Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][CH:8]=2)[N:5]=[C:4]([CH3:17])[C:3]=1[C:18](=O)[CH3:19].[CH3:21][O:22][C:23]([C:25]1[CH:34]=[CH:33][C:28]([C:29]([NH:31][NH2:32])=[O:30])=[CH:27][CH:26]=1)=[O:24]>>[CH3:17][C:4]1[C:3](=[C:18]([NH:32][NH:31][C:29](=[O:30])[C:28]2[CH:33]=[CH:34][C:25]([C:23]([O:22][CH3:21])=[O:24])=[CH:26][CH:27]=2)[CH3:19])[C:2](=[O:1])[N:6]([C:7]2[CH:12]=[CH:11][C:10]([C:13]([F:15])([F:16])[F:14])=[CH:9][CH:8]=2)[N:5]=1
Reactant: COC(=O)c1ccc(C(=O)NN)cc1
Reactant: CC(=O)c1c(C)nn(-c2ccc(C(F)(F)F)cc2)c1O
Product: COC(=O)c1ccc(C(=O)NNC(C)=C2C(=O)N(c3ccc(C(F)(F)F)cc3)N=C2C)cc1

Procedure:
From 1-(5-hydroxy-3-methyl-1-(4-trifluoromethylphenyl)-1H-pyrazol-4-yl)-ethanone and 4-methoxycarbonylbenzhydrazide, 58.9 mg of the desired product was obtained in the same manner as in Synthetic Example 4 as a yellow solid (yield 65%).
Reaction SMILES: [K].CC(C)([O-])C.[O:7]1[CH2:11][CH:10](O)[CH2:9][CH2:8]1.[N+:13]([C:16]1[C:17]([C:25]([OH:27])=[O:26])=[CH:18][C:19]2[O:23][CH2:22][O:21][C:20]=2[CH:24]=1)([O-:15])=[O:14].[CH2:28](Br)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CN(C)C=O>[N+:13]([C:16]1[CH:24]=[C:20]([O:21][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:19]([O:23][CH:22]2[CH2:10][CH2:11][O:7][CH2:8][CH2:9]2)=[CH:18][C:17]=1[C:25]([OH:27])=[O:26])([O-:15])=[O:14]
Reactant: O=C(O)c1cc2c(cc1[N+](=O)[O-])OCO2
Reactant: BrCc1ccccc1
Reactant: OC1CCOC1
Agent: CC(C)(C)[O-]
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [K]
Solvent: CN(C)C=O
Product: O=C(O)c1cc(OC2CCOCC2)c(OCc2ccccc2)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h

Procedure:
42.60 g potassium-tert.-butoxide are added to 38 ml of tetrahydrofuran-4-ol in 228 ml N,N-dimethylformamide while cooling with an ice bath. The mixture is stirred for one hour at ambient temperature, then 22.90 g 6-nitro-benzo[1,3]dioxol-5-carboxylic acid are added. After 1.5 hours the reaction is complete according to thin layer chromatography and 28.94 ml of benzylbromide are added dropwise while cooling with an ice bath. The reaction mixture is stirred overnight at ambient temperature, combined with 100 ml 10% citric acid and stirred for another day at ambient temperature. Then the reaction mixture is evaporated down in vacuo at 60° C. and added to 800 ml ice water. The aqueous phase is extracted with ethyl acetate and the combined extracts are washed with water and saturated sodium chloride solution, dried over magnesium sulphate and evaporated. The residue is stirred with diethyl ether, while 2-nitro-4-benzyloxy-5-(tetrahydropyran-4-yloxy)-benzoic acid crystallises out as a by-product. This is filtered off and the filtrate is evaporated down. The main product remaining is benzyl 2-nitro-4-benzyloxy-5-(tetrahydro-pyran-4-yloxy)-benzoate, which is saponified without any further purification to form carboxylic acid (see Example V).
Reaction SMILES: C[C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[CH3:9])[NH2:5].[CH3:10][CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][C:12]1=O.N1C2C=CC=C[C:21]=2N=N1>>[CH3:10][CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH:12]1[NH:5][C:4]1[CH:3]=[CH:2][C:8]([CH3:9])=[CH:7][C:6]=1[CH3:21]
Reactant: CC1CCCCC1=O
Reactant: c1ccc2[nH]nnc2c1
Reactant: Cc1ccc(N)cc1C
Product: Cc1ccc(NC2CCCCC2C)c(C)c1
Temperature: 120 °C

