Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1](OCCC(C)C)=[O:2].[F:9][C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[NH:15][CH2:14][C:13]2([CH3:20])[CH3:19].O>C(Cl)Cl>[F:9][C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[N:15]([N:1]=[O:2])[CH2:14][C:13]2([CH3:20])[CH3:19]
Reactant: CC(C)CCON=O
Reactant: CC1(C)CNc2ccc(F)cc21
Solvent: ClCCl
Solvent: O
Product: CC1(C)CN(N=O)c2ccc(F)cc21
Yield: 96 %

Procedure:
Isoamyl nitrite (3.4 mL, 25.42 mmol) is added to a solution of 5-fluoro-3,3-dimethyl-2,3-dihydro-1H-indole (3.75 g, 22.69 mmol) in DCM. The mixture is refluxed overnight. The mixture is cooled and portioned between DCM and water. The organic phase is separated, washed with saturated aqueous NaHCO3, water and brine, dried (MgSO4), filtered and concentrated in vacuo to afford 5-fluoro-3,3-dimethyl-1-nitroso-2,3-dihydro-1H-indole (4.23 g, 96%) as a solid. MS: 195 (M+H). 1H NMR (300 MHz, CD3Cl)): δ 7.77 (dd, 1H), 7.08-6.98 (m, 2H), 3.94 (s, 2H), 1.39 (s, 6H).
Reaction SMILES: [CH2:1]([C:3]1([NH2:9])[CH2:8][O:7][CH2:6][O:5][CH2:4]1)[CH3:2].[OH-].[Na+].O.[Cl:13][CH2:14][C:15](Cl)=[O:16]>C(Cl)Cl>[Cl:13][CH2:14][C:15]([NH:9][C:3]1([CH2:1][CH3:2])[CH2:8][O:7][CH2:6][O:5][CH2:4]1)=[O:16]
Reactant: O=C(Cl)CCl
Reactant: CCC1(N)COCOC1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: CCC1(NC(=O)CCl)COCOC1

Procedure:
Five and two-tenths g (0.04 mole) of 5-ethyl-5-amino-1,3-dioxane, 3.2 g (0.04 mole) of 50% sodium hydroxide, 10 ml of water, and 90 ml of methylene chloride were combined in a reaction flask. The mixture was cooled to below 35° C. Four and one-half g of chloroacetylchloride were added dropwise. The reaction mixture was stirred for one-half hour, washed with water and dried over magnesium sulfate. The solvent was vacuum stripped. Yield was 5.8 g of 5-chloroacetylamino-5-ethyl-1,3-dioxane. m.p.=89°-95° C. Structure was confirmed by NMR.
Reaction SMILES: [C:1]([C:5]1[C:10]([O:11][CH3:12])=[CH:9][C:8]([C:13](=[O:15])[CH3:14])=[C:7]([OH:16])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl[C:18]1[C:27]2[C:22](=[CH:23][C:24]([O:30][CH3:31])=[C:25]([O:28][CH3:29])[CH:26]=2)[N:21]=[CH:20][CH:19]=1.O>CN(C)C1C=CN=CC=1.ClC1C=CC=CC=1Cl>[C:1]([C:5]1[C:10]([O:11][CH3:12])=[CH:9][C:8]([C:13](=[O:15])[CH3:14])=[C:7]([O:16][C:18]2[C:27]3[C:22](=[CH:23][C:24]([O:30][CH3:31])=[C:25]([O:28][CH3:29])[CH:26]=3)[N:21]=[CH:20][CH:19]=2)[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1cc2nccc(Cl)c2cc1OC
Reactant: COc1cc(C(C)=O)c(O)cc1C(C)(C)C
Agent: CN(C)c1ccncc1
Solvent: Clc1ccccc1Cl
Solvent: O
Product: COc1cc2nccc(Oc3cc(C(C)(C)C)c(OC)cc3C(C)=O)c2cc1OC
Temperature: 140 °C
Reaction time: 24 h
Yield: 12.7 %

