Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([Br:17])=[C:4]2[N:11]([OH:12])[C:10]([C:13]([F:16])([F:15])[F:14])=[N:9][C:5]2=[N:6][C:7]=1[Br:8].[CH3:18][N:19]=[C:20]=[O:21].C(N(CC)CC)C>C(OCC)C>[CH3:18][NH:19][C:20]([O:12][N:11]1[C:4]2[C:5](=[N:6][C:7]([Br:8])=[C:2]([Cl:1])[C:3]=2[Br:17])[N:9]=[C:10]1[C:13]([F:14])([F:16])[F:15])=[O:21]
Reactant: On1c(C(F)(F)F)nc2nc(Br)c(Cl)c(Br)c21
Reactant: CN=C=O
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CNC(=O)On1c(C(F)(F)F)nc2nc(Br)c(Cl)c(Br)c21

Procedure:
6-Chloro-5,7-dibromo-1-hydroxy-2-(trifluoromethyl)-1H-imidazo(4,5-b)pyridine (0.9 gram) was mixed with ether (15 milliliters) and methyl isocyanate (2 milliliters) and stirred for fifteen minutes. Triethylamine (0.01 milliliter) was added, and the solution became homogenous. It was permitted to stand for sixteen hours, diluted with 50 milliliters diethyl ether; washed with 0.5N HCl, water, and saturated NaCl; then dried over magnesium sulfate, and evaporated. The resulting 1-(methylcarbamoyloxy)-6 -chloro-5,7 -dibromo-2-(trifluoromethyl)-1H-imidazo(4,5-b)pyridine product was recrystallized from chloroform, m.p., 216° C.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH2:6][NH:7][C:8]2=[O:13])([O-])=O.C([O-])=O.[NH4+]>CO.[Pd]>[NH2:1][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH2:6][NH:7][C:8]2=[O:13]
Reactant: O=C1NCc2c1cccc2[N+](=O)[O-]
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: Nc1cccc2c1CNC2=O
Temperature: 35 °C
Reaction time: 2 h
Yield: 92 %

Procedure:
A mixture of 4-nitro-2,3-dihydro-1H-isoindol-1-one (20 g), ammonium formate (35 g) and 7.5% Pd/C (0.6 g) in methanol (60 ml) was stirred for 2 hours by heating up to 35° C. Pd/C was filtered and the filtrate concentrated under reduced pressure. The residue was recrystallized from water to give 15.3 g of light yellow solid. yield: 92%. mp: 195.6-197° C.
Reaction SMILES: [CH3:1][CH:2]([C:5]1[C:17]([OH:18])=[C:16]2[C:8]([CH:9]3[CH:14]([CH:15]2[NH:19][CH3:20])[CH2:13][CH2:12][CH2:11][CH2:10]3)=[C:7]([CH3:21])[CH:6]=1)[CH:3]=[CH2:4].Cl.[C:23](Cl)(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[N:26][CH:25]=1>N1C=CC=CC=1>[CH3:1][CH:2]([C:5]1[C:17]([OH:18])=[C:16]2[C:8]([CH:9]3[CH:14]([CH:15]2[N:19]([CH3:20])[C:23](=[O:30])[C:24]2[CH:29]=[CH:28][CH:27]=[N:26][CH:25]=2)[CH2:13][CH2:12][CH2:11][CH2:10]3)=[C:7]([CH3:21])[CH:6]=1)[CH:3]=[CH2:4]
Reactant: C=CC(C)c1cc(C)c2c(c1O)C(NC)C1CCCCC21
Reactant: O=C(Cl)c1cccnc1
Agent: Cl
Solvent: c1ccncc1
Product: C=CC(C)c1cc(C)c2c(c1O)C(N(C)C(=O)c1cccnc1)C1CCCCC21
Temperature: 25 °C
Reaction time: 5 h
Yield: 51.2 %