Procedure:
In a 100-mL flask, the following mixture is heated at 120° C. for 24 h: 12 g 3,4-dimethylaniline, 11 g 2-methylcyclohexanone and 12 g benzotriazole. The 2-methylcyclohexyl-2,4-dimethylphenylamine is isolated after reduction, as in step 1 of Example 1. 18 g of an oily product are isolated.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[CH2:27][CH2:28]C(O)=O)=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].C(O)(C)(C)C.C1(P([N:51]=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:16]=[CH:17][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[CH2:27][CH2:28][NH2:51])=[CH:19][CH:20]=3)=[CH:13][CH:14]=2)[CH2:7][CH2:8]1)=[O:5])[CH3:2]
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4CCC(=O)O)cc3)cc2)CC1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Solvent: CC(C)(C)O
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4CCN)cc3)cc2)CC1
Temperature: 100 °C
Reaction time: 4 h

Procedure:
1-{4′-[4-(2-Carboxy-ethyl)-3-methyl-isoxazol-5-yl]-biphenyl-4-yl}-cyclopropanecarboxylic acid ethyl ester (0.825 g, 1.97 mmol), tert-butanol (0.21 mL, 2.16 mmol), diphenylphosphoryl azide (0.47 mL, 2.16 mmol), and triethylamine (0.3 mL, 2.16 mmol) were combined in toluene (8 mL) and stirred at 100° C. for 4 hours. The reaction was cooled to 80° C. and additional tert-butanol (0.21 mL, 2.16 mmol) was added. After stirring overnight at 80° C., the reaction was cooled to room temperature and submitted to aqueous workup. The crude material was purified by silica gel chromatography (0-100% EtOAc in hexanes). Then, the isolated product was treated with 4 N HCl in 1,4-dioxane and stirred at 60° C. overnight. The solution was filtered and concentrated to give the title compound.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@H:8]([NH:12][P:13]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:14])[CH2:9][CH:10]=[CH2:11].NC1C=CC=CC=1O.[O-2].[Al+3].[O-2].[O-2].[Al+3].[CH2:40]([N:44](CCCC)[C:45]1C=C[C:48](/C=N/P(C2C=CC=CC=2)(C2C=CC=CC=2)=O)=[CH:47][CH:46]=1)[CH2:41][CH2:42][CH3:43]>ClCCl.C(OCC)C.CO>[CH2:40]([N:44]([CH2:45][CH2:46][CH2:47][CH3:48])[C:6]1[CH:5]=[CH:4][C:3]([C@H:8]([NH:12][P:13]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:14])[CH2:9][CH:10]=[CH2:11])=[CH:2][CH:7]=1)[CH2:41][CH2:42][CH3:43]
Reactant: CCCCN(CCCC)c1ccc(/C=N/P(=O)(c2ccccc2)c2ccccc2)cc1
Reactant: C=CC[C@@H](NP(=O)(c1ccccc1)c1ccccc1)c1ccccc1F
Agent: Nc1ccccc1O
Agent: [Al+3]
Agent: [O-2]
Solvent: CO
Solvent: ClCCl
Solvent: CCOCC
Product: C=CC[C@@H](NP(=O)(c1ccccc1)c1ccccc1)c1ccc(N(CCCC)CCCC)cc1
Reaction time: 6 h
Yield: 93 %

