Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][O:13]1)[N:7]=[CH:6]2)#[CH:2].[CH2:18]1COC[CH2:19]1.CN(CCN(C)C)C.[Li]CCCC.ICC>>[C:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][O:13]1)[N:7]=[CH:6]2)#[C:2][CH2:18][CH3:19]
Reactant: C#Cc1ccc2c(cnn2C2CCCCO2)c1
Reactant: C1CCOC1
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: CCI
Product: CCC#Cc1ccc2c(cnn2C2CCCCO2)c1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
A 250-mL round-bottom flask equipped with a magnetic stir bar, a rubber septum, and a N2 inlet was charged with 5-ethynyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (4.2 g, 18.6 mmol; Intermediate 2) and anhydrous THF/TMEDA (9:1, 93 mL). This solution was cooled to −78° C. in an IPA/dry ice bath, and n-BuLi (17.4 mL solution in hexanes, 27.84 mmol) was added dropwise over 15 minutes. The resulting mixture was stirred for 30 minutes at −78° C., and then iodoethane (2.23 mL, 27.84 mmol) was added dropwise over 5 minutes. The mixture was gradually warmed to room temperature, stirred for 1 h, and then heated at 40° C. overnight. Upon completion by LCMS, the reaction mixture was cooled to room temperature, quenched with water (100 mL), and extracted with ethyl acetate (2×100 mL). The combined organics were washed with water (100 mL), washed with brine (50 mL), dried over sodium sulfate, filtered, concentrated, and purified by silica gel chromatography (0-10% ethyl acetate in hexanes) to give the title compound (1.42 g) as a pale yellow solid. 1H NMR (300 MHz, DMSO-d6): δ 8.08 (s, 1H), 7.82 (s, 1H), 7.69 (d, 1H), 7.39 (d, 1H), 5.84 (dd, 1H), 3.89-3.86 (m, 1H), 3.76-3.72 (m, 1H), 2.45-2.36 (m, 3H), 2.04-1.94 (m, 2H), 1.74 (m, 1H), 1.57-1.20 (m, 2H), 1.16 (t, 3H); LCMS: 255 (M+H)+.
Reaction SMILES: [CH2:1](Br)[C:2]#[CH:3].[Br:5][C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][C:7]=1[OH:13].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Br:5][C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][C:7]=1[O:13][CH2:3][C:2]#[CH:1]
Reactant: Oc1cc(F)ccc1Br
Reactant: C#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C#CCOc1cc(F)ccc1Br
Temperature: 25 °C
Reaction time: 2 h
Yield: 97.4 %

Procedure:
A solution of 42.95 g (0.36 mol) of propargyl bromide in 30 ml of dimethylformamide was added dropwise to a suspension of 50 g (0.26 mol) of 2-bromo-5-fluoro-phenol and 55 g of potassium carbonate in 300 ml of dimethylformamide and the mixture was subsequently stirred at room temperature for two hours. The mixture was poured on to 1500 ml of ice-water and extracted three times with 600 ml of dichloromethane each time. After drying over sodium sulfate concentration was carried out in a vacuum. The crude product obtained was purified by column chromatography on silica gel (dichloromethane/hexane 1:1). 58 g (97%) of 1-bromo-4-fluoro-2-prop-2-ynyloxy-benzene were obtained as a pale yellow oil.
Reaction SMILES: C[O:2][C:3]([C:5]1[N:6]([CH3:14])[CH:7]=[C:8]([C:10]([CH3:13])([CH3:12])[CH3:11])[N:9]=1)=[O:4].[OH-].[Na+].Cl>CO>[C:10]([C:8]1[N:9]=[C:5]([C:3]([OH:4])=[O:2])[N:6]([CH3:14])[CH:7]=1)([CH3:13])([CH3:11])[CH3:12]
Reactant: COC(=O)c1nc(C(C)(C)C)cn1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cn1cc(C(C)(C)C)nc1C(=O)O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 4-tert-butyl-1-methyl-1H-imidazole-2-carboxylic acid methyl ester (680 mg, 3.46 mmol, prepared as described in the previous step) and 1N NaOH (3.81 mL, 3.81 mmol) in MeOH (10 mL) was stirred at room temperature for 2 h. To the resulting mixture was then added 1.0 N aqueous HCl (3.85 mL). The solvent was removed under reduced pressure and the residue was treated with DCM (50 mL). The solid was filtered off through diatomaceous earth and washed with DCM. The combined organic layers were dried with Na2SO4 and concentrated in vacuo to yield 4-tert-butyl-1-methyl-1H-imidazole-2-carboxylic acid as a white solid. 1H-NMR (400 MHz, CDCl3) δ: 7.00 (s, 1H), 4.18 (s, 3H), 1.49 (s, 9H). Mass Spectrum (LCMS, ESI pos.) Calculated For C9H14N2O2: 183.1 (M+H). Measured: 183.1.
Reaction SMILES: [CH2:1]([C:4]1[C:12]([OH:13])=[C:11]2[C:7]([CH2:8][O:9][C:10]2=[O:14])=[C:6]([CH3:15])[C:5]=1[CH2:16][CH3:17])[CH:2]=[CH2:3].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[CH3:37][Si:38]([CH3:43])([CH3:42])[CH2:39][CH2:40]O.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[CH2:1]([C:4]1[C:12]([O:13][CH2:40][CH2:39][Si:38]([CH3:43])([CH3:42])[CH3:37])=[C:11]2[C:7]([CH2:8][O:9][C:10]2=[O:14])=[C:6]([CH3:15])[C:5]=1[CH2:16][CH3:17])[CH:2]=[CH2:3]
Reactant: C=CCc1c(O)c2c(c(C)c1CC)COC2=O
Reactant: C[Si](C)(C)CCO
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C=CCc1c(CC)c(C)c2c(c1OCC[Si](C)(C)C)C(=O)OC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 92 %

