Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([NH:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)[C:11]3=[C:22]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[CH:23]=[CH:24][N:10]3[N:9]=2)[CH:5]=[N:6][CH:7]=1.N1C=CC=CC=1.Cl[C:38](=[O:45])[CH2:39][CH2:40][C:41]([O:43][CH3:44])=[O:42].O>C(Cl)Cl>[O:45]=[C:38]([NH:1][C:2]1[CH:7]=[N:6][CH:5]=[C:4]([C:8]2[N:13]=[C:12]([NH:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)[C:11]3=[C:22]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[CH:23]=[CH:24][N:10]3[N:9]=2)[CH:3]=1)[CH2:39][CH2:40][C:41]([O:43][CH3:44])=[O:42]
Reactant: COC(=O)CCC(=O)Cl
Reactant: Nc1cncc(-c2nc(NCc3ccccn3)c3c(-c4ccccc4)ccn3n2)c1
Solvent: ClCCl
Solvent: O
Solvent: c1ccncc1
Product: COC(=O)CCC(=O)Nc1cncc(-c2nc(NCc3ccccn3)c3c(-c4ccccc4)ccn3n2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 65.9 %

Procedure:
2-(5-Aminopyridin-3-yl)-5-phenyl-N-(pyridin-2-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-4-amine (0.200 g, 0.508 mmol, synthesized as described in Example 3) was dissolved in DCM (10 mL) and pyridine (0.0820 mL, 1.02 mmol) was added, followed by the addition of methyl 4-chloro-4-oxobutanoate (77.0 mg, 0.508 mmol). The reaction mixture was stirred at room temperature for 30 min. Water (10 mL) was added to the reaction mixture followed by addition of CH2Cl2 (4×10 mL). The combined organic extracts were separated, dried over sodium sulfate, filtered and concentrated under reduced pressure to afford methyl 4-oxo-4-((5-(5-phenyl-4-((pyridin-2-ylmethyl)amino) pyrrolo[2,1-f][1,2,4]triazin-2-yl)pyridin-3-yl)amino)butanoate (0.170 g, 65.9%). 60 mg of the residue was further purified by preparative HPLC (Condition B-89 as described in general methods) to obtain methyl 4-oxo-4-(5-(5-phenyl-4-(pyridin-2-ylmethylamino) pyrrolo[1,2-f][1,2,4]triazin-2-yl)pyridin-3-ylamino)butanoate. LCMS Condition B-79: retention time 1.88 min, [M+1]=508.0. 1H NMR (400 MHz, DMSO-d6) δ ppm 2.62-2.78 (m, 4H), 3.62 (s, 3H), 4.93 (s, 2H), 6.81 (d, J=2.4 Hz, 1H), 7.23-7.34 (m, 2H), 7.41-7.64 (m, 6H), 7.72-7.82 (m, 1H), 7.90-7.93 (m, 1H), 8.33-8.44 (m, 1H), 8.79-8.89 (m, 2H), 9.04-9.12 (m, 1H), 10.37 (s, 1H).
Reaction SMILES: FC(F)(F)S(O[CH2:7][C@@H:8]1[O:12][CH2:11][C@@H:10]([S:13][C:14](=[O:16])[CH3:15])[CH2:9]1)(=O)=O.[N-:19]=[N+:20]=[N-:21].C([N+](CCCC)(CCCC)CCCC)CCC>C(Cl)Cl>[N:19]([CH2:7][C@@H:8]1[O:12][CH2:11][C@@H:10]([S:13][C:14](=[O:16])[CH3:15])[CH2:9]1)=[N+:20]=[N-:21]
Reactant: CC(=O)S[C@@H]1CO[C@@H](COS(=O)(=O)C(F)(F)F)C1
Reactant: [N-]=[N+]=[N-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: ClCCl
Product: CC(=O)S[C@@H]1CO[C@@H](CN=[N+]=[N-])C1
Reaction time: 0.5 h
Yield: 90.8 %

