Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5](Cl)[S:4][C:3]=1[S:8]([NH2:11])(=[O:10])=[O:9].[F:12][C:13]1[CH:18]=[CH:17][C:16](B(O)O)=[CH:15][CH:14]=1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.[Cl-].[Na+].O.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>[NH2:1][C:2]1[CH:6]=[C:5]([C:16]2[CH:17]=[CH:18][C:13]([F:12])=[CH:14][CH:15]=2)[S:4][C:3]=1[S:8]([NH2:11])(=[O:10])=[O:9]
Reactant: OB(O)c1ccc(F)cc1
Reactant: Nc1cc(Cl)sc1S(N)(=O)=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: C1COCCO1
Solvent: O
Product: Nc1cc(-c2ccc(F)cc2)sc1S(N)(=O)=O
Yield: 33 %

Procedure:
To a solution of 3b (104 mg, 0.5 mmol) in 1,4-dioxane/water (40 mL, 3:1) was added 4-fluorophenylboronic acid (140 mg, 1 mmol), Na2CO3 (212 mg, 2 mmol), and Pd(PPh3)4 (9% Pd, 59 mg, 0.05 mmoL). The resultant mixture was heated at 110° C. for 3 h, diluted with brine solution (50 mL) and extracted with ethyl acetate (50 mL, 3×). The combined organic phases were dried over MgSO4, filtered, and concentrated. Flash chromatography (hexanes/ethyl acetate, 1:1) then provided 3c (45 mg, 33%) as a yellow solid: MS (ES) 273 (M+H)+; 1H NMR (400 MHz, MeOD) δ7.52 (m, 2 H), 7.04 (m, 2 H), 6.72 (s, 1 H).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[S:14][CH:13]=[N:12][CH:11]=2)[C:5]([C:15]#[N:16])=[C:4]([SH:17])[N:3]=1.Cl[CH2:19][C:20]1[N:21]=[C:22]([C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=2)[S:23][CH:24]=1.C(=O)(O)[O-].[Na+].C(#N)C>CN(C=O)C.O>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[S:14][CH:13]=[N:12][CH:11]=2)[C:5]([C:15]#[N:16])=[C:4]([S:17][CH2:19][C:20]2[N:21]=[C:22]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)[S:23][CH:24]=2)[N:3]=1
Reactant: ClCc1csc(-c2ccc(Cl)cc2)n1
Reactant: N#Cc1c(N)nc(S)c(C#N)c1-c1cncs1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1c(N)nc(SCc2csc(-c3ccc(Cl)cc3)n2)c(C#N)c1-c1cncs1

Procedure:
765 mg (2.950 mmol) of 2-amino-6-sulfanyl-4-(1,3-thiazol-5-yl)pyridine-3,5-dicarbonitrile, together with 792 mg (3.245 mmol) of 4-(chloromethyl)-2-(4-chlorophenyl)-1,3-thiazole and 744 mg (8.850 mmol) of sodium bicarbonate, were stirred in 15 ml DMF at room temperature for 1 h. The reaction mixture was added to 150 ml of acetonitrile, and 100 ml of water were then added. The resulting precipitate was filtered off and washed initially with a little acetonitrile and then with diethyl ether. Drying under reduced pressure gave 889 mg (53% of theory) of the target compound.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[Cl:11][C:12]1[CH:13]=[C:14]([CH:18]=[C:19]([CH2:21][OH:22])[CH:20]=1)[C:15]([OH:17])=[O:16].C(N(CC)CC)C>C(Cl)Cl>[CH:21]([C:19]1[CH:18]=[C:14]([CH:13]=[C:12]([Cl:11])[CH:20]=1)[C:15]([OH:17])=[O:16])=[O:22]
Reactant: O=C(O)c1cc(Cl)cc(CO)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: O=Cc1cc(Cl)cc(C(=O)O)c1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
In a 2 liter 4-necked round-bottomed flask were placed 500 ml of methylene chloride and cooled down to -78° C. 44.6 g (0.35 mole) of oxalyl chloride were added slowly, followed by dropwise addition of 57.7 g (0.74 mole) of dry dimethylsulfoxide in 40 ml of methylene chloride, keeping the temperature below -70° C. After the addition was completed, the reaction mixture was stirred at -78° C. for 30 minutes and 71.5 g (0.38 mole) of the previously prepared 3-chloro-5-hydroxymethylbenzoic acid were added in 1 portion and 60 ml more of methylene chloride followed by dropwise addition of 149.5 g (1.48 mole) of triethylamine, keeping the temperature below -65° C. The reaction mixture was then warmed up slowly to room temperature and stirred during 90 minutes and washed with 2% aqueous sodium hydroxide (4×500 ml). The combined basic layers were washed with hexane once, then acidified with concentrated hydrochloric acid and then extracted with ethyl acetate (4×500 ml). The combined organic layers were washed with water (1×500 ml) and then with brine (1×300 ml) and dried over anhydrous magnesium sulfate. The solvent was then eliminated in a rotavap, yielding 52 g of 3-formyl-5-chlorobenzoic acid.
