Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[CH:4]=[C:5]([CH:18]=[CH:19][CH:20]=1)[C:6]([NH:8][C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=1)[C:12]([OH:14])=O)=[O:7].ClC1N=C(OC)N=C(OC)N=1.CN1CCOCC1.[N:41]1([CH2:46][CH2:47][CH2:48][S:49]([C:52]2[CH:57]=[CH:56][C:55]([NH:58][C:59]3[N:64]=[CH:63][C:62]([NH2:65])=[CH:61][N:60]=3)=[CH:54][CH:53]=2)(=[O:51])=[O:50])[CH2:45][CH2:44][CH2:43][CH2:42]1>C(Cl)Cl.CN(C=O)C>[N:41]1([CH2:46][CH2:47][CH2:48][S:49]([C:52]2[CH:53]=[CH:54][C:55]([NH:58][C:59]3[N:60]=[CH:61][C:62]([NH:65][C:12](=[O:14])[C:11]4[CH:15]=[CH:16][CH:17]=[C:9]([NH:8][C:6](=[O:7])[C:5]5[CH:18]=[CH:19][CH:20]=[C:3]([C:2]([F:1])([F:22])[F:21])[CH:4]=5)[CH:10]=4)=[CH:63][N:64]=3)=[CH:56][CH:57]=2)(=[O:50])=[O:51])[CH2:42][CH2:43][CH2:44][CH2:45]1
Reactant: O=C(O)c1cccc(NC(=O)c2cccc(C(F)(F)F)c2)c1
Reactant: Nc1cnc(Nc2ccc(S(=O)(=O)CCCN3CCCC3)cc2)nc1
Agent: COc1nc(Cl)nc(OC)n1
Solvent: CN1CCOCC1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Nc1cnc(Nc2ccc(S(=O)(=O)CCCN3CCCC3)cc2)nc1)c1cccc(NC(=O)c2cccc(C(F)(F)F)c2)c1
Temperature: 25 °C
Reaction time: 1.25 h
Yield: 51.1 %

Procedure:
To a solution of intermediate 5 (Example 9) (240 mg, 0.8 mmol) in anhydrous CH2Cl2 (15 mL), 2-chloro-4,6-dimethoxy-1,3,5-triazine (170 mg, 1 mmol) and 4-methylmorpholine (160 mg, 1.6 mmol) were added. After the reaction mixture was stirred at room temperature for 75 minutes, intermediate 2 (Example 3) (100 mg, 0.3 mmol) in anhydrous DMF (2.5 mL) was added into the solution. The solution was stirred under argon for overnight. The residue was dissolved in CH2Cl2 (20 mL) and washed with aqueous saturated NaHCO3 solution (20 mL). The aqueous layer was extracted with CH2Cl2 (50 mL). The combined organic phase was dried (Na2SO4) and the solvent was removed. The crude product was purified by silica gel column with CHCl3 to 10% CH3OH/CHCl3 as eluents to give the final product as a pale yellow solid (100 mg, 19%).
Reaction SMILES: [CH2:1]([O:3][C:4]#[C:5][C:6]1[CH:7]=[C:8]([O:23][C:24]([F:27])([F:26])[F:25])[CH:9]=[C:10]2[C:15]=1[O:14][CH:13]([C:16]([F:19])([F:18])[F:17])[C:12]([C:20]([OH:22])=[O:21])=[CH:11]2)[CH3:2].[OH:28]S(O)(=O)=O>CC(C)=O.O.[Cl-].[Na+].O>[CH2:1]([O:3][C:4](=[O:28])[CH2:5][C:6]1[CH:7]=[C:8]([O:23][C:24]([F:25])([F:27])[F:26])[CH:9]=[C:10]2[C:15]=1[O:14][CH:13]([C:16]([F:17])([F:18])[F:19])[C:12]([C:20]([OH:22])=[O:21])=[CH:11]2)[CH3:2]
Reactant: O=S(=O)(O)O
Reactant: CCOC#Cc1cc(OC(F)(F)F)cc2c1OC(C(F)(F)F)C(C(=O)O)=C2
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: CCOC(=O)Cc1cc(OC(F)(F)F)cc2c1OC(C(F)(F)F)C(C(=O)O)=C2
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 198.8 %