Procedure:
The title compound is synthesized analogously to 4b except for the following changes: 1) 2.5 mol % aminophenol 2g (instead of 3 mol % 2g) 2) 1.5 equiv. MeOH (instead of 2.5 equiv.). 3) Reaction time is six h. 4) After NaIO4 workup (see representative procedure above), the unpurified mixture is treated for 12 h while allowing it to stir with ˜1 g basic aluminum oxide in 4 mL dichloromethane:diethyl ether (1:1) to hydrolyze unreacted 3j, after which the aluminum oxide is filtered off and washed with dichloromethane and ethyl acetate (20 mL). The product is purified as described for 4b, affording 4j (44.2 mg, 0.0931 mmol, 93% yield) as a white solid. M.p.=83-84° C. IR (neat): 3154 (w, br), 3071 (w), 2955 (m), 2930 (m), 2870 (m), 1614 (m), 1519 (m), 1455 (m), 1436 (m), 1368 (w), 1283 (w), 1181 (s), 1107 (s), 1066 (m), 925 (m), 900 (m), 752 (w), 722 (s), 693 (s), 553 (s), 521 (s) cm−1; 1H NMR (400 MHz, CDCl3): δ 7.89-7.79 (4H, m), 7.49-7.32 (6H, m), 7.03 (2H, d, J=8.8 Hz), 6.54 (2H, d, J=8.8 Hz), 5.63 (1H, app ddt, J=17.2, 10.0, 7.2 Hz), 5.10-4.99 (2H, m), 4.26-4.19 (1H, m), 3.23 (4H, app dd, J=7.8, 7.2 Hz), 3.26-3.21 (1H, m, overlapping with the dd at 3.23), 2.75-2.58 (2H, m), 1.59-1.52 (4H, m), 1.40-1.30 (4H, app sextet, J=7.6 Hz), 0.96 (6H, t, J=7.6 Hz); 13C NMR (100 MHz, CDCl3): δ 147.3, 134.6, 133.6 (d, J=127.0 Hz), 132.6 (d, J=9.5 Hz), 132.4 (d, J=130.0 Hz), 131.9 (d, J=9.3 Hz), 131.7 (d, J=2.7 Hz), 131.6 (d, J=2.7 Hz), 129.2 (d, J=6.3 Hz), 128.4 (d, J=12.3 Hz), 128.3 (d, J=12.4 Hz), 127.6, 118.1, 111.5, 54.3, 50.9, 43.5 (d, J=3.7 Hz), 29.5, 20.4, 14.1; HRMS Calcd for C30H40N2OP [M+H]+: 475.28782. Found: 475.28783. [α]20D=+61.6 (c=1.33, CHCl3) for a 92:8 er sample. The enantiomeric purity of this compound was determined by HPLC analysis in comparison with authentic racemic material (Chiracel OD-H, 92:8 hexanes:i-PrOH, 0.5 mL/min, 220 nm): tR of 4j: 12 min (major) and 14 min (minor).
Reaction SMILES: C([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([CH2:17][C:18]2([O:52][CH3:53])[C:24](=[O:25])[N:23]([CH2:26][C:27]([N:29]([CH:38]([CH3:40])[CH3:39])[C:30]3[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=3)=[O:28])[C:22]3[CH:41]=[CH:42][CH:43]=[CH:44][C:21]=3[N:20]([C:45]3[CH:46]=[N:47][CH:48]=[CH:49][CH:50]=3)[C:19]2=[O:51])=[N:9]1)C1C=CC=CC=1.C(O)=O>[Cl-].[Na+].O.C(OCC)(=O)C.[Pd]>[NH:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([CH2:17][C:18]2([O:52][CH3:53])[C:24](=[O:25])[N:23]([CH2:26][C:27]([N:29]([CH:38]([CH3:40])[CH3:39])[C:30]3[CH:31]=[CH:32][C:33]([O:36][CH3:37])=[CH:34][CH:35]=3)=[O:28])[C:22]3[CH:41]=[CH:42][CH:43]=[CH:44][C:21]=3[N:20]([C:45]3[CH:46]=[N:47][CH:48]=[CH:49][CH:50]=3)[C:19]2=[O:51])=[N:9]1
Reactant: COc1ccc(N(C(=O)CN2C(=O)C(Cc3nn(Cc4ccccc4)c4ccccc34)(OC)C(=O)N(c3cccnc3)c3ccccc32)C(C)C)cc1
Agent: [Pd]
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: O=CO
Product: COc1ccc(N(C(=O)CN2C(=O)C(Cc3n[nH]c4ccccc34)(OC)C(=O)N(c3cccnc3)c3ccccc32)C(C)C)cc1
Temperature: 25 °C
Yield: 54.8 %

