Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH2:10][CH2:9][C:5]2[S:6][CH:7]=[CH:8][C:4]=2[CH:3]=1.C([Li])(C)(C)C.C([O:19][B:20](OC(C)C)[O:21]C(C)C)(C)C.Cl>C(Cl)Cl.CO>[S:6]1[CH:7]=[CH:8][C:4]2[CH:3]=[C:2]([B:20]([OH:21])[OH:19])[CH2:10][CH2:9][C:5]1=2
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: BrC1=Cc2ccsc2CC1
Agent: Cl
Agent: [Li]C(C)(C)C
Solvent: CO
Solvent: ClCCl
Product: OB(O)C1=Cc2ccsc2CC1

Procedure:
Following the general method described in example 19a, 5-bromo-6,7-dihydro-benzo[b]thiophene was reacted with tert.-butyllithium solution followed by triisopropylborate and 3N HCl. The title compound was obtained as a white crystalline material after chromatography (SiO2 with CH2Cl2-MeOH=98:2). MS: m/e=179 (M-H−).
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[C:10]2([CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)[CH:9]([NH2:16])[CH2:8][CH2:7]1)=[O:5])[CH3:2].C([O-])(O)=O.[Na+].Cl[C:23]([O:25][CH2:26][CH3:27])=[O:24]>C(Cl)(Cl)Cl>[CH2:1]([O:3][C:4]([N:6]1[C:10]2([CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)[CH:9]([NH:16][C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CCC(N)C12CCCCC2
Reactant: CCOC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CCOC(=O)NC1CCN(C(=O)OCC)C12CCCCC2
Temperature: 25 °C
Yield: 79.8 %

Procedure:
To a stirring suspension of 5.7 g of 1-ethoxycarbonyl-4-amino-1-azaspiro[4.5]decane of Example 1e and 7. g of NaHCO3 in 100 ml of CHCl3 was added in a dropwise fashion 3.8 g of ethyl chloroformate. The mixture was refluxed for 4 hours, cooled to room temperature, filtered, washed with water, 3 N-HCl, saturated sodium bicarbonate solution and saturated NaCl solution, dried over Na2SO4 and then evaporated to give 6 g of 1-ethoxycarbonyl-4-(ethoxycarbonylamino)-1-azaspiro[4.5]decane.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[N:19]=[C:18]([NH:20][C:21]3[CH:25]=[C:24]([CH3:26])[NH:23][N:22]=3)[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]=2)=[O:9])=[CH:4][C:3]=1[O:27]C.B(Br)(Br)Br.C(Cl)Cl.O>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[N:19]=[C:18]([NH:20][C:21]3[CH:25]=[C:24]([CH3:26])[NH:23][N:22]=3)[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]=2)=[O:9])=[CH:4][C:3]=1[OH:27]
Reactant: COc1cc(C(=O)c2nc(Nc3cc(C)[nH]n3)c3ccccc3n2)ccc1F
Agent: BrB(Br)Br
Solvent: O
Solvent: ClCCl
Product: Cc1cc(Nc2nc(C(=O)c3ccc(F)c(O)c3)nc3ccccc23)n[nH]1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 20.8 %

