Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([I:8])=[CH:4][C:3]=1[C:9]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH3:19])=[CH:13][CH:12]=1)=O.C(#N)C.C([SiH](CC)CC)C.C(=O)(O)[O-].[Na+]>C(OC)(C)(C)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([I:8])=[CH:4][C:3]=1[CH2:9][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH3:19])=[CH:13][CH:12]=1
Reactant: CCOc1ccc(C(=O)c2cc(I)ccc2Cl)cc1
Agent: CC[SiH](CC)CC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: COC(C)(C)C
Product: CCOc1ccc(Cc2cc(I)ccc2Cl)cc1
Temperature: 5 °C
Reaction time: 0.5 h

Procedure:
A jacketed 1 L three-necked round bottom flask with mechanical stirrer, rubber septum with temperature probe and gas bubbler was charged with crude (2-chloro-5-iodophenyl)(4-ethoxyphenyl)methanone (30.13 g, 77.93 mmol), acetonitrile (300 mL, KF=0.004 wt % water) and the suspension was set stirring under nitrogen and was cooled to about 5° C. Then triethylsilane (28 mL, 175.30 mmol, 2.25 equiv) was added followed by boron trifluoride-diethyletherate (24 mL, 194.46 mmol, 2.50 equiv) which was added over about 30 seconds. The reaction was warmed to ambient over 30 min and was stirred for 17 hours. The reaction was diluted with methyl tert-butyl ether (150 mL) followed by saturated aq sodium bicarbonate (150 mL) which was added over about 1 minutes. Mild gas evolution was noticed and the biphasic solution was stirred at ambient for 45 minutes. The upper organic phase was washed with saturated aq. sodium bicarbonate (100 mL), and with saturated aq. sodium chloride (50 mL). The washed extract was concentrated on a rotary evaporator to about one half of its original volume and was diluted with water (70 mL). Further concentration in vacuo at 45° C. was done until white prills formed which were allowed to cool to ambient while stirring. After about 30 minutes at ambient, the suspended solids were isolated by filtration, washed with water (30 mL), and were dried in vacuo at 45° C. After about 2.5 hours, this afforded 1-chloro-2-(4-ethoxybenzyl)-4-iodobenzene as a slightly waxy white granular powder (28.28 g, 98.2 area % by HPLC at 220 nm, 97.4% “as-is” yield).
Reaction SMILES: [C:1]1([O:7][CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:9](Cl)(=[O:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[Cl-].[Al+3].[Cl-].[Cl-]>CCCCCC>[CH3:8][O:7][C:1]1[CH:6]=[CH:5][C:4]([C:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:16])=[CH:3][CH:2]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: COc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCCCCC
Product: COc1ccc(C(=O)c2ccccc2)cc1
Reaction time: 0.25 h

Procedure:
Anisole (0.1 mole, 10.8 grams) and benzoyl chloride (0.1 mole, 14 grams) were dissolved in 200 milliliters of hexane and stirred at room temperature while 15 grams of anhydrous aluminum chloride were added slowly over a period of 15 minutes. The reaction mixture was stirred an additional 15 minutes and then the hexane decanted. The resulting viscous residue in the reaction flask was carefully hydrolyzed with 200 milliliters of a mixture of ice and dilute hydrochloric acid. The resulting organic fraction was taken up in dichloromethane and the resulting solution washed with water. Dichloromethane solvent was removed on a rotary evaporator leaving an oil product that solidified on standing. The solidified product was broken-up, washed with two 50 milliliters portions of pentane, and suction dried yielding 4-methoxybenzophenone.
Reaction SMILES: C[Si]([C:5]#[C:6][C:7]1[CH:16]=[CH:15][C:10]([C:11]([O:13][CH3:14])=[O:12])=[C:9]([OH:17])[CH:8]=1)(C)C.C1COCC1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O>[C:6]([C:7]1[CH:16]=[CH:15][C:10]([C:11]([O:13][CH3:14])=[O:12])=[C:9]([OH:17])[CH:8]=1)#[CH:5]
Reactant: COC(=O)c1ccc(C#C[Si](C)(C)C)cc1O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: C#Cc1ccc(C(=O)OC)c(O)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 113.5 %

