Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CO[C:3]([C:5]1[N:10]=[CH:9][C:8]2[N:11]=[C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[O:13][C:7]=2[C:6]=1[OH:20])=[O:4].[NH2:21][CH2:22][C:23]([OH:25])=[O:24]>C[O-].[Na+].CO>[OH:20][C:6]1[C:7]2[O:13][C:12]([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)=[N:11][C:8]=2[CH:9]=[N:10][C:5]=1[C:3]([NH:21][CH2:22][C:23]([OH:25])=[O:24])=[O:4]
Reactant: COC(=O)c1ncc2nc(-c3ccccc3)oc2c1O
Reactant: NCC(=O)O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: O=C(O)CNC(=O)c1ncc2nc(-c3ccccc3)oc2c1O
Yield: 89.7 %

Procedure:
7-Hydroxy-2-phenyl-oxazolo[4,5-c]pyridine-6-carboxylic acid methyl ester (100 mg, 0.37 mmol), and glycine (583 mg, 7.77 mmol) were suspended in 14.8 mL of 0.5N sodium methoxide in methanol. The reaction mixture was heated at reflux temperature overnight, then cooled, and concentrated. The residue was dissolved in water (30 mL), and the solution was acidified to pH 1-2 with 2N HCl, and subsequently extracted with ethyl acetate. The combined organic layers were dried, and concentrated to produce 104 mg of the title compound as a yellow solid. MS: (+) m/z 314.0 (M+1).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][NH:9][C:10]([NH:12][CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[S:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:21]([C:26](O)=[O:27])#[C:22][C:23]([OH:25])=[O:24]>>[O:27]=[C:26]1[C:21](=[CH:22][C:23]([OH:25])=[O:24])[S:11][C:10](=[N:9][CH2:8][CH2:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:12]1[CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: S=C(NCCc1ccccc1)NCCc1ccccc1
Reactant: O=C(O)C#CC(=O)O
Product: O=C(O)C=C1SC(=NCCc2ccccc2)N(CCc2ccccc2)C1=O
Yield: 52.6 %

Procedure:
Prepared by the method described in Example 1 from N,N'-bis(2-phenylethyl)thiourea (20.0 g, 0.11 moles) and acetylenedicarboxylic acid (12.7 g, 0.11 moles). Rinsing the crude precipitate with toluene then hexane gave the product (22 g), mp 148°-149° C.
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]([C:14]2[O:18][N:17]=[C:16]([C:19]3[CH:28]=[CH:27][CH:26]=[C:25]4[C:20]=3[CH:21]=[CH:22][N:23]=[C:24]4[CH2:29][CH2:30][CH2:31][C:32]([O:34]CC)=[O:33])[N:15]=2)[CH:7]=[N:8][C:9]=1[O:10][CH:11]([CH3:13])[CH3:12]>C(O)(C)C.O>[Cl:3][C:4]1[CH:5]=[C:6]([C:14]2[O:18][N:17]=[C:16]([C:19]3[CH:28]=[CH:27][CH:26]=[C:25]4[C:20]=3[CH:21]=[CH:22][N:23]=[C:24]4[CH2:29][CH2:30][CH2:31][C:32]([OH:34])=[O:33])[N:15]=2)[CH:7]=[N:8][C:9]=1[O:10][CH:11]([CH3:12])[CH3:13]
Reactant: CCOC(=O)CCCc1nccc2c(-c3noc(-c4cnc(OC(C)C)c(Cl)c4)n3)cccc12
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: O
Product: CC(C)Oc1ncc(-c2nc(-c3cccc4c(CCCC(=O)O)nccc34)no2)cc1Cl
Temperature: 80 °C
Yield: 56 %

