Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:8][C@@H:9]([C:13]([OH:15])=O)[CH2:10][CH2:11][CH3:12])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].Cl.[F:17][CH:18]1[CH2:21][NH:20][CH2:19]1.C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[C:4]([O:3][C:1](=[O:2])[NH:8][C@@H:9]([C:13]([N:20]1[CH2:21][CH:18]([F:17])[CH2:19]1)=[O:15])[CH2:10][CH2:11][CH3:12])([CH3:5])([CH3:6])[CH3:7]
Reactant: FC1CNC1
Reactant: CCC[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCC[C@@H](NC(=O)OC(C)(C)C)C(=O)N1CC(F)C1
Temperature: 25 °C
Reaction time: 48 h
Yield: 110.1 %

Procedure:
A round-bottomed flask was charged with Boc-D-norvaline (300 mg, 1.38 mmol) and 3-fluoroazetidine hydrochloride (216 mg, 1.93 mmol). DMF (6 ml) was added followed by N,N-diisopropylethylamine (0.65 ml, 3.72 mmol) and HATU (578 mg, 1.52 mmol). The yellow reaction mixture was stirred at room temperature for 48 h the quenched with water and extracted with diethyl ether (2×). The combined organic layers were washed twice with water and once with brine then dried over sodium sulfate, filtered and concentrated to give 417 mg of [(R)-1-(3-fluoro-azetidine-1-carbonyl)-butyl]-carbamic acid tert-butyl ester as a light yellow solid.
Reaction SMILES: [F:1][C:2]1C=C[C:5](Br)=[CH:4][C:3]=1C.[Li]CCCC.CN(C)C=O.[CH2:20]1[CH2:24][O:23][CH2:22][CH2:21]1>>[F:1][C:2]1[CH:24]=[CH:20][C:21]([CH:22]=[O:23])=[C:4]([CH3:5])[CH:3]=1
Reactant: Cc1cc(Br)ccc1F
Reactant: C1CCOC1
Agent: [Li]CCCC
Solvent: CN(C)C=O
Product: Cc1cc(F)ccc1C=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 86 %

Procedure:
A -78° C. solution of 2-fluoro-5-bromotoluene (25.764 gm, 136.3 mmol) in THF (200 ml) was treated with n-BuLi (2.5M in hexane, 60 ml, 150 mmol) over a 12-minute period. After stirring for one hour, the cloudy white mixture was treated with neat dimethylformamide (30 ml, 28.3 gm, 387 mmol) over a two-minute period. Stirring continued for an additional hour. The mixture was then quenched with saturated NH4Cl, warmed to room temperature, and made acidic with 10% HCl. The mixture was extracted with Et2O and the ether extract was washed with H2O and brine, then dried (Na2SO4), filtered, and stripped. The dark residue was distilled (bp 55° C. @ 1 mm) to give the title compound (16.286 gm, 86%).
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:3].C(O)(=O)/C=C\C(O)=O.[F:19][C:20]1[CH:21]=[C:22]([CH:26]2[S:40][C:33]3([CH2:38][CH2:37][N:36](C)[CH2:35][CH2:34]3)[C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][C:27]2=3)[CH:23]=[CH:24][CH:25]=1>ClCCl>[F:19][C:20]1[CH:21]=[C:22]([CH:26]2[S:40][C:33]3([CH2:34][CH2:35][N:36]([C:2]([O:4][C:5]4[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=4)=[O:3])[CH2:37][CH2:38]3)[C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][C:27]2=3)[CH:23]=[CH:24][CH:25]=1
Reactant: CN1CCC2(CC1)SC(c1cccc(F)c1)c1ccccc12
Reactant: O=C(Cl)Oc1ccccc1
Agent: O=C(O)/C=C\C(=O)O
Solvent: ClCCl
Product: O=C(Oc1ccccc1)N1CCC2(CC1)SC(c1cccc(F)c1)c1ccccc12
Temperature: 25 °C
Reaction time: 21 h

