Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([O:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=3)[N:13]=[CH:12][CH:11]=2)[CH:6]=[CH:5][C:3]=1[NH2:4].[CH3:24][O:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[N:32]=[C:33]=[O:34].CO>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:8]=[C:7]([O:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=3)[N:13]=[CH:12][CH:11]=2)[CH:6]=[CH:5][C:3]=1[NH:4][C:33]([NH:32][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=1[O:25][CH3:24])=[O:34]
Reactant: COc1ccccc1N=C=O
Reactant: COc1cc2nccc(Oc3ccc(N)c(Cl)c3)c2cc1OC
Solvent: CO
Solvent: ClC(Cl)Cl
Product: COc1ccccc1NC(=O)Nc1ccc(Oc2ccnc3cc(OC)c(OC)cc23)cc1Cl
Temperature: 60 °C
Reaction time: 8 h
Yield: 76.5 %

Procedure:
2-Chloro-4-[(6,7-dimethoxy-4-quinolyl)oxy]aniline (100 mg) was dissolved in chloroform (10 ml), and 2-methoxyphenyl isocyanate (54 mg) was added to the solution. The mixture was stirred at 60° C. overnight. Methanol was added to the reaction solution, and the solvent was removed by distillation under the reduced pressure. The residue was purified by chromatography on silica gel by development with chloroform/acetone (6/4) to give 111 mg (yield 77%) of the title compound.
Reaction SMILES: [C:1]1([C:7]2[N:11]=[C:10]([N:12]3[CH2:17][CH2:16][C:15](=O)[CH2:14][CH2:13]3)[O:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:19]1([NH2:22])[CH2:21][CH2:20]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>ClCCl>[CH:19]1([NH:22][CH:15]2[CH2:16][CH2:17][N:12]([C:10]3[O:9][N:8]=[C:7]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)[N:11]=3)[CH2:13][CH2:14]2)[CH2:21][CH2:20]1
Reactant: O=C1CCN(c2nc(-c3ccccc3)no2)CC1
Reactant: NC1CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: c1ccc(-c2noc(N3CCC(NC4CC4)CC3)n2)cc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A mixture of 1-(3-phenyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-one (400 mg), cyclopropylamine (120 μL), sodium triacetoxyborohydride (420 mg) and glacial acetic acid (0.20 mL) in dichloromethane (7 mL) is stirred for two days at room temperature. Dichloromethane is added and the mixture is washed with aqueous K2CO3 solution. The organic phase is dried over Na2SO4 and concentrated in vacuo to afford the title compound. TLC: rf=0.30 (silica gel, CH2Cl2/MeOH 95:5); Mass spectrum (ESI+): m/z=285 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:26]=[CH:25][C:5]2[N:6]=[C:7]([C:9]3[CH:14]=[CH:13][C:12]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)=[C:11]([C:21]([F:24])([F:23])[F:22])[CH:10]=3)[S:8][C:4]=2[CH:3]=1.C1C(=O)N([Br:34])C(=O)C1.CC(N=NC(C#N)(C)C)(C#N)C>C(Cl)(Cl)(Cl)Cl>[Br:34][CH2:1][C:2]1[CH:26]=[CH:25][C:5]2[N:6]=[C:7]([C:9]3[CH:14]=[CH:13][C:12]([C:15]4[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=4)=[C:11]([C:21]([F:22])([F:23])[F:24])[CH:10]=3)[S:8][C:4]=2[CH:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc2nc(-c3ccc(-c4ccccc4)c(C(F)(F)F)c3)sc2c1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: FC(F)(F)c1cc(-c2nc3ccc(CBr)cc3s2)ccc1-c1ccccc1
Yield: 72.1 %

