Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[H-].[Na+].Cl[C:15]1[C:20]([N+:21]([O-:23])=[O:22])=[CH:19][C:18]([CH3:24])=[CH:17][N:16]=1.Cl>COCCOC>[CH2:10]([O:9][C:1](=[O:8])[CH:2]([C:15]1[C:20]([N+:21]([O-:23])=[O:22])=[CH:19][C:18]([CH3:24])=[CH:17][N:16]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4])[CH3:11]
Reactant: Cc1cnc(Cl)c([N+](=O)[O-])c1
Reactant: CCOC(=O)CC(=O)OCC
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: CCOC(=O)C(C(=O)OCC)c1ncc(C)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of diethyl malonate (72 g, 0.436 mol) in DME (200 mL) is added dropwise to a magnetically stirred suspension of NaH (23 g, 0.58 mol) in dry 1,2-dimethoxyethane (DME, 350 mL). The mixture is stirred at room temperature for 1 hour and then a solution of 2-chloro-5-methyl-3-nitro-pyridine (50 g, 0.290 mol) in DME (100 mL) is added to give a dark red solution. After stirring for 18 hours, the reaction mixture is poured into ice-cold water and acidified to pH 3 with 6N HCl solution. The mixture is extracted with ethyl acetate. The organic phase is washed with water, brine, dried over Na2SO4, and concentrated. The excess diethymalonate is removed at 50° C. under high vacuum to give 2-(5-Methyl-3-nitro-pyridin-2-yl)-malonic acid diethyl ester i as a dark red-colored thick residue; 1H NMR (300 MHz, CDCl3) δ 1.28 (t, J=9 Hz, 6H), 4.26 (q, J=9 Hz, 4H), 8.27 (s, 1H), 8.63 (s, 1H).
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:14]=[CH:13][CH:12]=[CH:11][C:4]=1[O:5][CH:6]1[CH2:9][CH2:8][C:7]1=O.[NH2:17][CH2:18][CH2:19][OH:20].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>ClCCCl.C(O)(=O)C>[F:1][C:2]([F:16])([F:15])[C:3]1[CH:14]=[CH:13][CH:12]=[CH:11][C:4]=1[O:5][C@H:6]1[CH2:9][CH2:8][C@H:7]1[NH:17][CH2:18][CH2:19][OH:20]
Reactant: O=C1CCC1Oc1ccccc1C(F)(F)F
Reactant: NCCO
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: OCCN[C@@H]1CC[C@@H]1Oc1ccccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of C4 (3.5 g, 15 mmol) and 2-aminoethanol (1.03 g, 16.8 mmol) in 1,2-dichloroethane (100 mL) was treated with sodium triacetoxyborohydride (5.62 g, 25.2 mmol) and stirred at room temperature for 2 hours. The reaction was treated with acetic acid (4 mL) and stirred at room temperature for 16 hours. Aqueous sodium hydroxide solution (1 N, 100 mL) was added and the mixture was extracted with dichloromethane (2×100 mL). The combined organic layers were dried over magnesium sulfate and concentrated in vacuo. Purification via silica gel chromatography (Gradient: 0% to 70% [10% 2 N ammonia in methanol/90% ethyl acetate] in ethyl acetate) afforded the title compound as a light amber oil. Yield: 2.1 g, 7.6 mmol, 51%. The indicated cis stereochemistry was tentatively assigned, based on NOE (nuclear Overhauser enhancement) experiments. 1H NMR (400 MHz, CDCl3) δ 7.57 (br dd, J=7.7, 1.3 Hz, 1H), 7.41-7.47 (m, 1H), 6.99 (br dd, J=7.6, 7.6 Hz, 1H), 6.80 (d, J=8.2 Hz, 1H), 4.88-4.93 (m, 1H), 3.54-3.66 (m, 3H), 2.81-2.88 (m, 1H), 2.63-2.70 (m, 1H), 2.22-2.31 (m, 1H), 1.97-2.16 (m, 2H), 1.86-1.94 (m, 1H).
