Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[C:2]1[C:11]2[C:6](=[C:7]([CH3:12])[CH:8]=[CH:9][CH:10]=2)[C:5]([S:13]([NH2:16])(=[O:15])=[O:14])=[CH:4][N:3]=1.O=P(Cl)(Cl)[Cl:19]>>[Cl:19][C:2]1[C:11]2[C:6](=[C:7]([CH3:12])[CH:8]=[CH:9][CH:10]=2)[C:5]([S:13]([NH2:16])(=[O:15])=[O:14])=[CH:4][N:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1cccc2c(O)ncc(S(N)(=O)=O)c12
Product: Cc1cccc2c(Cl)ncc(S(N)(=O)=O)c12
Temperature: 110 °C
Yield: 80 %

Procedure:
A mixture of 1-hydroxy-5-methylisoquinolin-4-sulfonamide (Intermediate-40) (4 mmol) in POCl3 (10 mL) was heated to 110° C. for 30 min. Then, it was poured into ice water to give precipitate that was filtered, washed with water, and dried to yield the desired compound in 80-86% yield.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[N:5][N:6]=1.[CH2:7]([C:11]1[CH:16]=[CH:15][C:14]([S:17](Cl)(=[O:19])=[O:18])=[CH:13][CH:12]=1)[CH2:8][CH2:9][CH3:10].O>N1C=CC=CC=1>[CH2:7]([C:11]1[CH:16]=[CH:15][C:14]([S:17]([NH:1][C:2]2[S:3][CH:4]=[N:5][N:6]=2)(=[O:19])=[O:18])=[CH:13][CH:12]=1)[CH2:8][CH2:9][CH3:10]
Reactant: CCCCc1ccc(S(=O)(=O)Cl)cc1
Reactant: Nc1nncs1
Solvent: c1ccncc1
Solvent: O
Product: CCCCc1ccc(S(=O)(=O)Nc2nncs2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 58.9 %

Procedure:
To a stirred solution of 2-amino-1,3,4-thiadiazole (2.0 g, 19.7 mmol) in pyridine (30 mL) under argon at −20° C. was added p-butylbenzenesulfonyl chloride (4.89 g, 21 mmol) over 10 min. The reaction mixture was stirred at room temperature for 16 hours. Water (300 mL) was added to quench the reaction. The mixture was extracted with CH2Cl2 and the organic extracts washed with 2N HCl (2×150 mL), brine, dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by flash chromatography on silica gel eluted with methanol:DCM 1:33 to give the product (3.46 g, 11.6 mmol, 59% yield) as a solid, mp 120-121° C.; 1H NMR (300 MHz, CDCl3) δ 0.91 (t, 3H, J=7 Hz), 1.29-1.37 (m, 2H), 1.56-1.61 (m, 2H), 2.65 (t, 2H, J=7 Hz), 7.27 (d, 2H, J=8 Hz), 7.84 (d, 2H, J=8 Hz), 8.25 (s, 1H); 13C NMR (75 MHz, CDCl3) 13.9, 22.3, 33.2, 33.6, 126.5, 129.1, 138.1, 142.7, 148.6, 167.4; MS (Q-TOF) Calcd for C12H16N3O2S2 298.0684, found 298.0695 (M+H)+; Calcd for C12H15N3N3O2S2 320.0503, found 320.0361 (M+Na)+.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:12][C:13]2[CH:17]=[C:16]([CH3:18])[NH:15][N:14]=2)[N:3]=1.[N:19]1[CH:24]=[CH:23][C:22]([NH2:25])=[CH:21][CH:20]=1>>[CH3:18][C:16]1[NH:15][N:14]=[C:13]([NH:12][C:4]2[N:3]=[C:2]([NH:25][C:22]3[CH:23]=[CH:24][N:19]=[CH:20][CH:21]=3)[C:11]3[C:6]([CH:5]=2)=[CH:7][CH:8]=[CH:9][CH:10]=3)[CH:17]=1
Reactant: Nc1ccncc1
Reactant: Cc1cc(Nc2cc3ccccc3c(Cl)n2)n[nH]1
Product: Cc1cc(Nc2cc3ccccc3c(Nc3ccncc3)n2)n[nH]1