Procedure:
To a solution of 6-allyl-5-ethyl-7-hydroxy-4-methyl-3H-isobenzofuran-1-one (199 mg, 0.857 mmol), PPh3 (337 mg, 1.286 mmol), and 2-trimethylsilylethanol in THF (3 mL) at 0° C. was added diisopropyl azodicarboxylate (259 mg, 1.286 mmol). The resulting yellow solution was allowed to warm to room temperature and stirred for one hour. The solvent was removed in vacuo and the crude material was dissolved in diethyl ether (3 mL). Hexanes (1.5 mL) were added. Triphenylphosphine oxide was removed by filtration and the filtrate was concentrated and purified by silica gel chromatography to provide the desired product (261 mg, 92%) as a clear oil. 1H NMR (300 MHz, CDCl3): δ=0.04 (s, 9H), 1.15 (t, J=7.8 Hz, 3H), 1.25 (m, 2H), 2.20 (s, 3H), 2.73 (q, J=7.8 Hz, 2H), 3.54 (m, 2H), 4.28 (m, 2H), 4.95 (d, J=17.1 Hz, 1H), 5.02 (d, J=10.2 Hz, 1H), 5.15 (s, 2H), 5.95 (m, 1H) ppm.
Reaction SMILES: COC1C=CC([C:7]([O:22][CH2:23][CH2:24][CH2:25][C:26]([O:28][C:29]2[CH:34]=[CH:33][C:32]([N+:35]([O-:37])=[O:36])=[CH:31][CH:30]=2)=[O:27])([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:8]2[CH:13]=[CH:12][C:11](OC)=[CH:10][CH:9]=2)=CC=1.C1C=CC(C2(Cl)C3C(=CC=CC=3)[O:53][C:52]3[C:47]2=[CH:48][CH:49]=[CH:50][CH:51]=3)=CC=1.COC1C(OC)=C(C=CC=1)C(Cl)(C1C=CC=CC=1)C1C=CC=CC=1>CCOC(C)=O>[C:16]1([C:7]2([O:22][CH2:23][CH2:24][CH2:25][C:26]([O:28][C:29]3[CH:30]=[CH:31][C:32]([N+:35]([O-:37])=[O:36])=[CH:33][CH:34]=3)=[O:27])[C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[O:53][C:52]3[C:51]2=[CH:50][CH:49]=[CH:48][CH:47]=3)[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: ClC1(c2ccccc2)c2ccccc2Oc2ccccc21
Reactant: COc1ccc(C(OCCCC(=O)Oc2ccc([N+](=O)[O-])cc2)(c2ccccc2)c2ccc(OC)cc2)cc1
Agent: COc1cccc(C(Cl)(c2ccccc2)c2ccccc2)c1OC
Solvent: CCOC(C)=O
Product: O=C(CCCOC1(c2ccccc2)c2ccccc2Oc2ccccc21)Oc1ccc([N+](=O)[O-])cc1
Yield: 80 %