Procedure:
To a solution of 6-methyl-2-(2-trifluoromethyl-biphenyl-4-yl)benzothiazole (120 mg, 0.325 mmol) in CCl4 (3.5 ml) is added NBS (64 mg, 1.1 eq.). The mixture is heated to reflux for 15 minutes before AIBN (5 mg, 0.1 eq.) is added. The reaction is refluxed overnight, filtered through celite and washed with CCl4. The filtrate is concentrated and purified by column chromatography (EtOAc/Hexane=9/95). 6-Bromomethyl-2-(2-trifluoromethyl-biphenyl-4-yl)benzothiazole (105 mg, 72%) is isolated.
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][CH:14]=[C:13]([CH3:17])[C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:5].O=C1CCC(=O)N1O[C:26](=O)[CH:27]([NH:30][C:31]([O:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[O:32])[CH2:28][CH3:29].CN(C1C=CC=CN=1)C.C(N(C(C)C)CC)(C)C>C1(C)C=CC=CC=1>[CH2:34]([O:33][C:31](=[O:32])[NH:30][CH:27]([C:26]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:4](=[O:5])[C:3]2[C:2](=[CH:16][CH:15]=[CH:14][C:13]=2[CH3:17])[N:1]=1)[CH2:28][CH3:29])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: Cc1cccc(N)c1C(=O)Nc1ccccc1
Reactant: CCC(NC(=O)OCc1ccccc1)C(=O)ON1C(=O)CCC1=O
Agent: CN(C)c1ccccn1
Solvent: Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: CCC(NC(=O)OCc1ccccc1)c1nc2cccc(C)c2c(=O)n1-c1ccccc1
Temperature: 110 °C
Reaction time: 22 h

Procedure:
Compound 15 (1.20 g, 5.30 mmol) was combined with 2-benzyloxycarbonylaminobutyric acid 2,5-dioxo-pyrrolidin-1-yl ester (2.13 g, 6.36 mmol), dimethylaminopyridine (915 mg, 7.49 mmol), and diisopropylethylamine (1.10 mL, 6.36 mmol) in toluene (15 mL). The mixture was heated to 110° C. and stirred at that temperature for 22 hours. After cooling, the reaction Was purified by flash chromatography to provide the quinazolinone (16) as a pale yellow solid. MS (ES): m/z 428 (M+H). 1H NMR (300 MHz, DMSO-d6) δ 10.26 (s, 1H), 7.75 (d, 2H, J=7.9 Hz), 7.32 (t, 2H, J=7.8 Hz), 7.07 (t, 1H, J=7.3 Hz), 7.00 (t, 1H, J=7.8 Hz), 6.58 (d, 1H, J=8.1 Hz), 6.46 (d, 1H, J=7.4 Hz), 4.98 (br. s, 2H), 2.21 (s, 3H). The reaction described above and compound 16 are shown below.
Reaction SMILES: Cl.Cl.Cl.[CH2:4]1[C:13]2[C:8](=[CH:9][CH:10]=[N:11][CH:12]=2)[CH2:7][CH2:6][N:5]1[C:14]1[CH:20]=[CH:19][C:17]([NH2:18])=[C:16]([CH3:21])[CH:15]=1.C(N(CC)C(C)C)(C)C.[C:31]1([CH3:40])[CH:36]=[CH:35][CH:34]=[C:33]([N:37]=[C:38]=[O:39])[CH:32]=1>C(Cl)Cl>[CH2:4]1[C:13]2[C:8](=[CH:9][CH:10]=[N:11][CH:12]=2)[CH2:7][CH2:6][N:5]1[C:14]1[CH:20]=[CH:19][C:17]([NH:18][C:38]([NH:37][C:33]2[CH:34]=[CH:35][CH:36]=[C:31]([CH3:40])[CH:32]=2)=[O:39])=[C:16]([CH3:21])[CH:15]=1
Reactant: Cc1cc(N2CCc3ccncc3C2)ccc1N
Reactant: Cc1cccc(N=C=O)c1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cccc(NC(=O)Nc2ccc(N3CCc4ccncc4C3)cc2C)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 56.4 %

