Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1)#[N:2].Br[C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][C:14]=1[CH3:20]>>[OH:19][C:16]1[CH:17]=[CH:18][C:13]([C:6]2[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=2)=[C:14]([CH3:20])[CH:15]=1
Reactant: Cc1cc(O)ccc1Br
Reactant: N#Cc1ccc(B(O)O)cc1
Product: Cc1cc(O)ccc1-c1ccc(C#N)cc1
Yield: 60 %

Procedure:
4-Cyanophenylboronic acid and 4-bromo-3-methylphenol were processed as described in Example 167A to provide the title compound (60% yield). 1HNMR (300 MHz, CDCl3) δ2.20 (s, 3H), 4.68 (bs, 1H), 6.78 (m, 2H), 7.15 (m, 1H), 7.42 (m, 2H), 7.76(m, 2H); MS (CDI) m/z 227 (M+NH4)+.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[CH2:4][C:5]3[CH2:9][N:8]([C@@H:10]([CH2:14][CH:15]4[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]4)[C:11]([OH:13])=O)[C:7](=[O:21])[C:6]=3[O:22][C:23]=2[CH:24]=[CH:25][CH:26]=1.[NH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=1.ON1C2C=CC=CC=2N=N1>C(Cl)Cl.O>[Cl:1][C:2]1[C:3]2[CH2:4][C:5]3[CH2:9][N:8]([C@@H:10]([CH2:14][CH:15]4[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]4)[C:11]([NH:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=4)=[O:13])[C:7](=[O:21])[C:6]=3[O:22][C:23]=2[CH:24]=[CH:25][CH:26]=1
Reactant: O=C(O)[C@H](CC1CCCCC1)N1CC2=C(Oc3cccc(Cl)c3C2)C1=O
Reactant: Nc1ccccn1
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: O
Product: O=C(Nc1ccccn1)[C@H](CC1CCCCC1)N1CC2=C(Oc3cccc(Cl)c3C2)C1=O
Yield: 17.6 %

Procedure:
A solution of (S)-2-(8-chloro-3-oxo-3,9-dihydro-1H-chromeno[2,3-c]pyrrol-2-yl)-3-cyclohexyl-propionic acid (200 mg, 2.1 mmol), commercially available 2-aminopyridine (60 mg, 0.63 mmol), N-ethyl-N-dimethyaminopropyl carbodiimide hydrochloride (EDCI. HCl) (112 mg, 0.59 mmol), and N-hydroxybenzotriazole (HOBt) (79 mg, 0.59 mmol) in methylene chloride (10 mL) was stirred for 16 hours at 25° C. The reaction mixture was diluted with water and extracted with ethyl acetate (3×). The combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo. The resulting residue, upon silica gel flash chromatography using hexane-ethyl acetate gradiant elution, to afford (S)-2-(8-chloro-3-oxo-3,9-dihydro-1H-chromeno[2,3-c]pyrrol-2-yl)-3-cyclohexyl-N-pyridin-2-ylpropionamide (50 mg, 20.8%), as a white solid. 1H NMR (DMSO-d6) δ: 10.87 (s, 1H), 8.28-8.41 (m, 1H), 8.00 (d, J=8.8 Hz, 1H), 7.70-7.86 (m, 1H), 7.20-7.40 (m, 2H), 7.03-7.16 (m, 2H), 5.09 (br. s., 1H), 5.00-5.01 (m, 1H), 4.36-4.37 (m, 1H), 4.43 (d, J=18.6 Hz, 1H), 4.07 (d, J=18.6 Hz, 3H), 3.99-4.15 (m, 1H), 3.75 (s, 2H), 1.49-1.90 (m, 6H), 1.05-1.29 (m, 4H), 0.88-1.02 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]([C@H:5]1[NH:17][C:16](=[O:18])[CH2:15][CH2:14][CH2:13][O:12][C:11](=[O:19])[C:10]2[C:20]([CH3:34])=[C:21]([O:32][CH3:33])[CH:22]=[C:23]([O:24][Si](C(C)(C)C)(C)C)[C:9]=2[CH2:8][S:7][CH2:6]1)=[O:4].[F-].[NH4+]>CO>[CH3:1][O:2][C:3]([C@H:5]1[NH:17][C:16](=[O:18])[CH2:15][CH2:14][CH2:13][O:12][C:11](=[O:19])[C:10]2[C:20]([CH3:34])=[C:21]([O:32][CH3:33])[CH:22]=[C:23]([OH:24])[C:9]=2[CH2:8][S:7][CH2:6]1)=[O:4]
Reactant: COC(=O)[C@@H]1CSCc2c(O[Si](C)(C)C(C)(C)C)cc(OC)c(C)c2C(=O)OCCCC(=O)N1
Agent: [F-]
Agent: [NH4+]
Solvent: CO
Product: COC(=O)[C@@H]1CSCc2c(O)cc(OC)c(C)c2C(=O)OCCCC(=O)N1

