Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]([O:12][CH3:13])=[C:10]([O:14][CH3:15])[C:9]([O:16][CH3:17])=[C:8]2[C:4]=1[CH2:5][CH:6]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][OH:26])[CH2:7]2.[CH2:27]([N:29]=[C:30]=[O:31])[CH3:28]>C1COCC1.N1C=CC=CC=1>[CH2:27]([NH:29][C:30](=[O:31])[O:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH:6]1[CH2:7][C:8]2[C:4](=[C:3]([O:2][CH3:1])[C:11]([O:12][CH3:13])=[C:10]([O:14][CH3:15])[C:9]=2[O:16][CH3:17])[CH2:5]1)[CH3:28]
Reactant: CCN=C=O
Reactant: COc1c2c(c(OC)c(OC)c1OC)CC(CCCCCCCCO)C2
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CCNC(=O)OCCCCCCCCC1Cc2c(c(OC)c(OC)c(OC)c2OC)C1
Temperature: 40 °C
Reaction time: 12 h

Procedure:
To a solution of 8-(4,5,6,7-tetramethoxyindan-2-yl)octanol (1.20 g) and ethyl isocyanate (0.517 ml) in THF (12 ml) was added one drop of pyridine. After being stirred for 12 hr at 40° C., the reaction mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=2:1) to yield the entitled compound (1.42 g) as crystals.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[C:8]([CH3:10])[C:5]([CH:6]=[O:7])=[C:4]([CH3:11])[CH:3]=1.Cl[CH2:13][C:14]([N:16]1[CH2:20][CH2:19][CH2:18][CH2:17]1)=[O:15].C([O-])([O-])=O.[Cs+].[Cs+]>CC(C)=O>[CH3:11][C:4]1[CH:3]=[C:2]([O:1][CH2:13][C:14](=[O:15])[N:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)[CH:9]=[C:8]([CH3:10])[C:5]=1[CH:6]=[O:7]
Reactant: Cc1cc(O)cc(C)c1C=O
Reactant: O=C(CCl)N1CCCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Product: Cc1cc(OCC(=O)N2CCCC2)cc(C)c1C=O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 4-hydroxy-2,6-dimethyl-benzaldehyde (87 mg), 2-chloro-1-pyrrolidin-1-yl-ethanone (102 mg), and Cs2CO3 (375 mg, 1.15 mmol) in acetone (4 mL) was stirred at room temperature for 16 h. The mixture was concentrated, diluted with water, and extracted with EtOAc. The organic extracts were washed with brine, dried over Na2SO4, and concentrated under reduced pressure to give 2,6-dimethyl-4-(2-oxo-2-pyrrolidin-1-yl-ethoxy)-benzaldehyde: MS (m/z) 262 (M+1).
Reaction SMILES: [OH:1][CH:2]([C:5]1[O:9][N:8]=[C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:6]=1)[CH2:3][CH3:4].[Cr](O)(O)(=O)=O>C(O)(=O)C.O>[C:2]([C:5]1[O:9][N:8]=[C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:6]=1)(=[O:1])[CH2:3][CH3:4]
Reactant: CCC(O)c1cc(-c2ccccc2)no1
Agent: O=[Cr](=O)(O)O
Solvent: CC(=O)O
Solvent: O
Product: CCC(=O)c1cc(-c2ccccc2)no1
Temperature: 60 °C