Procedure:
To a mixture of 4-(3,4-dihydro-2,7-naphthyridin-2(1H)-yl)-2-methylaniline trihydrochloride (35 mg, 0.10 mmol) and N,N-diisopropylethylamine (0.061 mL, 0.35 mmol) in 1.5 mL CH2Cl2 at rt was added meta-tolyl isocyanate (0.019 mL, 0.15 mmol) and the reaction stirred at rt for 3 hours. The reaction was quenched into a brine/aqueous Na2CO3 solution, then extracted with EtOAc. The EtOAc layer was washed with brine/aqueous Na2CO3 solution, dried with anhydrous Na2SO4, and evaporated to a solid. The solid was triturated with EtOAc and then with 20% CHCl3/EtOAc to give the title compound as a beige solid (21 mg, 56%). 1H NMR (Acetone-d6) δ: 8.44 (s, 1H), 8.31 (d, J=5.0 Hz, 1H), 8.07 (s, 1H), 7.56-7.61 (m, 1H), 7.35-7.38 (m, 1H), 7.26-7.34 (m, 2H), 7.08-7.16 (m, 2H), 6.92-6.95 (m, 1H), 6.87-6.92 (m, 1H), 6.75-6.80 (m, 1H), 4.39 (s, 2H), 3.55 (t, J=5.9 Hz, 2H), 2.98 (td, J=5.9, 0.9 Hz, 2H), 2.27 (s, 3H), 2.26 (s, 3H)
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14]Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:16]([O:24][CH2:25][CH3:26])(=[O:23])[CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19]>>[CH2:25]([O:24][C:16]([CH:17]([CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:18]([O:20][CH2:21][CH3:22])=[O:19])=[O:23])[CH3:26]
Reactant: BrCCCCCCOCc1ccccc1
Reactant: CCOC(=O)CC(=O)OCC
Product: CCOC(=O)C(CCCCCCOCc1ccccc1)C(=O)OCC
Yield: 60 %

Procedure:
Ethyl 2-ethoxycarbonyl-8-benzyloxyoctanoate was prepared from 6-benzyloxyhexyl bromide (3.52 g, 13 mmol) and diethyl malonate (2.29 g, 14 mmol) according to the general procedure given above. Yield 60%, bp 152°-158° C./0.15 torr. 1H-NMR: 1.24 (t, 6H), 1.2-1.9 (m, 1OH), 3.43 (t, 2H), 4.18 (q, 4H), 4.45 (s, 2H), 7.27 (m, 5H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:11][C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[N:8]=[C:7]([N:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)[C:6]=2[CH:22]=1.Cl[C:24]([O:26][CH2:27][CH3:28])=[O:25].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:11][C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[N:8]=[C:7]([N:16]3[CH2:21][CH2:20][N:19]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:18][CH2:17]3)[C:6]=2[CH:22]=1
Reactant: CCOC(=O)Cl
Reactant: Clc1ccc2c(c1)C(N1CCNCC1)=Nc1ccccc1O2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)N1CCN(C2=Nc3ccccc3Oc3ccc(Cl)cc32)CC1
Temperature: 80 °C
Reaction time: 3 h
Yield: 97 %

Procedure:
A mixture of 2.20 g of 2-chloro-11-(1-piperazinyl)dibenz[b,f][1,4]oxazepine, 0.76 g of ethyl chloroformate and 0.97 g of potassium carbonate in 20 ml of N,N-dimethylformamide was stirred at 80° C. for 3 hrs. Ice water was added to the reaction mixture and extracted with ether. The etheral layer was washed with water, dried and concentrated. The residue was chromatographed on silica gel using a mixture of n-hexane and ethyl acetate (1:2) as eluents to give 2.62 g of colorless crystals, which were recrystallized from isopropyl ether to give colorless prisms, mp 121.5°-122.5° C.
Reaction SMILES: [CH3:1][C:2]([CH:4]1[CH2:21][CH2:20][C:19]2[CH:18]3[O:22][CH:7]([C:8]4[C:17]3=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH:9]=4)[C:6]=2[CH2:5]1)=[O:3].FC(F)(F)C(O)=[O:26].C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl>[C:2]([CH:4]1[CH2:21][CH2:20][C:19]2[C:18](=[O:26])[C:17]3[C:8](=[CH:9][C:10]4[C:15]([CH:16]=3)=[CH:14][CH:13]=[CH:12][CH:11]=4)[C:7](=[O:22])[C:6]=2[CH2:5]1)(=[O:3])[CH3:1]
Reactant: CC(=O)C1CCC2=C(C1)C1OC2c2cc3ccccc3cc21
Reactant: O=C(O)C(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CC(=O)C1CCC2=C(C1)C(=O)c1cc3ccccc3cc1C2=O
Reaction time: 20 h
Yield: 38 %

