Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]([C:7]([O:9][CH2:10][CH:11]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:17]2[C:12]1=[CH:13][CH:14]=[CH:15][CH:16]=2)=[O:8])[C@H:2]([C:4](O)=[O:5])[CH3:3].CN1CCOCC1.ClC(OCC(C)C)=O.[F:39][C:40]1[CH:45]=[C:44]([NH:46][C:47]2[CH:52]=[CH:51][C:50]([F:53])=[CH:49][CH:48]=2)[C:43]([NH2:54])=[CH:42][CH:41]=1.[NH4+].[Cl-]>C(Cl)Cl>[F:39][C:40]1[CH:41]=[CH:42][C:43]([NH:54][C:4](=[O:5])[C@@H:2]([NH:1][C:7](=[O:8])[O:9][CH2:10][CH:11]2[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:17]=3[C:18]3[C:23]2=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH3:3])=[C:44]([NH:46][C:47]2[CH:48]=[CH:49][C:50]([F:53])=[CH:51][CH:52]=2)[CH:45]=1
Reactant: Nc1ccc(F)cc1Nc1ccc(F)cc1
Reactant: C[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Agent: CC(C)COC(=O)Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: C[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)Nc1ccc(F)cc1Nc1ccc(F)cc1
Temperature: -10 °C
Reaction time: 0.5 h

Procedure:
To a −10° C. solution (NaCl-ice bath) of Fmoc-L-Ala-OH (4.45 g, 14.30 mmol) and N-methylmorpholine (1.573 mL, 14.30 mmol) in DCM (34.1 mL) was added isobutyl chloroformate (1.782 mL, 13.62 mmol). The resulting cloudy colorless mixture was stirred at −10° C. for 30 min. To the mixture was then added a solution of 5-fluoro-N1-(4-fluorophenyl)benzene-1,2-diamine (1.500 g, 6.81 mmol) in DCM (12.75 mL). The resulting mixture was stirred at −10° C. for 1 h, to which the cold mixture was added satd. aq. NH4Cl solution (100 mL). The precipitate was collected by filtration and washed with water (100 mL) to give (S)-(9H-fluoren-9-yl)methyl 1-(4-fluoro-2-(4-fluorophenylamino)phenylamino)-1-oxopropan-2-ylcarbamate as an off-white solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 9.42 (1H, s), 7.89 (2H, d, J=7.6 Hz), 7.63-7.78 (3H, m), 7.22-7.46 (6H, m), 6.96-7.14 (4H, m), 6.83 (1H, dd, J=11.2, 2.7 Hz), 6.67 (1H, td, J=8.5, 2.8 Hz), 4.11-4.33 (4H, m), 1.28 (3H, d, J=7.0 Hz); LC-MS (ESI) m/z 514.2 [M+H]+. The off-white solid was carried on crude without purification.
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[O:7][C:6]2[CH:8]=[CH:9][C:10]([N+:12]([O-:14])=[O:13])=[CH:11][C:5]=2[N:4]2[C:15](=[O:18])[NH:16][N:17]=[C:3]12.I[CH3:21].[H-].[Na+].O>CN(C=O)C>[CH3:21][N:16]1[C:15](=[O:18])[N:4]2[C:5]3[CH:11]=[C:10]([N+:12]([O-:14])=[O:13])[CH:9]=[CH:8][C:6]=3[O:7][C:2]([CH3:19])([CH3:1])[C:3]2=[N:17]1
Reactant: CC1(C)Oc2ccc([N+](=O)[O-])cc2-n2c1n[nH]c2=O
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cn1nc2n(c1=O)-c1cc([N+](=O)[O-])ccc1OC2(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 92 %

