Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:14]=[C:13]2[C:8]([CH2:9][CH2:10][CH2:11][C:12]2=O)=[CH:7][CH:6]=1)=[O:4].C[Si]([C:20]#[N:21])(C)C.N1C=CC=CC=1.P(Cl)(Cl)(Cl)=O>C1C=CC=CC=1.[I-].[Zn+2].[I-]>[C:20]([C:12]1[C:13]2[CH:14]=[C:5]([C:3]([O:2][CH3:1])=[O:4])[CH:6]=[CH:7][C:8]=2[CH2:9][CH2:10][CH:11]=1)#[N:21]
Reactant: COC(=O)c1ccc2c(c1)C(=O)CCC2
Reactant: C[Si](C)(C)C#N
Agent: [I-]
Agent: [Zn+2]
Solvent: c1ccncc1
Solvent: c1ccccc1
Solvent: O=P(Cl)(Cl)Cl
Product: COC(=O)c1ccc2c(c1)C(C#N)=CCC2
Yield: 47.1 %

Procedure:
A solution of 1-tetralon-7-carboxylic acid methyl ester (3.50 g, 0.017 mol), trimethylsilylcyanide (1.98 g, 0.02 mol) and zinc iodide (0.10 g) in benzene (20 mL) was stirred at ambient temperature over 15 hours. Then added, sequentially and dropwise, was pyridine (20 mL) and phosphorous oxychloride (4.0 mL, 6.55 g, 0.0425 mol). The reaction mixture was stirred at reflux over 1 hour then evaporated to dryness under reduced pressure. The residue was taken up in chloroform, backwashed with water, dried over anhydrous magnesium sulfate and evaporated to dryness under reduced pressure to give methyl 8-cyano-5,6-dihydro-2-naphthoate (1.70 g, 0.008 mol, 47%) as a yellow solid. mp=73°-75° C.; 1H NMR (CDCl3) d 8.0-7.9 (m, 1H), 7.3-7.2 (m, 1H), 6.95 (t, 1H, J=4.8 Hz), 3.95 (s, 3H), 2.9 (t, 2H, J=8.3 Hz), 2.6-2.4 (m, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[CH:11][C:10]([Br:13])=[CH:9][C:3]=1[C:4]([N:6]([CH3:8])[CH3:7])=[O:5].[C:14](Cl)(Cl)=[O:15]>ClCCl.C(=O)(O)[O-].[Na+].C1(C)C=CC=CC=1>[Br:13][C:10]1[CH:11]=[CH:12][C:2]([N:1]=[C:14]=[O:15])=[C:3]([CH:9]=1)[C:4]([N:6]([CH3:7])[CH3:8])=[O:5]
Reactant: CN(C)C(=O)c1cc(Br)ccc1N
Reactant: O=C(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: CN(C)C(=O)c1cc(Br)ccc1N=C=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
2-amino-5-bromo-N,N-dimethyl-benzamide (1.48 g, 6.09 mmol) was dissolved in a mixture of dichloromethane (60 mL) and saturated aqueous sodium bicarbonate (60 mL). 16 mL of 20% w/w phosgene in toluene was added and the mixture stirred at room temperature for 30 min. The layers were separated and the aqueous layer extracted three times with dichloromethane (20 mL). The combined organic layers were dried over sodium sulfate and evaporated. The residue was concentrated down several times from ether and dichloromethane to afford 5-bromo-2-isocyanato-N,N-dimethyl-benzamide as a yellow power. 1H-NMR (250 MHz, d6-DMSO) δ 7.95 (d, J=2.4 Hz, 1H), 7.80 (dd, J=6.3, 2.7 Hz, 1H), 7.16 (d, J=8.88 Hz, 1H), 3.10 (s, 6H).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]2[CH:9]=[CH:8][C:7]([O:10][C:11]3[CH:12]=[C:13]([NH:17][C:18]([C:20]4[CH:25]=[CH:24][CH:23]=[C:22]([CH3:26])[N:21]=4)=[O:19])[CH:14]=[CH:15][CH:16]=3)=[CH:6][N:5]2[CH:27]=1.[C:28](Cl)(=[O:30])[CH3:29]>CN(C)C(=O)C.C(=O)([O-])O.[Na+]>[C:28]([NH:1][C:2]1[N:3]=[C:4]2[CH:9]=[CH:8][C:7]([O:10][C:11]3[CH:12]=[C:13]([NH:17][C:18]([C:20]4[CH:25]=[CH:24][CH:23]=[C:22]([CH3:26])[N:21]=4)=[O:19])[CH:14]=[CH:15][CH:16]=3)=[CH:6][N:5]2[CH:27]=1)(=[O:30])[CH3:29]
Reactant: Cc1cccc(C(=O)Nc2cccc(Oc3ccc4nc(N)cn4c3)c2)n1
Reactant: CC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: CC(=O)Nc1cn2cc(Oc3cccc(NC(=O)c4cccc(C)n4)c3)ccc2n1
Temperature: 25 °C
Reaction time: 11 h
Yield: 32.5 %