Procedure:
A mixture of 0.68 g of (1,2,3,4,5,12-hexahydro-5,12-epoxynaphthacen-2-yl) methyl ketone, 15 ml of chloroform and 0.9 ml of trifluoroacetic acid was left to stand at room temperature for 20 hours, neutralised with sodium hydrogen carbonate and extracted with methylene chloride. The extract was dried over sodium sulphate and concentrated to dryness. The residue was treated with 50 ml of methylene chloride, 1 ml of diethyl ether and 12 g of silicic acid and the mixture was stirred in the air for 48 hours. After concentration to dryness, the residue was chromatographed on silicic acid. There were obtained 475 g (38%) of crude 2-acetyl-1,2,3,4-tetrahydro-5,12-naphthacenedione which, after washing with methanol, had a melting point of 189°-192° C. (from ethanol).
Reaction SMILES: [CH3:1][C:2]1([CH3:7])[CH2:5][NH:4][C:3]1=[O:6].C=O.[C:10](=O)([O-])[O-:11].[K+].[K+]>>[OH:11][CH2:10][N:4]1[CH2:5][C:2]([CH3:7])([CH3:1])[C:3]1=[O:6]
Reactant: CC1(C)CNC1=O
Reactant: O=C([O-])[O-]
Agent: C=O
Agent: [K+]
Product: CC1(C)CN(CO)C1=O
Reaction time: 0.25 h

Procedure:
A flask is charged with 3,3-dimethyl-azetidin-2-one (0.159 g, 1.524 mmol), aqueous formaldehyde (37% wt., 0.124 g, 1.524 mmol) and crushed potassium carbonate (0.009 g, 0.061 mmol). The flask is lowered in a pre-heated oil bath (75° C.). After 15 min, the flask is removed from the oil bath and allowed to stand at room temperature. After 2 h, the mixture is taken up in acetone, dried over magnesium sulfate and filtered through a plug of silica gel. Concentration in vacuo (30° C., 40 Torr) gives 1-hydroxymethyl-3,3-dimethyl-azetidin-2-one, which is used in the next step without further purification. 1H NMR (400 MHz, CDCl3) δ ppm 1.32 (s, 6H), 3.23 (s, 2H), 4.69 (d, J=7.5 Hz, 2H).
Reaction SMILES: [O:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=O.[Cl-].[C:12]([C:14]1[CH:39]=[CH:38][C:17]([CH2:18][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[CH:16][CH:15]=1)#[N:13].[K].CC(C)([O-])C>C1(C)C(C)=CC=CC=1>[O:1]1[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[CH:3]=[C:2]1[CH2:18][C:17]1[CH:38]=[CH:39][C:14]([C:12]#[N:13])=[CH:15][CH:16]=1
Reactant: N#Cc1ccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: O=C1Cc2ccccc2O1
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K]
Solvent: Cc1ccccc1C
Product: N#Cc1ccc(Cc2cc3ccccc3o2)cc1