Procedure:
To a stirring solution of 350 mg (0.49 mmol) of 2-[3-(1-Benzyl-1H-indazol-3-ylmethyl)-3-methoxy-2,4-dioxo-5-pyridin-3-yl-2,3,4,5-tetrahydro-benzo[b][1,4]diazepin-1-yl]-N-isopropyl-N-(4-methoxy-phenyl)-acetamide, prepared as in Intermediate 55, in a 10 mL solution of 5% formic acid (v/v) in absolute ethanol/DMF 1/1 is added 350 mg of 10% palladium on carbon. The resulting mixture is heated to reflux for 3 h, then cooled to RT and filtered through a pad of Celite to remove the catalyst. The filtrate is concentrated, then poured into 50 mL of EtOAc and washed successively with 1N NaOH (1×50 mL) and H2O (1×50 mL). The organic layer is separated, dried (MgSO4), and the solvents removed in vacuo. Purification by silica gel flash column chromatography using hexane/EtOAc 1/2 as eluent afforded 166 mg of the title compound as a white solid: mp 207°-209° C.; 1H NMR (CDCl3, 400 MHz) δ10.05 (s, br, 1H), 8.43 (d, 1H, J=4.6), 8.29 (s, 1H), 7.94 (d, 1H, J=8.2), 7.56 (d, 1H, J=7.2), 7.39 (d, 1H, J=7.8), 7.29 (m, 2H), 7.25-7.09 (m, 5H), 6.98 (m, 3H), 6.65 (d, 1H, J=8.1), 5.06 (m, 1H), 4.25 (dd, 2H, J=16.0, 198.0), 4.07 (dd, 2H, J=16.2, 107.8), 3.84 (s, 3H), 3.21 (s, 3H), 1.12 (2×d, 6H, J=7.2); low resolution MS (FAB)m/e 619 (MH+), 618 (M+); Anal. (C35H34N6O5) Calcd. C, 67.95; H, 5.54; N, 13.58 Found C, 67.85; H, 5.51; N, 13.59.
Reaction SMILES: ClC1C=CC(O[C:7]2[CH:31]=[CH:30][C:10]([CH2:11][N:12]3[CH2:17][CH2:16][CH:15]([C:18]4[CH:19]=[C:20]([NH:24][C:25](=[O:29])[CH:26]([CH3:28])[CH3:27])[CH:21]=[CH:22][CH:23]=4)[CH2:14][CH2:13]3)=[CH:9][CH:8]=2)=CC=1.[CH2:34]([N:36]1C2C=CC(CN3CCC(C4C=CC(NC(=O)C(C)C)=CC=4)CC3)=CC=2[C:42]2[C:37]1=[CH:38][CH:39]=[CH:40][CH:41]=2)[CH3:35].C(N1C2C=CC(C=O)=CC=2C2C1=CC=CC=2)C.CC(C)C(NC1C=CC=C(C2CCNCC2)C=1)=O>>[CH2:34]([N:36]1[C:7]2[CH:8]=[CH:9][C:10]([CH2:11][N:12]3[CH2:17][CH2:16][CH:15]([C:18]4[CH:19]=[C:20]([NH:24][C:25](=[O:29])[CH:26]([CH3:28])[CH3:27])[CH:21]=[CH:22][CH:23]=4)[CH2:14][CH2:13]3)=[CH:30][C:31]=2[C:42]2[C:37]1=[CH:38][CH:39]=[CH:40][CH:41]=2)[CH3:35]
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(Cc3ccc(Oc4ccc(Cl)cc4)cc3)CC2)c1
Reactant: CCn1c2ccccc2c2cc(CN3CCC(c4ccc(NC(=O)C(C)C)cc4)CC3)ccc21
Agent: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Agent: CCn1c2ccccc2c2cc(C=O)ccc21
Product: CCn1c2ccccc2c2cc(CN3CCC(c4cccc(NC(=O)C(C)C)c4)CC3)ccc21
Yield: 95 %

