Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([CH3:10])[C:4]=1[C:11]1[N:16]2[N:17]=[C:18]([S:28][CH3:29])[C:19]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[C:15]2[CH:14]=[CH:13][CH:12]=1.[H-].[Na+].Br[CH2:33][CH:34]1[CH2:36][CH2:35]1.O>CN(C)C=O.C(OCC)(=O)C>[CH:34]1([CH2:33][N:20]([C:19]2[C:18]([S:28][CH3:29])=[N:17][N:16]3[C:11]([C:4]4[C:5]([CH3:10])=[CH:6][C:7]([CH3:9])=[CH:8][C:3]=4[O:2][CH3:1])=[CH:12][CH:13]=[CH:14][C:15]=23)[C:21](=[O:27])[O:22][C:23]([CH3:25])([CH3:24])[CH3:26])[CH2:36][CH2:35]1
Reactant: BrCC1CC1
Reactant: COc1cc(C)cc(C)c1-c1cccc2c(NC(=O)OC(C)(C)C)c(SC)nn12
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1cc(C)cc(C)c1-c1cccc2c(N(CC3CC3)C(=O)OC(C)(C)C)c(SC)nn12
Temperature: 40 °C
Reaction time: 1 h

Procedure:
After dissolving tert-butyl N-[7-(2-methoxy-4,6-dimethylphenyl)-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]carbamate (400 mg) in N,N-dimethylformamide (5 mL), sodium hydride (60%, 58 mg) was added while cooling on ice, and then (bromomethyl)cyclopropane (111 μL) was added and the mixture was stirred for 1 hour at 40° C. Water was added to the reaction mixture, extraction was performed with ethyl acetate and the extract was washed with brine. After drying the obtained organic layer over anhydrous magnesium sulfate and filtering it, the solvent was concentrated under reduced pressure to obtain crude tert-butyl N-cyclopropylmethyl-N-[7-(2-methoxy-4,6-dimethylphenyl)-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]carbamate. This was dissolved in ethyl acetate (10 mL) without purification, a 4 N hydrochloric acid/ethyl acetate solution (20 mL) was added, and the mixture was stirred at 40° C. for 1 hour. The reaction mixture was neutralized with 5 N aqueous sodium hydroxide while cooling on ice, and then extraction was performed with ethyl acetate and the organic layer was washed with brine. After drying over anhydrous magnesium sulfate and filtration, the solvent was distilled off under reduced pressure to obtain the title compound (368 mg) as a yellow oil.
Reaction SMILES: [CH3:1][C:2]1[CH2:7][CH2:6][CH2:5][C:4]([CH3:9])([CH3:8])[C:3]=1/[CH:10]=[CH:11]/[C:12](/[CH3:22])=[CH:13]/[CH:14]=[CH:15]/[C:16](/[CH3:21])=[CH:17]/[C:18](F)=[O:19].[O:23]=[CH:24][C@@H:25]([C@H:27]([C@@H:29]([C@@H:31]([C:33]([OH:35])=[O:34])[OH:32])[OH:30])[OH:28])[OH:26].O.C(=O)(O)[O-].[Na+]>CC(C)=O.O>[CH3:1][C:2]1[CH2:7][CH2:6][CH2:5][C:4]([CH3:9])([CH3:8])[C:3]=1/[CH:10]=[CH:11]/[C:12](/[CH3:22])=[CH:13]/[CH:14]=[CH:15]/[C:16](/[CH3:21])=[CH:17]/[C:18]([O:23][C@@H:24]1[O:32][C@H:31]([C:33]([OH:35])=[O:34])[C@@H:29]([OH:30])[C@H:27]([OH:28])[C@H:25]1[OH:26])=[O:19]
Reactant: CC1=C(/C=C/C(C)=C/C=C/C(C)=C/C(=O)F)C(C)(C)CCC1
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)C(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: CC1=C(/C=C/C(C)=C/C=C/C(C)=C/C(=O)O[C@@H]2O[C@H](C(=O)O)[C@@H](O)[C@H](O)[C@H]2O)C(C)(C)CCC1
Temperature: 25 °C
Reaction time: 22 h

