Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1COCC1.[NH:6]1[CH2:20][CH2:19][CH2:18][C@H:7]1[C:8]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9].Cl.C1C=CC2N(O)N=NC=2C=1.[NH:32]([C:46]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:47])[C@H:33]([C:43](O)=[O:44])[CH2:34][O:35][CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>CN(C=O)C>[NH:32]([C:46]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:47])[C@H:33]([C:43]([N:6]1[CH2:20][CH2:19][CH2:18][C@H:7]1[C:8]([O:10][CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)=[O:9])=[O:44])[CH2:34][O:35][CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: O=C(OCc1ccccc1)[C@@H]1CCCN1
Reactant: CC(C)(C)OC(=O)N[C@@H](COCc1ccccc1)C(=O)O
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@@H](COCc1ccccc1)C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
THF (100 ml, H-Pro-OBzl.HCl (31.5 g, 0.13 M) and HOBT (17.5 g, 0.13 M) were added to BOC-Ser(Bzl)-OH (35.4 g, 0.12 M), and then DMF (50 ml) was added thereto to prepare a solution. WSCI (24.8 ml) was added dropwise and stirred at 0° C. for one hour and then at room temperature overnight. The solvent was distilled off in vacuo and benzene was added to the residue, which was then washed three times with 5% sodium bicarbonate solution, three times with 1 N HCl and three times with water, in that order. After drying with anhydrous sodium sulfate, the solution was dried in vacuo to obtain the substance [17] as an oil material (58 g, yield: 100%).
Reaction SMILES: C([S:4][C@@H:5]1[CH2:9][N:8]([C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=2)=[O:11])[C@H:7]([CH2:23][O:24][CH2:25][C:26]([O:28][CH2:29][CH:30]=[CH2:31])=[O:27])[CH2:6]1)(=O)C.[H-].[Na+].C(O)(=O)C>C(O)C=C.C(OCC)(=O)C>[CH2:29]([O:28][C:26]([CH2:25][O:24][CH2:23][C@@H:7]1[CH2:6][C@H:5]([SH:4])[CH2:9][N:8]1[C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=1)=[O:11])=[O:27])[CH:30]=[CH2:31]
Reactant: C=CCOC(=O)COC[C@@H]1C[C@H](SC(C)=O)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C=CCO
Solvent: CC(=O)O
Product: C=CCOC(=O)COC[C@@H]1C[C@H](S)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1
Reaction time: 1 h
Yield: 59.4 %

Procedure:
To a solution of (2S,4S)-4-acetylthio- 2-(allyloxycarbonylmethyloxymethyl)-1-(4-nitrobenzyloxycarbonyl)pyrrolidine (4.25 g) in allyl alcohol (40 ml) was added sodium hydride (62.8% in oil suspension) (0.5 g) at -5°~0° C. in a nitrogen stream. After stirring for 1 hour, acetic acid (1 ml) was added to the mixture. The mixture was concentrated under reduced pressure to give a syrup. The syrup was dissolved in ethyl acetate (50 ml), washed in turn with water (50 ml) and brine (50 ml), dried over magnesium sulfate, and concentrated under reduced pressure to give a syrup. The syrup was subjected to a column chromatography on silica gel (30 g) and eluted with chloroform to give (2S,4S)-2-(allyloxycarbonylmethyloxymethyl)-4-mercapto-1-(4-nitrobenzyloxycarbonyl)pyrrolidine (2.29 g).
Reaction SMILES: O.NN.C1(=O)[N:8]([CH2:9][CH2:10][CH2:11][S:12][C:13]2[O:14][CH:15]=[CH:16][N:17]=2)C(=O)C2=CC=CC=C12>C(O)C>[NH2:8][CH2:9][CH2:10][CH2:11][S:12][C:13]1[O:14][CH:15]=[CH:16][N:17]=1
Reactant: O=C1c2ccccc2C(=O)N1CCCSc1ncco1
Agent: NN
Solvent: CCO
Solvent: O
Product: NCCCSc1ncco1

