Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[C:21]([F:23])[C:20]([N:24]2[C:29](=[O:30])[CH:28]=[C:27]([C:31]([F:34])([F:33])[F:32])[N:26]([CH3:35])[C:25]2=[O:36])=[CH:19][C:3]=1[O:4][C:5]1[CH:18]=[CH:17][C:8]([O:9]CC2C=CC=CC=2)=[CH:7][CH:6]=1.C(OCC)(=O)C>[Pd].C(O)C>[Cl:1][C:2]1[CH:22]=[C:21]([F:23])[C:20]([N:24]2[C:29](=[O:30])[CH:28]=[C:27]([C:31]([F:32])([F:33])[F:34])[N:26]([CH3:35])[C:25]2=[O:36])=[CH:19][C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]([OH:9])=[CH:17][CH:18]=1
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(Oc3ccc(OCc4ccccc4)cc3)c(Cl)cc2F)c1=O
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(Oc3ccc(O)cc3)c(Cl)cc2F)c1=O
Temperature: 25 °C
Reaction time: 5 h
Yield: 80.6 %

Procedure:
To 0.72 g of ([4-{2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}phenoxy]methyl)benzene, were added 2 ml of ethyl acetate, 0.7 ml of ethanol and 36 mg of 10% palladium/carbon, and the mixture was stirred for 5 hours at room temperature under hydrogen atmosphere. The reaction system was purged with nitrogen, then, the reaction solution was filtrated through Celite, the filtrate was concentrated to obtain 0.48 g of 4-{2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}phenol.
Reaction SMILES: [I:1][C:2]1[C:3]([OH:12])=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH:5]=[O:6].CI.[C:15]([O-])([O-])=O.[K+].[K+]>CC(C)=O>[CH3:15][O:12][C:3]1[C:2]([I:1])=[C:9]([O:10][CH3:11])[CH:8]=[CH:7][C:4]=1[CH:5]=[O:6]
Reactant: O=C([O-])[O-]
Reactant: COc1ccc(C=O)c(O)c1I
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: COc1ccc(C=O)c(OC)c1I

Procedure:
Methylation of the phenolic --OH group in (12) with MeI-K2CO3 in refluxing acetone proceed smoothly to give 2,4-dimethoxy-3-iodobenzaldehyde (13), m.p. 103.3° C. [1H-NMR: (90 MHz, CDCl3, δ): 3.90 (overlapping s, 2×3H, C2 and C4-OCH3), 6.62 and 7.78 (pair of doublets. Jab=8Hz, C5-H and C6-H), 10.12 (s, 1H, HC=O).]
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=O)[C:5]([OH:11])=[CH:4][CH:3]=1.[O:12]1[CH2:17][CH2:16][N:15]([C:18]2[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][C:19]=2[NH2:20])[CH2:14][CH2:13]1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([CH:10]=1)[C:7]([NH:20][C:19]1[CH:21]=[C:22]([C:25]([F:26])([F:27])[F:28])[CH:23]=[CH:24][C:18]=1[N:15]1[CH2:14][CH2:13][O:12][CH2:17][CH2:16]1)=[O:9]
Reactant: O=C(O)c1cc(Br)ccc1O
Reactant: Nc1cc(C(F)(F)F)ccc1N1CCOCC1
Product: O=C(Nc1cc(C(F)(F)F)ccc1N1CCOCC1)c1cc(Br)ccc1O
Yield: 65.9 %