Procedure:
According to the procedure used for the synthesis of N-(3-{1-[4-(4-CHLOROPHENOXY)BENZYL]-4-PIPERIDINYL}PHENYL)-2-METHYLPROPANAMIDE (Example 108) N-(4-{1-[(9-ethyl-9H-carbazol-3-yl)methyl]-4-piperidinyl}phenyl)-2-methylpropanamide, 9-ethyl-9H-carbazole-3-carbaldehyde and 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide afforded N-(3-{1-[(9-ethyl-9H-carbazol-3-yl)methyl]-4-piperidinyl}phenyl)-2-methylpropanamide (37 mg, 95%). 1H NMR (400 MHz, CDCl3) δ 8.24–6.29 (m, 12H), 4.37 (q, 2H, J=7.2 Hz), 3.82 (s, 2H), 3.23–3.06 (m, 2H), 2.65–2.38 (m, 2H), 2.31–2.11 (m, 2H), 2.01–1.73 (m, 4H), 1.43 (t, 3H, J=7.2 Hz), 1.25 (d, 6H, J=4.0 Hz); ESMS m/e: 454.3 (M+H)+.
Reaction SMILES: [CH3:1][C:2]([CH3:17])([CH3:16])[C:3]#[C:4][C:5]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[C:7]([F:14])[C:6]=1[NH2:15].N1C=CC=CC=1.[C:24](Cl)(=[O:28])[CH2:25][CH2:26][CH3:27]>C(Cl)Cl>[CH3:1][C:2]([CH3:17])([CH3:16])[C:3]#[C:4][C:5]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[C:7]([F:14])[C:6]=1[NH:15][C:24](=[O:28])[CH2:25][CH2:26][CH3:27]
Reactant: CCCC(=O)Cl
Reactant: CC(C)(C)C#Cc1cc([N+](=O)[O-])cc(F)c1N
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCC(=O)Nc1c(F)cc([N+](=O)[O-])cc1C#CC(C)(C)C
Temperature: 0 °C
Reaction time: 5 h
Yield: 61.4 %

Procedure:
To a solution of 2-(3,3-dimethyl-but-1-ynyl)-6-fluoro-4-nitro-phenylamine (4.0 g, 17 mmol) and pyridine (2.7 g, 34 mmol) in anhydrous CH2Cl2 (30 mL) was added and butyryl chloride (1.8 g, 17 mmol) dropwise at 0° C. After stirring for 5 h at 0° C., the reaction mixture was poured into ice (50 g) and extracted with CH2Cl2 (30 mL×3). The combined organic extracts were dried over anhydrous Na2SO4 and evaporated under vacuum to give N-[2-(3,3-dimethyl-but-1-ynyl)-6-fluoro-4-nitro-phenyl]-butyramide (3.2 g, 62%), which was used in the next step without further purification. 1H NMR (300 MHz, DMSO) δ 8.10 (dd, J=1.5, 2.7 Hz, 1H), 7.95 (dd, J=2.4, 9.6 Hz, 1H), 7.22 (brs, 1H), 2.45 (t, J=−7.5 Hz, 2H), 1.82 (m, 2H), 1.36 (s, 9H), 1.06 (t, J=7.5 Hz, 3H).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8]([CH:17]=[O:18])=[CH:7][CH:6]=1)(=[O:4])=[O:3].[Si]([C:23]([F:26])([F:25])[F:24])(C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-].Cl>C1COCC1>[F:24][C:23]([F:26])([F:25])[CH:17]([C:8]1[CH:7]=[CH:6][C:5]([S:2]([CH3:1])(=[O:3])=[O:4])=[CH:10][C:9]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[OH:18]
Reactant: CS(=O)(=O)c1ccc(C=O)c(-c2ccccc2)c1
Reactant: C[Si](C)(C)C(F)(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [F-]
Solvent: C1CCOC1
Product: CS(=O)(=O)c1ccc(C(O)C(F)(F)F)c(-c2ccccc2)c1
Reaction time: 2 h

