Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Li+].[OH:3][CH2:4][C:5]1[CH:10]=[C:9]([CH3:11])[N:8]=[C:7]([O:12][C@@H:13]([C:18]([O:31][CH3:32])([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:14]([O:16][CH3:17])=[O:15])[N:6]=1.[CH2:33](Br)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>O1CCCC1.CN(C)C=O>[CH2:33]([O:3][CH2:4][C:5]1[CH:10]=[C:9]([CH3:11])[N:8]=[C:7]([O:12][C@@H:13]([C:18]([O:31][CH3:32])([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:14]([O:16][CH3:17])=[O:15])[N:6]=1)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: COC(=O)[C@@H](Oc1nc(C)cc(CO)n1)C(OC)(c1ccccc1)c1ccccc1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COC(=O)[C@@H](Oc1nc(C)cc(COCc2ccccc2)n1)C(OC)(c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 68.7 %

Procedure:
To a 0° C. mixture of lithium hydride (0.235 g, 29.4 mmol) in tetrahydrofuran and dimethylformamide (30 mL: 10 mL) is added the compound of Example 11 (3.0 g, 7.3 mmol) and the mixture stirred for 0.5 hr. Benzyl bromide (1.257 g, 7.3 mmol) is then added and the reaction stirred 12 hr at room temperature. The reaction is poured into ice-water (100 mL) and the quenched mixture extracted with ethyl acetate (2×100 mL). Concentration gives crude product that is purified by column chromatography on silica gel eluted with ethyl acetate-hexane (1:9) to yield the title compound (2.5 g, 69%). MS m/z 499.0 (M+.1).
Reaction SMILES: [NH2:1][C@H:2]([C:6]([OH:8])=[O:7])[CH:3]([CH3:5])[CH3:4].[O:9]1[CH:13]=[CH:12][CH:11]=[C:10]1[C:14]1[O:18][C:17](=[O:19])[C:16]2([CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)[N:15]=1>CN1CCOCC1>[O:9]1[CH:13]=[CH:12][CH:11]=[C:10]1[C:14]([NH:15][C:16]1([C:17]([NH:1][C@H:2]([C:6]([OH:8])=[O:7])[CH:3]([CH3:5])[CH3:4])=[O:19])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1)=[O:18]
Reactant: CC(C)[C@H](N)C(=O)O
Reactant: O=C1OC(c2ccco2)=NC12CCCCC2
Solvent: CN1CCOCC1
Product: CC(C)[C@H](NC(=O)C1(NC(=O)c2ccco2)CCCCC1)C(=O)O
Yield: 12.5 %

Procedure:
10 ml of N-methylmorpholine was added to 1.0 g (9.1 mmol) of L-valine and 2.0 g (9.1 mmol) of 2-(2-furanyl)-3-oxa-1-azaspiro[4.5]dec-1-en-4-one, and the mixture was stirred and heated under reflux overnight. Under reduced pressure the reaction mixture was distilled off, ethyl acetate was added thereto, and the mixture was washed with a 10% aqueous potassium hydrogensulfate solution and then saturated brine, followed by drying with anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel chromatography to obtain 384 mg (12.5%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].Br.[NH2:15][C:16]1[S:17][C:18]([Br:21])=[CH:19][N:20]=1>N1C=CC=CC=1>[Br:21][C:18]1[S:17][C:16]([NH:15][C:6](=[O:7])[C:5]2[CH:9]=[CH:10][C:2]([Cl:1])=[C:3]([N+:11]([O-:13])=[O:12])[CH:4]=2)=[N:20][CH:19]=1
Reactant: O=C(Cl)c1ccc(Cl)c([N+](=O)[O-])c1
Reactant: Nc1ncc(Br)s1
Agent: Br
Solvent: c1ccncc1
Product: O=C(Nc1ncc(Br)s1)c1ccc(Cl)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 68.8 %