Procedure:
To a 0° C. solution of 5.768 g of product from Example 22 in 16 ml of methylene chloride, under argon, is added, via syringe, a 0° C. solution of 5.86 g of tetrabutylammonium azide in 16 ml of methylene chloride. The reaction is stirred in an ice bath for 30 minutes and then concentrated in vacuo. The residue is purified by chromatography (Silica Gel: 50% ethyl acetate/hexane) to give 3.418 g of the desired product.
Reaction SMILES: S(O[CH2:12][CH:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]1)(C1C=CC(C)=CC=1)(=O)=O.BrCC1CCCCO1.[F:34][C:35]1[C:36]([F:53])=[CH:37][C:38]2[O:52][CH2:51][C:41]3([C:49]4[C:44](=[CH:45][CH:46]=[CH:47][CH:48]=4)[NH:43][C:42]3=[O:50])[C:39]=2[CH:40]=1>>[F:34][C:35]1[C:36]([F:53])=[CH:37][C:38]2[O:52][CH2:51][C:41]3([C:49]4[C:44](=[CH:45][CH:46]=[CH:47][CH:48]=4)[N:43]([CH2:12][CH:13]4[CH2:14][CH2:15][N:16]([C:19]([O:21][C:22]([CH3:23])([CH3:24])[CH3:25])=[O:20])[CH2:17][CH2:18]4)[C:42]3=[O:50])[C:39]=2[CH:40]=1
Reactant: Cc1ccc(S(=O)(=O)OCC2CCN(C(=O)OC(C)(C)C)CC2)cc1
Reactant: O=C1Nc2ccccc2C12COc1cc(F)c(F)cc12
Agent: BrCC1CCCCO1
Product: CC(C)(C)OC(=O)N1CCC(CN2C(=O)C3(COc4cc(F)c(F)cc43)c3ccccc32)CC1

Procedure:
Following the procedure as described in EXAMPLE 4 and making non-critical variations using tert-butyl 4-(tosyloxymethyl)piperidine-1-carboxylate to replace 2-(bromomethyl)tetrahydro-2H-pyran, and 5,6-difluorospiro[1-benzofuran-3,3′-indol]-2′(1′H)-one to replace 5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2″(1′H)-one, tert-butyl 4-[(5,6-difluoro-2′-oxospiro[1-benzofuran-3,3′-indol]-1′(2′H)-yl)methyl]piperidine-1-carboxylate was obtained (57%) as a colorless solid: 1H NMR (300 MHz, CDCl3) δ 7.34 (ddd, J=9.0, 7.6, 1.5 Hz, 1H), 7.16-7.06 (m, 2H), 6.92 (d, J=7.8 Hz, 1H), 6.78 (dd, J=10.3, 6.3 Hz, 1H), 6.49 (dd, J=10.3, 6.3 Hz, 1H), 4.95 (d, J=9.0 Hz, 1H), 4.70 (d, J=9.0 Hz, 1H), 4.13 (br s, 2H), 3.74-3.56 (m, 2H), 2.69 (t, J=12.4 Hz, 2H), 2.07-1.96 (m, 1H), 1.68-1.63 (m, 2H), 1.45 (s, 9H), 1.32-1.26 (m, 2H); MS (ES+) m/z 493.3 (M+23).
Reaction SMILES: C[O:2][C:3](=[O:13])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH:11]=[CH2:12].[OH-].[Na+]>>[C:3]([OH:13])(=[O:2])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH:11]=[CH2:12]
Reactant: C=CCCCCCCCC(=O)OC
Agent: [Na+]
Agent: [OH-]
Product: C=CCCCCCCCC(=O)O

