Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[C:5](=[CH:10][C:11]([NH:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[C:12]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:13]=1)[C:6](OC)=[O:7].[NH3:29]>C(O)CO>[NH:14]([C:12]1[CH:13]=[C:4]2[C:3](=[O:2])[NH:29][C:6](=[O:7])[C:5]2=[CH:10][C:11]=1[NH:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: N
Reactant: COC(=O)c1cc(Nc2ccccc2)c(Nc2ccccc2)cc1C(=O)OC
Solvent: OCCO
Product: O=C1NC(=O)c2cc(Nc3ccccc3)c(Nc3ccccc3)cc21
Reaction time: 24 h

Procedure:
A suspension of 230 mg (0.7 mmol) of 4,5-bis(anilino)phthalic acid dimethyl ester in 23 ml of ethylene glycol is heated at 120°; ammonia gas is passed through the suspension, with stirring, for 24 hours. The reaction mixture is cooled and extracted with ethyl acetate. The ethyl acetate phases are washed in succession three times with water and once with saturated sodium chloride solution, dried with sodium sulfate and concentrated by evaporation. The evaporation residue is chromatographed on silica gel with dichloromethane/methanol 40:1 and the product fractions are combined and concentrated by evaporation, yielding the title compound in the form of yellow crystals, m.p. 215°-217°, FAB-MS: 330 [M+ +H].
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]([Br:12])[CH:9]=[CH:8][C:3]=1[C:4](=[N:6][OH:7])Cl.[CH2:13]([O:15][C:16](=[O:20])[C:17]#[C:18][CH3:19])[CH3:14].C(N(CC)CC)C>C(OCC)C>[CH2:13]([O:15][C:16]([C:17]1[C:4]([C:3]2[CH:8]=[CH:9][C:10]([Br:12])=[CH:11][C:2]=2[F:1])=[N:6][O:7][C:18]=1[CH3:19])=[O:20])[CH3:14]
Reactant: CC#CC(=O)OCC
Reactant: ON=C(Cl)c1ccc(Br)cc1F
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CCOC(=O)c1c(-c2ccc(Br)cc2F)noc1C
Yield: 83.1 %

Procedure:
In a fashion similar to that described for preparation 15, 2-fluoro-4-bromo-benzoyl chloride oxime (2.00 g, 7.92 mmol), ethyl-2-butynoate (1.33 g, 11.9 mmol), triethylamine (2.2 ml, 15.8 mmol) in diethyl ether (10 ml), and diethyl ether (20 ml) gave 4-ethoxycarbonyl-5-methyl-3-(2-fluoro-4-bromophenyl)isoxazole (2.16 g, 83%) after column chromatography (silica gel, hexanes/diethyl ether gradient). 1H NMR (400 MHz, CDCl3) δ 7.36-7.29 (m, 3H), 4.16 (q, 2H, J=6.8 Hz), 2.70 (s, 3H), 1.15 (t, 3H, J=6.9 Hz)ppm.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:14]=[C:13]([NH:15][CH3:16])[C:12]([C:17]([F:20])([F:19])[F:18])=[CH:11][N:10]=2)=[C:4]([O:21][CH3:22])[CH:3]=1.C([O-])([O-])=O.[K+].[K+].[CH3:29][N:30]1[CH:34]=[C:33](B2OC(C)(C)C(C)(C)O2)[CH:32]=[N:31]1>O1CCOCC1.O.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>[CH3:22][O:21][C:4]1[CH:3]=[C:2]([C:33]2[CH:32]=[N:31][N:30]([CH3:29])[CH:34]=2)[CH:7]=[CH:6][C:5]=1[NH:8][C:9]1[N:14]=[C:13]([NH:15][CH3:16])[C:12]([C:17]([F:20])([F:19])[F:18])=[CH:11][N:10]=1
Reactant: CNc1nc(Nc2ccc(Br)cc2OC)ncc1C(F)(F)F
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
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: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CNc1nc(Nc2ccc(-c3cnn(C)c3)cc2OC)ncc1C(F)(F)F
Yield: 24.8 %

