Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH:2]([C:5]1[C:6]([Cl:12])=[N:7][C:8]([Cl:11])=[N:9][CH:10]=1)[CH2:3][CH3:4].[CH3:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][CH:16]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>C(#N)C>[Cl:11][C:8]1[N:7]=[C:6]([Cl:12])[C:5]([CH:2]([NH:21][C:18]2[CH:19]=[CH:20][C:15]([O:14][CH3:13])=[CH:16][CH:17]=2)[CH2:3][CH3:4])=[CH:10][N:9]=1
Reactant: CCC(Br)c1cnc(Cl)nc1Cl
Reactant: COc1ccc(N)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Product: CCC(Nc1ccc(OC)cc1)c1cnc(Cl)nc1Cl
Temperature: 25 °C
Reaction time: 16 h

Procedure:
(±)-5-(1-Bromopropyl)-2,4-dichloro-pyrimidine (0.26 g; 0.96 mmol) (from Example 7b supra) was dissolved in acetonitrile (2.5 mL). p-Anisidine (0.12 g; 0.96 mmol) (Aldrich), potassium carbonate (0.15 g; 1.05 mmol) and potassium iodide (0.04 g; 0.24 mmol) were added and the mixture was stirred at room temperature. After 16 hours, the mixture was partitioned between ethyl acetate and water. The organic phase was washed with water and brine, dried over anhydrous sodium sulfate, filtered and concentrated. Purification by flash chromatography (Biotage 40S, 15:85 to 20:80 ethyl acetate-hexanes gradient) gave crude (±)-[1-(2,4-dichloro-pyrimidin-5-yl)-propyl]-(4-methoxy-phenyl)-amine. (Yield 0.19 g; 64.3%). This material again showed 3 peaks for the pyrimidine ring proton in the same ratio as was seen in the starting material. This material was used without further purification.
Reaction SMILES: C[O-].[Na+].[CH3:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]([CH3:13])=[O:12])=[CH:7][CH:6]=1.C[O:15][C:16](=O)[C:17]([F:20])([F:19])[F:18].Cl>C1(C)C=CC=CC=1>[F:18][C:17]([F:20])([F:19])[C:16](=[O:15])[CH2:13][C:11]([C:8]1[CH:9]=[CH:10][C:5]([CH3:4])=[CH:6][CH:7]=1)=[O:12]
Reactant: CC(=O)c1ccc(C)cc1
Reactant: COC(=O)C(F)(F)F
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: Cc1ccccc1
Product: Cc1ccc(C(=O)CC(=O)C(F)(F)F)cc1
Temperature: 22.5 °C
Reaction time: 0.5 h
Yield: 92.1 %

Procedure:
Sodium methoxide (25.6 g) and toluene (105 ml) were taken in a flask. A solution of 4-methylacetophenone (50 g) in toluene (52 ml) was added at 20-25° C. in 30 minutes. The resultant reaction mixture was stirred further at 20-25° C. for 30 minutes. A solution of methyltrifluoroacetate (56.8 g) in toluene (52 ml) was added slowly at 20-25° C. for about 1 hour and the reaction mixture was heated to about 110° C. for 24 hours. The reaction mixture was cooled to 30° C. and poured into a flask containing aqueous hydrochloric acid (210 ml, 3N). The layers were separated and the aqueous layer was extracted with toluene (2×50 ml). The organic layers were combined and washed with water (2×50 ml). The solvent was removed completely under vacuum to afford the title compound (Yield: 79 g).
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N+:9]([O-])=O.[CH3:12][C:13]([OH:18])([CH:15]([OH:17])[CH3:16])[CH3:14]>>[NH2:9][C:3]1[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=1[O:17][CH:15]([CH3:16])[C:13]([CH3:14])([OH:18])[CH3:12]
Reactant: CC(O)C(C)(C)O
Reactant: O=[N+]([O-])c1ccc(F)cc1F
Product: CC(Oc1cc(F)ccc1N)C(C)(C)O

