Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC1C=CC(S(CCC)(=O)=O)=CC=1C#C[Si](C)(C)C.[C:20]([O:24][C:25](=[O:37])[CH2:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][C:29]=1[C:35]#[CH:36])([CH3:23])([CH3:22])[CH3:21].Br[C:39]1[CH:52]=[CH:51][C:42]2[CH:43]([OH:50])[C:44]([CH3:49])([CH3:48])[S:45](=[O:47])(=[O:46])[C:41]=2[CH:40]=1>>[C:20]([O:24][C:25](=[O:37])[CH2:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][C:29]=1[C:35]#[C:36][C:39]1[CH:52]=[CH:51][C:42]2[CH:43]([OH:50])[C:44]([CH3:49])([CH3:48])[S:45](=[O:46])(=[O:47])[C:41]=2[CH:40]=1)([CH3:23])([CH3:22])[CH3:21]
Reactant: C#Cc1cc(Cl)ccc1OCC(=O)OC(C)(C)C
Reactant: CC1(C)C(O)c2ccc(Br)cc2S1(=O)=O
Agent: CCCS(=O)(=O)c1ccc(F)c(C#C[Si](C)(C)C)c1
Product: CC(C)(C)OC(=O)COc1ccc(Cl)cc1C#Cc1ccc2c(c1)S(=O)(=O)C(C)(C)C2O

Procedure:
Following the general method as outlined in Intermediate 107, starting from (4-chloro-2-ethynyl-phenoxy)-acetic acid tert-butyl ester (Intermediate 3) and 6-bromo-2,2-dimethyl-2,3-dihydro-1-benzothiophene-3-ol 1,1-dioxide (Intermediate 244), the title compound was obtained after purification by flash column chromatography (silica), eluting with cyclohexane containing increasing amounts of EtOAc.
Reaction SMILES: Br[C:2]1[CH:14]=[CH:13][C:5]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])=[C:4]([F:15])[CH:3]=1.[Li]CCCC.CN([CH:24]=[O:25])C>C1COCC1>[F:15][C:4]1[CH:3]=[C:2]([CH:24]=[O:25])[CH:14]=[CH:13][C:5]=1[C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7]
Reactant: CC(C)(C)OC(=O)c1ccc(Br)cc1F
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)c1ccc(C=O)cc1F
Temperature: 0 °C
Reaction time: 1 h
Yield: 61 %

Procedure:
To a stirred solution of tert-butyl 4-bromo-2-fluorobenzoate (1.5 g, 5.45 mmol) in THF (70 mL) at −100° C. under argon was carefully added BuLi (2.5 M in hexane, 2.3 mL, 5.75 mmol). The mixture was kept at −100° C. to −80° C. for 1 h and then DMF (1.0 mL) in THF (5 mL) was added. After 1 h, the mixture was warmed to 0° C. and quenched by adding sat. aq NH4Cl, and extracted with EtOAc. The organic layer was separated, washed with brine, dried (MgSO4), and concentrated under vacuum. The residue was purified by column chromatography on silica gel using EtOAc/hexane (0-10%) as eluent to give the product (750 mg, 61%) as a white solid.
Reaction SMILES: [CH3:1][C:2]([O:4][C@H:5]1[C:14]2[C@@:15]3([CH3:30])[C@@H:26]([CH2:27][O:28][CH3:29])[O:25][C:23](=[O:24])[C:17]4=[CH:18][O:19][C:20]([C:21](=[O:22])[C:13]=2[C@@H:8]2[CH2:9][CH2:10][C@H:11]([OH:12])[C@@:7]2([CH3:31])[CH2:6]1)=[C:16]34)=[O:3].[CH2:32]([N:39]1[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>C(Cl)Cl>[C:2]([O:4][C@H:5]1[C:14]2[C@:15]3([CH3:30])[C:16](/[C:17](=[CH:18]\[N:42]4[CH2:43][CH2:44][N:39]([CH2:32][C:33]5[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=5)[CH2:40][CH2:41]4)/[C:23](=[O:24])[O:25][C@@H:26]3[CH2:27][O:28][CH3:29])=[C:20]([OH:19])[C:21](=[O:22])[C:13]=2[CH:8]2[C@@:7]([CH3:31])([C@@H:11]([OH:12])[CH2:10][CH2:9]2)[CH2:6]1)(=[O:3])[CH3:1]
Reactant: c1ccc(CN2CCNCC2)cc1
Reactant: COC[C@H]1OC(=O)c2coc3c2[C@@]1(C)C1=C(C3=O)[C@@H]2CC[C@H](O)[C@@]2(C)C[C@H]1OC(C)=O
Solvent: ClCCl
Product: COC[C@H]1OC(=O)/C(=C/N2CCN(Cc3ccccc3)CC2)C2=C(O)C(=O)C3=C([C@H](OC(C)=O)C[C@@]4(C)C3CC[C@@H]4O)[C@]21C
Temperature: 25 °C
Reaction time: 8 h
Yield: 17.9 %