Procedure:
A mixture of N2-(4-bromo-2-methoxyphenyl)-N4-methyl-5-(trifluoromethyl)pyrimidine-2,4-diamine (0.365 g, 1 mmol), Pd(PPh3)4 (115 mg, 0.1 mmol), K2CO3 (0.415 g, 3 mmol) and 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.415 g, 2 mmol) in dioxane (10 mL) and water (1.25 mL) was degassed under a stream of nitrogen for 10 min. The reaction tube was sealed and the mixture irradiated in the microwave at 100° C. for 20 min. The mixture was cooled and concentrated under reduced pressure. The residue was partitioned between ethyl acetate (20 mL) and water (20 mL) and the product extracted into ethyl acetate (2×20 mL). The combined organics were passed through a phase separation cartridge and the solvent removed under reduced pressure. Purification of the residue via silica gel column chromatography (0-100% ethyl acetate/isohexane) afforded a residue that was triturated with diethyl ether yielding N2-(2-methoxy-4-(1-methyl-1H-pyrazol-4-yl)phenyl)-N4-methyl-5-(trifluoromethyl)pyrimidine-2,4-diamine as an off-white solid (94 mg, 25%). LCMS (10 cm_ESCI_Formic_MeCN): [MH+]=379 at 3.11 min. 1H NMR (400 MHz, CDCl): δ 8.49 (d, J=8.4, 1H); 8.17 (s, 1H); 7.76-7.68 (m, 2H); 7.58 (s, 1H); 7.10 (dd, J=8.4, 1.9, 1H); 6.98 (d, J=1.9, 1H); 5.20 (s, 1H); 3.95 (s, 6H); 3.12 (d, J=4.7, 3H).
Reaction SMILES: [Br-:1].[NH2:2][CH2:3][CH2:4][CH2:5][CH2:6][N+:7]([CH2:10][CH2:11][NH:12][C:13]([C:15]1[C:20]([NH2:21])=[N:19][C:18]([NH2:22])=[C:17]([Cl:23])[N:16]=1)=[O:14])([CH3:9])[CH3:8].[Cl:24][C:25]1[CH:30]=[CH:29][C:28]([S:31](Cl)(=[O:33])=[O:32])=[CH:27][CH:26]=1.CN1CCOCC1>CN(C=O)C>[Br-:1].[Cl:24][C:25]1[CH:30]=[CH:29][C:28]([S:31]([NH:2][CH2:3][CH2:4][CH2:5][CH2:6][N+:7]([CH2:10][CH2:11][NH:12][C:13]([C:15]2[C:20]([NH2:21])=[N:19][C:18]([NH2:22])=[C:17]([Cl:23])[N:16]=2)=[O:14])([CH3:9])[CH3:8])(=[O:33])=[O:32])=[CH:27][CH:26]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Reactant: C[N+](C)(CCCCN)CCNC(=O)c1nc(Cl)c(N)nc1N
Agent: [Br-]
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: C[N+](C)(CCCCNS(=O)(=O)c1ccc(Cl)cc1)CCNC(=O)c1nc(Cl)c(N)nc1N

Procedure:
A solution of (4-amino-butyl)-{2-[(3,5-diamino-6-chloro-pyrazine-2-carbonyl)-amino]-ethyl}-dimethyl-ammonium bromide (Intermediate N) (0.25 g, 0.60 mmol), 4-chlorobenzenesulfonyl chloride (0.125 g, 0.59 mmol) and N-methylmorpholine (0.3 mL, 2.73 mmol) in DMF (5 mL) is shaken at RT for 16 h. The reaction mixture is concentrated in vacuo, and the residue is purified by chromatography (basic alumina, 0-15% methanol in DCM) to obtain the title compound. M+ 504.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][C:6]1([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:10][C:9](=O)[NH:8][CH2:7]1)C.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[C:12]1([C:6]2([CH2:5][CH2:4][OH:3])[CH2:10][CH2:9][NH:8][CH2:7]2)[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: CCOC(=O)CC1(c2ccccc2)CNC(=O)C1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCCC1(c2ccccc2)CCNC1
Temperature: 5 °C
Reaction time: 18 h

