Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[Cl:18])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C(N(CC)CC)C.[S:26]1[C:30]2[C:31]3[CH:39]=[CH:38][CH:37]=[CH:36][C:32]=3[O:33][CH2:34][CH2:35][C:29]=2[CH:28]=[C:27]1[C:40](Cl)=[O:41]>O1CCCC1>[Si:1]([O:8][CH2:9][CH2:10][N:11]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[Cl:18])[C:40]([C:27]1[S:26][C:30]2[C:31]3[CH:39]=[CH:38][CH:37]=[CH:36][C:32]=3[O:33][CH2:34][CH2:35][C:29]=2[CH:28]=1)=[O:41])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: O=C(Cl)c1cc2c(s1)-c1ccccc1OCC2
Reactant: CC(C)(C)[Si](C)(C)OCCNc1ccccc1Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OCCN(C(=O)c1cc2c(s1)-c1ccccc1OCC2)c1ccccc1Cl
Reaction time: 8 h
Yield: 71.9 %

Procedure:
To a solution of N-(2-(tert-butyldimethylsilyloxy)ethyl)-2-chloroaniline (0.145 g, 0.508 mmol) and triethylamine (0.113 mL, 0.812 mmol) in tetrahydrofuran (1 mL, 10 mmol) was added a solution of 4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2-carbonyl chloride (0.107 g, 0.406 mmol) in tetrahydrofuran (4 mL). The reaction was stirred overnight and concentrated in vacuo. Aqueous work up gave a yellow solid which was purified on silica by MPLC to give 150 mg of N-(2-(tert-butyldimethylsilyloxy)ethyl)-N-(2-chlorophenyl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2-carboxamide.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=O)=[C:4]([Cl:12])[CH:3]=1.[F:13][C:14]1[C:23]2[O:22][CH2:21][C:20](=[O:24])[N:19]([CH3:25])[C:18]=2[CH:17]=[CH:16][CH:15]=1.[Al+3].[Cl-].[Cl-].[Cl-]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([C:16]2[CH:15]=[C:14]([F:13])[C:23]3[O:22][CH2:21][C:20](=[O:24])[N:19]([CH3:25])[C:18]=3[CH:17]=2)=[O:11])=[C:4]([Cl:12])[CH:3]=1
Reactant: O=C(O)Cc1ccc(Br)cc1Cl
Reactant: CN1C(=O)COc2c(F)cccc21
Agent: [Al+3]
Agent: [Cl-]
Product: CN1C(=O)COc2c(F)cc(C(=O)Cc3ccc(Br)cc3Cl)cc21

Procedure:
In analogy to Example 1, step 1, (4-bromo-2-chloro-phenyl)-acetic acid was converted to the acid chloride and reacted with 8-fluoro-4-methyl-4H-benzo[1,4]oxazin-3-one in the presence of AlCl3 to give the title compound as a light-brown solid. MS (m/e, ISP neg. ion)=411.9 [M−H+].
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:15]2[N:20]=[CH:19][N:18]=[C:17]([NH:21][C:22]3[CH:23]=[C:24]([CH:28]=[CH:29][CH:30]=3)[C:25](O)=[O:26])[CH:16]=2)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:31][NH:32][O:33][CH3:34].Cl.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:34][O:33][N:32]([CH3:31])[C:25](=[O:26])[C:24]1[CH:28]=[CH:29][CH:30]=[C:22]([NH:21][C:17]2[CH:16]=[C:15]([NH:14][C:11]3[CH:12]=[CH:13][C:8]([O:1][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)=[CH:9][CH:10]=3)[N:20]=[CH:19][N:18]=2)[CH:23]=1
Reactant: O=C(O)c1cccc(Nc2cc(Nc3ccc(Oc4ccccc4)cc3)ncn2)c1
Reactant: CNOC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CON(C)C(=O)c1cccc(Nc2cc(Nc3ccc(Oc4ccccc4)cc3)ncn2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 47.2 %