Procedure:
To a stirred suspension of (4-fluoro-3-methoxyphenyl)(4-(5-methyl-1H-pyrazol-3-ylamino)quinazolin-2-yl)methanone from Example 76 (100 mg, 0.265 mmol) in DCM (4 mL) at 0° C., was added dropwise 1.0 M boron tribromide/DCM (2.12 mL, 2.12 mmol). The mixture was stirred at 0° C. for 30 min. Additional 1.0 M boron tribromide/DCM (1.50 mL, 1.50 mmol) was added and the mixture was allowed to warm to rt and stir for a further 2.5 h. Water (10 mL) was added, and the mixture was extracted with 25% 2-propanol/DCM (2×). The combined organic layers were dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was triturated with diethyl ether and the resulting solid was collected by filtration and dried. The solid was further purified by reverse-phase HPLC eluting with a mixture of water and acetonitrile to afford (4-fluoro-3-hydroxyphenyl)(4-(5-methyl-1H-pyrazol-3-ylamino)quinazolin-2-yl)methanone as a yellow solid (20 mg, 21%). 1H NMR (300 MHz, DMSO-d6) δ ppm 2.19 (s, 3H), 6.51 (s, 1H), 7.28 (dd, J=10.8, 8.4 Hz, 1H), 7.39 (m, 1H), 7.58 (dd, J=8.7, 1.8 Hz, 1H), 7.67 (ddd, J=8.1, 8.1, 1.5 Hz, 1H), 7.83-7.92 (m, 2H), 8.73 (d, J=8.4 Hz, 1H), 10.65 (br s, 1H), 12.22 (br s, 1H); LC-MS (ESI) m/z 364 (M+H)+.
Reaction SMILES: [C:1]([C:5]1[C:6]([N+:19]([O-])=O)=[CH:7][C:8]([N+]([O-])=O)=[C:9](/[CH:11]=[CH:12]/[N:13](C)C)[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].O.O.[Sn](Cl)Cl>C(O)C>[C:1]([C:5]1[CH:10]=[C:9]2[C:8](=[CH:7][C:6]=1[NH2:19])[NH:13][CH:12]=[CH:11]2)([CH3:2])([CH3:3])[CH3:4]
Reactant: CN(C)/C=C/c1cc(C(C)(C)C)c([N+](=O)[O-])cc1[N+](=O)[O-]
Agent: Cl[Sn]Cl
Solvent: O
Solvent: CCO
Product: CC(C)(C)c1cc2cc[nH]c2cc1N
Temperature: 25 °C
Yield: 11.8 %

Procedure:
A solution of (E)-2-(5-tert-butyl-2,4-dinitrophenyl)-N,N-dimethylethen-amine (5.3 g, 18 mmol) and tin (II) chloride dihydrate (37 g, 0.18 mol) in ethanol (200 mL) was heated at reflux overnight. The mixture was cooled to room temperature and the solvent was removed under vacuum. The residual slurry was diluted with water (500 mL) and was basifed with 10% aq. Na2CO3 to pH 8. The resulting suspension was extracted with ethyl acetate (3×100 mL). The ethyl acetate extract washed with water and brine, dried over Na2SO4, and concentrated. The residual solid washed with CH2Cl2 to afford a yellow powder, which was purified by column chromatography to give 5-tert-butyl-1H-indol-6-amine (0.40 g, 12%). 1H NMR (DMSO-d6) δ 10.34 (br s, 1H), 7.23 (s, 1H), 6.92 (s, 1H), 6.65 (s, 1H), 6.14 (s, 1H), 4.43 (br s, 2H), 2.48 (s, 9H); MS (ESI) m/e (M+H+) 189.1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13]3[CH:14]=[C:15]([C:18]4[O:22][C:21]([SH:23])=[N:20][N:19]=4)[CH:16]=[CH:17][C:12]=3[N:11]=[CH:10]2)=[CH:5][CH:4]=1.Cl[CH2:25][C:26]1[CH:27]=[C:28]([CH:32]=[CH:33][CH:34]=1)[C:29]([OH:31])=[O:30]>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13]3[CH:14]=[C:15]([C:18]4[O:22][C:21]([S:23][CH2:25][C:26]5[CH:27]=[C:28]([CH:32]=[CH:33][CH:34]=5)[C:29]([OH:31])=[O:30])=[N:20][N:19]=4)[CH:16]=[CH:17][C:12]=3[N:11]=[CH:10]2)=[CH:5][CH:4]=1
Reactant: COc1ccc(-n2cnc3ccc(-c4nnc(S)o4)cc32)cc1
Reactant: O=C(O)c1cccc(CCl)c1
Product: COc1ccc(-n2cnc3ccc(-c4nnc(SCc5cccc(C(=O)O)c5)o4)cc32)cc1
Yield: 31 %