Procedure:
This compound was synthesized using the same method used to synthesize 1a except that pixyl chloride (PxCl) was substituted for dimethoxytrityl chloride, to give 1b in 80% yield, mp 130°-130.5° C. (EtOAc). 1H NMR (CDCl3) δ 1.98 (m, 2H, H3), 2.7 (t, J=7.3 Hz, 2H, H2), 3.0 (t, J=5.8 Hz, 2H, H4), 7.0-7.5 (m, 15H, ArH), 8.2 (d, J=7.1 Hz, 2H PhNO2 m-H). 13C NMR (CDCl3) δ 25.0 (C3), 31.5 (C2), 61.8 (C4), 75.4 (CPh3), 116.3, 123.2, 123.5, 126.4, 126.6, 127.9, 129.1, 129.4, 148.9, 151.3 (Px C), 122.4, 125.1, 145.2, 155.4 (PhNO2C), 171.0 (CO2). Anal. Calcd for C29H23NO6 : C, 72.3; H, 4.8; N, 2.9. Found: C, 72.0; H, 4.4; N, 3.2.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([NH:20][C:21]3[CH:22]=[C:23]([CH:27]=[CH:28][CH:29]=3)[C:24](O)=[O:25])([CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=3)[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.[CH3:30][N:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1.CCN=C=NCCCN(C)C.Cl>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=3)([NH:20][C:21]3[CH:29]=[CH:28][CH:27]=[C:23]([C:24]([N:34]4[CH2:35][CH2:36][N:31]([CH3:30])[CH2:32][CH2:33]4)=[O:25])[CH:22]=3)[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1
Reactant: O=C(O)c1cccc(NC2(Cc3cccc(Cl)c3)C(=O)Nc3cc(Cl)ccc32)c1
Reactant: CN1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Product: CN1CCN(C(=O)c2cccc(NC3(Cc4cccc(Cl)c4)C(=O)Nc4cc(Cl)ccc43)c2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The mixture of rac-3-[6-chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-1H-indol-3-ylamino]-benzoic acid (60 mg, 0.14 mmol), 1-methyl-piperazine (56 mg, 0.56 mmol) and EDCl (54 mg, 0.28 mmol) in dichlorometahne (2 mL) was stirred at room temperature for overnight. The reaction mixture was purified by preparative HPLC to give rac-6-chloro-3-(3-chloro-benzyl)-3-[3-(4-methyl-piperazine-1-carbonyl)-phenylamino]-1,3-dihydro-indol-2-one as a powder. 1H NMR (CDCl3, 400 MHz): δ 7.21-6.74 (m, 9H), 6.49 (d, 1H), 6.17 (s, 1H), 4.70 (s, 1H), 3.80-3.45 (br, 8H), 3.28-3.15 (q, 2H), 2.66 (s, 3H). MS: [M+H]+=509
Reaction SMILES: Cl.[CH:2]1([NH:8][C:9]2[C:14]([CH3:15])=[C:13]([CH3:16])[N:12]=[C:11]([NH:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=CN=3)[N:10]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[N:25]1C=CC=C(CN)[CH:26]=1>>[CH:2]1([NH:8][C:9]2[C:14]([CH3:15])=[C:13]([CH3:16])[N:12]=[C:11]([NH:17][CH2:18][C:19]3[CH:26]=[N:25][CH:22]=[CH:23][CH:24]=3)[N:10]=2)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]1
Reactant: Cc1nc(NCc2ccccn2)nc(NC2CCCCC2)c1C
Reactant: NCc1cccnc1
Agent: Cl
Product: Cc1nc(NCc2cccnc2)nc(NC2CCCCC2)c1C

