Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:10]2[NH:9][C:8]3[CH2:11][CH2:12][N:13]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:14][C:7]=3[C:6]=2[CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Cl[C:29]([O:31][CH2:32][CH3:33])=[O:30]>C(Cl)Cl.O>[CH2:32]([O:31][C:29]([NH:1][C:2]1[C:10]2[NH:9][C:8]3[CH2:11][CH2:12][N:13]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:14][C:7]=3[C:6]=2[CH:5]=[CH:4][CH:3]=1)=[O:30])[CH3:33]
Reactant: CC(C)(C)OC(=O)N1CCc2[nH]c3c(N)cccc3c2C1
Reactant: CCOC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)Nc1cccc2c3c([nH]c12)CCN(C(=O)OC(C)(C)C)C3
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 605.1 %

Procedure:
To a solution of tert-butyl 6-amino-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indole-2-carboxylate (7 g, 24.3 mmol) in CH2Cl2 (40 mL) at rt was added saturated K2CO3 (30 mL), ethyl chloroformate (2.4 mL, 4.0 mmol) and stirred at 25° C. for 0.5 hour. The solution was diluted with water (30 mL) and extracted with CH2Cl2 (2×30 mL). The combined extracts were dried over magnesium sulfate, and concentrated to afford tert-butyl 6-[(ethoxycarbonyl)amino]-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indole-2-carboxylate (8.7 g, 100%) as an crude oil. MS [M+H]+360.
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[F-].[K+].C(=O)([O-])[O-].[K+].[K+].[CH3:20][NH2:21].O>ClCCl>[F:8][C:6]1[CH:5]=[CH:4][C:3]([N+:9]([O-:11])=[O:10])=[C:2]([CH:7]=1)[NH:21][CH3:20]
Reactant: CN
Reactant: O=[N+]([O-])c1ccc(F)cc1F
Agent: O=C([O-])[O-]
Agent: [F-]
Agent: [K+]
Solvent: ClCCl
Solvent: O
Product: CNc1cc(F)ccc1[N+](=O)[O-]
Temperature: 90 °C

Procedure:
2,4-Difluoronitrobenzene (1.00 g, 6.29 mmol), potassium fluoride (0.365 g, 6.29 mmol), potassium carbonate (0.869 g, 6.29 mmol), and 40% methylamine in water (0.58 mL, 7.5 mmol) were added to a vial and heated in a microwave at 90° C. for 10 min. The reaction was then diluted with dichloromethane, washed with water and brine, dried over magnesium sulfate, and concentrated to provide the title compound: 1H NMR (500 MHz, CDCl3) δ 8.22 (dd, J=9.4, 6.1 Hz, 1 H), 8.16 (br s, 1 H), 6.48 (dd, J=11.5, 2.6 Hz, 1 H), 6.40-6.36 (m, 1 H), 3.01 (d, J=5.0 Hz, 3 H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][C:5]1[C:6]2[N:7]([C:15](=[O:18])[NH:16][N:17]=2)[CH:8]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[N:10]=1.[C:19]1([S:25](Cl)(=[O:27])=[O:26])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(N(C(C)C)CC)(C)C>CN(C=O)C.CCOC(C)=O>[C:11]([C:9]1[N:10]=[C:5]([NH:4][CH2:3][CH2:2][NH:1][S:25]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)(=[O:27])=[O:26])[C:6]2[N:7]([C:15](=[O:18])[NH:16][N:17]=2)[CH:8]=1)([CH3:12])([CH3:13])[CH3:14]
Reactant: CC(C)(C)c1cn2c(=O)[nH]nc2c(NCCN)n1
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)c1cn2c(=O)[nH]nc2c(NCCNS(=O)(=O)c2ccccc2)n1

