Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:11]3[CH2:18][C:17](=[O:19])[NH:16][C:12]=3[N:13]=[CH:14][N:15]=2)[CH:5]=[CH:6][C:7]=1[F:8].[CH:20]([C:22]1[NH:26][C:25]([C:27]([OH:29])=[O:28])=[CH:24][C:23]=1[CH3:30])=O>N1CCCCC1.C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:11]3[C:18](=[CH:20][C:22]4[NH:26][C:25]([C:27]([OH:29])=[O:28])=[CH:24][C:23]=4[CH3:30])[C:17](=[O:19])[NH:16][C:12]=3[N:13]=[CH:14][N:15]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: Cc1cc(C(=O)O)[nH]c1C=O
Reactant: O=C1Cc2c(ncnc2Nc2ccc(F)c(Cl)c2)N1
Solvent: C1CCNCC1
Solvent: CCO
Product: Cc1cc(C(=O)O)[nH]c1C=C1C(=O)Nc2ncnc(Nc3ccc(F)c(Cl)c3)c21
Temperature: 25 °C
Reaction time: 96 h
Yield: 85.8 %

Procedure:
A mixture of 4-(3-chloro-4-fluoro-phenylamino)-5,7-dihydro-pyrrolo[2,3-d]pyrimidin-6-one (70 mg, 0.25 mmol), 5-formyl-4-methyl-1H-pyrrole-2-carboxylic acid (45.9 mg, 0.3 mmol) and piperidine (3 drops) in ethanol (2 mL) was stirred at room temperature for 4 days.The precipitate was collected by vacuum filtration, washed with ethanol and dried, then washed with 1N HCl (3×), water (5×) and dried to give 88.8 mg (86%) of the title compound. 1H NMR (360 MHz, DMSO-d6) δ 13.55 (br s, 1H, NH), 11.84 (br s, 1H, NH), 9.28 (s, 1H), 8.34 (s, 1H), 7.74 (m, 1H), 7.43 (m, 1H), 7.41 (s, 1H), 7.38 (t, J=9.1 Hz, 1H), 6.74 (d, J=2.15 Hz, 1H), 2.22 (s, 3H, CH3). MS 414 [M++1].
Reaction SMILES: [CH:1]1([CH2:7][O:8][C:9]([NH:11][C@@H:12]([CH2:32][CH:33]([CH3:35])[CH3:34])[C:13]([NH:15][C@@H:16]([CH:29]([CH3:31])[CH3:30])[C@@H:17]([C:19]2[C:20](=[O:28])[C:21]=2[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[OH:18])=[O:14])=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:36](Cl)(=[O:38])[CH3:37].Cl>C(Cl)Cl.C(N(CC)CC)C>[C:36]([O:18][C@H:17]([C:19]1[C:20](=[O:28])[C:21]=1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C@@H:16]([NH:15][C:13](=[O:14])[C@@H:12]([NH:11][C:9]([O:8][CH2:7][CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)=[O:10])[CH2:32][CH:33]([CH3:35])[CH3:34])[CH:29]([CH3:30])[CH3:31])(=[O:38])[CH3:37]
Reactant: CC(C)C[C@H](NC(=O)OCC1CCCCC1)C(=O)N[C@@H](C(C)C)[C@H](O)c1c(-c2ccccc2)c1=O
Reactant: CC(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)O[C@H](c1c(-c2ccccc2)c1=O)[C@@H](NC(=O)[C@H](CC(C)C)NC(=O)OCC1CCCCC1)C(C)C
Yield: 45.1 %