Procedure:
To 1.5 ml of pyridine were added 1.0 g of 7-(1-methyl-2-propenyl)-8-hydroxy-5-methyl-9-methylamino-1,2,3,4,4a,9a-hexahydrofluorene and 0.7 g of nicotinoylchloride hydrochloride, followed by stirring at room temperature for 5 hours. The reaction mixture was concentrated and then extracted with chloroform. The chloroform layer was washed with water, dried with sodium sulfate and then concentrated. The residue was purified by a silica gel column chromatography (eluent: ethyl acetate) and then recrystallized from ethyl acetate-n-hexane to obtain 0.7 g of 7-(1-methyl-2-propenyl)-8-hydroxy-5-methyl-9-(N-methyl-N-nicotinoylamino)- 1,2,3,4,4a,9a-hexahydrofluorene having a melting point of 183°-184° C. and of colorless powdery crystal.
Reaction SMILES: [I-].[Na+].Br[CH2:4][CH2:5][CH2:6][O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[CH2:15]([CH2:17][NH2:18])[OH:16]>C(O)C>[CH2:8]([O:7][CH2:6][CH2:5][CH2:4][NH:18][CH2:17][CH2:15][OH:16])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: BrCCCOCc1ccccc1
Reactant: NCCO
Agent: [I-]
Agent: [Na+]
Solvent: CCO
Product: OCCNCCCOCc1ccccc1
Temperature: 25 °C
Yield: 90 %

Procedure:
Sodium iodide (1.67 g, 11.1 mmol) was added to a solution of benzyl 3-bromopropyl ether (26.0 g, 111 mmol) and ethanolamine (35.0 g, 556 mmol) in ethanol (250 ml). The reaction mixture was heated at reflux for 1 h, then cooled to room temperature and evaporated under vacuum. The residue was partitioned between sat. aq. ammonium chloride solution and ethyl acetate. The aqueous layer was basified with 40% aq. sodium hydroxide solution and extracted three times with ethyl acetate. The organic phases were pooled, dried (MgSO4), filtered, and evaporated to afford the title compound (20.9 g, 90%). Light yellow liquid, MS (ISP)=210.2 (M+H)+.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][N:9]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[S:11][C:10]2=[NH:18])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[C:19]12([C:29](O)=[O:30])[CH2:28][CH:23]3[CH2:24][CH:25]([CH2:27][CH:21]([CH2:22]3)[CH2:20]1)[CH2:26]2>>[N:1]1([CH2:7][CH2:8][N:9]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[S:11]/[C:10]/2=[N:18]\[C:29]([C:19]23[CH2:28][CH:23]4[CH2:22][CH:21]([CH2:27][CH:25]([CH2:24]4)[CH2:26]2)[CH2:20]3)=[O:30])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: O=C(O)C12CC3CC(CC(C3)C1)C2
Reactant: N=c1sc2ccccc2n1CCN1CCOCC1
Product: O=C(/N=c1\sc2ccccc2n1CCN1CCOCC1)C12CC3CC(CC(C3)C1)C2
Yield: 25.4 %

Procedure:
The product of Example 108A (0.20 g, 0.76 mmol) and adamantane-1-carboxylic acid (0.15 g, 0.84 mmol) were processed according to the method of Example 77B. Purification by column chromatography (SiO2, 0-30% methanol/methylene gradient) afforded 82 mg (25%) of the title compound. 1H NMR (CDCl3, 300 MHz) δ ppm 1.67-1.82 (m, 6 H), 1.99 (d, J=2.7 Hz, 6 H), 2.06 (s, 3 H), 2.62 (s, 4 H), 2.78 (s, 2 H), 3.70 (s, 4 H), 4.53 (s, 2 H), 7.22-7.37 (m, 2 H), 7.43 (t, J=7.6 Hz, 1 H), 7.65 (d, J=7.8 Hz, 1 H); MS (DCI/NH3) m/z 426 (M+H)+. Anal. Calculated for C24H31N3O2S.0.2H2O: C, 67.16; H, 7.37; N, 9.79. Found: C, 66.92; H, 7.59; N, 9.83.
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[CH:8][C:7]([C:10]([N:12]2[CH2:17][CH2:16][N:15]([C:18]3[C:23]([NH:24][CH2:25][CH3:26])=[CH:22][CH:21]=[CH:20][N:19]=3)[CH2:14][CH2:13]2)=[O:11])=[N:6][CH:5]=1>CO.C(N)(C)C>[CH2:25]([NH:24][C:23]1[C:18]([N:15]2[CH2:16][CH2:17][N:12]([C:10]([C:7]3[CH:8]=[CH:9][C:4]([C:3](=[O:2])[NH:6][CH:7]([CH3:10])[CH3:8])=[CH:5][N:6]=3)=[O:11])[CH2:13][CH2:14]2)=[N:19][CH:20]=[CH:21][CH:22]=1)[CH3:26]
Reactant: CCNc1cccnc1N1CCN(C(=O)c2ccc(C(=O)OC)cn2)CC1
Solvent: CC(C)N
Solvent: CO
Product: CCNc1cccnc1N1CCN(C(=O)c2ccc(C(=O)NC(C)C)cn2)CC1
Yield: 74 %

