Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:4][C@H:5]1[CH2:22][CH2:21][C@@:20]2([CH3:23])[C@@H:7]([CH2:8][CH2:9][C@:10]3([CH3:34])[C@@H:19]2[CH2:18][CH2:17][C@H:16]2[C@@:11]3([CH3:33])[CH2:12][CH2:13][C@@:14]3([C:30](O)=[O:31])[CH2:26][CH2:25][C@@H:24]([C:27]([CH3:29])=[CH2:28])[C@@H:15]32)[C:6]1([CH3:36])[CH3:35])(=[O:3])[CH3:2].[NH2:37][C@H:38]1[CH2:41][C@@H:40]([C:42]([N:44]2[CH2:49][CH2:48][CH2:47][CH2:46][CH2:45]2)=[O:43])[C:39]1([CH3:51])[CH3:50].CCN(CC)CC>C(Cl)Cl>[C:1]([O:4][C@H:5]1[CH2:22][CH2:21][C@@:20]2([CH3:23])[C@@H:7]([CH2:8][CH2:9][C@:10]3([CH3:34])[C@@H:19]2[CH2:18][CH2:17][C@H:16]2[C@@:11]3([CH3:33])[CH2:12][CH2:13][C@@:14]3([C:30](=[O:31])[NH:37][C@H:38]4[CH2:41][C@@H:40]([C:42]([N:44]5[CH2:49][CH2:48][CH2:47][CH2:46][CH2:45]5)=[O:43])[C:39]4([CH3:51])[CH3:50])[CH2:26][CH2:25][C@@H:24]([C:27]([CH3:29])=[CH2:28])[C@@H:15]32)[C:6]1([CH3:36])[CH3:35])(=[O:3])[CH3:2]
Reactant: C=C(C)[C@@H]1CC[C@]2(C(=O)O)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC[C@H](OC(C)=O)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Reactant: CC1(C)[C@@H](N)C[C@H]1C(=O)N1CCCCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=C(C)[C@@H]1CC[C@]2(C(=O)N[C@H]3C[C@@H](C(=O)N4CCCCC4)C3(C)C)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC[C@H](OC(C)=O)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 25 °C
Reaction time: 3 h
Yield: 68.4 %

Procedure:
To a stirred solution of (1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-9-acetoxy-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)icosahydro-1H-cyclopenta[a]chrysene-3a-carboxylic acid (0.4 g, 0.803 mmol) in DCM (1 ml) (COCl)2 (0.69 ml, 8.03 mmol) in DCM (4 ml) was added at about 0° C. and the reaction mixture was stirred at room temperature for about 3 hours. After completion of the reaction (monitored by TLC) the solvent was evaporated under nitrogen atmosphere and dissolved in DCM (4 ml), which was added to a stirred solution of ((1R,3S)-3-amino-2,2-dimethylcyclobutyl)(piperidin-1-yl)methanone (Intermediate 12, 0.306 g, 1.45 mmol) in DCM (5 ml) and Et3N (0.22 ml, 1.61 mmol) at about 0° C. and allowed to stir at room temperature for about 16 hours. After completion of the reaction (monitored by TLC) the reaction mixture was diluted with DCM and washed with water, 1N HCl, water, brine and dried over Na2SO4, the solvent was evaporated and purified by silica gel column (100-200 mesh, elution 10% EtOAc in hexane) to afford the title compound as an off white solid. Wt: 0.380 g: Yield: 68.4%; δ 5.94 (d, 1H, J=7.8 Hz), 4.74 (s, 1H), 4.59 (s, 1H), 4.54-4.41 (m, 1H), 4.17-4.05 (m, 1H), 3.74-3.62 (m, 1H), 3.37 (brs, 2H), 3.18-3.07 (m, 1H), 2.89 (t, 1H, 7.8 Hz), 2.51-2.40 (m, 1H), 2.39-2.28 (m, 2H), 2.04 (s, 3H), 2.01-1.84 (m, 2H), 1.81-1.75 (m, 1H), 1.74-1.45 (m, 7H), 1.44-1.21 (m, 15H), 1.21-1.09 (m, 2H), 0.95, 0.93 (s, 9H), 0.83-0.82 (m, 12H); Mass: [M+Na]+ 714 (100%); IR (KBr, cm−1): 3372, 2943, 2864, 1736, 1730, 1652, 1636, 1623, 1501, 1459, 1444, 1369, 1248, 1192, 1024, 979, 881, 853.
Reaction SMILES: [Si]([O:18][CH2:19][CH2:20][N:21]([CH2:29][CH2:30][CH:31]([S:40]([C:43]1[CH:48]=[CH:47][C:46]([Cl:49])=[CH:45][CH:44]=1)(=[O:42])=[O:41])[C:32]1[CH:37]=[C:36]([F:38])[CH:35]=[CH:34][C:33]=1[F:39])[C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O.C(OCC)(=O)C>O1CCCC1>[Cl:49][C:46]1[CH:45]=[CH:44][C:43]([S:40]([CH:31]([C:32]2[CH:37]=[C:36]([F:38])[CH:35]=[CH:34][C:33]=2[F:39])[CH2:30][CH2:29][N:21]([CH2:20][CH2:19][OH:18])[C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])(=[O:42])=[O:41])=[CH:48][CH:47]=1
Reactant: CC(C)(C)OC(=O)N(CCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)CCC(c1cc(F)ccc1F)S(=O)(=O)c1ccc(Cl)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N(CCO)CCC(c1cc(F)ccc1F)S(=O)(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 85.2 %