Procedure:
9-decenoic acid methyl ester prepared according to the method set forth in Example 12 is isolated then hydrolyzed under basic conditions (reflux with an excess of dilute aqueous NaOH), followed by removal of methanol. The resulting aqueous solution is then treated with an excess of dilute HCl, and the solution is distilled to provide 9-decenoic acid. Oligomers are then prepared according to the methods set forth in Examples 1 and 2, wherein the oleic acid is replaced with 9-decenoic acid.
Reaction SMILES: [OH:1][C@@H:2]1[C@@H:6]([CH3:7])[CH2:5][N:4]([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])[CH2:3]1.[S:18](Cl)([C:21]1[CH:27]=[CH:26][C:24]([CH3:25])=[CH:23][CH:22]=1)(=[O:20])=[O:19]>N1C=CC=CC=1>[CH3:7][C@@H:6]1[C@@H:2]([O:1][S:18]([C:21]2[CH:27]=[CH:26][C:24]([CH3:25])=[CH:23][CH:22]=2)(=[O:20])=[O:19])[CH2:3][N:4]([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])[CH2:5]1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: C[C@H]1CN(C(=O)OCc2ccccc2)C[C@@H]1O
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)O[C@H]2CN(C(=O)OCc3ccccc3)C[C@@H]2C)cc1
Reaction time: 8 h
Yield: 92.8 %

Procedure:
(3R,4S)-Benzyl 3-hydroxy-4-methylpyrrolidine-1-carboxylate (19.6 g, 83 mmol) was dissolved in pyridine (83 ml). To the above solution, Ts-Cl (22.2 g, 117 mmol) was added in portions at rt. After overnight stirring, the reaction mixture was concentrated in vacuo to remove pyridine. The residue was quenched with ice water (200 mL), extracted with ethyl acetate (3×150 mL). The combined ethyl acetate phase was washed with water, 1N HCl, water and sat. NaHCO3, then dried with Na2SO4. After concentration, (3S,4R)-benzyl 3-methyl-4-(tosyloxy)pyrrolidine-1-carboxylate (30 g, 92% yield) was obtained as light yellow oil. 1H NMR (400 MHz, chloroform-d) δ ppm 7.76-7.83 (2H, m), 7.30-7.40 (7H, m), 5.11 (2H, s), 4.57-4.64 (1H, m), 3.56-3.73 (2H, m), 3.38-3.54 (1H, m), 3.08-3.19 (1H, m), 2.33-2.55 (4H, m), 0.97 (3H, dd, J=14.86, 7.15 Hz); LCMS (CHROMOLITH® RP-18e 2.0×50 mm, 0.8 mL/min, Solvent A: 10% MeOH/water with 0.1% TFA, Solvent B: 90% MeOH/water with 0.1% TFA, gradient with 0-100% B over 4 minutes) retention time: 3.60 min; MS(ES+) m/z: 390 (M+H+).
Reaction SMILES: C(C1[CH:4]=[CH:5][C:6]2[CH:12]=[CH:11][C:10]3[CH:13]=[C:14]([OH:17])[CH:15]=[CH:16][C:9]=3[S:8](=[O:18])[C:7]=2[CH:19]=1)#N.[OH-].[Na+].[C:22]([OH:25])(=[O:24])[CH3:23]>>[OH:17][C:14]1[CH:15]=[CH:16][C:9]2[S:8](=[O:18])[C:7]3[CH:19]=[C:23]([C:22]([OH:25])=[O:24])[CH:4]=[CH:5][C:6]=3[CH:12]=[CH:11][C:10]=2[CH:13]=1
Reactant: N#Cc1ccc2c(c1)S(=O)c1ccc(O)cc1C=C2
Reactant: CC(=O)O
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)c1ccc2c(c1)S(=O)c1ccc(O)cc1C=C2

