Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][Mg]Br.[C:4]([C:8]1[C:13]([O:14][SiH:15]([CH3:17])[CH3:16])=[C:12]([Br:18])[C:11]([O:19][CH3:20])=[CH:10][C:9]=1[CH2:21][CH:22]1[C:27](=[O:28])[CH:26]=[CH:25][CH2:24][C:23]1([CH3:30])[CH3:29])([CH3:7])([CH3:6])[CH3:5]>CCOCC.[Cu]I>[C:4]([C:8]1[C:13]([O:14][SiH:15]([CH3:16])[CH3:17])=[C:12]([Br:18])[C:11]([O:19][CH3:20])=[CH:10][C:9]=1[CH2:21][C@H:22]1[C:23]([CH3:30])([CH3:29])[CH2:24][C@@H:25]([CH3:1])[CH2:26][C:27]1=[O:28])([CH3:7])([CH3:5])[CH3:6]
Reactant: C[Mg]Br
Reactant: COc1cc(CC2C(=O)C=CCC2(C)C)c(C(C)(C)C)c(O[SiH](C)C)c1Br
Agent: [Cu]I
Solvent: CCOCC
Product: COc1cc(C[C@@H]2C(=O)C[C@H](C)CC2(C)C)c(C(C)(C)C)c(O[SiH](C)C)c1Br
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To a suspension of copper(I) iodide (2 mg) in 1 mL of anhydrous ether at 0°C. was added methylmagnesium bromide (0.106 mL of a 3.0 M solution in ether, 0.319 mmol, 1.00 equiv). Then enone 13 (149 mg, 0.319 mmol) in 2 mL of anhydrous ether was added slowly to the stirring cuprate mixture at a temperature maintained below 5° C., and upon completion of the addition, the reaction mixture was stirred at 0° C. for 3 h before quenching with a 4:1 mixture of saturated aqueous NH4Cl/NH4OH. The resultant biphasic mixture was extracted with ether, dried over Na2SO4, and concentrated under diminished pressure. Purification by flash column chromatography (silica gel, hexanes/ethyl acetate, 9:1) afforded 36 mg (30%) of the desired conjugate addition product as a white solid. 1H NMR (400 MHz, CDCl3) δ0.22 (s, 6H, Si(CH3)2), 1.00 [m, 18H, 3,3,5-CH3 and SiC(CH3)3 ], 1.50 (dd, 2H, J=15.1, 6.5 Hz, 4-Hz, 4-H), 2.02 (m, 1H, 5-H), 2.14 and 2.23 (ABq, 2H, JAB =12.0 Hz, 6-H), 2.42 (dd, 1H, J=10.4, 6.4 Hz, 2-H), 2.88 and 2.89 (d of ABq, 2H, JAB =12.0 Hz, JA =10.4 Hz, JB =6.3 Hz, benzylic-CH2), 3.82 (s, 3H, OCH3), 6.65 (s, 1H, 6'-H), 6.92 ppm (s, 1H, 3'-H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH2:21][OH:22])[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.Br[CH2:24][C:25]1[CH:26]=[C:27]([C:42]([F:45])([F:44])[F:43])[CH:28]=[C:29]2[C:33]=1[N:32]([CH2:34][O:35][CH2:36][CH2:37][Si:38]([CH3:41])([CH3:40])[CH3:39])[N:31]=[CH:30]2.[H-].[Na+]>CN(C)C=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([CH2:21][O:22][CH2:24][C:25]3[CH:26]=[C:27]([C:42]([F:45])([F:43])[F:44])[CH:28]=[C:29]4[C:33]=3[N:32]([CH2:34][O:35][CH2:36][CH2:37][Si:38]([CH3:39])([CH3:40])[CH3:41])[N:31]=[CH:30]4)[CH2:9][CH2:10][N:11]([C:14]([O:16][C:17]([CH3:18])([CH3:19])[CH3:20])=[O:15])[CH2:12][CH2:13]2)=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC(CO)(c2ccc(F)cc2)CC1
Reactant: C[Si](C)(C)CCOCn1ncc2cc(C(F)(F)F)cc(CBr)c21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(COCc2cc(C(F)(F)F)cc3cnn(COCC[Si](C)(C)C)c23)(c2ccc(F)cc2)CC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of tert-butyl 4-(4-fluorophenyl)-4-(hydroxymethyl)piperidine-1-carboxylate (0.16 g, 0.517 mmol) and 7-(bromomethyl)-5-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole (0.212 g, 0.517 mmol) in dimethylformamide (6 mL) at 0° C. was added sodium hydride (60% in mineral oil, 0.027 g, 0.672 mmol). The resulting solution was stirred at 0° C. for 30 