Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.C(B(CC)[C:13]1[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=1)C.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(OCC)(=O)C.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>[N:15]1[CH:16]=[CH:17][CH:18]=[C:13]([C:2]2[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=2)[CH:14]=1
Reactant: O=Cc1ccc(Br)cc1
Reactant: CCB(CC)c1cccnc1
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: [Na+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: O=Cc1ccc(-c2cccnc2)cc1
Yield: 72.3 %

Procedure:
A mixture of 4-bromobenzaldehyde (2 g, 10.8 mmol), diethyl(3-pyridyl)borane (1.75 g, 11.9 mmol), tetrakis(triphenylphosphine)palladium (375 mg, 0.32 mmol), and 2N sodium carbonate aqueous solution(10.8 ml, 21.6 mmol) in toluene (40 ml) was heated under reflux under a nitrogen atmosphere overnight. The reaction mixture was allowed to return to room temperature and diluted with ethyl acetate. The mixture was washed with water and brine, and dried over sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane/ethyl acetate=1/1) to afford 4-(pyridin-3-yl)benzaldehyde (1.43 g, yield 72%) as a pale yellow crystalline powder.
Reaction SMILES: Cl.[NH2:2][OH:3].C(=O)([O-])[O-].[Na+].[Na+].[CH3:10][C:11]1[C:17](=[O:18])[C:16]2[N:19]3[C@@:23]([O:30][CH3:31])([C@H:24]([CH2:25][O:26][C:27]([NH2:29])=[O:28])[C:15]=2[C:13](=[O:14])[C:12]=1OC)[C@H:22]1[N:32]([CH3:33])[C@H:21]1[CH2:20]3>>[NH2:29][C:27]([O:26][CH2:25][CH:24]1[C:15]2[C:13]([OH:14])=[C:12]([N:2]=[O:3])[C:11]([CH3:10])=[C:17]([OH:18])[C:16]=2[N:19]2[CH2:20][CH:21]3[N:32]([CH3:33])[CH:22]3[C:23]12[O:30][CH3:31])=[O:28]
Reactant: COC1=C(C)C(=O)C2=C(C1=O)[C@@H](COC(N)=O)[C@@]1(OC)[C@@H]3[C@H](CN21)N3C
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: COC12C(COC(N)=O)c3c(O)c(N=O)c(C)c(O)c3N1CC1C2N1C
Yield: 97.7 %

Procedure:
In a similar manner to that described in Example 1, hydroxylamine hydrochloride (0.038 g), anhydrous sodium carbonate (0.033 g) and mitomycin F (0.100 g) are used to obtain the desired product (0.098 g; yield 87.0%).
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][CH2:7][CH:6]([NH2:10])[CH2:5]1)(=[O:3])[CH3:2].C(O[CH:15]1[C:28]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[O:22][C:21]2[C:16]1=[CH:17][CH:18]=[CH:19][CH:20]=2)(=O)C>C1(C)C=CC=CC=1>[C:1]([N:4]1[CH2:9][CH2:8][CH2:7][CH:6]([NH:10][CH:15]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:21]=3[O:22][C:23]3[C:28]2=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC1c2ccccc2Oc2ccccc21
Reactant: CC(=O)N1CCCC(N)C1
Solvent: Cc1ccccc1
Product: CC(=O)N1CCCC(NC2c3ccccc3Oc3ccccc32)C1

