Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][CH:3]=[CH:4][CH2:5][N:6]1[C:10](=[O:11])[C:9]2=[CH:12][CH:13]=[CH:14][CH:15]=[C:8]2[C:7]1=[O:16].[C:17]1([CH:23]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[N:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[Na+]>CN(C)C=O>[C:30]1([CH:23]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:24]2[CH2:25][CH2:26][N:27]([CH2:2][CH:3]=[CH:4][CH2:5][N:6]3[C:10](=[O:11])[C:9]4=[CH:12][CH:13]=[CH:14][CH:15]=[C:8]4[C:7]3=[O:16])[CH2:28][CH2:29]2)[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: O=C1c2ccccc2C(=O)N1CC=CCBr
Reactant: c1ccc(C(c2ccccc2)N2CCNCC2)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1CC=CCN1CCN(C(c2ccccc2)c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 20 h
Yield: 50.9 %

Procedure:
A mixture of 5.0 g of N-(4-bromo-2-butenyl)phthalimide [cf. Chem. Ber., 93, 2282 (1960)], 5.0 g of 1-diphenylmethylpiperazine, 3.0 g of potassium carbonate, 3.0 g of sodium iodide, and 100 ml of dimethylformamide is stirred at room temperature for 20 hours. After removal of the dimethylformamide by distillation under reduced pressure below 50° C., 50 ml of water is added, and the aqueous mixture is extracted with three 50-ml portions of chloroform. The combined extracts are washed with water, dried over magnesium sulfate, and concentrated. The residue is chromatographed on silica gel with toluene to give 4.1 g of N-[4-(4-diphenylmethyl-1-piperazinyl)-2-butenyl]phthalimide.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([F:9])[CH:3]=1.[CH:10](O)([CH3:12])[CH3:11].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH:10]([CH3:12])[CH3:11])=[C:4]([F:9])[CH:3]=1
Reactant: CC(C)O
Reactant: Oc1ccc(Br)cc1F
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)Oc1ccc(Br)cc1F
Temperature: 45 °C
Yield: 107.4 %

Procedure:
To a solution of 4-bromo-2-fluorophenol (10 g, 52.35 mmol) in THF (100 ml), isopropyl alcohol (4.8 ml, 62.62 mmol) and triphenylphosphine (20.6 g, 78.52 mmol) were added and heated to 45° C. followed by diisopropylazodicarboxylate (15.4 ml, 78.52 mmol). The mixture was refluxed for 1 h, concentrated and the residue was purified by column chromatography with ethyl acetate: petroleum ether to afford the title compound as a colourless liquid (13.1 g, 99%) which was used without purification in the next step.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]2[N:8]=[C:9]([N:11]([CH:13]3[CH2:15][CH2:14]3)[CH3:12])[N:10]=[C:4]2[CH:3]=1.[C:16](=[O:23])([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[NH2:17]>>[C:19]([O:18][C:16](=[O:23])[NH:17][C:2]1[CH:7]=[CH:6][N:5]2[N:8]=[C:9]([N:11]([CH:13]3[CH2:15][CH2:14]3)[CH3:12])[N:10]=[C:4]2[CH:3]=1)([CH3:22])([CH3:21])[CH3:20]
Reactant: CN(c1nc2cc(Br)ccn2n1)C1CC1
Reactant: CC(C)(C)OC(N)=O
Product: CN(c1nc2cc(NC(=O)OC(C)(C)C)ccn2n1)C1CC1
Yield: 55.2 %

Procedure:
The product was prepared in the same manner as described in example 8e using 7-bromo-N-cyclopropyl-N-methyl-[1,2,4]triazolo[1,5-a]pyridin-2-amine (540 mg, 2.02 mmol) and tert-butyl carbamate (284 mg, 2.43 mmol) as starting materials. The reaction affords [2-(cyclopropyl-methyl-amino)-[1,2,4]triazolo[1,5-a]pyridin-7-yl]-carbamic acid tert-butyl ester (338 mg, 55.03%) as light yellow crystals. mp: 323.1° C., MS: m/z=397.1 (M+H+).
Reaction SMILES: [O:1]([C:8]([NH:10][C@H:11]([C:15]([OH:17])=[O:16])[CH:12]([CH3:14])[CH3:13])=[O:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+:19]>C1(C)C=CC=CC=1.O>[Na+:19].[O:1]([C:8]([NH:10][C@H:11]([C:15]([O-:17])=[O:16])[CH:12]([CH3:14])[CH3:13])=[O:9])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)[C@H](NC(=O)Oc1ccccc1)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)[C@H](NC(=O)Oc1ccccc1)C(=O)[O-]
Temperature: 0 °C
Reaction time: 2 h
Yield: 110.8 %

