Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: P(Cl)(Cl)(Cl)(Cl)[Cl:2].[CH3:7][O:8][C:9]1[CH:10]=[C:11]([P:19](=[O:36])(OCC2C=CC=CC=2)[O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:12]=[C:13]([O:17][CH3:18])[C:14]=1[O:15][CH3:16]>C(Cl)(Cl)Cl>[CH3:7][O:8][C:9]1[CH:10]=[C:11]([P:19]([Cl:2])(=[O:36])[O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:12]=[C:13]([O:17][CH3:18])[C:14]=1[O:15][CH3:16]
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: COc1cc(P(=O)(OCc2ccccc2)OCc2ccccc2)cc(OC)c1OC
Solvent: ClC(Cl)Cl
Product: COc1cc(P(=O)(Cl)OCc2ccccc2)cc(OC)c1OC
Temperature: 60 °C

Procedure:
Phosphorous pentachloride (1.15 mmol) is added to a mixture of diester 2 (1 mmol) in 5 mL of CHCl3. The mixture is heated at 60° C. until 1H NMR of an aliquot shows that no starting material remains (approximately 4 hours). The mixture is cooled to room temperature, and the volatile components are removed in vacuo overnight
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8]([C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[F:20])([CH3:13])[CH2:9][C:10]([NH2:12])=O)=[CH:4][CH:3]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:37])=CC=1>C1(C)C=CC=CC=1.[Cl-].[Na+].O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8]([C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[F:20])([CH3:13])[CH2:9][C:10]([NH2:12])=[S:37])=[CH:4][CH:3]=1
Reactant: C[SH](CC(N)=O)(c1ccc(F)cc1)(c1ccc(F)cc1)c1ccccc1F
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: C[SH](CC(N)=S)(c1ccc(F)cc1)(c1ccc(F)cc1)c1ccccc1F
Temperature: 80 °C
Reaction time: 1.5 h

Procedure:
A solution of 2-[bis-(4-fluoro-phenyl)-(2-fluoro-phenyl)-methylsulfanyl]-acetamide (0.5 g) in toluene (20 ml) was treated with Lawesson's reagent (0.26 g) at room temperature under Argon and stirred for 1.5 hours at 80° C. After pouring into saturated brine the organics were extracted with dichloromethane (3×). Drying of the combined organic extracts (Na2SO4), filtration, concentration and flash-chromatography of the residue gave the title compound (42%; Isolated as an oil).
Reaction SMILES: [CH3:1][NH:2][CH3:3].Cl.Cl[CH2:6][C:7]1[N:16]=[C:15]([OH:17])[C:14]2[C:9](=[CH:10][C:11]([O:18][CH3:19])=[CH:12][CH:13]=2)[N:8]=1>>[CH3:1][N:2]([CH2:6][C:7]1[N:16]=[C:15]([OH:17])[C:14]2[C:9](=[CH:10][C:11]([O:18][CH3:19])=[CH:12][CH:13]=2)[N:8]=1)[CH3:3]
Reactant: COc1ccc2c(O)nc(CCl)nc2c1
Reactant: CNC
Agent: Cl
Product: COc1ccc2c(O)nc(CN(C)C)nc2c1
Temperature: 50 °C
Reaction time: 1.5 h
Yield: 97.6 %

Procedure:
To a solution of dimethylamine (2M solution in tetrahydrofuran, 40.0 mL, 80.0 mmol) was added 2-(chloromethyl)-7-(methyloxy)quinazolin-4-ol hydrochloride (7.5 g, 29 mmol) and the reaction mixture was stirred for 90 minutes at 50° C. After cooling it to room temperature the reaction mixture was concentrated and the residue was partitioned between water (100 mL) and ethyl acetate (250 mL). The organic layer was separated and washed with water (100 mL), saturated sodium bicarbonate (100 mL) and brine (100 mL), dried over sodium sulfate, filtered and concentrated to give 2-[(dimethylamino)methyl]-7-(methyloxy)quinazolin-4-ol (6.6 g, 97%). MS (EI) for C12H15N3O2: 234 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([CH:9](O)[CH3:10])=[CH:5][CH:4]=1.C(N(CC)CC)C.CS(Cl)(=O)=O>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH:9]=[CH2:10])=[CH:7][N:8]=1
Reactant: COc1ccc(C(C)O)cn1
Agent: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C=Cc1ccc(OC)nc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 37.2 %