Procedure:
Sodium hydroxide (50 mg) was added to a suspension of ethyl 4-[5-(5-{5-chloro-6-[(1-methylethyl)oxy]-3-pyridinyl}-1,2,4-oxadiazol-3-yl)-1-isoquinolinyl]butanoate (D44; 0.36 g) in isopropanol (5 ml) and water (5 ml). The reaction mixture was heated to 80° C. for 2 hours. After cooling, isopropanol was evaporated in vacuo and the remaining aqueous solution was acidified with aq. HCl (0.5 N) to pH=5. The solid was collected and washed with DMF (5 ml) and acetonitrile (5 ml) to afford the title compound (0.19 g). δH (DMSO-d6, 400 MHz): 1.39 (6H, d), 2.05 (2H, m), 2.40 (2H, m), 3.37 (2H, m), 5.46 (1H, m), 7.88 (1H, dd), 8.57 (5H, m), 8.97 (1H, d), 12.04 (1H, s). MS (ES): C23H21ClN4O4 requires 452. found 453.2 (M+H+).
Reaction SMILES: [NH2:1][OH:2].Cl.CC(O[Na])=O.[CH3:9][NH:10][C:11]1([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:23]=2[Cl:24])[C:16](=O)[CH2:15][CH2:14][CH2:13][CH2:12]1>CO.O.O>[Cl:24][C:23]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[C:11]1([NH:10][CH3:9])[CH2:12][CH2:13][CH2:14][CH2:15][C:16]1=[N:1][OH:2]
Reactant: NO
Reactant: CNC1(c2ccccc2Cl)CCCCC1=O
Agent: CC(=O)O[Na]
Agent: Cl
Solvent: CO
Solvent: O
Product: CNC1(c2ccccc2Cl)CCCCC1=NO
Temperature: 25 °C

Procedure:
To as solution of NH2OH. HCl and CH3COONa. H2O in MeOH:H2O (7:3) stirred at room temperature for 15 minutes, was added ketamine and the resulting solution was stirred at reflux for 16 hrs before cooling to room temperature. The reaction mixture was filtered and the filtrate was partitioned between CH2Cl2 and sat. NaHCO3 solution. The filtrate was extracted with CH2Cl2 (2×30 mL) and the combined organic layer was washed with brine solution. The organic layer was dried over anhydrous. Na2SO4 and concentrated under reduced pressure. The crude reaction mixture received was purified over silica gel column chromatography by eluting with initially CH2Cl2 and later with (1:9) MeOH:CH2Cl2 to receive oxime 2 as pale yellow solid. 1H NMR (250 MHz, CDCl3) δ 7.4-7.5 (m, 1H), 7.0-7.3 (m, 3H), 2.6-2.8 (m, 1H), 2.4-2.5 (q, J=5.8 Hz, 1H), 2.1-2.3 (m, 1H), 2.0-2.1 (m, 3H), 1.5-1.7 (m, 5H). 13C NMR (63 MHz, CDCl3) δ 160.1, 140.1, 133.8, 131.6, 129.1, 128.1, 126.5, 64.0, 37.1, 29.4, 24.5, 22.2, 21.7.
Reaction SMILES: [CH:1]1(B(O)O)[CH2:3][CH2:2]1.FC(F)(F)S(O[C:13]1[CH:18]=[CH:17][N:16]([C:19]2[S:20][C:21]([C:25](=[O:34])[NH:26][CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[C:22]([CH3:24])[N:23]=2)[C:15](=[O:35])[CH:14]=1)(=O)=O>>[CH2:27]([NH:26][C:25]([C:21]1[S:20][C:19]([N:16]2[CH:17]=[CH:18][C:13]([CH:1]3[CH2:3][CH2:2]3)=[CH:14][C:15]2=[O:35])=[N:23][C:22]=1[CH3:24])=[O:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: OB(O)C1CC1
Reactant: Cc1nc(-n2ccc(OS(=O)(=O)C(F)(F)F)cc2=O)sc1C(=O)NCc1ccccc1
Product: Cc1nc(-n2ccc(C3CC3)cc2=O)sc1C(=O)NCc1ccccc1
Yield: 54 %

