Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)(=[O:4])=[O:3].O[CH2:13][CH2:14][C@@H:15]1[CH2:17][C@@H:16]1[CH:18]1[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>O1CCCC1.C(OCC)(=O)C.O>[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:13][CH2:14][C@@H:15]2[CH2:17][C@@H:16]2[CH:18]2[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:28])([CH3:30])[CH3:29])=[O:25])[CH2:20][CH2:19]2)=[CH:7][CH:6]=1)(=[O:3])=[O:4]
Reactant: CS(=O)(=O)c1ccc(O)cc1
Reactant: CC(C)(C)OC(=O)N1CCC([C@H]2C[C@H]2CCO)CC1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC([C@H]2C[C@H]2CCOc2ccc(S(C)(=O)=O)cc2)CC1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
4-(methylsulfonyl)phenol (17 mg, 0.1 mmol), tert-butyl 4-[(1R,2S)-2-(2-hydroxyethyl)cyclopropyl)piperidine-1-carboxylate (27 mg, 0.1 mmol), and triphenylphosphine (70 mg, 0.21 mmol) were dissolved in tetrahydrofuran (1 mL) under an atmosphere of nitrogen and cooled at 0° C. DIAD (32 mg, 0.14 mmol) was added and the resulting mixture was warmed to RT and stirred overnight. The mixture was diluted with ethyl acetate (10 mL) and water (5 mL), and the layers were separated. The organic layer was washed with brine (2×10 mL), dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue was purified by MS directed HPLC (30 minute, standard gradient 0-90% acetonitrile/water 0.1% formic acid buffer) and the fractions containing product combined. The solution was concentrated to dryness via GenoVac to afford the title compound. LC/MS (m/z): 424 (M+H)+. GPR119 Human EC50: 0.9 nM
Reaction SMILES: C([O:3][C:4]([C:6]1([NH:15][C:16]([C@H:18]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH2:21][CH2:20][CH2:19]2)=[O:17])[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1)=[O:5])C.[OH-].[K+].O>CCO>[C@H:18]1([C:16]([NH:15][C:6]2([C:4]([OH:5])=[O:3])[CH2:14][C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[CH2:7]2)=[O:17])[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH2:21][CH2:20][CH2:19]1
Reactant: CCOC(=O)C1(NC(=O)[C@@H]2CCCc3ccccc32)Cc2ccccc2C1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(NC1(C(=O)O)Cc2ccccc2C1)[C@@H]1CCCc2ccccc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 96.3 %

Procedure:
The mixture of 2-[((R)-1,2,3,4-tetrahydro-naphthalene-1-carbonyl)-amino]-indan-2-carboxylic acid ethyl ester (67) (440 mg, 1.21 mmol) and KOH (500 mg, 8.9 mmol) is dissolved in EtOH (10 mL) and water (0.5 mL) under a water bath. The water bath is removed when KOH is completely dissolved and the resulting reaction solution is stirred at RT for 3 h. After concentration in vacuo, the residue is dissolved in water (30 mL) and acidified with conc. HCl until no more precipitate came out of the water. The precipitate is filtered to give a pure product (68) as white solid (391 mg, 96%).
Reaction SMILES: [C:1]1([CH3:53])[CH:6]=[CH:5][C:4]([S:7]([CH2:10][CH2:11][O:12][C:13](=[O:52])[CH2:14][O:15][C:16]2[CH:21]=[C:20](C)[C:19]([S:23]([N:26]3[C:30]4[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=4[N:28]=[C:27]3[S:35]([CH2:37][C:38]3[C:43]([CH3:44])=[C:42]([O:45][CH2:46][C:47]([F:50])([F:49])[F:48])[CH:41]=[CH:40][N:39]=3)=[O:36])(=[O:25])=[O:24])=[C:18](C)[CH:17]=2)(=[O:9])=[O:8])=[CH:3][CH:2]=1.C([O-])(O)=O.[Na+]>C1COCC1.O>[C:1]1([CH3:53])[CH:6]=[CH:5][C:4]([S:7]([CH2:10][CH2:11][O:12][C:13](=[O:52])[CH2:14][O:15][C:16]2[CH:17]=[CH:18][C:19]([S:23]([N:26]3[C:30]4[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=4[N:28]=[C:27]3[S:35]([CH2:37][C:38]3[C:43]([CH3:44])=[C:42]([O:45][CH2:46][C:47]([F:50])([F:48])[F:49])[CH:41]=[CH:40][N:39]=3)=[O:36])(=[O:24])=[O:25])=[CH:20][CH:21]=2)(=[O:8])=[O:9])=[CH:3][CH:2]=1
Reactant: Cc1ccc(S(=O)(=O)CCOC(=O)COc2cc(C)c(S(=O)(=O)n3c(S(=O)Cc4nccc(OCC(F)(F)F)c4C)nc4ccccc43)c(C)c2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(S(=O)(=O)CCOC(=O)COc2ccc(S(=O)(=O)n3c(S(=O)Cc4nccc(OCC(F)(F)F)c4C)nc4ccccc43)cc2)cc1
Yield: 60.1 %