Procedure:
In the same manner as in Example 1 and using 5-[1-(4-methoxyphenyl)-1H-benzimidazol-6-yl]-1,3,4-oxadiazole-2-thiol instead of 5-(benzothiazol-6-yl)-1,3,4-oxadiazole-2-thiol and 3-(chloromethyl)benzoic acid instead of 3-(trifluoromethyl)benzyl chloride, the title compound (yield 31%) was obtained as colorless crystals.
Reaction SMILES: [CH2:1]([C:3]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)([CH2:6][CH:7]1[CH2:9][O:8]1)[C:4]#[N:5])[CH3:2].[CH:16]([NH2:19])([CH3:18])[CH3:17]>C(O)C>[CH2:1]([C:3]1([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:4](=[NH:5])[O:8][CH:7]([CH2:9][NH:19][CH:16]([CH3:18])[CH3:17])[CH2:6]1)[CH3:2]
Reactant: CC(C)N
Reactant: CCC(C#N)(CC1CO1)c1ccccc1
Solvent: CCO
Product: CCC1(c2ccccc2)CC(CNC(C)C)OC1=N

Procedure:
A solution of α-ethyl-α-phenyloxiranepropanenitrile and isopropylamine in ethanol is placed in a pressure bottle and heated overnight in a steam bath. After cooling, the bottle is opened and the solvent removed in vacuo. Solvent-solvent extraction by the method described in Example 4 yields the title compound.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH:7]2[C:13]3=[CH:14][CH:15]=[CH:16][N:12]3[CH2:11][C:10]3[CH:17]=[CH:18][CH:19]=[CH:20][C:9]=3[O:8]2)[CH2:3][CH2:2]1.[C:21]1([N:27]=[C:28]=[O:29])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C1C=CC=CC=1>[C:21]1([NH:27][C:28]([N:1]2[CH2:2][CH2:3][CH:4]([CH:7]3[C:13]4=[CH:14][CH:15]=[CH:16][N:12]4[CH2:11][C:10]4[CH:17]=[CH:18][CH:19]=[CH:20][C:9]=4[O:8]3)[CH2:5][CH2:6]2)=[O:29])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=C=Nc1ccccc1
Reactant: c1ccc2c(c1)Cn1cccc1C(C1CCNCC1)O2
Solvent: c1ccccc1
Product: O=C(Nc1ccccc1)N1CCC(C2Oc3ccccc3Cn3cccc32)CC1
Yield: 89.6 %

Procedure:
A solution of 11-(piperidin-4-yl)-5H,11H-pyrrolo[2,1-c][1,4]benzoxazepine (4.8 g, 0.018 mole) and phenylisocyanate (2.14 ml, 0.02 mole) in 140 ml benzene was heated at 65° C. for 1 hour. The reaction mixture was then cooled. The product was filtered and dried to yield 6.25 g (90%) of a solid, m.p. 184°-192° C. This was recrystallized from tetrahydrofuran/diethyl ether (1:4) to yield 5.9 g (85%) of an analytically pure solid, m.p. 167°-170° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[CH2:12][CH:13]([CH:22]([C:27](OC)=[O:28])[C:23]([O:25][CH3:26])=[O:24])[C:14]1[CH:19]=[CH:18][C:17](OC)=[CH:16][CH:15]=1.[CH3:31][O-:32].[Na+].Cl>CO>[CH3:26][O:25][C:23]([CH:22]1[CH:13]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:19]=2[O:32][CH3:31])[CH2:12][C:3]2[CH:4]=[C:5]([C:8]([F:10])([F:11])[F:9])[CH:6]=[CH:7][C:2]=2[NH:1][C:27]1=[O:28])=[O:24]
Reactant: C[O-]
Reactant: COC(=O)C(C(=O)OC)C(Cc1cc(C(F)(F)F)ccc1N)c1ccc(OC)cc1
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: COC(=O)C1C(=O)Nc2ccc(C(F)(F)F)cc2CC1c1ccccc1OC
Temperature: 0 °C