Procedure:
To a solution of 5-(methylsulfonyl)-[1,1′-biphenyl]-2-carbaldehyde (1 g, 3.8 mmol) was added TMS-CF3 (1.0 g, 7.7 mmol) in THF (10 mL). The reaction was cooled to 0° C. to and TBAF (0.57 mL, 0.57 mmol) was added dropwise. The reaction mixture was stirred for 2 h, then 3 N HCl (2 mL) was added to the mixture and the reaction mixture was stirred for an additional 30 min. The mixture was extracted with ethyl acetate, washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. Purification on normal phase silica gel provided 2,2,2-trifluoro-1-(5-(methylsulfonyl)-[1,1′-biphenyl]-2-yl)ethanol as a white solid.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10](Cl)(=[O:12])=[O:11])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].CCN(CC)CC.[NH:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1>C(Cl)Cl>[N:21]1([S:10]([C:7]2[CH:8]=[CH:9][C:4]([C:1](=[O:3])[CH3:2])=[CH:5][CH:6]=2)(=[O:12])=[O:11])[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1
Reactant: C1COCCN1
Reactant: CC(=O)c1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)c1ccc(S(=O)(=O)N2CCOCC2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 72 %

Procedure:
To a suspension of 4-acetylbenzenesulfonyl chloride (5.5 g, 25 mmol) in CH2Cl2 (75 mL) and Et3N (2 equiv, 7.0 mL, 50 mmol) was added morpholine (1.5 equiv, 3.3 mL, 38 mmol) dropwise. The mixture was stirred at room temperature for 30 min. The mixture was then diluted with CH2Cl2 (100 mL) and washed with 5% HCl (2×50 mL), water (50 mL), and then brine (50 mL). The organic layer was dried (Na2SO4), filtered, and concentrated to afford crude 1-[4-(morpholine-4-sulfonyl)phenyl]ethanone (2) (4.78 g, 18 mmol, 71%): HPLC Retention Time; 5.82 min. (Method B) M+1, 270.0.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].[OH:30][C:31]1[CH:32]=[C:33]2[C:37](=[CH:38][CH:39]=1)[N:36]([CH3:40])[CH:35]=[CH:34]2>CC(N(C)C)=O>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH2:15][CH2:16][CH2:17][N:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1)[N:5]=[CH:4][N:3]=[C:2]2[O:30][C:31]1[CH:32]=[C:33]2[C:37](=[CH:38][CH:39]=1)[N:36]([CH3:40])[CH:35]=[CH:34]2
Reactant: Cn1ccc2cc(O)ccc21
Reactant: COc1cc2c(Cl)ncnc2cc1OCCCN1CCCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: COc1cc2c(Oc3ccc4c(ccn4C)c3)ncnc2cc1OCCCN1CCCCC1
Temperature: 90 °C
Reaction time: 4 h
Yield: 48.7 %