Procedure:
4,4-Dimethyl-8-nitro-2,4-dihydro-1H-benzo[b][1,2,4]triazolo[4,3-d][1,4]oxazin-1-one, iodomethane (73 μL, 1.2 eq.) were dissolved in DMF (4 mL). Sodium hydride (58 mg, 60% suspension in oil, 1.5 eq.) was added to the solution in an ice bath. The reaction mixture was stirred at room temperature for two hours. Water (15 mL) was added to the reaction. White precipitation was filtered and washed with water to give 2,4,4-trimethyl-8-nitro-2,4-dihydro-1H-benzo[b][1,2,4]triazolo[4,3-d][1,4]oxazin-1-one (249 mg, 92% yield in two steps).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[NH:5][CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1)[CH3:2].F[C:17]1[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[CH:19][CH:18]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[CH2:1]([O:3][C:4](=[O:15])[NH:5][CH2:6][CH2:7][C:8]1[CH:9]=[CH:10][C:11]([O:14][C:17]2[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[CH:19][CH:18]=2)=[CH:12][CH:13]=1)[CH3:2]
Reactant: CCOC(=O)NCCc1ccc(O)cc1
Reactant: N#Cc1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)NCCc1ccc(Oc2ccc(C#N)cc2)cc1
Temperature: 85 °C
Yield: 119.5 %

Procedure:
Combine 6.2 mmol of [2-(4-hydroxy-phenyl)-ethyl]-carbamic acid ethyl ester (3.6.0 g, 17.2 mmol), 4-fluorobenzonitrile (2.1 g, 17.2 mmol), cesium carbonate (11.2 g, 34.4 mmol), and N,N-dimethylformamide (80 mL), stir and heat at 85° C. for 18 hours. Cool to room temperature and evaporate on a rotary evaporator, took up residue in brine then extracted with ethyl acetate (3×50 mL). Dry the combined ethyl acetate extracts over sodium chloride/magnesium sulfate, filter, and concentrate on a rotary evaporator to yield the crude product (4.5 g). The crude product is purified by flash column chromatography on silica gel eluting with ethyl acetate and hexanes to yield {2-[4-(4-cyano-phenoxy)-phenyl]-ethyl}-carbamic acid ethyl ester (2.3 g): 1H NMR (CDCl3, 300.00 MHz): 7.66-7.60 (m, 2H), 7.31-7.24 (m, 2H), 7.07-7.00 (m, 4H), 4.72 (s, 1H), 4.16 (q, 2H, J=7.0 Hz), 3.48 (q, 2H, J=6.7 Hz), 2.86 (t, 2H, J=7.0 Hz), 1.27 (t, 3H, J=7.0 Hz).
Reaction SMILES: [N:1]1[C:8]([Cl:9])=[N:7][C:5](Cl)=[N:4][C:2]=1[Cl:3].[NH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(=O)(O)[O-].[Na+]>CC(C)=O>[Cl:9][C:8]1[N:1]=[C:2]([Cl:3])[N:4]=[C:5]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:7]=1
Reactant: Clc1nc(Cl)nc(Cl)n1
Reactant: Nc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Product: Clc1nc(Cl)nc(Nc2ccccc2)n1
Temperature: 0 °C
Yield: 94.2 %

