Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:5]1[O:6][C:7]2[CH:22]=[CH:21][CH:20]=[CH:19][C:8]=2[C:9]=1[C:10](=[O:18])[C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)[CH2:2][CH2:3][CH3:4].[Br:23]N1C(=O)CCC1=O.CN(C)C=O>O>[CH2:1]([C:5]1[O:6][C:7]2[CH:22]=[CH:21][CH:20]=[CH:19][C:8]=2[C:9]=1[C:10](=[O:18])[C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[C:13]([Br:23])[CH:12]=1)[CH2:2][CH2:3][CH3:4]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCCCc1oc2ccccc2c1C(=O)c1ccc(O)cc1
Solvent: O
Solvent: CN(C)C=O
Product: CCCCc1oc2ccccc2c1C(=O)c1ccc(O)c(Br)c1

Procedure:
A mixture of 10.0 g. (0.034 mol.) of 2-n-butyl-3-(4'-hydroxybenzoyl)benzofuran and 6.1 g. (0.034 mol.) of N-bromosuccinimide in 150 ml. of damp dimethylformamide was refluxed for 12 hours. The reaction mixture was poured into water and extracted with chloroform. The extracts were washed repeatedly with water, then dried (Na2SO4) and concentrated to give 2-n-butyl-3-(3'-bromo-4'-hydroxybenzoyl)-benzofuran.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:17]=[CH:18][CH:19]=1)[CH2:7][C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[NH:10][CH:9]=1)([O-:3])=[O:2].[H-].[Na+].[C:22]([O:35][CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)(=[O:34])[CH2:23][CH2:24][C:25](OC1C=CC=CC=1)=[O:26].Cl>CN(C)C=O.C(OCC)(=O)C>[N+:1]([C:4]1[CH:5]=[C:6]([CH:17]=[CH:18][CH:19]=1)[CH2:7][C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]([C:25](=[O:26])[CH2:24][CH2:23][C:22]([O:35][CH2:36][C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)=[O:34])[CH:9]=1)([O-:3])=[O:2]
Reactant: O=C(CCC(=O)Oc1ccccc1)OCc1ccccc1
Reactant: O=[N+]([O-])c1cccc(Cc2c[nH]c3ccccc23)c1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C(CCC(=O)n1cc(Cc2cccc([N+](=O)[O-])c2)c2ccccc21)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 74.1 %

Procedure:
A solution of 3-(3-nitrobenzyl)indole (280 mg) in N,N-dimethylforma/nide (5 ml) was added to a suspension of sodium hydride (60% dispersion in mineral oil, 66.6 mg) in N,N-dimethylformamide (10 ml) at 0° C. The mixture was stirred at 25° C. for 40 minutes, and a solution of benZyl phenyl succinate (316 mg) in N,N-dimethylformamide was added at -40° C. After stirred at -40° C. for 20 minutes, the reaction mixture was poured into a mixture of ethyl acetate and 1N hydrochloric acid. The organic layer was separated, washed with water and brine, and dried over, magnesium sulfate. After evaporation of the solvent, the crude crystals were washed with hot isopropyl ether to give benzyl 4-[3-(3-nitrobenzyl)indol-l-yl]-4-oxobutyrate (364 mg).
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:4]=[C:5]([NH2:10])[CH:6]=[C:7]([NH2:9])[CH:8]=1.[CH3:13][S:14](Cl)(=[O:16])=[O:15]>N1C=CC=CC=1.C(Cl)Cl>[NH2:9][C:7]1[CH:6]=[C:5]([NH:10][S:14]([CH3:13])(=[O:16])=[O:15])[CH:4]=[C:3]([C:2]([F:11])([F:12])[F:1])[CH:8]=1
Reactant: CS(=O)(=O)Cl
Reactant: Nc1cc(N)cc(C(F)(F)F)c1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CS(=O)(=O)Nc1cc(N)cc(C(F)(F)F)c1
Temperature: 8 °C

