Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([NH:3][CH2:4][C:5]([C:7]1[CH:18]=[CH:17][C:10]([S:11][CH2:12][C:13]([O:15][CH3:16])=[O:14])=[CH:9][CH:8]=1)=[O:6])=O.[ClH:19]>CO>[ClH:19].[NH2:3][CH2:4][C:5]([C:7]1[CH:8]=[CH:9][C:10]([S:11][CH2:12][C:13]([O:15][CH3:16])=[O:14])=[CH:17][CH:18]=1)=[O:6]
Reactant: COC(=O)CSc1ccc(C(=O)CNC=O)cc1
Agent: Cl
Solvent: CO
Product: COC(=O)CSc1ccc(C(=O)CN)cc1

Procedure:
A mixture of methyl 4-[N-(formyl)aminoacetyl]-thiophenoxyacetate (10.1g.) and a saturated solution of hydrogen chloride in methanol (100ml.) was left at room temperature for 4 days. The mixture was then evaporated in vacuo and the residue recrystallised from a mixture of ether and methanol to give methyl 4-(aminoacetyl)thiophenoxyacetate hydrochloride (Example 33) (9.5g.), m.p. 161°-165° C. (decomposition, monohydrate).
Reaction SMILES: Br[C:2]1[CH:15]=[CH:14][C:13]2[C:4](=[C:5]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:6]3[C:11]([C:12]=2[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:10][CH:9]=[CH:8][CH:7]=3)[CH:3]=1.C([Li])CCC.C[O:34][B:35](OC)[O:36]C.Cl>C1COCC1>[C:16]1([C:12]2[C:11]3[C:6]([C:5]([C:4]4[CH:13]=[CH:14][CH:15]=[CH:2][CH:3]=4)=[C:22]4[C:23]=2[CH:24]=[C:25]([B:35]([OH:36])[OH:34])[CH:26]=[CH:27]4)=[CH:7][CH:8]=[CH:9][CH:10]=3)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: COB(OC)OC
Reactant: Brc1ccc2c(-c3ccccc3)c3ccccc3c(-c3ccccc3)c2c1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: OB(O)c1ccc2c(-c3ccccc3)c3ccccc3c(-c3ccccc3)c2c1
Temperature: -78 °C
Reaction time: 1 h
Yield: 80.8 %

Procedure:
In an argon atmosphere, 50 mL of dehydrated THF were added to 3.5 g (8.6 mmol) of 2-bromo-9,10-diphenylanthracene, and the temperature of the mixture was cooled to −78° C. Then, 6.0 mL of n-butyllithium (in hexane, 1.6 mol/L) were dropped. After the mixture had been stirred at −78° C. for 1 hour, the temperature of the mixture was increased to 0° C. The temperature of the mixture was cooled to −78° C. again, and 2.9 mL (26 mmol) of trimethoxyborane were dropped. The mixture was stirred at −78° C. for 1 hour, and was then stirred at room temperature for 2 hours. 50 mL of 10-mass % hydrochloric acid were added, and the whole was stirred for 1 hour, followed by filtration. The resultant solid was washed with toluene to obtain 2.6 g of 9,10-diphenylanthracene-2-boronic acid (80% yield).
Reaction SMILES: C1N=C(N)C2N=CN([C@@H]3O[C@H](COP(OP(OC[C@H]4O[C@@H](N5C=C(C(N)=O)CC=C5)[C@H](O)[C@@H]4O)(O)=O)(O)=O)[C@@H](O)[C@H]3O)C=2N=1.[CH3:45][N+:46]([CH2:49][C:50]([CH2:52][C:53]([OH:55])=[O:54])=[O:51])([CH3:48])[CH3:47].[Cl-]>>[OH:51][C@H:50]([CH2:52][C:53](=[O:54])[O-:55])[CH2:49][N+:46]([CH3:48])([CH3:45])[CH3:47]
Reactant: C[N+](C)(C)CC(=O)CC(=O)O
Agent: NC(=O)C1=CN([C@@H]2O[C@H](COP(=O)(O)OP(=O)(O)OC[C@H]3O[C@@H](n4cnc5c(N)ncnc54)[C@H](O)[C@@H]3O)[C@@H](O)[C@H]2O)C=CC1
Agent: [Cl-]
Product: C[N+](C)(C)C[C@H](O)CC(=O)[O-]
Reaction time: 30 h
Yield: 27 %