Procedure:
To a solution of N-phenoxycarbonyl-L-Valine (5.00 g, 21.1 mmol) in 350 mL of toluene cooled to 0° C. in an ice bath was added dropwise a solution of sodium hydroxide (840 mg, 21 mmol) in 2 mL of distilled water. The reaction was stirred at 0° C. for 2 hours and then concentrated under reduced pressure. The residue was chased three time with toluene (150 mL) to afford the title compound as an oil (6.03 g).
Reaction SMILES: Br[C:2]1[C:11]2[CH2:10][O:9][C:8](=[O:12])[NH:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[C:13]([N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1)([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.CC([O-])(C)C.[Na+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:16]([O:15][C:13]([N:20]1[CH2:25][CH2:24][N:23]([C:2]2[C:11]3[CH2:10][O:9][C:8](=[O:12])[NH:7][C:6]=3[CH:5]=[CH:4][CH:3]=2)[CH2:22][CH2:21]1)=[O:14])([CH3:19])([CH3:17])[CH3:18]
Reactant: O=C1Nc2cccc(Br)c2CO1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCN(c2cccc3c2COC(=O)N3)CC1
Temperature: 25 °C
Yield: 30.7 %

Procedure:
A solution of 5-bromo-1,4-dihydro-benzo[d][1,3]oxazin-2-one (96 mg, 0.42 mmol) and 1-Boc-piperazine (100 mg, 0.54 mmol) in 2 ml toluene was added to a mixture of Pd2(dba)3 (8 mg, 0.009 mmol), BINAP (13 mg, 0.022 mmol), NaOt-Bu (121 mg, 1.26 mmol). With stirring, the solution was heated at 95° C.–100° C. for 4 hours and was allowed to cool to room temperature. The reaction mixture was filtered through celite and washed with ethyl acetate. The filtrate was washed with water and brine. After drying over MgSO4, the organic fraction was concentrated in vacuo and the resulting brown residue was purified by prep TLC to give 43 mg 4-(2-oxo-1,4-dihydro-2H-benzo[d][1,3]oxazin-5-yl)-piperazine-1-carboxylic acid tert-butyl ester as a yellow solid (31%).
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[C:6]2=[N:7][CH:8]=[C:9]([N:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)[CH:10]=[C:5]2[NH:4][C:3]1=O.[H-].COCCO[Al+]OCCOC.[Na+].[H-]>C1(C)C=CC=CC=1>[CH3:1][C:2]1([CH3:18])[C:6]2=[N:7][CH:8]=[C:9]([N:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)[CH:10]=[C:5]2[NH:4][CH2:3]1
Reactant: CC1(C)C(=O)Nc2cc(N3CCOCC3)cnc21
Agent: COCCO[Al+]OCCOC
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CC1(C)CNc2cc(N3CCOCC3)cnc21
Temperature: 25 °C