Procedure:
Refluxing 1-acetyl-3-aminopiperidine with 9-acetoxyxanthene in dry toluene by the procedure of Example 1 gives N-(N-acetyl-3-piperidinyl)-9-xanthenylamine.
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3[N:17]=[CH:18][N:19]=[C:20]([C:21]4[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:22]=4[O:28][CH2:29][CH:30]4[CH2:32][CH2:31]4)[C:15]=3[NH:14][C:13]=2[CH3:33])=[O:11])[CH2:5][CH2:4]1.C([O:37][CH2:38][C:39](Cl)=[O:40])(=O)C>>[CH:30]1([CH2:29][O:28][C:22]2[CH:23]=[C:24]([F:27])[CH:25]=[CH:26][C:21]=2[C:20]2[C:15]3[NH:14][C:13]([CH3:33])=[C:12]([C:10]([NH:9][C@H:6]4[CH2:7][CH2:8][C@H:3]([NH:2][C:38](=[O:37])[CH2:39][OH:40])[CH2:4][CH2:5]4)=[O:11])[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:31][CH2:32]1
Reactant: Cc1[nH]c2c(-c3ccc(F)cc3OCC3CC3)ncnc2c1C(=O)N[C@H]1CC[C@H](N)CC1
Reactant: CC(=O)OCC(=O)Cl
Agent: Cl
Product: Cc1[nH]c2c(-c3ccc(F)cc3OCC3CC3)ncnc2c1C(=O)N[C@H]1CC[C@H](NC(=O)CO)CC1

Procedure:
Starting from N-(trans-4-aminocyclohexyl)-4-[2-(cyclopropylmethoxy)-4-fluorophenyl]-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f7) and commercially available 2-chloro-2-oxoethyl acetate the title compound is obtained as colorless solid.
Reaction SMILES: [CH:1]([C:3]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[NH:5][CH:4]=1)=O.[NH:12]1[C:20]2[C:15](=[CH:16][C:17]([S:21]([OH:24])(=[O:23])=[O:22])=[CH:18][CH:19]=2)[CH2:14][C:13]1=[O:25]>C(O)C>[NH:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][N:7]=2)[C:3]([CH:1]=[C:14]2[C:15]3[C:20](=[CH:19][CH:18]=[C:17]([S:21]([OH:24])(=[O:22])=[O:23])[CH:16]=3)[NH:12][C:13]2=[O:25])=[CH:4]1
Reactant: O=C1Cc2cc(S(=O)(=O)O)ccc2N1
Reactant: O=Cc1c[nH]c2ncccc12
Solvent: CCO
Product: O=C1Nc2ccc(S(=O)(=O)O)cc2C1=Cc1c[nH]c2ncccc12
Temperature: 0 °C
Yield: 70 %

Procedure:
A solution of 3-formyl-7-azaindoie (1.46 g, 0.010 mol) and 2-oxindole-5-sulfonic acid (2.55 g, 0.012 mol) in absolute ethanol (10 ml) was heated to reflux for 1 h. The reaction mixture was chilled with ice water, the precipitate filtered, the residue washed with ice-cooled ethanol and dried under vacuum. Almost pure titie compound was obtained in about 70% yield (2.389 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:16]2[C:15](=[O:17])[N:14](COC(=O)C(C)(C)C)[C:13](=[O:26])[NH:12][C:11]=2[N:10]=[C:9]1[N:27]1[CH2:32][CH2:31][N:30](C(OC(C)(C)C)=O)[CH2:29][CH2:28]1.Br[CH:41]1[CH2:44][CH2:43][CH2:42]1.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:16]2[C:15](=[O:17])[NH:14][C:13]([O:26][CH:41]3[CH2:44][CH2:43][CH2:42]3)=[N:12][C:11]=2[N:10]=[C:9]1[N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2nc3[nH]c(=O)n(COC(=O)C(C)(C)C)c(=O)c3n2-c2ccccc2Cl)CC1
Reactant: BrC1CCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=c1[nH]c(OC2CCC2)nc2nc(N3CCNCC3)n(-c3ccccc3Cl)c12
Temperature: 50 °C
Reaction time: 8 h