Procedure:
Following the procedure as described in Example 19, making variations only as required to use cyclopropylboronic acid in place of phenethylboronic acid to react with -(5-(benzylcarbamoyl)-4-methylthiazol-2-yl)-2-oxo-1,2-dihydropyridin-4-yl trifluoromethanesulfonate, the title compound was obtained as a colorless solid in 54% yield: mp 149-151° C. (ethyl acetate/hexanes); 1H NMR (300 MHz, CDCl3) δ 8.63 (d, J=7.6 Hz, 1H), 7.39-7.25 (m, 5H), 6.39 (d, J=1.5 Hz, 1H), 6.10-6.05 (m, 2H), 4.58 (d, J=5.6 Hz, 2H), 2.69 (s, 3H), 1.81-1.72 (m, 1H), 1.14-1.07 (m, 2H), 0.86-0.81 (m, 2H); 13C NMR (75 MHz, CDCl3) δ 162.2, 160.3, 158.8, 153.4, 152.3, 137.7, 130.3, 128.8, 127.9, 127.6, 127.7, 114.7, 106.6, 44.1, 17.3, 15.4, 10.4; MS (ES+) m/z 366.1 (M+1).
Reaction SMILES: ClC1C=C(C=CC=1)C(OO)=[O:6].[CH2:12]([O:14][C:15]1[C:19]([Cl:20])=[C:18]([O:21][CH3:22])[S:17][N:16]=1)[CH3:13]>C(Cl)Cl>[CH2:12]([O:14][C:15]1[C:19]([Cl:20])=[C:18]([O:21][CH3:22])[S:17](=[O:6])[N:16]=1)[CH3:13]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCOc1nsc(OC)c1Cl
Solvent: ClCCl
Product: CCOC1=NS(=O)C(OC)=C1Cl
Temperature: 25 °C
Reaction time: 12 h
Yield: 42.4 %

Procedure:
A solution of m-chloroperoxybenzoic acid (100 mg, 0.49 mmol) in methylene chloride (1.5 ml) wad added dropwise with stirring to an ice-cooled solution of 3-ethoxy-4-chloro-5-methoxyisothiazole (87 mg, 0.45 mmol) in methylene chloride (1.0 ml). The solution was then stirred for 12 hours at room temperature. The m-chlorobenzoic acid, which precipitated out of solution, was filtered off. The filtrate was concentrated in vacuo, and the residue was chromatographed on a silica gel column, eluting with toluene followed by chloroform, to give 40 mg of the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[NH:5][C:4](=[O:9])[C:3]=1[CH2:10][NH:11][C:12]([C:14]1[C:15]2[CH:28]=[N:27][N:26]([CH:29]([CH3:31])[CH3:30])[C:16]=2[N:17]=[C:18]([C:20]2[CH2:21][CH2:22][NH:23][CH2:24][CH:25]=2)[CH:19]=1)=[O:13].CCN(CC)CC.[NH:39]1[CH2:42][CH:41]([C:43](O)=[O:44])[CH2:40]1.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>CS(C)=O.O>[NH:39]1[CH2:42][CH:41]([C:43]([N:23]2[CH2:22][CH:21]=[C:20]([C:18]3[CH:19]=[C:14]([C:12]([NH:11][CH2:10][C:3]4[C:4](=[O:9])[NH:5][C:6]([CH3:8])=[CH:7][C:2]=4[CH3:1])=[O:13])[C:15]4[CH:28]=[N:27][N:26]([CH:29]([CH3:31])[CH3:30])[C:16]=4[N:17]=3)[CH2:25][CH2:24]2)=[O:44])[CH2:40]1
Reactant: Cc1cc(C)c(CNC(=O)c2cc(C3=CCNCC3)nc3c2cnn3C(C)C)c(=O)[nH]1
Reactant: O=C(O)C1CNC1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: O
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: Cc1cc(C)c(CNC(=O)c2cc(C3=CCN(C(=O)C4CNC4)CC3)nc3c2cnn3C(C)C)c(=O)[nH]1
Reaction time: 8 h
Yield: 81.9 %

