Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S(Cl)(Cl)=O.[NH2:5][C@H:6]1[CH2:12][C:11]2[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=2[CH2:9][N:8]([CH2:17][C:18]([OH:20])=[O:19])[C:7]1=[O:21].[CH3:22]O>>[NH2:5][C@H:6]1[CH2:12][C:11]2[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=2[CH2:9][N:8]([CH2:17][C:18]([O:20][CH3:22])=[O:19])[C:7]1=[O:21]
Reactant: N[C@H]1Cc2ccccc2CN(CC(=O)O)C1=O
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)CN1Cc2ccccc2C[C@H](N)C1=O
Temperature: 25 °C
Reaction time: 0.02 h
Yield: 97 %

Procedure:
MeOH (5 mL) was cooled with an ice-acetone bath, and thionyl chloride (60 μL) was added. This solution was stirred for 1 min, and then the amino acid from Example 7 (163 mg, 0.70 mmol) was added all at once. After removing the cooling bath, the reaction was stirred while warming to ambient temperature over 1 hr, and then heated to 40° C. for another 1.5 hr. When the reaction mixture was concentrated to dryness, HPLC analysis of the residue indicated that the reaction was incomplete, so the above reaction sequence was repeated, this time heating the reaction for 0.5 hr at the end. The reaction mixture was concentrated to dryness, giving the product as a light yellow solid (168 mg, 97%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=3[N:12]=2)=[CH:4][CH:3]=1.[C:17](OC(=O)C)(=[O:19])[CH3:18]>C1C=CC=CC=1>[C:17]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:9][C:10]3[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=3[N:12]=2)=[CH:6][CH:7]=1)(=[O:19])[CH3:18]
Reactant: Nc1ccc(-c2nc3ccccc3o2)cc1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccccc1
Product: CC(=O)Nc1ccc(-c2nc3ccccc3o2)cc1

Procedure:
2-(4'-Aminophenyl)benzoxazole (1.0 g, 4.76 mmol) was treated with acetic anhydride (5 g) in benzene according to the above-described general procedure for acetylation. A red powder was afforded (0.9 g, 75%), m.p. 213.5-214.8° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:31]([F:34])([F:33])[F:32])[O:13][N:12]=[C:11]([C:14]3[CH:29]=[CH:28][C:17]([C:18]([NH:20][CH2:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=4)=[O:19])=[C:16](F)[CH:15]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.[CH3:35][S:36](C)=O>O>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:31]([F:34])([F:33])[F:32])[O:13][N:12]=[C:11]([C:14]3[CH:29]=[CH:28][C:17]([C:18]([NH:20][CH2:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=4)=[O:19])=[C:16]([S:36][CH3:35])[CH:15]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: O=C(NCc1ccccn1)c1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1F
Reactant: CS(C)=O
Solvent: O
Product: CSc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1C(=O)NCc1ccccn1
Temperature: 25 °C

Procedure:
In a solution of 0.92 g of 4-[5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazole-3-yl]-2-fluoro-N-(2-pyridylmethyl)benzoic acid amide (Compound of the present invention No. 5-041) synthesized similarly to Synthetic Example 4 in 12 ml of dimethylsulfoxide, 0.12 g of sodium methane thiolate was added with stirring at room temperature, and stirred at 100° C. for 90 minutes. After the completion of the reaction, the reaction mixture was poured in 30 ml of water, and extracted with ethyl acetate (20 ml×3). The organic phase was washed with 30 ml of water, dehydrated with saturated sodium chloride aqueous solution and dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified with silica gel column chromatography that was eluated with chloroform, and 0.89 g of the aimed product was obtained as colorless oily substance.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[CH:11]=[CH:10][N:9]=[C:8]3[N:12]([C:15]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)[N:13]=[CH:14][C:7]=23)[CH:3]=[N:2]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:41][C:42]#[N:43].[Cl-].[Na+].O.CCOC(C)=O>C1COCC1>[C:15]([N:12]1[C:8]2=[N:9][CH:10]=[CH:11][C:6]([C:4]3[CH:5]=[N:1][N:2]([CH2:41][C:42]#[N:43])[CH:3]=3)=[C:7]2[CH:14]=[N:13]1)([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)([C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: N#CCBr
Reactant: c1ccc(C(c2ccccc2)(c2ccccc2)n2ncc3c(-c4cn[nH]c4)ccnc32)cc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: N#CCn1cc(-c2ccnc3c2cnn3C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Temperature: 90 °C