Procedure:
Combine (3-phenyl-5-oxopyrrolidin-3-yl)acetic acid ethyl ester (171 g, 0.69 mol) and tetrahydrofuran (2 L). Cool to about 5° C. Slowly, add over about 15 minutes a solution of lithium aluminum hydride in tetrahydrofuran (2.24 L, 1 M, 2.24 mol). After the addition is complete heat to about 60° C. After 18 hours, cool in an ice-bath. Slowly quench by adding a saturated aqueous solution of sodium potassium tartrate (208 mL). After the quench is complete, add Na2SO4 (100 g) and celite (150 g) and stir. After 3 hours, dilute the reaction mixture with tetrahydrofuran (2 L) and filter. Suspend the solids in diethyl ether (2 L) and and filter. Combine the filtrates and concentrate the in vacuo to give the title compound: mp; 106-110° C. Rf=0.12 (silica gel dichloromethane/methanol/concentrated aqueous ammonia, 9/1/0.1).
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH:5]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[NH:4][C:3]1=[O:14].O=[C:16]1N(C(OCC2C=CC=CC=2)=O)[C@H](C(O)=O)CN1.CI.[H-].[Na+]>CN(C)C=O>[CH3:1][N:2]1[CH2:6][CH:5]([C:7]([O:9][C:10]([CH3:11])([CH3:13])[CH3:12])=[O:8])[N:4]([CH3:16])[C:3]1=[O:14]
Reactant: O=C(O)[C@@H]1CNC(=O)N1C(=O)OCc1ccccc1
Reactant: CN1CC(C(=O)OC(C)(C)C)NC1=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CI
Product: CN1CC(C(=O)OC(C)(C)C)N(C)C1=O
Temperature: -10 °C
Reaction time: 8 h
Yield: 79 %

Procedure:
A stirred solution of 1,1-dimethylethyl 1-methyl-2-oxo-4-imidazolidinecarboxylate (1.75 g, 8.74 mmol) (prepared as described in step (i) of Example 49 from 5-(1,1-dimethylethyl)1-(phenylmethyl)3-methyl-2-oxo-1,5-imidazolidinedicarboxylate, itself prepared as described in step (ii) of Example 13, starting originally from (4S)-2-oxo-3-{[(phenylmethyl)oxy]carbonyl}-4-imidazolidinecarboxylic acid) in N,N-dimethylformamide (22 ml) was cooled to −10° C. under argon, and then the methyl iodide (2.186 ml, 35.0 mmol) was added. Sodium hydride (60% dispersion in oil) (0.329 g, 8.22 mmol) was then added portion wise. The reaction mixture was allowed to warm to RT while stirring under argon overnight. The solvent was evaporated in vacuo and then the residue partitioned between ethyl acetate (40 ml) and brine (30 ml). The aqueous layer was re-extracted with ethyl acetate (×2) and then the combined organic extracts were washed with water (×2, 50 ml), brine (50 ml) and dried over magnesium sulphate. The solvent was evaporated in vacuo. The crude product was purified by flash-silica gel chromatography, eluting with 25-100% ethyl acetate/iso-hexane. The fractions containing product were combined and solvent evaporated in vacuo to give a yellow oil, 1,1-dimethylethyl 1,3-dimethyl-2-oxo-4-imidazolidinecarboxylate (1.48 g, 79% yield). (ii) A solution of 1,1-dimethylethyl 1,3-dimethyl-2-oxo-4-imidazolidinecarboxylate (1.92 g, 8.96 mmol) in dichloromethane (12 ml)/trifluoroacetic acid (6.00 ml) was stirred at room temperature for 24 hours. The solution was evaporated and the residue was co-evaporated with toluene (×3) and then dichloromethane (×2). The product was then dried to give crude 1,3-dimethyl-2-oxo-4-imidazolidinecarboxylic acid (1.65 g) which was dissolved in dichloromethane (90 ml) to give a ˜0.1M solution in dichloromethane which was used in subsequent reactions. LC/MS [M+H]+=159.
Reaction SMILES: [Cl:1][C:2]1[C:18]([N+:19]([O-])=O)=[C:17]([F:22])[CH:16]=[CH:15][C:3]=1[C:4]([NH:6][S:7]([N:10]([CH:12]([CH3:14])[CH3:13])[CH3:11])(=[O:9])=[O:8])=[O:5].CO.[H][H]>C1(C)C=CC=CC=1.[Pt]>[Cl:1][C:2]1[C:18]([NH2:19])=[C:17]([F:22])[CH:16]=[CH:15][C:3]=1[C:4]([NH:6][S:7]([N:10]([CH:12]([CH3:14])[CH3:13])[CH3:11])(=[O:9])=[O:8])=[O:5]
Reactant: CC(C)N(C)S(=O)(=O)NC(=O)c1ccc(F)c([N+](=O)[O-])c1Cl
Reactant: [H][H]
Agent: [Pt]
Solvent: CO
Solvent: Cc1ccccc1
Product: CC(C)N(C)S(=O)(=O)NC(=O)c1ccc(F)c(N)c1Cl
Temperature: 70 °C
Reaction time: 12 h

