Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2](=[O:6])[CH:3]=[CH:4][CH3:5].[CH:7]1[CH2:11][CH:10]=[CH:9][CH:8]=1.Cl(O)(=O)(=O)=O.C([C@@H]1N[C@H](C2OC(C)=CC=2)N(C)C1=O)C1C=CC=CC=1>O>[CH3:5][C@H:4]1[C@@H:9]2[CH2:10][C@H:11]([CH:7]=[CH:8]2)[C@@H:3]1[C:2](=[O:6])[CH3:1]
Reactant: CC=CC(C)=O
Reactant: C1=CCC=C1
Agent: Cc1ccc([C@H]2N[C@@H](Cc3ccccc3)C(=O)N2C)o1
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: O
Product: CC(=O)[C@@H]1[C@@H](C)[C@H]2C=C[C@H]1C2
Yield: 85 %

Procedure:
Prepared according to general procedure A from 3-penten-2-one (68 μL, 0.70 mmol), cyclopentadiene (69 μL, 0.84 mmol), 70% aqueous perchloric acid (12.1 μL, 0.14 mmol) and (2S, 5S)-5-benzyl-3-methyl-2-(5-methyl-furan-2-yl)-imidazolidin-4-one (37.8 mg, 0.14 mmol) in water (175 μL) for 2.5 hours at 0° C. Purification by silica gel chromatography (9:1 pentane:ether) provided the title compound as a colorless oil in 85% yield (89 mg, 0.59 mmol); 14:1 endo:exo, endo 61% ee. IR (film) 3061, 2962, 2871, 1708,1461, 1426, 1359,1333, 1267, 1183, 1170,114, 1095, 1055,906.8, 797.8, 719.4, 654.5, 597.0 cm−1; 1H NMR (300 MHz, CDCl3) δ 6.21 (dd, J=6.0, 3.3 Hz, 1 H, CH═CH), 5.90 (dd, J=5.7, 2.7 Hz, 1H, CH═CH), 3.13 (m, 1H, CHCH═CH), 2.44 (m, 1H, CHCH═CH), 2.42 (dd, J=4.8, 3.9 Hz, 1H, CHCO), 2.10 (s, 3H, CH3CO), 1.86 (m, 1 H, CHCH3), 1.57 (m, 1H, C(H)H), 1.43 (m, 1H, C(H)H), 1.14 (d, J=6.9 Hz, 3H, CHCH3); 13C NMR (75 MHz, CDCl3) δ 209.2, 138.8, 132.6, 61.9, 49.3, 46.6, 46.5, 35.9, 29.5, 21.4; HRMS (CI) exact mass calc'd for (C10H14O) requires nm/z 150.1045, found m/z 150.1041. [α]D=+70.4 (c=1.0, CHCl3). Product ratios were determined by GLC analysis (120° C., 23 psi); (1R, 2R, 3S, 4R) endo isomer tr=6.9 min, and (1S, 2S, 3R, 4S) endo isomer tr=6.3 min, exo isomers tr=5.7, 5.5 min.
Reaction SMILES: Cl[C:2]1[C:3]2[NH:11][N:10]=[N:9][C:4]=2[N:5]=[C:6]([NH2:8])[N:7]=1.C([Sn](CCCC)(CCCC)[C:17]1[O:18][CH:19]=[CH:20][CH:21]=1)CCC>CN1CCCC1=O.CCOC(C)=O.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>[O:18]1[CH:19]=[CH:20][CH:21]=[C:17]1[C:2]1[C:3]2[NH:11][N:10]=[N:9][C:4]=2[N:5]=[C:6]([NH2:8])[N:7]=1
Reactant: Nc1nc(Cl)c2[nH]nnc2n1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccco1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: Nc1nc(-c2ccco2)c2[nH]nnc2n1
Temperature: 80 °C
Reaction time: 5 h