Procedure:
To a stirred solution of 3-(6-(4-phenoxyphenylamino)pyrimidin-4-ylamino)benzoic acid (0.05 g, 0.12 mmol) in DMF (2 mL) were added MeNH—OMe.HCl (0.0084 g, 0.12 mmol), EDCI HCl (0.0361 g, 0.18 mmol), HOBT (0.0084 g, 0.062 mmol) and DIPEA (0.023 g, 0.18 mmol). The reaction mixture was stirred at room temperature for 1 h and was quenched with water. A white solid was isolated by filtration and dried under vacuum to give N-methoxy-N-methyl-3-(6-(4-phenoxyphenylamino)pyrimidin-4-ylamino)benzamide (0.025 g, 44.5%) as a white solid.
Reaction SMILES: [C:1]1([SH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:8][C:9](=[CH2:11])[CH3:10]>>[C:9]([C:4]1[CH:5]=[CH:6][C:1]([SH:7])=[CH:2][CH:3]=1)([CH3:11])([CH3:10])[CH3:8]
Reactant: Sc1ccccc1
Reactant: C=C(C)C
Product: CC(C)(C)c1ccc(S)cc1
Temperature: 70 °C
Yield: 67.4 %

Procedure:
To a mixture of 1100 grams (10.0 moles) of thiophenol, and 300 grams of boron trifluoride-phosphoric acid complex was slowly added, with stirring, 620 grams (10.9 moles) of isobutylene at 0° C. After addition was complete the mixture was stirred at 0°-10° C. for two hours. The mixture was then heated to 70° C. and stirred at 70°-75° C. for two hours. The reaction mixture was cooled to 25° C. and the organic layer was separated from the lower catalyst layer and added to 500 ml of toluene. The toluene layer was washed four times with 1000-ml portions of water and then dried with magnesium sulfate. The toluene was evaporated from the mixture in vacuo and the residue was distilled in a 10-tray column to give 1120 grams of 4-(tert-butyl)thiophenol, b.p. 58°-60°/1.00 mm (yield 68%). The nmr spectrum agreed with the structure. The residue from the above distillation was 470 grams of tert-butyl 4-(tert-butyl)phenyl sulfide. Neuworth et al (1963) report b.p. 120°/20 mm for 4-(tert-butyl)thiophenol.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5](=[O:12])[CH:6]=[C:7]1[CH2:11][CH2:10][CH2:9][NH:8]1.[C:13]([C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=1)[CH2:18]Br)#[N:14].Cl>C1(C)C=CC=CC=1>[CH3:3][O:4][C:5](=[O:12])[C:6](=[C:7]1[CH2:11][CH2:10][CH2:9][NH:8]1)[CH2:18][C:17]1[CH:20]=[CH:21][CH:22]=[C:15]([C:13]#[N:14])[CH:16]=1
Reactant: N#Cc1cccc(CBr)c1
Reactant: COC(=O)C=C1CCCN1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: COC(=O)C(Cc1cccc(C#N)c1)=C1CCCN1
Temperature: 0 °C
Yield: 55.1 %

Procedure:
To a flask containing a 60% dispersion of NaH (0.91 g, 22.7 mmol), and toluene (60 mL), under nitrogen, is added Pyrrolidin-2-ylidene-acetic acid methyl ester (3.2 g, 22.7 mmol) and the mixture is refluxed for 1 h. The reaction mixture was cooled to 0° C. and a solution of m-cyanobenzylbromide (4.45 g, 22.7 mmol) in toluene (60 mL) is added dropwise. The reaction is allowed to warm to RT and then heated at 60° C. overnight. The mixture is cooled to RT and with vigorous stirring 1 N HCl is added to obtain a pH of 6. The toluene was decanted and dried over Na2SO4 and concentrated. Purification by flash chromatography (9:9:1 of CH2Cl2:hexanes:EtOAc) gave the title compound as a wet solid (3.2 g, 12.5 mmol). 1H NMR (CDCl3, 300 MHz) 8.32(br. s, 1H), 7.48-7.25(m, 4H), 3.63(s, 3H), 3.62-3.55(m, 2H), 3.53(s, 2H), 2.66-2.48(m, 2H), 2.10-1.90(m, 2H).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([CH3:12])[CH:8]=[C:7]2[N:13]1[CH2:22][CH2:21][C:16]2([O:20][CH2:19][CH2:18][O:17]2)[CH2:15][CH2:14]1.[Cl:23][C:24]1[CH:29]=[C:28]([Cl:30])[CH:27]=[CH:26][C:25]=1OB(O)O.C(=O)([O-])[O-].[Na+].[Na+].O>[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(O)C.C1(C)C=CC=CC=1>[Cl:23][C:24]1[CH:29]=[C:28]([Cl:30])[CH:27]=[CH:26][C:25]=1[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([CH3:12])[CH:8]=[C:7]2[N:13]1[CH2:22][CH2:21][C:16]2([O:17][CH2:18][CH2:19][O:20]2)[CH2:15][CH2:14]1
Reactant: OB(O)Oc1ccc(Cl)cc1Cl
Reactant: Cc1cc(N2CCC3(CC2)OCCO3)c2cccc(Br)c2n1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: O
Product: Cc1cc(N2CCC3(CC2)OCCO3)c2cccc(-c3ccc(Cl)cc3Cl)c2n1
Temperature: 25 °C
Yield: 87.1 %

