Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH:7]=[CH:8][C:9]2[CH:21]=[CH:20][C:12]([O:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]#[N:19])=[CH:11][CH:10]=2)=[CH:3][CH:2]=1.[N-:22]=[N+:23]=[N-:24].[Na+].[Cl-].[NH4+]>CN(C)C=O>[N:1]1[CH:6]=[CH:5][C:4]([CH:7]=[CH:8][C:9]2[CH:10]=[CH:11][C:12]([O:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]3[NH:24][N:23]=[N:22][N:19]=3)=[CH:20][CH:21]=2)=[CH:3][CH:2]=1
Reactant: N#CCCCCOc1ccc(C=Cc2ccncc2)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C(=Cc1ccc(OCCCCc2nnn[nH]2)cc1)c1ccncc1
Temperature: 125 °C
Reaction time: 72 h

Procedure:
A mixture of 5.3 g (19 mmol) of compound of Example 1, 3.7 g (57 mmol) sodium azide, 3.0 g (57 mmol) ammonium chloride and 40 ml N,N-dimethylformamide is stirred for 3 days at 125° C. One adds thereto a further 2.5 g sodium azide and 2.0 g ammonium chloride, stirs for a further 6 h at 125° C., evaporates, takes up the residue in water, extracts with dichloromethane, dries, evaporates and triturates with 2-propanol. There remain 2.7 g of title compound (44% of theory) of the m.p. 158°-159° C.
Reaction SMILES: [C:1]1(=O)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[C:11]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])(=[O:14])[NH:12][NH2:13]>CO.C(O)(=O)C>[C:16]([O:15][C:11]([NH:12][N:13]=[C:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1)=[O:14])([CH3:19])([CH3:18])[CH3:17]
Reactant: CC(C)(C)OC(=O)NN
Reactant: O=C1CCc2ccccc21
Solvent: CO
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)NN=C1CCc2ccccc21

Procedure:
A solution of indan-1-one (5.0 g) and tert-butyl carbazate (5.0 g) in methanol (20 ml) containing glacial acetic acid (1 drop) was boiled and stirred under reflux for 1.5 hours. The mixture was cooled and evaporated under reduced pressure. The residue was recrystallized from ethanol to give indan-1-one tert-butyloxycarbonyl-hydrazone.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C@@:15]3([CH2:20][CH2:19][O:18][C:17]([NH2:21])=[N:16]3)[C:14]3[CH:13]=[C:12]([Cl:22])[N:11]=[C:10]([F:23])[C:9]=3[O:8][C:5]2=[CH:6][CH:7]=1.[N-:24]=[N+:25]=[N-:26].[Na+].CCO>[Cu]I.O>[N:24]([C:2]1[CH:3]=[C:4]2[C@@:15]3([CH2:20][CH2:19][O:18][C:17]([NH2:21])=[N:16]3)[C:14]3[CH:13]=[C:12]([Cl:22])[N:11]=[C:10]([F:23])[C:9]=3[O:8][C:5]2=[CH:6][CH:7]=1)=[N+:25]=[N-:26]
Reactant: [N-]=[N+]=[N-]
Reactant: NC1=N[C@@]2(CCO1)c1cc(Br)ccc1Oc1c2cc(Cl)nc1F
Agent: [Cu]I
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: [N-]=[N+]=Nc1ccc2c(c1)[C@@]1(CCOC(N)=N1)c1cc(Cl)nc(F)c1O2
Temperature: 85 °C
Yield: 45.7 %