Procedure:
Carnitine dehydrogenase obtained as in example 1 was used in that synthesis. Synthesis of L-carnitine was carried out in the same conditions as in example 1, except as concerns the NADH regeneration system which was the yeast alcohol dehydrogenase and ethanol system instead of the glucose dehydrogenase and glucose system. Glucose was thus substituted with ethanol (concentration in the reactor: 4% by volume) and glucose dehydrogenase with 4 mg (700 units) of purified yeast alcohol dehydrogenase (Sigma ref. A 3263). Nitrogen was bubbled through the reactor (80 ml/mn) to eliminate the acetaldehyde formed by alcohol oxidation and thus improve the NADH regeneration. After 30 h, 0.325 g of L-carnitine was produced from dehydrocarnitine hydrochloride with a yield of 27%.
Reaction SMILES: N(OCCC(C)C)=O.N[C:10]1[CH:29]=[C:28]([F:30])[C:27]([N:31]2[C:36](=[O:37])[CH:35]=[C:34]([C:38]([F:41])([F:40])[F:39])[N:33]([CH3:42])[C:32]2=[O:43])=[CH:26][C:11]=1[O:12][C:13]1[C:14]([O:19][CH:20]([C:22]([O:24][CH3:25])=[O:23])[CH3:21])=[N:15][CH:16]=[N:17][CH:18]=1.[ClH:44]>[Cu]Cl.[Cu](Cl)Cl.C(#N)C>[Cl:44][C:10]1[CH:29]=[C:28]([F:30])[C:27]([N:31]2[C:36](=[O:37])[CH:35]=[C:34]([C:38]([F:41])([F:40])[F:39])[N:33]([CH3:42])[C:32]2=[O:43])=[CH:26][C:11]=1[O:12][C:13]1[C:14]([O:19][CH:20]([C:22]([O:24][CH3:25])=[O:23])[CH3:21])=[N:15][CH:16]=[N:17][CH:18]=1
Reactant: COC(=O)C(C)Oc1ncncc1Oc1cc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c(F)cc1N
Reactant: Cl
Agent: Cl[Cu]
Agent: Cl[Cu]Cl
Agent: CC(C)CCON=O
Solvent: CC#N
Product: COC(=O)C(C)Oc1ncncc1Oc1cc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c(F)cc1Cl
Reaction time: 1 h

Procedure:
Isoamyl nitrite is added to a mixture of 5-{2-amino-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}-4-{1-(methoxycarbonyl)ethoxy}pyrimidine, copper(I) chloride, copper(II) chloride and acetonitrile dropwise at room temperature, and the mixture is stirred for 1 hour. This reaction solution is poured into 2% hydrochloric acid, and extracted with ethyl acetate. The organic layer is washed with saturated saline, dried over anhydrous magnesium sulfate, and concentrated. The residue is subjected to silica gel column chromatography to obtain 5-{2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}-4-{1-(methoxycarbonyl)ethoxy}pyrimidine [present compound 4-2].
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[CH3:11].S(=O)(=O)(O)O.[CH2:17](O)[CH:18]=[CH2:19]>>[OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH2:19][CH:18]=[CH2:17])=[O:7])=[CH:4][C:3]=1[CH3:11]
Reactant: Cc1cc(C(=O)O)ccc1O
Reactant: C=CCO
Agent: O=S(=O)(O)O
Product: C=CCOC(=O)c1ccc(O)c(C)c1
Temperature: 100 °C
Yield: 92 %

