Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:7]2[C:8](C)=[CH:9][NH:10][C:6]=2[C:5](=[O:12])[N:4]([CH3:13])[C:3]1=[O:14].Br[CH2:16][C:17]([NH:19][C:20]1[S:21][CH:22]=[C:23]([C:25]2[CH:30]=[C:29]([F:31])[C:28]([O:32][CH2:33][C:34]([F:37])([F:36])[F:35])=[C:27]([F:38])[CH:26]=2)[N:24]=1)=[O:18].[H-].[Na+]>CN(C=O)C>[F:38][C:27]1[CH:26]=[C:25]([C:23]2[N:24]=[C:20]([NH:19][C:17](=[O:18])[CH2:16][N:10]3[C:6]4[C:5](=[O:12])[N:4]([CH3:13])[C:3](=[O:14])[N:2]([CH3:1])[C:7]=4[CH:8]=[CH:9]3)[S:21][CH:22]=2)[CH:30]=[C:29]([F:31])[C:28]=1[O:32][CH2:33][C:34]([F:35])([F:36])[F:37]
Reactant: O=C(CBr)Nc1nc(-c2cc(F)c(OCC(F)(F)F)c(F)c2)cs1
Reactant: Cc1c[nH]c2c(=O)n(C)c(=O)n(C)c12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1c(=O)c2c(ccn2CC(=O)Nc2nc(-c3cc(F)c(OCC(F)(F)F)c(F)c3)cs2)n(C)c1=O

Procedure:
The title compound was prepared according to the general procedure (Method A) by coupling Intermediate 1 (29 mg, 0.166 mmol) with 2-bromo-N-{4-[3,5-difluoro-4-(2,2,2-trifluoroethoxy)phenyl]-1,3-thiazol-2-yl}acetamide (60 mg, 0.139 mmol) in the presence of NaH (5.0 mg, 0.208 mmol) in dry DMF (5.0 mL) to give 20 mg of the product as a white solid; 1H NMR (δ ppm, DMSO-d6, 300 MHz) 3.17 (s, 3H), 3.39 (s, 3H), 4.86 (q, J=8.7 Hz, 2H), 5.32 (s, 2H), 6.23 (s, 1H), 7.35 (s, 1H), 7.69 (s, 1H), 7.72 (s, 1H), 7.83 (s, 1H), 12.70 (br s, 1H); ESI-MS (m/z) 530.11 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[N:6]2[C:7]3[CH:19]=[CH:18][CH:17]=[CH:16][C:8]=3[NH:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[C:5]2=[N:4][CH:3]=1.[CH2:20]=O.[CH:22]([OH:24])=O>>[CH3:1][C:2]1[N:6]2[C:7]3[CH:19]=[CH:18][CH:17]=[CH:16][C:8]=3[N:9]([CH3:20])[C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[C:5]2=[N:4][C:3]=1[CH2:22][OH:24]
Reactant: O=CO
Reactant: Cc1cnc2n1-c1ccccc1Nc1ccccc1-2
Reactant: C=O
Product: Cc1c(CO)nc2n1-c1ccccc1N(C)c1ccccc1-2