Procedure:
Hydrazine hydrate (5.3 g.) was added carefully to a solution of 2-(3-phthalimidopropylthio)oxazole (10 g.) in ethanol (173 ml.) with stirring. The solution was then heated under reflux for 25 minutes. After cooling, and filtration from phthalhydrazide, the filtrate was concentrated under reduced pressure and the residue was re-evaporated with ethanol to yield crude 2-(3-aminopropylthio)-oxazole which was washed twice with ether and dissolved in ethanol (60 ml.). Methyl isothiocyanate (2.54 g.) was added and the solution was heated under reflux for 30 minutes. Following cooling and filtration from insoluble material, the filtrate was concentrated to an oil which was chromatographed on a column of silica gel with ethyl acetate as eluant. The product obtained crystallised from ethanol-ether-n-hexane to give N-methyl-N'-[3-(2-oxazoylyl)-thiopropyl]thiourea (2.4 g.), m.p. 43°-45°.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([C:13]1[C:21]2[C:16](=[CH:17][C:18]([CH3:29])=[C:19]([O:22][C:23]3[CH:24]=[N:25][CH:26]=[N:27][CH:28]=3)[CH:20]=2)[NH:15][CH:14]=1)[CH2:9][N+:10]([O-])=O>CO.[Ni]>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([C:13]1[C:21]2[C:16](=[CH:17][C:18]([CH3:29])=[C:19]([O:22][C:23]3[CH:24]=[N:25][CH:26]=[N:27][CH:28]=3)[CH:20]=2)[NH:15][CH:14]=1)[CH2:9][NH2:10]
Reactant: Cc1cc2[nH]cc(C(C[N+](=O)[O-])c3ccccc3F)c2cc1Oc1cncnc1
Agent: [Ni]
Solvent: CO
Product: Cc1cc2[nH]cc(C(CN)c3ccccc3F)c2cc1Oc1cncnc1
Reaction time: 3 h
Yield: 91.7 %

Procedure:
To a spatula of Raney-Ni in a hydrogenation flask was added 3-(1-(2-fluorophenyl)-2-nitroethyl)-6-methyl-5-(pyrimidin-5-yloxy)-1H-indole (0.284 g, 0.724 mmol) in methanol (12.06 mL). The reaction was hydrogenated at 53 psi. After 3 hr, the vessel was evacuated and flushed with nitrogen. The solution was filtered through a pad of CELITE® and rinsed with MeOH. The filtrate was concentrated in vacuo, dissolved in CH2Cl2, dried over Na2SO4, filtered and concentrated in vacuo to give the desired product (0.2405 g, 0.664 mmol, 92% yield).
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[C:7]([N:13]2[N:22]=[CH:21][C:20]3[C:15](=[C:16]([F:27])[CH:17]=[C:18]([C:23]([CH3:26])([CH3:25])[CH3:24])[CH:19]=3)[C:14]2=[O:28])=[N:8][CH:9]=[CH:10][C:11]=1Cl)(=[O:3])[CH3:2].[B:29]1(B2OC(C)(C)C(C)(C)O2)[O:33]C(C)(C)C(C)(C)[O:30]1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.C([O-])(=O)C.[K+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O1CCOCC1>[C:1]([O:4][CH2:5][C:6]1[C:7]([N:13]2[N:22]=[CH:21][C:20]3[C:15](=[C:16]([F:27])[CH:17]=[C:18]([C:23]([CH3:26])([CH3:25])[CH3:24])[CH:19]=3)[C:14]2=[O:28])=[N:8][CH:9]=[CH:10][C:11]=1[B:29]([OH:33])[OH:30])(=[O:3])[CH3:2]
Reactant: CC1(C)OB(B2OC(C)(C)C(C)(C)O2)OC1(C)C
Reactant: CC(=O)OCc1c(Cl)ccnc1-n1ncc2cc(C(C)(C)C)cc(F)c2c1=O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: C1COCCO1
Product: CC(=O)OCc1c(B(O)O)ccnc1-n1ncc2cc(C(C)(C)C)cc(F)c2c1=O
Temperature: 65 °C
Yield: 96.8 %