Procedure:
To a solution of the crude product from Step 1 (2.13 g) in a mixture of acetone (80 mL) and H2O (10 mL) was added H2SO4 (0.250 g, 2.55 mmole) and the resulting mixture was stirred at room temperature for 2.5 hrs. Brine (200 mL) was added and the mixture was extracted with EtOAc (2×100 mL). The combined extracts were washed with brine, dried over MgSO4, filtered and concentrated in vacuo to give 2.10 g of the crude product as a yellow oil: ESLRMS m/z 414.0 (M+H, C16H12F6O6, Calc'd 415.0).
Reaction SMILES: [CH3:1][O-:2].[Na+].[F:4][C:5]1[C:10]([C:11]#[N:12])=[C:9](F)[C:8]([F:14])=[C:7](F)[C:6]=1[F:16].[CH3:17][OH:18]>>[CH3:1][O:2][C:9]1[C:8]([F:14])=[C:7]([O:18][CH3:17])[C:6]([F:16])=[C:5]([F:4])[C:10]=1[C:11]#[N:12]
Reactant: N#Cc1c(F)c(F)c(F)c(F)c1F
Reactant: C[O-]
Reactant: CO
Agent: [Na+]
Product: COc1c(F)c(F)c(C#N)c(OC)c1F
Temperature: 25 °C
Yield: 71 %

Procedure:
A solution of sodium methoxide (18 g, 83 mmol, 25% in methanol) is added dropwise to a solution of pentafluorobenzonitrile (7.72 g, 40 mmol) in 60 mL methanol over 15 min. The reaction is heated to reflux for 3 hours, cooled to room temperature and then poured into 150 mL ice water. The product is then extracted with diethyl ether (100 mL×2), and the combined organic layers are washed with brine (50 mL), dried over magnesium sulfate and concentrated in vacuo. The residue is then chromatographed on silica gel, eluting with hexane:ethyl acetate (97:3 to 88:12 gradient) to yield 6.18 g (71%) of Compound 43 as a colorless oil. 1H-NMR (CDCl3) 4.16 (s, 3H); 4.10 (s, 3H). 19F-NMR (CDCl3) 134.39 (dd, J=10.1 and 20.3 Hz, 1 F); 150.80 (d, J=7.1 Hz, 1 F); 158.00 (d, J=21.4 Hz, 1 F). Anal. calc. for C9H6F3NO2 : C, 49.78; H, 2.78; N, 6.45. Found: C, 49.71; H, 2.78; N, 6.56. A second product, 3,5-difluoro-2,4,6-trimethoxybenzonitrile, is also isolated from the reaction mixture as a colorless solid (1.09 g; 12%). 1H-NMR (CDCl3) 4.12 (s, 3H); 4.07 (s, 6H). 19F-NMR (CDCl3) 152.11 (s).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][O:4][C:5]([C:7]1[CH:8]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([N+:25]([O-:27])=[O:26])[CH:20]=2)[C:9]([C:15]([O:17][CH3:18])=[O:16])=[C:10]([CH3:14])[NH:11][C:12]=1[CH3:13])=[O:6].[C:28]1([C:33]([CH:35]2[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]2)=[O:34])[S:32][CH:31]=[CH:30][CH:29]=1.N12CCCN=C1CCCCC2>C(OCC)(=O)C>[ClH:1].[C:28]1([C:33]([CH:35]2[CH2:36][CH2:37][N:38]([CH2:2][CH2:3][O:4][C:5]([C:7]3[CH:8]([C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([N+:25]([O-:27])=[O:26])[CH:20]=4)[C:9]([C:15]([O:17][CH3:18])=[O:16])=[C:10]([CH3:14])[NH:11][C:12]=3[CH3:13])=[O:6])[CH2:39][CH2:40]2)=[O:34])[S:32][CH:31]=[CH:30][CH:29]=1
Reactant: O=C(c1cccs1)C1CCNCC1
Reactant: COC(=O)C1=C(C)NC(C)=C(C(=O)OCCCl)C1c1cccc([N+](=O)[O-])c1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CCOC(C)=O
Product: COC(=O)C1=C(C)NC(C)=C(C(=O)OCCN2CCC(C(=O)c3cccs3)CC2)C1c1cccc([N+](=O)[O-])c1
Product: Cl
Reaction time: 1 h