Procedure:
To a solution of 50 mg (0.12 mmol) 17-hydroxywortmannin in 0.5 mL CH2Cl2 is added 42.3 mg (0.24 mmol) 1-benzyl-piperazine. The reaction mixture is stirred at room temperature overnight. CH2Cl2 is removed in vacuo. The residue is triturated with Et2O to give 13 mg (17.8%) product as an orange powder. MS (ESI) m/z 607.2 (M+1).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[OH:7][CH:8]([C:17]1[C:26]([CH3:27])=[C:25]([O:28]C(=O)C)[C:24]2[C:19](=[CH:20][CH:21]=[C:22]([F:32])[CH:23]=2)[N:18]=1)/[CH:9]=[CH:10]/[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].CO.Cl>O>[OH:7][CH:8]([C:17]1[CH:26]([CH3:27])[C:25](=[O:28])[C:24]2[C:19](=[CH:20][CH:21]=[C:22]([F:32])[CH:23]=2)[N:18]=1)/[CH:9]=[CH:10]/[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCC/C=C/C(O)c1nc2ccc(F)cc2c(OC(C)=O)c1C
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: CCCCCC/C=C/C(O)C1=Nc2ccc(F)cc2C(=O)C1C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 72.4 %

Procedure:
A solution of 715 mg (5.18 mmols) of potassium carbonate in 3 ml of water was added to a solution of 1.86 g (5.18 mmols) of 2-(trans-1-hydroxy-2-nonenyl)-3-methyl-4-acetoxy-6-fluoroquinoline, 50 ml of methanol and 2 ml of water and stirred at room temperature for 10 minutes. After neutralization by addition of 1N hydrochloric acid, the solvent was distilled off under reduced pressure and 30 ml of chloroform was added to the resultant residue, followed by washing with water and drying with anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the resultant residue was purified by silica gel column chromatography (solvent: chloroform : methanol=40:1) to obtain 1.19 g (yield 72 %) of 2-(trans-1-hydroxy-2-nonenyl)-3-methyl-6-fluoro-4-quinolone.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:12]3[N:13]=[C:14]4[C:20]([C:21]([O:23]C)=[O:22])=[CH:19][N:18]([CH2:25][O:26][C:27](=[O:32])[C:28]([CH3:31])([CH3:30])[CH3:29])[C:15]4=[N:16][CH:17]=3)=[N:7][N:8]2[CH3:11])=[CH:4][CH:3]=1.[OH-].[K+].O.Cl>O1CCOCC1>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:12]3[N:13]=[C:14]4[C:20]([C:21]([OH:23])=[O:22])=[CH:19][N:18]([CH2:25][O:26][C:27](=[O:32])[C:28]([CH3:30])([CH3:29])[CH3:31])[C:15]4=[N:16][CH:17]=3)=[N:7][N:8]2[CH3:11])=[CH:4][CH:3]=1
Reactant: COC(=O)c1cn(COC(=O)C(C)(C)C)c2ncc(-c3nn(C)c4cc(F)ccc34)nc12
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: Cn1nc(-c2cnc3c(n2)c(C(=O)O)cn3COC(=O)C(C)(C)C)c2ccc(F)cc21
Temperature: 100 °C
Reaction time: 5 h
Yield: 69.3 %