Procedure:
3.07 g (12.4 mmol) of methyl 4-trimethylsilanylethynyl-2-hydroxybenzoate are mixed, in a 500 ml three-necked flask, with 50 ml of THF, and 13.7 ml of a tetrabutylammonium fluoride solution (1 M/THF) are added dropwise. The reaction medium is stirred for 1 h at room temperature and is then poured into water and extracted with ethyl ether. After separation of the phases by settling, the organic phase is dried over magnesium sulphate and concentrated. 2.48 g (100%) of a beige-coloured powder are obtained. m.p.=62° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[OH:9].[Br:10][CH2:11][CH2:12][CH2:13]Br.[OH-].[Na+]>O>[Br:10][CH2:11][CH2:12][CH2:13][O:9][C:3]1[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][C:4]=1[Cl:8]
Reactant: BrCCCBr
Reactant: Oc1c(Cl)cccc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Clc1cccc(Cl)c1OCCCBr
Temperature: 100 °C
Yield: 71.3 %

Procedure:
A mixture of 2,6-dichlorophenol (163 g, 1 mol) and 1,3-dibromopropane (262 g, 1.3 mol) was heated to 100° C., and a solution of sodium hydroxide (40 g) in water (1000 ml) was added dropwise over 75 min. The mixture was heated under reflux for 5 h and then cooled to room temperature upon which a biphasic solution developed. The organic layer was separated and the aqueous layer was extracted with diethyl ether (3×250 ml). The combined organic fractions were washed with 2N aqueous sodium hydroxide solution (4×250 ml) and water (250 ml), dried (MgSO4), filtered and concentrated in vacuo to afford the crude product. The residue was distilled at 100-120° C./0.3 mm of mercury to afford the title compound as an oil (202.5 g, 71%).
Reaction SMILES: [Si]([O:8][CH2:9][C@@H:10]1[CH2:14][S:13][C@@H:12]([P:15]([O:20][CH2:21][CH3:22])([O:17][CH2:18][CH3:19])=[O:16])[S:11]1)(C(C)(C)C)(C)C>CO.C(Cl)(=O)C.[Cl-].[NH4+]>[CH2:18]([O:17][P:15]([O:20][CH2:21][CH3:22])([C@H:12]1[S:11][C@H:10]([CH2:9][OH:8])[CH2:14][S:13]1)=[O:16])[CH3:19]
Reactant: CCOP(=O)(OCC)[C@@H]1SC[C@@H](CO[Si](C)(C)C(C)(C)C)S1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CC(=O)Cl
Solvent: CO
Product: CCOP(=O)(OCC)[C@@H]1SC[C@@H](CO)S1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 86.1 %

Procedure:
To a solution of trans-4-(t-butyldimethylsilyloxymethyl)-2-(diethyloxyphosphinoyl)-1,3-dithiolane (example 49) (9.84 g, 25.46 mmol) in anhydrous methanol (150 mL) was added acetyl chloride (12 drops) at 0° C. The solution was stirred at 0° C. for 30 min and then at room temperature for 3.5 hrs. A saturated solution of ammonium chloride (5 drops) was added and the solution was stirred for 15 min followed by evaporation of the solvents. The crude material was purified by flash chromatography with a mixture of dichloromethane and methanol (94:6) to give a white solid (5.97 g) in 86% yield.
Reaction SMILES: C([O:3][C:4](=[O:38])[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][N:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]3[CH:25]=[CH:24][C:23]([NH:26][C:27]([NH:29][C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=4[CH3:36])=[O:28])=[CH:22][CH:21]=3)[C:15]2=[O:37])=[CH:9][CH:8]=1)C.[OH-].[Li+].Cl>O1CCCC1.O>[O:37]=[C:15]1[C:16]([C:20]2[CH:25]=[CH:24][C:23]([NH:26][C:27]([NH:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=3[CH3:36])=[O:28])=[CH:22][CH:21]=2)=[CH:17][CH:18]=[CH:19][N:14]1[CH2:13][C:10]1[CH:11]=[CH:12][C:7]([CH2:6][CH2:5][C:4]([OH:38])=[O:3])=[CH:8][CH:9]=1
Reactant: CCOC(=O)CCc1ccc(Cn2cccc(-c3ccc(NC(=O)Nc4ccccc4C)cc3)c2=O)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccccc1NC(=O)Nc1ccc(-c2cccn(Cc3ccc(CCC(=O)O)cc3)c2=O)cc1