Procedure:
A solution of 50 mg of 8-(2-amino-ethylamino)-6-tert-butyl-2H-[1,2,4]triazolo[4,3-a]pyrazin-3-one, 97 mg of phenylsulfonyl chloride and 61 mg of diisopropylethylamine in DMF (1.0 mL) was stirred at ambient temperature for 16 h. The reaction mixture was diluted with EtOAc and washed with water and then sat. sodium chloride solution. The organic layer was dried over sodium sulfate, filtered, and concentrated. The residue was purified by silica gel chromatography to provide the title compound as a white solid. MS (M+H+)=391.4.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:19][CH2:20][CH2:21][C:22]2[N:23]=[C:24]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[O:25][C:26]=2[CH3:27])=[C:6]([C:8]2[C:9]([C:14]([O:16]CC)=[O:15])=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:7]=1.CO.C1COCC1.[OH-].[Na+]>C(OCC)(=O)C.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:19][CH2:20][CH2:21][C:22]2[N:23]=[C:24]([C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)[O:25][C:26]=2[CH3:27])=[C:6]([C:8]2[C:9]([C:14]([OH:16])=[O:15])=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:7]=1
Reactant: CCOC(=O)c1ccccc1-c1cc(F)ccc1OCCc1nc(-c2ccccc2)oc1C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1oc(-c2ccccc2)nc1CCOc1ccc(F)cc1-c1ccccc1C(=O)O
Yield: 63 %

Procedure:
A mixture of the compound obtained in Example 5 (0.128 g; 0.287 mmol), methanol (2.5 ml), THF (5 ml), aqueous 1N sodium hydroxide (0.37 ml; 0.37 mmol) and water (2.5 ml) is stirred at reflux for 1 hour. The medium is then cooled and poured into water. After extracting with ethyl ether, the aqueous phase is acidified with concentrated hydrochloric acid. The white precipitate formed is taken up in ethyl acetate. Evaporation gives a beige-coloured solid (76 mg; 63% yield).
Reaction SMILES: CN(C)C=O.Cl.[CH2:7]([C:9]1[S:13][C:12](=[NH:14])[N:11]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[C:28]3[NH:32][N:31]=[N:30][N:29]=3)=[CH:18][CH:17]=2)[N:10]=1)[CH3:8].[C:33]12[C:41](=[O:42])[O:40][C:38](=[O:39])[C:34]=1[CH2:35][CH2:36][CH2:37]2>O>[CH2:7]([C:9]1[S:13][C:12](=[N:14][C:41]([C:33]2[CH2:37][CH2:36][CH2:35][C:34]=2[C:38]([OH:40])=[O:39])=[O:42])[N:11]([CH2:15][C:16]2[CH:17]=[CH:18][C:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[C:28]3[NH:29][N:30]=[N:31][N:32]=3)=[CH:20][CH:21]=2)[N:10]=1)[CH3:8]
Reactant: CCc1nn(Cc2ccc(-c3ccccc3-c3nnn[nH]3)cc2)c(=N)s1
Reactant: O=C1OC(=O)C2=C1CCC2
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Product: CCc1nn(Cc2ccc(-c3ccccc3-c3nnn[nH]3)cc2)c(=NC(=O)C2=C(C(=O)O)CCC2)s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 67.8 %

Procedure:
To 2 ml of N,N-dimethylformamide, 200 mg of 5-ethyl-2-imino-3-[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl-1,3,4-thiadiazoline hydrochloride and 76 mg of 1-cyclopentene-1,2-dicarboxylic anhydride were added and the resulting mixture was stirred at room temperature for 2 hours. Water was added to the reaction mixture and the crystals so precipitated were collected by filtration. The crystals were washed with water and ethanol and then dried, whereby 170 mg of the title compound was obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:22]=[C:23]([O:25][CH3:26])[CH:24]=1)[C:6]1[O:7][C:8]2[C:13]([C:14](=[O:16])[CH:15]=1)=[CH:12][CH:11]=[C:10]([O:17][CH2:18][CH:19]1[O:21][CH2:20]1)[CH:9]=2.[C:27]([NH2:31])([CH3:30])([CH3:29])[CH3:28]>CO>[C:27]([NH:31][CH2:20][CH:19]([OH:21])[CH2:18][O:17][C:10]1[CH:9]=[C:8]2[C:13]([C:14](=[O:16])[CH:15]=[C:6]([C:5]3[CH:4]=[C:3]([O:2][CH3:1])[CH:24]=[C:23]([O:25][CH3:26])[CH:22]=3)[O:7]2)=[CH:12][CH:11]=1)([CH3:30])([CH3:29])[CH3:28]
Reactant: CC(C)(C)N
Reactant: COc1cc(OC)cc(-c2cc(=O)c3ccc(OCC4CO4)cc3o2)c1
Solvent: CO
Product: COc1cc(OC)cc(-c2cc(=O)c3ccc(OCC(O)CNC(C)(C)C)cc3o2)c1