Procedure:
In 130 ml of acetic acid, 19 g (93.6 mmol) of 5-(1-hydroxypropyl)-3-phenylisoxazole were dissolved. A solution which had been obtained by dissolving 6.4 g (64 mmol) of chromic acid in a mixed solution of 50 ml of acetic acid and 10 ml of water was added dropwise. The reaction mixture was heated at 60° C. for 3 hours and the solvent was distilled off under reduced pressure. The residue thus obtained was poured in ice water. Colorless crystals precipitated were collected by filtration and then dried under reduced pressure. The crystals were purified by chromatography on a silica gel (eluent: 2:8 hexane/chloroform), whereby 5-propionyl-3-phenylisoxazole was obtained as colorless crystals.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([N:14]2[C:22]3[C:17](=[CH:18][C:19]([Cl:24])=[CH:20][C:21]=3[Cl:23])[CH2:16][CH2:15]2)[C:5](=[O:13])[N:6]([CH:8]([CH2:11][CH3:12])[CH2:9][CH3:10])[CH:7]=1.[CH3:25][N:26](C)C=O>O.[C-]#N.[Zn+2].[C-]#N.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>[Cl:24][C:19]1[CH:18]=[C:17]2[C:22](=[C:21]([Cl:23])[CH:20]=1)[N:14]([C:4]1[C:5](=[O:13])[N:6]([CH:8]([CH2:11][CH3:12])[CH2:9][CH3:10])[CH:7]=[C:2]([C:25]#[N:26])[N:3]=1)[CH2:15][CH2:16]2
Reactant: CN(C)C=O
Reactant: CCC(CC)n1cc(Br)nc(N2CCc3cc(Cl)cc(Cl)c32)c1=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: O
Product: CCC(CC)n1cc(C#N)nc(N2CCc3cc(Cl)cc(Cl)c32)c1=O
Temperature: 175 °C
Yield: 21 %

Procedure:
A solution of 5-bromo-3-(5,7-dichloro-2,3-dihydro-1H-indol-1-yl)-1-(1-ethylpropyl)-2(1H)-pyrazinone (Example 507) (100 mg, 0.23 mmol), zinc cyanide (32 mg, 0.28 mmol), and tetrakis(triphenylphosphine)palladium(0) (32 mg, 25 μmol) in dimethylforamide (3 ml) was degassed with nitrogen and heated to 175° C. in a microwave for 5 min. The reaction mixture was diluted with water (5 mL) and extracted with ethyl acetate (5 mL×2). The combined organic extracts were dried (MgSO4), filtered, and concentrated in vacuo to give a crude residue. Purification by HPLC (reverse phase C18, 95% water in acetonitrile containing 0.1% trifluroacetic acid to 5% water in acetonitrile containing 0.1% trifluroacetic acid, flow rate 18 ml/min, retention time 38.4 min) gave the product (18 mg, 21%) as a yellow solid. mp 197-199° C.; 1H NMR (300 MHz, CDCl3): δ 7.27 (s, 1 H), 7.19 (d, J=2.2 Hz, 1H), 7.14 (d, J=1.8 Hz, 1 H), 4.82-4.77 (m, 1 H), 4.33 (t, J=7.9 Hz, 2 H), 3.15 (t, J=7.7 Hz, 2 H), 1.92-1.78 (m, 2 H), 1.75-1.60 (m, 2 H), 0.89 (t, J=7.3 Hz, 6 H); HRMS (ESI) calcd for C18H19N4OCl2 (M+H)+: 377.0936; Found m/z 377.0910.
Reaction SMILES: [N:1]1[C:6]2[NH:7][C:8]3[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=3[C:10](=[O:12])[NH:11][C:5]=2[CH:4]=[CH:3][CH:2]=1.[C:17](Cl)(=[O:20])[O:18][CH3:19]>O1CCOCC1.C1(C)C=CC=CC=1>[CH3:19][O:18][C:17]([N:7]1[C:8]2[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=2[C:10](=[O:12])[NH:11][C:5]2[CH:4]=[CH:3][CH:2]=[N:1][C:6]1=2)=[O:20]
Reactant: O=C1Nc2cccnc2Nc2ccccc21
Reactant: COC(=O)Cl
Solvent: Cc1ccccc1
Solvent: C1COCCO1
Product: COC(=O)N1c2ccccc2C(=O)Nc2cccnc21