Reaction SMILES: Cl.[CH2:2]([NH:9][CH2:10][CH:11]1[CH2:20][CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[C:16]([O:21][CH3:22])[CH:17]=2)[CH2:12]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:23]1([CH:29]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH2:30][CH2:31]I)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[CH2:2]([N:9]([CH2:10][CH:11]1[CH2:20][CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[C:16]([O:21][CH3:22])[CH:17]=2)[CH2:12]1)[CH2:31][CH2:30][CH:29]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: ICCC(c1ccccc1)c1ccccc1
Reactant: COc1ccc2c(c1)CCC(CNCc1ccccc1)C2
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc2c(c1)CCC(CN(CCC(c1ccccc1)c1ccccc1)Cc1ccccc1)C2
Temperature: 25 °C
Reaction time: 24 h
Yield: 37.2 %

Procedure:
2-(N-benzylamino)methyl-6-methoxytetralin hydrochloride (0.602 g; obtained in Reference Example 6), 3,3-diphenylpropyl iodide (0.803 g) and potassium carbonate (0.800 g) were added to DMF (20 ml). The reaction mixture was stirred at room temperature for 24 hours, and water was added thereto, which was then extracted with ethyl acetate. The organic layer was washed with water and a saturated aqueous sodium chloride solution, then dried, and concentrated. The residue was purified by silica gel column chromatography (eluent:ethyl acetate/hexane=1/1) to obtain the entitled compound (0.335 g).
Reaction SMILES: S(S([O-])=O)([O-])=O.[Na+].[Na+].[Cl:9][C:10]1[CH:11]=[CH:12][C:13]([NH:16][C:17](=[O:29])[C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH3:25])[C:19]=2[N+:26]([O-])=O)=[N:14][CH:15]=1.O1CCCC1.C(=O)([O-])[O-].[K+].[K+]>O.O1CCOCC1>[Cl:9][C:10]1[CH:11]=[CH:12][C:13]([NH:16][C:17](=[O:29])[C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH3:25])[C:19]=2[NH2:26])=[N:14][CH:15]=1
Reactant: COc1cccc(C(=O)Nc2ccc(Cl)cn2)c1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: O=S([O-])S(=O)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: C1COCCO1
Solvent: O
Product: COc1cccc(C(=O)Nc2ccc(Cl)cn2)c1N
Temperature: 25 °C
Reaction time: 16 h
Yield: 88.8 %

Procedure:
To a solution of sodium hydrosulfite (300 g, 1.7 mol) in water (4 L) was added N-(5-chloropyridin-2-yl)-2-nitro-3-methoxybenzamide (140 g, 0.45 mol). Tetrahydrofuran (2 L) and 1,4-dioxane (2 L) were added and the resulting mixture stirred at ambient temperature. After 16 hours, the solution was made basic by addition of potassium carbonate and the phases separated. The organic phase was concentrated of all volatiles in vacuo to give an off-white solid. The solid was washed with water, filtered, and dried under vacuum to afford 111 g (88% yield) of N-(5-chloropyridin-2-yl)-2-amino-3-methoxybenzamide; NMR (CDCl3) 8.8 (br, 1), 8.3 (d, 1), 8.1 (s, 1), 7.7 (dd, 1), 7.1 (dd, 1), 6.8 (d, 1), 6.6 (t, 1), 5.9 (br, 1), 3.9 (s, 3) ppm.