Procedure:
3-methyl-9H-dibenzo[b,f]imidazo[1,2-d][1,4]diazepine is dissolved in 88% formic acid, treated with 37% aqueous formalin solution and heated for 24 hours, to give 3,9-dimethyl-2-hydroxymethyl-9H-dibenzo [b,f]-imidazo[1,2-d][1,4]diazepine.
Reaction SMILES: [Br:1][C:2]1[C:3]([O:18][C:19]2[CH:27]=[CH:26][C:22]([C:23]([OH:25])=O)=[CH:21][CH:20]=2)=[C:4]([Cl:17])[CH:5]=[C:6]2[C:11]=1[O:10][CH2:9][CH2:8][CH:7]2[C:12]([O:14][CH2:15][CH3:16])=[O:13].Cl.[Cl:29][C:30]1[CH:35]=[CH:34][C:33]([C:36]2[N:41]=[C:40]([NH2:42])[CH:39]=[CH:38][CH:37]=2)=[CH:32][CH:31]=1.C(N(CC)C(C)C)(C)C>S(Cl)(Cl)=O.C(OCC)(=O)C.Cl>[Br:1][C:2]1[C:3]([O:18][C:19]2[CH:20]=[CH:21][C:22]([C:23](=[O:25])[NH:42][C:40]3[CH:39]=[CH:38][CH:37]=[C:36]([C:33]4[CH:34]=[CH:35][C:30]([Cl:29])=[CH:31][CH:32]=4)[N:41]=3)=[CH:26][CH:27]=2)=[C:4]([Cl:17])[CH:5]=[C:6]2[C:11]=1[O:10][CH2:9][CH2:8][CH:7]2[C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: CCOC(=O)C1CCOc2c1cc(Cl)c(Oc1ccc(C(=O)O)cc1)c2Br
Reactant: Nc1cccc(-c2ccc(Cl)cc2)n1
Agent: Cl
Solvent: O=S(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CCOC(=O)C1CCOc2c1cc(Cl)c(Oc1ccc(C(=O)Nc3cccc(-c4ccc(Cl)cc4)n3)cc1)c2Br
Temperature: 25 °C
Reaction time: 3 h
Yield: 58.4 %

Procedure:
A solution of 4-(8-bromo-6-chloro-4-(ethoxycarbonyl)chroman-7-yloxy)benzoic acid (0.18 g, 0.40 mmol) in thionyl chloride (5 mL) was stirred and heated to gentle reflux for 30 minutes. The solution was cooled to ambient temperature and concentrated. The residual light yellow solid was dissolved in dichloromethane (4 mL). To the resulting stirred solution at ambient temperature was added 6-(4-chlorophenyl)pyridin-2-amine hydrochloride (96.6 mg, 0.40 mmol), followed by N,N-diisopropylethylamine (0.28 mL, 1.60 mmol). A solution formed, and stirring was continued at ambient temperature for 3 hours. The solution was diluted with ethyl acetate (20 mL) and 1M hydrochloric acid (10 mL), then transferred to a separatory funnel. After shaking, the organic layer was washed successively with 10 mL portions of water, 10% sodium carbonate, and brine, dried over sodium sulfate and evaporated. The residual oil was purified by chromatography on silica gel, eluting with 80/20 hexanes/ethyl acetate, to afford the desired compound as a colorless oil (0.15 g, 58% yield).
Reaction SMILES: [Cl:1][C:2]1[NH:3][C:4]2[CH:10]=[C:9]([Br:11])[C:8]([Br:12])=[CH:7][C:5]=2[N:6]=1.C[Si](/N=C(/O[Si](C)(C)C)\C(F)(F)F)(C)C.C(O[C@@H:32]1[O:44][C@H:43]([CH2:45][O:46][C:47](=[O:49])[CH3:48])[C@@H:38]([O:39][C:40](=[O:42])[CH3:41])[C@H:33]1[O:34][C:35](=[O:37])[CH3:36])(=O)C.O([Si](C)(C)C)S(C(F)(F)F)(=O)=O>CC#N.CCOC(C)=O>[Cl:1][C:2]1[N:3]([C@@H:32]2[O:44][C@H:43]([CH2:45][O:46][C:47](=[O:49])[CH3:48])[C@@H:38]([O:39][C:40](=[O:42])[CH3:41])[C@H:33]2[O:34][C:35](=[O:37])[CH3:36])[C:4]2[CH:10]=[C:9]([Br:11])[C:8]([Br:12])=[CH:7][C:5]=2[N:6]=1
Reactant: CC(=O)OC[C@H]1O[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: Clc1nc2cc(Br)c(Br)cc2[nH]1
Agent: C[Si](C)(C)/N=C(/O[Si](C)(C)C)C(F)(F)F
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CC(=O)OC[C@H]1O[C@@H](n2c(Cl)nc3cc(Br)c(Br)cc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 55.5 %