Procedure:
N-((4,6-Dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-1-isopropyl-6-(1,2,3,6-tetrahydropyridin-4-yl)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide (1 equiv.) was dissolved in DMSO, to it Et3N (3 equiv.) and azetidine-3-carboxylic acid (2 equiv.) was added to it. The reaction mixture was stirred at room temperature for 15 min before PYBOP (1.5 equiv.) was added to it and stirring was continued overnight. After completion of the reaction, water was added to it. Extraction was carried out using DCM; the combined organic layers were washed with water, brine and dried over anhydrous Na2SO4; filtered and concentrated under reduced pressure to afford crude material which was purified by column chromatography to give the desired compound (81.9% yield). LCMS: 504.25 (M+1)+; HPLC: 99.74% (@ 254 nm) (Rt; 4.829); 1H NMR (DMSO-d6, 400 MHz) δ 11.55 (bs, 1H), 8.84 (m, 2H), 8.64 (bs, 1H), 8.30 (s, 1H), 7.86 (s, 1H), 6.93 (s, 1H), 5.89 (s, 1H), 5.22-5.17 (m, 1H), 4.38 (d, 2H, J=4.8 Hz), 4.26 (bs, 1H), 4.20-4.10 (m, 4H), 4.05-3.97 (m, 1H), 3.75 (t, 1H, J=5.2 Hz), 3.49 (m, 2H), 2.74 (m, 2H), 2.20 (s, 3H), 2.12 (s, 3H), 1.51 (d, 6H, J=6.4 Hz).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[C:7]1[O:11][N:10]=[C:9]([C:12]2[CH:13]=[C:14]([CH:17]=[CH:18][CH:19]=2)[C:15]#[N:16])[N:8]=1.Cl.Cl[CH2:22][C:23]1[CH:32]=[CH:31][C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[N:24]=1.C(N(C(C)C)CC)(C)C.Cl>CN(C=O)C.CCOCC.O>[N:24]1[C:25]2[C:30](=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:31]=[CH:32][C:23]=1[CH2:22][N:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[C:7]1[O:11][N:10]=[C:9]([C:12]2[CH:13]=[C:14]([CH:17]=[CH:18][CH:19]=2)[C:15]#[N:16])[N:8]=1
Reactant: N#Cc1cccc(-c2noc(C3CCCCN3)n2)c1
Reactant: ClCc1ccc2ccccc2n1
Agent: Cl
Solvent: CCOCC
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1cccc(-c2noc(C3CCCCN3Cc3ccc4ccccc4n3)n2)c1