Procedure:
Is prepared in a similar manner as intermediate III.1 from 2,4-difluoro-1-nitro-benzene and 2-methylbutane-2,3-diol.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[OH:11].C(=O)([O-])[O-].[Na+].[Na+].[CH2:18](Br)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CC(C)=O>[CH2:18]([O:11][C:3]1[CH:4]=[C:5]([N+:8]([O-:10])=[O:9])[CH:6]=[CH:7][C:2]=1[CH3:1])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: BrCc1ccccc1
Reactant: Cc1ccc([N+](=O)[O-])cc1O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)=O
Product: Cc1ccc([N+](=O)[O-])cc1OCc1ccccc1
Yield: 33.5 %

Procedure:
To a stirred suspension of 2-methyl-5-nitrophenol (2.0 g, 13 mmol) and sodium carbonate (1.94 g, 18.3 mmol) in acetone was added benzyl bromide (1.7 mL, 14 mmol). The mixture was heated to reflux for 24 h, cooled, filtered, and the solid washed with acetone. The filtrate and acetone washings were combined and concentrated in vacuo. Recrystallization from ether/hexanes gave 1.06 g (33%) of the title product as an off-white solid.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[O:11][C:12]1[CH:18]=[CH:17][C:15]([NH2:16])=[CH:14][CH:13]=1.C[N:20]([CH:22]=O)C.Br[CH2:25][C:26]([C:28]1[CH:33]=[CH:32][C:31]([O:34][CH2:35][CH2:36][CH2:37][N:38]([CH2:41][CH3:42])[CH2:39][CH3:40])=[CH:30][CH:29]=1)=O>O.CCOC(C)=O>[CH2:10]([C:22]1[N:16]([C:15]2[CH:17]=[CH:18][C:12]([O:11][C:2]3[CH:3]=[CH:4][C:5]4[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=4)[CH:1]=3)=[CH:13][CH:14]=2)[CH:25]=[C:26]([C:28]2[CH:33]=[CH:32][C:31]([O:34][CH2:35][CH2:36][CH2:37][N:38]([CH2:41][CH3:42])[CH2:39][CH3:40])=[CH:30][CH:29]=2)[N:20]=1)[CH2:1][CH2:2][CH3:3]
Reactant: CN(C)C=O
Reactant: CCN(CC)CCCOc1ccc(C(=O)CBr)cc1
Reactant: Nc1ccc(Oc2ccc3ccccc3c2)cc1
Solvent: O
Solvent: CCOC(C)=O
Product: CCCCc1nc(-c2ccc(OCCCN(CC)CC)cc2)cn1-c1ccc(Oc2ccc3ccccc3c2)cc1
Temperature: 25 °C

Procedure:
To a stirred solution of 4-(naphthalen-2-yloxy)aniline (1.2 eq., 5 mmol) in anhydrous DMF (5 mL) DIEA (3 eq. 15 mmol) was added, followed by slow addition of the 2-bromo-1-{4-[3-(diethylamino)propoxy]phenyl}ethanone described above (4.6 mmol), according to General Procedure R2. The reaction mixture was stirred under nitrogen at rt until completion, as indicated by TLC or HPLC. The reaction mixture was then diluted with cold H2O and the product was isolated in EtOAc. The combined organic layers were washed with brine and dried over sodium sulfate. Evaporation of solvent in vacuuo afforded the desired product. The crude alkylated aniline was used for further transformation without additional purification.
Reaction SMILES: [F-].[K+].[Br:3][C:4]1[C:11]([OH:12])=[C:10]([O:13][CH:14]2CCCC2)[CH:9]=[CH:8][C:5]=1[CH:6]=[O:7].F[C:20]1[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][CH:21]=1.O>CS(C)=O>[Br:3][C:4]1[C:11]([O:12][C:20]2[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][CH:21]=2)=[C:10]([O:13][CH3:14])[CH:9]=[CH:8][C:5]=1[CH:6]=[O:7]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: O=Cc1ccc(OC2CCCC2)c(O)c1Br
Agent: [F-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: COc1ccc(C=O)c(Br)c1Oc1ccc([N+](=O)[O-])cc1
Temperature: 140 °C
Reaction time: 6 h
Yield: 81 %