Procedure:
A 100-mL single-neck round-bottomed flask equipped with a magnetic stirrer and a reflux condenser was charged with 116b (1.0 g, 2.5 mmol), Pin2B2 (3.2 g, 12.5 mmol), Pd(dppf)Cl2 (75 mg, 0.125 mmol), X-phos (75 mg, 0.25 mmol), potassium acetate (750 mg, 7.5 mmol), and dioxane (60 mL). After three cycles of vacuum/argon flush, the mixture was heated at 65° C. for 15 h. It was then cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure and the resulting residue was washed with 3:1 petroleum ether/ethyl acetate (10 mL) to afford 116c as yellow solid (1.0 g, LCMS purity: 75%). MS: [M+H]+ 414.2.
Reaction SMILES: [CH:1](=[C:8]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].C(=O)(O)[O-:20].[K+].OO>CO>[CH2:2]([CH:1]1[O:20][C:8]1([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CCCCCCC=C(C(=O)OCC)C(=O)OCC
Reactant: O=C([O-])O
Agent: OO
Agent: [K+]
Solvent: CO
Product: CCCCCCC1OC1(C(=O)OCC)C(=O)OCC
Reaction time: 16 h

Procedure:
A mixture of 31 g of diethyl heptylidenepropanedioate (B. Wojcik and H. Adkins, J. Am. Chem. Soc., 56, 2424 (1934), prepared by the method of A. C. Cope and K. E. Hoyle, J. Am. Chem. Soc., 63, 733 (1941)), 5 g of potassium bicarbonate and 17 g of 30% hydrogen peroxide in 200 ml of methanol was stirred for two hours at 40° C., then allowed to stand at 20° C. for 16 hours. The mixture then was concentrated to 50 ml; 100 ml of water was added and the solution was extracted with two 50-ml volumes of methylene chloride. The solvent was evaporated to give a colorless liquid, which was vacuum distilled to give diethyl 3-hexyloxiranedicarboxylate (2A), bp: 117°-126° C. at 0.1 Torr.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH:17]([CH3:18])[CH2:16][C:15]3[C:10](=[CH:11][C:12]([C:19]4[CH:20]=[CH:21][C:22]([C:25](O)=[O:26])=[N:23][CH:24]=4)=[CH:13][CH:14]=3)[CH2:9]2)[CH:5]=[C:4]([N:28]2[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]2)[N:3]=1.Cl.[NH:36]1[CH2:39][CH:38]([C:40]#[N:41])[CH2:37]1>>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH:17]([CH3:18])[CH2:16][C:15]3[C:10](=[CH:11][C:12]([C:19]4[CH:20]=[CH:21][C:22]([C:25]([N:36]5[CH2:39][CH:38]([C:40]#[N:41])[CH2:37]5)=[O:26])=[N:23][CH:24]=4)=[CH:13][CH:14]=3)[CH2:9]2)[CH:5]=[C:4]([N:28]2[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]2)[N:3]=1
Reactant: CC1Cc2ccc(-c3ccc(C(=O)O)nc3)cc2CN1c1cc(N2CCN(C)CC2)nc(N)n1
Reactant: N#CC1CNC1
Agent: Cl
Product: CC1Cc2ccc(-c3ccc(C(=O)N4CC(C#N)C4)nc3)cc2CN1c1cc(N2CCN(C)CC2)nc(N)n1

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 50A starting from 5-{2-[2-amino-6-(4-methylpiperazin-1-yl)pyrimidin-4-yl]-3-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl}pyridine-2-carboxylic acid (Example 50A, Step 1) and azetidine-3-carbonitrile hydrochloride (Astatech, Cat. No. 52028). LCMS (M+H)+: m/z=524.3.
Reaction SMILES: [C:1]12([CH2:11][CH:12]3[C:17]4[NH:18][C:19]5[C:24]([C:16]=4[CH2:15][CH2:14][NH:13]3)=[CH:23][CH:22]=[CH:21][CH:20]=5)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[C:25]1(=[O:31])[O:30][C:28](=[O:29])[CH2:27][CH2:26]1>O1CCOCC1>[C:1]12([CH2:11][CH:12]3[C:17]4[NH:18][C:19]5[C:24]([C:16]=4[CH2:15][CH2:14][N:13]3[C:25]([CH2:26][CH2:27][C:28]([OH:30])=[O:29])=[O:31])=[CH:23][CH:22]=[CH:21][CH:20]=5)[CH2:10][CH:5]3[CH2:4][CH:3]([CH2:9][CH:7]([CH2:6]3)[CH2:8]1)[CH2:2]2
Reactant: c1ccc2c3c([nH]c2c1)C(CC12CC4CC(CC(C4)C1)C2)NCC3
Reactant: O=C1CCC(=O)O1
Solvent: C1COCCO1
Product: O=C(O)CCC(=O)N1CCc2c([nH]c3ccccc23)C1CC12CC3CC(CC(C3)C1)C2