Procedure:
A solution of 4-chloro-3-nitrobenzoyl chloride (1.539 g, 7.694 mmol) in anhydrous pyridine (40 mL) was treated with 2-amino-5-bromothiazole monohydrobromide (2.00 g, 7.694 mmol), and the reaction stirred under a nitrogen atmosphere at room temperature for 18 hours. The solvent was removed by rotary evaporation in vacuo and the oil dried on hi-vacuum. The residue was taken up in ethyl acetate (150 mL) and washed with water (4×50 mL) and brine (50 mL), then dried the organic phase over anhydrous sodium sulfate, filtered, and concentrated in vacuo. Trituration with 6% ethyl acetate/methylene chloride afforded the title compound as a pinkish-tan solid (1.92 g, 69%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:31]=[CH:32][CH:33]=1)[CH2:5][NH:6][C:7]([C:9]1[CH:22]=[CH:21][C:20]2[S:19][C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[N:12]([CH:23]([CH3:30])[CH2:24][N:25]3[CH2:29][CH2:28][CH2:27][CH2:26]3)[C:11]=2[CH:10]=1)=S.C(O)(=O)/C=C/C(O)=[O:38]>C(O)(=O)C.C(O)C>[F:1][C:2]1[CH:3]=[C:4]([CH:31]=[CH:32][CH:33]=1)[CH2:5][NH:6][C:7]([C:9]1[CH:22]=[CH:21][C:20]2[S:19][C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[N:12]([CH:23]([CH3:30])[CH2:24][N:25]3[CH2:29][CH2:28][CH2:27][CH2:26]3)[C:11]=2[CH:10]=1)=[O:38]
Reactant: CC(CN1CCCC1)N1c2ccccc2Sc2ccc(C(=S)NCc3cccc(F)c3)cc21
Reactant: O=C(O)/C=C/C(=O)O
Solvent: CC(=O)O
Solvent: CCO
Product: CC(CN1CCCC1)N1c2ccccc2Sc2ccc(C(=O)NCc3cccc(F)c3)cc21
Temperature: 20 °C
Reaction time: 20 h
Yield: 70.4 %

Procedure:
Mercuric acetate (0.80 g) is added to a solution of N-(3-fluorobenzyl)-10-[(2RS)-1-(1-pyrrolidinyl)-2-propyl]-2-phenothiazinecarbothioamide neutral fumarate (1.30 g) in acetic acid (20 cc), and the mixture obtained is stirred for 20 hours at a temperature in the region of 20° C. The black suspension obtained is filtered on sintered glass plugged with celite and the yellow filtrate is concentrated under reduced pressure (30 mm Hg; 4 kPa) at 40° C. The residue is taken up with ethyl acetate (100 cc) and the organic phase is washed successively with normal sodium hydroxide (2×20 cc) and distilled water (2×20 cc) and with aqueous sodium chloride solution (20 cc) and dried over magnesium sulphate. After filtration, the yellow filtrate is concentrated under reduced pressure (30 mm Hg; 4 kPa) at 40° C. and a crude yellow oil (0.90 g) is thereby obtained. This residue is dissolved in hot ethanol (3 cc) and treated with fumaric acid (0.25 g) dissolved in ethanol (2 cc). After 4 hours' cooling to 4° C., the crystallized solid is separated by filtration, washed with cold ethanol (2×5 cc) and then dried at 50° C. under reduced pressure (5 mm Hg; 0.7 kPa) to give N-(3-fluorobenzyl)-10-[(2RS)-1-(1-pyrrolidinyl)-2-propyl]-2-phenothiazinecarboxamide neutral fumarate (0.7 g), m.p. 165° C.
Reaction SMILES: [CH3:1][C:2]([C:5]1[C:10]([CH3:11])=[CH:9][C:8]([OH:12])=[C:7]([CH:13]([CH3:15])[CH3:14])[CH:6]=1)([CH3:4])[CH3:3].[CH2:16]=[O:17].[OH-].[K+].O>CCCCCC>[CH3:4][C:2]([C:5]1[CH:6]=[C:7]([CH:13]([CH3:15])[CH3:14])[C:8]([OH:12])=[C:9]([CH2:16][OH:17])[C:10]=1[CH3:11])([CH3:1])[CH3:3]
Reactant: C=O
Reactant: Cc1cc(O)c(C(C)C)cc1C(C)(C)C
Agent: [K+]
Agent: [OH-]
Solvent: CCCCCC
Solvent: O
Product: Cc1c(C(C)(C)C)cc(C(C)C)c(O)c1CO
Temperature: 25 °C
Yield: 8.6 %