Procedure:
To a solution of N-{3-[(2-aminoimidazo[1,2-a]pyridin-6-yl)oxy]phenyl}-6-methylpyridine-2-carboxamide (300 mg, 0.835 mmol) in N,N-dimethylacetamide (5 mL) was added acetyl chloride (59.4 μL, 0.835 mmol), and the mixture was stirred at room temperature for 11 hr. The reaction mixture was diluted with aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate. The organic layer was washed with aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate and filtrated. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (NH silica gel, 0%→100% ethyl acetate-hexane) to give the title compound (109 mg, 33%) as a pale-yellow solid.
Reaction SMILES: [NH:1]([C:30]([CH3:32])=[O:31])[C@H:2]([C:7]([NH:9][C@H:10]([C:15]([NH:17][C@H:18]([C:26]([O:28]C)=[O:27])[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:16])[CH2:11][CH:12]([CH3:14])[CH3:13])=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5].[OH-].[Na+]>CO>[NH:1]([C:30]([CH3:32])=[O:31])[C@H:2]([C:7]([NH:9][C@H:10]([C:15]([NH:17][C@H:18]([C:26]([OH:28])=[O:27])[CH2:19][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)=[O:16])[CH2:11][CH:12]([CH3:13])[CH3:14])=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5]
Reactant: COC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(C)C)NC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](Cc1ccccc1)C(=O)O
Yield: 94 %

Procedure:
Ac-Leu-Leu-Phe-OMe was dissolved in 150 mL of methanol and 26 mL of 1N sodium hydroxide was added and the rection was stirred 4 hours at which time the methanol was removed under reduced pressure and an additional 7 mL of sodium hydroxide was added. This water fraction was then washed with ethyl acetate (10 mL) and neutralized by the addition of 1N HCL. The resulting mixture was extracted with ethyl acetate 2×100 mL and the extract washed with 1N HCL, brine and dried over MgSO4, filtered and the solvents were removed under reduced pressure to give 7.56 g (94%) of Ac-Leu-Leu-Phe-OH as a white solid. The NMR (100 MHz, CDCl3) of the product acid bears striking resemblance to that of the precursor ester except for the loss of a signal at δ 3.6 and the appearance of a broad singlet at 10.1 (1H).
Reaction SMILES: C(O[C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH:13]([OH:24])[CH2:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=1)=[O:7])(C)(C)C.[CH2:25]([O:32][C:33]([N:35]1[CH2:42][CH2:41][CH2:40][C@H:36]1C(O)=O)=[O:34])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>Cl.O1CCOCC1>[CH2:25]([O:32][C:33]([N:35]1[CH2:42][CH2:41][CH2:40][C@H:36]1[C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH:13]([OH:24])[CH2:14][O:15][C:16]1[CH:17]=[CH:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=1)=[O:7])=[O:34])[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: COc1ccc(OCC(O)[C@@H]2CCCN2C(=O)OC(C)(C)C)cc1
Reactant: O=C(O)[C@@H]1CCCN1C(=O)OCc1ccccc1
Agent: Cl
Solvent: C1COCCO1
Product: COc1ccc(OCC(O)[C@@H]2CCCN2C(=O)[C@@H]2CCCN2C(=O)OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 57 %