Procedure:
Retinoyl fluoride can be mixed with commercially available glucuronic acid. The reaction is carried out in acetone/water to facilitate the solubility of the water-insoluble retinoyl fluoride and the water-soluble glucuronic acid. The reaction takes place in slightly alkaline pH and hence sodium bicarbonate is used in the reaction mixture. Stirring the mixture at room temperature for 20-24 hours followed by acidification of the solution and extraction with ethyl acetate yields retinoyl glucuronide as the major product. Pure all-trans retinoyl β-glucuronide can be obtained by a combination of column and high-performance liquid chromatography (HPLC).
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[C:10]([NH:31][C@@H:32]2[C@@H:37]3[CH2:38][C@@H:34]([CH:35]=[CH:36]3)[C@@H:33]2[C:39]([NH2:41])=[O:40])=[C:11]2[N:17]=[C:16]([C:18]3[CH:23]=[CH:22][C:21](CN4CCOCC4)=[CH:20][CH:19]=3)[NH:15][C:12]2=[N:13][CH:14]=1.NC1C(N)=C(N[C@@H]2[C@@H]3C[C@@H](C=C3)[C@@H]2C(N)=O)C(Cl)=CN=1.[N:62]1(C2C=CC(C=O)=CC=2)[CH2:67][CH2:66][O:65][CH2:64][CH2:63]1>>[Cl:8][C:9]1[C:10]([NH:31][C@@H:32]2[C@@H:37]3[CH2:38][C@@H:34]([CH:35]=[CH:36]3)[C@@H:33]2[C:39]([NH2:41])=[O:40])=[C:11]2[N:17]=[C:16]([C:18]3[CH:23]=[CH:22][C:21]([N:62]4[CH2:67][CH2:66][O:65][CH2:64][CH2:63]4)=[CH:20][CH:19]=3)[NH:15][C:12]2=[N:13][CH:14]=1
Reactant: O=Cc1ccc(N2CCOCC2)cc1
Reactant: NC(=O)[C@@H]1[C@H](Nc2c(Cl)cnc3[nH]c(-c4ccc(CN5CCOCC5)cc4)nc23)[C@H]2C=C[C@@H]1C2
Agent: NC(=O)[C@@H]1[C@H](Nc2c(Cl)cnc(N)c2N)[C@H]2C=C[C@@H]1C2
Solvent: O=C(O)C(F)(F)F
Product: NC(=O)[C@@H]1[C@H](Nc2c(Cl)cnc3[nH]c(-c4ccc(N5CCOCC5)cc4)nc23)[C@H]2C=C[C@@H]1C2
Yield: 20 %

Procedure:
In the same fashion as for Compound III, (1S,2S,3R,4R)-3-(2,3-Diamino-5-chloro-pyridin-4-ylamino)-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid amide and 4-morpholin-4-yl-benzaldehyde were reacted to produce the title compound (20%). 1H NMR (d-chloroform): 15.43 (br s, 1H), 8.06 (d, J=9 Hz, 1H), 8.00 (d, J=9 Hz, 2H), 7.77 (s, 1H), 7.02 (d, J=9 Hz, 2H), 6.50 (m, 1H), 6.42 (m, 1H), 5.91 (br s, 1H), 5.53 (br s, 1H), 5.40 (t, J=8 Hz, 1H), 3.90 (t, J=5 Hz, 4H), 3.30 (t, J=5 Hz, 4H), 3.17 (s, 1H), 3.04 (s, 1H), 2.68 (d, J=8 Hz, 1H), 2.38 (d, J=9 Hz, 1H), 1.67 (d, J=9 Hz, 1H). MS: 466.07 (M+H). HPLC retention time: 2.42 minutes (G Method).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[CH:5]=[C:6](Cl)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[CH3:13])[CH3:2].[C:16]([O:20][C:21]([N:23]1[C:32]2[C:27](=[CH:28][CH:29]=[C:30]([CH2:33][CH2:34][O:35][C:36]3[CH:44]=[CH:43][C:42]4[C:38](=[CH:39][CH2:40][N:41]=4)[CH:37]=3)[N:31]=2)[CH2:26][CH2:25][CH2:24]1)=[O:22])([CH3:19])([CH3:18])[CH3:17]>>[C:16]([O:20][C:21]([N:23]1[C:32]2[C:27](=[CH:28][CH:29]=[C:30]([CH2:33][CH2:34][O:35][C:36]3[CH:37]=[C:38]4[C:42](=[CH:43][CH:44]=3)[N:41]([C:6]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[CH3:13])=[CH:5][C:4]([O:3][CH2:1][CH3:2])=[O:15])[CH:40]=[CH:39]4)[N:31]=2)[CH2:26][CH2:25][CH2:24]1)=[O:22])([CH3:19])([CH3:17])[CH3:18]
Reactant: CCOC(=O)C=C(Cl)c1ccccc1C
Reactant: CC(C)(C)OC(=O)N1CCCc2ccc(CCOc3ccc4c(c3)=CCN=4)nc21
Product: CCOC(=O)C=C(c1ccccc1C)n1ccc2cc(OCCc3ccc4c(n3)N(C(=O)OC(C)(C)C)CCC4)ccc21