Procedure:
A mixture of 11 g of 2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid methyl ester 2-chloroethyl ester, 6.4 g of 4-(2-thenoyl)-piperidine and 8.8 ml of 1,8-diazabicyclo[5.4.0]undec-7-ene is stirred under argon for 1 hour in a bath at 150°. After cooling, the melt is dissolved in 100 ml of ethyl acetate and the solution is washed three times with 1N hydrochloric acid. The aqueous-acidic solution is adjusted to pH 9-10 with 50% potassium carbonate solution and extracted with ethyl acetate. The organic phase is dried over sodium sulphate and concentrated by evaporation and the residue is dissolved in ether. By the addition of a solution of hydrogen chloride in ether there is obtained 2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid methyl ester 2-[4-(2-thenoyl)-piperidino]-ethyl ester hydrochloride which melts at 140°-145°; it sinters from 120°.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([CH2:7][OH:8])=[CH:4][CH:3]=1.[C:9](N1C=CN=C1)(N1C=CN=C1)=[O:10].[NH2:21][C:22]1[C:31]2[C:26](=[CH:27][C:28]([CH2:32][N:33]3[CH2:38][CH2:37][NH:36][CH2:35][C:34]3=[O:39])=[CH:29][CH:30]=2)[N:25]=[CH:24][N:23]=1>C(Cl)Cl.CN(C1C=CN=CC=1)C.O.CO>[Cl:1][C:2]1[S:6][C:5]([CH2:7][O:8][C:9]([N:36]2[CH2:37][CH2:38][N:33]([CH2:32][C:28]3[CH:27]=[C:26]4[C:31]([C:22]([NH2:21])=[N:23][CH:24]=[N:25]4)=[CH:30][CH:29]=3)[C:34](=[O:39])[CH2:35]2)=[O:10])=[CH:4][CH:3]=1
Reactant: OCc1ccc(Cl)s1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Nc1ncnc2cc(CN3CCNCC3=O)ccc12
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: O
Solvent: CO
Product: Nc1ncnc2cc(CN3CCN(C(=O)OCc4ccc(Cl)s4)CC3=O)ccc12
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 5-chloro-2-thiophene-methanol (0.10 g, 0.67 mmol, prepared by NaBH4 reduction of 5-chloro-2-thiophene-carboxaldehyde) in 6 mL of CH2Cl2 is added 1,1′-carbonyldiimidazole (0.11 g, 0.67 mmol). The mixture is stirred at room temperature for 3 hours. Then 1-(4-aminoquinazoline-7-ylmethyl)piperazine-2-one (0.17 g, 0.67 mmol, EXAMPLE 72) and a catalytic amount of DMAP is added to the solution and the resulting mixture is heated at 35° C. for 18 hours. The mixture is dissolved in water/MeOH and the crude product is purified by RP-HPLC eluting in a gradient of 10% CH3CN/H2O (0.1% TFA) to 100% CH3CN. The appropriate fractions are combined and lyoppholized to provide the title compound as a white solid. ESI MS, [M+H]+=432,434 (Cl pattern).
Reaction SMILES: [CH2:1]([NH:8][C:9]([N:11]1[CH2:16][CH2:15][C:14](=[O:17])[N:13]2[C@@H:18]([CH2:35][C:36]3[CH:41]=[CH:40][C:39]([OH:42])=[CH:38][CH:37]=3)[C:19](=[O:34])[N:20]([CH2:23][C:24]3[C:33]4[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=4)[CH:27]=[CH:26][CH:25]=3)[C@@H:21]([CH3:22])[CH:12]12)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1COCC1.[C:48](Cl)(=[O:54])[CH2:49][CH2:50][CH2:51][CH2:52][CH3:53].C(N(CC)CC)C>C(OCC)(=O)C>[C:48]([O:42][C:39]1[CH:40]=[CH:41][C:36]([CH2:35][C@@H:18]2[N:13]3[C:14](=[O:17])[CH2:15][CH2:16][N:11]([C:9](=[O:10])[NH:8][CH2:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)[CH:12]3[C@H:21]([CH3:22])[N:20]([CH2:23][C:24]3[C:33]4[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=4)[CH:27]=[CH:26][CH:25]=3)[C:19]2=[O:34])=[CH:37][CH:38]=1)(=[O:54])[CH2:49][CH2:50][CH2:51][CH2:52][CH3:53]
Reactant: C[C@H]1C2N(C(=O)NCc3ccccc3)CCC(=O)N2[C@@H](Cc2ccc(O)cc2)C(=O)N1Cc1cccc2ccccc12
Reactant: CCCCCC(=O)Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCCCCC(=O)Oc1ccc(C[C@H]2C(=O)N(Cc3cccc4ccccc34)[C@@H](C)C3N(C(=O)NCc4ccccc4)CCC(=O)N32)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 66.5 %