Procedure:
To (2S)-1-[t-butoxycarbonyl)-2-[1-hydroxy-2-(4-methoxyphenoxy)ethyl]pyrrolidine (14.03 g) was added 4N hydrochloric acid/1,4-dioxane (220 ml), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated to dryness, and the residue was dissolved in DMF (100 ml), followed by condensation reaction as in Example 1-C) w i t h known N-benzyloxycarbonyl-L-proline (10.70 g) to give 11.10 g of the title compound.
Reaction SMILES: S(Cl)([Cl:3])=O.[CH:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[CH:7][C:6]=1[CH:15](O)[CH2:16][N:17]1[CH:21]=[CH:20][N:19]=[CH:18]1>>[ClH:3].[CH:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[CH:7][C:6]=1[CH:15]([Cl:3])[CH2:16][N:17]1[CH:21]=[CH:20][N:19]=[CH:18]1
Reactant: O=S(Cl)Cl
Reactant: OC(Cn1ccnc1)c1ccc2ccccc2c1
Product: Cl
Product: ClC(Cn1ccnc1)c1ccc2ccccc2c1

Procedure:
Thionyl chloride (5 ml.) and 2.0 g. of 1-[2-(2-naphthyl)-2-hydroxyethyl]imidazole are stirred at room temperature for about 20 minutes. Thereafter, the solution is evaporated to dryness and the residue is treated with ethyl acetate and filtered to yield 1-[2-(2-naphthyl)-2-chloroethyl]imidazole hydrochloride as a white solid.
Reaction SMILES: C([CH:8]([C:29](=[O:31])[OH:30])[C@@H:9]([C:21]([NH:23][C@@H:24]([C:26]([NH2:28])=[O:27])[CH3:25])=[O:22])[NH:10]C(OCC1C=CC=CC=1)=[O:12])C1C=CC=CC=1.[H][H]>[Pd].C(O)(=O)C>[OH2:12].[NH2:10][C@H:9]([C:21]([NH:23][C@@H:24]([C:26]([NH2:28])=[O:27])[CH3:25])=[O:22])[CH2:8][C:29](=[O:30])[OH:31]
Reactant: C[C@@H](NC(=O)[C@@H](NC(=O)OCc1ccccc1)C(Cc1ccccc1)C(=O)O)C(N)=O
Reactant: [H][H]
Agent: [Pd]
Solvent: CC(=O)O
Product: C[C@@H](NC(=O)[C@@H](N)CC(=O)O)C(N)=O
Product: O

Procedure:
To a solution of 61.10 parts of β-benzyl N-benzyloxycarbonyl-L-aspartyl-D-alanine amide in 800 parts by volume of 75% acetic acid is added 6 parts of palladium black metal catalyst, and the resulting mixture is shaken with hydrogen at room temperature at atmospheric pressure for about 6.5 hours. The catalyst is removed by filtration, and the solvents removed by distillation under reduced pressure to obtain an oil. This oil is triturated with water and stripped under reduced pressure three times to afford a solid. The solid is then triturated with ethanol, filtered, and dried under vacuum to yield L-aspartyl-D-alanine amide monohydrate. This product is represented by the following structural formula.
Reaction SMILES: [C:1]1([C:7]2[NH:8][C:9]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[Br:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34]Br.O>CN(C)C=O>[Br:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][N:11]1[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[C:9]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[N:8]=[C:7]1[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: BrCCCCCCCCBr
Reactant: c1ccc(-c2nc(-c3ccccc3)c(-c3ccccc3)[nH]2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: BrCCCCCCCCn1c(-c2ccccc2)nc(-c2ccccc2)c1-c1ccccc1
Temperature: 45 °C
Reaction time: 1 h
Yield: 49.9 %

