Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH:2]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:3][CH2:4][C:5]([N:7]1[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1)=[O:6].[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1>C(Cl)Cl>[O:1]=[C:2]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:3][CH2:4][C:5]([N:7]1[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1)=[O:6]
Reactant: O=C(CCC(O)c1ccccc1)N1CCCCC1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: O=C(CCC(=O)N1CCCCC1)c1ccccc1
Temperature: 25 °C
Reaction time: 2.25 h
Yield: 92.1 %

Procedure:
A mixture of 4-hydroxy-4-phenyl-1-piperidine-1-yl-butan-1-one (4.00 g, 16.2 mmol), prepared in the previous step, and pyridinium chlorochromate (5.23 g, 24.3 mmol) in 150 ml of methylene chloride was stirred at room temperature for 2.25 hours. The reaction was poured onto 400 g of silica gel (230-400 mesh) and the material eluted with methylene chloride-ethyl acetate. Isolation of the major component gave 4-oxo-4-phenyl-1-piperidine-1-yl-butan-1-one (3.66 g, 92%) as a green solid. Recrystallization of a portion of this solid from ethyl acetate-hexane gave an analytically pure sample, mp 52-54° C.
Reaction SMILES: [CH2:1]([Li])CCC.[CH:6]([C:8]1[N:9]=[C:10](/[CH:13]=[CH:14]/[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[O:11][CH:12]=1)=O.O.C(OCC)(=O)C>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCCC1>[CH:13](/[C:10]1[O:11][CH:12]=[C:8]([CH:6]=[CH2:1])[N:9]=1)=[CH:14]\[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=Cc1coc(/C=C/c2ccccc2)n1
Reactant: [Li]CCCC
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: C=Cc1coc(/C=C/c2ccccc2)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
n-Butyllithium (1.54N hexane solution, 14.2 ml) was added dropwise to a solution of methyl-triphenylphosphonium bromide (8.16 g) in tetrahydrofuran (80 ml) at 0° C., and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was cooled again to 0° C., a solution of 4-formyl-2-(trans-styryl)oxazole (3.64 g) in tetrahydrofuran (20 ml) was added, and the mixture was warmed to room temperature. After stirring for 2 hours, water (200 ml) and ethyl acetate (100 ml) were added and an organic layer was separated. The water layer was extracted with ethyl acetate (50 ml). After the organic layers were combined, washed with saturated saline (100 ml) and dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The residue was purified by column chromatography on silica gel (hexane:ethyl acetate=4:1→3:1) to obtain the title compound (2.84 g) as a pale yellow oil.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[O:7][C:6](=[O:8])[N:5]([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH2:16][CH2:17][N:18]([CH2:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[CH2:19][CH:20]=3)=[C:11]([F:28])[CH:10]=2)[CH2:4]1.C(N(C(C)C)CC)(C)C.C1(C)C(S([NH:47][N:48]=[C:49]([CH3:53])[CH:50](Cl)Cl)(=O)=O)=CC=CC=1.CO>C(OCC)(=O)C>[CH2:21]([N:18]1[CH2:17][CH:16]=[C:15]([C:12]2[CH:13]=[CH:14][C:9]([N:5]3[CH2:4][C@H:3]([CH2:2][N:1]4[CH:50]=[C:49]([CH3:53])[N:48]=[N:47]4)[O:7][C:6]3=[O:8])=[CH:10][C:11]=2[F:28])[CH2:20][CH2:19]1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: NC[C@H]1CN(c2ccc(C3=CCN(Cc4ccccc4)CC3)c(F)c2)C(=O)O1
Reactant: CC(=NNS(=O)(=O)c1ccccc1C)C(Cl)Cl
Solvent: CCOC(C)=O
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cn(C[C@H]2CN(c3ccc(C4=CCN(Cc5ccccc5)CC4)c(F)c3)C(=O)O2)nn1
Yield: 34 %