Procedure:
(R)-15-(tert-Butyl-dimethylsilanyloxy)-13-methoxy-12-methyl-6,11-dioxo-3,4,5,6,7,8,9,11-octahydro-1H-10,2,5-benzoxathiaazacyclotridecine-4-carboxylic acid methyl ester was treated with ammonium fluoride in methanol in an analogous manner to the procedure described in Example 1 to yield (R)-15-hydroxy-13-methoxy-12-methyl-6,11-dioxo-3,4,5,6,7,8,9,11-octahydro-1H-10,2,5-benzoxathiaazacyclotridecine-4-carboxylic acid methyl ester as a white solid.
Reaction SMILES: [CH3:1][N:2]1[C:7]2[N:8]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:9](=[O:19])[N:10]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:11](=[O:12])[C:6]=2[C:5](SC)=[N:4][C:3]1=[O:28].C1(C)C=CC=CC=1.[Cl:36][C:37]1[CH:43]=[CH:42][C:40]([NH2:41])=[CH:39][CH:38]=1>C(OCC)C>[Cl:36][C:37]1[CH:43]=[CH:42][C:40]([NH:41][C:5]2[C:6]3[C:11](=[O:12])[N:10]([C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=4)[C:9](=[O:19])[N:8]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[C:7]=3[N:2]([CH3:1])[C:3](=[O:28])[N:4]=2)=[CH:39][CH:38]=1
Reactant: CSc1nc(=O)n(C)c2c1c(=O)n(-c1ccccc1)c(=O)n2-c1ccccc1
Reactant: Nc1ccc(Cl)cc1
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: Cn1c(=O)nc(Nc2ccc(Cl)cc2)c2c(=O)n(-c3ccccc3)c(=O)n(-c3ccccc3)c21
Temperature: 25 °C
Yield: 52.5 %

Procedure:
To 8-methyl-5-methylsulfanyl-1,3-diphenyl-1H,8H-pyrimido[4,5-d]pyrimidine-2,4,7-trione 26 (149 mg) obtained in Step 6 was added toluene (2 ml), 4-chloroaniline 27 (97 mg) was added, and the mixture was stirred under reflux for 3.5 hrs. After allowing to cool to room temperature, diethyl ether was added. The crystals were collected by filtration, washed with diethyl ether and dried to give 5-(4-chloro-phenylamino)-8-methyl-1,3-diphenyl-1H,8H-pyrimido[4,5-d]pyrimidine-2,4,7-trione 28 (94 mg, yield 53%) as colorless crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:21]2[C:26](=[O:27])[NH:25][C:24](=[O:28])[CH:23]=[N:22]2)[CH:5]=[C:6]([Cl:20])[C:7]=1[O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([N+:17]([O-:19])=[O:18])[CH:10]=1.[H-].[Na+].[CH3:31][Si:32]([CH2:35][CH2:36][O:37][CH2:38]Cl)([CH3:34])[CH3:33]>CN(C=O)C.O>[Cl:1][C:2]1[CH:3]=[C:4]([N:21]2[C:26](=[O:27])[N:25]([CH2:38][O:37][CH2:36][CH2:35][Si:32]([CH3:34])([CH3:33])[CH3:31])[C:24](=[O:28])[CH:23]=[N:22]2)[CH:5]=[C:6]([Cl:20])[C:7]=1[O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([N+:17]([O-:19])=[O:18])[CH:10]=1
Reactant: COc1ccc(Oc2c(Cl)cc(-n3ncc(=O)[nH]c3=O)cc2Cl)cc1[N+](=O)[O-]
Reactant: C[Si](C)(C)CCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(Oc2c(Cl)cc(-n3ncc(=O)n(COCC[Si](C)(C)C)c3=O)cc2Cl)cc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 48.2 %