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[C:11]2[C:6](=[CH:7][C:8]([CH:12]([CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH2:13][OH:14])=[CH:9][CH:10]=2)[NH:5][CH2:4][CH2:3]1.C=O.[C:23](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>C(#N)C.O>[CH3:23][N:5]1[C:6]2[C:11](=[CH:10][CH:9]=[C:8]([CH:12]([CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH2:13][OH:14])[CH:7]=2)[C:2]([CH3:20])([CH3:1])[CH2:3][CH2:4]1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: CCCCCC(CO)c1ccc2c(c1)NCCC2(C)C
Agent: C=O
Agent: [Na+]
Solvent: CC#N
Solvent: CC(=O)O
Solvent: O
Product: CCCCCC(CO)c1ccc2c(c1)N(C)CCC2(C)C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 90.2 %

Procedure:
A solution of 2-(4,4-dimethyl-1,2,3,4-tetrahydro-quinolin-7-yl)-heptan-1-ol (from Example 5.5, step 6) (2.52 g, 9.15 mmole) in 35 mL of acetonitrile was cooled to 0° C. and treated with 6.68 mL of a 37% formaldehyde solution, 5.82 g of sodium triacetoxyborohydride and 2.36 mL of acetic acid. The reaction mixture was stirred at 0° C. for 30 minutes then at room temperature for four hours, diluted with 50 mL of water and extracted with two 50 mL portions of ethyl acetate. The combined organic extracts were dried over MgSO4, filtered and concentrated in vacuo to give a yellow oil. The product was purified by flash chromatography (SiO2, 25% ethyl acetate in hexanes) to yield 2.39 g of 2-(1,4,4-trimethyl-1,2,3,4-tetrahydro-quinolin-7-yl)-heptan-1-ol as a pale yellow oil.
Reaction SMILES: [CH:1]1[C:9]2[C:8]3[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=3[O:6][C:5]=2[C:4]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([CH3:22])=[CH2:21])=[CH:16][N:15]=2)=[CH:3][CH:2]=1>[Pd].[Pt].CCO>[CH:1]1[C:9]2[C:8]3[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=3[O:6][C:5]=2[C:4]([C:14]2[CH:19]=[CH:18][C:17]([CH:20]([CH3:22])[CH3:21])=[CH:16][N:15]=2)=[CH:3][CH:2]=1
Reactant: C=C(C)c1ccc(-c2cccc3c2oc2ccccc23)nc1
Agent: [Pd]
Agent: [Pt]
Solvent: CCO
Product: CC(C)c1ccc(-c2cccc3c2oc2ccccc23)nc1
Reaction time: 1 h
Yield: 99.2 %

Procedure:
2-(Dibenzo[b,d]furan-4-yl)-5-(prop-1-en-2-yl)pyridine (7.5 g, 26.3 mmol) was added to a hydrogenator bottle containing EtOH (150 mL). The reaction mixture was degassed by bubbling nitrogen for 10 min. Pd/C (0.28 g, 2.63 mmol) and Pt/C (0.26 g, 1.3 mmol) were added to the reaction mixture. The reaction mixture was placed on the Parr hydrogenator for 1 h. The reaction mixture was filtered on a tightly packed Celite® bed and washed with dichloromethane to yield 7.5 g (99%) of the desired product. The product was confirmed by GC/MS and NMR.
Reaction SMILES: [P:1](Cl)([S:6][CH2:7][CH2:8][CH3:9])([S:3][CH2:4][CH3:5])=[S:2].C(N(CC)CC)C.[OH:18][C:19]1[CH:26]=[CH:25][CH:24]=[CH:23][C:20]=1[CH:21]=[O:22]>C(Cl)Cl>[P:1]([O:18][C:19]1[CH:26]=[CH:25][CH:24]=[CH:23][C:20]=1[CH:21]=[O:22])([S:6][CH2:7][CH2:8][CH3:9])([S:3][CH2:4][CH3:5])=[S:2]
Reactant: O=Cc1ccccc1O
Reactant: CCCSP(=S)(Cl)SCC
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCSP(=S)(Oc1ccccc1C=O)SCC
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of S-ethyl S-propyl chlorotrithiophosphate (0.03 mole) in methylene chloride (50 ml) is charged into a glass reaction vessel equipped with a mechanical stirrer. Triethylamine (0.03 mole) is added and the mixture is cooled to a temperature of about 0° C. A solution of 2-hydroxybenzaldehyde (0.03 mole) in methylene chloride (15 ml) is slowly added with stirring while maintaining the temperature of the reaction mixture at about 0° C. After the addition is completed the reaction mixture is allowed to warm to room temperature and stirring is continued for a period of about 1 hour. After this time the reaction mixture is transferred to a separatory funnel and methylene chloride (100 ml) is added. The resulting solution is then washed with water, dilute aqueous sodium hydroxide and again with water. The washed solution is dried over anhydrous magnesium sulfate, is filtered and stripped of solvent under vacuum to yield the desired product S-ethyl S-propyl O-(2-formylphenyl)trithiophosphate.