Procedure:
(5S)-5-(Aminomethyl)-3-[4-(1-benzyl-1,2,3,6-tetrahydropyridin-4-yl)-3-flurophenyl]-oxazolidin-2-one (Intermediate 57) (13 g, 34 mmol) was reacted with diisopropylethylamine (23 ml, 136 mmol) and 1,1-dichloroacetone toluenesulfonylhydrazone (15.1 g, 51 mmol) as described for Example 3. Chromatography on silica gel with 0-5% methanol in ethyl acetate gave 5.17 g of the title product.
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][C:5]2[S:6][CH2:7][CH:8]([C:9](=[O:18])[CH2:10]OC3C=CC=CC=3)[C:4]=2[CH:3]=1>S(=O)(=O)(O)O.C(O)(=O)C>[C:9]([C:8]1[C:4]2[CH:3]=[C:2]([Cl:1])[CH:20]=[CH:19][C:5]=2[S:6][CH:7]=1)(=[O:18])[CH3:10]
Reactant: O=C(COc1ccccc1)C1CSc2ccc(Cl)cc21
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: CC(=O)c1csc2ccc(Cl)cc12
Yield: 101.2 %

Procedure:
A mixture of 1-(5-chloro-2,3-dihydrobenzo[b]thiophen-3-yl)-2-phenoxyethanone (15.3 g), acetic acid (75 ml) and concentrated sulphuric acid (15 drops) was heated at 90°-95° C. under nitrogen for 20 hours, then the solvent was removed in vacuo. The residue was partitioned between dichloromethane (250 ml) and 5M aqueous sodium hydroxide solution (100 ml), then the aqueous phase was separated and washed with dichloromethane (50 ml). The combined dichloromethane solutions were washed with water (100 ml), dried (MgSO4), and the solvent removed in vacuo to leave 3-acetyl-5-chlorobenzo[b]thiophen as a red-brown oil (10.7 g) which solidified slowly at ambient temperature.
Reaction SMILES: [O:1]1CCO[CH:2]1[C:6]1[S:7][C:8]([C:11]([OH:13])=[O:12])=[CH:9][N:10]=1>Cl>[CH:2]([C:6]1[S:7][C:8]([C:11]([OH:13])=[O:12])=[CH:9][N:10]=1)=[O:1]
Reactant: O=C(O)c1cnc(C2OCCO2)s1
Agent: Cl
Product: O=Cc1ncc(C(=O)O)s1
Temperature: 25 °C
Yield: 91.4 %

Procedure:
2-(1,3-dioxolan-2-yl)-1,3-thiazole-5-carboxylic acid (1.40 g, 6.96 mmol) was dissolved in 15 mL of 6N HCl and heated to reflux for 30 min and then cooled to ambient temperature. The organics were extracted twice with EtOAc and then dried(Na2SO4), filtered and concentrated to give the title compound (1.00 g, 6.36 mmol, 91% yield) as an orange solid. 1H NMR (CDCl3, 400 MHz) δ 10.0 (s, 1H), 8.66 (s, 1H), 6.70–6.00 (bs, 1H).
Reaction SMILES: [OH:1][C:2]1[CH:24]=[CH:23][C:5]([C:6]([C:8]2[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[O:10][C:9]=2[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:7])=[CH:4][CH:3]=1.[CH2:25]([N:27]([CH2:32][CH3:33])[CH2:28][CH2:29][CH2:30]Cl)[CH3:26].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:25]([N:27]([CH2:32][CH3:33])[CH2:28][CH2:29][CH2:30][O:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([C:8]2[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[O:10][C:9]=2[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)=[O:7])=[CH:23][CH:24]=1)[CH3:26]
Reactant: O=C(c1ccc(O)cc1)c1c(-c2ccccc2)oc2ccccc12
Reactant: CCN(CC)CCCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCN(CC)CCCOc1ccc(C(=O)c2c(-c3ccccc3)oc3ccccc23)cc1