Procedure:
A mixture of 4-(1H-pyrazol-4-yl)-1-trityl-pyrazolo[5,4-b]pyridine (3.824 g, 8.945 mmol) and potassium carbonate (9.890 g, 71.56 mmol) in dry THF (100.0 mL) was treated with 2-bromoacetonitrile (8.583 g, 4.984 mL, 71.56 mmol) and heated at 90° C. for 5 hours. The reaction was allowed to cool and treated with brine/ EtOAc and the 2 layers separated. The combined organics were dried (MgSO4), filtered, concentrated and purified by column chromatography (1:1 Petroleum ether/EtOAc) to give a white solid on concentration. The material was taken forward to the next step. 1H NMR (CDCl3, 400 MHz) δ 5.21 (2H, s), 7.06 (1H, s), 7.27-7.28 (15H, m), 8.04 (2H, m), 8.25 (2H, m); MS (ES+) 467.19
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.[CH2:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[OH:19])[CH3:12].C([O-])([O-])=O.[K+].[K+]>CN(C)C=O>[CH2:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[O:19][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1)[CH3:12]
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Reactant: CCc1ccccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCc1ccccc1Oc1ccc([N+](=O)[O-])cn1
Temperature: 110 °C

Procedure:
In a 20 mL microwave vial 2-chloro-5-nitropyridine (500 mg, 3.15 mmol) was dissolved in N,N-dimethylformamide (10 mL) to give a light brown solution. 2-ethylphenol (0.378 mL, 3.15 mmol) and K2CO3 (1308 mg, 9.46 mmol) were added. The reaction vessel was sealed and heated in Biotage Initiator at 110° C. for 1 hour. After cooling the reaction was complete. The reaction mixture was quenched with 10 mL of water and diluted with 10 mL of Et2O. Phases were separated through a separating funnel. The organic phase was washed with 3×10 mL of water, 10 mL of brine, dried over sodium sulphate, filtered and evaporated under vacuum to give the title compound as a pale orange oil. (623 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([C:29]2[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=2)[NH:10][C:11]([C:13]2[C:18]([NH:19][C:20]3[CH:25]=[C:24]([CH3:26])[CH:23]=[C:22]([CH3:27])[N:21]=3)=[CH:17][C:16](Br)=[CH:15][N:14]=2)=[O:12])=[CH:5][CH:4]=1.[C:37]([NH:40][CH2:41][CH:42]([NH:45][C:46](=[O:52])[O:47][C:48]([CH3:51])([CH3:50])[CH3:49])[CH2:43][NH2:44])(=[O:39])[CH3:38].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C(=O)([O-])[O-].[Cs+].[Cs+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCOCC1>[C:37]([NH:40][CH2:41][CH:42]([NH:45][C:46](=[O:52])[O:47][C:48]([CH3:51])([CH3:50])[CH3:49])[CH2:43][NH:44][C:16]1[CH:15]=[N:14][C:13]([C:11](=[O:12])[NH:10][CH:9]([C:29]2[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=2)[C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)=[C:18]([NH:19][C:20]2[CH:25]=[C:24]([CH3:26])[CH:23]=[C:22]([CH3:27])[N:21]=2)[CH:17]=1)(=[O:39])[CH3:38]
Reactant: COc1ccc(C(NC(=O)c2ncc(Br)cc2Nc2cc(C)cc(C)n2)c2ccc(OC)cc2)cc1
Reactant: CC(=O)NCC(CN)NC(=O)OC(C)(C)C
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: COc1ccc(C(NC(=O)c2ncc(NCC(CNC(C)=O)NC(=O)OC(C)(C)C)cc2Nc2cc(C)cc(C)n2)c2ccc(OC)cc2)cc1
Temperature: 80 °C
Reaction time: 16 h