Procedure:
8 mg of t-butyl 4-[7-(2-chlorophenyl)-1-(2,2-dimethylpropionyloxymethyl)-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]piperazine-1-carboxylate was dissolved in 0.3 ml of N,N-dimethylformamide, and 0.05 ml of bromocyclobutane and 20 mg of potassium carbonate were added thereto. The mixture was stirred at 50° C. overnight. Ethyl acetate was added to the reaction mixture, and the mixture was washed with water. The organic layer was concentrated. The residue was dissolved in methanol, and 5 mg of sodium hydride was added to the solution. The mixture was stirred at room temperature for three hours. The reaction mixture was neutralized with 1N hydrochloric acid, and extracted with ethyl acetate. The solvent was concentrated, and the residue was dissolved in trifluoroacetic acid. The mixture was concentrated, and the residue was purified by reverse-phase high performance liquid chromatography (using an acetonitrile-water mobile phase (containing 0.1% trifluoroacetic acid)) to give 1.89 mg of the title compound.
Reaction SMILES: [CH3:1][C:2]1([CH3:23])[C:11]2[C:6](=[C:7]([O:18][CH:19]([CH3:21])[CH3:20])[CH:8]=[C:9]([C:12]#[C:13][Si](C)(C)C)[CH:10]=2)[C:5](=[O:22])[CH2:4][CH2:3]1.C(=O)([O-])[O-].[K+].[K+]>CO>[CH3:23][C:2]1([CH3:1])[C:11]2[C:6](=[C:7]([O:18][CH:19]([CH3:20])[CH3:21])[CH:8]=[C:9]([C:12]#[CH:13])[CH:10]=2)[C:5](=[O:22])[CH2:4][CH2:3]1
Reactant: CC(C)Oc1cc(C#C[Si](C)(C)C)cc2c1C(=O)CCC2(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: C#Cc1cc(OC(C)C)c2c(c1)C(C)(C)CCC2=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.1 %

Procedure:
A solution 4,4-dimethyl-8-(2-propoxy)-6-trimethylsilanylethynyl-3,4-dihydro-2H-naphthalen-1-one (Intermediate 126, 0.055 g, 0.167 mmol) in methanol (5 mL) was treated with potassium carbonate (0.03 g, 0.22 mmol) and the resulting reaction mixture was stirred at ambient temperature overnight. The solvent was evaporated in vacuo, the residue was diluted with water and extracted with ethyl acetate. The organic phase was washed with brine, dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo to afford the title compound (0.042 g, 98%).
Reaction SMILES: [Cl:1][CH:2]([SiH:4]([CH2:6][CH2:7]Cl)[CH3:5])[CH3:3].[CH2:9]([Mg]Br)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C(OCC)C>[Cl:1][CH:2]([SiH:4]([CH2:6][CH2:7][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH3:5])[CH3:3]
Reactant: CC(Cl)[SiH](C)CCCl
Reactant: Br[Mg]Cc1ccccc1
Solvent: CCOCC
Product: CC(Cl)[SiH](C)CCCc1ccccc1

Procedure:
To a solution of (α-chloroethyl)chloroethylmethylsilane (0.171 g, 1 mmol) in diethyl ether (5 ml) was added a solution of benzylmagnesium bromide (1 mmol, 1 eq). The mixture was refluxed for 12 hours, then filtered. The product was purified by distillation.
Reaction SMILES: [O:1]([C:3]1[CH:26]=[CH:25][C:6]2[N:7]=[C:8]([C:10]3[CH:24]=[CH:23][C:13]([CH2:14]P(=O)(OCC)OCC)=[CH:12][CH:11]=3)[S:9][C:5]=2[CH:4]=1)[CH3:2].[N+:27]([C:30]1[CH:37]=[CH:36][CH:35]=[CH:34][C:31]=1[CH:32]=O)([O-:29])=[O:28].C[O-].[Na+].Cl>CO.O>[N+:27]([C:30]1[CH:37]=[CH:36][CH:35]=[CH:34][C:31]=1[CH:32]=[CH:14][C:13]1[CH:12]=[CH:11][C:10]([C:8]2[S:9][C:5]3[CH:4]=[C:3]([O:1][CH3:2])[CH:26]=[CH:25][C:6]=3[N:7]=2)=[CH:24][CH:23]=1)([O-:29])=[O:28]
Reactant: O=Cc1ccccc1[N+](=O)[O-]
Reactant: CCOP(=O)(Cc1ccc(-c2nc3ccc(OC)cc3s2)cc1)OCC
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COc1ccc2nc(-c3ccc(C=Cc4ccccc4[N+](=O)[O-])cc3)sc2c1
Temperature: 25 °C
Yield: 44.3 %