Procedure:
From 5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one and methyl chlorocarbonate in a mixture of dioxan and toluene, 5,11-dihydro-11-methoxycarbonyl-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one was obtained, m.p. 266°-267° C. (D) (from 1,2-dichloroethane);
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3](=O)[CH2:4][C:5]([C:7]1[CH:8]=[N:9][N:10]([C:12]2[C:17]([C:18]([F:21])([F:20])[F:19])=[CH:16][CH:15]=[CH:14][N:13]=2)[CH:11]=1)=O.[C:25]([CH2:27][C:28]([NH:30][CH2:31][C:32]1[CH:37]=[CH:36][C:35]([F:38])=[CH:34][C:33]=1[F:39])=[O:29])#[N:26].N12CCCN=C1CCCCC2>C1C=CC=CC=1>[F:39][C:33]1[CH:34]=[C:35]([F:38])[CH:36]=[CH:37][C:32]=1[CH2:31][N:30]1[C:5]([C:7]2[CH:8]=[N:9][N:10]([C:12]3[C:17]([C:18]([F:21])([F:20])[F:19])=[CH:16][CH:15]=[CH:14][N:13]=3)[CH:11]=2)=[CH:4][C:3]([C:2]([F:24])([F:23])[F:1])=[C:27]([C:25]#[N:26])[C:28]1=[O:29]
Reactant: N#CCC(=O)NCc1ccc(F)cc1F
Reactant: O=C(CC(=O)C(F)(F)F)c1cnn(-c2ncccc2C(F)(F)F)c1
Solvent: C1CCC2=NCCCN2CC1
Solvent: c1ccccc1
Product: N#Cc1c(C(F)(F)F)cc(-c2cnn(-c3ncccc3C(F)(F)F)c2)n(Cc2ccc(F)cc2F)c1=O
Temperature: 90 °C
Yield: 36.2 %

Procedure:
4,4,4-Trifluoro-1-[1-(3-trifluoromethyl-pyridin-2-yl)-1H-pyrazol-4-yl]-butane-1,3-dione (143 mg, 0.41 mmol) and 2-cyano-N-(2,4-difluoro-benzyl)-acetamide (86 mg, 0.41 mmol) were suspended in 1.5 mL anhydrous benzene. To the above reaction mixture was added 1,8-diazabicyclo[5,4,0]undec-7-ene (DBU (31 mg, 0.21 mmol). The mixture was heated at 90° C. under nitrogen atmosphere for overnight. After this period of time, the mixture was evaporated in vacuo and the resulting residue was purified by column chromatography on silica gel (35% EtOAC/Hexane) to give 1-(2,4-difluoro-benzyl)-2-oxo-4-trifluoromethyl-6-[1-(3-trifluoromethyl-pyridin-2-yl)-1H-pyrazol-4-yl]-1,2-dihydro-pyridine-3-carbonitrile as a yellow solid (78 mg, 36% yield). 1H-NMR (400 MHz, CDCl3): δ 5.42 (s, 2H), 6.61 (s, 1H), 6.82 (m, 1H), 6.89 (m, 1H), 7.12 (m, 1H), 7.58 (dd, 1H, J=4.80, J=8.08), 7.73 (s, 1H), 8.28 (dd, 1H, J=1.77, J=8.08), 8.32 (s, 1H), 8.72 (dd, 1H, J=1.77, J=4.80).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][NH2:5].F[C:11]1[CH:19]=[N:18][CH:17]=[CH:16][C:12]=1[C:13]([OH:15])=[O:14]>>[NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][NH:5][C:16]1[CH:17]=[N:18][CH:19]=[CH:11][C:12]=1[C:13]([OH:15])=[O:14]
Reactant: NCc1ccccc1N
Reactant: O=C(O)c1ccncc1F
Product: Nc1ccccc1CNc1cnccc1C(=O)O
Yield: 9 %

