Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C@:2]12[C@@:19]3([CH3:20])[C@@H:10]([C@:11]4([CH3:33])[C@@H:16]([CH2:17][CH2:18]3)[C:15]([CH3:22])([CH3:21])[C:14]([C:23]3[CH:32]=[CH:31][C:26]([C:27]([O:29]C)=[O:28])=[CH:25][CH:24]=3)=[CH:13][CH2:12]4)[CH2:9][CH2:8][C@@H:7]1[C@H:6]1[C@H:34]([C:37]([CH3:39])=[CH2:38])[CH2:35][CH2:36][C@:5]1([NH:40][CH2:41][CH2:42][N:43]1[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]1)[CH2:4][CH2:3]2.[CH:49]1([CH2:54][C:55]([OH:57])=O)[CH2:53][CH2:52][CH2:51][CH2:50]1>>[CH:49]1([CH2:54][C:55]([N:46]2[CH2:47][CH2:48][N:43]([CH2:42][CH2:41][NH:40][C@:5]34[CH2:36][CH2:35][C@@H:34]([C:37]([CH3:39])=[CH2:38])[C@@H:6]3[C@@H:7]3[C@@:2]([CH3:1])([CH2:3][CH2:4]4)[C@@:19]4([CH3:20])[C@@H:10]([C@:11]5([CH3:33])[C@@H:16]([CH2:17][CH2:18]4)[C:15]([CH3:22])([CH3:21])[C:14]([C:23]4[CH:24]=[CH:25][C:26]([C:27]([OH:29])=[O:28])=[CH:31][CH:32]=4)=[CH:13][CH2:12]5)[CH2:9][CH2:8]3)[CH2:44][CH2:45]2)=[O:57])[CH2:50][CH2:51][CH2:52][CH2:53]1
Reactant: C=C(C)[C@@H]1CC[C@]2(NCCN3CCNCC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Reactant: O=C(O)CC1CCCC1
Product: C=C(C)[C@@H]1CC[C@]2(NCCN3CCN(C(=O)CC4CCCC4)CC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12

Procedure:
The title compound (3.1 mg) was prepared from methyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-3a-((2-(piperazin-1-yl)ethyl)amino)-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate following the general procedure as described above using cyclopentylacetic acid as the acylating agent. LCMS: m/e 752.9 (M+H)+, 3.93 min (method 14). 1H NMR (500 MHz, METHANOL-d4) δ 7.89 (d, J=8.2 Hz, 2H), 7.17 (d, J=8.2 Hz, 2H), 5.30 (d, J=4.6 Hz, 1H), 4.80 (s, 1H), 4.69 (s, 1H), 3.70 (br. s., 1H), 3.66-3.53 (m, 3H), 3.12-3.01 (m, 1H), 2.95-2.89 (m, 1H), 2.86-2.72 (m, 2H), 2.71-2.61 (m, 3H), 2.60-2.54 (m, 1H), 2.51-2.47 (m, 1H), 2.45 (d, J=7.3 Hz, 2H), 2.27-1.90 (m, 6H), 1.89-1.79 (m, 3H), 1.76 (s, 3H), 1.73-1.18 (m, 22H), 1.23 (s, 3H), 1.11 (s, 3H), 1.06 (s, 3H), 0.97 (s, 3H), 0.97 (s, 3H).
Reaction SMILES: Cl.[CH2:2]([C@@H:4]1[CH2:9][O:8][CH2:7][CH2:6][NH:5]1)[CH3:3].[Cl:10][CH2:11][C:12]#[C:13][CH2:14]Cl.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:10][CH2:11][C:12]#[C:13][CH2:14][N:5]1[CH2:6][CH2:7][O:8][CH2:9][C@H:4]1[CH2:2][CH3:3]
Reactant: CC[C@@H]1COCCN1
Reactant: ClCC#CCCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC[C@@H]1COCCN1CC#CCCl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of (3R)-3-ethylmorpholine hydrochloride (0.2 g), 1,4-dichloro-2-butyne (0.5 ml) and potassium carbonate (0.71 g) in N,N-dimethylformamide (10 ml) was stirred at room temperature for 2 hours. After removal of the solvent, ethyl acetate and sodium hydrogen carbonate solution were added thereto. The organic layer was separated and the aqueous layer was extracted with ethyl acetate twice. The combined organic layer was dried over magnesium sulfate and evaporated in vacuo. The residue was purified by column chromatography on silica gel with a mixture of ethyl acetate and n-hexane (1:1) as an eluent to give (3R)-4-(4-chloro-2-butynyl)-3-ethylmorpholine (0.2 g) as an oil.