Reaction SMILES: CO[CH:3](OC)[CH2:4]Br.Cl.C(=O)(O)[O-].[Na+].[CH3:14][O:15][C:16](=[O:27])[CH:17]=[C:18]([C:20]1[CH:21]=[N:22][C:23]([NH2:26])=[CH:24][CH:25]=1)[CH3:19]>O>[CH3:14][O:15][C:16](=[O:27])[CH:17]=[C:18]([C:20]1[CH:25]=[CH:24][C:23]2[N:22]([CH:3]=[CH:4][N:26]=2)[CH:21]=1)[CH3:19]
Reactant: COC(CBr)OC
Reactant: COC(=O)C=C(C)c1ccc(N)nc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: COC(=O)C=C(C)c1ccc2nccn2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Bromoacetaldehyde dimethyl acetal (0.692 mL, 5.85 mmol) was refluxed in a solution of water (10 mL) and concentrated HCl (0.1 mL) for 30 min. The reaction was cooled to ambient temperature, and sodium bicarbonate (629 mg, 7.49 mmol) was added in several portions. After the addition was complete, 3-(6-amino-pyridin-3-yl)-but-2-enoic acid methyl ester (900 mg, 4.68 mmol) was added, and the reaction stirred overnight. During this time, the reaction became homogenous. After extracting the reaction mixture with ethyl acetate (3×20 mL), the organic layers were combined, dried over MgSO4 and concentrated in vacuo. The residue was purified by chromatography (chromatotron, 4μ plate, 50% ethyl acetate in hexanes) to yield 3-imidazo[1,2-a]pyridin-6-yl-but-2-enoic acid methyl ester as an off white solid (223.3 mg, 22%). 1H NMR (250 MHz, CDCl3): δ 8.32 (bs, 1H), 7.58-7.70 (m, 3H), 7.35 (dd, 1H, J=7.5, J=3.1), 6.24 (d, 1H, J=0.62), 3.31 (s, 3H), 2.64 (d, 3H, J=0.62). MS [EI+] 217 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]([C:6]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][CH3:18])=[CH:14][CH:15]=3)[C:10]([CH2:19][NH:20][OH:21])=[C:9]2[CH3:22])=[O:7])=[CH:4][CH:3]=1.Cl[C:26]([O:28][CH3:29])=[O:27].C([O-])(=O)C.[Na+]>O1CCOCC1.O>[Cl:1][C:2]1[CH:24]=[CH:23][C:5]([C:6]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][CH3:18])=[CH:14][CH:15]=3)[C:10]([CH2:19][N:20]([OH:21])[C:26](=[O:27])[O:28][CH3:29])=[C:9]2[CH3:22])=[O:7])=[CH:4][CH:3]=1
Reactant: COc1ccc2c(c1)c(CNO)c(C)n2C(=O)c1ccc(Cl)cc1
Reactant: COC(=O)Cl
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: COC(=O)N(O)Cc1c(C)n(C(=O)c2ccc(Cl)cc2)c2ccc(OC)cc12
Yield: 63 %

Procedure:
According to the procedure of Example 62, 1-(4-chlorobenzoyl)-N-hydroxy-5-methoxy-2-methyl-lH-indole-3-methanamine is reacted with 1.1 eq of methyl chloroformate in dioxane/water (2:1) in the presence of sodium acetate (2.5 eq). The crude product is recrystallized from isopropyl ether:cyclohexane to give pure [[1-(4-chlorobenzoyl)-5-methoxy-2-methyl-lH-indol-3-yl]methyl]hydroxycarbamic acid, methyl ester (63%); mp 113°-114° C.