Procedure:
A solution of 7-chloro-1H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine (570 mg, 3.34 mmol) in N-methyl-2-pyrrolidinone (4 mL) was treated with PdCl2(PPh3)2 (117 mg, 0.17 mmol) and 2-(tributylstannyl)furan (1.05 mL, 1 mmol), stirred at 80° C. for 5 h, diluted with EtOAc, filtered through a silica pad and concentrated in vacuo. The residue was triturated with diethyl ether and the title compound isolated as a yellow solid (438 mg, 65%).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:13]=[C:12]2[C:8]([C:9]([C:29]#[N:30])=[C:10]([C:16]3[CH:21]=[CH:20][C:19]([NH:22][S:23]([CH2:26][CH2:27][CH3:28])(=[O:25])=[O:24])=[CH:18][CH:17]=3)[N:11]2[CH2:14][CH3:15])=[CH:7][CH:6]=1)=[O:4].NC1C=CC(C2N(CC)C3C(C=2C#N)=CC=C(C(OC)=O)C=3)=CC=1.[OH-].[K+].Cl>>[C:29]([C:9]1[C:8]2[C:12](=[CH:13][C:5]([C:3]([OH:4])=[O:2])=[CH:6][CH:7]=2)[N:11]([CH2:14][CH3:15])[C:10]=1[C:16]1[CH:21]=[CH:20][C:19]([NH:22][S:23]([CH2:26][CH2:27][CH3:28])(=[O:24])=[O:25])=[CH:18][CH:17]=1)#[N:30]
Reactant: CCCS(=O)(=O)Nc1ccc(-c2c(C#N)c3ccc(C(=O)OC)cc3n2CC)cc1
Agent: CCn1c(-c2ccc(N)cc2)c(C#N)c2ccc(C(=O)OC)cc21
Agent: Cl
Agent: [K+]
Product: CCCS(=O)(=O)Nc1ccc(-c2c(C#N)c3ccc(C(=O)O)cc3n2CC)cc1
Temperature: 25 °C
Yield: 91.9 %

Procedure:
3-Cyano-1-ethyl-2-[4-(propane-1-sulfonylamino)-phenyl]-1H-indole-6-carboxylic acid methyl ester (1.25 g, 3.04 mmol), prepared by the method described in example 1Y from methyl 2-(4-aminophenyl)-3-cyano-1-ethyl-1H-indole-6-carboxylate, is treated with 0.5N KOH (30 mL, 15.2 mmol) and heated at reflux for 2.5 h. After cooling to room temperature, the aqueous phase is acidified with 3N HCl to pH 2 and the resultant precipitate is filtered, washed with water (2×) and dried until constant weight to afford 1.15 g (96%) of 3-cyano-1-ethyl-2-[4-(propane-1-sulfonylamino)-phenyl]-1H-indole-6-carboxylic acid as a white solid.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([NH:8][NH2:9])=[O:7])=[CH:4][CH:3]=1.[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([N:19]=[C:20]=S)=[CH:15][C:14]=1[C:22]([F:25])([F:24])[F:23].CCOC(C)=O.CO>CO.[Hg]=O>[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([NH:19][C:20]2[O:7][C:6]([C:5]3[CH:10]=[CH:11][C:2]([OH:1])=[CH:3][CH:4]=3)=[N:8][N:9]=2)=[CH:15][C:14]=1[C:22]([F:23])([F:24])[F:25]
Reactant: NNC(=O)c1ccc(O)cc1
Reactant: FC(F)(F)c1cc(N=C=S)ccc1Cl
Agent: O=[Hg]
Solvent: CO
Solvent: CCOC(C)=O
Product: Oc1ccc(-c2nnc(Nc3ccc(Cl)c(C(F)(F)F)c3)o2)cc1
Temperature: 25 °C
Yield: 60.8 %