Procedure:
In tetrahydrofuran (20 ml) was dissolved t-butyl N-[2-(t-butyldiphenylsilyloxy)ethyl]-N-[3-[(4-chlorophenyl)sulfonyl]-3-(2,5-difluorophenyl)propyl]carbamate (1.13 g, 1.55 mmol). Under ice cooling, a tetrahydrofuran solution (1.0M, 5.0 ml, 5.0 mmol) of tetrabutylammonium fluoride was added dropwise. The resulting mixture was stirred at room temperature for 1 hour. Water (2 ml) was added to the reaction mixture. The residue obtained by concentrating the resulting mixture under reduced pressure was subjected to flash silica gel chromatography, and the fraction obtained from the hexane:ethyl acetate=1:1 eluate was concentrated under reduced pressure, whereby the title compound (651 mg, 1.32 mmol, 85%) was obtained as a white foam.
Reaction SMILES: S(=O)(=O)(O)O.C([O:9][C:10]1[CH:15]=[CH:14][C:13]([N:16]2[C:21](=[O:22])[N:20]([CH3:23])[C:19](=[O:24])[CH:18]=[N:17]2)=[C:12]([F:25])[CH:11]=1)(C)C>>[OH:9][C:10]1[CH:15]=[CH:14][C:13]([N:16]2[C:21](=[O:22])[N:20]([CH3:23])[C:19](=[O:24])[CH:18]=[N:17]2)=[C:12]([F:25])[CH:11]=1
Reactant: CC(C)Oc1ccc(-n2ncc(=O)n(C)c2=O)c(F)c1
Agent: O=S(=O)(O)O
Product: Cn1c(=O)cnn(-c2ccc(O)cc2F)c1=O
Temperature: 0 °C

Procedure:
Concentrated sulfuric acid (5 mL) that had been cooled to 0°-5° C. was mixed with 2.80 g (0.010 mole) of 2-(4-isopropoxy-2-fluorophenyl)-4-methyl-1,2,4-triazine-3,5-dione that had been cooled to 0° C. The mixture was maintained at 0° C. for ten minutes, during which time it became homogeneous. The mixture was then poured into ice-water, and the resulting mixture was extracted with ethyl acetate. The extract was washed in succession with a saturated aqueous solution of sodium bicarbonate and a saturated aqueous solution of sodium chloride. The extract was dried over anhydrous magnesium sulfate and filtered. The solvent was evaporated from the filtrate under reduced pressure, leaving a residue. This residue was placed on a column of silica gel and eluted with ethyl acetate/hexane (1:1). After the product-containing fractions were combined and the solvents evaporated under reduced pressure, 1.38 g of 2-(4-hydroxy-2-fluorophenyl)-4-methyl-1,2,4-triazine-3,5-dione was recovered as a stiff syrup. The NMR was consistent with the proposed structure.
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:7])[C:4]#[C:5][CH3:6].Cl[C:9]1[N:14]=[CH:13][N:12]=[C:11]([N:15]2[C@H:20]([CH3:21])[CH2:19][CH2:18][CH2:17][C@@H:16]2[CH3:22])[CH:10]=1.[Cl-].[NH4+]>O1CCCC1>[CH2:3]([O:7][C:9]1[CH:10]=[C:11]([N:15]2[C@H:16]([CH3:22])[CH2:17][CH2:18][CH2:19][C@@H:20]2[CH3:21])[N:12]=[CH:13][N:14]=1)[C:4]#[C:5][CH3:6]
Reactant: C[C@@H]1CCC[C@H](C)N1c1cc(Cl)ncn1
Reactant: CC#CCO
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC#CCOc1cc(N2[C@H](C)CCC[C@@H]2C)ncn1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 91.6 %