Procedure:
Nitrogen was bubbled through a mixture of 4-chloro-6-methoxy-7-(3-piperidinopropoxy)quinazoline (335 mg, 0.68 mmol), (prepared as described for the starting material in Example 67), potassium carbonate (281.5 mg, 2.04 mmol), 5-hydroxy-1-methylindole (100 mg, 0.68 mmol) and DMA (4.0 ml) for 5 minutes. The mixture was then stirred at 90° C. for 4 hours under an atmosphere of nitrogen and allowed to cool to ambient temperature. The reaction mixture was filtered and the filtrate evaporated under vacuum. The residue was purified by trituration with methanol then water to give 6-methoxy-4-(1-methylindol-5-yloxy)-7-(3-piperidinopropoxy)quinazoline (148 mg, 49%).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([NH:20][C@H:21]2[CH2:25][CH2:24][N:23]([C:26](OC(C)(C)C)=[O:27])[CH2:22]2)[C:5]2[N:10]=[C:9]([CH2:11][CH2:12][C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)[S:8][C:6]=2[N:7]=1.FC(F)(F)C(O)=O.C(N(C(C)C)CC)(C)C.[Cl:49][C:50]1[CH:60]=[CH:59][C:53]([O:54][CH2:55]C(Cl)=O)=[CH:52][CH:51]=1>ClCCl>[NH2:1][C:2]1[N:3]=[C:4]([NH:20][C@H:21]2[CH2:25][CH2:24][N:23]([C:26](=[O:27])[CH2:55][O:54][C:53]3[CH:59]=[CH:60][C:50]([Cl:49])=[CH:51][CH:52]=3)[CH2:22]2)[C:5]2[N:10]=[C:9]([CH2:11][CH2:12][C:13]3[CH:14]=[CH:15][C:16]([F:19])=[CH:17][CH:18]=3)[S:8][C:6]=2[N:7]=1
Reactant: O=C(Cl)COc1ccc(Cl)cc1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](Nc2nc(N)nc3sc(CCc4ccc(F)cc4)nc23)C1
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Nc1nc(N[C@H]2CCN(C(=O)COc3ccc(Cl)cc3)C2)c2nc(CCc3ccc(F)cc3)sc2n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 46.8 %

Procedure:
To a solution of 5-amino-2-[2-(4-fluorophenyl)ethyl]-7-(1-tert-butoxycarbonyl-pyrrolidin-3-(S) -ylamino)-thiazolo[5,4-d]pyrimidine (70 mg, 0.15 mmol) in dichloromethane (1 ml) was added trifluoroacetic acid (1 ml). The reaction mixture was stirred at room temperature for 2 hours after which the solvents were removed in vacuo. The residue was dissolved in dichloromethane (3 ml) and diisopropylethylamine (1.5 mmol, 252 μL) and 4-chlorophenoxyacetyl chloride (0.17 mmol) were added. The reaction mixture was stirred at room temperature for 16 hours whereupon the solvent was removed in vacuo. The resulting residue was purified by flash chromatography on silica, the mobile phase being a mixture of methanol and dichloromethane (in a ratio gradually ranging from 100% CH2Cl2 to 1.5% CH3OH in CH2Cl2), yielding the pure title compound (37 mg) which was characterized by its mass spectrum: MS m/z (%): 527 ([M+H]+, 100).
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9]2[C:14]([O:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:13][N:12]=[C:11]([C:23]([O:25]CC3C=CC=CC=3)=[O:24])[CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.[OH-].[K+].Cl>O1CCCC1>[C:1]1([CH2:7][O:8][C:9]2[C:14]([O:15][CH2:16][C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][N:12]=[C:11]([C:23]([OH:25])=[O:24])[CH:10]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(OCc1ccccc1)c1cc(OCc2ccccc2)c(OCc2ccccc2)cn1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1cc(OCc2ccccc2)c(OCc2ccccc2)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.6 %

Procedure:
To a solution of 11.8 g (28 mmol) of 4,5-bis(phenylmethoxy)-2-pyridinecarboxylic acid, phenylmethyl ester in 115 ml of tetrahydrofuran was added 16 ml of water and 35 ml of 1N potassium hydroxide. After stirring overnight at room temperature, 115 ml of water was added and the pH was adjusted to 2.5 with 1N hydrochloric acid. The acid was filtered off, washed with water and dried in vacuo, yielding 8.6 g of the title compound, melting point 203.6° C.
Reaction SMILES: C(O)(=O)COCCOCC(O)=O.C(Cl)(=O)C(Cl)=O.N[C:20]1[C:33]2[C:34]3=[C:35]4[C:30](=[CH:31][CH:32]=2)[CH:29]=[CH:28][CH:27]=[C:26]4[CH:25]=[CH:24][C:23]3=[CH:22][CH:21]=1.C(N(CC)CC)C>ClCCl.CN(C=O)C>[CH:27]1[C:26]2[C:35]3=[C:34]4[C:23](=[CH:24][CH:25]=2)[CH:22]=[CH:21][CH:20]=[C:33]4[CH:32]=[CH:31][C:30]3=[CH:29][CH:28]=1
Reactant: Nc1ccc2ccc3cccc4ccc1c2c34
Agent: O=C(Cl)C(=O)Cl
Agent: O=C(O)COCCOCC(=O)O
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: c1cc2ccc3cccc4ccc(c1)c2c34
Temperature: 25 °C
Reaction time: 4 h
Yield: 65 %