Procedure:
Mercury (II) oxide (yellow) (4.55 g, 21.0 mmol) was suspended in 60 mL of anhydrous MeOH under Ar. A bright-orange suspension was formed. To this suspension was added 4-hydroxybenzoic acid hydrazide (3.20 g, 21.0 mmol) and 4-chloro-3-trifluoromethyl-phenylisothiocyanate (5.0 g, 21.0 mmol). The reaction mixture was refluxed for 2 hours. The solvent was removed in vacuo. The black residue was redissolved in 100 mL of EtOAc and the resulting black suspension was filtered through a short pad of silica gel. The filtrate was mixed with 10 g of dry silica gel and solvent was removed in vacuo. The impregnated silica gel was loaded on silica gel column and the product was separated using a gradient of hexane:ethyl acetate mixture starting from 50:50 ratio and finishing at 0:100. All fractions containing the product were combined; solvent was removed in vacuo to give a grey solid. The solid was heated in 50 mL of 4:1 mixture of EtOAc/MeOH. The formed suspension was cooled down to ambient temperature and filtered to give the title product as a white crystalline solid (4.54 g, 60.7% yield).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7](B(O)O)=[CH:6][CH:5]=1)([OH:3])=[O:2].Br[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C>[N:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[C:7]1[CH:8]=[CH:9][C:4]([C:1]([OH:3])=[O:2])=[CH:5][CH:6]=1
Reactant: O=C(O)c1ccc(B(O)O)cc1
Reactant: Brc1ccccn1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: O=C(O)c1ccc(-c2ccccn2)cc1
Temperature: 90 °C
Yield: 83.5 %

Procedure:
To a suspension of 4-carboxybenzeneboronic acid (0.660 g, 3.98 mmol) and 2-bromopyridine (0.38 mL, 3.98 mmol) in dry acetonitrile (20 mL) was added 0.4 M aqueous sodium carbonate (20 mL) and mixture purged with nitrogen for 10 minutes. Tetrakis(triphenylphosphine)palladium(0) (0.240 g) was then added and the reaction mixture heated to 90° C. for 20 hours. The hot mixture was filtered through celite and concentrated in vacuo to remove acetonitrile. The resulting aqueous suspension was diluted with water (20 mL), washed with dichloromethane (2×40 mL), and then acidified to pH 6 by the addition of concentrated hydrochloric acid. The resulting white suspension was diluted with water (20 mL), filtered and the solid product dried in vacuo at 50° C. overnight to give the title compound (0.662 g, 84%) as a white solid, m.p. 232-234° C.
Reaction SMILES: C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+].Cl[C:54]1[CH:63]=[CH:62][C:61]2[C:56](=[CH:57][CH:58]=[CH:59][CH:60]=2)[N:55]=1.[NH2:64][CH2:65][CH2:66][NH:67][C:68](=[O:74])[O:69][C:70]([CH3:73])([CH3:72])[CH3:71]>O1CCOCC1.C(OCC)(=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[N:55]1[C:56]2[C:61](=[CH:60][CH:59]=[CH:58][CH:57]=2)[CH:62]=[CH:63][C:54]=1[NH:64][CH2:65][CH2:66][NH:67][C:68](=[O:74])[O:69][C:70]([CH3:72])([CH3:71])[CH3:73]
Reactant: CC(C)(C)OC(=O)NCCN
Reactant: Clc1ccc2ccccc2n1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)NCCNc1ccc2ccccc2n1
Temperature: 110 °C
Reaction time: 3 h