Procedure:
To a flask were added N-[bis(4-methoxyphenyl)methyl]-5-bromo-3-[(4,6-dimethylpyridin-2-yl)amino]pyridine-2-carboxamide (100 mg, 0.183 mmol) (PrepEx 1.11), tert-butyl [1-(acetylamino)-3-aminopropan-2-yl]carbamate (51 mg, 0.22 mmol), tris(dibenzylideneacetone)dipalladium(0) (17 mg, 0.018 mmol), Xantphos (21 mg, 0.037 mmol) and cesium carbonate (131 mg, 0.402 mmol). 1,4-Dioxane (1 mL) was added, and the reaction mixture was purged with nitrogen for 5 minutes. The reaction mixture was then stirred at 80° C. for 16 hours. The reaction mixture was cooled to room temperature, and then diluted with ethyl acetate and saturated aqueous ammonium chloride. The organics were separated, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by chromatography on silica gel to afford tert-butyl {1-(acetylamino)-3-[(6-{[bis(4-methoxyphenyl)methyl]carbamoyl}-5-[(4,6-dimethylpyridin-2-yl)amino]pyridin-3-yl)amino]propan-2-yl}carbamate. MS ESI calc'd for C38H48N7O6 [M+H]+ 698. found 698.
Reaction SMILES: [CH2:1]([Li])[CH3:2].Br[CH2:5][C:6]([CH3:14])([CH3:13])[CH2:7][C:8]([CH3:12])([CH3:11])[C:9]#[N:10]>CCOCC>[CH3:5][C:6]1([CH3:14])[CH2:7][C:8]([CH3:12])([CH3:11])[CH2:9][N:10]=[C:13]1[CH2:1][CH3:2]
Reactant: [Li]CC
Reactant: CC(C)(C#N)CC(C)(C)CBr
Solvent: CCOCC
Product: CCC1=NCC(C)(C)CC1(C)C
Reaction time: 0.5 h
Yield: 40 %

Procedure:
0.1 mol of ethyl lithium dissolved in 200 ml of anhydrous ether is added drop by drop in an inert atmosphere to 22 g of 5-bromo-2,2,4,4-tetramethyl-pentane nitrile in 60 ml of anhydrous ether. This reaction medium is maintained between 0° and 5° C. during the addition and then for an additional 30 minutes and then is kept at room temperature for 4 hours. After hydrolysis, the aqueous phase is extracted with ether. The 3,3,5,5 tetramethyl-2-ethyl-3,4,5,6-tetrahydropyridine is then isolated by distillation. A colorless liquid of B.P.2.10 -2=40° C. is obtained in a yield of 40%.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([OH:12])=O)=[CH:9][C:4]=2[N:3]=[CH:2]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[Cl:46][C:47]1[CH:52]=[CH:51][C:50]([CH2:53][CH2:54][NH2:55])=[CH:49][CH:48]=1>CN(C=O)C.O.CO>[Cl:46][C:47]1[CH:52]=[CH:51][C:50]([CH2:53][CH2:54][NH:55][C:10]([C:8]2[CH:7]=[CH:6][C:5]3[NH:1][CH:2]=[N:3][C:4]=3[CH:9]=2)=[O:12])=[CH:49][CH:48]=1
Reactant: NCCc1ccc(Cl)cc1
Reactant: O=C(O)c1ccc2[nH]cnc2c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCCc1ccc(Cl)cc1)c1ccc2[nH]cnc2c1
Reaction time: 8 h
Yield: 100 %

Procedure:
To a mixture of 1H-benzo[d]imidazole-5carboxylic acid (1.00 g, 6.17 mmol) and HBTU (2.57 g, 6.78 mmol) in 10 mL DMF was added DIEA (1.29 mL, 7.40 mmol) followed by 2-(4-chlorophenyl)ethanamine (1.15 g, 6.78 mmol). The reaction was stirred overnight and then diluted with water. The reaction mixture was extracted with ethyl acetate. The combined organic layers were washed with brine, dried, filtered and concentrated onto silica gel. The residue was purified by flash column chromatography, eluting with 12:1 DCM:MeOH, to provide N-(4chlorophenethyl)-1H-benzo[d]imidazole-5-carboxamide (0.944 g, 6.17 mmol, 51%) as a light pink solid. MS (APCI)=300.3 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:13])=[C:6](/[CH:8]=[C:9](\C)/[CH:10]=O)[CH:7]=1.CC1C=CC(S([NH:24][NH2:25])(=O)=O)=CC=1.[OH-].[Na+]>C(#N)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:13])=[C:6]([C:8]2[CH:9]=[CH:10][NH:25][N:24]=2)[CH:7]=1
Reactant: C/C(C=O)=C\c1cc(Cl)ccc1O
Reactant: Cc1ccc(S(=O)(=O)NN)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Product: Oc1ccc(Cl)cc1-c1cc[nH]n1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of (E)-3-(5-chloro-2-hydroxyphenyl)-2-methylacrylaldehyde (40 mg, 0.203 mmol) and 4-methylbenzenesulfonohydrazide (41.7 mg, 0.224 mmol) in Acetonitrile (3 mL) were stirred at room temperature for 3 h and then acetonitrile (2 mL), Sodiumhydroxide (8.95 mg, 0.224 mmol) were added and the mixture was heated at reflux for 16 h. Product was used for further reaction without purification.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH3:8])[NH:5][C:4]2=[CH:9][C:10]([CH3:12])=[N:11][C:3]=12.[NH2:13][CH2:14][CH2:15][N:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1.C([O-])([O-])=O.[K+].[K+]>O>[CH3:8][C:6]1[NH:5][C:4]2[C:3]([N:11]=[C:10]([CH3:12])[CH:9]=2)=[C:2]([NH:13][CH2:14][CH2:15][N:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)[N:7]=1
Reactant: NCCN1CCOCC1
Reactant: Cc1cc2[nH]c(C)nc(Cl)c-2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: Cc1cc2[nH]c(C)nc(NCCN3CCOCC3)c-2n1
Yield: 25.1 %