Procedure:
To a solution of 2-[3,5-dichloro-4-(4-methoxy-3-nitro-phenoxy)-phenyl]-2H-[1,2,4]-triazin-3,5-dione (1.32 g, 3.1 mmol) in 12 mL of DMF at 0° C. was added sodium hydride (60% dispersion in mineral oil, 0.15 g, 3.7 mmol). After stirring at 0° C. for 5 min, the mixture was stirred at room temperature for 30 min as a clear reddish brown solution. To the solution at room temperature was added SEMCl (0.63 g, 3.74 mmol). After stirring at room temperature for 20 h, the solution was diluted with H2O (30 mL) and extracted with EtOAc (2×50 mL). The combined EtOAc extracts were washed with 1N HCl (100 mL), H2O (3×50 mL), brine (100 mL), dried and concentrated. The residue was dissolved in CH2Cl2followed by addition of ether to give the title compound (0.83 g) of Step A as light brown crystals. NMR (400 Mhz, CD3OD) d 0.02 (m, 9H), 1.01 (m, 2H), 3.75 (m, 2H), 5.45 (s, 2H).
Reaction SMILES: C(C1C=CC(C=O)=CC=1)CCCCCC.C(O)(=O)CC(O)=O.[CH2:23]([C:30]1[CH:40]=[CH:39][C:33]([CH:34]=[CH:35][C:36](O)=[O:37])=[CH:32][CH:31]=1)[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29].S(Cl)([Cl:43])=O>N1CCCCC1.CCOCC.N1C=CC=CC=1>[CH2:23]([C:30]1[CH:40]=[CH:39][C:33]([CH:34]=[CH:35][C:36]([Cl:43])=[O:37])=[CH:32][CH:31]=1)[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]
Reactant: CCCCCCCc1ccc(C=CC(=O)O)cc1
Reactant: O=S(Cl)Cl
Agent: CCCCCCCc1ccc(C=O)cc1
Agent: O=C(O)CC(=O)O
Solvent: C1CCNCC1
Solvent: c1ccncc1
Solvent: CCOCC
Product: CCCCCCCc1ccc(C=CC(=O)Cl)cc1

Procedure:
8.8 G. of p-n-heptylbenzaldehyde and 8.74 g. of malonic acid are dissolved in 7 ml. of absolute pyridine, treated with 8 drops of piperidine and heated at 90°-100° C. for 68 hours. The mixture is then taken up in ether and washed with dilute hydrochloric acid. After recrystallization from ether/hexane, there are obtained 7.5 g. of p-n-heptylcinnamic acid having a melting point of 121°-122° C. and a clearing point of 150°-153° C. 8.2 G. of this acid are boiled at reflux in 120 ml. of thionyl chloride for 30 minutes. The excess thionyl chloride is removed by distillation, the residue taken up three times in absolute toluene, concentrated and dried. The p-n-heptylcinnamic acid chloride obtained can be used in the process directly.
Reaction SMILES: [O:1]=[C:2]1[NH:7][CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:3]1.[H-].[Na+].[Br:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24]Br)=[CH:20][CH:19]=1>CN(C)C=O>[Br:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][N:7]2[CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:3][C:2]2=[O:1])=[CH:20][CH:19]=1
Reactant: CC(C)(C)OC(=O)N1CCNC(=O)C1
Reactant: BrCc1ccc(Br)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(Cc2ccc(Br)cc2)C(=O)C1
Reaction time: 0.5 h
Yield: 82.7 %