Procedure:
10.4 g (77.3 mmol) of 2-coumaranone are dissolved in 200 ml xylene and after the addition of 32 g (77.3 mmol) of 4-cyanobenzyl-triphenylphosphonium chloride and 8.7 g (77.3 mmol) of potassium-tert.butoxide the mixture is refluxed for 3 hours under a nitrogen atmosphere. The solvent is distilled off, the residue is taken up in ethyl acetate, combined with silica gel and concentrated by evaporation. Then it is chromatographed on silica gel and eluted with petroleum ether/ethyl acetate (8:2). The desired fractions are combined and concentrated by evaporation.
Reaction SMILES: [C:1]1([C:7]2[O:8][C:9]3[C:17]([CH2:18][C:19]([OH:21])=[O:20])=[CH:16][CH:15]=[CH:14][C:10]=3[C:11](=[O:13])[CH:12]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.[CH3:34][C:35]([CH3:39])([CH3:38])[CH2:36]O.O>CN(C)C=O>[C:1]1([C:7]2[O:8][C:9]3[C:17]([CH2:18][C:19]([O:21][CH2:34][C:35]([CH3:39])([CH3:38])[CH3:36])=[O:20])=[CH:16][CH:15]=[CH:14][C:10]=3[C:11](=[O:13])[CH:12]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1
Reactant: O=C(O)Cc1cccc2c(=O)cc(C3=CCCCC3)oc12
Reactant: CC(C)(C)CO
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)COC(=O)Cc1cccc2c(=O)cc(C3=CCCCC3)oc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 23 %

Procedure:
[2-(1-Cyclohexenyl)-4-oxo-4H-[1]-benzopyran-8-yl]acetic acid (2.84 g) was dissolved in dimethylformamide (30 ml) and carbodiimidazole (1.78 g) was added to the solution. After stirring at room temperature for 2 hours, 2,2-dimethyl-propanol (0.88 g) was added. After stirring at 60° C. for 4 hours, water was added and the mixture was extracted with ethyl acetate. The extracted layer was washed with water, dried and concentrated. The residue was purified by silica gel column chromatography to obtain the title compound (0.82 g), yield 23%, m.p. 138°-139° C. (recrystallized from hexane-ethyl acetate).
Reaction SMILES: [Br:1][C:2]1[CH:17]=[CH:16][C:5]([C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:7])=[C:4](F)[CH:3]=1.[C:19]1([OH:25])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Br:1][C:2]1[CH:17]=[CH:16][C:5]([C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:7])=[C:4]([O:25][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:3]=1
Reactant: Oc1ccccc1
Reactant: O=C(OCc1ccccc1)c1ccc(Br)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(OCc1ccccc1)c1ccc(Br)cc1Oc1ccccc1
Temperature: 85 °C

Procedure:
Phenylmethyl 4-bromo-2-fluorobenzoate (Example 189, 260 mg, 0.84 mmol) was combined with phenol (160 mg, 1.68 mmol, 2.0 eq.) and solid potassium carbonate (580 mg, 4.21 mmol, 5.0 eq.) in anhydrous N,N-dimethylformamide and was heated at 85° C. for 5 hours. The mixture was cooled and partitioned between diethyl ether and water. The aqueous layer was separated and extracted with fresh ether. The organic layers were combined, washed with brine (4×), dried (MgSO4), and concentrated in vacuo to a crude oil. The crude was purified by flash chromatography on silica gel eluted with 95:5 hexanes/ether to provide the title compound as a colorless oil that crystallized upon standing (110 mg, 34%): 1H NMR (300 MHz, CDCl3) δ 7.84 (d, 1 H), 7.39-7.27 (m, 7 H), 7.17-7.10 (m, 1 H), 6.98-6.91 (m, 2 H), 6.85 (d, 2 H), 5.30 (s, 2 H); Rf 0.51 (4:1 hexanes/diethyl ether).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([NH:8][S:9]([C:12]2[S:16][C:15]3[CH:17]=[CH:18][C:19]([F:21])=[CH:20][C:14]=3[C:13]=2[CH3:22])(=[O:11])=[O:10])=[C:4]([C:23]([F:26])([F:25])[F:24])[CH:3]=1.[F:27][C:28]1[CH:29]=[C:30](B(O)O)[CH:31]=[N:32][CH:33]=1>COCCOC.C(O)C.C(=O)([O-])[O-].[Na+].[Na+].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>[F:27][C:28]1[CH:29]=[C:30]([C:2]2[CH:7]=[CH:6][C:5]([NH:8][S:9]([C:12]3[S:16][C:15]4[CH:17]=[CH:18][C:19]([F:21])=[CH:20][C:14]=4[C:13]=3[CH3:22])(=[O:11])=[O:10])=[C:4]([C:23]([F:26])([F:25])[F:24])[CH:3]=2)[CH:31]=[N:32][CH:33]=1
Reactant: OB(O)c1cncc(F)c1
Reactant: Cc1c(S(=O)(=O)Nc2ccc(Br)cc2C(F)(F)F)sc2ccc(F)cc12
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: COCCOC
Solvent: CCO
Product: Cc1c(S(=O)(=O)Nc2ccc(-c3cncc(F)c3)cc2C(F)(F)F)sc2ccc(F)cc12
Yield: 52.4 %