Reaction SMILES: [C:1]1(=[O:19])[N:5]([CH2:6][C:7](=O)[CH2:8][CH2:9][C:10](=O)[CH3:11])[C:4](=[O:14])[C:3]2=[CH:15][CH:16]=[CH:17][CH:18]=[C:2]12.[C:20]([NH:23][CH2:24][CH2:25][NH2:26])(=[O:22])[CH3:21]>C(O)(=O)C>[C:20]([NH:23][CH2:24][CH2:25][N:26]1[C:10]([CH3:11])=[CH:9][CH:8]=[C:7]1[CH2:6][N:5]1[C:4](=[O:14])[C:3]2=[CH:15][CH:16]=[CH:17][CH:18]=[C:2]2[C:1]1=[O:19])(=[O:22])[CH3:21]
Reactant: CC(=O)CCC(=O)CN1C(=O)c2ccccc2C1=O
Reactant: CC(=O)NCCN
Solvent: CC(=O)O
Product: CC(=O)NCCn1c(C)ccc1CN1C(=O)c2ccccc2C1=O

Procedure:
4.6 g (0.018 mol) of 6-phthalimido-2,5-hexanedione and 1.8 g (0.018 mol) of 2-(acetylamino)-ethylamine are stirred in 120 ml of acetic acid at 80° C. for 4 hours. Working up is carried out as described in Example 1:
Reaction SMILES: [CH2:1]([N:3]1[C:8](=[O:9])[CH:7]=[CH:6][C:5]([C:10]2[C:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[N:14][C:13]([NH:22]CC3C=CC(OC)=CC=3)=[CH:12][N:11]=2)=[N:4]1)[CH3:2].Cl>C1(C)C=CC=CC=1>[NH2:22][C:13]1[N:14]=[C:15]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:10]([C:5]2[CH:6]=[CH:7][C:8](=[O:9])[N:3]([CH2:1][CH3:2])[N:4]=2)=[N:11][CH:12]=1
Reactant: CCn1nc(-c2ncc(NCc3ccc(OC)cc3)nc2-c2ccccc2)ccc1=O
Agent: Cl
Solvent: Cc1ccccc1
Product: CCn1nc(-c2ncc(N)nc2-c2ccccc2)ccc1=O
Yield: 60 %

Procedure:
A suspension of 2-ethyl-6-{5-[(4-methoxybenzyl)amino]-3-phenyl-2-pyrazinyl}-3(2H)-pyridazinone (500 mg) in a mixture of conc. HCl (1.5 ml) and toluene (0.5 ml) was refluxed for 4 hours. After removal of an organic layer, an aqueous layer was adjusted to pH 4 with 6N aq. NaOH under ice-cooling. The precipitate was purified by column chromatography on silica gel eluting with a mixture of n-hexane and EtOAc (20:80 v/v) to give 6-(5-amino-3-phenyl-2-pyrazinyl)-2-ethyl-3(2H)-pyridazinone (213 mg).