Procedure:
2,4,5-Triphenylimidazole (5 g) was added to a suspension of sodium hydride (1.0 g) (50% dispersion in oil, washed with hexane) in dry dimethylformamide (80 ml) under nitrogen. The reaction was stirred at 45° C. for 1 h, cooled and added, over 1 h to a solution of 1,8-dibromo-octane (30 g) in dry dimethylformamide (100 ml) under nitrogen. The reaction was stirred at room temperature for 24 h, water was carefully added and the solvent was removed in vacuo. The residue was dissolved in ethyl acetate (500 ml), washed with water (250 ml), 2N aqueous hydrochloric acid (250 ml), saturated sodium chloride solution (250 ml), dried over anhydrous magnesium sulphate and evaporated to dryness in vacuo. Distillation to remove 1,8-dibromooctane and chromatography on silica gel eluted with dichloromethane gave 1-(8-bromooctyl)-2,4,5-triphenylimidazole (4.1 g, 50%) as an oil; NMR d (CDCl3) 0.9-1.7 (12H, m, 6×CH2), 3.3 (2H, t, BrCH2), 3.9 (2H, t, N--CH2), 7.1-7.7(15H, m, 3×Ph) ppm.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.[NH2:10][C:11]1[N:16]([CH3:17])[C:15](=[O:18])[N:14]([CH3:19])[C:13](=[O:20])[CH:12]=1.[CH3:21][C:22]1[N:23]([CH:29]([CH3:40])[CH2:30][O:31][CH2:32][C:33](=O)[CH2:34][C:35]([O:37][CH3:38])=[O:36])[C:24]([CH3:28])=[C:25]([CH3:27])[N:26]=1>>[Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]1[C:12]2[C:13](=[O:20])[N:14]([CH3:19])[C:15](=[O:18])[N:16]([CH3:17])[C:11]=2[NH:10][C:33]([CH2:32][O:31][CH2:30][CH:29]([N:23]2[C:24]([CH3:28])=[C:25]([CH3:27])[N:26]=[C:22]2[CH3:21])[CH3:40])=[C:34]1[C:35]([O:37][CH3:38])=[O:36]
Reactant: Cn1c(N)cc(=O)n(C)c1=O
Reactant: COC(=O)CC(=O)COCC(C)n1c(C)nc(C)c1C
Reactant: O=Cc1ccccc1Cl
Product: COC(=O)C1=C(COCC(C)n2c(C)nc(C)c2C)Nc2c(c(=O)n(C)c(=O)n2C)C1c1ccccc1Cl
Yield: 5.2 %

Procedure:
The title compound (150 mg) was prepared from 2-chlorobenzaldehyde (747 mg), 6-amino-1,3-dimethyl-2,4-dioxopyrimidine (824 mg) and methyl 4-[2-(2,4,5-trimethylimidazol-1-yl)propoxyl]3-oxobutanoate (1.5 g) by the method of Example 1. M.p. 180°-182° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[N:10]=[N:11][C:12]([C:23]#[C:24][C:25]2[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[C:27](C)[CH:26]=2)=[CH:13][C:14]=1[O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OC1N=NC(C#C)=CC=1OCC1C=CC=CC=1)C1C=CC=CC=1.BrC1C=CC(C(F)(F)F)=CC=1[Cl:71]>>[CH2:1]([O:8][C:9]1[N:10]=[N:11][C:12]([C:23]#[C:24][C:25]2[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][C:26]=2[Cl:71])=[CH:13][C:14]=1[O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cc(C#Cc2cc(OCc3ccccc3)c(OCc3ccccc3)nn2)ccc1C(F)(F)F
Reactant: FC(F)(F)c1ccc(Br)c(Cl)c1
Agent: C#Cc1cc(OCc2ccccc2)c(OCc2ccccc2)nn1
Product: FC(F)(F)c1ccc(C#Cc2cc(OCc3ccccc3)c(OCc3ccccc3)nn2)c(Cl)c1
Yield: 75 %