Procedure:
Using 5-bromosalicylic acid and 2-morpholino-5-(trifluoromethyl)aniline as the raw materials, the same operation as the example 16 gave the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:14])[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:4][C:3]=1[N+:15]([O-:17])=[O:16].[C:18](OC(=O)C)(=[O:20])[CH3:19]>N1C=CC=CC=1>[C:18]([O:14][CH:8]([C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([N+:15]([O-:17])=[O:16])[CH:4]=1)[C:9]([O:11][CH2:12][CH3:13])=[O:10])(=[O:20])[CH3:19]
Reactant: CCOC(=O)C(O)c1ccc(Cl)c([N+](=O)[O-])c1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CCOC(=O)C(OC(C)=O)c1ccc(Cl)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution (6 mL) of the compound (1.46 g) prepared in Example 22 in pyridine, acetic anhydride (2 mL) was added, and the mixture was stirred for 1 hour at room temperature. The title compound (135 mg) having the following physical data was obtained by concentrating the reaction mixture and azeotroping in toluene.
Reaction SMILES: O1CCCC1.[N:6]1([C:11]2[CH:16]=[CH:15][C:14]([CH:17]([CH3:20])[C:18]#[N:19])=[CH:13][CH:12]=2)[CH:10]=[CH:9][N:8]=[CH:7]1.CC(C)([O-])C.[K+].[CH3:27][N:28]=[C:29]=[S:30]>O>[CH3:27][NH:28][C:29](=[S:30])[C:17]([C:14]1[CH:13]=[CH:12][C:11]([N:6]2[CH:10]=[CH:9][N:8]=[CH:7]2)=[CH:16][CH:15]=1)([C:18]#[N:19])[CH3:20]
Reactant: CC(C#N)c1ccc(-n2ccnc2)cc1
Reactant: CN=C=S
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: CNC(=S)C(C)(C#N)c1ccc(-n2ccnc2)cc1
Reaction time: 0.5 h
Yield: 54.4 %

Procedure:
To a 10 ml tetrahydrofuran solution containing 1.00 g (5.1 mmole) of 2-[4-(1-imidazolyl)-phenyl]propionitrile was added a 10 ml tetrahydrofuran solution containing 0.69 g (6.2 mmole) of potassium tert-butoxide at 0 C. After stirring for 0.5 hour, a 5 ml tetrahydrofuran solution containing 0.45 g (6.2 mmole) of methyl isothiocyanate was added to the mixture and the mixture was stirred at room temperature for 2 hours. Water was added to the mixture and the mixture was extracted with 20 ml of ethyl acetate, dried and condensed under reduced pressure, and then purified by silica gel chromatography and condensed. The resulting condensate was suspended in 30 ml of toluene and the suspension was refluxed under heating for 0.5 hour and a solid was collected by filtration to obtain 0.75 g (yield: 54 %) of N-methyl-2-[4-(1-imidazolyl)-phenyl]-2cyanothiopropionamide as a crystalline solid.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[C:8](=[O:9])[N:7]([C:10]2[S:11][C:12]([C:16]([NH:18][CH2:19][C:20]3[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=3)=[O:17])=[C:13]([CH3:15])[N:14]=2)[CH:6]=[N:5]1.[H-].[Na+].Br[CH2:29][C:30]1[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=1>O1CCCC1.C(OCC)(=O)C>[F:36][C:33]1[CH:34]=[CH:35][C:30]([CH2:29][O:1][CH2:2][CH2:3][N:4]2[C:8](=[O:9])[N:7]([C:10]3[S:11][C:12]([C:16]([NH:18][CH2:19][C:20]4[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=4)=[O:17])=[C:13]([CH3:15])[N:14]=3)[CH:6]=[N:5]2)=[CH:31][CH:32]=1
Reactant: Fc1ccc(CBr)cc1
Reactant: Cc1nc(-n2cnn(CCO)c2=O)sc1C(=O)NCc1cccnc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1nc(-n2cnn(CCOCc3ccc(F)cc3)c2=O)sc1C(=O)NCc1cccnc1
Reaction time: 0.5 h
Yield: 46 %