Procedure:
1-(4-Tert-butyl-2-hydroxy-5-methoxyphenyl)-ethanone (30 mg), 4-chloro-6,7-dimethoxyquinoline (87 mg), and 4-dimethylaminopyridine (48 mg) were suspended in o-dichlorobenzene (4 ml) to prepare a suspension which was then stirred at 140° C. for 24 hr. The reaction solution was cooled to room temperature, water was then added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and saturated brine and was dried over anhydrous magnesium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using acetone-hexane to give the title compound (7 mg, yield 13%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:19](C2C=CC(F)=CC=2)[C:20]([C:22]2([C:25]([NH2:27])=[O:26])[CH2:24][CH2:23]2)=[O:21])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[CH:15]=[C:16](I)[S:17][C:10]=12.[C:35]([CH:37]1[CH2:42][CH2:41][N:40]([C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[CH2:39][CH2:38]1)#[CH:36]>>[C:25]([C:22]1([C:20]([NH:19][C:4]2[CH:5]=[CH:6][C:7]([O:8][C:9]3[CH:14]=[CH:13][N:12]=[C:11]4[CH:15]=[C:16]([C:36]#[C:35][CH:37]5[CH2:38][CH2:39][N:40]([C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[CH2:41][CH2:42]5)[S:17][C:10]=34)=[C:2]([F:1])[CH:3]=2)=[O:21])[CH2:23][CH2:24]1)(=[O:26])[NH2:27]
Reactant: NC(=O)C1(C(=O)N(c2ccc(F)cc2)c2ccc(Oc3ccnc4cc(I)sc34)c(F)c2)CC1
Reactant: C#CC1CCN(C(=O)OC(C)(C)C)CC1
Product: CC(C)(C)OC(=O)N1CCC(C#Cc2cc3nccc(Oc4ccc(NC(=O)C5(C(N)=O)CC5)cc4F)c3s2)CC1

Procedure:
Prepared from N-(3-fluoro-4-(2-iodothieno[3,2-b]pyridin-7-yloxy)phenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (Example 12, Step A, 350 mg, 0.592 mmol) and tert-butyl 4-ethynylpiperidine-1-carboxylate (186 mg, 0.888 mmol) using the procedure described for Example 6, Step B. The crude was purified by Biotage Flash 40M eluting with 20% EtOAc/hexanes (500 mL), 1:1 EtOAc/hexanes (1 L), followed by 2:1 EtOAc/hexanes (1.5 L). The product was isolated as a wax (293 mg, 68%). HPLC: 92% purity (254 nm); LRMS (APCI+): m/z 673, 573 (loss of BOC) (M+1) detected; 1H NMR (400 MHz, CDCl3) δ 10.12 (s, 1H), 8.47 (d, J=6 Hz, 1H), 8.33 (s, 1H), 7.77 (m, 1H), 7.44 (m, 2H), 7.25 (m, 3H), 7.06 (t, J=9 Hz, 2H), 6.50 (d, J=6 Hz, 1H), 3.77 (m, 2H), 3.23 (m, 2H), 2.87 (m, 1H), 1.89 (m, 2H), 1.80 (m, 2H), 1.70 (m, 2H), 1.62 (m, 2H), 1.47 (s, 9H).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH3:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[NH:15][CH2:16][N:17]1[C:21](=[O:22])[CH2:20][S:19][C:18]1=[O:23].[Cl:24][CH2:25][C:26](Cl)=[O:27]>C(Cl)(Cl)Cl>[Cl:24][CH2:25][C:26]([N:15]([CH2:16][N:17]1[C:21](=[O:22])[CH2:20][S:19][C:18]1=[O:23])[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[O:8][CH3:7])=[O:27]
Reactant: COc1ccccc1NCN1C(=O)CSC1=O
Reactant: O=C(Cl)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Product: COc1ccccc1N(CN1C(=O)CSC1=O)C(=O)CCl
Temperature: 25 °C
Reaction time: 48 h
Yield: 58.9 %