Procedure:
Prepared as described for 3,4-bis(benzyloxy)-6-((3-methyl-4-(trifluoromethyl)phenyl)-ethynyl)pyridazine (Intermediate 74) from 3,4-bis(benzyloxy)-6-ethynylpyridazine (Intermediate 5) and 1-bromo-2-chloro-4-(trifluoromethyl)benzene in 75% yield.
Reaction SMILES: [NH:1]1[CH:9]=[C:7]([NH2:8])[C:5](=[O:6])[NH:4][C:2]1=[O:3].[Cl:10][C:11]1[CH:18]=[CH:17][C:14]([CH2:15]Br)=[CH:13][CH:12]=1.[H-].[Na+].C(OCC)(=O)C>CS(C)=O>[Cl:10][C:11]1[CH:18]=[CH:17][C:14]([CH2:15][N:4]2[C:5](=[O:6])[C:7]([CH3:9])=[N:8][NH:1][C:2]2=[O:3])=[CH:13][CH:12]=1
Reactant: Clc1ccc(CBr)cc1
Reactant: Nc1c[nH]c(=O)[nH]c1=O
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: Cc1n[nH]c(=O)n(Cc2ccc(Cl)cc2)c1=O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 84.2 %

Procedure:
According to Scheme 4 Step 1: To a solution of Azathymine (300 mg, 2.36 mmol) and 4-chlorobenzyl bromide (485 mg, 2.36 mmol) in DMSO (10 mL) was added portionwise NaH (55%) (103 mg, 2.36 mmol) at room temperature under nitrogen atmosphere. The mixture was stirred for 15 min at room temperature. Ethyl Acetate was then added (150 mL) and the organic layer was extracted thrice with water (100 mL). The organic layer was dried over MgSO4, filtered and concentrated under reduced pressure to afford a yellow solid. The crude solid was purified by flash chromatography with silica gel using CH2Cl2/MeOH 98/2 as eluant to afford 4-(4-chlorobenzyl)-6-methyl-1,2,4-triazine-3,5(2H,4H)-dione 8(A) (500 mg, 84%) as a white solid.
Reaction SMILES: [CH2:1]([N:8]1[C:12](=[O:13])[C:11]([CH3:15])([CH3:14])[N:10]([CH2:16][C:17]#[CH:18])[C:9]1=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[I:20]N1C(=O)CCC1=O>CC(C)=O.[N+]([O-])([O-])=O.[Ag+]>[CH2:1]([N:8]1[C:12](=[O:13])[C:11]([CH3:14])([CH3:15])[N:10]([CH2:16][C:17]#[C:18][I:20])[C:9]1=[O:19])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CCC(=O)N1I
Reactant: C#CCN1C(=O)N(Cc2ccccc2)C(=O)C1(C)C
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Solvent: CC(C)=O
Product: CC1(C)C(=O)N(Cc2ccccc2)C(=O)N1CC#CI
Temperature: 25 °C
Reaction time: 5 h
Yield: 63.7 %