Procedure:
Similar procedure as described in example 273 was used, starting (1-chloro-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine and pyridin-4-ylamine to give N3-(5-methyl-1H-pyrazol-3-yl)-N1-pyridin-4-yl-isoquinoline-1,3-diamine. LC-MS m/e 317(MH+).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[CH:6][C:5]([CH:8]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH3:9])=[CH:4][CH:3]=1.C([Li])(C)(C)C.[I:23]I>C1COCC1>[I:23][C:4]1[CH:3]=[C:2]([CH3:1])[N:7]=[CH:6][C:5]=1[CH:8]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH3:9]
Reactant: Cc1ccc(C(C)NC(=O)OC(C)(C)C)cn1
Reactant: II
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: Cc1cc(I)c(C(C)NC(=O)OC(C)(C)C)cn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 5.9 %

Procedure:
Add a solution of tert-butyl 1-(6-methylpyridin-3-yl)ethylcarbamate (6.85 g, 29 mmol) to a solution of tert-butyllithium (51.1 mL, 87 mmol) in THF (70 mL) at −78° C. in THF (20 mL) under N2 using a double-tipped needle. After 30 min, add iodine (11.0 g, 43.5 mmol) in THF (25 mL) over 30 min at −78° C. Stir for 1 h and then warm up to RT. Quench with water, extract in ethyl acetate, wash with saturated aqueous sodium chloride, and dry over Na2SO4. Purify on column chromatography 5% to 50% ethyl acetate in hexanes to obtain the title compound (620 mg). MS (ES) m/z 363 [M+1]+.
Reaction SMILES: N1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7]CCCl.[N:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[N:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1.[I-].[K+].[CH3:25][N:26]([CH3:29])C=O>>[N:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[N:17]1[CH2:18][CH2:19][N:20]([CH2:6][CH2:5][CH2:4][C:3]2[CH:25]=[N:26][CH:29]=[CH:7][CH:2]=2)[CH2:21][CH2:22]1
Reactant: c1ccc(N2CCNCC2)nc1
Reactant: CN(C)C=O
Reactant: ClCCCc1ccccn1
Agent: [I-]
Agent: [K+]
Product: c1ccc(N2CCN(CCCc3cccnc3)CC2)nc1
Temperature: 80 °C

Procedure:
A solution of 3-pyridinylpropylchloride (Example A) (3.0 g, 0.0193 mol), 1-(2-pyridinyl)piperazine (3.15 g, 0.0193 mol), potassium iodide (0.8 g, 0.005 mol) is dissolved in N,N-dimethylformamide (80 mL) and heated to 80° C. for 12 hours. The reaction is cooled and the precipitate is filtered. The filtrate is washed with sodium carbonate and extracted with dichloromethane. The organic layer is evaporated in vacuo and the residue is purified by column chromatography (silica gel, 10% ethanol/ethyl acetate). The major product is taken up in diethyl ether and the precipitate is filtered. The filtrate is evaporated in vacuo to give 0.8 g of 1-(2-pyridinyl)-4-[3-(3-pyridinyl)propyl]piperazine as a white solid; mp 51-52° C.
Reaction SMILES: [CH:1]1([N:7]2[CH2:13][C:12]([F:15])([F:14])[C:11](=[O:16])[N:10]([CH3:17])[C:9]3[CH:18]=[N:19][C:20]([NH:22][C:23]4[CH:31]=[CH:30][C:26]([C:27](O)=[O:28])=[CH:25][C:24]=4[O:32][CH3:33])=[N:21][C:8]2=3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:58][N:59]([CH3:64])[CH2:60][CH2:61][CH2:62][NH2:63]>>[CH:1]1([N:7]2[CH2:13][C:12]([F:15])([F:14])[C:11](=[O:16])[N:10]([CH3:17])[C:9]3[CH:18]=[N:19][C:20]([NH:22][C:23]4[CH:31]=[CH:30][C:26]([C:27]([NH:63][CH2:62][CH2:61][CH2:60][N:59]([CH3:64])[CH3:58])=[O:28])=[CH:25][C:24]=4[O:32][CH3:33])=[N:21][C:8]2=3)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCCC1)CC(F)(F)C(=O)N2C
Reactant: CN(C)CCCN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: COc1cc(C(=O)NCCCN(C)C)ccc1Nc1ncc2c(n1)N(C1CCCCC1)CC(F)(F)C(=O)N2C