Procedure:
A microwave vial was charged with (S)-7-bromo-3-chloro-1-fluoro-5′,6′-dihydrospiro[chromeno[2,3-c]pyridine-5,4′-[1,3]oxazin]-2′-amine (2.08 g, 5.22 mmol), (+)-sodium 1-ascorbate (0.103 g, 0.522 mmol), sodium azide (0.550 ml, 15.65 mmol) and copper(i) iodide (0.035 ml, 1.044 mmol). The vial was sealed, purged with N2 and followed by the addition of trans-n,n′-dimethyl-1,2-cyclohexanediamine (0.247 ml, 1.565 mmol), EtOH (12 mL) and water (4.6 mL). The resulting mixture was heated at 85° C. for 1.5 h. The mixture was poured into water and extracted with EtOAc. The combined organics were washed with brine, dried over Na2SO4, filtered, concentrated and chromatographed on silica gel using 0-50% MeOH/DCM to afford a light yellow solid as (S)-7-azido-3-chloro-1-fluoro-5′,6′-dihydrospiro[chromeno[2,3-c]pyridine-5,4′-[1,3]oxazin]-2′-amine (0.86 g, 45.7% yield).
Reaction SMILES: Cl.[N+:2]([C:5]1[C:6]([N:11]2[CH2:16][CH2:15][CH:14]([NH2:17])[CH2:13][CH2:12]2)=[N:7][CH:8]=[CH:9][CH:10]=1)([O-:4])=[O:3].[Br:18][C:19]1[CH:20]=[C:21]([C:25](OC2C(F)=C(F)C(F)=C(F)C=2F)=[O:26])[NH:22][C:23]=1[CH3:24]>CC(N(C)C)=O>[Br:18][C:19]1[CH:20]=[C:21]([C:25]([NH:17][CH:14]2[CH2:15][CH2:16][N:11]([C:6]3[C:5]([N+:2]([O-:4])=[O:3])=[CH:10][CH:9]=[CH:8][N:7]=3)[CH2:12][CH2:13]2)=[O:26])[NH:22][C:23]=1[CH3:24]
Reactant: Cc1[nH]c(C(=O)Oc2c(F)c(F)c(F)c(F)c2F)cc1Br
Reactant: NC1CCN(c2ncccc2[N+](=O)[O-])CC1
Agent: Cl
Solvent: CC(=O)N(C)C
Product: Cc1[nH]c(C(=O)NC2CCN(c3ncccc3[N+](=O)[O-])CC2)cc1Br
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1-(3-Nitropyridin-2-yl)piperidin-4-amine hydrochloride salt (Intermediate 39) (41 mg, 1.35 mmol) and TEA (37 μl, 1.35 mmol) were added to pentafluorophenyl 4-bromo-5-methyl-1H-pyrrole-2-carboxylate (Intermediate 17): (50 mg, 1.35 mmol) in anhydrous DMA (1 ml). The mixture was stirred at room temperature overnight. The crude mixture was filtered and purified by semi-preparative HPLC using CH3CN/H2O (0.1% TFA) to yield the title compound as a yellow solid (26 mg).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:23][CH3:24])=[C:17]([N+:20]([O-])=O)[CH:18]=3)[N:13]=[CH:12][C:11]=2[C:25]#[N:26])[CH:5]=[CH:6][C:7]=1[F:8].[Cl-].[NH4+]>O.CO.C(OCC)(=O)C.[Fe]>[NH2:20][C:17]1[CH:18]=[C:19]2[C:14](=[CH:15][C:16]=1[O:23][CH3:24])[N:13]=[CH:12][C:11]([C:25]#[N:26])=[C:10]2[NH:9][C:4]1[CH:5]=[CH:6][C:7]([F:8])=[C:2]([Br:1])[CH:3]=1
Reactant: COc1cc2ncc(C#N)c(Nc3ccc(F)c(Br)c3)c2cc1[N+](=O)[O-]
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: O
Product: COc1cc2ncc(C#N)c(Nc3ccc(F)c(Br)c3)c2cc1N
Yield: 78.4 %