Procedure:
The title compound was synthesized from 3-chloro-3-o-tolyl-acrylic acid ethyl ester and 7-[2-(2H-indol-5-yloxy)-ethyl]-3,4-dihydro-2H-[1,8]naphthyridine-1-carboxylic acid tert-butyl ester using the procedure outlined in Example 18, step (d), in a 35% yield of an E/Z isomeric mixture. 1H NMR (CDCl3) δ 7.46 (m, 0.6H), 7.30 (m, 4.8H), 7.10 (m, 1.6H), 7.03 (d, 0.6H, J=3.6 Hz), 6.94 (m, 1H), 6.85 (m, 0.4H), 6.70 (m, 1H), 6.53 (d, 0.8H, J=2.8 Hz), 6.47 (d, 0.2H, J=2.8 Hz), 6.30 (s, 0.2H), 5.82 (s, 0.8H), 4.39 (m, 2H), 4.10 (m, 2H), 3.78 (m, 2H), 3.22 (t, 2H, J=6.8), 2.75 (t, 2H, J=6.8), 2.07 (s, 2.4H), 2.02 (s, 0.6H), 1.94 (m, 2H), 1.53 (s, 9H), 1.05 (m, 3H).
Reaction SMILES: [OH:1][C:2]1[NH:7][C:6](=[O:8])[N:5]([CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:4](=[O:16])[C:3]=1[C:17]([NH:19][CH2:20][C:21]([O:23]CC)=[O:22])=[O:18].[Cl:26][C:27]1[CH:34]=[CH:33][CH:32]=[C:31]([Cl:35])[C:28]=1[CH2:29]Br.C(=O)([O-])[O-].[Na+].[Na+].Cl>CN(C)C=O>[Cl:26][C:27]1[CH:34]=[CH:33][CH:32]=[C:31]([Cl:35])[C:28]=1[CH2:29][N:7]1[C:2]([OH:1])=[C:3]([C:17]([NH:19][CH2:20][C:21]([OH:23])=[O:22])=[O:18])[C:4](=[O:16])[N:5]([CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:6]1=[O:8]
Reactant: CCOC(=O)CNC(=O)c1c(O)[nH]c(=O)n(Cc2ccccc2)c1=O
Reactant: Clc1cccc(Cl)c1CBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(O)CNC(=O)c1c(O)n(Cc2c(Cl)cccc2Cl)c(=O)n(Cc2ccccc2)c1=O
Temperature: 100 °C
Reaction time: 2.5 h
Yield: 11.2 %