Procedure:
A mixture of (R/S)-1-(1-adamantyl)methyl-1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indole (640 mg, 2.0 mmol) and succinic anhydride (250 mg, 2.5 mmol) was stirred in dioxan (5 ml) at room temperature for 17 hours. The white precipiate which had formed was isolated by filtration, washed with dioxan and dried. (640 mg, 76%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([NH:11][C:12]([CH:14]2[CH2:18][CH:17]([O:19][C:20]3[CH:25]=[C:24]([C:26]([CH3:29])([CH3:28])[CH3:27])[N:23]=[C:22]([O:30][CH3:31])[N:21]=3)[CH2:16][CH:15]2[C:32](=[O:41])[N:33]([CH2:35][CH2:36][CH2:37][CH2:38][CH:39]=C)[CH3:34])=[O:13])[CH2:8][CH:7]1[CH:9]=C)=[O:5])[CH3:2]>CC1C=C(C)C(N2C(=[Ru](Cl)(Cl)=CC3C=CC=CC=3OC(C)C)N(C3C(C)=CC(C)=CC=3C)CC2)=C(C)C=1>[CH2:1]([O:3][C:4]([C:6]12[CH2:8][CH:7]1[CH:9]=[CH:39][CH2:38][CH2:37][CH2:36][CH2:35][N:33]([CH3:34])[C:32](=[O:41])[CH:15]1[CH:14]([CH2:18][CH:17]([O:19][C:20]3[CH:25]=[C:24]([C:26]([CH3:28])([CH3:29])[CH3:27])[N:23]=[C:22]([O:30][CH3:31])[N:21]=3)[CH2:16]1)[C:12](=[O:13])[NH:11]2)=[O:5])[CH3:2]
Reactant: C=CCCCCN(C)C(=O)C1CC(Oc2cc(C(C)(C)C)nc(OC)n2)CC1C(=O)NC1(C(=O)OCC)CC1C=C
Agent: Cc1cc(C)c(N2CCN(c3c(C)cc(C)cc3C)C2=[Ru](Cl)(Cl)=Cc2ccccc2OC(C)C)c(C)c1
Product: CCOC(=O)C12CC1C=CCCCCN(C)C(=O)C1CC(Oc3cc(C(C)(C)C)nc(OC)n3)CC1C(=O)N2
Yield: 74.1 %

Procedure:
Compound 3h (500 mg, 0.87 mmol) and Hoveyda-Grubbs catalyst, 2nd generation (50 mg) were dissolved in degassed and dry DCE (500 ml). The mixture was heated to reflux over night under N2-atmosphere. The material was mixed with silica, the solvent was evaporated and the residue was purified by column chromatography, EtOAc/Heptane 30:70→50:50 which gave the title compound (350 mg, 74%), MS (M+H)+543.
Reaction SMILES: [Cl-].[Cl-].[Cl-].[Al+3].[H-].[Al+3].[Li+].[H-].[H-].[H-].[CH:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][C:12]=1[CH2:21][C:22]#[N:23]>CCOCC>[CH:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][C:12]=1[CH2:21][CH2:22][NH2:23]
Reactant: N#CCc1ccc2ccccc2c1
Agent: [Al+3]
Agent: [Cl-]
Agent: [H-]
Solvent: CCOCC
Product: NCCc1ccc2ccccc2c1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 65.7 %