Procedure:
The title compound was synthesized from 4-(9-cyclohexyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b][1,4]diazepin-2-ylamino)-3-methoxybenzoic acid as described in the General procedure for amide bond synthesis using HATU and N,N-dimethyl-1,3-propanediamine. The final compound was purified by reverse phase HPLC and basified to give the free base. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.14-1.49 (m, 3 H) 1.53-1.87 (m., 9 H) 2.13 (s, 6 H) 2.25 (t, J=6.44 Hz, 2 H) 3.29 (m, 2 H) 3.31 (s, 3 H) 3.93 (s, 3 H) 4.06 (t, J=13.26 Hz, 2 H) 4.46 (m, 1 H) 7.46 (d, J=8.0 Hz, 1 H) 7.51 (s, 1 H) 7.90 (s, 1 H) 8.21 (s, 1 H) 8.27 (d, J=8.08 Hz, 1 H) 8.48 (br. s., 1 H). [M+H] calculated for C27H37F2N7O3, 546; found 546.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].S([O:12][CH3:13])(OC)(=O)=O.[C:14]([NH:22][C:23]1[CH:31]=[C:30]([I:32])[CH:29]=[CH:28][C:24]=1[C:25](O)=[O:26])(=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.Cl>C(OCC)(=O)C.CN(C)C=O>[C:14]([NH:22][C:23]1[CH:31]=[C:30]([I:32])[CH:29]=[CH:28][C:24]=1[C:25]([O:12][CH3:13])=[O:26])(=[O:21])[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: O=C(Nc1cc(I)ccc1C(=O)O)c1ccccc1
Reactant: COS(=O)(=O)OC
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(I)cc1NC(=O)c1ccccc1
Reaction time: 1 h

Procedure:
0.62 g of potassium carbonate and 0.43 ml of dimethyl sulfate were added to 15 mL of N,N-dimethylformamide solution containing 1.5 g of 2-(benzamido)-4-iodobenzoic acid at room temperature and stirred at the same temperature for 1 hour. Ethyl acetate and 1.0 mol/L hydrochloric acid were added to the reaction mixture. The organic layer was separated and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residual was purified with silica gel column chromatography [eluent; hexane:ethyl acetate=5:1] to obtain 1.3 g of methyl 2-(benzamido)-4-iodobenzoate as white solid.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][C@@H:7]([CH2:12][OH:13])[CH2:6][CH2:5]2.[Si:14](Cl)([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15].N1C=CN=C1.O>CN(C=O)C>[I:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][C@@H:7]([CH2:12][O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15])[CH2:6][CH2:5]2
Reactant: OC[C@H]1CCc2cc(I)ccc2O1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)[Si](C)(C)OC[C@H]1CCc2cc(I)ccc2O1
Temperature: 27 °C
Reaction time: 8 h
Yield: 79 %

Procedure:
A reaction mixture containing [(2R)-6-iodo-3,4-dihydro-2H-chromen-2-yl]methanol (Example 8, 5 g, 17.2 mmol, 1.0 eq), tert-butyldimethylsilyl chloride (20.6 mmol, 1.2 eq), and imidazole (43 mmol, 2.5 eq) in anhydrous DMF (35 mL) was stirred at 27° C. overnight. The resulting mixture was then cooled to room temperature, poured into water, and extracted with diethyl ether. The organic extract was washed with water, brine, dried over anhydrous sodium sulfate, concentrated, and purified by medium pressure column chromatography (Biotage 40S normal phase silica gel column) providing the product in 79% yield; m/z=405 [MH=].
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[C:11]([CH2:13][S:14]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)(=[O:16])=[O:15])[CH:10]=[CH:9][C:8]=2[NH:23][C:24]([C:26]2[N:27](COCC[Si](C)(C)C)[CH:28]=[C:29]([C:31]#[N:32])[N:30]=2)=[O:25])[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl.CCO>[C:1]1([C:7]2[CH:12]=[C:11]([CH2:13][S:14]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)(=[O:15])=[O:16])[CH:10]=[CH:9][C:8]=2[NH:23][C:24]([C:26]2[NH:27][CH:28]=[C:29]([C:31]#[N:32])[N:30]=2)=[O:25])[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1
Reactant: C[Si](C)(C)CCOCn1cc(C#N)nc1C(=O)Nc1ccc(CS(=O)(=O)N2CCOCC2)cc1C1=CCCCC1
Solvent: CCO
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#Cc1c[nH]c(C(=O)Nc2ccc(CS(=O)(=O)N3CCOCC3)cc2C2=CCCCC2)n1
Temperature: 25 °C
Reaction time: 6 h
Yield: 95 %