Procedure:
To a stirred suspension of 3,3-dimethyl-6-morpholino-1H-pyrrolo[3,2-b]pyridin-2(3H)-one (425 mg, 1.719 mmol) in toluene (14 mL) at 0° C. was added sodium bis(2-methoxyethoxy)aluminum hydride (3.3 M solution in toluene, 1.56 mL, 5.16 mmol). The reaction was stirred while warming to rt for 4 h. After this time the reaction was carefully quenched with water (5 mL) and then diluted with DCM (50 mL) and treated with saturated aqueous solution Na2S2O3 (20 mL). The separated aqueous layer was then extracted with DCM (20 mL) and the combined organic layers were washed with brine (20 mL) and then dried over MgSO4, filtered and evaporated in vacuo to give 4-(3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-6-yl)morpholine. Mass Spectrum (ESI) m/e=234.2 (M+1).
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH3:7])[C:5](=[O:8])[C:4]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21](Br)[CH:20]=2)([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH:16]([F:18])[F:17])=[CH:11][CH:10]=2)[N:3]=1.[CH3:26][O:27][CH2:28][C:29]#[CH:30].O>N1CCCC1.[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>[NH2:1][C:2]1[N:6]([CH3:7])[C:5](=[O:8])[C:4]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH:16]([F:18])[F:17])=[CH:11][CH:10]=2)([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([C:30]#[C:29][CH2:28][O:27][CH3:26])[CH:20]=2)[N:3]=1
Reactant: CN1C(=O)C(c2ccc(OC(F)F)cc2)(c2cccc(Br)c2)N=C1N
Reactant: C#CCOC
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCNC1
Product: COCC#Cc1cccc(C2(c3ccc(OC(F)F)cc3)N=C(N)N(C)C2=O)c1
Temperature: 80 °C
Yield: 63 %

Procedure:
A solution of 2-amino-5-(3-bromophenyl)-5-[4-(difluoromethoxy)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one (0.65 g, 1.6 mmol) in pyrrolidine was treated with 3-methoxy-propyne (0.27 mL, 3.2 mmol) followed by tetrakis(triphenylphosphine) palladium(0) (90 mg, 0.08 mmole), heated to 80° C. for 4 hrs, poured into water and extracted with ethyl acetate. The extracts were combined, washed sequentially with water and brine, dried over magnesium sulfate and concentrated in vacuo. The resultant residue was purified by flash chromatography on silica gel in ethyl acetate to give the title product as a brown wax, 0.4 g (63% yield), identified by NMR and mass spectral analyses.
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([CH:19]=[O:20])[N:5]([CH2:8][C:9]2[C:17]([Cl:18])=[CH:16][C:12]3[O:13][CH2:14][O:15][C:11]=3[CH:10]=2)[C:6]=1[Br:7].C1(C)C=CC=CC=1.[CH2:28](O)[CH2:29][OH:30]>C(OC(C)C)(C)C>[Br:1][C:2]1[N:3]=[C:4]([CH:19]2[O:30][CH2:29][CH2:28][O:20]2)[N:5]([CH2:8][C:9]2[C:17]([Cl:18])=[CH:16][C:12]3[O:13][CH2:14][O:15][C:11]=3[CH:10]=2)[C:6]=1[Br:7]
Reactant: O=Cc1nc(Br)c(Br)n1Cc1cc2c(cc1Cl)OCO2
Reactant: OCCO
Solvent: CC(C)OC(C)C
Solvent: Cc1ccccc1
Product: Clc1cc2c(cc1Cn1c(C3OCCO3)nc(Br)c1Br)OCO2

Procedure:
The product obtained in Stage 2 above is introduced into 200 ml of toluene, 20 ml of ethylene glycol is added and the reaction medium is taken to reflux overnight then evaporated to dryness. 200 ml of a saturated solution of sodium hydrogen carbonate is added which is extracted 3 times with 200 ml of ethyl acetate. The organic phase is washed with saturated sodium chloride, then dried and evaporated to dryness. The residue obtained is impasted in isopropyl ether, filtered and dried. In this way 13.5 g of expected product (solid) is obtained. M.p.=188° C.
Reaction SMILES: ClC1C=CC(Cl)=CC=1N=[N:10][C:11]1[C:20]2[C:15](=[C:16]([NH:21][S:22]([C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([C:31](=[O:69])[N:32]([CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH2:66][CH2:67][CH3:68])[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH3:50])[CH:26]=3)(=[O:24])=[O:23])[CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][C:12]=1[OH:70]>[Pd]>[NH2:10][C:11]1[C:20]2[C:15](=[C:16]([NH:21][S:22]([C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([C:31](=[O:69])[N:32]([CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH2:66][CH2:67][CH3:68])[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH3:50])[CH:26]=3)(=[O:24])=[O:23])[CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][C:12]=1[OH:70]
Reactant: CCCCCCCCCCCCCCCCCCN(CCCCCCCCCCCCCCCCCC)C(=O)c1cccc(S(=O)(=O)Nc2cccc3c(N=Nc4cc(Cl)ccc4Cl)c(O)ccc23)c1
Agent: [Pd]
Product: CCCCCCCCCCCCCCCCCCN(CCCCCCCCCCCCCCCCCC)C(=O)c1cccc(S(=O)(=O)Nc2cccc3c(N)c(O)ccc23)c1