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][C:7](=[C:10]2[C:16]3=[N:17][CH:18]=[C:19]([C:21]([CH3:24])([CH3:23])[CH3:22])[CH:20]=[C:15]3[CH2:14][CH2:13][C:12]3[CH:25]=[C:26]([Cl:29])[CH:27]=[CH:28][C:11]2=3)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].ClC1C=C(C=CC=1)C(OO)=[O:35].[OH-].[Na+]>C(Cl)Cl>[C:1]([N+:4]1([O-:35])[CH2:9][CH2:8][C:7](=[C:10]2[C:16]3=[N:17][CH:18]=[C:19]([C:21]([CH3:24])([CH3:23])[CH3:22])[CH:20]=[C:15]3[CH2:14][CH2:13][C:12]3[CH:25]=[C:26]([Cl:29])[CH:27]=[CH:28][C:11]2=3)[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCC(=C2c3ccc(Cl)cc3CCc3cc(C(C)(C)C)cnc32)CC1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CC(=O)[N+]1([O-])CCC(=C2c3ccc(Cl)cc3CCc3cc(C(C)(C)C)cnc32)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 41.7 %

Procedure:
To a mixture of 450 mg of 1-acetyl-4-(8-chloro-5,6-dihydro-3-(1,1-dimethylethyl)-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)-piperidine in 30 ml of dry methylene chloride at -10° C. and under a nitrogen atmosphere was added 260 mg of 3-chloroperoxybenzoic acid in four portions ten minutes apart (mCPBA). The reaction mixture was kept at -10° C. for 3 hours and then slowly warmed to room temperature. The next day the mixture was poured into 1.0 N aqueous sodium hydroxide and extracted 3 times with methylene chloride. The combined organic portions were dried over magnesium sulfate, filtered and concentrated in vacuo to give a product which was purified via flash chromatography and triturated with pentane to give 195 mg (42%) of the title compound as a glass.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[NH:17][C:16]([CH3:22])([CH3:21])[CH:15]=[C:14]2[CH2:23][NH:24][C:25](=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.[CH3:33]I>C1COCC1>[CH3:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[NH:17][C:16]([CH3:22])([CH3:21])[CH:15]=[C:14]2[CH2:23][N:24]([CH3:33])[C:25](=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: COc1ccccc1-c1ccc2c(c1)C(CNC(=O)c1ccccc1)=CC(C)(C)N2
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccccc1-c1ccc2c(c1)C(CN(C)C(=O)c1ccccc1)=CC(C)(C)N2
Reaction time: 5 h

Procedure:
A round bottom flask equipped with a stir bar and under argon atmosphere was charged with NaH (60% in oil) (0.04 mmol, 1 equiv) and 1 mL of THF. Another vessel containing N-[6-(2-methoxyphenyl)-2,2-dimethyl-1,2-dihydroquinolin-4-ylmethyl]benzamide (Example 3) was diluted with THF and this solution was added to the NaH solution. Lastly, MeI (0.06 mmol, 1.5 equiv) was added and the reaction was stirred 5 hours under argon. The reaction was quenched with water and extracted with EtOAc. The combined organics were subsequently washed with brine and concentrated in vacuo. The residue was taken up in methylene chloride and adsorbed onto silica gel and flash chromatographed using 25% EtOAc/hexanes to elute product. The product fractions were pooled and concentrated in vacuo to afford 7.2 mg of the title compound as a oil.
Reaction SMILES: [O:1]1[CH2:4][CH:3]([N:5]2[CH2:10][CH2:9][CH:8]([N:11]3[CH2:16][CH2:15][N:14](C(OC(C)(C)C)=O)[CH2:13][CH2:12]3)[CH2:7][CH2:6]2)[CH2:2]1.FC(F)(F)C(O)=O>ClCCl>[O:1]1[CH2:4][CH:3]([N:5]2[CH2:6][CH2:7][CH:8]([N:11]3[CH2:12][CH2:13][NH:14][CH2:15][CH2:16]3)[CH2:9][CH2:10]2)[CH2:2]1
Reactant: CC(C)(C)OC(=O)N1CCN(C2CCN(C3COC3)CC2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C1CN(C2CCN(C3COC3)CC2)CCN1
Reaction time: 0.5 h

Procedure:
In a 100 ml round-bottom flask 1.63 g (5.01 mmol) of tert-butyl 4-(1-(oxetan-3-yl)-piperidin-4-yl)-piperazine-1-carboxylate were dissolved in 5 ml of dichloromethane. 3 ml (38.9 mmol) of trifluoroacetic acid were added and the reaction was stirred for 30 min. The solution was concentrated and digested in 40 ml of methyl-tert-butyl ether. The solid was filtered and washed with 20 ml of methyl-tert-butyl ether to yield 2.79 of the title compound as a white solid.