Procedure:
0.06 g of sodium hydride (60% oil suspension) was suspended in 1.5 ml of tetrahydrofuran. 0.3 ml of tetrahydrofuran solution of 0.08 g of 2-butyn-1-ol was added dropwise at room temperature therein, and the mixture was stirred for 10 minutes. Into the mixture was added dropwise 0.3 ml of tetrahydrofuran solution of 0.19 g of 6-chloro-4-(cis-2,6-dimethylpiperidino)pyrimidine at room temperature, and stirred for 6 hours at 60° C. After the reaction mixture was cooled to near room temperature, the reaction mixture was poured into a saturated ammonium chloride aqueous solution, and the mixture was extracted with tert-butyl methyl ether three times. The organic layers were washed with a saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to obtain 0.20 g of 4-(2-butynyloxy)-6-(cis-2,6-dimethylpiperidino)pyrimidine (hereinafter, referred to as Compound (48)).
Reaction SMILES: [C:1]([C:3]1[C:4](=[O:19])[NH:5][C:6]([C:9]2[CH:14]=[CH:13][C:12]([S:15][CH3:16])=[CH:11][C:10]=2[O:17][CH3:18])=[CH:7][CH:8]=1)#[N:2].ClC1C=CC=C(C(OO)=[O:28])C=1>ClCCl>[C:1]([C:3]1[C:4](=[O:19])[NH:5][C:6]([C:9]2[CH:14]=[CH:13][C:12]([S:15]([CH3:16])=[O:28])=[CH:11][C:10]=2[O:17][CH3:18])=[CH:7][CH:8]=1)#[N:2]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COc1cc(SC)ccc1-c1ccc(C#N)c(=O)[nH]1
Solvent: ClCCl
Product: COc1cc(S(C)=O)ccc1-c1ccc(C#N)c(=O)[nH]1

Procedure:
A solution of 3-cyano-6-(2-methoxy-4-methylthiophenyl)-2(1H)-pyridinone (1.24 g) in dichloromethane (500 ml) was treated with m-chloroperbenzoic acid (85%, 0.92 g). After 2 hours the solution was washed with sodium bicarbonate solution and evaporated to give the crude product (1.27 g, m.p. 239-241° C.). Purification by chromatography (silica, dichloromethane) followed by recrystallization from aqueous ethanol yielded the pure title compound, 0.81 g, m.p. 243-245° C.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]3[CH:15]=[C:16]([S:20](Cl)(=[O:22])=[O:21])[CH:17]=[CH:18][CH:19]=3)[N:9]=2)[CH:5]=[C:4]([C:24]2[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=2)[CH:3]=1.[CH3:34][O:35][CH2:36][CH2:37][O:38][CH2:39][CH2:40][O:41][CH2:42][CH2:43][O:44][CH2:45][CH2:46][NH:47][CH2:48][CH2:49][O:50][CH2:51][CH2:52][O:53][CH2:54][CH2:55][O:56][CH2:57][CH2:58][O:59][CH3:60].CCN(CC)CC>C1COCC1.CCOC(C)=O>[CH3:60][O:59][CH2:58][CH2:57][O:56][CH2:55][CH2:54][O:53][CH2:52][CH2:51][O:50][CH2:49][CH2:48][N:47]([CH2:46][CH2:45][O:44][CH2:43][CH2:42][O:41][CH2:40][CH2:39][O:38][CH2:37][CH2:36][O:35][CH3:34])[S:20]([C:16]1[CH:17]=[CH:18][CH:19]=[C:14]([C:10]2[N:9]=[C:8]([C:6]3[CH:5]=[C:4]([C:24]4[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=4)[CH:3]=[C:2]([CH3:1])[N:7]=3)[CH:13]=[CH:12][CH:11]=2)[CH:15]=1)(=[O:22])=[O:21]
Reactant: COCCOCCOCCOCCNCCOCCOCCOCCOC
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2cccc(-c3cccc(S(=O)(=O)Cl)c3)n2)n1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COCCOCCOCCOCCN(CCOCCOCCOCCOC)S(=O)(=O)c1cccc(-c2cccc(-c3cc(-c4ccc(C(F)(F)F)cc4)cc(C)n3)n2)c1
Yield: 35.2 %

