Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1Cl)=[CH:13][CH:12]=[CH:11][CH:10]=2)=[O:5])C.[NH:17]([C:19]1[CH:27]=[CH:26][C:22]([C:23]([OH:25])=[O:24])=[CH:21][CH:20]=1)[NH2:18].CCCCCCC>C(O)CCC>[O:5]=[C:4]1[C:6]2=[CH:7][NH:8][C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=3[C:15]2=[N:18][N:17]1[C:19]1[CH:20]=[CH:21][C:22]([C:23]([OH:25])=[O:24])=[CH:26][CH:27]=1
Reactant: NNc1ccc(C(=O)O)cc1
Reactant: CCOC(=O)c1cnc2ccccc2c1Cl
Solvent: CCCCCCC
Solvent: CCCCO
Product: O=C(O)c1ccc(-n2nc3c4ccccc4[nH]cc-3c2=O)cc1
Temperature: 60 °C
Yield: 8.5 %

Procedure:
A solution of 4-chloro-quinoline-3-carboxylic acid ethyl ester (11.8 mg, 0.5 mmol) and 4-hydrazino-benzoic acid (7.6 mg, 0.5 mmol) in n-butanol (0.5 mL) was stirred at 115° C. over night in a sealed tube. After cooling to 50-70° C., heptane (1.0 mL) was added and the product was allowed to crystallize upon further cooling to room temperature. The solvent was removed and the product was washed with heptane and dried under vacuum to yield 4-(3-oxo-3,5-dihydro-pyrazolo[4,3-c]quinolin-2-yl)-benzoic acid (13 mg). 1H NMR (400 MHz, DMSO-d6) δ 12.9 (1H, s), 8.77 (1H, d), 8.38 (2H, d), 8.25 (1H, d), 8.03 (2H, d), 7.65-7.77 (2H, m), 7.58 (1H, t).
Reaction SMILES: [CH:1]1([N:4]([CH2:39][C:40]2[CH:45]=[C:44]([CH2:46][CH2:47][CH2:48][O:49][CH3:50])[CH:43]=[C:42]([OH:51])[CH:41]=2)[C:5]([C@@H:7]2[C@@H:12]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][O:22][C:23]4[C:28]([Cl:29])=[CH:27][C:26]([CH3:30])=[CH:25][C:24]=4[Cl:31])=[CH:15][CH:14]=3)[CH2:11][CH2:10][N:9]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:8]2)=[O:6])[CH2:3][CH2:2]1.Br[CH2:53][CH2:54][CH2:55][C:56]([O:58][CH2:59][CH3:60])=[O:57].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.CCOC(C)=O>[CH:1]1([N:4]([CH2:39][C:40]2[CH:45]=[C:44]([CH2:46][CH2:47][CH2:48][O:49][CH3:50])[CH:43]=[C:42]([O:51][CH2:53][CH2:54][CH2:55][C:56]([O:58][CH2:59][CH3:60])=[O:57])[CH:41]=2)[C:5]([C@@H:7]2[C@@H:12]([C:13]3[CH:14]=[CH:15][C:16]([O:19][CH2:20][CH2:21][O:22][C:23]4[C:28]([Cl:29])=[CH:27][C:26]([CH3:30])=[CH:25][C:24]=4[Cl:31])=[CH:17][CH:18]=3)[CH2:11][CH2:10][N:9]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:8]2)=[O:6])[CH2:3][CH2:2]1
Reactant: CCOC(=O)CCCBr
Reactant: COCCCc1cc(O)cc(CN(C(=O)[C@H]2CN(C(=O)OC(C)(C)C)CC[C@@H]2c2ccc(OCCOc3c(Cl)cc(C)cc3Cl)cc2)C2CC2)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)CCCOc1cc(CCCOC)cc(CN(C(=O)[C@H]2CN(C(=O)OC(C)(C)C)CC[C@@H]2c2ccc(OCCOc3c(Cl)cc(C)cc3Cl)cc2)C2CC2)c1
Temperature: 80 °C