Procedure:
Under a nitrogen atmosphere, 8-bromo-4-(1,4-dioxa-8-azaspiro [4.5]dec-8-yl)-2-methylquinoline (10.2 g), 2,4-dichlorophenylboric acid (6.0 g) and sodium carbonate (8.93 g) were suspended in a mixed solvent of deaerated water (24 mL), toluene (12 mL) and ethanol (12 mL), followed by adding thereto tetrakis-(triphenylphosphine) palladium (1.6 g), and the resulting mixture was heated under reflux for 16 hours. The reaction mixture was cooled to room temperature and separated with ethyl acetate and a saturated aqueous ammonium chloride solution. After the aqueous phase was extracted with ethyl acetate, the combined organic phase was dried over anhydrous sodium sulfate. The desiccating agent was filtered off, after which the filtrate was concentrated under reduced pressure and the resultant residue was crystallized from diisopropyl ether. The crystals were collected by filtration and washed with a small amount of diisopropyl ether to obtain the title compound (10.5 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:10][CH2:11][N:12]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:13][CH2:14][N:15]2C(=O)C3=CC=CC=C3C2=O)=[CH:4][CH:3]=1.O.NN>CO>[NH2:15][CH2:14][CH2:13][N:12]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:11][CH2:10][N:9]([CH2:8][C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=1)[C:33](=[O:34])[O:35][C:36]([CH3:39])([CH3:38])[CH3:37]
Reactant: CC(C)(C)OC(=O)N(CCN(Cc1ccc(F)cc1)C(=O)OC(C)(C)C)CCN1C(=O)c2ccccc2C1=O
Agent: NN
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)N(CCN)CCN(Cc1ccc(F)cc1)C(=O)OC(C)(C)C
Yield: 42.8 %

Procedure:
To a solution of N-[7-(p-fluorophenyl)-3,6-di(tert-butoxycarbonyl)-3,6-diaza-1-heptyl]phthalimide (14.5 g, 26.7 mmol) in methanol (200 ml) was added hydrazine monohydrate (1.4 ml) and heated under reflux for 5 hours. After completion of the reaction, the solvent was distilled off under reduced pressure. To the residue was added chloroform (200 ml) and washed with aqueous ammonia (150 ml×2). The organic layer was dried over anhydrous potassium carbonate and the solvent was distilled off under reduced pressure. The resulting colorless oily substance was chromatographed using silica gel column to give 4.7 g of the title compound from the fraction from methylene chloride-methanol-aqueous ammonia (90/10/0.5) as a colorless oily substance. Yield=43%.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([NH:12][CH3:13])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[CH:15]=3)[CH:8]=2)[N:3]=1.[N:22]1[CH:27]=[C:26](B(O)O)[CH:25]=[N:24][CH:23]=1.C(=O)([O-])[O-].[K+].[K+].O>COCCOC.CCO.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>[CH3:21][O:20][C:16]1[CH:15]=[C:14]([C:7]2[CH:8]=[C:9]3[C:4](=[CH:5][CH:6]=2)[N:3]=[C:2]([C:26]2[CH:27]=[N:22][CH:23]=[N:24][CH:25]=2)[N:11]=[C:10]3[NH:12][CH3:13])[CH:19]=[CH:18][CH:17]=1
Reactant: OB(O)c1cncnc1
Reactant: CNc1nc(Cl)nc2ccc(-c3cccc(OC)c3)cc12
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: COCCOC
Solvent: O
Product: CNc1nc(-c2cncnc2)nc2ccc(-c3cccc(OC)c3)cc12
Yield: 38.2 %