Procedure:
To a suspension of cyanuric chloride (20 g, 108 mmol) in acetone (120 mL) and ice (50 mL) at 0° C. was added dropwise a solution of aniline (10 g, 107 mmol) in acetone (45 mL). At the end of the addition, the pH of the solution was adjusted from 1 to 7 with 5% aqueous sodium bicarbonate (150 mL). The precipitate was filtered, washed several times with water and dried in vacuo. This gave 2,4-dichloro-6-phenylamino-1,3,5-triazine as an off-white solid (24.3 g, 93% yield). The product was used in the next step without further purification. To a solution of the dichlorotriazine (6.2 g, 25.7 mmol) in THF (300 mL) at room temperature was added a solution of 2-(4-hydroxyphenyl)ethylamine (3.6 g, 25.9 mmol) in acetone (100 mL) and water (100 mL), followed by 5% aqueous sodium bicarbonate (50 mL). After 20 h reaction at room temperature, the solution was diluted with water (50 mL) and ethyl acetate (50 mL). The aqueous layer was extracted with ethyl acetate (2×50 mL). The organic layers were washed with brine (150 mL), dried over anhydrous sodium sulphate, filtered and evaporated to dryness. This gave 2-chloro-4-(2-[4-hydroxyphenyl]ethylamino)-6-phenylamino-1,3,5-triazine as an off-white solid (8.5 g, 97% yield). The product was used for the next step without further purification. This triazine derivative (384 mg, 1.1 mmol) was dissolved in THF (11 mL) at room temperature. To this solution was added ethylenediamine (68 μL, 1.0 mmol) followed by diisopropylethylamine (355 μL, 2.0 mmol). After 20 h at 50° C., the solution was diluted with methanol (10 mL) and concentrated under reduced pressure. The crude residue was purified on a Biotage™ 25S column (silica, hexane/AcOEt 9:1 to 0:1) to yield compound 1 as a white solid. Yield of product: 267 mg (78%); 1H NMR (300 MHz, CD3OD) δ 7.63 (m, 4H), 7.21 (t, 4H, J=7.6 Hz), 6.98 (m, 6H), 6.68 (d, 4H, J=7.9 Hz), 3.48 (m, 8H), 2.84 (m, 4H); LRMS (FAB+): m/z 672.0 (MH+); HRMS: Calc. for MH+ C36H39N12O2, 671.33191; found 671.33060; HPLC (method 1): 8.0 min.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][C:11]([N:13]([CH2:25]C(O)=O)[CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=1)=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:29]([C:35]([O:37][CH3:38])=[O:36])#[C:30][C:31]([O:33][CH3:34])=[O:32]>C(OC(=O)C)(=O)C>[CH3:34][O:33][C:31]([C:30]1[C:29]([C:35]([O:37][CH3:38])=[O:36])=[CH:25][N:13]([CH2:14][CH2:15][C:16]2[CH:17]=[CH:18][C:19]([N+:22]([O-:24])=[O:23])=[CH:20][CH:21]=2)[C:11]=1[CH2:10][CH2:9][NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])=[O:32]
Reactant: COC(=O)C#CC(=O)OC
Reactant: CC(C)(C)OC(=O)NCCC(=O)N(CCc1ccc([N+](=O)[O-])cc1)CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: COC(=O)c1cn(CCc2ccc([N+](=O)[O-])cc2)c(CCNC(=O)OC(C)(C)C)c1C(=O)OC
Temperature: 85 °C

Procedure:
To a mixture of {(3-tert-Butoxycarbonylamino-propionyl)-[2-(4-nitro-phenyl)-ethyl]-amino}-acetic acid (0.253 mmol) in 1 ml acetic anhydride is dimethyl acetylene dicarboxylate (0.278 mmol) added. After stirring at 85° C. for 4½ hours the solvent is evaporated in vacuo. The dark brown oil is chromatographed using ethyl acetate 2:Hexane 3 as a mobile phase to yield 2-(2-tert-Butoxycarbonylamino-ethyl)-1-[2-(4-nitro-phenyl)-ethyl]-1H-pyrrole-3,4-dicarboxylic acid dimethyl ester, 79 mg, as a yellow oil (66%): 1H NMR (CD3OD) 1.50 (s, 9H), 2.84 (t, 2H), 3.14-3.34 (m, 4H), 3.77 (s, 3H), 3.82 (s, 3H), 4.33 (t, 2H), 6.74 (t, 1H), 7.29 (s, 1H), 7.44 (d, 2H), 8.16 (d, 2H) LRMS calcd 475.50, found [M] 475.1.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH:7]([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[C:11]([F:21])[CH:10]=2)[CH3:8])[N:6]=1.[C:22](Cl)(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(N(CC)CC)C>O1CCCC1>[C:22]([NH:1][C:2]1[S:3][CH:4]=[C:5]([CH:7]([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)=[C:11]([F:21])[CH:10]=2)[CH3:8])[N:6]=1)(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CC(c1ccc(-c2ccccc2)c(F)c1)c1csc(N)n1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(c1ccc(-c2ccccc2)c(F)c1)c1csc(NC(=O)c2ccccc2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 68.6 %

Procedure:
To 2-amino-4-(1-(2-fluoro-4-biphenylyl)ethyl)thiazole (300 mg, 1.01 mmol) in tetrahydrofuran (15 ml) was added benzoyl chloride (145 mg, 1.03 mmol) and triethylamine (101 mg, 1.00 mmol) and the mixture was stirred at room temperature overnight. After reaction, the reaction mixture was filterated and evaporated under reduced pressure to a residue, which was chromatographed to afford 2-benzamido-4-(1-(2-fluoro-4-biphenylyl)ethyl)thiazole (279 mg, 69% yield): mp 147°-147.5° C.
Reaction SMILES: [CH:1]1([O:7][CH:8]([C:10]2[CH:19]=[CH:18][C:13]([C:14]([O:16]C)=[O:15])=[CH:12][CH:11]=2)[CH3:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Li+].Cl>CO.O>[CH:1]1([O:7][CH:8]([C:10]2[CH:19]=[CH:18][C:13]([C:14]([OH:16])=[O:15])=[CH:12][CH:11]=2)[CH3:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)c1ccc(C(C)OC2CCCCC2)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(OC1CCCCC1)c1ccc(C(=O)O)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 82.3 %