Procedure:
A mixture of 4-(1,1-dimethylethyl)-2-(1-methylethyl)-5-methylphenol (103.2 g, 0.5 mol), 40% formaldehyde solution (375 mL, 5 mol), potassium hydroxide (49.5 g, 0.75 mol) and poly(ethylene glycol) avg. M.W. 300 (1 g) was heated at reflux for 24 hour. The mixture was cooled to 25° C. and water (1 L) and hexane (700 mL) were added. The aqueous layer was extracted with hexane (2×100 mL). The combined organic extracts were washed with water (3×100 mL), brine (2×100 mL) and dried (Na2SO4). Evaporation of solvents and crystallization of the residue from hexane gave 10.2 g (8.6% yield) of 5-(1,1-dimethylethyl)-6-methyl-3-(1-methylethyl)-2-hydroxy benzenemethanol, mp 143°-146° C.; 1H-NMR (CDCl3)δ 1.25 (6H, d, J=7 Hz), 1.40 (9H, s), 2.31 (3H, s), 3.0-3.6 (1H, m), 4.85 (2H, s), 7.01 (1H, s), 7.23 (1H, s); IR (CHCl3)νmax 3550, 3350, 2940, 1575, 1470, 1360 cm-1 ; M m/e 236, 218, 206, 203, 191, 161, UVλmax (ethanol) 224 nm (ε=6690), 287 nm (ε=2480).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11]([O:13]C)=O)=[CH:3]1.[CH3:15][NH2:16]>>[CH3:15][NH:16][C:11]([C:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[N:2]([CH3:1])[CH:3]=1)=[O:13]
Reactant: CN
Reactant: COC(=O)c1cn(C)c2ccccc12
Product: CNC(=O)c1cn(C)c2ccccc12
Temperature: 25 °C
Yield: 56 %

Procedure:
A suspension of methyl 1-methyl-1H-indole-3-carboxylate (4.30 g, 22.74 mmole) in 40% aqueous CH3NH2 (400 mL) was stirred at RT. The flask was tightly stoppered to keep the material inside the flask. As the reaction proceeded the product began to precipitate. The reaction was stirred at RT for 3 days, then was concentrated to remove approximately 200 mL of the solvent. The remaining residue was diluted with H2O (500 mL), and the solid was collected by suction filtration and washed with H2O. Flash chromatography on silica gel (ethyl acetate) gave the title compound (2.4 g, 56%) as a white solid: MS (ES) m/e 189 (M+H)+.
Reaction SMILES: C1(P(=[CH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH:28]([C:30]1[C:38]2[C:33](=[CH:34][C:35]([C:39]#[N:40])=[CH:36][CH:37]=2)[NH:32][CH:31]=1)=O>C(#N)C>[C:39]([C:35]1[CH:34]=[C:33]2[C:38]([C:30](/[CH:28]=[CH:20]/[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])=[CH:31][NH:32]2)=[CH:37][CH:36]=1)#[N:40]
Reactant: N#Cc1ccc2c(C=O)c[nH]c2c1
Reactant: CC(C)(C)OC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CC#N
Product: CC(C)(C)OC(=O)/C=C/c1c[nH]c2cc(C#N)ccc12
Reaction time: 3.5 h
Yield: 58.4 %