Procedure:
To 5 ml of a methylene chloride solution of 149 mg of 2-[(1R,2S)-2-{(S)-2-cyclohexylmethoxycarbonylamino-4-methylvalerylamino}-1-hydroxy-3-methylbutyl]-3-phenylcyclopropenone obtained in Example 2 were added 81 mg of acetyl chloride and 102 mg of triethylamine. The resultant mixture was stirred at room temperature for 3 hours, mixed with diluted hydrochloric acid and shaken with methylene chloride. The organic layer was washed with water, saturated aqueous sodium bicarbonate and saturated brine in that order, dried over magnesium sulfate and filtered. The filtrate was concentrated and chromatographed on a column of silica gel, eluting with hexane:ethyl acetate (1:1) to give 73 mg of the titled product.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6][CH:5]1[C:13]1[N:17]=[C:16]([CH2:18][CH2:19][CH3:20])[O:15][N:14]=1)(=O)C.[OH-].[Na+]>C(O)C.C(Cl)Cl>[CH2:18]([C:16]1[O:15][N:14]=[C:13]([CH:5]2[CH2:6][C:7]3[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=3)[NH:4]2)[N:17]=1)[CH2:19][CH3:20]
Reactant: CCCc1nc(C2Cc3ccccc3N2C(C)=O)no1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: ClCCl
Product: CCCc1nc(C2Cc3ccccc3N2)no1
Temperature: 57.5 °C
Yield: 56.1 %

Procedure:
A solution of compound 89 (0.0035 mole) in ethanol (60 ml) was treated with 3M NaOH (60 ml), and the reaction mix was heated to 55-60° C. for 5.5 hours. The reaction was rapidly cooled in an ice bath, diluted with DCM, and treated with cold distilled water. The layers were separated and the aqueous fraction was extracted three times with DCM. The organic fractions were combined, washed once with 1M NaOH, and dried over Na2SO4 and concentrated in vacuo. The residue was purified by prep column chromatography, yielding 0.45 g of 2,3-dihydro-2-(5-propyl-1,2,4-oxadiazol-3-yl)-1H-indole.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7]([CH2:13][CH:14]1[CH2:16][CH2:15]1)[CH:6]=[C:5]2[CH:17]=[O:18].[CH:19]1([NH:22][C:23](=[O:41])[C:24]2[CH:29]=[C:28](B3OC(C)(C)C(C)(C)O3)[C:27]([CH3:39])=[C:26]([F:40])[CH:25]=2)[CH2:21][CH2:20]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[CH:19]1([NH:22][C:23](=[O:41])[C:24]2[CH:25]=[C:26]([F:40])[C:27]([CH3:39])=[C:28]([C:2]3[CH:3]=[C:4]4[C:9](=[CH:10][CH:11]=3)[C:8](=[O:12])[N:7]([CH2:13][CH:14]3[CH2:16][CH2:15]3)[CH:6]=[C:5]4[CH:17]=[O:18])[CH:29]=2)[CH2:20][CH2:21]1
Reactant: O=Cc1cn(CC2CC2)c(=O)c2ccc(Br)cc12
Reactant: Cc1c(F)cc(C(=O)NC2CC2)cc1B1OC(C)(C)C(C)(C)O1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1c(F)cc(C(=O)NC2CC2)cc1-c1ccc2c(=O)n(CC3CC3)cc(C=O)c2c1
Temperature: 60 °C

Procedure:
To a mixture of the product of Example 59 step ii) (3.17 g), N-cyclopropyl-3-fluoro-4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (3.3 g) [prepared as described in WO06110173] and potassium carbonate (2.86 g) in DMF (40 mL) was added Pd-118 (0.20 g) and the mixture heated at 60° C. under nitrogen for 11 hours. The reaction mixture was diluted with ethyl acetate and washed with water and brine. The organics were dried over magnesium sulphate, filtered and evaporated. The residue was purified (SiO2, eluting with 3:2 ethyl acetate:isohexane) to give the sub-title compound (4.24 g).
Reaction SMILES: [H-].[Na+].F[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N+:10]([O-:12])=[O:11].[NH2:13][C:14]1[S:15][C:16]([CH3:21])=[CH:17][C:18]=1[C:19]#[N:20]>O1CCCC1>[N+:10]([C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[NH:13][C:14]1[S:15][C:16]([CH3:21])=[CH:17][C:18]=1[C:19]#[N:20])([O-:12])=[O:11]
Reactant: O=[N+]([O-])c1ccccc1F
Reactant: Cc1cc(C#N)c(N)s1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1cc(C#N)c(Nc2ccccc2[N+](=O)[O-])s1
Temperature: 25 °C
Reaction time: 24 h
Yield: 67.9 %