Procedure:
A suspension of 931 mg (3 mmole) of 2-chloro-5,6-dibromobenzimidazole (17) in 15 ml of dry CH3CN was treated with 0.8 mL (3 mmole) of N,O-bis(trimethylsilyl) trifluoroacetamide (BSTFA) at 75° C. for 10 min to give a clear solution. To this solution, was added 955 mg (3 mmole) of 1,2,3,5-tetra-O-acetyl-β-D-ribofuranose and 0 64 mL (3.3 mmole) of trimethylsilyl triflate (TMSTf). Stirring was continued at 75° C. for 1 hr. The reaction mixture was cooled to room temperature and then diluted with 100 mL of EtOAc. The EtOAc solution was washed with a sat. NaHCO3 solution (100 mL×2), sat. NaCl solution (100 mL), dried (Na2SO4), and evaporated. The residue was chromatographed on a silica column (3×20 cm, eluted with CHCl3). Evaporation of fractions 4-10 and recrystallization of the residue from MeOH gave 946 mg (56%) of 56 as white crystals. mp 140°-142° C.; MS m/e 565.9082 (0.9%, M+ =565.9091); 1H NMR (DMSO-d6) d 8.20 (s, 1,7-H), 8.11 (s, 1, 4-H), 6.25 (d, 1, 1'-H), 5.55 (t, 1, 2'-H), 5.43 (dd, 1, 3'-H), 4.47 (m, 2, 5'-H, 4'-H), 4.37 (m, 1, 5"-H), 2.15, 2.14, 2.02 (3×s, 3×, 3.3×Ac). Evaporation of fractions 13-15 gave 392 mg (23%) of the a anomer as a white foam. 1H NMR (DMSO-6) d 8.07, 8.06 (2×s, 2, 4-H, 7-H), 6.70 (d, 1, 1'-H), 5.71 (t, 1, 2'-H), 5.50 (dd, 1, 3 '-H), 4.81 (m. 1, 4'-H), 4. 36 (dd, 1, 5'-H), 427 (dd, 1, 5"-H).
Reaction SMILES: C([N:8]1[CH2:12][CH2:11][C:10]([C:17]2[CH:22]=[C:21]([C:23]([F:26])([F:25])[F:24])[N:20]=[C:19]([C:27]([F:30])([F:29])[F:28])[CH:18]=2)([C:13]([F:16])([F:15])[F:14])[CH2:9]1)C1C=CC=CC=1.ClC(OC(Cl)C)=O>ClC(Cl)C>[F:30][C:27]([F:28])([F:29])[C:19]1[CH:18]=[C:17]([C:10]2([C:13]([F:14])([F:15])[F:16])[CH2:11][CH2:12][NH:8][CH2:9]2)[CH:22]=[C:21]([C:23]([F:24])([F:25])[F:26])[N:20]=1
Reactant: FC(F)(F)c1cc(C2(C(F)(F)F)CCN(Cc3ccccc3)C2)cc(C(F)(F)F)n1
Agent: CC(Cl)OC(=O)Cl
Solvent: CC(Cl)Cl
Product: FC(F)(F)c1cc(C2(C(F)(F)F)CCNC2)cc(C(F)(F)F)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 70.1 %

Procedure:
The solution of 4-[1-benzyl-3-(trifluoromethyl)pyrrolidin-3-yl]-2,6-bis(trifluoromethyl)pyridine (1.4 g) and 1-chloroethyl chloroformate (0.905 g) in dichloroethane was heated to reflux for 3 hours. The mixture was cooled to room temperature and then concentrated under the reduced pressure. Methanol was added to the resultant residue, which was then heated with stirring at 60° C. for two hours. The mixture was cooled to room temperature, to which was then added water. The solution was washed twice with the mixed solvent of hexane. The solution was neutralized with sodium hydroxide and then extracted with tert-butyl methyl ether three times. The organic layers were combined, washed with brine and dried over anhydrous magnesium sulfate. After the drying agent was filtered off, the solvent was removed under reduced pressure to yield 2,6-bis(trifluoromethyl)-4-[3-(trifluoromethyl)pyrrolidin-3-yl]pyridine (0.781 g).
Reaction SMILES: C[Si]([N:5]=[N+]=[N-])(C)C.[Br:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]C(Cl)=O.[O:17]1[CH2:22]COCC1>>[Br:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][N:5]=[C:22]=[O:17]
Reactant: O=C(Cl)CCCCCBr
Reactant: C[Si](C)(C)N=[N+]=[N-]
Reactant: C1COCCO1
Product: O=C=NCCCCCBr
Temperature: 80 °C
Yield: 78 %