Procedure:
To a solution of tert-butyl (3R,4S)-3-({cyclopropyl[3-hydroxy-5-(3-methoxy-propyl)benzyl]amino}carbonyl)-4-{4-[2-(2,6-dichloro-4-methylphenoxy)ethoxy]-phenyl}piperidine-1-carboxylate (1 eq.) from Example 1/Step 2 in DMF (0.2 M) was added ethyl 4-bromobutanoate (1.6 eq.) and cesium carbonate (1.3 eq.). The reaction was heated to 80° C. for 3 h. After cooling down to rt, the reaction was diluted with EtOAc. The organic extract was washed with water, brine, dried over MgSO4, and concentrated in vacuo. The crude product was purified by flash column chromatography (SiO2, 50% EtOAc in Hex) to afford the title compound as an oil.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[K+].[NH2:11][C:12]1[CH:21]=[CH:20][C:19]([C:22]([C:24]2[N:32]3[C:27]([CH:28]=[CH:29][CH:30]=[CH:31]3)=[C:26]([OH:33])[C:25]=2[CH3:34])=[O:23])=[CH:18][C:13]=1[C:14]([O:16][CH3:17])=[O:15].[C:35]([O:39][C:40](=[O:51])[CH2:41][O:42][C:43]1[CH:48]=[CH:47][CH:46]=[C:45]([CH2:49]Br)[CH:44]=1)([CH3:38])([CH3:37])[CH3:36].S([O-])(O)(=O)=O.[K+]>O1CCCC1>[NH2:11][C:12]1[CH:21]=[CH:20][C:19]([C:22]([C:24]2[N:32]3[C:27]([CH:28]=[CH:29][CH:30]=[CH:31]3)=[C:26]([O:33][CH2:49][C:45]3[CH:46]=[CH:47][CH:48]=[C:43]([O:42][CH2:41][C:40]([O:39][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:51])[CH:44]=3)[C:25]=2[CH3:34])=[O:23])=[CH:18][C:13]=1[C:14]([O:16][CH3:17])=[O:15]
Reactant: CC(C)(C)OC(=O)COc1cccc(CBr)c1
Reactant: COC(=O)c1cc(C(=O)c2c(C)c(O)c3ccccn23)ccc1N
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: C1CCOC1
Product: COC(=O)c1cc(C(=O)c2c(C)c(OCc3cccc(OCC(=O)OC(C)(C)C)c3)c3ccccn23)ccc1N
Temperature: 40 °C
Reaction time: 0.25 h
Yield: 68.4 %

Procedure:
5.43 ml (2.71 mmol) of potassium bis(trimethylsilyl)amide at −20° C. are added to the solution of 0.80 g (2.47 mmol) of methyl 2-amino-5-[(1-hydroxy-2-methylindolizin-3-yl)carbonyl]benzoate in 12 ml of tetrahydrofuran. After 15 minutes, 1.49 g (4.93 mmol) of tert-butyl[3-(bromomethyl)phenoxy]acetate (CAS 176673-59-9 described in Patent Application WO2004014366) in solution in 2 ml of tetrahydrofuran are added and the mixture is then heated at 40° C. for 12 hours. The reaction medium is poured into a saturated aqueous solution of potassium hydrogen sulphate, and the mixture is extracted with ethyl acetate. The organic phase is washed with water and then with a saturated aqueous solution of sodium chloride, dried over sodium sulphate and concentrated under reduced pressure. After purification by flash chromatography on silica gel (toluene/ethyl acetate gradient=100/00 to 60/40), 0.92 g (61%) of a yellow oil is obtained.
Reaction SMILES: Cl[P:2]1[O:7][CH2:6][C:5]([CH3:9])([CH3:8])[CH2:4][O:3]1.[C:10]([C:14]1[CH:19]=[C:18]([C:20](C)(C)C)[CH:17]=[C:16]([C:24]2[CH2:29][CH2:28][CH2:27][CH2:26][CH:25]=2)[C:15]=1[OH:30])([CH3:13])([CH3:12])[CH3:11].C(N(CC)CC)C>C1(C)C=C(C)C=C(C)C=1>[C:24]1([C:16]2[C:15]([O:30][P:2]3[O:7][CH2:6][C:5]([CH3:9])([CH3:8])[CH2:4][O:3]3)=[C:14]([C:10]([CH3:12])([CH3:11])[CH3:13])[CH:19]=[C:18]([CH3:20])[CH:17]=2)[CH2:29][CH2:28][CH2:27][CH2:26][CH:25]=1
Reactant: CC1(C)COP(Cl)OC1
Reactant: CC(C)(C)c1cc(C2=CCCCC2)c(O)c(C(C)(C)C)c1
Solvent: CCN(CC)CC
Solvent: Cc1cc(C)cc(C)c1
Product: Cc1cc(C2=CCCCC2)c(OP2OCC(C)(C)CO2)c(C(C)(C)C)c1
Yield: 57.1 %