Procedure:
To the solution of methyl 4-(1-(cyclohexyloxy)ethyl)benzoate (60 mg, 0.23 mmol) in methanol and water (50 mL/10 mL) was added lithium hydroxide (100 mg, 4.2 mmol), the solution was stirred at room temperature for 12 hours. Then the solution was acidified by hydrogen chloride (1 N/mol) pH to 6, extracted with dichloromethane (80 mL*3), evaporated the solvent to give 4-(1-(cyclohexyl oxy)ethyl)benzoic acid (47 mg 82%).
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:12][CH2:11][C:10]2[C:13](Br)=[CH:14][S:15][C:9]=2[CH2:8][CH2:7]1)=[O:5])[CH3:2].[Zn](C)[CH3:18]>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH2:1]([O:3][C:4]([N:6]1[CH2:12][CH2:11][C:10]2[C:13]([CH3:18])=[CH:14][S:15][C:9]=2[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: C[Zn]C
Reactant: CCOC(=O)N1CCc2scc(Br)c2CC1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: C1COCCO1
Product: CCOC(=O)N1CCc2scc(C)c2CC1

Procedure:
The product of step (f) (375 mg, 1.23 mmol) was dissolved in 4 mL dioxane and treated with Me2Zn (1.25 mL of 2M in toluene) and Pd(dppf)2Cl2. After heating to 100° C. for 3h, the reaction was cooled, quenched with water, filtered through silica gel (washing with EtOAc), and concentrated to give 337 mg of the sub-title compound as an oil.
Reaction SMILES: [CH:1]([O:3][CH2:4][CH2:5][N:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]=[C:8]([C:16]([OH:18])=O)[C:7]1=[O:19])=[O:2].[NH2:20][C:21]1[NH:25][N:24]=[N:23][N:22]=1>O1CCCC1.CN(C)C=O>[CH:1]([O:3][CH2:4][CH2:5][N:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]=[C:8]([C:16]([NH:20][C:21]2[NH:25][N:24]=[N:23][N:22]=2)=[O:18])[C:7]1=[O:19])=[O:2]
Reactant: Nc1nnn[nH]1
Reactant: O=COCCn1c(=O)c(C(=O)O)nc2ccccc21
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: O=COCCn1c(=O)c(C(=O)Nc2nnn[nH]2)nc2ccccc21

Procedure:
4(2-Formyloxyethyl)-3,4-dihydro-3-oxo-2-quinoxalinecarboxylic acid (1 g) and N,N'-carbonyldiimidazole (0.6 g) in dry tetrahydrofuran (100 ml) were heated under reflux for 15 minutes. 5-Amino-1H-tetrazole (0.5 g) in dimethylformamide (5 ml) was added and the mixture was heated under reflux for 1 hour. The solid was collected and treated with aqueous hydrochloric acid (25 ml., 2N). It was filtered off, dried and crystallised from aqueous dimethylformamide. It had m.p. 240°-241° (d).
Reaction SMILES: [CH:1]1([C:6](=[O:17])[CH2:7][S:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:18](OC)(=[O:23])[CH2:19][C:20]([CH3:22])=[O:21]>>[CH:1]1([C:6]2([CH2:7][S:8][C:9]3[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=3)[O:17][C:18](=[O:23])[CH2:19][C:20](=[O:21])[CH2:22]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1ccc(SCC(=O)C2CCCC2)cc1
Reactant: COC(=O)CC(C)=O
Product: COc1ccc(SCC2(C3CCCC3)CC(=O)CC(=O)O2)cc1