Procedure:
A solution of 5-trifluoromethyl-benzene-1,3-diamine (250 mg, 1.42 mmol) in pyridine (0.52 mL) and CH2Cl2 (6.5 mL) was cooled to 0° C. Methanesulfonyl chloride (171 mg, 1.49 mmol) was slowly added at such a rate that the temperature of the solution remained below 10° C. The mixture was stirred at ˜8° C. and then allowed to warm to room temperature after 30 min. After stirring at room temperature for 4 h, reaction was almost complete as indicated by LCMS analysis. The reaction mixture was quenched with sat. aq. NH4Cl (10 mL) solution, extracted with CH2Cl2 (4×10 mL), dried over Na2SO4, filtered, and concentrated to yield N-(3-amino-5-trifluoromethyl-phenyl)-methanesulfonamide (D-19) as a reddish semisolid (0.35 g, 97%), which was used without further purification. 1H-NMR (CDCl3, 300 MHz) δ 6.76 (m, 1H), 6.70 (m, 1H), 6.66 (s, 1H), 3.02 (s, 3H); ESI-MS 255.3 m/z (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[NH:15][CH:16]2[CH2:21][CH2:20][N:19]([C:22](=[O:24])[CH3:23])[CH2:18][CH2:17]2)=[CH:4][CH:3]=1.ClC1C=CC=C(C(OO)=[O:33])C=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[NH:15][CH:16]2[CH2:17][CH2:18][N:19]([C:22](=[O:24])[CH3:23])[CH2:20][CH2:21]2)=[O:33])=[CH:4][CH:3]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC(=O)N1CCC(Nc2ccccc2Sc2ccc(Cl)cc2)CC1
Product: CC(=O)N1CCC(Nc2ccccc2S(=O)c2ccc(Cl)cc2)CC1
Reaction time: 2 h
Yield: 81 %

Procedure:
A solution of 1-{4-[2-(4-chloro-phenylsulfanyl)-phenylamino]-piperidin-1-yl}-ethanone (AMR01098, STX1832, 140 mg, 0.388 mmol) was treated with m-chloroperbenzoic acid (77%, 104.33 mg, 0.466 mmol) and stirred for 2 h, keeping the temperature between −30 and −10° C. The reaction mixture was quenched with saturated NaHCO3 solution. The aqueous layer was washed with DCM (2×20 mL), and the combined organic layers were dried (MgSO4), filtered and evaporated to dryness. Column chromatography on silica gel of the crude product using DCM/MeOH 95:5 as eluent gave 1-{4-[2-(4-chloro-benzenesulfinyl)-phenylamino]-piperidin-1-yl}-ethanone (119 mg, 81%) as an oil. LC/MS (APCI) tr=4.53 min, m/z 379.28 (39), 377.26 (M++H, 100). HPLC tr=2.38 min (98.44%) 1H NMR (270 MHz, CDCl3) δ 1.12 (1H, m, ½CH2), 1.45 (1H, m, ½CH2), 1.62 (1H, m, ½CH2), 1.95 (2H, m, CH2), 2.04, 2.07 (3H, 2s, CH3), 2.94-4.00 (5H, m, CH and 2CH2), 6.20, 6.28 (1H, 2d, J=6.9 and 7.4 Hz, NH), 4.20 (1H, m), 6.60 (1H, d, J=8.4 Hz, ArH), 6.70 (1H, m, ArH) and 7.27-7.48 (6H, m, ArH). 13C NMR (270 MHz, CDCl3) δ 21.58 (CH3), 30.89, 31.17, 31.28, 31.83, 39.23, 39.46, 43.80, 44.44 (CH2), 47.77, 48.18 (CH), 112.17, 112.44, 115.67, 115.73, 122.13, 122.58, 126.13, 126.25, 128.97, 129.04, 129.53, 129.70, 133.88, 133.93, 136.39, 136.61, 142.28, 147.47, 147.56 (ArC), and 168.96 (C═O).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([C@H:11]1[CH2:15][NH:14][C@H:13]([C:16]([NH:18][C:19]2([C:22]#[N:23])[CH2:21][CH2:20]2)=[O:17])[CH2:12]1)(=[O:10])=[O:9].[CH3:24][C:25]1([CH3:38])[CH2:30][CH:29]([N:31]2[CH2:34][CH2:33][CH:32]2[C:35]([O-])=[O:36])[CH2:28][CH2:27][O:26]1.[Li+]>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([C@H:11]1[CH2:15][N:14]([C:35]([CH:32]2[CH2:33][CH2:34][N:31]2[CH:29]2[CH2:28][CH2:27][O:26][C:25]([CH3:38])([CH3:24])[CH2:30]2)=[O:36])[C@H:13]([C:16]([NH:18][C:19]2([C:22]#[N:23])[CH2:21][CH2:20]2)=[O:17])[CH2:12]1)(=[O:10])=[O:9]
Reactant: N#CC1(NC(=O)[C@@H]2C[C@@H](S(=O)(=O)c3ccccc3Cl)CN2)CC1
Reactant: CC1(C)CC(N2CCC2C(=O)[O-])CCO1
Agent: [Li+]
Product: CC1(C)CC(N2CCC2C(=O)N2C[C@H](S(=O)(=O)c3ccccc3Cl)C[C@H]2C(=O)NC2(C#N)CC2)CCO1