Procedure:
To a solution of 1,1-dimethylethyl 3-oxo-1-piperazinecarboxylate (500 mg, 2.497 mmol) in N,N-dimethylformamide (DMF) (8 mL) at room temperature under nitrogen was added sodium hydride (60% w/w in mineral oil, 120 mg, 3.00 mmol) and the resulting suspension was stirred at this temperature for 30 min. 1-Bromo-4-(bromomethyl)benzene (749 mg, 3.00 mmol) in DMF (5 mL) was then added via syringe. The resulting mixture was stirred at room temperature for 1.5 h then partitioned between AcOEt and water. The layers were separated and the aqueous phase was extracted three times with AcOEt. The combined organic phases were washed three times with brine, dried over MgSO4 and concentrated in vacuo. Purification of the residue by SP4 using a 25 G silica cartridge (gradient: 13 to 63% AcOEt in Hexanes) gave 1,1-dimethylethyl 4-[(4-bromophenyl)methyl]-3-oxo-1-piperazinecarboxylate (763 mg, 2.066 mmol, 83% yield) as an oil which solidified to a white solid over 16 h.
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([C:13](=[O:15])[CH3:14])=[CH:10][CH:11]=2)[CH2:6][C:5]1=[O:16])(=[O:3])[CH3:2].[Cl:17][C:18]1[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=1[C:20](O)=[O:21]>>[C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([C:13](=[O:15])[CH3:14])=[CH:10][CH:11]=2)[C:6](=[C:20]([C:19]2[CH:23]=[CH:24][CH:25]=[CH:26][C:18]=2[Cl:17])[OH:21])[C:5]1=[O:16])(=[O:3])[CH3:2]
Reactant: O=C(O)c1ccccc1Cl
Reactant: CC(=O)c1ccc2c(c1)CC(=O)N2C(C)=O
Product: CC(=O)c1ccc2c(c1)C(=C(O)c1ccccc1Cl)C(=O)N2C(C)=O

Procedure:
Prepared from 1,5-diacetyl-2-indolinone and 2-chlorobenzoic acid
Reaction SMILES: [CH2:1]([N:8]([CH3:20])[C:9]1[CH:18]=[N:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14](Cl)[CH:15]=2)[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:21]([N:28]1[CH:32]=[C:31](B2OC(C)(C)C(C)(C)O2)[CH:30]=[N:29]1)([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22].C(=O)([O-])[O-].[Cs+].[Cs+].[I-].[K+]>O1CCOCC1>[C:24]([O:23][C:21]([N:28]1[CH:32]=[C:31]([C:14]2[CH:15]=[C:16]3[C:11](=[CH:12][CH:13]=2)[N:10]=[C:9]([N:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH3:20])[CH:18]=[N:17]3)[CH:30]=[N:29]1)=[O:22])([CH3:27])([CH3:25])[CH3:26]
Reactant: CN(Cc1ccccc1)c1cnc2cc(Cl)ccc2n1
Reactant: CC(C)(C)OC(=O)n1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [I-]
Solvent: C1COCCO1
Product: CN(Cc1ccccc1)c1cnc2cc(-c3cnn(C(=O)OC(C)(C)C)c3)ccc2n1
Temperature: 100 °C