Procedure:
This compound was prepared according to the method described in Example 46(e) by employing 4-chloro-2,6-dimethylpyrrolo[3,2-d]pyrimidine (Example 46(d)) (0.10 g, 0.55 mmol) with 4-(2-aminoethyl)morpholine (Aldrich Chemical Company) (0.388 mL, 2.95 mmol) and K2CO3 (0.36 g, 2.6 mmol) in water (2.5 mL) to give 0.038 g (25%) of the title compound as an off-white solid after recrystallization from EtOAc. Mp: 237-238.5° C. 1H NMR (CDCl3; 500 MHz): δ 2.43 (s, 3), 2.50 (t, 4, J=5.2), 2.58 (s, 3), 2.65 (t, 2, J=5.7), 3.67 (t, 4, J=4.6), 3.70 (q, 2, J=5.4), 5.55 (br s, 1), 6.18 (s, 1), 9.88 (br s, 1). MS m/z: 276 (M+1). Anal. Calcd for C14H21N5O: C, 61.07; H, 7.69; N 25.43. Found: C, 61.19; H, 7.77; N, 25.39.
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11](=[O:36])[NH:12][C:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:16]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][N:28]=[C:27]([NH:31][C:32](=[O:35])[CH2:33]Cl)[CH:26]=3)=[CH:15][CH:14]=2)[N:7]([C:37]2[CH:42]=[CH:41][C:40]([CH3:43])=[CH:39][CH:38]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].CC[N:46]([CH:50]([CH3:52])C)[CH:47]([CH3:49])C.N1CCCC1>C(Cl)Cl.CN(C=O)C>[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11](=[O:36])[NH:12][C:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:16]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][N:28]=[C:27]([NH:31][C:32](=[O:35])[CH2:33][N:46]4[CH2:47][CH2:49][CH2:52][CH2:50]4)[CH:26]=3)=[CH:15][CH:14]=2)[N:7]([C:37]2[CH:42]=[CH:41][C:40]([CH3:43])=[CH:39][CH:38]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CCN(C(C)C)C(C)C
Reactant: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)Nc2ccc(OCc3ccnc(NC(=O)CCl)c3)c3ccccc23)cc1
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: C1CCNC1
Product: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)Nc2ccc(OCc3ccnc(NC(=O)CN4CCCC4)c3)c3ccccc23)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 33.6 %

