Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN(C)C=O.[CH3:6][O:7][C:8]1[CH:13]=[C:12]([C:14](=[O:16])[CH3:15])[CH:11]=[CH:10][C:9]=1[OH:17].Br[CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21].C(=O)([O-])[O-].[K+].[K+]>O>[CH3:6][O:7][C:8]1[CH:13]=[C:12]([C:14](=[O:16])[CH3:15])[CH:11]=[CH:10][C:9]=1[O:17][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21]
Reactant: CCOC(=O)CBr
Reactant: COc1cc(C(C)=O)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)COc1ccc(C(C)=O)cc1OC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To dimethylformamide (200 ml) are added 2-methoxy-4-acetylphenol (20 g), ethyl α-bromoacetate (15 ml) and potassium carbonate (18.3 g), and the mixture is stirred at room temperature overnight. After the reaction is complete, water is added to the mixture, and the mixture is extracted with ethyl acetate. The extract is washed with aqueous sodium hydrogen carbonate solution, and dried over magnesium sulfate, and concentrated under reduced pressure to remove the solvent. The resulting crystals are collected, and washed with n-hexane-diethyl ether to give ethyl α-(2-methoxy-4-acetylphenoxy)acetate (23.86 g).
Reaction SMILES: Br[C:2]1[N:6]2[CH:7]=[CH:8][C:9]([CH2:11][F:12])=[N:10][C:5]2=[N:4][CH:3]=1.[F:13][C:14]1[CH:19]=[CH:18][C:17](B2OC(C)(C)C(C)(C)O2)=[CH:16][C:15]=1[C:29]1[C:30]([C:35]#[N:36])=[CH:31][CH:32]=[CH:33][CH:34]=1>>[F:13][C:14]1[CH:19]=[CH:18][C:17]([C:2]2[N:6]3[CH:7]=[CH:8][C:9]([CH2:11][F:12])=[N:10][C:5]3=[N:4][CH:3]=2)=[CH:16][C:15]=1[C:29]1[C:30]([C:35]#[N:36])=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: CC1(C)OB(c2ccc(F)c(-c3ccccc3C#N)c2)OC1(C)C
Reactant: FCc1ccn2c(Br)cnc2n1
Product: N#Cc1ccccc1-c1cc(-c2cnc3nc(CF)ccn23)ccc1F
Yield: 67 %

Procedure:
3-Bromo-7-fluoromethylimidazo[1,2-α]pyrimidine (115 mg, 0.50 mmol) was coupled with 2′-fluoro-5′-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)biphenyl-2-carbonitrile as described in Example 1 to give 2′-fluoro-5′-(7-fluoromethylimidazo[1,2-α]pyrimidin-3-yl)biphenyl-2-carbonitrile (116 mg, 67%) as a white powder: δH (400 MHz, CDCl3) 5.57 (2H, d, J 47), 7.20 (1H, dd, J 7 and 1), 7.42 (1H, dt, J 9 and 1), 7.55 (1H, dt, J 8 and 1), 7.60-7.66 (3H, m), 7.70-7.74 (1H, m), 7.85 (1H, dd, J 8 and 1), 7.90 (1H, s), 8.91 (1H, d, J 7); m/z (ES+) 347 (M++H).
Reaction SMILES: [C:1]([NH:6][C@H:7]([C:11]([NH:13][C@H:14]([C:27]([O:29]CC1C=CC=CC=1)=[O:28])[CH2:15][CH2:16][C:17]([O:19]CC1C=CC=CC=1)=[O:18])=[O:12])[CH:8]([CH3:10])[CH3:9])(=[O:5])[CH2:2][CH2:3][CH3:4]>CO.[Pd]>[C:1]([NH:6][C@H:7]([C:11]([NH:13][C@H:14]([C:27]([OH:29])=[O:28])[CH2:15][CH2:16][C:17]([OH:19])=[O:18])=[O:12])[CH:8]([CH3:9])[CH3:10])(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: CCCC(=O)N[C@H](C(=O)N[C@@H](CCC(=O)OCc1ccccc1)C(=O)OCc1ccccc1)C(C)C
Agent: [Pd]
Solvent: CO
Product: CCCC(=O)N[C@H](C(=O)N[C@@H](CCC(=O)O)C(=O)O)C(C)C
Yield: 87.8 %