Procedure:
A mixture of 6.2 g. (19.7 mmol.) of 3-(4-hydroxybenzoyl)-2-phenylbenzofuran, 2.95 g. (19.7 mmol.) of 3-diethylaminopropyl chloride and 10.9 g. (0.079 mol.) of potassium carbonate in 300 ml. of acetone is refluxed for 12 hours. After cooling, the mixture is filtered and the filtrate is concentrated to give the title compound.
Reaction SMILES: F[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][N:11]=1)[N:8]=[CH:7][C:6]([C:12]#[N:13])=[C:5]2[NH:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH:21]([CH3:23])[CH3:22])[CH:16]=1.[CH3:24][O:25][C:26]1[CH:31]=[CH:30][C:29]([CH2:32][NH2:33])=[CH:28][CH:27]=1>>[CH:21]([C:17]1[CH:16]=[C:15]([NH:14][C:5]2[C:4]3[C:9](=[CH:10][N:11]=[C:2]([NH:33][CH2:32][C:29]4[CH:30]=[CH:31][C:26]([O:25][CH3:24])=[CH:27][CH:28]=4)[CH:3]=3)[N:8]=[CH:7][C:6]=2[C:12]#[N:13])[CH:20]=[CH:19][CH:18]=1)([CH3:23])[CH3:22]
Reactant: COc1ccc(CN)cc1
Reactant: CC(C)c1cccc(Nc2c(C#N)cnc3cnc(F)cc23)c1
Product: COc1ccc(CNc2cc3c(Nc4cccc(C(C)C)c4)c(C#N)cnc3cn2)cc1
Yield: 25 %

Procedure:
Following the procedure described above in Example 34, 6-fluoro-4-[(3-isopropylphenyl)amino]-1,7-naphthyridine-3-carbonitrile was reacted with (4-methoxyphenyl)methanamine. The crude product was purified by flash column chromatography (1% methanol in methylene chloride) to give a yellow solid (0.209 g, 25%). 1H NMR (400 MHz, DMSO-D6) δ ppm 1.2 (d, J=6.8 Hz, 6 H) 2.8 (none, 1 H) 2.9 (dq, J=6.9 Hz, 1 H) 3.7 (s, 3 H) 4.4 (d, J=6.3 Hz, 2 H) 6.9 (m, 2 H) 7.1 (m, 2 H) 7.1 (dd, J=4.3, 2.5 Hz, 2 H) 7.3 (m, 4 H) 8.2 (s, 1 H) 8.8 (s, 1 H) 9.6 (s, 1 H)
Reaction SMILES: C[C@H]1O[C@H]2O[C@H]3[C@H](O[C@@]2(O)C(=O)C1)[C@@H](NC)[C@@H](O)[C@@H](NC)[C@@H]3O.OC1O[C@H](CO)[C@@H](O[C@@H]2O[C@H](CO)[C@H](O)[C@H](O)[C@H]2O)[C@H](O)[C@H]1O.OP([O-])(O)=O.[K+].OP([O-])([O-])=O.[K+].[K+].[NH2:60][C@H:61]([C:69]([OH:71])=[O:70])[CH2:62][CH2:63][CH2:64][NH:65]C(=N)N.C([O-])([O-])=O.[Ca+2]>>[NH2:60][C@H:61]([C:69]([OH:71])=[O:70])[CH2:62][CH2:63][CH2:64][NH2:65]
Reactant: N=C(N)NCCC[C@H](N)C(=O)O
Agent: CN[C@@H]1[C@H](O)[C@H](NC)[C@H]2O[C@@]3(O)C(=O)C[C@@H](C)O[C@H]3O[C@@H]2[C@H]1O
Agent: O=C([O-])[O-]
Agent: O=P([O-])(O)O
Product: NCCC[C@H](N)C(=O)O
Temperature: 30 °C
Reaction time: 16 h