Procedure:
A mixture of 2.9 g (6.95 mmol) of 4-[(3-bromo-4-fluorophenyl)amino]7-methoxy-6-nitro-quinoline-3-carbonitrile, 6.5 g (121.6 mmol) of ammonium chloride and 4.05 g (73 mmol) of iron in 50 ml of water and 50 ml of methanol for 6 hours. The mixture was diluted with hot ethyl acetate and the hot mixture was filtered. The filtration was washed with saturated sodium chloride solution then the organic layer was dried over sodium sulfate. The solvent was removed and the residue was chromatographed on silica gel eluting with mixture of ethyl acetate and methanol to give 2.11 g of light yellow solid: mass spectrum (electrospray, m/e): M+H 386.7 and 388.8.
Reaction SMILES: [C:1]1([C@H:7]2[CH2:12][CH2:11][CH2:10][CH2:9][C@H:8]2[N:13]2[CH2:22][CH2:21][C:16]3(OCC[O:17]3)[CH2:15][CH2:14]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[Na+].[Na+]>CO.Cl>[C:1]1([C@H:7]2[CH2:12][CH2:11][CH2:10][CH2:9][C@H:8]2[N:13]2[CH2:22][CH2:21][C:16](=[O:17])[CH2:15][CH2:14]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: c1ccc([C@H]2CCCC[C@H]2N2CCC3(CC2)OCCO3)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Product: O=C1CCN([C@@H]2CCCC[C@@H]2c2ccccc2)CC1
Yield: 75.3 %

Procedure:
A solution of (+/−)-8-(cis 2-phenyl-cyclohexyl)-1,4-dioxa-8-aza-spiro[4,5]decane (44.8 g) in MeOH (100 ml) and 6N HCl (445 ml) was heated to reflux for 16 h. The reaction mixture was then made basic with solid sodium carbonate, extracted with dichloromethane, dried over sodium sulphate, filtered and evaporated. The crude product was purified by flash chromatography over silica gel with n-heptane as eluent. (+/−)-1-(cis-2-phenyl-cyclohexyl)-piperidin-4-one (28.8 g, 75%) was obtained as a sticky yellow oil, MS (ISP): m/e=258.3 (M+H+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:10])[C:5]([NH:8][CH3:9])=[N:6][CH:7]=1.[CH2:11]([S:13][C:14]1[CH:22]=[CH:21][CH:20]=[CH:19][C:15]=1[C:16](O)=O)[CH3:12].CCN=C=NCCCN(C)C.N1C=CC=CC=1>C1C=CC2N(O)N=NC=2C=1.O>[Br:1][C:2]1[CH:3]=[C:4]2[N:10]=[C:16]([C:15]3[CH:19]=[CH:20][CH:21]=[CH:22][C:14]=3[S:13][CH2:11][CH3:12])[N:8]([CH3:9])[C:5]2=[N:6][CH:7]=1
Reactant: CCSc1ccccc1C(=O)O
Reactant: CNc1ncc(Br)cc1N
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: c1ccncc1
Solvent: O
Product: CCSc1ccccc1-c1nc2cc(Br)cnc2n1C
Temperature: 120 °C
Reaction time: 8 h
Yield: 49.7 %

Procedure:
A mixture of 5-bromo-N2-methylpyridin-2,3-diamine (0.70 g), 2-ethylsulfanylbenzoic acid (0.66 g), WSC (0.80 g), HOBt (23 mg), and pyridine (20 ml) was stirred under reflux at 120° C. for 30 minutes. After the reaction mixture was allowed to stand overnight, the mixture was stirred under reflux at 120° C. for 9.5 hours again. Into the reaction mixture cooled to room temperature, water was poured under ice-cooling, and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. A mixture of the resulting residue and acetic anhydride (7 ml) was stirred under reflux at 140° C. for 1 hour. Aqueous sodium hydroxide solution was added to the reaction mixture cooled to room temperature to neutralize, and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography to give 0.60 g of 6-bromo-2-(2-ethylsulfanylphenyl)-3-methyl-3H-imidazo[4,5-b]pyridine (hereinafter referred to as Present Compound 42).
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.[CH3:6][N:7]1[C:11](=O)[CH:10]=[C:9]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[NH:8]1>O>[Cl:3][C:11]1[N:7]([CH3:6])[N:8]=[C:9]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:10]=1
Reactant: Cn1[nH]c(-c2ccccc2)cc1=O
Reactant: O=P(Cl)(Cl)Cl
Solvent: O
Product: Cn1nc(-c2ccccc2)cc1Cl
Reaction time: 30 h
Yield: 66.4 %