Procedure:
A suspension of 7 g of anhydrous potassium carbonate, 7.3 g of N-(2-methoxyphenylaminomethyl)-2,4-thiazolidinedione, and 5.3 g of chloroacetyl chloride in 50 ml of chloroform was cooled in an ice bath and stirred at ambient temperature for 48 hrs. The resulting precipitate was filtered, washed with water and recrystallized from nitromethane-ethanol to give 5.6 g of 2-chloro-N-(2,4-dioxothiazolidin-3-ylmethyl)-N-(2-methoxyphenyl)acetamide; mp 188°-191° C; M+ = 328.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[N:6]([CH3:21])[C:7](=[O:20])[C:8]([F:19])([F:18])[CH2:9][N:10]([CH:13]3[CH2:17][CH2:16][CH2:15][CH2:14]3)[C:11]=2[N:12]=1.[F:22][C:23]1[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:24]=1[NH2:25]>Cl.CC(O)C>[CH:13]1([N:10]2[CH2:9][C:8]([F:19])([F:18])[C:7](=[O:20])[N:6]([CH3:21])[C:5]3[CH:4]=[N:3][C:2]([NH:25][C:24]4[CH:26]=[C:27]([F:30])[CH:28]=[CH:29][C:23]=4[F:22])=[N:12][C:11]2=3)[CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: Nc1cc(F)ccc1F
Reactant: CN1C(=O)C(F)(F)CN(C2CCCC2)c2nc(Cl)ncc21
Agent: Cl
Solvent: CC(C)O
Product: CN1C(=O)C(F)(F)CN(C2CCCC2)c2nc(Nc3cc(F)ccc3F)ncc21

Procedure:
2-Chloro-9-cyclopentyl-7,7-difluoro-5-methyl-8,9-dihydro-5H-pyrimido[5,4-b][1,4]diazepin-6(7H)-one (50 mg, 0.16 mmol), 2,5-difluoroaniline (31 mg, 0.24 mmol), i-PrOH (2 mL) and conc. HCl (5 drops) were heated to 100° C. overnight to give the title compound. The final compound was purified by reverse phase HPLC and basified to give the free base (20 mg, 31%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.23-1.85 (m, 11H) 4.02 (t, J=14 Hz, 2H) 4.68 (d, J=8 Hz, 1H) 6.88 (t, J=8 Hz, 1H) 7.26 (td, J=10, 6 Hz, 1H) 7.74-7.96 (m, 1H) 8.24 (s, 1H) 9.04 (br. s., 1H). [M+H] calc'd for C19H19F4N5O, 410. found 410.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:23]=[C:14]3[CH2:15][N:16]([CH2:19][CH2:20][C:21]#[N:22])[CH2:17][CH2:18][N:13]3[N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.[C:24]([O:27][CH2:28][C:29]1[C:30]([N:44]2[CH2:55][CH2:54][N:53]3[C:46](=[CH:47][C:48]4[CH2:49][C:50]([CH3:57])([CH3:56])[CH2:51][C:52]=43)[C:45]2=[O:58])=[N:31][CH:32]=[CH:33][C:34]=1B1OC(C)(C)C(C)(C)O1)(=[O:26])[CH3:25]>>[C:24]([O:27][CH2:28][C:29]1[C:30]([N:44]2[CH2:55][CH2:54][N:53]3[C:46](=[CH:47][C:48]4[CH2:49][C:50]([CH3:57])([CH3:56])[CH2:51][C:52]=43)[C:45]2=[O:58])=[N:31][CH:32]=[CH:33][C:34]=1[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:23]=[C:14]3[CH2:15][N:16]([CH2:19][CH2:20][C:21]#[N:22])[CH2:17][CH2:18][N:13]3[N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1)(=[O:26])[CH3:25]
Reactant: CC(=O)OCc1c(B2OC(C)(C)C(C)(C)O2)ccnc1N1CCn2c(cc3c2CC(C)(C)C3)C1=O
Reactant: Cn1cc(Br)cc(Nc2cc3n(n2)CCN(CCC#N)C3)c1=O
Product: CC(=O)OCc1c(-c2cc(Nc3cc4n(n3)CCN(CCC#N)C4)c(=O)n(C)c2)ccnc1N1CCn2c(cc3c2CC(C)(C)C3)C1=O
Yield: 51.3 %