Procedure:
To a solution of 3-benzyl-1-propargyl-5,5-dimethylhydantoin (2 g, 7.81 mmole) in acetone (35 mL) at room temperature was added N-iodosuccinimide (2.1 g, 9.2 mmole), followed by silver nitrate (0.265 g, 1.56 mmole). The reaction mixture was stirred at room temperature for 5 hr. The reaction mixture was then passed through Celite by suction-filtration and washed with acetone. The filtrate was concentrated on a rotary evaporator and diluted with ethyl acetate. The solution was washed with water and brine and dried over sodium sulfate. The solvent was evaporated on a rotary evaporator to give 1.9 g of 3-benzyl-1-(3-iodo-2-propynyl)-5,5-dimethylhydantoin as a light brown oil which slowly solidified, mp=83°-85° C. An NMR spectrum also showed the desired structure.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][C:6]([C@H:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][CH3:17])=[O:15])[C@@H:10]([C:18]2[CH:19]=[N:20][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:22][CH:23]=2)[CH2:9]1)=[O:7])C.[OH-].[Na+].[NH2:31]O.Cl>CO>[O:3]=[C:4]1[CH:5]=[C:6]([C@H:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][CH3:17])=[O:15])[C@@H:10]([C:18]3[CH:19]=[N:20][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:22][CH:23]=3)[CH2:9]2)[O:7][NH:31]1
Reactant: CCOC(=O)CC(=O)[C@H]1CCN(C(=O)OC)[C@@H](c2ccc(C(F)(F)F)nc2)C1
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COC(=O)N1CC[C@H](c2cc(=O)[nH]o2)C[C@@H]1c1ccc(C(F)(F)F)nc1
Temperature: -45 °C
Reaction time: 0.33 h
Yield: 16 %

Procedure:
Cis-methyl 4-(3-ethoxy-3-oxopropanoyl)-2-(6-(trifluoromethyl)pyridin-3-yl)piperidine-1-carboxylate (1.085 g, 2.70 mmol) was dissolved in MeOH (12 mL) and cooled to −45° C. under nitrogen. Sodium hydroxide (0.793 mL, 2.70 mmol) was added during 10 min and the yellow solution continued to stir at −45° C. for 20 min. Hydroxylamine (50% by weight in water, 0.165 mL, 2.70 mmol) was added during 8 min. The resulting solution was stirred at −45° C. for 3 h. The mixture was then rapidly poured into a prewarmed (80° C.) solution of 6 M hydrogen chloride (13.89 mL, 83.32 mmol) and the mixture continued to stir at 80° C. for 20 min. The solvent was evaporated and DCM/water added. The phases were separated and the organic phase passed through a phase separator and evaporated to yield a white solid. The compound was purified by preparative HPLC on a Kromasil C8 column (10 μm 250×50 ID mm) using a gradient of 10-60% Acetonitrile in H2O/MeCN/AcOH 95/5/0.2 buffer over 30 minutes with a flow of 100 mL/min. Cis-methyl 4-(3-oxo-2,3-dihydroisoxazol-5-yl)-2-(6-(trifluoromethyl)pyridin-3-yl)piperidine-1-carboxylate (160 mg, 16%) was isolated. MS m/z 372 (M+H)+
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:27]=[CH:28][C:29]=1[O:30][CH3:31])[CH2:6][CH:7]1[C:16]2[C:11](=[C:12]([O:25][CH3:26])[CH:13]=[CH:14][C:15]=2[O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:10][CH2:9][NH:8]1.Br[CH2:33][C:34](Br)=[O:35].[N:37]1[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=1[CH2:43][NH2:44]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:27]=[CH:28][C:29]=1[O:30][CH3:31])[CH2:6][CH:7]1[C:16]2[C:11](=[C:12]([O:25][CH3:26])[CH:13]=[CH:14][C:15]=2[O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:10][CH2:9][N:8]1[CH2:33][C:34]([NH:44][CH2:43][C:38]1[CH:39]=[CH:40][CH:41]=[CH:42][N:37]=1)=[O:35]
Reactant: NCc1ccccn1
Reactant: COc1ccc(CC2NCCc3c(OC)ccc(OCc4ccccc4)c32)cc1OC
Reactant: O=C(Br)CBr
Product: COc1ccc(CC2c3c(OCc4ccccc4)ccc(OC)c3CCN2CC(=O)NCc2ccccn2)cc1OC