Procedure:
To a solution of trimethylsilylazide (7.46 mL, 93.67 mmol) in dioxane (10 mL), 6-bromohexanoyl chloride (10 g, 46.83 mmol) was added and the solution was heated at 80° C. for 4 hours. The reaction mixture was concentrated to give a liquid. Distillation (oil bath temp. 135° C., distilling temperature 94° C.) of the liquid yielded 7 g (78%) of the product as a liquid: 1H-NMR (CDCl3) δ1.50-1.92 (m, 6 H), 3.33 (t, J=7.0 Hz, 2H), 3.43 (t, J=7.0 Hz, 2H). IR: 2360 cm-1.
Reaction SMILES: Cl.[C:2]([O:6][NH2:7])([CH3:5])([CH3:4])[CH3:3].CN1CCOCC1.[Cl:15][C:16]1[CH:41]=[CH:40][C:19]([C:20]([CH:22]2[CH2:27][CH2:26][N:25]([S:28]([N:31]3[CH2:36][CH2:35][CH2:34][CH2:33][C@@H:32]3[C:37](O)=[O:38])(=[O:30])=[O:29])[CH2:24][CH2:23]2)=[O:21])=[CH:18][CH:17]=1.C1C[C@H](C(O)=O)NCC1.[Cl-]>C(Cl)Cl.C(OCC)(=O)C>[C:2]([O:6][NH:7][C:37]([C@H:32]1[CH2:33][CH2:34][CH2:35][CH2:36][N:31]1[S:28]([N:25]1[CH2:24][CH2:23][CH:22]([C:20](=[O:21])[C:19]2[CH:18]=[CH:17][C:16]([Cl:15])=[CH:41][CH:40]=2)[CH2:27][CH2:26]1)(=[O:30])=[O:29])=[O:38])([CH3:5])([CH3:4])[CH3:3]
Reactant: O=C(c1ccc(Cl)cc1)C1CCN(S(=O)(=O)N2CCCC[C@@H]2C(=O)O)CC1
Reactant: CC(C)(C)ON
Agent: Cl
Agent: O=C(O)[C@H]1CCCCN1
Agent: [Cl-]
Solvent: ClCCl
Solvent: CN1CCOCC1
Solvent: CCOC(C)=O
Product: CC(C)(C)ONC(=O)[C@H]1CCCCN1S(=O)(=O)N1CCC(C(=O)c2ccc(Cl)cc2)CC1
Reaction time: 8 h
Yield: 65 %

Procedure:
O-tert-butylhydroxylamine hydrochloride (127 mg, 1.01 mmol), 1-(3-dimethylaminopropyl)-3-ethylcaibodiimide hydrochloride (129 mg, 0.67 mmol), N,N-dimethylaminopyridine (41 mg, 0.34 mmol), and N-methylmorpholine (0.15 ml, 1.3 mmol) were added to a solution of 1-[4-(4-chlorobenzoyl)piperidine-1-sulfonyl]piperidine-2-(R)-carboxylic acid (140 mg, 0.34 mmol), [prepared by proceeding as described in Example 9, but replacing D-valine and 4-(4chlorophenoxy)piperidinesulfamoyl chloride with D-pipecolinic acid and 4-(4-chlorobenzoylpiperidinesulfamoyl chloride, respectively], in methylene chloride (2 ml). After stirring overnight, the reaction mixture was diluted with ethyl acetate, washed with 1M HCl, and brine, and dried over MgSO4. The organics were evaporated in vacuo and the residue was chromatographed (PTLC, SiO2, 40% ethyl acetate/hexane) to give N-tert-butoxy-1-[4-(4-chlorobenzoyl)piperidine-1-sulfonyl]piperidine-2-(R)-carboxamide as a white solid (65%).
Reaction SMILES: C(NC(C)C)(C)C.[Li+].CCC[CH2-].[CH3:13][S:14][C:15]1[N:20]=[C:19]([CH3:21])[CH:18]=[CH:17][N:16]=1.CON(C)[C:25](=[O:36])[C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:34])[F:33])[CH:27]=1>C1COCC1>[CH3:13][S:14][C:15]1[N:20]=[C:19]([CH2:21][C:25]([C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:33])([F:34])[F:35])[CH:27]=2)=[O:36])[CH:18]=[CH:17][N:16]=1
Reactant: CSc1nccc(C)n1
Reactant: CON(C)C(=O)c1cccc(C(F)(F)F)c1
Agent: [CH2-]CCC
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CSc1nccc(CC(=O)c2cccc(C(F)(F)F)c2)n1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 80.9 %