Procedure:
Following the procedure of Example 309d, and starting with 338c (150 mg, 0.45 mmol) and {3-[(acetoxy)methyl]-2-{4,4-dimethyl-9-oxo-1,10-diazatricyclo[6.4.0.02,6]dodeca-2(6),7-dien-10-yl}pyridin-4-yl}boronic acid 199e (358 mg, 0.90 mmol) afforded 338d as a yellow solid (150 mg, 52%). MS-ESI: [M+H]+ 650.3
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([Cl:14])[CH:9]=2)[CH:5]=[CH:4][N:3]=1.[CH2:15]([NH2:21])[CH:16]1[O:20][CH2:19][CH2:18][CH2:17]1>>[Cl:14][C:10]1[CH:9]=[C:8]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:21][CH2:15][CH:16]3[CH2:17][CH2:18][CH2:19][O:20]3)[N:7]=2)[CH:13]=[CH:12][N:11]=1
Reactant: NCC1CCCO1
Reactant: Clc1cc(-c2ccnc(Cl)n2)ccn1
Product: Clc1cc(-c2ccnc(NCC3CCCO3)n2)ccn1

Procedure:
The title compound was prepared from 2-chloro-4-(2-chloro-4-pyridinyl)pyrimidine (i.e., the product of Example 6, Step A) and tetrahydrofurfurylamine in the same fashion as described in Example 9, Step A, m.p. 74-75° C.
Reaction SMILES: Br[C:2]1[N:3]=[N:4][C:5]([CH2:8][CH2:9][CH3:10])=[CH:6][CH:7]=1.[C:11]([C@H:13]1[CH2:18][CH2:17][C@H:16]([CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH2:15][CH2:14]1)#[CH:12]>C(N(CC)CC)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[CH2:19]([C@H:16]1[CH2:15][CH2:14][C@H:13]([C:11]#[C:12][C:2]2[N:3]=[N:4][C:5]([CH2:8][CH2:9][CH3:10])=[CH:6][CH:7]=2)[CH2:18][CH2:17]1)[CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: C#C[C@H]1CC[C@H](CCCCC)CC1
Reactant: CCCc1ccc(Br)nn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: CCCCC[C@H]1CC[C@H](C#Cc2ccc(CCC)nn2)CC1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
8.0 g of 3-bromo-6-propylpyridazine were dissolved in 50 ml of triethylamine in a sulphonation flask under nitrogen. The solution was cooled to 0° C., treated with 562 mg of bis-(triphenylphosphine)-palladium (II) dichloride and 76 mg of copper (I) iodide and then treated dropwise within 20 minutes with 7.5 g of trans-1-ethynyl-4-pentylcyclohexane (prepared according to Example 2). The mixture was subsequently stirred overnight while cooling with an ice-bath and then heated to 50° C. for a further 3 hours. The mixture was concentrated on a rotary evaporator. The residue was taken up in 100 ml of hexane and washed with 100 ml of water, whereby the pH value of the aqueous phase was made neutral with ammonium chloride. The aqueous phase was back-extracted twice with 50 ml of hexane each time. The combined organic phases were washed with 100 ml of water and the aqueous phase was back-extracted with 50 ml of hexane. The organic phases were dried over sodium sulphate and freed from solvent on a rotary evaporator. Chromatography of the resulting brown crystallizing oil on silica gel with hexane/ethyl acetate (vol. 2:1) gave a fraction of the desired product 3-[2-(trans-4-pentylcyclohexyl)ethynyl]-6-propylpyridazine (5.2 g) as well as a mixed fraction (4.8 g) consisting of 3-bromo-6-propylpyridazine and product. The pure fraction was recrystallized from 15 ml of ethanol at -20° C. There were thus obtained 4.0 g of white crystals which were recrystallized from 25 ml of pentane at -20° C. The crystals were subsequently dried for 2 hours in a vacuum drying oven at 40° C. and then overnight at room temperature with a slight stream of nitrogen in a high vacuum, there being obtained 3.4 g of 3-[2-(trans-4-pentylcyclohexyl)ethynyl]-6-propylpyridazine as white crystals of melting point (C-I) 118°-118.5° C.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][OH:13])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].Cl[C:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[NH:20][C:19](=[O:27])[N:18]=1.O>O1CCCC1>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([CH2:11][CH2:12][O:13][C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[NH:20][C:19](=[O:27])[N:18]=2)=[CH:9][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc(CCO)cc1
Reactant: O=c1nc(Cl)c2ccccc2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)c1ccc(CCOc2nc(=O)[nH]c3ccccc23)cc1