Reaction SMILES: O.[NH2:2][C:3]1[N:8]=[C:7](Cl)[CH:6]=[C:5]([OH:10])[N:4]=1.[CH:11]1([NH2:14])[CH2:13][CH2:12]1>C(O)C>[NH2:2][C:3]1[N:8]=[C:7]([NH:14][CH:11]2[CH2:13][CH2:12]2)[CH:6]=[C:5]([OH:10])[N:4]=1
Reactant: Nc1nc(O)cc(Cl)n1
Reactant: NC1CC1
Solvent: O
Solvent: CCO
Product: Nc1nc(O)cc(NC2CC2)n1

Procedure:
2-Amino-4-chloro-6-hydroxypyrimidine monohydrate (5.0 g) was refluxed in ethanol (150 mL) with cyclopropylamine for 12 h. The mixture was evaporated in vacuo, codistilled with ethanol (3×50 mL), adsorbed from methanol on silica gel and applied on a column of silica gel (200 mL) in chloroform. Elution with chloroform-ethanol gradient afforded crystalline product which was filtered from ether and dried in vacuo to afford 2-amino-4-cyclopropylamino-6-hydroxypyrimidine, m.p.229° C. Yield, 3.0 g. For C7H10N4O (166.18) calculated 50.59% C, 6.07% H, 33.71% N; found 50.49% C, 6.25% H, 33.61% N. 1H NMR (DMSO): 9.73 brs, 1H (OH); 6.55 bs, 2H (NH); 6.08 brs, 2H (NH2); 4.66 s, 1H (H-5); 2.30 m, 1H and 0.62 m, 2H and 0.40, m, 2H (C—CH2, N—CH).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH2:8]O)[CH:5]=[CH:4][N:3]=1.[C:10]12[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=1)[NH:15][C:14](=[O:21])[O:13][C:11]2=[O:12].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[NH2:1][C:2]1[CH:7]=[C:6]([CH2:8][N:15]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:10]=3[C:11](=[O:12])[O:13][C:14]2=[O:21])[CH:5]=[CH:4][N:3]=1
Reactant: O=c1[nH]c2ccccc2c(=O)o1
Reactant: Nc1cc(CO)ccn1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Nc1cc(Cn2c(=O)oc(=O)c3ccccc32)ccn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred mixture of 2-aminopyridine-4-methanol (commercially available from CB Research, 25.05 g, 201.79 mmol), isatoic anhydride (32.91 g/201.74 mmol), and triphenylphosphine (52.92 g/201.76 mmol) in THF (400 ml) at 20° C. was added diisopropyl azodicarboxylate (40.8 g/201.77 mmol) drop-wise. The reaction mixture was stirred at room temperature for 1 hour. The mixture was cooled to 0° C. and the precipitated material was isolated by filtration and washed with a small amount of THF, to afford the title compound as a yellow solid material (18.93 g). The filtrate was evaporated under reduced pressure. To the residual oil was added dichloromethane. The resulting precipitate was isolated by filtration affording more product (1.21 g). The filtrate was extracted with 0.1M HClaq., and the pH of the aqueous layer was adjusted to ca. 7-8 with aqueous sodium bicarbonate, then extracted with EtOAc. The organic layer was evaporated under reduced pressure, and the resulting solid material was suspended in THF (100 ml). The solid material was isolated by filtration to yield more product (9.10 g). The filtrate was concentrated to ca. 45 ml, affording more precipitate and an additional amount of the title compound (1.77 g) after filtration and drying under vacuum. 13C-NMR (DMSO-d6) δ 160.0, 158.7, 148.1, 148.0, 145.0, 141.2, 137.1, 129.5, 123.8, 115.0, 111.7, 109.9, 104.5, 46.8.