Procedure:
A mixture of the azo dye, 1-(2,5-dichlorophenylazo)-5-(m-dioctadecylcarbamoylbenzenesulfonamido)-2-naphthol (10.2 g, 0.01 mol) and 10 percent palladium on carbon (1.5 g) was hydrogenated at 40 psi and room temperature for 2 hours. The catalyst was filtered and the solution kept under nitrogen during its immediate use in the above reaction.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH:11]1[C:15]2[C:16]3[N:17]([N:20]=[C:21]([CH3:28])[C:22]=3[C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:18]=[CH:19][C:14]=2[CH2:13][CH2:12]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CC(NCCC#N)CC1C=CC=CC=1.Cl.CCCCCC>CCCCCC.C(O)C>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][C@@H:11]1[C:15]2[C:16]3[N:17]([N:20]=[C:21]([CH3:28])[C:22]=3[C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:18]=[CH:19][C:14]=2[CH2:13][CH2:12]1)=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: CCOC(=O)c1c(C)nn2ccc3c(c12)C(CCNC(=O)OC(C)(C)C)CC3
Agent: CC(Cc1ccccc1)NCCC#N
Agent: Cl
Solvent: CCCCCC
Solvent: CCO
Product: CCOC(=O)c1c(C)nn2ccc3c(c12)[C@@H](CCNC(=O)OC(C)(C)C)CC3
Yield: 46.7 %

Procedure:
Ethyl 9-{2-[(tert-butoxycarbonyl)amino]ethyl}-2-methyl-8,9-dihydro-7H-cyclopenta[c]pyrazolo[1,5-a]pyridine-1-carboxylate (300 mg) was fractionated by high performance liquid chromatography (instrument: Prep LC 2000 (manufactured by Nihon Waters K.K.), column: CHIRALPAK AD (50 mm ID×500 mm L, manufactured by Dicel Chemical Industries, Ltd.), mobile phase: A) hexane 100%, B) hexane/ethanol=70/30, mixing ratio: A/B=80/20, flow rate: 60 mL/min, column temperature: 30° C., sample concentration: 10 mg/mL (hexane/ethanol=95/5), injection amount: 300 mg). A fraction solution containing an optically active compound having a longer retention time under the above-mentioned high performance liquid chromatography conditions was concentrated to give the title compound (140 mg, 99.7% ee). The enantiomer excess (ee) was measured by high performance liquid chromatography (column: CHIRALPAK AD (4.6 mm ID×250 mm L, manufactured by Dicel Chemical Industries, Ltd.), mobile phase: hexane/ethanol=95/5, flow rate: 0.5 mL/min, column temperature: 30° C., sample concentration: 0.25 mg/mL (hexane/ethanol=95/5), injection volume: 10 μL).
Reaction SMILES: F[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[N+:12]([O-:14])=[O:13])[NH:8][C:7](=[O:15])[N:6]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])[C:5]2=[O:21].[NH:22]1[CH:26]=[C:25]([CH2:27][CH2:28][NH2:29])[N:24]=[CH:23]1>>[NH:22]1[CH:26]=[C:25]([CH2:27][CH2:28][NH:29][C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][C:11]=2[N+:12]([O-:14])=[O:13])[NH:8][C:7](=[O:15])[N:6]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])[C:5]3=[O:21])[N:24]=[CH:23]1
Reactant: NCCc1c[nH]cn1
Reactant: CS(=O)(=O)Nn1c(=O)[nH]c2cc([N+](=O)[O-])c(F)cc2c1=O
Product: CS(=O)(=O)Nn1c(=O)[nH]c2cc([N+](=O)[O-])c(NCCc3c[nH]cn3)cc2c1=O
Yield: 37 %