Procedure:
To a solution of diisopropylamine (7.9 mL, 0.056 mole) in THF (100 mL) at -78° C. under argon was added 2.5M N-butyllithium (22.5 mL, 0.056 mole), followed after 5 minutes by a solution of 2-methylthio-4-methylpyrimidine (5.27 g, 0.0376 mole) in THF (20 mL). Upon stirring for 15 min. at -78° C., a solution of N-methoxy-N-methyl-3-trifluoromethylbenzamide (9.63 g, 0.041 mole) in THF (90 mL) was added. The reaction was allowed to warm to 0° C. and then quenched by pouring into water (400 mL) and ethyl acetate (400 mL). The layers were separated and the aqueous layer washed with ethyl acetate (200 mL). The ethyl acetate extracts were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to a solid (11.9 g). Trituration with 10% ether/hexane (100 mL) gave 9.5 g of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][CH3:12])=[C:6]2[C:10]=1[NH:9][N:8]=[CH:7]2.[F:13][C:14]1[CH:15]=[C:16](B(O)O)[CH:17]=[CH:18][C:19]=1[O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.N1C=CC=CC=1>C(Cl)Cl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][CH3:12])=[C:6]2[C:10]=1[N:9]([C:16]1[CH:17]=[CH:18][C:19]([O:20][CH2:21][C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)=[C:14]([F:13])[CH:15]=1)[N:8]=[CH:7]2
Reactant: OB(O)c1ccc(OCc2ccccc2)c(F)c1
Reactant: COc1ccc(F)c2[nH]ncc12
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1ccc(F)c2c1cnn2-c1ccc(OCc2ccccc2)c(F)c1
Yield: 25.9 %

Procedure:
7-Fluoro-4-(methyloxy)-1H-indazole (D26) (500 mg, 3.01 mmol), the {3-fluoro-4-[(phenylmethyl)oxy]phenyl}boronic acid (1.48 g, 6.02 mmol), copper (II) acetate (820 mg, 4.51 mmol), powdered molecular sieves (550 mg) and pyridine (0.49 mL, 6.02 mmol) in DCM (15 mL) were stirred at room temperature in the presence of air. After 4 hours the mixture was filtered through a pad of celite and washed with water. The aqueous was re-extracted with DCM (3×) and the combined organics were washed with brine and dried over MgSO4. The crude (1.71 g) was purified by flash chromatography (Biotage SP4) with a gradient of EtOAc (0 to 20%) in hexane to afford 286 mg of title compound (D27).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[Cl:7][C:8]1[CH:9]=[C:10]([C:14]2[C:15]3[N:16]([C:35]([CH2:38][CH3:39])=[CH:36][CH:37]=3)[N:17]=[C:18]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C:19]=2[CH2:20][CH2:21][CH2:22][CH2:23][C:24](OCC)=[O:25])[CH:11]=[CH:12][CH:13]=1>O1CCCC1>[Cl:7][C:8]1[CH:9]=[C:10]([C:14]2[C:15]3[N:16]([C:35]([CH2:38][CH3:39])=[CH:36][CH:37]=3)[N:17]=[C:18]([C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)[C:19]=2[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][OH:25])[CH:11]=[CH:12][CH:13]=1
Reactant: CCOC(=O)CCCCc1c(-c2ccccc2)nn2c(CC)ccc2c1-c1cccc(Cl)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCc1ccc2c(-c3cccc(Cl)c3)c(CCCCCO)c(-c3ccccc3)nn12
Temperature: 0 °C
Reaction time: 2 h
Yield: 87.7 %