Procedure:
A mixture of methyl 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5-(pivaloyloxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylate (0.24 g, 0.546 mmol), KOH (0.611 g, 10.9 mmol), water (4 mL) and dioxane (10 mL) was stirred at 100° C. for 5 hours. Then the reaction mixture was cooled to room temperature and treated with 1N HCl to pH=2. The solvent was evaporated at 40° C. under reduced pressure and the residue was triturated with water (10 mL), then decanted and dried at 40° C. under reduced pressure to give 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5-(pivaloyloxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (0.161 g, 94.8%) as a yellow solid. 1H NMR (300 MHz, DMSO): δ 12.87 (s, 1H), 12.28 (s, 1H), 9.05 (s, 1H), 8.82 (dd, 1H, J1=9.0 Hz, J2=5.7 Hz), 8.48 (d, 1H, J=2.7 Hz), 7.61 (dd, 1H, J1=10.2 Hz, J2=2.7 Hz), 7.15 (t, 1H, J=12.0 Hz), 4.12 (s, 3H). LCMS: 312.0 [M+H]+, 334.0 [M+Na]+.
Reaction SMILES: [Na+].[NH2:2][C:3]1[CH:4]=[C:5]([OH:12])[C:6](=[CH:10][CH:11]=1)[C:7]([O-:9])=[O:8].[CH3:13]O>Cl>[NH2:2][C:3]1[CH:4]=[C:5]([OH:12])[C:6](=[CH:10][CH:11]=1)[C:7]([O:9][CH3:13])=[O:8]
Reactant: CO
Reactant: Nc1ccc(C(=O)[O-])c(O)c1
Agent: Cl
Agent: [Na+]
Product: COC(=O)c1ccc(N)cc1O
Reaction time: 0.5 h

Procedure:
To a solution of 25 g (118.5 mmol) of 4-aminosalicylic acid sodium salt in 250 ml of methanol is bubbled in anhydrous HCl gas at room temperature. Addition of HCl gas is continued for 30 minutes. Excess methanol is removed in vacuo and the residue taken up in ethyl acetate and washed with saturated aqueous NaHCO3. The organic layer is dried over MgSO4, filtered and concentrated, giving methyl 4-aminosalicylate which is used directly in the next step.
Reaction SMILES: [O:1]=[C:2]1[N:7]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C@H:6]([C:15]([OH:17])=O)[CH2:5][O:4][CH2:3]1.[CH3:18][NH:19][CH3:20].C(Cl)CCl.C1C=NC2N(O)N=NC=2C=1.CN1CCOCC1>C1COCC1>[CH3:18][N:19]([CH3:20])[C:15]([C@@H:6]1[CH2:5][O:4][CH2:3][C:2](=[O:1])[N:7]1[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:17]
Reactant: O=C(O)[C@@H]1COCC(=O)N1Cc1ccccc1
Reactant: CNC
Agent: On1nnc2cccnc21
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Solvent: ClCCCl
Product: CN(C)C(=O)[C@@H]1COCC(=O)N1Cc1ccccc1
Reaction time: 8 h