Procedure:
In a 10 mL microwave vial was added 2-chloro-6-(3-methoxyphenyl)-N-methylquinazolin-4-amine (0.080 g, 0.267 mmol), pyrimidine-5-boronic acid (0.099 g, 0.801 mmol), dichlorobis(triphenylphosphine)palladium (II) (Pd(PPh3)2Cl2) (9.37 mg, 0.013 mmol), and potassium carbonate (0.111 g, 0.801 mmol) in DME (3 mL), EtOH (1.286 mL), and water (0.857 mL) to give a yellow suspension. The vial was irradiated at 120° C. for 15 min under argon. Water (10 rill) was added to the mixture and extracted with ethyl acetate (2×10 mL). The organic layers were combined and washed with brine (1×20 mL) and then dried over MgSO4, filtered and concentrated. The residue was washed with MeOH-CH2Cl2 and dried to give 35 mg of 6-(3-methoxyphenyl)-N-methyl-2-(pyrimidin-5-yl)quinazolin-4-amine as a white solid (38%). LCMS m/z=344 (M+1) (Method D) (retention time=1.78 min) 1H NMR (300 MHz, DMSO) δ 9.79-9.59 (m, 2H), 9.30 (s, 1H), 8.72 (d, J=4.6 Hz, 1H), 8.59 (s, 1H), 8.16 (d, J=8.6 Hz, 1H), 7.85 (d, J=8.7 Hz, 1H), 7.53-7.28 (m, 3H), 7.00 (d, J=6.8 Hz, 1H), 3.86 (s, 3H), 3.18 (d, J=3.9 Hz, 3H).
Reaction SMILES: [CH3:1][C:2]1[C:7]2[N:8]=[C:9]([C:54]3[S:58][CH:57]=[C:56]([CH:59]([CH3:61])[CH3:60])[N:55]=3)[CH:10]=[C:11]([O:12][C@H:13]3[CH2:33][N:32]4[C@H:15]([C:16]([NH:18][C@@:19]5([C:45]([NH:47][S:48]([CH:51]6[CH2:53][CH2:52]6)(=[O:50])=[O:49])=[O:46])[C@H:21]([CH:22]=[CH:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][C@H:29]([CH2:34][C:35]([N:37]6[CH2:42][C:41]([F:44])([F:43])[CH2:40][CH2:39][CH2:38]6)=[O:36])[C:30]4=[O:31])[CH2:20]5)=[O:17])[CH2:14]3)[C:6]=2[CH:5]=[CH:4][C:3]=1[O:62][CH3:63].[OH-].[Na+:65]>CO>[CH3:1][C:2]1[C:7]2[N:8]=[C:9]([C:54]3[S:58][CH:57]=[C:56]([CH:59]([CH3:61])[CH3:60])[N:55]=3)[CH:10]=[C:11]([O:12][C@H:13]3[CH2:33][N:32]4[C@H:15]([C:16]([NH:18][C@@:19]5([C:45]([N-:47][S:48]([CH:51]6[CH2:52][CH2:53]6)(=[O:49])=[O:50])=[O:46])[C@H:21]([CH:22]=[CH:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][C@H:29]([CH2:34][C:35]([N:37]6[CH2:42][C:41]([F:44])([F:43])[CH2:40][CH2:39][CH2:38]6)=[O:36])[C:30]4=[O:31])[CH2:20]5)=[O:17])[CH2:14]3)[C:6]=2[CH:5]=[CH:4][C:3]=1[O:62][CH3:63].[Na+:65]
Reactant: COc1ccc2c(O[C@@H]3C[C@H]4C(=O)N[C@]5(C(=O)NS(=O)(=O)C6CC6)C[C@H]5C=CCCCCC[C@H](CC(=O)N5CCCC(F)(F)C5)C(=O)N4C3)cc(-c3nc(C(C)C)cs3)nc2c1C
Agent: COc1ccc2c(O[C@@H]3C[C@H]4C(=O)N[C@]5(C(=O)NS(=O)(=O)C6CC6)C[C@H]5/C=C\CCCCC[C@H](CC(=O)N5CCCC(F)(F)C5)C(=O)N4C3)cc(-c3nc(C(C)C)cs3)nc2c1C
Agent: COc1ccc2c(O[C@@H]3C[C@H]4C(=O)N[C@]5(C(=O)[N-]S(=O)(=O)C6CC6)C[C@H]5/C=C\CCCCC[C@H](CC(=O)N5CCCC(F)(F)C5)C(=O)N4C3)cc(-c3nc(C(C)C)cs3)nc2c1C
Agent: [Na+]
Solvent: CO
Product: COc1ccc2c(O[C@@H]3C[C@H]4C(=O)N[C@]5(C(=O)[N-]S(=O)(=O)C6CC6)C[C@H]5C=CCCCCC[C@H](CC(=O)N5CCCC(F)(F)C5)C(=O)N4C3)cc(-c3nc(C(C)C)cs3)nc2c1C