Procedure:
The titled compound was synthesized according to the general procedure described for preparation of N4-cyclohexyl-5,6-dimethyl-N2-(pyridin-2-ylmethyl)pyrimidine-2,4-diamine (Example 1) using 1-pyridin-3-ylmethanamine instead of (pyridin-2-ylmethyl)amine to afford the crude product. The solvent was removed by distillation, and the crude product was purified by HPLC (column: YMC-PACK ODS-AQ C18, 250 mm×20 mm, 10 μm; gradient: 20-50% acetonitrile in 0.02% trifluoroacetic acid/water over fifteen minutes; 50-100% acetonitrile in 0.02% trifluoroacetic acid/water over five minutes; flow rate: 25 mL/min; temperature: 25° C.) to afford the titled compound as the trifluoroacetate as a white solid. 1H NMR (400 MHz, CDCl3) δ ppm 1.08-1.34 (m, 5H), 1.50-1.61 (m, 3H) 1.62-1.69 (m, 2H), 1.87 (s, 3H), 2.23 (s, 3H), 3.71-3.79 (m, 1H), 4.63 (d, J=5.10 Hz, 2H), 7.60 (d, J=7.79 Hz, 1H), 7.64 (dd, J=7.66, 5.24 Hz, 1H), 8.05 (d, J=7.79 Hz, 1H), 8.62 (d, J=4.57 Hz, 1H) 8.62-8.69 (m, 1H) 8.71 (s, 1H), 12.61 (bs, 1H); MS (ESI) m/z 312.5 (M+1)+.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH:6]=[O:7].CN1C[CH2:12][CH2:11][C:10]1=O.BrCCC.C(=O)([O-])[O-].[K+].[K+]>O>[CH2:10]([N:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH:6]=[O:7])[CH2:11][CH3:12]
Reactant: CN1CCCC1=O
Reactant: O=Cc1ncc[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCCBr
Product: CCCn1ccnc1C=O
Temperature: 40 °C
Reaction time: 12 h

Procedure:
To 1H-imidazole-2-carboaldehyde (800 mg), N-methylpyrrolidone (10 mL) was added, followed by dissolution with heating. To this solution, 1-bromopropane (2.05 g) and potassium carbonate (1.15 g) were added. The reaction solution was stirred at 40° C. for 12 hours. To the reaction solution, water (10 mL) was added. The aqueous layer was extracted twice with ethyl acetate. The organic layers were combined, washed with saturated brine and then dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (dichloromethane) to obtain the title compound (893 mg) having the following physical properties.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[NH:8][C:9]1[N:14]=[C:13]([NH:15][C:16]2[CH:21]=[CH:20][C:19](C3ON=CC=3)=[CH:18][CH:17]=2)[C:12]([C:27]([NH2:29])=[O:28])=[CH:11][N:10]=1.[NH:30]1[C:34](C2C=C(C=CC=2)N)=[CH:33][CH:32]=[N:31]1>>[NH:30]1[C:34]([C:18]2[CH:17]=[C:16]([NH:15][C:13]3[C:12]([C:27]([NH2:29])=[O:28])=[CH:11][N:10]=[C:9]([NH:8][C@@H:3]4[CH2:4][CH2:5][CH2:6][CH2:7][C@@H:2]4[NH2:1])[N:14]=3)[CH:21]=[CH:20][CH:19]=2)=[CH:33][CH:32]=[N:31]1
Reactant: NC(=O)c1cnc(N[C@@H]2CCCC[C@@H]2N)nc1Nc1ccc(-c2ccno2)cc1
Reactant: Nc1cccc(-c2ccn[nH]2)c1
Product: NC(=O)c1cnc(N[C@@H]2CCCC[C@@H]2N)nc1Nc1cccc(-c2ccn[nH]2)c1

Procedure:
This compound was synthesised using the synthetic scheme described for the synthesis of compound 122, and using 3-(1H-pyrazol-5-yl)aniline in step 1. MS: 393.0 (M+H).
Reaction SMILES: Br[CH:2]([C:7]1[CH:12]=[CH:11][C:10]([I:13])=[CH:9][CH:8]=1)[C:3]([O:5][CH3:6])=[O:4].[C:14]1([SH:20])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>CO>[C:14]1([S:20][CH:2]([C:7]2[CH:12]=[CH:11][C:10]([I:13])=[CH:9][CH:8]=2)[C:3]([O:5][CH3:6])=[O:4])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: COC(=O)C(Br)c1ccc(I)cc1
Reactant: Sc1ccccc1
Solvent: CO
Product: COC(=O)C(Sc1ccccc1)c1ccc(I)cc1

Procedure:
In a similar manner as in Example 29, 14.2 g of methyl α-bromo-α-(p-iodophenyl)acetate is reacted with 5.5 g of thiophenol in methanol to yield white crystals, mp 62.5°-65° C.
Reaction SMILES: [C:1]1([S:7]([C:10]([C:16]#[N:17])=[C:11]([S:14][CH3:15])SC)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:18][C:19]1[N:20]=[CH:21][NH:22][C:23]=1[CH2:24][S:25][CH2:26][CH2:27][NH2:28]>>[C:1]1([S:7]([C:10]([C:16]#[N:17])=[C:11]([S:14][CH3:15])[NH:28][CH2:27][CH2:26][S:25][CH2:24][C:23]2[NH:22][CH:21]=[N:20][C:19]=2[CH3:18])(=[O:8])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Cc1nc[nH]c1CSCCN
Reactant: CSC(SC)=C(C#N)S(=O)(=O)c1ccccc1
Product: CSC(NCCSCc1[nH]cnc1C)=C(C#N)S(=O)(=O)c1ccccc1