Reaction SMILES: [I:1][C:2]1[C:3]([O:16][CH3:17])=[C:4]2[C:8](=[C:9]([O:12][CH3:13])[C:10]=1[I:11])[C:7](=[NH:14])[NH:6][C:5]2=N.[ClH:18].[CH2:19]([N:21]([CH2:28][CH3:29])[C:22]1[S:23][CH2:24][C:25](=[NH:27])[N:26]=1)[CH3:20].Cl.N1(C2SCC(=N)N=2)CCCCC1>>[ClH:18].[NH:14]=[C:7]1[C:8]2[C:4](=[C:3]([O:16][CH3:17])[C:2]([I:1])=[C:10]([I:11])[C:9]=2[O:12][CH3:13])[C:5](=[C:24]2[S:23][C:22]([N:21]([CH2:28][CH3:29])[CH2:19][CH3:20])=[N:26][C:25]2=[NH:27])[NH:6]1
Reactant: COc1c(I)c(I)c(OC)c2c1C(=N)NC2=N
Reactant: CCN(CC)C1=NC(=N)CS1
Agent: Cl
Agent: N=C1CSC(N2CCCCC2)=N1
Product: CCN(CC)C1=NC(=N)C(=C2NC(=N)c3c(OC)c(I)c(I)c(OC)c32)S1

Procedure:
Following the procedure described in Example 9, part B above but using equivalent amounts of 5,6-diiodo-4,7-dimethoxy-1,3-diiminoisoindoline and 2-diethylamino-4-imino-2-thiazoline hydrochloride in place of 1,3-diiminoisoindoline and 2-piperidino-4-imino-2-thiazoline hydrochloride respectively, there is obtained as the product 1-imino-5,6-diiodo-4,7-dimethoxy-3-(2-diethylamino-4-imino-2-thiazolin-5-ylidene)isoindoline hydrochloride.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:13]=1[C:12](=[O:14])[N:11]([CH:15]([C:20]1[CH:25]=[CH:24][C:23]([O:26][CH:27]([F:29])[F:28])=[C:22]([O:30][CH2:31][CH3:32])[CH:21]=1)[CH2:16][C:17](O)=[O:18])[CH2:10]2)(=[O:3])[CH3:2].C1N=[CH:36][N:35](C(N2C=NC=C2)=O)[CH:34]=1.CNC>C1COCC1>[C:1]([NH:4][C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:13]=1[C:12](=[O:14])[N:11]([CH:15]([C:20]1[CH:25]=[CH:24][C:23]([O:26][CH:27]([F:29])[F:28])=[C:22]([O:30][CH2:31][CH3:32])[CH:21]=1)[CH2:16][C:17]([N:35]([CH3:36])[CH3:34])=[O:18])[CH2:10]2)(=[O:3])[CH3:2]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CCOc1cc(C(CC(=O)O)N2Cc3cccc(NC(C)=O)c3C2=O)ccc1OC(F)F
Agent: CNC
Solvent: C1CCOC1
Product: CCOc1cc(C(CC(=O)N(C)C)N2Cc3cccc(NC(C)=O)c3C2=O)ccc1OC(F)F
Yield: 47.8 %

Procedure:
3-(7-Acetylamino-1-oxo-1,3-dihydro-isoindol-2-yl)-3-(4-difluoromethoxy-3-ethoxy-phenyl)-N,N-dimethyl-propionamide was prepared by the procedure of example 13 from 3-(7-acetylamino-1-oxo-1,3-dihydro-isoindol-2-yl)-3-(4-difluoromethoxy-3-ethoxy-phenyl)-propionic acid (0.1 g, 0.22 mmol), CDI (0.05 g, 0.33 mmol) and dimethylamine (0.33 ml, 0.66 mmol) in THF (10 ml) to give as 3-(7-acetylamino-1-oxo-1,3-dihydro-isoindol-2-yl)-3-(4-difluoromethoxy-3-ethoxy-phenyl)-N,N-dimethyl-propionamide white solid (0.05 g, 50% yield): mp 141-143° C.; 1HNMR (CDCl3): δ 1.44 (t, J=7.0 Hz, 3H, OCH2CH3), 2.25 (s, 3H, CH3CO), 2.93 (s, 3H, NCH3), 3.04 (dd, J=5, 15 Hz, 1H, CH2), 3.10 (s, 3H, NCH3), 3.60 (dd, J=10, 15 Hz, 1H, CH2), 4.09 (q, J=7.0 Hz, 2H, OCH2CH3), 4.33 (d, J=18 Hz, 1H, CH2N), 4.44 (d, J=18 Hz, 1H, CH2N), 5.59 (m, 1H, CHN), 6.55 (t, JH-F=75 Hz, 1H, CF2H), 7.04 (m, 4H, Ar), 7.45 (t, J=7.5 Hz, 1H, Ar), 8.45 (d, J=7.5 Hz, 1H, Ar), 10.35 (s, 1H, NHCO). 13CNMR (DMSO-d6): δ 14.5, 24.8, 35.5, 35.9, 37.2, 49.0, 53.8, 64.7, 111.9, 113.4, 113.5, 116.0, 116.8, 117.5, 117.8, 119.1, 119.1, 120.1, 122.6, 133.0, 137.7, 138.2, 139.7, 138.2, 139.6, 139.7, 141.5, 150.6, 168.9, 169.2, 169.5; Anal. Calcd. for C24H27F2N3O5: C, 60.62; H, 5.72; N, 8.84. Found: C, 59.90; H, 5.46; N, 8.66.