Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][CH2:2][CH:3]([C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][CH:6]=1)[CH3:4].[Sb](Cl)(Cl)[Cl:15].II.P(Cl)(Cl)Cl.ClCl>>[Cl:15][C:6]1[CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[CH:9]=[CH:10][C:5]=1[CH:3]([CH2:2][Cl:1])[CH3:4]
Reactant: CC(CCl)c1ccc([N+](=O)[O-])cc1
Reactant: Cl[Sb](Cl)Cl
Agent: ClCl
Agent: II
Solvent: ClP(Cl)Cl
Product: CC(CCl)c1ccc([N+](=O)[O-])cc1Cl
Temperature: 25 °C

Procedure:
24 g (0.12 Mol) of 4(1-chloromethyl-ethyl)-nitrobenzene, 1 g of antimony trichloride, 50 mg of iodine and 16 mg of PCl3 are gradually warmed to 60°. Through the resulting homogeneous syrup a current of dry chlorine is passed at such a rate that the temperature inside the flask does not rise above 70°. When little more than the theoretical amount of chlorine is absorbed (5.3 g/20 minutes) the brown reaction mixture is cooled to ambient temperature and then taken up in 125 ml of toluene. The toluene solution is washed with five 150 ml portions of water, dried (Na2SO4) and evaporaed in vacuo.
Reaction SMILES: Cl[C:2]1[CH:23]=[CH:22][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[C:11]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)[CH:10]=2)=[O:7])=[C:4]([CH3:24])[N:3]=1.[CH3:25][S:26]([N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1)(=[O:28])=[O:27]>C(O)CCC>[Cl:15][C:12]1[CH:13]=[CH:14][C:9]([NH:8][C:6](=[O:7])[C:5]2[CH:22]=[CH:23][C:2]([N:32]3[CH2:33][CH2:34][N:29]([S:26]([CH3:25])(=[O:28])=[O:27])[CH2:30][CH2:31]3)=[N:3][C:4]=2[CH3:24])=[CH:10][C:11]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=1
Reactant: CS(=O)(=O)N1CCNCC1
Reactant: Cc1nc(Cl)ccc1C(=O)Nc1ccc(Cl)c(-c2ccccn2)c1
Solvent: CCCCO
Product: Cc1nc(N2CCN(S(C)(=O)=O)CC2)ccc1C(=O)Nc1ccc(Cl)c(-c2ccccn2)c1

Procedure:
1.3 mL of methanesulfonyl chloride was slowly added to a solution of 2 g of 1-Boc-piperazine and 1.3 mL of pyridine in 6 mL of dichloromethane at 0° C. The reaction mixture was allowed to warm to room temperature and stirred for 2 h while being monitored by TLC. Upon completion, the mixture was diluted with dichloromethane, washed with H2O, dried (MgSO4) and evaporated. Purified by silica gel chromatograph (20-100% ethyl acetate/hexane) to afford tert-butyl-4-(methylsulfonyl)piperazine-1-carboxylate. 930 mg of tert-butyl-4-(methylsulfonyl)piperazine-1-carboxylate was treated with 4N HCl in dioxane for 2 h. The reaction mixture was evaporated to give the HCl salt of 1-(methylsulfonyl)piperazine. Procedure F was performed using 50 mg of 6-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-2-methylnicotinamide, 69 mg of 1-(methylsulfonyl)piperazine and DEPA (1 eq) in 0.5 mL of BuOH. Purified by reverse phase HPLC to yield N-(4-chloro-3-(pyridin-2-yl)phenyl)-2-methyl-6-(4-(methylsulfonyl)piperazin-1-yl)nicotinamide. MS (Q1) 486.3 (M)+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[N:12]=[C:11]([CH3:13])[O:10][N:9]=2)[CH:5]=[CH:4][C:3]=1[C:14]1[CH:19]=[CH:18][C:17]([C:20]([OH:22])=O)=[CH:16][CH:15]=1.C(OC([NH:30][CH2:31][CH2:32][O:33][C:34]1[CH:35]=[C:36]([CH:38]=[CH:39][C:40]=1[O:41][CH3:42])[NH2:37])=O)(C)(C)C.Cl>CO>[NH2:30][CH2:31][CH2:32][O:33][C:34]1[CH:35]=[C:36]([NH:37][C:20]([C:17]2[CH:16]=[CH:15][C:14]([C:3]3[CH:4]=[CH:5][C:6]([C:8]4[N:12]=[C:11]([CH3:13])[O:10][N:9]=4)=[CH:7][C:2]=3[CH3:1])=[CH:19][CH:18]=2)=[O:22])[CH:38]=[CH:39][C:40]=1[O:41][CH3:42]
Reactant: Cc1nc(-c2ccc(-c3ccc(C(=O)O)cc3)c(C)c2)no1
Reactant: COc1ccc(N)cc1OCCNC(=O)OC(C)(C)C
Agent: Cl
Solvent: CO
Product: COc1ccc(NC(=O)c2ccc(-c3ccc(-c4noc(C)n4)cc3C)cc2)cc1OCCN
Reaction time: 20 h
Yield: 19 %