Procedure:
To a solution of 1-(6-methoxy-pyridin-3-yl)-ethanol (14.3 g, 93.5 mmol) in anhydrous THF was added triethylamine (32.3 mL), followed by MsCl (8.6 mL, 112 mmol). The resulting mixture was stirred at room temperature for 15 hours before it was filtered through a pad of celite. The filtrate was concentrated in vacuo and the residue was purified by flash column chromatography to afford the desired product (4.7 g, 37% yield). 1H NMR (300 MHz, CDCl3): δ 3.94 (s, 3 H), 5.20–5.23 (m, 1H), 5.61–5.67 (m, 1 H), 6.60–6.78 (m, 2 H), 7.67–7.72 (m, 1 H), 8.12 (s, 1 H).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][NH:16][CH2:17][CH2:18][CH3:19])=[CH:11][CH:10]=1)#[N:2].C(N)CC.BrCC1C=CC(C2C=CC=CC=2C#N)=CC=1.Cl[C:41]1[N:46]2[N:47]=[CH:48][CH:49]=[C:45]2[N:44]=[C:43]([CH3:50])[CH:42]=1>C(O)C>[C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:10]=[CH:11][C:12]([CH2:15][N:16]([C:41]2[N:46]3[N:47]=[CH:48][CH:49]=[C:45]3[N:44]=[C:43]([CH3:50])[CH:42]=2)[CH2:17][CH2:18][CH3:19])=[CH:13][CH:14]=1)#[N:2]
Reactant: Cc1cc(Cl)n2nccc2n1
Reactant: CCCNCc1ccc(-c2ccccc2C#N)cc1
Agent: N#Cc1ccccc1-c1ccc(CBr)cc1
Solvent: CCO
Solvent: CCCN
Product: CCCN(Cc1ccc(-c2ccccc2C#N)cc1)c1cc(C)nc2ccnn12

Procedure:
2.5 g (10.0 mmol) of N-(2'-cyanobiphenyl-4-yl)methyl-N-propyl amine (prepared from n-propylamine and 4-bromomethyl-2'-cyanobiphenyl by the method described in EP 490 820) and 1.8 g (10.7 mmol) 7-chloro-5-methylpyrazolo[1,5-a]pyrimidine (prepared according to Y. Makisumi, Chem. Pharm. Bull. 1962, 10, 620) were heated with reflux in 20 ml dry ethanol for 4 h. The mixture was concentrated to halve of the volume in vacuo and cooled with ice, while the remaining starting amine crystallized. It was filtered with suction, and the rest of the solvent was removed. The title compound was obtained from the residue after column chromatography (silica gel, acetone / hexane 1:9 and 2:3) as a yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([N+:17]([O-])=O)[CH:15]=3)[N:10](COCCOC)[N:9]=2)=[CH:4][CH:3]=1.[CH:26](=O)[CH3:27]>C(O)C.[Pd].[C]>[CH2:26]([NH:17][C:14]1[CH:15]=[C:16]2[C:11](=[CH:12][CH:13]=1)[NH:10][N:9]=[C:8]2[C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=1)[CH3:27]
Reactant: COCCOCn1nc(-c2ccc(F)cc2)c2cc([N+](=O)[O-])ccc21
Reactant: CC=O
Agent: [Pd]
Solvent: CCO
Product: CCNc1ccc2[nH]nc(-c3ccc(F)cc3)c2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 11 %