Procedure:
Palladium acetate (63 mg, 0.28 mmol), BINAP (250 mg, 0.4 mmol) and cesium carbonate (1.3 g, 4 mmol) were suspended in anhydrous 1,4-dioxane (9 ml) under an argon atmosphere and sonicated for 40 minutes. 2-Chloroquinoline (343 mg, 2 mmol) and tert-butyl N-(2-aminoethyl)carbamate (320 mg, 2 mmol) were added and the resulting mixture was stirred at 110° C. for three hours. The reaction mixture was diluted with ethyl acetate, the resulting precipitate was removed by centrifugation and decantation. The supernatant was evaporated to dryness under reduced pressure. The residue was dissolved in DCM, filtered through a short silica column; the product was eluted with a 1-to-1 mixture of DCM and diethylether. After evaporation of the solvent under reduced pressure 137 mg of a solid were obtained (0.44 mmol, 22%). MS(ESI) m/z=288.2 [M+1]+.
Reaction SMILES: [C:1]1(/[CH:7]=[CH:8]/[C:9]([O:11][CH3:12])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(#N)C.[NH:16]1[CH:20]=[C:19]([C:21]2[C:22]3[CH:29]=[CH:28][N:27]([CH2:30][O:31][CH2:32][CH2:33][Si:34]([CH3:37])([CH3:36])[CH3:35])[C:23]=3[N:24]=[CH:25][N:26]=2)[CH:18]=[N:17]1.C1CCN2C(=NCCC2)CC1>>[C:1]1([CH:7]([N:16]2[CH:20]=[C:19]([C:21]3[C:22]4[CH:29]=[CH:28][N:27]([CH2:30][O:31][CH2:32][CH2:33][Si:34]([CH3:37])([CH3:36])[CH3:35])[C:23]=4[N:24]=[CH:25][N:26]=3)[CH:18]=[N:17]2)[CH2:8][C:9]([O:11][CH3:12])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)/C=C/c1ccccc1
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cn[nH]c3)ncnc21
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: COC(=O)CC(c1ccccc1)n1cc(-c2ncnc3c2ccn3COCC[Si](C)(C)C)cn1
Temperature: 25 °C
Yield: 52.3 %

Procedure:
A solution of methyl (2E)-3-phenylacrylate (500 mg, 0.003 mol) in ACN (2 mL, 0.04 mol) was slowly added to a solution of 4-(1H-pyrazol-4-yl)-7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidine (0.5 g, 0.002 mol) in ACN (2 mL, 0.04 mol) and DBU (500 μL, 0.003 mol). The reaction was stirred at room temperature over the weekend. The reaction was partitioned between water and EtOAc. The organic layer was washed with saturated sodium chloride, dried over MgSO4, filtered and concentrated to give an oil. The product was purified by FCC on silica gel using EtOAc/Hexane (1:2 to 1:1) gave methyl 3-phenyl-3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanoate (500 mg, 70%) as a semisolid residue. 1H NMR (400 MHz, CDCl3): δ 8.9 (s, 1H), 8.4 (s, 2H), 7.4 (m, 5H), 6.8 (d, 1H), 6 (m, 1H), 5.7 (s, 2H), 3.7-3.8 (m, 3H), 3.6 (m, 2H), 2.2 (m, 1H), 1.4 (m, 2H), 1.1 (m, 2H), 0.02 (s, 9H), m/z=478 (M+1).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[CH:10][C:9]=2[C:13]([OH:15])=O)=[CH:4][CH:3]=1.[CH2:16]([CH:23]1[CH2:27][CH2:26][CH2:25][NH:24]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[CH2:16]([CH:23]1[CH2:27][CH2:26][CH2:25][N:24]1[C:13]([C:9]1[CH:10]=[N:11][O:12][C:8]=1[C:5]1[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][CH:6]=1)=[O:15])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: Cc1ccc(-c2oncc2C(=O)O)cc1
Reactant: c1ccc(CC2CCCN2)cc1
Product: Cc1ccc(-c2oncc2C(=O)N2CCCC2Cc2ccccc2)cc1

Procedure:
The title compound was prepared from 5-(4-methylphenyl)isoxazole-4-carboxylic acid (10.2 mg, 0.050 mmol) and 2-benzylpyrrolidine (9.7 mg, 0.060 mmol) as described in synthetic method B and thereafter purified by preparative HPLC method B to give a solid (6.8 mg). Calcd for C22H22N2O2: 346.1681, found 346.1694.
Reaction SMILES: CC1(C)[O:6][C:5](=O)[CH:4]([CH:8]([C:13]([N:15]2[CH2:19][CH2:18][CH2:17][C@H:16]2[C:20]([NH2:22])=[O:21])=[O:14])[CH2:9][CH2:10][CH2:11][CH3:12])[O:3]1.[NH2:24][OH:25]>O1CCOCC1>[OH:25][NH:24][C:5](=[O:6])[C@@H:4]([OH:3])[C@@H:8]([CH2:9][CH2:10][CH2:11][CH3:12])[C:13]([N:15]1[CH2:19][CH2:18][CH2:17][C@H:16]1[C:20]([NH2:22])=[O:21])=[O:14]
Reactant: CCCCC(C(=O)N1CCC[C@H]1C(N)=O)C1OC(C)(C)OC1=O
Reactant: NO
Solvent: C1COCCO1
Product: CCCC[C@@H](C(=O)N1CCC[C@H]1C(N)=O)[C@H](O)C(=O)NO