Procedure:
4.85 g (29.0 mmol) of 2-chloro-5,5-dimethyl-1,3,2-dioxaphosphorinane are added drop-wise over a period of about 15 minutes to a solution of 6.6 g (27.0 mmol) of 6-(cyclohexen-1-yl)-2-tert-butyl-4-methylphenol (compound (102), Example 1) and 4.0 ml (29.0 mmol) of triethylamine in 25 ml of mesitylene (1,3,5-trimethylbenzene). The reaction mixture is then refluxed for 18 hours, cooled, filtered, and the filtrate is concentrated on a vacuum rotary evaporator. Crystallization of the residue from dry acetonitrile gives 5.8 g (57%) of 2-[6-(cyclohexen-1-yl)-2-tert-butyl-4-methyl-phenoxy]-5,5-dimethyl-1,3,2-dioxaphosphorinane, m.p. 97°-102° C. (compound (201), Table 2).
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[C:10]([CH3:12])([CH3:11])[S:9][CH2:8][CH2:7][N:6]1[S:13]([C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=1)(=[O:15])=[O:14])=[O:4].[O:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH:24]1[O:29][CH2:30][CH2:31][CH2:32][C:33]#[C:34][CH2:35]O>>[CH3:1][O:2][C:3]([CH:5]1[C:10]([CH3:12])([CH3:11])[S:9][CH2:8][CH2:7][N:6]1[S:13]([C:16]1[CH:17]=[CH:18][C:19]([O:22][CH2:35][C:34]#[C:33][CH2:32][CH2:31][CH2:30][O:29][CH:24]2[CH2:25][CH2:26][CH2:27][CH2:28][O:23]2)=[CH:20][CH:21]=1)(=[O:15])=[O:14])=[O:4]
Reactant: OCC#CCCCOC1CCCCO1
Reactant: COC(=O)C1N(S(=O)(=O)c2ccc(O)cc2)CCSC1(C)C
Product: COC(=O)C1N(S(=O)(=O)c2ccc(OCC#CCCCOC3CCCCO3)cc2)CCSC1(C)C
Yield: 64.4 %

Procedure:
According to the procedure of Step 4 of Example 243, Mitsunobu coupling of 3.4 g (9.842 mmol) of 4-(4-hydroxy-benzenesulfonyl)-2,2-dimethyl-thiomorpholine-3-carboxylic acid methyl ester and 2.34 g (11.81 mmol) of 6-(tetrahydro-2H-pyran-2-yloxy)-2-hexyn-1-ol provided 3.33g (64%) of methyl-2,2-dimethyl4-[(4-{[6-(tetrahydro-2H-pyran-2-yloxy)-2-hexynyl]oxy}phenyl)sulfonyl]-3-thiomorpholine carboxylate as a colorless oil. Electrospray Mass Spec: 526.3 (M+H)+
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[CH:5][N:6]=1.Cl[C:8]1[N:9]=[C:10]([NH:21][CH2:22][C:23]2[CH:28]=[CH:27][C:26]3[O:29][CH2:30][CH2:31][O:32][C:25]=3[CH:24]=2)[C:11]2[C:16]3[CH2:17][CH2:18][CH2:19][CH2:20][C:15]=3[S:14][C:12]=2[N:13]=1>>[CH3:1][C:2]1[N:3]([C:8]2[N:9]=[C:10]([NH:21][CH2:22][C:23]3[CH:28]=[CH:27][C:26]4[O:29][CH2:30][CH2:31][O:32][C:25]=4[CH:24]=3)[C:11]3[C:16]4[CH2:17][CH2:18][CH2:19][CH2:20][C:15]=4[S:14][C:12]=3[N:13]=2)[CH:4]=[CH:5][N:6]=1
Reactant: Cc1ncc[nH]1
Reactant: Clc1nc(NCc2ccc3c(c2)OCCO3)c2c3c(sc2n1)CCCC3
Product: Cc1nccn1-c1nc(NCc2ccc3c(c2)OCCO3)c2c3c(sc2n1)CCCC3