Procedure:
To the solution of 2-(1-(2-hydroxyethyl)-5-oxo-1H-1,2,4-triazol-4(5H)-yl)-4-methyl-N-(pyridin-3-ylmethyl)thiazole-5-carboxamide (0.11 g, 0.31 mmol) in anhydrous tetrahydrofuran was added sodium hydride (60% in mineral oil, 0.015 g, 0.35 mmol) at 0° C. The reaction mixture was stirred for 30 minutes, followed by the addition of 1-(bromomethyl)-4-fluorobenzene (0.04 mL, 0.31 mmol). The resulting mixture was stirred at ambient temperature for 17 hours, diluted with ethyl acetate and washed with water and brine. The organic solution was dried over anhydrous sodium sulphate, filtered and concentrated in vacuo. The residue was purified by column chromatography eluted with ethyl acetate to afford the title compound as a white solid in 46% yield (0.06 g): mp 235-236° C. (ethyl acetate); 1H NMR (300 MHz, DMSO-d6) δ 9.14 (br s, 1H), 9.11-9.06 (m, 1H), 8.95 (t, J=5.5 Hz, 1H), 8.73 (s, 1H), 8.56-8.48 (m, 1H), 8.15-8.08 (m, 1H), 7.65-7.56 (m, 2H), 7.32-7.22 (m, 2H), 5.81 (s, 2H), 4.57 (d, J=5.5 Hz, 2H), 3.79 (t, J=5.4 Hz, 2H), 3.64 (t, J=5.4 Hz, 2H), 2.54 (s, 3H); 13C NMR (75 MHz, DMSO-d6) δ 162.0, 161.4, 152.6, 152.1, 150.6, 145.1, 143.8, 14-3.7, 141.1, 131.9, 131.9, 131.0, 128.7, 121.9, 116.6, 62.9, 58.6, 48.3, 40.7, 17.5; MS (ES+) m/z 469.2 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6](Br)[N:5]=[C:4]([C:9]([O:11][CH3:12])=[O:10])[C:3]=1[Cl:13].[F:14][C:15]1[C:23]2[O:22][C:21]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[N:20][C:19]=2[CH:18]=[CH:17][C:16]=1B(O)O.C([O-])([O-])=O.[K+].[K+].O>O1CCOCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[NH2:1][C:2]1[CH:7]=[C:6]([C:16]2[CH:17]=[CH:18][C:19]3[N:20]=[C:21]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[O:22][C:23]=3[C:15]=2[F:14])[N:5]=[C:4]([C:9]([O:11][CH3:12])=[O:10])[C:3]=1[Cl:13]
Reactant: COC(=O)c1nc(Br)cc(N)c1Cl
Reactant: OB(O)c1ccc2nc(-c3ccccc3)oc2c1F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: COC(=O)c1nc(-c2ccc3nc(-c4ccccc4)oc3c2F)cc(N)c1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 35.6 %

Procedure:
0.024 g (0.03 mmol) of (PPh3)2PdCl2 is added to a solution of 0.3 g (1.13 mmol) of methyl 4-amino-6-bromo-3-chloropyridine-2-carboxylate in 20 ml of dioxane, and this mixture is stirred at room temperature (RT) for 30 min. In succession, 0.35 g (1.35 mmol) of (7-fluoro-2-phenyl-1,3-benzoxazol-6-yl)boronic acid, 0.47 g (3.4 mmol) of K2CO3 and 2 g (111 mmol) of H2O are then added to this mixture, which is then stirred under reflux for 6 h. The mixture is allowed to stand at RT for a further 12 h and then added to 40 ml of H2O. This mixture is extracted repeatedly with CH2Cl2, and the combined organic phase is dried over Na2SO4 and then concentrated. Purification by chromatography on silica gel using the mobile phase heptane/ethyl acetate (3/7) gives 0.16 g (36%) of product. 1H-NMR (CDCl3): δ 8.30, 8.00, 7.55 (3m, 5H, C6H5), 7.60, 7.55 (2d, 2H, benzoxazole ring), 7.30 (s, 1H, pyridine) 4.85 (bs, 2H, NH2), 4.00 (S, 3H, COOCH3).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:17]([OH:19])=O)[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:20][C@@H:21]([CH2:42][C:43]1[N:44]=[CH:45][NH:46][CH:47]=1)[C:22]([NH:24][C@@H:25]([CH2:35][CH:36]1[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]1)[C@@H:26]([OH:34])[CH2:27][C@@H:28]([CH:31]([CH3:33])[CH3:32])[CH:29]=[CH2:30])=[O:23].C(N1CCOCC1)C.C1C=CC2N(O)N=NC=2C=1.C1CCC(N=C=NC2CCCCC2)CC1>CN(C)C=O>[CH:36]1([CH2:35][C@H:25]([NH:24][C:22]([C@@H:21]([NH:20][C:17]([C@@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[CH2:10][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)=[O:19])[CH2:42][C:43]2[N:44]=[CH:45][NH:46][CH:47]=2)=[O:23])[C@@H:26]([OH:34])[CH2:27][C@@H:28]([CH:31]([CH3:33])[CH3:32])[CH:29]=[CH2:30])[CH2:37][CH2:38][CH2:39][CH2:40][CH2:41]1
Reactant: C=C[C@@H](C[C@H](O)[C@H](CC1CCCCC1)NC(=O)[C@@H](N)Cc1c[nH]cn1)C(C)C
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CCN1CCOCC1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: C=C[C@@H](C[C@H](O)[C@H](CC1CCCCC1)NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C)C(C)C