Procedure:
To a solution of 1-{[3-(4-fluorophenyl)-5-nitro(1H-indazolyl)]methoxy}-2-methoxyethane (100 mg, 0.29 mmol) in ethanol (30 mL, containing a contaminant of acetaldehyde) was added a scoup of Pd/carbon. The reaction was stirred overnight at room temperature under an atmosphere of hydrogen. It was filtered over celite and the solution concentrated to an oil. The oil was taken up in methanol (20 mL) and 6N HCl (20 mL) and heated to 75° C. for 3 hours. The solution was concentrated under vacuo, added to saturated bicarbonate (100 mL), and extracted with ethyl acetate (3×30 mL). The organic layers were dried (Na2SO4), concentrated to an oil and chromatographed on silica gel, eluting with 50% ethyl acetate/hexane to give the title compound (8 mg, 11% yield). 1H NMR (CDCl3) δ 10.4 (br s, 1H), 7.91 (dd, 2H), 7.26–7.17 (m, 3H), 6.99 (s, 1H), 6.84 (dd, 1H), 3.21 (q, 2H), 1.31 (t, 3H); ES-MS (m/z) 256 [M+1]+.
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([O:10][C:11]2[CH:22]=[CH:21][C:14]3[S:15][C:16]([C:18](O)=[O:19])=[CH:17][C:13]=3[CH:12]=2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2].Cl.[F:24][C:25]1([F:31])[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(C(C)C)C(C)C)C>C1COCC1>[F:24][C:25]1([F:31])[CH2:30][CH2:29][N:28]([C:18]([C:16]2[S:15][C:14]3[CH:21]=[CH:22][C:11]([O:10][CH:7]4[CH2:6][CH2:5][N:4]([CH:1]([CH3:3])[CH3:2])[CH2:9][CH2:8]4)=[CH:12][C:13]=3[CH:17]=2)=[O:19])[CH2:27][CH2:26]1
Reactant: CC(C)N1CCC(Oc2ccc3sc(C(=O)O)cc3c2)CC1
Reactant: FC1(F)CCNCC1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(C)N1CCC(Oc2ccc3sc(C(=O)N4CCC(F)(F)CC4)cc3c2)CC1
Yield: 64.7 %

Procedure:
In a flask were mixed together the above prepared 5-(1-isopropyl-piperidin-4-yloxy)-benzo[b]thiophene-2-carboxylic acid (0.128 g, 0.333 mmol, corrected for purity), 4,4-difluoropiperidine hydrochloride (0.063 g, 1.2 eq.), (benzotriazol-1-yloxy)-tris-(dimethylamino)phosphonium hexafluorophosphate (0.181 g, 1.23 eq.) and 2.4 eq. of N-ethyldiisopropylamine (0.225 mL) in 1.3 mL of abs. THF and allowed to react during one night at ambient temperature. Pouring onto crashed ice/AcOEt/NH4Cl-solution, twofold extraction with AcOEt, washing with water, drying over sodium sulfate, and evaporation of the solvents, followed by flash chromatography (SiO2, NEt3/AcOEt=4/96) produced 0.091 g of the title compound as light yellow solid.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[O:10][CH2:11][CH3:12].C(=O)([O-])[O-].[K+].[K+].Br[CH2:20][C:21]([O:23]C(C)(C)C)=[O:22]>CN(C=O)C>[CH:6]([C:5]1[CH:8]=[CH:9][C:2]([O:1][CH2:20][C:21]([OH:23])=[O:22])=[C:3]([O:10][CH2:11][CH3:12])[CH:4]=1)=[O:7]
Reactant: CCOc1cc(C=O)ccc1O
Reactant: CC(C)(C)OC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOc1cc(C=O)ccc1OCC(=O)O
Yield: 120.2 %