Reaction SMILES: [N:1]1([C:7]2[CH:12]=[CH:11][N:10]=[CH:9][N:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C(N(CC)CC)C.Br[CH2:21][C:22]([C:24]1[CH:35]=[CH:34][C:27]([O:28][CH2:29][C:30]([O:32][CH3:33])=[O:31])=[CH:26][CH:25]=1)=[O:23]>C(#N)C>[N:10]1[CH:11]=[CH:12][C:7]([N:1]2[CH2:6][CH2:5][N:4]([CH2:21][C:22]([C:24]3[CH:35]=[CH:34][C:27]([O:28][CH2:29][C:30]([O:32][CH3:33])=[O:31])=[CH:26][CH:25]=3)=[O:23])[CH2:3][CH2:2]2)=[N:8][CH:9]=1
Reactant: COC(=O)COc1ccc(C(=O)CBr)cc1
Reactant: c1cc(N2CCNCC2)ncn1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COC(=O)COc1ccc(C(=O)CN2CCN(c3ccncn3)CC2)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 26.1 %

Procedure:
To a mixture of 4-(1-piperazinyl)pyrimidine (preparation described in DE 2316920) (1.57 g) and triethylamine (3.87 g) in acetonitrile (40 ml) at room temperature was added dropwise over about 0.5 hour a solution of methyl 4-bromoacetylphenoxyacetate (2.73 g) in acetonitrile (25 ml). On completion of the addition the reaction mixture was stirred at room temperature for 2 days. The precipitated solid was filtered off, washed with acetonitrile and the combined filtrate and washings evaporated to dryness. The resultant red oil was purified by flash chromatography, first on silica by elution with 1-5% v/v methanol/dichloromethane, then on neutral alumina by elution with 3% v/v methanol/dichloromethane, to yield the title compound (0.92 g) as an off-white solid: NMR (CDCl3) δ2.69 (4H, m), 3.72 (4H, m), 3.80 (2H, s), 3.82 (3H, s), 4.71 (2H, s), 6.49 (1H, m), 6.94 (2H, d), 8.01 (2H, d), 8.20 (1H, d), 8.60 (1H, s); m/Z 371 (M+H)+ ; calculated for C19H22N4O4. 0.4 H2O: C 60.4%; H, 6.09%; N, 14.8%; found: C, 60.7%; H, 6.2%; N, 14.7%.
Reaction SMILES: [CH2:1]([Si:3]([CH2:17][CH3:18])([CH2:15][CH3:16])[O:4][C@@H:5]1[C@H:8]([C:9]2[O:10][CH:11]=[CH:12][CH:13]=2)[NH:7][C:6]1=[O:14])[CH3:2].C(N(C(C)C)CC)(C)C.[CH2:28]([O:32][C:33](Cl)=[O:34])[CH2:29][CH2:30][CH3:31]>ClCCl.CN(C1C=CN=CC=1)C>[CH2:17]([Si:3]([CH2:15][CH3:16])([CH2:1][CH3:2])[O:4][C@@H:5]1[C@H:8]([C:9]2[O:10][CH:11]=[CH:12][CH:13]=2)[N:7]([C:33]([O:32][CH2:28][CH2:29][CH2:30][CH3:31])=[O:34])[C:6]1=[O:14])[CH3:18]
Reactant: CCCCOC(=O)Cl
Reactant: CC[Si](CC)(CC)O[C@H]1C(=O)N[C@H]1c1ccco1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCCCOC(=O)N1C(=O)[C@H](O[Si](CC)(CC)CC)[C@@H]1c1ccco1
Reaction time: 1 h
Yield: 65.6 %

Procedure:
(3R,4R)-3-Triethylsilyloxy-4-(2-furyl)azetidin-2-one (0.58 g, 2.17 mmol) in 30 mL of dichloromethane was stirred with diisopropylethyl amine (0.4 mL, 2.30 mmol) and butylchloroformate (0.3 mL, 2.36 mmol) in addition to a catalytic amount of DMAP. The solution was stirred for 1 h and diluted with dichloromethane and washed with brine, dried over MgSO4 and concentrated. The residue was chromatographed over silica gel (eluted with 3:1 hexane/ethyl acetate) to give 523 mg of product (Y: 65%); IR(KBr) 1820, 1734, 1318, 1018, 734 cm-1 ; 1H-NMR (CDCl3, 300 MHz) δ 7.38 (m, 1H), 6.35 (m, 2H), 5.09 (ABq, J=15.5, 5.6 Hz, 2H), 4.14 (m, 2H), 1.56 (m, 2H), 1.28 (s, 2H), 0.87 (t, J=8.7 Hz, 3H), 0.82 (t, J=7.9, 9H), 0.50 (m, 6H); 13C-NMR (CDCl3, 75.5 Hz) δ 165.4, 149.1, 147.6, 142.9, 110.5, 109.9, 77.7, 66.6, 55.9, 30.5, 18.8, 13.6, 6.3, 4.3; DCIMS M+H calcd for C18H29NO5Si: 368, Found: 368.