Procedure:
N-(6-Fluoro-7-nitro-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)-methanesulfonamide (20 mg, 0.0628 mmol) is reacted with 2-(1H-imidazol-4-yl)-ethylamine according to the GPA affording 9.6 mg (37%) of a red powder. Rt=2.65 min.
Reaction SMILES: [OH:1][CH:2]1[CH2:6][CH2:5][NH:4][CH2:3]1.F[C:8]1[C:19]2=[C:20]3[N:15]([C:16](=[CH2:21])[CH2:17][CH2:18]2)[CH:14]=[C:13]([C:22]([OH:24])=[O:23])[C:12](=[O:25])[C:11]3=[CH:10][C:9]=1[F:26]>CS(C)=O>[F:26][C:9]1[CH:10]=[C:11]2[C:20]3[N:15]([CH:14]=[C:13]([C:22]([OH:24])=[O:23])[C:12]2=[O:25])[C:16](=[CH2:21])[CH2:17][CH2:18][C:19]=3[C:8]=1[N:4]1[CH2:5][CH2:6][CH:2]([OH:1])[CH2:3]1
Reactant: C=C1CCc2c(F)c(F)cc3c(=O)c(C(=O)O)cn1c23
Reactant: OC1CCNC1
Solvent: CS(C)=O
Product: C=C1CCc2c(N3CCC(O)C3)c(F)cc3c(=O)c(C(=O)O)cn1c23
Yield: 22.5 %

Procedure:
4 ml of dimethyl sulfoxide and 100 mg of 3-hydroxypyrrolidine were added to 100 mg of 8,9-difluoro-5-methylene-1-oxo-6,7-dihydro-1H,5H-benzo(ij)quinolizine-2-carboxylic acid and the resulting mixture was allowed to react for 2 hours at 120° C. The solvent was distilled off. The residue was purified by silica gel column chromatography and purified by preparative thin layer chromatography on silica gel and then recrystallized from a mixture of ethanol and chloroform to give 28 mg of 9-fluoro-8-(3-hydroxy-1-pyrrolidinyl)-5-methylene-1-oxo-6,7-dihydro-1H,5H-benzo(ij)quinolizine-2-carboxylic acid as microcrystals with mp 190°-196° C.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](I)[C:5]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:4][CH:3]=1.[Br:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1B(O)O.C(=O)([O-])[O-].[K+].[K+].C(OCC)C>C1(C)C=CC=CC=1.C(O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[Br:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[C:6]1[C:5]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:4][CH:3]=[C:2]([Cl:1])[N:7]=1
Reactant: Clc1ccc(OCc2ccccc2)c(I)n1
Reactant: OB(O)c1ccccc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: Cc1ccccc1
Solvent: O
Product: Clc1ccc(OCc2ccccc2)c(-c2ccccc2Br)n1
Temperature: 90 °C
Yield: 82.2 %

Procedure:
6-Chloro-2-iodo-3-[(phenylmethyl)oxy]pyridine (346 mg, 1 mmol) and 2-bromophenylboronic acid (201 mg, 1 mmol) were dissolved in 1:1 toluene/ethanol (10 ml) and potassium carbonate (1.1 g, 8 mmol) and tetrakis(triphenylphosphine)palladium(0) (116 mg, 0.1 mmol) added. The mixture was stirred under nitrogen and heated at 90° C. for 2 hours. After cooling, diethyl ether and water were added and the organic layer washed with water, dried (MgSO4) and evaporated. The yellow oil was flash chromatographed, eluting with 2-10% ethyl acetate/isohexane to give the title compound as a clear oil (308 mg) LC/MS t=3.77, [MH+] 376, 378.
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[C@@H:3]1[CH2:7][CH2:6][CH2:5][NH:4]1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[Cl:20][C:21]1[CH:26]=[C:25](Cl)[N:24]=[C:23]([S:28][CH3:29])[N:22]=1.Cl>C1COCC1.O>[Cl:20][C:21]1[CH:26]=[C:25]([N:4]2[CH2:5][CH2:6][CH2:7][C@H:3]2[C:2]([F:9])([F:8])[F:1])[N:24]=[C:23]([S:28][CH3:29])[N:22]=1
Reactant: FC(F)(F)[C@@H]1CCCN1
Reactant: CSc1nc(Cl)cc(Cl)n1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CSc1nc(Cl)cc(N2CCC[C@H]2C(F)(F)F)n1
Reaction time: 0.08 h
Yield: 77.3 %