Procedure:
3,6-dioxaoctanedioic acid (0.28 mmol) was dispersed in 100 ml of dichloromethane (CH2Cl2) in which 0.1 ml of oxalyl chloride ((COCl)2) and 15 μl of DMF were added, to prepare a solution. After the solution was stirred at ambient temperature for 4 hours, volatiles were removed from the solution and the residue was re-dissolved in a small amount of dichloromethane. After the solution was added slowly to dichloromethane solution in which 152 mg (0.70 mmol) of 1-aminopyrene and 0.2 ml (1.4 mmol) of triethylamine were dissolved, the solution was reacted at ambient temperature for 4 hours and the volatiles were removed. And then, the resulting product was partitioned between water and dichloromethane and the organic phase was separated and washed with water; the solvent was removed from the obtained organic phase; and then, re-crystallization was carried out with a solvent combination of dichloromethane and methanol. The target product, a pyrene compound of 3,6-dioctanedioic acid was obtained (reddish green solid, yield: 65%).
Reaction SMILES: [C:1](=[S:3])=[S:2].[NH2:4][CH2:5][P:6](=[O:13])([O:10][CH2:11][CH3:12])[O:7][CH2:8][CH3:9].[OH-].[K+].[CH3:16]I>C(O)C>[CH2:8]([O:7][P:6]([O:10][CH2:11][CH3:12])([CH2:5][NH:4][C:1](=[S:3])[S:2][CH3:16])=[O:13])[CH3:9]
Reactant: S=C=S
Reactant: CCOP(=O)(CN)OCC
Reactant: CI
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CCOP(=O)(CNC(=S)SC)OCC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Carbon disulfide (0.88 ml, 1.11 g) was added dropwise to a stirred solution of 2.45 g (14.6 mmol) of diethyl aminomethylphosphonate and 0.82 g (14.6 mmol) of potassium hydroxide in 25 ml of ethanol. During addition the temperature of the reaction mixture rose from 26° to 33°. A second portion of 0.88 ml of carbon disulfide was added and the mixture was stirred at 50° for 1 hour. The mixture was cooled to ambient temperature, 2.08 g. (14.6 mmol) of methyl iodide was added dropwise and the resulting mixture was stirred for 1.5 hours. The mixture was evaporated to dryness, the residue was dissolved in water and the aqueous solution was extracted twice with ethyl acetate. The extracts were combined, dried (MgSO4) and evaporated to dryness to give methyl 1-diethoxyphosphinylmethyldithiocarbamate.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12](=[O:16])[CH2:13][CH2:14][CH3:15])=[C:5]2Cl.[NH2:18][C@H:19]1[CH2:24][CH2:23][C@H:22]([NH:25][C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])[CH2:21][CH2:20]1>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12](=[O:16])[CH2:13][CH2:14][CH3:15])=[C:5]2[NH:18][C@H:19]1[CH2:24][CH2:23][C@H:22]([NH:25][C:26](=[O:32])[O:27][C:28]([CH3:30])([CH3:29])[CH3:31])[CH2:21][CH2:20]1
Reactant: CCCC(=O)c1cnc2ccc(Br)cc2c1Cl
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](N)CC1
Product: CCCC(=O)c1cnc2ccc(Br)cc2c1N[C@H]1CC[C@H](NC(=O)OC(C)(C)C)CC1

Procedure:
Following general procedure B, 1-(6-bromo-4-chloroquinolin-3-yl)butan-1-one (470 mg, 1.50 mmol) was reacted with tert-butyl (trans-4-aminocyclohexyl)carbamate (643 mg, 3 mmol) to afford the desired product (498 mg, 68%) as a light orange solid. ESI MS m/z 490 [C24H32BrN3O3+H]+