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[OH-].[K+].Cl[C:10]1[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:11]=1[C:12]([OH:14])=[O:13].[NH2:20][CH2:21][C:22]([OH:24])=[O:23]>O>[C:22]([CH2:21][NH:20][C:10]1[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:11]=1[C:12]([OH:14])=[O:13])([OH:24])=[O:23]
Reactant: NCC(=O)O
Reactant: O=C(O)c1ccc(Cl)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: O=C(O)CNc1cc(Cl)ccc1C(=O)O
Temperature: 30 °C
Yield: 87.7 %

Procedure:
To a solution of potassium carbonate (50.7 g), potassium hydroxide (47.3 g), 2,4-dichlorobenzoic acid (VI) (70 g) and glycine (VII) (96.3 g) in water (700 ml) was added cupric chloride (0.7 g) and the resulting solution was refluxed for 4 hours. After this reaction solution was cooled to 30° C., the copper salt was removed by filtration and concentrated hydrochloric acid (288 g) was added to the resultant filtrate at temperature of not more than 40° C. Then, the resulting precipitate was collected by filtration, washed with water and dried under vacuum to give 73.8 g of 2-carboxymethylamino-4-chlorobenzoic acid (yield, 87.7%).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]2[NH:9][C:10]([C:15]3[CH:20]=[C:19](Cl)[CH:18]=[CH:17][N:16]=3)=[CH:11][C:12](=[O:14])[CH:13]=2)[CH:3]=1.[CH2:22]([N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1)[CH2:23][CH2:24][CH3:25]>CC(O)(CC)C>[CH2:22]([N:26]1[CH2:31][CH2:30][N:29]([C:2]2[CH:7]=[CH:6][N:5]=[C:4]([C:8]3[NH:9][C:10]([C:15]4[CH:20]=[C:19]([N:29]5[CH2:30][CH2:31][N:26]([CH2:22][CH2:23][CH2:24][CH3:25])[CH2:27][CH2:28]5)[CH:18]=[CH:17][N:16]=4)=[CH:11][C:12](=[O:14])[CH:13]=3)[CH:3]=2)[CH2:28][CH2:27]1)[CH2:23][CH2:24][CH3:25]
Reactant: O=c1cc(-c2cc(Cl)ccn2)[nH]c(-c2cc(Cl)ccn2)c1
Reactant: CCCCN1CCNCC1
Solvent: CCC(C)(C)O
Product: CCCCN1CCN(c2ccnc(-c3cc(=O)cc(-c4cc(N5CCN(CCCC)CC5)ccn4)[nH]3)c2)CC1

Procedure:
A mixture of 1.12 g (3.52 mmol) 4,4″-dichlor-1′H-[2,2′;6′,2″]terpyridin-4′-on, 10.0 g (70 mmol) 1-butyl-piperazine and 24 mg (0.18 mmol) Zn(II)-chloride in 20 ml 2-methyl-2butanol is refluxed for 18 hours. Afterwards, the solution is concentrated by a rotary evaporator. The raw product is recrystallized from a methanol/water mixture. The yellowish 4,4″-bis-(4-butyl-piperazin-1-yl)-1′H-[2,2′;6′,2″]terpyridin-4′-on is obtained. 1H-NMR (360 MHz, CDCl3): 8.31 (d, 2H, J=5.9 Hz); 7.18 (sm, 2H); 6.94 (s, 2H); 6.65 (dd, 2H, J=5.9,1.8 Hz); 3.39-3.31 (tm, 8H); 2.55-2.47 (tm, 8H); 2.36-2,28 (tm, 4H); 1.5-1.38 (m, 4H); 1.36-1.22 (m, 4H); 0.87 (t, J=7.2 Hz, 6H).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][NH2:5].C(N(CC)CC)C.Br[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16]>C1C=CC=CC=1>[CH2:18]([O:17][C:15](=[O:16])[CH2:14][NH:5][CH2:4][CH2:3][O:2][CH3:1])[CH3:19]
Reactant: CCOC(=O)CBr
Reactant: COCCN
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: CCOC(=O)CNCCOC
Yield: 75.3 %