Procedure:
1-Cyclopentyl-2-(4-methoxy-phenylsulfanyl)-ethanone (from Step 2 below) was subjected to the methyl acetoacetate dianion addition reaction described in the synthesis of Example A(82), to yield the title compound as a white solid. 1H NMR (CDCl3): δ 1.35-1.86 (brm, 8H), 2.35 (m, 1H), 2.61-3.62 (m, 6H), 3.85 (s, 3H), 6.82 (d, J=8.2 Hz, 2H), 7.44 (d, J=8.2 Hz, 2H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:12][CH2:11][CH:10]([C:13](Cl)=[O:14])[CH2:9][CH2:8]2)=[CH:3][CH:2]=1.[CH:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[CH:18][C:17]=1[S:26]([N:29]1[CH2:35][CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1)(=[O:28])=[O:27]>>[CH:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[CH:18][C:17]=1[S:26]([N:29]1[CH2:35][CH2:34][CH2:33][N:32]([C:13]([CH:10]2[CH2:11][CH2:12][N:7]([C:4]3[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=3)[CH2:8][CH2:9]2)=[O:14])[CH2:31][CH2:30]1)(=[O:28])=[O:27]
Reactant: O=C(Cl)C1CCN(c2ccncc2)CC1
Reactant: O=S(=O)(c1ccc2ccccc2c1)N1CCCNCC1
Product: O=C(C1CCN(c2ccncc2)CC1)N1CCCN(S(=O)(=O)c2ccc3ccccc3c2)CC1
Yield: 42 %

Procedure:
Using an analogous procedure to that described in Example 1, 1-(4-pyridyl)piperidine-4-carbonyl chloride was reacted with 1-(2-naphthylsulphonyl)-1,4-diazepane to give 1-(2-naphthylsulphonyl)-4-[1-(4-pyridyl)piperidin-4-ylcarbonyl]-1,4-diazepane in 42% yield, m.p. 178-180° C.;
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[OH:11].Br[CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17].C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CN(C)C=O>[F:1][C:2]([F:12])([F:13])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[O:11][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17]
Reactant: Oc1ccccc1OCC(F)(F)F
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)COc1ccccc1OCC(F)(F)F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 2-(2,2,2-trifluoroethoxy)phenol (200 mg) in dry N,N-dimethylformamide (2 ml) were added ethyl bromoacetate (138 μl) and potassium carbonate (216 mg), and the mixture was reacted with stirring at room temperature for 1 hour, and then for 1 hour at 60° C. To the reaction mixture was added ethyl acetate, and ethyl acetate solution was washed with water and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give 270 mg of ethyl 2-(2,2,2-trifluoroethoxy)phenoxyacetate as an oil.
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]1[C:20]([OH:21])=[C:19]([O:22][CH3:23])[C:18]([O:24][CH3:25])=[C:17]([O:26][Si:27]([C:40]([CH3:43])([CH3:42])[CH3:41])([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:16]=1[CH3:44])(=[O:3])[CH3:2].C(N(CC)CC)C.[C:52](Cl)(=[O:54])[CH3:53]>ClCCl>[C:52]([O:21][C:20]1[C:15]([CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][O:4][C:1](=[O:3])[CH3:2])=[C:16]([CH3:44])[C:17]([O:26][Si:27]([C:40]([CH3:43])([CH3:42])[CH3:41])([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)=[C:18]([O:24][CH3:25])[C:19]=1[O:22][CH3:23])(=[O:54])[CH3:53]
Reactant: CC(=O)Cl
Reactant: COc1c(O)c(CCCCCCCCCCOC(C)=O)c(C)c(O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)c1OC
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1c(O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)c(C)c(CCCCCCCCCCOC(C)=O)c(OC(C)=O)c1OC
Reaction time: 0.5 h
Yield: 71.5 %

Procedure:
6-(10-Acetoxydecyl)-4-tert-butyldiphenylsilyloxy-2,3-dimethoxy-5-methylphenol (0.65 g) was dissolved in dichloromethane (5 ml), and triethylamine (0.2 ml) followed by acetyl chloride (0.08 g) was added. The mixture was stirred at the same temperature for 30 minutes. The reaction mixture was concentrated, and then the residue was subjected to column chromatography on silica gel and eluted with hexane/ethyl acetate (9:1) to obtain the desired compound (0.483 g).
Reaction SMILES: [C:1]1([CH:7]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH2:8][NH:9][C:10]2[N:18]=[C:17]([CH2:19][NH:20][S:21]([CH2:24][CH:25]([CH3:27])[CH3:26])(=[O:23])=[O:22])[N:16]=[C:15]3[C:11]=2[N:12]=[CH:13][N:14]3C2CCCCO2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[ClH:40]>C(O)C>[ClH:40].[C:34]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:8][NH:9][C:10]2[N:18]=[C:17]([CH2:19][NH:20][S:21]([CH2:24][CH:25]([CH3:27])[CH3:26])(=[O:22])=[O:23])[N:16]=[C:15]3[C:11]=2[N:12]=[CH:13][NH:14]3)[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1
Reactant: CC(C)CS(=O)(=O)NCc1nc(NCC(c2ccccc2)c2ccccc2)c2ncn(C3CCCCO3)c2n1
Agent: Cl
Solvent: CCO
Product: CC(C)CS(=O)(=O)NCc1nc(NCC(c2ccccc2)c2ccccc2)c2nc[nH]c2n1
Reaction time: 18 h

