Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:12]=[CH:11][C:8]([CH2:9][NH2:10])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[Cl:19][CH2:20][C:21](Cl)=[O:22].O>ClCCl>[Cl:19][CH2:20][C:21]([NH:10][CH2:9][C:8]1[CH:7]=[CH:6][C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])=[CH:12][CH:11]=1)=[O:22]
Reactant: O=C(Cl)CCl
Reactant: CC(C)(C)c1ccc(CN)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)c1ccc(CNC(=O)CCl)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension of commercially available 4-tert-butylbenzylamine (8.16 g, 50 mmol) and potassium carbonate (7.95 g, 57.5 mmol) in dichloromethane (100 ml) was added drop wise a solution of 2-chloroacetyl chloride (6.21 g, 55 mmol) in dichloromethane (25 ml) at room temperature. After stirring the reaction mixture at room temperature for 30 min, the reaction mixture was refluxed for 4 h. The reaction mixture was cooled and water (100 ml) was added. The phases were separated and the organic phase was dried over MgSO4 and evaporated in vacuo. The title compound was obtained as a white crystalline material which was used in the next step without any further purification.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([S:7](Cl)(=[O:9])=[O:8])[CH2:3][CH2:2]1.[NH2:11][C:12]1[C:21]([C:22]([NH:24][C:25]2[CH:26]=[N:27][CH:28]=[C:29]([F:37])[C:30]=2[N:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)=[O:23])=[C:15]2[N:16]=[CH:17][C:18]([F:20])=[CH:19][N:14]2[N:13]=1.CCN(CC)CC>CN(C=O)C>[NH2:11][C:12]1[C:21]([C:22]([NH:24][C:25]2[CH:26]=[N:27][CH:28]=[C:29]([F:37])[C:30]=2[N:31]2[CH2:36][CH2:35][N:34]([S:7]([CH:4]3[CH2:5][CH2:6][O:1][CH2:2][CH2:3]3)(=[O:9])=[O:8])[CH2:33][CH2:32]2)=[O:23])=[C:15]2[N:16]=[CH:17][C:18]([F:20])=[CH:19][N:14]2[N:13]=1
Reactant: Nc1nn2cc(F)cnc2c1C(=O)Nc1cncc(F)c1N1CCNCC1
Reactant: O=S(=O)(Cl)C1CCOCC1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Nc1nn2cc(F)cnc2c1C(=O)Nc1cncc(F)c1N1CCN(S(=O)(=O)C2CCOCC2)CC1

Procedure:
Tetrahydropyran-4-sulfonyl chloride (16.28 mg, 0.08815 mmol) was added to a suspension of 2-amino-6-fluoro-N-(5-fluoro-4-piperazin-1-yl-3-pyridyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide (30 mg, 0.08014 mmol) (synthesized according to the procedure similar to Example 2) and Et3N (12.16 mg, 16.75 μL, 0.1202 mmol) in DMF (0.2 mL). The crude mixture was purified by Fractionlynx HPLC. The clean aqueous fractions were combined and lyophilised, yielding 2-amino-6-fluoro-N-(5-fluoro-4-(4-((tetrahydro-2H-pyran-4-yl)sulfonyl)piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide. MS (ES+) 523.1.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([O:12][Si:13]([CH:20]([CH3:22])[CH3:21])([CH:17]([CH3:19])[CH3:18])[CH:14]([CH3:16])[CH3:15])[CH:11]=1)[N:8]=[C:7]([CH3:23])[CH:6]=[CH:5]2.[Se](=O)=[O:25]>O1CCOCC1.O>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([O:12][Si:13]([CH:20]([CH3:22])[CH3:21])([CH:17]([CH3:19])[CH3:18])[CH:14]([CH3:15])[CH3:16])[CH:11]=1)[N:8]=[C:7]([CH:23]=[O:25])[CH:6]=[CH:5]2
Reactant: Cc1ccc2cc(F)cc(O[Si](C(C)C)(C(C)C)C(C)C)c2n1
Reactant: O=[Se]=O
Solvent: O
Solvent: C1COCCO1
Product: CC(C)[Si](Oc1cc(F)cc2ccc(C=O)nc12)(C(C)C)C(C)C