Procedure:
Each strain was cultured with shaking in NB medium at 30° C. for 16 hours. For the culture of the transformant, spectinomycin was added to NB medium at a concentration of 100 μg/ml. Then, 0.5 ml of the seed culture was inoculated into 5 ml of a production medium (pH 7.0) comprising 80 g/l lactose, 40 g/l (NH4)2SO4, 0.5 g/l KH2PO4, 0.5 g/l K2HPO4, 100 mg/l L-arginine and 20 g/l CaCO3 in a test tube, and shaking culture was carried out at 30° C. for 72 hours. After the culturing was finished, the culture filtrate was subjected to paper chromatography and the amount of L-ornithine formed was determined colorimetrically by using the color development with ninhydrin. The results are shown in Table 20.
Reaction SMILES: OC(C(F)(F)F)=O.C([O:14][CH2:15][C@@H:16]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])[C:17]1[C:18]([C:30]2[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=2)=[C:19]2[C:24](=[CH:25][C:26]=1[CH3:27])[N:23]=[C:22]([CH:28]=[CH2:29])[CH:21]=[CH:20]2)(=O)C(C)(C)C.[OH-].[Na+]>C1COCC1.CO.O>[C:38]([O:37][C@@H:16]([C:17]1[C:18]([C:30]2[CH:31]=[CH:32][C:33]([Cl:36])=[CH:34][CH:35]=2)=[C:19]2[C:24](=[CH:25][C:26]=1[CH3:27])[N:23]=[C:22]([CH:28]=[CH2:29])[CH:21]=[CH:20]2)[CH2:15][OH:14])([CH3:39])([CH3:40])[CH3:41]
Reactant: C=Cc1ccc2c(-c3ccc(Cl)cc3)c([C@@H](COC(=O)C(C)(C)C)OC(C)(C)C)c(C)cc2n1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: C=Cc1ccc2c(-c3ccc(Cl)cc3)c([C@@H](CO)OC(C)(C)C)c(C)cc2n1
Temperature: 0 °C
Reaction time: 6 h

Procedure:
To a stirred solution of (S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-7-methyl-2-vinylquinolin-6-yl)ethyl pivalate TFA salt (14 mg, 0.024 mmol) in THF and methanol (3 mL/1 mL) was added 1 M NaOH solution (0.5 mL, excess). The mixture was stirred at 0° C. for 6 hours and diluted with water. The resulting mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried and concentrated in vacuo. The obtained residue was used in the next reaction without purification. LCMS-ESI+ (m/z): 396.2, 398.2 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[CH2:4][CH:5]([CH3:19])[C:6]([NH:8][CH2:9][C:10]1[CH:11]=[N:12][CH:13]=[C:14]([Cl:18])[C:15]=1[CH2:16]O)=[O:7].O=S(Cl)[Cl:23].ClC1C=NC=C(Cl)C=1CCl>>[CH3:1][O:2][C:3](=[O:20])[CH2:4][CH:5]([CH3:19])[C:6]([NH:8][CH2:9][C:10]1[CH:11]=[N:12][CH:13]=[C:14]([Cl:18])[C:15]=1[CH2:16][Cl:23])=[O:7]
Reactant: COC(=O)CC(C)C(=O)NCc1cncc(Cl)c1CO
Reactant: O=S(Cl)Cl
Agent: ClCc1c(Cl)cncc1Cl
Product: COC(=O)CC(C)C(=O)NCc1cncc(Cl)c1CCl