Procedure:
4-Hydroxy-3-ethoxybenzaldehyde (5.0 g, 36 mmol), potassium carbonate (5.0 g, 36 mmol), and t-butyl bromoacetate (5.9 mL, 36 mmol) were heated to 55° C. overnight in DMF (35 mL). After removal of solvent, the mixture was extracted with EtOAc and water, then brine. After drying (Na2SO4), solvent was removed no yield a white solid (9.7 g). mp 90°-92.6° C. MS(NH3): 298 (base, M+NH4).
Reaction SMILES: [C:1]([OH:6])(=O)[C:2]([CH3:4])=[CH2:3].C(OC(Cl)=O)C.C(N(CC)CC)C.[CH:20]1[C:25]([NH2:26])=[CH:24][CH:23]=[C:22]([OH:27])[CH:21]=1.Cl>C(#N)C>[OH:27][C:22]1[CH:23]=[CH:24][C:25]([NH:26][C:1](=[O:6])[C:2]([CH3:4])=[CH2:3])=[CH:20][CH:21]=1
Reactant: C=C(C)C(=O)O
Reactant: Nc1ccc(O)cc1
Agent: CCOC(=O)Cl
Agent: Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: C=C(C)C(=O)Nc1ccc(O)cc1
Reaction time: 1 h
Yield: 56.1 %

Procedure:
Into a 1 liter flask 600 ml of acetonitrile, 95.2 g (1.1 mol) of methacrylic acid and 120.1 g (1.1 mol) of chloroformic acid ethyl ester were added. To this mixture 111.8 g (1.1 mol) of triethylamine was added over a period of 1 hour in cool bath. Stirring was continued for 1 hour at room temperature and 120.0 g (1 mol) of p-aminophenol was added. The mixture was heated for 5 hours at 5020 C. The mixture was poured into 5 liter of 1% HCl solution. The deposit was filtered, washed and dried to produce 99.35 g of N-(4-Hydroxyphenyl)methacrylamide.
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[C:6]([OH:11])[CH:5]=1)([O-:3])=[O:2].[Br:12][C:13]1[CH:18]=[C:17]([Br:19])[CH:16]=[CH:15][C:14]=1[N:20]=[C:21]=[O:22]>>[OH:11][C:6]1[CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:10]=[CH:9][C:7]=1[NH:8][C:21]([NH:20][C:14]1[CH:15]=[CH:16][C:17]([Br:19])=[CH:18][C:13]=1[Br:12])=[O:22]
Reactant: O=C=Nc1ccc(Br)cc1Br
Reactant: Nc1ccc([N+](=O)[O-])cc1O
Product: O=C(Nc1ccc([N+](=O)[O-])cc1O)Nc1ccc(Br)cc1Br
Yield: 39.4 %

Procedure:
The urea was prepared from 4-nitro 2-hydroxy aniline (308 mg, 2 mmol) and 2,4-dibromo phenyl isocyanate (2 mmol) by general Method B. It was purified by dilution with methylene chloride and precipitation with hexane. Filtering afforded the title compound (0.34 g, 39%). EI-MS m/z 430 (M+H)+
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:10][C:11]3[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=3[CH:13]=2)=[CH:5][CH:4]=1.[C:18]1([CH3:27])[CH:23]=[CH:22][C:21]([C:24](Cl)=[O:25])=[CH:20][CH:19]=1.C(Cl)Cl>O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:10][C:11]3[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=3[C:13]=2[C:24](=[O:25])[C:21]2[CH:22]=[CH:23][C:18]([CH3:27])=[CH:19][CH:20]=2)=[CH:5][CH:4]=1
Reactant: Cc1ccc(C(=O)Cl)cc1
Reactant: COc1ccc(-c2cc3ccccc3o2)cc1
Solvent: ClCCl
Solvent: O
Product: COc1ccc(-c2oc3ccccc3c2C(=O)c2ccc(C)cc2)cc1
Reaction time: 1.5 h