Procedure:
2'-methyl-4'-(5-methyl-1,2,4-oxadiazol-3-yl)biphenyl-4-carboxylic acid (EP 0533268 A1) was reacted with 3-(2-(t-butyloxycarbonylamino)ethoxy)-4-methoxyaniline (D11) following a procedure similar to that described in Example 1. The product was dissolved in methanol (10 ml), and treated with 3.3M ethereal HCl solution (3 ml) and left to stand at room temperature for 20 hours. After removal of the solvent in vacuo, the residue was dissolved in H2O solid potassium carbonate was added and the mixture extracted with EtOAC (3×). The combined organic extracts were dried and concentrated in vacuo. Flash column chromatography on silica gel eluting with 5% MeOH/CH2Cl2 gave the title compound as a white solid (0.06 g, 19%) mp 150°-153° C.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH3:12][C:13]1[C:14]([N:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)=[N:15][CH:16]=[C:17]([CH3:19])[CH:18]=1>>[Br:1][C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4]([N:23]1[CH2:24][CH2:25][N:20]([C:14]2[C:13]([CH3:12])=[CH:18][C:17]([CH3:19])=[CH:16][N:15]=2)[CH2:21][CH2:22]1)=[O:6]
Reactant: O=C(O)c1ccc(Cl)cc1Br
Reactant: Cc1cnc(N2CCNCC2)c(C)c1
Product: Cc1cnc(N2CCN(C(=O)c3ccc(Cl)cc3Br)CC2)c(C)c1
Yield: 98.7 %

Procedure:
Using 2-bromo-4-chlorobenzoic acid (2.09 g) and 1-(3,5-dimethylpyridin-2-yl)piperazine (1.7 g) described in Preparation Example 79 and by the reaction and treatment in the same manner as in Preparation Example 111, the title compound (3.58 g) was obtained.
Reaction SMILES: [CH2:1]([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[NH:12][C:13]([C:15]2[N:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:18]3=[N:17][CH:16]=2)=[O:14])[N:5]([CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([CH:31]=O)[N:26]=2)[N:4]=1)[CH3:2].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[N:47]1([C:53]([O:55][C:56]([CH3:59])([CH3:58])[CH3:57])=[O:54])[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]1>ClCCl.CO>[CH2:1]([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[NH:12][C:13]([C:15]2[N:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:18]3=[N:17][CH:16]=2)=[O:14])[N:5]([CH2:24][C:25]2[N:26]=[C:27]([CH2:31][N:50]3[CH2:51][CH2:52][N:47]([C:53]([O:55][C:56]([CH3:59])([CH3:58])[CH3:57])=[O:54])[CH2:48][CH2:49]3)[CH:28]=[CH:29][CH:30]=2)[N:4]=1)[CH3:2]
Reactant: CCc1nn(Cc2cccc(C=O)n2)c2cccc(NC(=O)c3cnc4ccccn34)c12
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: CCc1nn(Cc2cccc(CN3CCN(C(=O)OC(C)(C)C)CC3)n2)c2cccc(NC(=O)c3cnc4ccccn34)c12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 45 %