Procedure:
3-(4-{2-Oxo-3-[4-(3-o-tolyl-ureido)phenyl)2H-pyridin-1-ylmethyl}phenyl)propionic acid ethyl ester (P9, 55 mg, 0.11 mmol) and lithium hydroxide (50 mg, 2.5 mmol) were stirred at 60° C. for 30 minutes in tetrahydrofuran (5 mL) and water (5 mL). The reaction mixture was acidified to pH 1 with 1 N aqueous hydrochloric acid and extracted with ethyl acetate. The organic layer was dried (anhydrous magnesium sulfate) and evaporated to dryness to afford the title compound as a solid.
Reaction SMILES: [N:1]1[CH2:2][CH:3]=[CH:4][CH:5]=[CH:6][C:7]=1[NH2:8].Cl.C(=O)([O-])[O-].[K+].[K+].[N:16]1[CH:21]=[CH:20][C:19]([C:22](=O)[CH2:23][C:24](OCC)=[O:25])=[N:18][CH:17]=1>C(O)C>[N:16]1[CH:21]=[CH:20][C:19]([C:22]2[N:8]=[C:7]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][N:1]3[C:24](=[O:25])[CH:23]=2)=[N:18][CH:17]=1
Reactant: CCOC(=O)CC(=O)c1ccncn1
Reactant: NC1=NCC=CC=C1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: O=c1cc(-c2ccncn2)nc2n1CCCCC2
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 28.7 %

Procedure:
To a suspension of 77.9 g (524.1 mmol) of 2H-azepin-7-amine, 3,4,5,6-tetrahydro, monohydrochloride (synthesis as described in WO96/14844 or in Journal of Medicinal Chemistry (1998), 41(9), 1361-1366) in 390 mL of ethanol was added 72.4 g (524.1 mmol) of potassium carbonate. The reaction mixture was stirred at room temperature for 10 min, 101.7 g (524.1 mmol) of ethyl 3-(4-pyrimidinyl)-3-oxopropionate was added and the resulting mixture was stirred under reflux for 16 h. The cooled solution was evaporated to remove solvent. The mixture was dissolved in dichloromethane, washed with a saturated aqueous solution of sodium chloride, dried over sodium sulfate and evaporated to dryness. The residue was filtrate through a pad of silica, rinsing with dichloromethane and then ethyl acetate. After evaporation, the resulting solid was triturated in diethyl ether, filtrated to afford 36.4 g (28%) of the desired compound as a white-brown powder.
Reaction SMILES: [C@@H:1]([NH:5][CH2:6][C:7]1[NH:8][C:9](=[O:17])[C:10]2[CH2:16][O:15][CH2:14][CH2:13][C:11]=2[N:12]=1)([CH2:3][CH3:4])[CH3:2].[F:18][C:19]1[CH:36]=[CH:35][C:22]([C:23]([CH:25]2[CH2:30][CH2:29][N:28]([CH2:31][C:32](O)=[O:33])[CH2:27][CH2:26]2)=[O:24])=[CH:21][CH:20]=1>>[C@@H:1]([N:5]([CH2:6][C:7]1[NH:8][C:9](=[O:17])[C:10]2[CH2:16][O:15][CH2:14][CH2:13][C:11]=2[N:12]=1)[C:32](=[O:33])[CH2:31][N:28]1[CH2:29][CH2:30][CH:25]([C:23](=[O:24])[C:22]2[CH:21]=[CH:20][C:19]([F:18])=[CH:36][CH:35]=2)[CH2:26][CH2:27]1)([CH2:3][CH3:4])[CH3:2]
Reactant: O=C(O)CN1CCC(C(=O)c2ccc(F)cc2)CC1
Reactant: CC[C@H](C)NCc1nc2c(c(=O)[nH]1)COCC2
Product: CC[C@H](C)N(Cc1nc2c(c(=O)[nH]1)COCC2)C(=O)CN1CCC(C(=O)c2ccc(F)cc2)CC1