min. The reaction was quenched by the cautious addition of saturated ammonium chloride and diluted with diethyl ether. The ethereal was washed with water (2×), then brine, dried over magnesium sulfate, and concentrated. Column chromatography (12% EtOAc/Hex) gave 280 mg (85%) as an oil. 1H-NMR (CDCl3, 500 MHz) δ 8.16 (s, 1H), 8.10 (s, 1H), 7.51 (s, 1H), 7.24 (m, 2H), 6.98 (m, 2H), 5.58 (s, 2H), 4.86 (s, 2H), 3.78 (m, 2H), 3.55 (s, 2H), 3.52 (m, 2H), 3.11 (m, 2H), 2.19 (m, 2H), 1.87 (m, 2H), 1.53 (s, 9H), 0.89 (m, 2H), 0.00 (s, 9H); 13C-NMR (CDCl3, 126 MHz) δ 162.3, 160.3, 155.0, 139.2, 138.4, 134.8, 128.63, 128.57, 125.7, 124.8, 124.6 (q, J=272 Hz), 123.5 (q, J=32 Hz), 121.9, 119.3 (q, J=3.8 Hz), 115.2, 115.0, 79.5, 79.2, 78.7, 70.5, 66.2, 41.1, 40.0 (br), 32.3, 28.5, 17.8, −1.4. Mass spec.: 638.12 (MH)+.
Reaction SMILES: C[N:2](C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([S:20]([CH3:23])(=[O:22])=[O:21])[CH:15]=2)[N:8]=1)=O.[NH:25]([C:27]1[CH:35]=[CH:34][CH:33]=[CH:32][C:28]=1[C:29]([OH:31])=[O:30])N>>[CH3:23][S:20]([C:16]1[CH:15]=[C:14]([N:9]2[CH:10]=[CH:11][C:12](=[O:13])[C:7]([C:5]3[N:25]([C:27]4[CH:35]=[CH:34][CH:33]=[CH:32][C:28]=4[C:29]([OH:31])=[O:30])[N:2]=[CH:3][CH:4]=3)=[N:8]2)[CH:19]=[CH:18][CH:17]=1)(=[O:22])=[O:21]
Reactant: NNc1ccccc1C(=O)O
Reactant: CN(C)/C=C/C(=O)c1nn(-c2cccc(S(C)(=O)=O)c2)ccc1=O
Product: CS(=O)(=O)c1cccc(-n2ccc(=O)c(-c3ccnn3-c3ccccc3C(=O)O)n2)c1

Procedure:
Reaction of 3-((E)-3-dimethylamino-acryloyl)-1-(3-methansulfonyl-phenyl)-1H-pyridazin-4-one (A-7) and 2-hydrazino-benzoic acid according to example 43 gave the desired product. MS: M=437.0 (M+H)+
Reaction SMILES: [NH2:1][C:2]1[C:3](Br)=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[CH:6]=[CH:5]2.[C:21]1(Cl)[C:25](Cl)=[S+:24]S[N:22]=1.[Cl-]>C(Cl)Cl.CCOC(C)=O.N1C=CC=CC=1.[Cu]I>[C:21]([C:25]1[S:24][C:3]2[C:4]3[C:9](=[CH:8][C:7]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[CH:6][CH:5]=3)[CH:10]=[CH:11][C:2]=2[N:1]=1)#[N:22]
Reactant: CC(C)(C)OC(=O)Nc1ccc2c(Br)c(N)ccc2c1
Reactant: Clc1ns[s+]c1Cl
Agent: [Cu]I
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)Nc1ccc2c(ccc3nc(C#N)sc32)c1
Temperature: 110 °C
Yield: 28.4 %

Procedure:
To a stirred solution of tert-butyl (6-amino-5-bromonaphthalen-2-yl)carbamate (540 mg, 1.6 mmol) in dry DCM, 351 mg of Appel's salt (1.68 mmol) was added. Upon completion, the reaction was diluted with EtOAc and washed with water. The organic layer was dried over Na2SO4 and evaporated. The crude material thus obtained was dissolved in 10 mL of pyridine and treated with 529 mg (2.78 mmol) of CuI. The reaction was heated in a 110° C. oil bath for 40 min, and then the solvents were removed under reduced pressure. The resulting solids were taken up in EtOAc and filtered. The filtrate was washed with 1 N HCl, the aqueous layer extracted with 2×EtOAc, and the combined organic layers dried over Na2SO4. The solvents were removed under reduced pressure, and the resulting material subjected to silica gel chromatography eluting with 15→35% EtOAc in heptanes to yield 148 mg of a yellow solid. 1H NMR (CD2Cl2) d 8.21 (d, 1H); 8.12 (d, 1H); 8.03 (d, 1H); 7.96 (d, 1H); 7.64 (dd, 1H); 6.90 (br s, 1H); 1.55 (s, 9H).