Procedure:
3′,5′-Dimethoxy-7-(2,3-epoxy-propoxy)-flavone, 32 (500 mg, 1.41 mmol) and tert-butyl amine (0.6 mL, 5.64 mmol) in dry methanol (100 mL) were reacted in a similar manner to that described under 34 to afford 43. Yield 400 mg (66%); mp 145-146° C.; MS (FAB) 428 (M+1); IR (KBr) 3431, 1631; 1H NMR (200 MHz, DMSO-d6) δ 7.93 (d, J=8.8 Hz, 1H), 7.32 (d, J=1.9 Hz, 1H), 7.15 (d, J=2.0 Hz, 2H), 7.08 (dd, J=8.9 Hz, 2.0 Hz, 1H), 6.92 (s, 1H), 6.68 (s, 1H), 4.17-4.01 (m, 3H), 3.82 (s, 6H), 2.77-2.59 (m, 2H), 1.08 (s, 9H). Analysis Calcd for C24H29NO6: C, 67.43; H, 6.84; N, 3.28. Found: C, 67.59; H, 6.73; N, 3.39.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:12]2[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[N:15]=[C:14]([N:22]3[CH:26]=[C:25]([Sn](CCCC)(CCCC)CCCC)[N:24]=[CH:23]3)[N:13]=2)[CH:5]=[CH:6][C:7]=1[C:8]([F:11])([F:10])[F:9].[CH3:40][C:41]([NH:44][S:45]([C:48]1[S:52][C:51](Br)=[CH:50][CH:49]=1)(=[O:47])=[O:46])([CH3:43])[CH3:42].CCCCCCC>C1(C)C=CC=CC=1>[C:41]([NH:44][S:45]([C:48]1[S:52][C:51]([C:25]2[N:24]=[CH:23][N:22]([C:14]3[N:13]=[C:12]([C:4]4[CH:5]=[CH:6][C:7]([C:8]([F:11])([F:9])[F:10])=[C:2]([CH3:1])[CH:3]=4)[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[N:15]=3)[CH:26]=2)=[CH:50][CH:49]=1)(=[O:46])=[O:47])([CH3:43])([CH3:40])[CH3:42]
Reactant: CCCC[Sn](CCCC)(CCCC)c1cn(-c2nc(-c3ccc(C(F)(F)F)c(C)c3)cc(C(F)(F)F)n2)cn1
Reactant: CC(C)(C)NS(=O)(=O)c1ccc(Br)s1
Solvent: Cc1ccccc1
Solvent: CCCCCCC
Product: Cc1cc(-c2cc(C(F)(F)F)nc(-n3cnc(-c4ccc(S(=O)(=O)NC(C)(C)C)s4)c3)n2)ccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 81.4 %