Procedure:
1,1-Dimethylethyl (triphenyl-λ5-phosphanylidene)acetate (1.540 g) was added to a suspension of 3-formyl-1H-indole-6-carbonitrile (D13) (604 mg) in acetonitrile (20 mL) at RT. The reaction mixture was heated to refluxing and stirred for 3.5 hours. Another portion of 1,1-dimethylethyl (triphenyl-λ5-phosphanylidene)acetate (1 g) was added and the resulting suspension was refluxed for 3 more hours. Another portion of 1,1-dimethylethyl (triphenyl-λ5-phosphanylidene)acetate (1 g) was added and the resulting suspension was refluxed for 2.5 more hours. Another portion of 1,1-dimethylethyl (triphenyl-λ5-phosphanylidene)acetate (1 g) was added and the resulting suspension was refluxed for 3 more hours. Another portion of 1,1-dimethylethyl (triphenyl-λ5-phosphanylidene)acetate (1.5 g) was added and the resulting suspension was refluxed for 3.5 more hours. The solvent was evaporated. The residue was purified by Biotage (33% EtOAc in hexane) to afford 1,1-dimethylethyl (2E)-3-(6-cyano-1H-indol-3-yl)-2-propenoate (D14) as a white solid (556 mg). MS (ES): C16H16N2O2 requires 268; found 267.0 (M−H+).
Reaction SMILES: [OH:1][CH:2]1[C:9](=[CH2:10])[CH2:8][C@H:7]2[C@@H:3]1[CH2:4][C@@H:5]([O:27][Si:28]([C:31]([CH3:34])([CH3:33])[CH3:32])([CH3:30])[CH3:29])[C@H:6]2/[CH:11]=[CH:12]/[C@@H:13]([O:19][Si:20]([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21])[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[C:35]1([CH3:45])[CH:40]=[CH:39][C:38]([S:41](Cl)(=[O:43])=[O:42])=[CH:37][CH:36]=1>>[C:35]1([CH3:45])[CH:40]=[CH:39][C:38]([S:41]([O:1][CH:2]2[C:9](=[CH2:10])[CH2:8][C@H:7]3[C@@H:3]2[CH2:4][C@@H:5]([O:27][Si:28]([C:31]([CH3:33])([CH3:32])[CH3:34])([CH3:29])[CH3:30])[C@H:6]3/[CH:11]=[CH:12]/[C@@H:13]([O:19][Si:20]([C:23]([CH3:24])([CH3:25])[CH3:26])([CH3:21])[CH3:22])[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])(=[O:43])=[O:42])=[CH:37][CH:36]=1
Reactant: C=C1C[C@@H]2[C@H](/C=C/[C@H](CCCCC)O[Si](C)(C)C(C)(C)C)[C@H](O[Si](C)(C)C(C)(C)C)C[C@@H]2C1O
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Product: C=C1C[C@@H]2[C@H](/C=C/[C@H](CCCCC)O[Si](C)(C)C(C)(C)C)[C@H](O[Si](C)(C)C(C)(C)C)C[C@@H]2C1OS(=O)(=O)c1ccc(C)cc1
Yield: 77.1 %

Procedure:
In the same way as in Example 8, (1S,2RS,5S,6S,7R)-2-hydroxy-3-methylene-6-[(E,3S)-3-t-butyldimethylsilyloxy- 1-octenyl]-7-t-butyldinmethylsilyloxybicyclo[3.3.0]octane (178 mg, 0.35 mmole) obtained in Example 3 was reacted with p-toluenesulfonyl chloride (133 mg, 0.70 mmole). The reaction mixture was worked up and column-chromatographed to give (1S,2RS,5S,6S,7R)-2-p-toluenesulfonyloxy-3-methylene-6-[(E,3S)-3-t-butyldimethylsilyloxy-l-octenyl]-7-t-butyldimethylsilyloxybicyclo[3.3.0]octane (179 mg, 0.27 mmole, 78%).
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:3]=1[CH:4]=O.C(O)(=O)[CH2:12][C:13]([OH:15])=[O:14].N1CCCCC1>N1C=CC=CC=1>[F:1][C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:3]=1[CH:4]=[CH:12][C:13]([OH:15])=[O:14]
Reactant: O=C(O)CC(=O)O
Reactant: O=Cc1ccc(F)cc1F
Solvent: C1CCNCC1
Solvent: c1ccncc1
Product: O=C(O)C=Cc1ccc(F)cc1F
Temperature: 100 °C
Reaction time: 2 h
Yield: 73.3 %

Procedure:
2,4-Difluoro-benzaldehyde (10.0 g, 70.4 mmol), malonic acid (16.5 g, 158.3 mmol), and piperidine (5.8 mL, 58.4 mmol) were added to pyridine (42.7 mL). The reaction mixture was stirred at 100° C. for 2 hours, concentrated under reduced pressure, and then distilled water was added thereto. The mixture was filtered and then the resulting solid was dried under reduced pressure to give 9.5 g of the titled compound as a yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([C:9]([OH:11])=O)=[CH:7][C:6]([C:12]([NH2:14])=[O:13])=[CH:5][CH:4]=1.[F:15][C:16]([F:25])([F:24])[C:17]1[CH:18]=[C:19]([CH:21]=[CH:22][CH:23]=1)[NH2:20]>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:12]([NH2:14])=[O:13])=[CH:7][C:8]=1[C:9]([NH:20][C:19]1[CH:21]=[CH:22][CH:23]=[C:17]([C:16]([F:15])([F:24])[F:25])[CH:18]=1)=[O:11]
Reactant: Nc1cccc(C(F)(F)F)c1
Reactant: COc1ccc(C(N)=O)cc1C(=O)O
Product: COc1ccc(C(N)=O)cc1C(=O)Nc1cccc(C(F)(F)F)c1