Procedure:
To a solution of (3S)-5-oxo-4-(phenylmethyl)-3-morpholinecarboxylic acid (1.5 g, 6.4 mmol) (J. Chem. Soc., Perkin Trans. 1, 1985, 2577-2580) in THF (50 mL) was added dimethylamine (3.8 mL, 7.6 mmol, 2M in THF), EDC (1.46 g, 7.7 mmol), HOAt (1.06 g, 7.7 mmol) and NMM (3.5 mL, 30 mmol). The reaction mixture was stirred overnight and the THF was evaporated, replacing it with EtOAc. 1 M HCl was added and the phases were separated. The aqueous layer was extracted twice with EtOAc and the combined organics were dried over sodium sulfate. Concentration in vacuo yielded (3S)—N,N-dimethyl-5-oxo-4-(phenylmethyl)-3 morpholinecarboxamide, which was purified by RP-HPLC. LCMS: (M+H)+: 263.1.
Reaction SMILES: [S:1]1[C:5]2[C:6]3[CH:14]=[CH:13][CH:12]=[CH:11][C:7]=3[O:8][CH2:9][CH2:10][C:4]=2[CH:3]=[CH:2]1.C(O)(=O)C.[Br:19]N1C(=O)CCC1=O>ClCCl>[Br:19][C:2]1[S:1][C:5]2[C:6]3[CH:14]=[CH:13][CH:12]=[CH:11][C:7]=3[O:8][CH2:9][CH2:10][C:4]=2[CH:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: c1ccc2c(c1)OCCc1ccsc1-2
Solvent: CC(=O)O
Solvent: ClCCl
Product: Brc1cc2c(s1)-c1ccccc1OCC2
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirred solution of 4,5-dihydrobenzo[b]thieno[2,3-d]oxepine (440 mg, 2.2 mmol) and acetic acid (10 ml) in dichloromethane (10 ml) at 0° C., was added N-bromosuccinimide in portions. Reaction mixture was stirred for 18 hours, allowing solution to raise to room temperature before being concentrated in-vacuo. Residue was dissolved in ethyl acetate and sat. sodium carbonate solution. Organic phase was washed with water and brine, dried (Na2SO4) and concentrated in-vacuo to give 2-bromo-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine.
Reaction SMILES: C([O:4][CH:5]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH:6]=[CH:7]C1C=CC=CC=1)(=O)C.C(OC)(=O)CC(OC)=O.CC([O-])=O.[K+]>C(Cl)Cl>[C:14]1([CH:5]([OH:4])[CH2:6][CH3:7])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CC(=O)OC(C=Cc1ccccc1)c1ccccc1
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: COC(=O)CC(=O)OC
Product: CCC(O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
General procedure for the asymmetric Pd(0)-catalyzed allylic substitution reaction: To a Schlenk tube comprising (±) 1,3-dipheylprop-2-en-1-yl acetate (252 mg, 1.0 mmol), [Pd(allyl)Cl]2 (3.7 mg, 0.01 mmol, 1 mol %), was added (S, aR)-1,2,3,4-tetrahydro-2-methyl-1-(2-(diphenylphosphino)naphthalen-1-yl)isoquinoline (9.0 mg, 0.02 mmol, 2 mol %) in CH2Cl2 (2 mL). The reaction mixture was stirred at room temperature over a period of 30 minutes. Dimethyl malonate (396 mg, 3.0 mmol), KOAc (2.8 mg, 0.02 mmol) and BSA (613 mg, 3.0 mmol) were subsequently added at −78° C. The reaction mixture was stirred at −25° C. over a period of 48 hours, quenched using a saturated aqueous NH4Cl, solution and extracted with EtOAc (3×5 mL). The organic phase was washed with a saturated aqueous NaHCO3 solution, brine, dried using Na2SO4, and concentrated under reduced pressure. The residue was purified by means of flash chromatography on silica gel using hexane/EtOAc (6:1) as the eluent system to yield the desired product as a colorless oil (78% ee). 1H NMR (300 MHz, CDCl3): δ 3.54 (s, 3H), 3.70 (s, 3H), 3.96 (d, J=10.8 Hz, 1H), 4.25 (dd, J=10.8, 8.7 Hz, 1H), 6.33 (dd, J=15.4, 8.6 Hz, 1H), 6.46 (d, J=15.8 Hz, 1H), 7.17-7.24 (m, 10H). The enantiomeric purity (ee), as determined by means of chiral HPLC (Chiralpak AD, hexane/isopropanol=90:10, flow rate 1.0 mL/min); (tR=9.4 min., tS=12.7 min).
Reaction SMILES: Cl.Cl.[N:3]1([CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:22]=[C:21]3[C:16]([CH2:17][CH2:18][NH:19][CH2:20]3)=[CH:15][CH:14]=2)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.CCN(CC)CC.[F:30][C:31]1[CH:36]=[CH:35][C:34]([S:37]([Cl:40])(=[O:39])=[O:38])=[CH:33][CH:32]=1>>[ClH:40].[F:30][C:31]1[CH:36]=[CH:35][C:34]([S:37]([N:19]2[CH2:18][CH2:17][C:16]3[C:21](=[CH:22][C:13]([O:12][CH2:11][CH2:10][CH2:9][N:3]4[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]4)=[CH:14][CH:15]=3)[CH2:20]2)(=[O:39])=[O:38])=[CH:33][CH:32]=1
Reactant: c1cc2c(cc1OCCCN1CCCCC1)CNCC2
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Agent: Cl
Solvent: CCN(CC)CC
Product: O=S(=O)(c1ccc(F)cc1)N1CCc2ccc(OCCCN3CCCCC3)cc2C1