Procedure:
Into a round bottom flask there are introduced 9.5 g (62 mmoles) of 4-hydroxy-3-methylbenzoic acid and 70 ml of allyl alcohol. 1.8 ml of concentrated sulfuric acid are added and the mixture is heated at 100° C. for 8 hours. The reaction mixture is then evaporated to dryness, neutralized with sodium bicarbonate and extracted with dichloromethane. The organic phase is decanted, washed with water, dried over magnesium sulfate and evaporated. The resulting residue is purified simply by filtration over silica (eluant: dichloromethane). After evaporation of the solvents, 8.76 g (92% yield) of the expected ester whose melting point is obtained.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.O[CH2:10][C:11]1[CH:12]=[C:13]([C:21]2[CH:26]=[CH:25][C:24]([C:27]#[N:28])=[CH:23][CH:22]=2)[CH:14]=[C:15]([C:17]([F:20])([F:19])[F:18])[CH:16]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[Br:1][CH2:10][C:11]1[CH:12]=[C:13]([C:21]2[CH:26]=[CH:25][C:24]([C:27]#[N:28])=[CH:23][CH:22]=2)[CH:14]=[C:15]([C:17]([F:20])([F:19])[F:18])[CH:16]=1
Reactant: N#Cc1ccc(-c2cc(CO)cc(C(F)(F)F)c2)cc1
Reactant: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: N#Cc1ccc(-c2cc(CBr)cc(C(F)(F)F)c2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 63.7 %

Procedure:
N-bromosuccinimide (2.24 g, 12.6 mmol) was added to a 0° C. solution of 3′-(hydroxymethyl)-5′-(trifluoromethyl)biphenyl-4-carbonitrile (1.66 g, 6.0 mmol) and triphenylphosphine (3.14 g, 12.0 mmol) in THF (100 mL). The reaction was warmed to ambient temperature and stirred for 18 hours. The solvent was evaporated and the residue was purified by chromatography on SiO2 with a gradient of ethyl acetate/hexanes of 5% to 40%. The product 3′-(bromomethyl)-5′-(trifluoromethyl)biphenyl-4-carbonitrile (1.30 g, 64%) was obtained as a white solid. 1H-NMR (CDCl3, 400 MHz) δ 7.65-7.80 (m, 7H), 4.56 (s, 2H).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[N+:7]([C:10]1[CH:11]=[C:12]2[CH:18]=[C:17]([C:19](=[O:21])[CH3:20])[N:16](S(C3C=CC=CC=3)(=O)=O)[C:13]2=[N:14][CH:15]=1)([O-:9])=[O:8].C(OCC)(=O)C>CO.O>[N+:7]([C:10]1[CH:11]=[C:12]2[CH:18]=[C:17]([C:19](=[O:21])[CH3:20])[NH:16][C:13]2=[N:14][CH:15]=1)([O-:9])=[O:8]
Reactant: CC(=O)c1cc2cc([N+](=O)[O-])cnc2n1S(=O)(=O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(=O)c1cc2cc([N+](=O)[O-])cnc2[nH]1
Temperature: 40 °C
Yield: 100.8 %