Procedure:
A stirred mixture of 4-(3-methyl-4-trifluoromethyl-phenyl)-2-(4-tributylstannanyl-imidazol-1-yl)-6-trifluoromethyl-pyrimidine (Example G.7) (0.33 g, 0.5 mmol), commercially available 5-bromothiophene-2-N-tert-butylsulfonamide (0.16 g, 0.55 mmol), tetrakis(triphenyl-phosphine)palladium (0.035 g, 0.03 mmol) in toluene (6 mL) was heated under reflux conditions for 15 h, heptane (10 mL) was added and the mixture was stirred at RT for 1 h. The precipitate was collected by filtration and dried to yield 5-{1-[4-(3-methyl-4-trifluoromethyl-phenyl)-6-trifluoromethyl-pyrimidin-2-yl]-1H-imidazol-4-yl}-thiophene-2-sulfonic acid tert-butyl amide (0.24 g) as a light yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:12]3[N:13]=[C:14]4[C:20]([C:21]([OH:23])=O)=[CH:19][NH:18][C:15]4=[N:16][CH:17]=3)=[N:7][N:8]2[CH3:11])=[CH:4][CH:3]=1.CCN=C=NCCCN(C)C.[Si:35]([O:42][CH2:43][CH2:44][C:45]([CH3:48])([NH2:47])[CH3:46])([C:38]([CH3:41])([CH3:40])[CH3:39])([CH3:37])[CH3:36].O>CN(C=O)C.CN(C1C=CN=CC=1)C>[Si:35]([O:42][CH2:43][CH2:44][C:45]([NH:47][C:21]([C:20]1[C:14]2[C:15](=[N:16][CH:17]=[C:12]([C:6]3[C:5]4[C:9](=[CH:10][C:2]([F:1])=[CH:3][CH:4]=4)[N:8]([CH3:11])[N:7]=3)[N:13]=2)[NH:18][CH:19]=1)=[O:23])([CH3:48])[CH3:46])([C:38]([CH3:41])([CH3:40])[CH3:39])([CH3:37])[CH3:36]
Reactant: Cn1nc(-c2cnc3[nH]cc(C(=O)O)c3n2)c2ccc(F)cc21
Reactant: CC(C)(N)CCO[Si](C)(C)C(C)(C)C
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Solvent: O
Product: Cn1nc(-c2cnc3[nH]cc(C(=O)NC(C)(C)CCO[Si](C)(C)C(C)(C)C)c3n2)c2ccc(F)cc21
Reaction time: 16 h
Yield: 42.8 %

Procedure:
To a stirred solution of 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (100 mg, 0.32 mmol) in 6 mL of DMF were added EDCI (123 mg, 0.64 mmol), 4-(tert-butyldimethylsilyloxy)-2-methylbutan-2-amine (139 mg, 0.64 mmol) and DMAP (78 mg, 0.64 mmol) in one portion at room temperature and stirred for 16 hours. The reaction mixture was poured into 35 mL of water filtered and the solid obtained was passed through a pad of silica gel (200-300 mesh, eluting with a mixture of methanol and ethyl acetate (1:20, v/v) to give N-(4-(tert-butyldimethylsilyloxy)-2-methylbutan-2-yl)-2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (70 mg, 42.8%) as a pale yellow solid which was used for the next step without further purification. MS: (M+H)+=511.2.
Reaction SMILES: [OH-].[Na+].C[C:4]([CH:6]1[CH:8]([CH2:9][C:10](Cl)([Cl:12])[Cl:11])[C:7]1([CH3:15])[CH3:14])=[O:5].BrBr.S([O-])([O-])=[O:19].[Na+].[Na+]>O.CO>[CH3:14][C:7]1([CH3:15])[CH:8]([CH:9]=[C:10]([Cl:12])[Cl:11])[CH:6]1[C:4]([OH:5])=[O:19]
Reactant: CC(=O)C1C(CC(Cl)(Cl)Cl)C1(C)C
Reactant: O=S([O-])[O-]
Agent: BrBr
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC1(C)C(C=C(Cl)Cl)C1C(=O)O
Temperature: 70 °C
Reaction time: 2 h
Yield: 67.5 %

Procedure:
To 250 ml of methanol solution containing 24 g of sodium hydroxide were added 17 g of 2,2-dimethyl-3-(2',2',2'-trichloroethyl)-cyclopropyl methyl ketone (purity: 97.9%, cis/trans ratio 91.5/8.5) under cooling with ice, and then 40 g of bromine were added dropwise at -10° C. to -5° C. for 20 minutes and after stirring the mixture at the same temperature for 2 hours, 25.2 g of sodium sulfite (7 hydrate) and 250 ml of water were added thereto, and the mixture was heated up to 70° C. and stirred for 47 hours with heating. Then the methanol was distilled off, water was added to the reaction mixture and neutral part was removed by extraction with ether. The water layer was acidified with conc. hydrochloric acid under cooling with ice. The deposited crystals were filtered, washed with water and dried to obtain 9.85 g of 2,2-dimethyl-3-(2',2'-dichlorovinyl)-cyclopropanecarboxylic acid, cis/trans ratio 89.8/10.2, purity 91.8%, yield 72.9%.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](F)=[C:6]([C:8](=[O:13])[C:9]([F:12])([F:11])[F:10])[CH:7]=1.[N-:15]=[N+]=[N-].[Na+].Cl[Sn]Cl.O.[O-]S([O-])(=O)=O.[Na+].[Na+]>CS(C)=O.CCOC(C)=O>[NH2:15][C:5]1[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][C:6]=1[C:8](=[O:13])[C:9]([F:12])([F:11])[F:10]
Reactant: O=C(c1cc(Br)ccc1F)C(F)(F)F
Reactant: [N-]=[N+]=[N-]
Agent: Cl[Sn]Cl
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Solvent: O
Product: Nc1ccc(Br)cc1C(=O)C(F)(F)F
Temperature: 25 °C