Procedure:
Suspend 100 mg. of the cyano compound of Step 2 in 5 ml. of acetic acid and 5 ml. of 20% aqueous sodium hydroxide. Reflux under nitrogen for 1 hour. Evaporate the alcohol and dilute the residue with water. Extract with ether and acidify the aqueous phase with 6N hydrochloric acid. Separate the solids by filtration. Dissolve the solids in ethanol and strip to dryness to obtain the title product (m.p., 288°-291° C. dec.).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([NH:10][C:11](=[O:18])[C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[N:7][C:6]=2[CH:19]=1.Cl[C:21]1[C:30]2[C:25](=[CH:26][C:27]([O:42][CH3:43])=[C:28]([O:31][CH2:32][CH2:33][CH2:34][N:35]3[CH2:40][CH2:39][N:38]([CH3:41])[CH2:37][CH2:36]3)[CH:29]=2)[N:24]=[CH:23][N:22]=1.Cl.O1CCOCC1>C(O)CCC>[CH3:43][O:42][C:27]1[CH:26]=[C:25]2[C:30]([C:21]([NH:1][C:2]3[CH:3]=[CH:4][C:5]4[S:9][C:8]([NH:10][C:11](=[O:18])[C:12]5[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=5)=[N:7][C:6]=4[CH:19]=3)=[N:22][CH:23]=[N:24]2)=[CH:29][C:28]=1[O:31][CH2:32][CH2:33][CH2:34][N:35]1[CH2:36][CH2:37][N:38]([CH3:41])[CH2:39][CH2:40]1
Reactant: Nc1ccc2sc(NC(=O)c3ccccc3)nc2c1
Reactant: COc1cc2ncnc(Cl)c2cc1OCCCN1CCN(C)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCCCO
Product: COc1cc2ncnc(Nc3ccc4sc(NC(=O)c5ccccc5)nc4c3)c2cc1OCCCN1CCN(C)CC1

Procedure:
N-(5-{7-Methoxy-6-[3-(4-methyl-piperazin-1-yl)-propoxy]-quinazolin-4-ylamino}-benzothiazol-2-yl)-benzamide was prepared by heating a mixture of N-(5-aminobenzothiazol-2-yl)benzamide (IM 5, 35 mg, 0.13 mmol), 4-chloro-7-methoxy-6-[3-(4-methylpiperazin-1-yl)propoxy]quinazoline (IM 8, 46 mg, 0.13 mmol) and 4 M HCl in dioxane (0.09 mL, 0.39 mmol) in n-butanol (3 mL) to 110° C. for 5 h. The HCl salt of the product precipitated. It was separated by filtration and washed twice with CH2Cl2. No ether purification was necessary (65 mg, 0.1 mmol, 93%). LC:/ESI-MS: m/z=620 [M+H]+; m/z=618 [M−H]−; Rt=2.43 min.
Reaction SMILES: [C:1]([C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].CO[CH:16](OC)[N:17]([CH3:19])[CH3:18]>CO>[CH3:16][N:17]([CH3:19])/[CH:18]=[CH:2]/[C:1]([C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=1)=[O:3]
Reactant: COC(=O)c1ccc(C(C)=O)cc1
Reactant: COC(OC)N(C)C
Solvent: CO
Product: COC(=O)c1ccc(C(=O)/C=C/N(C)C)cc1
Temperature: 0 °C
Yield: 84 %

Procedure:
A mixture of methyl 4-acetylbenzoate (25 g, 140 mmol) and N,N-dimethylformamide dimethyl acetal (100 mL) was heated to reflux for 2 days, diluted with MeOH (100 mL) and cooled to 0° C. The precipitate was collected by filtration and washed with MeOH to give (E)-methyl 4-(3-(dimethylamino)acryloyl)benzoate as a brown solid (27.65 g, 84% yield). MS (ES+) m/z: 234 (M+H); LC retention time: 2.91 min (analytical HPLC Method A).
Reaction SMILES: Br.[Br:2][C:3]1[C:13]2[CH2:12][CH2:11][NH:10][CH2:9][CH:8]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=3)[C:7]=2[CH:6]=[C:5]([O:22][CH3:23])[C:4]=1[O:24][CH3:25].[CH:26]1([C:32](O)=O)[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1.[BH4-].[Na+]>>[Br:2][C:3]1[C:13]2[CH2:12][CH2:11][N:10]([CH2:32][CH:26]3[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]3)[CH2:9][CH:8]([C:14]3[CH:15]=[CH:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=3)[C:7]=2[CH:6]=[C:5]([O:22][CH3:23])[C:4]=1[O:24][CH3:25]
Reactant: COc1ccc(C2CNCCc3c2cc(OC)c(OC)c3Br)cc1
Reactant: O=C(O)C1CCCCC1
Agent: Br
Agent: [BH4-]
Agent: [Na+]
Product: COc1ccc(C2CN(CC3CCCCC3)CCc3c2cc(OC)c(OC)c3Br)cc1