Procedure:
8.00 g (23.0 mmol) of N-(2-chloro-4-fluoro-3-nitrobenzoyl)-N′-isopropyl-N′-methylsulfamide in 33 g of toluene and 8 g of methanol were admixed with 190 mg (0.055 mol %) of 3% Pt/C and hydrogenated with 5 bar of hydrogen with stirring at 70° C. After 12 h the solution was depressurized, the reaction mixture was filtered and the solvent was removed by distillation. This gave 4.7 g (64%) of the title compound in the form of a solid (m.p.: 147-149° C.).
Reaction SMILES: [C:1]([NH:16][C@@H:17]1[C@@H:46]([OH:47])[C@H:45]([OH:48])[C@@H:44]([CH2:49][OH:50])[O:43][C@@H:18]1[O:19][CH:20]([CH2:32][C:33]([O:35][CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)=[O:34])[CH2:21][C:22]([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:23])(=[O:15])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].[C:51]([NH:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH2:66][C:67](O)=[O:68])(=[O:58])[C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1>>[C:51]([NH:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH2:66][C:67]([O:47][C@H:46]1[C@H:45]([OH:48])[C@@H:44]([CH2:49][OH:50])[O:43][C@H:18]([O:19][CH:20]([CH2:21][C:22]([O:24][CH2:25][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)=[O:23])[CH2:32][C:33]([O:35][CH2:36][C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)=[O:34])[C@@H:17]1[NH:16][C:1](=[O:15])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])=[O:68])(=[O:58])[C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1
Reactant: CCCCCCCCCCCCCC(=O)N[C@H]1[C@@H](OC(CC(=O)OCc2ccccc2)CC(=O)OCc2ccccc2)O[C@H](CO)[C@@H](O)[C@@H]1O
Reactant: O=C(O)CCCCCCCNC(=O)c1ccccc1
Product: CCCCCCCCCCCCCC(=O)N[C@H]1[C@@H](OC(CC(=O)OCc2ccccc2)CC(=O)OCc2ccccc2)O[C@H](CO)[C@@H](O)[C@@H]1OC(=O)CCCCCCCNC(=O)c1ccccc1

Procedure:
In the same manner as in Example 8, Step 4, 2-benzyloxycarbonyl-1-(benzyloxycarbonylmethyl)ethyl 2-deoxy-2-tetradecanoylamino-α-D-glucopyranoside was once protected with an isopropylidene group and then reacted with 8-benzoylaminooctanoic acid, followed by removal of the isopropylidene group to obtain the titled compound as a colorless oily substance.
Reaction SMILES: [F:1][C:2]1[C:10]([O:11][C:12]2[C:21]3[C:16](=[CH:17][C:18]([OH:24])=[C:19]([O:22][CH3:23])[CH:20]=3)[N:15]=[N:14][CH:13]=2)=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH3:25])[NH:6]2.O[CH2:27][CH2:28][CH2:29][N:30]1[CH2:35][CH2:34][N:33]([CH3:36])[CH2:32][CH2:31]1>>[F:1][C:2]1[C:10]([O:11][C:12]2[C:21]3[C:16](=[CH:17][C:18]([O:24][CH2:27][CH2:28][CH2:29][N:30]4[CH2:35][CH2:34][N:33]([CH3:36])[CH2:32][CH2:31]4)=[C:19]([O:22][CH3:23])[CH:20]=3)[N:15]=[N:14][CH:13]=2)=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH3:25])[NH:6]2
Reactant: CN1CCN(CCCO)CC1
Reactant: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3F)cnnc2cc1O
Product: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3F)cnnc2cc1OCCCN1CCN(C)CC1
Yield: 27.8 %