Procedure:
Potassium carbonate (1.20 g, 8.69 mmol) was added to a solution of 1-(5-nitro-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)ethanone (0.50 g, 1.45 mmol) in methanol (13 mL) and water (4.3 mL). The reaction mixture was heated at 40° C. for 30 minutes. The reaction mixture was then cooled down and treated with water and ethyl acetate. The layers were then separated. The organic layers were washed twice with water, dried over sodium sulfate, filtered, and evaporated to afford 1-(5-nitro-1H-pyrrolo[2,3-b]pyridin-2-yl)ethanone (0.30 g, quantitative yield).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]3[N:15]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:30])([CH3:29])[CH3:28])[CH:16]=[C:17]([C:19]([F:22])([F:21])[F:20])[N:18]=3)=[CH:10][N:9]=2)[CH:5]=[CH:4][C:3]=1[OH:31].O[CH2:33][C:34]([CH3:43])([CH3:42])[C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36]>>[CH3:33][C:34]([CH3:43])([CH2:42][O:31][C:3]1[CH:4]=[CH:5][C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]3[N:15]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:30])([CH3:29])[CH3:28])[CH:16]=[C:17]([C:19]([F:20])([F:22])[F:21])[N:18]=3)=[CH:10][N:9]=2)=[CH:7][C:2]=1[CH3:1])[C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36]
Reactant: Cc1cc(-c2ccc(-c3nc(C(F)(F)F)cn3COCC[Si](C)(C)C)cn2)ccc1O
Reactant: CC(C)(C)OC(=O)C(C)(C)CO
Product: Cc1cc(-c2ccc(-c3nc(C(F)(F)F)cn3COCC[Si](C)(C)C)cn2)ccc1OCC(C)(C)C(=O)OC(C)(C)C
Yield: 34.5 %

Procedure:
By using 2-methyl-4-[5-[4-(trifluoromethyl)-1-(2-trimethylsilylethoxymethyl)-imidazol-2-yl]-2-pyridyl]phenol (224 mg) and tert-butyl 3-hydroxy-2,2-dimethylpropanoate (284 mg), the procedure was carried out in the same manner as in Example 1-1) to obtain tert-butyl 2,2-dimethyl-3-[2-methyl-4-[5-[4-(trifluoromethyl)-1-(2-trimethylsilylethoxymethyl)imidazol-2-yl]-2-pyridyl]phenoxy]propanoate (104 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:13][N+:14]([O-])=O)[CH2:9][N+:10]([O-])=O)=[CH:4][CH:3]=1.[H][H]>CO.[Pt](=O)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([CH2:13][NH2:14])[CH2:9][NH2:10])=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])CC(C[N+](=O)[O-])c1ccc(Cl)cc1
Reactant: [H][H]
Agent: O=[Pt]=O
Solvent: CO
Product: NCC(CN)c1ccc(Cl)cc1
Yield: 99.4 %

Procedure:
According to the procedure described in Eur. J. Org. Chem. 2010, 3, 484-493, a mixture of 1-chloro-4-[2-nitro-1-(nitromethyl)ethyl]benzene (80 mg, 0.327 mmol) and 18 mg platinum (IV) oxide in 5 mL MeOH contained in a pressure tube was reacted under 50 PSI hydrogen. After 15 hours the mixture was filtered through Celite, rinsed with MeOH and evaporated to give a quantitative yield (60 mg) of the title compound as a yellow-orange oil. 1H NMR (CD3OD) δ: 7.34-7.38 (m, 2H), 7.21-7.29 (m, 2H), 2.88-2.98 (m, 2H), 2.73-2.86 (m, 3H).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]([O:13][CH3:14])=[O:12])=[CH:7][C:6]=1[NH:15][C:16](=[O:33])[CH2:17][CH:18]([C:24]1[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][C:25]=1[O:31][CH3:32])[CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])([CH3:4])([CH3:3])[CH3:2].Br[CH2:35][C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37]>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]([O:13][CH3:14])=[O:12])=[CH:7][C:6]=1[NH:15][C:16](=[O:33])[CH2:17][CH:18]([C:24]1[CH:29]=[CH:28][C:27]([O:30][CH2:35][C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])=[CH:26][C:25]=1[O:31][CH3:32])[CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCCCCC(CC(=O)Nc1cc(C(=O)OC)ccc1C(C)(C)C)c1ccc(O)cc1OC
Reactant: CC(C)(C)OC(=O)CBr
Product: CCCCCC(CC(=O)Nc1cc(C(=O)OC)ccc1C(C)(C)C)c1ccc(OCC(=O)OC(C)(C)C)cc1OC