Procedure:
Following the procedure of Example 97, the reaction of 2-methylimidazole with 2-chloro-5,6,7,8-tetrahydro-4-(3,4-ethylendioxybenzylamino)-[1]-benzothieno-[2,3-d]-pyrimidine gives 2-(2-methylimidazol-1-yl)-5,6,7,8-tetrahydro-4-(3,4-ethylendioxybenzylamino)-[1]-benzothieno-[2,3-d]-pyrimidine.
Reaction SMILES: [C:1]([Si:5]([CH3:12])([CH3:11])[O:6][CH2:7][C@@H:8]1[CH2:10][O:9]1)([CH3:4])([CH3:3])[CH3:2].[NH2:13][C:14]1[CH:15]=[CH:16][C:17]2[S:22][CH2:21][C:20](=[O:23])[NH:19][C:18]=2[CH:24]=1>CC#N>[C:1]([Si:5]([CH3:12])([CH3:11])[O:6][CH2:7][C@@H:8]([OH:9])[CH2:10][NH:13][C:14]1[CH:15]=[CH:16][C:17]2[S:22][CH2:21][C:20](=[O:23])[NH:19][C:18]=2[CH:24]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OC[C@@H]1CO1
Reactant: Nc1ccc2c(c1)NC(=O)CS2
Solvent: CC#N
Product: CC(C)(C)[Si](C)(C)OC[C@@H](O)CNc1ccc2c(c1)NC(=O)CS2
Temperature: 50 °C
Reaction time: 6 h
Yield: 47.3 %

Procedure:
To a solution of tert-butyl-dimethyl-((S)-1-oxiranylmethoxy)-silane (commercial; 13.0 g, 69 mmol) in MeCN (220 mL) was added LiClO4 (22 g, 207 mmol). 6-amino-4H-benzo[1,4]thiazin-3-one (commercial; 11.45 g, 64 mmol) was added and the mixture was stirred at 50° C. for 6 h. The solvent was removed in vacuo and the residue was purified by CC (DCM/MeOH/NH4OH 1000:25:2 to 1000:100:2) to afford the title compound as a pale brown foam (11.16 g, 44% yield).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]1[CH:14]=[CH:13][CH:12]=[CH:11]1)([OH:3])=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.ClN1C(=O)CCC1=O.[Cl:42][C:43]1[CH:64]=[C:63]([NH2:65])[CH:62]=[CH:61][C:44]=1[C:45]([N:47]1[C:53]2[CH:54]=[CH:55][CH:56]=[CH:57][C:52]=2[CH2:51][N:50]2[CH:58]=[CH:59][CH:60]=[C:49]2[CH2:48]1)=[O:46].C(N(CC)CC)C>ClCCl.O1CCCC1.ClCCl>[Cl:42][C:43]1[CH:64]=[C:63]([NH:65][C:1](=[O:3])[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[N:10]2[CH:14]=[CH:13][CH:12]=[CH:11]2)[CH:62]=[CH:61][C:44]=1[C:45]([N:47]1[C:53]2[CH:54]=[CH:55][CH:56]=[CH:57][C:52]=2[CH2:51][N:50]2[CH:58]=[CH:59][CH:60]=[C:49]2[CH2:48]1)=[O:46]
Reactant: Nc1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)c(Cl)c1
Reactant: O=C(O)c1ccccc1-n1cccc1
Agent: O=C1CCC(=O)N1Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: C1CCOC1
Product: O=C(Nc1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)c(Cl)c1)c1ccccc1-n1cccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 53.3 %