Procedure:
To a stirred solution of diethyl 4-(6-methoxylbenzothiazol-2-yl)benzylphosphonate (0.10 g, 0.25 mmol) and 2-nitrobenzaldehyde (0.39 g, 0.25 mmol) in dry MeOH (10 ml) at 0° C. was added dropwise a solution of 0.5 M sodium methoxide (1.02 ml, 0.51 mmol). The reaction mixture was then allowed to rise to room temperature and heated under reflux for 18 h. The reaction mixture was cooled to room temperature and water (30 ml) was added followed by 1 M HCl until the reaction mixture became acidic. The reaction mixture was then extracted with DCM (3×80 ml) and the combined organic extracts washed with brine (50 ml) and dried (Na2SO4). The solvent was removed under reduced pressure to give a solid which was purified by flash chromatography (DCM) to give the title compound (0.043 g, 43%) as a yellow solid.
Reaction SMILES: COC1C=C(OC)C=CC=1C[N:6]1[CH2:12][CH:11]([C:13]([OH:15])=[O:14])[C:8]2([CH2:10][CH2:9]2)[C:7]1=[O:16].C1(OC)C=CC=CC=1.FC(F)(F)C(O)=O>>[O:16]=[C:7]1[NH:6][CH2:12][CH:11]([C:13]([OH:15])=[O:14])[C:8]21[CH2:9][CH2:10]2
Reactant: COc1ccc(CN2CC(C(=O)O)C3(CC3)C2=O)c(OC)c1
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: O=C(O)C1CNC(=O)C12CC2
Temperature: 80 °C
Reaction time: 4 h
Yield: 76.2 %

Procedure:
To an optically active compound of 5-(2,4-dimethoxybenzyl)-4-oxo-5-azaspiro[2.4]heptane-7-carboxylic acid (372 mg) were sequentially added anisole (159 μl) and trifluoroacetic acid (5.6 ml) at room temperature, and the mixture was stirred at 80° C. for 4 hours. This reaction mixture was concentrated under reduced pressure, and diisopropyl ether (10 ml) was added thereto. The precipitated solid was collected by filtration to give the titled compound (144 mg).
Reaction SMILES: [Br:1]Br.[CH3:3][N:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:14]3[CH:15]=[N:16][C:17]([CH3:20])=[CH:18][CH:19]=3)[CH:10]=2)[C:5]1=[O:21].O.[OH-].[Na+]>C(O)(=O)C>[Br:1][C:12]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:14]3[CH:15]=[N:16][C:17]([CH3:20])=[CH:18][CH:19]=3)[CH:10]=2)[C:5](=[O:21])[N:4]([CH3:3])[CH:13]=1
Reactant: Cc1ccc(-c2ccc3c(=O)n(C)ccc3c2)cn1
Reactant: BrBr
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: Cc1ccc(-c2ccc3c(=O)n(C)cc(Br)c3c2)cn1
Temperature: 25 °C
Reaction time: 0.28 h
Yield: 67.2 %

Procedure:
Bromine (97 mg, 0.61 mmol) in acetic acid (0.61 mL) was added dropwise to 2-methyl-6-(6-methylpyridin-3-yl)isoquinolin-1-one (160 mg, 0.64 mmol) in acetic acid (6 mL) at 0° C. After stirring at room temperature for 17 min, water (22 mL) was added and the pH was adjusted to 7-8 with 1M NaOH. Extractive work up with ethyl acetate and purification by silica gel chromatography (PE:EA=2:1 to 3:2) gave the title compound (135 mg, 64.3%) as a yellow solid. LCMS: 329.0 (M+H)+
Reaction SMILES: C[N:2]([CH3:5])C=O.Cl[CH:7]1[C:15]2[CH:14]=[CH:13][CH:12]=[C:11]([C:16]([OH:18])=[O:17])[C:10]=2[CH2:9][CH2:8]1.[C-]#N.[Na+].Cl>O>[C:5]([CH:7]1[C:15]2[CH:14]=[CH:13][CH:12]=[C:11]([C:16]([OH:18])=[O:17])[C:10]=2[CH2:9][CH2:8]1)#[N:2]
Reactant: O=C(O)c1cccc2c1CCC2Cl
Reactant: CN(C)C=O
Agent: Cl
Agent: [C-]#N
Agent: [Na+]
Solvent: O
Product: N#CC1CCc2c(C(=O)O)cccc21
Reaction time: 5 h