Procedure:
A solution of (3,5-dimethyl-4-{2-[3-methyl-4-(2,2,2-trifluoro-ethoxy)-pyridin-2-ylmethanesulfinyl]-benzimidazole-1-sulfonyl}phenoxy)acetic acid 2-(toluene-4-sulfonyl)ethyl ester (Intermediate 14, 400 mg, 0.50 mmol) and NaHCO3 (51 mg, 0.60 mmol, 1.2 eq) in THF-H2O (6 mL-3 mL) was heated to 70° C. for 3 h. Then volatile materials were removed, the residual gummy oil was dissolved in THF and the mixture was filtered to remove un-dissolved solid. The filtrate was dried, the solvent was removed by evaporation to give a yellow foam which was treated with ether-EtOAc (5:1) to precipitate a solid. The solid was treated with CH3CN, and then collected by filtration to give Compound 5 (230 mg, 72%) as a light yellow solid.
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]([CH2:11][S:12][CH2:13][CH2:14][NH2:15])[CH:6]=1)[CH3:3].[CH3:16][S:17][C:18](=[N:21][C:22]#[N:23])SC>C(O)C>[C:22]([NH:21][C:18](=[N:15][CH2:14][CH2:13][S:12][CH2:11][C:7]1[CH:6]=[C:5]([CH2:4][N:2]([CH3:1])[CH3:3])[CH:10]=[CH:9][N:8]=1)[S:17][CH3:16])#[N:23]
Reactant: CSC(=NC#N)SC
Reactant: CN(C)Cc1ccnc(CSCCN)c1
Solvent: CCO
Product: CSC(=NCCSCc1cc(CN(C)C)ccn1)NC#N
Reaction time: 0.5 h
Yield: 67.6 %

Procedure:
A solution of 2-(4-dimethylaminomethyl-2-pyridylmethylthio)ethylamine (1 g) in ethanol (10 ml) was added over 10 minutes to a solution of dimethylcyanodithioimidocarbonate (0.71 g) in ethanol (15 ml). The solution was stirred for 30 minutes, evaporated to dryness and the residue purified by elution from a column of silica gel with 7.5% methanol/chloroform to yield N-cyano-S-methyl-N'-[2-(4-dimethylaminomethyl-2-pyridylmethylthio)ethyl]-isothiourea (0.97 g) as a clear oil.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:20][O:21][CH2:22][CH3:23])[N:14]([CH2:15][C:16]([OH:19])([CH3:18])[CH3:17])[C:10]=2[C:9]2[CH:8]=[CH:7][C:6]([OH:24])=[CH:5][C:4]=2[N:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:31](Br)[C:32]#[CH:33].C(=O)([O-])[O-].[K+].[K+]>O.CN(C=O)C>[NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:20][O:21][CH2:22][CH3:23])[N:14]([CH2:15][C:16]([CH3:18])([OH:19])[CH3:17])[C:10]=2[C:9]2[CH:8]=[CH:7][C:6]([O:24][CH2:33][C:32]#[CH:31])=[CH:5][C:4]=2[N:3]=1
Reactant: CCOCc1nc2c(N)nc3cc(O)ccc3c2n1CC(C)(C)O
Reactant: C#CCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: C#CCOc1ccc2c(c1)nc(N)c1nc(COCC)n(CC(C)(C)O)c12
Reaction time: 8 h
Yield: 68.8 %