Procedure:
To a stirred slurry of sodium hydride (14.4 g, 50% dispersion in oil, 0.3 mol) in dry tetrahydrofuran (50 mL) under nitrogen was added, dropwise, a solution of 2-fluoro-nitrobenzene (28.2 g, 0.2 mol) and 2-amino-5-methylthiophene-3-carbonitrile (27.6 g, 0.2 mol) in dry tetrahydrofuran (250 mL). The mixture was stirred at 25° C. for 24 hours, poured onto cracked ice and extracted into dichloromethane (3×500 mL). The combined extracts were washed with 2N hydrochloric acid (2×200 mL) water (2×200 mL), dried over magnesium sulfate and the solvent removed under reduced pressure. The residue was crystallized from ethanol to give the title compound, (35.2 g), m.p. 99°-102° C.
Reaction SMILES: [Br-:1].[Mg+2].[Br-].S(O[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]/[CH:14]=[CH:15]\[CH2:16]/[CH:17]=[CH:18]\[CH2:19]/[CH:20]=[CH:21]\[CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])(=O)(=O)C.O>CCOCC>[CH2:9]([Br:1])[CH2:10][CH2:11][CH2:12][CH2:13]/[CH:14]=[CH:15]\[CH2:16]/[CH:17]=[CH:18]\[CH2:19]/[CH:20]=[CH:21]\[CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: CCCCC/C=C\C/C=C\C/C=C\CCCCCOS(C)(=O)=O
Reactant: [Br-]
Agent: [Mg+2]
Solvent: O
Solvent: CCOCC
Product: CCCCC/C=C\C/C=C\C/C=C\CCCCCBr
Reaction time: 8 h

Procedure:
Magnesium bromide etherate (34 g, 110 mmol) and a stir bar were added to a 2000 mL round bottom flask. The flask was sealed and flushed with nitrogen. Anhydrous diethyl ether (400 mL) was added via canulla. A solution of γ-linolenyl mesylate (20 g, 58 mmol) in anhydrous ether (300 mL) was then added, and the suspension stirred overnight. The suspension was poured into 500 mL of chilled water and transferred to a 2000-mL separating funnel. After shaking, the organic phase was separated. The aqueous phase was then extracted with ether (2×250 mL) and all ether phases combined. The ether phase was washed with water (2×250 mL), brine (250 mL) and dried over anhydrous Mg2SO4. The solution was filtered, concentrated and purified by flash chromatography. Final yield 18.9 g, 99%.