Procedure:
In 15 ml. of dimethylformamide is dissolved 1.97 g. of 1-chloroindan-4-carboxylic acid, followed by the addition of 1.47 g. of sodium cyanide. The mixture is stirred for 5 hours, after which 150 ml. of water and 10 ml. of concentrated hydrochloric acid are added. The resultant crystals are collected by filtration and recrystallized from benzene. The described procedure gives 1-cyanoindan-4-carboxylic acid, melting point: 206°-208°C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:18]2[C:14]3[S:15][CH:16]=[CH:17][C:13]=3[CH:12]=[C:11]([O:19][CH3:20])[C:10]=2[C:6]2[S:7][CH:8]=[CH:9][C:5]=2[CH:4]=1.[C:21](Cl)(=[O:33])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32].[Cl-].[Cl-].[Cl-].[Al+3].CCCCCC>ClCCl>[CH3:20][O:19][C:11]1[C:10]2[C:6]3[S:7][C:8]([C:21](=[O:33])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])=[CH:9][C:5]=3[CH:4]=[C:3]([O:2][CH3:1])[C:18]=2[C:14]2[S:15][CH:16]=[CH:17][C:13]=2[CH:12]=1
Reactant: COc1cc2ccsc2c2c(OC)cc3ccsc3c12
Reactant: CCCCCCCCCCCC(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCCCCC
Solvent: ClCCl
Product: CCCCCCCCCCCC(=O)c1cc2cc(OC)c3c4sccc4cc(OC)c3c2s1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 53.9 %

Procedure:
4,9-Dimethoxynaphtho[1,2-b:5,6-b′]dithiophene (0.90 g, 3.0 mmol) was solubilized in anhydrous dichloromethane (20 mL). Dodecanoyl chloride (0.765 g, 3.5 mmol) was then added and stirring was continued for 10 minutes at this temperature. Aluminum trichloride (0.465 g, 3.5 mmol) was then added in 3 portions. The mixture was stirred overnight at room temperature. The mixture was cooled in ice water and extracted with chloroform (200 mL) and washed with water (100 mL) and brine (50 mL). After the solvent was removed, the residual was purified using a silica column with dichloromethane:hexane (1/3) to give compound 1-(4,9-dimethoxynaphtho[1,2-b:5,6-b′]dithiophen-2-yl)dodecan-1-one as a pale yellow solid (0.78 g, ˜54% yield). 1H NMR (500 MHz, CDCl3): δ 8.72 (s, 1H), 7.69 (d, J=5.5 Hz, 1H), 7.50 (m, 2H), 7.42 (s, 1H), 4.24 (s, 3H), 4.22 (s, 3H) 3.07. (t, J=7.0 Hz, 2H), 1.83 (m, 2H), 1.39 (m, 18H); 0.88 (m, J=6.0 Hz, 3H).
Reaction SMILES: [C:1]([C:4]1[N:12]=[C:11]([C:13]2[C:21]3[C:16](=[N:17][CH:18]=[CH:19][CH:20]=3)[N:15]([CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[F:29])[N:14]=2)[N:10]=[C:9]2[C:5]=1[N:6]([CH3:31])[C:7](=[O:30])[NH:8]2)(=[O:3])[CH3:2].[CH3:32][Mg]Br.Cl>O1CCCC1.C(OCC)C>[F:29][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=1[CH2:22][N:15]1[C:16]2=[N:17][CH:18]=[CH:19][CH:20]=[C:21]2[C:13]([C:11]2[N:10]=[C:9]3[C:5]([N:6]([CH3:31])[C:7](=[O:30])[NH:8]3)=[C:4]([C:1]([OH:3])([CH3:32])[CH3:2])[N:12]=2)=[N:14]1
Reactant: C[Mg]Br
Reactant: CC(=O)c1nc(-c2nn(Cc3ccccc3F)c3ncccc23)nc2[nH]c(=O)n(C)c12
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOCC
Product: Cn1c(=O)[nH]c2nc(-c3nn(Cc4ccccc4F)c4ncccc34)nc(C(C)(C)O)c21
Reaction time: 1 h