Procedure:
Equimolar amounts of 1-benzenesulfonyl-1-cyano-2,2-bis(methylthio)ethylene [prepared according to the procedure described by M. Augustin et al., Z. Chem., 17, 289 (1977)] and 2-[(4-methyl-1H-imidazol-5-yl)methylthio]ethylamine [prepared according to the procedure described in U.S. Pat. No. 3,950,353] are reacted according to the general procedure of Example 6A, and the title product is produced.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=O)[CH3:12])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[H-].[Na+].[CH2:16](Br)[CH2:17]CC.O>CN(C)C=O>[CH2:11]([NH:10][C:7]1[CH:8]=[CH:9][C:4]([CH:1]([CH3:3])[CH3:2])=[CH:5][CH:6]=1)[CH2:12][CH2:16][CH3:17]
Reactant: CCCCBr
Reactant: CC(=O)Nc1ccc(C(C)C)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCNc1ccc(C(C)C)cc1
Reaction time: 8 h

Procedure:
To a solution of N-(4-isopropylphenyl)acetamide (1.8 g) in dimethylformamide (18 mL) was added, under ice-cooling, 60% sodium hydride (0.44 g). Further, butyl bromide (1.4 mL) was added and the mixture was stirred overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed, dried and concentrated under reduced pressure. 4N Hydrochloric acid (13 mL) was added to the residue and the mixture was refluxed for 7 hr. Water was added to the reaction mixture followed by neutralization and the mixture was extracted with ethyl acetate. The organic layer was washed, dried and concentrated under reduced pressure to give butyl(4-isopropylphenyl)amine (1.8 g).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([CH:8]=1)[NH2:7].[CH3:12][O-:13].[Na+]>CO>[CH3:12][O:13][C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([CH:8]=1)[NH2:7]
Reactant: C[O-]
Reactant: Nc1cc(Cl)ccc1[N+](=O)[O-]
Agent: [Na+]
Solvent: CO
Product: COc1ccc([N+](=O)[O-])c(N)c1
Yield: 93.9 %

Procedure:
10 g of 5-chloro-2-nitroaniline are dissolved in 100 ml of methanol, and 32.3 g of sodium methoxide are added. The reaction mixture is heated at the boil under reflux for 18 hours. After cooling, the mixture is evaporated to dryness, 500 ml of water are added, and the crude product is isolated by filtration. Drying gives 9.15 g of 5-methoxy-2-nitroaniline.
Reaction SMILES: [Na].Cl.[C:3]([NH2:9])(=[NH:8])[CH2:4][CH2:5][CH2:6][CH3:7].[Cl:10][C:11]1[CH:12]=[C:13]([N:17]=[C:18]=[O:19])[CH:14]=[CH:15][CH:16]=1>CC(C)=O>[Cl:10][C:11]1[CH:12]=[C:13]([NH:17][C:18]([NH:8][C:3](=[NH:9])[CH2:4][CH2:5][CH2:6][CH3:7])=[O:19])[CH:14]=[CH:15][CH:16]=1
Reactant: CCCCC(=N)N
Reactant: O=C=Nc1cccc(Cl)c1
Agent: Cl
Agent: [Na]
Solvent: CC(C)=O
Product: CCCCC(=N)NC(=O)Nc1cccc(Cl)c1

Procedure:
Following a procedure similar to that described in Example 1 but using 6.9 g. sodium in 300 ml. dry acetone, 41.1 g. valeramidine hydrochloride, and 46.2 g. 3-chlorophenyl isocyanate in 200 ml. dry acetone, there was obtained after recrystallization from acetone 27.1 g. of tjhe hydrochloride of 1-(3-chlorophenyl)-3-(pentanimidoyl)urea; m.p. 135°-137°C.
Reaction SMILES: [CH2:1]([NH:8][CH2:9][CH2:10]O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:14])=O>C1C=CC=CC=1>[CH2:1]([NH:8][CH2:9][CH2:10][Cl:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCCNCc1ccccc1
Reactant: O=S(Cl)Cl
Solvent: c1ccccc1
Product: ClCCNCc1ccccc1
Temperature: 80 °C