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([C:8]#[C:9][CH:10]([CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)O)[CH:5]=[CH:4][CH:3]=1.CC1C=CC=C(C#CC=C2CCNCC2)N=1.Cl[C:35]1[S:36][CH:37]=[CH:38][C:39]=1[N+:40]([O-:42])=[O:41]>>[CH3:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]([C:8]#[C:9][CH:10]=[C:12]2[CH2:17][CH2:16][N:15]([C:35]3[S:36][CH:37]=[CH:38][C:39]=3[N+:40]([O-:42])=[O:41])[CH2:14][CH2:13]2)[N:7]=1
Reactant: Cc1cccc(C#CC(O)C2CCNCC2)n1
Reactant: O=[N+]([O-])c1ccsc1Cl
Agent: Cc1cccc(C#CC=C2CCNCC2)n1
Product: Cc1cccc(C#CC=C2CCN(c3sccc3[N+](=O)[O-])CC2)n1

Procedure:
The title compound was prepared following the procedure described for the compound of Example 237, using the Compound of Example 3 instead of Compound 237a and 2-chloro-3-nitrothiophene instead of 2-bromo-3-nitropyridine. The crude was purified by automated flash liquid chromatography (Horizon™-Biotage) eluting with Petroleum Ether-EtOAc 1:1 affording the title product as a yellow solid.
Reaction SMILES: [CH2:1](/[C:3](=[CH:9]\[CH3:10])/[CH:4]=[CH:5]/[C:6]([OH:8])=O)[CH3:2].C(N(CC)CC)C.ClC(OCC)=O.[CH2:24]([NH2:28])[CH2:25][CH2:26][CH3:27]>O1CCCC1>[CH2:24]([NH:28][C:6](=[O:8])/[CH:5]=[CH:4]/[C:3](/[CH2:1][CH3:2])=[CH:9]/[CH3:10])[CH2:25][CH2:26][CH3:27]
Reactant: CCCCN
Reactant: C/C=C(/C=C/C(=O)O)CC
Agent: CCOC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C/C=C(/C=C/C(=O)NCCCC)CC
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
(E,E)-4-Ethyl-2,4-hexadienoic acid (5 g) was dissolved in tetrahydrofuran (300 ml) and triethylamine (5 ml) was added to the solution. The mixture was stirred at room temperature for 30 minutes and then ethyl chloroformate (3.4 ml) was added dropwise thereto at -20° C. with stirring. The resulting mixture was stirred at the same temperature for 60 minutes. n-Butylamine (3.6 ml) was added to the reaction mixture at -20° C. The resulting mixture was stirred at the same temperature for 60 minutes. The reaction mixture was concentrated and the concentrate was diluted with water, and then extracted with two portions of ethyl acetate (100 ml×2). The combined extracts were washed with successively an aqueous sodium carbonate solution and brine, dried over magnesium sulfate and then evaporated to dryness to given an oil (6.5 g) which was subjected to column chromatography on silicagel, eluting with chloroform containing 2% methanol, to give (E,E)-N-n-butyl-4-ethyl-2,4-hexadienamide (5.8 g).