Procedure:
To a stirred suspension of potassium fluoride (125 mg, 2.104 mmol) in dry DMSO (2.5 ml) was added a solution of 2-bromo-4-cyclopentoxy-3-hydroxy-benzaldehyde (500 mg, 1.754 mmol) in DMSO (2.5 ml). A solution of 4-fluoronitrobenzene (500 mg, 2.631 mmol) in DMSO (2.5 ml) was added to the above suspension and the reaction mixture was stirred at 140° C. for 6 h. The reaction mixture was cooled to room temperature and the contents were poured into water (100 ml) and extracted with ethyl acetate (50 ml×3). The organic extracts were combined and washed with 1N sodium hydroxide (25 ml×2), water and brine and dried over anhydrous sodium sulfate. The dried organic layer was concentrated in vacuo to give 2-bromo-3-(p-nitrophenoxy)-4-methoxy benzaldehyde as a pale yellow solid (500 mg) mp: 115–117° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[CH2:10][CH2:11][C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:13].Cl[Si](C)(C)[CH3:22].[C:25]([O-:28])(O)=O.[Na+]>C(O)CO>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[CH2:10][CH2:11][C:12]1([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[O:28][CH2:25][CH2:22][O:13]1
Reactant: COc1ccc(Br)c(CCC(=O)c2ccccc2)c1
Reactant: C[Si](C)(C)Cl
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: OCCO
Product: COc1ccc(Br)c(CCC2(c3ccccc3)OCCO2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 97 %

Procedure:
To a solution of crude 3-(2-Bromo-5-methoxy-phenyl)-1-phenyl-propan-1-one (19.43 g, 61 mmol) in dry ethylene glycol (300 ml) under a N2 atmosphere was added chlorotrimethylsilane (31 ml, 0.25 mol). The reaction was stirred at room temperature for 1 h. A 5% aqueous NaHCO3 (300 ml) was added. The mixture was extracted with diisopropyl ether, and the extracts were washed with brine. The combined ether extracts were dried with Na2SO4 and the solvent was removed under reduced pressure to produce a weight of 21.52 g crude 2-[2-(2-Bromo-5-methoxy-phenyl)-ethyl]-2-phenyl-[1,3]dioxolane (yield: 97%).
Reaction SMILES: [F:1][C:2]1[CH:10]=[N:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.ClC1N=C(OC)N=C(OC)[N:13]=1.CN1CCOCC1.[Cl:29][C:30]1[C:31]([C:40]2[CH:45]=[CH:44][C:43](N)=[CH:42][CH:41]=2)=[CH:32][C:33]2[O:37][C:36]([CH3:38])=[N:35][C:34]=2[CH:39]=1.C([O-])(O)=O.[Na+].CC(=O)OCC>C(Cl)Cl>[Cl:29][C:30]1[C:31]([C:40]2[CH:45]=[CH:44][CH:43]=[C:42]([NH:13][C:4]([C:3]3[CH:7]=[CH:8][N:9]=[CH:10][C:2]=3[F:1])=[O:6])[CH:41]=2)=[CH:32][C:33]2[O:37][C:36]([CH3:38])=[N:35][C:34]=2[CH:39]=1
Reactant: COc1nc(Cl)nc(OC)n1
Reactant: O=C(O)c1ccncc1F
Reactant: Cc1nc2cc(Cl)c(-c3ccc(N)cc3)cc2o1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: Cc1nc2cc(Cl)c(-c3cccc(NC(=O)c4ccncc4F)c3)cc2o1
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.7 %

