Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([CH:7]([NH2:10])[CH2:8][NH2:9])[CH:4]=[N:3]1.[F:11][C:12]1[CH:33]=[CH:32][CH:31]=[C:30]([F:34])[C:13]=1[CH2:14][O:15][C:16]1[N:21]2[N:22]=[C:23]([CH3:28])[C:24]([C:25](Cl)=[O:26])=[C:20]2[CH:19]=[C:18]([CH3:29])[CH:17]=1.N1C=CC=CC=1>ClC(Cl)C>[NH2:10][CH:7]([C:5]1[CH:4]=[N:3][N:2]([CH3:1])[CH:6]=1)[CH2:8][NH:9][C:25]([C:24]1[C:23]([CH3:28])=[N:22][N:21]2[C:16]([O:15][CH2:14][C:13]3[C:30]([F:34])=[CH:31][CH:32]=[CH:33][C:12]=3[F:11])=[CH:17][C:18]([CH3:29])=[CH:19][C:20]=12)=[O:26]
Reactant: Cc1cc(OCc2c(F)cccc2F)n2nc(C)c(C(=O)Cl)c2c1
Reactant: Cn1cc(C(N)CN)cn1
Solvent: CC(Cl)Cl
Solvent: c1ccncc1
Product: Cc1cc(OCc2c(F)cccc2F)n2nc(C)c(C(=O)NCC(N)c3cnn(C)c3)c2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
14.0 mg (0.10 mmol) of 1-(1-methyl-1H-pyrazol-4-yl)ethane-1,2-diamine were initially charged in a 96-well deep well multititre plate. A solution of 35.1 mg (0.10 mmol) of 7-[(2,6-difluorobenzyl)oxy]-2,5-dimethylpyrazolo[1,5-a]pyridine-3-carbonyl chloride in 0.6 ml of dichloroethane and 0.032 ml (0.40 mmol) of pyridine were added successively and the mixture was stirred at RT overnight. Then the solvent was evaporated off completely, the residue was dissolved in 0.8 ml of DMF and filtered, and the target compound was isolated from the filtrate by preparative LC-MS (Method 9). The product-containing fractions were concentrated under reduced pressure using a centrifugal dryer. The residue of each product fraction was dissolved in 0.6 ml of DMSO. These were combined and finally freed of the solvent in a centrifugal dryer. 18 mg (37% of theory; 94% purity) of the title compound were obtained.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:13]2[C:14]([CH2:19][OH:20])=[N:15][C:16]([Cl:18])=[CH:17][C:12]=2[N:11]([C:21]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.[C:49](Cl)([CH3:51])=[O:50]>C(Cl)Cl>[C:49]([O:20][CH2:19][C:14]1[C:13]2[C:9]([O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[N:10][N:11]([C:21]([C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[C:12]=2[CH:17]=[C:16]([Cl:18])[N:15]=1)(=[O:50])[CH3:51]
Reactant: CC(=O)Cl
Reactant: OCc1nc(Cl)cc2c1c(OCc1ccccc1)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(=O)OCc1nc(Cl)cc2c1c(OCc1ccccc1)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
A solution of (3-(benzyloxy)-6-chloro-1-trityl-1H-pyrazolo[4,3-c]pyridin-4-yl)methanol (2.443 g, 4.59 mmol) and DIPEA (3.0 ml, 17.18 mmol) in DCM (25 ml) was charged with AcCl (0.70 ml, 9.84 mmol). Stirred at RT for 45 min. Diluted with DCM, washed organics with 2N HCl, dried over MgSO4, filtered, concentrated in vacuo and obtained (3-(benzyloxy)-6-chloro-1-trityl-1H-pyrazolo[4,3-c]pyridin-4-yl)methyl. MS: [M+H]+ m/z 574.
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9]2[CH:18]=[C:17]([CH2:19][N:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)[C:16]([C:26]([F:29])([F:28])[F:27])=[CH:15][C:10]=2[C:11]([O:13]C)=[O:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Li+].[OH-].O.Cl>O1CCCC1>[C:1]1([CH2:7][O:8][C:9]2[CH:18]=[C:17]([CH2:19][N:20]3[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]3)[C:16]([C:26]([F:29])([F:27])[F:28])=[CH:15][C:10]=2[C:11]([OH:13])=[O:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)c1cc(C(F)(F)F)c(CN2CCCCC2)cc1OCc1ccccc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1cc(C(F)(F)F)c(CN2CCCCC2)cc1OCc1ccccc1
Temperature: 40 °C