Procedure:
6-[1-[3-(ethylamino)-2-pyridyl]piperazin-4-yl-carbonyl]nicotinic acid methyl ester (2 g) was dissolved in methanol (25 ml) and with the addition of isopropylamine (5 ml), the mixture was heated to reflux for 12 hours. The mixture was concentrated under reduced pressure to remove the solvent. The residue was treated with ether for crystallization, and the solid was recrystallized with chloroform and hexane to give a desired compound of 1.59 g (yield: 74%).
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C:3]1[CH:4]=[C:5]([CH:29]=[CH:30][CH:31]=1)[CH2:6][NH:7][C:8](=[O:28])[C:9]1[CH:14]=[CH:13][N:12]=[C:11]([C:15]2[CH:20]=[C:19]([N:21]([CH2:25][CH3:26])[CH2:22][CH2:23][CH3:24])[CH:18]=[CH:17][C:16]=2[NH2:27])[CH:10]=1.[CH3:34][N:35]([CH2:47][CH2:48][N:49]1[CH2:54][CH2:53][O:52][CH2:51][CH2:50]1)[C:36]([C:38]1[CH:39]=[C:40]([CH:44]=[CH:45][CH:46]=1)[C:41](O)=[O:42])=[O:37].CCN=C=NCCCN(C)C.Cl>ClCCl.CN(C)C1C=CN=CC=1.C(OCC)(=O)C>[F:33][C:2]([F:32])([F:1])[C:3]1[CH:4]=[C:5]([CH:29]=[CH:30][CH:31]=1)[CH2:6][NH:7][C:8]([C:9]1[CH:14]=[CH:13][N:12]=[C:11]([C:15]2[CH:20]=[C:19]([N:21]([CH2:25][CH3:26])[CH2:22][CH2:23][CH3:24])[CH:18]=[CH:17][C:16]=2[NH:27][C:41](=[O:42])[C:40]2[CH:44]=[CH:45][CH:46]=[C:38]([C:36]([N:35]([CH3:34])[CH2:47][CH2:48][N:49]3[CH2:50][CH2:51][O:52][CH2:53][CH2:54]3)=[O:37])[CH:39]=2)[CH:10]=1)=[O:28]
Reactant: CN(CCN1CCOCC1)C(=O)c1cccc(C(=O)O)c1
Reactant: CCCN(CC)c1ccc(N)c(-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCCN(CC)c1ccc(NC(=O)c2cccc(C(=O)N(C)CCN3CCOCC3)c2)c(-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.8 %