Procedure:
The captioned compound was synthesized from 6-methoxyisophthalamic acid and 3-trifluoromethylaniline by the same procedure as in the manufacturing method described in step C of Example 1-3-1.
Reaction SMILES: [CH:1]([NH:4][NH:5][C:6](=[O:15])[C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[C:9]([Cl:14])[CH:8]=1)([CH3:3])[CH3:2].[C:16](Cl)(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[OH-]>C(Cl)CCl>[C:16]([N:4]([CH:1]([CH3:3])[CH3:2])[NH:5][C:6](=[O:15])[C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[C:9]([Cl:14])[CH:8]=1)(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CC(C)NNC(=O)c1ccc(Cl)c(Cl)c1
Reactant: O=C(Cl)c1ccccc1
Agent: [OH-]
Solvent: ClCCCl
Product: CC(C)N(NC(=O)c1ccc(Cl)c(Cl)c1)C(=O)c1ccccc1

Procedure:
A mixture of 3,4-dichlorobenzoic acid, 2-isopropylhydrazide (0.98 g, 0.004 mole) and benzoyl chloride (0.56 g, 0.004 mole) is stirred overnight in 1.2 mL of ethylene dichloride and 6.5 mL of 10% soldium hydroxide. The organic phase is removed and the aqueous mixture is extracted with 25 mL of ethylene dichloride. The organic extracts are combined and concentrated to a yellow oil which is taken up in hot isopropyl alcohol. Cooling the alcohol solution causes precipitation of the title compound as a white crystalline product, which is collected by filtration and has a mp of 157° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[CH2:10][NH:9][CH2:8][CH2:7][N:6]1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[O:4].[CH2:18](Cl)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(N(CC)CC)C>C(#N)C>[CH3:1][O:2][C:3]([C@@H:5]1[CH2:10][N:9]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:8][CH2:7][N:6]1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[O:4]
Reactant: ClCc1ccccc1
Reactant: COC(=O)[C@@H]1CNCCN1C(=O)OC(C)(C)C
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COC(=O)[C@@H]1CN(Cc2ccccc2)CCN1C(=O)OC(C)(C)C
Temperature: 71 °C
Yield: 52 %

Procedure:
To a dry 100.0 ml one necked round bottom flask equipped with a stirring bar is added (S)-1-N-Boc-piperazine-2-carboxylic methyl ester (800 mg, 3.275 mmol) under N2. Anhydrous acetonitrile (20 ml) is added to the flask followed by benzyl chloride (0.38 ml, 3.275 mmol) and triethylamine (1.28 ml, 9.17 mmol). Condenser is then put on to the flask and the reaction mixture is heated at 71° C. for 20 minutes. The reaction mixture is allowed to come to room temperature and concentrated under reduced pressure. It is then diluted with dicholoromethane and washed with water and brine. The organic layer is dried over Na2SO4, filtered and concentrated under reduced pressure. The crude compound is flash column purified using hexane and ethylacetate gradient solvent system to yield 570 mg (52%) of the desired product.
Reaction SMILES: [CH3:1][C:2]1[C:9]([C:10]([F:21])([F:20])[C:11]([F:19])([F:18])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4]Br.[C:22]1(=[O:32])[NH:26][C:25](=[O:27])[C:24]2=[CH:28][CH:29]=[CH:30][CH:31]=[C:23]12.[K]>CN(C)C=O>[CH3:1][C:2]1[C:9]([C:10]([F:21])([F:20])[C:11]([F:19])([F:18])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][N:26]1[C:25](=[O:27])[C:24]2=[CH:28][CH:29]=[CH:30][CH:31]=[C:23]2[C:22]1=[O:32]
Reactant: Cc1c(CBr)cccc1C(F)(F)C(F)(F)c1ccccc1
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: CN(C)C=O
Product: Cc1c(CN2C(=O)c3ccccc3C2=O)cccc1C(F)(F)C(F)(F)c1ccccc1