Procedure:
To 5.0 g of phenyl chloroformate in 80 ml of dichloromethane is added 7.89 g of the free base, 3-(3-fluorophenyl)-1,3-dihydro-1'-methylspiro[benzo(c)thiophene-1,4'-piperidine] of Example 55, in 10 ml of dichloromethane over 20 minutes. The reaction mixture is stirred at room temperature for 21 hours, then diluted with 200 ml of dichloromethane. The resultant mixture is washed with two 175 ml portions of 10% aqueous sodium hydroxide solution, two 150 ml portions of water and one 70 ml portion of saturated aqueous sodium chloride solution, and dried over magnesium sulfate to give an oil. The oil is chromatographed on silica gel with dichloromethane to give an oil, which crystallizes to yield 3-(3-fluorophenyl)-1,3-dihydro-1'-phenoxycarbonylspiro[benzo(c)thiophene-1,4'-piperidine], m.p. 134°-142° C. A portion is recrystallized twice from toluene:hexane, m.p. 144°-146° C.
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=[O:5])[CH:3]=[CH:2]1.[C:8]([NH2:12])([CH3:11])([CH3:10])[CH3:9]>C(#N)C>[C:8]([NH:12][C:1](=[O:7])/[CH:2]=[CH:3]\[C:4]([OH:6])=[O:5])([CH3:11])([CH3:10])[CH3:9]
Reactant: CC(C)(C)N
Reactant: O=C1C=CC(=O)O1
Solvent: CC#N
Product: CC(C)(C)NC(=O)/C=C\C(=O)O
Temperature: -7 °C

Procedure:
To a 12 L four necked round bottom flask with a mechanical stirrer, thermometer and an addition funnel, under nitrogen, was added 1072.6 grams of maleic anhydride (10.9 moles) and 6062 grams of acetonitrile. The mixture was stirred to dissolve the solids and cooled to −7° C. To this was added 800 grams of t-butylamine (10.9 moles) slowly at a rate such that the temperature remained below 0° C. (approximately 2.5 hour addition). Following the addition the mixture was stirred at −7° C. for one hour and overnight at room temperature. The solid was collected by filtration, washed with 500 mL of acetonitrile and dried to give 1355 grains of (Z)-4-(tert-butylamino)-4-oxo-2-butenoic acid as a white solid. 13-C NMR shows this to be 94.62 wt % (Z)-4-(tert-butylamino)-4-oxo-2-butenoic acid, and 5.38 wt % t-butylamine. This material was used without further purification for the next reaction.
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.O1CCCC1.[Si]([O:31][CH2:32][C:33]1[C:38]([CH3:39])=[C:37]([O:40][CH3:41])[C:36]([F:42])=[CH:35][N:34]=1)(C(C)(C)C)(C)C>ClCCl>[F:42][C:36]1[C:37]([O:40][CH3:41])=[C:38]([CH3:39])[C:33]([CH2:32][OH:31])=[N:34][CH:35]=1
Reactant: COc1c(F)cnc(CO[Si](C)(C)C(C)(C)C)c1C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: ClCCl
Solvent: C1CCOC1
Product: COc1c(F)cnc(CO)c1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 70.9 %

Procedure:
Tetrabutylammonium fluoride (1 M solution, 1.49 ml) was added to a tetrahydrofuran (10 ml) solution of the above 2-({[tert-butyl(dimethyl)silyl]oxy}methyl)-5-fluoro-4-methoxy-3-methylpyridine (353 mg) under cooling in an ice bath, and the resulting mixture was stirred at room temperature for 1 hour. The reaction solution was diluted with dichloromethane, and was then washed with water. The organic layer was dried over anhydrous sodium sulfate, and the filtrate was then concentrated. The residue was purified by silica gel column chromatography (hexane-ethyl acetate), so as to obtain the title compound (150 mg) as a solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:18]([NH2:20])=O)[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[C:10](=[O:17])[O:9]2)=[CH:4][CH:3]=1.[NH2:21][CH2:22][CH2:23][CH2:24]N.C1(C)C=CC=CC=1>O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([OH:9])[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[C:10](=[O:17])[N:20]3[CH2:24][CH2:23][CH2:22][N:21]=[C:18]23)=[CH:6][CH:7]=1
Reactant: NCCCN
Reactant: NC(=O)C1(c2ccc(F)cc2)OC(=O)c2ccccc21
Solvent: Cc1ccccc1
Solvent: O
Product: O=C1c2ccccc2C(O)(c2ccc(F)cc2)C2=NCCCN12
Temperature: 25 °C