Procedure:
This compound was prepared in analogy to Example 2 starting from 5-fluoro-3-methyl-benzo[b]thiophene-2-sulfonic acid(4-bromo-2-trifluoromethyl-phenyl)-amide (0.12 g) and 5-fluoropyridine-3-boronic acid (0.072 g) in 1,2-dimethoxyethane (1.5 ml), ethanol (0.32 ml) and 2 M aqueous sodium carbonate solution (1.0 ml) with tetrakis(triphenylphosphine)palladium (0.015 g) to obtain the title compound (0.065 g) as a colorless solid. MS (ISP): 485.3 (M+H)+
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:17]=[C:18]([CH:20]=[CH:21][CH:22]=1)[NH2:19].[C:23]([C:27]1[CH:31]=[C:30]([NH:32][C:33](=O)[O-:34])[N:29]([C:36]2[CH:41]=[CH:40][N:39]=[C:38]([CH3:42])[CH:37]=2)[N:28]=1)([CH3:26])([CH3:25])[CH3:24]>C1COCC1.CN(C1C=CN=CC=1)C>[C:23]([C:27]1[CH:31]=[C:30]([NH:32][C:33]([NH:19][C:18]2[CH:20]=[CH:21][CH:22]=[C:16]([O:15][C:6]3[C:5]4[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=4)[N:9]=[CH:8][N:7]=3)[CH:17]=2)=[O:34])[N:29]([C:36]2[CH:41]=[CH:40][N:39]=[C:38]([CH3:42])[CH:37]=2)[N:28]=1)([CH3:26])([CH3:25])[CH3:24]
Reactant: Cc1cc(-n2nc(C(C)(C)C)cc2NC(=O)[O-])ccn1
Reactant: COc1cc2ncnc(Oc3cccc(N)c3)c2cc1OC
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Product: COc1cc2ncnc(Oc3cccc(NC(=O)Nc4cc(C(C)(C)C)nn4-c4ccnc(C)c4)c3)c2cc1OC
Yield: 39.2 %

Procedure:
Using the procedure described in Example 306B, to a solution of 3-(6,7-dimethoxyquinazolin-4-yloxy)aniline (88 mg, 0.29 mmol), prepared as described in Example 113A, in THF (2 ml) was added DMAP (20 mg, 0.16 mmol) and 3-tert-butyl-1-(2-methylpyridin-4-yl)-1H-pyrazol-5-ylcarbamate (130 mg, 0.37 mmol) described in the previous step. The crude was purified by silica gel chromatography (DCM/MeOH 0-10%) to afford 1-(3-tert-butyl-1-(2-methylpyridin-4-yl)-1H-pyrazol-5-yl)-3-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)urea (63 mg, 39%) as a solid. 1H NMR (300 MHz, DMSO-d6) δ 1.27 (s, 9H), 2.49 (s, 3H), 3.98 (s, 6H), 6.40 (s, 1H), 6.95 (d, J=7.8 Hz, 1H), 7.22 (d, J=7.8 Hz, 1H), 7.39-7.44 (m, 3H), 7.45-7.55 (m, 3H), 8.49 (d, J=6 Hz, 1H), 8.52 (s, 1H), 8.66 (s, 1H), 9.27 (s, 1H); LC-MS (ESI) m/z 554 (M+H)+.
Reaction SMILES: [NH2:1][C:2](=[N:5][C:6](=[O:9])OC)[S:3][CH3:4].[F:10][C:11]([F:22])([F:21])[C:12]1[CH:13]=[C:14]([N:18]=[C:19]=[O:20])[CH:15]=[CH:16][CH:17]=1.[Na]>C(Cl)Cl.CO>[F:10][C:11]([F:21])([F:22])[C:12]1[CH:13]=[C:14]([N:18]2[C:19](=[O:20])[NH:1][CH:2]([S:3][CH3:4])[NH:5][C:6]2=[O:9])[CH:15]=[CH:16][CH:17]=1
Reactant: COC(=O)N=C(N)SC
Reactant: O=C=Nc1cccc(C(F)(F)F)c1
Agent: [Na]
Solvent: ClCCl
Solvent: CO
Product: CSC1NC(=O)N(c2cccc(C(F)(F)F)c2)C(=O)N1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 84.9 %