Reaction SMILES: C[O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([C:13]3[C:17]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=4)=[N:16][N:15]4[CH2:24][CH2:25][CH2:26][C:14]=34)=[CH:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1.C([S-])C.[Na+]>CN(C)C=O>[N:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[C:17]1[C:13]([C:7]2[C:6]3[C:11](=[CH:12][C:3]([OH:2])=[CH:4][CH:5]=3)[N:10]=[CH:9][CH:8]=2)=[C:14]2[CH2:26][CH2:25][CH2:24][N:15]2[N:16]=1
Reactant: COc1ccc2c(-c3c(-c4ccccn4)nn4c3CCC4)ccnc2c1
Agent: CC[S-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Oc1ccc2c(-c3c(-c4ccccn4)nn4c3CCC4)ccnc2c1

Procedure:
To a solution of 7-methoxy-4-(2-pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-quinoline (53 mg, 0.16 mmol) in N,N-dimethylformamide (3 mL) at room temperature is added sodium ethanthiolate (133 mg, 1.6 mmol). The solution is refluxed for 4 h, cooled, and concentrated in vacuo. The residue is dissolved in methanol and loaded onto an SCX column. The column is washed with water, methanol, and 7 N ammonia in methanol. The appropriate fraction is concentrated in vacuo to yield the title compound, 28 mg (56%), as a yellow solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([OH:7])[NH:5][N:6]=1.C[O-].[Na+].C([O:13][C:14](=[O:21])[C:15](=O)[CH2:16][C:17](=O)[CH3:18])C>CO>[OH:7][C:4]1[C:3]2[C:2](=[N:1][C:15]([C:14]([OH:21])=[O:13])=[CH:16][C:17]=2[CH3:18])[NH:6][N:5]=1
Reactant: Nc1cc(O)[nH]n1
Reactant: CCOC(=O)C(=O)CC(C)=O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: Cc1cc(C(=O)O)nc2[nH]nc(O)c12

Procedure:
5-Amino-2H-pyrazol-3-ol (3.1 g, 31.6 mmol) were suspended in 100 ml of methanol. Then sodium methoxide (5.1 g, 95 mmol) and 2,4-dioxopentanoic acid ethyl ester (5 g, 31.6 mmol) were added, and the mixture was heated up under reflux for 12 h. The solvent was removed in a rotary evaporator, water was added to the residue, the precipitate was filtered off with suction, and the filtrate was adjusted to pH 6 with dilute hydrochloric acid. The precipitated product (both precipitates) was filtered off with suction and dried. Yield: 4.9 g (70%), M+H+: 194.09.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([C@H:19]([CH2:23][CH:24]([CH3:26])[CH3:25])[C:20]([NH2:22])=[O:21])[CH2:12][CH:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.CCN(CC)CC.Cl[CH2:35][C:36]([C:38]1[CH:45]=[CH:44][C:41]([C:42]#[N:43])=[CH:40][CH:39]=1)=[O:37]>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([C@H:19]([CH2:23][CH:24]([CH3:26])[CH3:25])[C:20]([NH2:22])=[O:21])[CH2:12][CH:13]2[CH2:14][CH2:15][N:16]([CH2:35][C:36]([C:38]3[CH:45]=[CH:44][C:41]([C:42]#[N:43])=[CH:40][CH:39]=3)=[O:37])[CH2:17][CH2:18]2)(=[O:9])=[O:10])=[CH:4][CH:3]=1