Procedure:
Aluminum trichloride (7.6 g, 57 mmole) was added in portions to 30 mL of ether cooled to 0° C. under nitrogen. In a separate flask, lithium aluminum hydride (2.2 g, 57 mmole) was slurried in 30 mL of ether and cooled to -5° C. with an ice/acetone bath. The etherial aluminum trichloride solution was added dropwise to the LiAlH4 slurry at such a rate as to maintain a temperature of 0° C. Fifteen minutes after addition was complete, 2-naphthylacetonitrile (4.0 g, 24 mmole) in 40 mL of ether was added dropwise while maintaining a temperature of 0° C. The reaction mixture was stirred for an additional 15 minutes at 0° C. and then allowed to warm to room temperature for 1 hour. After recooling to 0° C., the reaction was quenched by careful dropwise addition of water. The mixture was diluted with ether, partitioned, and the aqueous phase was basified with 30% NH4OH solution. Extraction of the aqueous phase with ether, combination of the organic phases, drying, and concentration gave a colorless oil (2.7g, 67% yield).
Reaction SMILES: [C:1]1([S:7][CH2:8][C@H:9]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([S:21](=[O:24])(=[O:23])[NH2:22])=[CH:17][C:16]=2[S:25]([C:28]([F:31])([F:30])[F:29])(=[O:27])=[O:26])[CH2:10][C:11](O)=[O:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[Si:33]([O:50][CH2:51][C@@H:52]1[CH2:57][O:56][CH2:55][CH2:54][NH:53]1)([C:46]([CH3:49])([CH3:48])[CH3:47])([C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[Si:33]([O:50][CH2:51][C@H:52]1[N:53]([C:11](=[O:12])[CH2:10][C@@H:9]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([S:21]([NH2:22])(=[O:24])=[O:23])=[CH:17][C:16]=2[S:25]([C:28]([F:30])([F:31])[F:29])(=[O:27])=[O:26])[CH2:8][S:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:54][CH2:55][O:56][CH2:57]1)([C:46]([CH3:47])([CH3:48])[CH3:49])([C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1
Reactant: CC(C)(C)[Si](OC[C@@H]1COCCN1)(c1ccccc1)c1ccccc1
Reactant: NS(=O)(=O)c1ccc(N[C@@H](CSc2ccccc2)CC(=O)O)c(S(=O)(=O)C(F)(F)F)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)[Si](OC[C@@H]1COCCN1C(=O)C[C@H](CSc1ccccc1)Nc1ccc(S(N)(=O)=O)cc1S(=O)(=O)C(F)(F)F)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 37.4 %

Procedure:
(R)-4-(Phenylthio)-3-(4-sulfamoyl-2-(trifluoromethylsulfonyl)phenylamino)butanoic acid (INTERMEDIATE 8, 0.8 g, 1.60 mmol) was added to a solution of (S)-3-((tert-butyldiphenylsilyloxy)methyl)morpholine, hydrochloride salt (INTERMEDIATE 103, 0.57 g, 1.60 mmol), DIPEA (0.84 ml, 4.81 mmol) and HATU (0.92 g, 2.41 mmol) in DCM (10 ml) and the resulting mixture was stirred at room temperature for 2 hours. The mixture was diluted with DCM and washed with H2O (2×), 1N aq. NaHSO4 and saturated aq. NaHCO3. The organic layer was dried (Na2SO4), concentrated under reduced pressure and purified by column chromatography (ISCO, eluting with 0→100% DCM/10% MeOH in DCM) to provide the title product (0.5 g, yield: 37%).
Reaction SMILES: [NH2:1][C:2]1[C:3](Cl)=[N:4][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:7]=1.[CH3:13][O:14][C:15]1[CH:22]=[CH:21][C:18]([CH2:19][NH2:20])=[CH:17][CH:16]=1.C(=O)(O)[O-].[Na+]>C(O)CC(C)C.CO>[CH3:13][O:14][C:15]1[CH:22]=[CH:21][C:18]([CH2:19][NH:20][C:3]2[C:2]([NH2:1])=[CH:7][CH:6]=[C:5]([C:8]([F:11])([F:10])[F:9])[N:4]=2)=[CH:17][CH:16]=1
Reactant: COc1ccc(CN)cc1
Reactant: Nc1ccc(C(F)(F)F)nc1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)CCO
Solvent: CO
Product: COc1ccc(CNc2nc(C(F)(F)F)ccc2N)cc1
Temperature: 220 °C