Procedure:
Following a similar procedure to that described in Preparation 45A(i), but using N-(2-t-butyl-5-methoxycarbonylphenyl)-3-(4-hydroxy-2-methoxyphenyl)-octanamide (prepared as described in Preparation 46) and t-butyl bromoacetate, the title compound was obtained as a foam-like substance.
Reaction SMILES: [N:1]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]([O:11]C)=[O:10])=[N+:2]=[N-:3].CO.O.[Li+].[OH-]>[Cl-].[Na+].O>[N:1]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]([OH:11])=[O:10])=[N+:2]=[N-:3]
Reactant: COC(=O)CCCCCN=[N+]=[N-]
Agent: [Cl-]
Agent: [Li+]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: [N-]=[N+]=NCCCCCC(=O)O
Temperature: 25 °C
Reaction time: 5 h
Yield: 93 %

Procedure:
AHA was synthesized following a reported method with modifications. To methyl 6-azidohexanoate (3.4 g, 20 mmol) in 20 ml of mixture of MeOH/H2O (4/1 v/v) LiOH (2.5 g, 60 mmol) was added. After being stirred for 5 h at room temperature, the reaction mixture was poured into brine and washed with hexane to remove unreacted Ester. The aqueous fraction was acidified with HCl, extracted with ethyl acetate. Combined organic fractions were washed with brine and died over MgSO4. Ethyl acetate was removed under reduced pressure that resulted to transparent liquid. Yield 93%.
Reaction SMILES: [F:1][CH2:2][C:3]1([CH2:14][F:15])[O:7][B:6]([OH:8])[C:5]2[CH:9]=[CH:10][C:11]([CH3:13])=[CH:12][C:4]1=2.C1C(=O)N(Br)C(=[O:19])C1.C([O-])([O-])=O.[Na+].[Na+].Cl>C(Cl)(Cl)(Cl)Cl>[F:1][CH2:2][C:3]1([CH2:14][F:15])[O:7][B:6]([OH:8])[C:5]2[CH:9]=[CH:10][C:11]([CH:13]=[O:19])=[CH:12][C:4]1=2
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc2c(c1)C(CF)(CF)OB2O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClC(Cl)(Cl)Cl
Product: O=Cc1ccc2c(c1)C(CF)(CF)OB2O
Yield: 107.3 %

Procedure:
A solution of 3,3-bis(fluoromethyl)-5-methylbenzo[c][1,2]oxaborol-1(3H)-ol (350 mg, 1.65 mmol), NBS (647 mg, 3.63 mmol), and BPO (40 mg, 0.17 mmol) in CCl4 (10 mL) was refluxed overnight. After treating with aqueous Na2CO3, the aqueous phase was acidified with HCl (3 N) to pH of 3, and then extracted with EA. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure to afford the crude product (400 mg) as a yellow solid that was used directly in the next step without purification. 1H NMR (300 MHz, CDCl3): δ 10.09 (s, 1H), 7.98-7.94 (m, 3H), 4.79-4.74 (m, 2H), 4.63-4.59 (m, 2H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][C@@H:9]1[C:14]([OH:16])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C(O[N:25]1[N:33]=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.O.NN>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[C:14]([NH:25][NH2:33])=[O:16])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCCC[C@@H]1C(=O)O
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: NN
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCCCC1C(=O)NN
Temperature: 0 °C
Reaction time: 1 h