Procedure:
To a solution of N-(4-((4-(3-(3-tert-butyl-1-p-tolyl-1H-pyrazol-5-yl)ureido)naphthalen-1-yloxy)methyl)pyridin-2-yl)-2-chloroacetamide (Intermediate B) (50 mg, 0.08 mmol) in DCM (1.0 mL), DMF (0.1 mL) and DIPEA (22 μl, 0.13 mmol) was added pyrrolidine (7.0 μl, 0.08 mmol). The reaction mixture was stirred at RT for 3 hr. LC-MS indicated 50% conversion to product. The reaction mixture was heated to 40° C. and stirred for 12 hr. LC-MS indicated 95% conversion to product. A further portion of pyrolidine (7.0 μl, 0.08 mmol) was added and the reaction mixture continued to stir at 40° C. for 5 hr. LC-MS indicated complete conversion to product. The crude reaction mixture was purified by column chromatography (12 g, 0-10% MeOH in DCM, gradient elution) to afford N-(4-((4-(3-(3-tert-butyl-1-p-tolyl-1H-pyrazol-5-yl)ureido)naphthalen-1-yloxy)methyl)pyridin-2-yl)-2-(pyrrolidin-1-yl)acetamide (Example 8) as a light orange solid (17 mg, 32%): m/z 632 (M+H)+ (ES+). 1H NMR (400 MHz, DMSO-d6) δ: 1.27 (9H, s), 1.76 (4H, m), 2.39 (3H, s), 2.62 (4H, m), 5.39 (2H, s), 6.35 (1H, s), 7.01 (1H, d), 7.28 (1H, d), 7.34 (2H, d), 7.44 (2H, d), 7.65-7.55 (3H, m), 7.92 (1H, d), 8.36-8.29 (3H, m), 8.58 (1H, s), 8.79 (1H, s), 9.93 (1H, s).
Reaction SMILES: CS(Cl)(=O)=O.[CH3:6][C:7]1[S:11][C:10]2[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=2[C:8]=1[S:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH2:23]O.[CH2:25]([N:27](CC)CC)C.CN.C([O-])(O)=O.[Na+]>C1COCC1>[CH3:25][NH:27][CH2:23][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[S:16][C:8]1[C:9]2[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=2[S:11][C:7]=1[CH3:6]
Reactant: CCN(CC)CC
Reactant: Cc1sc2ccccc2c1Sc1ccccc1CO
Agent: CN
Agent: CS(=O)(=O)Cl
Agent: O=C([O-])O
Solvent: C1CCOC1
Product: CNCc1ccccc1Sc1c(C)sc2ccccc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Methanesulfonyl chloride (170 μL, 2.2 mmol) is added to a solution of [2-(2-Methyl-benzo[b]thiophen-3-ylsulfanyl)-phenyl]-methanol (590 mg, 2.1 mmol) and triethyl amine (350 μL, 2.5 mmol) in 10 mL dry THF at 0° C. under an argon atmosphere. The reaction mixture is stirred for 1 hour at room temperature and cooled to 0° C. 2 M methyl amine in THF is added and the reaction is stirred at room temperature for 3 hours. Saturated aqueous NaHCO3 is added and the mixture is extracted with ethyl acetate. The organic phase is washed with brine, dried with MgSO4 and concentrated in vacuo. The residue is purified by flash chromatography on silica gel using ethyl acetate and then ethyl acetate-methanol-triethyl amine (3:1:1) as eluents. This furnishes 460 mg (75%) of the title compound as an oil.
Reaction SMILES: [NH2:1][CH2:2][C:3]([OH:5])=[O:4].[OH-].[Na+].[C:8](Cl)(=[O:24])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23].Cl>O.C(O)(C)C>[NH:1]([C:8]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[O:24])[CH2:2][C:3]([OH:5])=[O:4]
Reactant: NCC(=O)O
Reactant: CCCCCCCCCCCCCCCC(=O)Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)O
Product: CCCCCCCCCCCCCCCC(=O)NCC(=O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 31.9 %

Procedure:
First, 27.3 g (364 mmol) of glycine and 29.1 g (727 mmol) of sodium hydroxide were dissolved in a mixed solvent of 450 g composed of i-propanol and 200 g of water under stirring at room temperature, then cooled to 10° C. Next, 100 g (364 mmol) of palmitic acid chloride was added dropwise thereto over a period of 1 hour. The reaction product was returned to room temperature, then stirred for about 15 hours. Next, 400 g of water was added thereto, following which 73.8 g (727 mmol) of 35% hydrochloric acid was added dropwise. The solid that deposited out was recovered, slurry washed, and purified by re-crystallization from methanol, giving 36.4 g (yield, 32%) of N-palmitoyl-Gly as a white solid.
Reaction SMILES: [C:1]([NH:5][C:6]1[CH:11]=[C:10](Cl)[N:9]=[CH:8][N:7]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][CH:16]=1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>C1(C)C=CC=CC=1.CC([O-])=O.CC([O-])=O.[Pd+2]>[C:1]([NH:5][C:6]1[CH:11]=[C:10]([NH:21][C:18]2[CH:19]=[CH:20][C:15]([O:14][CH3:13])=[CH:16][CH:17]=2)[N:9]=[CH:8][N:7]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1ccc(N)cc1
Reactant: CC(C)(C)Nc1cc(Cl)ncn1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: Cc1ccccc1
Product: COc1ccc(Nc2cc(NC(C)(C)C)ncn2)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 48 %