Procedure:
A mixture of ethyl N-{[6-hydroxy-2,4-dioxo-3-(phenylmethyl)-1,2,3,4-tetrahydro-5-pyrimidinyl]carbonyl}glycinate (example 11a, 388 mg, 1.12 mmoles), 2,6-dichlorobenzyl bromide (295 uL, 1.23 mmoles) and sodium carbonate (330 mg, 3.1 mmoles) in dimethylformamide (6.0 mL) was stirred under argon at 100° C. for 2.5 hours. The mixture was cooled, poured into 1 molar hydrochloric acid and extracted with ethyl acetate (×2). The ester was hydrolysed by stirring in a mixture of ethanol (3 mL) and 1 molar sodium hydroxide solution (3 mL) for 3 hours. The mixture was acidified and extracted with ethyl acetate. Purification by preparative HPLC (acetonitrile-water—0.1% TFA, 20-100%) and crystallization from ethanol-water gave the title compound (60 mg, 11%). 1H NMR (400 MHz, DMSO-d6) δ ppm 13.12 (br. s., 1 H), 10.02 (br. s., 1 H), 7.42 (d, 2 H), 7.22-7.35 (m, 6 H), 5.30 (s, 2 H), 5.01 (s, 2 H), 4.12 (d, J=5.81 Hz, 2 H).
Reaction SMILES: Cl.[CH3:2][N:3](C)[CH2:4]CCN=C=NCC.C[O:14][CH2:15][CH:16]([O:18][C:19]1[CH:20]=[C:21]([CH:25]=[C:26]([O:28][C:29]2[CH:34]=[CH:33][C:32]([C:35]3[O:36][C:37]([CH3:40])=[N:38][N:39]=3)=[CH:31][CH:30]=2)[CH:27]=1)[C:22](O)=[O:23])[CH3:17].[NH2:41][C:42]1[S:43][CH:44]=[CH:45][N:46]=1>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH3:40][C:37]1[O:36][C:35]([C:32]2[CH:33]=[CH:34][C:29]([O:28][C:26]3[CH:25]=[C:21]([CH:20]=[C:19]([O:18][CH:16]4[CH2:17][CH2:2][N:3]([CH3:4])[C:15]4=[O:14])[CH:27]=3)[C:22]([NH:41][C:42]3[S:43][CH:44]=[CH:45][N:46]=3)=[O:23])=[CH:30][CH:31]=2)=[N:39][N:38]=1
Reactant: CCN=C=NCCCN(C)C
Reactant: Nc1nccs1
Reactant: COCC(C)Oc1cc(Oc2ccc(-c3nnc(C)o3)cc2)cc(C(=O)O)c1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: Cc1nnc(-c2ccc(Oc3cc(OC4CCN(C)C4=O)cc(C(=O)Nc4nccs4)c3)cc2)o1
Temperature: 25 °C
Reaction time: 16 h
Yield: 46.9 %

Procedure:
4-(Dimethylamino)pyridine (DMAP) (0.149 g), N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (EDCI.HCl) (0.524 g) were added to a solution of 3-(1-Methoxypropan-2-yloxy)-5-(4-(5-methyl-1,3,4-oxadiazol-2-yl)phenoxy)benzoic acid (0.5 g) (Intermediate 1) in dry DCM under nitrogen at 0-5° C. 2-Aminothiazole (0.134 g) was added and the mixture was stirred for 16 h at room temperature. It was diluted with commercially available DCM. Organic phase was washed with dil HCl, saturated solution of NaHCO3, water, brine, dried over Na2SO4, filtered and concentrated in vacuo to get the crude residue. The residue was chromatographed using silica gel as stationary phase and MeOH: CHCl3 gradient as mobile phase up to yield the product (0.3 g) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:12])=[CH:4][C:5](F)=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[OH-].[Na+].CN1CCCC1=[O:21]>O>[Cl:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=[O:8])[C:5]([OH:21])=[CH:4][C:3]=1[F:12]
Reactant: CN1CCCC1=O
Reactant: O=C(O)c1cc(Cl)c(F)cc1F
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)c1cc(Cl)c(F)cc1O
Temperature: 130 °C
Reaction time: 3 h
Yield: 92.1 %

Procedure:
1.93 g (0.01 mole) of 5-chloro-2,4-difluorobenzoic acid, 1.62 g (0.04 mole) of powdery 99% sodium hydroxide and 20 ml of 1-methyl-2-pyrrolidone were fed into a 100-ml four-necked flask provided with a thermometer, a stirrer and a reflux condenser. The mixture was stirred at 130° C. for 3 hours to give rise to a reaction. After the completion of the reaction, part of 1-methyl-2-pyrrolidone was recovered. The resulting reaction mixture was diluted with 500 ml of water and then subjected to precipitation with a 10% aqueous hydrochloric acid solution. The resulting crystals were collected by filtration, washed with water, and dried to obtain 1.76 g of 5-chloro-4-fluorosalicylic acid. The isolated yield was 92.1% relative to the 5-chloro-2,4-difluorobenzoic acid used.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([F:12])[CH:11]=1)[C:6]([OH:8])=O)#[N:2].[N:13]1([C:18]([N:20]2[CH:24]=[CH:23][N:22]=[CH:21]2)=[O:19])[CH:17]=[CH:16]N=C1.[BH4-].[Na+].O1CCC[CH2:28]1>O>[F:12][C:10]1[CH:11]=[C:3]([CH:4]=[C:5]([CH2:6][O:8][C:17]2[CH:16]=[C:21]3[N:22]([CH3:28])[CH2:23][CH2:24][N:20]3[C:18](=[O:19])[N:13]=2)[CH:9]=1)[C:1]#[N:2]
Reactant: N#Cc1cc(F)cc(C(=O)O)c1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: C1CCOC1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Product: CN1CCn2c1cc(OCc1cc(F)cc(C#N)c1)nc2=O
Temperature: 20 °C
Reaction time: 1 h