Procedure:
prepared by reaction of 1-(3,4-Dimethoxy-benzyl)-8-benzyloxy-5-methoxy-1,2,3,4-tetrahydroisoquinoline and 2-bromoacetyl bromide with 2-picolylamine
Reaction SMILES: [Cl-].O[NH3+].[C:4](=[O:7])([O-])[OH:5].[Na+].[F:9][C:10]1[CH:11]=[C:12]([C:45]2[C:46]([C:51]#[N:52])=[CH:47][CH:48]=[CH:49][CH:50]=2)[CH:13]=[C:14]([F:44])[C:15]=1[CH2:16][N:17]1[C:22]2[S:23][C:24]([CH2:26][C:27]([F:30])([F:29])[F:28])=[CH:25][C:21]=2[C:20](=[O:31])[N:19]([CH2:32][C:33]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=2[O:41][CH3:42])=[O:34])[C:18]1=[O:43].[N:53]12CCCN=C1CCCCC2>C(Cl)(Cl)Cl.C(Cl)Cl.CS(C)=O>[F:9][C:10]1[CH:11]=[C:12]([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][C:46]=2[C:51]2[NH:53][C:4](=[O:7])[O:5][N:52]=2)[CH:13]=[C:14]([F:44])[C:15]=1[CH2:16][N:17]1[C:22]2[S:23][C:24]([CH2:26][C:27]([F:30])([F:29])[F:28])=[CH:25][C:21]=2[C:20](=[O:31])[N:19]([CH2:32][C:33]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=2[O:41][CH3:42])=[O:34])[C:18]1=[O:43]
Reactant: C1CCC2=NCCCN2CC1
Reactant: O=C([O-])O
Reactant: COc1ccccc1C(=O)Cn1c(=O)c2cc(CC(F)(F)F)sc2n(Cc2c(F)cc(-c3ccccc3C#N)cc2F)c1=O
Agent: [Cl-]
Agent: [NH3+]O
Agent: [Na+]
Solvent: CS(C)=O
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: COc1ccccc1C(=O)Cn1c(=O)c2cc(CC(F)(F)F)sc2n(Cc2c(F)cc(-c3ccccc3-c3noc(=O)[nH]3)cc2F)c1=O
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 43 %

Procedure:
A mixture of hydroxylammonium chloride (0.53 g), sodium hydrogencarbonate (0.77 g) and dimethyl sulfoxide (10 mL) was stirred at 40° C. for 30 min, 3′,5′-difluoro-4′-{[3-[2-(2-methoxyphenyl)-2-oxoethyl]-2,4-dioxo-6-(2,2,2-trifluoroethyl)-3,4-dihydrothieno[2,3-d]pyrimidin-1(2H)-yl]methyl}biphenyl-2-carbonitrile (0.48 g) was added, and the mixture was stirred at 90° C. for 16 hr. The reaction mixture was diluted with chloroform, washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue obtained by silica gel column chromatography was dissolved in methylene chloride (30 mL), N,N′-carbonyldiimidazole (0.14 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.12 mL) were added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with chloroform, washed successively with saturated aqueous potassium hydrogensulfate solution and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. To the obtained residue were added 20% sulfuric acid (5 mL) and ethanol (10 ml). The mixture was stirred at 100° C. for 1 hr and extracted with chloroform and water. The chloroform layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound as colorless crystals (0.23 g, 43%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[C:5]([N+:10]([O-:12])=[O:11])[CH:4]=1.[C:13]([C:17]1[CH:25]=[CH:24][C:20]([C:21](Cl)=[O:22])=[CH:19][CH:18]=1)([CH3:16])([CH3:15])[CH3:14]>>[CH3:1][O:2][C:3]1[CH:9]=[CH:8][C:6]([NH:7][C:21](=[O:22])[C:20]2[CH:24]=[CH:25][C:17]([C:13]([CH3:15])([CH3:14])[CH3:16])=[CH:18][CH:19]=2)=[C:5]([N+:10]([O-:12])=[O:11])[CH:4]=1
Reactant: CC(C)(C)c1ccc(C(=O)Cl)cc1
Reactant: COc1ccc(N)c([N+](=O)[O-])c1
Product: COc1ccc(NC(=O)c2ccc(C(C)(C)C)cc2)c([N+](=O)[O-])c1
Yield: 100 %