Procedure:
The title compound was prepared from 3-[6′-methyl-4′-(4-trifluoromethyl-phenyl)-[2,2′]bipyridinyl-6-yl]-benzenesulfonyl chloride (example I.2) (0.258 g, 0.528 mmol) by treatment with bis-[2-[2-[2-(2-methoxy-ethoxy)-ethoxy]-ethoxy]-ethyl]-amine [CAS-no. 123852-08-4] (0.210 g, 0.528 mmol) and Et3N (0.221 mL, 1.58 mmol) in THF (5 mL) at 23° C. for 1 h. Diluted with EtOAc, washed with 5% citric acid, sat. NaHCO3-sol.+2 M Na2CO3-sol. and brine, dried organic layer over Na2SO4. Removal of the solvent in vacuum left a crude product, which was purified by silica gel column chromatography with EtOAc/EtOH gave the title compound (0.158 g, 63%) as a yellow oil. MS (ISP) 850.5 [(M+H)+].
Reaction SMILES: C(OC([N:11]1[CH2:19][CH2:18][C:13]2([O:17][CH2:16][CH2:15][O:14]2)[CH2:12]1)=O)C1C=CC=CC=1>C(O)C.[Pd]>[O:14]1[C:13]2([CH2:18][CH2:19][NH:11][CH2:12]2)[O:17][CH2:16][CH2:15]1
Reactant: O=C(OCc1ccccc1)N1CCC2(C1)OCCO2
Agent: [Pd]
Solvent: CCO
Product: C1CC2(CN1)OCCO2
Reaction time: 0.33 h
Yield: 99.3 %

Procedure:
A mixture of 7-benzyloxycarbonyl-1,4-dioxa-7-azaspiro[4.4]nonane (34.79 g, step iii, no more than 123.7 mmol) and 10% Pd—C (13.9 g) in ethanol (90 mL) was hydrogenolyzed (60 psi) in a Parr shaker apparatus at room temperature for 1.5 hour. The catalyst was filtered off, the solvent was evaporated in vacuo and the residue was pumped under high vacuum for 20 min. to yield 15.86 g of the title compound (yield 99.3%).
Reaction SMILES: [C:1]1([C:7]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:8]2[CH:12]=[C:11]([CH2:13][CH2:14][C:15](O)=[O:16])[N:10]=[CH:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(N=C=NC2CCCCC2)CCCCC1.ON1C2C=CC=CC=2N=N1.Cl.Cl.[N:57]1([C:63]2[CH:68]=[CH:67][C:66]([N:69]3[CH2:73][C@H:72]([CH2:74][O:75][C:76]4[CH:80]=[CH:79][O:78][N:77]=4)[O:71][C:70]3=[O:81])=[CH:65][C:64]=2[F:82])[CH2:62][CH2:61][NH:60][CH2:59][CH2:58]1.C(N(CC)C(C)C)(C)C>ClCCl>[C:24]1([C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[N:8]2[CH:12]=[C:11]([CH2:13][CH2:14][C:15]([N:60]3[CH2:59][CH2:58][N:57]([C:63]4[CH:68]=[CH:67][C:66]([N:69]5[CH2:73][C@H:72]([CH2:74][O:75][C:76]6[CH:80]=[CH:79][O:78][N:77]=6)[O:71][C:70]5=[O:81])=[CH:65][C:64]=4[F:82])[CH2:62][CH2:61]3)=[O:16])[N:10]=[CH:9]2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: O=C1O[C@@H](COc2ccon2)CN1c1ccc(N2CCNCC2)c(F)c1
Reactant: O=C(O)CCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(CCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1)N1CCN(c2ccc(N3C[C@H](COc4ccon4)OC3=O)cc2F)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 63.3 %

