:4]2[N:13]=[CH:12][C:11]3[C:10](=[O:14])[NH:9][CH:8]=[N:7][C:6]=3[CH:5]=2)[CH2:3][CH2:2]1
Reactant: C[Si](C)(C)CCOCn1cnc2cc(C3CC3)ncc2c1=O
Agent: [K+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=c1[nH]cnc2cc(C3CC3)ncc12
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To 7-cyclopropyl-3-(2-trimethylsilylethoxymethyl)pyrido[4,3-d]pyrimidin-4-one (6, 2.0 g, 6.3 mmol) in dichloromethane (10 mL) at 0° C. was added a 20% trifluoroacteic acid solution in dichloromethane (10 mL, 6.3 mmol). The reaction mixture was warmed to room temperature and stirred for 3 h. After complete deprotection as indicated by TLC the reaction mixture was concentrated, taken up in dichloromethane and concentrated. This process was repeated 2-3 times. Tetrahydrofuran (20 mL) was added to the crude residue and cooled to 0° C. 3 M potassium hydroxide solution (10 mL, 6.3 mmol) was added to the solution bringing the pH to 9-10. The suspension was stirred for 6-7 h. The reaction was concentrated, the residue was diluted with 10% methanol in dichloromethane and the organic layers were washed with 10 mL water and 10 mL of a saturated brine solution. The organic layers were separated, dried over magnesium sulfate, filtered and concentration to dryness to afford 7-cyclopropyl-3H-pyrido[4,3-d]pyrimidin-4-one (7) as a brown solid. Yield: 1.00 g, 85%; MS (ESI) m/z 188.18 [M+1]+; 1H NMR (400 MHz, DMSO-d6) δ 12.57 (bs, 1H), 9.15 (s, 1H), 8.32 (s, 1H), 7.38 (s, 1H), 2.27 (bs, 1H), 1.03 (bs, 4H).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[CH:7][C:8]([CH3:28])=[C:9]([NH:11][C:12]2[C:21]3[C:16](=[C:17](Cl)[N:18]=[CH:19][CH:20]=3)[C:15]3[CH:23]=[C:24]([F:27])[CH:25]=[CH:26][C:14]=3[N:13]=2)[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].Cl.C([O-])(O)=[O:31].[Na+]>C1COCC1>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([CH3:28])=[C:9]([NH:11][C:12]2[C:21]3[CH:20]=[CH:19][NH:18][C:17](=[O:31])[C:16]=3[C:15]3[CH:23]=[C:24]([F:27])[CH:25]=[CH:26][C:14]=3[N:13]=2)[CH:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccc(C(C)(C)C)cc1Nc1nc2ccc(F)cc2c2c(Cl)nccc12
Reactant: O=C([O-])O
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1ccc(C(C)(C)C)cc1Nc1nc2ccc(F)cc2c2c(=O)[nH]ccc12
Temperature: 25 °C

Procedure:
N-(5-tert-butyl-2-methylphenyl)-1-chloro-9-fluorobenzo[c]-2,6-naphthridin-5-amine (110 mg, 0.28 mmol) was taken up in THF (3.5 mL) and 6 N HCl (3.5 mL) and heated to 85° C. for 2 hr. The reaction was cooled to room temperature, neutralized with saturated NaHCO3 and extracted with EtOAc. The organic layers were dried over Mg2SO4, filtered, and concentrated. Column chromatography on silica gel (100% hexane to 100% EtOAc) provided the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([O:19][C:20]([F:23])([F:22])[F:21])[CH:14]=3)=[CH:11][C:10]([C:24]([OH:26])=O)=[N:9]2)[CH:5]=[CH:6][CH:7]=1.ClC1C=C(N2C(C3C=C(F)C=C(Cl)C=3)=CC(C([N:50]3[CH2:54][C:53](=[O:55])[NH:52][CH2:51]3)=O)=N2)C=CC=1F>>[Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([O:19][C:20]([F:22])([F:21])[F:23])[CH:14]=3)=[CH:11][C:10]([C:24]([N:50]3[CH2:54][C:53](=[O:55])[NH:52][CH2:51]3)=[O:26])=[N:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CN(C(=O)c2cc(-c3cc(F)cc(Cl)c3)n(-c3ccc(F)c(Cl)c3)n2)CN1
Reactant: O=C(O)c1cc(-c2cccc(OC(F)(F)F)c2)n(-c2cccc(Cl)c2)n1
Product: O=C1CN(C(=O)c2cc(-c3cccc(OC(F)(F)F)c3)n(-c3cccc(Cl)c3)n2)CN1