Reaction SMILES: [F:1][C:2]1[C:7]([CH:8]([CH3:10])[CH3:9])=[CH:6][C:5]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][C:12]=2[CH:21]2[N:25]([CH2:26][C:27]3[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=3)[C:24](=[O:35])[NH:23][CH2:22]2)=[C:4]([O:36][CH3:37])[CH:3]=1.[H-].[Na+].[F:40][C:41]([F:55])([F:54])[C:42]1[CH:43]=[C:44]([CH:47]=[C:48]([C:50]([F:53])([F:52])[F:51])[CH:49]=1)[CH2:45]Br>CN(C=O)C>[F:40][C:41]([F:54])([F:55])[C:42]1[CH:43]=[C:44]([CH:47]=[C:48]([C:50]([F:53])([F:51])[F:52])[CH:49]=1)[CH2:45][N:23]1[CH2:22][CH:21]([C:12]2[CH:13]=[C:14]([C:17]([F:20])([F:18])[F:19])[CH:15]=[CH:16][C:11]=2[C:5]2[CH:6]=[C:7]([CH:8]([CH3:9])[CH3:10])[C:2]([F:1])=[CH:3][C:4]=2[O:36][CH3:37])[N:25]([CH2:26][C:27]2[CH:28]=[CH:29][C:30]([O:33][CH3:34])=[CH:31][CH:32]=2)[C:24]1=[O:35]
Reactant: FC(F)(F)c1cc(CBr)cc(C(F)(F)F)c1
Reactant: COc1ccc(CN2C(=O)NCC2c2cc(C(F)(F)F)ccc2-c2cc(C(C)C)c(F)cc2OC)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(CN2C(=O)N(Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)CC2c2cc(C(F)(F)F)ccc2-c2cc(C(C)C)c(F)cc2OC)cc1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a 0° C. solution of 19 mg of 5-[4′-fluoro-5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]-1-(4-methoxybenzyl)imidazolidin-2-one (INTERMEDIATE 32) in 1 mL of DMF was added 3 mg of NaH (60% dispersion in oil). The solution was stirred for 10 min at 0° C. and then 8 μL of 3,5-bistrifluoromethylbenzyl bromide was added and the mixture was stirred for 3 h at 0° C. The reaction mixture was quenched with a drop of water and then filtered and purified by reverse-phase HPLC [Waters XTerra C8 19×50 mm column, eluting at 20 mL/min with 90% water (0.1% TFA) to 100% acetonitrile (0.1% TFA) over 5.15 min, hold for 1.45 min, then back to 90% water over 0.5 min] to provide the title compound. Mass spectrum (ESI) 743.2 (M+1).
Reaction SMILES: C(O[C:5](=[O:7])C)(=O)C.[CH3:8][NH:9][CH:10]1[CH2:15][CH2:14][N:13]([CH2:16][CH:17]2[C:20]3=[CH:21][CH:22]=[CH:23][CH:24]=[C:19]3[CH2:18]2)[CH2:12][CH2:11]1>C(O)=O>[C:17]1([CH2:16][N:13]2[CH2:14][CH2:15][CH:10]([N:9]([CH3:8])[CH:5]=[O:7])[CH2:11][CH2:12]2)[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[CH:18]=1
Reactant: CNC1CCN(CC2Cc3ccccc32)CC1
Reactant: CC(=O)OC(C)=O
Solvent: O=CO
Product: CN(C=O)C1CCN(CC2=Cc3ccccc32)CC1