Procedure:
To a stirred solution of 165.2 g of 2-methoxyethylamine and 202.4 g of triethylamine in 1 l of benzene was added dropwise a solution of 334.0 g of ethyl bromoacetate in 200 ml of benzene in one hour at room temperature. At the end of this period, the mixture was heated at reflux for 2 hours to complete the reaction. Upon chilling, the triethylamine hydrobromide was removed by filtration and washed with benzene. After removal of the solvent, the product was distilled in vacuo to yield 242.8 g (75.3 percent) of N-(2-methoxyethyl)glycine ethyl ester, B.P. 73°-5° C/4 mmHg.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:10]([NH2:12])=[O:11])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[H-].[Na+].[CH3:15][CH:16]([S:18](Cl)(=[O:20])=[O:19])[CH3:17]>O1CCCC1.C(OCC)(=O)C>[N+:1]([C:4]1[CH:5]=[C:6]([C:10]([NH:12][S:18]([CH:16]([CH3:17])[CH3:15])(=[O:20])=[O:19])=[O:11])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: NC(=O)c1cccc([N+](=O)[O-])c1
Reactant: CC(C)S(=O)(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)S(=O)(=O)NC(=O)c1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A solution of 3-nitrophenylcarboxamide (2 g) in 150 ml of dry tetrahydrofuran was cooled to 0° C. and treated with 530 mg of sodium hydride (60% oil dispersion). The reaction mixture was stirred for 20 minutes and then 2-propylsulfonylchloride (1.5 ml) was introduced dropwise via syringe. After 5 minutes the reaction mixture became homogeneous and was warmed to room temperature and stirred for 2 hours. The reaction mixture was diluted with 300 ml of ethyl acetate and was washed with brine. The organic extracts were dried, concentrated in vacuo, and the residue was chromatographed on silica gel (chloroform-methanol, 95:5 v/v) to yield 0.6 g of the title compound in pure form.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:9]=[N:10][CH:11]=1.[CH3:20][NH2:21]>CO>[CH3:20][NH:21][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[N:10][CH:9]=[C:8]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:7]=1
Reactant: CN
Reactant: ClCCCOc1cncc(OCc2ccccc2)c1
Solvent: CO
Product: CNCCCOc1cncc(OCc2ccccc2)c1
Temperature: 100 °C
Yield: 71.7 %

Procedure:
The 5-(3-chloropropoxy)-3-(phenylmethoxy)pyridine (1.52 g, 5.49 mmol) was dissolved in methanol (25 mL) and added to a 40 wt % aqueous solution of methylamine (50 mL) in a heavy-walled glass pressure-tube apparatus. The tube was sealed and the mixture was stirred and heated at 100° C. (oil bath temperature) for 4 h. After cooling, the mixture was concentrated by rotary evaporation. Saturated NaCl solution (25 mL) was added to the residue. The pH of the solution was adjusted to 6, and impurities were extracted with ether (3×15 mL). The aqueous layer was basified to pH 10 with 10% NaOH solution and extracted with chloroform (4×15 mL). The combined chloroform extracts were dried (Na2SO4), filtered, and concentrated by rotary evaporation to a residue that was dried briefly under high vacuum to give 1.07 g (71.7%) of an oil.