Procedure:
4-Amino-2-ethoxymethyl-1-(2-hydroxy-2-methylpropyl)-1H-imidazo[4,5-c]quinolin-7-ol (2.35 g, 7.1 mmol), cesium carbonate (4.6 g, 14.2 mmol), and DMF (50 mL) were combined. Propargyl bromide (80% in toluene, 3.2 g, 21.3 mmol) was added and the reaction was stirred overnight. The reaction was poured into 500 mL of water and solid potassium carbonate was added to keep the mixture basic. A precipitate formed. Filtration of the reaction followed by air drying of the recovered solid provided 1.8 g of 1-[4-amino-2-ethoxymethyl-7-(prop-2-ynyloxy)-1H-imidazo[4,5-c]quinolin-1-yl]-2-methylpropan-2-ol as an off white powder.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:14]([C:15]([NH2:17])=[O:16])=[C:13]([NH:18][C:19]([NH:21][CH2:22][CH2:23][CH2:24][N:25]3[CH2:29][CH2:28][CH2:27][CH2:26]3)=[O:20])[S:12][N:11]=2)=[CH:6][CH:5]=1)([O-])=O>[Pd].O1CCCC1.CCOCC>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:14]([C:15]([NH2:17])=[O:16])=[C:13]([NH:18][C:19]([NH:21][CH2:22][CH2:23][CH2:24][N:25]3[CH2:29][CH2:28][CH2:27][CH2:26]3)=[O:20])[S:12][N:11]=2)=[CH:6][CH:5]=1
Reactant: NC(=O)c1c(-c2ccc([N+](=O)[O-])cc2)nsc1NC(=O)NCCCN1CCCC1
Agent: [Pd]
Solvent: CCOCC
Solvent: C1CCOC1
Product: NC(=O)c1c(-c2ccc(N)cc2)nsc1NC(=O)NCCCN1CCCC1
Yield: 92.9 %

Procedure:
3-(4-nitrophenyl)-5-({[(3-pyrrolidin-1-ylpropyl)amino]carbonyl}amino)isothiazole-4-carboxamide (16.0 g,) and 10% palladium on carbon (6 g) in tetrahydrofuran (1500 mL) was hydrogenated at 80 psi over 24 hr in metal bomb. Filter the catalyst on celite and washed with tetrahydrofuran. The filtrate was concentrated in vacuo to give off white solid, which was stirred in ether (200 mL) and filtered to give the title compound as a white solid (13.8 g, 93%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([CH:16](O)[CH2:17][CH2:18][CH2:19][N:20]2[CH2:25][CH2:24][CH:23]([C:26]3[CH:27]=[C:28]([NH:32][C:33](=[O:37])[CH:34]([CH3:36])[CH3:35])[CH:29]=[CH:30][CH:31]=3)[CH2:22][CH2:21]2)=[CH:12][CH:11]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH:16]([C:13]2[CH:12]=[CH:11][C:10]([Cl:9])=[CH:15][CH:14]=2)[CH2:17][CH2:18][CH2:19][N:20]2[CH2:25][CH2:24][CH:23]([C:26]3[CH:27]=[C:28]([NH:32][C:33](=[O:37])[CH:34]([CH3:36])[CH3:35])[CH:29]=[CH:30][CH:31]=3)[CH2:22][CH2:21]2)=[CH:4][CH:3]=1
Reactant: Oc1ccc(Cl)cc1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCC(O)c3ccc(Cl)cc3)CC2)c1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCC(Oc3ccc(Cl)cc3)c3ccc(Cl)cc3)CC2)c1