Procedure:
To a solution of 4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylic acid [2-cyclohex-1-enyl-4-(morpholine-4-sulfonylmethyl)-phenyl]-amide (as prepared in the previous step, 33.7 mg, 0.057 mmol) in DCM (0.5 mL) and EtOH (10 μL), TFA (0.10 mL) was added. The resulting solution was stirred at RT for 6 h and concentrated in vacuo. The residue obtained was dried and purified on silica (30% EtOAc/hexane) to obtain the title compound (11 mg, 95%): 1H-NMR (CDCl3; 400 MHz): δ 9.63 (s, 1H), 8.43 (d, 1H, J=8.4 Hz), 7.73 (s, 1H), 7.36 (dd, 1H, J=8.4, 1.9 Hz), 7.25 (d, 1H, J=1.9 Hz), 5.85 (br s, 1H), 4.12 (s, 2H), 3.66-3.68 (m, 4H), 3.17-3.19 (m, 4H), 2.19-2.23 (m, 4H), 1.62-1.85 (m, 4H). Mass spectrum (ESI, m/z): Calcd. for C22H25N5O4S, 456.2 (M+H). found 455.9.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][C:5]([C:7]1[CH:17]=[CH:16][C:15]2[C:18]3[C:8]=1[CH2:9][CH2:10][C:11]=3[CH:12]=[CH:13][C:14]=2[C:19](=[O:24])[CH2:20][CH2:21][CH2:22]Cl)=[O:6].[I-].[K+].[CH2:27]([NH:29][CH2:30][CH3:31])[CH3:28]>>[ClH:1].[ClH:1].[CH2:27]([N:29]([CH2:30][CH3:31])[CH2:2][CH2:3][CH2:4][C:5]([C:7]1[CH:17]=[CH:16][C:15]2[C:18]3[C:8]=1[CH2:9][CH2:10][C:11]=3[CH:12]=[CH:13][C:14]=2[C:19](=[O:24])[CH2:20][CH2:21][CH2:22][N:29]([CH2:30][CH3:31])[CH2:27][CH3:28])=[O:6])[CH3:28]
Reactant: CCNCC
Reactant: O=C(CCCCl)c1ccc2c(C(=O)CCCCl)ccc3c2c1CC3
Agent: [I-]
Agent: [K+]
Product: CCN(CC)CCCC(=O)c1ccc2c(C(=O)CCCN(CC)CC)ccc3c2c1CC3
Product: Cl
Temperature: 120 °C