Reactant: CC(C)C[C@H](C(N)=O)N(CC1CCNCC1)S(=O)(=O)c1ccc(Cl)cc1
Reactant: N#Cc1ccc(C(=O)CCl)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)C[C@H](C(N)=O)N(CC1CCN(CC(=O)c2ccc(C#N)cc2)CC1)S(=O)(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 44.3 %

Procedure:
To a solution of (2R)-2-[N-(4-chlorobenzenesulfonyl)-N-(piperidin-4-ylmethyl)amino]-4-methyl-pentanoic acid amide (Example 126, 0.050 g, 0.12 mmol) and Et3N (0.040 mL, 0.30 mmol) in CH2Cl2 (2.0 mL) was added 4-(2-chloro-acetyl)-benzonitrile (55 mg, 0.30 mmol). The reaction was stirred at rt for 18 h and then was concentrated to residue. The residue was purified on a BIOTAGE® system (eluted with 80% EtOAc/hexanes) to produce 29 mg (48%) of the desired product as a white solid. MS (ESI), (M+H)+545.16; 1H NMR (CDCl3, 500 MHz) δ 7.72 (d, 2H, J=8.5), 7.50-7.65 (m, 2H), 7.50 (d, 2H, J=7.0), 7.35-7.45 (m, 2H), 6.67 (s, 1H), 5.32 (s, 1H), 4.14 (dd, 1H, J=5.0, 9.0), 3.52 (br s, 1H), 3.28 (t, 1H, J=14), 2.97 (dd, 1H, J=3.5, 14), 2.82 (br s, 1H), 1.00-2.00 (m, 10H), 0.71 (d, 3H, J=6.5), 0.66 (d, 3H, J=6.5).
Reaction SMILES: [OH:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][NH:7][C:8]2[N:12]([C@@H:13]3[O:19][C@H:18]([CH2:20][OH:21])[C@@H:16]([OH:17])[C@H:14]3[OH:15])[C:11]3[CH:22]=[CH:23][CH:24]=[CH:25][C:10]=3[N:9]=2)=[CH:4][C:3]=1[O:28][CH2:29][CH2:30][CH2:31][CH2:32][OH:33].C(=O)([O-])[O-].[K+].[K+].[CH2:40](I)[CH3:41]>CN(C)C=O>[CH2:40]([O:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][NH:7][C:8]2[N:12]([C@@H:13]3[O:19][C@H:18]([CH2:20][OH:21])[C@@H:16]([OH:17])[C@H:14]3[OH:15])[C:11]3[CH:22]=[CH:23][CH:24]=[CH:25][C:10]=3[N:9]=2)=[CH:4][C:3]=1[O:28][CH2:29][CH2:30][CH2:31][CH2:32][OH:33])[CH3:41]
Reactant: OCCCCOc1cc(CNc2nc3ccccc3n2[C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)ccc1O
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOc1ccc(CNc2nc3ccccc3n2[C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)cc1OCCCCO
Temperature: 55 °C
Reaction time: 16 h

Procedure:
2-[4-Hydroxy-3-(4-hydroxybutoxy)benzylamino]-1-(β-D-ribofuranosyl)-1H-benzimidazole (30 mg) and potassium carbonate (18 mg) was suspended in N,N-dimethylformamide (0.7 mL). To the mixture was added ethyl iodide (20 μL), and the mixture was stirred at 55° C. for 16 hour. The insoluble material was removed by filtration, and the reaction mixture was concentrated under reduced pressure. The obtained residue was purified by preparative reverse phase column chromatography (Shiseido CAPSELL PAC C18UG80, 5 μm, 20×50 mm, flow rate 30 mL/minutes linear gradient, water/methanol=90/10-10/90) to give the title compound (13 mg).