Procedure:
(2S)-2-(Trifluoromethyl)pyrrolidine (858 mg, 6.17 mmol) was dissolved in THF (10 mL) in a 250 mL RB flask. The mixture was cooled in an ice bath. Then molecular sieves were added and let stir for 5 minutes. LiHMDS (6.78 mL, 6.78 mmol) was added slowly followed by addition of 4,6-dichloro-2-(methylthio)pyrimidine (1.444 g, 7.40 mmol), and the reaction was stirred at 0° C. for an additional 10 minutes. Then water (10 mL) was added followed by dropwise addition of 6N HCl until pH was acidic. The mixture was then extracted with EtOAc (3×30 mL) and the organic was combined, washed with saturated NaCl, filtered and concentrated. The crude oil was purified on Biotage 25 g SNAP column with a gradient of 0 to 35% EtOAc in Hexane over 25 minutes to afford the title compound (1.42 g) as a clear oil. LC-MS (ES) m/z=298 [M+H]+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([S:7]([NH2:10])(=[O:9])=[O:8])=[CH:3][CH:2]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Cl[C:18]1[CH:23]=[C:22]([O:24][C@H:25]([CH3:47])[CH2:26][O:27][C:28]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[N:21]=[C:20]([S:48][CH2:49][C:50]2[CH:55]=[CH:54][CH:53]=[C:52]([F:56])[C:51]=2[F:57])[N:19]=1>O1CCOCC1.C(Cl)Cl.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:57][C:51]1[C:52]([F:56])=[CH:53][CH:54]=[CH:55][C:50]=1[CH2:49][S:48][C:20]1[N:19]=[C:18]([NH:10][S:7]([C:4]2[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=2)(=[O:9])=[O:8])[CH:23]=[C:22]([O:24][C@H:25]([CH3:47])[CH2:26][O:27][C:28]([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)([C:41]2[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=2)[C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[N:21]=1
Reactant: NS(=O)(=O)c1ccncc1
Reactant: C[C@H](COC(c1ccccc1)(c1ccccc1)c1ccccc1)Oc1cc(Cl)nc(SCc2cccc(F)c2F)n1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: ClCCl
Product: C[C@H](COC(c1ccccc1)(c1ccccc1)c1ccccc1)Oc1cc(NS(=O)(=O)c2ccncc2)nc(SCc2cccc(F)c2F)n1
Temperature: 100 °C

Procedure:
A mixture of 4-pyridinesulfonamide (the product from step i) (0.21 g), tris(dibenzylideneacetone)dipalladium (0) (50 mg), 2-dicyclohexylphosphino-2′,4′,6′-tri-isopropyl-1,r-biphenyl (XPHOS) (50 mg), cesium carbonate (0.66 g) and 4-chloro-2-[[(2,3-difluorophenyl)methyl]thio]-6-[(1R)-1-methyl-2-(triphenylmethoxy)ethoxy]-pyrimidine (the product from step iii) (0.40 g) in dioxane (20 mL) was heated at reflux in a microwave at 100° C., 300 W, open vessel with cooling for 3 h. The reaction mixture was diluted with DCM, filtered through arbocel and the filtrate evaporated. The residue was purified by reverse phase HPLC using a TFA (0.2%)/MeCN system to give the title compound as a yellow solid. Yield: 0.21 g.
Reaction SMILES: [C:1]1([C:7]2([OH:12])[CH:10]3[CH2:11][CH:8]2[CH2:9]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:13](Cl)(=[O:15])[CH3:14]>N1C=CC=CC=1>[C:13]([O:12][C:7]1([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:8]2[CH2:9][CH:10]1[CH2:11]2)(=[O:15])[CH3:14]
Reactant: OC1(c2ccccc2)C2CC1C2
Reactant: CC(=O)Cl
Solvent: c1ccncc1
Product: CC(=O)OC1(c2ccccc2)C2CC1C2
Temperature: 0 °C
Reaction time: 1 h
Yield: 79.8 %