Reaction SMILES: [F:1][C:2]([F:48])([F:47])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[C:25]([C:26]4[C:27]([O:39][CH3:40])=[N:28][CH:29]=[C:30]([C:32]5[C:33]([CH3:38])=[N:34][NH:35][C:36]=5[CH3:37])[CH:31]=4)=[CH:24][N:23]=[C:22]([N:41]4[CH2:44][CH:43]([F:45])[CH2:42]4)[N:21]=3)[C@H:14]2[CH3:46])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[H-].[Na+].I[CH2:52][CH2:53][CH3:54]>C1COCC1>[F:48][C:2]([F:47])([F:1])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[C:25]([C:26]4[C:27]([O:39][CH3:40])=[N:28][CH:29]=[C:30]([C:32]5[C:33]([CH3:38])=[N:34][N:35]([CH2:52][CH2:53][CH3:54])[C:36]=5[CH3:37])[CH:31]=4)=[CH:24][N:23]=[C:22]([N:41]4[CH2:44][CH:43]([F:45])[CH2:42]4)[N:21]=3)[C@H:14]2[CH3:46])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: COc1ncc(-c2c(C)n[nH]c2C)cc1-c1cnc(N2CC(F)C2)nc1CN1C(=O)O[C@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H]1C
Reactant: CCCI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCn1nc(C)c(-c2cnc(OC)c(-c3cnc(N4CC(F)C4)nc3CN3C(=O)O[C@H](c4cc(C(F)(F)F)cc(C(F)(F)F)c4)[C@@H]3C)c2)c1C
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of (4S,5R)-5-[3,5-Bis(trifluoromethyl)phenyl]-3-({5-[5-(3,5-dimethyl-1H-pyrazol-4-yl)-2-methoxypyridin-3-yl]-2-(3-fluoroazetidin-1-yl)pyrimidin-4-yl}methyl)-4-methyl-1,3-oxazolidin-2-one (EXAMPLE 17, 0.020 g, 0.029 mmol) in THF (2 mL) was added sodium hydride (0.011 g, 0.29 mmol) at 0° C. The resulting mixture was stirred for 10 minutes at room temperature, after which iodopropane (0.075 g, 0.044 mmol) was added. The resulting mixture was stirred for 24 hours at room temperature until the starting material was consumed completely. Water (1 mL) was added to quench the reaction. The aqueous layer was extracted with Ethyl acetate (2×2 mL), the combined organic layer was concentrated in vacuum and the residue was dissolved in 1 mL of DMSO and filtered. This clear DMSO filtrate was purified by preparative HPLC (reverse phase, Waters SunFire Prep C18 OBD5 um 19×100 mm) eluting with acetonitrile/water+0.14% HCOOH (30% to 100% organic in 5 minutes, 25 mL/minutes). Related fractions were pooled and evaporated under reduced pressure to afford a fluffy white solid of 2.8 mg as the titled compound. LCMS (M+H)+: 722.4. 1H NMR (DMSO-d6, 500 MHz): δ 8.24 (s, 1H), 8.16-8.14 (d, J=8.5 Hz, 2H), 7.92 (s, 2H), 7.62 (s, 1H), 5.87 (d, J=8.5 Hz, 1H), 5.60 (s, 1H), 5.42 (s, 1H), 4.53-3.98 (br m, 4H), 3.84 (s, 3H), 2.52 (s, 3H), 2.10 (m, 3H), 2.04 (m, 2H), 1.68 (m, 1H), 1.60-1.44 (m, 2H), 0.83 (t, J=6.5 Hz, 3H), 0.54 (d, J=6.5 Hz, 3H). RTA IC50: 12 nM
Reaction SMILES: O.[CH3:2][C:3]1O[C:5]([CH3:14])=[CH:6][C:7](=[O:13])[C:8]=1[C:9]([O:11][CH3:12])=[O:10].[NH2:15][CH:16]1[CH2:21][C:20]([CH3:23])([CH3:22])[NH:19][C:18]([CH3:25])([CH3:24])[CH2:17]1>C1(C)C=CC=CC=1>[CH3:2][C:3]1[N:15]([CH:16]2[CH2:17][C:18]([CH3:25])([CH3:24])[NH:19][C:20]([CH3:23])([CH3:22])[CH2:21]2)[C:5]([CH3:14])=[CH:6][C:7](=[O:13])[C:8]=1[C:9]([O:11][CH3:12])=[O:10]
Reactant: COC(=O)c1c(C)oc(C)cc1=O
Reactant: CC1(C)CC(N)CC(C)(C)N1
Solvent: O
Solvent: Cc1ccccc1
Product: COC(=O)c1c(C)n(C2CC(C)(C)NC(C)(C)C2)c(C)cc1=O
Temperature: 25 °C

Procedure:
A 500 ml, 3-neck, round-bottom flask is equipped with a mechanical stirrer, thermometer and a Dean-Stark water trap topped with a water cooled condenser. The flask is charged with a mixture of 45.5 g (0.25 moles) of the methyl 2,6-dimethyl-4-oxopyran-3-carboxylate prepared as described above, 39.1 g (0.25 m) 4-amino-2,2,6,6-tetramethylpiperidine, and 300 ml toluene. The stirred mixture in the flask is heated to boiling by means of an oil bath and the water formed during the reaction is collected in the trap. After 4 hours of reflux a total of 3.8 ml water is collected and the flask and its contents are cooled to room temperature. The toluene is removed by means of a rotary evaporator. On standing and cooling the residue deposits crystals of the title product which are further purified by fractional crystallization.