Procedure:
11 ml of acetic anhydride are added dropwise to a solution of 32 ml of 88% formic acid and 3 g of 1-[(4-methylaminopiperid-1-yl)-methyl]-benzocyclobutene (cf. Stage E of Example 25) that has been preheated to 40° C.
Reaction SMILES: Br[CH2:2][C:3]1[N:4]=[C:5]([C:8](=[O:10])[CH3:9])[S:6][CH:7]=1.[C:11]([OH:14])(=[O:13])[CH3:12].C([O-])(=O)C.[K+]>C(OCC)(=O)C>[C:8]([C:5]1[S:6][CH:7]=[C:3]([CH2:2][O:14][C:11](=[O:13])[CH3:12])[N:4]=1)(=[O:10])[CH3:9]
Reactant: CC(=O)c1nc(CBr)cs1
Reactant: CC(=O)O
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Product: CC(=O)OCc1csc(C(C)=O)n1
Yield: 70 %

Procedure:
Bromide 3a (4.95 g, 0.0224 mol) was heated with acetic acid (50 mL) and potassium acetate (2.64 g, 0.0269 mol) at 100° C. for 16 h. Diluted with ethyl acetate and washed with water 3 times. The organic layer was dried (Na2SO4) and concentrated in vacuo to give a crude oil that was subjected to flash chromatography (20% ethyl acetate/80% hexanes) to give 2.48 g (70%) of the desired product 4a. 1H NMR (CDCl3) δ 7.8 (s, 1H), 5.2 (s, 2H), 2.8 (s, 3H), 2.2 (s, 3H).
Reaction SMILES: C(O[C:6]([NH:8][CH:9]1[CH2:14][C:13]([CH3:19])([C:15]([O:17][CH3:18])=[O:16])[CH2:12][CH2:11][CH2:10]1)=O)(C)(C)C.Cl.CCN(C(C)C)C(C)C.[Cl:30][C:31]1[N:36]=C(Cl)[C:34]([F:38])=[CH:33][N:32]=1>CO>[Cl:30][C:31]1[N:36]=[C:6]([NH:8][C@H:9]2[CH2:10][CH2:11][CH2:12][C@@:13]([CH3:19])([C:15]([O:17][CH3:18])=[O:16])[CH2:14]2)[C:34]([F:38])=[CH:33][N:32]=1
Reactant: COC(=O)C1(C)CCCC(NC(=O)OC(C)(C)C)C1
Reactant: Fc1cnc(Cl)nc1Cl
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: COC(=O)[C@]1(C)CCC[C@H](Nc2nc(Cl)ncc2F)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A stirred solution of methyl 5-(tert-butoxycarbonylamino)-1-methylcyclohexanecarboxylate, 52g, (5.63 g, 20.75 mmol) in MeOH (20 mL) was treated with HCl gas for 10 minutes. The resulting solution was stirred at room temperature for 1 hour, then concentrated to dryness and redissolved in THF (50 mL). To the reaction mixture was added iPr2NEt (10.84 mL, 62.25 mmol) and 2,4-dichloro-5-fluoro-pyrimidine (5.20 g, 31.12 mmol) sequentially. The reaction was stirred at reflux overnight, concentrated in vacuo and resulting residue was purified by silica gel chromatography (1:1 Hexane:EtOAc), yielding 2.2 g of the racemic product as a yellow oil. 300 mg of the racemic methyl 3-(2-chloro-5-fluoropyrimidin-4-ylamino)-1-methylcyclohexanecarboxylate was submitted for SFC chiral separation, yielding 100 mg of the desired product, 52h, as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[N:12]([CH3:15])[C:11]3[CH:16]=[C:17]([O:20][CH:21]([C:23]([O:25]CC)=[O:24])[CH3:22])[CH:18]=[CH:19][C:10]=3[S:9]2(=[O:29])=[O:28])=[CH:4][CH:3]=1.[OH-].[Na+]>C(O)C.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[N:12]([CH3:15])[C:11]3[CH:16]=[C:17]([O:20][CH:21]([C:23]([OH:25])=[O:24])[CH3:22])[CH:18]=[CH:19][C:10]=3[S:9]2(=[O:28])=[O:29])=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(C)Oc1ccc2c(c1)N(C)C(=O)N(c1ccc(Cl)cc1)S2(=O)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(Oc1ccc2c(c1)N(C)C(=O)N(c1ccc(Cl)cc1)S2(=O)=O)C(=O)O
Yield: 64.1 %