Procedure:
To a cooled (0°) mixture of 4.07 g. (0.018 mol.) of 2-p-methoxyphenylbenzofuran and 4.17 g. (0.027 mol.) of p-toluic acid chloride in 100 ml. of methylene chloride was added dropwise 11.25 g. (0.043 mol.) of stannic chloride. The reaction mixture was stirred for 1.5 hours at 0°, then for 0.5 hour at 25 °. The mixture was poured into water and stirred vigorously, the layers were separated and the organic phase was washed with saturated aqueous sodium bicarbonate, dried (MgSO4) and concentrated to give 2-p-methoxyphenyl-3-p-methylbenzoylbenzofuran.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([CH2:7][CH2:8][CH2:9][C:10]2[N:11]([CH2:38][CH2:39][CH3:40])[N:12]=[C:13]3[C:22]=2[C:21]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[N:15]=[C:14]3[N:23](C(OC(C)(C)C)=O)C(OC(C)(C)C)=O)[O:4][N:3]=1.[OH-].[K+]>Cl.C(O)C.O.[OH-].[K+]>[CH3:1][C:2]1[CH:6]=[C:5]([CH2:7][CH2:8][CH2:9][C:10]2[N:11]([CH2:38][CH2:39][CH3:40])[N:12]=[C:13]3[C:22]=2[C:21]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[N:15]=[C:14]3[NH2:23])[O:4][N:3]=1
Reactant: CCCn1nc2c(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)nc3ccccc3c2c1CCCc1cc(C)no1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCCn1nc2c(N)nc3ccccc3c2c1CCCc1cc(C)no1
Temperature: 25 °C
Yield: 41.1 %

Procedure:
A solution of di(tert-butyl) 1-[3-(3-methylisoxazol-5-yl)propyl]-2-propyl-2H-pyrazolo[3,4-c]quinolin-4-ylimidodicarbonate (0.471 g, 0.856 mmol) in 6 M HCl in ethanol (5 mL) was heated at 60° C. for 1 hour. The solution was allowed to cool to room temperature, then was concentrated under reduced pressure to yield an oil that was dissolved in water (20 mL). The solution was adjusted to pH 12 with a few drops of 50% aqueous potassium hydroxide and then to pH 14 with 1 M aqueous potassium hydroxide. A precipitate formed that was isolated by filtration and crystallized from ethyl acetate/hexanes. The crystals were isolated by filtration and dried under vacuum at 70° C. to afford 0.123 g 1-[3-(3-methylisoxazol-5-yl)propyl]-2-propyl-2H-pyrazolo[3,4-c]quinolin-4-amine as white needles, mp 183.0-184.0° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([C:12](O)=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1N=CN(C(N2C=NC=C2)=O)C=1.[CH3:27][C:28]1[CH:29]=[C:30]([NH2:35])[C:31]([NH2:34])=[CH:32][CH:33]=1>CN(C=O)C.N1C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([C:12]2[NH:34][C:31]3[CH:32]=[CH:33][C:28]([CH3:27])=[CH:29][C:30]=3[N:35]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CC(C(=O)O)C1
Reactant: Cc1ccc(N)c(N)c1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: Cc1ccc2[nH]c(C3CN(C(=O)OC(C)(C)C)C3)nc2c1
Temperature: 100 °C
Reaction time: 2 h
Yield: 65.1 %