Procedure:
To a mixture of N-(3-ethyl-1-((6-formylpyridin-2-yl)methyl)-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide (20 mg, 0.0471 mmol) and sodium triacetoxyborohydride (49.9 mg, 0.236 mmol) in a 1:1 mixture of dichloromethane/methanol (1 mL) was added tert-butyl piperazine-1-carboxylate (10.5 mg, 0.0565 mmol). The mixture was stirred for 30 minutes at ambient temperature. The solvent was removed under reduced pressure and the residue was purified using preparative thin layer chromatography on silica, eluting with 12% methanol and 0.5% ammonium hydroxide in dichloromethane to give the desired product (12.6 mg).
Reaction SMILES: [F:1][C:2]([F:12])([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[N:6]=1)[CH2:3][OH:4].[CH3:13][S:14](Cl)(=[O:16])=[O:15].C(N(CC)CC)C>C1COCC1>[F:12][C:2]([F:1])([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[N:6]=1)[CH2:3][O:4][S:14]([CH3:13])(=[O:16])=[O:15]
Reactant: CS(=O)(=O)Cl
Reactant: Cc1cccc(C(F)(F)CO)n1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1cccc(C(F)(F)COS(C)(=O)=O)n1
Reaction time: 2.5 h
Yield: 90.3 %

Procedure:
To a solution of 2,2-difluoro-2-(6-methyl-pyridin-2-yl)-ethanol (2.82 g, 16.3 mmol) (prepared essentially as described in Example 1f) in anhydrous THF (60 mL) at 0° C. was added methanesulfonyl chloride (1.52 mL, 19.6 mmol), followed by triethylamine (4.54 mL, 32.6 mmol). After 2.5 hours, the reaction mixture was quenched with ice/water. The resulting mixture was extracted with ethyl acetate. The combined organic layers were dried over Na2SO4 and evaporated to afford the desired product as a clear oil (3.7 g, 97%). 1H NMR (CDCl3) δ 7.73 (t, J=7.77 Hz, 1H), 7.51 (d, J=7.75 Hz, 1H), 7.28 (d, J=8.04 Hz, 1H), 4.89 (t, J=12.88 Hz, 2H), 3.07 (s, 3H), 2.58 (s, 3H); LC/MS (m/z) [M+1] 252.2 (calculated for C9H12F2NO3S, 252.0).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([CH3:17])[C:8]2[NH:12][C:11]([CH2:13][CH2:14][CH3:15])=[N:10][C:9]=2[CH:16]=1)=[O:4].CC(C)([O-])C.[K+].Br[CH2:25][C:26]1[CH:43]=[CH:42][C:29]2/[C:30](=[CH:39]/[C:40]#[N:41])/[C:31]3[CH:38]=[CH:37][CH:36]=[CH:35][C:32]=3[CH2:33][CH2:34][C:28]=2[CH:27]=1.C(OCC)(=O)C>CN(C=O)C>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([CH3:17])[C:8]2[N:12]=[C:11]([CH2:13][CH2:14][CH3:15])[N:10]([CH2:25][C:26]3[CH:43]=[CH:42][C:29]4/[C:30](=[CH:39]/[C:40]#[N:41])/[C:31]5[CH:38]=[CH:37][CH:36]=[CH:35][C:32]=5[CH2:33][CH2:34][C:28]=4[CH:27]=3)[C:9]=2[CH:16]=1)=[O:4]
Reactant: N#C/C=C1\c2ccccc2CCc2cc(CBr)ccc21
Reactant: CCCc1nc2cc(C(=O)OC)cc(C)c2[nH]1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCc1nc2c(C)cc(C(=O)OC)cc2n1Cc1ccc2c(c1)CCc1ccccc1/C2=C\C#N
Reaction time: 0.17 h
Yield: 73 %