Procedure:
Compound 31 (1 equivalent) was dissolved in dichloromethane, cooled to 5° C. and trifluoroacetic acid (2-3 w/v) was added and stirred at room temperature for 4h. The reaction mixture was concentrated and the residue dissolved in dimethylfomamide and cooled to 5° C. before addition of diisopropylethyl amine (10 equivalents). TBTU (1.8 equivalents) was added followed by 3,3-difluoropiperidine hydrochloride (1.2 equivalents). The reaction was stirred until completion and added to 1M citric acid and solid collected by filtration. The solid was crystallized from ethylacetate/heptane to give ACH-0142684 (purity >98%). ACH-0142684 was suspended in methanol and aqueous sodium hydroxide (1.05 equivalents) was added at about 5° C. to give a clear solution. The reaction mixture was concentrated to dryness and the residue was stirred with IPA to give crystalline ACH-0142684.Na (Form G). The crystalline ACH-0142684.Na was dissolved in a mixture of methanol/ethyl acetate and the solution was added to pentane. The solid was collected by filtration and dried to give ACH-0142684.Na in the amorphous form (purity >98%).
Reaction SMILES: [N:1]([O-])=O.[Na+].[F:5][C:6]1[CH:12]=[C:11]([O:13][CH2:14][CH2:15][N:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)[CH:10]=[CH:9][C:7]=1[NH2:8].O.O.[Sn](Cl)Cl.[OH-].[Na+]>O.Cl.ClCCl>[F:5][C:6]1[CH:12]=[C:11]([O:13][CH2:14][CH2:15][N:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)[CH:10]=[CH:9][C:7]=1[NH:8][NH2:1]
Reactant: O=N[O-]
Reactant: Nc1ccc(OCCN2CCOCC2)cc1F
Agent: Cl
Agent: Cl[Sn]Cl
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: NNc1ccc(OCCN2CCOCC2)cc1F
Temperature: 25 °C
Reaction time: 14 h