Procedure:
N-(5-Chloro-4-hydroxymethyl-pyridin-3-ylmethyl)-3-methyl-succinamic acid methyl ester (1.39 mg, 0.0046 mmol) was chlorinated with SOCl2 according to the synthesis of 3,5-dichloro-4-chloromethyl-pyridine. The resulting title compound was used for the next reaction without purification. MS (m/z): 318.9 [M+H+].
Reaction SMILES: [C:1]([O:5][N:6]=[C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([OH:17])[CH:15]=2)[O:10][C:9]([C:18]2[N:23]=[CH:22][N:21]3[CH:24]=[CH:25][CH:26]=[C:20]3[CH:19]=2)=[CH:8]1)([CH3:4])([CH3:3])[CH3:2].Cl[CH2:28][CH:29]([OH:32])[CH2:30][OH:31]>>[C:1]([O:5][N:6]=[C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH2:28][CH:29]([OH:32])[CH2:30][OH:31])[CH:15]=2)[O:10][C:9]([C:18]2[N:23]=[CH:22][N:21]3[CH:24]=[CH:25][CH:26]=[C:20]3[CH:19]=2)=[CH:8]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: OCC(O)CCl
Reactant: CC(C)(C)ON=c1cc(-c2cc3cccn3cn2)oc2ccc(O)cc12
Product: CC(C)(C)ON=c1cc(-c2cc3cccn3cn2)oc2ccc(OCC(O)CO)cc12
Yield: 74 %

Procedure:
6-(2,3-Dihydroxy-propoxy)-2-pyrrolo[1,2-c]pyrimidin-3-yl-chromen-4-one O-tert-butyl oxime was prepared in 74% yield using the method described in example 85A, starting from 6-Hydroxy-2-pyrrolo[1,2-c]pyrimidin-3-yl-chromen-4-one O-tert-butyl-oxime (example 81A) and 3-chloro-1,2-propandiol. The title compound was isolated as a yellow solid.
Reaction SMILES: [O:1]([CH2:8][C:9](Cl)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH4+:12].[OH-]>C1COCC1>[O:1]([CH2:8][C:9]([NH2:12])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [NH4+]
Reactant: O=C(Cl)COc1ccccc1
Agent: [OH-]
Solvent: C1CCOC1
Product: NC(=O)COc1ccccc1
Temperature: 23 °C
Reaction time: 16 h
Yield: 74 %

Procedure:
To a solution of phenoxyacetyl chloride (6.18 g, 36.2 mmol) in 175 mL of THF was added 75 mL of NH4OH over 15 minutes. The reaction was stirred for 16 hours at 23° C. then concentrated under reduced pressure. The crude product was dissolved in 200 mL of EtOAc and washed with 100 mL of 2 N HCL, 100 mL NaHCO3, and 100 mL of brine. The organic phase was dried over Na2SO4 and concentrated. The product was purified by recrystallization from EtOAc/hexanes to provide 4.05 g (74% yield) of the desired product as a white powder.
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[CH:4][CH:3]=1.[CH3:24][C@@H:25]1[O:29][C:28](=[O:30])[NH:27][CH2:26]1>>[CH3:22][C:21]1[C:16]([N:13]2[CH2:14][CH2:15][N:10]([C:8]([C:5]3[CH:4]=[CH:3][C:2]([N:27]4[CH2:26][C@H:25]([CH3:24])[O:29][C:28]4=[O:30])=[N:7][CH:6]=3)=[O:9])[CH2:11][CH2:12]2)=[N:17][CH:18]=[C:19]([CH3:23])[CH:20]=1
Reactant: C[C@H]1CNC(=O)O1
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(Br)nc3)CC2)c(C)c1
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4C[C@H](C)OC4=O)nc3)CC2)c(C)c1
Yield: 89.6 %