Procedure:
3 g of (R)-Piperidine-1,2-dicarboxylic acid 1-tert-butyl ester were dissolved in 30 ml DMF. 5 g HATU and 2.2 ml DIPEA were added and the reaction mixture cooled to 0° C. 4 eq. of Hydrazine-Monohydrate in 30 ml DMF were added and the reaction warmed to rt and stirred for 1 h. The crude product was extracted from ethylacetate/aq. NaHCO3.
Reaction SMILES: [CH:1]1[C:2]([CH2:10][C@@H:11]([NH2:28])[CH2:12][C:13]([N:15]2[CH2:27][C:19]3=[N:20][N:21]=[C:22]([C:23]([F:26])([F:25])[F:24])[N:18]3[CH2:17][CH2:16]2)=[O:14])=[C:3]([F:9])[CH:4]=[C:5]([F:8])[C:6]=1[F:7].[C:29]([OH:42])(=[O:41])/[CH:30]=[CH:31]/[C:32]1[CH:40]=[CH:39][C:37]([OH:38])=[C:34]([O:35][CH3:36])[CH:33]=1>C(#N)C>[CH:1]1[C:2]([CH2:10][C@@H:11]([NH2:28])[CH2:12][C:13]([N:15]2[CH2:27][C:19]3=[N:20][N:21]=[C:22]([C:23]([F:26])([F:25])[F:24])[N:18]3[CH2:17][CH2:16]2)=[O:14])=[C:3]([F:9])[CH:4]=[C:5]([F:8])[C:6]=1[F:7].[C:29]([O-:42])(=[O:41])/[CH:30]=[CH:31]/[C:32]1[CH:40]=[CH:39][C:37]([OH:38])=[C:34]([O:35][CH3:36])[CH:33]=1
Reactant: COc1cc(/C=C/C(=O)O)ccc1O
Agent: N[C@@H](CC(=O)N1CCn2c(nnc2C(F)(F)F)C1)Cc1cc(F)c(F)cc1F
Solvent: CC#N
Product: COc1cc(/C=C/C(=O)[O-])ccc1O
Reaction time: 48 h

Procedure:
Sitagliptin free base (2.0 gms) and ferulic acid (0.95 gms) were dissolved in acetonitrile (16 ml) at 60° C. to 65° C. and the reaction mass left for slow solvent evaporation at room temperature for 48 hours. Precipitated solids were filtered off and dried at 50° C. to 55° C. for 6 hours to obtain the title compound. Yield: 1.45 gms.
Reaction SMILES: [C:1]([O:4][C:5]1[C:10]([CH3:11])=[C:9]([C:12]2[O:13][C:14]3[CH:20]=[C:19](OS(C(F)(F)F)(=O)=O)[CH:18]=[CH:17][C:15]=3[CH:16]=2)[O:8][C:7](=[O:29])[C:6]=1[CH3:30])(=[O:3])[CH3:2].CCN(CC)CC.C1(P(CCC)C2C=CC=CC=2)C=CC=CC=1>C1COCC1.CS(C)=O.CO.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:1]([O:4][C:5]1[C:10]([CH3:11])=[C:9]([C:12]2[O:13][C:14]3[CH:20]=[C:19]([C:1]([O:4][CH3:5])=[O:3])[CH:18]=[CH:17][C:15]=3[CH:16]=2)[O:8][C:7](=[O:29])[C:6]=1[CH3:30])(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1c(C)c(-c2cc3ccc(OS(=O)(=O)C(F)(F)F)cc3o2)oc(=O)c1C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCCP(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc2cc(-c3oc(=O)c(C)c(OC(C)=O)c3C)oc2c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
After adding a solution of 4-acetyloxy-3,5-dimethyl-6-(6-(trifluoromethanesulfonyloxy)benzofuran-2-yl)-2H-pyran-2-one (350 mg) in THF (5 ml) and Et3N (80 mg) to a mixed solution of palladium acetate (3.5 mg) and diphenylphospinopropane (6.5 mg) in DMSO (5 ml) and MeOH (5 ml), the mixture was stirred at room temperature for one hour under a carbon monoxide atmosphere, and then further stirred at 80° C. for 2 hours. The reaction solution was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (n-hexane/AcOEt=1/1) to obtain 4-acetyloxy-3,5-dimethyl-6-(6-(methoxycarbonyl) benzofuran-2-yl)-2H-pyran-2-one.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[CH2:6][CH2:5]2.Br.[Br:14][CH2:15][CH2:16][NH:17][CH2:18][CH2:19]Br.C(=O)([O-])[O-].[Na+].[Na+]>CO>[BrH:14].[N:1]1([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[NH:8][C:7](=[O:12])[CH2:6][CH2:5]3)[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1
Reactant: Nc1ccc2c(c1)CCC(=O)N2
Reactant: BrCCNCCBr
Agent: Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Product: O=C1CCc2cc(N3CCNCC3)ccc2N1
Yield: 50.5 %