Reaction SMILES: [CH3:1][C@@H:2]([C:5]([N:7]1[C@H:11]([C:12]([OH:14])=[O:13])[CH2:10][CH2:9][CH2:8]1)=[O:6])[CH2:3][SH:4].C(N(CC)C(C)C)(C)C.Cl[C:25]([O:27][CH2:28][Cl:29])=[O:26]>O1CCOCC1.O>[Cl:29][CH2:28][O:27][C:25]([S:4][CH2:3][C@@H:2]([CH3:1])[C:5]([N:7]1[CH2:8][CH2:9][CH2:10][C@H:11]1[C:12]([OH:14])=[O:13])=[O:6])=[O:26]
Reactant: O=C(Cl)OCCl
Reactant: C[C@H](CS)C(=O)N1CCC[C@H]1C(=O)O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: C[C@H](CSC(=O)OCCl)C(=O)N1CCC[C@H]1C(=O)O
Temperature: 0 °C
Reaction time: 4 h
Yield: 73.6 %

Procedure:
Captopril (2.48 g, 0.0114 Mol) and N,N-diisopropyl ethylamine (4.50 ml, 0.0258 Mol) were dissolved in dioxane/H2O (30 ml, 1:1). The mixture was cooled to 0° C. and 1-chloromethyl chloroformate (1.20 ml, 0.0147 Mol) was added. The reaction was stirred at 0° C. for 4 h, then partitioned between HCl (4%, 30 ml) and CH2Cl2 (30 ml). The aqueous phase was extracted with CH2Cl2 (2×30 ml) and the combined organic phases were washed with HCl (4%, 30 ml) and brine (3×30 ml), dried over sodium sulphate and evaporated under reduced pressure affording 1-[(2S)-3-(chloromethoxycarbonyl)mercapto-2-methyl-1-oxopropyl]-L-proline as a clear oil (2.60 g) that was used without further purification.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[CH:8][C:9]2[C:10]3[N:19]([NH:20][CH:21]([CH3:23])[CH3:22])[C:18]([CH2:24][O:25][CH2:26][CH3:27])=[N:17][C:11]=3[C:12]([NH2:16])=[N:13][C:14]=2[CH:15]=1.C(N(CC)CC)C.[CH3:35][S:36](Cl)(=[O:38])=[O:37]>C(Cl)Cl.C(Cl)(Cl)Cl>[NH2:16][C:12]1[C:11]2[N:17]=[C:18]([CH2:24][O:25][CH2:26][CH3:27])[N:19]([NH:20][CH:21]([CH3:22])[CH3:23])[C:10]=2[C:9]2[CH:8]=[CH:7][C:6]([O:5][CH2:4][CH2:3][CH2:2][NH:1][S:36]([CH3:35])(=[O:38])=[O:37])=[CH:15][C:14]=2[N:13]=1
Reactant: CCOCc1nc2c(N)nc3cc(OCCCN)ccc3c2n1NC(C)C
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: CCOCc1nc2c(N)nc3cc(OCCCNS(C)(=O)=O)ccc3c2n1NC(C)C
Reaction time: 16 h

Procedure:
A solution of 7-(3-aminopropoxy)-2-ethoxymethyl-N1-isopropyl-1H-imidazo[4,5-c]quinoline-1,4-diamine (0.84 g, 2.26 mmol) in 25 mL of CH2Cl2 was placed under an atmosphere of nitrogen. The solution was treated with triethylamine (0.63 mL, 4.75 mmol) and cooled in an ice water bath. The solution was slowly treated with methanesulfonyl chloride (0.184 mL, 2.37). The reaction was stirred and allowed to slowly come to ambient temperature. After 16 h, the reaction mixture was diluted with CHCl3 (20 mL) and transferred to a separatory funnel. The organic solution was washed with 10% Na2CO3 solution (15 mL), H2O (15 mL) and brine (15 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to yield a tan foam. The foam was purified by chromatography (SiO2, 10–50% (80:18:2 CHCl3:MeOH:NH4OH) in CHCl3) to give a light yellow solid. The solid was crystallized from MeCN to yield N-(3-{[4-amino-2-(ethoxymethyl)-1-(isopropylamino)-1H-imidazo[4,5-c]quinolin-7-yl]oxy}propyl)methanesulfonamide (0.295 g) as white crystals. mp 181–183° C.; 1H NMR (300 MHz, DMSO-d6) δ 8.46 (d, J=9.0 Hz, 1H), 7.09 (t, J=6.8 Hz, 1H), 7.02 (d, J=2.6 Hz, 1H), 6.90 (d, J=2.1 Hz, 1H), 6.87 (d, J=2.5 Hz, 1H), 6.54 (s, 2H), 4.71 (s, 2H), 4.11 (t, J=6.1 Hz, 2H), 3.64–3.58 (m, 3H), 3.14 (q, J=6.1 Hz, 2H), 2.91 (s, 3H), 1.96 (p, J=6.6 Hz, 2H), 1.15 (t, J=7.0 Hz, 3H), 1.01 (d, J=6.1 Hz, 6H); 13C NMR (75 MHz, DMSO-d6) δ 158.1, 152.6, 149.4, 147.2, 133.7, 122.6, 111.5, 109.1, 107.9, 65.8, 65.0, 63.0, 51.6, 29.7, 20.6, 15.3; MS (APCI) m/z 451 (M+H)+; Anal. Calcd for C20H30N6O4S: C, 53.32; H, 6.71; N, 18.65; S, 7.12; Found: C, 53.44; H, 6.68; N, 18.83; S, 7.09.