Procedure:
N-benzyl-6-chloro-N-methylquinoxalin-2-amine (0.250 g, 0.88 mmol), N-Boc-4-pyrazole boronic acid pinacol ester (0.310 g, 1.05 mmol), caesium carbonate (1.14 g, 3.52 mmol), potassium iodide (0.014 g, 0.088 mmol) were added to 1,4-dioxane (12 mL) at RT. The mixture was degassed under vacuum and was placed under an atmosphere of nitrogen (the process was repeated twice). Fu's catalyst (Bis(tri-tert-butylphosphine) palladium(0)) (0.022 g, 0.04 mmol) was added at RT. The reaction mixture was heated at 100° C. by irradiation for 180 min in a microwave reactor. The organic mixture was diluted with ethyl acetate (150 mL) and washed with water (20 mL×3) followed by brine (20 mL). The organic solvent was distilled under vacuum to afford crude compound.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([O:14][C:15]2[CH:16]=[N:17][C:18]([S:21]([CH3:24])(=[O:23])=[O:22])=[CH:19][CH:20]=2)[CH:5]=[C:6]2[C:10]=1[NH:9][C:8]([C:11]([OH:13])=[O:12])=[CH:7]2.Cl.O.[CH3:27]O>C1(C)C=CC=CC=1>[OH:1][C:2]1[CH:3]=[C:4]([O:14][C:15]2[CH:16]=[N:17][C:18]([S:21]([CH3:24])(=[O:23])=[O:22])=[CH:19][CH:20]=2)[CH:5]=[C:6]2[C:10]=1[NH:9][C:8]([C:11]([O:13][CH3:27])=[O:12])=[CH:7]2
Reactant: CO
Reactant: CS(=O)(=O)c1ccc(Oc2cc(O)c3[nH]c(C(=O)O)cc3c2)cn1
Agent: Cl
Solvent: O
Solvent: Cc1ccccc1
Product: COC(=O)c1cc2cc(Oc3ccc(S(C)(=O)=O)nc3)cc(O)c2[nH]1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 74 %

Procedure:
To a solution of 7-hydroxy-5-{[6-(methylsulfonyl)pyridin-3-yl]oxy}-1H-indole-2-carboxylic acid (4.7 g) in a mixture of methanol (30 mL) and toluene (90 mL) was added dropwise 2M trimethylsilyldiazomethane diethyl ether solution (7.4 mL) at 0° C. The mixture was stirred at 0° C. for 30 min, and 2M trimethylsilyldiazomethane diethyl ether solution (3.7 mL) was added dropwise to the mixture. After stirring at 0° C. for 30 min, 1M hydrochloric acid (2 mL) was added to the mixture to quench the reaction. Water was added to the mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, filtered and concentrated. The residual yellow oil was solidified with ethyl acetate-diethyl ether. The resulting solid was washed with diethyl ether to give the title compound (3.6 g, 74%) as a pale orange solid. MS 363 (MH+).
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[C:5]([S:9][C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[C@H:16]([CH2:20][NH2:21])[CH2:15][CH2:14][CH2:13]3)[CH:6]=[CH:7][CH:8]=1.[NH2:22][C:23](N)=[O:24].Cl.O>CN1C(=O)CCC1>[F:2][C:3]1[CH:4]=[C:5]([S:9][C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[C@H:16]([CH2:20][NH:21][C:23]([NH2:22])=[O:24])[CH2:15][CH2:14][CH2:13]3)[CH:6]=[CH:7][CH:8]=1
Reactant: NC[C@@H]1CCCc2cc(Sc3cccc(F)c3)ccc21
Reactant: NC(N)=O
Agent: Cl
Solvent: O
Solvent: CN1CCCC1=O
Product: NC(=O)NC[C@@H]1CCCc2cc(Sc3cccc(F)c3)ccc21
Temperature: 100 °C
Reaction time: 24 h
Yield: 80.5 %