Procedure:
2-(4-tert-butylphenyl) ethanol (0.3 g, 1.68 mmol) is dissolved in dry tetrahydrofuran (7 ml) and to it is added sodium hydride (48.5 mg, 2.02 mmol). The resulting solution is stirred at room temperature for 30 minutes after which 4-chloro-2-quinazolone (0.302 g, 1.68 mmol) is added to the above solution. The solution is then stirred for 6 hours after which water is added to the mixture. The solution is then extracted in dichloromethane. The organic layer is washed, dried and then concentrated to yield the crude product which is purified by flash chromatography (silica gel; ethyl acetate/hexanes) to give the product.
Reaction SMILES: [N+](C1C=CC=CC=1)([O-])=O.[Cl-].[Al+3].[Cl-].[Cl-].[CH3:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:17][CH:16]=1.[Cl:27][C:28]1[CH:29]=[C:30]([CH:34]=[CH:35][C:36]=1[Cl:37])[C:31](Cl)=[O:32]>O>[CH3:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:22]=[CH:23][C:24]([C:31]([C:30]3[CH:34]=[CH:35][C:36]([Cl:37])=[C:28]([Cl:27])[CH:29]=3)=[O:32])=[CH:25][CH:26]=2)=[CH:17][CH:16]=1
Reactant: O=C(Cl)c1ccc(Cl)c(Cl)c1
Reactant: Cc1ccc(-c2ccccc2)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: O=[N+]([O-])c1ccccc1
Product: Cc1ccc(-c2ccc(C(=O)c3ccc(Cl)c(Cl)c3)cc2)cc1
Temperature: 25 °C

Procedure:
35 ml of nitrobenzene are cooled in an ice-bath and then treated in succession with 5.2 g of aluminum chloride and 5.0 g of 4-methylbiphenyl. The mixture is brought to room temperature and then treated with 7.7 g of 3,4-dichlorobenzoyl chloride. The mixture is stirred at room temperature, poured into water and extracted with methylene chloride. The extracts are washed with 2N hydrochloric acid and water, dried over magnesium sulfate and evaporated. The residue is chromatographed on silica gel with toluene/ethyl acetate 9:1. 3,4-Dichlorophenyl 4'-methyl-4-biphenylyl ketone is obtained.
Reaction SMILES: [NH2:1][C:2]1[C:10]([Cl:11])=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([O:12][CH3:13])[CH:3]=1.[CH2:14](O)[CH3:15].[OH-].[Na+]>Cl>[NH2:1][C:2]1[C:10]([Cl:11])=[CH:9][C:5]([C:6]([O:8][CH2:14][CH3:15])=[O:7])=[C:4]([O:12][CH3:13])[CH:3]=1
Reactant: COc1cc(N)c(Cl)cc1C(=O)O
Reactant: CCO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CCOC(=O)c1cc(Cl)c(N)cc1OC
Yield: 78 %