Reaction SMILES: [C@@H]1(C2C=CC=C(CC3SC(CC)=CC=3)C=2)O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O.[C:26]1([C:32]2[S:36][C:35]([C:37]([C:39]3[CH:44]=[C:43]([Br:45])[CH:42]=[CH:41][C:40]=3[C:46]([F:49])([F:48])[F:47])=O)=[CH:34][CH:33]=2)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.O1CCCC1.[BH4-].[Na+]>CO>[Br:45][C:43]1[CH:42]=[CH:41][C:40]([C:46]([F:49])([F:47])[F:48])=[C:39]([CH2:37][C:35]2[S:36][C:32]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[CH:33][CH:34]=2)[CH:44]=1
Reactant: O=C(c1ccc(-c2ccccc2)s1)c1cc(Br)ccc1C(F)(F)F
Agent: CCc1ccc(Cc2cccc([C@@H]3O[C@H](CO)[C@@H](O)[C@H](O)[C@H]3O)c2)s1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: FC(F)(F)c1ccc(Br)cc1Cc1ccc(-c2ccccc2)s1
Temperature: 25 °C
Reaction time: 3 h
Yield: 87.3 %

Procedure:
To a solution of the above methyl 5-bromo-2-iodobenzoate (4.65 g) in N-methyl-2-pyrrolydinone (20 ml) were added copper (I) bromide (235 mg) and methyl 2,2-difluoro-2-(fluorosulfonyl)acetate (2.6 ml), and the mixture was stirred under heating at 120° C. for 1.5 hours. The reaction mixture was cooled, and added thereto were 10% aqueous hydrochloric acid solution and ethyl acetate. Insoluble materials were filtered off, and an organic layer of the filtrate was washed with water for 4 times, and subsequently washed with a saturated aqueous sodium hydrogen carbonate solution and brine. The filtrate was dried over sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexan:ethyl acetate=80:1) to give methyl 5-bromo-2-trifluoromethylbenzoate (3.55 g) as colorless oil. (3) The above methyl 5-bromo-2-trifluoromethylbenzoate was treated in a manner similar to Reference Example 4-(1) to give 5-bromo-2-trifluoromethylbenzoic acid as pale brown crystals. ESI-Mass m/Z 267/269 (M−H). (4) The above 5-bromo-2-trifluoromethylbenzoic acid and 2-phenylthiophene were treated in a manner similar to Reference Example 5-(1) to give 5-bromo-2-trifluoromethylphenyl 5-phenyl-2-thienyl ketone as pale yellow crystals. APCI-Mass m/Z 411/413 (M+H). (5) To a mixed solution of the above 5-bromo-2-trifluoromethylphenyl 5-phenyl-2-thienyl ketone (670 mg) in methanol (20 ml)-tetrahydrofuran (10 ml) was added sodium borohydride (62 mg), and the mixture was stirred at room temperature for 3 hours. The solvent was evaporated under reduced pressure, and the residue was dissolved in chloroform (10 ml)acetonitrile (20 ml). Thereto was added triethylsilane (0.78 ml), and the mixture was cooled to 0° C. Thereto was added dropwise boron trifluoride•diethyl ether complex (0.52 ml). The mixture was stirred at room temperature for 45 minutes, and added thereto was a saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The extract was washed with brine, and dried over sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane) to give the desired 5-bromo-1-(5-phenyl-2-thienylmethyl)-2-trifluoromethylbenzene (565 mg) as colorless oil.