Procedure:
6-Fluoro-2-methyl-8-(triisopropylsilyloxy)quinoline (1.76 g, 5.29 mmol) was dissolved in dioxane (58 mL) and water (0.49 mL). The reaction was treated with selenium dioxide (0.76 g, 6.8 mmol) and the mixture was heated to reflux for 13 hours. The mixture was cooled and filtered through GF/F paper. The filtered solids were washed with Et2O then all the filtrates were concentrated in vacuo. The crude mixture was chromatographed on silica gel, eluting with a gradient of 1-5% Et2O/hexanes, (0.515 g). 1H NMR (400 MHz, CDCl3) δ 10.19 (s, 1H), 8.18 (d, J =8.7 Hz, 1H), 8.01 (d, J=8.4 Hz, 1H), 7.14-7.08 (m, 1H), 7.06-7.00 (m, 1H), 1.52-1.41 (m, 3H), 1.16 (d, 18H).
Reaction SMILES: [Cl:1][C:2]1[C:7]2[CH:8]=[C:9]([C:11]([O:13][CH3:14])=[O:12])[NH:10][C:6]=2[CH:5]=[CH:4][N:3]=1.[C:15]([O:19][C:20]1[CH:29]=[CH:28][C:23]([O:24][CH2:25][CH2:26]O)=[CH:22][CH:21]=1)([CH3:18])([CH3:17])[CH3:16].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1(C)C=CC=CC=1>[C:15]([O:19][C:20]1[CH:21]=[CH:22][C:23]([O:24][CH2:25][CH2:26][N:10]2[C:6]3[CH:5]=[CH:4][N:3]=[C:2]([Cl:1])[C:7]=3[CH:8]=[C:9]2[C:11]([O:13][CH3:14])=[O:12])=[CH:28][CH:29]=1)([CH3:17])([CH3:16])[CH3:18]
Reactant: COC(=O)c1cc2c(Cl)nccc2[nH]1
Reactant: CC(C)(C)Oc1ccc(OCCO)cc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: COC(=O)c1cc2c(Cl)nccc2n1CCOc1ccc(OC(C)(C)C)cc1
Yield: 104.6 %