Procedure:
A mixture of the 3-amino-2-chloro-6-(trifluoromethyl)pyridine (416 mg, 2.1 mmol, Matrix), 4-methoxy-benzylamine (294 mg, 2.1 mmol, Aldrich) and sodium bicarbonate (265 mg, 3.2 mmol) in isoamyl alcohol (0.6 mL) was heated at 220° C. in a microwave synthesizer for 30 min. The reaction mixture was then cooled to room temperature, diluted with MeOH (5 mL), filtered and the filtrate was evaporated in vacuo. The residue was purified by preparative HPLC (gradient 0.1% trifluoroacetic acid in acetonitrile) to give the title compound as a yellow oil. MS (ESI, pos. ion) m/z: 298 (M+1)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[Cl:12])[N:8]=[C:7]([Br:13])[C:6]([CH2:14]Br)=[CH:5]2.[CH3:16][O:17][P:18]([O:21]C)[O:19][CH3:20]>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[Cl:12])[N:8]=[C:7]([Br:13])[C:6]([CH2:14][P:18]([O:19][CH3:20])([O:17][CH3:16])=[O:21])=[CH:5]2
Reactant: Clc1cc2cc(CBr)c(Br)nc2cc1Cl
Reactant: COP(OC)OC
Product: COP(=O)(Cc1cc2cc(Cl)c(Cl)cc2nc1Br)OC

Procedure:
A mixture of 6,7-dichloro-2-bromo-3-bromomethylquinoline (0.74 g, 2 mmol) and trimethylphosphite (5 ml) was heated at 80°-90° C. for 2-3h. Then the excess trimethylphosphite was removed in vacuo at 70°-80° C. and the oily residue was made crystalline by treating with hexane-ethyl ether (1:1). The crystalls were collected, washed with toluene and dried in vacuo to give 0.65 g of 6,7-dichloro-3-dimethylphosphonomethyl-2-bromoquinoline.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[N:8]([C:9]([C:11]2[N:12]=[C:13]([CH3:23])[S:14][C:15]=2[C:16]2[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=2)=[O:10])[CH2:7][C@H:6]2[C@@H:4]1[CH2:5]2.[CH3:24][C:25]1[CH:26]=[C:27]([CH:31]=[CH:32][C:33]=1[CH3:34])[C:28](O)=[O:29]>>[CH3:24][C:25]1[CH:26]=[C:27]([CH:31]=[CH:32][C:33]=1[CH3:34])[C:28]([NH:1][CH2:2][C@H:3]1[N:8]([C:9]([C:11]2[N:12]=[C:13]([CH3:23])[S:14][C:15]=2[C:16]2[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=2)=[O:10])[CH2:7][C@H:6]2[C@@H:4]1[CH2:5]2)=[O:29]
Reactant: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CN)c1
Reactant: Cc1ccc(C(=O)O)cc1C
Product: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CNC(=O)c2ccc(C)c(C)c2)c1

Procedure:
prepared by reaction of ((1S,2S,5R)-2-Aminomethyl-3-aza-bicyclo[3.1.0]hex-3-yl)-(2-methyl-5-m-tolyl-thiazol-4-yl)-methanone with 3,4-Dimethyl-benzoic acid.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]2[C:6]3[CH:15]=[CH:14][CH:13]=[CH:12][C:7]=3[CH2:8][CH2:9][C:10]=2[CH:11]=1.[NH2:16][NH2:17]>N1C=CC=CC=1>[NH:16]([C:2]1[N:3]=[N:4][C:5]2[C:6]3[CH:15]=[CH:14][CH:13]=[CH:12][C:7]=3[CH2:8][CH2:9][C:10]=2[CH:11]=1)[NH2:17]
Reactant: NN
Reactant: Clc1cc2c(nn1)-c1ccccc1CC2
Solvent: c1ccncc1
Product: NNc1cc2c(nn1)-c1ccccc1CC2