Procedure:
A mixture of 36.1 g (0.10 mole) of 3,6-bis(4-chlorobutyryl)acenaphthene, 2 g of potassium iodide, 100 ml of diethylamine and 100 ml of tetrhydrofuran is placed in a bomb and heated for 24 hours at 120°C. Upon cooling, the mixture is filtered and the filtrate evaporated to dryness. The cooled residue is dissolved in 300 ml of 10% hydrochloric acid, filtered and the acid filtrate made alkaline with a 20% sodium hydroxide solution. The resulting 3,6-bis[4-(diethylamino)butyryl]acenaphthene so obtained is filtered and subsequently recrystallized from a methanol-ethyl acetate solution.
Reaction SMILES: C(OC(=O)[N:7]([CH2:14][CH2:15][NH:16][C:17]1[N:22]2[N:23]=[C:24]([CH3:36])[C:25]([C:26]3[C:31]([Cl:32])=[CH:30][C:29]([CH2:33][CH3:34])=[CH:28][C:27]=3[Cl:35])=[C:21]2[N:20]=[C:19]([CH3:37])[CH:18]=1)[CH:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1)(C)(C)C>C(O)C>[ClH:32].[Cl:35][C:27]1[CH:28]=[C:29]([CH2:33][CH3:34])[CH:30]=[C:31]([Cl:32])[C:26]=1[C:25]1[C:24]([CH3:36])=[N:23][N:22]2[C:17]([NH:16][CH2:15][CH2:14][NH:7][CH:8]3[CH2:9][CH2:10][O:11][CH2:12][CH2:13]3)=[CH:18][C:19]([CH3:37])=[N:20][C:21]=12
Reactant: CCc1cc(Cl)c(-c2c(C)nn3c(NCCN(C(=O)OC(C)(C)C)C4CCOCC4)cc(C)nc23)c(Cl)c1
Solvent: CCO
Product: CCc1cc(Cl)c(-c2c(C)nn3c(NCCNC4CCOCC4)cc(C)nc23)c(Cl)c1
Product: Cl
Temperature: 50 °C
Reaction time: 0.25 h
Yield: 194 %

Procedure:
To {2-[3-(2,6-dichloro-4-ethyl-phenyl)-2,5-dimethyl-pyrazolo[1,5-a]pyrimidin-7-ylamino]-ethyl}-(tetrahydro-pyran-4-yl)-carbamic acid tert-butyl ester (0.18 g, 0.31 mmol) 2:1 ethanol/concentrated aqueous hydrochloric acid (3 mL). The reaction was stirred 15 minutes at 50° C., concentrated under reduced pressure, and then concentrated 3 additional times from ethanol to give a solid that was triturated from ether to afford the title compound (0.15 g, quantitative): +APcI MS (M+1)+462; 1H NMR (methanol-d4) δ: 7.48 (s, 2H), 6.81 (s, 1H), 2.72 (q, 2H), 2.60 (s, 3H), 2.30 (s, 3H), 1.28 (t, 3H
Reaction SMILES: [CH:1]1[C:6]2[C:7]([O:9][C:10](=[O:11])[C:5]=2[CH:4]=[C:3]2[C:12]([O:14][C:15](=[O:16])[C:2]=12)=[O:13])=[O:8].C(N(C(C)C)CC)(C)C.[O:26]([C:33]1[CH:34]=[C:35]([CH:48]=[CH:49][CH:50]=1)[CH2:36][NH:37][C@@H:38]1[C:47]2[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=2)[CH2:41][CH2:40][CH2:39]1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.[N:51]#[C:52][NH2:53]>>[C:52]([NH:53][C:7]([C:6]1[CH:1]=[C:2]([C:15]([N:37]([CH2:36][C:35]2[CH:48]=[CH:49][CH:50]=[C:33]([O:26][C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH:34]=2)[C@@H:38]2[C:47]3[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=3)[CH2:41][CH2:40][CH2:39]2)=[O:16])[C:3]([C:12]([OH:14])=[O:13])=[CH:4][C:5]=1[C:10]([OH:9])=[O:11])=[O:8])#[N:51]
Reactant: c1ccc(Oc2cccc(CN[C@H]3CCCc4ccccc43)c2)cc1
Reactant: N#CN
Reactant: O=c1oc(=O)c2cc3c(=O)oc(=O)c3cc12
Solvent: CCN(C(C)C)C(C)C
Product: N#CNC(=O)c1cc(C(=O)N(Cc2cccc(Oc3ccccc3)c2)[C@H]2CCCc3ccccc32)c(C(=O)O)cc1C(=O)O
Yield: 9 %