Procedure:
50 mg of N-tert-butyl-6-chloropyrimidin-4-amine, 39 mg of p-anisidine, 104 mg of CsCO3, 1.2 mg of Pd(OAc)2 and 3 mg of BINAP were taken in a screw cap vial under argron in 2 mL of dry toluene and the vial obtained was kept in a heating block at 150° C. for 12 hours. The mixture obtained was cool to r.t. and purification was carried out by column chromatography using 30% EtOAc in PE. N4-tert-Butyl-N6-(4-methoxyphenyl)pyrimidine-4,6-diamine was obtained.
Reaction SMILES: Cl[CH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C:3]1=O.[C:9]([NH2:12])(=[S:11])[CH3:10]>C(O)C>[CH3:10][C:9]1[S:11][C:2]2[CH2:7][CH2:6][CH2:5][CH2:4][C:3]=2[N:12]=1
Reactant: O=C1CCCCC1Cl
Reactant: CC(N)=S
Solvent: CCO
Product: Cc1nc2c(s1)CCCC2

Procedure:
5.00 g (37.7 mmol) of 2-chlorocyclohexanone and 2.83 g (37.7 mmol) of thioacetamide are heated in 25 ml of ethanol at the reflux temperature overnight. After cooling, the volatile components are removed in a rotary evaporator, and the remaining residue is taken up in 2 N sodium carbonate solution. It is extracted three times with dichloromethane, and the combined organic phases are dried with magnesium sulfate. The solvent is removed in a rotary evaporator, and the residue is then purified by column chromatography (silica gel, mobile phase: cyclohexane/ethyl acetate 7:3). 3.35 g (58% of theory) of the title compound are obtained.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][C@@H:2]1[C:6]([NH:8][C@H:9]([C:11]1[CH:20]=[CH:19][C:14]([C:15]([O:17][CH3:18])=[O:16])=[CH:13][CH:12]=1)[CH3:10])=[O:7].[F:21][C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][C:29]=1[F:30])[CH2:25]Br.C([O-])([O-])=O.[Na+].[Na+]>>[F:21][C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][C:29]=1[F:30])[CH2:25][N:1]1[CH2:5][CH2:4][CH2:3][C@@H:2]1[C:6]([NH:8][C@H:9]([C:11]1[CH:12]=[CH:13][C:14]([C:15]([O:17][CH3:18])=[O:16])=[CH:19][CH:20]=1)[CH3:10])=[O:7]
Reactant: Fc1ccc(CBr)cc1F
Reactant: COC(=O)c1ccc([C@H](C)NC(=O)[C@H]2CCCN2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: COC(=O)c1ccc([C@H](C)NC(=O)[C@H]2CCCN2Cc2ccc(F)c(F)c2)cc1
Yield: 53.8 %

Procedure:
The title compound (D34) (39 mg) was prepared according to the general procedure for substituted benzyl amines preparation starting from methyl 4-((S)-1-((R)-pyrrolidine-2-carboxamido)ethyl)benzoate (D14) (50 mg, 0.18 mmol) and 3,4-difluorobenzyl bromide (0.046 ml, 0.36 mmol). (Na2CO3: 2.5 eq; reaction time: 5 hrs; 70° C.)
Reaction SMILES: F[C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[Br:12][C:13]1[CH:19]=[CH:18][C:16]([NH2:17])=[CH:15][CH:14]=1.C([O-])(C)(C)C.[K+]>CS(C)=O>[Br:12][C:13]1[CH:19]=[CH:18][C:16]([NH:17][C:2]2[C:3]([N+:9]([O-:11])=[O:10])=[CH:4][CH:5]=[CH:6][C:7]=2[CH3:8])=[CH:15][CH:14]=1
Reactant: Cc1cccc([N+](=O)[O-])c1F
Reactant: Nc1ccc(Br)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: Cc1cccc([N+](=O)[O-])c1Nc1ccc(Br)cc1