Procedure:
To a solution of (6S,9S)—N-benzyl-6-(4-hydroxybenzyl)-9-methyl-8-(naphthalen-1-ylmethyl)-4,7-dioxooctahydro-1H-pyrazino[1,2-a]pyrimidine-1-carboxamide 60 mg (0.106 mmol) in dry-THF (2 ml), hexanoyl chloride 44 μl (0.319 mmol) and then triethylamine 45 μl (0.319 mmol) were added and stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate (10 ml) and washed with water (10 ml), saturated sodium bicarbonate (10 ml), water (10 ml), and brine (10 ml). The organic layer was dried with sodium sulfate and filtered. The filtrate was concentrated in vacuo and the residue was purified by Büchi silica gel column chromatography (chloroform:methanol=99:1 to 98:2) to obtain title compound 46.6 mg (66%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([C:19](O)=[O:20])[CH:14]=1)[C:7](=[O:22])[NH:6][C:5]2=[O:23].F[C:25]1[CH:26]=[C:27]2[C:32](=[CH:33][CH:34]=1)N[C:30](=O)[NH:29][C:28]2=[O:36].BrCC1C=C(C=CC=1)C(OC)=O.COC(C1C=[C:55](C=CC=1)[CH2:56][N:57]1C2C(=CC=CC=2)C(=O)N[C:58]1=O)=O>>[CH:27]1([C:28]([N:29]2[CH2:55][CH2:56][N:57]([C:19]([C:15]3[CH:14]=[C:13]([CH:18]=[CH:17][CH:16]=3)[CH2:12][N:8]3[C:3]4[C:4](=[CH:9][CH:10]=[CH:11][C:2]=4[F:1])[C:5](=[O:23])[NH:6][C:7]3=[O:22])=[O:20])[CH2:58][CH2:30]2)=[O:36])[CH2:32][CH2:33][CH2:34][CH2:25][CH2:26]1
Reactant: O=C(O)c1cccc(Cn2c(=O)[nH]c(=O)c3cc(F)ccc32)c1
Reactant: O=c1[nH]c(=O)c2cc(F)ccc2[nH]1
Reactant: COC(=O)c1cccc(Cn2c(=O)[nH]c(=O)c3ccccc32)c1
Agent: COC(=O)c1cccc(CBr)c1
Product: O=C(c1cccc(Cn2c(=O)[nH]c(=O)c3cccc(F)c32)c1)N1CCN(C(=O)C2CCCCC2)CC1

Procedure:
The following compounds were prepared from 6-fluoro-1-(3-carboxybenzyl)quinazoline-2,4(1H,3H)-dione (prepared from 6-fluoroquinazoline-2,4(1H,3H)-dione and methyl 3-(bromomethyl)benzoate using procedures similar to those of compounds of Examples 1 and 2), and the corresponding substituted piperazine using a procedure similar to those described for the synthesis of compound of Example 3.
Reaction SMILES: I[C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][N:8]2[S:11]([C:14]2[C:19]([CH3:20])=[CH:18][C:17]([CH3:21])=[CH:16][C:15]=2[CH3:22])(=[O:13])=[O:12])=[CH:4][CH:3]=1.[CH3:23][O:24][C:25]1[CH:26]=[C:27](B(O)O)[CH:28]=[CH:29][C:30]=1[O:31][CH2:32][O:33][CH3:34].C(N(CC)CC)C.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O.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>[CH3:23][O:24][C:25]1[CH:26]=[C:27]([C:2]2[CH:10]=[C:9]3[C:5]([CH:6]=[N:7][N:8]3[S:11]([C:14]3[C:19]([CH3:20])=[CH:18][C:17]([CH3:21])=[CH:16][C:15]=3[CH3:22])(=[O:13])=[O:12])=[CH:4][CH:3]=2)[CH:28]=[CH:29][C:30]=1[O:31][CH2:32][O:33][CH3:34]
Reactant: COCOc1ccc(B(O)O)cc1OC
Reactant: Cc1cc(C)c(S(=O)(=O)n2ncc3ccc(I)cc32)c(C)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Solvent: O
Product: COCOc1ccc(-c2ccc3cnn(S(=O)(=O)c4c(C)cc(C)cc4C)c3c2)cc1OC
Temperature: 90 °C