Procedure:
3-(1-Triphenylmethyl-4-imidazolyl)propionic acid (420 mg, 1.1 mmol) was suspended in dichloromethane (10 ml) under nitrogen, and treated successively with dicyclohexylcarbodiimide (227 mg, 1.1 mmol) and 1-hydroxybenzotriazole (149 mg, 1.1 mmol), then stirred at ambient temperature for 30 minutes. To it was added a solution of 3-(4-(piperazin-1-yl)-3-fluorophenyl)-5(R)-(isoxazol-3-yloxymethyl)oxazolidin-2-one dihydrochloride (435 mg, 1 mmol) and N,N-diisopropylethylamine (258 mg, 2 mmol) in dichloromethane (5 ml). The mixture was stirred for 18 hours at the same temperature, solid filtered off, and the organic phase purified by chromatography on a 20 g silica Mega Bond Elut® column, eluting with a gradient increasing in polarity from 0 to 15% MeOH in dichloromethane. Relevant fractions were combined and evaporated to give the desired product (460 mg).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:14]#[C:15][C:16]2[C:21]([C:22]([F:25])([F:24])[F:23])=[CH:20][N:19]=[C:18]([NH:26][C:27]3[CH:32]=[CH:31][C:30]([CH:33]4[CH2:38][CH2:37][N:36]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:35][CH2:34]4)=[CH:29][CH:28]=3)[N:17]=2)[CH2:7][CH2:6]1)=[O:4].CCN(CC)CC>CN(C=O)C.CCOC(C)=O.[Pd]>[CH3:1][O:2][C:3]([C:5]1([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[CH2:14][CH2:15][C:16]2[C:21]([C:22]([F:23])([F:25])[F:24])=[CH:20][N:19]=[C:18]([NH:26][C:27]3[CH:32]=[CH:31][C:30]([CH:33]4[CH2:34][CH2:35][N:36]([C:39]([O:41][C:42]([CH3:44])([CH3:45])[CH3:43])=[O:40])[CH2:37][CH2:38]4)=[CH:29][CH:28]=3)[N:17]=2)[CH2:7][CH2:6]1)=[O:4]
Reactant: COC(=O)C1(c2ccccc2C#Cc2nc(Nc3ccc(C4CCN(C(=O)OC(C)(C)C)CC4)cc3)ncc2C(F)(F)F)CC1
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)C1(c2ccccc2CCc2nc(Nc3ccc(C4CCN(C(=O)OC(C)(C)C)CC4)cc3)ncc2C(F)(F)F)CC1
Reaction time: 16 h
Yield: 162.4 %

Procedure:
A suspension of 10% Pd/C (200 mg), tert-butyl 4-(4-((4-((2-(1-(methoxycarbonyl)cyclopropyl)phenyl)ethynyl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)piperidine-1-carboxylate (A3) (0.302 g, 0.487 mmol) and Et3N (1.0 mL) in DMF (10 mL) was stirred under an atmosphere of hydrogen for 16 hours. The resulting mixture was diluted with EtOAc (60 mL) and filtered through Celite. The filtrate was evaporated under reduced pressure to give the title compound A4 as a yellow oil (494 mg, 99%); 1H NMR (400 MHz, d6-DMSO) δ 10.15 (s, 1H), 8.68 (s, 1H), 7.67 (d, J=8.6 Hz, 2H), 7.33-7.26 (m, 3H), 7.22-7.17 (m, 3H), 4.07 (d, J=11.6 Hz, 2H), 3.49 (s, 3H), 3.15-3.07 (m, 2H), 3.07-3.00 (m, 2H), 2.86-2.75 (m, peaks obscured by solvent), 2.70-2.58 (m, 1H), 1.74 (d, J=11.3 Hz, 2H), 1.58 (d, J=3.4 Hz, 2H), 1.48 (dt, J=12.6, 6.2 Hz, 2H), 1.42 (s, 9H), 1.21 (s, 2H). LCMS-A: rt 7.175 min; m/z 625 [M+H]+.
Reaction SMILES: [CH3:1][CH:2]1[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[NH:3]1.N1C=CC=CC=1.[C:25](Cl)(=[O:27])[CH3:26]>ClCCl>[CH3:1][CH:2]1[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:3]1[C:25](=[O:27])[CH3:26]
Reactant: CC1CCc2c(cccc2Oc2ccccc2)N1
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)N1c2cccc(Oc3ccccc3)c2CCC1C
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 32 %