Procedure:
To a suspension of 2-(4-chlorophenyl)-6-[1-(ethoxycarbonyl)ethoxyl]-4-methyl-2H-1,2,4-benzothiadiazine-3(4H)-one 1,1-dioxide (400 mg) in a mixture of ethanol (5 ml) and water (5 ml) was added aqueous 1N-sodium hydroxide solution (1.1) ml in one portion. The mixture was refluxed for half hour and concentrated in vacuo. The residue was dissolved in water and washed with ethyl ether. The aqueous layer was acidified with hydrochlonic acid. The separated oil was extracted with ethyl acetate. The organic layer was washed with brine, dried, and evaporated to dryness. The residue was crystallized from a mixture of n-hexane and ethyl acetate to yield 2-(4-chlorophenyl)-6-(1-carboxyethoxy)-4-methyl-2H-1,2,4-benzothiadiazine-3(4H)-one 1,1-dioxide (240 mg).
Reaction SMILES: [Br:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][C:7]23[CH2:24][CH2:23][CH2:22][CH:21]=[C:8]2[N:9]([C:13]2[CH:18]=[C:17]([Cl:19])[CH:16]=[C:15]([Cl:20])[CH:14]=2)[C:10](=[O:12])[NH:11]3)=[CH:4][CH:3]=1.[H-].[Na+].[CH3:29]I>CN(C=O)C>[Br:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][C:7]23[CH2:24][CH2:23][CH2:22][CH:21]=[C:8]2[N:9]([C:13]2[CH:14]=[C:15]([Cl:20])[CH:16]=[C:17]([Cl:19])[CH:18]=2)[C:10](=[O:12])[N:11]3[CH3:29])=[CH:4][CH:3]=1
Reactant: O=C1NC2(Cc3ccc(Br)cc3)CCCC=C2N1c1cc(Cl)cc(Cl)c1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1C(=O)N(c2cc(Cl)cc(Cl)c2)C2=CCCCC21Cc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
3a-(4-Bromo-benzyl)-1-(3,5-dichlorophenyl)-1,3,3a,4,5,6-hexahydro-benzimidazol-2-one (3.0 g) (0.0066 mol) in DMF (50 ml) was carefully dropped on a suspension of NaH 60% (0.32 g) (1.2 eq) in DMF (20 ml) at RT. The reaction mixture was stirred 1 h at RT then methyl iodide (0.6 ml) (1.5 eq) was added. After one night, the reaction mixture was partitioned between water and tBuOMe. The obtained precipitate was filtered, washed with water and tBuOMe, and dried to give 3a-(4-Bromo-benzyl)-1-(3,5-dichlorophenyl)-3-methyl-1,3,3a,4,5,6-hexahydro-benzimidazol-2-one (1.8 g) as a white solid. 1H NMR (CDCl3): 7.39 (2H, d), 7.10 (1H, m), 7.0 (2H, d), 6.77 (2H, m), 4.90 (1H, m), 3.0 (3H, s), 2.95 (2H, s), 2.5-2.2 (2H, m), 2.2-1.9 (3H, m), 1.8-1.6 (1H, m).
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[CH:12][C:5](/[CH:6]=[CH:7]/[C:8]([O:10][CH3:11])=[O:9])=[C:4]([NH:14]S(C2C=CC=CC=2)(=O)=O)[CH:3]=1.[CH:24]1([C:27]([CH2:29]Br)=[O:28])[CH2:26][CH2:25]1>>[CH3:11][O:10][C:8](=[O:9])[CH2:7][C:6]1[C:5]2[C:4](=[CH:3][C:2]([Cl:1])=[CH:13][CH:12]=2)[NH:14][C:29]=1[C:27]([CH:24]1[CH2:26][CH2:25]1)=[O:28]
Reactant: COC(=O)/C=C/c1ccc(Cl)cc1NS(=O)(=O)c1ccccc1
Reactant: O=C(CBr)C1CC1
Product: COC(=O)Cc1c(C(=O)C2CC2)[nH]c2cc(Cl)ccc12

Procedure:
The title compound was prepared according to the procedure described in Example 57 from methyl trans-4-chloro-2-(phenylsulfonylamino)cinnamate (step 1 of Example 8, Method A) and bromomethyl cyclopropyl ketone*.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][C@H:15]1[CH2:17][O:16]1)[N:9]=[CH:8][N:7]=[C:6]2[O:18][C:19]1[CH:20]=[C:21]2[C:25](=[CH:26][CH:27]=1)[NH:24][C:23]([CH3:28])=[CH:22]2.[NH:29]1[CH2:33][CH2:32][CH2:31][CH2:30]1>C1COCC1>[OH:16][C@H:15]([CH2:17][N:29]1[CH2:33][CH2:32][CH2:31][CH2:30]1)[CH2:14][O:13][C:12]1[CH:11]=[C:10]2[C:5]([C:6]([O:18][C:19]3[CH:20]=[C:21]4[C:25](=[CH:26][CH:27]=3)[NH:24][C:23]([CH3:28])=[CH:22]4)=[N:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[O:2][CH3:1]
Reactant: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3)ncnc2cc1OC[C@H]1CO1
Reactant: C1CCNC1
Solvent: C1CCOC1
Product: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3)ncnc2cc1OC[C@H](O)CN1CCCC1
Temperature: 75 °C
Reaction time: 3 h
Yield: 55 %