Procedure:
A solution of 1-(5-bromo-2-fluorophenyl)-2,2,2-trifluoroethanone (6.67 g, 24.6 mmol, Intermediate 7, step a) in DMSO (6.2 mL) was treated with NaN3 (1.76 g, 27.0 mmol) and stirred under air (lightly capped) at 95° C. for 1 hour. The brownish-red opaque reaction was then cooled to room temperature on an ice bath, diluted with EtOAc (49 mL), treated with SnCl2.dihydrate (6.66 g, 29.5 mmol) in several portions over ˜30 seconds followed by water (1.33 mL, 73.8 mmol), and the mixture was stirred at room temperature for 30 minutes. The reddish solution with heavy off-white particulates was then treated with anhydrous Na2SO4 (˜6 g) and stirred vigorously for a few minutes. The mixture was then filtered over a bed of Celite®, and the cloudy orange filtrate was dry load flash chromatographed (˜60 g silica gel) with a heptane to 50% DCM/heptane gradient to provide the title compound as an orange oil that crystallized upon standing.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[N+:5]([O-:35])[CH:6]=[C:7]([Cl:34])[C:8]=1[CH2:9][C@@H:10]([C:19]1[CH:24]=[CH:23][C:22]([O:25][CH:26]([F:28])[F:27])=[C:21]([O:29][CH2:30][CH:31]2[CH2:33][CH2:32]2)[CH:20]=1)[O:11][C:12]([C@H:14]1[NH:18][CH2:17][CH2:16][S:15]1)=[O:13].[CH:36]([C:38]1[CH:39]=[C:40]([CH:44]=[CH:45][CH:46]=1)[C:41]([OH:43])=[O:42])=O.CC(O)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].Cl>C(Cl)Cl>[C:41]([C:40]1[CH:39]=[C:38]([CH:46]=[CH:45][CH:44]=1)[CH2:36][N:18]1[CH2:17][CH2:16][S:15][C@H:14]1[C:12]([O:11][C@H:10]([C:19]1[CH:24]=[CH:23][C:22]([O:25][CH:26]([F:28])[F:27])=[C:21]([O:29][CH2:30][CH:31]2[CH2:33][CH2:32]2)[CH:20]=1)[CH2:9][C:8]1[C:7]([Cl:34])=[CH:6][N+:5]([O-:35])=[CH:4][C:3]=1[Cl:2])=[O:13])([OH:43])=[O:42]
Reactant: O=Cc1cccc(C(=O)O)c1
Reactant: O=C(O[C@@H](Cc1c(Cl)c[n+]([O-])cc1Cl)c1ccc(OC(F)F)c(OCC2CC2)c1)[C@H]1NCCS1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: O=C(O)c1cccc(CN2CCS[C@H]2C(=O)O[C@@H](Cc2c(Cl)c[n+]([O-])cc2Cl)c2ccc(OC(F)F)c(OCC3CC3)c2)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirred solution of 3,5-dichloro-4-((S)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-((S)-thiazolidine-2-carbonyloxy)ethyl)pyridine 1-oxide hydrochloride (I5, 570 mg, 1.0 mmol) in DCM (5 mL) was added 3-formylbenzoic acid (180 mg, 1.2 mmol) followed by glacial AcOH (0.17 mL, 3.3 mmol). The reaction was stirred at room temperature for 18 h. Sodium triacetoxyborohydride (690 mg, 3.12 mmol) was added and the reaction was stirred at room temperature for 1.5 h. Additional 3-formylbenzoic acid (180 mg, 1.2 mmol) was added and the reaction mixture was stirred at room temperature for 2 days. DCM (25 mL) and 1 N HCl (15 mL) were added to quench the reaction and the mixture was passed through a hydrophobic fit and the solvent was removed in vacuo to give the title compound.
Reaction SMILES: [C:1]([CH2:3][C:4]1([N:15]2[CH:19]=[C:18]([C:20]3[N:25]4[CH:26]=[CH:27][N:28]=[C:24]4[CH:23]=[C:22]([C:29]4[CH:30]=[N:31][N:32]([CH:34]5[CH2:37][O:36][CH2:35]5)[CH:33]=4)[N:21]=3)[CH:17]=[N:16]2)[CH2:7][N:6](C(OC(C)(C)C)=O)[CH2:5]1)#[N:2].[C:38]([OH:44])([C:40]([F:43])([F:42])[F:41])=[O:39]>C(Cl)Cl.C1(C)C=CC=CC=1>[F:41][C:40]([F:43])([F:42])[C:38]([OH:44])=[O:39].[F:41][C:40]([F:43])([F:42])[C:38]([OH:44])=[O:39].[O:36]1[CH2:37][CH:34]([N:32]2[CH:33]=[C:29]([C:22]3[N:21]=[C:20]([C:18]4[CH:17]=[N:16][N:15]([C:4]5([CH2:3][C:1]#[N:2])[CH2:7][NH:6][CH2:5]5)[CH:19]=4)[N:25]4[CH:26]=[CH:27][N:28]=[C:24]4[CH:23]=3)[CH:30]=[N:31]2)[CH2:35]1
Reactant: CC(C)(C)OC(=O)N1CC(CC#N)(n2cc(-c3nc(-c4cnn(C5COC5)c4)cc4nccn34)cn2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: N#CCC1(n2cc(-c3nc(-c4cnn(C5COC5)c4)cc4nccn34)cn2)CNC1
Yield: 97.4 %