Procedure:
[step 1] 6-Methoxycarbonyl-4-methyl-2-propylbenzimidazole (EP502314; 1.19 g, 5.13 mmol) was dissolved in DMF (15 mL), potassium tert-butoxide (0.60 g, 5.3 mmol) was added at 0° C., and the mixture was stirred for 10 min. To this mixture was added a solution of (E)-(2-bromomethyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene)acetonitrile obtained in Reference Example B1 in DMF (8 mL), and the mixture was stirred at room temperature for 2 hr. Ethyl acetate was added to the mixture, and the organic layer was washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=3/1 tot/3) to give (E)-[2-(6-methoxycarbonyl-4-methyl-2-propylbenzimidazol-1-yl)methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene]acetonitrile (1.78 g, 73%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:18]3=[N:19][CH:20]=[N:21][C:22](Cl)=[C:17]3[CH:16]=[N:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:24]([C:26]1[CH:31]=[C:30]([OH:32])[N:29]=[C:28]([CH3:33])[N:27]=1)[CH3:25].C(=O)([O-])[O-].[K+].[K+]>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:18]3=[N:19][CH:20]=[N:21][C:22]([O:32][C:30]4[CH:31]=[C:26]([CH2:24][CH3:25])[N:27]=[C:28]([CH3:33])[N:29]=4)=[C:17]3[CH:16]=[N:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(n2ncc3c(Cl)ncnc32)CC1
Reactant: CCc1cc(O)nc(C)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCc1cc(Oc2ncnc3c2cnn3C2CCN(C(=O)OC(C)(C)C)CC2)nc(C)n1
Yield: 12.6 %

Procedure:
4-[4-(6-Ethyl-2-methyl-pyrimidin-4-yloxy)-pyrazolo[3,4-d]pyrimidin-1-yl]-piperidine-1-carboxylic acid tert-butyl ester (10 mg, 13%) was prepared using the procedure described for the preparation of Example 41 by the reaction of 4-(4-chloro-pyrazolo[3,4-d]pyrimidin-1-yl)-piperidine-1-carboxylic acid tert-butyl ester (Intermediate 19; 60 mg, 0.18 mmol) with 4-ethyl-6-hydroxy-2-methylpyrimidine (Synchem Inc., Des Plaines, Ill., USA; 25 mg, 0.18 mmol) in the presence of potassium carbonate (54 mg, 0.39 mmol). Mass spectrum MH+=440.
Reaction SMILES: [Br:1][C:2]1[CH:6]=[CH:5][NH:4][N:3]=1.Cl[C:8]1[C:13]([Cl:14])=[CH:12][CH:11]=[CH:10][N:9]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CN(C)C=O>O>[Br:1][C:2]1[CH:6]=[CH:5][N:4]([C:8]2[C:13]([Cl:14])=[CH:12][CH:11]=[CH:10][N:9]=2)[N:3]=1
Reactant: Clc1cccnc1Cl
Reactant: Brc1cc[nH]n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: Clc1cccnc1-n1ccc(Br)n1
Temperature: 100 °C
Reaction time: 8 h
Yield: 68.5 %

Procedure:
A mixture of 10.7 g of 3-bromo-1H-pyrazole, 11.8 g of 2,3-dichloropyridine, 57.3 g of cesium carbonate and 80 mL of N,N-dimethylformamide was stirred at 100° C. for 8 hours. After cooling to room temperature and adding water, the reaction mixture was extracted twice with methyl tert-butyl ether. The organic layers were combined, washed sequentially with water and a saturated sodium chloride solution, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography to obtain 12.9 g of 2-(3-bromo-1H-pyrazol-1-yl)-3-chloropyridine. 2-(3-bromo-1H-pyrazol-1-yl)-3-chloropyridine
Reaction SMILES: [C:1]([O:8][CH3:9])(=[O:7])/[CH:2]=[CH:3]/[C:4]([OH:6])=[O:5].Cl[CH2:11][C:12]([NH:14][CH2:15][CH2:16][CH2:17][C:18]([O:20]C(C)(C)C)=[O:19])=[O:13].C(=O)([O-])O.[Cs+]>CN1C(=O)CCC1>[CH3:9][O:8][C:1](/[CH:2]=[CH:3]/[C:4]([O:6][CH2:11][C:12]([NH:14][CH2:15][CH2:16][CH2:17][C:18]([OH:20])=[O:19])=[O:13])=[O:5])=[O:7]
Reactant: COC(=O)/C=C/C(=O)O
Reactant: CC(C)(C)OC(=O)CCCNC(=O)CCl
Agent: O=C([O-])O
Agent: [Cs+]
Solvent: CN1CCCC1=O
Product: COC(=O)/C=C/C(=O)OCC(=O)NCCCC(=O)O
Yield: 45.6 %