Procedure:
A mixture of 1-(4-fluorophenyl)-3-oxo-1,3-dihydro-2-benzofuran-1-carboxamide (17 g), 1,3-diaminopropane (25 mL), and toluene (125 mL) was heated at reflux for 19 h in a flask equipped with a water separator. The mixture was cooled to ambient temperature and extracted with water, and evaporated to dryness. The residue was crystallized from ethanol to give the title compound (26 g) as a solid, m.p. 126-128° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[NH:12][C:11](=[O:13])[N:10]([CH:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[CH2:9][CH2:8][C:7]=2[CH:20]=1.[CH2:21]([N:28]([CH2:38][C:39]([F:42])([F:41])[F:40])[C:29]([C:31]1[CH:36]=[C:35](Cl)[N:34]=[CH:33][N:32]=1)=[O:30])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH2:21]([N:28]([CH2:38][C:39]([F:42])([F:41])[F:40])[C:29]([C:31]1[CH:36]=[C:35]([N:17]2[CH2:18][CH2:19][CH:14]([N:10]3[CH2:9][CH2:8][C:7]4[CH:20]=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][C:6]=4[NH:12][C:11]3=[O:13])[CH2:15][CH2:16]2)[N:34]=[CH:33][N:32]=1)=[O:30])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=C(c1cc(Cl)ncn1)N(Cc1ccccc1)CC(F)(F)F
Reactant: COc1ccc2c(c1)CCN(C1CCNCC1)C(=O)N2
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc2c(c1)CCN(C1CCN(c3cc(C(=O)N(Cc4ccccc4)CC(F)(F)F)ncn3)CC1)C(=O)N2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
44 mg (0.16 mmol) 7-methoxy-3-piperidin-4-yl-1,3,4,5-tetrahydro-1,3-benzodiazepin-2-one were added to 50 mg (0.15 mmol) 6-chloropyrimidine-4-carboxylic acid-benzyl-(2,2,2-trifluorethyl)-amide and 34 μL (0.20 mmol) DIPEA in 5 mL DMF. The reaction mixture was stirred for 2 h at RT. The reaction mixture was purified by preparative HPLC-MS. The product fractions were combined and evaporated down i. vac.
Reaction SMILES: Br[CH:2](Br)[C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][C:4]=1[N+:11]([O-:13])=[O:12].C([O-])(O)=[O:16].[Na+]>O>[CH3:10][O:9][C:6]1[CH:7]=[CH:8][C:3]([CH:2]=[O:16])=[C:4]([N+:11]([O-:13])=[O:12])[CH:5]=1
Reactant: COc1ccc(C(Br)Br)c([N+](=O)[O-])c1
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: COc1ccc(C=O)c([N+](=O)[O-])c1
Temperature: 25 °C
Yield: 85 %