Procedure:
tert-Butyl 3-(cyanomethyl)-3-(4-(7-(1-(oxetan-3-yl)-1H-pyrazol-4-yl)imidazo[1,2-c]pyrimidin-5-yl)-1H-pyrazol-1-yl)azetidine-1-carboxylate (0.75 g, 1.5 mmol) was suspended in DCM (15 mL) and TFA (5 mL) and stirred at ambient temperature for 2 hours. The reaction mixture was diluted with toluene and concentrated under reduced pressure. The material was transferred to another flask with DCM and MeOH and concentrated under reduced pressure to afford the crude 2-(3-(4-(7-(1-(oxetan-3-yl)-1H-pyrazol-4-yl)imidazo[1,2-c]pyrimidin-5-yl)-1H-pyrazol-1-yl)azetidin-3-yl)acetonitrile bis(2,2,2-trifluoroacetate) (1.31 g, 1.46 mmol, 97.4% yield), which was used in the next step without further purification.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH2:7][CH:6]([CH2:11][OH:12])[CH2:5]2.[CH3:13][N:14](C=O)C>[C-]#N.[C-]#N.[Zn+2].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>[OH:12][CH2:11][CH:6]1[CH2:5][C:4]2[C:8](=[CH:9][CH:10]=[C:2]([C:13]#[N:14])[CH:3]=2)[CH2:7]1
Reactant: OCC1Cc2ccc(Br)cc2C1
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: N#Cc1ccc2c(c1)CC(CO)C2
Temperature: 110 °C