Procedure:
A mixture of 313 mg 1.18 mmol) of t-butoxycarbonyl-L-phenylalanine. 460 mg (1.18 mmol) of (S)-α-amino-N-[(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropyl-5-hexenyl]imidazole-4-propionamide, 0.15 ml (1.18 mmol) of 4-ethylmorpholine, 320 mg (2.36 mmol) of HOBT and 292 mg (1.42 mmol) of DCC in 20 ml of dimethylformamide was stirred at room temperature overnight. Thereafter, the separated precipitate was filtered off and the solvent was evaporated in a high vacuum. The residue was dissolved in ethyl acetate and then washed in succession with 2N sodium bicarbonate solution, saturated ammonium chloride solution, again with 2N sodium bicarbonate solution and again with saturated ammonium chloride solution. After drying the organic solution over sodium sulfate, the solvent was evaporated under reduced pressure and, for purification, the residue (870 mg) was chromatographed on 30 g of silica gel using a 20:1:0.1 mixture of methylene chloride, methanol and ammonia as the eluting agent. Crystallization of the thus-obtained crude product from methylene chloride/ether yielded 410 mg of t-butyl [(S)-α-[[(S)-1-[[(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropyl-5-hexenyl]carbamoyl]-2-imidazol-4-ylethyl]-carbamoyl]phenethyl]carbamate, melting point 161°.
Reaction SMILES: [NH2:1][OH:2].[C:3]([C:5]1[CH:6]=[CH:7][C:8]([F:23])=[C:9]([NH:11][C:12]([C:14]2[N:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:17]3=[N:16][CH:15]=2)=[O:13])[CH:10]=1)#[N:4]>CCO>[F:23][C:8]1[CH:7]=[CH:6][C:5]([C:3](=[N:1][OH:2])[NH2:4])=[CH:10][C:9]=1[NH:11][C:12]([C:14]1[N:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]2=[N:16][CH:15]=1)=[O:13]
Reactant: N#Cc1ccc(F)c(NC(=O)c2cnc3ccccn23)c1
Reactant: NO
Solvent: CCO
Product: NC(=NO)c1ccc(F)c(NC(=O)c2cnc3ccccn23)c1
Temperature: 70 °C