Procedure:
Prepared by Procedure B and Scheme AN using 4-chlorophenol and N-(3-{1-[4-(4-chlorophenyl)-4-hydroxybutyl]-4-piperidinyl}phenyl)-2-methylpropanamide: ESMS m/e: 562.9 (M+23)+.
Reaction SMILES: C([O:3][C:4](=[O:35])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([S:13][C:14]2[CH:19]=[C:18]([C:20]#[C:21][CH2:22][N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)[CH:17]=[C:16]([O:29][CH2:30][CH:31]([CH3:33])[CH3:32])[CH:15]=2)=[CH:9][C:8]=1[CH3:34])C.[OH-].[Na+].Cl>C(O)C>[CH2:30]([O:29][C:16]1[CH:15]=[C:14]([S:13][C:10]2[CH:11]=[CH:12][C:7]([O:6][CH2:5][C:4]([OH:35])=[O:3])=[C:8]([CH3:34])[CH:9]=2)[CH:19]=[C:18]([C:20]#[C:21][CH2:22][N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[CH:17]=1)[CH:31]([CH3:33])[CH3:32]
Reactant: CCOC(=O)COc1ccc(Sc2cc(C#CCN3CCOCC3)cc(OCC(C)C)c2)cc1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1cc(Sc2cc(C#CCN3CCOCC3)cc(OCC(C)C)c2)ccc1OCC(=O)O
Reaction time: 1 h

Procedure:
{4-[3-Isobutoxy-5-(3-morpholin-4-yl-prop-1-ynyl)-phenylsulfanyl]-2-methylphenoxy}-acetic acid ethyl ester (140 mg; 0.28 mmol) was dissolved in ethanol (15 mL), and aqueous 1 N sodium hydroxide (3 mL) was added. The reaction mixture was stirred for 1 h, acidified with 1 N aqueous hydrochloric acid, and extracted with ethyl acetate. The organic phase was dried and evaporated to dryness. Yield: 130 mg. HPLC-MS: m/z: 470.0 (M+); Rt: 1.76 min. δH (400 MHz; CDCl3) 1.00 (d, 6H), 1.98-2.09 (m, 1H), 2.27 (s, 3H), 3.13-3.29 (m, 2H), 3.43-3.57 (m, 2H), 3.66 (d, 2H), 3.92-4.09 (m, 4H), 4.12 (s, 2H), 4.71 (s, 2H), 6.55 (m, 1H), 6.71-6.75 (m, 2H), 6.79 (m, 1H), 7.25-7.29 (m, 1H), 7.30 (m, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[CH:14][C:4]=1[CH2:5][NH:6][C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][N:8]=1.[F:20][C:21]1[C:26]([Cl:27])=[CH:25][C:24]([S:28](Cl)(=[O:30])=[O:29])=[CH:23][CH:22]=1>>[Cl:27][C:26]1[CH:25]=[C:24]([S:28]([N:6]([CH2:5][C:4]2[CH:14]=[CH:15][C:16]([O:18][CH3:19])=[CH:17][C:3]=2[O:2][CH3:1])[C:7]2[CH:12]=[CH:11][C:10]([F:13])=[CH:9][N:8]=2)(=[O:29])=[O:30])[CH:23]=[CH:22][C:21]=1[F:20]
Reactant: COc1ccc(CNc2ccc(F)cn2)c(OC)c1
Reactant: O=S(=O)(Cl)c1ccc(F)c(Cl)c1
Product: COc1ccc(CN(c2ccc(F)cn2)S(=O)(=O)c2ccc(F)c(Cl)c2)c(OC)c1