Procedure:
3-Chloro-5,6-dihydrobenzo[h]cinnoline was heated at 100° C. in a mixture of anhydrous pyridine (30 mL) and anhydrous hydrazine (5 mL) for 3.25 h. The solvent was removed under vacuum and the residue was partitioned between chloroform and 1M aqueous potassium carbonate solution. The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was triturated with diethyl ether and filtered to give 3-hydrazinyl-5,6-dihydrobenzo[h]cinnoline as a beige solid; 1H NMR (DMSO-d6, 300 MHz) 8.17 (d, 1H), 7.91 (br s, 1H), 7.28 (m, 3H), 6.87 (s, 1H), 4.34 (br s, 2H), 2.92 (m, 4H) ppm; 13C NMR (DMSO-d6, 75 MHz) 162.49, 147.92, 137.95, 137.39, 132.97, 128.87, 128.75, 127.56, 123.59, 110.55, 28.01, 27.66; MS (ES) 213 (M+H).
Reaction SMILES: [Na+].[C:2]([C:4]1[CH:5]=[C:6]([CH:12]=[CH:13][CH:14]=1)[CH2:7][S:8]([O-])(=[O:10])=[O:9])#[N:3].P(Cl)(Cl)(Cl)(Cl)[Cl:16]>P(Cl)(Cl)(Cl)=O>[C:2]([C:4]1[CH:5]=[C:6]([CH:12]=[CH:13][CH:14]=1)[CH2:7][S:8]([Cl:16])(=[O:10])=[O:9])#[N:3]
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: N#Cc1cccc(CS(=O)(=O)[O-])c1
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Product: N#Cc1cccc(CS(=O)(=O)Cl)c1
Temperature: 80 °C
Reaction time: 0.25 h

Procedure:
5 g (22.83 mmol) of 3-cyanobenzylsulfonic acid sodium salt were moistened with approx. 20 ml of phosphoryl chloride, after which 5.2 g (25.11 mmol) of PCl5 were added and the mixture was stirred for 15 min while being cooled with ice. The mixture was then heated at 80° C. for 4 h. After that, the mixture was poured onto ice and stirred vigorously for 30 min in connection with which the product sedimented as a white solid on the ice. After the ice had been partially thawed, the mixture was filtered through a frit and the product/ice mixture which remained was washed several times with water. The crystals which remained were dried in vacuo and used directly for the next step in the synthesis.
Reaction SMILES: I[C:2]1[N:3]=[CH:4][N:5]([CH3:7])[CH:6]=1.CC[Mg+].[Br-].[Sn:12](Cl)([CH2:21][CH2:22][CH2:23][CH3:24])([CH2:17][CH2:18][CH2:19][CH3:20])[CH2:13][CH2:14][CH2:15][CH3:16]>C(Cl)Cl>[CH2:21]([Sn:12]([CH2:13][CH2:14][CH2:15][CH3:16])([CH2:17][CH2:18][CH2:19][CH3:20])[C:2]1[N:3]=[CH:4][N:5]([CH3:7])[CH:6]=1)[CH2:22][CH2:23][CH3:24]
Reactant: Cn1cnc(I)c1
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Agent: CC[Mg+]
Agent: [Br-]
Solvent: ClCCl
Product: CCCC[Sn](CCCC)(CCCC)c1cn(C)cn1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 4-iodo-1-methylimidazole (0.424 g, 2.04 mmol) in CH2Cl2 at rt was added EtMgBr (3.0 M in Et2O, 0.75 mL, 2.25 mmol) and the resulting solution was allowed to stir for 30 min at rt. To this solution was then added Bu3SnCl (0.60 mL, 2.21 mmol) and the mixture was stirred for another 7 h. The resulting mixture was then washed (sat. NH4C1, H2O, brine), dried (Na2SO4) and evaporated to give the title compound, which was used directly in the following step without further purification:
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1>C1(C)C=CC=CC=1>[CH3:1][C@H:2]1[CH2:11][NH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[NH:3]1
Reactant: Cc1cnc2ccccc2n1
Solvent: Cc1ccccc1
Product: C[C@H]1CNc2ccccc2N1
Temperature: 40 °C
Reaction time: 13 h
Yield: 97 %