Procedure:
Following general procedure of Example 4, the title compound was prepared (8.7 mg) from (S)-2-((sec-butylamino)methyl)-7,8-dihydro-3H-pyrano[4,3-d]pyrimidin-4(5H)-one and 2-(4-(4-fluorobenzoyl)piperidin-1-yl)acetic acid. Exact mass calculated for C26H33FN4O4 484.6. found 485.4 (ESI, M+H); 1H NMR (400 MHz, dichloromethane-d2) δ ppm 7.87-8.08 (m, 2H) 7.09-7.25 (m, 2H) 4.41-4.57 (m, 2H) 4.20-4.40 (m, 3H) 4.16 (d, J=8.08 Hz, 1H) 3.83-3.97 (m, 2H) 3.19-3.42 (m, 3H) 3.11 (d, J=5.56 Hz, 1H) 2.93 (d, J=8.59 Hz, 1H) 2.43-2.71 (m, 3H) 2.17-2.36 (m, 2H) 2.00 (br. s., 1H) 1.68-1.92 (m, 3H) 1.22 (d, J=6.57 Hz, 2H) 1.09 (d, J=7.07 Hz, 1H) 0.66-0.83 (m, 3H).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2C=C[C:17]([F:20])=[CH:16][C:15]=2F)=[CH:10][C:9]=1[NH:22][C:23](=[O:35])[CH2:24][C:25]([C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([C:33]#[N:34])[CH:28]=1)=O)(C)(C)C.[C:37](O)([C:39]([F:42])(F)F)=O>C(Cl)Cl>[F:42][C:39]1[CH:37]=[C:17]([F:20])[CH:16]=[CH:15][C:14]=1[C:11]1[CH:12]=[CH:13][C:8]2[N:7]=[C:25]([C:27]3[CH:28]=[C:29]([CH:30]=[CH:31][CH:32]=3)[C:33]#[N:34])[CH2:24][C:23](=[O:35])[NH:22][C:9]=2[CH:10]=1
Reactant: O=C(O)C(F)(F)F
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2ccc(F)cc2F)cc1NC(=O)CC(=O)c1cccc(C#N)c1
Solvent: ClCCl
Product: N#Cc1cccc(C2=Nc3ccc(-c4ccc(F)cc4F)cc3NC(=O)C2)c1

Procedure:
Prepared from {3-[3-(3-cyano-phenyl)-3-oxo-propionylamino]-2′,4′-difluoro-biphenyl-4-yl}-carbamic acid tert.-butyl ester (Example K85) by treatment with TFA in CH2Cl2 according to the general procedure M. Obtained as a light yellow solid (37 mg).
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[CH2:10][CH2:9][N:8]([CH2:11][C:12]([F:15])([F:14])[F:13])[CH2:7][CH2:6]1)=[O:4].C(=O)([O-])[O-].[K+].[K+].[C:22]([NH:26][C:27]([C:29]1[C:37]2[C:32](=[N:33][CH:34]=[C:35]([C:38]3[C:46]4[C:41](=[CH:42][CH:43]=[C:44]([O:47][CH:48]([F:50])[F:49])[CH:45]=4)[NH:40][N:39]=3)[N:36]=2)[N:31]([CH2:51][O:52][CH2:53][CH2:54][Si:55]([CH3:58])([CH3:57])[CH3:56])[CH:30]=1)=[O:28])([CH3:25])([CH3:24])[CH3:23]>CN(C=O)C>[C:22]([NH:26][C:27]([C:29]1[C:37]2[C:32](=[N:33][CH:34]=[C:35]([C:38]3[C:46]4[C:41](=[CH:42][CH:43]=[C:44]([O:47][CH:48]([F:49])[F:50])[CH:45]=4)[N:40]([CH2:2][C:3](=[O:4])[N:5]4[CH2:10][CH2:9][N:8]([CH2:11][C:12]([F:15])([F:14])[F:13])[CH2:7][CH2:6]4)[N:39]=3)[N:36]=2)[N:31]([CH2:51][O:52][CH2:53][CH2:54][Si:55]([CH3:58])([CH3:57])[CH3:56])[CH:30]=1)=[O:28])([CH3:25])([CH3:24])[CH3:23]
Reactant: O=C(CCl)N1CCN(CC(F)(F)F)CC1
Reactant: CC(C)(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3n[nH]c4ccc(OC(F)F)cc34)nc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(CC(=O)N4CCN(CC(F)(F)F)CC4)c4ccc(OC(F)F)cc34)nc12
Temperature: 60 °C
Reaction time: 1 h
Yield: 99044.6 %