Reaction SMILES: Cl[C:2]1[C:11]([C:12]#[N:13])=[C:10]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:20])[CH:8]=2)[N:3]=1.[NH:21]1[CH2:25][CH2:24][CH2:23][CH2:22]1.C(N(CC)CC)C.O>CN(C=O)C>[Cl:20][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[N:3]=[C:2]([N:21]1[CH2:25][CH2:24][CH2:23][CH2:22]1)[C:11]([C:12]#[N:13])=[C:10]2[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: N#Cc1c(Cl)nc2ccc(Cl)cc2c1-c1ccccc1
Reactant: C1CCNC1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: N#Cc1c(N2CCCC2)nc2ccc(Cl)cc2c1-c1ccccc1
Temperature: 120 °C
Yield: 83.9 %

Procedure:
2,6-Dichloro-4-phenyl-quinoline-3-carbonitrile (30 mg, 100 μmol, Eq: 1.00), pyrrolidine (14.3 mg, 16.6 μl, 201 μmol, Eq: 2) and triethylamine (30.4 mg, 41.9 μl, 301 μmol, Eq: 3) were dissolved in DMF (0.5 ml) and the reaction mixture was heated to 120° C. for 20 min in a microwave. Then water was added and the mixture was extracted with ethyl acetate (3×). The combined organic layers were dried with Na2SO4 and evaporated to dryness. The remaining residue was purified by column chromatography (silica gel, DCM/heptane 1:1) to afford the title compound as yellow solid (28 mg). MS (ESI): 334.2 (M+H)+.
Reaction SMILES: [N:1]1[N:9]2[C:4]([O:5][CH2:6][CH2:7][CH2:8]2)=[C:3]([C:10]([OH:12])=O)[CH:2]=1.Cl.CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1.CCN(C(C)C)C(C)C.Cl.[CH3:46][NH:47][O:48][CH3:49].C([O-])(O)=O.[Na+]>CN(C)C1C=CN=CC=1.C(#N)C>[CH3:49][O:48][N:47]([CH3:46])[C:10]([C:3]1[CH:2]=[N:1][N:9]2[CH2:8][CH2:7][CH2:6][O:5][C:4]=12)=[O:12]
Reactant: CNOC
Reactant: O=C(O)c1cnn2c1OCCC2
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CC#N
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CON(C)C(=O)c1cnn2c1OCCC2
Temperature: 25 °C
Reaction time: 72 h
Yield: 88.2 %

Procedure:
To a stirred solution of 6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxylic acid (8.14 g, 48.4 mmol), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (10.21 g, 53.3 mmol), 1-hydroxybenzotriazole hydrate (8.16 g, 53.3 mmol), 4-dimethylaminopyridine (300 mg, 2 mmol), and DIPEA (16.5 mL, 97 mmol) in anhydrous acetonitrile (200 mL) was added a solution of N,O-dimethylhydroxylamine hydrochloride (9.44 g, 97 mmol) and DIPEA (16.5 mL, 97 mmol) in anhydrous acetonitrile (100 mL). The mixture was stirred for 3 days at room temperature, then poured into saturated NaHCO3 solution (200 mL) and extracted with EtOAc (3×1000 mL). The combined organic layers were washed with brine (200 mL), dried (Na2SO4), filtered and concentrated. Flash chromatography (0 to 5% MeOH in DCM) afforded the amide as a solid (9.02 g, 88%). 1H NMR (400 MHz, DMSO-d6) δ7.62 (s, 1H), 4.35 (t, 2H, J=5.24 Hz), 4.08 (t, 2H, J=6.20 Hz), 3.63 (s, 3H), 3.12 (s, 3H), 2.20-2.15 (m, 2H).