Procedure:
The title compound was prepared in 9% yield from 2-aminobenzylamine and 3-fluoroisonicotinic acid according to the procedure for the preparation of Example 3. 1H NMR (400 MHz, DMSO-d6): δ 8.16 (s, 1H), 7.82 (d, 1H, J=5.0 Hz), 7.56 (d, 1H, J=5.0 Hz), 7.05 (d, 1H, J=7.5 Hz), 6.97 (td, 1H, J=7.8, 1.4 Hz), 6.66 (d, 1H, J=7.9 Hz), 6.52 (td, 1H, J=7.4, 1.0 Hz), 4.35 (s, 2H). [M+H] calc'd for C13H13N3O2, 244. found 244.
Reaction SMILES: [F:1][CH:2]([F:18])[C:3]1[N:4]=[C:5]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)[S:6][C:7]=1[CH2:8]O.C(N(CC)CC)C.CS([Cl:30])(=O)=O>ClCCl>[Cl:30][CH2:8][C:7]1[S:6][C:5]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)=[N:4][C:3]=1[CH:2]([F:18])[F:1]
Reactant: CS(=O)(=O)Cl
Reactant: COc1ccc(-c2nc(C(F)F)c(CO)s2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(-c2nc(C(F)F)c(CCl)s2)cc1
Temperature: 25 °C

Procedure:
2.70 g [4-Difluoromethyl-2-(4-methoxy-phenyl)-thiazol-5-yl]-methanol were dissolved in 15 ml dichloromethane and cooled in an ice bath. 2.07 ml triethylamine were added, followed by the addition of 0.92 ml methanesulfonylchloride. The ice bath was removed and the resulting mixture stirred at room temperature over night. Then 2.07 ml triethylamine and 0.92 ml methanesulfonylchloride were added again and the reaction mixture stirred at room temperature for additional four hours. The reaction mixture was then washed with water and brine, dried over MgSO4 and the solvent removed in vacuo to obtain 3.0 g crude 5-chloromethyl-4-difluoromethyl-2-(4-methoxy-phenyl)-thiazole as an oil which was used without further purification.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][OH:19])=[CH:12][CH:11]=2)[C:5]([C:20]#[N:21])=[C:4]([SH:22])[N:3]=1.Cl[CH2:24][C:25]1[N:26]=[C:27]([C:30]2[CH:35]=[CH:34][C:33]([Cl:36])=[C:32]([CH3:37])[CH:31]=2)[O:28][CH:29]=1.C(=O)(O)[O-].[Na+]>CN(C=O)C>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[CH:11]=[CH:12][C:13]([O:16][CH2:17][CH2:18][OH:19])=[CH:14][CH:15]=2)[C:5]([C:20]#[N:21])=[C:4]([S:22][CH2:24][C:25]2[N:26]=[C:27]([C:30]3[CH:35]=[CH:34][C:33]([Cl:36])=[C:32]([CH3:37])[CH:31]=3)[O:28][CH:29]=2)[N:3]=1
Reactant: Cc1cc(-c2nc(CCl)co2)ccc1Cl
Reactant: N#Cc1c(N)nc(S)c(C#N)c1-c1ccc(OCCO)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc(-c2nc(CSc3nc(N)c(C#N)c(-c4ccc(OCCO)cc4)c3C#N)co2)ccc1Cl
Temperature: 25 °C
Reaction time: 12 h