Procedure:
To a solution of 3-cyano-5-fluorobenzoic acid (1.00 g, 6.06 mmol) in tetrahydrofuran (THF) (20 mL) was added di(1H-imidazol-1-yl)methanone (1.08 g, 6.66 mmol). The reaction mixture was stirred at 20° C. for 1 h. Then a suspension of NaBH4 (0.687 g, 18.2 mmol) in water (5 mL) was added dropwise. The reaction mixture was stirred at 20° C. for 20 h, quenched with saturated aqueous NH4Cl and extracted with ethyl acetate (20 mL×3). Combined organic portions were washed with saturated aqueous NaHCO3 (20 mL), brine (20 mL), dried over Na2SO4 and concentrated in vacuo to get the desired product as a white solid. 1HNMR (400 MHz, CDCl3): δ 4.697 (m, 2H) & 7.104˜7.400 (m, 3H).
Reaction SMILES: [H-].[Na+].[C:3]12([C:13]3[CH:14]=[C:15]([C:20]#[C:21][C:22]4[CH:31]=[CH:30][C:25]([C:26]([O:28][CH3:29])=[O:27])=[CH:24][CH:23]=4)[CH:16]=[CH:17][C:18]=3[OH:19])[CH2:12][CH:7]3[CH2:8][CH:9]([CH2:11][CH:5]([CH2:6]3)[CH2:4]1)[CH2:10]2.I[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41]>CN(C=O)C>[C:3]12([C:13]3[CH:14]=[C:15]([C:20]#[C:21][C:22]4[CH:31]=[CH:30][C:25]([C:26]([O:28][CH3:29])=[O:27])=[CH:24][CH:23]=4)[CH:16]=[CH:17][C:18]=3[O:19][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])[CH2:12][CH:7]3[CH2:8][CH:9]([CH2:11][CH:5]([CH2:6]3)[CH2:4]1)[CH2:10]2
Reactant: COC(=O)c1ccc(C#Cc2ccc(O)c(C34CC5CC(CC(C5)C3)C4)c2)cc1
Reactant: CCCCCCCCCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCCCCCCOc1ccc(C#Cc2ccc(C(=O)OC)cc2)cc1C12CC3CC(CC(C3)C1)C2
Reaction time: 4 h

Procedure:
75 mg (2.6 mmol) of sodium hydride (80% in oil) and 10 ml of DMF were introduced into a three-necked flask under a stream of nitrogen. A solution of 1 g (2.6 mmol) of methyl 4-[3-(1-adamantyl)-4-hydroxyphenylethynyl]benzoate dissolved in 70 ml of DMF was added dropwise and stirring was carried out at room temperature until gas evolution had ceased. 610 μl (3.1 mmol) of 1-iodononane were then added dropwise and stirring was carried out at room temperature for four hours. The reaction mixture was poured into ice-cold water and extracted with ethyl ether and the organic phase was separated by settling, dried over magnesium sulphate and evaporated.
Reaction SMILES: OS(O)(=O)=O.O=S(=O)=O.[C:10]([O:22][CH3:23])(=[O:21])[C:11]1[CH:20]=[CH:19][C:14]([C:15]([O:17][CH3:18])=[O:16])=[CH:13][CH:12]=1.[CH2:24]=O>C(O)C>[CH2:23]([O:22][C:10]([C:11]1[CH:20]=[C:19]2[C:14](=[CH:13][CH:12]=1)[C:15](=[O:16])[O:17][CH2:18]2)=[O:21])[CH3:24]
Reactant: COC(=O)c1ccc(C(=O)OC)cc1
Reactant: C=O
Agent: O=S(=O)(O)O
Agent: O=S(=O)=O
Solvent: CCO
Product: CCOC(=O)c1ccc2c(c1)COC2=O
Temperature: 125 °C
Reaction time: 5 h