Procedure:
A solution of 1-(2-carboxyphenyl)pyrrole (188 mg, 1 mmol) and triphenylphosphine (264 mg, 1 mmol) in dichloromethane (6 ml) was cooled to 0° C. To this solution was added, portionwise, N-chlorosuccinimide (131 mg, 0.9 mmol). The solution was stirred for 30 minutes and allowed to warm to room temperature. To this solution was added a solution of 10,11-dihydro-10-(2-chloro-4-aminobenzoyl)-5H-pyrrolo[2,1-c][1,4]benzodiazepine (338 mg, 1 mmol) and triethylamine (0.15 ml, 1.06 mmol) in 15 ml of a mixture of a tetrahydrofuran-dichloromethane (1:2). The reaction was stirred for two hours at room temperature and then was concentrated to a solid in vacuo. The solid was disolved in ether (100 ml) and filtered. The filtrate was concentrated in vacuo and chromatographed over silica gel with ethyl acetate-hexane (1:1) as the mobile phase to afford 270 mg of the product as a yellow solid. Recrystallization from ethyl acetate-ether-hexane gave 180 mg of the product as a colorless solid. MS (EI),m/z 506/508 (M+).
Reaction SMILES: [CH:1](=O)[C:2]1[C:3]([O:8][CH3:9])=[CH:4][CH:5]=[CH:6][CH:7]=1.C(S)CCS.S1CCCCS1.[Li]CCCC.[C:27](OC)(=[O:36])[CH:28]=[CH:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.CN1CCN(C)C1=O>C(Cl)Cl>[CH3:9][O:8][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:2]=1[CH2:1][CH:29]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH2:28][C:27]2=[O:36]
Reactant: COc1ccccc1C=O
Reactant: COC(=O)C=Cc1ccccc1
Agent: C1CCSSC1
Agent: SCCCS
Agent: [Li]CCCC
Solvent: CN1CCN(C)C1=O
Solvent: ClCCl
Product: COc1cccc2c1CC(c1ccccc1)CC2=O

Procedure:
o- Anisaldehyde (20.5 g) was treated with 1,3-propanedithiol (24 ml) in the presence of BF. etherate (4 ml) and CH2Cl2 (300 ml). This dithiane derivative (4.7 g) was reacted with n-BuLi (2.5 M hexane solution) (7.3 ml), methyl cinnamate (3.4 g) and 1,3-dimethyl-2-imidazolidone (4.6 ml) affording the desired product (M+H)+ 389. Desulfurization was accomplished with Raney Nickel and EtOH, followed by hydrolysis to the desired carboxylic acid. Cyclization to the desired 5-methoxy-3-phenyl-1-tetralone was accomplished by heating with polyphosphoric acid, (M+H)+ 253.
Reaction SMILES: [C:1]1([B:7]([CH:9]([O:16][CH:17]([B:24]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[OH:25])[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[OH:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:32][NH:33][CH:34](O)[CH3:35]>C(O)C>[C:1]1([B:7]([CH:9]([O:16][CH:17]([B:24]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[O:25][CH2:35][CH2:34][NH:33][CH3:32])[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[O:8][CH2:35][CH2:34][NH:33][CH3:32])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CNC(C)O
Reactant: OB(c1ccccc1)C(OC(B(O)c1ccccc1)c1ccccc1)c1ccccc1
Solvent: CCO
Product: CNCCOB(c1ccccc1)C(OC(B(OCCNC)c1ccccc1)c1ccccc1)c1ccccc1

Procedure:
The entitled compound (8 mg) was obtained by allowing 20 mg of bis(4,4′-(phenylhydroxyboryl)benzyl) ether and 7.3 mg of N-methylaminoethanol to act in 0.7 mL of ethanol at room temperature.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].I[C:8]1[CH:13]=[CH:12][C:11]([Br:14])=[CH:10][CH:9]=1.[O:15]1[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[CH:17]=[C:16]1B(O)O>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.C1(C)C=CC=CC=1>[Br:14][C:11]1[CH:10]=[C:9]([C:16]2[O:15][C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=3[CH:17]=2)[CH:8]=[CH:13][CH:12]=1
Reactant: Brc1ccc(I)cc1
Reactant: OB(O)c1cc2ccccc2o1
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: Cc1ccccc1
Product: Brc1cccc(-c2cc3ccccc3o2)c1