Procedure:
Following general procedure A, methyl hydrogen fumarate (MHF) (0.56 g, 4.33 mmol) dissolved in NMP was reacted at ca. 55° C. with tert-butyl 4-(2-chloroacetylamino)butanoate (0.85 g, 3.61 mmol) in the presence of CsHCO3 (0.98 g, 5.05 mmol) of the tert-butyl-protected intermediate and then purified by silica gel column chromatography (Biotage) using a mixture of ethyl acetate (EtOAc) and hexanes (1:1) as eluent. The purified product was treated with 50% trifluoroacetic acid (TFA) in dichloromethane (DCM). Removal of solvents afforded 0.45 g (46% yield) of the title compound (7). 1H NMR (CD3OD, 400 MHz): δ 6.94-6.91 (m, 2H), 4.65 (s, 2H), 3.81 (s, 3H), 3.28 (t, J=6.8 Hz, 2H), 2.33 (t, J=7.2 Hz, 2H), 1.81 (p, J=7.1 Hz, 2H). MS (ESI): m/z 274.03 (M+H)+272.06 (M−H)−.
Reaction SMILES: [C:1]([C:5]1[CH:12]=[CH:11][C:8]([CH:9]=O)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[Cl:13][C:14]1[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:15]=1[CH2:21][CH2:22][NH2:23].[BH4-].[Na+].Cl>CO>[C:1]([C:5]1[CH:12]=[CH:11][C:8]([CH2:9][NH:23][CH2:22][CH2:21][C:15]2[CH:16]=[CH:17][C:18]([Cl:20])=[CH:19][C:14]=2[Cl:13])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1ccc(C=O)cc1
Reactant: NCCc1ccc(Cl)cc1Cl
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)c1ccc(CNCCc2ccc(Cl)cc2Cl)cc1
Temperature: 25 °C
Yield: 68.5 %

Procedure:
0.753 ml of 4-tert-butylbenzaldehyde (4.5 mmol) and 0.436 ml of 2-(2,4-dichloro-phenyl)-ethylamine (3 mmol) were dissolved in 8 ml methanol at rt and after 30 min at rt refluxed for 3.5 h. After cooling down to rt, 170 mg (4.5 mmol) of sodium borohydride were added in portions and the reaction mixture was then refluxed overnight. After cooling down to rt, the reaction mixture was treated with 1 N HCl and concentrated in vacuo. The residue was diluted with water/EtOAc. After separation of the organic phase, the aqueous phase was extracted with EtOAc and the combined organic phases were washed with brine, dried with magnesium sulfate, filtered off and concentrated in vacuo. The residue was purified by column chromatography (40 g silica gel; EtOAc/heptane 1:2) to give 691 mg colorless oil (68%). MS(ISP) 336.3 (M+H)+.
Reaction SMILES: [OH:1][C@@H:2]([C:6]1[CH:15]=[CH:14][C:9]([C:10]([O:12][CH3:13])=[O:11])=[CH:8][CH:7]=1)[CH2:3][CH2:4][CH3:5].C(N(CC)CC)C.[CH3:23][S:24](Cl)(=[O:26])=[O:25]>C(OC)(C)(C)C>[CH3:23][S:24]([O:1][C@@H:2]([C:6]1[CH:15]=[CH:14][C:9]([C:10]([O:12][CH3:13])=[O:11])=[CH:8][CH:7]=1)[CH2:3][CH2:4][CH3:5])(=[O:26])=[O:25]
Reactant: CS(=O)(=O)Cl
Reactant: CCC[C@@H](O)c1ccc(C(=O)OC)cc1
Solvent: COC(C)(C)C
Solvent: CCN(CC)CC
Product: CCC[C@@H](OS(C)(=O)=O)c1ccc(C(=O)OC)cc1