Procedure:
Oleum (20-25% SO3, 800 g), dimethyl terephthalate (234 g) and paraformaldehyde (48 g) are heated with stirring for 5 hours at 125° C. The reaction mixture is cooled to 70° C. and poured into ethanol (1,6 L) having room temperature. This mixture is heated to reflux for 1½ hour before ice (800 g) is added. The suspension is stirred overnight, filtered off and washed with ethanol (150 ml). The crude product is suspended in water (800 ml) and pH is adjusted to 4 with NaOH (27%). The precipitate is filtered off and washed with water and dried.
Reaction SMILES: C([O:4][C@H:5]1[C@H:10]([O:11]C(=O)C)[C@@H:9]([O:15]C(=O)C)[C@H:8]([C:19]2[CH:24]=[CH:23][C:22]([C:25]#[N:26])=[C:21]([CH2:27][C:28]3[CH:33]=[CH:32][C:31]([O:34][CH2:35][CH:36]=[N:37][O:38][CH3:39])=[CH:30][CH:29]=3)[CH:20]=2)[O:7][C@@H:6]1[CH2:40][O:41]C(=O)C)(=O)C.CO.O.O.[OH-].[Li+]>C1COCC1>[CH3:39][O:38][N:37]=[CH:36][CH2:35][O:34][C:31]1[CH:30]=[CH:29][C:28]([CH2:27][C:21]2[CH:20]=[C:19]([C@H:8]3[C@H:9]([OH:15])[C@@H:10]([OH:11])[C@H:5]([OH:4])[C@@H:6]([CH2:40][OH:41])[O:7]3)[CH:24]=[CH:23][C:22]=2[C:25]#[N:26])=[CH:33][CH:32]=1
Reactant: CON=CCOc1ccc(Cc2cc([C@@H]3O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]3OC(C)=O)ccc2C#N)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CON=CCOc1ccc(Cc2cc([C@@H]3O[C@H](CO)[C@@H](O)[C@H](O)[C@H]3O)ccc2C#N)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.4 %

Procedure:
To a solution of (2R,3R,4R,5S,6S)-2-(acetoxymethyl)-6-(4-cyano-3-(4-(2-(methoxyimino)ethoxy)benzyl)phenyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate (60.0 mg, 0.10 mmol), in THF (0.33 mL), methanol (0.5 mL) and water (0.16 mL) was added lithium hydroxide monohydrate (5.37 mg, 0.12 mmol) at 0° C. The reaction was stirred at r.t. for 1 h. After the completion of reaction as confirmed by TLC, volatiles were evaporated in vacuo and the compound was diluted with ethyl acetate (20 mL). The organic layer was washed with water (5 mL), dried over Na2SO4 and concentrated to afford title compound (40 mg, 93%) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([NH:10][CH2:11][C:12]2[NH:13][C:14](=[O:22])[C:15]3[CH2:21][O:20][CH2:19][CH2:18][C:16]=3[N:17]=2)[CH3:9])=[CH:4][CH:3]=1.[F:23][C:24]1[CH:41]=[CH:40][C:27]([C:28]([CH:30]2[CH2:35][CH2:34][N:33]([CH2:36][C:37](O)=[O:38])[CH2:32][CH2:31]2)=[O:29])=[CH:26][CH:25]=1>>[F:23][C:24]1[CH:25]=[CH:26][C:27]([C:28]([CH:30]2[CH2:31][CH2:32][N:33]([CH2:36][C:37]([N:10]([C@@H:8]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)[CH3:9])[CH2:11][C:12]3[NH:13][C:14](=[O:22])[C:15]4[CH2:21][O:20][CH2:19][CH2:18][C:16]=4[N:17]=3)=[O:38])[CH2:34][CH2:35]2)=[O:29])=[CH:40][CH:41]=1
Reactant: O=C(O)CN1CCC(C(=O)c2ccc(F)cc2)CC1
Reactant: C[C@@H](NCc1nc2c(c(=O)[nH]1)COCC2)c1ccc(F)cc1
Product: C[C@H](c1ccc(F)cc1)N(Cc1nc2c(c(=O)[nH]1)COCC2)C(=O)CN1CCC(C(=O)c2ccc(F)cc2)CC1