Procedure:
The reaction of (2S,4R)-4-(2-chlorophenylsulfonyl)-N-(1-cyanocyclopropyl)pyrrolidine-2-carboxamide 7H and lithium 1-(2,2-dimethyltetrahydro-2H-pyran-4-yl)azetidine-2-carboxylate 20H carried out according to the general procedure L yielded (2S,4R)-4-(2-chlorophenylsulfonyl)-N-(1-cyanocyclopropyl)-1-(1-(2,2-dimethyltetrahydro-2H-pyran-4-yl)azetidine-2-carbonyl)pyrrolidine-2-carboxamide 1:1 epimers as an off-white solid (quant.). MS ISP (m/e): 549.3 (100) [(M+H)]]+.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[CH3:12][N:13]([CH3:17])[CH2:14][CH2:15][NH2:16]>C(O)CC>[CH3:8][C:5]1[CH:6]=[CH:7][C:2]([NH:16][CH2:15][CH2:14][N:13]([CH3:17])[CH3:12])=[C:3]([N+:9]([O-:11])=[O:10])[CH:4]=1
Reactant: CN(C)CCN
Reactant: Cc1ccc(Cl)c([N+](=O)[O-])c1
Solvent: CCCO
Product: Cc1ccc(NCCN(C)C)c([N+](=O)[O-])c1
Yield: 11.2 %