Procedure:
A mixture of 9.36 g of 6-amino-3,4-dihydrocarbostyril, 18 g of bis(β-bromoethyl)amine monohydrobromide and 70 ml of methanol was refluxed for 15 hours while stirring. After cooling, 3.06 g of sodium carbonate was added and the resulting mixture was refluxed for 8 hours while stirring. The reaction mixture was cooled to precipitate crystals which then were collected by filtration, the crystals were washed with methanol to give 9.1 g of 6-(1-piperazinyl)-3,4-dihydrocarbostyril hydrobromide, m.p. 289°-293° C. (decomp.) (methanol-water), colorless needles.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][C:9]([I:14])=[C:10]([CH3:13])[CH:11]=2)[CH:6]=[N:5]1)(=O)C.N>CO.C1COCC1>[I:14][C:9]1[CH:8]=[C:7]2[C:12](=[CH:11][C:10]=1[CH3:13])[NH:4][N:5]=[CH:6]2
Reactant: CC(=O)n1ncc2cc(I)c(C)cc21
Agent: N
Solvent: C1CCOC1
Solvent: CO
Product: Cc1cc2[nH]ncc2cc1I
Yield: 100.8 %

Procedure:
1-Acetyl-5-iodo-6-methylindazole (1.5 g, 5.0 mmol) was stirred with ammonia (7 M in methanol, 4 mL) in methanol/THF (2/1, 15 mL) for 1 h. The solution was evaporated to give the subtitle compound (1.3 g, 100%) as an off-white powder.
Reaction SMILES: [CH:1]([N:3]1[CH2:7][CH2:6][C:5]([OH:21])([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:4]1)=O>C1COCC1>[OH:21][C:5]1([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:6][CH2:7][N:3]([CH3:1])[CH2:4]1
Reactant: O=CN1CCC(O)(c2ccccc2Cc2ccccc2)C1
Solvent: C1CCOC1
Product: CN1CCC(O)(c2ccccc2Cc2ccccc2)C1

Procedure:
A solution of 5.90 g of 1-formyl-3-hydroxy-3-(α-phenyl-2-tolyl)pyrrolidine in 60 ml of dry THF is added dropwise to a suspension of 3 g of LiAlH in 30 ml of dry THF and the mixture is refluxed for 4 hours. After cooling the mixture is separated and the residue extracted with ether. The combined organic solution is dried (Na2SO4) and concentrated to an oil. This oil is dissolved in 100 ml of hexane and after cooling 16 hours the product is isolated by filtration to provide 3-hydroxy-1-methyl-3-(α-phenyl-2-tolyl)pyrrolidine, mp 108°-109° C. Dilution of the mother liquor with 50 ml of hexane gives a second crop of 3-hydroxy-1-methyl-3-(α-phenyl-2-tolyl)pyrrolidine, mp 107°-108° C.
Reaction SMILES: [Cl:1][C:2]1[CH:44]=[CH:43][C:5]2[N:6](CC3C=CC(OC)=CC=3)[C:7](=[O:33])[C@H:8]([CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[Cl:32])[N:9]=[C:10]([C:11]3[CH:24]=[CH:23][C:14]4[NH:15][C:16](=[O:22])[N:17]([CH2:18][CH2:19][CH2:20][OH:21])[C:13]=4[CH:12]=3)[C:4]=2[CH:3]=1.C1(OC)C=CC=CC=1.[Al+3].[Cl-].[Cl-].[Cl-]>ClC(Cl)C.C(OCC)(=O)C.C(Cl)Cl>[Cl:1][C:2]1[CH:44]=[CH:43][C:5]2[NH:6][C:7](=[O:33])[C@H:8]([CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[Cl:32])[N:9]=[C:10]([C:11]3[CH:24]=[CH:23][C:14]4[NH:15][C:16](=[O:22])[N:17]([CH2:18][CH2:19][CH2:20][OH:21])[C:13]=4[CH:12]=3)[C:4]=2[CH:3]=1
Reactant: COc1ccc(CN2C(=O)[C@H](Cc3ccccc3Cl)N=C(c3ccc4[nH]c(=O)n(CCCO)c4c3)c3cc(Cl)ccc32)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: COc1ccccc1
Solvent: ClCCl
Product: O=C1Nc2ccc(Cl)cc2C(c2ccc3[nH]c(=O)n(CCCO)c3c2)=N[C@H]1Cc1ccccc1Cl
Temperature: 87.5 °C