Procedure:
A mixture of 1-(dibromomethyl)-4-methoxy-2-nitrobenzene (42 g, 0.23 mol) and NaHCO3 (3 Eq) in water (400 mL) is refluxed for 22 h. The reaction mixture is cooled to room temperature and the product is extracted with EtOAc (2×150 mL). The organic layer is washed with a solution of 1.5N HCl (2×100 mL), water (2×100 mL) and brine then dried over Na2SO4. The solvent is removed under reduced pressure to afford 20 g (85%) of the title compound as a brown solid. 1H NMR (DMSO-d6, 400 MHz) δ 10.03 (s, 1H), 7.93-7.95 (m, 1H), 7.61 (s, 1H), 7.40-7.41 (m, 1H), 3.93 (s, 3H).
Reaction SMILES: C1N=CN(C(N2C=NC=C2)=O)C=1.[CH:13]1[C:18]([C:19]2[CH:20]=[CH:21][C:22]([F:26])=[CH:23][C:24]=2[F:25])=[CH:17][C:16]([C:27]([OH:29])=[O:28])=[C:15]([OH:30])[CH:14]=1.C(O)(C)(C)C.[CH2:36]1[CH2:46]CN2C(=NCCC2)[CH2:38][CH2:37]1.C([O-])(O)=O.[Na+]>CN(C=O)C>[F:25][C:24]1[CH:23]=[C:22]([F:26])[CH:21]=[CH:20][C:19]=1[C:18]1[CH:13]=[CH:14][C:15]([OH:30])=[C:16]([C:27]([O:29][CH2:46][CH2:36][CH2:37][CH3:38])=[O:28])[CH:17]=1
Reactant: O=C(O)c1cc(-c2ccc(F)cc2F)ccc1O
Reactant: C1CCC2=NCCCN2CC1
Agent: O=C([O-])O
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(C)(C)O
Product: CCCCOC(=O)c1cc(-c2ccc(F)cc2F)ccc1O
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 68 %

Procedure:
CDI (1.29 g, 7.99 mmol) was added to a solution of diflunisal (2.02 g, 8.07 mmol) in DMF (20 mL). The reaction mixture was stirred at 50° C. for 30 min and tert-butyl alcohol (1.50 mL, 14.97 mmol) and DBU (2.40 mL, 16.064 mmol) were dropwise added. The reaction mixture was stirred at 50° C. for 20 h and allowed to reach r.t. It was poured into NaHCO3 (100 mL, saturated aqueous solution) and extracted with EtOAc (100 mL). The organic layer was dried over Na2SO4 (anhydrous), filtered and concentrated. The crude residue was flash chromatographed on SiO2 (5% EtOAc/hexanes) to furnish 1.677 g of ten-butyl 2′,4′-difluoro-4-hydroxybiphenyl-3-carboxylate (colourless oil, yield: 68%).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH2:8][NH:9][C:10]2[CH:28]=[CH:27][CH:26]=[CH:25][C:11]=2[C:12]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:16]=2)=[O:13])[CH:5]=[CH:4][N:3]=1.[CH3:29][N:30]([CH2:32][CH2:33][NH2:34])[CH3:31]>N1C=CC=CC=1>[CH3:29][N:30]([CH3:31])[CH2:32][CH2:33][NH:34][C:2]1[CH:7]=[C:6]([CH2:8][NH:9][C:10]2[CH:28]=[CH:27][CH:26]=[CH:25][C:11]=2[C:12]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:23])([F:24])[F:22])[CH:16]=2)=[O:13])[CH:5]=[CH:4][N:3]=1
Reactant: CN(C)CCN
Reactant: O=C(Nc1cccc(C(F)(F)F)c1)c1ccccc1NCc1ccnc(Br)c1
Solvent: c1ccncc1
Product: CN(C)CCNc1cc(CNc2ccccc2C(=O)Nc2cccc(C(F)(F)F)c2)ccn1
Temperature: 200 °C

Procedure:
90 mg (0.2 mmol) of 2-[(2-bromo-pyridin-4-ylmethyl)-amino]-N-(3-trifluoromethyl-phenyl)-benzamide is dissolved in 3 ml of pyridine and mixed with 1 ml of N,N-dimethyl-aminoethylamine and heated in a pressure vessel for 5 hours to a bath temperature of 200° C. After cooling, it is concentrated by evaporation, and 90 mg of 2-{[2-(2-dimethylamino-ethylamino)-pyridin-4-ylmethyl]-amino}-N-(3-trifluoromethyl-phenyl)-benzamide is obtained.
Reaction SMILES: C[O:2][C:3]1[C:8]([O:9]C)=[CH:7][C:6]2[C:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][N:19]4[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]4)[CH2:13][C:12]=3[C:25](=[O:27])[O:26][C:5]=2[CH:4]=1.O>Br>[OH:2][C:3]1[C:8]([OH:9])=[CH:7][C:6]2[C:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][N:19]4[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]4)[CH2:13][C:12]=3[C:25](=[O:27])[O:26][C:5]=2[CH:4]=1
Reactant: COc1cc2oc(=O)c3c(c2cc1OC)CCN(CCN1CCCCC1)C3
Agent: Br
Solvent: O
Product: O=c1oc2cc(O)c(O)cc2c2c1CN(CCN1CCCCC1)CC2