Procedure:
A solution of 4-amino-5-chloro-2-methoxybenzoic acid (6.6 g, 0.031 mol) in hydrogen chloride 1.25M in Ethanol (250 mL, 0.31 mol) was stirred in a pressure vessel for 6 h at 65° C. The reaction mixture was basified with sodium hydroxide 2N and extracted with methylene chloride. The organic layer was washed with water, dried and filtered. The solvent was removed under reduced pressure giving the title compound as a white solid (78%), which was used in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[Cl:12])[CH:8]=[C:7]([N:13]1[CH2:17][CH2:16][CH2:15]C1)[CH2:6][CH2:5]2.C(N)(=[O:21])C=C.C1(C)C=CC(S(O)(=O)=O)=CC=1>>[Cl:1][C:2]1[C:11]([Cl:12])=[CH:10][C:9]2[C:8]3[CH2:15][CH2:16][C:17](=[O:21])[NH:13][C:7]=3[CH2:6][CH2:5][C:4]=2[CH:3]=1
Reactant: C=CC(N)=O
Reactant: Clc1cc2c(cc1Cl)CCC(N1CCCC1)=C2
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: O=C1CCC2=C(CCc3cc(Cl)c(Cl)cc32)N1

Procedure:
A melt of 10.1 g (0.038 mol) of 1-(6,7-dichloro-3,4-dihydro-2-naphthyl)pyrrolidine. 5.36 g (0.075 mol) of acrylamide and 0.3 g of p-toluenesulfonic acid is stirred under nitrogen at 100° for 2 hours and at 150° for 2 hours. Recrystallization of the melt cake from ethanol yields 8,9-dichloro-1,4,5,6-tetrahydrobenzo[f]quinolin -3(2H)-one with melting point 260-261°.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:15]2[CH:20]=[CH:19][N:18]=[CH:17][C:16]=2[CH2:21][NH2:22])[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:23][C:24]([F:31])([F:30])[CH2:25][S:26](Cl)(=[O:28])=[O:27].C(=O)([O-])[O-].[K+].[K+]>ClCCCl.N1C=CC=CC=1>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:15]2[CH:20]=[CH:19][N:18]=[CH:17][C:16]=2[CH2:21][NH:22][S:26]([CH2:25][C:24]([F:31])([F:30])[F:23])(=[O:28])=[O:27])[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=S(=O)(Cl)CC(F)(F)F
Reactant: NCc1cnccc1-c1cccc(OCc2ccccc2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCCl
Solvent: c1ccncc1
Product: O=S(=O)(CC(F)(F)F)NCc1cnccc1-c1cccc(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of N-(4-(3-benzyloxyphenyl)pyridin-3-ylmethylamine (1.0 equiv.) in 2:1 DCE/Pyridine (0.15 M) was cooled to 0° C. and treated with 2,2,2-trifluoroethanesulfonyl chloride (1.8 equiv.). The mixture was allowed to warm to ambient temperature and stir overnight. The reaction was treated with anhydrous potassium carbonate, stirred for 40 min, and filtered. The filtrate was purified via preparative HPLC eluting with 70:30 to 60:40 DCM/ethyl acetate, evaporated, and then triturated with diethyl ether to give the title compound. Anal Calcd for C21H19F3N2O3S: C, 57.79; H, 4.39; N, 6.42. Found: C, 57.60; H, 4.47; N, 6.41. 1H NMR (400 MHz) 3.77 (2H, q, J=9.0 Hz), 4.86 (2H, d), 4.99 (2H, d), 6.82 (2H, m), 6.95 (1H, m), 7.25 (2H, m), 7.34-7.40 (5H, m), 7.67 (1H, td, J=2.0, 8.0 Hz), 8.32 (1H, bs), 8.50 (1H, d, J=4.0 Hz). MS found 437.1 [M+H]+
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([C:19]([F:22])([F:21])[F:20])[CH:13]=2)[C:7]([F:23])=[CH:6][C:3]=1[C:4]#[N:5].C(=O)([O-])[O-:25].[K+].[K+].OO.O>CS(C)=O>[F:1][C:2]1[CH:9]=[C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([C:19]([F:20])([F:22])[F:21])[CH:13]=2)[C:7]([F:23])=[CH:6][C:3]=1[C:4]([NH2:5])=[O:25]
Reactant: O=C([O-])[O-]
Reactant: N#Cc1cc(F)c(OCc2ccc(Cl)c(C(F)(F)F)c2)cc1F
Agent: OO
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: NC(=O)c1cc(F)c(OCc2ccc(Cl)c(C(F)(F)F)c2)cc1F
Temperature: 25 °C
Reaction time: 3 h
Yield: 87.5 %