Procedure:
By reaction and treatment in the same manner as in Example 1 and using (6-bromopyridin-3-yl)[4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl]methanone (748 mg) described in Preparation Example 73 and (S)-5-methyloxazolidin-2-one (243 mg) described in Preparation Example 42, the title compound (706 mg) was obtained.
Reaction SMILES: [OH:1][C:2]1([C:12]#[C:13]/[C:14](/[C:21]([F:24])([F:23])[F:22])=[CH:15]\[C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:7]([CH3:9])([CH3:8])[CH2:6][C:5](=O)[CH:4]=[C:3]1[CH3:11].Cl.[CH3:26][O:27][NH2:28].C([O-])(=O)C.[Na+]>C(O)C.O>[OH:1][C:2]1([C:12]#[C:13]/[C:14](/[C:21]([F:24])([F:22])[F:23])=[CH:15]\[C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:7]([CH3:8])([CH3:9])[CH2:6][C:5](=[N:28][O:27][CH3:26])[CH:4]=[C:3]1[CH3:11]
Reactant: CCOC(=O)/C=C(\C#CC1(O)C(C)=CC(=O)CC1(C)C)C(F)(F)F
Reactant: CON
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCOC(=O)/C=C(\C#CC1(O)C(C)=CC(=NOC)CC1(C)C)C(F)(F)F
Temperature: 60 °C
Reaction time: 4 h
Yield: 63 %

Procedure:
Ethyl (2E)-5-(1-hydroxy-2,6,6-trimethyl-4-oxocyclohex-2-en-1-yl)-3-(trifluoromethyl)pent-2-en-4-ynoate (60 mg, 0.17 mmol), O-methylhydroxylamine hydrochloride (17 mg, 0.21 mmol) and sodium acetate (30 mg, 0.37 mmol) were dissolved in a 1:1 mixture of ethanol and water (4 ml) and then stirred at a temperature of 60° C. for 4 h. After cooling to room temperature, ethanol was removed under reduced pressure and the aqueous phase was extracted repeatedly with dichloromethane. The combined organic phases were dried over magnesium sulfate, filtered and concentrated under reduced pressure. By column chromatography purification of the resulting crude product (ethyl acetate/heptane gradient), ethyl (2E)-5-[1-hydroxy-4-(methoxyimino)-2,6,6-trimethylcyclohex-2-en-1-yl]-3-(trifluoromethyl)pent-2-en-4-ynoate (40 mg, 58% of theory) was obtained in the form of a colorless solid. 1H-NMR (400 MHz, CDCl3 δ, ppm) 6.65/6.63 (s, 1H), 6.00/5.94 (s, 1H), 4.27 (q, 2H), 3.89/3.86 (s, 3H), 2.62/2.56 (br. s, 1H, OH), 2.46 (d, 1H), 2.39 (m, 1H), 2.08/2.05 (s, 3H), 1.31 (t, 3H), 1.18 (s, 3H), 1.11 (s, 3H).
Reaction SMILES: [CH:1]([C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[C:5]([O:11][CH3:12])[CH:4]=1)=[O:2].[CH2:13]([O:15][C:16](=[O:19])[CH2:17]Cl)[CH3:14].CC[O-].[Na+].O>C1C=CC=CC=1.C(O)C>[C:7]([C:6]1[CH:9]=[CH:10][C:3]([CH:1]2[O:2][CH:17]2[C:16]([O:15][CH2:13][CH3:14])=[O:19])=[CH:4][C:5]=1[O:11][CH3:12])#[N:8]
Reactant: COc1cc(C=O)ccc1C#N
Reactant: CCOC(=O)CCl
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Solvent: c1ccccc1
Solvent: O
Product: CCOC(=O)C1OC1c1ccc(C#N)c(OC)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 4-formyl-2-methoxybenzonitrile (383 mg, 2.38 mmol) and chloroacetic acid ethyl ester (291 mg, 2.38 mmol) were dissolved in 10 mL of dry benzene. Freshly prepared EtONa (3.09 mmol) in 2.5 mL of ethanol was added, and the mixture were stirred at room temperature for 2 hours. The mixture was added water, then extracted with EtOAc. The organic layers were dried over Na2SO4 and concentrated to afford ethyl 3-(4-cyano-3-methoxyphenyl)oxirane-2-carboxylate. MS m/z: 248 (M+1)+.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH:4]1[CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:13][CH3:14])[CH:10]=2)[C:5]1=[O:15].[CH:16]([C:18]([CH2:20][CH3:21])=[O:19])=[CH2:17].C[O-].[Na+]>CO.CCOC(C)=O>[OH:1][CH2:2][CH2:3][C:4]1([CH2:17][CH2:16][C:18](=[O:19])[CH2:20][CH3:21])[CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:13][CH3:14])[CH:10]=2)[C:5]1=[O:15]
Reactant: C=CC(=O)CC
Reactant: COc1ccc2c(c1)CC(CCO)C2=O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Product: CCC(=O)CCC1(CCO)Cc2cc(OC)ccc2C1=O
Temperature: 60 °C