Procedure:
3-(5-Piperidin-2-yl-[1,2,4]oxadiazol-3-yl)-benzonitrile (50.8 mg, 0.2 mmol) was mixed with 2-(chloromethyl)quinoline monohydrochloride (47.1 mg, 0.22 mmol) and diisopropylethylamine (129.3 mg, 1.0 mmol) in DMF (2 mL) at 80° C. for 20 h. The reaction mixture was poured into water and extracted with dichloromethane. The organic layer was washed with water and brine, dried with sodium sulfate, purified by column chromatography with 5˜10% ethyl acetate in hexanes to give a colorless sticky oil. This sticky oil was mixed with 1 M HCl in ether (0.4 mL) and triturated with ethyl acetate to give an off-white solid, 45 mg (48%). 1H NMR (CDCl3+DMSO-d6), δ(ppm): 8.92 (d, 1H), 8.70 (d, 1H), 8.16 (m, 3H), 8.07 (d, 1H), 8.00 (t, 1H), 7.84 (m, 2H), 7.63 (m, 1H), 4.64 (m, 3H), 3.30 (m, 1H), 2.86(m, 1H), 2.04–2.38 (m, 2H), 1.57–1.90 (m, 4H).
Reaction SMILES: [BH4-].[Na+].[CH3:3][O:4][C:5](=[O:32])[CH2:6][C@H:7]1[C:11]2[CH:12]=[CH:13][C:14]([O:16][C@H:17]3[C:25]4[C:20](=[C:21]([CH:30]=[O:31])[C:22]([C:26]([F:29])([F:28])[F:27])=[CH:23][CH:24]=4)[CH2:19][CH2:18]3)=[CH:15][C:10]=2[O:9][CH2:8]1.Cl>O1CCCC1.O>[CH3:3][O:4][C:5](=[O:32])[CH2:6][C@H:7]1[C:11]2[CH:12]=[CH:13][C:14]([O:16][C@H:17]3[C:25]4[C:20](=[C:21]([CH2:30][OH:31])[C:22]([C:26]([F:27])([F:28])[F:29])=[CH:23][CH:24]=4)[CH2:19][CH2:18]3)=[CH:15][C:10]=2[O:9][CH2:8]1
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c3ccc(C(F)(F)F)c4C=O)ccc21
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c3ccc(C(F)(F)F)c4CO)ccc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
NaBH4 (18 mg) is added to a solution of {(S)-6-[(R)-4-formyl-5-trifluoromethyl-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester (0.20 g) in tetrahydrofuran (4 mL) and water (1 mL) at room temperature. The mixture is stirred at room temperature for 30 min. 1 N aqueous HCl solution is added and the mixture is extracted with ethyl acetate. The combined extract is washed with brine, dried (Na2SO4), and concentrated to give the title compound. The crude product is submitted to the next reaction step without further purification. LC (method 4): tR=1.09 min; Mass spectrum (ESI+): m/z=445 [M+Na]+.
Reaction SMILES: [Br:1][C:2]1[C:3]([NH2:11])=[C:4]([NH2:10])[CH:5]=[C:6]([Cl:9])[C:7]=1[Cl:8].[CH:12]1([N:15]=[C:16]=S)[CH2:14][CH2:13]1.CC1C=CC(S([O-])(=O)=O)=CC=1.C[N+]1(CCN=C=NC2CCCCC2)CCOCC1>N1C=CC=CC=1>[Br:1][C:2]1[C:3]2[N:11]=[C:16]([NH:15][CH:12]3[CH2:14][CH2:13]3)[NH:10][C:4]=2[CH:5]=[C:6]([Cl:9])[C:7]=1[Cl:8]
Reactant: S=C=NC1CC1
Reactant: Nc1cc(Cl)c(Cl)c(Br)c1N
Agent: C[N+]1(CCN=C=NC2CCCCC2)CCOCC1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Solvent: c1ccncc1
Product: Clc1cc2[nH]c(NC3CC3)nc2c(Br)c1Cl
Yield: 34.7 %

Procedure:
3-Bromo-4,5-dichloro-1,2-phenylenediamine (5.12 g, 20.0 mmol), cyclopropyl isothiocyanate (2.18 g, 21.98 mmol), 1-cyclohexyl-3-(2-morpholinoethyl)carbodiimide metho-p-toluenesulfonate (11.0 g, 25.97 mmol) and pyridine (75 mL) were used according to general procedure I. The product was recrystallized from 1,4-dioxane to afford 2.23 g (53%) of a white solid. MS (CI): m/z 319 amu. Anal. Calcd for C10H8BrCl2N3-(0.35 C4H8O2): C, 38.92; H, 3.09; N, 11.94. Found: C, 39.17; H, 3.05; N, 11.94.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[CH:8]=[C:9]([C:11]#[N:12])[N:10]=1)=[O:5])C.[OH-].[K+:22]>C(O)C>[K+:22].[C:11]([C:9]1[N:10]=[C:6]([C:4]([O-:5])=[O:3])[N:7]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:18])([CH3:19])[CH3:20])[CH:8]=1)#[N:12]
Reactant: CCOC(=O)c1nc(C#N)cn1COCC[Si](C)(C)C
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: C[Si](C)(C)CCOCn1cc(C#N)nc1C(=O)[O-]
Reaction time: 0.17 h
Yield: 100 %