Procedure:
237 mg (0.568 mmol) of the compound obtained in example 134 in tetrahydrofuran were cooled to 0° C. and admixed with 0.568 ml of a 3M solution of methylmagnesium bromide in diethyl ether, and the mixture was stirred at this temperature for 1 h and then at RT overnight. Then 2 portions, each of 0.379 ml, of a 3M solution of methylmagnesium bromide in diethyl ether were added and the mixture was stirred at RT for a further night. After cooling, first ice and then 4N hydrochloric acid (20 ml) were added and the mixture was stirred vigorously. The mixture was then extracted three times with ethyl acetate and the combined organic phases were washed with saturated aqueous sodium chloride solution. After drying over sodium sulfate, the mixture was filtered and concentrated, and the residue was purified by means of preparative HPLC (acetonitrile:water (+0.05% formic acid) gradient). 29 mg of the title compound were obtained (10% of theory).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][OH:8])[CH:2]=1.CN(C)C=O.[CH2:14]([O:16][C:17](=[O:25])[C:18]1[CH:23]=[CH:22][CH:21]=[N:20][C:19]=1Cl)[CH3:15]>O>[CH2:14]([O:16][C:17](=[O:25])[C:18]1[CH:23]=[CH:22][CH:21]=[N:20][C:19]=1[O:8][CH2:7][C:3]1[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=1)[CH3:15]
Reactant: CCOC(=O)c1cccnc1Cl
Reactant: OCc1cccnc1
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1cccnc1OCc1cccnc1
Reaction time: 0.5 h

Procedure:
To a solution of Pyridin-3-yl-methanol (0.59 grams, 5.4 mmole) in dimethylformamide (20 ml) sodium hydride (0.259 grams, 6.5 mmole) was added and stirred for 30 minutes. 2-Chloro-nicotinic acid ethyl ester (1.0 grams, 5.4 mmole) was added via syringe and stirred at room temperature over night. The mixture was diluted with water (150 ml) and extracted by diethyl ether and ethyl acetate. The combined extracts were washed with 1N NaOH, water and brine, dried over Na2SO4, filtered, and concentrated to an oil (1.3 g). MW 258.28; MS (m/e) 259 (M++1).
Reaction SMILES: [NH2:1][CH2:2][C:3]([N:5]1[C@H:9]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:8][S:7][CH:6]1[CH2:17][CH2:18][CH2:19][CH3:20])=[O:4].[CH3:21][C:22]1[CH:23]=[C:24]([N:28]=[C:29]=[O:30])[CH:25]=[CH:26][CH:27]=1>>[CH3:21][C:22]1[CH:23]=[C:24]([NH:28][C:29](=[O:30])[NH:1][CH2:2][C:3]([N:5]2[C@H:9]([C:10]([O:12][C:13]([CH3:14])([CH3:15])[CH3:16])=[O:11])[CH2:8][S:7][CH:6]2[CH2:17][CH2:18][CH2:19][CH3:20])=[O:4])[CH:25]=[CH:26][CH:27]=1
Reactant: Cc1cccc(N=C=O)c1
Reactant: CCCCC1SC[C@@H](C(=O)OC(C)(C)C)N1C(=O)CN
Product: CCCCC1SC[C@@H](C(=O)OC(C)(C)C)N1C(=O)CNC(=O)Nc1cccc(C)c1
Yield: 46.3 %