Procedure:
A mixture of 6-iodo-1-(2,4,6-trimethyl-benzenesulfonyl)-1H-indazole (5.78 g, 13.56 mmol, 1.00 equiv) and 3-methoxy-4-(methoxymethoxy)benzene-boronic acid (3.45 g, 16.27 mmol, 1.20 equiv) under argon was dissolved in dioxane (15 mL) and water (2.0 mL). To this solution was added triethylamine (2.83 mL, 20.3 mmol, 1.5 equiv), potassium carbonate (2.8 g, 20.3 mmol, 1.5 equiv) and dichlorobis(triphenylphosphine)palladium (476 mg, 0.678 mmol, 0.05 equiv). The reaction mixture was heated to 90° C. for 2 h and then was cooled to 23° C. The mixture was separated between ethyl acetate (250 mL) and saturated sodium bicarbonate (150 mL). The organic material was dried over sodium sulfate, decanted and concentrated under reduced pressure to give crude 6-(3-methoxy-4-methoxymethoxy-phenyl)-1-(2,4,6-trimethyl-benzenesulfonyl)-1H-indazole that was dried under high vacuum for 15 h and was used without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[NH:12][CH2:13][CH:14]([OH:16])[CH3:15])=[CH:9][CH:8]=[CH:7][CH:6]=2.[CH:17](OCC)(OCC)OCC>C(O)=O>[OH:16][CH:14]([CH3:15])[CH2:13][N:12]1[C:11]2[C:10]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[N:4]=[CH:3][C:2]=2[N:1]=[CH:17]1
Reactant: CCOC(OCC)OCC
Reactant: CC(O)CNc1c(N)cnc2ccccc12
Solvent: O=CO
Product: CC(O)Cn1cnc2cnc3ccccc3c21
Temperature: 150 °C

Procedure:
A mixture of 32.9 g of 3-amino-4-(2-hydroxypropylamino)quinoline in 100 ml of triethyl orthoformate and 10 drops of formic acid was heated at 150° C. for two hours. The mixture was evaporated under vacuum, then 200 ml of water was added and the pH was adjusted to pH 2 to 3 with concentrated hydrochloric acid. The solution was basified with ammonium hydroxide, then with 50 percent sodium hydroxide solution. An oily product eventually solidified and was separated by filtration. Recrystallization from a mixture of hexane and dichloromethane gave an off-white solid 1-(2-hydroxypropyl)-1H-imidazo[4,5-c]quinoline, m.p. 171° C.
Reaction SMILES: [CH3:1]I.[OH:3][CH2:4][CH2:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[CH2:8][C:9](=[O:15])[NH:10]2>ClCCl.FC(F)(F)S([O-])(=O)=O.[Ag+]>[CH3:1][O:3][CH2:4][CH2:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[CH2:8][C:9](=[O:15])[NH:10]2
Reactant: O=C1Cc2c(CCO)cccc2N1
Reactant: CI
Agent: [Ag+]
Agent: O=S(=O)([O-])C(F)(F)F
Solvent: ClCCl
Product: COCCc1cccc2c1CC(=O)N2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Methyl iodide (1.41 g, 10 mmol) was added to a stirred mixture of silver trifluoromethanesulfonate (2.56 g, 10 mmol) and 4-(2-hydroxy-ethyl)-1,3-dihydro-indol-2-one (0.88 g, 5 mmol) in dichloromethane (20 mL) at 0° C. The precipitate formed after 5-10 minutes changed color from yellow to gray then dark purple. The mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with dichloromethane and filtered through celite. The filtrate was concentrated and chromatographed on silica gel to give 4-(2-methoxy-ethyl)-1,3-dihydro-indol-2-one.
Reaction SMILES: Cl[S:2][C:3]1[CH:11]=[C:10]([O:12][CH3:13])[C:9]([O:14][CH3:15])=[CH:8][C:4]=1[C:5](Cl)=[O:6].Cl.[CH3:17][NH2:18].C(OCC)(=O)C>N1C=CC=CC=1>[CH3:15][O:14][C:9]1[C:10]([O:12][CH3:13])=[CH:11][C:3]2[S:2][N:18]([CH3:17])[C:5](=[O:6])[C:4]=2[CH:8]=1
Reactant: CN
Reactant: COc1cc(SCl)c(C(=O)Cl)cc1OC
Agent: Cl
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: COc1cc2sn(C)c(=O)c2cc1OC
Temperature: 25 °C
Reaction time: 48 h