Procedure:
To a solution of phosphorous oxychloride (2,015 g, 19 moles) is added solid 1-methyl-3-phenylpyrazolin-5-one (2,073 g, 11.9 moles) with stirring and warming. At 100°C. the mixture becomes homogeneous. The reflux temperature rises from 119°C. to 143°C. over a period of 30 hours. After cooling the mixture is poured into ice and water (8 l) with stirring. After 4 hours the slurry is filtered and the filter cake added to 4 l of water containing 1.5 l of 10% sodium hydroxide solution with stirring. Removal of the solid by filtration followed by a recrystallization from hexane yields 1,523 g of product, having a melting point ranging from 61°C. to 62°C.
Reaction SMILES: [CH3:1][C@@H:2]1[C@H:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[O:5][C:4](=[O:13])[NH:3]1.C([Li])CCC.[CH3:19][CH:20]([CH2:24][C:25]([F:28])([F:27])[F:26])[C:21](Cl)=[O:22]>O1CCCC1>[CH3:1][C@@H:2]1[C@H:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[O:5][C:4](=[O:13])[N:3]1[C:21](=[O:22])[C@H:20]([CH3:19])[CH2:24][C:25]([F:28])([F:27])[F:26]
Reactant: C[C@H]1NC(=O)O[C@H]1c1ccccc1
Reactant: CC(CC(F)(F)F)C(=O)Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: C[C@H](CC(F)(F)F)C(=O)N1C(=O)O[C@@H](c2ccccc2)[C@H]1C
Reaction time: 0.25 h
Yield: 41.5 %

Procedure:
To a mixture of (4R,5S)-(+)-4-methyl-5-phenyl-2-oxazolidinone (3.22 g) and tetrahydrofuran (35 ml) at -70° C., under nitrogen was added 1.625M n-butyllithium (12.31 mL) and the mixture was stirred for 15 min. 2-Methyl-4,4,4-trifluorobutyryl chloride (3.5 g) was added to the reaction mixture which was stirred for 15 min at -70° C. and then at 0° C. for 1 hour. The reaction was quenched with ammonium chloride and extracted with ethyl acetate. The organic phase was washed (saturated NaHCO3, brine) and dried (MgSO4). Evaporation and flash chromatography, eluting with 5:95 then 1:9 ethyl acetate:petroelum ether, afforded the two diastereomeric products. Recrystallization from hexane at 20° C. gave (4R,5S)-4-methyl-3-((2R)-2-methyl-4,4,4-trifluorobutyryl)-5-phenyl-2-oxazolidinone (2.376 g, 42%) as colorless needles; mp 72.5°-73.5° C.; TLC, Rf =0.43, 1:9 ethyl acetate:petroleum ether; MS(CI): 316 (M+H).
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[S:5][C:6]2[CH:23]=[CH:22][CH:21]=[CH:20][C:7]=2[N:8]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([NH2:19])=[CH:15][CH:14]=2)[C:9](=[O:11])[CH:10]=1.C/C(/O[Si](C)(C)C)=N\[Si](C)(C)C.[C:36]1([C:42]2[CH:50]=[CH:49][CH:48]=[CH:47][C:43]=2[C:44](Cl)=[O:45])[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.C1(C2C=CC=CC=2)C(C(O)=O)=CC=CC=1>C1COCC1.O>[OH:1][CH2:2][CH2:3][C:4]1[S:5][C:6]2[CH:23]=[CH:22][CH:21]=[CH:20][C:7]=2[N:8]([CH2:12][C:13]2[CH:14]=[CH:15][C:16]([NH:19][C:44](=[O:45])[C:43]3[CH:47]=[CH:48][CH:49]=[CH:50][C:42]=3[C:36]3[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=3)=[CH:17][CH:18]=2)[C:9](=[O:11])[CH:10]=1
Reactant: O=C(Cl)c1ccccc1-c1ccccc1
Reactant: Nc1ccc(CN2C(=O)C=C(CCO)Sc3ccccc32)cc1
Agent: C/C(=N\[Si](C)(C)C)O[Si](C)(C)C
Agent: O=C(O)c1ccccc1-c1ccccc1
Solvent: C1CCOC1
Solvent: O
Product: O=C(Nc1ccc(CN2C(=O)C=C(CCO)Sc3ccccc32)cc1)c1ccccc1-c1ccccc1
Reaction time: 1 h
Yield: 83 %