Procedure:
Methyl 4-chloro-1H-pyrrolo[3,2-c]pyridine-2-carboxylate (500 mg, 2.374 mmole), 2-(4-tert-butoxyphenoxy)ethanol (624 mg, 2.97 mmole), and PPh3 (778 mg, 2.97 mmole) were combined in toluene (10 mL) at RT. To this was added DIAD (0.58 mL, 2.98 mmole) slowly at RT. After 3 hr the mixture was concentrated. Flash column chromatography (Biotage-SNAP-50 g SiO2, 0-25% EtOAc/hexanes) gave the title compound (1.0 g, 105%) as a white solid. 1H NMR (400 MHz, CDCl3): δ 8.18 (d, J=6.0 Hz, 1 H); 7.44 (d, J=1.0 Hz, 1 H); 7.43-7.38 (m, 1 H); 6.85-6.81 (m, 2 H); 6.64-6.60 (m, 2 H); 4.92 (t, J=5.0 Hz, 2 H); 4.31 (t, J=5.0 Hz, 2 H); 3.95 (s, 3H); 1.26 (s, 9 H).
Reaction SMILES: [C:1]([C:5]1[C:6]([O:23]S(C2C=CC(C)=CC=2)(=O)=O)=[N:7][N:8]2[C:13]=1[C:12]([CH3:14])=[N:11][N:10]=[C:9]2[C:15]1[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:16]=1[F:22])([CH3:4])([CH3:3])[CH3:2].[CH2:34]([N:36]1[C:40]([CH2:41]O)=[N:39][CH:38]=[N:37]1)[CH3:35].[H-].[Na+].O>CN(C=O)C>[C:1]([C:5]1[C:6]([O:23][CH2:41][C:40]2[N:36]([CH2:34][CH3:35])[N:37]=[CH:38][N:39]=2)=[N:7][N:8]2[C:13]=1[C:12]([CH3:14])=[N:11][N:10]=[C:9]2[C:15]1[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:16]=1[F:22])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCn1ncnc1CO
Reactant: Cc1ccc(S(=O)(=O)Oc2nn3c(-c4cc(F)ccc4F)nnc(C)c3c2C(C)(C)C)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCn1ncnc1COc1nn2c(-c3cc(F)ccc3F)nnc(C)c2c1C(C)(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To toluene-4-sulfonic acid 3-tert-butyl-7-(2,5-difluorophenyl)-4-methylpyrazolo[1,5-d][1,2,4]triazin-2-yl ester (0.3 g, 0.636 mmol) and (2-ethyl-2H-[1,2,4]triazol-3-yl)methanol (97.3 mg, 1.2 molar eq; prepared as described in EP-A-170073) in DMF (10 ml) was added sodium hydride (30 mg of a 60% dispersion in mineral oil; 1.2 molar eq) and the mixture was stirred at room temperature for 1 h. Water (150 ml) was added then the solution was extracted with diethyl ether (4×50 ml). The combined ether layers were washed with brine (1×100 ml), dried (Na2SO4), the solvent was removed in vacuo and the residue was purified by flash chromatography on silica gel eluting with 0 to 50% ethyl acetate in dichloromethane. 3-tert-Butyl-7-(2,5-difluorophenyl)-2-(2-ethyl-2H-[1,2,4]triazol-3-ylmethoxy)-4-methylpyrazolo[1,5-d][1,2,4]triazine was isolated as a gum, which solidified upon trituration under diethyl ether/isohexane (10 mg, mp=109° C.). 1H NMR (360 MHz, CDCl3) δ 1.40 (3H, t, J=7.3 Hz), 1.55 (9H, s), 3.08 (3H, s), 4.14 (2H, q, J=7.3 Hz), 5.48 (2H, s), 7.18-7.41 (3H, m), 7.88 (1H, s); MS (ES+) m/e 428 [MH]+.
Reaction SMILES: [NH2:1][CH:2]([C:11]1[C:16]([O:17][CH3:18])=[CH:15][CH:14]=[CH:13][C:12]=1[O:19][CH3:20])[CH2:3][CH:4]([CH3:10])[C:5]([O:7]CC)=O.[CH3:21][C:22]1[O:26][N:25]=[C:24]([C:27]2[CH:28]=[C:29]([CH:32]=[CH:33][CH:34]=2)[CH:30]=O)[N:23]=1>>[CH3:18][O:17][C:16]1[CH:15]=[CH:14][CH:13]=[C:12]([O:19][CH3:20])[C:11]=1[CH:2]1[N:1]([CH2:30][C:29]2[CH:32]=[CH:33][CH:34]=[C:27]([C:24]3[N:23]=[C:22]([CH3:21])[O:26][N:25]=3)[CH:28]=2)[C:5](=[O:7])[CH:4]([CH3:10])[CH2:3]1
Reactant: CCOC(=O)C(C)CC(N)c1c(OC)cccc1OC
Reactant: Cc1nc(-c2cccc(C=O)c2)no1
Product: COc1cccc(OC)c1C1CC(C)C(=O)N1Cc1cccc(-c2noc(C)n2)c1

Procedure:
Prepared according to the described general procedure 2 (GP2) by reaction of ethyl 4-amino-4-(2,6-dimethoxyphenyl)-2-methylbutanoate with commercially available 3-(5-methyl-1,2,4-oxadiazol-3-yl)benzaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.82 min.; [M+H]+: 408.01 g/mol.
Reaction SMILES: [OH:1][CH:2]([CH3:10])/[CH:3]=[CH:4]/[C:5]([O:7][CH2:8][CH3:9])=[O:6].[CH2:11]([N:18]=[C:19]=[O:20])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C1(C)C=CC=CC=1>[CH2:11]([NH:18][C:19]([O:1][CH:2]([CH3:10])/[CH:3]=[CH:4]/[C:5]([O:7][CH2:8][CH3:9])=[O:6])=[O:20])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C=NCc1ccccc1
Reactant: CCOC(=O)/C=C/C(C)O
Solvent: Cc1ccccc1
Product: CCOC(=O)/C=C/C(C)OC(=O)NCc1ccccc1