Procedure:
The title compound was prepared according to the method described for Preparation 18 using N-(2,4-dimethoxybenzyl)-5-fluoropyridin-2-amine (Preparation 20) and 4-fluoro-5-chlorobenzenesulfonyl chloride.
Reaction SMILES: [NH2:1][C:2]([NH2:4])=[O:3].[CH:5]1[CH:6]=[CH:7][C:8]2N[C:18]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[CH:12]=[CH:11][C:9]=2[CH:10]=1>C(O)(=O)C.P(=O)(O)(O)O>[CH:5]1[CH:6]=[CH:7][C:8]2[N:1]([C:2]([NH2:4])=[O:3])[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[CH:12]=[CH:11][C:9]=2[CH:10]=1
Reactant: NC(N)=O
Reactant: C1=Cc2ccccc2Nc2ccccc21
Agent: O=P(O)(O)O
Solvent: CC(=O)O
Product: NC(=O)N1c2ccccc2C=Cc2ccccc21
Temperature: 27.5 °C

Procedure:
To a suspension of urea (80 g, 1.333 mols) in acetic acid (100 ml), phosphoric acid (8 ml) was added, followed by iminostilbene (20 g, 0.103 mols), under stirring at 25-30° C. The resulting reaction mixture was worked up according to the method of Example 1 to produce carbamazepine, which was identical to the product of Example 1.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[C:5]2[S:10][C:9]([CH2:11][N:12]3[CH2:17][CH2:16][N:15](S(C)(=O)=O)[CH2:14][CH2:13]3)=[CH:8][C:6]=2[N:7]=1.[C:28]([C:30]1[CH:31]=[N:32][CH:33]=[C:34](B2OC(C)(C)C(C)(C)O2)[CH:35]=1)#[N:29]>>[O:25]1[CH2:26][CH2:27][N:22]([C:4]2[C:5]3[S:10][C:9]([CH2:11][N:12]4[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]4)=[CH:8][C:6]=3[N:7]=[C:2]([C:34]3[CH:35]=[C:30]([C:28]#[N:29])[CH:31]=[N:32][CH:33]=3)[N:3]=2)[CH2:23][CH2:24]1
Reactant: CC1(C)OB(c2cncc(C#N)c2)OC1(C)C
Reactant: CS(=O)(=O)N1CCN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CC1
Product: N#Cc1cncc(-c2nc(N3CCOCC3)c3sc(CN4CCNCC4)cc3n2)c1

Procedure:
2-Chloro-6-(4-methanesulfonyl-piperazin-1-ylmethyl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidine, prepared via General Procedure B-3, was reacted with 3-cyanopyridine-5-boronic acid pinacol ester via General Procedure A. Purification on silica yielded 170. (400 MHz CDCl3): 2.68-2.71 (4H, m, CH2), 2.81 (3H, s, CH3), 3.30-3.32 (4H, m, CH2), 3.90-3.92 (6H, m, CH2), 4.06-4.08 (4H, m, CH2), 7.35 (1H, s, ar), 8.92 (1H, d(J=2.09), ar), 8.96-8.97 (1H, m, ar), 9.81 (1H, d(J=2.03), ar). MH+ 500.20
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:43])[C@@H:6]([O:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:26]=[CH:25][C:24]([C:27]3[C:31]4[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=4[O:29][C:28]=3[CH2:36][C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)=[CH:23][CH:22]=2)=[CH:17][CH:16]=1)[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.CO.Cl>O.O1CCCC1>[CH2:36]([C:28]1[O:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[C:27]=1[C:24]1[CH:23]=[CH:22][C:21]([C:18]2[CH:19]=[CH:20][C:15]([O:14][C@@H:6]([CH2:7][C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:5]([OH:43])=[O:4])=[CH:16][CH:17]=2)=[CH:26][CH:25]=1)[C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1
Reactant: COC(=O)[C@H](Cc1ccccc1)Oc1ccc(-c2ccc(-c3c(Cc4ccccc4)oc4ccccc34)cc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: O=C(O)[C@H](Cc1ccccc1)Oc1ccc(-c2ccc(-c3c(Cc4ccccc4)oc4ccccc34)cc2)cc1
Reaction time: 1 h
Yield: 95.1 %