Procedure:
Under an argon atmosphere, a stirred solution of [2-(2-amino-5-trifluoromethylphenyl)-1-(4-methoxyphenyl)ethyl]propanedioic acid, dimethyl ester (20.0 g; 0.047 mol) in 200 ml of methanol was treated with 13.3 ml of 25% sodium methoxide in methanol and heated to reflux. After about 2.75 hours of heating, the mixture was cooled in ice water and 1N hydrochloric acid was added to precipitate the product. Stirring in an ice water bath, followed by filtering, washing with water and air-drying yielded 19.0 g of product. The product was suspended in 30 ml of isopropanol, allowed to stand for one hour, filtered and washed with isopropanol and hexane to yield 13.64 g of the title compound, melting point 161°-163° C.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([NH:18][CH:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)[S:5][C:6]=1[C:7]([C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([F:17])[CH:10]=1)=[O:8].[CH3:25][N:26]([CH3:31])[S:27](Cl)(=[O:29])=[O:28].C(N(C(C)C)CC)(C)C>C(OCC)(=O)C>[CH3:25][N:26]([CH3:31])[S:27]([N:22]1[CH2:23][CH2:24][CH:19]([NH:18][C:4]2[S:5][C:6]([C:7](=[O:8])[C:9]3[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([F:17])[CH:10]=3)=[C:2]([NH2:1])[N:3]=2)[CH2:20][CH2:21]1)(=[O:29])=[O:28]
Reactant: COc1ccc(C(=O)c2sc(NC3CCNCC3)nc2N)cc1F
Reactant: CN(C)S(=O)(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: COc1ccc(C(=O)c2sc(NC3CCN(S(=O)(=O)N(C)C)CC3)nc2N)cc1F
Yield: 22 %

Procedure:
[4-Amino-2-(piperidin-4-ylamino)thiazol-5-yl]-(3-fluoro-4-methoxy-phenyl)methanone (0.08 g, 0.022 mmol) (Example 7)) was treated with dimethylsulfamoyl chloride in a manner similar to Example 9 except that diisopropylethylamine was additionally used as a catalyst and short plug of silica gel (ethyl acetate was used to pre-purify the sample to give 30 mg (22% yield) of 4-[4-amino-5-(3-fluoro-4-methoxybenzoyl)thiazol-2-ylamino]piperidine-1-sulfonic acid dimethylamide. 1H NMR (DMSO−d6, 300 MHz) δ1.51 (m, 2H, CH2), 1.97 (m, 2H, CH2), 2.77 (s, 6H, 2× NCH2), 2.99 (m, 2H, CH2), 3.52 (m, 2H, CH2), 3.6-4.0 (broad, 1H, CH), 3.89 (s, 3H, OCH3), 7.9-8.5 (brd, 2H, 2NH), 8.71 (brd, 1H, NH). HRMS: (M+H)+: observed: 458.1331; calcd for 4581327.
Reaction SMILES: OO.[OH:3][CH:4]1[CH2:9][C:8]([CH3:11])([CH3:10])[N:7]([OH:12])[C:6]([CH3:14])([CH3:13])[CH2:5]1.[C:15]([OH:19])([CH3:18])([CH3:17])[CH3:16]>O>[OH:3][CH:4]1[CH2:9][C:8]([CH3:10])([CH3:11])[N:7]([O:12][CH2:16][C:15]([OH:19])([CH3:18])[CH3:17])[C:6]([CH3:14])([CH3:13])[CH2:5]1
Reactant: CC(C)(C)O
Reactant: CC1(C)CC(O)CC(C)(C)N1O
Agent: OO
Solvent: O
Product: CC(C)(O)CON1C(C)(C)CC(O)CC1(C)C
Temperature: 40 °C
Reaction time: 8 h