Procedure:
52 mg (0.17 mmol) of the compound from Example 1A and 89 mg (0.18 mmol) of the compound from Example 28A, together with 42 mg (0.50 mmol) of sodium bicarbonate, are suspended in 1.8 ml of dry DMF. The reaction mixture is stirred at RT for 12 h. The mixture is then filtered and the filtrate is purified directly by preparative HPLC (column: YMC GEL ODS-AQ S-5/15 μm; mobile phase gradient: acetonitrile/water 10:90→95:5). After removal of the solvent on a rotary evaporator, the product is obtained as a white solid.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:8](Cl)=[C:7]([S:10]([CH3:13])(=[O:12])=[O:11])[S:6](=[O:14])[N:5]=1)[CH3:2].C[Si]([NH:19][Si](C)(C)C)(C)C.CO>C(#N)C>[CH2:1]([O:3][C:4]1[C:8]([NH2:19])=[C:7]([S:10]([CH3:13])(=[O:12])=[O:11])[S:6](=[O:14])[N:5]=1)[CH3:2]
Reactant: C[Si](C)(C)N[Si](C)(C)C
Reactant: CCOC1=NS(=O)C(S(C)(=O)=O)=C1Cl
Solvent: CC#N
Solvent: CO
Product: CCOC1=NS(=O)C(S(C)(=O)=O)=C1N
Temperature: 25 °C
Yield: 60.3 %

Procedure:
To a solution of crude 3-ethoxy-4-chloro-5- methylsulfonylisothiazole-1-oxide (0.90 g, 1.6 mmol) in acetonitrile (10 ml) under a nitrogen atmosphere was added hexamethyldisilizane (0.70 ml, 3.3 mmol). The reaction mixture was heated at 70° for 11/2 hours, cooled to room temperature and methanol (1.0 ml) was added. The reaction was filtered and evaporated. The residue was triturated with methanol/ethyl acetate to afford crude title compound (0.3 g). Recrystallization from methanol/ethyl acetate after treatment with charcoal gave 0.23 g of pure product, mp 191°-193°.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH2:8]Br)=[CH:6][CH:5]=1)([O-:3])=[O:2].[NH:12]1[CH:16]=[N:15][CH:14]=[N:13]1.C1CCN2C(=NCCC2)CC1>C(Cl)Cl>[N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH2:8][N:12]2[CH:16]=[N:15][CH:14]=[N:13]2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Reactant: c1nc[nH]n1
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Product: O=[N+]([O-])c1ccc(Cn2cncn2)cc1

Procedure:
1.0 g (4.63 mmol) of 4-nitrobenzyl bromide (Fluka, Buchs, Switzerland), 799 mg (11.6 mmol) of 1,2,4-triazole and 0.692 mL (4.63 mmol) of 1,5-diazabicyclo[5.4.0]-5-undecene (Fluka, Buchs, Switzerland) in 10 ml of CH2Cl2 are stirred at rt for 1.5 h. The reaction mixture is quenched with sat. aqueous NaHCO3 and extracted with CH2Cl2 (2×). The organic layers are washed with brine, dried over MgSO4, filtered and evaporated. The residue is purified by flash chromatography (CH2Cl2-MeOH 49:1 to 19:1) to provide the title compound as a pale yellow solid. ES-MS: 205 (M+H)+; analytical HPLC: tret=2.54 minutes (Grad 1).
Reaction SMILES: [F:1][C:2]1[CH:33]=[CH:32][C:5]([CH2:6][C:7]2[CH:16]=[C:15]3[C:10]([C:11]([OH:31])=[C:12]([C:26](OCC)=[O:27])[C:13](=[O:25])[N:14]3[CH2:17][CH2:18][N:19]3[CH2:23][CH2:22][CH2:21][C:20]3=[O:24])=[N:9][CH:8]=2)=[CH:4][CH:3]=1.[CH3:34][O:35][CH2:36][CH2:37][NH2:38]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][C:7]2[CH:16]=[C:15]3[C:10]([C:11]([OH:31])=[C:12]([C:26]([NH:38][CH2:37][CH2:36][O:35][CH3:34])=[O:27])[C:13](=[O:25])[N:14]3[CH2:17][CH2:18][N:19]3[CH2:23][CH2:22][CH2:21][C:20]3=[O:24])=[N:9][CH:8]=2)=[CH:32][CH:33]=1
Reactant: COCCN
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCN2CCCC2=O)c1=O
Product: COCCNC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCN2CCCC2=O)c1=O