Procedure:
A suspension of 3-fluoroisonicotinic acid (20 mg, 0.14 mmol), 2-chloro-4,6-dimethoxy-1,3,5-triazine (CDMT)(28 mg, 0.16 mmol) and 40 μl N-methyl morpholine in 1 ml DCM was stirred at r.t. for 1 h before addition of 56 (20 mg, 0.078 mmol). The resulting reaction mixture was stirred at r.t. for overnight. The reaction mixture was worked up with aq. NaHCO3/EA. Org. phase was washed with brine, concentrated, subjected to silica flash column chromatography to furnish 28.5 mg title compound 60 as off-white solid. (Yield: 95.7%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:16](O)[C:10]3[N:11]=[C:12]([CH3:15])[N:13]([CH3:14])[C:9]=3[CH:8]=[CH:7][C:6]=2[CH:18]=1.[CH3:19][N:20]1[CH:27]=[CH:26][C:24](=[O:25])[NH:23][C:21]1=[O:22].B(F)(F)F.CCOCC.CO>C(#N)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:16]([C:26]3[C:24](=[O:25])[NH:23][C:21](=[O:22])[N:20]([CH3:19])[CH:27]=3)[C:10]3[N:11]=[C:12]([CH3:15])[N:13]([CH3:14])[C:9]=3[CH:8]=[CH:7][C:6]=2[CH:18]=1
Reactant: Cn1ccc(=O)[nH]c1=O
Reactant: Cc1nc2c(n1C)C=Cc1cc(Cl)ccc1C2O
Agent: FB(F)F
Solvent: CCOCC
Solvent: CO
Solvent: CC#N
Product: Cc1nc2c(n1C)C=Cc1cc(Cl)ccc1C2c1cn(C)c(=O)[nH]c1=O
Temperature: 50 °C

Procedure:
A mixture of the product from step (iii) (0.91 g), and 1-methyluracil (0.44 g) in acetonitrile (40 ml) was treated with boron trifluoride etherate (2.47 g) and heated at 50° C. for 4 h. The solution was treated with methanol (1 ml) and evaporated. Purification was by chromatography on a biotage silica column, using 3% methanol/0.1% 0.880 ammonia in dichloromethane as eluant to give the subtitled product as a cream powder.
Reaction SMILES: [CH2:1]([C:3]1[O:7][C:6]([NH:8][C:9](=[O:16])OCC(Cl)(Cl)Cl)=[N:5][N:4]=1)[CH3:2].[C:17]1([C:23]2[N:27]=[C:26]([N:28]3[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]3)[S:25][N:24]=2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(N(C(C)C)CC)(C)C.O>CS(C)=O>[CH2:1]([C:3]1[O:7][C:6]([NH:8][C:9]([N:31]2[CH2:32][CH2:33][N:28]([C:26]3[S:25][N:24]=[C:23]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[N:27]=3)[CH2:29][CH2:30]2)=[O:16])=[N:5][N:4]=1)[CH3:2]
Reactant: CCc1nnc(NC(=O)OCC(Cl)(Cl)Cl)o1
Reactant: c1ccc(-c2nsc(N3CCNCC3)n2)cc1
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CCc1nnc(NC(=O)N2CCN(c3nc(-c4ccccc4)ns3)CC2)o1

Procedure:
A mixed solution of 2,2,2-trichloroethyl (5-ethyl-1,3,4-oxadiazol-2-yl)carbamate (213 mg, 0.738 mmol), 1-(3-phenyl-1,2,4-thiadiazol-5-yl)piperazine (200 mg, 0.812 mmol) and diisopropylethylamine (0.129 ml, 0.738 mmol) in dimethyl sulfoxide (2.5 ml) was stirred at 70° C. for 3 hours and half. Water was poured to the reaction mixture, and the resulting solution was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. Chloroform was poured to the residue, and 140 mg (49.1%) of the desired product as a solid was separated by filtration.
Reaction SMILES: CC(C)([O-])C.[K+].[C:7](#[N:9])[CH3:8].[Cl:10][C:11]1[CH:12]=[C:13]([CH:16]=[CH:17][C:18]=1[Cl:19])[C:14]#[N:15]>>[NH2:15][C:14]([C:13]1[CH:16]=[CH:17][C:18]([Cl:19])=[C:11]([Cl:10])[CH:12]=1)=[CH:8][C:7]#[N:9]
Reactant: N#Cc1ccc(Cl)c(Cl)c1
Reactant: CC#N
Agent: CC(C)(C)[O-]
Agent: [K+]
Product: N#CC=C(N)c1ccc(Cl)c(Cl)c1