Procedure:
A solution of 2-(2-hydroxyethyl)-5-methoxy-1-indanone (105 mg, 0.51 mmol) in methanol (2.0 mL) at room temperature was treated with ethyl vinyl ketone (EVK, 0.102 mL) and 0.5M sodium methoxide in methanol (0.204 mL, 0.1 mmol). The mixture was stirred in a capped flask and heated in an oil bath at 60° C. for 8 hours. After cooling, the reaction mixture was diluted with EtOAc (25 mL), washed with 0.2N HCl (15 mL), water (15 mL), and brine (15 mL), dried over MgSO4, filtered, and evaporated under vacuum to afford 2-(2-hydroxyethyl)-5-methoxy-2-(3-oxopentyl)-1-indanone as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][N:11]3[C:14](=[O:17])[NH:15][N:16]=[C:10]3[C:9]=2[C:18]2[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=2)=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Cl[CH2:31][C:32]1[CH:37]=[CH:36][C:35]([S:38]([CH3:41])(=[O:40])=[O:39])=[CH:34][CH:33]=1.O>CN(C=O)C.CCOC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][N:11]3[C:14](=[O:17])[N:15]([CH2:31][C:32]4[CH:33]=[CH:34][C:35]([S:38]([CH3:41])(=[O:40])=[O:39])=[CH:36][CH:37]=4)[N:16]=[C:10]3[C:9]=2[C:18]2[CH:19]=[CH:20][N:21]=[CH:22][CH:23]=2)=[CH:4][CH:3]=1
Reactant: O=c1[nH]nc2c(-c3ccncc3)c(-c3ccc(Cl)cc3)ccn12
Reactant: CS(=O)(=O)c1ccc(CCl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1ccc(Cn2nc3c(-c4ccncc4)c(-c4ccc(Cl)cc4)ccn3c2=O)cc1
Temperature: 70 °C
Reaction time: 0.17 h
Yield: 59.1 %

Procedure:
To a stirring solution of 7-(4-chlorophenyl)-8-(pyridin-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one (16 mg, 0.05 mmol) in DMF (0.25 mL) at room temperature under argon was added K2CO3 (14 mg, 0.1 mmol), followed by 1-(chloromethyl)-4-(methylsulfonyl)benzene (11 mg, 0.0547 mmol). The reaction mixture was stirred at 70° C. for 10 min. After the reaction mixture was cooled to room temperature, water (2 mL) and EtOAc (5 mL) were added. The layers were separated. The organic layer was dried (MgSO4), filtered, and concentrated under reduced pressure to obtain crude product. This was purified by reverse phase preparative HPLC (without TFA) to isolate 14.5 mg of the title compound as a pale yellow solid. HPLC/MS: retention time=2.27 min, [M+H]+=491.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][N:3]=1.[C:9](=[O:16])([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[NH2:10].C(=O)([O-])[O-].[Cs+].[Cs+]>[Pd].[Pd].C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.O1CCCC1>[F:8][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([NH:10][C:9](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[CH:7]=1
Reactant: CC(C)(C)OC(N)=O
Reactant: Fc1ccnc(Cl)c1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(C=Cc1ccccc1)C=Cc1ccccc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1cc(F)ccn1
Temperature: 25 °C
Yield: 70.1 %