Procedure:
Into a 50-mL round-bottom flask, was placed a solution of N-(3-(trifluoromethyl)benzyl)-2-(2-amino-5-(ethyl(propyl)amino)phenyl)isonicotinamide (150 mg, 0.30 mmol, 1.00 equiv, 90%) in dichloromethane (8 mL), 3-(methyl(2-morpholinoethyl)carbamoyl)benzoic acid (144 mg, 0.44 mmol, 1.50 equiv, 90%), EDC.HCl (126 mg, 0.66 mmol, 2.00 equiv), 4-dimethylaminopyridine (80 mg, 0.66 mmol, 2.00 equiv). The resulting solution was stirred overnight at room temperature. The resulting solution was diluted with 100 mL of ethyl acetate. The resulting mixture was washed with 2×20 mL of NH4Cl aq. and 1×20 mL of sodium bicarbonate (10%). The resulting mixture was washed with 1×20 mL of brine. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. The crude product (250 mg) was purified by Prep-HPLC with the following conditions (1#-Waters 2767-3): Column, SunFire Prep C18, 19*150 mm 5 um; mobile phase, water with 0.05% TFA and CH3CN (25% CH3CN up to 39% in 6 min); Detector, Waters2545 UvDector 254&270 nm. 183.7 mg product was obtained. This resulted in 183.7 mg (56%) of N1-(2-(4-((3-(trifluoromethyl)benzyl)carbamoyl)pyridin-2-yl)-4-(ethyl(propyl)amino)phenyl)-N3-methyl-N3-(2-morpholinoethyl)isophthalamide as a yellow solid. LC-MS (ES, m/z) 731 [M+H]+; H-NMR (300 MHz, DMSO, ppm): 9.83 (s, 1H), 9.52 (t, J=18 Hz, 1H), 8.89 (d, J=3 Hz, 1H), 8.26 (s, 1H), 8.13 (s, 1H), 7.99 (m, 2H), 7.82 (d, 1H), 7.54-7.69 (m, 6H), 6.95-7.54 (m, 2H), 4.60 (s, 2H), 3.85-4.02 (m, 4H), 3.64 (m, 4H), 3.36-3.47 (m, 6H), 3.18 (m, 2H), 2.95 (s, 3H), 1.60 (m, 2H), 1.09-1.13 (m, 3H), 0.87-0.92 (m, 3H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][S:4][CH2:5][C:6]1[O:10][C:9]([CH2:11][N:12]([CH3:14])[CH3:13])=[C:8]([CH3:15])[CH:7]=1.[CH3:16][NH:17][C:18](SC)=[CH:19][N+:20]([O-:22])=[O:21]>>[CH3:13][N:12]([CH2:11][C:9]1[O:10][C:6]([CH2:5][S:4][CH2:3][CH2:2][NH:1][C:18]([NH:17][CH3:16])=[CH:19][N+:20]([O-:22])=[O:21])=[CH:7][C:8]=1[CH3:15])[CH3:14]
Reactant: Cc1cc(CSCCN)oc1CN(C)C
Reactant: CNC(=C[N+](=O)[O-])SC
Product: CNC(=C[N+](=O)[O-])NCCSCc1cc(C)c(CN(C)C)o1
Yield: 27.2 %

Procedure:
A mixture of 5-[[2-(amino)-ethyl]thio]methyl-N,N,3-trimethyl-2-furanmethanamine (1.15 g) and N-methyl-1-(methylthio)-2-nitroethenamine (0.76 g) was heated in vacuo for 4 hours. The reaction mixture was purified by column chromatography (silica/methanol:0.88 ammonia 79:1) affording the title compound (0.45 g).
Reaction SMILES: [CH:1]([CH:3]([C:6]#[C:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH2:4]O)=[CH2:2].[C:14]1(=[O:24])[NH:18][C:17](=[O:19])[C:16]2=[CH:20][CH:21]=[CH:22][CH:23]=[C:15]12.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1(C)C=CC=CC=1>[CH:1]([CH:3]([C:6]#[C:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH2:4][N:18]1[C:14](=[O:24])[C:15]2[C:16](=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:17]1=[O:19])=[CH2:2]
Reactant: C=CC(C#Cc1ccccc1)CO
Reactant: O=C1NC(=O)c2ccccc21
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: C=CC(C#Cc1ccccc1)CN1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 31.8 %

Procedure:
55 ml of toluene, 1.80 g of 2-vinyl-4-phenyl-3-butyn-ol, 1.93 g of phthalimide, and 3.45 g of triphenylphosphine were added to a nitrogen-substituted flask. Then, 5.30 g of diethyl azodicarboxylate (40% toluene solution) was slowly added dropwise to the above obtained solution under cooling on ice. The temperature was increased to a room temperature, and the obtained mixture was then stirred for 1 day. Thereafter, the reaction solution was concentrated, and 200 ml of diethyl ether was then added to the residue. The appearing solid was removed by filtration. The residue was concentrated, and it was then purified by flash chromatography (manufactured by Biotage AB; Isolera™), so as to obtain 1.00 g of 2-(2-vinyl-4-phenyl-3-butynyl)isoindol-1,3-dione.
Reaction SMILES: [C:1]([CH2:3][C:4]1([N:8]2[CH:12]=[C:11]([C:13]3[CH:18]=[N:17][N:16]4[C:19]([C:22]5[CH:23]=[C:24]([NH:28][C:29]([NH:31][CH2:32][C:33]([F:36])([F:35])[F:34])=[O:30])[CH:25]=[CH:26][CH:27]=5)=[CH:20][N:21]=[C:15]4[CH:14]=3)[CH:10]=[N:9]2)[CH2:7][NH:6][CH2:5]1)#[N:2].[CH3:37][C:38]1[O:42][N:41]=[CH:40][C:39]=1[S:43](Cl)(=[O:45])=[O:44]>>[C:1]([CH2:3][C:4]1([N:8]2[CH:12]=[C:11]([C:13]3[CH:18]=[N:17][N:16]4[C:19]([C:22]5[CH:23]=[C:24]([NH:28][C:29]([NH:31][CH2:32][C:33]([F:35])([F:36])[F:34])=[O:30])[CH:25]=[CH:26][CH:27]=5)=[CH:20][N:21]=[C:15]4[CH:14]=3)[CH:10]=[N:9]2)[CH2:5][N:6]([S:43]([C:39]2[CH:40]=[N:41][O:42][C:38]=2[CH3:37])(=[O:45])=[O:44])[CH2:7]1)#[N:2]
Reactant: Cc1oncc1S(=O)(=O)Cl
Reactant: N#CCC1(n2cc(-c3cnn4c(-c5cccc(NC(=O)NCC(F)(F)F)c5)cnc4c3)cn2)CNC1
Product: Cc1oncc1S(=O)(=O)N1CC(CC#N)(n2cc(-c3cnn4c(-c5cccc(NC(=O)NCC(F)(F)F)c5)cnc4c3)cn2)C1