Procedure:
Using a similar procedure to that of Preparation IX-2, but using 1.5 equivalents of potassium t-butoxide and 1.5 equivalents of acetonitrile per 1 equivalent of 3,4-dichlorobenzonitrile, there is obtained 3-amino-3-(3,4-dichlorophenyl)acrylonitrile.
Reaction SMILES: [CH2:1]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[CH2:5][CH2:4][NH:3][CH2:2]1.N1C=CC=CC=1.Cl[C:19]([O:21][CH2:22][CH3:23])=[O:20]>ClCCl>[CH2:5]1[C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[CH2:1][CH2:2][N:3]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:4]1
Reactant: c1ccc2c(c1)CCNCC2
Reactant: CCOC(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOC(=O)N1CCc2ccccc2CC1
Reaction time: 8 h

Procedure:
To a solution of 1.75 g of 2,3,4,5-tetrahydro-1H-3-benzazepine in 20 ml of dichloromethane was added 2.884 ml of pyridine. The reaction mixture was ice-cooled, and 1.705 ml of ethyl chloroformate which had been dissolved in 5 ml of dichloromethane was added dropwise thereto, followed by stirring overnight. The reaction mixture was concentrated under reduced pressure and the residue was purified by silica gel chromatography (elution solvent: HEX-EtOAc) to obtain 2.15 g of ethyl 1,2,4,5-tetrahydro-3H-3-benzazepine-3-carboxylate as a pale yellow oily substance.
Reaction SMILES: [CH3:1][C:2]([CH3:8])([C:6]#[CH:7])[C:3](O)=O.[NH2:9][NH:10][C:11]([NH2:13])=[S:12].P(Cl)(Cl)(Cl)=O>>[CH3:1][C:2]([C:3]1[S:12][C:11]([NH2:13])=[N:10][N:9]=1)([CH3:8])[C:6]#[CH:7]
Reactant: C#CC(C)(C)C(=O)O
Reactant: NNC(N)=S
Solvent: O=P(Cl)(Cl)Cl
Product: C#CC(C)(C)c1nnc(N)s1

Procedure:
Commercially available, 2,2-dimethylbut-3-ynoic acid (Betapharma), thiosemicarbazide (Aldrich) and phosphorus oxychloride (Aldrich) were processed as described for Example 1A to obtain the title compound. MS (ESI+) m/z 168 (M+H)+.
Reaction SMILES: CO[C:3](=[O:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH3:11][C:12]#[N:13].[H-].[Na+]>C1COCC1>[O:10]=[C:3]([C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1)[CH2:11][C:12]#[N:13]
Reactant: CC#N
Reactant: COC(=O)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: N#CCC(=O)c1ccccc1
Temperature: 70 °C
Reaction time: 8 h