Procedure:
A mixture of 8.02 g. (0.022 mole) of 2-methyl-3-(α,α,β,β-tetrafluorophenethyl)-benzyl bromide, 4.10 g. (0.022 mole) of potassium phthalimide, and 40 ml. of dimethylformamide is stirred 30 minutes at room temperature, 4 hours at 95°C., and 3 hours at reflux. The cooled mixture is diluted with 100 ml. of chloroform and washed with 150 ml. of water. After re-extraction of the aqueous layer with chloroform, the combined organic extracts are washed with 0.1 N. sodium hydroxide, water, dried over anhydrous magnesium sulfate, and evaporated to dryness in vacuo. Recrystallization of the residual solid from isopropyl alchol affords the white crystalline product, m.p. 135°-137°C.
Reaction SMILES: [CH3:1][C:2]12[CH2:17][N:16](C(OC(C)(C)C)=O)[CH2:15][CH2:14][CH:3]1[N:4]1[CH2:13][CH2:12][O:11][C:6]3[CH:7]=[CH:8][CH:9]=[C:10]2[C:5]1=3.FC(F)(F)C(O)=O.[OH-].[Na+]>C(Cl)Cl>[CH3:1][C:2]12[CH2:17][NH:16][CH2:15][CH2:14][CH:3]1[N:4]1[CH2:13][CH2:12][O:11][C:6]3[CH:7]=[CH:8][CH:9]=[C:10]2[C:5]1=3
Reactant: CC(C)(C)OC(=O)N1CCC2N3CCOc4cccc(c43)C2(C)C1
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC12CNCCC1N1CCOc3cccc2c31
Temperature: 25 °C
Reaction time: 4 h
Yield: 91.5 %

Procedure:
tert-Butyl 6b-methyl-1,2,6b,9,10,10a-hexahydro[1,4]-oxazino[2,3,4-hi]pyrido[4,3-b]indole-8(7H)-carboxylate (0.0711 g, 0.215 mmol) was dissolved in CH2Cl2 (2 mL). Trifluoroacetic acid (0.50 mL, 0.46 mmol) was added and the reaction mixture was stirred in a sealed reaction vessel for 4 hours at room temperature. The reaction mixture was cooled in an ice bath and 1N aqueous NaOH (15 mL) was added and the resulting mixture was extracted with CH2Cl2 (2×25 mL) and 25:1 CH2Cl2:CH3OH (1×26 mL). The combined organic extracts were dried over Na2SO4, filtered and concentrated to yield a crude product (0.0464 g), which was purified by chromatography (SiO2 10 g, eluted with 90:10:1 CH2Cl2:CH3OH:concentrated aqueous NH4OH) to yield 6b-methyl-1,2,6b,7,8,9,10,10a-octahydro[1,4]oxazino[2,3,4-hi]pyrido[4,3-b]indole (0.0453 g) in 91% yield. 1H NMR (400 MHz, CD3OD) δ1.42 (s, 3 H), 1.78-1.87 (m, 1 H), 1.90-1.96 (m, 1 H), 2.68 (ddd, J=10.8, 9.5, 3.5 Hz, 1 H), 2.71 (d, J=13.3 Hz, 1H), 2.74 (d, J=13.3 Hz, 1 H), 2.81-2.94 (m, 3 H) 3.40 (ddd, J=11.0, 2.1, 2.1 Hz, 1 H), 4.37-4.47 (m,2H), 6.53 (dd, J=7.5, 1.7 Hz, 1 H), 6.59-6.65 (m, 2 H); 1.96 (m, 1 H MS (ESI+) for C14H18N2O m/z 231.1 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][C:10]([OH:12])=O)[CH:6]=[CH:7][CH:8]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:37][C:38]1[N:43]([C:44]2[CH:49]=[CH:48][C:47]([NH2:50])=[CH:46][CH:45]=2)[CH2:42][N:41]=[C:40]2[O:51][CH:52]=[CH:53][C:39]=12.C(N(CC)C(C)C)(C)C>CN(C=O)C>[NH2:37][C:38]1[N:43]([C:44]2[CH:45]=[CH:46][C:47]([NH:50][C:10](=[O:12])[CH2:9][C:5]3[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=3)=[CH:48][CH:49]=2)[CH2:42][N:41]=[C:40]2[O:51][CH:52]=[CH:53][C:39]=12
Reactant: NC1=c2ccoc2=NCN1c1ccc(N)cc1
Reactant: COc1cccc(CC(=O)O)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cccc(CC(=O)Nc2ccc(N3CN=c4occc4=C3N)cc2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The carboxylic acid of choice (3-methoxyphenyl acetic acid, 0.055 mmol) and 0.055 mmol of HBTU were dissolved in 0.5 mL amine-free DMF. To this solution was added dropwise a solution of 4-Amino-3-(4-aminophenyl)furo[2,3-d]pyrimidine (9) in 0.5 mL DMF. The resulting solution was treated with 0.024 mL of N,N-diisopropylethylamine. The system was stirred at room temperature overnight and then was concentrated to dryness in a Speedvac system, reconstituted in 1 mL DMSO and purified by prep HPLC to give the title compound. MS(ES) m/e 375 [M+H]+.
Reaction SMILES: [CH2:1]([N:8]([CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:9]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]#[C:19][Si](C)(C)C)=[CH:14][CH:13]=2)[CH2:11][CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+]>CO>[CH2:24]([N:8]([CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:9]1([C:12]2[CH:13]=[CH:14][C:15]([C:18]#[CH:19])=[CH:16][CH:17]=2)[CH2:11][CH2:10]1)[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: C[Si](C)(C)C#Cc1ccc(C2(N(Cc3ccccc3)Cc3ccccc3)CC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: C#Cc1ccc(C2(N(Cc3ccccc3)Cc3ccccc3)CC2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Using General Procedure E; dibenzyl-[1-(4-trimethylsilanylethynyl-phenyl)-cyclopropyl]-amine (Intermediate 128, 100.0 mg, 0.26 mmol) in methanol (5 mL) was treated with potassium carbonate (60.0 mg, 0.44 mmol) and stirred overnight at ambient temperature. The crude alkyne (80 mg, 99%) was used directly in the next reaction.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([CH2:13][O:14][C:15]3[CH:16]=[CH:17][C:18]([C:21](O)=[O:22])=[N:19][CH:20]=3)=[C:11]([CH2:24][OH:25])[O:10][N:9]=2)=[CH:4][CH:3]=1.[CH3:26][N:27]1[CH:31]=[C:30]([NH2:32])[CH:29]=[N:28]1>>[CH3:26][N:27]1[CH:31]=[C:30]([NH:32][C:21]([C:18]2[CH:17]=[CH:16][C:15]([O:14][CH2:13][C:12]3[C:8]([C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=4)=[N:9][O:10][C:11]=3[CH2:24][OH:25])=[CH:20][N:19]=2)=[O:22])[CH:29]=[N:28]1
Reactant: Cn1cc(N)cn1
Reactant: O=C(O)c1ccc(OCc2c(-c3ccc(F)cc3)noc2CO)cn1
Product: Cn1cc(NC(=O)c2ccc(OCc3c(-c4ccc(F)cc4)noc3CO)cn2)cn1
Yield: 54 %