Procedure:
To a solution of 4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylic acid ethyl ester (0.4 g, 1.3 mmol) (as prepared in the previous step) in ethanol (3 mL) was added a solution of 6M KOH (0.2 mL) and the reaction was stirred for 10 min and then concentrated to give 0.40 g (100%) of the title compound as a yellow solid. 1H-NMR (400 MHz, CD3OD) δ 7.98 (s, 1H), 5.92 (s, 2H), 3.62 (m, 2H), 0.94 (m, 2H), 0.00 (s, 9H). Mass spectrum (ESI-neg, m/z) Calcd. for C11H17N3O3Si, 266.1 (M−H). found 266.0.
Reaction SMILES: [Br:1][C:2]1[S:3][C:4]2[C:10]([OH:11])=[C:9]([C@H:12]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:8]([CH3:23])=[CH:7][C:5]=2[N:6]=1.[B-](F)(F)(F)[F:25].[B-](F)(F)(F)F.C1[N+]2(CCl)CC[N+](F)(CC2)C1>C(#N)C>[Br:1][C:2]1[S:3][C:4]2[C:10]([OH:11])=[C:9]([C@H:12]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:8]([CH3:23])=[C:7]([F:25])[C:5]=2[N:6]=1
Reactant: F[B-](F)(F)F
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(Br)sc2c1O
Agent: F[N+]12CC[N+](CCl)(CC1)CC2
Solvent: CC#N
Product: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)c(F)c2nc(Br)sc2c1O
Yield: 34.4 %

Procedure:
The reaction mixture of (S)-ethyl 2-(2-bromo-7-hydroxy-5-methylbenzo[d]thiazol-6-yl)-2-tert-butoxyacetate (75A) (380 mg, 0.948 mmol), Selectfluor (1.9 g, 4.74 mmol) in acetonitrile (7 mL) was reacted at 0° C. for 5 days. The reaction mixture was washed by 1.5 M KH2PO4, extracted by EtOAc, the organic phase was dried over MgSO4, filtered, concentrated down and purified by silica gel column, eluting by 0-40% EtOAc in hexanes to give 75B (137 mg, 35%). LCMS-ESI+: calc'd for C16H19FNO4S: 420.0 (M+H+). Found: 420.1 (M+H+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]([OH:19])([CH:16]([SH:18])[CH3:17])[CH2:10][N:11]1[CH:15]=[N:14][CH:13]=[N:12]1.ClCCl.C(N(CC)CC)C.[CH2:30]([N:32]([CH2:36][CH3:37])[C:33](Cl)=[S:34])[CH3:31]>O>[CH2:30]([N:32]([CH2:36][CH3:37])[C:33](=[S:34])[S:18][CH:16]([C:9]([C:3]1[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=1[F:1])([OH:19])[CH2:10][N:11]1[CH:15]=[N:14][CH:13]=[N:12]1)[CH3:17])[CH3:31]
Reactant: CCN(CC)C(=S)Cl
Reactant: CC(S)C(O)(Cn1cncn1)c1ccc(F)cc1F
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CCN(CC)C(=S)SC(C)C(O)(Cn1cncn1)c1ccc(F)cc1F
Yield: 30.9 %

Procedure:
(2RS,3RS)-2-(2,4-difluorophenyl)-3-mercapto-1-[1H-1,2,4-triazol-1-yl]-2-butanol (0.3 g) was added to dichloromethane (5 ml), to which triethylamine (0.16 ml) was added under ice-cooling, and then, N,N-diethylthiocarbamoyl chloride (0.18 g) was added. The resultant solution was stirred for 1 hour at room temperature. Thereafter, water (20 ml) was added to the reaction mixture. The resultant mixture was then extracted with dichloromethane (40 ml). The extract was washed with water (20 ml), dried (MgSO4) and distilled off to remove the solvent under reduced pressure. The residue was purified by a silica gel column chromatography (2.9×30cm, eluent: ethyl acetate-dichloromethane=1:3). The objective fractions were concentrated. Hexane was added to the residue to give the compound (1), i.e., [(2RS,3RS)-3-(2,4-difluorophenyl)-3-hydroxy-4-(1H-1,2,4-triazol-1-yl)-2butyl] N,N-diethyldithiocarbamate (0.13 g) as colorless needles.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)=O)[CH:5]=[N:6][CH:7]=1.B.C([O-])(O)=O.[Na+]>C1COCC1.O.CCOC(C)=O>[Br:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[CH:5]=[N:6][CH:7]=1
Reactant: O=C(Cc1cncc(Br)c1)N1CCOCC1
Agent: B
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Brc1cncc(CCN2CCOCC2)c1
Temperature: 55 °C
Reaction time: 8 h
Yield: 53 %