Procedure:
Methyl 2-[(phenylmethyl)oxy]-4-(1-piperidinylmethyl)-5-(trifluoromethyl)benzoate (may be prepared as described in Description 52; 232 mg, 0.57 mmol) was dissolved in tetrahydrofuran (4 ml) and LiOH (38.8 mg, 1.62 mmol) and water (1 ml) were added. The mixture was heated at 40° C. for 2 hours. The mixture was cooled and 2M hydrochloric acid (0.84 ml, 1.69 mmol) was added and the solvent removed in vacuo to give the title compound as oil. 223 mg.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]3[CH:18]=[C:17]([CH2:19][C:20]4[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=4)[C:16](=[O:26])[C:8]4[CH:9]=[C:10]([OH:15])[CH:11]=[C:12]([C:13]=2[CH:14]=1)[C:7]3=4.C(=O)([O-])[O-].[K+].[K+].Br[CH2:34][C:35]([O:37][CH:38]([CH3:40])[CH3:39])=[O:36]>CS(C)=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]3[CH:18]=[C:17]([CH2:19][C:20]4[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=4)[C:16](=[O:26])[C:8]4[CH:9]=[C:10]([O:15][CH2:34][C:35]([O:37][CH:38]([CH3:40])[CH3:39])=[O:36])[CH:11]=[C:12]([C:13]=2[CH:14]=1)[C:7]3=4
Reactant: O=c1c(Cc2cccnc2)cn2c3ccc(Br)cc3c3cc(O)cc1c32
Reactant: CC(C)OC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CC(C)OC(=O)COc1cc2c(=O)c(Cc3cccnc3)cn3c4ccc(Br)cc4c(c1)c23
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 59 %

Procedure:
10-bromo-2-hydroxy-5-(3-pyridylmethyl)-4H-pyrido [3,2,1-jk]carbazole-4-one (3.6 g) obtained in Example 2 was suspended in dimethyl sulfoxide (200 ml), and to the suspension was added potassium carbonate (2.5 g), and the mixture was stirred at room temperature for 30 minutes. i-propyl bromoacetate (1.4 ml) was added, and the mixture was stirred at room temperature for 12 hours. The reaction mixture was poured into ice water (300 ml) and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous solution of sodium chloride, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel flash column chromatography (eluent: methylene chloride containing 3% methanol), and the crude product was washed with ether and a small amount of methanol in succession, and recovered by filtration to obtain the title compound (2.6 g, 59%).
Reaction SMILES: CC([O-:5])(C)C.[Na+].[Br:7][C:8]1[CH:13]=[CH:12][C:11]([CH:14]2[CH2:16]O2)=[CH:10][CH:9]=1.[CH3:17][CH2:18][O:19][CH2:20][CH3:21]>COCCOC.[NH4+].[Cl-].O>[Br:7][C:8]1[CH:9]=[CH:10][C:11]([C@@H:14]2[CH2:16][C@H:17]2[C:18]([O:19][CH2:20][CH3:21])=[O:5])=[CH:12][CH:13]=1
Reactant: CC(C)(C)[O-]
Reactant: Brc1ccc(C2CO2)cc1
Reactant: CCOCC
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: CCOC(=O)[C@@H]1C[C@H]1c1ccc(Br)cc1
Temperature: 70 °C
Reaction time: 0.5 h