Procedure:
As described for example 34b, 5-[3-(4-fluoro-phenyl)-5-hydroxymethyl-isoxazol-4-ylmethoxy]-pyridine-2-carboxylic acid (75 mg, 0.22 mmol) was converted, using 1-methyl-1H-pyrazol-4-ylamine instead of S-(+)-1-amino-2-propanol, to the title compound (50 mg, 54%), which was obtained as a colourless gum. MS: m/e=424.2 [M+H]+.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH2:25]([O:32][N:33]1[C:39](=[O:40])[N:38]2[CH2:41][C@H:34]1[CH2:35][CH2:36][C@H:37]2[C:42]([NH:44][NH2:45])=[O:43])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.[NH2:46][C:47](=[O:51])[C:48](O)=[O:49].CCN(C(C)C)C(C)C>CN(C=O)C>[CH2:25]([O:32][N:33]1[C:39](=[O:40])[N:38]2[CH2:41][C@H:34]1[CH2:35][CH2:36][C@H:37]2[C:42]([NH:44][NH:45][C:48](=[O:49])[C:47]([NH2:46])=[O:51])=[O:43])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: NNC(=O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Reactant: NC(=O)C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: NC(=O)C(=O)NNC(=O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 75.1 %

Procedure:
HATU (0.95 g, 2.5 mmol) was added to a 0° C. solution of (2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide (1.00 g, 2.5 mmol), 2-amino-2-oxoacetic acid (0.18 g, 2.1 mmol) and DIPEA (1.08 g, 8.4 mmol) in DMF (10 mL). The reaction mixture was stirred at 0° C. for 1 h then quenched with saturated sodium chloride (50 mL) and the organic layer was separated. The aqueous layer was exacted with EtOAc (3×). The combined organic layer was washed with saturated sodium chloride (2×), dried over Na2SO4, and concentrated. The residue was purified by silica gel column chromatography (1:1 EtOAc/hexane) to give 2-(2-((2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carbonyl)hydrazinyl)-2-oxoacetamide (0.57 g, 64%). ESI-MS (EI+, m/z): 362 [M+H]+.