Procedure:
To 1-(2,2-dimethyl-4-oxo-1,3-dioxolan-5-yl)-1-(2-(S)-aminocarbonylpyrrolidin-1-ylcarbonyl)pentane C-3 in dioxane was treated with 50% aqueous hydroxylamine for 4 h. The reaction mixture was then purified by preparative reverse-phase (C18) HPLC to afford N-hydroxy-3-(R)-n-butyl-3-[2-(S)-aminocarbonylpyrrolidin-1-ylcarbonyl)-2-(S)-hydroxypropionamide C-4.
Reaction SMILES: [C:1]([O:4][C:5]1[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][C:6]=1[CH2:12][CH:13]=[CH2:14])(=[O:3])[CH3:2].[BrH:15].C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>CCCCCC>[C:1]([O:4][C:5]1[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][C:6]=1[CH2:12][CH2:13][CH2:14][Br:15])(=[O:3])[CH3:2]
Reactant: C=CCc1cccc(C)c1OC(C)=O
Reactant: Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: CCCCCC
Product: CC(=O)Oc1c(C)cccc1CCCBr
Yield: 58.1 %

Procedure:
The protected monohydroxy compound, 1-acetoxy,2-(2 propenyl)-6-methylbenzene was the starting material. Halogenation was achieved by bubbling HBr through a hexane solution (250 ml.) of the starting material (61.3 g, 0.323 moles) and dibenzoyl peroxide (2 g) for 2 hours. The reaction mixture was washed twice with saturated NaHCO3 solution (2×200 ml.) and once with H2O. The hexane layer was dried over Na2SO4 and the solvent evaporated. The desired 1-acetoxy,2-(3-bromopropyl)-6-methylbenzene was isolated by distillation. The % yield was 58.1% (40.84 g, BP=164°-166° C. at 0.03 Torr).
Reaction SMILES: [CH2:1]([C:9]1[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=1[C:11](O)=[O:12])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(Cl)(=O)C(Cl)=O.CN(C=O)C>ClCCl>[CH2:1]([C:9]1[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=1[CH:11]=[O:12])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: O=C(O)c1ccccc1CCc1ccccc1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=Cc1ccccc1CCc1ccccc1
Temperature: -70 °C
Reaction time: 1.5 h
Yield: 74 %