Procedure:
A solution of sodium nitrite (0.38 g, 5.4 mmol) in 20 mL water is slowly added dropwise at −15° C. to a solution of 2-fluoro-4-(2-morpholin-4-yl-ethoxy)aniline (1.7 g, 4.5 mmol) in 20 mL conc. hydrochloric acid. The resulting suspension is stirred for 4 h at −10° C., before a solution of tin(II)chloride dihydrate (2.6 g, 11.3 mmol) in 20 mL conc. hydrochloric acid is added dropwise. After 14 h stirring at RT the reaction mixture is adjusted to pH 10 with 10 N NaOH and combined with dichloromethane. After filtration through Celite® the filtrate is extracted with dichloromethane. The combined organic phases are dried on magnesium sulphate and evaporated down in vacuo. Yield: 1.5 g.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([O:29][CH:30]2[CH2:34][CH2:33][CH2:32][CH2:31]2)[C:5]2[C:10]([C:11]3[CH:20]=[CH:19][C:14]4[N:15]=[C:16]([CH3:18])[O:17][C:13]=4[CH:12]=3)=[CH:9][N:8]([CH2:21][O:22][CH2:23][CH2:24][Si:25]([CH3:28])([CH3:27])[CH3:26])[C:6]=2[N:7]=1.[Cl:35][C:36]1[N:40]([CH:41]2[CH2:46][CH2:45][O:44][CH2:43][CH2:42]2)[N:39]=[CH:38][C:37]=1[NH2:47].C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Cl:35][C:36]1[N:40]([CH:41]2[CH2:42][CH2:43][O:44][CH2:45][CH2:46]2)[N:39]=[CH:38][C:37]=1[NH:47][C:2]1[N:3]=[C:4]([O:29][CH:30]2[CH2:31][CH2:32][CH2:33][CH2:34]2)[C:5]2[C:10]([C:11]3[CH:20]=[CH:19][C:14]4[N:15]=[C:16]([CH3:18])[O:17][C:13]=4[CH:12]=3)=[CH:9][N:8]([CH2:21][O:22][CH2:23][CH2:24][Si:25]([CH3:28])([CH3:26])[CH3:27])[C:6]=2[N:7]=1
Reactant: Nc1cnn(C2CCOCC2)c1Cl
Reactant: Cc1nc2ccc(-c3cn(COCC[Si](C)(C)C)c4nc(Cl)nc(OC5CCCC5)c34)cc2o1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: Cc1nc2ccc(-c3cn(COCC[Si](C)(C)C)c4nc(Nc5cnn(C6CCOCC6)c5Cl)nc(OC5CCCC5)c34)cc2o1
Temperature: 100 °C
Reaction time: 2 h

Procedure:
To a degassed mixture of 6-(2-chloro-4-(cyclopentyloxy)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-methylbenzo[d]oxazole (1 equiv), 5-chloro-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-amine (1.2 equiv), and cesium carbonate (2 equiv) in 1,4-dioxane (0.05M), was added palladium acetate (0.1 equiv) and 2,2′-bis-diphenyl-phosphanyl-[1,1′]binaphthalenyl (0.3 equiv). The reaction was stirred at 100° C. for 2 h. Upon completion, the reaction mixture was cooled to room temperature and concentrated. The residue was purified by silica gel chromatography (1-2% MeOH in DCM) to afford the desired product as a yellow solid which was used in next step without further purification. MS (ESI) m/z 664.2 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]2[N:11]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]([O:22][CH3:23])=[O:21])=[CH:16][CH:15]=3)[C:10](=[O:24])[CH2:9][CH2:8][C:7]=2[C:6]([CH:25]=O)=[CH:5][CH:4]=1.[S:27]1[CH2:31][C:30](=[O:32])[NH:29][C:28]1=[O:33]>C1(C)C=CC=CC=1.N1CCCCC1.C(O)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH:25]=[C:31]2[S:27][C:28](=[O:33])[NH:29][C:30]2=[O:32])=[C:7]2[C:12]=1[N:11]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]([O:22][CH3:23])=[O:21])=[CH:16][CH:15]=1)[C:10](=[O:24])[CH2:9][CH2:8]2
Reactant: COC(=O)c1ccc(CN2C(=O)CCc3c(C=O)ccc(OC)c32)cc1
Reactant: O=C1CSC(=O)N1
Solvent: CC(=O)O
Solvent: C1CCNCC1
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(CN2C(=O)CCc3c(C=C4SC(=O)NC4=O)ccc(OC)c32)cc1
Yield: 89.3 %