Procedure:
A solution of N-({6-[(2,2-diphenylethyl)amino]-9-tetrahydro-2H-pyran-2-yl-9H-purin-2-yl}methyl)-2-methyl-1-propanesulphonamide (4.30 g, 7.84 mmol) (Preparation 7) in ethanol (100 ml) was heated to 37° C. and then treated with 2M aqueous hydrochloric acid (15 ml). The mixture was left to stand at room temperature for 18 hours, after which time a crystalline precipitate was filtered off, washed with ethanol (10 ml) and dried to afford the title compound as a solid (3.0 g).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[CH:15]=[CH:14][C:13]([CH2:16]C#N)=[CH:12][C:11]=1[F:19].Cl.[C:21](=[O:24])(O)[O-:22].[Na+].C>>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[CH:15]=[CH:14][C:13]([CH2:16][C:21]([OH:22])=[O:24])=[CH:12][C:11]=1[F:19]
Reactant: O=C([O-])O
Reactant: N#CCc1ccc(-c2nc3ccccc3o2)c(F)c1
Agent: Cl
Agent: [Na+]
Product: O=C(O)Cc1ccc(-c2nc3ccccc3o2)c(F)c1

Procedure:
A mixture of 0.7 gm. of the above crude 4-(benzoxazol-2-yl)-3-fluorophenylacetonitrile and 30 cc. of concentrated hydrochloric acid is heated on the steam bath for 1 hour. The reaction mixture is then filtered through a sintered glass filter into ice water and the resulting precipitate collected to give 0.65 gm. of crude product. The crude acid is stirred with 50-60 cc. of saturated sodium bicarbonate solution, a small amount of charcoal is added, and the mixture is then filtered. The filtrate is acidified with concentrated hydrochloric acid and the resulting precipitate collected and dried to give 4-(benzoxazol-2-yl)-3-fluorophenylacetic acid, m.p. 207°-211°C. dec.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:8][NH:9][C:10]([C:12]2[C:20]3[C:15](=[CH:16][C:17]([OH:21])=[CH:18][CH:19]=3)[N:14]([CH2:22][C:23]3[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=3)[C:13]=2[CH:29]([CH3:31])[CH3:30])=[O:11])[CH:5]=[N:6][CH:7]=1.[CH:32]1(I)[CH2:36][CH2:35][CH2:34][CH2:33]1>>[CH:32]1([O:21][C:17]2[CH:16]=[C:15]3[C:20]([C:12]([C:10]([NH:9][CH2:8][C:4]4[CH:5]=[N:6][CH:7]=[C:2]([F:1])[CH:3]=4)=[O:11])=[C:13]([CH:29]([CH3:31])[CH3:30])[N:14]3[CH2:22][C:23]3[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=3)=[CH:19][CH:18]=2)[CH2:36][CH2:35][CH2:34][CH2:33]1
Reactant: IC1CCCC1
Reactant: CC(C)c1c(C(=O)NCc2cncc(F)c2)c2ccc(O)cc2n1Cc1cccnc1
Product: CC(C)c1c(C(=O)NCc2cncc(F)c2)c2ccc(OC3CCCC3)cc2n1Cc1cccnc1