Procedure:
Reaction of 21 (rac-Ethyl (2E)-4-hydroxypent-2-enoate) (1.44 g, 10 mmol) with benzyl isocyanate (1.73 g, 13 mmol) in toluene (8 ml) according to Example 1. Purification by flash chromatography (AcOiPr:heptane fraction 25:75) yields 3 (rac-Ethyl (2E)-4-(benzylaminocarbonyloxy)pent-2-enoate) (2.49 g, 90%) as a with solid.
Reaction SMILES: C(O)(C(F)(F)F)=O.[F:8][C:9]1[C:10]([CH:23]2[CH2:28][CH2:27][N:26]([CH:29]3[CH2:32][O:31][CH2:30]3)[CH2:25][CH2:24]2)=[C:11]([NH:15]C(=O)OC(C)(C)C)[CH:12]=[N:13][CH:14]=1>C(Cl)Cl>[F:8][C:9]1[C:10]([CH:23]2[CH2:28][CH2:27][N:26]([CH:29]3[CH2:32][O:31][CH2:30]3)[CH2:25][CH2:24]2)=[C:11]([NH2:15])[CH:12]=[N:13][CH:14]=1
Reactant: CC(C)(C)OC(=O)Nc1cncc(F)c1C1CCN(C2COC2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Nc1cncc(F)c1C1CCN(C2COC2)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 87.6 %

Procedure:
TFA (1 mL, 12.98 mmol) was added to a stirred solution of tert-butyl N-[5-fluoro-4-[1-(oxetan-3-yl)-4-piperidyl]-3-pyridyl]carbamate (174 mg, 0.4951 mmol) in DCM (5 mL) and the reaction stirred at ambient temperature for 4 hours. The solvent was removed in vacuo and the residue azeotroped with DCM (×2) and ether (×2). The residue was passed through a 5 g SCX-2 cartridge and washed with MeOH/DCM mixtures. The product was eluted by washing the cartridge with 2M NH3 in MeOH/DCM mixtures and concentrated in vacuo to give 5-fluoro-4-(1-(oxetan-3-yl)piperidin-4-yl)pyridin-3-amine as a yellow oil (109 mg, 88% Yield). MS (ES+) 252.1.
Reaction SMILES: [SH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].C(=O)([O-])[O-].[K+].[K+].Cl[C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][N:17]=1.O>CN(C)C=O>[Cl:22][C:19]1[CH:20]=[CH:21][C:16]([O:8][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[S:1][C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][N:17]=2)=[N:17][CH:18]=1
Reactant: Clc1ccc(Cl)nc1
Reactant: Oc1ccccc1S
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Clc1ccc(Oc2ccccc2Sc2ccc(Cl)cn2)nc1