Procedure:
To the mixture of 1-(tert-butoxycarbonyl)azetidine-3-carboxylic acid (4.94 g, 24.6 mmol) in DMF (30 mL) and pyridine (30 mL) was added CDI (4.38 g, 27 mmol) at 45° C. and the mixture was stirred for another 2 h at this temperature. Then 4-methyl-benzene-1,2-diamine (3 g, 24.6 mmol) was added and the mixture was stirred at RT overnight. Solvents were removed in vacuo and the residue was dissolved in HOAc (30 mL) and heated for 1 h at 100° C. Then the reaction mixture was concentrated and the residue was partitioned between DCM and aqueous of Na2CO3. The organic layer was dried over Na2SO4 and concentrated to give the crude product which was purified by column chromatography (ethyl acetate:petroleum ether=1:2) to give the compound (4.6 g, yield 61%) as yellow solid.
Reaction SMILES: [O:1]=[C:2]1[NH:10][C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C@:3]21[CH2:24][C:13]1[CH:14]=[C:15]3[C:20](=[CH:21][C:12]=1[CH2:11]2)[N:19]=[C:18]([CH:22]=[O:23])[CH:17]=[CH:16]3.[BH4-].[Na+]>CO.CS(C)=O>[OH:23][CH2:22][C:18]1[CH:17]=[CH:16][C:15]2[C:20](=[CH:21][C:12]3[CH2:11][C@:3]4([C:4]5[C:5](=[N:6][CH:7]=[CH:8][CH:9]=5)[NH:10][C:2]4=[O:1])[CH2:24][C:13]=3[CH:14]=2)[N:19]=1
Reactant: O=Cc1ccc2cc3c(cc2n1)C[C@]1(C3)C(=O)Nc2ncccc21
Agent: [BH4-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CO
Product: O=C1Nc2ncccc2[C@@]12Cc1cc3ccc(CO)nc3cc1C2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred suspension of (s)-2′-oxo-1′,2′,6,8-tetrahydrospiro[cyclopenta[g]quinoline-7,3′-pyrrolo[2,3-b]pyridine]-2-carbaldehyde (80 mg, 0.25 mmol, described in Intermediate 10) in a mixture of MeOH (5 mL) and DMSO (1 mL) was added sodium borohydride (19 mg, 0.51 mmol). The resulting mixture was stirred at ambient temperature for 1 h, then the MeOH was removed in vacuo. The residue was partitioned between saturated aqueous NaHCO3 (20 mL) and CH2Cl2 (20 mL). The aqueous layer was extracted further with CH2Cl2 (2×20 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated in vacuo to give the title compound in sufficient purity for use in the next step. MS: m/z=318 (M+1).
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[C:11](=[C:12](OS(C(F)(F)F)(=O)=O)[N:13]([CH2:18][CH3:19])[N:14]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[CH3:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1B(O)O>>[CH2:18]([N:13]1[C:12]([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=2[CH3:28])=[C:11]2[C:15]([CH2:16][CH2:17][NH:8][CH2:9][CH2:10]2)=[N:14]1)[CH3:19]
Reactant: Cc1ccccc1B(O)O
Reactant: CCn1nc2c(c1OS(=O)(=O)C(F)(F)F)CCN(C(=O)OC(C)(C)C)CC2
Product: CCn1nc2c(c1-c1ccccc1C)CCNCC2
Yield: 108.5 %

Procedure:
The title compound (138 mg) was prepared according to Example 263 using 206 mg of 2-ethyl-3-trifluoromethanesulfonyloxy-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (Example 193, Step A) and 95 mg of 2-methylphenylboronic acid. MS (ESI): exact mass calculated for C16H21N3, 255.17; found, m/z 256.5 [M+H]+. 1H NMR (500 MHz, CD3OD): 7.49-7.42 (m, 2H), 7.38-7.35 (m, 1H), 7.25-7.24 (m, 1H), 4.69 (br s, 2H), 4.03-3.17 (m, 5H), 2.76-2.68 (m, 2H), 2.15 (s, 3H), 1.28 (t, J=7.2 Hz, 3H).
Reaction SMILES: [CH3:1][N:2]([S:15]([C:18]1[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=1)(=[O:17])=[O:16])[C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12](=[S:14])[NH2:13])=[CH:8]2.[C:24]([O:29][CH2:30][CH3:31])(=[O:28])[C:25]#[C:26][CH3:27].C(P(CCCC)CCCC)CCC.ClCCl>O1CCCC1>[CH3:1][N:2]([S:15]([C:18]1[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=1)(=[O:17])=[O:16])[C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12]1[S:14][CH:26]([CH2:25][C:24]([O:29][CH2:30][CH3:31])=[O:28])[CH2:27][N:13]=1)=[CH:8]2
Reactant: CC#CC(=O)OCC
Reactant: CN(c1cccc2cc(C(N)=S)[nH]c12)S(=O)(=O)c1cccnc1
Agent: CCCCP(CCCC)CCCC
Solvent: C1CCOC1
Solvent: ClCCl
Product: CCOC(=O)CC1CN=C(c2cc3cccc(N(C)S(=O)(=O)c4cccnc4)c3[nH]2)S1
Temperature: 25 °C
Reaction time: 15 h
Yield: 30.2 %