Procedure:
To a cold (ice-bath) solution of 2-(2-hydroxyethyl)-5-(4-aminobenzyl)-1,5-benzothiazepine-4-one as prepared in Example 21 (0.865 g, 2.6 mM) in dry THF was added N,O-bis(trimethylsilyl)acetamide (1.16 ml, 5.2 mM). After 1 hour, 2-phenylbenzoyl chloride (0.570 g, 2.6 mM), prepared from 2-biphenylcarboxylic acid as described in Example 3, was added and stirring was continued for an addition hour. Water (80 ml) was added and the mixture was extracted with ethyl acetate (2×80 ml). The organic extract was dried (MgSO4), filtered and evaporated in vacuo to give a crude product. Purification by flash column chromatography (EM silica gel 60; 30% EtOAc in CH2Cl2) yielded the desired product as a white solid (1.1 g, 83%) m.p.116-120° C. 1H NMR (300 MHz, DMSOd6) δ7.8 (d, J=7 Hz, 1H); 5.09(d, J=15 Hz, H); 4.89(d,J=15 Hz,1H); 3.79 (m, 3H); 2.69-2.24(m, 2H); 1.71 (m, 2H); m/z (MH+)509.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:10]Br)[C:5]([CH2:8]Br)=[N:6][CH:7]=1.[C:12]([NH2:31])([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[CH2:10][N:31]([C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH2:8][C:5]2=[N:6][CH:7]=1
Reactant: BrCc1cc(Br)cnc1CBr
Reactant: NC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Brc1cnc2c(c1)CN(C(c1ccccc1)(c1ccccc1)c1ccccc1)C2
Temperature: 60 °C
Reaction time: 2 h

Procedure:
A mixture of 0.87 mmol 5-Bromo-2,3-bis-bromomethyl-pyridine, 1.1 mmol tritylamine, and 2.61 mmol DIPEA in 3 ml DMF was stirred at 60° C. for 2 h. The reaction mixture was evaporated in vacuo. The residue was taken in water and extracted with ethylacetate. The combined organic phases were washed with water, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by chromatography (SiO2, heptane/dichloromethane) to yield the title compound as a light brown solid. MS (m/e): 243.4 (tritylion, 100%)
Reaction SMILES: [N+:1]([C:4]1[CH:16]=[CH:15][C:7]2[S:8][C:9]([C:11]([O:13]C)=[O:12])=[CH:10][C:6]=2[CH:5]=1)([O-:3])=[O:2].Cl>CO.[OH-].[Na+]>[N+:1]([C:4]1[CH:16]=[CH:15][C:7]2[S:8][C:9]([C:11]([OH:13])=[O:12])=[CH:10][C:6]=2[CH:5]=1)([O-:3])=[O:2]
Reactant: COC(=O)c1cc2cc([N+](=O)[O-])ccc2s1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1cc2cc([N+](=O)[O-])ccc2s1
Temperature: 25 °C
Reaction time: 20 h
Yield: 97.7 %