Procedure:
This compound was prepared from ethyl 7-(4-fluorobenzyl)-4-hydroxy-2-oxo-1-[2-(2-oxopyrrolidin-1-yl)ethyl]-1,2-dihydro-1,5-naphthyridine-3-carboxylate and 2-methoxyethylamine by methods similar to those described in Example 6. The product was obtained as a white solid: 1H NMR (CDCl3) δ 10.27 (1H, br m), 8.55 (1H, s), 8.06 (1H, s), 7.24 (2H, m), 6.99 (2H, t, J=8.6 Hz), 4.35 (2H, t, J=7 Hz), 4.14 (2H, s), 3.65 (2H, m), 3.59 (2H, m), 3.50 (2H, t, J=7 Hz), 3.44 (2H, m), 3.42 (3H, s), 2.31 (2H, t, J=8 Hz), 1.97 (2H, m); ES+ MS: 483 (M+H+, 100).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH:7]=O)([O-:3])=[O:2].Cl.[OH:13][NH2:14].C([O-])([O-])=O.[Na+].[Na+]>C(O)C.O>[OH:13][N:14]=[CH:7][C:6]1[CH:9]=[CH:10][CH:11]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1
Reactant: O=Cc1cccc([N+](=O)[O-])c1
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: O=[N+]([O-])c1cccc(C=NO)c1
Reaction time: 1 h
Yield: 90.7 %

Procedure:
3-Nitrobenzaldehyde (3.00 g, 19.9 mmol) and hydroxyamine HCl (1.79 g, 25.8 mmol) were dissolved in 60 mL of ethyl alcohol/water (1/1, v/v) solution. While stirring the reaction mixture, Na2CO3 (2.74 g, 25.8 mmol) was added slowly at below 0. The reaction was continued for 1 hr in an oil bath preheated to 60-65. After the reaction was completed, 3.0 g (92%) of the target product was obtained by extracting with ethyl acetate, drying over anhydrous MgSO4 and removing the solvent under reduced pressure.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][NH2:6].[CH3:10][C:11]([CH3:16])([CH3:15])[C:12](Cl)=[O:13].CCN(CC)CC>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][NH:6][C:12](=[O:13])[C:11]([CH3:16])([CH3:15])[CH3:10]
Reactant: NCc1cccc(Cl)c1
Reactant: CC(C)(C)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)C(=O)NCc1cccc(Cl)c1
Reaction time: 2 h

Procedure:
3-chlorobenzylamine (3.54 g, 25 mmol) was added dropwise to trimethylacetyl chloride (2.65 ml, 21.5 mmol) and Et3N (3.5 ml, 25 mmol) in DCM (25 ml). After two hours, the reaction mixture was washed with 1 N HCl and the organic layer collected and dried over MgSO4. N-3-chlorobenzyltrimethylacetamide was precipitated from DCM/hexane as a white solid, 3.95 g,
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[C:6]([F:9])[C:5]([F:10])=[C:4]([CH3:11])[C:3]=1[C:12](=[O:19])[CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15].[CH:20](OCC)(OCC)[O:21][CH2:22][CH3:23]>C(OC(=O)C)(=O)C>[F:1][C:2]1[C:7]([F:8])=[C:6]([F:9])[C:5]([F:10])=[C:4]([CH3:11])[C:3]=1[C:12]([C:13](=[CH:20][O:21][CH2:22][CH3:23])[C:14]([O:16][CH2:17][CH3:18])=[O:15])=[O:19]
Reactant: CCOC(=O)CC(=O)c1c(C)c(F)c(F)c(F)c1F
Reactant: CCOC(OCC)OCC
Solvent: CC(=O)OC(C)=O
Product: CCOC=C(C(=O)OCC)C(=O)c1c(C)c(F)c(F)c(F)c1F
Temperature: 25 °C
Yield: 93.6 %