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 73, Step 4 starting from N-[3-(7-{1-[3-(cyanomethyl)azetidin-3-yl]-1H-pyrazol-4-yl}imidazo[1,2-b]pyridazin-3-yl)phenyl]-N′-(2,2,2-trifluoroethyl)urea and 5-methylisoxazole-4-sulfonyl chloride. LCMS (M+H)+: m/z=641.2.
Reaction SMILES: [CH:1]1([N:4]2[C:8]([N:9]3[CH2:15][CH2:14][CH:13]([O:16][CH3:17])[CH:12]([NH:18]C(=O)OC(C)(C)C)[CH2:11][CH2:10]3)=[C:7]([N+:26]([O-])=O)[CH:6]=[N:5]2)[CH2:3][CH2:2]1.C(OC([NH:36][C:37]1[S:41][C:40]([C:42]2[C:47]([F:48])=[CH:46][CH:45]=[CH:44][C:43]=2[F:49])=[N:39][C:38]=1[C:50](O)=[O:51])=O)(C)(C)C>>[NH2:36][C:37]1[S:41][C:40]([C:42]2[C:47]([F:48])=[CH:46][CH:45]=[CH:44][C:43]=2[F:49])=[N:39][C:38]=1[C:50]([NH:26][C:7]1[CH:6]=[N:5][N:4]([CH:1]2[CH2:2][CH2:3]2)[C:8]=1[N:9]1[CH2:15][CH2:14][C@@H:13]([O:16][CH3:17])[C@@H:12]([NH2:18])[CH2:11][CH2:10]1)=[O:51]
Reactant: CC(C)(C)OC(=O)Nc1sc(-c2c(F)cccc2F)nc1C(=O)O
Reactant: COC1CCN(c2c([N+](=O)[O-])cnn2C2CC2)CCC1NC(=O)OC(C)(C)C
Product: CO[C@@H]1CCN(c2c(NC(=O)c3nc(-c4c(F)cccc4F)sc3N)cnn2C2CC2)CC[C@@H]1N
Yield: 23 %

Procedure:
Following the procedure for Example 101 starting from tert-butyl 1-(1-cyclopropyl-4-nitro-1H-pyrazol-5-yl)-5-methoxyazepan-4-ylcarbamate and 5-(tert-butoxycarbonylamino)-2-(2,6-difluorophenyl)-thiazole-4-carboxylic acid gave 386 as an off-white solid (29 mg, 23% over three steps). 1H NMR (400 MHz, CDCl3) δ 8.96 (s, 1H), 7.86 (s, 1H), 7.36-7.28 (m, 1H), 7.02 (t, J=8.9 Hz, 2H), 6.19-6.10 (m, 2H), 3.50-3.35 (m, 4H), 3.33 (s, 3H), 3.25-3.11 (m, 2H), 2.19-2.05 (m, 1H), 2.03-1.96 (m, 1H), 2.01-1.60 (m, 2H), 1.57 (s, 3H), 1.27-1.12 (m, 2H), 0.97 (d, J=7.1 Hz, 2H). LCMS (ES+) m/z 504 (M+1)
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([Cl:9])[CH:6]=[CH:5][C:3]=1[NH2:4].[C:10]1([CH2:16][O:17][C:18]2[CH:19]=[C:20]([CH2:24][C:25](Cl)=[O:26])[CH:21]=[CH:22][CH:23]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(N(CC)CC)C.C(=O)(O)[O-].[Na+]>ClCCl>[Cl:1][C:2]1[CH:8]=[C:7]([Cl:9])[CH:6]=[CH:5][C:3]=1[NH:4][C:25](=[O:26])[CH2:24][C:20]1[CH:21]=[CH:22][CH:23]=[C:18]([O:17][CH2:16][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:19]=1
Reactant: O=C(Cl)Cc1cccc(OCc2ccccc2)c1
Reactant: Nc1ccc(Cl)cc1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Cc1cccc(OCc2ccccc2)c1)Nc1ccc(Cl)cc1Cl
Reaction time: 3 h
Yield: 69 %