Procedure:
To a solution of 4-[(5-bromopyridin-3-yl)acetyl]morpholine (1.26 g, 4.40 mmol) in THF (15 mL) was added a 1M solution of borane in THF (23.2 mL, 23.2 mmol). The reaction mixture was allowed to stir at 55° C. overnight and then was allowed to cool to rt and then diluted with water (100 mL) and EtOAc (100 mL). The organic solution was separated and the aqueous solution was extracted with EtOAc (2×50 mL). The organic solutions were combined, dried over MgSO4, filtered and concentrated to give a yellow oil, which was dissolved in 1N HCl (100 mL). This solution was allowed to stir at 80° C. overnight. The reaction mixture was neutralized with sat. aq. NaHCO3 (100 mL) and then extracted with EtOAc (3×50 mL). The combined organic solutions were washed with brine, dried over MgSO4, filtered and concentrated to give 4-[2-(5-bromopyridin-3-yl)ethyl]morpholine (0.631 g, 2.33 mmol, 53%) as a light yellow oil. LCMS (FA): Rt=0.50 min, m/z=273.0 (M+H).
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:4].[CH3:12][NH:13][CH3:14]>O>[CH3:12][N:13]([CH2:2][C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:4])[CH3:14]
Reactant: CNC
Reactant: O=C(CCl)Nc1ccccc1
Solvent: O
Product: CN(C)CC(=O)Nc1ccccc1
Yield: 97 %

Procedure:
A mixture of chloroacetanilide (10.0 g, 59 mmol) in dimethylamine, 40% wt in water (100 ml) was refluxed for 4 hours. The cooled reaction mixture was partitioned between dichloromethane (100 ml) and 1M NaOH aqueous solution (100 ml). The aqueous layer was extracted twice more with dichloromethane (2×100 ml), the combined organic layers were concentrated in vacuo to a volume of approximately 100 ml and washed with water (2×100 ml) in order to remove the remaining dimethylamine. The organic layer was collected, dried over sodium sulfate and the solvent evaporated in vacuo to provide 10.2 g (97% yield) of the pure dimethylaminoacetanilide. 1H NMR (CDCl3, 200 MHz) δ: 9.1 (br. s, NH, 1H), 7.6-7.0 (m, Ar, 5H) 3.1 (s, CH2, 2H), 2.4 (s CH3, 6H).
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[N:11]([CH2:12][CH3:13])[C:10](=[O:14])[C:9]([F:16])([F:15])[CH2:8][N:7]([CH:17]3[CH2:21][CH2:20][CH2:19][CH2:18]3)[C:6]=2[N:22]=1.[NH2:23][C:24]1[CH:39]=[CH:38][C:27]([C:28]([NH:30][CH:31]2[CH2:36][CH2:35][N:34]([CH3:37])[CH2:33][CH2:32]2)=[O:29])=[CH:26][CH:25]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CC(O)C>[CH:17]1([N:7]2[CH2:8][C:9]([F:16])([F:15])[C:10](=[O:14])[N:11]([CH2:12][CH3:13])[C:5]3[CH:4]=[N:3][C:2]([NH:23][C:24]4[CH:25]=[CH:26][C:27]([C:28]([NH:30][CH:31]5[CH2:36][CH2:35][N:34]([CH3:37])[CH2:33][CH2:32]5)=[O:29])=[CH:38][CH:39]=4)=[N:22][C:6]2=3)[CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: CCN1C(=O)C(F)(F)CN(C2CCCC2)c2nc(Cl)ncc21
Reactant: CN1CCC(NC(=O)c2ccc(N)cc2)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)O
Solvent: O
Product: CCN1C(=O)C(F)(F)CN(C2CCCC2)c2nc(Nc3ccc(C(=O)NC4CCN(C)CC4)cc3)ncc21
Yield: 51.8 %