Procedure:
A solution of 50% aqueous hydrogen peroxide is added at a rate of approximately 100 mmol per hour and, simultaneously, a solution of 17.2 g (100 mmol) of 4-hydroxy-1-oxyl-2,2,6,6-tetramethylpiperidine dissolved in 40-45 mL of water is added at a rate of 35-50mmol per hour to a mixture of metal salt, acid if used, 25 mL of water and 200 mL of tert-butyl alcohol maintained at 35-45° C. The reaction mixture is maintained at 35-45° C. after all reactants are added, and in some cases the reaction mixture is stirred overnight at room temperature. The reaction is monitored by gas chromatography. Results are tabulated below.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([S:10]([N:13]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][C:21]=2[O:28][CH3:29])[C:14]2[S:18][N:17]=[CH:16][N:15]=2)(=[O:12])=[O:11])[CH:6]=[CH:7][C:8]=1F)#[N:2].C(=O)([O-])[O-].[K+].[K+].[I:36][C:37]1[CH:42]=[C:41]([C:43]([F:46])([F:45])[F:44])[CH:40]=[CH:39][C:38]=1[OH:47].O>CS(C)=O>[C:1]([C:3]1[CH:4]=[C:5]([S:10]([N:13]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][C:21]=2[O:28][CH3:29])[C:14]2[S:18][N:17]=[CH:16][N:15]=2)(=[O:12])=[O:11])[CH:6]=[CH:7][C:8]=1[O:47][C:38]1[CH:39]=[CH:40][C:41]([C:43]([F:44])([F:45])[F:46])=[CH:42][C:37]=1[I:36])#[N:2]
Reactant: Oc1ccc(C(F)(F)F)cc1I
Reactant: COc1ccc(CN(c2ncns2)S(=O)(=O)c2ccc(F)c(C#N)c2)c(OC)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: COc1ccc(CN(c2ncns2)S(=O)(=O)c2ccc(Oc3ccc(C(F)(F)F)cc3I)c(C#N)c2)c(OC)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 84 %

Procedure:
To a solution of 3-cyano-N-(2,4-dimethoxybenzyl)-4-fluoro-N-1,2,4-thiadiazol-5-ylbenzenesulfonamide (Preparation 68, 25 g, 57.5 mmol) in DMSO (125 mL) was added potassium carbonate (20.4 g, 148 mmol) followed by dropwise addition of the 2-iodo-4-(trifluoromethyl)phenol (Preparation 224, 17.4 g, 60.6 mmol). The reaction was stirred at room temperature for 2 hours. The reaction was poured into water (1 L) and extracted with ethyl acetate (3×300 mL). The organic layers were combined and washed with water (2×250 mL), dried over sodium sulfate and concentrated in vacuo. The residue was slurried in methanol (150 mL) for 1 hour before filtering and drying under vacuum to afford 33.92 g of the title compound as a white solid (83%).
Reaction SMILES: [C:1]([C:4]1[C:9]([CH2:10][CH3:11])=[N:8][CH:7]=[CH:6][N:5]=1)(=[O:3])[CH3:2].[Br:12]Br>C(Cl)(Cl)Cl>[Br:12][CH2:2][C:1]([C:4]1[C:9]([CH2:10][CH3:11])=[N:8][CH:7]=[CH:6][N:5]=1)=[O:3]
Reactant: CCc1nccnc1C(C)=O
Reactant: BrBr
Solvent: ClC(Cl)Cl
Product: CCc1nccnc1C(=O)CBr
Temperature: 40 °C
Reaction time: 4 h

Procedure:
To a solution of 2-acetyl-3-ethylpyrazine (1.0 g, 6.66 mmol) in chloroform (15 mL) was added Br2 (0.38 mL, 7.32 mmol, 1.1 eq) dropwise at 0° C. The reaction mixture was stirred at 40° C. for 4 h. The reddish solution turned to dark brown. The reaction mixture was concentrated in vacuo and used in the step 2 without further purification. MS LC-MS (MH+=231)
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([OH:23])=[C:8]2[C:15]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)=[N:14][S:13][C:9]2=[C:10](Br)[N:11]=1)=[O:5])[CH3:2].[C:24]1(B(O)O)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[CH2:1]([O:3][C:4]([C:6]1[C:7]([OH:23])=[C:8]2[C:15]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)=[N:14][S:13][C:9]2=[C:10]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[N:11]=1)=[O:5])[CH3:2]
Reactant: OB(O)c1ccccc1
Reactant: CCOC(=O)c1nc(Br)c2snc(-c3ccc(F)cc3)c2c1O
Product: CCOC(=O)c1nc(-c2ccccc2)c2snc(-c3ccc(F)cc3)c2c1O