Procedure:
A mixture of dibenzyl N-(N-butanoyl-L-valyl)-L-glutamate (613 mg) and palladium black (50 mg) in methanol (50 ml) was subjected to catalytic hydrogenation under atmospheric pressure. After the reaction mixture was filtered, the filtrate was concentrated under reduced pressure to give a residue which was recrystallized from petroleum ether to afford N-(N-butanoyl-L-valyl)-L-glutamic acid as crystals (343 mg).
Reaction SMILES: [OH-].[Na+].[CH3:3][O:4][C:5]1[C:10]2[O:11][CH2:12][CH2:13][CH2:14][O:15][C:9]=2[C:8]([C:16]([O:18]C)=[O:17])=[CH:7][CH:6]=1>C1COCC1>[CH3:3][O:4][C:5]1[C:10]2[O:11][CH2:12][CH2:13][CH2:14][O:15][C:9]=2[C:8]([C:16]([OH:18])=[O:17])=[CH:7][CH:6]=1
Reactant: COC(=O)c1ccc(OC)c2c1OCCCO2
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1ccc(C(=O)O)c2c1OCCCO2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A NaOH solution (500 ml, 2N) was added to a solution of intermediate (7) in THF (250 ml). The mixture was stirred at room temperature overnight. The solvent was evaporated partially. The residue was extracted with DCM. The mixture was separated into its layers. The aqueous layer was acidified with a concentrated HCl solution until pH=1 to 2. The solid was filtered off, washed with water and dried, yielding 35.5 g of 9-methoxy-3,4-dihydro-2H-1,5-benzodioxepin-6-carboxylic acid (intermediate 8).
Reaction SMILES: [CH2:1]([S:3]([N:6]1[CH2:11][CH2:10][C:9]([CH2:19][NH2:20])([CH2:12][CH:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[CH2:8][CH2:7]1)(=[O:5])=[O:4])[CH3:2].N=C=N.[Cl:24][C:25]1[CH:33]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:31]=[CH:30][C:26]=1[C:27](O)=[O:28]>ClCCl>[Cl:24][C:25]1[CH:33]=[C:32]([C:34]([F:35])([F:36])[F:37])[CH:31]=[CH:30][C:26]=1[C:27]([NH:20][CH2:19][C:9]1([CH2:12][CH:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[CH2:10][CH2:11][N:6]([S:3]([CH2:1][CH3:2])(=[O:5])=[O:4])[CH2:7][CH2:8]1)=[O:28]
Reactant: CCS(=O)(=O)N1CCC(CN)(CC2CCOCC2)CC1
Reactant: O=C(O)c1ccc(C(F)(F)F)cc1Cl
Agent: N=C=N
Solvent: ClCCl
Product: CCS(=O)(=O)N1CCC(CNC(=O)c2ccc(C(F)(F)F)cc2Cl)(CC2CCOCC2)CC1
Reaction time: 0.5 h