Procedure:
6-Bromo-7,8-dimethoxy-1-(p-methoxyphenyl)-2,3,4,5-tetrahydro-1H-3-benzazepine hydrobromide (3 g) is reacted with cyclohexylcarboxylic acid in the presence of sodium borohydride as in Example 1 to give 6-bromo-3-cyclohexylmethyl-7,8-dimethoxy-1-(p-methoxyphenyl)-2,3,4,5-tetrahydro-1H-3-benzazepine base and, after treatment with boron tribromide, 6-bromo-3-cyclohexylmethyl-7,8-dihydroxy-1-(p-hydroxyphenyl)-2,3,4,5-tetrahydro-1H-3-benzazepine hydrobromide.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[O:12][CH3:13])[C:6](Cl)=[O:7].[Br:14][C:15]1[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][C:16]=1[NH2:17].Cl>O>[Br:14][C:15]1[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][C:16]=1[NH:17][C:6](=[O:7])[C:5]1[CH:9]=[CH:10][C:11]([O:12][CH3:13])=[C:3]([O:2][CH3:1])[CH:4]=1
Reactant: COc1ccc(C(=O)Cl)cc1OC
Reactant: Nc1cc([N+](=O)[O-])ccc1Br
Agent: Cl
Solvent: O
Product: COc1ccc(C(=O)Nc2cc([N+](=O)[O-])ccc2Br)cc1OC
Temperature: 100 °C
Yield: 52.9 %

Procedure:
3,4-Dimethoxybenzoyl chloride (2 g) was added to a stirred solution of 2-bromo-5-nitroaniline (2.17 g) at 25° C. The reaction mixture was heated at 100° C. for 5 hours. After cooling, water (25 ml) and 3M hydrochloric acid (100 ml) were added. The resulting solid was filtered off and washed with water (50 ml) and dried. The solid was triturated under diethyl ether to give N-(2-bromo-5-nitrophenyl)-3,4-dimethoxybenzamide (2.01 g ) as a sandy-coloured solid, m.p. 183-184° C.; NMR Spectrum: (DMSOd6) 3.92(s, 6H), 7.08 (d, 1H), 7.56 (d, 1H), 7.65 (m, 1H), 8.0 (s, 2H), 8.4 (s, 1H), 10.09 (s, 1H).
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[N:5]([C:12]2[CH:17]=[CH:16][C:15]([CH2:18][C:19](O)=[O:20])=[CH:14][CH:13]=2)[N:4]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[C:36]1([CH:42]2[CH2:46][CH2:45][CH2:44][NH:43]2)[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>ClCCl>[O:20]=[C:19]([N:43]1[CH2:44][CH2:45][CH2:46][CH:42]1[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[CH2:18][C:15]1[CH:16]=[CH:17][C:12]([N:5]2[C:6]3[CH2:7][CH2:8][CH2:9][CH2:10][C:11]=3[C:3]([C:2]([F:22])([F:23])[F:1])=[N:4]2)=[CH:13][CH:14]=1
Reactant: c1ccc(C2CCCN2)cc1
Reactant: O=C(O)Cc1ccc(-n2nc(C(F)(F)F)c3c2CCCC3)cc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Product: O=C(Cc1ccc(-n2nc(C(F)(F)F)c3c2CCCC3)cc1)N1CCCC1c1ccccc1
Reaction time: 0.25 h
Yield: 60.6 %