Procedure:
To a suspension of lithium aluminum hydride (98.8 mg) in tetrahydrofuran (10 mL) was added ethyl 5-[4-(3-chlorophenyl)-7-ethyl-2-phenylpyrrolo[1,2-b]pyridazin-3-yl]pentanoate (600 mg) in tetrahydrofuran (10 mL) under ice-water cooling and the mixture was stirred at 0° C. for 2 hours. The reaction was quenched with saturated potassium sodium tartrate solution and the insolubles were filtereed off and washed with ethyl acetate. The filtrates were washed with brine, dried over magnesium sulfate, and evaporated in vacuo. The residue was purified by silica gel column chromatography eluting with a mixture of hexane and ethyl acetate (10:1–2:1) to give 5-[4-(3-chlorophenyl)-7-ethyl-2-phenylpyrrolo[1,2-b]pyridazin-3-yl]-1-pentanol as an yellow oil (478 mg).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:12]1[C:13]3[C:18]([C:19]4C=CC=C[C:24]=4[CH:25]=1)=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH:6]=[CH:5]2.CCCCCC.[CH2:32]([Li])[CH2:33][CH2:34][CH3:35].[B:37](OC(C)C)([O:42]C(C)C)[O:38]C(C)C.Cl>C(OCC)C.C1(C)C=CC=CC=1>[CH:32]1[C:24]2[CH:25]=[C:12]([C:7]3[CH:6]=[CH:5][C:4]4[C:9](=[CH:10][CH:11]=[C:2]([B:37]([OH:42])[OH:38])[CH:3]=4)[CH:8]=3)[C:13]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:19]=2[CH:35]=[CH:34][CH:33]=1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: Brc1ccc2cc(-c3cc4ccccc4c4ccccc34)ccc2c1
Reactant: [Li]CCCC
Agent: Cl
Solvent: CCOCC
Solvent: CCCCCC
Solvent: Cc1ccccc1
Product: OB(O)c1ccc2cc(-c3cc4ccccc4c4ccccc34)ccc2c1
Temperature: -10 °C
Yield: 58 %

Procedure:
Under an argon gas atmosphere, a mixture of 9.80 g (25.6 mmol) of 6-bromo-2-(9-phenanthrenyl)naphthalene, 100 mL of dehydrated toluene and 100 mL of dehydrated diethylether was cooled down to −10 degrees C., and added with 19.7 mL (30.7 mmol) of hexane solution of 1.56M n-butyllithium in drops while being stirred. Then, the reaction mixture was stirred for four hours at −10 degree C. The reaction mixture was further cooled down to −60 degrees C., and added with 14.4 g (76.7 mmol) of triisopropyl borate in drops. The reaction mixture was subsequently warmed up to room temperature, and stirred for 16 hours at room temperature. The reaction mixture was further added with solution of hydrochloric acid to be stirred for one night at room temperature. After the reaction, the reaction mixture experienced liquid separation, organic phase thereof was cleansed with water, and the solvent was distilled away under reduced pressure until the reaction mixture became slurry. By adding residue thereof with hexane, filtering the solid and recrystallizing the residue by THF and hexane, 5.20 g of 2-(9-phenanthrenyl)naphthalene-6-boronic acid was obtained at an yield of 58%.
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH:4]1[C:9]2[NH:10][C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:16]=3[C:8]=2[S:7][CH2:6][CH2:5]1.C(N(CC)CC)C.[C:24]([O:28][C:29](ON=C(C1C=CC=CC=1)C#N)=[O:30])([CH3:27])([CH3:26])[CH3:25]>O1CCCC1>[CH3:1][N:2]([CH2:3][CH:4]1[C:9]2[NH:10][C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:16]=3[C:8]=2[S:7][CH2:6][CH2:5]1)[C:29]([O:28][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:30]
Reactant: CNCC1CCSc2c1[nH]c1ccccc21
Reactant: CC(C)(C)OC(=O)ON=C(C#N)c1ccccc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CN(CC1CCSc2c1[nH]c1ccccc21)C(=O)OC(C)(C)C
Reaction time: 4 h
Yield: 68.1 %