Procedure:
In a large glass container with a sealable lid was placed 1-[1-(ethylsulfonyl)-4-(tetrahydro-2H-pyran-4-ylmethyl)piperidin-4-yl]methanamine (11, 350 mg, 1.15 mmol). Dichloromethane (50 ml) and PS-carbodiimide resin (474 mg, 2.299 mmol) were added along with 2-chloro-4(trifluoromethyl)benzoic acid (336 mg, 1.495 mmol). The lid was sealed and the bottle was shaken for 0.5 hours. The resin was filtered off and washed with EtOAc (3×25 ml) and the organics concentrated in vacuo to give an off-white solid. The residue was purified by column chromatography on silica gel, eluting with EtOAc/Hexanes to give 2-chloro-N-{[1-(ethylsulfonyl)-4-(tetrahydro-2H-pyran-4-ylmethyl)piperidin-4-yl]methyl}-4-(trifluoromethyl)benzamide (12) as a white solid. Calculated HRMS 511.164 Found 511.1649. 1H NMR (300 MHz D6DMSO): δ 8.51 (s, 1 H)), 7.96 (s, 1 H), 7.80 (d, J=8.1 Hz, 1 H), 7.61 (d, J=7.8 Hz, 1 H), 3.77 (d, J=9.3 Hz, 2 H), 3.41 (s, 2 H), 3.32 (m, 2 H), 3.29 (s, 2H), 3.21 (s, 4 H), 3.45 (q, J=9 Hz, 2 H), 1.66 (m, 1 H), 1.61 (m, 2 H), 1.564 (s, 2 H), 1.47 (m, 2 H), 1.30 (d, J=4.5 Hz, 2 H), 1.21 (t, J=7.5 Hz, 3 H).
Reaction SMILES: [CH2:1]([C:15]1[CH:16]=[C:17]([OH:21])[CH:18]=[CH:19][CH:20]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]>N1C=CC=CC=1.C(Cl)(Cl)Cl>[C:17]([O:21][C:17]1[CH:18]=[CH:19][CH:20]=[C:15]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[CH:16]=1)(=[O:21])[CH2:16][CH2:15][CH2:1][CH2:2][CH3:3]
Reactant: CCCCCCCCCCCCCCc1cccc(O)c1
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: CCCCCCCCCCCCCCc1cccc(OC(=O)CCCCC)c1
Reaction time: 24 h
Yield: 195.2 %

Procedure:
To a solution of 10.73 g of 3-tetradecylphenol in 30 ml of pyridine was added 8.02 g of hexanoic anyhydride. The mixture was stirred 24 hours, then diluted with chloroform, washed with water, then saturated aqueous sodium bicarbonate, dried and the solvent evaporated, giving 14.01 g of the desired compound.
Reaction SMILES: C[O:2][C:3]([C:5]1([NH:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1)=[O:4].[Cl:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[S:26](Cl)(=[O:28])=[O:27].CCN(CC)CC.C([O-])(O)=O.[Na+]>C(Cl)Cl>[C:15]([O:14][C:12]([NH:11][C:5]1([C:3]([OH:2])=[O:4])[CH2:10][CH2:9][N:8]([S:26]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[Cl:19])(=[O:28])=[O:27])[CH2:7][CH2:6]1)=[O:13])([CH3:18])([CH3:17])[CH3:16]
Reactant: COC(=O)C1(NC(=O)OC(C)(C)C)CCNCC1
Reactant: O=S(=O)(Cl)c1ccccc1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC1(C(=O)O)CCN(S(=O)(=O)c2ccccc2Cl)CC1
Temperature: 25 °C
Yield: 87.8 %

Procedure:
A mixture of 2 g (7.8 mmol) 4-tert-Butoxycarbonylamino-piperidine-4-carboxylic acid methyl ester, 1.72 g (8.1 mmol) 2-chlorobenzenesulfonyl chloride and 2.36 g (23 mmol) NEt3 in 30 mL DCM was stirred at room temperature over night. DCM and NaHCO3 aq. was added and the organic phase was dried with MgSO4 and evaporated. The ester (MS (m/e): 433.3 [(M+H)+]) was used without further purification. 3 g of the crude product was dissolved in methanol and 2.7 mL KOH aq. (5M), 30 mL water and 10 mL THF was added and the mixture was stirred at 55° C. for 5 h. The organic solvents were removed under vacuum and acetic acid was added. The mixture was extracted with ethyl acetate and the combined organic phases were washed with water, dried with MgSO4 and evaporated to yield 2.87 g of the title compound as white foam. MS (m/e): 419.1 [(M+H)+]
Reaction SMILES: O=C1CCC(=O)N1O[C:9](=[O:27])[C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17](=[O:26])[N:18]([CH3:25])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:12][CH:11]=1.[CH:28]1([NH2:34])[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1>>[CH:28]1([NH:34][C:9]([C:10]2[CH:11]=[CH:12][C:13]([O:16][C:17](=[O:26])[N:18]([CH3:25])[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)=[CH:14][CH:15]=2)=[O:27])[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1
Reactant: NC1CCCCC1
Reactant: CN(C(=O)Oc1ccc(C(=O)ON2C(=O)CCC2=O)cc1)c1ccccc1
Product: CN(C(=O)Oc1ccc(C(=O)NC2CCCCC2)cc1)c1ccccc1