Procedure:
To a suspension of 2,5-difluoro-4-[4-chloro-3-(trifluoromethyl)phenylmethoxy]-benzonitrile (Preparation 61, 0.2 g, 0.5 mmol) and potassium carbonate (0.39 g, 2.5 mmol) in DMSO (3 mL), was added hydrogen peroxide (30% solution in water, 0.6 mL, 5 mmol) at room temperature. The resulting mixture was stirred for 3 hours at room temperature. Water (30 mL) was then added and the precipitate formed was filtered. The filtrate was extracted twice with EtOAc and combined with the solid. The resulting organic solution was dried over magnesium sulphate, filtered and evaporated to afford the title compound as a white solid (160 mg, 76%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[Cl:10])[CH2:5][NH2:6].Cl[C:12]1[C:13]2[CH:26]=[C:25]([CH2:27][CH3:28])[S:24][C:14]=2[N:15]=[C:16]([C:18]2[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=2)[N:17]=1>>[N:21]1[CH:20]=[CH:19][C:18]([C:16]2[N:17]=[C:12]([NH:6][CH2:5][C:4]3[CH:7]=[CH:8][C:9]([Cl:10])=[C:2]([Cl:1])[CH:3]=3)[C:13]3[CH:26]=[C:25]([CH2:27][CH3:28])[S:24][C:14]=3[N:15]=2)=[CH:23][CH:22]=1
Reactant: CCc1cc2c(Cl)nc(-c3ccncc3)nc2s1
Reactant: NCc1ccc(Cl)c(Cl)c1
Product: CCc1cc2c(NCc3ccc(Cl)c(Cl)c3)nc(-c3ccncc3)nc2s1

Procedure:
With the procedure of Example 1, the reaction of 3,4-dichlorobenzylamine with 4-chloro-2-(pyridin-4-yl)-6-ethyl-thieno-[2,3-d]-pyrimidine yields 2-(pyridin-4-yl)-4-(3,4-dichlorobenzylamino)-6-ethyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[C:5]([CH2:16][C:17](O)=[O:18])([N:11]1[CH:15]=[CH:14][CH:13]=[CH:12]1)[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2].O[N:22]1C(=O)CCC1=O.Cl.C(N=C=NCCCN(C)C)C.N>ClCCl.C(#N)C>[CH2:1]([O:3][C:4](=[O:20])[C:5]([CH2:16][C:17](=[O:18])[NH2:22])([N:11]1[CH:15]=[CH:14][CH:13]=[CH:12]1)[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2]
Reactant: CCOC(=O)C(CC(=O)O)(C(=O)OCC)n1cccc1
Reactant: O=C1CCC(=O)N1O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: N
Solvent: ClCCl
Solvent: CC#N
Product: CCOC(=O)C(CC(N)=O)(C(=O)OCC)n1cccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 80.8 %