Procedure:
A suspension of methyl 5-nitrobenzo[b]thiophene-2-carboxylate (32.49 g, 0.137) in methanol (400 mL) and 1 N aqueous sodium hydroxide (150 mL) was heated to reflux for 1 h after which time everything had gone into solution. After cooling to r.t. the solution was acidified with concentrated hydrochloric acid. The resulting solid was filtered off, washed with water (3×50 mL), air dried, and then placed in a vacuum oven at 60° C. for 20 h to yield 5-nitrobenzo[b]thiophene-2-carboxylic acid (29.87 g, 98%) as a cream amorphous solid. 1H NMR δ (d6-DMSO, 400 MHz) 8.30 (dd, J=9, 2 Hz, 1 H), 8.35 (d, J=9 Hz, 1 H), 8.36 (s, 1 H), 8.98 (s, 1 H), 13.89 (br. s., 1 H).
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[C:9]2[C:5]([CH2:6][C:7](=[CH:13][CH3:14])[C:8]2=[O:12])=[CH:4][C:3]=1[O:15][CH2:16][C:17]([OH:19])=[O:18].S(=O)(=O)(O)O.[CH3:25]O>>[Cl:1][C:2]1[C:10]([Cl:11])=[C:9]2[C:5]([CH2:6][C:7](=[CH:13][CH3:14])[C:8]2=[O:12])=[CH:4][C:3]=1[O:15][CH2:16][C:17]([O:19][CH3:25])=[O:18]
Reactant: CC=C1Cc2cc(OCC(=O)O)c(Cl)c(Cl)c2C1=O
Reactant: CO
Agent: O=S(=O)(O)O
Product: CC=C1Cc2cc(OCC(=O)OC)c(Cl)c(Cl)c2C1=O

Procedure:
[(6,7-Dichloro-2-ethylidene-1-oxo-2,3-dihydro-1H-inden-5-yl)oxy]acetic acid (U.S. Pat. No. 3,704,314) (30.1 gm., 0.1 mole) is dissolved in methanol (150 ml.) and conc. sulfuric acid (0.5 ml.) added. The mixture is stirred and refluxed for 2 hours. The solvent is removed in vacuo by evaporation on a rotary evaporator and the residue dissolved in ethyl ether, washed with water and dried over sodium sulfate. The ether is removed by evaporation in vacuo in a rotary evaporator to give methyl [(6,7-dichloro-2-ethylidene-1-oxo-2,3-dihydro-1H-inden-5-yl)oxy]acetate.
Reaction SMILES: [CH2:1]([O:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:14]=[CH:15][C:16]3[N:22]([S:23]([CH3:26])(=[O:25])=[O:24])[CH2:21][CH2:20][C:19]([C:27]([OH:29])=O)=[CH:18][C:17]=3[CH:30]=2)=[CH:9][CH:8]=1)[CH3:2].S(Cl)(Cl)=O.[CH3:35][N:36]([CH:38]=O)[CH3:37]>C1COCC1>[CH2:1]([O:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]2[CH:14]=[CH:15][C:16]3[N:22]([S:23]([CH3:26])(=[O:25])=[O:24])[CH2:21][CH2:20][C:19]([C:27]([NH:22][C:16]4[CH:17]=[CH:30][C:13]([CH2:38][N:36]([CH3:35])[CH:37]5[CH2:5][CH2:4][O:3][CH2:1][CH2:2]5)=[CH:14][CH:15]=4)=[O:29])=[CH:18][C:17]=3[CH:30]=2)=[CH:11][CH:12]=1)[CH3:2]
Reactant: CCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)O)CCN3S(C)(=O)=O)cc1
Reactant: CN(C)C=O
Solvent: C1CCOC1
Solvent: O=S(Cl)Cl
Product: CCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CN(C)C4CCOCC4)cc2)CCN3S(C)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In THF (15 ml) was suspended 7-[4-(2-ethoxyethoxy)phenyl]-1-methanesulfonyl-2,3-dihydro-1H-1-benzazepine-4-carboxylic acid (0.14 g). To the suspension were added, under ice-cooling, thionyl chloride (0.04 ml) and DMF (catalytic amount), and the mixture was stirred at room temperature for 1.5 hours. Under reduced pressure, the solvent was evaporated, and the residue was dissolved in THF (15 ml). The solution was added dropwise to a solution of 4-[N-methyl-N-(tetrahydro-2H-pyran-4-yl)aminomethyl]aniline (0.08 g) and triethylamine (0.14 ml) in THF (15 ml), under ice-cooling, and the mixture was stirred under nitrogen atmosphere at room temperature for 1 hour. Under reduced pressure, the solvent was evaporated. To the residue was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried with anhydrous magnesium sulfate, and the solvent was evaporated to give 7-[4-(2-ethoxyethoxy)phenyl]-1-methanesulfonyl-N-[4-[[N-methyl-N-(tetrahydro-2H-pyran-4-yl)amino]methyl]phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide (Compound 7) (0.15 g) as colorless amorphous.
Reaction SMILES: [C:1]([OH:10])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[NH2:4].[C:11]1(=O)[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1>>[C:11]1(=[N:4][C:3]2[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=2[C:1]([OH:10])=[O:9])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: Nc1ccccc1C(=O)O
Reactant: O=C1CCCCC1
Product: O=C(O)c1ccccc1N=C1CCCCC1
Temperature: 25 °C
Yield: 69.4 %