Procedure:
2-(4-Fluoro-benzenesulfonyl)-7-(3-piperidin-1-yl-propoxy)-1,2,3,4-tetrahydro-isoquinoline hydrochloride is prepared from 7-(3-piperidin-1-yl-propoxy)-1,2,3,4-tetrahydro-isoquinoline dihydrochloride (158 mg, 0.45 mmol), NEt3 (0.21 mL, 1.5 mmol), and 4-fluorobenzenesulfonyl chloride (115 mg, 0.55 mmol) via a procedure substantially analogous to Procedure F except that an additional SCX column purification step is performed to give 140 mg of free base product. The free base is converted to the HCl salt (150 mg, 71% yld) via a procedure substantially analogous Procedure D. MS (ES+)433.2(M+H)+ free base.
Reaction SMILES: [CH3:1][C:2](C)([O-])[CH3:3].[K+].C[C@@H]1C[C:24]2[CH2:23][C:22](=[O:26])[CH2:21][CH2:20][C:19]=2[C@@H:18]2[C@@H:9]1[C@H:10]1[C@@:14]([CH2:16][CH2:17]2)([CH3:15])[C@@H:13](O)[CH2:12][CH2:11]1.[CH2:28]1COCC1>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:28][C@@H:17]1[CH2:16][C:14]2[CH2:15][C:2](=[CH2:1])[CH2:3][CH2:9][C:10]=2[C@@H:11]2[C@@H:18]1[C@H:19]1[C@@:20]([CH2:13][CH2:12]2)([CH3:21])[C@@H:22]([OH:26])[CH2:23][CH2:24]1
Reactant: C[C@@H]1CC2=C(CCC(=O)C2)[C@H]2CC[C@]3(C)[C@@H](O)CC[C@H]3[C@H]12
Reactant: CC(C)(C)[O-]
Reactant: C1CCOC1
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [K+]
Product: C=C1CCC2=C(C1)C[C@@H](C)[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](O)CC[C@@H]12
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
Methyltriphenylphosphonium bromide (4.21 g, 11.8 mmol) was added to a stirred solution of potassium t-butoxide (1.26 g, 11.2 mmol) in 20 ml dry THF under a nitrogen atmosphere. The yellow suspension was stirred for 45 minutes at room temperature. A solution of (7α,17β)-7-methyl-3-keto-estr-5(10)-en-17-ol (3.4 g, 11.8 mmol) in 25 ml dry THF was added rapidly to the suspension. The yellow reaction mixture was stirred for 30 minutes at room temperature, poured on ice-water and extracted with ethyl acetate. The organic layer was washed with water, dried (Na2SO4) and evaporated to dryness to give 5.3 g of the title compound as a yellow oil. Column chromatography using toluene/ethyl acetate 95/5 (v/v %) as eluent gave 2.3 g of a colorless oil. Crystallization using heptane/petroleum ether gave (7α,17β)-7-methyl-3-methyleneestr-5(10)-en-17-ol (1.47 g, 44%) as a white solid, mp 111.8° C.
Reaction SMILES: [OH:1][CH2:2][C@:3]1([CH3:18])[CH2:7][CH2:6][CH2:5][N:4]1[C:8]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9].N1C=CC=CC=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)(Cl)Cl>[CH:2]([C@:3]1([CH3:18])[CH2:7][CH2:6][CH2:5][N:4]1[C:8]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9])=[O:1]
Reactant: C[C@@]1(CO)CCCN1C(=O)OCc1ccccc1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: C[C@@]1(C=O)CCCN1C(=O)OCc1ccccc1
Yield: 92.5 %