Reaction SMILES: [F:1][CH2:2][CH:3]([O:6][C:7]1[CH:8]=[C:9]([CH:19]=[C:20]([OH:22])[CH:21]=1)[C:10]([NH:12][C:13]1[CH:17]=[CH:16][N:15]([CH3:18])[N:14]=1)=[O:11])[CH2:4][F:5].[N:23]1([C:27]([C:29]2[CH:34]=[CH:33][C:32](Br)=[CH:31][N:30]=2)=[O:28])[CH2:26][CH2:25][CH2:24]1.C(=O)([O-])[O-].[Cs+].[Cs+].N1(C(C2N=CC(OC3C=C(C=C(OC(CF)=C)C=3)C(NC3C=CN(C)N=3)=O)=CC=2)=O)CCC1.C(O)(C(F)(F)F)=O>CC(N(C)C)=O.C(Cl)(Cl)Cl.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu]Br.O.C(OCC)(=O)C>[N:23]1([C:27]([C:29]2[N:30]=[CH:31][C:32]([O:22][C:20]3[CH:19]=[C:9]([CH:8]=[C:7]([O:6][CH:3]([CH2:2][F:1])[CH2:4][F:5])[CH:21]=3)[C:10]([NH:12][C:13]3[CH:17]=[CH:16][N:15]([CH3:18])[N:14]=3)=[O:11])=[CH:33][CH:34]=2)=[O:28])[CH2:26][CH2:25][CH2:24]1
Reactant: Cn1ccc(NC(=O)c2cc(O)cc(OC(CF)CF)c2)n1
Reactant: O=C(c1ccc(Br)cn1)N1CCC1
Agent: [Cu]Br
Agent: C=C(CF)Oc1cc(Oc2ccc(C(=O)N3CCC3)nc2)cc(C(=O)Nc2ccn(C)n2)c1
Agent: O=C([O-])[O-]
Solvent: CC(=O)N(C)C
Solvent: O
Solvent: CCOC(C)=O
Product: Cn1ccc(NC(=O)c2cc(Oc3ccc(C(=O)N4CCC4)nc3)cc(OC(CF)CF)c2)n1
Reaction time: 2 h
Yield: 8.6 %

Procedure:
A mixture 3-{[2-fluoro-1-(fluoromethyl)ethyl]oxy}-5-hydroxy-N-(1-methyl-1H-pyrazol-3-yl)benzamide (100 mg, 0.32 mmol), 2-(azetidin-1-ylcarbonyl)-5-bromopyridine (86 mg, 0.35 mmol), cesium carbonate (209 mg, 0.64 mmol) and bromotris(triphenylphosphine)copper(I) (150 mg, 0.16 mmol) in DMA (5 mL) was stirred in a ‘Biotage initiator Microwave’ at 160° C. for 3 hours. The reaction mixture was added to ethyl acetate (50 mL) and water (50 mL), the organic layer washed with brine (50 mL), dried (MgSO4), filtered and the solvent removed in vacuo to give a brown oil. The residue was chromatographed on silica, eluting with 0-100% ethyl acetate in isohexane, to give a colorless oil which appeared to be a mixture of product and eliminated product (3-{[6-(azetidin-1-ylcarbonyl)pyridin-3-yl]oxy}-5-{[1-(fluoromethyl)ethenyl]oxy}-N-(1-methyl-1H-pyrazol-3-yl)benzamide). This mixture was dissolved in chloroform (5 mL), TFA (0.5 mL) added and the mixture stirred for 2 hours. Complete degradation of eliminated product was observed by LCMS and the mixture concentrated in vacuo then water added. The mixture was neutralised and extracted into ethyl acetate (2×30 mL), washed with brine (30 mL), dried (MgSO4), filtered and reduced to give a yellow oil which was chromatographed on silica, eluting with 0-100% ethyl acetate in isohexane, to give the desired compound (13 mg).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[N:10]([CH2:33][O:34][CH2:35][CH2:36][Si:37]([CH3:40])([CH3:39])[CH3:38])[C:11]([C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:22]=1[CH2:21][N:20]([C:23]1[S:24][C:25](I)=[C:26]([C:28]([O:30][CH3:31])=[O:29])[N:27]=1)[CH2:19][CH2:18]2)=[O:12].