Procedure:
To a solution of (R)-methyl 4-(1-hydroxybutyl)benzoate, intermediate (26) (10 g, 48 mmol) in methyl t-butyl ether (80 mL) containing triethylamine (6.32 g, 62 mmol) was added methanesulfonyl chloride (6.05 g, 53 mmol) slowly at 20° C. The solution was filtered to remove triethylamine salts and the solution used in the next step without isolation.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6](=[O:24])[S:7][C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][C:11]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[CH:10][CH:9]=2)=[O:4].[C:25]([Si:29]([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[CH2:30][CH2:31]O)([CH3:28])([CH3:27])[CH3:26].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[CH3:1][O:2][C:3]([C:5]1[C:6](=[O:24])[S:7][C:8]2[C:13]([C:14]=1[O:15][CH2:31][CH2:30][Si:29]([C:25]([CH3:26])([CH3:28])[CH3:27])([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[CH:12][C:11]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[CH:10][CH:9]=2)=[O:4]
Reactant: CC(C)(C)[Si](CCO)(c1ccccc1)c1ccccc1
Reactant: COC(=O)c1c(O)c2cc(OCc3ccccc3)ccc2sc1=O
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1c(OCC[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)c2cc(OCc3ccccc3)ccc2sc1=O
Yield: 66.2 %

Procedure:
To a mixture of 6-benzyloxy-4-hydroxy-2-oxo-2H-thiochromene-3-carboxylic acid methyl ester (Compound 62 (h), 591 mg, 1.73 mmol) and 2-(tert-Butyl-diphenyl-silanyl)-ethanol (687 mg, 2.42 mmol) (prepared according to the procedure published in J. Org. Chem. 2005, 70(4), 1467-1470) in THF (7 mL) was added triphenylphosphine (634 mg, 2.42 mmol), and DIAD (489 mg, 2.42 mmol). The resultant mixture was stirred at rt for 3.5 h. After concentration, the crude residue was purified by silica gel chromatography (eluting with 0-75% EtOAc/hexanes) to provide the title compound (697 mg). 1H NMR (200 MHz, CDCl3): δ (ppm)=7.69-7.14 (m, 18H), 5.83 (s, 2H), 4.25-4.09 (m, 2H), 3.49 (s, 3H), 1.89-1.81 (m, 2H), 1.08 (s, 9H).
Reaction SMILES: Cl.[F:2][C:3]1[CH:22]=[C:21]([CH3:23])[C:20]([O:24]C(OC)=O)=[CH:19][C:4]=1[NH:5][C:6]1[C:15]2[C:10](=[CH:11][C:12]([OH:18])=[C:13]([O:16][CH3:17])[CH:14]=2)[N:9]=[CH:8][N:7]=1.[C:29]([NH:32][C:33]1[S:34][CH:35]=[C:36]([CH2:38]Cl)[N:37]=1)(=[O:31])[CH3:30]>>[C:29]([NH:32][C:33]1[S:34][CH:35]=[C:36]([CH2:38][O:18][C:12]2[CH:11]=[C:10]3[C:15]([C:6]([NH:5][C:4]4[CH:19]=[C:20]([OH:24])[C:21]([CH3:23])=[CH:22][C:3]=4[F:2])=[N:7][CH:8]=[N:9]3)=[CH:14][C:13]=2[O:16][CH3:17])[N:37]=1)(=[O:31])[CH3:30]
Reactant: COC(=O)Oc1cc(Nc2ncnc3cc(O)c(OC)cc23)c(F)cc1C
Reactant: CC(=O)Nc1nc(CCl)cs1
Agent: Cl
Product: COc1cc2c(Nc3cc(O)c(C)cc3F)ncnc2cc1OCc1csc(NC(C)=O)n1
Yield: 25.2 %