Procedure:
The title compound was synthesized in analogy to Example 1 from 7-bromo-3-(4-fluoro-phenyl)-4-hydroxy-isothiazolo[5,4-c]pyridine-5-carboxylic acid ethyl ester and phenylboronic acid: MS (m/z) 395.2 (M+1).
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5]Br.[CH3:7][O:8][C:9]([CH:11]1[CH2:14][CH2:13][CH2:12]1)=[O:10]>>[CH3:7][O:8][C:9]([C:11]1([CH2:5][CH2:4][CH2:3][CH2:2][Br:1])[CH2:14][CH2:13][CH2:12]1)=[O:10]
Reactant: BrCCCCBr
Reactant: COC(=O)C1CCC1
Product: COC(=O)C1(CCCCBr)CCC1

Procedure:
1-(4-Bromobutyl)cyclobutane carboxylic acid methyl ester was prepared from 1,4-dibromobutane and cyclobutane carboxylic acid methyl ester using the general procedure described in example 168.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH2:9])[CH:5]=[C:6]([NH2:8])[CH:7]=1.[F:10][C:11]([F:21])([F:20])[C:12](=[O:19])[CH2:13][C:14](OCC)=[O:15]>C(O)C>[NH2:8][C:6]1[CH:7]=[C:2]([Cl:1])[CH:3]=[C:4]2[C:5]=1[C:12]([OH:19])([C:11]([F:21])([F:20])[F:10])[CH2:13][C:14](=[O:15])[NH:9]2
Reactant: Nc1cc(N)cc(Cl)c1
Reactant: CCOC(=O)CC(=O)C(F)(F)F
Solvent: CCO
Product: Nc1cc(Cl)cc2c1C(O)(C(F)(F)F)CC(=O)N2
Yield: 37 %

Procedure:
To a solution of 5-chloro-1,3-phenylenediamine (15.0 g, 0.105 mol) in 70 mL ethanol was added ethyl 4,4,4-trifluoroacetoacetate (20.4 g, 0.111 mol), then the mixture was heated at reflux for 18 h. The solvent was removed under reduced pressure until the product began to precipitate. The material was allowed to crystallize for 2 h, whereupon it was filtered and rinsed with cold ether to afford 10.9 g (37%) of 5-amino-7-chloro-3,4-dihydro-4-hydroxy-4-(trifluoromethyl)-1H-quinolin-2-one, a tan solid. The filtrate was concentrated until solid began to precipitate and afforded an additional 3.0 g (10%). 1H NMR (400 MHz, acetone-d6) δ 11.0 (broad s, 1H), 9.64 (s, 1H), 7.42 (t, 1H, J=8.1), 6.99 (d, 1H, J=8.1), 6.90 (s, 1H), 6.79 (d, 1H, J=8.1).
Reaction SMILES: [Cl:1][C:2]1[CH:30]=[CH:29][C:5]2[S:6][C:7]3[CH:28]=[CH:27][CH:26]=[CH:25][C:8]=3[C:9]([N:11]3[CH2:19][C@H:18]4[N:14]([CH2:15][C@@H:16]([O:20]C(C)(C)C)[CH2:17]4)[CH2:13][CH2:12]3)=[N:10][C:4]=2[CH:3]=1.C(N(CC)CC)C>FC(F)(F)C(O)=O>[Cl:1][C:2]1[CH:30]=[CH:29][C:5]2[S:6][C:7]3[CH:28]=[CH:27][CH:26]=[CH:25][C:8]=3[C:9]([N:11]3[CH2:19][C@H:18]4[N:14]([CH2:15][C@@H:16]([OH:20])[CH2:17]4)[CH2:13][CH2:12]3)=[N:10][C:4]=2[CH:3]=1
Reactant: CC(C)(C)O[C@H]1C[C@H]2CN(C3=Nc4cc(Cl)ccc4Sc4ccccc43)CCN2C1
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Product: O[C@H]1C[C@H]2CN(C3=Nc4cc(Cl)ccc4Sc4ccccc43)CCN2C1
Reaction time: 1 h
Yield: 72.5 %