Procedure:
A solution of 8.1 g (29.1 mmol) of ethyl 3-(2,3,4,5-tetrafluoro-6-methylphenyl)-β-oxopropanoate, 7.2 g (43.3 mmol) of triethyl orthoformate, and 70 ml of acetic anhydride was refluxed for 3.5 hours. The solution was cooled to room temperature and concentrated under high vacuum to give 9.1 g of the title compound. The product was used as is in the next step.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Br[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[Br:17][C:18]1[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=1>>[Br:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])=[CH:20][CH:19]=1
Reactant: CCCCCCCCCBr
Reactant: Oc1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCCCCCCCCOc1ccc(Br)cc1

Procedure:
Quantities: anhydrous potassium carbonate (60 g, 0.43 mol), 1-bromononane (45.3 g, 0.22 mol) and 4-bromophenol (34.6 g, 0.2 mol). The experimental procedure was as described in Example 119.
Reaction SMILES: Cl[CH2:2][C:3]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[O:7][C:6]2[CH:14]=[CH:15][CH:16]=[CH:17][C:5]=2[N:4]=1.[C:18]([O:22][C:23]([NH:25][CH:26]1[CH2:31][CH2:30][CH2:29][N:28]([C:32]2[N:33]([CH2:42][C:43]#[C:44][CH3:45])[C:34]3[C:39](=[O:40])[NH:38][N:37]=[CH:36][C:35]=3[N:41]=2)[CH2:27]1)=[O:24])([CH3:21])([CH3:20])[CH3:19].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[C:18]([O:22][C:23]([NH:25][CH:26]1[CH2:31][CH2:30][CH2:29][N:28]([C:32]2[N:33]([CH2:42][C:43]#[C:44][CH3:45])[C:34]3[C:39](=[O:40])[N:38]([CH2:2][C:3]4[C:9]5[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=5[O:7][C:6]5[CH:14]=[CH:15][CH:16]=[CH:17][C:5]=5[N:4]=4)[N:37]=[CH:36][C:35]=3[N:41]=2)[CH2:27]1)=[O:24])([CH3:21])([CH3:20])[CH3:19]
Reactant: ClCC1=Nc2ccccc2Oc2ccccc21
Reactant: CC#CCn1c(N2CCCC(NC(=O)OC(C)(C)C)C2)nc2cn[nH]c(=O)c21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC#CCn1c(N2CCCC(NC(=O)OC(C)(C)C)C2)nc2cnn(CC3=Nc4ccccc4Oc4ccccc43)c(=O)c21
Temperature: 80 °C
Reaction time: 2 h