Procedure:
A mixture of the (2R)-6-methoxy-4-(2-methylindol-5-yloxy)-7-(oxiran-2-ylmethoxy)quinazoline (250 mg, 0.66 mmol), (prepared as described for the starting material in Example 269), and pyrrolidine (1.5 ml) in THF (10 ml) was stirred at 75° C. for 3 hours under an atmosphere of nitrogen and then allowed to cool to ambient temperature. The mixture was filtered and the filtrate evaporated in vacuo. The residue was purified by silica gel chromatography using gradient elution with dichloromethane/methanolic ammonia (7M) (100/0 to 90/10) to give (2R)-7-(2-hydroxy-3-(pyrrolidin-1-yl)propoxy)-6-methoxy-4-(2-methylindol-5-yloxy)quinazoline (165 mg, 55%).
Reaction SMILES: C([O:3][C:4](=[O:28])[C:5]1[CH:10]=[C:9]([O:11][CH2:12][CH3:13])[C:8]([O:14][CH2:15][CH3:16])=[C:7]([O:17][CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:21]=2[Cl:27])[CH:6]=1)C.O.[OH-].[Na+].Cl>O1CCOCC1>[Cl:27][C:21]1[CH:22]=[C:23]([Cl:26])[CH:24]=[CH:25][C:20]=1[CH2:19][CH2:18][O:17][C:7]1[CH:6]=[C:5]([CH:10]=[C:9]([O:11][CH2:12][CH3:13])[C:8]=1[O:14][CH2:15][CH3:16])[C:4]([OH:28])=[O:3]
Reactant: CCOC(=O)c1cc(OCC)c(OCC)c(OCCc2ccc(Cl)cc2Cl)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: CCOc1cc(C(=O)O)cc(OCCc2ccc(Cl)cc2Cl)c1OCC
Temperature: 60 °C
Reaction time: 16 h

Procedure:
0.66 g (1.54 mmol) of 3-[2-(2,4-Dichlorophenyl)-ethoxy]-4,5-diethoxy-benzoic acid ethyl ester was dissolved in 6 ml of dioxan. 5 ml of water and 2N aqueous NaOH was added to the solution to give a pH of 13. The reaction solution was heated at 60° C. for 4 h and stirred at room temperature for 16 h. The reaction solution was cooled to 0° C. and concentrated hydrochloric acid was added to give a pH of 1-2, whereupon the product precipitated from solution. The suspension was stirred for 30 min, then the product was filtered off and dried under reduced pressure.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:16])[CH3:15])[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]=1[NH:21][C:22](=[O:37])[CH2:23][C:24]([C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([N:32]2[CH:36]=[CH:35][N:34]=[CH:33]2)[CH:27]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:15][N:14]([CH3:16])[C:12]1[C:11]([C:17]([F:18])([F:19])[F:20])=[CH:10][C:9]2[NH:21][C:22](=[O:37])[CH2:23][C:24]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([N:32]4[CH:36]=[CH:35][N:34]=[CH:33]4)[CH:27]=3)=[N:7][C:8]=2[CH:13]=1
Reactant: CN(C)c1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-n3ccnc3)c2)cc1C(F)(F)F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN(C)c1cc2c(cc1C(F)(F)F)NC(=O)CC(c1cccc(-n3ccnc3)c1)=N2

Procedure:
The title compound was prepared from {5-dimethylamino-2-[3-(3-imidazol-1-yl-phenyl)-3-oxo-propionylamino]-4-trifluoromethyl-phenyl}-carbamic acid tert.-butyl ester (Example M57) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a yellow solid (132 mg).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([O:12][CH:13]([CH3:15])[CH3:14])=[C:7]([CH:11]=1)[C:8]([OH:10])=O)#[N:2].[C:16]1([C:22]2[N:26]=[C:25]([N:27]3[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]3)[S:24][N:23]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[CH:13]([O:12][C:6]1[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:11][C:7]=1[C:8]([N:30]1[CH2:31][CH2:32][N:27]([C:25]2[S:24][N:23]=[C:22]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[N:26]=2)[CH2:28][CH2:29]1)=[O:10])([CH3:15])[CH3:14]
Reactant: CC(C)Oc1ccc(C#N)cc1C(=O)O
Reactant: c1ccc(-c2nsc(N3CCNCC3)n2)cc1
Product: CC(C)Oc1ccc(C#N)cc1C(=O)N1CCN(c2nc(-c3ccccc3)ns2)CC1
Yield: 74 %