Procedure:
The product (2.44 g) is obtained according to the method of stage 1 of Example 4, by using 1.8 g of 2-fluoro-3-methyl-nitrobenzene and 3 g of 4-bromo-aniline in the presence of 2.09 g of potassium tert-butanolate in 20 mL of DMSO.
Reaction SMILES: [O:1]1[C:10]2[S:9][CH2:8][CH:7]=[CH:6][C:5]=2[CH2:4][CH2:3][CH:2]1[O:11][CH2:12][CH2:13]Br.[C:15]1([N:21]([CH:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)[C:22](=[O:25])[CH2:23][CH3:24])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[O:1]1[C:10]2[S:9][CH2:8][CH:7]=[CH:6][C:5]=2[CH2:4][CH2:3][CH:2]1[O:11][CH2:12][CH2:13][N:29]1[CH2:28][CH2:27][CH:26]([N:21]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:22](=[O:25])[CH2:23][CH3:24])[CH2:31][CH2:30]1
Reactant: CCC(=O)N(c1ccccc1)C1CCNCC1
Reactant: BrCCOC1CCC2=C(O1)SCC=C2
Product: CCC(=O)N(c1ccccc1)C1CCN(CCOC2CCC3=C(O2)SCC=C3)CC1

Procedure:
Using the procedure of Example I step B and starting from (8-thiachromanyloxyethyl) bromide and 4-(N-phenyl N-propionylamino) piperidine, N (8-thiachromanyloxyethyl) 4-(N'-phenyl N'-propionylamino) piperidine is obtained and isolated as its oxalate which melts at 182°-184°.
Reaction SMILES: [F:1][CH2:2][C:3]([C:7]1[O:11][N:10]=[C:9]([NH:12][C:13](=[O:21])OC2C=CC=CC=2)[CH:8]=1)([CH3:6])[CH2:4][F:5].[CH3:22][O:23][C:24]1[CH:25]=[C:26]2[C:31](=[CH:32][C:33]=1[O:34][CH3:35])[N:30]=[CH:29][N:28]=[C:27]2[S:36][C:37]1[CH:38]=[C:39]([CH:41]=[CH:42][CH:43]=1)[NH2:40]>CN(C)C1C=CN=CC=1.C1COCC1>[F:5][CH2:4][C:3]([C:7]1[O:11][N:10]=[C:9]([NH:12][C:13]([NH:40][C:39]2[CH:41]=[CH:42][CH:43]=[C:37]([S:36][C:27]3[C:26]4[C:31](=[CH:32][C:33]([O:34][CH3:35])=[C:24]([O:23][CH3:22])[CH:25]=4)[N:30]=[CH:29][N:28]=3)[CH:38]=2)=[O:21])[CH:8]=1)([CH3:6])[CH2:2][F:1]
Reactant: COc1cc2ncnc(Sc3cccc(N)c3)c2cc1OC
Reactant: CC(CF)(CF)c1cc(NC(=O)Oc2ccccc2)no1
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Product: COc1cc2ncnc(Sc3cccc(NC(=O)Nc4cc(C(C)(CF)CF)on4)c3)c2cc1OC
Yield: 31 %

Procedure:
Using the procedure described in Example 162B, phenyl 5-(1,3-difluoro-2-methylpropan-2-yl)isoxazol-3-ylcarbamate as described in Example 162A (0.089 g, 0.3 mmol) was reacted with 3-(6,7-dimethoxyquinazolin-4-ylthio)aniline from Example 115B (0.094 g, 0.3 mmol), and 4-(dimethylamino)pyridine (0.03 g) in THF (6 mL), to afford 1-[5-(1,3-difluoro-2-methylpropan-2-yl)isoxazol-3-yl]-3-[3-(6,7-dimethoxyquinazolin-4-ylthio)phenyl]urea as solid (0.048 g, 31%). 1H NMR (300 MHz, DMSO-d6) δ 9.71 (s, 1H), 9.02 (s, 1H), 8.70 (s, 1H), 7.85 (d, 1H), 7.52 (d, 1H), 7.46 (t, 1H), 7.35 (d, 2H), 7.29 (d, 1H), 6.78 (s, 1H), 4.72 (s, 2H), 4.56 (s, 2H), 3.99 (s, 6H), 1.29 (s, 3H); LC-MS (ESI) m/z 516 (M+H)+.