Procedure:
To a solution obtained by dissolving 377 mg of the compound [63-2] and 147 mg of pyridine in 7.5 mL of chloroform, 673 mg of Dess-Martin periodinane was added at room temperature, and the mixture was heated under reflux for 1 hour. To the reaction solution, a saturated aqueous sodium thiosulfate solution was added, and the mixture was extracted with chloroform. The obtained organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution and saturated brine, sequentially, and dried over anhydrous sodium sulfate. The insolubles were filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate 100/0 to 60/40) to obtain 346 mg of benzyl (2S)-2-formyl-2-methylpyrrolidine-1-carboxylate [63-3] (hereinafter, referred to as the compound [63-3].
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]#[N:11])=[CH:2]1.[CH2:12]([O:14][CH:15](OCC)[O:16][CH2:17][CH3:18])[CH3:13]>>[CH2:12]([O:14][CH:15]([O:16][CH2:17][CH3:18])[N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]#[N:11])=[CH:2]1)[CH3:13]
Reactant: CCOC(OCC)OCC
Reactant: N#Cc1c[nH]c2ccccc12
Product: CCOC(OCC)n1cc(C#N)c2ccccc21
Yield: 86 %

Procedure:
1H-Indole-3-carbonitrile (5.07 g, 35.7 mmol) was heated with triethylorthoformate (60 mL) in a pressure vessel at 160° C. for 3 d. Upon cooling, the solvent was evaporated and the residue was submitted to chromatography (20% ether in hexanes) to afford the title compound (7.46 g, 86%). NMR (300 MHz, CDCl3, δ): 7.92 (s, 1H), 7.76 (m, 1H), 7.62 (m, 1H), 7.32 (m, 2H), 6.23 (s, 1H), 3.63 (m, 4H), 1.23 (t, J=7.2 Hz, 6H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[CH:5]([S:14][CH2:15][C:16]([O:18]C(C)(C)C)=[O:17])[CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH3:2].FC(F)(F)C(O)=O>ClCCl>[CH2:1]([O:3][C:4](=[O:23])[CH:5]([S:14][CH2:15][C:16]([OH:18])=[O:17])[CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH3:2]
Reactant: CCOC(=O)C(CCc1ccccc1)SCC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)C(CCc1ccccc1)SCC(=O)O
Temperature: 25 °C
Reaction time: 16 h
Yield: 104.3 %