Procedure:
To a solution of 2,4-dichloroaniline (2.67 g, 0.0165 mol) in dichloromethane (20 ml) was slowly added a solution of 2-[3-(phenylmethoxy)phenyl]acetyl chloride (3.84 g, 0.015 mol) in dichloromethane (10 ml). After stirring for three hours, triethylamine (2 ml, 0.015 mol) was added to the reaction and the reaction was allowed to stir overnight. To the reaction was added an aqueous solution of sodium bicarbonate. The mixture was extracted with dichloromethane. The organic layer was washed with brine, dried over MgSO4, filtered and concentrated. The solid was triturated with ether and hexane, then filtered to provide the title compound (4.0 g, 70% yield): ES-MS (m/z) 372 [M+H]+.
Reaction SMILES: C([Li])CCC.[F:6][C:7]1[CH:8]=[C:9]([O:13][CH3:14])[CH:10]=[CH:11][CH:12]=1.CN(C)[CH:17]=[O:18].O>O1CCCC1>[F:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH3:14])[C:8]=1[CH:17]=[O:18]
Reactant: COc1cccc(F)c1
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: COc1cccc(F)c1C=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of butyllithium in hexanes (2.5 M; 15.9 ml) was added to a stirring solution of 3-fluoroanisole (5.0 g) in dry tetrahydrofuran (100 ml) at -78° C. and the mixture stirred at that temperature for 30 min. Dry dimethylformamide (3.1 ml) was added and the mixture stirred and allowed to warm to ambient temperature during one hour. Water (150 ml) was added and the mixture extracted with ethyl acetate (3×100 ml). The combined extracts were washed with brine (100 ml), dried over magnesium sulphate, and the solvent removed in vacuo. Distillation of the residue under reduced pressure gave 2-fluoro-6-methoxybenzaldehyde (4.6 g) as an oil b.p. 120° C. at 10.66 mbar.
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[C:16]3[O:15][CH2:14][CH:13]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[N:12]4[C:23](=O)[NH:24][C:10]([C:11]=34)=[CH:9][CH:8]=2)=[C:5]([CH3:26])[O:4][N:3]=1.P(Cl)(Cl)([Cl:29])=O>>[Cl:29][C:23]1[N:12]2[CH:13]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:14][O:15][C:16]3=[C:11]2[C:10](=[CH:9][CH:8]=[C:7]3[C:6]2[C:2]([CH3:1])=[N:3][O:4][C:5]=2[CH3:26])[N:24]=1
Reactant: Cc1noc(C)c1-c1ccc2[nH]c(=O)n3c2c1OCC3c1ccccc1
Reactant: O=P(Cl)(Cl)Cl
Product: Cc1noc(C)c1-c1ccc2nc(Cl)n3c2c1OCC3c1ccccc1
Temperature: 95 °C
Yield: 99.8 %