Procedure:
Prepared in analogy to example 1 (b) from 5-cyano-2-isopropoxy-benzoic acid (Example A28) and 3-phenyl-5-piperazino-1,2,4-thiadiazole. The crude material was purified by chromatography (SiO2, ethyl acetate/heptane) to yield the title compound as a white solid (yield 74%). MS (m/e): 434.1 (M+H+, 100%).
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[C:13]2[C:8](=[N:9][CH:10]=[N:11][C:12]=2[NH:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=3)=[C:17]([Cl:29])[CH:16]=2)[NH:7][N:6]=1.[CH2:30]([N:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1)[CH3:31]>>[Cl:29][C:17]1[CH:16]=[C:15]([NH:14][C:12]2[N:11]=[CH:10][N:9]=[C:8]3[NH:7][N:6]=[C:5]([O:4][CH2:3][CH2:2][N:35]4[CH2:36][CH2:37][N:32]([CH2:30][CH3:31])[CH2:33][CH2:34]4)[C:13]=23)[CH:20]=[CH:19][C:18]=1[O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=1
Reactant: ClCCOc1n[nH]c2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c12
Reactant: CCN1CCNCC1
Product: CCN1CCN(CCOc2n[nH]c3ncnc(Nc4ccc(OCc5ccccn5)c(Cl)c4)c23)CC1
Yield: 45 %

Procedure:
The procedure described in Example 23 was repeated using 3-(2-chloroethoxy)-N-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine and N-ethylpiperazine to give the title compound in 45% yield; NMR Spectrum: 0.95 (t, 3H), 2.25 (q, 2H), 2.32 (br s, 4H), 2.50 (hidden under DMSO, 4H), 2.78 (t, 2H), 4.41 (t, 2H), 5.28 (s, 2H), 7.24 (d, 1H), 7.36 (t, 1H), 7.56 (s, 1H), 7.58 (s, 1H), 7.86-7.91 (m, 2H), 8.29 (s, 1H), 8.48 (br s, 1H), 8.59 (d, 1H); Mass Spectrum: 509 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:11][S:12]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([C:22]([F:25])([F:24])[F:23])[CH:16]=2)(=[O:14])=[O:13])[C:5]([C:8](O)=[O:9])=[N:6][CH:7]=1.[CH3:26][C:27]1[CH:28]=[CH:29][C:30]2[O:35][CH2:34][CH2:33][NH:32][C:31]=2[CH:36]=1.C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC>CCN(CC)CC>[Cl:21][C:18]1[CH:19]=[CH:20][C:15]([S:12]([NH:11][C:4]2[C:5]([C:8]([N:32]3[C:31]4[CH:36]=[C:27]([CH3:26])[CH:28]=[CH:29][C:30]=4[O:35][CH2:34][CH2:33]3)=[O:9])=[N:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)(=[O:13])=[O:14])=[CH:16][C:17]=1[C:22]([F:25])([F:23])[F:24]
Reactant: O=C(O)c1ncc(Cl)cc1NS(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Reactant: Cc1ccc2c(c1)NCCO2
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CCN(CC)CC
Product: Cc1ccc2c(c1)N(C(=O)c1ncc(Cl)cc1NS(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1)CCO2

Procedure:
6-Methyl-3,4-dihydro-2H-benzo[1,4]oxazine 5-chloro-3-(4-chloro-3-(trifluoromethyl)phenylsulfonamido)picolinic acid, T3P, and Et3N were reacted according to the procedure D to provide the title compound. HPLC purification provided 4-chloro-N-[5-chloro-2-(6-methyl-2,3-dihydro-benzo[1,4]oxazine-4-carbonyl)-pyridin-3-yl]-3-trifluoromethyl-benzenesulfonamide: Reverse phase HPLC gradient acetonitrile 0.1% TFA 20-95% in 4 min: 3.099 min; MS m/z: 546.1 (M+H).