Procedure:
A solution of 4-methylaminomethyl-2,3,4,5-tetrahydrothiopyrano[3,2-b]indole (5.47 g) in dry tetrahydrofuran (50 ml) is mixed with triethylamine (3.58 g) and 2-t-butoxycarbonyloxyimino-2-phenylacetonitrile (5.93 g), allowed to stand at room temperature for 4 hours and evaporated to dryness. The residue is dissolved in methylene chloride and washed with a dilute sodium hydroxide solution. The solution is washed with water, dried and evaporated to dryness. The residue is applied to column chromatography on silica gel eluted with benzene/ether (20:1) to give 4-(N-methyl-N-t-butoxycarbonylaminomethyl)-2,3,4,5-tetrahydrothiopyrano[ 3,2-b]indole (5.33 g): Yield 68.2%. Recrystallization from benzene/petroleum benzine gives crystals melting at 151°-153° C. (decomp.).
Reaction SMILES: [CH2:1]([NH:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[Cl:11])[CH3:2].[CH:13]([Si:15](Cl)([CH3:17])[CH3:16])=[CH2:14]>>[CH2:1]([NH:3][C:4](=[O:12])[C:5]1[C:10]([Si:15]([CH:13]=[CH2:14])([CH3:17])[CH3:16])=[CH:9][CH:8]=[CH:7][C:6]=1[Cl:11])[CH3:2]
Reactant: CCNC(=O)c1ccccc1Cl
Reactant: C=C[Si](C)(C)Cl
Product: C=C[Si](C)(C)c1cccc(Cl)c1C(=O)NCC

Procedure:
The title compound was prepared from the compound of Example f and 1.5 eq vinyldimethylsilyl chloride according to General Method C. Purification by HPLC with 1:4 ethyl acetate/hexanes gave 630 mg of the desired product as a white solid, a 9% yield. m.p. 86-89° C.
Reaction SMILES: [CH2:1]([OH:3])[CH3:2].CN([CH:7]=[O:8])C.C(P(C1C=CC=CC=1)C1C=CC=CC=1)CCP(C1C=CC=CC=1)C1C=CC=CC=1.FC(F)(F)S(O[C:44]1[CH:45]=[N:46][CH:47]=[C:48]([Cl:50])[CH:49]=1)(=O)=O>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CCN(CC)CC>[Cl:50][C:48]1[CH:47]=[N:46][CH:45]=[C:44]([CH:49]=1)[C:7]([O:3][CH2:1][CH3:2])=[O:8]
Reactant: O=S(=O)(Oc1cncc(Cl)c1)C(F)(F)F
Reactant: CN(C)C=O
Reactant: CCO
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(CCCP(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: CCOC(=O)c1cncc(Cl)c1
Temperature: 50 °C
Reaction time: 4 h

Procedure:
To ethanol (66 mL) and DMF (66 mL) was added Et3N (29.4 mL), 1,3-propanediylbis(diphenylphosphine) (3.48 g) and palladium acetate (1.9 g) in ice-water bath. To this was added 5-chloro-3-pyridinyl trifluoromethanesulfonate (22.1 g) at the temperature. The mixture was stirred at 50° C. for 4 hours under CO (1 atom). The mixture was partitioned betwwen EtOAc and water. The aqueous layer was extracted with EtOAc. The combined organic layer was washed with water three times, dried over MgSO4 and evaporated in vacuo. The residue was purified by silica gel column chromatography (silica gel, 200 mL) eluted with hexane-EtOAc=15-1 and 10-1 to give ethyl 5-chloronicotinate (10.5 g) as a pale brown oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C@H:9]1[CH2:13][CH2:12][CH2:11][N:10]1[C:14]1[CH:19]=[CH:18][N:17]2[N:20]=[CH:21][C:22]([NH2:23])=[C:16]2[N:15]=1.C1N=CN([C:29]([N:31]2[CH:35]=N[CH:33]=[CH:32]2)=[O:30])C=1.Cl.N1CC([OH:41])C1.CCN(C(C)C)C(C)C>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C@H:9]1[CH2:13][CH2:12][CH2:11][N:10]1[C:14]1[CH:19]=[CH:18][N:17]2[N:20]=[CH:21][C:22]([NH:23][C:29]([N:31]3[CH2:32][CH:33]([OH:41])[CH2:35]3)=[O:30])=[C:16]2[N:15]=1
Reactant: OC1CNC1
Reactant: Nc1cnn2ccc(N3CCC[C@@H]3c3cc(F)ccc3Cl)nc12
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1cnn2ccc(N3CCC[C@@H]3c3cc(F)ccc3Cl)nc12)N1CC(O)C1
Reaction time: 2 h
Yield: 85.1 %