Procedure:
NaOtBu (3.23 g, 33.6 mmol) and 10 mL of dry DME were charged in round bottom flask previously inerted with nitrogen. Triethyl phosphonoacetate (7.7 mL, 38.64 mmol) was added at a rate such to maintain internal temperature below 30° C., about 30 minutes. The mixture was stirred until complete dissolution was observed, about 30 minutes. A solution of chiral 2-(4-bromophenyl)oxirane Enantiomer 1 (Intermediate 9 Enantiomer 1) (3.35 g, 16.8 mmol) in 6 mL of dry DME was added dropwise maintaining internal temperature between 20° C. and 30° C. The reaction mixture was stirred at 60° C. for 24 h. The temperature was increased to 70° C. and maintained at this temperature for further 6 h. Mixture was cooled to room temperature, taken up with 100 mL Et2O, cooled to 0° C. and poured in approx. 80 mL cold ss NH4Cl. The solution was diluted with approx. 20 mL water, the phases were separated and the aqueous one extracted with Et2O 2×100 mL. Combined organics were dried over Na2SO4 and evaporated to dryness to get crude title material that was purified by SiO2 flash chromatography (Horizon 65M) eluting with Et2O/n-hexane 5/95 to get after evaporation of the solvent, pure title material, 3.35 g as a colourless oil.
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[F:12][C:13]([F:30])([F:29])[C:14]1[N:19]=[CH:18][C:17]([CH:20]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[CH2:21][NH2:22])=[CH:16][N:15]=1>>[Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:22][CH2:21][CH:20]([N:23]1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1)[C:17]1[CH:18]=[N:19][C:14]([C:13]([F:29])([F:30])[F:12])=[N:15][CH:16]=1)=[O:6]
Reactant: O=C(O)c1cccc(Cl)c1Cl
Reactant: NCC(c1cnc(C(F)(F)F)nc1)N1CCOCC1
Product: O=C(NCC(c1cnc(C(F)(F)F)nc1)N1CCOCC1)c1cccc(Cl)c1Cl

Procedure:
From 2,3-dichlorobenzoic acid and 2-(2-(trifluoromethyl)pyrimidin-5-yl)-2-morpholin-4-yl-ethylamine.
Reaction SMILES: [CH2:1]([N:8]([C@H:16]([C:24](=[O:35])[CH:25]=[C:26]([NH2:34])[CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.Cl[C:43]([O:45][CH2:46][CH3:47])=[O:44].O>C1(C)C=CC=CC=1>[CH2:1]([N:8]([C@H:16]([C:24](=[O:35])[CH:25]=[C:26]([NH:34][C:43]([O:45][CH2:46][CH3:47])=[O:44])[CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH2:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)Cl
Reactant: NC(=CC(=O)[C@H](Cc1ccccc1)N(Cc1ccccc1)Cc1ccccc1)Cc1ccccc1
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Solvent: O
Product: CCOC(=O)NC(=CC(=O)[C@H](Cc1ccccc1)N(Cc1ccccc1)Cc1ccccc1)Cc1ccccc1
Temperature: 70 °C
Reaction time: 12 h
Yield: 28.5 %