Procedure:
A mixture of 2-phenethylbenzoic acid (11.3 g), oxalyl chloride (5.2 ml), DMF (0.2 ml) and dichloromethane (100 ml) was stirred for 1.5 hours. The solvent was evaporated, diglyme (75 ml) added and the mixture cooled to −70° C. Lithium tri-(tert-butoxy)aluminium hydride (100 ml, 0.5M solution in diglyme) was added dropwise over 45 minutes maintaining the reaction temperature below −60° C. The reaction was stirred at −70° C. for 1 hour and poured into a 2N HCl and ice mixture. The mixture was extracted with iso-hexane (3×100 ml). The extracts were washed with saturated aqueous sodium hydrogen carbonate, water and brine, dried (MgSO4), filtered and evaporated. The residue was purfied by MPLC eluting with dichloromethane/iso-hexane (1:1) to give 2-(phenethyl)benzaldehyde (7.77 g).
Reaction SMILES: [Si:1]([O:18][CH2:19][C@@H:20]1[CH2:22][C@H:21]1[CH2:23][OH:24])([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:25][S:26](Cl)(=[O:28])=[O:27].C1COCC1>O>[CH3:25][S:26]([O:24][CH2:23][C@@H:21]1[CH2:22][C@H:20]1[CH2:19][O:18][Si:1]([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)(=[O:28])=[O:27]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)[Si](OC[C@@H]1C[C@H]1CO)(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)[Si](OC[C@@H]1C[C@H]1COS(C)(=O)=O)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
TEA (0.450 mL, 3.23 mmol) was added to a mixture of trans-(2-((tert-butyldiphenylsilyloxy)methyl)cyclopropyl)methanol (1 g, 2.94 mmol), methanesulfonyl chloride (0.250 mL, 3.23 mmol) and THF (10 mL) at 0° C., and the mixture was stirred at room temperature for 2 hr. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, and dried over magnesium sulfate, and the solvent was evaporated under reduced pressure to give trans-(2-(((tert-butyldiphenylsilyl)oxy)methyl)cyclopropyl)methyl methanesulfonate (1.230 g, 2.94 mmol, 100%) as a colorless oil.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][N:8]=[C:9]2Cl)=[CH:4][CH:3]=1.BrC1C=C2C(=CC=1)C([O:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=NC=C2>>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][N:8]=[C:9]2[O:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:4][CH:3]=1
Reactant: Brc1ccc2c(Oc3ccccc3)nccc2c1
Reactant: Clc1nccc2ccc(Br)cc12
Product: Brc1ccc2ccnc(Oc3ccccc3)c2c1

Procedure:
Compound 37c was prepared from 37b using the procedure described for 1c. 1H-NMR 200 MHz (CDCl3) δ: 6.76-6.97 (2H, m), 7.18-8.09 (7H, m), 8.60-8.64 (1H, m).
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[C:13]2[C:8](=[C:9]([O:16][CH:17]3[CH2:21][CH2:20][CH2:19][CH2:18]3)[C:10]([O:14][CH3:15])=[CH:11][CH:12]=2)[O:7][C:6](=[O:22])[CH:5]=1.[Cl:23][C:24]1[CH:25]=[N:26][CH:27]=[C:28]([Cl:31])[C:29]=1Cl.OP([O-])(O)=O.[K+]>CS(C)=O>[CH:17]1([O:16][C:9]2[C:10]([O:14][CH3:15])=[CH:11][CH:12]=[C:13]3[C:8]=2[O:7][C:6](=[O:22])[CH:5]=[C:4]3[NH:3][C:29]2[C:28]([Cl:31])=[CH:27][N:26]=[CH:25][C:24]=2[Cl:23])[CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: COc1ccc2c(N)cc(=O)oc2c1OC1CCCC1
Reactant: Clc1cncc(Cl)c1Cl
Agent: O=P([O-])(O)O
Agent: [H-]
Agent: [K+]
Solvent: CS(C)=O
Product: COc1ccc2c(Nc3c(Cl)cncc3Cl)cc(=O)oc2c1OC1CCCC1
Reaction time: 4 h