Procedure:
The title product was prepared from 4-(methyl-phenyl-carbamoyloxy)-benzoic acid 2,5-dioxo-pyrrolidin-1-yl ester and cyclohexylamine. The crude product was used without further purification (79%, off-white crystals). HPLC-MS: m/z=353.2 (M+1); Rt: 3.98 min.
Reaction SMILES: C[O:2][C:3](=[O:40])[CH2:4][CH:5]([NH:7][C:8](=[O:39])[C:9]1[CH:14]=[CH:13][C:12]([O:15][CH:16]([C:23]2[CH:24]=[N:25][C:26]([C:29]3[CH:34]=[CH:33][C:32]([C:35]([F:38])([F:37])[F:36])=[CH:31][CH:30]=3)=[CH:27][CH:28]=2)[CH2:17][CH2:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[CH:11][CH:10]=1)[CH3:6].[OH-].[Na+].Cl>C1COCC1>[CH3:21][C:19]([CH3:20])([CH3:22])[CH2:18][CH2:17][CH:16]([C:23]1[CH:24]=[N:25][C:26]([C:29]2[CH:30]=[CH:31][C:32]([C:35]([F:38])([F:37])[F:36])=[CH:33][CH:34]=2)=[CH:27][CH:28]=1)[O:15][C:12]1[CH:13]=[CH:14][C:9]([C:8]([NH:7][CH:5]([CH3:6])[CH2:4][C:3]([OH:40])=[O:2])=[O:39])=[CH:10][CH:11]=1
Reactant: COC(=O)CC(C)NC(=O)c1ccc(OC(CCC(C)(C)C)c2ccc(-c3ccc(C(F)(F)F)cc3)nc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(CC(=O)O)NC(=O)c1ccc(OC(CCC(C)(C)C)c2ccc(-c3ccc(C(F)(F)F)cc3)nc2)cc1
Yield: 72 %

Procedure:
3-(4-{4,4-Dimethyl-1-[6-(4-trifluoromethyl-phenyl)-pyridin-3-yl]-pentyloxy}-benzoylamino)-butyric acid methyl ester are taken into THF (1.0 mL) and treated with NaOH (1.0 mL, 5.0 N), then refluxed under nitrogen. The reaction mixture is neutralized with HCl (1.0 mL, 5.0 N), extracted with ethyl ether, dried over sodium sulfate. Concentration gives the title compound, (163 mg, 0.15 mmol) 72% 2 steps. MS (ES): 541.3 [M+H]−, the structure is also confirmed by proton NMR.
Reaction SMILES: [Cl:1][C:2]([Cl:11])([Cl:10])[C:3]([C:5]1[NH:6][CH:7]=[CH:8][CH:9]=1)=[O:4].[I:12]I>FC(F)(F)C([O-])=O.[Ag+].C(Cl)(Cl)Cl>[I:12][C:8]1[CH:9]=[C:5]([C:3](=[O:4])[C:2]([Cl:1])([Cl:10])[Cl:11])[NH:6][CH:7]=1
Reactant: O=C(c1ccc[nH]1)C(Cl)(Cl)Cl
Reactant: II
Agent: [Ag+]
Agent: O=C([O-])C(F)(F)F
Solvent: ClC(Cl)Cl
Product: O=C(c1cc(I)c[nH]1)C(Cl)(Cl)Cl
Reaction time: 1 h