Procedure:
1,2,4,5-Benzenetetracarboxylic dianhydride (1 mmol), diisopropylethyl amine, N-(3-phenoxybenzyl)-N-[(1S)-1,2,3,4-tetrahydro-1-naphthalenyl]amine and cyanamide were processed as described in Example 100 to provide the title compounds as a white solid (52 mg, 9% yield).
Reaction SMILES: [OH:1][C:2]1[C:15]2[C@:14]34[CH2:16][CH2:17][N:18]([CH3:19])[C@@H:8]([C@@H:9]3[CH2:10][CH2:11][C:12](=[O:20])[CH2:13]4)[CH2:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[C:21](OC(=O)C)(=[O:23])[CH3:22]>N1C=CC=CC=1>[C:21]([O:1][C:2]1[C:15]2[C@:14]34[CH2:16][CH2:17][N:18]([CH3:19])[C@@H:8]([C@@H:9]3[CH2:10][CH2:11][C:12](=[O:20])[CH2:13]4)[CH2:7][C:6]=2[CH:5]=[CH:4][CH:3]=1)(=[O:23])[CH3:22]
Reactant: CN1CC[C@]23CC(=O)CC[C@H]2[C@H]1Cc1cccc(O)c13
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)Oc1cccc2c1[C@]13CCN(C)[C@H](C2)[C@@H]1CCC(=O)C3
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of (-)-4-hydroxy-N-methylmorphinan-6-one (500 mg, 1.84 mmol), acetic anhydride (5 ml), and pyridine (10 ml) was stirred at room temperature overnight. Acetic anhydride and pyridine were evaporated under vacuum and the residue was taken into toluene and evaporated again. The crude product was taken into CHCl3 and washed with H2O, dried and evaporated to give a foam which was recrystallized from iPr2O-hexane to afford (301 mg, 65%). An analytical sample was recrystallized from iPr2 : mp 96°-97°; [α]D26 -46.7° (c 1.126, CHCl3).
Reaction SMILES: [CH2:1]([N:5]1[C:14]2[C:13]3[CH2:15][CH2:16][CH2:17][NH:18][C:12]=3[CH:11]=[CH:10][C:9]=2[NH:8][C:7](=[O:19])[C:6]1=[O:20])[CH2:2][CH2:3][CH3:4].CN(C)C=O.ClCCl.[CH3:29][S:30](Cl)(=[O:32])=[O:31]>C(N(CC)CC)C>[CH2:1]([N:5]1[C:14]2[C:13]3[CH2:15][CH2:16][CH2:17][N:18]([S:30]([CH3:29])(=[O:32])=[O:31])[C:12]=3[CH:11]=[CH:10][C:9]=2[NH:8][C:7](=[O:19])[C:6]1=[O:20])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCn1c(=O)c(=O)[nH]c2ccc3c(c21)CCCN3
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCCCn1c(=O)c(=O)[nH]c2ccc3c(c21)CCCN3S(C)(=O)=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 19 %

Procedure:
The product from Example 89 (0.12 g, 0.45 mmol) was solubilized in a minimal amount of dimethylformamide and then treated with 2 mL dichloromethane, methanesulfonyl chloride (0.17 g) and triethylamine (0.15 g). After stirring at room temperature for 4 h, the mixture was washed with water, dried over sodium sulfate, filtered and evaporated. The residue was purified by silica gel chromatography (4:1 heptane:ethyl acetate as eluant) to give the title compound (30 mg, 17% yield).
Reaction SMILES: [C:1]([C:3]1[CH:23]=[CH:22][C:6]([O:7][CH2:8][CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)=[CH:5][CH:4]=1)#[N:2].Cl.[NH2:25][OH:26].C(N(CC)CC)C>C(O)C>[OH:26][N:25]=[C:1]([C:3]1[CH:4]=[CH:5][C:6]([O:7][CH2:8][CH:9]2[CH2:10][CH2:11][N:12]([C:15]([O:17][C:18]([CH3:19])([CH3:20])[CH3:21])=[O:16])[CH2:13][CH2:14]2)=[CH:22][CH:23]=1)[NH2:2]
Reactant: CC(C)(C)OC(=O)N1CCC(COc2ccc(C#N)cc2)CC1
Reactant: NO
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC(COc2ccc(C(N)=NO)cc2)CC1
Temperature: 25 °C
Yield: 78.7 %