Procedure:
A solution of 5 g of (2S)-2-(N,N-dibenzylamino)-5-amino-1,6-diphenyl-4-hexene-3-one in toluene (100 ml) was chilled with ice water. To the solution, 5 ml of pyridine and 5 ml of ethyl chloroformate were gradually added. The reaction mixture was stirred at 70° C. for 12 hours, and then chilled with ice water. 5 ml of water was added to the reaction mixture, and the mixture was held at the same temperature for 1 hour. The reaction mixture was then washed with 50 ml of water and 50 ml of a dilute solution of potassium hydrogensulfate, and further with water, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using n-hexane-ethyl acetate (10:1) as an eluent, thereby obtaining 1.65 g (28.5%) of the title compound as pale yellow powder from the eluate.
Reaction SMILES: [CH:1]1([N:4]([CH3:11])[CH2:5]/[CH:6]=[CH:7]/[C:8](O)=[O:9])[CH2:3][CH2:2]1.CN(C=O)C.C(Cl)(=O)C([Cl:20])=O>C(Cl)Cl>[CH:1]1([N:4]([CH3:11])[CH2:5]/[CH:6]=[CH:7]/[C:8]([Cl:20])=[O:9])[CH2:3][CH2:2]1
Reactant: O=C(Cl)C(=O)Cl
Reactant: CN(C/C=C/C(=O)O)C1CC1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CN(C/C=C/C(=O)Cl)C1CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of (E)-4-(cyclopropyl(methyl)amino)but-2-enoic acid (2.00 g, 12.9 mmol) in DCM (60 mL) was added DMF (0.2 mL) and oxalyl chloride (4.42 mL, 51.6 mmol). The mixture was stirred at RT for 4 h and concentrated in vacuo to dryness to afford (E)-4-(cyclopropyl(methyl)amino)but-2-enoyl chloride. In a similar manner as described in Example 70, (R,E)-3-(1-(4-(cyclopropyl(methyl)amino)but-2-enoyl)pyrrolidin-3-ylamino)-5-(4-(morpholine-4-carbonyl)phenylamino)-1,2,4-triazine-6-carboxamide (85) was prepared using (E)-4-(cyclopropyl(methyl)amino)but-2-enoyl chloride. MS found for C27H35N9O4 as (M+H)+ 550.2, (M−H)− 548.3. UV: λ=248 nm.
Reaction SMILES: C[C:2]1([CH3:22])[CH2:8][CH2:7][CH2:6][N:5]([C:9]([C:11]2[CH:15]=[C:14]([CH:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)[S:13][CH:12]=2)=[O:10])[CH2:4][CH2:3]1.[C:23](Cl)(=[O:25])[CH3:24].[CH2:27]([N:29](CC)CC)C>C(Cl)Cl>[CH2:6]1[N:5]([C:9]([C:11]2[CH:15]=[C:14]([CH:16]3[CH2:17][CH2:18][N:19]([C:23](=[O:25])[CH3:24])[CH2:20][CH2:21]3)[S:13][CH:12]=2)=[O:10])[CH2:4][CH2:3][N:29]2[CH2:27][CH2:22][CH2:2][CH2:8][CH:7]12
Reactant: CC(=O)Cl
Reactant: CCN(CC)CC
Reactant: CC1(C)CCCN(C(=O)c2csc(C3CCNCC3)c2)CC1
Solvent: ClCCl
Product: CC(=O)N1CCC(c2cc(C(=O)N3CCN4CCCCC4C3)cs2)CC1
Reaction time: 1 h

Procedure:
(4,4-Dimethyl-azepan-1-yl)-(5-piperidin-4-yl-thiophen-3-yl)-methanone (0.02 g) was dissolved in DCM (2 mL) and triethylamine (0.1 mL). Acetyl chloride (0.1 mL) was added and the mixture stirred for 1 hour. The organic solution was washed with 1 N hydrochloric acid, dried over anhydrous magnesium sulphate, filtered and evaporated to give a colourless oil. The oil was purified by flash chromatography on silica eluting with 10% methanol in ethyl acetate. The fractions containing the desired product were concentrated under vacuum to give the title compound (38 mg) as a clear oil. LCMS m/z 363.13 [M+H]+RT=9.40 min (Analytical Method 2). 1H NMR (400 MHz, CHCl3-d): δ 7.3 (s, 1H), 6.9 (s, 1H), 4.4 (m, 1H), 3.9 (m, 1H), 3.7-3.4 (m, 4H), 3.2 (m, 1H), 3.0 (m, 1H), 2.6 (m, 1H), 2.15 (s, 3H), 2.1-2.0 (m, 2H), 1.8-1.4 (m, 9H), 1.0 (s, 3H), 0.9 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][OH:9])=[CH:4][CH:3]=1.[H-].[Na+].CS(O[CH:17]1[CH2:20][N:19]([C:21]([N:23]2[CH2:29][CH2:28][CH2:27][N:26]([CH:30]3[CH2:33][CH2:32][CH2:31]3)[CH2:25][CH2:24]2)=[O:22])[CH2:18]1)(=O)=O>CS(C)=O.CCOC(C)=O>[CH:30]1([N:26]2[CH2:27][CH2:28][CH2:29][N:23]([C:21]([N:19]3[CH2:20][CH:17]([O:9][CH2:8][C:5]4[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=4)[CH2:18]3)=[O:22])[CH2:24][CH2:25]2)[CH2:31][CH2:32][CH2:33]1
Reactant: OCc1ccc(F)cc1
Reactant: CS(=O)(=O)OC1CN(C(=O)N2CCCN(C3CCC3)CC2)C1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: O=C(N1CCCN(C2CCC2)CC1)N1CC(OCc2ccc(F)cc2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 22.1 %