Procedure:
8.4 g (39.5 mmol) of 2-trichloroacetylpyrrole and 100 ml of chloroform were introduced into a three-necked flask under a stream of nitrogen and 8.6 g (39.5 mmol) of silver trifluoroacetate and 10.16 g (39.5 mmol) of iodine were added successively. Stirring was carried out at room temperature for one hour and the reaction mixture was poured into ice and extracted with dichloromethane. The organic phase was separated by settling, dried over magnesium sulfate and evaporated. The residue obtained was triturated in hexane and filtered. 8.2 g (61%) of the expected compound, with a melting point of 118°-119° C., were recovered.
Reaction SMILES: COC(=O)[C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[C:6]([CH:11]=[O:12])[CH:5]=1.[Br:14]C1C=CC([N+]([O-])=O)=C(C)C=1>>[NH2:10][C:7]1[CH:8]=[CH:9][C:4]([Br:14])=[CH:5][C:6]=1[CH:11]=[O:12]
Reactant: COC(=O)c1ccc(N)c(C=O)c1
Reactant: Cc1cc(Br)ccc1[N+](=O)[O-]
Product: Nc1ccc(Br)cc1C=O

Procedure:
The title intermediate was synthesized as described for Compound 7 in five steps starting from 5-bromo-2-nitrotoluene instead of 3-methyl-4-nitrobenazoic acid methyl ester. MS: 199.97 & 201.97 (M+H+); H1-NMR (CDCl3): δ (ppm) 9.75 (s, 1H), 7.71 (s, 1H), 7.39 (d, 1H, J=9.3 Hz), 7.22 (s, 2H), 6.72 (d, 1H, J=9.3 Hz);
Reaction SMILES: [C:1]1([C:7]2[CH:11]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[NH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].S(OC)(O[CH3:24])(=O)=O.O>C(C(C)=O)C(C)C>[CH3:24][N:8]1[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[CH:11][C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[N:9]1
Reactant: c1ccc(-c2cc(-c3ccccc3)[nH]n2)cc1
Reactant: COS(=O)(=O)OC
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)CC(C)C
Solvent: O
Product: Cn1nc(-c2ccccc2)cc1-c1ccccc1
Temperature: 90 °C

Procedure:
Five parts of 3,5-diphenylpyrazole are dissolved in 25 parts (by volume) of methyl isobutyl ketone. Solid anhydrous sodium hydroxide (1.1 parts) is added and the mixture is heated to 90°C. Dimethyl sulfate (3.43 parts) is added and the mixture is next heated to 112°C. to 115°C. The reaction mixture is sampled after 1.5 hours, and no unreacted 3,5-diphenylpyrazole is found to be present. The reaction mixture is cooled to 50°C., and 30 parts of water are added. The pH is next adjusted to between 11 and 12 by the addition of aqueous sodium hydroxide. The organic layer is washed twice with 30 parts water. For yield determination the methyl isobutyl ketone is removed in vacuo, producing 4.95 parts (93% crude yield) of an oil which crystallizes on cooling (melting point 52°C. to 53°C). Analysis of the product shows it to be 85.5% pure as 1-methyl-3,5-diphenylpyrazole.
Reaction SMILES: [C:1]([N:9]1[CH2:14][CH2:13][CH2:12][CH:11]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:10]1)(=[O:8])[C:2]1C=[CH:6][CH:5]=[CH:4][CH:3]=1.[S:20]1C=CC=C1CC(Cl)=O>>[S:20]1[CH:6]=[CH:5][CH:4]=[C:3]1[CH2:2][C:1]([N:9]1[CH2:14][CH2:13][CH2:12][C@H:11]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:10]1)=[O:8]
Reactant: O=C(Cl)Cc1cccs1
Reactant: CCOC(=O)C1CCCN(C(=O)c2ccccc2)C1
Product: CCOC(=O)[C@H]1CCCN(C(=O)Cc2cccs2)C1