Procedure:
Sodium hydride (12 mg, 60%, 0.30 mmol) was added to a solution of 4-amino-8-(cyclopentyloxy)-7-methoxy-2H-chromen-2-one (40 mg, 0.15 mmol), 3,4,5-trichloropyridine (27 mg, 0.15 mmol), and anhydrous DMSO (3 mL) at rt under N2. After 4 h, the reaction was poured into 1M KH2PO4 (40 mL) and extracted with ethyl acetate (40 mL×2). The combined extracts were dried, filtered, concentrated, and purified by silica gel chromatography (13:7→9:11; hexanes:ethyl acetate) to give 8-(cyclopentyloxy)-4-(3,5-dichloropyridin-4-ylamino)-7-methoxy-2H-chromen-2-one: 1H NMR (400 MHz, DMSO-d6): δ 9.50 (s, 1H), 8.81 (s, 2H), 7.93 (d, 1H), 7.20 (d, 1H), 4.83 (m, 1H), 4.63 (s, 1H), 3.91 (s, 3H), 1.80-1.00 (m, 8H); MS (ESI): 421.1.
Reaction SMILES: [Li]CCCC.Br[C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=[C:9]([C:17]([CH3:19])=[CH2:18])[CH:8]=1.[CH:20]([C:22]1[CH:31]=[CH:30][C:25]([C:26]([O:28][CH3:29])=[O:27])=[CH:24][CH:23]=1)=[O:21]>C1COCC1>[OH:21][CH:20]([C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=[C:9]([C:17]([CH3:19])=[CH2:18])[CH:8]=1)[C:22]1[CH:23]=[CH:24][C:25]([C:26]([O:28][CH3:29])=[O:27])=[CH:30][CH:31]=1
Reactant: COC(=O)c1ccc(C=O)cc1
Reactant: C=C(C)c1cc(Br)c2ccccc2n1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: C=C(C)c1cc(C(O)c2ccc(C(=O)OC)cc2)c2ccccc2n1
Temperature: -78 °C
Reaction time: 3 h
Yield: 45.6 %

Procedure:
A solution of n-BuLi (2.5 M, 7.5 mmol, 3 mL) was added to a solution of (56b) (1.55 g, 6.25 mmol) in 20 mL of anhydrous THF at −78° C. The resulting solution was cannulated to another flask charged with methyl 4-formylbenzoate (1.34 g, 8.1 mmol) in 20 mL of anhydrous THF at −78° C. The reaction mixture was stirred for 3 h at −78° C. before quenched with MeOH. The solution was then diluted with ethyl acetate and washed with H2O and brine, and dried over MgSO4. After filtration and concentration, the residue was purified on silica gel column to provide methyl 4-[hydroxy(2-isopropenyl-4-quinolinyl)methyl]benzoate (0.95 g, 46%). MS (AP+): 333 (M+1).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[N:7]1[CH:11]=[CH:10][CH:9]=[N:8]1.[B:12](OC(C)C)([O:17]C(C)C)[O:13]C(C)C.Cl>C1COCC1.C([Li])CCC>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[N:7]1[CH:11]=[CH:10][CH:9]=[N:8]1.[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[N:7]1[C:11]([B:12]([OH:17])[OH:13])=[CH:10][CH:9]=[N:8]1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: Cl
Agent: [Li]CCCC
Agent: c1cnn(C2CCCCO2)c1
Solvent: C1CCOC1
Product: OB(O)c1ccnn1C1CCCCO1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
A mixture of pyrazole (14.3 g, 0.21 mmol), 3,4-dihydro-2H-pyrane (29 mL, 0.32 mmol) and trifluoroacetic acid (0.1 mL, 0.0013 mmol) was heated under reflux for 5 hours. After the mixture was cooled to room temperature, sodium hydride (60%, 0.2 g, 0.008 mmol) was added thereto, and the mixture was stirred for 10 minutes. The reaction mixture was subjected to distillation under reduced pressure (60-65° C., 0.5-1 mmHg), whereby 1-(tetrahydropyran-2-yl)-1H-pyrazole (30.8 g, 96%) was obtained. To a stirred solution of the obtained 1-(tetrahydropyran-2-yl)-1H-pyrazole (30 g, 197 mmol) in THF (197 mL), n-butyl lithium (2.6 M hexane solution, 79 mL) was added at −78° C., and the reaction solution was stirred at −78° C. for 30 minutes. To the reaction solution, triisopropyl borate (50.0 mL, 217 mmol) was added at −78° C., and the solution was stirred for 1 hour. To the reaction solution, 2 N hydrochloric acid (200 mL) was added, and the solution was stirred at room temperature for 30 minutes. The solution was extracted three times with chloroform-ethanol. The extracted organic layer was washed sequentially with water and saturated brine and then dried over magnesium sulfate. After the drying agent was removed by filtration, the solvent was evaporated under reduced pressure. The residue was crystallized from ethyl acetate-hexane, whereby the objective compound (16.0 g, 41.4%) was obtained as a colorless solid.
Reaction SMILES: I[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([NH:11][C:12]([CH:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)=[O:13])[N:10]=2)[N:7]=1.[NH2:20][C:21]1[CH:22]=[C:23]([OH:27])[CH:24]=[CH:25][CH:26]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[NH2:20][C:21]1[CH:22]=[C:23]([CH:24]=[CH:25][CH:26]=1)[O:27][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([NH:11][C:12]([CH:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)=[O:13])[N:10]=2)[N:7]=1
Reactant: Nc1cccc(O)c1
Reactant: O=C(Nc1cn2nc(I)ccc2n1)C1CCOCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Nc1cccc(Oc2ccc3nc(NC(=O)C4CCOCC4)cn3n2)c1
Temperature: 180 °C
Yield: 49 %