Procedure:
To a mixture of 3.0 grams (0.023 mole) of 2-mercaptophenol and 7.0 grams of potassium carbonate stirring in 50 ml of dimethylformamide, 9.0 grams of 2,5-dichloropyridine is added and the stirred mixture heated at 130° overnight. After pouring into excess H2O, the aqueous mixture is extracted with ethyl ether (200 ml) and the extract washed with H2O, saturated NaHCO3, and brine, dried (MgSO4), filtered, and the solvent evaporated to give the crude product which is recrystallized from 1-chlorobutane.
Reaction SMILES: [C:1]1([C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=2)[CH:6]=[CH:5][C:4]([C@@:7]2([S:45][CH2:46][CH2:47][CH2:48][CH3:49])[CH2:11][N:10]([C:12](=[O:31])[C@@H:13]([NH:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C:14](C)(C)[CH2:15][CH2:16][CH2:17][CH2:18]C=C)[C@H:9]([C:32]([NH:34][C@:35]3([C:40]([O:42][CH2:43][CH3:44])=[O:41])[CH2:37][C@H:36]3[CH:38]=[CH2:39])=[O:33])[CH2:8]2)=[CH:3][CH:2]=1.SC1N=CC=CC=1C(O)=O>ClCCl.CC1C=C(C)C(N2C(=[Ru](Cl)(Cl)=CC3C=CC=CC=3OC(C)C)N(C3C(C)=CC(C)=CC=3C)CC2)=C(C)C=1>[C:1]1([C:50]2[CH:51]=[CH:52][CH:53]=[CH:54][CH:55]=2)[CH:2]=[CH:3][C:4]([C@@:7]2([S:45][CH2:46][CH2:47][CH2:48][CH3:49])[CH2:11][N:10]3[C:12](=[O:31])[C@@H:13]([NH:23][C:24]([O:26][C:27]([CH3:30])([CH3:28])[CH3:29])=[O:25])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH:39]=[CH:38][C@@H:36]4[CH2:37][C@@:35]4([C:40]([O:42][CH2:43][CH3:44])=[O:41])[NH:34][C:32](=[O:33])[C@@H:9]3[CH2:8]2)=[CH:5][CH:6]=1
Reactant: C=CCCCCC(C)(C)[C@H](NC(=O)OC(C)(C)C)C(=O)N1C[C@](SCCCC)(c2ccc(-c3ccccc3)cc2)C[C@H]1C(=O)N[C@]1(C(=O)OCC)C[C@H]1C=C
Agent: Cc1cc(C)c(N2CCN(c3c(C)cc(C)cc3C)C2=[Ru](Cl)(Cl)=Cc2ccccc2OC(C)C)c(C)c1
Agent: CCCCS[C@@]1(c2ccc(-c3ccccc3)cc2)C[C@H]2C(=O)N[C@]3(C(=O)OCC)C[C@H]3/C=C\CCCCC[C@H](NC(=O)OC(C)(C)C)C(=O)N2C1
Agent: O=C(O)c1cccnc1S
Solvent: ClCCl
Product: CCCCS[C@@]1(c2ccc(-c3ccccc3)cc2)C[C@H]2C(=O)N[C@]3(C(=O)OCC)C[C@H]3C=CCCCCC[C@H](NC(=O)OC(C)(C)C)C(=O)N2C1

Procedure:
A solution of (1R,2S)-ethyl 1-((2S,4R)-4-(biphenyl-4-yl)-1-((S)-2-(tert-butoxycarbonylamino)-3,3-dimethylnon-8-enoyl)-4-(butylthio)pyrrolidine-2-carboxamido)-2-vinylcyclopropanecarboxylate (75 mg, 0.097 mmol) in dichloromethane (30 mL) was purged with nitrogen for 3 min. And then Hoveyda-Grubbs Catalyst 2nd Generation (73.1 mg, 0.116 mmol) was added. The resulting green solution was heated to reflux for 5 hours. The reaction was quenched with 2-mercaptonicotinic acid (30.1 mg, 0.194 mmol) and washed with saturated Na2CO3, and brine. Dried over MgSO4, filtered, and concentrated in vacuo. The brown residue was purified by BIOTAGE® column, eluted with gradient 5%˜50% ethyl acetate-hexane to afford the desired product (2R,6S,13aS,14aR,16aS,Z)-ethyl 2-(biphenyl-4-yl)-6-(tert-butoxycarbonylamino)-2-(butylthio)-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecine-14a-carboxylate (59 mg, 0.074 mmol, 76% yield) as an off-white solid. 1H NMR (500 MHz, MeOD) δ ppm 0.83 (t, 3 H) 1.14-1.37 (m, 8 H) 1.38-1.54(m, 17 H) 1.52-1.68 (m, 4 H) 1.79-1.95 (m, 1 H) 1.97-2.10 (m, 1 H) 2.25-2.37 (m, 2 H) 2.37-2.49 (m, 2 H) 2.53 (dd, J=12.51, 10.07 Hz, 1 H) 2.88 (dd, J=12.51, 7.02 Hz, 1 H) 3.97-4.08 (m, 2 H) 4.07-4.22 (m, 3 H) 4.50 (dd, J=10.22, 2.90 Hz, 1 H) 5.17 (d, J=10.68 Hz, 1 H) 5.34 (t, J=9.77 Hz, 1 H) 5.56-5.68 (m, 1 H) 7.30-7.41 (m, 1 H) 7.41-7.50 (m, 2 H) 7.60 (d, J=8.24 Hz, 4 H) 7.77 (d, J=8.24 Hz, 2 H). LC-MS (retention time: 3.55 min, method C), MS m/z 718 (M+H).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[C:5](C(OC)=O)[CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH3:16][Mg+].[Br-].CC[O:21][CH2:22][CH3:23]>C1COCC1>[CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[C:5]([C:22]([OH:21])([CH3:23])[CH3:16])[CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: CCOCC
Reactant: COC(=O)c1cccc2ccc(C)nc12
Reactant: C[Mg+]
Agent: [Br-]
Solvent: C1CCOC1
Product: Cc1ccc2cccc(C(C)(C)O)c2n1
Temperature: -15 °C
Reaction time: 0.5 h
Yield: 90 %