Procedure:
Anthranilic acid (10 g, 73 mmol) and cyclohexanone (9.8 mL, 95 mmol) were dissolved in xylenes (110 mL) in a flask equipped with a Dean-Stark apparatus and heated to reflux over 18 hours. The reaction mixture was cooled to room temperature and the resulting precipitate collected by filtration. The filter cake was washed with hexanes and dried in vacuo to give the desired imine (11 g, 69% yield) as a beige solid.
Reaction SMILES: [C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:39][CH2:38][N:37]([CH2:40][C:41]([OH:43])=O)[CH2:36][CH2:35]3)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:44][CH2:45][CH3:46])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:47]([NH2:53])[C:48]1[O:52][CH:51]=[CH:50][CH:49]=1>>[C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:35][CH2:36][N:37]([CH2:40][C:41]([NH:53][CH2:47][C:48]4[O:52][CH:51]=[CH:50][CH:49]=4)=[O:43])[CH2:38][CH2:39]3)=[O:33])[C@@:13]([C:25]3[CH:26]=[CH:27][C:28]([Cl:31])=[CH:29][CH:30]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:44][CH2:45][CH3:46])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCN(CC(=O)O)CC1
Reactant: NCc1ccco1
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCN(CC(=O)NCc2ccco2)CC1

Procedure:
In a manner analogous to the method described in example 99, {4-[(4S,5R)-2-(6-tert-Butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl]-piperazin-1-yl}-acetic acid was coupled with furfurylamine (Acros Organics) to give the title compound. HR-MS (ES, m/z) calculated for C40H47Cl2N6O4 [(M+H)+] 745.3031, observed 745.3028.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH:16]3[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][S:24]([CH3:27])(=[O:26])=[O:25])[CH2:18][CH2:17]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[OH:28][C:29]1[CH:38]=[C:37]2[C:32]([CH:33]=[CH:34][CH:35]=[N:36]2)=[CH:31][CH:30]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH2:15][CH:16]1[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][S:24]([CH3:27])(=[O:26])=[O:25])[CH2:18][CH2:17]1)[N:5]=[CH:4][N:3]=[C:2]2[O:28][C:29]1[CH:38]=[C:37]2[C:32]([CH:33]=[CH:34][CH:35]=[N:36]2)=[CH:31][CH:30]=1
Reactant: COc1cc2c(Cl)ncnc2cc1OCC1CCN(CCS(C)(=O)=O)CC1
Reactant: Oc1ccc2cccnc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3ccc4cccnc4c3)ncnc2cc1OCC1CCN(CCS(C)(=O)=O)CC1
Temperature: 100 °C
Reaction time: 2 h
Yield: 75.2 %