Procedure:
To a D CM (0.8 mL) solution of (R)-5-(2-(2-chloro-5-fluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-amine (30 mg, 0.090 mmol) was added CDI (29 mg, 0.18 mmol) at ambient temperature in one portion. After stirring two hours, azetidin-3-ol hydrochloride (20 mg, 0.18 mmol) was added in one portion, followed by addition of DIEA (0.047 mL, 0.27 mmol). The reaction was stirred for 5 minutes before it was concentrated and directly purified by reverse-phase column chromatography, eluting with 5 to 50% acetonitrile/water to yield the final product as a yellowish foamy powder (33 mg, 85% yield). MS (apci) m/z=431.1 (M+H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][C:3]=1[CH3:12].C[CH2:14][N:15](C(C)C)C(C)C.CN>CN(C)C=O.CO>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:15][CH3:14])(=[O:10])=[O:9])=[CH:4][C:3]=1[CH3:12]
Reactant: Cc1cc(S(=O)(=O)Cl)ccc1Br
Reactant: CCN(C(C)C)C(C)C
Agent: CN
Solvent: CO
Solvent: CN(C)C=O
Product: CNS(=O)(=O)c1ccc(Br)c(C)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.2 %

Procedure:
To a solution of 4-bromo-3-methylbenzene-1-sulfonyl chloride (500 mg, 1.86 mmol) and DIEA (0.65 mL, 3.7 mmol) in N,N-dimethylformamide (5 mL) was added methylamine as a 2.0 M solution in methanol. The reaction mixture was allowed to stir at room temperature overnight. The reaction mixture was evaporated to dryness and was dissolved in dichloromethane (3 mL). The solution was washed with 1 N HCl (2×3 mL) and a saturated solution of NaHCO3 (3 mL). The organics were dried over Na2SO4 and evaporated to dryness to give 4-bromo-N,3-dimethylbenzenesulfonamide (340 mg).
Reaction SMILES: [C:1]([C@H:3]1[O:8][CH2:7][C@H:6]([CH2:9][O:10][Si](C(C)(C)C)(C)C)[N:5]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:4]1)#[CH:2].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1.CCOC(C)=O>[C:1]([C@H:3]1[O:8][CH2:7][C@@H:6]([CH2:9][OH:10])[N:5]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:4]1)#[CH:2]
Reactant: C#C[C@@H]1CN(C(=O)OC(C)(C)C)[C@@H](CO[Si](C)(C)C(C)(C)C)CO1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C#C[C@@H]1CN(C(=O)OC(C)(C)C)[C@H](CO)CO1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of tert-butyl (2R,5R)-2-ethynyl-5-(tert-butyldimethylsilyloxy-methyl)morpholine-4-carboxylate (Example 79, step 4) (2.0 g, 5.7 mmol) in 20 mL of THF was added tetrabutylammonium fluoride (1.0 M in THF, 15 mL, 15 mmol). The solution was stirred at ambient temperature for 1 h and then diluted with EtOAc, washed with aqueous NH4Cl, and brine. The solution was dried (MgSO4), filtered, and the solvent was removed in vacuo. The residue was chromatographed on an 80 g SiO2 column using a gradient elution of 0-10% MeOH in CHCl3 to give the product as an oil.