Procedure:
A mixed solution of 4-chloro-3-nitrotoluene (1.30 g) and N,N-dimethylethylenediamine (1.34 g) in 1-propanol (20 ml) was refluxed for 24 hours and the solvent was distilled off under reduced pressure. The residue was dissolved in ethyl acetate and the solution was successively washed with water (×2) and saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate. The solvent was then distilled off under reduced pressure and the residue was purified by silica gel chromatography (eluent: chloroform:methanol=30:1) to give 0.19 g of N-(4-methyl-2-nitrophenyl)-N',N'-dimethylethylenediamine.
Reaction SMILES: [C:1]([C:5]1[N:10]=[C:9]([N:11]2[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][CH2:19][CH2:20][C:21]#[N:22])[CH2:13][CH2:12]2)[CH:8]=[C:7]([CH:23]2[CH2:26][CH2:25][CH2:24]2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:27]([OH:29])[CH3:28].[ClH:30]>ClCCl>[ClH:30].[CH2:27]([O:29][C:21](=[NH:22])[CH2:20][CH2:19][CH2:18][CH2:17][N:14]1[CH2:13][CH2:12][N:11]([C:9]2[CH:8]=[C:7]([CH:23]3[CH2:26][CH2:25][CH2:24]3)[N:6]=[C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[N:10]=2)[CH2:16][CH2:15]1)[CH3:28]
Reactant: CCO
Reactant: CC(C)(C)c1nc(C2CCC2)cc(N2CCN(CCCCC#N)CC2)n1
Agent: Cl
Solvent: ClCCl
Product: CCOC(=N)CCCCN1CCN(c2cc(C3CCC3)nc(C(C)(C)C)n2)CC1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
1.5 g of 5-[4-(2-tert-butyl-6-cyclobutyl-pyrimidin-4-yl)-piperazin-1-yl]-pentanenitrile (4.22 mmol) were dissolved in 40 ml of dichloromethane and 0.4 g of dry ethanol (8.7 mmol). Gaseous hydrochloric acid was introduced into the solution until saturation at 0° C. The reaction was stirred for 15 h at room temperature and concentrated to dryness. The resulting crude product (2.18 g) was directly used in the next reaction step.
Reaction SMILES: C[O:2][C:3](=[O:30])[C:4]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:5]=1[CH:11]1[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][N:19]2[C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=3[O:22][CH2:21][C:20]2=[O:29])[CH2:13][CH2:12]1.[OH-].[Na+].Cl>CO>[Cl:10][C:8]1[CH:7]=[CH:6][C:5]([CH:11]2[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][N:19]3[C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=4[O:22][CH2:21][C:20]3=[O:29])[CH2:13][CH2:12]2)=[C:4]([CH:9]=1)[C:3]([OH:30])=[O:2]
Reactant: COC(=O)c1cc(Cl)ccc1C1CCN(CCN2C(=O)COc3ccccc32)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1cc(Cl)ccc1C1CCN(CCN2C(=O)COc3ccccc32)CC1
Reaction time: 24 h
Yield: 64.1 %

Procedure:
Compound 4-6 (1.00 g, 2.33 mmol) was dissolved in methanol (3 mL), treated with 3N sodium hydroxide solution (3.1 mL, 9.33 mmol) at rt, and stirred for 24 hrs. The reaction was neutralized with 2N hydrochloric acid solution (7 mL, 14 mmol) and purified by RP HPLC (gradient elution with 15-90% acetonitrile in water, each containing 0.1% TFA). Lyophilization afforded product Compound 4-7 as a white solid (trifluoroacetate salt, 0.62 g, 64%). 1H NMR (300 MHz, DMSO) δ 7.76 (br s, 1H), 7.64 (br d, J=8 Hz, 1H), 7.41 (d, J=8.5 Hz, 1H), 7.30 (d, J=6.9 Hz, 1H), 7.11-7.06 (m, 3H), 4.70 (s, 2H), 4.33 (m, 2H), 3.86-3.20 (m, 7H), 2.04-1.86 (m, 4H); MS (ES+) m/z 414.9 (M+1); Anal Calcd. for C22H23ClN2O4-1.75CF3CO2H: C, 50.05; H, 4.08; N, 4.60. Found: C, 50.11; H, 4.23; N, 4.56.
Reaction SMILES: Cl[CH2:2][C:3]1[N:7]=[C:6]([C:8]2[CH:13]=[C:12]([C:14]([CH3:17])([CH3:16])[CH3:15])[C:11]([OH:18])=[C:10]([C:19]([CH3:22])([CH3:21])[CH3:20])[CH:9]=2)[O:5][N:4]=1.[CH3:23][NH2:24]>>[CH3:15][C:14]([C:12]1[CH:13]=[C:8]([C:6]2[O:5][N:4]=[C:3]([CH2:2][NH:24][CH3:23])[N:7]=2)[CH:9]=[C:10]([C:19]([CH3:22])([CH3:21])[CH3:20])[C:11]=1[OH:18])([CH3:17])[CH3:16]
Reactant: CN
Reactant: CC(C)(C)c1cc(-c2nc(CCl)no2)cc(C(C)(C)C)c1O
Product: CNCc1noc(-c2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)n1