Procedure:
To a stirred solution of methyl 2-methylquinoline-8-carboxylate (0.290 g, 1.44 mmol) in THF (1 mL) was added dropwise a solution of MeMgBr in ether (3.0 M, 1.44 mL, 4.32 mmol) at −15° C. under nitrogen. The reaction mixture was stirred at −15° C. for 30 minutes and then quenched by the addition of saturated aqueous NH4Cl solution. The reaction mixture was extracted with EtOAc. The combined organic layers were washed with brine, dried and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (1:1 hexanes/EtOAc) to give 2-(2-methylquinolin-8-yl)propan-2-ol (0.260 g, 90%).
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]2[CH2:8][C@@H:9]3[CH2:21][C@@H:10]3[C:11]=2[N:12]([C:14]2[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][N:15]=2)[N:13]=1)=[O:5])C.[Li+].[OH-].Cl>O1CCOCC1.O>[Cl:20][C:18]1[CH:17]=[CH:16][N:15]=[C:14]([N:12]2[C:11]3[C@H:10]4[CH2:21][C@H:9]4[CH2:8][C:7]=3[C:6]([C:4]([OH:5])=[O:3])=[N:13]2)[CH:19]=1
Reactant: CCOC(=O)c1nn(-c2cc(Cl)ccn2)c2c1C[C@@H]1C[C@H]21
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: O=C(O)c1nn(-c2cc(Cl)ccn2)c2c1C[C@@H]1C[C@H]21
Temperature: 40 °C
Reaction time: 4 h

Procedure:
To a solution of (1aS,5aS)-2-(4-bromo-pyridin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic acid ethyl ester (2.1 g, 6.0 mmol) in acetonitrile (30 mL) was added concentrated HCl (1.4 mL, 18.0 mmol). The reaction was stirred for 6 h at 80° C., and then diluted with H2O. The solid was filtered, washed with H2O, and dried to give (1aS,5aS)-2-(4-chloro-pyridin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic acid ethyl ester (1.7 g) which contained ˜20% of the hydrolyzed acid. The aforementioned ester was dissolved in dioxane (10 mL). After addition of 1 N LiOH (9.0 mL), the reaction was stirred for 4 h at 40° C. The reaction was cooled down to room temperature, diluted with H2O, and acidified with 4 N HCl to form a precipitate. The solid was filtered, washed with H2O, and dried to give the title compound. LCMS m/z=276.1 [M+H]+.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[Cl:11][C:12]1[C:13]([CH3:19])=[C:14]([CH:16]=[CH:17][CH:18]=1)[NH2:15]>>[Cl:11][C:12]1[C:13]([CH3:19])=[C:14]([CH:16]=[CH:17][CH:18]=1)[NH:15][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: Cc1c(N)cccc1Cl
Reactant: O=[N+]([O-])c1cccnc1Cl
Product: Cc1c(Cl)cccc1Nc1ncccc1[N+](=O)[O-]
Temperature: 50 °C
Reaction time: 0.17 h