Procedure:
NH2OH (10 mL, 32.1 mmol) was added in one portion to a stirred suspension of N-(5-cyano-2-fluorophenyl)imidazo[1,2-a]pyridine-3-carboxamide (49) (3.6 g, 12.85 mmol) in EtOH (100 mL). The resulting suspension was heated at 70° C. for 3 hours and then the solvent was removed to yield N-(2-fluoro-5-(N′-hydroxycarbamimidoyl)phenyl)imidazo[1,2-a]pyridine-3-carboxamide (50). 1H NMR (400 MHz, d6-DMSO) δ 10.21 (s, 1H), 9.70 (s, 1H), 9.45 (td, J=1.2, 7.2 Hz, 1H), 8.61 (s, 1H), 7.95 (dd, J=2.4, 7.6 Hz, 1H), 7.79 (td, J=1.2, 8.8 Hz, 1H), 7.51-7.60 (m, 2H), 7.31-7.37 (m, 1H), 7.19 (dt, J=1.2, 6.8, 1H), 5.88 (s, 2H). MS m/z 314.1 (M+1)+.
Reaction SMILES: [C:1]1([CH:7]([O:14][C:15]([C@@H:17]2[N:22]3[C:23](=[O:35])[C@@H:24]([NH:25][C:26](=[O:34])[CH2:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[C@H:21]3[S:20][CH2:19][C:18]2=C)=[O:16])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O=O.[O:39]=[O+][O-].O=[O+][O-].CSC>CO>[C:8]1([CH:7]([O:14][C:15]([CH:17]2[N:22]3[C:23](=[O:35])[C@@H:24]([NH:25][C:26](=[O:34])[CH2:27][C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=4)[C@H:21]3[S:20][CH2:19][C:18]2=[O:39])=[O:16])[C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=[O+][O-]
Reactant: C=C1CS[C@@H]2[C@H](NC(=O)Cc3ccccc3)C(=O)N2[C@H]1C(=O)OC(c1ccccc1)c1ccccc1
Agent: O=O
Solvent: CSC
Solvent: CO
Product: O=C(Cc1ccccc1)N[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)C(=O)CS[C@H]12
Temperature: -70 °C
Reaction time: 1 h

Procedure:
A solution of 0.50 g of 3-methylene-7β-phenylacetylamino-cepham-4α-carboxylic acid diphenylmethyl ester in 100 ml of methanol is treated for 6.5 minutes at -70° C. with an oxygen-ozone stream containing 0.175 mmol of ozone/minute. The reaction mixture is mixed with 0.5 ml of dimethyl sulphide and stirred for one hour at -70° C., then for 2 hours at room temperature and evaporated to dryness. The residue, in methylene chloride is chromatographed on 15 g of silica gel. Elution with methylene chloride yields amorphous 7β-phenylacetylaminocepham-3-one-4ξ-carboxylic acid diphenylmethyl ester, thin layer chromatography (silica gel): Rf~0.47 (system: toluene/acetone/methanol/acetic acid, 80:10:5:5); infrared absorption spectrum (in methylene chloride): characteristic bands at 2.95μ, 5.61μ, 5.77μ, 5.85μ, 5.95μ, 6.21μ and 6.87μ; the compound shows a positive reaction with iron-III chloride.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[N:6][CH:5]=[C:4]([Cl:8])[N:3]=1.[Li+].[Cl-].Br[CH2:12][C:13](=[CH2:19])[C:14]([O:16][CH2:17][CH3:18])=[O:15].C([Cu])#N>C1COCC1>[Cl:1][C:2]1[C:7]([CH2:19][C:13](=[CH2:12])[C:14]([O:16][CH2:17][CH3:18])=[O:15])=[N:6][CH:5]=[C:4]([Cl:8])[N:3]=1
Reactant: C=C(CBr)C(=O)OCC
Reactant: Clc1cncc(Cl)n1
Agent: N#C[Cu]
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: C=C(Cc1ncc(Cl)nc1Cl)C(=O)OCC
Temperature: -50 °C
Yield: 71.6 %

Procedure:
2,6-Dichloropyrazine (9) (149 mg, 1.0 mmol) in THF (2 mL) was added to a solution of TMPZnCl.LiCl (2) (1.3 M in THF, 0.85 mL, 1.1 mmol) at 25° C. and the reaction mixture was then stirred at this temperature for 30 min according to TP 2. After cooling down to −50° C., ethyl 2-(bromomethyl)acrylate (230 mg, 1.2 mmol) and CuCN.2LiCl (1.0 M solution in THF, 5 drops) were added and the resulting mixture was allowed to warm up slowly to −20° C. The reaction mixture was quenched with a sat. aq. NH4Cl solution (20 mL), extracted with diethyl ether (3×50 mL) and dried over anhydrous Na2SO4. After filtration, the solvent was evaporated in vacuo. Purification by flash-chromatography (CH2Cl2/n-pentane, 1:3) furnished compound 11c (187 mg, 72%) as a colourless oil.
Reaction SMILES: C(N(CC)CC)C.Cl[C:9]1[N:14]=[C:13]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:12]=[C:11](Cl)[N:10]=1>O1CCCC1.[C].[Pd]>[N:10]1[CH:11]=[CH:12][C:13]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[N:14][CH:9]=1
Reactant: CCOC(=O)c1cc(Cl)nc(Cl)n1
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)c1ccncn1
Reaction time: 6 h
Yield: 86605.9 %