Procedure:
(R)-6-(3-fluorophenylsulfanyl)-1,2,3,4-tetrahydronaphthalen-1-methylamine hydrochloride salt (4.6 kg) and urea (3.4 kg) were suspended in fresh NMP (9.5 kg). Concentrated aqueous 37% HCl (0.15 kg) was added and the reaction mixture was heated to 100° C. for three hours. On completion of reaction (confirmed by HPLC), the reaction mixture was cooled to 60° C. and water (45 kg) was added. The resulting slurry was stirred vigorously while cooling down to 20° C., and the mixture was allowed to sit for 24 hours. The resulting solid was filtered and washed with water. The wet filter cake was taken into toluene (23.6-kg) and heated to 80° C., then washed with water (twice with 13.5 L) and the reaction mixture was cooled to 40° C. [(R)-6-(3-Fluoro-phenylsulfanyl)-1,2,3,4-tetrahydro-naphthalen-1-ylmethyl]-urea crystallized on addition of n-heptane (7.8 kg). The product was filtered and dried under reduced pressure at 50° C. to afford 3.78-kg of [(R)-6-(3-fluoro-phenylsulfanyl)-1,2,3,4-tetrahydro-naphthalen-1-ylmethyl]-urea: MP=115.1-116.0° C.; MS (M+1)=288; H1 NMR (300 MHz): δ ppm (DMSO): 1.59-1.84 (3H, m), 2.59-2.78 (2H, m), 2.86 (1H, m), 3.10 (1H, ddd, J=6.03, 9.04 Hz), 3.28 (1H, ddd, J=5.65, 6.03), 3.34 (1H, s), 5.46 (2H, s, NH), 6.11 (1H, t, J=6.03 Hz) 6.96-7.09 (3H, m), 7.17-7.23 (2H, m), 7.26-7.31 (1H, m), 7.32-7.41 (1H, m): [α]D=25.5° (MeOH). Chiral Assay (Area Norm): Column: Chiralpak AS-H (150×4.6 mm), mobile phase 80/20 hexane/ethanol(isocratic), flow rate 0.7 ml/min, 25° C., uv @230 nm.: (R)-isomer 99.03/(S)-isomer 0.97.
Reaction SMILES: [C:1]([NH2:5])([CH3:4])([CH3:3])[CH3:2].C(N(CC)C(C)C)(C)C.[C:15]1([CH2:21][S:22](Cl)(=[O:24])=[O:23])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>ClCCl>[C:1]([NH:5][S:22]([CH2:21][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)(=[O:24])=[O:23])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)N
Reactant: O=S(=O)(Cl)Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)NS(=O)(=O)Cc1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 77.5 %

Procedure:
To a solution of tert-butylamine (2 g, 27.3 mmol) in dichloromethane (90 mL) was added N,N-diisopropylethylamine (5.7 mL, 32.8 mmol), followed by phenylmethanesulfonyl chloride (6.25 g, 32.8 mmol) and the reaction was stirred at ambient temperature for 16 hours. The reaction was then diluted with dichloromethane, washed with water and brine, dried with MgSO4, and purified by silica gel column chromatography (0-50% EtOAc in heptane) to give N-tert-butyl-1-phenyl-methanesulfonamide (4.81 g, 77% yield). 1H NMR (400 MHz, CDCl3) δ 7.51-7.44 (m, 2H), 7.41 (dd, J=4.9, 2.0 Hz, 3H), 4.49 (s, 2H), 4.27 (s, 1H), 1.68 (s, 6H); LCMS (m/z) ES+ 228 [M+1]+.
Reaction SMILES: [CH3:1][S:2][C:3]1[N:8]=[C:7]([N:9]2[C:17]3[C:12](=[C:13]([O:18][Si](C(C)C)(C(C)C)C(C)C)[CH:14]=[CH:15][CH:16]=3)[CH:11]=[CH:10]2)[CH:6]=[CH:5][N:4]=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-].C1COCC1>C1COCC1>[CH3:1][S:2][C:3]1[N:8]=[C:7]([N:9]2[C:17]3[CH:16]=[CH:15][CH:14]=[C:13]([OH:18])[C:12]=3[CH:11]=[CH:10]2)[CH:6]=[CH:5][N:4]=1
Reactant: CSc1nccc(-n2ccc3c(O[Si](C(C)C)(C(C)C)C(C)C)cccc32)n1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CSc1nccc(-n2ccc3c(O)cccc32)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 93.3 %

Procedure:
1-(2-methylsulfanyl-pyrimidin-4-yl)-4-triisopropylsilanyloxy-1H-indole (7.75 g) in THF (50 mL) was mixed with TBAF/THF (8 mL) and allowed to stir at RT for 2 h, then quenched with water. The aqueous layer was acidified with 1N HCl. The resulting solid was filtered, washed with water and dried at 50° C. in vacuo overnight to yield 1-(2-methylsulfanyl-pyrimidin-4-yl)-1H-indol-4-ol (4.5 g).
Reaction SMILES: [CH:1](=[CH:8][C:9](=[O:11])[CH3:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl>CCOCC>[CH:1](=[CH:8][C@@H:9]([OH:11])[CH3:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)C=Cc1ccccc1
Agent: Cl
Solvent: CCOCC
Product: C[C@H](O)C=Cc1ccccc1
Temperature: -78 °C
Reaction time: 3 h