Procedure:
Following general procedure of Example 4, the title compound was prepared (26.9 mg) from (R)-2-((1-(4-fluorophenyl)ethylamino)methyl)-7,8-dihydro-3H-pyrano[4,3-d]pyrimidin-4(5H)-one and 2-(4-(4-fluorobenzoyl)piperidin-1-yl)acetic acid. Exact mass calculated for C30H32FN4O4 550.6. found 551.4 (ESI, M+H); 1H NMR (400 MHz, dichloromethane-d2) δ ppm 7.97 (dd, J=8.84, 5.31 Hz, 2H) 7.31 (dd, J=8.59, 5.05 Hz, 1H) 7.13-7.27 (m, 3H) 6.88 (t, J=7.83 Hz, 1H) 6.03 (q, J=7.07 Hz, 1H) 4.27-4.57 (m, 5H) 4.11 (br. s., 2H) 3.85-4.03 (m, 4H) 3.36 (br. s., 1H) 3.30 (br. s., 2H) 2.97 (s, 1H) 2.70 (br. s., 2H) 2.59 (d, J=4.04 Hz, 1H) 2.12 (s, 4H) 1.68 (d, J=7.07 Hz, 1H) 1.49 (d, J=7.07 Hz, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][CH2:12][C:13]([N:15]2[CH2:20][C@H:19]([CH3:21])[N:18]([CH2:22][C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=3)[CH2:17][C@H:16]2[CH3:30])=[O:14])=[C:6]([CH:10]=1)[C:7]([OH:9])=O.Cl.CN(C)CCCN=C=NCC.[N:43]1([C:49]([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[O:50])[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]1>ClCCl.CN(C)C1C=CN=CC=1>[C:52]([O:51][C:49]([N:43]1[CH2:48][CH2:47][N:46]([C:7](=[O:9])[C:6]2[CH:10]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=2[O:11][CH2:12][C:13]([N:15]2[CH2:20][C@H:19]([CH3:21])[N:18]([CH2:22][C:23]3[CH:24]=[CH:25][C:26]([F:29])=[CH:27][CH:28]=3)[CH2:17][C@H:16]2[CH3:30])=[O:14])[CH2:45][CH2:44]1)=[O:50])([CH3:55])([CH3:53])[CH3:54]
Reactant: C[C@@H]1CN(Cc2ccc(F)cc2)[C@@H](C)CN1C(=O)COc1ccc(Cl)cc1C(=O)O
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: C[C@@H]1CN(Cc2ccc(F)cc2)[C@@H](C)CN1C(=O)COc1ccc(Cl)cc1C(=O)N1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 86 %

Procedure:
To a solution of (2R, 5S)-5-chloro-2-{2-[4-(4-fluoro-benzyl)-2,5-dimethyl-piperazin-1-yl]-2-oxo-ethoxy}-benzoic acid (0.10 g, 0.212 mmol) in dichloromethane (4 ml) was added 4-dimethylaminopyridine (0.039 g, 0.318 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.061 g, 0.318 mmol) and tert-butyl 1-piperazinecarboxylate (0.041 g 0.222 mmol). The resulting mixture was stirred overnight at ambient temperature. It was then diluted with dichloromethane and washed with brine. The organics were dried over magnesium sulfate, filtered and concentrated to give a clear oil. Chromatography on silica gel gave the title compound (0.110 g, 85% yield).
Reaction SMILES: Cl.Cl.[O:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[C:11]([CH:12]3[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C@H:20]4[CH2:25][CH2:24][C@H:23]([NH2:26])[CH2:22][CH2:21]4)[CH2:14][CH2:13]3)[C:6]=2[CH2:5][CH2:4]1.[C:27](O)(=[O:31])[CH2:28][CH2:29][CH3:30]>>[O:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[C:11]([CH:12]3[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C@H:20]4[CH2:21][CH2:22][C@H:23]([NH:26][C:27](=[O:31])[CH2:28][CH2:29][CH3:30])[CH2:24][CH2:25]4)[CH2:14][CH2:13]3)[C:6]=2[CH2:5][CH2:4]1
Reactant: CCCC(=O)O
Reactant: N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3CCO4)CC2)CC1
Agent: Cl
Product: CCCC(=O)N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3CCO4)CC2)CC1