Procedure:
Sodium hydroxide (2.5 N, 10 mL) was added into a mixture of (2S)-2-[4′-(2-benzyl-benzofuran-3-yl)-biphenyl-4-yloxy]-3-phenyl-propionic acid methyl ester (2.5 g, 4.65 mmol), methyl alcohol (40 mL) and tetrahydrofuran (40 mL). The reaction mixture was stirred for 1 hour, poured into water, acidified with HCl (2 N), and extracted with ethyl ether. The organic extracts were dried over MgSO4. Evaporation and crystallization from ethyl ether/hexanes gave a white solid (2.32 g, 95% yield): mp 167-169; MS m/e 376 (M+);
Reaction SMILES: [CH2:1]([O:4][C:5]([N:7]1[CH2:11][C@@H:10]([NH:12][C:13]([O:15][CH2:16][CH:17]=[CH2:18])=[O:14])[CH2:9][C@H:8]1[CH2:19][OH:20])=[O:6])[CH:2]=[CH2:3].N1C=CN=C1.[Si:26](Cl)([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:28])[CH3:27]>CN(C)C=O.C(OCC)(=O)C>[CH2:1]([O:4][C:5]([N:7]1[CH2:11][C@@H:10]([NH:12][C:13]([O:15][CH2:16][CH:17]=[CH2:18])=[O:14])[CH2:9][C@H:8]1[CH2:19][O:20][Si:26]([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:28])[CH3:27])=[O:6])[CH:2]=[CH2:3]
Reactant: C=CCOC(=O)N[C@H]1C[C@@H](CO)N(C(=O)OCC=C)C1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C=CCOC(=O)N[C@H]1C[C@@H](CO[Si](C)(C)C(C)(C)C)N(C(=O)OCC=C)C1
Reaction time: 12 h

Procedure:
To a solution of (2S,4S)-1-allyloxycarbonyl-4-(allyloxycarbonylamino)-2-hydroxymethylpyrrolidine (8.73 g in N,N-dimethylformamide (40 ml) were added imidazole (6.76 g) and t-butyldimethylsilyl chloride (5.10 g). The resulting mixture was allowed to stand at ambient temperature for 12 hours. The mixture was diluted with ethyl acetate (200 ml), washed in turn with water and brine, dried over magnesium sulfate and evaporated. The residue was chromatographed on silica gel (100 ml) eluting with a mixture of n-hexane and ethyl acetate (7:3 V/V) to give (2S,4S)-1-allyloxycarbonyl-4-(allyloxycarbonylamino)-2-t-butyldimethylsilyloxymethylpyrrolidine (10.97 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C@H:9]1[CH2:14][C@H:13]([C:15]2[O:19][NH:18][C:17](=[O:20])[CH:16]=2)[CH2:12][CH2:11][N:10]1C(OC)=O.Br>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C@H:9]1[CH2:14][C@H:13]([C:15]2[O:19][NH:18][C:17](=[O:20])[CH:16]=2)[CH2:12][CH2:11][NH:10]1
Reactant: COC(=O)N1CC[C@@H](c2cc(=O)[nH]o2)C[C@@H]1c1ccc(Cl)cc1Cl
Agent: Br
Product: O=c1cc([C@@H]2CCN[C@@H](c3ccc(Cl)cc3Cl)C2)o[nH]1
Temperature: 25 °C
Reaction time: 24 h
Yield: 60.7 %