Procedure:
To a stirred solution of 2-chloro-1-(4-(2,2,2-trifluoroethyl)piperazin-1-yl)ethanone (115 mg, 471 μmol) in DMF (16 mL) under Ar, potassium carbonate (200 mg, 1.45 mmol) was added in a single portion at 25° C. After 1 h, a solution of N-tert-butyl-2-(5-(difluoromethoxy)-1H-indazol-3-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (50 mg, 94.2 μmol) in DMF (4.00 mL) was added in a single portion and the reaction was stirred at 60° C. After 18 h, the reaction was cooled to 25° C. and quenched with water (400 mL). The product was extracted with ethyl acetate (3×150 mL) and the organics were washed with brine (200 mL). The organics were dried over sodium sulfate and concentrated to give a yellow oil. The oil was dried in vacuo (300 mTorr, 25° C.) and purified by chromatography (silica, 12 g Analogix column, 5-80% ethyl acetate in hexanes, gradient over 1 h) to give N-tert-butyl-2-(5-(difluoromethoxy)-1-(2-oxo-2-(4-(2,2,2-trifluoroethyl)piperazin-1-yl)ethyl)-1H-indazol-3-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (69.0 mg, 93.3 mmol, 99%) as a yellow solid. MS (M)'=739; 1H NMR (DMSO-d6) δ: 9.09 (s, 1H), 8.60 (s, 1H), 8.22 (d, J=2.0 Hz, 1H), 7.88 (s, 1H), 7.78 (d, J=9.3 Hz, 1H), 7.40 (dd, J=2.0, 8.8 Hz, 1H), 7.21 (t, J=74.3 Hz, 1H), 5.74 (s, 2H), 5.67 (s, 2H), 3.64 (br. s, 2H), 3.58 (t, J=8.0 Hz, 2H), 3.46 (d, J=4.5 Hz, 2H), 2.77 (br. s, 2H), 2.61 (d, J=18.8 Hz, 4H), 1.52 (s, 9H), 0.86 (t, J=8.0 Hz, 2H), −0.08 (s, 9H).
Reaction SMILES: [N+](=[C:3](P(=O)(OC)OC)C(=O)C)=[N-].C([O-])([O-])=O.[K+].[K+].[F:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]([CH3:30])([CH3:29])[CH:27]=O)=[CH:22][CH:21]=1>CO.CCOC(C)=O>[F:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]([CH3:29])([C:27]#[CH:3])[CH3:30])=[CH:22][CH:21]=1
Reactant: CC(C)(C=O)c1ccc(F)cc1
Reactant: COP(=O)(OC)C(=[N+]=[N-])C(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CO
Product: C#CC(C)(C)c1ccc(F)cc1
Reaction time: 1 h