Procedure:
7.0 g of 8-methoxy-1-(4-methoxycarbonylbenzyl)-2-oxo-1,2,3,4-tetrahydroquinoline-5-carboxaldehyde and 3.25 g of 2,4-thiazolidinedione were suspended in 70 ml of toluene. Ten drops of piperidine and ten drops of acetic acid were added, followed by heating and refluxing for 4 hours. The resultant was allowed to cool to precipitate a solid, and the precipitated solid was collected by filtration and dried, giving 8.0 g (90% yield) of 5-[8-methoxy-1-(4-methoxycarbonylbenzyl)-2-oxo-1,2,3,4-tetrahydroquinolin-5-ylmethylidene]thiazolidine-2,4-dione as a light yellow powder.
Reaction SMILES: [F:1][C:2]1[CH:30]=[C:29]([N+:31]([O-])=O)[CH:28]=[CH:27][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]2[CH:11]=[C:12]([C:14]3[N:19]=[CH:18][C:17]([CH2:20][N:21]4[CH2:25][CH2:24][CH2:23][C:22]4=[O:26])=[CH:16][CH:15]=3)[S:13][C:6]=12.[Cl-].[NH4+]>CO.O.[Fe]>[NH2:31][C:29]1[CH:28]=[CH:27][C:3]([O:4][C:5]2[CH:10]=[CH:9][N:8]=[C:7]3[CH:11]=[C:12]([C:14]4[N:19]=[CH:18][C:17]([CH2:20][N:21]5[CH2:25][CH2:24][CH2:23][C:22]5=[O:26])=[CH:16][CH:15]=4)[S:13][C:6]=23)=[C:2]([F:1])[CH:30]=1
Reactant: O=C1CCCN1Cc1ccc(-c2cc3nccc(Oc4ccc([N+](=O)[O-])cc4F)c3s2)nc1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CO
Product: Nc1ccc(Oc2ccnc3cc(-c4ccc(CN5CCCC5=O)cn4)sc23)c(F)c1
Temperature: 25 °C
Yield: 86.1 %

Procedure:
A suspension of 103 (270 mg, 0.581 mmol), iron (649 mg, 11.63 mmol), and ammonium chloride (187 mg, 3.49 mmol) in MeOH (10 mL) and water (1 mL), was heated to reflux for 3 h, then cooled to RT. The mixture was then filtered through celite and the cake was rinsed with methanol. The mother liquor was concentrated, and partitioned between a saturated aqueous solution of NaHCO3 and ethyl acetate. The aqueous phase was extracted 3 times with DCM. The combined organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, re-dissolved in ethyl acetate, washed with 1N NaOH, dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by Biotage (SNAP 50 g cartridge; MeOH/DCM: 0/100 to 20/80 over 20 CV), to afford the title compound 104 (220 mg, 0.50 mmol, 87% yield) as beige solid. MS (m/z): 435.5 (M+H).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].C(=S)=S.[CH2:8]([N:10]([CH2:18][CH3:19])[C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([CH3:17])[CH:12]=1)[CH3:9].[C:20](Cl)(=[O:24])[C:21](Cl)=[O:22]>C(Cl)(Cl)Cl.O>[CH2:18]([N:10]([CH2:8][CH3:9])[C:11]1[CH:16]=[CH:15][C:14]([C:20](=[O:24])[C:21]([C:14]2[CH:15]=[CH:16][C:11]([N:10]([CH2:18][CH3:19])[CH2:8][CH3:9])=[CH:12][C:13]=2[CH3:17])=[O:22])=[C:13]([CH3:17])[CH:12]=1)[CH3:19]
Reactant: CCN(CC)c1cccc(C)c1
Reactant: O=C(Cl)C(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: S=C=S
Product: CCN(CC)c1ccc(C(=O)C(=O)c2ccc(N(CC)CC)cc2C)c(C)c1
Yield: 23.3 %