Procedure:
Using an analogous procedure to that described in Example 27, 4-(2-fluoro-5-methoxycarbonyloxy-4-methylanilino)-7-hydroxy-6-methoxyquinazoline hydrochloride (470 mg 1.14 mmol), (prepared as described for the starting material in Example 22), and 2-acetamido-4-chloromethylthiazole (381 mg, 1.68 mmol) were combined to give 7-((2-acetamidothiazol-4-yl)methoxy)-4-(2-fluoro-5-hydroxy-4-methylanilino)-6-methoxyquinazoline (135 mg, 25%). 1H NMR Spectrum: (DMSOd6; CF3COOD) 2.16(s, 3H); 2.19(s, 3H); 4.00(s, 3H); 5.33(s, 2H); 6.91(d, 1H); 7.12(d, 1H); 7.33(s, 1H); 7.49(s, 1H); 8.16(s, 1H); 8.82(s, 1H) MS-ESI: 470 [MH]+
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:5]([CH2:6]N(C)C)=[C:4]([S:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[CH:3]=1.[Cl:22]C(OCC)=O>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:11]=[CH:10][C:5]([CH2:6][Cl:22])=[C:4]([S:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[CH:3]=1
Reactant: CCOC(=O)Cl
Reactant: COc1ccc(CSc2cc(Cl)ccc2CN(C)C)cc1
Solvent: Cc1ccccc1
Product: COc1ccc(CSc2cc(Cl)ccc2CCl)cc1
Temperature: 2.5 °C
Yield: 97.8 %

Procedure:
A solution of 4-chloro-2-(4-methoxybenzylthio)-N,N-dimethylbenzylamine (D19) (2.49 g, 7.7 mmol) in dry toluene (80 ml) was cooled in ice whilst ethyl chloroformate (0.9 ml, 9.4 mmol) was added dropwise. A solid slowly separated, and after 1 h at 0-5° C. the mixture was heated under reflux for 2 h. The solvent was removed in vacuo, then the residue was repeatedly dissolved in toluene and evaporated to dryness (3 times) to give the title compound as a light brown oil (2.36 g, 98%).
Reaction SMILES: [Br:1][C:2]1[C:3]([OH:10])=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=O.[C:11]([CH:16]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)(OCC)=[O:12]>CN1C(=O)CCC1>[Br:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:4]2[C:3]=1[O:10][C:11](=[O:12])[CH:16]=[CH:5]2
Reactant: O=Cc1cccc(Br)c1O
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN1CCCC1=O
Product: O=c1ccc2cccc(Br)c2o1
Temperature: 210 °C
Yield: 25.8 %

Procedure:
To a solution of 3-bromo-2-hydroxybenzaldehyde (402 mg, 2.0 mmol) in NMP (5 mL) was added carbethoxymethylene triphenylphosphorane (765 mg, 2.2 mmol). The reaction was heated at 210° C. for 3 h, then was cooled to RT and partitioned between water and ethyl acetate. The layers were separated and the organic layer was dried over MgSO4. Purification by flash chromatography on silica gel (2:1 hexanes/ethyl acetate) yielded the title compound (116 mg, 26%) as a light beige solid: MS (ES) m/e 227.0 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[C:7]([OH:14])[CH:8]=[N:9]2)([O-:3])=[O:2].[H-].[Na+].[CH3:17]I.O>CN(C=O)C>[CH3:17][O:14][C:7]1[CH:8]=[N:9][C:10]2[C:5]([CH:6]=1)=[C:4]([N+:1]([O-:3])=[O:2])[CH:13]=[CH:12][CH:11]=2
Reactant: O=[N+]([O-])c1cccc2ncc(O)cc12
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cnc2cccc([N+](=O)[O-])c2c1
Reaction time: 2 h