Procedure:
Triethylamine (48.03 g, 0.475 mmol) was added to a solution of ethyl 2,6-dichloropyrimidine-4-carboxylate (intermediate 4, 38.60 g, 0.175 mmol) in tetrahydrofuran (700 ml). The solution was added with Palladium-carbon(5%), and stirred under a hydrogen atmosphere for 6 hours. The solid in the reaction system was removed by filtration, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give ethyl pyrimidine-4-carboxylate (intermediate 5, 23.06 g, 87%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:33])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]2[N:17]([C:24]3[C:29]([Cl:30])=[CH:28][CH:27]=[CH:26][C:25]=3[Cl:31])[N:18]=[CH:19][C:20]=2[CH:21]([CH3:23])[CH3:22])=[CH:10][C:9]=1[CH3:32])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].I[CH3:37]>CN(C=O)C>[C:1]([O:5][C:6](=[O:33])[N:7]([C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]2[N:17]([C:24]3[C:29]([Cl:30])=[CH:28][CH:27]=[CH:26][C:25]=3[Cl:31])[N:18]=[CH:19][C:20]=2[CH:21]([CH3:23])[CH3:22])=[CH:10][C:9]=1[CH3:32])[CH3:37])([CH3:2])([CH3:3])[CH3:4]
Reactant: CI
Reactant: Cc1cc(OCc2c(C(C)C)cnn2-c2c(Cl)cccc2Cl)ccc1NC(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc(OCc2c(C(C)C)cnn2-c2c(Cl)cccc2Cl)ccc1N(C)C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 94 %

Procedure:
To a 0° C. solution of {4-[2-(2,6-dichloro-phenyl)-4-isopropyl-2H-pyrazol-3-ylmethoxy]-2-methyl-phenyl}-carbamic acid tert-butyl ester (1.9 g, 3.9 mmol) in DMF (15 mL) is added sodium hydride (60% dispersion in mineral oil, 0.19 g, 4.7 mmol) portionwise. The mixture is stirred at 0° C. for 30 minutes. Iodomethane (0.83 g, 5.9 mmol) is added dropwise. The reaction mixture is then stirred at room temperature for 1.0 h. The reaction is quenched with the addition of saturated ammonium chloride (20 mL) at 0° C. The reaction mixture is partitioned between EtOAc (30 mL) and water (20 mL). The organic phase is washed with brine (30 mL), dried (Na2SO4), filtered, and concentrated under reduced pressure to yield the title compound (1.85 g, 95%) as a foamy solid. LC-ES/MS m/e 526.0 (M+23).
Reaction SMILES: [CH2:1]([C:8]1[C:17]2[C:12](=[CH:13][C:14]([O:18][CH3:19])=[CH:15][CH:16]=2)[C:11](Cl)=[N:10][N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:21][CH:22]1[CH2:27][CH2:26][N:25]([CH2:28][C:29]2[CH:38]=[CH:37][C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[CH:30]=2)[CH2:24][CH2:23]1>>[CH2:1]([C:8]1[C:17]2[C:12](=[CH:13][C:14]([O:18][CH3:19])=[CH:15][CH:16]=2)[C:11]([NH:21][CH:22]2[CH2:23][CH2:24][N:25]([CH2:28][C:29]3[CH:38]=[CH:37][C:36]4[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=4)[CH:30]=3)[CH2:26][CH2:27]2)=[N:10][N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NC1CCN(Cc2ccc3ccccc3c2)CC1
Reactant: COc1ccc2c(Cc3ccccc3)nnc(Cl)c2c1
Product: COc1ccc2c(Cc3ccccc3)nnc(NC3CCN(Cc4ccc5ccccc5c4)CC3)c2c1