Procedure:
To 7-(3,5-dimethylisoxazol-4-yl)-4-phenyl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2(1H)-one (40.0 mg, 0.115 mmol) in a vial, phosphoryl chloride (1.5 mL, 16 mmol) was added and the mixture was heated at 95° C. overnight. The mixture was evaporated and extracted with EtOAc. The extracts were washed with saturated sodium bicarbonate, brine and dried over sodium sulfate. Filtration and evaporation gave the desired compound (42 mg, 100%). LCMS calc. for C20H17ClN3O2 (M+H)+: m/z=366.1. found: 366.1.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][O:9][C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[C:16](=[O:20])[NH:15][C:14](=[O:21])[CH2:13]3)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[C:22]([O:25][C:26](=O)C)(=O)C.COC(OC)OC>CN(C)C=O>[CH3:22][O:25][CH:26]=[C:13]1[C:12]2[C:17](=[CH:18][CH:19]=[C:10]([O:9][CH2:8][CH2:7][N:1]3[CH2:6][CH2:5][O:4][CH2:3][CH2:2]3)[CH:11]=2)[C:16](=[O:20])[NH:15][C:14]1=[O:21]
Reactant: CC(=O)OC(C)=O
Reactant: O=C1Cc2cc(OCCN3CCOCC3)ccc2C(=O)N1
Solvent: CN(C)C=O
Solvent: COC(OC)OC
Product: COC=C1C(=O)NC(=O)c2ccc(OCCN3CCOCC3)cc21

Procedure:
A mixture of 6-(2-morpholin-4-yl-ethoxy)-4H-isoquinoline-1,3-dione (390 mg, 1.34 mmole), 10 mL of a 4:1 mixture of acetic anhydride and N,N-dimethylformamide and trimethylorthoformate (1.1 mL, 10.1 mmole) is stirred and heated to reflux. After 30 minutes the solvents are removed and the residue treated with 2:1 hexanes/ethyl acetate, the product is collected by filtration, a yellow solid, 230 mg, (52%), MS (ES+): m/z 333.2 (M+H), used as is in the next step.
Reaction SMILES: [C:1]([O:5][O:6][C:7]([CH3:13])([CH3:12])[CH2:8][CH:9]([CH3:11])[OH:10])([CH3:4])([CH3:3])[CH3:2].[C:14](Cl)(=[O:18])[C:15]([Cl:17])=[O:16]>>[C:15]([Cl:17])(=[O:16])[C:14]([O:10][CH:9]([CH3:11])[CH2:8][C:7]([O:6][O:5][C:1]([CH3:4])([CH3:3])[CH3:2])([CH3:12])[CH3:13])=[O:18]
Reactant: CC(O)CC(C)(C)OOC(C)(C)C
Reactant: O=C(Cl)C(=O)Cl
Product: CC(CC(C)(C)OOC(C)(C)C)OC(=O)C(=O)Cl
Yield: 98.4 %

Procedure:
In this example the product was prepared in two synthetic steps. In the first step 3-t-butylperoxy-1,3-dimethylbutanol was reacted with 100% molar excess of oxalyl chloride. Upon completion of the reaction the excess oxalyl chloride was stripped from the product at reduced pressure to produce 3-t-butylperoxy-1,3-dimethylbutyl chlorooxalate having an assay of 98.1% and in a corrected yield of 98.4%. In the second step 3-t-butylperoxy-1,3-dimethylbutyl chlorooxalate was reacted with 3-hydroperoxy-1,3-dimethylbutanol in the presence of pyridine to yield the product as described below:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:11])=[C:6]([N:8]=[C:9]=[S:10])[CH:7]=1.[NH2:12][C:13]1[CH:14]=[CH:15][C:16]2[S:20][C:19]([CH3:21])=[N:18][C:17]=2[CH:22]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:11])=[C:6]([NH:8][C:9]([NH:12][C:13]2[CH:14]=[CH:15][C:16]3[S:20][C:19]([CH3:21])=[N:18][C:17]=3[CH:22]=2)=[S:10])[CH:7]=1
Reactant: Cc1ccc(Cl)cc1N=C=S
Reactant: Cc1nc2cc(N)ccc2s1
Product: Cc1nc2cc(NC(=S)Nc3cc(Cl)ccc3C)ccc2s1
Yield: 29.3 %