Procedure:
The reaction was run in the same manner as ethyl 1-benzoyl-3-piperidinecarboxylate, starting with commercially available S-ethyl nipecotate (1.0 g; 6.37 mmol; Chemi SpA; Italy) and 2-thiopheneacetyl chloride (785 μl; 6.37 mmol). The crude product was distilled as 225° C./0.1 torr, giving (S)-ethyl 1-(2-thiopheneacetyl)-3-piperidinecarboxylate (1.23 g) as a light yellow oil. MS m/z (positive ion), 585 (dimer+Na+; 10), 304 (M+Na+; 50), 282 (MH+; 100), 158 (50). OR (MeOH; 589) +62.96°. Product was shown to be >98% ee by chiral capillary electrophoresis using a 20% solution of ·-HSCD (highly sulfated cyclodextrin) at a voltage of 20 kV.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[N:8]=[CH:7][NH:6][CH:5]=1.Cl[C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][CH:11]=1>CC(O)C>[NH:6]1[CH:5]=[C:4]([CH2:3][CH2:2][NH:1][C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][CH:11]=2)[N:8]=[CH:7]1
Reactant: NCCc1c[nH]cn1
Reactant: O=[N+]([O-])c1ccc(Cl)cc1
Solvent: CC(C)O
Product: O=[N+]([O-])c1ccc(NCCc2c[nH]cn2)cc1

Procedure:
1.45 g (13.1 mmol) of histamine and 2.06 g (13.1 mmol) of 1-chloro-4-nitrobenzene are brought to reflux in 20 ml of 2-propanol for 3 days. The cooled reaction mixture is filtered, evaporated and chromatographed on a first column of silica gel, using a chloroform/methanol (99/1) mixture, and then on a second column, using a chloroform/methanol (9/1) mixture. The pure fractions were evaporated and the resulting solid was treated with oxalic acid in ethanol. Addition of ether provided the title compound in the form of an oxalate salt, M.p.: 185°-186° C.
Reaction SMILES: [BH4-].[Na+].[Br:3][C:4]1[C:11]([F:12])=[C:10]([F:13])[C:7]([CH:8]=[O:9])=[C:6]([F:14])[C:5]=1[F:15].O>CO>[Br:3][C:4]1[C:5]([F:15])=[C:6]([F:14])[C:7]([CH2:8][OH:9])=[C:10]([F:13])[C:11]=1[F:12]
Reactant: O=Cc1c(F)c(F)c(Br)c(F)c1F
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: OCc1c(F)c(F)c(Br)c(F)c1F
Temperature: 18 °C
Reaction time: 2 h
Yield: 90.8 %

Procedure:
Sodium borohydride (1.0 g) was added portionwise over a period of 30 minutes to a stirred solution of 4-bromo-2,3,5,6-tetrafluorobenzaldehyde (8.2 g) in methanol (80 cm3) whilst the temperature was maintained within the range from -5° C. to +5° C., after which the mixture was stirred for 2 hours at the ambient temperature (ca. 18° C.). The mixture was poured into water and the precipitated white solid collected by filtration, washed with water and air dried to yield 4-bromo-2,3,5,6-tetrafluorobenzyl alcohol (7.5 g), m.p. 60°-62° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]3[CH:13]=[N:14][CH:15]=[C:16]([C:17]([NH:19][C@H:20]([C:25]4[CH:30]=[CH:29][N:28]=[C:27]([S:31]([CH3:34])(=[O:33])=[O:32])[CH:26]=4)[CH2:21][C:22]([OH:24])=[O:23])=[O:18])[C:11]=3[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[CH3:35][Si](C=[N+]=[N-])(C)C>CO.C1C=CC=CC=1>[CH3:35][O:23][C:22](=[O:24])[CH2:21][C@H:20]([NH:19][C:17]([C:16]1[C:11]2[CH:10]=[N:9][N:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[C:12]=2[CH:13]=[N:14][CH:15]=1)=[O:18])[C:25]1[CH:30]=[CH:29][N:28]=[C:27]([S:31]([CH3:34])(=[O:33])=[O:32])[CH:26]=1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: CS(=O)(=O)c1cc([C@H](CC(=O)O)NC(=O)c2cncc3c2cnn3-c2ccc(F)cc2)ccn1
Solvent: c1ccccc1
Solvent: CO
Product: COC(=O)C[C@H](NC(=O)c1cncc2c1cnn2-c1ccc(F)cc1)c1ccnc(S(C)(=O)=O)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a slurry of (S)-3-{[1-(4-fluorophenyl)-1H-pyrazolo[3,4-c]pyridine-4-carbonyl]-amino}-3-(2-methanesulfonyl-pyridin-4-yl)-propionic acid in methanol (1 mL) and benzene (4 mL) was added a 2 M solution of (trimethylsilyl)diazomethane in hexanes (126 μL, 0.252 mmol). After 10 minutes, the mixture became homogeneous and the resulting reaction mixture was stirred at room temperature for 30 minutes. The reaction was concentrated in vacuo and the residue was purified by silica gel chromatography using a gradient of 0-8% methanol in dichloromethane to afford the title compound as a white solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:24])[N:8]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:9]2[C:14]([C:15]=1O)=[CH:13][CH:12]=[CH:11][N:10]=2)=[O:5])[CH3:2].O=P(Cl)(Cl)[Cl:27]>>[CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:24])[N:8]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:9]2[C:14]([C:15]=1[Cl:27])=[CH:13][CH:12]=[CH:11][N:10]=2)=[O:5])[CH3:2]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCOC(=O)c1c(O)c2cccnc2n(Cc2ccccc2)c1=O
Product: CCOC(=O)c1c(Cl)c2cccnc2n(Cc2ccccc2)c1=O
Yield: 98 %