Procedure:
To a solution of benzoic acid methyl ester (1.0 equiv.) and methyl cyanide (2.0 equiv.) in anhydrous THF (1.0 M) was added sodium hydride (60% in mineral oil, 2 equiv.) under nitrogen. After the resulting reaction mixture was stirred at 70° C. overnight, the reaction mixture was quenched with ice-water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and filtered. Concentration under vacuum afforded the crude product as a brown solid. 1H-NMR (400 MHz, CDCl3) δ (ppm) 7.94-7.92 (m, 2H), 7.69-7.65 (m, 1H), 7.55-7.54 (m, 2H), 4.08 (s, 2H).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[N:6]([CH2:23][C:24]2[CH:32]=[CH:31][C:27]([C:28]([OH:30])=[O:29])=[CH:26][CH:25]=2)[C:7](=[O:22])[C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][C:11]([Cl:21])=[CH:10][CH:9]=2)=[O:4].[C:33]([NH2:36])(=S)[CH3:34].O>CN(C=O)C>[NH2:36]/[C:33](/[CH3:34])=[CH:2]\[C:3]([C:5]1[N:6]([CH2:23][C:24]2[CH:32]=[CH:31][C:27]([C:28]([OH:30])=[O:29])=[CH:26][CH:25]=2)[C:7](=[O:22])[C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][C:11]([Cl:21])=[CH:10][CH:9]=2)=[O:4]
Reactant: O=C(O)c1ccc(Cn2c(C(=O)CBr)c(-c3ccccc3)c3cc(Cl)ccc3c2=O)cc1
Reactant: CC(N)=S
Solvent: CN(C)C=O
Solvent: O
Product: C/C(N)=C/C(=O)c1c(-c2ccccc2)c2cc(Cl)ccc2c(=O)n1Cc1ccc(C(=O)O)cc1
Temperature: 70 °C
Reaction time: 24 h
Yield: 51.2 %

Procedure:
To a solution (6 ml) of 4-[[3-(2-bromoacetyl)-6-chloro-1-oxo-4-phenyl-1H-isoquinolin-2-yl]methyl]benzoic acid (570 mg) in DMF was added thioacetamide (170 mg), and the mixture was stirred at 70° C. for 24 hrs. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was crystallized from ethyl acetate to give the title compound (270 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:11][CH2:10][C:9](=[O:12])[NH:8][C:7]=2[CH:13]=1.Br[CH2:15][C@@H:16]([CH3:26])[CH2:17][O:18][Si:19]([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20].C([O-])([O-])=O.[Cs+].[Cs+]>CCCCCCC.CCOC(C)=O>[Si:19]([O:18][CH2:17][C@@H:16]([CH3:26])[CH2:15][N:8]1[C:7]2[CH:13]=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][C:6]=2[O:11][CH2:10][C:9]1=[O:12])([C:22]([CH3:23])([CH3:24])[CH3:25])([CH3:20])[CH3:21]
Reactant: C[C@H](CBr)CO[Si](C)(C)C(C)(C)C
Reactant: COc1ccc2c(c1)NC(=O)CO2
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: COc1ccc2c(c1)N(C[C@H](C)CO[Si](C)(C)C(C)(C)C)C(=O)CO2
Yield: 73 %

Procedure:
6-Methoxy-4H-benzo[1,4]oxazin-3-one (111MF24) (2.7 g, 15.1 mmol), (S)-3-bromo-2-methylpropoxy-tert-butyldimethylsilane (4.03 g, 15.1 mmol) and Cs2CO3 (12.3 g, 38 mmol) were mixed according to GP7. CC (SiO2; Heptane/EtOAc 9:1) to give the title compound (111MF32) (4.03 g, 80%). 1H NMR (CDCl3) δ 6.89 (d, J=8.8 Hz, 1H), 6.71 (d, J=2.8 Hz, 1H), 6.50 (dd, J=2.8 Hz, J=8.6 Hz, 1H), 4.53 (q, J=14.8 Hz, J=29.2 Hz, 2H), 3.98 (dd, J=8.8 Hz, J=14.0 Hz, 1H), 3.85 (dd, J=5.8 Hz, J=14.2 Hz, 1H), 3.77 (s, 3H), 3.57 (dd, J=9.2 Hz, J=10.0 Hz, 1H), 3.47 (dd, J=7.2 Hz, J=10.0 Hz, 1H), 2.20-2.12 (m, 1H), 0.91 (s, 12H), 0.05 (d, J=1.2 Hz, 6H); 13C NMR (CDCl3) δ 165.3, 155.6, 139.7, 129.8, 117.2, 107.4, 103.3, 68.0, 66.2, 55.9, 43.9, 34.3, 26.1, 18.5, 14.7, −5.3, −5.4.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[N:16]=[C:15]([C:20]([F:23])([F:22])[F:21])[CH:14]=[C:13]2[OH:24].[C:25]([O-])([O-])=O.[K+].[K+].CI>CN(C=O)C>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[N:16]=[C:15]([C:20]([F:22])([F:21])[F:23])[CH:14]=[C:13]2[O:24][CH3:25]
Reactant: Oc1cc(C(F)(F)F)nc2ccc(-c3cc4ccccc4o3)cc12
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: COc1cc(C(F)(F)F)nc2ccc(-c3cc4ccccc4o3)cc12
Reaction time: 4 h
Yield: 67.1 %