Procedure:
Under an argon atmosphere, 300 mL of toluene and 150 mL of a 2-M aqueous solution of sodium carbonate were added to 28.3 g (100 mmol) of 4-iodobromobenzene, 17.0 g (105 mmol) of benzofuran-2-boronic acid, and 2.31 g (2.00 mmol) of tetrakis(triphenylphosphine)palladium(0), and the mixture was refluxed under heat for 10 hours.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=O)[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:5][CH:4]=1.COC(OC)[N:20]([CH3:22])C.Cl.[C:26]([NH:30]N)([CH3:29])([CH3:28])[CH3:27]>C1(C)C=CC=CC=1>[C:26]([N:30]1[C:9]([C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)=[C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:22]=[N:20]1)([CH3:29])([CH3:28])[CH3:27]
Reactant: COC(OC)N(C)C
Reactant: CCOC(=O)CC(=O)c1ccc(OC)cc1
Reactant: CC(C)(C)NN
Agent: Cl
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cnn(C(C)(C)C)c1-c1ccc(OC)cc1
Temperature: 80 °C
Reaction time: 20 h
Yield: 70.1 %

Procedure:
A solution of ethyl 3-(4-methoxyphenyl)-3-oxopropanoate (3 g, 13.5 mmol) and 1,1-dimethoxy-N,N-dimethylmethanamine (2.152 mL, 16.20 mmol) in toluene (10 ml) was stirred at 90° C. for 14 hr. The reaction mixture was concentrated under reduced pressure, and ethanol (15 mL) was added thereto. To the residue were added tert-butylhydrazine monohydrochloride (1.85 g, 14.85 mmol) and TEA (2.07 mL, 14.85 mmol), and the mixture was stirred at 80° C. for 20 hr. The reaction mixture was concentrated under reduced pressure, and ethyl acetate was added thereto. The organic layer was washed with water and saturated brine and dried, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (solvent gradient; 3→60% ethyl acetate/hexane) to give ethyl 1-tert-butyl-5-(4-methoxyphenyl)-1H-pyrazole-4-carboxylate (2.86 g, 9.46 mmol, 70.1%) as a pale-yellow powder.
Reaction SMILES: [Cl:1][CH:2]([CH3:17])[C:3]([C:5]1[C:6]([CH:14]([CH3:16])[CH3:15])=[N:7][N:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=12)=[O:4].C([N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1)(OC(C)(C)C)=O.[Na+].[I-]>CO>[ClH:1].[CH:14]([C:6]1[C:5]([C:3](=[O:4])[CH:2]([N:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[CH3:17])=[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][N:8]2[N:7]=1)([CH3:16])[CH3:15]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: CC(Cl)C(=O)c1c(C(C)C)nn2ccccc12
Agent: [I-]
Agent: [Na+]
Solvent: CO
Product: CC(C)c1nn2ccccc2c1C(=O)C(C)N1CCNCC1
Product: Cl
Temperature: 60 °C
Reaction time: 5 h
Yield: 11.4 %

Procedure:
A mixture of 980 mg (3.90 mmol) of 2-chloro-1-(2-isopropylpyrazolo[1,5-a]pyridin-3-yl)propan-1-one, 1.45 g (4 mmol) of N-Boc-piperazine and 100 mg of NaI in 10 ml of MeOH was stirred at 50-70° C. for 5 hours. The residue obtained after evaporation of the solvent was purified on an Al2O3 column. The fractions containing purified product were titrated with 4N HCl-dioxane to obtain a precipitate. Recrystallization from isopropanol/ether produced 150 mg of 1-(2-isopropylpyrazolo[1,5-a]pyridin-3-yl)-2-(piperazin-1-yl)propan-1-one hydrochloride. Compound 1037.
Reaction SMILES: [CH:1]([O:4][C:5]([N:7]1[CH2:12][CH2:11][CH:10]([O:13][C:14]2[C:19]([CH3:20])=[C:18](Cl)[N:17]=[CH:16][N:15]=2)[CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2].[F:22][C:23]1[CH:28]=[C:27]([CH2:29][CH2:30][N:31]2[CH2:36][CH2:35][O:34][CH2:33][CH2:32]2)[CH:26]=[CH:25][C:24]=1[OH:37].C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[CH:1]([O:4][C:5]([N:7]1[CH2:12][CH2:11][CH:10]([O:13][C:14]2[C:19]([CH3:20])=[C:18]([O:37][C:24]3[CH:25]=[CH:26][C:27]([CH2:29][CH2:30][N:31]4[CH2:36][CH2:35][O:34][CH2:33][CH2:32]4)=[CH:28][C:23]=3[F:22])[N:17]=[CH:16][N:15]=2)[CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2]
Reactant: Cc1c(Cl)ncnc1OC1CCN(C(=O)OC(C)C)CC1
Reactant: Oc1ccc(CCN2CCOCC2)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1c(Oc2ccc(CCN3CCOCC3)cc2F)ncnc1OC1CCN(C(=O)OC(C)C)CC1
Temperature: 25 °C