Procedure:
A mixture of 6.3 g. (0.04 mole) of 2-chloro-3-nitropyridine and 16.9 g. (0.12 mole) of 3-chloro-2-methylaniline was heated in an oil bath to 170° C. when the temperature spontaneously rose to 185° C. After an additional 10 minutes at 180° C., the mixture was cooled to 50° C. and extracted with a solution of 75 ml. of water and 25 ml. of acetic acid. The insolubles were collected, air dried, dissolved in methylene chloride, and the solution was dried over magnesium sulfate. The solution was concentrated to a small volume and diluted with 50 ml. of ether which caused crystallization of 6.6 g. of 2-(3-chloro-2-methylanilino)-3-nitropyridine, m.p. 134°-135° C.
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][C:8]([Cl:12])=[CH:9][CH:10]=2)[C:5](=[O:13])[O:4][C:3]=1[CH:14]([OH:16])[CH3:15].[C:17]1(B(O)O)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[Cl:12][C:8]1[CH:7]=[C:6]2[C:11]([C:2]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[C:3]([CH:14]([OH:16])[CH3:15])[O:4][C:5]2=[O:13])=[CH:10][CH:9]=1
Reactant: CC(O)c1oc(=O)c2cc(Cl)ccc2c1Br
Reactant: OB(O)c1ccccc1
Product: CC(O)c1oc(=O)c2cc(Cl)ccc2c1-c1ccccc1
Yield: 38.9 %

Procedure:
The title compound was made in a similar way of that of Intermediate B53 from 4-bromo-7-chloro-3-(1-hydroxyethyl)-1H-isochromen-1-one (intermediate A5, 1.4 g, 4.61 mmol) and phenylboronic acid (0.844 g, 6.92 mmol) to afford title compound as a yellow foam (0.540 g) which was used without any additional purification.
Reaction SMILES: [CH:1]1([C:4]2[N:9]=[C:8]([S:10]([CH3:13])(=[O:12])=[O:11])[N:7]=[C:6]([C:14]([OH:16])=[O:15])[CH:5]=2)[CH2:3][CH2:2]1.[CH3:17][Si](C=[N+]=[N-])(C)C.C(O)(=O)C>ClCCl.CO>[CH:1]1([C:4]2[N:9]=[C:8]([S:10]([CH3:13])(=[O:11])=[O:12])[N:7]=[C:6]([C:14]([O:16][CH3:17])=[O:15])[CH:5]=2)[CH2:2][CH2:3]1
Reactant: CS(=O)(=O)c1nc(C(=O)O)cc(C2CC2)n1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: CC(=O)O
Solvent: CO
Solvent: ClCCl
Product: COC(=O)c1cc(C2CC2)nc(S(C)(=O)=O)n1
Temperature: 0 °C

Procedure:
A suspension of 6-cyclopropyl-2-(methylsulfonyl)pyrimidine-4-carboxylic acid (200 mg, 0.82 mmol) in dichloromethane (2 mL) and methanol (0.5 mL) was cooled to 0° C. Trimethylsilyl diazomethane (2.0 M in diethyl ether, 1.0 mL, 2.0 mmol) was added dropwise as not to increase the internal temperature of the reaction. Upon complete addition the suspension became a yellow colored solution that was allowed to warm to RT and maintained for 1 h at that temperature. At this time, acetic acid was added dropwise until the mixture was colorless (c.a. 2 drops, 12 M) and the resulting solution was concentrated under vacuum to a residue. The resulting oily yellow solid was dissolved in sparing ice cold acetonitrile (0.5 mL) and allowed to precipitate to furnish an off white waxy solid. MS m/z 257.1 (M+1). 1H NMR (400 MHz, DMSO-d6): δ 8.22 (s, 1H), 3.81 (s, 3H), 3.28 (s, 3H), 2.40-2.36 (m, 1H), 1.20-1.15 (m, 2H), 1.12-1.06 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[C:11]([O:13][CH3:14])[CH:12]=1)[C@@H:9]([CH3:15])[NH:8][C@H:7]([CH3:16])[CH2:6]2.[CH2:17](Cl)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C([O-])([O-])=O.[K+].[K+].O>C(C(C)=O)C.CCOCC>[CH2:17]([N:8]1[C@H:7]([CH3:16])[CH2:6][C:5]2[C:10](=[C:11]([O:13][CH3:14])[CH:12]=[C:3]([O:2][CH3:1])[CH:4]=2)[C@H:9]1[CH3:15])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: COc1cc2c(c(OC)c1)[C@@H](C)N[C@H](C)C2
Reactant: ClCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOCC
Solvent: CCC(C)=O
Product: COc1cc2c(c(OC)c1)[C@@H](C)N(Cc1ccccc1)[C@H](C)C2
Yield: 95 %