Procedure:
A glass, screw-cap vial equipped with a magnetic stir bar was charged with a solution of rac-2-methyl-5-phenoxy-1,2,3,4-tetrahydroquinoline (0.050 g, 0.21 mmol) in dichloromethane (1 mL) and pyridine (0.051 mL, 0.630 mmol). The solution was cooled to 0° C. and acetyl chloride (0.015 mL, 0.210 mmol) was added. The ice bath was removed and the reaction mixture stirred at rt. After 10 min, the reaction mixture was diluted with dichloromethane and washed with 1 N aqueous hydrochloric acid solution (2×1 mL) followed by 5% aqueous sodium chloride solution (1 mL). The organic layer was concentrated to a yellow oil, which crystallized upon standing. The crude product was purified by preparative thin layer chromatography (1×1000 micron plate, eluting with 2:1 hexanes-ethyl acetate) to yield 1-(2-methyl-5-phenoxy-3,4-dihydroquinolin-1(2H)-yl)ethanone (0.0189 g, 32%) as a nearly colorless oil. 1H NMR (400 MHz, CDCl3) δ ppm 1.13 (d, J=6.60 Hz, 3 H), 1.36-1.55 (m, 1H), 2.11-2.27 (m, 4H), 2.36 (br s, 1H), 2.85 (dt, J=16.04, 6.09 Hz, 1H), 4.88 (br s, 1H), 6.76 (d, J=8.80 Hz, 1H), 6.89-6.96 (m, 2H), 6.96-7.04 (m, 1H), 7.04-7.11 (m, 1H), 7.12-7.19 (m, 1H), 7.29-7.37 (m, 2H). MS (ESI, pos. ion) m/z 282 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([CH3:13])([CH3:12])[C:7](=[O:14])[C:6]([C:15](OCC)=[O:16])=[C:5]2[OH:20].Cl.[C:22]([O:26][C:27](=[O:30])[CH2:28][NH2:29])([CH3:25])([CH3:24])[CH3:23].CCN(C(C)C)C(C)C>O1CCOCC1.CCOC(C)=O>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([CH3:13])([CH3:12])[C:7](=[O:14])[C:6]([C:15]([NH:29][CH2:28][C:27]([O:26][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:30])=[O:16])=[C:5]2[OH:20]
Reactant: CC(C)(C)OC(=O)CN
Reactant: CCOC(=O)C1=C(O)c2cc(Br)ccc2C(C)(C)C1=O
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)CNC(=O)C1=C(O)c2cc(Br)ccc2C(C)(C)C1=O
Temperature: 120 °C
Reaction time: 17 h
Yield: 49.2 %

Procedure:
A solution of crude ethyl 6-bromo-4-hydroxy-1,1-dimethyl-2-oxo-naphthalen-3-carboxylate (4100 mg, 12088 μmol) and glycine tert-butyl ester hydrochloride (2229 mg, 13297 μmol) in 1,4-dioxane (100 mL) was treated with DIPEA (4211 μL, 24176 μmol). The reaction was heated at 120° C. in a sealed vessel. After 17 hours, the reaction was cooled to 23° C., diluted with EtOAc (200 mL) and washed with 10% HCl solution (2×150 mL) and brine (100 mL). The organic layer was dried over MgSO4, concentrated in vacuo, and purified by silica gel chromatography (eluant: 5-10% EtOAc/hexane) affording 2523 mg of 1,1-dimethylethyl N-((6-bromo-4-hydroxy-1,1-dimethyl-2-oxo-naphthalen-3-yl)carbonyl)glycinate. MS m/e=422.0 (M−H)−.
Reaction SMILES: Br[C:2]1[N:7]2[N:8]=[C:9]([CH2:11][CH3:12])[CH:10]=[C:6]2[CH:5]=[CH:4][CH:3]=1.[Cl:13][C:14]1[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:15]=1OB(O)O.C(=O)([O-])[O-].[Na+].[Na+].O>C(O)C.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.C(OCC)(=O)C>[Cl:13][C:14]1[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:15]=1[C:2]1[N:7]2[N:8]=[C:9]([CH2:11][CH3:12])[CH:10]=[C:6]2[CH:5]=[CH:4][CH:3]=1
Reactant: OB(O)Oc1ccc(Cl)cc1Cl
Reactant: CCc1cc2cccc(Br)n2n1
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: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: Cc1ccccc1
Product: CCc1cc2cccc(-c3ccc(Cl)cc3Cl)n2n1
Temperature: 80 °C
Reaction time: 3 h
Yield: 97.9 %