Procedure:
8-chloro-11-[(6S,8S)-8-t-butoxy-1,4-diazabicyclo[4.3.0]non-4-yl]-dibenz[b,f]-1,4-thiazepine (0.311 g, 0.704 mmol) was dissolved in trifluoroacetic acid (20 mL) and stirred for 1 hour. The trifluoroacetic acid was removed under reduced pressure and the residue dissolved in methylene chloride (20 mL). Triethylamine (0.142 g, 1.40 mmol) was then added via syringe and the reaction stirred for 1 hour, washed with water, dried (MgSO4) and evaporated to dryness to give 8-chloro-11-[(6S,8S)-8-hydroxy-1,4-diazabicyclo[4.3.0]non-4-yl]-dibenz[b,f]-1,4-thiazepine as an off-white solid (0.197 g, 72%); mp 58°-60° C.; Rf (40% acetone/hexanes): 0.15; HRMS (FAB): MH+ of C20H20N3OSCl, calculated 386.1094, found 386.1085.
Reaction SMILES: [C:1]([C:3]1[CH:13]=[CH:12][C:6]([C:7]([N:9]([CH3:11])[CH3:10])=[O:8])=[CH:5][CH:4]=1)#[N:2].C(=O)([O-])[O-].[K+].[K+].Cl.[NH2:21][OH:22]>CCO.CCOC(C)=O>[OH:22][NH:21][C:1]([C:3]1[CH:13]=[CH:12][C:6]([C:7]([N:9]([CH3:11])[CH3:10])=[O:8])=[CH:5][CH:4]=1)=[NH:2]
Reactant: NO
Reactant: CN(C)C(=O)c1ccc(C#N)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CN(C)C(=O)c1ccc(C(=N)NO)cc1
Temperature: 80 °C
Reaction time: 25 h
Yield: 79 %

Procedure:
4-cyano-N,N-dimethylbenzamide (200 mg, 1.148 mmol), potassium carbonate (952 mg, 6.89 mmol) and hydroxylamine hydrochloride (479 mg, 6.89 mmol) were dissolved in EtOH (11.4 mL). The reaction mixture was stirred at 80° C. for 25 h. The mixture was diluted with EtOAc (50 mL), washed with water (10 mL), water phase extracted with EtOAc (20 mL). Combined organic phases were washed with brine (10 mL) and dried over sodium sulfate. The solvent was removed to give 188 mg of white crystalline needles. The crude material was used without further purification.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].C(=O)([O-])[O-].[K+].[K+].[F:17][CH:18]([F:21])[CH2:19][OH:20].O>CN(C)C=O>[F:17][CH:18]([F:21])[CH2:19][O:20][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9]
Reactant: OCC(F)F
Reactant: O=[N+]([O-])c1ccccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccccc1OCC(F)F
Temperature: 120 °C
Yield: 85 %

Procedure:
In a microwave tube a mixture of 1-fluoro-2-nitrobenzene (100 mg, 0.7 mmol), potassium carbonate (193 mg, 1.4 mmol), and 2,2-difluoroethanol in N,N-dimethylformamide (2 ml) was heated in a microwave oven at 120° C. for 20 minutes. For the workup, the reactrion mixture was poured into water (5 ml). The precipitated product was filtered and the aqueous layer was extracted with ether. The combined organic layers were dried and evaporated to yield together with the precipitated material 130 mg (85%) of the 1-(2,2-difluoro-ethoxy)-2-nitro-benzene which was sufficiently pure to be engaged in the next step without further purification; (calculated) C8H7F2NO3 [203.15]; (found) [M+H]+=204.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11](F)[C:12]=3[F:14])[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2)[CH2:3][CH2:2]1.[CH2:21]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:23][NH:22]1.CN(C=O)C>C(Cl)(Cl)Cl>[CH:21]1([C:5]2[N:4]([CH:1]3[CH2:3][CH2:2]3)[C:13]3[C:8]([C:7](=[O:17])[C:6]=2[C:18]([OH:20])=[O:19])=[CH:9][C:10]([F:16])=[CH:11][C:12]=3[F:14])[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:23][NH:22]1
Reactant: c1ccc2c(c1)CNC2
Reactant: O=C(O)c1cn(C2CC2)c2c(F)c(F)c(F)cc2c1=O
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: O=C(O)c1c(C2NCc3ccccc32)n(C2CC2)c2c(F)cc(F)cc2c1=O
Temperature: 120 °C
Yield: 67 %