Procedure:
To an argon-purged pressure-resistant glass vessel (100 mL) equipped with a magnetic stir bar, RuCl[(R)-daipena][(R)-dm-segphos] (3.1 mg, 2.6 μmol) and KO(t-Bu) (14.1 mg, 0.126 mmol) were added, and the vessel was purged with argon again. To this vessel, a toluene (2.5 mL) solution containing 2-methylquinoxaline (355.4 mg, 2.47 mmol) and being degassed by the freeze-pump-thaw technique in advance was added by pressure transfer using a cannula. An operation in which hydrogen was introduced into the pressure-resistant vessel up to 0.8 MPa and then released was repeated 10 times to completely substitute the inside with hydrogen. Then, hydrogen was introduced up to 2.0 MPa, and the vessel was stirred in a water bath at 40° C. for 13 hours. After hydrogen was released, the solution was concentrated under reduced pressure, and the residue was purified through a silica gel short path column (hexane:ethyl acetate=1:1) to obtain (S)-1,2,3,4-tetrahydro-2-methylquinoxaline (355.1 mg, 970). A result of an analysis conducted by gas chromatography (column: CHIRASIL-DEX CB) showed that the optical purity of this product was 99% ee or higher.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2[NH:17][C:18]1[CH:19]=[CH:20][C:21]([O:24][CH2:25][CH2:26][NH:27]C(=O)OC(C)(C)C)=[N:22][CH:23]=1.[Cl:35][C:36]1[CH:41]=[C:40](B2OC(C)(C)C(C)(C)O2)[CH:39]=[C:38]([Cl:51])[C:37]=1[OH:52]>>[NH2:27][CH2:26][CH2:25][O:24][C:21]1[N:22]=[CH:23][C:18]([NH:17][C:5]2[C:4]3[C:9](=[CH:10][CH:11]=[C:2]([C:40]4[CH:41]=[C:36]([Cl:35])[C:37]([OH:52])=[C:38]([Cl:51])[CH:39]=4)[CH:3]=3)[N:8]=[CH:7][C:6]=2[C:12]([CH:14]2[CH2:15][CH2:16]2)=[O:13])=[CH:19][CH:20]=1
Reactant: CC(C)(C)OC(=O)NCCOc1ccc(Nc2c(C(=O)C3CC3)cnc3ccc(Br)cc23)cn1
Reactant: CC1(C)OB(c2cc(Cl)c(O)c(Cl)c2)OC1(C)C
Product: NCCOc1ccc(Nc2c(C(=O)C3CC3)cnc3ccc(-c4cc(Cl)c(O)c(Cl)c4)cc23)cn1
Yield: 21.7 %

Procedure:
Following general procedure D, tert-butyl 2-(5-(6-bromo-3-(cyclopropanecarbonyl)quinolin-4-ylamino)pyridin-2-yloxy)ethylcarbamate (100 mg, 0.19 mmol) was reacted with 2,6-dichloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (81 mg, 0.28 mmol) to obtain the protected intermediate which was subjected to general procedure A-2 to afford the desired product (21 mg, 22% over two steps) as a yellow solid: 1H NMR (500 MHz, CD3OD+TFA-d) δ 9.40 (s, 1H), 8.33-8.24 (m, 2H), 8.13-8.04 (m, 2H), 7.83 (dd, J=8.8, 2.8 Hz, 1H), 7.37 (s, 2H), 7.14 (d, J=8.8 Hz, 1H), 4.66 (t, J=5.1 Hz, 2H), 3.43 (t, J=5.1 Hz, 2H), 2.87-2.80 (m, 1H), 1.22-1.15 (m, 4H); ESI MS m/z 509 [C26H22Cl2N4O3+H]+; HPLC 99.7% (AUC), tR=11.26 min.