Procedure:
A mixture of 2-carboxymethyl-2-(pyrrol-1-yl)-malonic acid diethyl ester (36.0 g), N-hydroxysuccinimide (16.1 g) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (29.2 g) in dichloromethane (200 ml) was stirred at 25° C. for 1 hour, followed by addition of 7.8% (w/w) ammonia in acetonitrile (110 ml). The resulting mixture was stirred at 25° C. for 1 hour and concentrated under reduced pressure at the same temperature. The residue was dissolved in ethyl acetate. The solution was washed with 5% hydrochloric acid and then with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and evaporated under reduced pressure. The residue was recrystallized from ethyl acetate/n-hexane to give the title compound (29.0 g, 80.8%) as colorless crystals, mp 94°-95° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:30]=[CH:29][C:6]([CH2:7][N:8]([C:19]2[CH:27]=[CH:26]C=C3[C:20]=2[CH2:21][O:22]C3=O)[C:9](=[O:18])[C:10](=O)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:5][CH:4]=1.[O-]S([O-])(=O)=O.[Na+].[Na+].[O-]CC.[Na+].C(O)C.[C:45]([O:49][CH2:50][CH3:51])(=[O:48])[CH2:46][CH3:47]>>[OH:22][C:21]1[C:20]2[C:46]([C:45]([O:49][CH2:50][CH3:51])=[O:48])=[CH:47][CH:26]=[CH:27][C:19]=2[N:8]([CH2:7][C:6]2[CH:29]=[CH:30][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[C:9](=[O:18])[C:10]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: COc1ccc(CN(C(=O)C(=O)c2ccccc2)c2cccc3c2COC3=O)cc1
Reactant: CCOC(=O)CC
Agent: CC[O-]
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)c1cccc2c1c(O)c(-c1ccccc1)c(=O)n2Cc1ccc(OC)cc1
Temperature: 0 °C
Reaction time: 18 h
Yield: 80 %

Procedure:
A mixture of N-(4-methoxybenzyl)-2-oxo-N-(1-oxo-1,3-dihydroisobenzofuran-4-yl)-2-phenylacetamide (4.7 g, 11.7 mmol) and anhydrous Na2SO4 (16.6 g, 117 mmol) in anhydrous ethyl propionate (120 mL) was cooled to 0° C. Then a solution of sodium ethoxide in ethanol (sodium (673 mg, 29.2 mmol) in anhydrous ethanol (70 mL)) was added dropwise. After the addition, the mixture was stirred at room temperature for 18 hr. The mixture was quenched with water (100 mL) and solvent was removed in vacuum. The residue was dissolved in water, and then extracted with ethyl acetate (250 mL×4). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and concentrated to give product (4.02 g, yield 80%). LC-MS (ESI) m/z: 430 (M+1)+. 1H-NMR (400 MHz, DMSO-d6) δ (ppm): 1.23-1.26 (t, J=6.8 Hz, 3H), 3.69 (s, 3H), 4.21-4.23 (m, 2H), 5.46 (s, 1H), 6.86-6.88 (d, J=7.6 Hz, 2H), 7.11-7.18 (m, 3H), 7.36-7.55 (m, 7H), 10.59 (s, 1H).
Reaction SMILES: C(OC([NH:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([CH3:18])([CH3:17])[CH3:16])=[C:11]([NH:19][C:20]([C:22]2[C:31](=[O:32])[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[NH:24][CH:23]=2)=[O:21])[CH:10]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([CH3:18])([CH3:17])[CH3:16])=[C:11]([NH:19][C:20]([C:22]2[C:31](=[O:32])[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[NH:24][CH:23]=2)=[O:21])[CH:10]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(C(C)(C)C)c(NC(=O)c2c[nH]c3ccccc3c2=O)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)c1ccc(N)cc1NC(=O)c1c[nH]c2ccccc2c1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 55.9 %

Procedure:
A mixture of [3-[(4-oxo-1H-quinolin-3-yl)carbonylamino]-4-tert-butyl-phenyl]aminoformic acid tert-butyl ester (353) (33 mg, 0.08 mmol), TFA (1 mL) and CH2Cl2 (1 mL) was stirred at room temperature overnight. The solution was concentrated and the residue was dissolved in DMSO (1 mL) and purified by HPLC (10-99% CH3CN/H2O) to yield the product, N-(5-amino-2-tert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide (260) (15 mg, 56%). 1H NMR (400 MHz, DMSO-d6) δ 13.23 (d, J=6.6 Hz, 1H), 12.20 (s, 1H), 10.22 (br s, 2H), 8.88 (d, J=6.8 Hz, 1H), 8.34 (d, J=7.8 Hz, 1H), 7.86-7.80 (m, 3H), 7.56-7.52 (m, 2H), 7.15 (dd, J=8.5, 2.4 Hz, 1H), 1.46 (s, 9H); HPLC ret. time 2.33 min, 10-99% CH3CN, 5 min run; ESI-MS 336.3 m/z (MH+).