Procedure:
A solution of 4.7 g of 1,2,3,4-tetrahydro-8,9-dimethoxy-3-(2-piperidinoethyl)-5H-[1]benzopyrano[3,4-c]pyridin-5-one in 70 cc of 48% HBr was refluxed for 17 hr and cooled. Precipitate was cryst from water affording 2.8 g of product; mp 291°-295°C.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]=[CH:13][N:14]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=4[Cl:21])[C:5]=3[C:4]=2[CH:3]=1.[Br:22]N1C(=O)CCC1=O>C(Cl)(Cl)Cl>[Br:22][C:13]1[N:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[Cl:21])[C:5]2[C:4]3[CH:3]=[C:2]([Cl:1])[CH:11]=[CH:10][C:9]=3[N:8]=[CH:7][C:6]=2[N:12]=1
Reactant: Clc1ccc2ncc3ncn(-c4ccccc4Cl)c3c2c1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)Cl
Product: Clc1ccc2ncc3nc(Br)n(-c4ccccc4Cl)c3c2c1
Temperature: 0 °C

Procedure:
2 g (6.36 mmol) of 8-chloro-1-(2-chloro-phenyl)-1H-imidazo[4,5-c]quinoline (Example 25), 6.6 g (37 mmol) N-bromosuccinimide, and 1.32 g (4.45 mmol) FeBr3 (98%; Aldrich) are heated and kept under reflux during 2½ h in 50 ml CHCl3. The cold solution is poured on ca. 300 ml ice-water, where a precipitate is formed. Extraction of the water phase with CH2Cl2 and chromatography of the raw material on silicagel (hexane-ethyl acetate 1:1) gives the desired title compound. mp: 183-192° C.; MS: 392 (M++1); HPLC: tret=12.44 min (Grad 1).
Reaction SMILES: [Cl:1][C:2]1[C:7]2[N:8]([CH2:11][C:12]([OH:14])=O)[CH:9]=[N:10][C:6]=2[CH:5]=[CH:4][C:3]=1[F:15].[NH2:16][CH:17]([C:19]1[CH:24]=[CH:23][C:22]([C:25]([CH3:29])([CH3:28])[C:26]#[N:27])=[C:21]([CH3:30])[CH:20]=1)[CH3:18].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C1C=CN=CC=1)C.CN(C=O)C.CO>[Cl:1][C:2]1[C:7]2[N:8]([CH2:11][C:12]([NH:16][CH:17]([C:19]3[CH:24]=[CH:23][C:22]([C:25]([C:26]#[N:27])([CH3:29])[CH3:28])=[C:21]([CH3:30])[CH:20]=3)[CH3:18])=[O:14])[CH:9]=[N:10][C:6]=2[CH:5]=[CH:4][C:3]=1[F:15]
Reactant: Cc1cc(C(C)N)ccc1C(C)(C)C#N
Reactant: O=C(O)Cn1cnc2ccc(F)c(Cl)c21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CN(C)c1ccncc1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CO
Product: Cc1cc(C(C)NC(=O)Cn2cnc3ccc(F)c(Cl)c32)ccc1C(C)(C)C#N
Yield: 159.6 %