Procedure:
The reaction solution was cooled to -78° C., added with a dry ether (5 ml) solution of benzylideneacetone (439 mg, 3 mmol) and reacted under stirring at the same temperature for 3 hours. After completion of the reaction, 1 N hydrochloric acid (42 ml) was added to separate the ether layer and the ether layer was washed with 1% hydrochloric acid (20 ml×2) and a saturated saline solution (20 ml×3), dried with anydrous magnesium sulfate and filtered, and the filtrate was concentrated under reduced pressure to obtain (S)(-)-benzylideneisopropanol. Yield: 435 mg (98%), [α]D20 =24.2° (C=5.16, CHCl3), optical purity: 98%.
Reaction SMILES: [CH2:1]([N:3]1[C:7](=[CH2:8])[C:6]2([CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[O:5][C:4]1=[O:14])[CH3:2].C(N(CC)CC)C.[I-].[K+].[F:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]([C:36]2[CH:41]=[CH:40][C:39]([F:42])=[CH:38][CH:37]=2)=[CH:32][CH2:33][CH2:34]Cl)=[CH:27][CH:26]=1>C(C(C)=O)C>[F:24][C:25]1[CH:26]=[CH:27][C:28]([C:31]([C:36]2[CH:37]=[CH:38][C:39]([F:42])=[CH:40][CH:41]=2)=[CH:32][CH2:33][CH2:34][N:11]2[CH2:12][CH2:13][C:6]3([O:5][C:4](=[O:14])[N:3]([CH2:1][CH3:2])[C:7]3=[CH2:8])[CH2:9][CH2:10]2)=[CH:29][CH:30]=1
Reactant: Fc1ccc(C(=CCCCl)c2ccc(F)cc2)cc1
Reactant: C=C1N(CC)C(=O)OC12CCNCC2
Agent: [I-]
Agent: [K+]
Solvent: CCC(C)=O
Solvent: CCN(CC)CC
Product: C=C1N(CC)C(=O)OC12CCN(CCC=C(c1ccc(F)cc1)c1ccc(F)cc1)CC2
Reaction time: 15 h
Yield: 68.7 %

Procedure:
A mixture containing 7.8 g of 3-ethyl-4-methylene-2-oxo-1-oxa-3,8-diazaspiro[4,5]decane, 8.5 ml of anhydrous triethylamine, 80 ml of anhydrous methyl ethyl ketone, 0.3 g of potassium iodide and 16.7 g of 4,4-bis(4-fluorophenyl)-3-butenyl chloride is refluxed under nitrogen while stirring for 15 hours, then the solvent is distilled off under reduced pressure. After adding benzene and water to the residue, the benzene layer is washed with water to neutral, dried over anhydrous magnesium sulfate, filtered through an aluminum oxide bed and evaporated under reduced pressure. After recrystallizing the residue from ethanol, the title product is obtained in 68.7% yield, m.p.: 138°-139° C.
Reaction SMILES: [Cl-].[NH4+].Cl[C:4]1(Cl)[C:17](=[O:18])[CH2:16][C:5]21[CH2:8][N:7]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:6]2>CO.O.[Zn]>[O:18]=[C:17]1[CH2:4][C:5]2([CH2:6][N:7]([C:9]([O:11][C:12]([CH3:14])([CH3:13])[CH3:15])=[O:10])[CH2:8]2)[CH2:16]1
Reactant: CC(C)(C)OC(=O)N1CC2(CC(=O)C2(Cl)Cl)C1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)N1CC2(CC(=O)C2)C1
Temperature: 25 °C
Reaction time: 12 h
Yield: 17.9 %