Procedure:
A solution of tert-butyl 4-[(4-cyanophenoxy)methyl]piperidine-1-carboxylate (Step 1, 1.47 g, 4.22 mmol, purity 91%), hydroxylamine hydrochloride (646 mg, 9.30 mmol) and triethylamine (1.30 mL, 9.30 mmol) in ethanol (24 mL) was stirred and heated at reflux for 1 h. After being cooled to rt, the reaction mixture was evaporated to dryness. The resulting material was treated with ethyl acetate, and the solid was filtered off. The ethyl acetate solution was washed with water and saturated sodium chloride solution, dried with anhydrous magnesium sulfate and filtered. After evaporation of the solvent, the crude product was stirred in tert-butyl methyl ether. The solid was filtered off and dried in vacuo to give the title compound (1.16 g, 78%): 1H NMR (400 MHz, CDCl3) δ 7.53 (d, 2H), 6.89 (d, 2H), 4.82 (s, 2H), 4.22-4.08 (broad m, 2H), 3.81 (d, 2H), 2.81-2.66 (m, 2H), 2.02-1.90 (m, 1H), 1.85-1.78 (d, 2H), 1.46 (s, 9H), 1.35-1.18 (m, 2H); ES-MS m/z 350, HPLC RT (Method D) 1.56 min.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[F:5][C:6]([F:19])([F:18])[C:7]1[CH:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:10]=[CH:9][C:8]=1[Br:17]>S(=O)(=O)(O)O>[N+:1]([C:9]1[C:8]([Br:17])=[C:7]([C:6]([F:5])([F:18])[F:19])[CH:12]=[C:11]([C:13]([F:16])([F:14])[F:15])[CH:10]=1)([O-:4])=[O:2]
Reactant: O=[N+]([O-])O
Reactant: FC(F)(F)c1ccc(Br)c(C(F)(F)F)c1
Agent: O=S(=O)(O)O
Product: O=[N+]([O-])c1cc(C(F)(F)F)cc(C(F)(F)F)c1Br
Temperature: 80 °C
Reaction time: 8 h

Procedure:
Concentrated nitric acid (2.6 ml) was cautiously added to a solution of 2,4-bis(trifluoromethyl)bromobenzene (16 g) in concentrated sulphuric acid (48 ml), and the mixture was heated to 80° C. for 6 hours. After cooling to ambient temperature and allowing to stand overnight, the reaction mixture was cautiously poured onto ice, and extracted with ethyl acetate. The organic extracts were washed with water and brine and dried over magnesium sulphate. Evaporation of the solvent, under reduced pressure, gave 6-nitro-2,4-bis(trifluoromethyl) bromobenzene as a yellow liquid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:16]2[C:20](Br)=[N:19][N:18]=[C:17]2[CH3:22])=[C:6]([CH:15]=1)[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=O.[NH3:23]>CS(C)=O.C(Cl)(Cl)Cl>[CH3:22][C:17]1[N:16]2[C:5]3[C:6]([C:7]([C:9]4[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=4)=[N:23][C:20]2=[N:19][N:18]=1)=[CH:15][C:2]([Cl:1])=[CH:3][CH:4]=3
Reactant: Cc1nnc(Br)n1-c1ccc(Cl)cc1C(=O)c1ccccc1
Reactant: N
Solvent: ClC(Cl)Cl
Solvent: CS(C)=O
Product: Cc1nnc2nc(-c3ccccc3)c3cc(Cl)ccc3n12
Temperature: 0 °C