Procedure:
To a stirring solution of 6-(1-benzofuran-2-yl)-4-hydroxy-2-(trifluoromethyl)-quinoline (1.33 g, 4.04 mmol) in DMF (40 mL) at room temperature was added K2CO3 (0.670 g, 4.85 mmol) followed by methyl iodide (0.276 mL, 4.44 mmol) drop-wise. The reaction mixture was stirred for 4 hours then concentrated and the residue was diluted with EtOAc (200 mL). The organic layer was washed with H2O (20 mL), sat. aq. NaHCO3 (20 mL), and brine (20 mL) and then dried (Na2SO4). After concentration, the residue was purified on a Biotage Flash 40 apparatus (5-15% EtOAc:petroleum ether) to afford the product (0.930 g) as a solid. Mass spectrum (+ESI, [M+H]+) m/z 344. 1H NMR (500 MHz, DMSO-d6): δ 8.67 (s, 1H), 8.46 (d, 1H, J=9.1 Hz), 8.19 (d, 1H, J=9.1 Hz), 7.68-7.79 (m, 3H), 7.48 (s, 1H), 7.40 (t, 1H, J=7.8 Hz), 7.32 (t, 1H, J=7.8 Hz), and 4.26 ppm (s, 3H).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:10]=[C:11]([C:14]([CH3:17])([CH3:16])[CH3:15])[C:12]=1[OH:13])[CH:8]=O)([CH3:4])([CH3:3])[CH3:2].[C:18]1([S:24]([CH2:27][C:28]#[N:29])(=[O:26])=[O:25])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[C:1]([C:5]1[CH:6]=[C:7](/[CH:8]=[C:27](/[S:24]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)(=[O:25])=[O:26])\[C:28]#[N:29])[CH:10]=[C:11]([C:14]([CH3:17])([CH3:16])[CH3:15])[C:12]=1[OH:13])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1cc(C=O)cc(C(C)(C)C)c1O
Reactant: N#CCS(=O)(=O)c1ccccc1
Product: CC(C)(C)c1cc(/C=C(\C#N)S(=O)(=O)c2ccccc2)cc(C(C)(C)C)c1O

Procedure:
M33 was prepared with 3,5-di-t-butyl-4-hydroxybenzaldehyde and phenylsulfonly acetonitrile under similar conditions as described for M26.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([Si:11]([CH3:14])([CH3:13])[CH3:12])[C:3]=1[C:4](Cl)=[O:5].[CH2:15]([NH2:17])[CH3:16]>>[Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([Si:11]([CH3:14])([CH3:13])[CH3:12])[C:3]=1[C:4]([NH:17][CH2:15][CH3:16])=[O:5]
Reactant: CCN
Reactant: C[Si](C)(C)c1cccc(Br)c1C(=O)Cl
Product: CCNC(=O)c1c(Br)cccc1[Si](C)(C)C
Yield: 92 %