Procedure:
Using an analogous procedure to that described in Example 16, 4-(4-fluoro-2-methylindol-5-yloxy)-7-hydroxy-6-methoxycinnoline (0.2 g, 0.6 mmol), (prepared as described in Example 4), was reacted with 1-(3-hydroxypropyl)-4-methylpiperazine (0.14 g, 0.9 mmol) to give 4-(4-fluoro-2-methylindol-5-yl)oxy-6-methoxy-7-(3-(4-methylpiperazin-1-yl)propoxy)cinnoline (80 mg, 28%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[CH:10]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=3)[S:8][C:7]=2[CH:19]=1.[C:20](Cl)(=[O:29])[C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=1.[Cl-].[Cl-].[Cl-].[Al+3]>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:10]([C:20]([C:21]3[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=3)=[O:29])=[C:9]([C:11]3[CH:12]=[CH:13][C:14]([O:17][CH3:18])=[CH:15][CH:16]=3)[S:8][C:7]=2[CH:19]=1
Reactant: COc1ccc(C(=O)Cl)cc1
Reactant: COc1ccc(-c2cc3ccc(OC)cc3s2)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: COc1ccc(C(=O)c2c(-c3ccc(OC)cc3)sc3cc(OC)ccc23)cc1
Reaction time: 8 h

Procedure:
To a suspension of 6-methoxy-2-(4-methoxyphenyl) -benzo[b]thiophene (2 g, 7.4 mmol), and ρ-anisoyl chloride in 110 mL of methylene chloride was added aluminum trichloride (4.93 g, 37 mmol) in three portions and the reaction was stirred overnight. It was then quenched with 200 mL of 2N sodium hydroxide and extracted with methylene chloride. The combined organic layers was washed with brine and dried over anhydrous magnesium sulfate. After filtration, concentration and silica gel column chromatography using 15% ethyl acetate—hexanes as eluant the title compound (1.73 g) was obtained.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][N:8]=[CH:9]2)=[CH:4][CH:3]=1.Br[CH:13]([CH2:23][O:24][CH3:25])[C:14]([NH:16][C:17]([CH3:22])([CH3:21])[C:18]#[C:19][CH3:20])=[O:15]>>[CH:9]1[C:10]2[C:5](=[CH:4][CH:3]=[C:2]([O:1][CH:13]([CH2:23][O:24][CH3:25])[C:14]([NH:16][C:17]([CH3:22])([C:18]#[C:19][CH3:20])[CH3:21])=[O:15])[CH:11]=2)[CH:6]=[CH:7][N:8]=1
Reactant: Oc1ccc2ccncc2c1
Reactant: CC#CC(C)(C)NC(=O)C(Br)COC
Product: CC#CC(C)(C)NC(=O)C(COC)Oc1ccc2ccncc2c1

Procedure:
In a similar procedure to Example 6, 7-hydroxyisoquinoline (commercially available) and 2-bromo-N-(4-methylpent-2-yn-4-yl) 3-methoxypropionamide were reacted to give 2-(7-isoquinolinyloxy)-N-(2-methylpent-3-yn-2-yl)-3-methoxypropionamide (Compound No. 2 of Table 49) as a colourless solid, m.p. 155-156° C.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[NH:9]1[C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[C:12]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[N:11]=[CH:10]1>C(#N)C>[Br:1][C:10]1[NH:9][C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[C:12]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[N:11]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)c1nc[nH]c1C(=O)OCC
Solvent: CC#N
Product: CCOC(=O)c1nc(Br)[nH]c1C(=O)OCC
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Under an argon atmosphere 3.30 g (18.54 mmol) N-bromosuccinimide were added to a solution of 2.60 g (12.25 mmol) diethyl imidazole-4,5-dicarboxylate in 30 ml acetonitrile. The solution was stirred for 24 hours in the dark at ambient temperature and then evaporated down. The residue was taken up in 150 ml of ethyl acetate and washed twice each with saturated aqueous sodium chloride solution and saturated aqueous sodium thiosulphate and once with saturated aqueous sodium chloride solution. The organic phase was dried over sodium sulphate and the solvent was removed.
Reaction SMILES: Cl.[OH:2][CH:3]([C:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[CH:19][CH:18]=1)[CH:4]([NH2:16])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([F:15])([F:14])[F:13])=[CH:8][CH:7]=1.[C:27]1([C:37](Cl)=[O:38])[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:30]=[CH:29][CH:28]=1.C(=O)([O-])O.[Na+]>C(OCC)(=O)C.O>[OH:2][CH:3]([C:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[CH:19][CH:18]=1)[CH:4]([NH:16][C:37]([C:27]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:30]=[CH:29][CH:28]=1)=[O:38])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([F:13])([F:14])[F:15])=[CH:8][CH:7]=1
Reactant: O=C(Cl)c1cccc2ccccc12
Reactant: NC(Cc1ccc(C(F)(F)F)cc1)C(O)c1cccc2ccccc12
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: O=C(NC(Cc1ccc(C(F)(F)F)cc1)C(O)c1cccc2ccccc12)c1cccc2ccccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.3 %