Procedure:
(2R,4R)-Methyl 2-(2,4-dichlorophenyl)-4-(3-oxo-2,3-dihydroisoxazol-5-yl)piperidine-1-carboxylate (75 mg, 0.20 mmol) (from example 51, step 3) was diluted with hydrogen bromide (33% in AcOH, 1062 μl, 6.06 mmol) and stirred at ambient temperature for 24 h. Evaporated and the residue purified by preparative HPLC (Instrument: FractionLynx II, Mobilphase: gradient 5-95% MeCN in 0.2% NH3, pH 10, Column: Xbridge Prep C18 5 μm OBD 19*150 mm) to yield 5-((2R,4R)-2-(2,4-dichlorophenyl)piperidin-4-yl)isoxazol-3(2H)-one (38 mg, 60%). 1H NMR (600 MHz, dmso) δ 1.47-1.54 (m, 1H), 1.78-1.85 (m, 1H), 1.93-1.99 (m, 1H), 2.05-2.11 (m, 1H), 2.67 (dt, 1H), 2.86-2.92 (m, 1H), 3.18-3.22 (m, 1H), 3.98 (dd, 1H), 5.93 (d, 1H), 7.41 (dd, 1H), 7.53 (d, 1H), 7.66 (d, 1H). HRMS Calculated for [C14H14Cl2N2O2+H]+: 313.0511. Found: 313.0494
Reaction SMILES: [NH2:1][C:2]1[C:9]([O:10]C)=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].B(Br)(Br)Br>C(Cl)Cl>[NH2:1][C:2]1[C:9]([OH:10])=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: COc1cccc(C#N)c1N
Agent: BrB(Br)Br
Solvent: ClCCl
Product: N#Cc1cccc(O)c1N
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2-amino-3-methoxybenzonitrile (Example 127b) (0.98 g, 6.59 mmol) in CH2Cl2 (25.0 mL), a solution of BBr3 in CH2Cl2 (1.0M, 19.8 mL, 19.77 mmol) was added drop wise at −78° C. under a nitrogen atmosphere. The obtained mixture was stirred at −78° C. for 30 min, and then at room temperature overnight. The reaction was quenched with water, basified with saturated aqueous NaHCO3 (pH˜8) and extracted with CH2Cl2. The combined extract was dried with MgSO4, filtered and evaporated. The title compound was obtained in amount of 0.80 g (91%) as orange solid and was used in the next step without further purification. 1H NMR (400 MHz, DMSO-d6) δ 9.86 (broad s, 1H), 6.82-6.87 (m, 2H), 6.46 (t, J=8.0 Hz, 1H), 5.34 (broad s, 2H).
Reaction SMILES: C([O:4][C:5]1[CH:10]=[C:9]([Cl:11])[C:8]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH3:21])=[CH:15][CH:14]=2)=[CH:7][C:6]=1[C@H:22]1[C@H:27]([O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C@@H:26]([O:36][CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[C@H:25]([O:44][CH2:45][C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)[C@@H:24]([CH2:52][O:53][CH2:54][C:55]2[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=2)[O:23]1)C=C.[BH4-].[Na+].[NH4+].[Cl-]>C1COCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:11][C:9]1[C:8]([CH2:12][C:13]2[CH:14]=[CH:15][C:16]([O:19][CH2:20][CH3:21])=[CH:17][CH:18]=2)=[CH:7][C:6]([C@H:22]2[C@H:27]([O:28][CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C@@H:26]([O:36][CH2:37][C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)[C@H:25]([O:44][CH2:45][C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=3)[C@@H:24]([CH2:52][O:53][CH2:54][C:55]3[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=3)[O:23]2)=[C:5]([OH:4])[CH:10]=1
Reactant: C=CCOc1cc(Cl)c(Cc2ccc(OCC)cc2)cc1[C@@H]1O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [BH4-]
Agent: [Cl-]
Solvent: C1CCOC1
Product: CCOc1ccc(Cc2cc([C@@H]3O[C@H](COCc4ccccc4)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)c(O)cc2Cl)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 68.6 %