Procedure:
A mixture of 0.05 g (0.15 mmole) of 2-chloro-9-cyclopentyl-5-ethyl-7,7-difluoro-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VII-138), 0.04 g (0.18 mmole) of 4-amino-N-(1-methyl-piperidin-4-yl)-benzamide, 0.04 g (0.23 mmole) of p-toluenesulfonic acid monohydrate and 4.0 mL of 2-propanol was heated at 160 degrees for 2 hours in a microwave reactor. The cooled reaction mixture was concentrated under reduced pressure. The residue was diluted with dichloromethane and washed twice with saturated aqueous sodium bicarbonate solution. The aqueous phases were extracted with dichloromethane, and the combined organic layers washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with methanol-dichloromethane (gradient, 0:100-25:75) to give 0.041 g of 4-(9-cyclopentyl-5-ethyl-7,7-difluoro-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-N-(1-methyl-piperidin-4-yl)-benzamide (I-141).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C@H:10]([CH3:11])[C@H:9]2[C:12]([O:14]CC)=[O:13])=[CH:4][CH:3]=1.[OH-].[K+]>CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[CH:10]([CH3:11])[CH:9]2[C:12]([OH:14])=[O:13])=[CH:6][CH:7]=1
Reactant: CCOC(=O)[C@@H]1[C@@H](C)[C@@H]1c1ccc(Cl)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CC1C(C(=O)O)C1c1ccc(Cl)cc1
Temperature: 25 °C

Procedure:
A solution of racemic ethyl (1R,2S,3S)-2-(4-chlorophenyl)-3-methyl-cyclopropanecarboxylate (818 mg, 3.36 mmol) and KOH (1.92 g) in methanol was heated at 80° C. for 2 hours, cooled to RT, and the solvent evaporated. The mixture was shaken between dichloromethane and water, then the aqueous phase was acidified and extracted with dichloromethane, to give the pure racemic (1R,2S,3S)-2-(4-chlorophenyl)-3-methyl-cyclopropanecarboxylic acid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9](=[CH2:20])[C:10]([C:12]1[CH:13]=[CH:14][C:15]([S:18][CH3:19])=[N:16][CH:17]=1)=[O:11].C([O:25]O)(C)(C)C.CC(C)(CC(C)C)C.[OH-].C([N+](C)(C)C)C1C=CC=CC=1>C1(C)C=CC=CC=1.CO>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1([C:10]([C:12]2[CH:13]=[CH:14][C:15]([S:18][CH3:19])=[N:16][CH:17]=2)=[O:11])[CH2:20][O:25]1
Reactant: CC(C)(C)OO
Reactant: C=C(C(=O)c1ccc(SC)nc1)c1ccc(F)cc1F
Agent: C[N+](C)(C)Cc1ccccc1
Agent: [OH-]
Solvent: CC(C)CC(C)(C)C
Solvent: Cc1ccccc1
Solvent: CO
Product: CSc1ccc(C(=O)C2(c3ccc(F)cc3F)CO2)cn1

Procedure:
A solution of the product of part (iv) (3.8 g, 13 mmol) in toluene (40 ml) was treated with a solution of t-butylhydroperoxide in 2,2,4-trimethylpentane (3M, 4.7ml, 14 mmol) followed by a solution of benzyltrimethylammonium hydroxide in methanol (40%, 100 μl). After 1 hour at room temperature the solvent was removed under reduced pressure. The residue was partitioned between dichloromethane (100 ml) and water (50 ml). The organic phase was separated, dried (MgSO4) and evaporated under reduced pressure to give the title compound as a colourless oil, (3.9 g).