Procedure:
N-Benzyl ethanolamine (15.1 g, 100 mmol) was stirred in benzene (160 ml) at room temperature. Thionyl chloride (30 ml) was added dropwise over ten minutes. A white precipitate began to form immediately and the reaction mixture was warmed to 80° C. for 30 minutes. After cooling to room temperature the white solid was filtered off, washed with ether and dried. This solid was neutralised with sodium hydroxide solution and extracted with ethylacetate, washed with brine, dried (MgSO4) and evaporated to a yellow oil which was chromatographed on silica gel. Elution with petrol/ethylacetate: 1/1 afforded the title amine as a colourless oil, yield 6.75 g (40%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:25]#[N:26])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH2:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C:10](=[O:24])[CH:9]=2)[CH:7]=1.FC(F)(F)S(O[CH2:33][CH:34]([F:36])[CH3:35])(=O)=O>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:25]#[N:26])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:33][CH:34]([F:36])[CH3:35])[C:17]([O:19][C:20]([CH3:21])([CH3:22])[CH3:23])=[O:18])[C:10](=[O:24])[CH:9]=2)[CH:7]=1
Reactant: CC(F)COS(=O)(=O)C(F)(F)F
Reactant: COc1cn(CC(=O)OC(C)(C)C)c(=O)cc1-c1cc(Cl)ccc1C#N
Product: COc1cn(C(CC(C)F)C(=O)OC(C)(C)C)c(=O)cc1-c1cc(Cl)ccc1C#N

Procedure:
450 mg (purity 94%, 1.13 mmol) of tert-butyl [4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]acetate in the presence of 1.24 ml (1.24 mmol, 1.1 eq.) of bis(trimethylsilyl)lithium amide (1M in THF) and 356 mg (1.69 mmol, 1.5 eq.) of 2-fluoropropyl trifluoromethanesulphonate (racemate) were reacted according to General Method 7B. Yield: 270 mg (52% of theory)
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:10]2[O:11][CH:12]=[C:13]([CH2:15][CH2:16][C:17]([C:19]3[C:24]([CH3:25])=[CH:23][CH:22]=[CH:21][N:20]=3)=[O:18])[N:14]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].Cl[CH:27]([F:29])[F:28]>>[F:28][CH:27]([F:29])[O:1][C:2]1[CH:3]=[C:4]([C:10]2[O:11][CH:12]=[C:13]([CH2:15][CH2:16][C:17]([C:19]3[C:24]([CH3:25])=[CH:23][CH:22]=[CH:21][N:20]=3)=[O:18])[N:14]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: FC(F)Cl
Reactant: COc1ccc(-c2nc(CCC(=O)c3ncccc3C)co2)cc1O
Product: COc1ccc(-c2nc(CCC(=O)c3ncccc3C)co2)cc1OC(F)F

Procedure:
Using the compound obtained in Example 136 and chlorodifluoromethane, white powdery 3-[2-(3-difluoromethoxy-4-methoxyphenyl)oxazol-4-yl]-1-(3-methylpyridin-2-yl)propan-1-one was obtained following the procedure of Example 4.
Reaction SMILES: [C:1]1([CH2:11][C:12]([OH:14])=O)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.S(Cl)([Cl:17])=O>>[C:1]1([CH2:11][C:12]([Cl:17])=[O:14])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)Cc1cccc2ccccc12
Reactant: O=S(Cl)Cl
Product: O=C(Cl)Cc1cccc2ccccc12
Reaction time: 2 h

Procedure:
15 g of 1-naphthyl acetic acid and 90 ml of thionyl chloride were heated with stirring for 2 hours and the solution was concentrated under reduced pressure. The residue was taken up in toluene and concentrated to dryness under reduced pressure to obtain 16.3 g of the expected product which used as is for the next step.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14](=[O:21])[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:10][C:9]=1[NH:22][C:23](=[O:34])[CH2:24][C:25]([C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([Cl:33])[CH:28]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[C:14]([C:11]1[CH:12]=[CH:13][C:8]2[N:7]=[C:25]([C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([Cl:33])[CH:28]=3)[CH2:24][C:23](=[O:34])[NH:22][C:9]=2[CH:10]=1)(=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(C(=O)c2ccccc2)cc1NC(=O)CC(=O)c1cccc(Cl)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C1CC(c2cccc(Cl)c2)=Nc2ccc(C(=O)c3ccccc3)cc2N1
Yield: 63.6 %