Procedure:
A 2 L flask was charged 2-chloro-4-fluoropyridine (20 g, 152 mmol), tert-butyl carbamate (89 g, 760 mmol), tris(dibenzylideneacetone) dipalladium (1.39 g, 1.52 mmol), X-PHOS (2-(dicyclohexylphosphino)-2′,4′,6′-triisopropyl-1,1′-biphenyl) (1.48 g, 3.10 mmol), cesium carbonate (99 g, 588 mmol), and tetrahydrofuran (500 mL) under an atmosphere of dry nitrogen. This mixture was heated at reflux under nitrogen for 7 hours. An additional 1 equivalent of cesium carbonate was added to drive the reaction to completion (heated a further 7 hours). The mixture was cooled to ambient temperature, filtered through Celite and washed with ethyl acetate. The filtrate was partitioned between saturated sodium bicarbonate and ethyl acetate. The aqueous phase was extracted with ethyl acetate twice. The combined organic phases were washed with brine and dried with sodium sulfate, concentrated under vacuum, and purified by column chromatography to give tert-butyl 4-fluoropyridin-2-ylcarbamate as a pale yellow solid (22.6 g).
Reaction SMILES: CN(C=O)C.[S:6]([Cl:10])(Cl)(=[O:8])=[O:7].[CH2:11]1[O:29][C:28]2[CH:27]=[CH:26][C:15]([CH2:16][C:17]3[S:21][C:20]4[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=4[CH:18]=3)=[CH:14][C:13]=2[O:12]1>>[CH2:11]1[O:29][C:28]2[CH:27]=[CH:26][C:15]([CH2:16][C:17]3[S:21][C:20]4[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=4[C:18]=3[S:6]([Cl:10])(=[O:8])=[O:7])=[CH:14][C:13]=2[O:12]1
Reactant: c1ccc2sc(Cc3ccc4c(c3)OCO4)cc2c1
Reactant: O=S(=O)(Cl)Cl
Solvent: CN(C)C=O
Product: O=S(=O)(Cl)c1c(Cc2ccc3c(c2)OCO3)sc2ccccc12

Procedure:
2-[3,4-(methylenedioxy)benzyl]benzo[b]thiophene-3-sulfonyl chloride was prepared by the method of Example 40B using DMF (9.1 mmoles, 0.70 ml), sulfuryl chloride (7.7 mmoles, 0.62 ml) and 2-[3,4-(methylenedioxy)benzyl]benzo[b]thiophene (4.6 mmoles, 1.2 g). Flash chromatography (5% ethyl acetate/hexanes) provided 0.71 g (42%) of a light yellow solid.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:9][C:10]([OH:12])=[O:11].[N+:13]([O-])([OH:15])=[O:14]>S(=O)(=O)(O)O>[F:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([N+:13]([O-:15])=[O:14])=[CH:4][C:3]=1[CH2:9][C:10]([OH:12])=[O:11]
Reactant: O=[N+]([O-])O
Reactant: O=C(O)Cc1cccc(F)c1F
Agent: O=S(=O)(O)O
Product: O=C(O)Cc1cc([N+](=O)[O-])cc(F)c1F
Temperature: -10 °C
Reaction time: 0.25 h

Procedure:
(2,3-Difluoro-phenyl)-acetic acid (11, 5 g, 0.0290 mol) is dissolved in concentrated sulfuric acid (20 ml) and the resulting solution cooled to −10° C. with vigorous stirring. A solution of nitric acid (1.88 ml, 69.3%, 0.0290 mol) and sulfuric acid (2 ml) is added dropwise at a rate such that the temperature remains below −5° C. The thickened slurry is stirred for 15 minutes and then poured on ice. The resulting white precipitate is filtered and dried under vacuum (6.3 g, 99%) and consists of a 50/50 mixture of 5 and 6-NO2 regioisomers suitable for use directly in the next step.