Reaction SMILES: Br[CH2:2][C:3]([O:5][CH3:6])=[O:4].C([O-])([O-])=O.[K+].[K+].[CH:13]1([N:16]2[C:24]3[C:19](=[C:20]([OH:49])[CH:21]=[C:22]([C:25]([N:27]4[CH2:32][CH2:31][C:30]5([CH2:41][C:40](=[O:42])[C:39]6[C:34](=[CH:35][CH:36]=[C:37]([C:43]7[CH:44]=[N:45][N:46]([CH3:48])[CH:47]=7)[CH:38]=6)[O:33]5)[CH2:29][CH2:28]4)=[O:26])[CH:23]=3)[CH:18]=[CH:17]2)[CH2:15][CH2:14]1>CN(C=O)C.CCOC(C)=O>[CH:13]1([N:16]2[C:24]3[C:19](=[C:20]([O:49][CH2:2][C:3]([O:5][CH3:6])=[O:4])[CH:21]=[C:22]([C:25]([N:27]4[CH2:28][CH2:29][C:30]5([CH2:41][C:40](=[O:42])[C:39]6[C:34](=[CH:35][CH:36]=[C:37]([C:43]7[CH:44]=[N:45][N:46]([CH3:48])[CH:47]=7)[CH:38]=6)[O:33]5)[CH2:31][CH2:32]4)=[O:26])[CH:23]=3)[CH:18]=[CH:17]2)[CH2:14][CH2:15]1
Reactant: COC(=O)CBr
Reactant: Cn1cc(-c2ccc3c(c2)C(=O)CC2(CCN(C(=O)c4cc(O)c5ccn(C6CC6)c5c4)CC2)O3)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)COc1cc(C(=O)N2CCC3(CC2)CC(=O)c2cc(-c4cnn(C)c4)ccc2O3)cc2c1ccn2C1CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Methyl bromoacetate (0.059 ml, 0.604 mmol) was added to a stirred mixture of K2CO3 (111 mg, 0.806 mmol), 1′-[(1-cyclopropyl-4-hydroxy-1H-indol-6-yl)carbonyl]-6-(1-methyl-1H-pyrazol-4-yl)spiro[chroman-2,4′-piperidin]-4-one (200 mg, 0.403 mmol) in DMF (2 ml) and the mixture was stirred at room temperature overnight. The mixture was diluted with EtOAc, washed with water, brine, and dried over MgSO4. After filteration and evaporation, the residue was purified by silicagel column chromatography (CHCl3/MeOH) to give intended compound as yellow oil.