Procedure:
(S)-7-Chloro-3-(2-chlorobenzyl)-5-(3-(3-hydroxypropyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)-1-(4-methoxybenzyl)-1H-benzo[e][1,4]diazepin-2(3H)-one was dissolved in dichloroethane (2 mL) and anisole (200 μL) was added followed by AlCl3 (165 mg). This mixture was heated to 85-90° C. for one hour. After cooling, the mixture was diluted with ethyl acetate and quenched with ice. 1M Citric acid was added and the layers separated. The organic layer was washed with brine, then dried (MgSO4). After filtration, the solvent was evaporated onto silica gel. Chromatography eluting with 5% ethyl acetate in hexanes for 5 min then a gradient over 30 minutes up to 100% ethyl acetate gave the crude product as a yellow foam (70 mg). The product was re-columned twice with DCM—10% MeOH in DCM to provide (S)-7-chloro-3-(2-chlorobenzyl)-5-(3-(3-hydroxypropyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)-1H-benzo[e][1,4]diazepin-2(3H)-one (20 mg) as a white solid that was 97% pure by HPLC: MP=210° C.; Optical rotation: C=1.0 (CHCl3), [α]D=−26°; MS (m/z): 509.6; 1H NMR (d6-DMSO) δ 11.5 (s, 1H), 10.7 (s, 1H), 7.6 (d, 1H) 7.5 (d, 1H), 7.4 (d, 1H), 7.3-7.2 (m, 4H), 7.1 (s, 1H), 6.95 (d, 1H), 6.85 (d, 1H), 4.3 (m, 2H), 3.8 (m, 2H), 3.7 (m, 1H), 3.5-3.3 (m, 2H), 2.1-2.0 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:35])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[C:11]([NH2:34])=[CH:12][C:13]2[N:17]=[C:16]([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)[N:15]([C:25]3[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=3)[C:14]=2[CH:33]=1.[Cl:36][C:37]1[CH:42]=[CH:41][C:40]([S:43](Cl)(=[O:45])=[O:44])=[CH:39][CH:38]=1>>[CH3:1][O:2][C:3](=[O:35])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[C:11]([NH:34][S:43]([C:40]2[CH:41]=[CH:42][C:37]([Cl:36])=[CH:38][CH:39]=2)(=[O:45])=[O:44])=[CH:12][C:13]2[N:17]=[C:16]([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)[N:15]([C:25]3[CH:26]=[CH:27][C:28]([O:31][CH3:32])=[CH:29][CH:30]=3)[C:14]=2[CH:33]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Reactant: COC(=O)CCCCCOc1cc2c(cc1N)nc(-c1ccc(F)cc1)n2-c1ccc(OC)cc1
Product: COC(=O)CCCCCOc1cc2c(cc1NS(=O)(=O)c1ccc(Cl)cc1)nc(-c1ccc(F)cc1)n2-c1ccc(OC)cc1

Procedure:
6-[(5-Amino-2-(4-fluorophenyl)-1-(4-methoxyphenyl)-1H-benzimidazol-6-yl)oxy]hexanoic acid methyl ester was reacted with 4-chlorobenzenesulfonic acid chloride according to general operating instructions 13.