Procedure:
A mixture of N-(6-iodoimidazo[1,2-b]pyridazin-2-yl)tetrahydro-2H-pyran-4-carboxamide, 3-aminophenol (436 mg, 4.0 mmol), potassium carbonate (552 mg, 4.0 mmol) and N,N-dimethylformamide (5.0 mL) was stirred with heating at 180° C. for 15 min using a microwave synthesizer. After cooling, the reaction mixture was filtrated, and the filtrate was purified by preparative HPLC to give the title compound (364 mg, 49%) as a dark brown powder.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]2[NH:12][C:11]3[N:13]=[C:14]([C:17]([F:20])([F:19])[F:18])[CH:15]=[CH:16][C:10]=3[CH2:9][N:8]([S:21]([C:24]3[CH:29]=[CH:28][C:27]([C:30]([CH3:33])([CH3:32])[CH3:31])=[CH:26][CH:25]=3)(=[O:23])=[O:22])[C:7]=2[C:34]=1[CH3:35])#[N:2].O.[OH-].[Li+].[O:39]1CCOCC1.O>CCOC(C)=O>[C:30]([C:27]1[CH:28]=[CH:29][C:24]([S:21]([N:8]2[C:7]3[C:34]([CH3:35])=[C:3]([C:1]([NH2:2])=[O:39])[CH:4]=[CH:5][C:6]=3[NH:12][C:11]3[N:13]=[C:14]([C:17]([F:19])([F:20])[F:18])[CH:15]=[CH:16][C:10]=3[CH2:9]2)(=[O:22])=[O:23])=[CH:25][CH:26]=1)([CH3:31])([CH3:32])[CH3:33]
Reactant: Cc1c(C#N)ccc2c1N(S(=O)(=O)c1ccc(C(C)(C)C)cc1)Cc1ccc(C(F)(F)F)nc1N2
Reactant: C1COCCO1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1c(C(N)=O)ccc2c1N(S(=O)(=O)c1ccc(C(C)(C)C)cc1)Cc1ccc(C(F)(F)F)nc1N2
Temperature: 100 °C
Reaction time: 0.5 h

Procedure:
A mixture of 8-cyano-6-[(4-tert-butylphenyl)sulfonyl]-7-methyl-2-(trifluoromethyl)-6,11-dihydro-5H-pyrido[2,3-b][1,5]benzodiazepine (199 mg, 0.398 mmol) and lithium hydroxide monohydrate (50.1 mg, 2.295 mmol) in 1:1 dioxane-water was heated in a microwave reactor for 15 min at 100° C., followed by 30 min at 120° C. The reaction mixture was cooled to room temperature, diluted with EtOAc, and the organic layer was separated, washed with water, brine, dried over MgSO4 and concentrated. The residue was purified via reverse-phase HPLC to provide the title compound. LC/MS: m/e 519.1 (M+H)+. 1H NMR (500 MHz, CD3OD): δ 7.60 (1H, d), 7.35 (1H, d), 7.15 (2H, d), 7.03-7.10 (3H, m), 6.93 (1H, d), 5.19 (1H, d), 4.40 (1H, d), 2.60 (3H, s), 1.25 (9H, s).