Procedure:
A solution of {4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]phenyl}acetic acid (65 mg, 0.2 mmol) in dichloromethane (2 ml) was treated with 1,1′-carbonyldiimidazole (32.5 mg, 0.2 mmol) in one portion at room temperature. Stirring was continued at room temperature for 15 minutes. Then 2-phenylpyrrolidine (29 mg, 0.2 mmol) was added and stirring continued for 1 hour. Most of the solvent was removed under reduced pressure and the crude product was further purified by MDAP to give the title compound (55 mg, 61%).
Reaction SMILES: [CH3:1][C@H:2]1[NH:7][CH2:6][CH2:5][N:4]([C:8]2[CH:9]=[CH:10][C:11]3[N:12]([C:14]([C:17]([F:20])([F:19])[F:18])=[N:15][N:16]=3)[N:13]=2)[CH2:3]1.[N:21]1[CH:26]=[CH:25][C:24]([CH:27]=O)=[CH:23][CH:22]=1>>[CH3:1][C@H:2]1[N:7]([CH2:27][C:24]2[CH:25]=[CH:26][N:21]=[CH:22][CH:23]=2)[CH2:6][CH2:5][N:4]([C:8]2[CH:9]=[CH:10][C:11]3[N:12]([C:14]([C:17]([F:18])([F:20])[F:19])=[N:15][N:16]=3)[N:13]=2)[CH2:3]1
Reactant: C[C@@H]1CN(c2ccc3nnc(C(F)(F)F)n3n2)CCN1
Reactant: O=Cc1ccncc1
Product: C[C@@H]1CN(c2ccc3nnc(C(F)(F)F)n3n2)CCN1Cc1ccncc1
Yield: 58 %

Procedure:
Obtained in 58% yield by General Synthetic Method 5, starting from 6-[(3R)-3-methylpiperazin-1-yl]-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine (obtained as described in Example 564, preparation of starting materials) and pyridine-4-carboxaldehyde.
Reaction SMILES: [NH2:1][C:2]1[C:7]([O:8][CH2:9][C:10]2[C:15]([F:16])=[CH:14][CH:13]=[C:12]([F:17])[C:11]=2[F:18])=[CH:6][CH:5]=[CH:4][N:3]=1.[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([N:26]=[C:27]=[S:28])=[CH:22][CH:21]=1.C1(C)C=CC=CC=1>C(OCC)C>[F:18][C:11]1[C:12]([F:17])=[CH:13][CH:14]=[C:15]([F:16])[C:10]=1[CH2:9][O:8][C:7]1[C:2]([NH:1][C:27]([NH:26][C:23]2[CH:24]=[CH:25][C:20]([Cl:19])=[CH:21][CH:22]=2)=[S:28])=[N:3][CH:4]=[CH:5][CH:6]=1
Reactant: S=C=Nc1ccc(Cl)cc1
Reactant: Nc1ncccc1OCc1c(F)ccc(F)c1F
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: Fc1ccc(F)c(COc2cccnc2NC(=S)Nc2ccc(Cl)cc2)c1F

Procedure:
A mixture of 2-amino-3-(2,3,6-trifluorobenzyloxy)pyridine (2.00 g, 0.0078 mol), 4chlorophenyl isothiocyanate (1.6 g, 0.094 mol) and toluene (10 ml) was refluxed for 3 hours, then cooled and treated with diethyl ether to induce crystallisation of the product. Yield 2.82 g (85.5%), m.p.174°-176 ° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[CH2:14][CH2:13][CH2:12][C:11]=2[C:15]#[N:16])[CH:5]=[C:6]([F:8])[CH:7]=1>[Ti](Cl)(Cl)(Cl)Cl.[OH-].[Na+]>[NH2:16][C:15]1[C:3]2[C:2]([F:1])=[CH:7][C:6]([F:8])=[CH:5][C:4]=2[N:9]=[C:10]2[CH2:14][CH2:13][CH2:12][C:11]=12
Reactant: N#CC1=C(Nc2cc(F)cc(F)c2)CCC1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Product: Nc1c2c(nc3cc(F)cc(F)c13)CCC2
Temperature: 140 °C