Procedure:
2-Chlorosulfenyl-4,5-dimethoxybenzoyl chloride (5.0 g) was dissolved in pyridine (30 ml) and methylamine hydrochloride (6.0 g) was added. The mixture was stirred at room temperature for 2 days. Ethyl acetate was added and the mixture was washed with 1 N HCl and water. Ethyl acetate was dried with Na2SO4 and evaporated to dryness. The crude product was purified by flash chromatography eluting with heptane-ethyl acetate (1:9).
Reaction SMILES: Br[CH2:2][C:3](=[O:8])[C:4]([CH3:7])([CH3:6])[CH3:5].[N-:9]=[N+:10]=[N-:11].[Na+]>CC(C)=O>[N:9]([CH2:2][C:3](=[O:8])[C:4]([CH3:7])([CH3:6])[CH3:5])=[N+:10]=[N-:11]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)(C)C(=O)CBr
Agent: [Na+]
Solvent: CC(C)=O
Product: CC(C)(C)C(=O)CN=[N+]=[N-]
Temperature: 25 °C

Procedure:
To a solution of 1-bromo-3,3-dimethylbutan-2-one (50 g, 279 mmol) in acetone (400 mL) is added NaN3 (22 g, 335 mmol) at 0° C. The reaction mixture is warmed to room temperature for 7 h. The reaction mixture is filtered and the filtrate is concentrated. The residue is diluted with EtOAc and washed with water and brine. The organic layer is dried (Na2SO4) and concentrated to afford the title crude compound which is used in the next step without purification.
Reaction SMILES: [Cl:1][C:2]1[C:12]2[CH2:11][CH2:10][N:9]([CH3:13])[CH2:8][CH2:7][C:6]=2[C:5]([CH2:14][CH2:15][CH2:16]Cl)=[CH:4][CH:3]=1.[Na].N1C=NC=N1.[Cl:24][C:25]1[CH:26]=[N:27][NH:28][CH:29]=1>>[ClH:1].[Cl:1][C:2]1[C:12]2[CH2:11][CH2:10][N:9]([CH3:13])[CH2:8][CH2:7][C:6]=2[C:5]([CH2:14][CH2:15][CH2:16][N:27]2[CH:26]=[C:25]([Cl:24])[CH:29]=[N:28]2)=[CH:4][CH:3]=1
Reactant: CN1CCc2c(Cl)ccc(CCCCl)c2CC1
Reactant: Clc1cn[nH]c1
Agent: [Na]
Agent: c1nc[nH]n1
Product: CN1CCc2c(Cl)ccc(CCCn3cc(Cl)cn3)c2CC1
Product: Cl
Yield: 60 %

Procedure:
Using the general procedure of Example 11, replacing [(9-chloro-2,3,4,5-tetrahydro-3-methyl-1H-3-benzazepin-6-yl)oxy]ethanol 4-methylbenzenesulfonate with 6-chloro-9-(3-chloropropyl)-2,3,4,5-tetrahydro-3-methyl-1H-3-benzazepine and 1H-1,2,4-triazole sodium salt with 4-chloro-1H-pyrazole gave 0.33 g (60%) of 6-chloro-9-[3-(4-chloro-1H-pyrazol-1-yl)propyl]-2,3,4,5-tetrahydro-3-methyl-1H-3-benzazepine hydrochloride; mp 142.5°-145° C.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]([OH:13])=[O:12].[Br:14]Br.II>C(O)(=O)C>[Br:14][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:5]=1[CH:4]=[CH:3][C:2]([C:11]([OH:13])=[O:12])=[CH:1]2
Reactant: O=C(O)c1ccc2ccccc2c1
Reactant: BrBr
Agent: II
Solvent: CC(=O)O
Product: O=C(O)c1ccc2c(Br)cccc2c1
Yield: 53.4 %