Procedure:
A mixture of (5-Bromo-2,3-dihydro-1H-inden-2-yl)methanol (10 g, 44 mmol), Zn(CN)2 (10.3 g, 88 mmol) and Pd(PPh3)4 (1 g, 0.88 mmol) in 100 mL of DMF was heated at 100-120° C. under N2 atmosphere overnight. Most of the solvent was concentrated and the residue was partitioned between water (100 mL) and EtOAc (100 mL) and separated. The aqueous layer was extracted with EtOAc (50 mL×2). The combined organic layers were washed with brine (200 mL), dried over Na2SO4 and concentrated to dryness. The residue was purified with column chromatography (EtOAc/PE=1:20) to give the title compound. 1H-NMR (400 MHz, CDCl3) δ 7.45 (s, 1H), 7.41 (d, J=7.6 Hz, 1H), 7.27 (d, J=8.0 Hz, 1H), 3.64 (d, J=6.6 Hz, 2H), 3.05-3.13 (m, 2H), 2.70-2.84 (m, 3H).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([CH2:10][CH2:11][N:12]3[CH2:16][CH2:15][CH2:14][C@H:13]3[CH3:17])=[CH:7][C:6]=2[CH:18]=1.C([Li])(C)(C)C.[CH2:24]([Sn:28](Cl)([CH2:33][CH2:34][CH2:35][CH3:36])[CH2:29][CH2:30][CH2:31][CH3:32])[CH2:25][CH2:26][CH3:27]>>[CH3:17][C@@H:13]1[CH2:14][CH2:15][CH2:16][N:12]1[CH2:11][CH2:10][C:8]1[O:9][C:5]2[CH:4]=[CH:3][C:2]([Sn:28]([CH2:29][CH2:30][CH2:31][CH3:32])([CH2:33][CH2:34][CH2:35][CH3:36])[CH2:24][CH2:25][CH2:26][CH3:27])=[CH:18][C:6]=2[CH:7]=1
Reactant: C[C@@H]1CCCN1CCc1cc2cc(Br)ccc2o1
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Agent: [Li]C(C)(C)C
Product: CCCC[Sn](CCCC)(CCCC)c1ccc2oc(CCN3CCC[C@H]3C)cc2c1

Procedure:
As shown in Scheme 13, (2R)-1-[2-(5-bromo-1-benzofuran-2-yl)ethyl]-2-methylpyrrolidine is treated with tert-butyl lithium and tributylstannyl chloride at −78° C. to provide (2R)-2-methyl-1-{2-[5-(tributylstannyl)-1-benzofuran-2-yl]ethyl}pyrrolidine. (2R)-2-Methyl-1-{2-[5-(tributylstannyl)-1-benzofuran-2-yl]ethyl}pyrrolidine is treated with a suitable starting material, for example, aryl halides, aryl triflates, or heterocyclic halides in the presence of a palladium catalyst, like palladium (II) acetate, and a trivalent phosphine, like tri(2-furyl)phosphine, in an organic solvent such as dimethylformamide at 25° C. to 120° C. to provide compounds of formula (50). Compounds of formula (50) can be isolated and purified by methods known to those skilled in the art. For example, compounds of formula (50) can be partitioned between dichloromethane and water, the organic phase concentrated, and the residue purified by chromatography on silica gel.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1.Br[C:11]1[S:12][CH:13]=[CH:14][N:15]=1.C([O-])([O-])=O.[K+].[K+].O>CS(C)=O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][C:11]2[S:12][CH:13]=[CH:14][N:15]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(O)cc1
Reactant: Brc1nccs1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: COc1ccc(Oc2nccs2)cc1
Temperature: 160 °C
Yield: 72.7 %

Procedure:
A mixture of 4-methoxyphenol (5.50 g, 44.3 mmol, 1.1 eq.), 2-bromothiazole (6.64 g, 40.0 mmol, 1.0 eq.), and K2CO3 (6.60 g, 47.8 mmol, 1.2 eq.) in dimethyl sulfoxide (40 mL) was heated to 160° C. for 5 hours. The reaction mixture was poured into water and extracted with ether. The ether layer washed with 10% NaOH, then brine, dried over MgSO4, filtered and concentrated. The residue was purified on silica gel eluting with ethyl acetate:hexane (0-20%) to give the title compound (6.03 g, 73%),
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:13]=[CH:14][CH:15]=1)[NH2:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+:16]([C:19]1[CH:27]=[CH:26][CH:25]=[CH:24][C:20]=1[C:21](Cl)=[O:22])([O-:18])=[O:17]>>[N+:16]([C:19]1[CH:27]=[CH:26][CH:25]=[CH:24][C:20]=1[C:21]([NH:12][C:11]1[CH:13]=[CH:14][CH:15]=[C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH:10]=1)=[O:22])([O-:18])=[O:17]
Reactant: O=C(Cl)c1ccccc1[N+](=O)[O-]
Reactant: Nc1cccc(OCc2ccccc2)c1
Product: O=C(Nc1cccc(OCc2ccccc2)c1)c1ccccc1[N+](=O)[O-]
Yield: 89 %