Procedure:
The procedure is similar to that described in Example 1A, but starting with 1.2 g of tert-butyl (4R)-3-(2-aminoacetyl)-2-butyl-4-thiazolidinecarboxylate (isomer A) and 0.53 g of 3-methylphenyl isocyanate. The crude product is purified by chromatography on silica [eluent: diisopropyl ether/ethyl acetate (95:5 by volume)]. The fractions containing the expected product are pooled and concentrated to dryness under reduced pressure at 40° C. 0.8 g of tert-butyl (4R)-3-{2-[3-(3-methylphenyl)-ureido]acetyl}-2-butyl-4-thiazolidinecarboxylate (isomer A) is thereby obtained in the form of an amorphous product; [α]D25 =-39°±1° (C %=0.53; DMF).
Reaction SMILES: [F:1][CH:2]([F:29])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[N:12][C:13]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:19][CH:18]=3)=[N:14][CH:15]=2)=[CH:6][CH:5]=1.C=O.[C:32]([O-])([O-])=[O:33].[Na+].[Na+]>CS(C)=O.CCOC(C)=O>[F:29][CH:2]([F:1])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[N:14][C:13]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([CH:23]([CH2:32][OH:33])[C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:19][CH:18]=3)=[N:12][CH:11]=2)=[CH:6][CH:5]=1
Reactant: O=C([O-])[O-]
Reactant: CCOC(=O)Cc1ccc(Nc2ncc(-c3ccc(OC(F)F)cc3)cn2)cc1
Agent: C=O
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CCOC(=O)C(CO)c1ccc(Nc2ncc(-c3ccc(OC(F)F)cc3)cn2)cc1

Procedure:
Ethyl 2-(4-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)phenyl)acetate 31 (1 mmol) and paraformaldehyde (5 mmol.) are dissolved in dry DMSO (0.2-0.5M) and heated at 70° C. in the presence of Na2CO3 (5 mmol.) for 2-6 h until greater than 50% conversion is achieved by LC/MS monitoring. The mixture is diluted with EtOAc and washed with water. After concentration, the residue is purified by silica gel chromatography to yield ethyl 2-(4-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)phenyl)-3-hydroxypropanoate 32. MS (m/z) (M+1)+: 432.1.
Reaction SMILES: [F:1][C:2]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:3]=1[CH2:4][C@H:5]1[CH2:10][C@H:9]([C:11](=[O:18])[CH2:12][C:13](OCC)=[O:14])[CH2:8][CH2:7][N:6]1[C:19]([O:21][CH3:22])=[O:20].[OH-].[Na+].[NH2:30]O.Cl>CO.O>[F:1][C:2]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:3]=1[CH2:4][C@H:5]1[CH2:10][C@H:9]([C:11]2[O:18][NH:30][C:13](=[O:14])[CH:12]=2)[CH2:8][CH2:7][N:6]1[C:19]([O:21][CH3:22])=[O:20]
Reactant: CCOC(=O)CC(=O)[C@@H]1CCN(C(=O)OC)[C@@H](Cc2ccc(F)cc2F)C1
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COC(=O)N1CC[C@@H](c2cc(=O)[nH]o2)C[C@@H]1Cc1ccc(F)cc1F
Temperature: -40 °C
Reaction time: 0.33 h
Yield: 101.4 %