Procedure:
To a solution of (7-chloro-6-fluoro-1H-benzimidazol-1-yl)acetic acid (100 mg, 0.44 mmol) prepared according to scheme 12, 2-{4-[1-aminoethyl]-2-methylphenyl}-2-methylpropanenitrile (88.5 mg 0.44 mmol) prepared according to scheme 16 and DMAP (106 mg, 0.88 mmol) stirred in anhydrous DMF (2.0 mL) is added HATU (166 mg, 0.44 mmol) after 18 hours of stirring, the mixture is diluted with methanol (200 μL) the solution is purified directly on a preparative LCMS system equipped with a Synergi Polar (4 u) 21.2×50 mm column, mobile phase: A=water (0.1% TFA), B=MeCN using a short 40 to 60% B 10 min. gradient method. The pure fractions are combined the TFA neutralized with a 4N NaOH solution and then extracted with ethyl acetate which is separated dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to provide the expected product (+) and (−)-2-(7-chloro-6-fluoro-1H-benzimidazol-1-yl)-N-{1-[4-(1-cyano-1-methylethyl)-3-methylphenyl]ethyl}acetamide (290 mg, 53%) as a white solid. 1H NMR (400 MHz, METHANOL-D4) δ ppm 1.48 (d, J=7.03 Hz, 3H) 1.76 (s, 6H) 2.61 (s, 3H) 4.99 (q, J=7.03 Hz, 1H) 5.19-5.36 (m, 2H) 7.13-7.25 (m, 3H) 7.33 (d, J=8.20 Hz, 1H) 7.59 (dd, J=8.98, 4.30 Hz, 1H) 8.14 (s, 1H), MS [M+H], calcd: 413.2, found: 413.3.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[C:7]2[CH:13]=[O:14])([O-:3])=[O:2].[C:15](=O)([O-])[O-].[K+].[K+].CI>CN(C)C=O>[CH3:15][N:9]1[C:10]2[C:6](=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:12][CH:11]=2)[C:7]([CH:13]=[O:14])=[CH:8]1
Reactant: O=C([O-])[O-]
Reactant: O=Cc1c[nH]c2ccc([N+](=O)[O-])cc12
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: Cn1cc(C=O)c2cc([N+](=O)[O-])ccc21
Temperature: 60 °C
Reaction time: 24 h
Yield: 92.7 %

Procedure:
5-Nitroindole-3-carboxaldehyde (2 g) was dissolved in N,N-dimethylformamide (40 ml), and potassium carbonate (4.0 g) and methyl iodide (5 ml) were added thereto, followed by stirring at 60° C. for 24 hours. The reaction solution was subjected to partitioning with chloroform, methanol and water, and the organic layer was dried over magnesium sulfate. After concentration under reduced pressure, the residue was rinsed with ethyl acetate to give 1-methyl-5-nitroindole-3-carboxaldehyde (Compound III-2, 1.99 g).
Reaction SMILES: [C:1]([N:9]=[C:10]=[O:11])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[S:12]1[CH:16]=[CH:15][C:14]2[CH:17]([NH2:21])[CH2:18][CH2:19][CH2:20][C:13]1=2>C(Cl)Cl>[C:1]([NH:9][C:10]([NH:21][CH:17]1[C:14]2[CH:15]=[CH:16][S:12][C:13]=2[CH2:20][CH2:19][CH2:18]1)=[O:11])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NC1CCCc2sccc21
Reactant: O=C=NC(=O)c1ccccc1
Solvent: ClCCl
Product: O=C(NC(=O)c1ccccc1)NC1CCCc2sccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A 2.94 g sample of benzoyl isocyanate in 5 ml of CH2Cl2 is added to 3.04 g of 4,5,6,7-tetrahydrobenzo[b]thiophen-4-amine in 50 ml of CH2Cl2 under N2 atmosphere. After stirring overnight at room temperature, the reaction mixture is evaporated to dryness in vacuo. The residue is then stirred in 100 ml of Et2O and filtered to afford 1-benzoyl-3-(4,5,6,7-tetrahydrobenzo[b]thien-4-yl)urea, m.p. 189° C. to 194° C. Substitution of trichloroacetyl isocyanate for benzoyl isocyanate affords 1-trichloroacetyl-3-(4,5,6,7-tetrahydrobenzo[b]thien-4-yl)urea. Use of 4,5,6,7-tetrahydrobenzo[b]thien-4-ylisocyanate and acetamide in the above manner affords 1-acetyl-3-(4,5,6,7-tetrahydrobenzo[b]thien-4-yl)urea.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13][O:14][C:15]1[CH:16]=[C:17]([C:25]([O:27][CH3:28])=[O:26])[C:18](=[CH:23][CH:24]=1)[C:19]([O:21][CH3:22])=[O:20])=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13][O:14][C:15]1[CH:16]=[C:17]([C:25]([O:27][CH3:28])=[O:26])[C:18](=[CH:23][CH:24]=1)[C:19]([O:21][CH3:22])=[O:20]
Reactant: COC(=O)c1ccc(OC[C@@H]2CCCN2C(=O)OC(C)(C)C)cc1C(=O)OC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)c1ccc(OC[C@@H]2CCCN2)cc1C(=O)OC
Temperature: 25 °C
Reaction time: 0.83 h
Yield: 18.4 %