Procedure:
Under nitrogen, titanium tetrachloride (1.2 ml; 2.1 g; 11.0 mmol) was added to the above enamine (Example 38) (2.2 g, 10.0 mmol) and the stirred mixture was heated at 140° C. for 1 hour. After cooling, sodium hydroxide (10M, 20 ml) was added and the mixture heated under reflux for 1 hour. After being allowed to cool, this was filtered and the solids were washed with dichloromethane. Any organics in the filtrate were also extracted into dichloromethane, the extracts were combined, dried (Na2SO4), filtered and the solvent evaporated. Kugelrohr distillation (180° C., 0.02 mmHg) gave the product as a very pale yellow powder.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]=[N:8][N:9]2[CH2:18][C:17]3[C:12](=[CH:13][CH:14]=[C:15]([C:19]([F:28])([C:24]([F:27])([F:26])[F:25])[C:20]([F:23])([F:22])[F:21])[CH:16]=3)[NH:11][C:10]2=[O:29])[CH:2]=1.[H-].[Na+].[CH3:32]I>CN(C)C=O>[CH3:32][N:11]1[C:12]2[C:17](=[CH:16][C:15]([C:19]([F:28])([C:24]([F:25])([F:26])[F:27])[C:20]([F:22])([F:21])[F:23])=[CH:14][CH:13]=2)[CH2:18][N:9]([N:8]=[CH:7][C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)[C:10]1=[O:29]
Reactant: O=C1Nc2ccc(C(F)(C(F)(F)F)C(F)(F)F)cc2CN1N=Cc1cccnc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1C(=O)N(N=Cc2cccnc2)Cc2cc(C(F)(C(F)(F)F)C(F)(F)F)ccc21
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 50.7 %

Procedure:
In 10 ml of dimethylformamide was dissolved 0.84 g (2.0 mmol) of 3-(3-pyridylmethylideneamino)-3,4-dihydro-6-[1,2,2,2-tetrafluoro-1-(trifluoromethyl)ethyl]-2(1H)-quinazolinone, and to the resulting solution was added 0.09 g (2.3 mmol) of sodium hydride (purity: 62.4%). The reaction was carried out at room temperature for 30 minutes, after which 0.34 g (2.4 mmol) of methyl iodide was added and the reaction was carried out for 4 hours. After completion of the reaction, the reaction solution was poured into ice water and the desired compound was extracted with ethyl acetate (20 ml×3). The extract solution was washed with water and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated in vacuo. The crude product thus obtained was purified by silica gel column chromatography (ethyl acetate−methanol=10:1) to obtain 0.44 g of the desired compound.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:14]=[C:13]([C:15]([O-:17])=O)[O:12][N:11]=2)=[CH:6][CH:5]=1.[Na+].CCN(C(C)C)C(C)C.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.[NH2:52][CH:53]([CH3:64])[CH:54]([OH:63])[CH2:55][C:56]1[CH:61]=[CH:60][CH:59]=[C:58]([Br:62])[CH:57]=1>C(Cl)Cl>[Br:62][C:58]1[CH:57]=[C:56]([CH2:55][CH:54]([OH:63])[CH:53]([NH:52][C:15]([C:13]2[O:12][N:11]=[C:10]([C:7]3[CH:6]=[CH:5][C:4]([O:3][C:2]([F:1])([F:19])[F:18])=[CH:9][CH:8]=3)[N:14]=2)=[O:17])[CH3:64])[CH:61]=[CH:60][CH:59]=1
Reactant: CC(N)C(O)Cc1cccc(Br)c1
Reactant: O=C([O-])c1nc(-c2ccc(OC(F)(F)F)cc2)no1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(NC(=O)c1nc(-c2ccc(OC(F)(F)F)cc2)no1)C(O)Cc1cccc(Br)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 41.2 %