Procedure:
A mixture of 7-[methyl(pyridin-3-ylsulfonyl)amino]-1H-indole-2-carbothioamide (150 mg), ethyl but-2-ynoate (120 mg), tributylphosphine (90 mg), dichloromethane (20 mL) and tetrahydrofuran (40 mL) was stirred at room temperature for 15 hr, and the mixture was stirred at 50° C. for 3 hr. The reaction mixture was concentrated, and the residue was subjected to basic silica gel column chromatography, and eluted with hexane-ethyl acetate (4:1-1:4, volume ratio). The obtained crystals were further subjected to silica gel column chromatography, and eluted with hexane-ethyl acetate (4:1-1:4, volume ratio) to give pale-yellow crystals. The crystals were recrystallized from ethyl acetate-hexane to give the title compound (60 mg, yield 30%) as pale-yellow prism crystals. melting point 146-147° C.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([N:6]=[C:7]([N:19]([CH3:23])[CH:20]([CH3:22])[CH3:21])[C:8]([C:12]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=3)=[N:9]2)=[CH:4][C:3]=1[C:24]([O:26]C)=[O:25].[OH-].[Li+]>O1CCCC1.O>[F:1][C:2]1[CH:11]=[C:10]2[C:5]([N:6]=[C:7]([N:19]([CH3:23])[CH:20]([CH3:22])[CH3:21])[C:8]([C:12]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=3)=[N:9]2)=[CH:4][C:3]=1[C:24]([OH:26])=[O:25]
Reactant: COC(=O)c1cc2nc(N(C)C(C)C)c(-c3ccc(F)cc3)nc2cc1F
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)N(C)c1nc2cc(C(=O)O)c(F)cc2nc1-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 84 %

Procedure:
To a solution of methyl 7-fluoro-2-(4-fluorophenyl)-3-[methyl(propan-2-yl)amino]quinoxaline-6-carboxylate (150 mg, 0.40 mmol) in tetrahydrofuran (30 ml) and water (1.0 ml) was added lithium hydroxide (38.8 mg, 1.62 mmol) with stirring overnight at room temperature. The reaction mixture was concentrated in vacuo, dissolved in water (30 ml), and adjusted to pH 5 with hydrochloric acid (3N) to give the precipitate, which was collected by filtration to afford 7-fluoro-2-(4-fluorophenyl)-3-[methyl(propan-2-yl)amino]quinoxaline-6-carboxylic acid as a light yellow solid (120 mg, 83%).
Reaction SMILES: [Cl:1][C:2]1[C:3](=[O:10])[NH:4][C:5]([CH3:9])=[CH:6][C:7]=1[OH:8].C1CCN2C(=NCCC2)CC1.[F:22][C:23]1[CH:30]=[C:29]([F:31])[CH:28]=[CH:27][C:24]=1[CH2:25]Br>CN1C(=O)CCC1>[Cl:1][C:2]1[C:3](=[O:10])[NH:4][C:5]([CH3:9])=[CH:6][C:7]=1[O:8][CH2:25][C:24]1[CH:27]=[CH:28][C:29]([F:31])=[CH:30][C:23]=1[F:22]
Reactant: Cc1cc(O)c(Cl)c(=O)[nH]1
Reactant: Fc1ccc(CBr)c(F)c1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN1CCCC1=O
Product: Cc1cc(OCc2ccc(F)cc2F)c(Cl)c(=O)[nH]1
Temperature: 80 °C
Yield: 12.8 %