Procedure:
15.13 g (0.283 mmol) of ammonium chloride are added to a solution containing 13.21 g (47.15 mmol) of tert-butyl 5,5-dichloro-6-oxo-2-azaspiro[3.3]heptane-2-carboxylate, obtained in the preceding step, in 250 mL of methanol. The reaction medium is cooled with the aid of an ice/water bath, and 30.83 g (0.471 mmol) of zinc are added. After stirring at room temperature for 12 hours, the Celite is filtered off and rinsed with methanol. The filtrate is evaporated to dryness. The residue obtained is taken up in water and extracted several times with ethyl acetate. The combined organic phases are dried over sodium sulfate and the filtrate is concentrated under reduced pressure. After evaporating off the solvent, the residue obtained is purified by chromatography on silica gel, eluting with a 90/10 mixture of cyclohexane and ethyl acetate. 1.78 g of pure product are thus obtained in the form of a white powder.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[CH2:10][N:9]([C@H:12]([CH:16]([CH3:18])[CH3:17])[C:13](O)=[O:14])[C:8](=[O:19])[C:7]3=[CH:20][NH:21][C:5]([C:6]=23)=[N:4][CH:3]=1.[NH2:22][C:23]1[CH:24]=[C:25]([CH:28]=[CH:29][CH:30]=1)[C:26]#[N:27].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C1COCC1>[Cl:1][C:2]1[C:11]2[CH2:10][N:9]([C@H:12]([CH:16]([CH3:17])[CH3:18])[C:13]([NH:22][C:23]3[CH:30]=[CH:29][CH:28]=[C:25]([C:26]#[N:27])[CH:24]=3)=[O:14])[C:8](=[O:19])[C:7]3=[CH:20][NH:21][C:5]([C:6]=23)=[N:4][CH:3]=1
Reactant: CC(C)[C@H](C(=O)O)N1Cc2c(Cl)cnc3[nH]cc(c23)C1=O
Reactant: N#Cc1cccc(N)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Product: CC(C)[C@H](C(=O)Nc1cccc(C#N)c1)N1Cc2c(Cl)cnc3[nH]cc(c23)C1=O
Yield: 13.8 %

Procedure:
To an 8 mL scintillation vial equipped for stirring was added (R)-2-(6-chloro-3-oxopyrrolo[4,3,2-de][2,6]naphthyridin-4(1H,3H,5H)-yl)-3-methylbutanoic acid (10 mg, 0.032 mmol). THF (0.5 mL), 3-aminobenzonitrile (7.68 mg, 0.065 mmol) and HATU (14.83 mg, 0.039 mmol) were added and the solution was stirred at 25° C. for 1 h. The reaction mixture was purified via preparative mass trigger LC-MS (AcCN/H2O, 5-50%). The fractions were collected, concentrated, and dried in vacuo to afford the title compound as a yellow oil (1.8 mg, 13.58%). 1H NMR (400 MHz, CD3OD) δ 1.00 (d, J=6.60 Hz, 3 H) 1.12 (d, J=6.57 Hz, 3 H) 2.60 (s, 1 H) 5.02 (d, J=19.71 Hz, 1 H) 5.20 (d, J=11.12 Hz, 1 H) 5.43 (d, J=19.71 Hz, 1 H) 7.43 (dt, J=7.77, 1.42 Hz, 1 H) 7.48 (t, J=7.96 Hz, 1 H) 7.81-7.85 (m, 1 H) 7.86 (s, 1 H) 8.08 (t, J=1.64 Hz, 1 H) 8.25 (s, 1 H). [M+H] calc'd for C21H18ClN5O2, 408; found, 408.4.
Reaction SMILES: [NH2:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][C:5]([C:6](O)=[O:7])=[C:4]([CH3:14])[CH:3]=1.S(Cl)([Cl:17])=O>ClC(Cl)C>[NH2:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][C:5]([C:6]([Cl:17])=[O:7])=[C:4]([CH3:14])[CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: Cc1cc(N)c([N+](=O)[O-])cc1C(=O)O
Solvent: CC(Cl)Cl
Product: Cc1cc(N)c([N+](=O)[O-])cc1C(=O)Cl

Procedure:
Prepared analogously to example 53a from 4-amino-2-methyl-5-nitro-benzoic acid and thionyl chloride in dichloroethane.