Procedure:
To a stirred solution of (4-fluorophenyl)methanol (27 mg, 0.2 mmol) in DMSO (1.5 mL) was added NaH (8.5 mg, 0.2 mmol, 60% purity) at RT. The mixture was stirred for 1 h and a solution of 1 1-[(4-cyclobutyl-1,4-diazepan-1-yl)carbonyl]azetidin-3-yl methanesulfonate (33 mg, 0.1 mmol) in DMSO (0.5 mL) was added. The resulting mixture was stirred at 100° C. overnight, cooled to RT and diluted with EtOAc. The crude mixture and washed with water/brine; 1/1 solution, dried (Na2SO4), filtered and concentrated at reduced pressure. Purification by preparative HPLC provided the title compound as colourless oil (8 mg, 18%).
Reaction SMILES: [OH-].[Na+].[C:3]([C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][C:7]=1[CH:15](C(OC)=O)[C:16]([O:18]C)=[O:17])([OH:5])=[O:4]>O.CO.C(OCC)(=O)C>[C:16]([CH2:15][C:7]1[CH:8]=[C:9]([N+:12]([O-:14])=[O:13])[CH:10]=[CH:11][C:6]=1[C:3]([OH:5])=[O:4])([OH:18])=[O:17]
Reactant: COC(=O)C(C(=O)OC)c1cc([N+](=O)[O-])ccc1C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CO
Product: O=C(O)Cc1cc([N+](=O)[O-])ccc1C(=O)O
Temperature: 25 °C
Reaction time: 3 h
Yield: 23.3 %

Procedure:
A solution of sodium hydroxide (5.0 g, 125 mmol) in water (60 mL) was added to a solution of dimethyl 2-(2-carboxy-5-nitrophenyl)malonate (7.0 g, 21.5 mmol) in methanol (60 mL) at room temperature. After the reaction solution was stirred at room temperature for 3 hours, methanol was distilled off. The resulting residue was acidified using 1N hydrochloric acid (11 mL). The suspension was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give a crude product. After the crude product was stirred in ethyl acetate (20 mL) at 70 to 80° C. overnight, the temperature was allowed to return to room temperature. The precipitate was collected by filtration, and dried under reduced pressure to give the title compound (1.13 g, 23%).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5]([NH:12][NH2:13])=[CH:6][C:7]=1[C:8]([CH3:11])([CH3:10])[CH3:9].[F:14][C:15]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:16]=1[CH:17]=O>Cl.C(O)C.O.O.O.O.O.O.[Fe](Cl)(Cl)Cl>[Cl:1][C:2]1[C:7]([C:8]([CH3:9])([CH3:10])[CH3:11])=[CH:6][C:5]2[N:4]([C:17]([C:16]3[CH:19]=[C:20]([F:23])[CH:21]=[CH:22][C:15]=3[F:14])=[N:13][N:12]=2)[N:3]=1
Reactant: CC(C)(C)c1cc(NN)nnc1Cl
Reactant: O=Cc1cc(F)ccc1F
Agent: Cl[Fe](Cl)Cl
Agent: Cl
Solvent: CCO
Solvent: O
Product: CC(C)(C)c1cc2nnc(-c3cc(F)ccc3F)n2nc1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 35.8 %