Procedure:
Into a stirred solution of (1R, 3R)-1,2,3,4-tetrahydro-6,8-dimethoxy-1,3-dimethyl-isoquinoline (114 mg, 0.5 mmol) and benzyl chloride (137 mg, 1.1 mmol) in methyl ethyl ketone was added K2CO3 (320 mg, 2.3 mmol). The resulting mixture was heated to reflux for 24 h, after which time it was cooled down and poured into H2O. Et2O was added and the organic layer was washed with H2O, brine, dried over MgSO4, and concentrated in vacuo. The crude product was purified by MPLC (hexanes/EtOAc/Et3N; 9:1:0.3) to yield N-benzyl-(1R, 3R)-1,2,3,4-tetrahydro-6,8-dimethoxy-1,3-dimethyl-isoquinoline (148 mg, 93%) as a colorless oil; 1H NMR (500 MHz, CDCl3): δ7.40-7.20 [m, benzyl ArH], 6.28 [d, J=2.0 Hz, ArH(7)], 6.23 [d, J=2.0 Hz, ArH(5)], 3.66 [q, J=6.5 Hz, ArCHCH3 ], 3.82 [d, J=14.0 Hz, NCHaHbPh], 3.78 [s, O(6)CH3 ], 3.70 [s, O(8)CH3, 3.50 [ddq, J=10.5, 5.0 and 6.5 Hz, CHaHbCHCH3 ], 3.29 [d, J=14.0 Hz, NCHaHbPh], 2.63 [dd, J=17.0 and 10.5 Hz, CHaHbCH], 2.58 [dd, J=17.0 and 5.0 Hz, CHaHbCH], 1.30 [d, J=6.5 Hz, CH3 (1)], and 1.25 [d, J=6.5 Hz, CH3 (3)]; 13C NMR (75 MHz, CDCl3): δ158.5, 158.4, 141.7, 136.8, 128.4 [2C], 128.1 [3C], 126.4, 104.1, 96.4, 55.2, 55.1, 51.4, 49.8, 45.8, 32.6, 20.0, and 19.5; LRMS (EI): m/z 296 (M+ --CH3, 100), and 91 (44); IR (neat NaCl plates): 2965, 1605, and 1148 cm-1 ; Anal. calcd for C20H25NO2 : C, 77.14; H, 8.09. Found: C, 77.30; H, 8.06.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]2[O:12]C(=O)[NH:10][CH:9]2[CH2:14][C:15]2[CH:16]=[CH:17][C:18]3[O:22][CH2:21][C:20]([CH3:24])([CH3:23])[C:19]=3[CH:25]=2)[CH:5]=[CH:6][CH:7]=1.[OH-].[Na+]>C(O)C>[NH2:10][CH:9]([CH2:14][C:15]1[CH:16]=[CH:17][C:18]2[O:22][CH2:21][C:20]([CH3:23])([CH3:24])[C:19]=2[CH:25]=1)[CH:8]([C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=1)[OH:12]
Reactant: CC1(C)COc2ccc(CC3NC(=O)OC3c3cccc(Cl)c3)cc21
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC1(C)COc2ccc(CC(N)C(O)c3cccc(Cl)c3)cc21
Yield: 74.4 %

Procedure:
To a solution of (4RS,5SR)-5-(3-chlorophenyl)-4-[(3,3-dimethyl-2,3-dihydro-1-benzofuran-5-yl)methyl]-1,3-oxazolidin-2-one (5.33 g, 14.9 mmol) in ethanol (100 ml) was added 8N aqueous sodium hydroxide solution (9.3 ml, 74.5 mmol), and the mixture was heated under reflux for 5 hrs. After completion of the reaction, ethanol was evaporated under reduced pressure. The residue was diluted with water, and the mixture was extracted with ethyl acetate. The organic layers were combined, washed with saturated brine, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by recrystallization (hexane-ethyl acetate) to give (1RS,2SR)-2-amino-1-(3-chlorophenyl)-3-(3,3-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-1-propanol (3.68 g, 74%) as colorless crystals.