Procedure:
To a boiling solution of 2-naphthoic acid (10.00 g, 58.14 mmol) in acetic acid (50 mL) is added dropwise bromine (3 mL) containing iodine (0.25 g). After the addition is complete, the solution is refluxed for 0.5 hr. A white precipitate forms during cooling and is isolated by filtration, washed with acetic acid and then water. The solid is triturated in methanol (100 mL) and 7.01 g (53.4% yield) of the desired product is obtained as a white solid. m.p. 248-250° C. 1H NMR (300 MHz, CD3OD): δ 8.94 (d, J=1.8 Hz, 1H), 8.52-8.42 (m, 3H), 8.27 (dd, J=1.8, 7.5 Hz, 1H), 7.79 (t, J=8.4 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:13]=[C:14]([Cl:17])[C:15]=1Cl)[C:5]([O:7][CH2:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:6].[F-:18].[K+].S1(CCCC1)(=O)=O>[Br-].C1([P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:13]=[C:14]([Cl:17])[C:15]=1[F:18])[C:5]([O:7][CH2:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:6]
Reactant: CC(C)(C)COC(=O)c1cc(Cl)c(Cl)c(Cl)c1
Reactant: [F-]
Agent: [Br-]
Agent: [K+]
Agent: c1ccc([P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: O=S1(=O)CCCC1
Product: CC(C)(C)COC(=O)c1cc(Cl)c(F)c(Cl)c1
Reaction time: 6 h
Yield: 63.3 %

Procedure:
The reaction was conducted in the same manner as in Example 1 for 6 hours by using 8.9 g (30 mmol) of neopentyl 3,4,5-trichlorobenzoate instead of neopentyl 2,3,4,5-tetrachlorobenzoate in Example 1, 2.6 g (45 mmol) of spray-dried potassium fluoride, 1.3 g (3 mmol) of tetraphenyl phosphonium bromide and 9 g of anhydrous sulfolane. The post-treatment was conducted in the same manner, followed by distillation under reduced pressure to obtain 5.3 g of neopentyl 3,5-dichloro-4-fluorobenzoate. Further, the distillation residue was subjected to silica gel column chromatography and eluted with benzene to obtain 2.0 g of neopentyl 3,5-dichloro-4-fluorobenzoate as slightly yellow plates. The combined yield was 87%. The physical properties are shown below.
Reaction SMILES: [OH:1][C:2]1[C:7]2[C:8]3[CH2:9][NH:10][CH2:11][CH2:12][C:13]=3[C:14]([CH3:17])([CH3:16])[O:15][C:6]=2[CH:5]=[C:4]([CH:18]([CH3:26])[CH:19]([CH3:25])[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH:3]=1.Cl[CH2:28][C:29]([N:31]([CH3:33])[CH3:32])=[O:30]>>[OH:1][C:2]1[C:7]2[C:8]3[CH2:9][N:10]([CH2:28][C:29]([N:31]([CH3:33])[CH3:32])=[O:30])[CH2:11][CH2:12][C:13]=3[C:14]([CH3:16])([CH3:17])[O:15][C:6]=2[CH:5]=[C:4]([CH:18]([CH3:26])[CH:19]([CH3:25])[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH:3]=1
Reactant: CCCCCC(C)C(C)c1cc(O)c2c(c1)OC(C)(C)C1=C2CNCC1
Reactant: CN(C)C(=O)CCl
Product: CCCCCC(C)C(C)c1cc(O)c2c(c1)OC(C)(C)C1=C2CN(CC(=O)N(C)C)CC1

Procedure:
The above-titled compound was prepared by reacting 10-hydroxy-5,5-dimethyl-8-(1,2-dimethylheptyl)-1,2,3,4-tetrahydro-5H-[1]benzopyrano[4,3-c]pyridine with 2-chloro-N,N-dimethylacetamide according to the method of Example 2; m.p. 122°-124°.
Reaction SMILES: [Br:1][C:2]1[CH:14]=[CH:13][C:12]([C:15]([NH2:17])=[O:16])=[C:11]2[C:3]=1[C:4]1[CH2:5][CH2:6][CH:7]([CH:18]=O)[CH2:8][C:9]=1[NH:10]2.C([O-])(=O)C.[NH4+:24].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C1COCC1>C(Cl)Cl>[NH2:24][CH2:18][CH:7]1[CH2:6][CH2:5][C:4]2[C:3]3[C:11](=[C:12]([C:15]([NH2:17])=[O:16])[CH:13]=[CH:14][C:2]=3[Br:1])[NH:10][C:9]=2[CH2:8]1
Reactant: NC(=O)c1ccc(Br)c2c3c([nH]c12)CC(C=O)CC3
Reactant: [NH4+]
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: NCC1CCc2c([nH]c3c(C(N)=O)ccc(Br)c23)C1
Reaction time: 0.17 h
Yield: 13 %