Procedure:
To a solution of 4-chloro-6-methoxy-7-((1-(2-methylsulphonylethyl)piperidin-4-yl)methoxy)quinazoline (115 mg, 0.28 mmol) and 7-hydroxyquinoline (50 mg, 0.33 mmol) in DMF (1.5 ml) was added potassium carbonate (60 mg, 0.42 mmol). The mixture was stirred for 2 hours at 100° C. After cooling, and removal of the volatiles by evaporation, the residue was partitioned between ethyl acetate and water. The organic layer was washed with water, brine, dried (MgSO4) and evaporated. The residue was purified by column chromatography eluting with ethylacetate/methylene chloride/methanol (1/1/0 followed by 40/50/10 and 0/9/1). After removal of the volatiles by evaporation, the residue was triturated with pentane, filtered and dried under vacuum to give 6-methoxy-7-((1-(2-methylsulphonylethyl)piperidin-4-yl)methoxy)-4-(quinolin-7-yloxy)quinazoline (110 mg, 76%).
Reaction SMILES: [CH2:1]([CH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=2)[NH:5][C:4]1=[O:13])[CH3:2].Br[CH2:15][CH2:16][CH2:17][CH2:18][Cl:19]>>[Cl:19][CH2:18][CH2:17][CH2:16][CH2:15][C:3]1([CH2:1][CH3:2])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=2)[NH:5][C:4]1=[O:13]
Reactant: ClCCCCBr
Reactant: CCC1C(=O)Nc2ccc(C)cc21
Product: CCC1(CCCCCl)C(=O)Nc2ccc(C)cc21

Procedure:
The title compound is prepared according to process E starting from 3-ethyl-5-methyl-1,3-dihydro-2H-indol-2-one and 1-bromo-4-chloro-butane.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:15]#[N:16])[CH:5]=[CH:4][N:3]=1.[S:17]([NH2:27])(=[O:26])([C:19]1[CH:24]=[CH:23][C:22]([NH2:25])=[CH:21][CH:20]=1)=[O:18].CO.N>C(O)CCC>[S:17]([C:19]1[CH:24]=[CH:23][C:22]([NH:25][C:2]2[N:7]=[C:6]([NH:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[C:15]#[N:16])[CH:5]=[CH:4][N:3]=2)=[CH:21][CH:20]=1)(=[O:18])(=[O:26])[NH2:27]
Reactant: Nc1ccc(S(N)(=O)=O)cc1
Reactant: N#Cc1ccccc1Nc1ccnc(Cl)n1
Agent: N
Solvent: CCCCO
Solvent: CO
Product: N#Cc1ccccc1Nc1ccnc(Nc2ccc(S(N)(=O)=O)cc2)n1
Temperature: 95 °C
Yield: 80.3 %

Procedure:
2-Chloro-4-(2-cyanoanilino)pyrimidine (250 mg, 1.09 mmol) was dissolved in n-butanol (3 ml) and sulphanilamide (150 mg, 0.87 mmol) was added. The resulting suspension was treated with methanol until all the solid dissolved. The reaction mixture was heated at 95° C. for 12 hours and allowed to cool to ambient temperature. The reaction mixture was then basified to pH 9–10 using methanolic ammonia and evaporated onto silica (5 ml). The residue was purified by column chromatography eluting with 0–15% 2.0M methanolic ammonia solution in dichloromethane to afford a solid product (256 mg). NMR (303.1K): 6.58 (d, 1H), 7.24 (br s, 2H), 7.56 (m, 5H), 7.69 (d, 1H), 7.82 (t, 1H), 7.95 (d, 1H), 10.88 (br s, 1H), 11.07 (br s, 1H); MS (M+H)+: 367.1.