Procedure:
The preparation of the title compound takes place starting from the compound of Example 76A in analogy to the synthesis of the compound of Example 1. 24 mg (64% of theory) of the title compound are obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([F:58])[C:5]([S:52]([CH:55]([CH3:57])[CH3:56])(=[O:54])=[O:53])=[C:6]([CH2:8][N:9]([CH3:51])[C:10]([CH:12]([NH:24][C:25]2[CH:26]=[C:27]3[C:32](=[C:33]([F:35])[CH:34]=2)[C:31]([N:36]([C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[C:37](=[O:43])[O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[N:30][CH:29]=[CH:28]3)[C:13]2[CH:18]=[CH:17][C:16]([C@@H:19]([CH3:22])[CH2:20][OH:21])=[C:15]([CH3:23])[CH:14]=2)=[O:11])[CH:7]=1.[C:59](Cl)(Cl)=[O:60]>C(#N)C.ClCCl>[C:39]([O:38][C:37]([N:36]([C:31]1[C:32]2[C:27](=[CH:26][C:25]([NH:24][C@H:12]3[C:10](=[O:11])[N:9]([CH3:51])[CH2:8][C:6]4[CH:7]=[C:2]([CH:3]=[C:4]([F:58])[C:5]=4[S:52]([CH:55]([CH3:57])[CH3:56])(=[O:53])=[O:54])[NH:1][C:59](=[O:60])[O:21][CH2:20][C@H:19]([CH3:22])[C:16]4[CH:17]=[CH:18][C:13]3=[CH:14][C:15]=4[CH3:23])=[CH:34][C:33]=2[F:35])[CH:28]=[CH:29][N:30]=1)[C:44](=[O:45])[O:46][C:47]([CH3:48])([CH3:49])[CH3:50])=[O:43])([CH3:42])([CH3:40])[CH3:41]
Reactant: Cc1cc(C(Nc2cc(F)c3c(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)nccc3c2)C(=O)N(C)Cc2cc(N)cc(F)c2S(=O)(=O)C(C)C)ccc1[C@@H](C)CO
Reactant: O=C(Cl)Cl
Solvent: ClCCl
Solvent: CC#N
Product: Cc1cc2ccc1[C@@H](C)COC(=O)Nc1cc(F)c(S(=O)(=O)C(C)C)c(c1)CN(C)C(=O)[C@@H]2Nc1cc(F)c2c(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)nccc2c1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 17.4 %

Procedure:
A solution of 20E (123 mg, 0.149 mmol) in acetonitrile (3 mL) and dichloromethane (6 mL) was cooled to 0° C. To this solution was added phosgene (20% in toluene, 0.081 mL, 0.164 mmol). The mixture was stirred at 0° C. for 5 min, and rt for 1 h. The mixture was bubbled with Ar for 10 min to remove excess phosgene. The resulting solution was added dropwise over 3 h via a syringe pump into a solution of TEA (0.208 mL, 1.489 mmol) in CH2Cl2 (260 mL) at rt. The solution was stirred at rt for 16 h. The solvent was concentrated and the crude product was purified by flash chromatography to give a mixture of diastereoisomers (60 mg, 47.3% yield). The diastereoisomers were separated by a prep chiral HPLC to give 20F (22 mg, 0.026 mmol, 37.9% yield).