Procedure:
To a slurry of 3-chloro-4-(1,1-dimethylethyl)-6-hydrazinylpyridazine (1.3 g, 6.5 mmol) in 0.1N hydrochloric acid (60 ml) was added 2,5-difluorobenzaldehyde (0.70 ml, 6.5 mmol) and the reaction mixture was stirred at room temperature for 30 minutes and then heated to 60° C. for 40 minutes. The reaction mixture was allowed to cool and the resultant solid was collected by filtration, dried and dissolved in ethanol (60 ml). To this solution was added iron(III) chloride hexahydrate (5.4 g, 32.5 mmol) in ethanol (15 ml) dropwise over 10 minutes at 80° C. The reaction mixture was stirred at 80° C. for 2 h, allowed to cool and the solvent removed by evaporation under vacuum. The residue was dissolved in dichloromethane (100 ml) and washed with water (3×100 ml), brine, dried (MgSO4), filtered and concentrated under vacuum to yield the title compound (0.75 g). Data for the title compound: 1H NMR (250 MHz, CDCl3) δ1.57 (9H, s), 7.22-7.29 (2H, m), 7.65-7.71 (1H, m), 8.19 (1H, s); MS (ES+) m/e 323 [MH]+.
Reaction SMILES: [CH3:1][CH:2]([OH:5])[C:3]#[CH:4].C([Li])CCC.[CH2:11]([O:13][C:14]([N:16]1[CH2:21][CH2:20][C:19](=[O:22])[CH2:18][CH2:17]1)=[O:15])[CH3:12].[NH4+].[Cl-]>C1COCC1.CCCCCC>[OH:5][CH:2]([CH3:1])[C:3]#[C:4][C:19]1([OH:22])[CH2:18][CH2:17][N:16]([C:14]([O:13][CH2:11][CH3:12])=[O:15])[CH2:21][CH2:20]1
Reactant: CCOC(=O)N1CCC(=O)CC1
Reactant: C#CC(C)O
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCOC(=O)N1CCC(O)(C#CC(C)O)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 3-butyn-2-ol (42 g, 0.6 mol) in dry THF (8OO ml) under nitrogen was cooled with a dry-ice/acetone bath. n-Butyl lithium (390 ml of 2.5M and 230 ml of 1.5M) in hexane was added rapidly, dropwise. The suspension became gelatinous and another 800 mls of dry THF was added. The reaction was stirred at approximately -78° for 1 hour and then at 0° for 20 minutes. The reaction was cooled to -78° and 1-ethoxycarbonyl-4-piperidinone (104 g, 0.607 mol) in 300 ml of dry THF was added rapidly dropwise. The reaction mixture was allowed to warm to room temperature and then stirred overnight. The reaction mixture was cooled in an ice-bath, diluted with THF (1.51), decomposed with saturated NH4Cl, and the THF layer was washed three times with 200 ml of saturated ammonium chloride. The aqueous layers were back-washed with THF (200 ml×3). The organic layers were combined and dried over MgSO4 and evaporated to give an oil. A one-fifth portion of the oil was purified by flash chromatography on silica gel and elution with 30% ethyl acetate/ether afforded the desired product diol (19.7 g).
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Li+].Br[CH2:6][C@H:7]1[C:12]2[C:13]([CH3:19])=[CH:14][CH:15]=[C:16]([O:17][CH3:18])[C:11]=2[CH2:10][C@@H:9]([CH2:20][OH:21])[O:8]1.C(OCC)C.O>CN(C=O)C>[N:1]([CH2:6][C@H:7]1[C:12]2[C:13]([CH3:19])=[CH:14][CH:15]=[C:16]([O:17][CH3:18])[C:11]=2[CH2:10][C@@H:9]([CH2:20][OH:21])[O:8]1)=[N+:2]=[N-:3]
Reactant: COc1ccc(C)c2c1C[C@@H](CO)O[C@H]2CBr
Reactant: [N-]=[N+]=[N-]
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: CCOCC
Solvent: O
Product: COc1ccc(C)c2c1C[C@@H](CO)O[C@H]2CN=[N+]=[N-]
Temperature: 70 °C

Procedure:
Lithium azide (1.0 g, 20 mmol) is added to a solution of [1R,3S] 1-bromomethyl-3,4-dihydro-3-hydroxymethyl-5-methoxy-8-methyl-1H-2-benzopyran (1.77 g, 5.87 mmol), from Step 3, in 20 mL of DMF. The reaction mixture is heated to 70° C. for 1.5 h then cooled to ambient temperature and poured into 50 mL of diethyl ether and 50 mL of water. The layers are separated and the aqueous layer is extracted with 2×50 mL of diethyl ether. The combined ether layers are washed with saturated aqueous sodium bicarbonate solution, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue is purified by column chromatography on silica gel to give the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:11])[CH2:5][CH:6]([OH:10])[CH2:7][CH2:8][CH3:9])[CH3:2].[C:12]([CH2:14][C:15](O)=[O:16])#[N:13].CN(C=O)C.C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:11])[CH2:5][CH:6]([O:10][C:15](=[O:16])[CH2:14][C:12]#[N:13])[CH2:7][CH2:8][CH3:9])[CH3:2]
Reactant: CCCC(O)CC(=O)OCC
Reactant: N#CCC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCCC(CC(=O)OCC)OC(=O)CC#N