Procedure:
Next, a solution of dimethyl (1-diazo-2-oxopropyl)phosphonate (1.4 eq.) in MeOH (0.6 M) was treated at 0° C. with K2CO3 (2.4 eq.) and 2-(4-fluorophenyl)-2-methylpropanal (1.0 eq.). The reaction mixture was stirred for 1 hour, diluted with EtOAc, washed with water, dried (Na2SO4) and concentrated giving 1-fluoro-4-(2-methylbut-3-yn-2-yl)benzene: 1H NMR (600 MHz, CDCl3) δ 7.48-7.50 (m, 2H), 6.97-7.00 (m, 2H), 2.33 (s, 1H), 1.57 (s, 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:5]([NH:6][C:7]2[C:16]3[C:11](=[CH:12][C:13]([OH:19])=[C:14]([O:17][CH3:18])[CH:15]=3)[N:10]=[CH:9][N:8]=2)=[C:4]([F:22])[CH:3]=1.Cl[CH2:24][CH2:25][N:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]1=[O:32].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[Cl:1][C:2]1[CH:21]=[CH:20][C:5]([NH:6][C:7]2[C:16]3[C:11](=[CH:12][C:13]([O:19][CH2:24][CH2:25][N:26]4[CH:31]=[CH:30][CH:29]=[CH:28][C:27]4=[O:32])=[C:14]([O:17][CH3:18])[CH:15]=3)[N:10]=[CH:9][N:8]=2)=[C:4]([F:22])[CH:3]=1
Reactant: O=c1ccccn1CCCl
Reactant: COc1cc2c(Nc3ccc(Cl)cc3F)ncnc2cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc2c(Nc3ccc(Cl)cc3F)ncnc2cc1OCCn1ccccc1=O
Temperature: 80 °C
Reaction time: 18 h
Yield: 12.1 %

Procedure:
A mixture of 4-(4-chloro-2-fluoroanilino)-7-hydroxy-6-methoxyquinazoline (300 mg, 0.94 mmol), (prepared as described for the starting material in Example 15), 1-(2-chloroethyl)-1,2-dihydro-2-pyridone (175 mg, 1.1 mmol), (J. Am. Chem. Soc. 1951, 73, 3635), and potassium carbonate (260 mg, 1.9 mmol) in DMF (30 ml) was heated at 80° C. for 3 hours, allowed to cool to ambient temperature and stirred for a further 18 hours. The mixture was diluted with water and extracted with ethyl acetate. The extract was washed with water, dried (MgSO4) and the solvent removed by evaporation. The residue was purified by column chromatography eluting with methylene chloride/methanol/triethylamine mixtures (100/0/0 increasing to 70/30/0.5) to give 4-(4-chloro-2-fluoroanilino)-6-methoxy-7-[2-(2-oxo-1,2-dihydro-1-pyridyl)ethoxy]quinazoline (50 mg, 12%). m.p. 209-211 ° C. 1H NMR Spectrum: (DMSOd6) 3.94(s, 3H); 4.35(t, 2H); 4.41 (t, 2H); 6.22(dd, 1H); 6.40(d, 1H); 7.14(s, 1H); 7.35(dd, 1H); 7.42(ddd, 1H); 7.5-7.6(m, 2H); 7.70(d, 1H); 7.80(s, 1H); 8.35(s, 1H); 9.53(s, 1H) MS-ESI: 441 [MH]+
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([C:12]2[S:16][C:15]([NH:17][C:18](=[O:20])[CH3:19])=[N:14][C:13]=2[CH3:21])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].[NH:22]1[CH:26]=[CH:25][N:24]=[CH:23]1.C(=O)([O-])[O-].[Cs+].[Cs+]>CS(C)=O>[N:22]1([C:2]2[CH:3]=[C:4]([C:12]3[S:16][C:15]([NH:17][C:18](=[O:20])[CH3:19])=[N:14][C:13]=3[CH3:21])[CH:5]=[CH:6][C:7]=2[S:8]([CH3:11])(=[O:10])=[O:9])[CH:26]=[CH:25][N:24]=[CH:23]1
Reactant: c1c[nH]cn1
Reactant: CC(=O)Nc1nc(C)c(-c2ccc(S(C)(=O)=O)c(F)c2)s1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Product: CC(=O)Nc1nc(C)c(-c2ccc(S(C)(=O)=O)c(-n3ccnc3)c2)s1
Temperature: 140 °C