Procedure:
In the next place, a solution of 0.5 g of the above-mentioned 5-chloro-2-(3-methyl-5-bromo-4H-1,2,4-triazol-4-yl)benzophenone in 20 ml of dimethylsulfoxide was heated, with stirring, at about 180° C for 10 hours, during which ammonia gas was continuously passed into the reaction mixture. After cooling, the reaction mixture was poured into ice-water and the resulting crystals were filtered, washed with water and dried. The crystals thus obtained was dissolved in chloroform and chromatographed on silica gel using chloroform as an eluent. The product thus separated was recrystallized from isopropyl ether to give 1-methyl-5-phenyl-7-chloro-s-triazolo[4,3-a]quinazoline, m.p. 325° - 327° C.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][C:10]([OH:12])=[O:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1CCC(N=C=NC2CCCCC2)CC1.[CH3:28][S:29]([O:32][C:33]1[CH:38]=[CH:37][C:36]([CH:39]=[CH:40][C:41](=[NH:43])[NH2:42])=[CH:35][CH:34]=1)(=[O:31])=[O:30]>N1C=CC=CC=1>[CH3:28][S:29]([OH:32])(=[O:31])=[O:30].[C:1]1([CH2:7][CH2:8][CH2:9][C:10]([O:12][C:33]2[CH:38]=[CH:37][C:36]([CH:39]=[CH:40][C:41](=[NH:42])[NH2:43])=[CH:35][CH:34]=2)=[O:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)CCCc1ccccc1
Reactant: CS(=O)(=O)Oc1ccc(C=CC(=N)N)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: c1ccncc1
Product: CS(=O)(=O)O
Product: N=C(N)C=Cc1ccc(OC(=O)CCCc2ccccc2)cc1
Reaction time: 0.5 h
Yield: 55.8 %

Procedure:
To a solution of 1.6 g of 4-phenylbutyric acid in 50 ml of dried pyridine, was added 3.1 g of DCC. After 30 minutes of stirring, 2.6 g of 4-(β-amidinoethenyl)-phenol methanesulfonate was added and the mixture was stirred overnight. The insolubles were removed by filtration and ethyl ether was added to the filtrate to precipitate crystals. The crystals were collected by filtration and recrystallized from ethanol to obtain 2.2 g of 4-(β-amidinoethenyl)phenyl 4-phenylbutyrate methanesulfonate.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:13](O)[CH3:14])[CH:5]=[C:6]([CH3:12])[C:7]=1[O:8][C:9](=[O:11])[CH3:10].OS([O-])(=O)=O.[K+].C(C1C=CC=C(O)C=1O)(C)(C)C>>[CH3:1][C:2]1[CH:3]=[C:4]([CH:5]=[C:6]([CH3:12])[C:7]=1[O:8][C:9](=[O:11])[CH3:10])[CH:13]=[CH2:14]
Reactant: CC(=O)Oc1c(C)cc(C(C)O)cc1C
Agent: CC(C)(C)c1cccc(O)c1O
Agent: O=S(=O)([O-])O
Agent: [K+]
Product: C=Cc1cc(C)c(OC(C)=O)c(C)c1
Yield: 81.8 %

Procedure:
(36.6 g, 0.30 mol) of 2,6-dimethylphenol are mixed in an Hastelloy C autoclave with 0.315 mol of acetic anhydride and 9 mols of hydrogen fluoride. The temperature is raised to 50° C. and the reaction runs for 3 hours. After extraction and wash, 47.4 g of a gray to purple solid mass of 3,5-dimethyl-4-hydroxyacetophenone is obtained. This solid is then esterified by refluxing with 4 mols of acetic anhydride for 19 hours. After removal of acetic acid and acetic anhydride by vacuum distillation the 3,5-dimethyl-4-acetoxyacetophenone is flash distilled to yield 47.7 g of a slightly yellow liquid. 0.1 mol of the 3,5-dimethyl-4-acetoxyacetophenone, 1.2 g of 5% Pd/C as catalyst and 100 ml ethanol are mixed in an autoclave and the autoclave is charged with hydrogen gas at a pressure of 215-220 mm Hg PSIG and the reaction is run for about 2 1/2 hours at a temperature of about 25°-30° C. Additional catalyst is added as needed. The catalyst is then removed and the ethanol evaporated to yield 21.5 g of a colorless oil which is 1-(3',5'-dimethyl-4'-acetoxyphenyl)ethanol. 0.168 mol of 1-(3',5'-dimethyl-4'-acetoxyphenyl)ethanol is added to a flask with 0.35 g KHSO4 and 0.5 g t-butyl catechol. The flask is heated to 185° to 190° C. at 1.5 to 2.0 mm Hg. A colorless liquid is distilled. After the addition of 0.15 g of t-butyl catechol, and redistillation, 26.1 g of 3,5- dimethyl-4-acetoxystyrene monomer is produced. The compound has a boiling point of 90°-91° C. at 0.5 mm of Hg and the yield is 81.8%.