Procedure:
317 mg 11-chloromethyl-dibenzo[b,f][1,4]oxazepin are added to 400 mg 2-[3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-3-(2-butyn-1-yl)-3,5-dihydro-imidazo[4,5-d]pyridazin-4-one and 276 mg potassium carbonate in 4 ml N,N-dimethylformamide. The reaction mixture is stirred for two hours at 80° C. For working up it is combined with water and the precipitate formed is suction filtered. The crude product is purified by chromatography over a silica gel column with methylene chloride/methanol (100:0 to 70:30) as eluant.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([Cl:16])=[C:6]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH:7]=1.C([O-])([O-])=O.[K+].[K+].CC1(C)C(C)(C)OB(/[CH:31]=[CH:32]/[C:33]([O:35][CH2:36][CH3:37])=[O:34])O1>C(#N)C.CCO.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>[C:11]([O:10][C:9]([NH:8][C:6]1[CH:7]=[C:2](/[CH:31]=[CH:32]/[C:33]([O:35][CH2:36][CH3:37])=[O:34])[CH:3]=[CH:4][C:5]=1[Cl:16])=[O:15])([CH3:14])([CH3:13])[CH3:12]
Reactant: CCOC(=O)/C=C/B1OC(C)(C)C(C)(C)O1
Reactant: CC(C)(C)OC(=O)Nc1cc(Br)ccc1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCO
Product: CCOC(=O)/C=C/c1ccc(Cl)c(NC(=O)OC(C)(C)C)c1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
To a solution of tert-butyl 5-bromo-2-chlorophenylcarbamate (6-1) (1.0 equiv.) in acetonitrile (0.3 M) and EtOH (0.5 M) was added K2CO3 (2.0 equiv.). The reaction was degassed and flushed with N2, then added (E)-ethyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)acrylate (6-2) (1.2 equiv.) and Pd(PPh3)4 (0.1 equiv.). The reaction was flushed again with N2 and stirred at 100° C. overnight. After cooling to room temperature, hexane was added, and the mixture was filtered through a pad of silica, eluting with EA/Hex (1:1) until the product was completely eluted. The filtrate was concentrated and purified on Combiflash, eluting with 0-15% EA in Hex to give (E)-ethyl 3-(3-(tert-butoxycarbonylamino)-4-chlorophenyl)acrylate (6-3) as a white solid.
Reaction SMILES: [CH3:1][C@:2]1([NH:7]C(=O)OC(C)(C)C)[CH2:6][CH2:5][NH:4][CH2:3]1.C(N(CC)CC)C.[C:22]([C:24]1[C:29]2[N:30]=[C:31]([C:33]([N:35]([CH3:37])[CH3:36])=[O:34])[O:32][C:28]=2[C:27](F)=[C:26]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[C:25]=1[CH3:45])#[N:23]>CS(C)=O>[NH2:7][C@@:2]1([CH3:1])[CH2:6][CH2:5][N:4]([C:27]2[C:28]3[O:32][C:31]([C:33]([N:35]([CH3:36])[CH3:37])=[O:34])=[N:30][C:29]=3[C:24]([C:22]#[N:23])=[C:25]([CH3:45])[C:26]=2[C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=2)[CH2:3]1
Reactant: Cc1c(-c2ccccc2)c(F)c2oc(C(=O)N(C)C)nc2c1C#N
Reactant: CC(C)(C)OC(=O)N[C@@]1(C)CCNC1
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: Cc1c(-c2ccccc2)c(N2CC[C@](C)(N)C2)c2oc(C(=O)N(C)C)nc2c1C#N
Temperature: 150 °C
Yield: 41.6 %

Procedure:
A dimethyl sulfoxide (1 ml) solution of tert-butyl [(3S)-3-methylpyrrolidin-3-yl]carbamate (I-345) (300 mg, 1.50 mmol) and triethylamine (244 μl, 1.75 mmol) was added to a dimethyl sulfoxide (6 ml) solution of 4-cyano-7-fluoro-N,N,5-trimethyl-6-phenyl-1,3-benzoxazole-2-carboxamide (I-114) (404 mg, 1.25 mmol) stirred in an oil bath at 150° C., followed by stirring in an oil bath at 150° C. for 30 minutes. The reaction liquid was concentrated under reduced pressure, the residue was dissolved in ethyl acetate, and washed with aqueous 10% citric acid solution, water and saturated brine. After drying over anhydrous sodium sulfate, the insoluble matter was separated by filtration, and the residue obtained by concentration was purified by silica gel column chromatography (eluent, n-hexane:ethyl acetate=1:1→1:2, v/v). The obtained yellow foamy substance was dissolved in dichloromethane (5 ml), and with cooling with ice, trifluoroacetic acid (10 ml) was added, followed by stirring at room temperature for 5 hours. The reaction liquid was concentrated under reduced pressure, then an aqueous saturated sodium hydrogencarbonate solution and water were added, followed by extraction with chloroform. After drying over anhydrous sodium sulfate, the insoluble matter was separated by filtration, the residue obtained by concentration was purified by preparative TLC (eluent, chloroform:methanol=10:1, v/v), and the obtained eluate was purified in slurry with isopropyl ether to obtain the entitled compound (210 mg, 41%) as a pale yellow solid.