Procedure:
To a solution of 4-(6-chloro-5-methyl-pyrimidin-4-yloxy)-piperidine-1-carboxylic acid isopropyl ester (270 mg, 0.84 mmol) and 2-fluoro-4-(2-morpholin-4-yl-ethyl)-phenol (225 mg, 0.84 mmol) in DMF (5 mL), was K2CO3 (137 mg, 0.84 mmol) added. The reaction mixture was irradiated under microwave for 1 hour at 150° C. The reaction was cooled to room temperature and poured into H2O (50 mL) and extracted with ethyl acetate (50 mL). The ethyl acetate was dried over MgSO4, and concentrated under vacuum and purified over SiO2 to afford Compound C146 (380 mg, 90%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 8.06 (s, 1H), 7.09˜7.02 (m, 1H), 6.93˜6.91 (m, 2H), 5.12 (m, 1H), 4.61 (m, 1H), 3.46˜3.37 (m, 6H), 3.18˜3.13 (m, 2H), 2.61˜2.57 (m,2H), 2.38˜2.26 (m, 2H), 2.25 (b, 2H), 1.96 (s, 3H), 1.79˜1.74 (m, 2H), 1.49˜1.45 (m, 2H), 1.03 (d, 6H). LCMS 503.5 [M+1].
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([O-:13])=[O:12])=[CH:5]2.[C:14]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.O[CH2:46][C@@H:47]1[O:52][CH2:51][CH2:50][N:49]([C:53]([O:55][C:56]([CH3:59])([CH3:58])[CH3:57])=[O:54])[CH2:48]1>C(Cl)Cl>[CH3:57][C:56]([O:55][C:53]([N:49]1[CH2:50][CH2:51][O:52][C@@H:47]([CH2:46][O:1][C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[NH:7][C:6]([C:11]([O:13][CH3:14])=[O:12])=[CH:5]3)[CH2:48]1)=[O:54])([CH3:59])[CH3:58]
Reactant: O=C([O-])c1cc2cc(O)ccc2[nH]1
Reactant: CC(C)(C)OC(=O)N1CCO[C@@H](CO)C1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Solvent: ClCCl
Product: COC(=O)c1cc2cc(OC[C@H]3CN(C(=O)OC(C)(C)C)CCO3)ccc2[nH]1
Yield: 76.8 %