Procedure:
Using the procedure described in Example 68, Part A, 4-methoxy-2-nitroaniline (1.0 g, 3.4 mmol) was reacted with 4-tert-butylbenzoyl chloride to yield 1.45 g (100%) of the title compound as a yellow solid.
Reaction SMILES: CS[C:3]([NH:8][CH2:9][C:10]#[CH:11])=[CH:4][N+:5]([O-:7])=[O:6].[S:12]1[CH:16]=[CH:15][N:14]=[C:13]1[CH2:17][S:18][CH2:19][CH2:20][NH2:21]>>[N+:5]([CH:4]=[C:3]([NH:8][CH2:9][C:10]#[CH:11])[NH:21][CH2:20][CH2:19][S:18][CH2:17][C:13]1[S:12][CH:16]=[CH:15][N:14]=1)([O-:7])=[O:6]
Reactant: C#CCNC(=C[N+](=O)[O-])SC
Reactant: NCCSCc1nccs1
Product: C#CCNC(=C[N+](=O)[O-])NCCSCc1nccs1

Procedure:
A solution of the product of Step A is treated with about an equimolar amount of 2-[(thiazol-2-yl)methylthio]ethylamine to produce, after workup, the title product.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([N:17]3[CH2:22][CH2:21][CH:20]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:19][CH2:18]3)=[O:16])[CH:10]=2)[C:5]([F:28])=[CH:4][N:3]=1.[OH:29][C:30]1[CH:31]=[C:32]([CH:34]=[CH:35][CH:36]=1)[NH2:33]>>[CH2:26]([O:25][C:23]([CH:20]1[CH2:21][CH2:22][N:17]([C:15]([C:11]2[CH:10]=[C:9]([NH:8][C:6]3[C:5]([F:28])=[CH:4][N:3]=[C:2]([NH:33][C:32]4[CH:34]=[CH:35][CH:36]=[C:30]([OH:29])[CH:31]=4)[N:7]=3)[CH:14]=[CH:13][CH:12]=2)=[O:16])[CH2:18][CH2:19]1)=[O:24])[CH3:27]
Reactant: Nc1cccc(O)c1
Reactant: CCOC(=O)C1CCN(C(=O)c2cccc(Nc3nc(Cl)ncc3F)c2)CC1
Product: CCOC(=O)C1CCN(C(=O)c2cccc(Nc3nc(Nc4cccc(O)c4)ncc3F)c2)CC1

Procedure:
In like manner to the preparation of 5-fluoro-N4-(3-hydroxyphenyl)-N2-[4-(3-phenyl-1,2,4-oxadiazol-5-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine, 2-chloro-N4-[3-[[4-(ethoxycarbonyl)piperidino]carbonyl]phenyl]-5-fluoro-4-pyrimidineamine and 3-hydroxyaniline were reacted to provide N4-[3-[[4-(ethoxycarbonyl)piperidino]carbonyl]phenyl]-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine. 1H NMR (CD3OD): δ 7.93 (d, 1H, J=3.6 Hz), 7.89 (t, 1H, J=1.8 Hz), 7.83 (td, 1H, J=1.2 and 8.4 Hz), 7.41 (t, 1H, J=7.8 Hz), 7.11-6.95 (m, 4H), 6.41 (td, 1H, J=1.8 and 7.2 Hz), 4.44 (bd, 1H, J=12.9 Hz), 4.10 (q, 2H, J=7.2 Hz), 3.73 (bd, 1H, J=12.3 Hz), 3.18-2.98 (m, 2H), 2.67-2.55 (m, 1H), 2.05-1.53 (m, 4H), 1.23 (t, 3H, J=7.2 Hz); 19F NMR (282 MHz, CD3OD): −47483; LCMS: purity: 99%; MS (m/e): 480 (MH+).