Procedure:
5.6 g (16.5 mmol) of 2-tert-butyloxycarbonylmethylthio-4-phenyl-butyric acid ethyl ester are placed at room temperature in 60 ml of dichloromethane. 3.8 ml (49.6 mmol) of trifluoro-acetic acid are added and the mixture is stirred for 16 hours at room temperature, then a further 3.8 ml of trifluoroacetic acid is added and the mixture is stirred for 24 hours at room temperature and then washed in succession with 25 ml of water and 25 ml of saturated sodium chloride solution. The aqueous phases are then washed with 2550 ml of dichloro-methane. The combined organic phases are dried over sodium sulfate, filtered and concentrated by evaporation. 4.86 g (100% of theory) of crude 2-carboxymethylthio-4-phenyl-butyric acid ethyl ester are obtained in the form of a brown oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:23]=[CH:22][C:18]([C:19](O)=[O:20])=[C:17]([C:24]([F:27])([F:26])[F:25])[CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>C1COCC1.C([O-])(O)=O.[Na+]>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([O:14][C:15]2[CH:23]=[CH:22][C:18]([CH2:19][OH:20])=[C:17]([C:24]([F:27])([F:25])[F:26])[CH:16]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(C(=O)O)c(C(F)(F)F)c2)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc(CO)c(C(F)(F)F)c2)CC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a stirred solution of 4-(N-tert-butyloxy-carbonyl-4-piperidinyloxy)-2-trifluoromethylbenzoic acid (0.66 g, 2.3 mmol) from Step 2 above in THF (10 mL) at 0° C. was added BH3.THF complex (3.5 mL of a 1.0 M solution in THF, 3.5 mmol). The solution was stirred at 0° C. for 1 h and then at ambient temperature for 14 h. The solution was diluted with saturated aqueous NaHCO3 (25 mL) and the solvents were removed under reduced pressure. The residue was partitioned between EtOAc (50 mL) and water (2×25 mL). The organic phase was dried (MgSO4), filtered, and the solvent was removed under reduced pressure to give 4-(N-tert-butyloxycarbonyl-4-piperidinyloxy)-2-trifluoromethylbenzyl alcohol as a colorless gum (HPLC retention time=10.2 min (method A)).
Reaction SMILES: C([NH:4][C@@H:5]([C:15]([OH:17])=[O:16])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=1)(=O)C.O.[ClH:19]>CN(C=O)C>[ClH:19].[CH3:14][O:13][C:10]1[CH:9]=[CH:8][C:7]([CH2:6][C@H:5]([C:15]([OH:17])=[O:16])[NH2:4])=[CH:12][CH:11]=1
Reactant: COc1ccc(C[C@@H](NC(C)=O)C(=O)O)cc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(C[C@@H](N)C(=O)O)cc1
Temperature: 25 °C

Procedure:
N-Acetyl-O-methyl-D-tyrosine, 24 g. is heated in 100 ml. of water and 100 ml. of concentrated hydrochloric acid for seven hours on a steam bath and let cool to room temperature overnight. The flask is swirled gently and the product crystallizes. It is separated by filtration, washed with a small amount of isopropanol, then with ether and dried to give 16.1 g. of the above named compound, [α]D23 +7.4° (c 2.02, DMF).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][C:12]([N+:14]([O-:16])=[O:15])=[CH:13][C:8]=2[O:7][C:6]1=[O:17].[CH3:18][N:19]1[CH2:24][CH2:23][CH2:22][CH:21]([OH:25])[CH2:20]1>>[CH3:18][N:19]1[CH2:24][CH2:23][CH2:22][CH:21]([O:25][C:6]([N:5]2[C:9]3[CH:10]=[CH:11][C:12]([N+:14]([O-:16])=[O:15])=[CH:13][C:8]=3[O:7][CH2:2][CH2:3][CH2:4]2)=[O:17])[CH2:20]1
Reactant: CN1CCCC(O)C1
Reactant: O=c1oc2cc([N+](=O)[O-])ccc2n1CCCCl
Product: CN1CCCC(OC(=O)N2CCCOc3cc([N+](=O)[O-])ccc32)C1