Procedure:
Methyl 5-{[((2R)-4-{[(1,1-dimethylethyl)oxy]carbonyl}-2-morpholinyl)methyl]oxy}-1H-indole-2-carboxylate was prepared in a similar manner as described herein from 5-hydroxy-1H-indole-2-carboxylate (0.10 g, 0.5 mmol), triphenylphosphine (0.28 g, 1.0 mmol), diethyl azodicarboxylate (0.18 g, 1.0 mmol), 1,1-dimethylethyl (2R)-2-(hydroxymethyl)-4-morpholinecarboxylate (0.23 g, 1.0 mmol) and CH2Cl2 (5 mL). The crude material was purified by Reverse-Phase HPLC (water/acetonitrile with 0.1% TFA). The desired fractions were neutralized and extracted with EtOAc. The organic extracts were combined, dried over Na2SO4, filtered and evaporated to afford the title compound (0.15 g, 73%) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ ppm 11.76 (s, 1H), 7.30 (d, 1H), 7.08 (d, 1H), 7.00 (d, 1H), 6.89 (dd, 1H), 3.94 (d, 2H), 3.81 (s, 3H), 3.78-3.92 (m, 2H), 3.59-3.73 (m, 2H), 3.35-3.46 (m, 1H), 2.76-2.97 (m, 2H), 1.36 (s, 9H)MS: m/z 391.2 (M+1).
Reaction SMILES: C([O:8][C:9]([NH:11][C:12]1[CH:13]=[CH:14][C:15]([N:19]2[CH2:24][CH2:23][N:22]([CH2:25][CH3:26])[C:21](=[O:27])[CH2:20]2)=[C:16]([F:18])[CH:17]=1)=[O:10])C1C=CC=CC=1.C([Li])CCC.[CH2:33](OC(=O)CCC)[C@@H:34]1[O:36][CH2:35]1.C(=O)(O)[O-].[Na+]>C1COCC1.C(OCC)(=O)C.CN1CCCN(C)C1=O>[F:18][C:16]1[CH:17]=[C:12]([N:11]2[CH2:33][C@H:34]([CH2:35][OH:36])[O:8][C:9]2=[O:10])[CH:13]=[CH:14][C:15]=1[N:19]1[CH2:24][CH2:23][N:22]([CH2:25][CH3:26])[C:21](=[O:27])[CH2:20]1
Reactant: CCN1CCN(c2ccc(NC(=O)OCc3ccccc3)cc2F)CC1=O
Reactant: CCCC(=O)OC[C@H]1CO1
Agent: O=C([O-])O
Agent: [Li]CCCC
Agent: [Na+]
Solvent: CN1CCCN(C)C1=O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCN1CCN(c2ccc(N3C[C@H](CO)OC3=O)cc2F)CC1=O
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
5-Benzyloxycarbonylamino-2-(4-ethyl-3-oxopiperazin-1-yl)fluorobenzene (3.25 g) was dissolved in dry THF (100 ml) under argon. The solution was cooled to -78° C., and treated with a solution of n-butyllithium (1.6 M in hexane, 6.02 ml), keeping the temperature below -60° C. 1,3-Dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidone (DMPU, 10 ml) was added to the resulting mixture to facilitate stirring, and (R)-glycidylbutyrate (1.29 ml) added. Stirring was continued at -78° C. for 30 minutes, before allowing the temperature to rise to ambient over 16 hours. Sodium bicarbonate solution (50 ml) was added, followed by sufficient ethyl acetate to form two layers. The organic layer was separated, washed twice with water, dried (MgSO4) and evaporated. The residue was chromatographed on silica, using as eluant a gradient increasing in polarity from 0 to 6% methanol in dichloromethane. Relevant fractions were combined and evaporated to give (5R)-3-(3-fluoro-4-{4-ethyl-3-oxopiperazine-1-yl}phenyl)-5-hydroxymethyloxazolidin-2-one (990 mg).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[C:4]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:8][CH:7]=1)=[O:5].[CH:19](OCC)(OCC)[O:20]CC.S(=O)(=O)(O)O.[C:34](=O)(O)[O-].[Na+]>CO>[CH3:1][O:2][C:3](=[O:18])[C:4]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:8][CH:7]=1)([O:20][CH3:19])[O:5][CH3:34]
Reactant: COC(=O)C(=O)c1ccc(-c2ccccc2)cc1
Reactant: CCOC(OCC)OCC
Reactant: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Product: COC(=O)C(OC)(OC)c1ccc(-c2ccccc2)cc1

Procedure:
A mixture of biphenyl-4-yl-oxo-acetic acid methyl ester (A. T. Jeffries, et al., J. Org. Chem., 46, 2885(1981)) (10 g), triethyl orthoformate (43 ml), methanol (60 ml) and conc. sulfuric acid (3 ml) was heated under reflux for 8.5 hours under a nitrogen atmosphere. The resulting mixture was poured into a saturated aqueous sodium bicarbonate solution and the resulting mixture was subjected to extraction with diethyl ether. The organic layer was washed with a saturated aqueous sodium chloride solution, then dried over sodium sulfate and thereafter concentrated under reduced pressure, to obtain the desired compound (10.5 g).