Procedure:
To a solution of dimethyl (S)-4-[1-(tert-butoxycarbonyl)-2-pyrrolidinylmethoxy]phthalate (5.75 g, 14.62 mmol) in CH2Cl2 (25 mL) was added TFA (20 mL), and the resulting mixture was stirred for 50 min at room temp. The resulting mixture was concentrated in vacuo and made basic with sat. NaHCO3. The mix was extracted with CH2Cl2, washed with brine, dried over MgSO4, and evaporated off in vacuo. The residue was purified by column chromatography on silica-gel with CHCl3—MeOH (50:1, v/v) as eluent to give 790 mg (18%) dimethyl (S)-4-(2-pyrrolidinylmethoxy)phthalate as a brown oil. 1H-NMR (CDCl3) δ1.48-1.57 (m, 1 H), 1.72-1.84 (m, 2 H), 1.89-1.98 (m, 2 H), 2.91-3.03 (m, 2 H), 3.48-3.54 (m, 1 H), 3.82-3.97 (m, total 8 H), 6.98 (dd, 1 H, J=2.4, 8.8 Hz), 7.06 (d, 1 H, J=2.4 Hz), 7.78 (d, 1 H, J=8.8 Hz).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[CH2:4][CH:5]([C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]([Cl:17])[CH:11]=1)[CH2:6][N+:7]([O-:9])=[O:8].[C:19]([O:23][CH3:24])(=[O:22])[CH:20]=[CH2:21].Cl>C(O)(C)(C)C.C(OCC)C>[CH3:1][O:2][C:3](=[O:18])[CH2:4][CH:5]([C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]([Cl:17])[CH:11]=1)[CH:6]([N+:7]([O-:9])=[O:8])[CH2:21][CH2:20][C:19]([O:23][CH3:24])=[O:22]
Reactant: COC(=O)CC(C[N+](=O)[O-])c1ccc(Cl)c(Cl)c1
Reactant: C=CC(=O)OC
Agent: Cl
Solvent: CCOCC
Solvent: CC(C)(C)O
Product: COC(=O)CCC(C(CC(=O)OC)c1ccc(Cl)c(Cl)c1)[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 94 h