Procedure:
Prepared using Method A from 4.5 g (24.5 mmol) of 5-chloro-2-methyl-phenyl isothiocyanate and 4.02 g (24.5 mmol) of 5-amino-2-methylbenzothiazole to give 6.0 g of crude material. Soxhlet extraction with EtOAc gave 2.5 g of pure title compound as a tan solid (29% yield, m.p. 173-174° C.).
Reaction SMILES: [OH:1][CH2:2][C:3]1([CH2:20][CH3:21])[CH:12]2[N:7]([CH2:8][CH2:9][C:10]3[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[NH:13][C:11]=32)[CH2:6][CH2:5][CH2:4]1.[CH3:22][O:23][C:24]1[CH:25]=[C:26]([CH:30]=[C:31]([O:35][CH3:36])[C:32]=1[O:33][CH3:34])[C:27](Cl)=[O:28]>N1C=CC=CC=1>[CH3:36][O:35][C:31]1[CH:30]=[C:26]([CH:25]=[C:24]([O:23][CH3:22])[C:32]=1[O:33][CH3:34])[C:27]([O:1][CH2:2][C:3]1([CH2:20][CH3:21])[CH:12]2[N:7]([CH2:8][CH2:9][C:10]3[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[NH:13][C:11]=32)[CH2:6][CH2:5][CH2:4]1)=[O:28]
Reactant: COc1cc(C(=O)Cl)cc(OC)c1OC
Reactant: CCC1(CO)CCCN2CCc3c([nH]c4ccccc34)C21
Solvent: c1ccncc1
Product: CCC1(COC(=O)c2cc(OC)c(OC)c(OC)c2)CCCN2CCc3c([nH]c4ccccc34)C21
Yield: 93.5 %

Procedure:
1.30 g. (4.58 mmoles) of 1-hydroxymethyl-1-ethyl-1,2,3,4,6,7,12,12b-octahydro-indolo[2,3-a]quinolizine and 2.30 g. (10 mmoles) of 3,4,5-trimethoxybenzoyl chloride are dissolved in 15 ml. of absolute pyridine, and the solution is heated on a steam bath for 10 hours under a reflux condenser. The solution is evaporated in vacuo, and the oily residue is stirred first with a 5% sodium hydrocarbonate solution and then with distilled water. The separated solids are filtered off, dried, and recrystallized from methanol. 2.05 g. (93.5%) of the title compound are obtained as white crystals melting at 170°-171° C.
Reaction SMILES: [NH2:1][C:2]1[C:3](Cl)=[N:4][CH:5]=[CH:6][CH:7]=1.[CH3:9][N:10]1CCCC1=O>>[NH2:1][C:2]1[C:3]([C:9]#[N:10])=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1cccnc1Cl
Reactant: CN1CCCC1=O
Product: N#Cc1ncccc1N
Temperature: 185 °C
Reaction time: 2 h

Procedure:
A mixture of 3-Amino-2-chloro-pyridine (5g) and cuprous cyanide (5 g) in 10 mL of N-Methylpyrrolidone was heated with stirring at 185° C. for 2 h under an atmosphere of nitrogen. The reaction mixture was concentrated in vacuo and concentrated ammonium hydroxide and 10% methanol/methylene chloride were added. The mixture was shaken and filtered, the organic layer separated and the aqueous layer extracted two times with methanol/methylene chloride. The combined organic extracts were dried over magnesium sulfate and the solvent removed in vacuo. The residue was recrystallized from ethyl acetate/hexane to afford 3-Amino-2-cyanopyridine as a tan solid.
Reaction SMILES: CON(C)[C:4]([C:6]1[CH:20]=[CH:19][C:9]2[N:10]([CH:13]3[CH2:18][CH2:17][CH2:16][CH2:15][O:14]3)[CH:11]=[N:12][C:8]=2[CH:7]=1)=[O:5].[CH3:22][CH2:23][Mg+].[Br-].[NH4+].[Cl-]>C1COCC1>[O:14]1[CH2:15][CH2:16][CH2:17][CH2:18][CH:13]1[N:10]1[C:9]2[CH:19]=[CH:20][C:6]([C:4](=[O:5])[CH2:22][CH3:23])=[CH:7][C:8]=2[N:12]=[CH:11]1
Reactant: CC[Mg+]
Reactant: CON(C)C(=O)c1ccc2c(c1)ncn2C1CCCCO1
Agent: [Br-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCC(=O)c1ccc2c(c1)ncn2C1CCCCO1
Temperature: 0 °C
Reaction time: 2 h
Yield: 72 %

Procedure:
To the solution of 168 (70 mg, 0.24 mmol) and THF cooled to 0° C. under Ar was added EtMgBr (0.72 mL, 1M solution). The mixture was stirred at 0° C. for 2 h then NH4Cl solution was added carefully. The mixture was extracted with EtOAc, washed sequentially with H2O and brine and dried (Na2SO4), filtered and concentrated in vacuo. The crude product was purified by SiO2 chromatography to afford 45 mg (72%) of 1-[1-(tetrahydro-pyran-2-yl)-1H-benzoimidazol-5-yl]-propan-1-one (170) as a colorless oil.