Procedure:
The compound of Example d (38.19 g, 0.13 mol) was reacted with 70% aqueous ethylamine (53 mL) according to General Method E1 and recrystallized from methylcyclohexane to afford the title compound as light tan crystals in 92% yield. m.p. 121-122° C.
Reaction SMILES: [NH2:1][CH2:2][C:3]([CH3:6])([OH:5])[CH3:4].[CH:7]1([C:10]2[N:15]=[C:14]([C:16]([NH:18][C:19]3[CH:27]=[N:26][CH:25]=[CH:24][C:20]=3[C:21](O)=[O:22])=[O:17])[C:13]([NH:28][C:29]3[CH:30]=[N:31][CH:32]=[N:33][CH:34]=3)=[CH:12][CH:11]=2)[CH2:9][CH2:8]1>>[OH:5][C:3]([CH3:6])([CH3:4])[CH2:2][NH:1][C:21]([C:20]1[CH:24]=[CH:25][N:26]=[CH:27][C:19]=1[NH:18][C:16]([C:14]1[C:13]([NH:28][C:29]2[CH:30]=[N:31][CH:32]=[N:33][CH:34]=2)=[CH:12][CH:11]=[C:10]([CH:7]2[CH2:9][CH2:8]2)[N:15]=1)=[O:17])=[O:22]
Reactant: CC(C)(O)CN
Reactant: O=C(O)c1ccncc1NC(=O)c1nc(C2CC2)ccc1Nc1cncnc1
Product: CC(C)(O)CNC(=O)c1ccncc1NC(=O)c1nc(C2CC2)ccc1Nc1cncnc1
Yield: 28 %

Procedure:
According to the general method described in step 3 of example 53, reaction of 1-amino-2-methyl-propan-2-ol with 3-{[6-cyclopropyl-3-(pyrimidin-5-ylamino)-pyridine-2-carbonyl]-amino}-isonicotinic acid provided the title compound (28%) as amorphous yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[CH:13]=[CH:14][C:15](OS(C(F)(F)F)(=O)=O)=[CH:16][C:11]=3[S:10][N:9]=2)=[CH:4][CH:3]=1.[CH2:25]([OH:28])[C:26]#[CH:27]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[CH:13]=[CH:14][C:15]([C:27]#[C:26][CH2:25][OH:28])=[CH:16][C:11]=3[S:10][N:9]=2)=[CH:4][CH:3]=1
Reactant: O=S(=O)(Oc1ccc2c(-c3ccc(Br)cc3)nsc2c1)C(F)(F)F
Reactant: C#CCO
Product: OCC#Cc1ccc2c(-c3ccc(Br)cc3)nsc2c1

Procedure:
In analogy to example 13.1, Trifluoro-methanesulfonic acid 3-(4-bromo-phenyl)-benzo[d]isothiazol-6-yl ester and 2-propyn-1-ol were converted to yield 3-[3-(4-Bromo-phenyl)-benzo[d]isothiazol-6-yl]-prop-2-yn-1-ol as light brown solid, MS: 343 (MH+, 1Br).
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:14][CH2:13][C:12]3([CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[C:11]2=[O:20])=[CH:6][CH:5]=1.O=C(Cl)[O:25][C:26](Cl)(Cl)Cl.[CH:31]1([NH:37][CH2:38][CH3:39])[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1>>[CH:31]1([N:37]([CH2:38][CH3:39])[C:26]([N:17]2[CH2:16][CH2:15][C:12]3([C:11](=[O:20])[N:10]([C:7]4[CH:8]=[CH:9][C:4]([O:3][C:2]([F:1])([F:21])[F:22])=[CH:5][CH:6]=4)[CH2:14][CH2:13]3)[CH2:19][CH2:18]2)=[O:25])[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1
Reactant: CCNC1CCCCC1
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Reactant: O=C1N(c2ccc(OC(F)(F)F)cc2)CCC12CCNCC2
Product: CCN(C(=O)N1CCC2(CC1)CCN(c1ccc(OC(F)(F)F)cc1)C2=O)C1CCCCC1
Temperature: 80 °C
Reaction time: 1 h

Procedure:
This material was prepared in analogy to example 251 step B) from 2-(4-trifluoromethoxy-phenyl)-2,8-diaza-spiro[4.5]decan-1-one, diphosgene and cyclohexyl-ethyl-amine. The reaction mixture was stirred for 1 h at room temperature, 2 h at 50° C. and 1 h at 80° C. before subjecting to work-up and purification. MS (ESI): 468.5 (MH+).