Procedure:
A solution of (1RS,2SR)-1-hydroxy-1-(1-naphthalenyl)-3-(4-(trifluoromethyl)phenyl)-2-propylamine hydrochloride (150 mg, 0.39 mmol) in ethyl acetate (5 ml) were added 1-naphthoyl chloride (89 ml, 0.59 mmol) and saturated aqueous sodium hydrogen carbonate (5 ml) and the mixture was stirred overnight at room temperature. The reaction solution was diluted with water (50 ml) and extracted with ethyl acetate (50 ml×2). The extract was washed with saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to give the title compound (172 mg, 88%).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[N:12]3[N:13]=[CH:14][CH:15]=[C:11]3[N:10]=[C:9]([NH2:16])[CH:8]=2)[CH2:3][CH2:2]1.[Br:17][C:18]1[CH:26]=[CH:25][C:21]([C:22](Cl)=[O:23])=[CH:20][CH:19]=1.O>N1C=CC=CC=1>[Br:17][C:18]1[CH:26]=[CH:25][C:21]([C:22]([NH:16][C:9]2[CH:8]=[C:7]([N:4]3[CH2:5][CH2:6][O:1][CH2:2][CH2:3]3)[N:12]3[N:13]=[CH:14][CH:15]=[C:11]3[N:10]=2)=[O:23])=[CH:20][CH:19]=1
Reactant: O=C(Cl)c1ccc(Br)cc1
Reactant: Nc1cc(N2CCOCC2)n2nccc2n1
Solvent: O
Solvent: c1ccncc1
Product: O=C(Nc1cc(N2CCOCC2)n2nccc2n1)c1ccc(Br)cc1
Reaction time: 1 h
Yield: 86.5 %

Procedure:
7-Morpholinopyrazolo[1,5-a]pyrimidin-5-amine (9A, 1.0 g, 4.6 mmol) was suspended in pyridine (10 ml), and 4-bromobenzoyl chloride (1.1 g, 4.8 mmol) was then added at 0° C. After 1 hour, water (200 ml) was added and the resulting precipitate was collected on a fritted glass funnel, washed with water twice, and then dried under a stream of nitrogen for 3 hours to give analytically pure product 4-bromo-N-(7-morpholinopyrazolo[1,5-a]pyrimidin-5-yl)benzamide (9B, 1.6 g, 87%). 1H NMR (400 MHz, DMSO-d6) δ=11.13 (s, 1 H), 8.10 (d, J=2.3 Hz, 1 H), 8.01-7.93 (m, 2 H), 7.77-7.71 (m, 2 H), 7.37 (s, 1 H), 6.38 (d, J=2.3 Hz, 1 H), 3.88-3.81 (m, 4 H), 3.77-3.70 (m, 4 H); ESI-MS: m/z 402.2 (M+H)+.
Reaction SMILES: [F:1][C:2]1[N:7]=[C:6]([CH:8]([OH:10])[CH3:9])[CH:5]=[CH:4][CH:3]=1.N1C=CN=C1.[Si:16](Cl)([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17].O>C(Cl)Cl>[CH3:20][C:19]([Si:16]([CH3:18])([CH3:17])[O:10][CH:8]([C:6]1[CH:5]=[CH:4][CH:3]=[C:2]([F:1])[N:7]=1)[CH3:9])([CH3:22])[CH3:21]
Reactant: CC(O)c1cccc(F)n1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: O
Solvent: ClCCl
Product: CC(O[Si](C)(C)C(C)(C)C)c1cccc(F)n1
Yield: 86 %