Procedure:
Trans-methyl 2-(2,4-difluorobenzyl)-4-(3-ethoxy-3-oxopropanoyl)piperidine-1-carboxylate (1.18 g, 3.08 mmol) (from example 134, step 1) was dissolved in MeOH (15 mL) and cooled to −40° C. Sodium hydroxide (0.123 g, 3.08 mmol) dissolved in water (1.7 mL) was added over 1 min and the resulting solution was stirred at −40° C. for 20 min. Then hydroxylamine (50% by weight in water, 0.2 mL, 3.26 mmol) was added over 1 min and stirring continued at −40° C. for 2 h. The reaction mixture was then transferred into a prewarmed (80° C.) solution of 6 M hydrogen chloride (30 mL, 180.00 mmol) and the mixture was continued to be stirred at 80° C. for 1 h. Then cooled to room temperature. Methanol was evaporated, then water was added. Extracted three times with DCM. Combined organic layers dried over MgSO4 and evaporated. Crude trans-methyl 2-(2,4-difluorobenzyl)-4-(3-oxo-2,3-dihydroisoxazol-5-yl)piperidine-1-carboxylate (1.1 g, 101%) was isolated as a pale orange foam. 1H NMR (500 MHz, cdcl3) δ 1.43-2.15 (m, 4H), 2.66-3.23 (m, 4H), 3.39-3.79 (m, 3H), 4.04-4.41 (m, 1H), 4.45-4.78 (m, 1H), 5.67 (s, 1H), 6.73-6.90 (m, 2H), 7.03-7.37 (m, 1H). MS m/z 353 (M+H)+
Reaction SMILES: [Br:1][C:2]1[C:3]([Cl:9])=[CH:4][C:5]([NH2:8])=[N:6][CH:7]=1.[C:10](Cl)(=[O:12])[CH3:11]>N1C=CC=CC=1>[Br:1][C:2]1[C:3]([Cl:9])=[CH:4][C:5]([NH:8][C:10](=[O:12])[CH3:11])=[N:6][CH:7]=1
Reactant: Nc1cc(Cl)c(Br)cn1
Reactant: CC(=O)Cl
Solvent: c1ccncc1
Product: CC(=O)Nc1cc(Cl)c(Br)cn1
Temperature: 25 °C
Reaction time: 3 h
Yield: 100 %

Procedure:
To a stirred solution of 5-bromo-4-chloropyridin-2-amine (11.6 g, 55.9 mmol) in pyridine (100 mL) at 0° C. was added acetyl chloride (3.98 mL, 55.9 mmol) and the reaction was stirred at rt for 3 hours. The reaction was quenched with cold water. The reaction mixture was concentrated under reduced pressure. The residue was reconstituted in ethyl acetate and water. The organics were extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with water (100 mL), brine (100 mL) and dried over sodium sulfate. The organics were concentrated under reduced pressure to afford N-(5-bromo-4-chloropyridin-2-yl)acetamide as a white solid (14.6 g, 55.9 mmol, quantitative yield) that was used without further purification in the next step. LCMS (ESI) m/e 249 [(M+H)+, calcd for C7H7BrClN2O 248.9 LC/MS retention time (method B): tR=1.64 min; 1H NMR (400 MHz, DMSO-d6) δ 10.87 (s, 1H), 8.58 (s, 1H), 8.33 (s, 1H), 2.11 (s, 3H).
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.[CH3:13][C:14]1[CH:19]=[N:18][CH:17]=[CH:16][N:15]=1.[C:20](OC)(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C1COCC1>[C:21]1([C:20](=[O:27])[CH2:13][C:14]2[CH:19]=[N:18][CH:17]=[CH:16][N:15]=2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: Cc1cnccn1
Reactant: COC(=O)c1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: O=C(Cc1cnccn1)c1ccccc1
Reaction time: 0.5 h
Yield: 33.3 %

Procedure:
To a mixture of diisopropyl-amine (1.29 g, 12.7 mmol) in anhydrous THF (10 mL) was added n-BuLi (2.5 M/L in hexane, 4.7 mL, 11.7 mmol) at −78° C., after being stirred for 30 minutes, a solution of 2-methylpyrazine (1 g, 10.6 mmol) in THF (5 mL) was added, and the mixture was stirred at −78° C. for 30 minutes, a solution of methyl benzoate (1.4 g, 10.6 mmol) in THF (5 mL) was added, and the mixture was stirred at this temperature for 3 hours. When TLC indicated that the starting material was consumed, the reaction mixture was diluted with EtOAc, and the mixture was washed with water and brine, and concentrated. The residue was purified by column chromatography (PE:EtOAc=30:1) to give Intermediate 26 (700 mg, yield 33.3%).