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8]([N:10]1[CH2:15][CH2:14][C:13]([C:17]2[CH:22]=[CH:21][C:20]([Br:23])=[CH:19][CH:18]=2)([OH:16])[CH2:12][CH2:11]1)=[O:9])([CH3:6])([CH3:5])[CH3:4].[CH3:24]I>C1COCC1>[C:3]([O:7][C:8]([N:10]1[CH2:11][CH2:12][C:13]([C:17]2[CH:22]=[CH:21][C:20]([Br:23])=[CH:19][CH:18]=2)([O:16][CH3:24])[CH2:14][CH2:15]1)=[O:9])([CH3:6])([CH3:4])[CH3:5]
Reactant: CC(C)(C)OC(=O)N1CCC(O)(c2ccc(Br)cc2)CC1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC1(c2ccc(Br)cc2)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 112.3 %

Procedure:
Sodium hydride (76 mg, 1.90 mmol) was added portionwise to a solution of 4-(4-bromophenyl)-4-hydroxypiperidine-1-carboxylic acid tert-butyl ester (519 mg, 1.46 mmol) in anhydrous THF (10 mL) at 0° C. After 1 h, methyl iodide (136 μL, 2.19 mmol) was added and the reaction mixture was allowed to warm to ambient temperature and stirred for 18 h. The reaction was quenched by the addition of water (10 mL), the organic layer was separated and the aqueous layer back-extracted with DCM (3×10 mL). The combined organic phase was concentrated in vacuo to afford the title compound (607 mg, quantitative). 1H NMR (CDCl3, 400 MHz): 7.49 (d, J=8.5 Hz, 2H), 7.25 (d, J=8.5 Hz, 2H), 3.97 (d, J=13.0 Hz, 2H), 3.15 (t, J=13.0 Hz, 2H), 2.97 (s, 3H), 1.97 (d, J=13.5 Hz, 2H), 1.83-1.74 (m, 2H), 1.47 (s, 9H). LCMS (Method B): RT=4.61 min.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:22])[C:8]=2[NH:12][C:13](=[O:21])[CH2:14][CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)[N:3]=1.[NH:23]1[CH2:27][CH2:26][C@@H:25]([OH:28])[CH2:24]1>>[Cl:22][C:7]1[C:8]([NH:12][C:13](=[O:21])[CH2:14][CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)=[C:9]2[C:4](=[CH:5][CH:6]=1)[N:3]=[C:2]([N:23]1[CH2:27][CH2:26][C@@H:25]([OH:28])[CH2:24]1)[CH:11]=[CH:10]2
Reactant: O=C(CC1CCCCC1)Nc1c(Cl)ccc2nc(Cl)ccc12
Reactant: O[C@@H]1CCNC1
Product: O=C(CC1CCCCC1)Nc1c(Cl)ccc2nc(N3CC[C@@H](O)C3)ccc12
Yield: 17.4 %

Procedure:
Prepared according to the method of example 27, using N-(2,6-dichloro-5-quinolinyl)-cyclohexaneacetamide (Example 1(a)) (0.05 g) and (3R)-3-pyrrolidinol (0.052 g) to afford the title compound (0.01 g).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH:12]([C:14]3[O:18][C:17]([CH3:19])=[N:16][C:15]=3[CH3:20])[OH:13])[CH:10]=2)[N:5]=[C:4]([O:21][CH3:22])[C:3]=1[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=1>[O-2].[O-2].[Mn+4].O1CCOCC1>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([C:14]3[O:18][C:17]([CH3:19])=[N:16][C:15]=3[CH3:20])=[O:13])[CH:10]=2)[N:5]=[C:4]([O:21][CH3:22])[C:3]=1[CH2:23][C:24]1[CH:25]=[CH:26][C:27]([C:30]([F:32])([F:31])[F:33])=[CH:28][CH:29]=1
Reactant: COc1nc2ccc(C(O)c3oc(C)nc3C)cc2c(Cl)c1Cc1ccc(C(F)(F)F)cc1
Agent: [Mn+4]
Agent: [O-2]
Solvent: C1COCCO1
Product: COc1nc2ccc(C(=O)c3oc(C)nc3C)cc2c(Cl)c1Cc1ccc(C(F)(F)F)cc1
Temperature: 85 °C

Procedure:
To a flask containing (4-chloro-2-methoxy-3-(4-(trifluoromethyl)benzyl)quinolin-6-yl)(2,4-dimethyloxazol-5-yl)methanol (960 mg, 2.01 mmol, Intermediate 11: step a) was added 1,4-dioxane (50 mL) followed by manganese dioxide (900 mg, 103 mmol) at room temperature. The mixture was heated to 85° C., for 60 minutes, and then the contents were filtered through Celite® while still warm and rinsed with THF. The solution was concentrated and the crude material was triturated with Et2O to afford the title compound as a white solid. The mother liquors were re-purified by chromatography on silica gel (2% MeOH-DCM increasing to 5% MeOH) to provide additional title compound.