Procedure:
Using the procedure described in Example 93, Part A, 3-benzyloxyaniline (10 mmol) and 2-nitrobenzoyl chloride (11 mmol) yielded 3.1 g (89%) of the title compound,
Reaction SMILES: Cl[C:2]1[CH:11]=[N:10][C:9]2[C:4](=[C:5]3[CH:19]=[CH:18][CH:17]=[CH:16][C:6]3=[C:7]3[CH:15]=[CH:14][CH:13]=[CH:12][C:8]3=2)[N:3]=1.[CH:20]1[C:32]2[N:31]([C:33]3[CH:34]=[C:35](B(O)O)[CH:36]=[C:37]([N:39]4[C:51]5[CH:50]=[CH:49][CH:48]=[CH:47][C:46]=5[C:45]5[C:40]4=[CH:41][CH:42]=[CH:43][CH:44]=5)[CH:38]=3)[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:24]=2[CH:23]=[CH:22][CH:21]=1.C(O)C.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.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>[CH:20]1[C:32]2[N:31]([C:33]3[CH:34]=[C:35]([C:2]4[CH:11]=[N:10][C:9]5[C:4](=[C:5]6[CH:19]=[CH:18][CH:17]=[CH:16][C:6]6=[C:7]6[CH:15]=[CH:14][CH:13]=[CH:12][C:8]6=5)[N:3]=4)[CH:36]=[C:37]([N:39]4[C:40]5[CH:41]=[CH:42][CH:43]=[CH:44][C:45]=5[C:46]5[C:51]4=[CH:50][CH:49]=[CH:48][CH:47]=5)[CH:38]=3)[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:24]=2[CH:23]=[CH:22][CH:21]=1
Reactant: OB(O)c1cc(-n2c3ccccc3c3ccccc32)cc(-n2c3ccccc3c3ccccc32)c1
Reactant: Clc1cnc2c3ccccc3c3ccccc3c2n1
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: CCO
Solvent: Cc1ccccc1
Product: c1ccc2c(c1)c1ccccc1c1nc(-c3cc(-n4c5ccccc5c5ccccc54)cc(-n4c5ccccc5c5ccccc54)c3)cnc21
Yield: 94 %

Procedure:
Into a 100-mL three-neck flask were put 1.2 g (4.8 mmol) of 2-chlorodibenzo[f,h]quinoxaline, 2.1 g (4.7 mmol) of 3,5-bis(9H-carbazol-9-yl)phenylboronic acid, and the air in the flask was replaced with nitrogen. To this mixture were added 18 mL of toluene, 6.0 mL of ethanol, and 6.0 mL of an aqueous solution of potassium carbonate (2.0 mol/L). This mixture was stirred to be degassed while the pressure was reduced. To this mixture was added 0.11 g (0.096 mmol) of tetrakis(triphenylphosphine)palladium(0), and the mixture was stirred at 80° C. for six hours under a nitrogen stream, so that a solid was precipitated. The precipitated solid was collected by suction filtration. To the obtained solid was added about 100 mL of water, washed by ultrasonic wave irradiation, and subjected to suction filtration to obtain a solid. To the obtained solid was added about 100 mL of ethanol, washed by ultrasonic wave irradiation, and subjected to suction filtration to obtain a solid. The obtained solid was dissolved in about 1.5 L of hot toluene, and this solution was suction-filtered through Celite and Florisil. A solid obtained by concentration of the filtrate was washed with toluene, so that 2.8 g of a yellow solid, which was the object of the synthesis, was obtained in a yield of 94%. The synthesis scheme of Step 3 is shown in (a-3).