Procedure:
Step 3 A solution of crude 5-bromo-2-formyl-2,3,4,9-tetrahydro-1H-carbazole-8-carboxamide (1 g, 3.11 mmol) in DCM (20 mL) was treated with ammonium acetate (3.60 g, 46.7 mmol) and sodium triacetoxyborohydride (0.990 g, 4.67 mmol) at rt and stirred for 10 min. THF (2 mL) was added to try to dissolve the starting material, but no reaction was observed after 1 h. The mixture was concentrated and the residue was dissolved in DMSO (10 mL). Additional sodium triacetoxyborohydride (500 mg) was added and the mixture was stirred at rt overnight. The mixture was diluted with water and the precipitate was removed by filtration. The filtrate was treated with 1 M aqueous sodium hydroxide and extracted three times with EtOAc. The combined organic phases were washed with water, dried and concentrated to provide 2-(aminomethyl)-5-bromo-2,3,4,9-tetrahydro-1H-carbazole-8-carboxamide as a white solid (130 mg, 13%), used without further purification. Mass spectrum m/z 322, 324 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13]3[CH:14]=[C:15]([F:18])[CH:16]=[CH:17][C:12]=3[N:11]=[C:10]2[C@@H:19]([NH2:21])[CH3:20])[CH:5]=[C:6]([F:8])[CH:7]=1.Cl[C:23]1[N:31]=[CH:30][N:29]=[C:28]2[C:24]=1[N:25]=[CH:26][N:27]2[CH:32]1[CH2:37][CH2:36][CH2:35][CH2:34][O:33]1.CCN(C(C)C)C(C)C>CC(O)C>[F:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13]3[CH:14]=[C:15]([F:18])[CH:16]=[CH:17][C:12]=3[N:11]=[C:10]2[C@@H:19]([NH:21][C:23]2[N:31]=[CH:30][N:29]=[C:28]3[C:24]=2[N:25]=[CH:26][N:27]3[CH:32]2[CH2:37][CH2:36][CH2:35][CH2:34][O:33]2)[CH3:20])[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: C[C@H](N)c1nc2ccc(F)cc2n1-c1cc(F)cc(F)c1
Reactant: Clc1ncnc2c1ncn2C1CCCCO1
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](Nc1ncnc2c1ncn2C1CCCCO1)c1nc2ccc(F)cc2n1-c1cc(F)cc(F)c1
Temperature: 90 °C
Yield: 40.2 %

Procedure:
A mixture of (S)-1-[1-(3,5-difluorophenyl)-6-fluoro-1H-benzoimidazol-2-yl]ethylamine (206 mg, 0.71 mmol), 6-chloro-9-(tetrahydropyran-2-yl)-9H-purine (169 mg, 0.71 mmol) and DIPEA (0.37 mL, 2.1 mmol) in IPA (1.4 mL) was heated in a sealed tube for 20 h at 90° C. After cooling to RT, the volatiles were removed in vacuo and the resulting residue purified by column chromatography (Si—PPC, gradient 0-10% 2M NH3 in MeOH/DCM) to afford the title compound as a colourless glass (141 mg, 40%). LCMS (Method C): RT 3.38 min [M+H]+ 494. 1H NMR (CDCl3, 400 MHz): δ 8.29-8.28 (1H, m), 7.97-7.96 (1H, m), 7.72-7.68 (1H, m), 7.10-7.01 (3H, m), 6.97-6.91 (1H, m), 6.86-6.82 (1H, m), 6.37 (1H, bs), 5.79-5.67 (2H, m), 4.18-4.13 (1H, m), 3.80-3.73 (1H, m), 2.11-1.97 (3H, m), 1.80-1.63 (6H, m).