[C:41]([C:43]1[CH:44]=[C:45]2[C:50](=[CH:51][CH:52]=1)[CH:49]=[C:48]([O:53][CH2:54][CH2:55][CH2:56][N:57]1[CH2:62][CH2:61][O:60][CH2:59][CH2:58]1)[CH:47]=[CH:46]2)#[CH:42]>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[N:10]([CH2:33][O:34][CH2:35][CH2:36][Si:37]([CH3:40])([CH3:39])[CH3:38])[C:11]([C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:22]=1[CH2:21][N:20]([C:23]1[S:24][C:25]([C:42]#[C:41][C:43]3[CH:52]=[CH:51][C:50]4[C:45](=[CH:46][CH:47]=[C:48]([O:53][CH2:54][CH2:55][CH2:56][N:57]5[CH2:58][CH2:59][O:60][CH2:61][CH2:62]5)[CH:49]=4)[CH:44]=3)=[C:26]([C:28]([O:30][CH3:31])=[O:29])[N:27]=1)[CH2:19][CH2:18]2)=[O:12]
Reactant: COC(=O)c1nc(N2CCc3cccc(C(=O)N(COCC[Si](C)(C)C)c4nc5ccccc5s4)c3C2)sc1I
Reactant: C#Cc1ccc2cc(OCCCN3CCOCC3)ccc2c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CN(C)C=O
Product: COC(=O)c1nc(N2CCc3cccc(C(=O)N(COCC[Si](C)(C)C)c4nc5ccccc5s4)c3C2)sc1C#Cc1ccc2cc(OCCCN3CCOCC3)ccc2c1
Temperature: 120 °C

Procedure:
To a mixture of compound 47D (200 mg, 0.283 mmol), compound 110C, (PPh3)2PdCl2 (49.7 mg, 0.071 mmol), TEA (0.394 ml, 2.83 mmol) in DMF (5 ml) was added copper (I) iodide (5.40 mg, 0.028 mmol). The resulting mixture was heated at 120° C. in oil bath for 5 h. The reaction mixture was concentrated and purified by RP HPLC, eluting with 10-95% acetonitrile in 0.1% TFA water over 70 min to provide compound 110D: LCMS (APCI) 875 (M+H).
Reaction SMILES: [NH2:1][CH:2]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:3]([NH:5][C@@H:6]1[C:11]2[CH:12]=[C:13]([C:16]#[N:17])[CH:14]=[CH:15][C:10]=2[O:9][C:8]([CH3:19])([CH3:18])[C@H:7]1[OH:20])=[O:4].[O:27]1CC[CH2:29][CH2:28]1>>[C:16]([C:13]1[CH:14]=[CH:15][C:10]2[O:9][C:8]([CH3:19])([CH3:18])[C@@H:7]([OH:20])[C@H:6]([NH:5][C:3](=[O:4])[CH:2]([NH:1][C:28](=[O:27])[CH3:29])[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:11]=2[CH:12]=1)#[N:17]
Reactant: CC1(C)Oc2ccc(C#N)cc2[C@@H](NC(=O)C(N)c2ccccc2)[C@@H]1O
Reactant: C1CCOC1
Product: CC(=O)NC(C(=O)N[C@@H]1c2cc(C#N)ccc2OC(C)(C)[C@H]1O)c1ccccc1

Procedure:
To a solution containing (3S-trans)-α-amino-N-(6-cyano-3,4-dihydro-3-hydroxy-2,2-dimethyl-2H-1-benzopyran-4-yl)benzeneacetamide (600 mg, 1.7 mmol; isomer B of the title compound of Example 2)in tetrahydrofuran (7 mL) at room temperature was slowly added excess acetyl chloride while maintaining the reaction at pH ~8.5 by simultaneous addition of 7% sodium carbonate solution. After the completion of the reaction, it was diluted with ethyl acetate and washed with water and brine. After drying over anhydrous magnesium sulfate, the solvent was evaporated to provide a colorless gum (518 mg, 77.2%) which was stirred with ether to give (3S-trans)-N-[2-[(6-cyano-3,4-dihydro-3-hydroxy-2,2-dimethyl-2H-1-benzopyran-4-yl)amino]-2-oxo-1-phenylethyl]acetamide, mp 133°-145° C. (starts shrinking@124° C). Analysis calculated for C22H23N3O4.0.4H2O: C, 65.95; H, 5.99; N, 10.49. Found: C, 66.09; H, 5.92; N, 10.30. [α]D =+62.4° (c=0.5, MeOH).