Procedure:
To 8.3 g of anhydrous aluminum chloride, 30 ml of carbon disulfide was added, followed by dropwise addition of 16.3 g of N,N-diethyl-m-toluidine under ice-cooling. Then, 5 g of oxalyl chloride was added dropwise thereto at 5° C. or lower, and reacted for 1 hour with stirring. After the reaction, 50 ml of water and 100 ml of chloroform were added to the reaction solution. The chloroform layer obtained by separation was washed with 2N hydrochloric acid, dried and concentrated. The residue was recrystallized from ethyl acetate to yield 3.5 g of yellow 1,2-bis(4-diethylamino-2-methylphenyl)ethane-1,2-dione.
Reaction SMILES: C([O:4][CH2:5][CH2:6][O:7][N:8]=[C:9]1[C:13](=[N:14][OH:15])[C:12]2[CH:16]=[CH:17][CH:18]=[CH:19][C:11]=2[O:10]1)(=O)C.[OH-].[Na+].Cl>CN(C)C=O>[OH:4][CH2:5][CH2:6][O:7][N:8]=[C:9]1[C:13](=[N:14][OH:15])[C:12]2[CH:16]=[CH:17][CH:18]=[CH:19][C:11]=2[O:10]1
Reactant: CC(=O)OCCON=C1Oc2ccccc2C1=NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: OCCON=C1Oc2ccccc2C1=NO
Yield: 31.5 %

Procedure:
At 20° C., 5.28 g (0.02 mol) of 2-(3-hydroxyimino-3H-benzofuran-2-ylideneaminooxy)-ethyl acetate (XVI-1) in 20 ml of dimethylformamide are stirred with 4.24 g (0.048 mol) of 45% strength aqueous sodium hydroxide solution for 3 hours. The mixture is acidified with 2 N hydrochloric acid and extracted with ethyl acetate, the organic phase is dried over sodium sulphate and the solvent is distilled off under reduced pressure. According to HPLC analysis, the crude product contains 23.4% of the stereoisomer A and 4.1% of the stereoisomer B of benzofuran-2,3-dione 2-[O-(2-hydroxy-ethyl)-oxime] 3-oxime (X-1). Stirring the crude product with diethyl ether affords 1.4 g (28.5% of theory) of crystalline benzofuran-2,3-dione 2-[O-(2-hydroxy-ethyl)-oxime] 3-oxime α-1) consisting of 84.7% of stereoisomer A and 6% of stereoisomer B (HPLC).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([O:8][C@@H:9]([C:11]2[CH:12]=[C:13]([CH:15]=[CH:16][CH:17]=2)[NH2:14])[CH3:10])[CH:5]=[N:4][CH:3]=1.[F:18][C:19]([F:30])([F:29])[C:20]1[CH:21]=[C:22]([CH:26]=[CH:27][CH:28]=1)[C:23](O)=[O:24].Cl.CN(C)CCCN=C=NCC.C(N(CC)CC)C>CN(C)C1C=CN=CC=1.ClCCl>[Cl:1][C:2]1[N:7]=[C:6]([O:8][C@@H:9]([C:11]2[CH:12]=[C:13]([NH:14][C:23](=[O:24])[C:22]3[CH:26]=[CH:27][CH:28]=[C:20]([C:19]([F:18])([F:29])[F:30])[CH:21]=3)[CH:15]=[CH:16][CH:17]=2)[CH3:10])[CH:5]=[N:4][CH:3]=1
Reactant: C[C@@H](Oc1cncc(Cl)n1)c1cccc(N)c1
Reactant: O=C(O)c1cccc(C(F)(F)F)c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@@H](Oc1cncc(Cl)n1)c1cccc(NC(=O)c2cccc(C(F)(F)F)c2)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 40.7 %

Procedure:
A mixture of (R)-3-(1-(6-chloropyrazin-2-yloxy)ethyl)aniline (160 mg, 0.64 mmol), 3-trifluoromethylbenzoic acid (183 mg, 0.96 mmol), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (246 mg, 1.28 mmol), 4-dimethylamino pyridine (4 mg, 0.032 mmol) and triethylamine (0.36 mL, 2.57 mmol) in dichloromethane (6 mL) was stirred at room temperature for 18 hours. After this time the mixture was diluted with dichloromethane (30 mL), washed successively with saturated aqueous sodium hydrogen carbonate (2×20 mL) and brine (20 mL), dried (Na2SO4) and concentrated under reduced pressure to give an orange oil which was purified by flash chromatography (silica, ethyl acetate/hexanes) to give (R)—N-(3-(1-(6-chloropyrazin-2-yloxy)ethyl)phenyl)-3-(trifluoromethyl)benzamide (110 mg, 30% over 2 steps) as a yellow foam.