Procedure:
To a solution of sodium 3-(4-(trifluoromethoxy)phenyl)-1,2,4-oxadiazole-5-carboxylate (500 mg, 1.7 mmol) in DCM (15 mL), DIEA (436 mg, 3.4 mmol), EDC.HCl (496 mg, 2.6 mmol), HOBT (351 mg, 2.6 mmol) and 3-amino-1-(3-bromophenyl)butan-2-ol (500 mg, 2.0 mmol) were added in sequence. The mixture was stirred at RT for 2 h, heated at 40 overnight, cooled to RT, quenched by the addition of H2O (50 mL), and extracted with DCM (50 mL×3). The combined organic layers were washed with H2O (10 mL) and brine (10 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (Petroleum ether:EtOAc=5:1) to afford N-(4-(3-bromophenyl)-3-hydroxybutan-2-yl)-3-(4-(trifluoromethoxy)phenyl)-1,2,4-oxadiazole-5-carboxamide (350 mg, 41%) as a white solid. MS (ES+) C20H13BrF3N3O3 requires: 499, 501 found: 500 [M+H]+, 502 [M+2+H]+(1:1).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([NH:15][CH2:16][C:17]([CH3:20])([OH:19])[CH3:18])=[C:7]([N+:12]([O-])=O)[CH:8]=[N:9]2)=[CH:4][CH:3]=1>C(#N)C.[Pt]>[NH2:12][C:7]1[CH:8]=[N:9][C:10]2[C:5]([C:6]=1[NH:15][CH2:16][C:17]([CH3:18])([OH:19])[CH3:20])=[CH:4][CH:3]=[C:2]([Br:1])[CH:11]=2
Reactant: CC(C)(O)CNc1c([N+](=O)[O-])cnc2cc(Br)ccc12
Agent: [Pt]
Solvent: CC#N
Product: CC(C)(O)CNc1c(N)cnc2cc(Br)ccc12
Yield: 85.7 %

Procedure:
A solution of 1-(7-bromo-3-nitroquinolin-4-ylamino)-2-methylpropan-2-ol (27.78 g, 81.66 mmol) in acetonitrile (1.2 L) was added to a Parr vessel charged with 5% platinum on carbon (0.84 g), and the reaction was placed under hydrogen pressure (50 psi, 3.4×105 Pa) for two days. The reaction mixture was filtered through a layer of CELITE filter aid, and the filter cake was washed with ethanol (1 L). The filtrate was concentrated under reduced pressure to provide 21.70 g of 1-(3-amino-7-bromoquinolin-4-ylamino)-2-methylpropan-2-ol as a yellow oil.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([C:8]([CH3:11])([CH3:10])[CH3:9])[CH:5]=[CH:4][C:3]=1[S:12]([N:15]([C:19]1[CH:23]=[CH:22][S:21][C:20]=1[C:24]([O:26][CH3:27])=[O:25])[CH2:16][O:17][CH3:18])(=[O:14])=[O:13].[C:28]1(/[CH:34]=[CH:35]/B(O)O)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C1(C)C=CC=CC=1>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.O.C(O)C>[C:8]([C:6]1[CH:5]=[CH:4][C:3]([S:12]([N:15]([C:19]2[CH:23]=[CH:22][S:21][C:20]=2[C:24]([O:26][CH3:27])=[O:25])[CH2:16][O:17][CH3:18])(=[O:14])=[O:13])=[C:2]([CH:35]=[CH:34][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:7]=1)([CH3:11])([CH3:10])[CH3:9]
Reactant: COCN(c1ccsc1C(=O)OC)S(=O)(=O)c1ccc(C(C)(C)C)cc1Br
Reactant: OB(O)/C=C/c1ccccc1
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: [Cs+]
Solvent: CCO
Solvent: Cc1ccccc1
Solvent: O
Product: COCN(c1ccsc1C(=O)OC)S(=O)(=O)c1ccc(C(C)(C)C)cc1C=Cc1ccccc1
Temperature: 25 °C
Yield: 62.4 %

Procedure:
A 2.5-5.0 mL microwave reaction tube was successively charged with 6 (200.0 mg, 0.43 mmol), trans-2-phenylvinylboronic acid (96.0 mg; 0.65 mmol), cesium carbonate (420.0 mg; 1.30 mmol), tetrakis(triphenylphosphine)palladium(0) (25.0 mg; 0.022 mmol), toluene (1.3 mL), ethanol (1.3 mL) and water (1.3 mL). The reaction tube was purged with nitrogen and subjected to the following microwave conditions: Temperature=140° C.; Power=250 W; Time=15 minutes; Cooling On; Absorption Very High. The reaction mixture was allowed to cool to room temperature and then was diluted with ethyl acetate (15 mL) and washed with aqueous hydrochloric acid (3×10 mL; 2N). The organic layer was dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The crude dark oil residue was purified by automated silica gel column chromatography (Biotage®) eluting with ethyl acetate/hexanes (0 to 30% v/v over 400 mL gradient elution) to give the title product as a white solid (134 mg).