Procedure:
To a solution of 5-nitroquinolin-3-ol in DMF is added sodium hydride at 0° C. Then, methyl iodide is added and the mixture is stirred for 2 h. Water is added and the mixture is extracted with ethyl acetate. The organic layer is dried, filtered and concentrated under reduced pressure to give 3-methoxy-5-nitroquinoline.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[CH2:8]([O:10][C:11]([C:13]1[CH:14]=[N:15][C:16]2[CH:17]=[C:18]3[O:28][CH:27]([CH2:29][O:30][CH2:31][CH3:32])[CH2:26][O:25][C:19]3=[C:20]([NH2:24])[C:21]=2[C:22]=1[OH:23])=[O:12])[CH3:9]>C(O)C>[CH2:8]([O:10][C:11]([C:13]1[CH:14]=[N:15][C:16]2[CH:17]=[C:18]3[O:28][CH:27]([CH2:29][O:30][CH2:31][CH3:32])[CH2:26][O:25][C:19]3=[C:20]([NH:24][C:1](=[O:3])[CH3:2])[C:21]=2[C:22]=1[OH:23])=[O:12])[CH3:9]
Reactant: CC(=O)OC(C)=O
Reactant: CCOCC1COc2c(cc3ncc(C(=O)OCC)c(O)c3c2N)O1
Solvent: CCO
Product: CCOCC1COc2c(cc3ncc(C(=O)OCC)c(O)c3c2NC(C)=O)O1
Temperature: 50 °C

Procedure:
3 portions of acetic acid anhydride totalling 3 ml were added at intervals of half an hour to a suspension of 0.13 g of 10-amino-3-(ethoxymethyl)-2,3-dihydro-9-hydroxy-p-dioxino [2,3-g] quinoline-8-carboxylic acid ethyl ester obtained by the method described in Example 29) in 15 ml of 96% ethanol. Before the last addition the reaction mixture was briefly heated to about 50°C, a clear solution being obtained. After the last addition the mixture was stirred for another hour and subsequently concentrated by evaporation in a vacuum. The concentrate was mixed with methylene chloride and water, after which the two layers were separated. The water layer was extracted 2 times with methylene chloride, the entire solution in methylene chloride was then washed thrice with water and subsequently dried over anhydrous sodium sulfate. Subsequently the solvent was distilled off in a vacuum. The residue having the superscribed structure was not purified any further.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8]CC#C)[C:5]([C:12]2[C:13](=[O:23])[N:14]([CH3:22])[C:15]([C:18]([F:21])([F:20])[F:19])=[CH:16][CH:17]=2)=[C:4]([F:24])[CH:3]=1.[F-].[Cs+].C(N(CC)[C:30]1[CH:35]=CC=C[CH:31]=1)C>>[Cl:1][C:2]1[C:7]2[CH:31]=[C:30]([CH3:35])[O:8][C:6]=2[C:5]([C:12]2[C:13](=[O:23])[N:14]([CH3:22])[C:15]([C:18]([F:20])([F:19])[F:21])=[CH:16][CH:17]=2)=[C:4]([F:24])[CH:3]=1
Reactant: C#CCOc1cc(Cl)cc(F)c1-c1ccc(C(F)(F)F)n(C)c1=O
Reactant: CCN(CC)c1ccccc1
Agent: [Cs+]
Agent: [F-]
Product: Cc1cc2c(Cl)cc(F)c(-c3ccc(C(F)(F)F)n(C)c3=O)c2o1
Yield: 21 %

Procedure:
2.78 g (7.73 mmol) of 3-[4-chloro-2-fluoro-6-propargyloxyphenyl]-1-methyl-6-trifluoromethyl-2(1H)-pyridone and 2.35 g (15.46 mmol) of cesium fluoride was heated to 180° C. in 50 ml of N,N-diethylaniline and reacted for 1 hour. The solvent was distilled off under reduced pressure, followed by extraction with ethyl acetate. The organic layer was washed with dilute hydrochloric acid and dried over magnesium sulfate. Then, the solvent was distilled off under reduced pressure. Then, the obtained residue was purified by silica gel column chromatography to obtain 0.58 g (yield: 21%) of the desired product. Melting point: 138-140° C.