Procedure:
The title compound was prepared from N-((5-fluoropyridin-3-yl)methyl)-6-hydroxy-2-isopropyl-1-(pyridin-3-ylmethyl)-1H-indole-3-carboxamide (Compound 162) and cyclopentyl iodide by General Procedure N.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:14][CH2:13][C@H:12]([C:15]([OH:17])=O)[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:18]([C:20]1[CH:34]=[CH:33][C:23]([O:24][C:25]2[CH:26]=[C:27]([NH2:32])[CH:28]=[C:29]([OH:31])[CH:30]=2)=[CH:22][CH:21]=1)#[N:19]>>[C:1]([O:5][C:6](=[O:7])[NH:8][C@H:9]1[CH2:10][CH2:11][C@H:12]([C:15](=[O:17])[NH:32][C:27]2[CH:28]=[C:29]([OH:31])[CH:30]=[C:25]([O:24][C:23]3[CH:22]=[CH:21][C:20]([C:18]#[N:19])=[CH:34][CH:33]=3)[CH:26]=2)[CH2:13][CH2:14]1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](C(=O)O)CC1
Reactant: N#Cc1ccc(Oc2cc(N)cc(O)c2)cc1
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@H](C(=O)Nc2cc(O)cc(Oc3ccc(C#N)cc3)c2)CC1

Procedure:
Following the procedure of Example 9(e) Trans-4-tert-butoxycarbonylamino-cyclohexanecarboxylic acid 0.72 g (2.96 mmol) and [3-(4-cyano-phenoxy)-5-hydroxy-phenyl]-amine (0.67 g, 2.96 mmol) were used to afford 1.0 g of the required product. Percentage purity (LCMS): 73.5%, (M+1)=451.5+1.
Reaction SMILES: [Br:1][C:2]1[S:6][C:5](=[N:7][C:8]2[N:13]=[C:12]([CH2:14][N:15]3[CH2:20][CH2:19][N:18]([C:21](=[O:28])[C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[CH2:17][CH2:16]3)[CH:11]=[CH:10][CH:9]=2)[N:4](COC)[CH:3]=1.Cl.O1CCOCC1>C(Cl)(Cl)Cl>[Br:1][C:2]1[S:6][C:5]([NH:7][C:8]2[CH:9]=[CH:10][CH:11]=[C:12]([CH2:14][N:15]3[CH2:16][CH2:17][N:18]([C:21](=[O:28])[C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=4)[CH2:19][CH2:20]3)[N:13]=2)=[N:4][CH:3]=1
Reactant: COCn1cc(Br)sc1=Nc1cccc(CN2CCN(C(=O)c3ccccc3)CC2)n1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClC(Cl)Cl
Product: O=C(c1ccccc1)N1CCN(Cc2cccc(Nc3ncc(Br)s3)n2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 43.5 %

Procedure:
81 mg (0.161 mmol) of 1-(6-(5-bromo-3-methoxymethyl-3H-thiazol-2-ylideneamino)-pyridin-2-ylmethyl)-4-benzoyl-piperazine was dissolved in 10 ml of chloroform, a hydrochloric acid-1,4-dioxane solution (4 M, 4 ml) was added thereto and the mixture was stirred at room temperature for 18 hours. The reaction mixture was concentrated in vacuo, the residue was recrystallized from methanol-ether and filtered and the resulting white solid was dissolved in water (10 ml) and neutralized with sodium bicarbonate. The resulting precipitate was filtered to give 32 mg (0.070 mmol) of the title compound as a white solid.
Reaction SMILES: [NH3:1].Cl[C:3]1[N:8]=[C:7]([Cl:9])[N:6]=[C:5]([N:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)[N:4]=1>O1CCOCC1>[NH2:1][C:3]1[N:8]=[C:7]([Cl:9])[N:6]=[C:5]([N:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)[N:4]=1
Reactant: N
Reactant: Clc1nc(Cl)nc(N2CCCCC2)n1
Solvent: C1COCCO1
Product: Nc1nc(Cl)nc(N2CCCCC2)n1
Temperature: 70 °C
Yield: 98 %

Procedure:
Ammonia was bubbled for 5 min in a solution of 2,4-dichloro-6-piperidin-1-yl-[1,3,5]triazine (500 mg, 2.15 mmol) in dry 1,4-dioxane (20 mL). The solution was heated at 70° C. for 16 h in a sealed tube. The reaction mixture was allowed to cool to room temperature, and partitioned between AcOEt and a solution of sat. NH4Cl. After separation, the organic layer was washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated to afford the title compound 221 (453 mg, 2.12 mmol, 98% yield). LRMS: [MH]+=214.1.