Procedure:
To a stirring solution of 2.7 g (16.8 mmol) of 2-phenylbicyclo[1.1.1]pentan-2-ol in pyridine (15 mL) at 0° C. was added dropwise acetyl chloride (1.5 mL, 21.0 mmol) in a nitrogen atmosphere. The reaction mixture was stirred for 0.5 h at 0° C. and for 1 h at room temperature. The solution was poured onto ice and extracted with 50 mL of diethyl ether twice. The combined diethyl ether solution was washed with saturated aqueous sodium bicarbonate solution and with saturated aqueous copper sulfate solution. After drying over anhydrous magnesium sulfate, the solution was concentrated and the crude product was purified by column chromatography (0-5% ethyl acetate in petroleum ether) to give the desired product (2.7 g, 13.4 mmol, yield: 80%). 1H NMR (400 MHz, CDCl3) δ ppm 7.47-7.26 (m, 5H), 3.31 (s, 2H), 2.43 (dd, J1=10.4 Hz, J2=2.8 Hz, 1H), 1.95 (s, 3H), 1.80 (d, J=2.8 Hz, 1H), 1.66 (d, J=3.2 Hz, 1H), 1.49 (dd, J1=10.4, J2=3.2 Hz, 1H).
Reaction SMILES: [Na:1].[C:2]([OH:7])([CH2:5][CH3:6])([CH3:4])[CH3:3]>>[C:2]([O:7][C:2]([CH2:5][CH3:6])([CH3:4])[CH3:3])([CH2:5][CH3:6])([CH3:4])[CH3:3].[Na:1]
Reactant: CCC(C)(C)O
Agent: [Na]
Product: CCC(C)(C)OC(C)(C)CC

Procedure:
860 mg of sodium were added to 18 ml of tertiary amylalcohol-absolute toluene (1:1), and the mixture was refluxed for 5 hours. Then, the reaction mixture was condensed to dryness, whereby sodium tertiary amyloxide was obtained. 20 ml of absolute toluene and 1.09 g of 1,2,3,4-tetrahydro-1-(3-methoxycarbonylpropyl)-2-benzyl-β-carboline were added to said sodium tertiary amyloxide under ice-cooling, and the mixture was stirred at the same temperature for 3 hours. After the reaction was completed, ethyl acetate was added to the reaction mixture. Said mixture was washed with an aqueous saturated sodium chloride solution, dried and then condensed. The residue thus obtained was purified by silica gel chromatography (Solvent: chloroform), and then recrystallized from a mixture of methanol and isopropyl ether, whereby 300 mg of 1,2,3,3a,4,5,6,7-octahydro-3-benzyl-7-oxo-azepino[1,2,3-lm]-β-carboline were obtained. Yield: 30.3%
Reaction SMILES: [C:1]1([N:7]2[CH:12]=[C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=3)[CH:10]=[CH:9][C:8]2=[O:19])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:20]N1C(=O)CCC1=O.CN(C)C=O>C1C(=O)N(Br)C(=O)C1.O>[Br:20][C:9]1[C:8](=[O:19])[N:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:12]=[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)[CH:10]=1
Reactant: O=c1ccc(-c2ccccn2)cn1-c1ccccc1
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Solvent: O
Product: O=c1c(Br)cc(-c2ccccn2)cn1-c1ccccc1
Temperature: 4 °C
Reaction time: 2.5 h
Yield: 77.9 %

Procedure:
1-Phenyl-5-pyridin-2-yl-2(1H)-pyridone (186 g), N-bromosuccinimide (141.7 g) and N,N-dimethylformamide (900 ml) were stirred at room temperature. After 2.5 hr, 6.45 g of NBS was added thereto. After depletion of the reactant was confirmed, the reaction solution was poured into water (4.5 L) under ice-cooling, followed by stirring in a cold-room (approximately 4° C.) overnight. The resulting crystals were collected by filtration under reduced pressure, followed by dissolving in IPA (3.25 L) and H2O (650 ml) under heating. After the complete dissolution was confirmed, the solution was left to cool gradually, and then ice-cooled. Then, the mixture was stirred in a cold-room overnight. The resulting crystals were collected by filtration under reduced pressure and air-dried at 60° C., to give 191 g (81%) of the title compound.