Procedure:
3-Nitro-7,8-dihydro-6H-5-oxa-9-aza-benzocycloheptene-9-carboxylic acid 1-methyl-piperidin-3-yl ester was prepared from 3-(3-chloro-propyl)-6-nitro-3H-benzoxazol-2-one and 1-methyl-piperidin-3-ol in an analogous manner to Example 1426a. Product isolated as a yellow oil (420 mg, 53%). LCMS (m/e) 336 (M+H); 1H-NMR (CDCl3, 400 MHz) δ 7.89-7.80 (m, 2H), 7.58-7.44 (m, 1H), 4.92-4.81 (m, 1H), 4.30-4.18 (m, 2H), 3.98-3.72 (m, 2H), 2.82-2.71 (m, 1H), 2.56-2.45 (m, 1H), 2.27 (s, 3H), 2.27-2.07 (m, 4H), 1.97-1.84 (m, 1H), 1.80-1.66 (m, 1H), 1.66-1.52 (m, 1H), 1.52-1.30 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1(C(O)=O)[CH:7]=[CH:6][C:5]([Cl:8])=[N:4][NH:3]1.[CH3:12][N:13]([CH:15]=[O:16])C.C(Cl)(=O)C(Cl)=O.[CH3:23][O:24][C:25]1[CH:26]=[C:27]([CH:30]=[CH:31][C:32]=1[O:33][CH3:34])CN>ClCCl.CN(C1C=CN=CC=1)C>[Cl:8][C:5]1[N:4]=[N:3][C:2]([Cl:1])=[CH:7][C:6]=1[C:15]([NH:13][CH2:12][C:30]1[CH:27]=[CH:26][C:25]([O:24][CH3:23])=[C:32]([O:33][CH3:34])[CH:31]=1)=[O:16]
Reactant: COc1ccc(CN)cc1OC
Reactant: O=C(O)C1(Cl)C=CC(Cl)=NN1
Reactant: CN(C)C=O
Agent: CN(C)c1ccncc1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: COc1ccc(CNC(=O)c2cc(Cl)nnc2Cl)cc1OC
Reaction time: 1 h

Procedure:
To a solution of 3,6-dichloropyridazinecarboxylic acid (1-1, 2.0 g, 10.4 mmol, 1.0 equiv) in dichloromethane (26 mL) was added catalytic DMF (0.16 mL, 2.1 mmol, 0.2 equiv) and oxalyl chloride (1.81 mL, 20.7 mmol, 2.0 equiv) at 0° C. The reaction mixture was stirred for 1 hour and concentrated. The crude residue was dissolved in dichloromethane (26 mL) and to the reaction was added 3,4-dimethoxybenzylamine (3.12 mL, 20.7 mmol, 2.0 equiv), TEA (1.81 mL, 20.8 mmol, 2.0 equiv), and DMAP (1.81 mL, 20.8 mmol, 2.0 equiv) at 0° C. The reaction mixture became cloudy with precipitate and was stirred 24 hours at ambient temperature. The reaction was partitioned between EtOAc and saturated NaHCO3. The organic phase was washed with NaHCO3, water and brine and dried over MgSO4. After concentration, the residue was purified by normal phase column chromatography (5 to 85% EtOAc in hexanes) to afford the product (1-2) as a yellow solid. ESI+MS [M+H]+ C14H13Cl2N3O3: 342.1 found, 342.0 required.
Reaction SMILES: [CH:1]1[C:9]2[C:8]3[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=3[O:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.O1CC[CH2:17]OO1.[Br-:20]>C(O)(=O)C.Br>[Br:20][CH2:17][C:2]1[CH:3]=[CH:4][C:5]2[O:6][C:7]3[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=3[C:9]=2[CH:1]=1
Reactant: c1ccc2c(c1)oc1ccccc12
Reactant: C1COOOC1
Reactant: [Br-]
Agent: Br
Solvent: CC(=O)O
Product: BrCc1ccc2oc3ccccc3c2c1
Reaction time: 28 h

Procedure:
A mixture of dibenzofuran (93.5 g, 0.557 M), trioxane (20 g, 0.222 M) and myrystyltrimethylammonium bromide (6.2 g, 18.5 mmol) in 1 L acetic acid and 135 mL of 48% HBr was stirred at 50˜60° C. for 28 h, then concentrated; the residue was dissolved in CH2Cl2, washed with water, dried over Na2SO4, evaporated to give the crude bromide 1a. Compound 1a was used without further purification in the next step.