Procedure:
To a suspension of compound 26 (1.50 g, 1.82 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.22 g, 0.18 mmol) in THF (20 mL) was added NaBH4 (0.56 g, 14.6 mmol) at 0° C. The mixture was warmed up to r.t. slowly and stirred at r.t. for 12 hours. The reaction mixture was cooled to 0° C. and aqueous saturated NH4Cl solution (50 mL) was added to the mixture. The mixture was extracted with EtOAc (100 mL). The organic layer was washed with brine, dried over anhydrous MgSO4, filtered and concentrated in vacuo. The residue was purified using normal phase column chromatography to provide the title product 27 (0.98 g, 68%).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[C:12]([N:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[CH:11]=[C:10]([F:20])[CH:9]=2)[CH:5]=[CH:4][N:3]=1.[BH-](OC(C)=O)(OC(C)=O)O[C:23]([CH3:25])=O.[Na+]>ClC(Cl)C>[Cl:1][C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[C:10]([F:20])[CH:11]=[C:12]([N:14]3[CH2:19][CH2:18][N:17]([CH2:23][CH3:25])[CH2:16][CH2:15]3)[CH:13]=2)[CH:5]=[CH:4][N:3]=1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: Fc1cc(-c2ccnc(Cl)n2)cc(N2CCNCC2)c1
Agent: [Na+]
Solvent: CC(Cl)Cl
Product: CCN1CCN(c2cc(F)cc(-c3ccnc(Cl)n3)c2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-Cloro-4-(3-fluoro-5-(piperazin-1-yl)phenyl)pyrimidine (0.29 g, 1 mmol) and ethyl aldehyde (0.13 g, 3 mmol) were mixed in dichloroethane (10 mL) and then added with NaBH(OAc)3 (0.64 g, 3 mmol). After stirring at room temperature under argon for overnight, the reaction mixture was quenched with saturated NaHCO3 and extracted with EtOAc. The organic layer was separated, dried with anhydrous MgSO4 and concentrated in vacuo to give desired product 2-Chloro-4-(3-(4-ethylpiperazin-1-yl)-5-fluorophenyl)pyrimidine.
Reaction SMILES: [CH2:1]([NH2:3])[CH3:2].[C:4]([NH:6][C:7](=[N:10][CH2:11][CH2:12][S:13][CH2:14][C:15]1[N:16]=[N:17][CH:18]=[CH:19][CH:20]=1)SC)#[N:5]>>[C:4]([NH:6][C:7]([NH:3][CH2:1][CH3:2])=[N:10][CH2:11][CH2:12][S:13][CH2:14][C:15]1[N:16]=[N:17][CH:18]=[CH:19][CH:20]=1)#[N:5]
Reactant: CSC(=NCCSCc1cccnn1)NC#N
Reactant: CCN
Product: CCNC(=NCCSCc1cccnn1)NC#N

Procedure:
Anhydrous ethylamine is reacted with N-cyano-N'-[2(3-pyridazinylmethylthio)ethyl]-S-methylisothiourea by the procedure of Example 4 to give N-cyano-N'-ethyl-N"-[2-(3-pyridazinylmethylthio)ethyl]guanidine.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:10]=[N:11][NH:12][CH:13]=2)[O:3]1.[C:15]1(B(O)O)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.CN(C=O)C.N1C=CC=CC=1>C(OCC)(=O)C.C([O-])(=O)C.C([O-])(=O)C.[Cu+2]>[C:15]1([N:12]2[CH:13]=[C:9]([B:4]3[O:5][C:6]([CH3:7])([CH3:8])[C:2]([CH3:14])([CH3:1])[O:3]3)[CH:10]=[N:11]2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: OB(O)c1ccccc1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC1(C)OB(c2cnn(-c3ccccc3)c2)OC1(C)C
Temperature: 80 °C

Procedure:
4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.07 g, 0.0003 mol) and phenylboronic acid (0.083 g, 0.00068 mol) were combined in DMF (1.50 mL, 0.0194 mol). Then copper(II) diacetate (0.010 g, 0.000055 mol) and pyridine (0.069 mL, 0.00085 mol) were added. The reaction was heated in an open tube to 80° C. for 40 minutes. The reaction was complete by HPLC, allowed to cool to rt, taken up in ethyl acetate, and washed with water saturated with sodium carbonate. The organic layer was washed with brine, dried over magnesium sulfate and concentrated to give 1-phenyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazo, 0.09 gm as an oily residue, LC/MS (M+H)+: 271.