Reaction SMILES: C(Cl)Cl.Br[C:5]1[N:10]=[C:9]([NH:11][C:12]2[CH:16]=[C:15]([C@@H:17]3[CH2:19][C@H:18]3[CH3:20])[NH:14][N:13]=2)[C:8]([Cl:21])=[CH:7][N:6]=1.[C:22]([NH:26][S:27]([C:30]1[S:34][C:33](B(O)O)=[CH:32][CH:31]=1)(=[O:29])=[O:28])([CH3:25])([CH3:24])[CH3:23]>O1CCOCC1.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]>[C:22]([NH:26][S:27]([C:30]1[S:34][C:33]([C:5]2[N:10]=[C:9]([NH:11][C:12]3[CH:16]=[C:15]([C@@H:17]4[CH2:19][C@H:18]4[CH3:20])[NH:14][N:13]=3)[C:8]([Cl:21])=[CH:7][N:6]=2)=[CH:32][CH:31]=1)(=[O:28])=[O:29])([CH3:25])([CH3:23])[CH3:24]
Reactant: C[C@@H]1C[C@H]1c1cc(Nc2nc(Br)ncc2Cl)n[nH]1
Reactant: CC(C)(C)NS(=O)(=O)c1ccc(B(O)O)s1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: C1COCCO1
Solvent: ClCCl
Product: C[C@@H]1C[C@H]1c1cc(Nc2nc(-c3ccc(S(=O)(=O)NC(C)(C)C)s3)ncc2Cl)n[nH]1
Temperature: 90 °C
Yield: 63.2 %

Procedure:
The mixture of Pd(dppf)Cl2.CH2Cl2 (74 mg, 0.09 mmol, 0.15 eq.), 2-bromo-5-chloro-N-(5-(trans-2-methylcyclopropyl)-1H-pyrazol-3-yl)pyrimidin-4-amine (200 mg, 0.61 mmol, 1.0 eq), 5-(N-tert-butylsulfamoyl)thiophen-2-ylboronic acid (192 mg, 0.73 mmol, 1.2 equiv.) and saturate Ka2CO3 (5 mL) in dioxane (10 mL) was heated to 90° C. for 1 h under nitrogen atmosphere. The reaction mixture was cooled to rt, and extracted with THF. The combined layers were purified by silica gel chromatography (EtOAc/Petroleum ether from 10:1 to 2:1) to afford compound N-tert-butyl-5-(5-chloro-4-(5-(trans-2-methylcyclopropyl)-1H-pyrazol-3-ylamino)pyrimidin-2-yl)thiophene-2-sulfonamide (180 mg, 63%).
Reaction SMILES: [N:1]1([C:7](Cl)=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[F:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:17]1[C:29]2[C:28]3[C:23](=[CH:24][C:25]([OH:30])=[CH:26][CH:27]=3)[NH:22][C:21]=2[C:20]([C:31]([NH2:33])=[O:32])=[CH:19][CH:18]=1>N1C=CC=CC=1.CCOC(C)=O>[N:1]1([C:7]([O:30][C:25]2[CH:26]=[CH:27][C:28]3[C:29]4[C:21](=[C:20]([C:31](=[O:32])[NH2:33])[CH:19]=[CH:18][C:17]=4[C:12]4[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=4[F:10])[NH:22][C:23]=3[CH:24]=2)=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: O=C(Cl)N1CCOCC1
Reactant: NC(=O)c1ccc(-c2ccccc2F)c2c1[nH]c1cc(O)ccc12
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: NC(=O)c1ccc(-c2ccccc2F)c2c1[nH]c1cc(OC(=O)N3CCOCC3)ccc12
Reaction time: 22 h
Yield: 31.4 %

Procedure:
Morpholine-4-carbonyl chloride (11.29 mg, 0.075 mmol) was added to a solution of 4-(2-fluorophenyl)-7-hydroxy-9H-carbazole-1-carboxamide (Example 40-1, 18.6 mg, 0.058 mmol) in pyridine (1 mL). After 22 h at rt, additional morpholine-4-carbonyl chloride (11.29 mg, 0.075 mmol) was added. After 15 h, the mixture was diluted with EtOAc (30 mL), washed with water (10 mL) and brine (5 mL), and dried and concentrated. The residue was purified by preparative HPLC to provide 8-carbamoyl-5-(2-fluorophenyl)-9H-carbazol-2-yl morpholine-4-carboxylate as a white solid (7.9 mg, 27%). 