Procedure:
A stirred mixture of N-[5-(3-Fluoro-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-acetamide (Example 64) (0.1 g, 0.30 mmol), imidazole (0.069 g, 0.90 mmol) and caesium carbonate (0.198 g, 0.60 mmol) in dry DMSO is heated under argon at 140° C. for 2 hours. The solvent is removed and water (30 ml) is added. The product is extracted with ethyl acetate (2×30 ml) and the combined organic extracts are washed with brine (20 ml) and dried (MgSO4). Removal of the solvent and trituration with methanol affords the titled compound as an orange solid. MH+: 377.9721
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([O:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3([C:23](=[S:25])[NH2:24])[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[CH:13][CH:12]=2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2].[CH2:26](OC(OCC)CBr)[CH3:27]>>[CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([O:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3([C:23]4[S:25][CH:26]=[CH:27][N:24]=4)[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[CH:13][CH:12]=2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2]
Reactant: CCOC(CBr)OCC
Reactant: CC(C)N1CCC(Oc2ccc(C3(C(N)=S)CCOCC3)cc2)CC1
Product: CC(C)N1CCC(Oc2ccc(C3(c4nccs4)CCOCC3)cc2)CC1
Yield: 74 %

Procedure:
The title compound (320 mg, 74%) was prepared from 4-{4-[(1-isopropylpiperidin-4-yl)oxy]phenyl}tetrahydro-2H-pyran-4-carbothioamide and bromoacetaldehyde diethylacetal similarly to the procedure used for example 137. 1H NMR (400 MHz, CD3OD) δ 1.10 (d, 6H), 1.75-1.80 (m, 2H), 1.98-2.02 (m, 2H), 2.37-2.44 (m, 2H), 2.47-2.51 (m, 2H), 2.61-2.65 (m, 2H), 2.75-2.84 (m, 3H), 3.66-3.70 (m, 2H), 3.78-3.83 (m, 2H), 4.37 (m, 1H), 6.89 (d, 2H), 7.28 (d, 2H), 7.46 (d, 1H), 7.70 (d, 1H). RMS ESI+ m/z 387.2090 [MH]+. Microanalysis: Found: C, 67.42; H, 7.83; N, 7.08%. C22H30N2O2S. 0.2H2O requires C, 67.73; H, 7.85; N, 7.18%.
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[NH:7][C@H:8]([CH:11]=[C:12]([CH3:20])[CH2:13][P:14]([O:18][CH3:19])([O:16][CH3:17])=[O:15])[CH2:9][OH:10])([CH3:4])([CH3:3])[CH3:2].C([OH:25])(C)C.C(OCC)(=O)C>CC(C)=O.[O-2].[O-2].[O-2].[Cr+6].S(=O)(=O)(O)O>[C:1]([O:5][C:6]([NH:7][C@H:8]([CH:11]=[C:12]([CH3:20])[CH2:13][P:14]([O:16][CH3:17])([O:18][CH3:19])=[O:15])[C:9]([OH:25])=[O:10])=[O:21])([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)O
Reactant: COP(=O)(CC(C)=C[C@H](CO)NC(=O)OC(C)(C)C)OC
Agent: [Cr+6]
Agent: O=S(=O)(O)O
Agent: [O-2]
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: COP(=O)(CC(C)=C[C@@H](NC(=O)OC(C)(C)C)C(=O)O)OC
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
To a solution of 0.323 g of 8 in 10 ml of acetone there is added 0.77 ml ofa solution that is 3.25 molar in chromium trioxide and 5.29 molar in sulphuric acid. The mixture is stirred at room temperature for 40 minutes and then there are added 2 ml of isopropanol followed by 50 ml of ethyl acetate. 0.1 g of activated carbon is then added to the mixture. After 10 minutes, the mixture is filtered and washed with 50 ml of ethyl acetate. The filtrate is extracted three times with 50 ml of 10% sodium hydrogen carbonate solution each time. The aqueous phase is extracted twice with 40ml of ethyl acetate each time, acidified to pH 1 using 2N hydrochloric acid, and then extracted three times with 70 ml of ethyl acetate each time. The organic extracts are washed with saturated sodium chloride solution, dried over magnesium sulphate and concentrated by evaporation. Chromatography on 8 g of silica gel using chloroform/methanol/acetic acid 18:1:1 as eluant yields 65 mg of 9. 1H-NMR (300 MHz, DMSO-d6): 1.37 (s, (CH3)3CO); 1.82 (d, J=2, CH3 --C(4)); 2.63 (d, J=22, 2H--C(5)); 3.61 (d, J=11, (CH3O)2PO); 4.62 (t, J=8, H--C(2)); 5.25 (m, H--C(3)); 7.18 (d, J=8, NH); 11.7-12.5 (CO2H).
Reaction SMILES: C[O:2][C:3](=[O:37])[CH:4]([NH:8][S:9]([C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:23]=[CH:22][C:21]([CH2:24][O:25][C:26]3[C:35]([CH3:36])=[CH:34][C:33]4[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=4)[N:27]=3)=[CH:20][CH:19]=2)=[CH:14][CH:13]=1)(=[O:11])=[O:10])[CH:5]([CH3:7])[CH3:6].CO.[OH-].[Na+]>C1COCC1>[CH3:6][CH:5]([CH3:7])[CH:4]([NH:8][S:9]([C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:23]=[CH:22][C:21]([CH2:24][O:25][C:26]3[C:35]([CH3:36])=[CH:34][C:33]4[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=4)[N:27]=3)=[CH:20][CH:19]=2)=[CH:14][CH:13]=1)(=[O:10])=[O:11])[C:3]([OH:37])=[O:2]
Reactant: COC(=O)C(NS(=O)(=O)c1ccc(-c2ccc(COc3nc4ccccc4cc3C)cc2)cc1)C(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cc2ccccc2nc1OCc1ccc(-c2ccc(S(=O)(=O)NC(C(=O)O)C(C)C)cc2)cc1
Reaction time: 72 h
Yield: 51.3 %