Procedure:
3-Chloro-4-hydroxy-6-methyl-1H-pyridin-2-one (19.2 g, 0.12 mol) and DBU (19.9 mL, 0.13 mol) were dissolved in 70 mL of NMP. 2,4-Difluorobenzylbromide (17 mL, 0.13 mol) was added dropwise and the reaction was heated at 80° C. for 6 hours. The reaction was cooled to room temperature, the solid was filtered, and washed with NMP and hexanes. The solid was dried in a vacuum oven overnight to give a white solid (4.4 g, 13%): 1H NMR (300 MHz, DMSO-d6) δ 11.88 (br s, 1H), 7.63 (app q, J=9 Hz, 1H), 7.33 (app t, J=10 Hz, 1H), 7.16 (app t, J=9 Hz, 1H), 6.37 (s, 1H), 5.24 (s, 2H), 2.20 (s, 3H).
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[CH:7][CH:6]=1.[Li]CCCC.CN([CH:23]=[O:24])C.O>CCOCC>[CH3:1][O:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]([F:12])([F:13])[F:14])=[CH:7][C:6]=1[CH:23]=[O:24]
Reactant: COCOc1ccc(C(F)(F)F)cc1
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: O
Product: COCOc1ccc(C(F)(F)F)cc1C=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 79 %

Procedure:
To the solution of 4-(trifluoromethyl)phenyl methoxymethyl ether (5 g) in anhydrous ether (50 ml) was gradually added dropwise 1.6M n-BuLi (16.7 ml) at room temperature. After stirring at room temperature for 2 hours, the solution of DMF (4.13 ml) in anhydrous ether (20 ml) was added dropwise over 30 minutes, and the solution was stirred for 1 hour. To the reaction solution was added water, and the ether layer was separated. The ether layer is was washed with water and saturated sodium chloride solution, and dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The resulting residue was purified by chromatography on a silica gel column (methylene chloride:hexane=1:1), to give the title compound (4.49 g; 79%).
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1B(O)O.Cl[C:16]1[N:21]=[C:20]([N:22]2[C:26]([CH3:27])=[CH:25][C:24]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[N:23]2)[CH:19]=[CH:18][CH:17]=1.C(O)CC.C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1>[CH3:27][C:26]1[N:22]([C:20]2[CH:19]=[CH:18][CH:17]=[C:16]([C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[O:3][C:2]([F:14])([F:13])[F:1])[N:21]=2)[N:23]=[C:24]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH:25]=1
Reactant: CCOC(=O)c1cc(C)n(-c2cccc(Cl)n2)n1
Reactant: OB(O)c1ccccc1OC(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCCO
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cc(C)n(-c2cccc(-c3ccccc3OC(F)(F)F)n2)n1
Temperature: 90 °C
Reaction time: 16 h
Yield: 12.3 %

Procedure:
To the solution of 2-trifluoromethoxyphenyl boronic acid (0.192 g, 0.92 mmol) and the 2-chloropyridine compound from Step 1 (0.165 g, 0.62 mmol) in toluene:n-propanol (3 mL:3 mL) were added tetrabis(triphenylphosphine)palladium (0.072 g, 0.062 mmol) and aqueous sodium bicarbonate (2.0M, 0.62 mL, 1.2 mmol). The reaction mixture was stirred at 90° C. for 16 hours. After cooling to room temperature, the mixture was filtered through a Celite pad, and washed with ethyl acetate (3 times). The filtrate was concentrated. The resulting residue was dissolved in ethyl acetate and washed with saturated sodium carbonate aqueous solution and brine, the organic layer was dried over anhydrous sodium sulfate. After concentration, the crude product was applied to column chromatography on silica gel to afford the titled compound, as yellow oil, 30 mg, 12.3% yield.