Procedure:
A mixture of 136 mg of 1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, 180 mg of isoindoline, and 1.5 ml of anhydrous DMF was heated at 120° C. for 1.5 hours while stirring. The resulting reaction mixture was evaporated under reduced pressure to dryness. The residue thus obtained was dissolved into 20 ml of chloroform. The solution was washed with 5% acetic acid and brine in this order, dried over anhydrous sodium sulfate, and condensed. The residue was crystallized by the addition of hot ethanol. After cooling the mixture, the crystals were collected by filtration and recrystallized from a mixed solvent of chloroform, methanol, and ethanol to obtain 123 mg of the target compound.
Reaction SMILES: [Br:1][C:2]1[C:3]2[N:4]([CH:8]=[C:9]([CH2:11][CH3:12])[N:10]=2)[CH:5]=[N:6][CH:7]=1.P(Cl)(Cl)(Cl)=O.CN(C)[CH:20]=[O:21]>>[Br:1][C:2]1[C:3]2[N:4]([C:8]([CH:20]=[O:21])=[C:9]([CH2:11][CH3:12])[N:10]=2)[CH:5]=[N:6][CH:7]=1
Reactant: CN(C)C=O
Reactant: CCc1cn2cncc(Br)c2n1
Solvent: O=P(Cl)(Cl)Cl
Product: CCc1nc2c(Br)cncn2c1C=O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
8-Bromo-2-ethylimidazo[1,2-c]pyrimidine (1.0 g) was added to a mixture of phosphorus oxychloride (1.2 mL) and N,N-dimethylformamide (4.4 mL) at room temperature. The mixture was heated under stirring as it was at 80° C. for 1 day. After cooled to room temperature, it was poured slowly on ice. The material was extracted with ethyl acetate and washed with water, and the solvent was evaporated. The resulting residue was purified by silica gel column chromatography (ethyl acetate:n-hexane=1:5) to give the title compound (0.5 g) as white crystals.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:5]=[CH:4][C:3]=1[C:17]1[N:18]=[CH:19][C:20]([NH2:23])=[N:21][CH:22]=1.[F:24][C:25]([F:35])([F:34])[O:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1Br>>[F:1][C:2]1[CH:7]=[C:6]([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=2[O:26][C:25]([F:24])([F:35])[F:34])[CH:5]=[CH:4][C:3]=1[C:17]1[N:18]=[CH:19][C:20]([NH2:23])=[N:21][CH:22]=1
Reactant: FC(F)(F)Oc1ccccc1Br
Reactant: CC1(C)OB(c2ccc(-c3cnc(N)cn3)c(F)c2)OC1(C)C
Product: Nc1cnc(-c2ccc(-c3ccccc3OC(F)(F)F)cc2F)cn1

Procedure:
The title compound was prepared using analogous conditions to those described in Example 1 utilizing 5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrazin-2-amine and 2-(trifluoromethoxy)bromobenzene. MS (ESI): mass calcd. for C17H11F4N3O, 349.08; m/z found, 350.0 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.39 (s, 1H), 8.02 (s, 1H), 7.96 (m, 1H), 7.65-7.47 (m, 4H), 7.42 (d, J=5.1, 1H), 7.39 (s, 1H), 6.73 (s, 2H).