Procedure:
Methyl N-[1-(amino)-1-(methylthio)methylene]carbamate (14.8 g.) was dissolved in methylene chloride (150 ml.). 3-Trifluoromethylphenyl isocyanate (18.7 g.) was added to the solution during 5 minutes and the mixture was stirred at room temperature for 2.5 hours. A freshly prepared solution of sodium (2.3 g.) in methanol (20 ml.) was then added during 5 minutes and the subsequent mixture was stirred at room temperature for 16 hours. The mixture was then evaporated and the residue was dissolved in water (400 ml.). The aqueous solution obtained, was extracted with ethyl acetate (2×400 ml.) to remove neutral byproducts, and then acidified with concentrated hydrochloric acid to pH1. The solid which precipitated was separated by filtration, washed with water (3×500 ml.), and dried (over phosphorus pentoxide) to give 3-(3-trifluoromethylphenyl)-6-methylthio-tetrahydro-1,3,5-triazine-2,4-dione (25.9 g., 86%) as a white solid, m.p. 225°-228° C.
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[CH:21]=[CH:20][C:9]2[NH:10][C:11]([CH2:16][C:17]([OH:19])=O)=[CH:12][S:13](=[O:15])(=[O:14])[C:8]=2[CH:7]=1)(=[O:4])=[O:3].[CH2:22]([O:25][C:26]([C:28]1[N:29]([NH:33][CH2:34][CH2:35][CH:36]([CH3:38])[CH3:37])[CH:30]=[CH:31][CH:32]=1)=[O:27])[CH:23]=[CH2:24].Cl.CN(C)CCCN=C=NCC.CN1CCOCC1.Cl>CN(C)C=O>[CH2:22]([O:25][C:26]([C:28]1[N:29]([N:33]([C:17](=[O:19])[CH2:16][C:11]2[NH:10][C:9]3[CH:20]=[CH:21][C:6]([NH:5][S:2]([CH3:1])(=[O:3])=[O:4])=[CH:7][C:8]=3[S:13](=[O:14])(=[O:15])[CH:12]=2)[CH2:34][CH2:35][CH:36]([CH3:38])[CH3:37])[CH:30]=[CH:31][CH:32]=1)=[O:27])[CH:23]=[CH2:24]
Reactant: C=CCOC(=O)c1cccn1NCCC(C)C
Reactant: CS(=O)(=O)Nc1ccc2c(c1)S(=O)(=O)C=C(CC(=O)O)N2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: C=CCOC(=O)c1cccn1N(CCC(C)C)C(=O)CC1=CS(=O)(=O)c2cc(NS(C)(=O)=O)ccc2N1
Temperature: 25 °C
Reaction time: 4 h
Yield: 100 %