Procedure:
This compound is obtained according to the procedure described in 1.4. by reacting 4-benzyl-1-chloro-7-methoxyphthalazine with 4-amino-1-(naphthalen-2-yl-methyl)piperidine.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH2:9][C:8](=[O:11])[N:7]([CH2:12][C:13]#[CH:14])[C:6]=2[CH:15]=1.[C:16](Cl)(Cl)=[O:17]>>[N:1]([C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH2:9][C:8](=[O:11])[N:7]([CH2:12][C:13]#[CH:14])[C:6]=2[CH:15]=1)=[C:16]=[O:17]
Reactant: O=C(Cl)Cl
Reactant: C#CCN1C(=O)COc2ccc(N)cc21
Product: C#CCN1C(=O)COc2ccc(N=C=O)cc21

Procedure:
6-Amino-3,4-dihydro-3-oxo-4-(2-propynyl)-2H-1,4-benzoxazine is treated with phosgene analogously to the procedure described in Example 103 in order to produce the 3,4-dihydro-6-isocyanato-3-oxo-4-(2-propynyl)-2H-1,4-benzoxazine which is used as the starting material in Example 3. 1H-NMR (CDCl3, 400 MHz): 6.98-6.92 ppm (m, 2H), 6.79 ppm (q, 1H), 4.66 ppm (d, 2H), 4.63 ppm (s, 2H), 2.31 ppm (t, 1H).
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][C:11]1[CH:12]=[CH:13][C:14]([O:55][CH3:56])=[C:15]([C:17]2([N:44]3[CH2:53][C@H:52]([OH:54])[CH2:51][C@H:45]3[C:46]([N:48]([CH3:50])[CH3:49])=[O:47])[C:25]3[C:20](=[CH:21][CH:22]=[C:23]([Cl:26])[CH:24]=3)[N:19]([S:27]([C:30]3[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][C:31]=3[O:38][C:39]([F:42])([F:41])[F:40])(=[O:29])=[O:28])[C:18]2=[O:43])[CH:16]=1)(C(C)(C)C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-].C1COCC1.O>C1COCC1>[Cl:26][C:23]1[CH:24]=[C:25]2[C:20](=[CH:21][CH:22]=1)[N:19]([S:27]([C:30]1[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][C:31]=1[O:38][C:39]([F:40])([F:42])[F:41])(=[O:28])=[O:29])[C:18](=[O:43])[C:17]2([N:44]1[CH2:53][C@H:52]([OH:54])[CH2:51][C@H:45]1[C:46]([N:48]([CH3:49])[CH3:50])=[O:47])[C:15]1[CH:16]=[C:11]([CH2:10][CH2:9][OH:8])[CH:12]=[CH:13][C:14]=1[O:55][CH3:56]
Reactant: COc1ccc(S(=O)(=O)N2C(=O)C(c3cc(CCO[Si](C)(C)C(C)(C)C)ccc3OC)(N3C[C@H](O)C[C@H]3C(=O)N(C)C)c3cc(Cl)ccc32)c(OC(F)(F)F)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(S(=O)(=O)N2C(=O)C(c3cc(CCO)ccc3OC)(N3C[C@H](O)C[C@H]3C(=O)N(C)C)c3cc(Cl)ccc32)c(OC(F)(F)F)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 74 %