Procedure:
A mixture of 100.14 g of ethyl-3-hydroxyhexanoate, 63.75 g of cyanoacetic acid, and 4.58 g of 4-dimethylaminopyridine (DMAP) in 625 ml of CH2Cl2 was stirred in a 2 L three-neck round bottom flask equipped with a mechanical stirrer. About 31 ml of N-N′-dimethylformide (DMF) was added to make a clear solution. The above clear solution was chilled in an ice water bath. A separately prepared dicyclohexylcarbodiimide (DCC) solution (154.75 g in 250 ml CH2Cl2) was added to the above chilled solution by using an addition funnel. White precipitate formed within five minutes after the start of the addition. The reaction mixture was left stirred overnight.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=S)[N:6]([CH2:13][CH2:14][CH3:15])[C:5]2=[O:16].C(Cl)([Cl:19])=O>C(OCCC)(=O)C>[Cl:19][C:7]1[N:6]([CH2:13][CH2:14][CH3:15])[C:5](=[O:16])[C:4]2[C:9](=[CH:10][CH:11]=[C:2]([I:1])[CH:3]=2)[N:8]=1
Reactant: CCCn1c(=S)[nH]c2ccc(I)cc2c1=O
Reactant: O=C(Cl)Cl
Solvent: CCCOC(C)=O
Product: CCCn1c(Cl)nc2ccc(I)cc2c1=O
Yield: 101.4 %

Procedure:
2,3-Dihydro-6-iodo-3-propyl-2-thioxo-4(1H)-quinazolinone (5 g, 0.014 mol) was slurried in n-propyl acetate and treated with phosgene (2.1 mL, 0.029 mol). The slurry was heated at reflux for 1 h. The excess phosgene was removed by co-distillation with n-propyl acetate at atmospheric pressure. The pot residue was then evaporated to dryness under vacuum. In this manner, 4.95 g of the title compound was obtained as a light pink solid. m.p. 98-100° C.; 1H NMR (Me2SO-d6): δ8.04 (d,1H), 8.16 (dd,1H), 7.31 (d,1H), 4.20 (m,2H), 1.78 (m,2H), 0.97 (t,3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]12[CH2:15][N:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:13][CH:12]1[CH2:11][O:10][NH:9]2.C(O)(=O)C.C(=O)(O)[O-].[Na+]>C(OCC)(=O)C.O.[Zn]>[NH2:9][C:8]1([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[F:1])[CH:12]([CH2:11][OH:10])[CH2:13][N:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:15]1
Reactant: CC(C)(C)OC(=O)N1CC2CONC2(c2ccccc2F)C1
Agent: O=C([O-])O
Agent: [Na+]
Agent: [Zn]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CC(CO)C(N)(c2ccccc2F)C1
Reaction time: 0.5 h
Yield: 87.5 %

Procedure:
A mixture of tert-butyl 6a-(2-fluorophenyl)-3,3a,4,6-tetrahydro-1H-pyrrolo[3,4-c]isoxazole-5-carboxylate (5 g, 16.2 mmol) and zinc dust (10.6 g 0.16 mol) is treated with acetic acid (65 mL) in one portion under nitrogen at room temperature. The resulting mixture is stirred for 0.5 hour, diluted with ethyl acetate, and filtered through diatomaceous earth. The filtrate is added drop-wise to a mixture of saturated sodium bicarbonate in water containing an excess of solid sodium bicarbonate (84 g, 1 mol). The mixture is extracted with ethyl acetate, the organic phase is dried over magnesium sulfate, and the solvent removed under vacuum. The residue is purified by silica gel chromatography eluting with ethyl acetate to give the title compound (4.4 g, 87%). ES/MS (m/e): 311(M+H).