Procedure:
3-Methyl-2-[4′-(3-methyl-quinolin-2-yloxymethyl)-biphenyl-4-sulfonylamino]-butyric acid methyl ester (203 mg, 0.39 mmol, 1 equiv.) was dissolved in THF (8 mL) and MeOH (4 mL) and hydrolyzed with IN NaOH (5.83 mL, 5.83 mmol, 13 equiv.). After stirring for 3 days, solvent was removed and the residue was dissolved in H2O. The mixture was then acidified to pH 3 using 1N HCl. Solid precipitated from the mixture was collected by filtration and washed with water. After drying in vacuum oven, 101 mg of 3-Methyl-2-[4′-(3-methyl-quinolin-2-yloxymethyl)-biphenyl-4-sulfonylamino]-butyric acid was obtained in 76.3% yield.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[O:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[CH2:15][NH:14][CH2:13][CH:12]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:11]2)=[CH:6][CH:5]=1.C(N(CC)CC)C.[CH:30]1([C:35](Cl)=[O:36])[CH2:34][CH2:33][CH2:32][CH2:31]1>ClCCl>[CH:30]1([C:35]([N:14]2[CH2:15][CH:10]([C:7]3[CH:8]=[CH:9][C:4]([O:3][C:2]([F:1])([F:21])[F:22])=[CH:5][CH:6]=3)[CH2:11][CH:12]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:13]2)=[O:36])[CH2:34][CH2:33][CH2:32][CH2:31]1
Reactant: CCOC(=O)C1CNCC(c2ccc(OC(F)(F)F)cc2)C1
Reactant: O=C(Cl)C1CCCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)C1CC(c2ccc(OC(F)(F)F)cc2)CN(C(=O)C2CCCC2)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1.76 g (5.08 mmol) of ethyl 5-[4-(trifluoromethoxy)phenyl]piperidine-3-carboxylate were dissolved in 12 ml of dichloromethane, and 0.77 g (7.62 mmol) of triethylamine were added at 0° C. 0.89 g (6.61 mmol) of cyclopentanecarbonyl chloride were then added dropwise. The reaction mixture was stirred at RT for 2 h. For work-up, the mixture was twice washed with water. The organic phase was dried over sodium sulphate and concentrated under reduced pressure. Yield: 2.1 g (100% of theory)