Procedure:
The title compound, white solid (76 mg, 77%), MS (ISP) m/z=399.3 [(M+H)+], mp 196° C., was prepared in accordance with the general method of example 1 from trans-4-{2-[4-(2,3-dihydro-benzofuran-4-yl)-piperidin-1-yl]-ethyl}-cyclohexylamine dihydro chloride (intermediate B) (100 mg, 0.25 mmol) and butyric acid.
Reaction SMILES: [F:1][C:2]1[CH:28]=[CH:27][C:5]2[N:6]=[C:7]([NH:9][C:10]3[CH:15]=[CH:14][C:13]([C:16]4[CH:21]=[CH:20][C:19]([C:22]([O:24]C)=[O:23])=[C:18]([Cl:26])[CH:17]=4)=[CH:12][CH:11]=3)[S:8][C:4]=2[CH:3]=1.CO.O.[OH-].[Na+]>C1COCC1>[F:1][C:2]1[CH:28]=[CH:27][C:5]2[N:6]=[C:7]([NH:9][C:10]3[CH:15]=[CH:14][C:13]([C:16]4[CH:21]=[CH:20][C:19]([C:22]([OH:24])=[O:23])=[C:18]([Cl:26])[CH:17]=4)=[CH:12][CH:11]=3)[S:8][C:4]=2[CH:3]=1
Reactant: COC(=O)c1ccc(-c2ccc(Nc3nc4ccc(F)cc4s3)cc2)cc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1ccc(-c2ccc(Nc3nc4ccc(F)cc4s3)cc2)cc1Cl
Temperature: 50 °C

Procedure:
Methyl 4′-[(6-fluoro-1,3-benzothiazol-2-yl)amino]-3-chlorobiphenyl-4-carboxylate (0.30 g, 0.71 mmol) was suspended in THF (5 mL), MeOH (5 mL) and water (2.5 mL), and then NaOH (0.28 g, 7.1 mmol) was added. The reaction mixture was heated at 50° C. for 3 h. Upon cooling to rt, the reaction mixture was concentrated under reduced pressure, acidified, and the resulting solid was collected by filtration. This yielded 0.34 g (quantitative) of the title compound. LC/MS m/z 399.2 (MH+), retention time 3.53 min.
Reaction SMILES: [N:1]1[C:8](Cl)=[N:7][C:5]([Cl:6])=[N:4][C:2]=1Cl.C([N:13](C(C)C)CC)(C)C.[CH3:19][NH:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.N>CCOC(C)=O.C1COCC1>[CH2:21]([N:20]([CH3:19])[C:8]1[N:1]=[C:2]([NH2:13])[N:4]=[C:5]([Cl:6])[N:7]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CNCc1ccccc1
Reactant: CCN(C(C)C)C(C)C
Reactant: Clc1nc(Cl)nc(Cl)n1
Agent: N
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CN(Cc1ccccc1)c1nc(N)nc(Cl)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To cyanuric chloride (250 mg, 1.4 mmol) were added anhydrous THF (10 mL), diisopropylethylamine (0.36 mL, 2.0 mmol) and N-methylbenzylamine (164 mg, 1.4 mmol). The mixture was stirred at 0 C for 0.5 h and then allowed to stir and warm to room temperature for an additional 1.5 h. The reaction mixture was treated with concentrated ammonia (d=0.88, 0.4 mL, 6.2 mmol) and allowed to stir at room temperature for 18 h. The solvent was evaporated and reaction mixture was diluted with EtOAc (10 mL) and washed with 1M aq. HCl (5 mL) and saturated sodium chloride (5 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to furnish the desired product which was used directly without further purification (350 mg, 103%). Method C HPLC-MS: MH+ requires m/z=250. Found: m/z=250, Rt=1.25 min (95%).