Procedure:
(7-Methanesulfonylamino-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,4]thiazin-3-yl)-acetic acid (Example 81, 0.1 g, 0.3 mmol) was dissolved in anhydrous N,N-dimethylformamide (3 mL). 1-(3-Methyl-butylamino)-1H-pyrrole-2-carboxylic acid allyl ester (Example 1c, 0.07 g, 0.3 mmol) was added followed by 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.06 g, 0.315 mmol). Then N-methylmorpholine (0.07 mL, 0.63 mmol) was added into the above reaction mixture. The mixture was stirred at 25° C. for 4 h. The solution was poured into 1.0 M aqueous hydrochloric acid solution (50 mL). The aqueous layer was extracted with ethyl acetate (2×50 mL). The organic phase was dried over sodium sulfate, filtered and concentrated in vacuo to afford the crude desired product, 1-[[2-(7-methanesulfonylamino-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,4]thiazin-3-yl)-acetyl]-(3-methyl-butyl)-amino]-1H-pyrrole-2-carboxylic acid allyl ester (0.3 mmol) as a yellow oil, which was used in the next step without further purification. LC-MS (ESI) calcd for C24H30N4O7S2 550.16. found 551.6 [M+H+].
Reaction SMILES: O.[CH2:2]([NH:9][C:10](=[O:19])[CH2:11][N:12]1[CH:15]([S:16][CH3:17])[CH2:14][C:13]1=[O:18])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C([O:24]O)(C)(C)C>C1(C)C=CC=CC=1.CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-]>[CH2:2]([NH:9][C:10](=[O:19])[CH2:11][N:12]1[CH:15]([S:16]([CH3:17])=[O:24])[CH2:14][C:13]1=[O:18])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CSC1CC(=O)N1CC(=O)NCc1ccccc1
Reactant: CC(C)(C)OO
Agent: [Ti+4]
Agent: CC(C)[O-]
Solvent: O
Solvent: Cc1ccccc1
Product: CS(=O)C1CC(=O)N1CC(=O)NCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
4RSR-(-)-N-Benzyl-(4-methylsulphinyl-2-oxoazetidin-1-yl )acetamide A solution of S(-)1,1'-bi-2-napthol (0.012 g, 4.2 μmol) in toluene (2 ml) was treated with titanium isopropoxide (0.012 g, 21 μmol) in water (6 mg, 0.033 mmol). The resulting mixture was stirred at room temperature for 1 h. A solution of (-)-N-Benzyl (4-methylthio-2-oxoazetidin-1-yl)acetamide (0.2 g, 0.76 mmol) in toluene was added. After 30 mins t-butylhydroperoxide (136 mg, 1.5 mmol) was added and the mixture stirred for 3h. After evaporation to dryness, the residue was purified by flash chromatography on silica (EtOAc/EtOH 6:1 to 3:1) to give (-)-N-benzyl-(4-methylsulphinyl-2-oxoazetidin-1-yl)acetamide as a solid, 70 mg, 33% m.p. 138-140° C, [α]D25 =-237° (c=1.35, EtOH).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8](F)[C:7]([F:11])=[CH:6][C:3]=1[CH:4]=[O:5].[CH3:12][O:13][CH2:14][CH2:15][O:16][CH2:17][CH2:18][OH:19].C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C)C=O>[Cl:1][C:2]1[CH:9]=[C:8]([O:19][CH2:18][CH2:17][O:16][CH2:15][CH2:14][O:13][CH3:12])[C:7]([F:11])=[CH:6][C:3]=1[CH:4]=[O:5]
Reactant: COCCOCCO
Reactant: O=Cc1cc(F)c(F)cc1Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: COCCOCCOc1cc(Cl)c(C=O)cc1F
Temperature: 90 °C
Reaction time: 8 h

Procedure:
To 2-chloro-4,5-difluoro-benzaldehyde (110, 0.40 g, 0.0023 mol) in N,N-dimethylformamide (10.0 mL), 2-(2-methoxyethoxy)-ethanol (0.327 g, 2.72 mmol) and cesium carbonate (0.886 g, 2.72 mmol) were added. The reaction was stirred at 90° C. overnight. The reaction was poured into water, acidified to pH around 5, and extracted with ethyl acetate. The organic layer was dried over an hydrous sodium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with 30% ethyl acetate in hexane to give a white solid (121, 0.15 g, 24.0%).