1H NMR (400 MHz, chloroform-d) δ 9.94 (1H, br. s.), 7.41-7.65 (3H, m), 7.33 (2H, t, J=8.14 Hz), 7.20 (1H, d, J=8.58 Hz), 6.92-7.15 (4H, m), 6.73 (1H, dd, J=8.58, 1.98 Hz), 3.80 (4H, t, J=4.62 Hz), 3.67-3.76 (2H, m), 3.62 (2H, br. s.). Mass spectrum m/z 434.0 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([C:8]#[C:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:6][CH:7]=1.[I-:16].[Na+].C(O)(=O)C.S(=O)(=O)(O)O>C(#N)C.C(OCC)(=O)C.O>[I:16][C:2]1[N:3]=[N:4][C:5]([C:8]#[C:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:6][CH:7]=1
Reactant: Clc1ccc(C#Cc2ccccc2)nn1
Reactant: [I-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: CC#N
Product: Ic1ccc(C#Cc2ccccc2)nn1
Temperature: 70 °C
Reaction time: 8 h
Yield: 57.5 %

Procedure:
To a solution of 100 mg (0.466 mmol) of 3-chloro-6-(phenylethynyl)pyridazine in 5 ml of acetonitrile were added sodium iodide (209 mg, 1.4 mmol, 3 equiv.), acetic acid (56 mg, 53.3 ml, 0.93 mmol, 2 equiv.), and 95% sulfuric acid (4.6 mg, 2.5 ml, 0.47 mmol, 1 equiv.). The orange solution was stirred for 8 hours at 70° C. and then left to cool overnight. After standard workup with ethyl acetate/water, the residue was adsorbed onto 4 g of silicagel and purified by flash chromatography over a 20 g silicagel column over a heptane to 50% ethyl acetate in heptane gradient to yield 82 mg (58% yield) of the title compound as a crystalline light yellow solid, MS: m/e=307.1 (M+H+).
Reaction SMILES: [Br:1][C:2]1[C:3](F)=[C:4]2[C:10]([NH:11][C:12](=[O:20])[C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[CH:14]=3)=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[NH:22]1[CH2:27][CH2:26][CH2:25][C@@H:24]([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])[CH2:23]1.CC#N.O>CCCCO>[Br:1][C:2]1[C:3]([N:22]2[CH2:27][CH2:26][CH2:25][C@@H:24]([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:33])([CH3:32])[CH3:34])[CH2:23]2)=[C:4]2[C:10]([NH:11][C:12](=[O:20])[C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[CH:14]=3)=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: O=C(Nc1c[nH]c2ncc(Br)c(F)c12)c1cccc(F)c1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCNC1
Solvent: O
Solvent: CC#N
Solvent: CCCCO
Product: CC(C)(C)OC(=O)N[C@@H]1CCCN(c2c(Br)cnc3[nH]cc(NC(=O)c4cccc(F)c4)c23)C1
Temperature: 155 °C
Yield: 27 %

Procedure:
N-(5-Bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-3-fluorobenzamide (306 mg, 0.869 mmol) and (R)-tert-butyl piperidin-3-ylcarbamate (522 mg, 2.61 mmol) were placed in n-BuOH (5 mL) and heated to 155° C. for 42 hours in a sealed tube. The reaction was cooled to room temperature and concentrated to dryness. The crude residue was purified by C-18 reverse phase flash chromatography (Biotage Horizon unit, C-18 25M column, 5-80% CH3CN/water gradient) to give (R)-tert-butyl 1-(5-bromo-3-(3-fluorobenzamido)-1H-pyrrolo [2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate (125 mg, 27% yield).