Procedure:
A solution of 350 g of 4-nitro-3-(3,4-dichlorophenyl)butanoic acid methyl ester, 118 g of methyl acrylate and 25 ml of Triton B in 500 ml of t-butanol is allowed to stir at room temperature for 94 hours. Excess aqueous hydrochloric acid (1 N) is added and the solution is diluted with diethyl ether. The organic layer is separated, dried over anhydrous magnesium sulfate and evaporated to give 4-nitro-3-(3,4-dichlorophenyl)heptanedioic acid dimethyl ester.
Reaction SMILES: [F:1][C:2]1[CH:26]=[C:25]([N+:27]([O-])=O)[CH:24]=[CH:23][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]2[CH:11]=[C:12]([C:14]([N:16]3[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]3)=[O:15])[S:13][C:6]=12.[Cl-].[NH4+]>CO.O.[Zn]>[NH2:27][C:25]1[CH:24]=[CH:23][C:3]([O:4][C:5]2[CH:10]=[CH:9][N:8]=[C:7]3[CH:11]=[C:12]([C:14]([N:16]4[CH2:17][CH2:18][N:19]([CH3:22])[CH2:20][CH2:21]4)=[O:15])[S:13][C:6]=23)=[C:2]([F:1])[CH:26]=1
Reactant: CN1CCN(C(=O)c2cc3nccc(Oc4ccc([N+](=O)[O-])cc4F)c3s2)CC1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CO
Solvent: O
Product: CN1CCN(C(=O)c2cc3nccc(Oc4ccc(N)cc4F)c3s2)CC1
Temperature: 25 °C
Yield: 65.6 %

Procedure:
Zinc (0.75 g, 11.53 mmol) was added to a suspension of 437 (1.2 g, 2.88 mmol) and ammonium chloride (0.31 g, 5.76 mmol) in a mixture of MeOH (30 mL) and water (5.10 mL). The suspension was heated to reflux for 50 min. After cooling to room temperature, the reaction mixture was filtered and concentrated. The residue was partitioned between DCM, water and ammonium hydroxide. The organic layer was collected, successively washed with water and brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by biotage (SNAP 50 g cartridge; MeOH/DCM: 0/100 to 20/80 over 30CV), to afford the title compound 438 (733 mg, 1.89 mmol, 66% yield) as a yellow solid. MS (m/z): 387.4 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:17]=[C:18]([CH:20]=[CH:21][CH:22]=1)[NH2:19].[F:23][C:24]([F:45])([F:44])[C:25]([C:28]1[CH:32]=[C:31]([NH:33][C:34](=O)[O:35]C2C=CC(Cl)=CC=2)[O:30][N:29]=1)([CH3:27])[CH3:26]>C1COCC1.CN(C)C1C=CN=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:17]=[C:18]([NH:19][C:34]([NH:33][C:31]2[O:30][N:29]=[C:28]([C:25]([CH3:27])([CH3:26])[C:24]([F:45])([F:44])[F:23])[CH:32]=2)=[O:35])[CH:20]=[CH:21][CH:22]=1
Reactant: CC(C)(c1cc(NC(=O)Oc2ccc(Cl)cc2)on1)C(F)(F)F
Reactant: COc1cc2ncnc(Oc3cccc(N)c3)c2cc1OC
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Product: COc1cc2ncnc(Oc3cccc(NC(=O)Nc4cc(C(C)(C)C(F)(F)F)no4)c3)c2cc1OC
Temperature: 25 °C
Reaction time: 6 h
Yield: 51 %

Procedure:
To a stirred solution of 3-(6,7-dimethoxyquinazolin-4-yloxy)aniline (89 mg, 0.3 mmol) described in Example 113A in anhydrous THF (1.5 mL), was added 4-chlorophenyl 3-(1,1,1-trifluoro-2-methylpropan-2-yl)isoxazol-5-ylcarbamate from the previous step (104 mg, 0.3 mmol) and 4-(dimethylamino)pyridine (18 mg, 0.15 mmol). The mixture was stirred at rt for 6 h. Concentration in vacuo followed by purification by silica gel chromatography (dichloromethane/ethyl acetate 1:1) afforded 1-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)-3-(3-(1,1,1-trifluoro-2-methylpropan-2-yl)isoxazol-5-yl)urea (79.9 mg, 51%) as a colorless solid. 1H NMR (300 MHz, DMSO-d6) δ 10.44 (s, 1H), 9.11 (s, 1H), 8.56 (s, 1H), 7.56-7.58 (m, 2H), 7.40-7.45 (m, 2H), 7.29-7.32 (m, 2H), 6.99-7.02 (m, 2H), 6.18 (s, 1H), 4.00 (s, 6H), 1.24 (s, 6H); LC-MS (ESI) m/z 518 (M+H)+.