Reaction SMILES: N(CCO)(CCO)CCO.Cl.O=C[C@@H]([C@H]([C@@H]([C@@H](CO)O)O)O)O.[Cl:24][CH2:25][C:26](=[O:33])[CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29].C([O-])([O-])=O.[Na+].[Na+]>O=C[C@@H]([C@H]([C@@H]([C@@H](CO)O)O)O)O.C1C=[N+]([C@@H]2O[C@H](COP(OP(OC[C@H]3O[C@@H](N4C5N=CN=C(N)C=5N=C4)[C@H](O)[C@@H]3O)(O)=O)([O-])=O)[C@@H](O)[C@H]2O)C=C(C(N)=O)C=1.C(OCCCC)(=O)C.O>[Cl:24][CH2:25][C@@H:26]([OH:33])[CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29]
Reactant: CCOC(=O)CC(=O)CCl
Agent: Cl
Agent: NC(=O)c1ccc[n+]([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)c1
Agent: O=C([O-])[O-]
Solvent: CCCCOC(C)=O
Solvent: OCCN(CCO)CCO
Solvent: O
Product: CCOC(=O)C[C@H](O)CCl
Reaction time: 0.17 h
Yield: 85.9 %

Procedure:
To a 3-necked jacketed 3 L flask equipped with a mechanical stirrer and connected to an automatic titrater by a pH electrode and a feeding tube for addition of base, was charged triethanolamine (6.6 mL) and H2O (492 mL) to make 100 mM triethanolamine solution. The pH was adjusted to 7 with 37% HCl. Then, D-Glucose (125 g) was added. The water circulating to the flask jacket was set to 30° C. After 10 minutes, ketoreductase SEQ ID NO: 2 (5.7 g) and glucose dehydrogenase S06 SEQ ID NO: 10 (3.1 g) powder were added. After 10 minutes, β-NAD (125 mg) was added and the resulting mixture was allowed to stir for 5 minutes. Then, butyl acetate (250 mL) was charged. Using an addition funnel, 2.4 M ethyl 4-chloroacetoacetate (250 mL, 100 g in 167 mL of butyl acetate) was slowly added over 3 hrs. The pH was maintained at 7 by the automatic titrater by the addition of 2 M Na2CO3 (152 mL) over 15 hrs. Subsequently, gas chromatography of a reaction sample showed complete conversion to product. Celite (16 g) was added and the reaction mixture was allowed to stir for 10 minutes. The solution was filtered through a celite pad and the organic layer was separated. The aqueous layer was extracted with butyl acetate (2×200 mL). The organic layers were combined and the solvent removed under vacuum by rotary evaporation to obtain 87 g of the ethyl (S) 4-chloro-3-hydroxybutyrate. The enantiomeric excess was >99%, as determined after its conversion to ethyl (R)-4-cyano-3-hydroxybutyrate in Example 8.
Reaction SMILES: Cl.[CH3:2][NH:3][CH3:4].[F:5][C:6]1[CH:11]=[CH:10][C:9]([S:12](Cl)(=[O:14])=[O:13])=[CH:8][CH:7]=1.C(N(CC)C(C)C)(C)C>ClCCl.O>[F:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([N:3]([CH3:4])[CH3:2])(=[O:14])=[O:13])=[CH:8][CH:7]=1
Reactant: CNC
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Agent: Cl
Solvent: O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)S(=O)(=O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Dimethylamine hydrochloride (1.27 g) was added to a solution of 4-fluoro-benzenesulphonyl chloride (3.0 g) and N,N-diisopropylethylamine (5.37 ml) in dichloromethane (30 ml), the mixture was stirred at RT for 1 h, diluted with water, extracted with dichloromethane, dried and evaporated under reduced, yield 3.0 g.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][C:9]2[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=2)[N:5]=[C:4]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[CH:3]=1.[NH2:21][NH2:22]>C1COCC1>[N:15]1([C:4]2[N:5]=[C:6]([O:8][C:9]3[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=3)[N:7]=[C:2]([NH:21][NH2:22])[CH:3]=2)[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1
Reactant: Clc1cc(N2CCOCC2)nc(Oc2cccnc2)n1
Reactant: NN
Solvent: C1CCOC1
Product: NNc1cc(N2CCOCC2)nc(Oc2cccnc2)n1
Temperature: 70 °C
Yield: 62.4 %

Procedure:
To a solution of 4-[6-chloro-2-(pyridin-3-yloxy)-pyrimidin-4-yl]-morpholine (295 mg, 1 mmol) in THF (10 mL) was added anhydrous hydrazine (0,320 ml, 10 mmol) under the nitrogen protection. The mixture was heated at 70° C. for 15 min. After cooling to room temperature, the reaction mixture was quenched by ice brine and extracted with EtOAc (100 mL). The organic phase was washed with brine (10 mL) and water (10 ml×2), dried (Na2SO4), filtered, evaporated, and purified by flash chromatography on a column of silica gel (CH2Cl2 and CH2Cl2—MeOH, 95:5) and to give [6-morpholin-4-yl-2-(pyridin-3-yloxy)-pyrimidin-4-yl]-hydrazine (180 mg) in 62% yield. M/Z (M+1) 289.2