Reaction SMILES: [CH:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.C[Mg]Cl.S(C1C=CC(C)=CC=1)(O[C:21]1[CH:30]=[CH:29][C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=1)(=O)=O.[Cl-].[NH4+]>C1(C)C=CC=CC=1.CC1(P(C(C)(C)C)C(C)(C)C)C(C2C=CC=CC=2)(C2C=CC=CC=2)C1.O.C1COCC1>[CH:27]1[C:28]2[C:23](=[CH:22][CH:21]=[CH:30][CH:29]=2)[CH:24]=[CH:25][C:26]=1[N:12]1[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:5]2[C:13]1=[CH:1][CH:2]=[CH:3][CH:4]=2
Reactant: c1ccc2c(c1)[nH]c1ccccc12
Reactant: Cc1ccc(S(=O)(=O)Oc2ccc3ccccc3c2)cc1
Agent: CC(C)(C)P(C(C)(C)C)C1(C)CC1(c1ccccc1)c1ccccc1
Agent: C[Mg]Cl
Agent: [Cl-]
Solvent: O
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: c1ccc2cc(-n3c4ccccc4c4ccccc43)ccc2c1
Temperature: 5 °C
Yield: 91.7 %

Procedure:
[PdCl(π-allyl)]2 (5.8 mg, 0.05 mol %) and cBRIDP (22.2 mg, 0.2 mol %) were placed into a 50 mL, two-necked, round bottomed flask equipped a gas inlet, and the flask was evacuated and filled with nitrogen. Subsequently, to the mixture was added dehydrated THF (4.1 mL, 50.5 mmol, 1.6 equivalents) to prepare a catalyst solution. A 200 mL, four-necked, round-bottomed flask equipped with a Teflon® coated magnetic stirring bar, condenser, dropping funnel, thermometer, and a gas inlet was evacuated and filled with nitrogen. Carbazole (5.4 g, 32.5 mmol, 1.03 equivalents) and dehydrated xylenes (33 mL) were charged into the flask, and the mixture was cooled to 5° C. using an ice bath. Subsequently, to the mixture was added a THF solution of MeMgCl (3.22 mol/L, 10.0 mL, 32.2 mmol, 1.02 equivalents) dropwise via the dropping funnel at such a rate that the temperature of the reaction solution was kept at 20° C. or lower, and then the dropping funnel was washed with dehydrated xylenes (6 mL). Subsequently, to the solution were added 2-naphthyl tosylate (9.4 g, 31.6 mmol, 1.0 equivalent) and the catalyst solution (4.1 mL) successively, and the solution was stirred for 15 minutes under reflux. After cooling the reaction mixture to room temperature, to the mixture were added water (100 mL) and ammonium chloride (850 mg). The aqueous layer was separated off, and the organic layer was concentrated under reduced pressure to give solid residue. The residue was dissolved in toluene, and the solution was decolorized by silica gel (500 mg) and filtered through a Celite pad. The filtrate was concentrated under reduced pressure to give the solid, which was recrystallized from toluene/methanol to afford 8.5 g of N-(2-naphthyl)carbazole as a white powder.