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:14])[N:4]([CH2:12][CH3:13])[C:5](=[O:11])[N:6]([CH2:9][CH3:10])[C:7]=1[NH2:8].[F:15][C:16]1[CH:26]=[CH:25][CH:24]=[CH:23][C:17]=1[CH:18]=[CH:19][C:20](O)=O>>[CH2:12]([N:4]1[C:3](=[O:14])[C:2]2[NH:1][C:20](/[CH:19]=[CH:18]/[C:17]3[CH:23]=[CH:24][CH:25]=[CH:26][C:16]=3[F:15])=[N:8][C:7]=2[N:6]([CH2:9][CH3:10])[C:5]1=[O:11])[CH3:13]
Reactant: CCn1c(N)c(N)c(=O)n(CC)c1=O
Reactant: O=C(O)C=Cc1ccccc1F
Product: CCn1c(=O)c2[nH]c(/C=C/c3ccccc3F)nc2n(CC)c1=O

Procedure:
Substantially the same procedure as in Reference Example 70 was repeated using 2.70 g (13.6 mmol) of 5,6-diamino-1,3-diethyluracil and 2.49 g (15.0 mmol) of 2-fluorocinnamic acid. Then, the resultant crude crystals were recrystallized from dioxane/water to give 1.81 g (yield of Compound 167 as a white powder.
Reaction SMILES: [C:1]1([CH3:25])[CH:6]=[CH:5][C:4]([S:7][CH:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17](=[O:24])[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH:12]=2)[C:9]#[N:10])=[CH:3][CH:2]=1.[CH3:26][O-].[Na+].CI.[Cl-].[NH4+]>CO>[C:1]1([CH3:25])[CH:2]=[CH:3][C:4]([S:7][C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17](=[O:24])[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH:12]=2)([CH3:26])[C:9]#[N:10])=[CH:5][CH:6]=1
Reactant: C[O-]
Reactant: Cc1ccc(SC(C#N)c2cccc(C(=O)c3ccccc3)c2)cc1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Solvent: CI
Product: Cc1ccc(SC(C)(C#N)c2cccc(C(=O)c3ccccc3)c2)cc1
Yield: 92 %

Procedure:
Anhydrous methanol (2 ml) was added to 439 mg of alpha-(p-tolylthio)(m-benzoylphenyl)acetonitrile, and the mixture was stirred under ice cooling. Then, 0.55 ml of a 2.5 M methanol solution of sodium methoxide was added, and 0.12 ml of methyl iodide was added dropwise. The mixture was further stirred for 30 minutes at room temperature. An aqueous solution of ammonium chloride (0.5 g/20 ml) was added, and the mixture was extracted with 15 ml of methylene chloride three times. The extract was washed with 10 ml of water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to afford an oily residue. The residue was purified by column chromatography (silica gel; benzene) to afford 422 mg (yield 92%) of alpha-(p-tolylthio)-alpha-(m-benzoylphenyl)propionitrile as a colorless oil.