Procedure:
After dissolving 7-bromo-2-ethylpyrazolo[1,5-a]pyridine (300 mg) in ethanol (2 mL) and toluene (4 mL), 2,4-dichlorophenylboric acid (508 mg), tetrakis(triphenylphosphine)palladium (0) complex (154 mg) and 2M aqueous sodium carbonate (1.33 mL) were added and the mixture was heated and stirred at 80° C. for 3 hours under a nitrogen stream. Water was added to the reaction mixture, extraction was performed with ethyl acetate and the organic layer was washed with brine. After drying over anhydrous magnesium sulfate and filtration, the solvent was concentrated under reduced pressure, the residue was purified by silica gel column chromatography, and the title compound (380 mg) was obtained from the n-hexane:ethyl acetate (100:1) fraction as a light yellow oil.
Reaction SMILES: C(O[CH:5]([O:10][C:11]1[CH:12]=[C:13]([CH3:17])[CH:14]=[CH:15][CH:16]=1)[C:6](Cl)([Cl:8])[Cl:7])(=O)C>C(O)(=O)C.[Zn]>[Cl:7][C:6]([Cl:8])=[CH:5][O:10][C:11]1[CH:12]=[C:13]([CH3:17])[CH:14]=[CH:15][CH:16]=1
Reactant: CC(=O)OC(Oc1cccc(C)c1)C(Cl)(Cl)Cl
Agent: [Zn]
Solvent: CC(=O)O
Product: Cc1cccc(OC=C(Cl)Cl)c1
Temperature: 25 °C

Procedure:
By a metallic reductive dehydrohalogenation method. 1(3-tolyloxy)-2,2,2-trichloroethyl acetate (14.2 g) was dissolved in glacial acetic acid (40 ml) and zinc dust (3.6 g) was slowly added to the solution with stirring at the ambient temperature. The temperature rose to 60° C in response to the exothermic reaction which occurred, after which the mixture was heated at 50°-60° C for 4 hours. The mixture was filtered and the filtrate poured in an excess of water and extracted with chloroform. The extracts were washed twice with water, with saturated sodium bicarbonate solution, and finally with water. After drying the chloroform extracts over anhydrous magnesium sulphate, the solvent was removed by evaporation under reduced pressure and the residual oil distilled to yield crude 3-tolyl 2,2-dichlorovinyl ether, collected as a fraction boiling at 92°-95° C/0.3 mm, which was redistilled and the fraction boiling at 84° C/0.2 mm Hg collected.
Reaction SMILES: [C:1]1([C:7]2[CH:11]=[CH:10]N[C:8]=2[C:12]([O:14][CH3:15])=[O:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].NCl.[CH3:20][N:21](C=O)C>>[NH2:21][CH:20]1[C:8]([C:12]([O:14][CH3:15])=[O:13])=[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:11]=[CH:10]1
Reactant: COC(=O)c1[nH]ccc1-c1ccccc1
Reactant: CN(C)C=O
Agent: NCl
Agent: [H-]
Agent: [Na+]
Product: COC(=O)C1=C(c2ccccc2)C=CC1N
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 82 %

Procedure:
To a solution of methyl 3-phenyl-1H-pyrrole-2-carboxylate (2.50 g, 12.4 mmol) in DMF (25 mL) was added NaH (0.358 g, 14.9 mmol) and the reaction mixture was stirred for 45 min at room temperature. Monochloramine (0.15 M, 150 mL, 0.225 g, 4.40 mmol) was added via syringe. The reaction was stirred for 2 h and was quenched by the addition of saturated aqueous sodium thiosulfite. The reaction mixture was diluted with water and the aqueous portion extracted with ethyl acetate. The organic layer dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography using CombiFlash (REDISEP®, neutral alumina, 40 g, 25% EtOAc/hexanes) to afford methyl 5-amino-2-phenylcyclopenta-1,3-dienecarboxylate (2.20 g, 82.0%). LCMS Condition B-38: retention time 1.79 min, [M+1]=217.0. 1H NMR (400 MHz, DMSO-d6) δ ppm 3.63 (s, 3H), 6.07 (d, J=2.8 Hz, 1H), 6.28 (s, 2H), 7.05 (d, J=2.8 Hz, 1H), 7.33-7.35 (m, 5H).