Procedure:
A solution of 1-benzyl-4-hydroxy-2-oxo-1,2-dihydro-[1,8]-naphthyridine-3-carboxylic acid ethyl ester (3) (0.94 g, 2.9 mmol) was heated in neat POCl3 at 90° C. for 3 h. The solution was cooled and the excess POCl3 was distilled under vacuum. The residue was suspended in water, neutralized by solid NaHCO3, and extracted by dichloromethane. The organic layer was subsequently washed by saturated NaHCO3 solution, water and brine, dried over Na2SO4, and evaporated to yield 0.9 g (98%) of 1-benzyl-4-chloro-2-oxo-1,2-dihydro-[1,8]-naphthyridine-3-carboxylic acid ethyl ester (4) as white solids. MP: 109° C.; 1H-NMR (DMSO-d6): δ 1.31 (t, J=6.9 Hz, 3H), 4.37 (q, J=6.9 Hz, 2H), 5.62 (s, 2H), 7.27 (m, 5H), 7.51 (dd, J=4.7, 8.0 Hz, 1H), 8.46 (dd, J=1.5, 7.5 Hz, 1H), 8.80 (dd, J=1.5, 7.5 Hz, 1H); EIMS: 343 (M+1), 365 (M+23).
Reaction SMILES: [I-].C1([C:8]([PH3+])([C:15]2[CH:20]=C[CH:18]=[CH:17][CH:16]=2)C2C=CC=CC=2)C=CC=CC=1.C([O-])(C)(C)C.[K+].[C:28]([N:35]1CCCC(=O)C1)([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29]>C1(C)C=CC=CC=1>[C:28]([N:35]1[CH2:18][CH2:17][CH2:16][C:15](=[CH2:20])[CH2:8]1)([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29]
Reactant: [PH3+]C(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCCC(=O)C1
Agent: CC(C)(C)[O-]
Agent: [I-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: C=C1CCCN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Yield: 70.7 %