Procedure:
To a solution of 500 mg of the compound obtained in Step 216-6 in THF (5.0 ml) was added dropwise a solution of 1 mol/L TBAF/THF (2.6 ml) under ice cooling. The solution was stirred at room temperature for two hours. Water was added to the reaction solution and the resulting mixture was extracted with EtOAc. The extract was dried over Na2SO4, then, the drying agent was separated by filtration and the solvent was evaporated under reduced pressure. The obtained residue was purified by column chromatography (silicagel 60; mobile phase: CHCl3/MeOH=8/1; v/v) to obtain 320 mg of the title compound (light yellow solid).
Reaction SMILES: [NH2:1][Al]CCl.[F:5][C:6]([F:24])([C:20]([F:23])([F:22])[F:21])[CH2:7][CH2:8][C:9]1[N:10]=[C:11]([C:18]#[N:19])[N:12]2[CH:17]=[CH:16][CH:15]=[N:14][C:13]=12.CO>C1(C)C=CC=CC=1>[F:24][C:6]([F:5])([C:20]([F:21])([F:23])[F:22])[CH2:7][CH2:8][C:9]1[N:10]=[C:11]([C:18](=[NH:1])[NH2:19])[N:12]2[CH:17]=[CH:16][CH:15]=[N:14][C:13]=12
Reactant: N[Al]CCl
Reactant: N#Cc1nc(CCC(F)(F)C(F)(F)F)c2ncccn12
Solvent: CO
Solvent: Cc1ccccc1
Product: N=C(N)c1nc(CCC(F)(F)C(F)(F)F)c2ncccn12
Temperature: 107 °C
Reaction time: 0.5 h

Procedure:
A solution of amino(chloro)methylaluminum (0.5 M in toluene, 18.13 mL, 9.06 mmol) was added quickly to a stirred solution of the intermediate from Step F (0.3006 g, 1.036 mmol) in toluene (12.63 mL) and the mixture was heated at 107° C. overnight. The reaction mixture was cooled to room temperature, MeOH was added and the mixture was stirred for 30 min. The reaction mixture was filtered through a plug of Celite™ (diatomaceous earth), washed through with 2M NH3 in MeOH and the filtrate was concentrated in vacuo to give the crude product. This was purified by flash chromatography using a DCM/MeOH (2 N NH3 in MeOH) gradient to afford the desired product, as a yellow solid. m/z=308.0 (M+H).
Reaction SMILES: Cl.Cl.[CH3:3][C:4]1([N:8]2[CH2:12][CH2:11][CH2:10][CH2:9]2)[CH2:7][NH:6][CH2:5]1.CCN(C(C)C)C(C)C.[CH3:22][C:23]([O:26][C:27]([N:29]([C:47]([O:49][C:50]([CH3:53])([CH3:52])[CH3:51])=[O:48])[N:30]([C:38]1[C:43]([F:44])=[C:42](Cl)[N:41]=[C:40]([Cl:46])[N:39]=1)[C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])=[O:28])([CH3:25])[CH3:24]>CN(C=O)C>[CH3:25][C:23]([O:26][C:27]([N:29]([C:47]([O:49][C:50]([CH3:53])([CH3:52])[CH3:51])=[O:48])[N:30]([C:38]1[C:43]([F:44])=[C:42]([N:6]2[CH2:7][C:4]([CH3:3])([N:8]3[CH2:12][CH2:11][CH2:10][CH2:9]3)[CH2:5]2)[N:41]=[C:40]([Cl:46])[N:39]=1)[C:31]([O:33][C:34]([CH3:35])([CH3:36])[CH3:37])=[O:32])=[O:28])([CH3:22])[CH3:24]
Reactant: CC1(N2CCCC2)CNC1
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)N(C(=O)OC(C)(C)C)c1nc(Cl)nc(Cl)c1F
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)N(C(=O)OC(C)(C)C)c1nc(Cl)nc(N2CC(C)(N3CCCC3)C2)c1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 76.4 %

Procedure:
To a stirred solution of 1-(3-methyl-3-azetidinyl)pyrrolidine dihydrochloride (0.128 g, 86% pure, 0.52 mmol) in DMF (8 mL) at 0° C. was added DIPEA (0.34 mL, 1.94 mmol) followed immediately by tris(1,1-dimethylethyl)2-(2,6-dichloro-5-fluoro-4-pyrimidinyl)-1,1,2-hydrazinetricarboxylate (0.24, 0.49 mmol). The reaction was warmed up to rt and stirred overnight. The mixture was purified by RP-HPLC to provide tris(1,1-dimethylethyl)2-{2-chloro-5-fluoro-6-[3-methyl-3-(1-pyrrolidinyl)-1-azetidinyl]-4-pyrimidinyl}-1,1,2-hydrazinetricarboxylate (0.225 g, 77%). LCMS: (M+H)+: 601.2.