Procedure:
Prepared from {4-benzoyl-2-[3-(3-chloro-phenyl)-3-oxo-propionylamino]-phenyl}-carbamic acid tert.-butyl ester (Example K17) (193 mg, 0.39 mmol) by treatment with TFA in CH2Cl2 according to the general procedure M. Obtained as a light yellow solid (93 mg).
Reaction SMILES: [CH3:1][S:2]([NH:5][C@H:6]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:7]([OH:9])=O)(=[O:4])=[O:3].Cl.[CH2:18]([O:25][C:26](=[O:32])[C@@H:27]1[CH2:31][CH2:30][CH2:29][NH:28]1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[CH2:18]([O:25][C:26]([C@@H:27]1[CH2:31][CH2:30][CH2:29][N:28]1[C:7](=[O:9])[C@H:6]([NH:5][S:2]([CH3:1])(=[O:3])=[O:4])[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:32])[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: CS(=O)(=O)N[C@H](Cc1ccccc1)C(=O)O
Reactant: O=C(OCc1ccccc1)[C@@H]1CCCN1
Agent: Cl
Product: CS(=O)(=O)N[C@H](Cc1ccccc1)C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Yield: 76.5 %

Procedure:
reaction of 0.65 g of 2-(R)-methanesulfonylamino-3-phenyl-propionic acid and 0.66 g of (L)-proline benzyl ester hydrochloride using the procedure described for example xib yielded 0.88 g (75%) of the title compound as a yellow oil. (+)-APCI-MS: 431 (MH+).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[C:5]([Cl:12])[CH:4]=1.[P:13]([O:20]CC)([O:17][CH2:18][CH3:19])[O:14][CH2:15][CH3:16]>>[Cl:12][C:5]1[CH:4]=[C:3]([CH:8]=[CH:7][C:6]=1[N+:9]([O-:11])=[O:10])[CH2:2][P:13](=[O:20])([O:17][CH2:18][CH3:19])[O:14][CH2:15][CH3:16]
Reactant: O=[N+]([O-])c1ccc(CBr)cc1Cl
Reactant: CCOP(OCC)OCC
Product: CCOP(=O)(Cc1ccc([N+](=O)[O-])c(Cl)c1)OCC

Procedure:
A solution of 4-(bromomethyl)-2-chloro-1-nitrobenzene (Compound 104D, 2.9 g, 12 mmol) in triethyl phosphite (2.6 mL, 15 mmol) was stirred at 120° C. for 16 h under nitrogen. The reaction mixture was concentrated in vacuo and the residue was purified on an Isco Combiflash eluting with 50 to 90% EtOAc in heptane to afford the title compound. MS (ES+): m/z: 308.0416 [MH+]. HPLC: tR=1.33 min (UPLC TOF MS: polar—3 min).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[C:5]1[C:10]([OH:11])=[CH:9][C:8]([OH:12])=[N:7][C:6]=1[C:13]([F:16])([F:15])[F:14])[CH3:2].[N+:18]([O-])([OH:20])=[O:19]>S(=O)(=O)(O)O>[CH2:1]([O:3][C:4](=[O:17])[C:5]1[C:10]([OH:11])=[C:9]([N+:18]([O-:20])=[O:19])[C:8]([OH:12])=[N:7][C:6]=1[C:13]([F:14])([F:15])[F:16])[CH3:2]
Reactant: O=[N+]([O-])O
Reactant: CCOC(=O)c1c(O)cc(O)nc1C(F)(F)F
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1c(C(F)(F)F)nc(O)c([N+](=O)[O-])c1O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
4,6-dihydroxy-2-trifluoromethyl-nicotinic acid ethyl ester (1 g, 3.9 mmol) was dissolved in 10 mL of concentrated sulfuric acid and 2 mL of fuming nitric acid was added dropwise at room temperature. Once the addition was complete, the mixture was stirred at room temperature for 30 minutes. The mixture was then poured into crushed ice and the white precipitate was collected, dissolved in 50 mL of ethyl acetate, washed with 50 mL of water and 50 mL of brine, dried over magnesium sulfate and the solvent was removed in vacuo to give 1.1 g of the title compound as a white solid.