Procedure:
(+/−)-1-(6-Fluoro-2-pyridinyl)ethanol (0.707 g, 5.01 mmol) was dissolved in 50 mL of DCM with stirring, imidazole (0.750 g, 11.0 mmol) and tert-butyldimethylsilyl chloride (0.831 g, 5.51 mmol) were added. The reaction was stirred for 16 h and poured into water. The layers were separated, and the aqueous layer was washed with 1:1 EtOAc/hexanes. The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo to provide 1.10 g (86%) of the title compound, 1H NMR (400 MHz, DMSO-d6) δ 7.97 (m, 1H), 7.37 (m, 1H), 7.00 (m, 1H), 4.79 (q, J=6.4 Hz, 1H), 1.34 (d, 6.4 Hz, 3H), 0.85 (s, 9H), 0.04 (s, 3H), 0.03 (s, 3H).
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([NH:12][CH2:13][CH2:14][NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH3:23])[CH:8]=2)[N:3]=1.[S:24]1[C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=2[CH2:28][NH:27][CH2:26][CH2:25]1.C(N(CC)CC)C>C(O)CCC>[S:24]1[C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=2[CH2:28][N:27]([C:2]2[N:11]=[C:10]([NH:12][CH2:13][CH2:14][NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[C:9]3[C:4](=[CH:5][CH:6]=[C:7]([CH3:23])[CH:8]=3)[N:3]=2)[CH2:26][CH2:25]1
Reactant: Cc1ccc2nc(Cl)nc(NCCNC(=O)OC(C)(C)C)c2c1
Reactant: c1ccc2c(c1)CNCCS2
Solvent: CCCCO
Solvent: CCN(CC)CC
Product: Cc1ccc2nc(N3CCSc4ccccc4C3)nc(NCCNC(=O)OC(C)(C)C)c2c1
Temperature: 100 °C
Reaction time: 4 h
Yield: 55 %

Procedure:
To a solution of tert-butyl {2-[(2-chloro-6-methylquinazolin-4-yl)amino]ethyl}carbamate (460 mg, 1.366 mmol) in n-butanol (6 mL) was added 2,3,4,5-tetrahydro-1,4-benzothiazepine (248 mg, 1.50 mmol) and triethylamine (276 mg, 2.732 mmol). The mixture was heated with stirring at 100° C. in a sealed tube for 4 hours, and then concentrated in vacuo. The residue was purified by flash column chromatography to afford 350 mg of the desired product as a white solid (yield was 55%).
Reaction SMILES: Br[C:2]1[CH:23]=[C:22]([C:24]([CH3:27])([CH3:26])[CH3:25])[C:21]([O:28][CH3:29])=[CH:20][C:3]=1[CH2:4][N:5]1[C@H:9]([C:10]([CH3:18])([CH3:17])[O:11][SiH2:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH2:8][CH2:7][C:6]1=[O:19].[CH2:30]([O:37][C:38]1[C:43](B(O)O)=[CH:42][CH:41]=[CH:40][N:39]=1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.C([O-])([O-])=O.[Na+].[Na+]>CO.C(Cl)Cl.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>[CH2:30]([O:37][C:38]1[C:43]([C:2]2[CH:23]=[C:22]([C:24]([CH3:27])([CH3:26])[CH3:25])[C:21]([O:28][CH3:29])=[CH:20][C:3]=2[CH2:4][N:5]2[C@H:9]([C:10]([CH3:18])([CH3:17])[O:11][SiH2:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH2:8][CH2:7][C:6]2=[O:19])=[CH:42][CH:41]=[CH:40][N:39]=1)[C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: COc1cc(CN2C(=O)CC[C@H]2C(C)(C)O[SiH2]C(C)(C)C)c(Br)cc1C(C)(C)C
Reactant: OB(O)c1cccnc1OCc1ccccc1
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: ClCCl
Solvent: CO
Product: COc1cc(CN2C(=O)CC[C@H]2C(C)(C)O[SiH2]C(C)(C)C)c(-c2cccnc2OCc2ccccc2)cc1C(C)(C)C
Yield: 75 %

Procedure:
step 2—A sealed tube containing 104 (141 mg, 0.29 mmol), 2-benzyloxy-pyridin-3-yl boronic acid (100 mg, 0.44 mmol), Na2CO3 (92 mg, 0.87 mmol) and Pd(PPh3)4 (33 mg, 0.029 mmol) in a mixture of MeOH (1.5 mL) and DCM (0.5 mL) was irradiated in a microwave synthesizer at 100° C. for 30 min. The reaction mixture was diluted with DCM, filtered through a pad of CELITE and the filtrate was concentrated. The crude residue was purified on a preparative SiO2 TLC plate developed with 40% EtOAc/hexanes to afford 128 mg (75%) of (S)-1-[2-(2-benzyloxy-pyridin-3-yl)-4-tert-butyl-5-methoxy-benzyl]-5-(tert-butyl-dimethyl-silanyloxymethyl)-pyrrolidin-2-one (106).