Procedure:
Triphenylmethyl phosphonium iodide (22.14 g) and toluene (135 ml) are added into a three mouth flask (500 ml), stirred at room temperature to obtain a milky white suspension and quickly changed to orange after potassium tert-butanolate (5.31 g) is added. Then N-Boc-3-piperidone (6.0 g) in toluene (66 ml) is added into a constant pressure funnel and dropped into the flask under argon with obvious exothermic phenomenon, and kept at the temperature of 30° C. and the reaction is tracked by TLC after addition. After reaction, the mixture is filtered and washed with a saturated brine (200 ml, 2 times) and then adjusted to pH≈3 with diluted HCl (1M), and then washed with a saturated brine to pH=7, dried with anhydrous sodium sulfate, and filtered to obtain a yellow transparent liquid. The yellow transparent liquid is purified together with silica gel by chromatography (elution liquid: petroleum ether:ethyl acetate=15:1) to obtain a yellow oil-liquid of N-Boc-3-methylene piperidine (4.2 g).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([NH:8]C(OCC)=O)[N+:5]([O-:14])=[C:4]([NH:15]C(OCC)=O)[CH:3]=1.[NH:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1.C(O)C.[OH-].[K+]>O>[NH2:15][C:4]1[CH:3]=[C:2]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[CH:7]=[C:6]([NH2:8])[N+:5]=1[O-:14]
Reactant: CCOC(=O)Nc1cc(Cl)cc(NC(=O)OCC)[n+]1[O-]
Reactant: C1COCCN1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Nc1cc(N2CCOCC2)cc(N)[n+]1[O-]
Reaction time: 24 h
Yield: 69 %

Procedure:
A mixture of 4-chloro-2,6-bis(ethoxycarbonylamino)pyridine 1-oxide (10.0 g., 0.03 mole) and 60 ml. of morpholine is refluxed with stirring under a nitrogen atmosphere for a period of 24 hrs. and concentrated to dryness. The residual material thus obtained is taken up in 200 ml. of absolute ethanol and 24.0 g. (0.36 mole) of 85% potassium hydroxide. After stirring at reflux temperature for a period of 16 hr., 200 ml. of absolute ethanol is added and reflux continued for an additional period of 30 hr. Concentration of the basic solution to dryness provides a residue which on stirring with water affords 4.4 g. (69% yield) of 2,6-diamino-4-(4-morpholinyl)pyridine 1-oxide as the free base, m.p. 315°-325° C. (dec.). The free base is taken up in absolute ethanol and acidified with ethanolic hydrogen chloride. Addition of ethyl acetate to the acidified ethanolic solution and cooling affords the product which is collected and crystallized from absolute ethanol to provide 2.8 g. of analytically pure 2,6-diamino-4-(4-morpholinyl)pyridine 1-oxide hydrochloride hydrate, m.p. 203.5°-206.5° C. (dec.) (corr.).
Reaction SMILES: O[C:2]1([C:22]2[CH:27]=[CH:26][C:25]3[O:28][CH2:29][O:30][C:24]=3[CH:23]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[C:3]1[C:17]([O:19][CH2:20][CH3:21])=[O:18].C([SiH](CC)CC)C.B(F)(F)F.CCOCC.Cl>C(Cl)Cl>[CH2:29]1[O:28][C:25]2[CH:26]=[CH:27][C:22]([CH:2]3[C:10]4[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=4)[C:4]([C:11]4[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=4)=[C:3]3[C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:23][C:24]=2[O:30]1
Reactant: CCOC(=O)C1=C(c2ccccc2)c2ccccc2C1(O)c1ccc2c(c1)OCO2
Agent: CC[SiH](CC)CC
Agent: Cl
Agent: FB(F)F
Solvent: ClCCl
Solvent: CCOCC
Product: CCOC(=O)C1=C(c2ccccc2)c2ccccc2C1c1ccc2c(c1)OCO2
Reaction time: 0.25 h
Yield: 100.8 %

Procedure:
To a solution of ethyl(1RS)-1-hydroxy-1-(3,4-methylenedioxyphenyl)-3-phenylindene-2-carboxylate (1.03 g, 2.58 mmol) in CH2Cl2 (40 mL) was added triethylsilane (0.49 ml, 3.07 mmol), followed by boron trifluoride etherate (1.55 ml, 12.6 mmol). The reaction mixture was allowed to stir for 15 min, at which time was added slowly 3M HCl. The mixture was extracted with EtOAc. The organic extract was washed successively with H2O, 5% aqueous NaHCO3 and saturated aqueous NaCl. The solvent was removed in vacuo to provide the title compound (1.00 g, 100%) as a mixture of Δ1 and Δ2 double bond isomers.