Procedure:
In a manner analogous to Example 70, 0.8 g (0.002 mole) of 4-[3-(chloromethyl)-1,2,4-oxadiazol5-yl]-2,6-bis(1,1-dimethylethyl)phenol is reacted with excess monomethylamine gas to give 0.2 g (31%) of analytically pure 2,6-bis(1,1-dimethylethyl)-4-[3-[(methylamino)methyl]-1,2,4-oxadiazol-5-yl]phenol, mp 120°-122° C.
Reaction SMILES: [C:1]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][C:13]([Cl:24])=[C:14]([NH:17][C:18]3[S:22][N:21]=[C:20]([CH3:23])[CH:19]=3)[N:15]=2)[N:10](COCC[Si](C)(C)C)[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].FC(F)(F)C(O)=O>ClCCl>[C:1]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][C:13]([Cl:24])=[C:14]([NH:17][C:18]3[S:22][N:21]=[C:20]([CH3:23])[CH:19]=3)[N:15]=2)[NH:10][CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cc(Nc2nc3c(C(=O)NC(C)(C)C)cn(COCC[Si](C)(C)C)c3nc2Cl)sn1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(Nc2nc3c(C(=O)NC(C)(C)C)c[nH]c3nc2Cl)sn1
Temperature: 25 °C
Reaction time: 16 h
Yield: 45.8 %

Procedure:
To a solution of N-tert-butyl-3-chloro-2-(3-methylisothiazol-5-ylamino)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (40 mg, 80.8 μmol) in dichloromethane (1.5 mL) was added trifluoroacetic acid (184 mg, 124 μL, 1.62 mmol) and the mixture stirred at room temperature for 16 h. The mixture was concentrated then re-dissolved in dichloromethane (1.5 mL), methanol (0.75 mL) and ammonium hydroxide (0.2 mL) and the mixture stirred at room temperature for 1 h. The mixture was concentrated in vacuo then triturated with water and filtered. The solid obtained was washed with ether then dried to give N-tert-butyl-3-chloro-2-(3-methylisothiazol-5-ylamino)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (15 mg, 37.0 μmol, 46%) as a dark orange solid. 1H NMR (400 MHz, DMSO-d) δ ppm: 12.76 (s, 1H), 10.91 (s, 1H), 8.30 (d, J=3.2, 1 H), 7.33 (s, 1H), 7.13 (s, 1H), 2.42 (s, 3H), 1.62 (s, 9H); MS (EI/CI) m/z: 365.0 [M+H].
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]([CH3:13])=[CH:5][C:6](=[C:8]([C:11]#[N:12])[C:9]#[N:10])[CH:7]=1.[CH:14]([C:16]1[CH:21]=[CH:20][C:19]([NH:22]C(=O)OC(C)(C)C)=[C:18]([O:30][CH3:31])[CH:17]=1)=O.N1CCCCC1>CCO>[NH2:22][C:19]1[CH:20]=[CH:21][C:16](/[CH:14]=[CH:13]/[C:4]2[O:3][C:2]([CH3:1])=[CH:7][C:6](=[C:8]([C:11]#[N:12])[C:9]#[N:10])[CH:5]=2)=[CH:17][C:18]=1[O:30][CH3:31]
Reactant: CC1=CC(=C(C#N)C#N)C=C(C)O1
Reactant: COc1cc(C=O)ccc1NC(=O)OC(C)(C)C
Solvent: C1CCNCC1
Solvent: CCO
Product: COc1cc(/C=C/C2=CC(=C(C#N)C#N)C=C(C)O2)ccc1N
Temperature: 80 °C
Reaction time: 7 h

Procedure:
A mixture of 2-(2,6-dimethyl-4H-pyran-4-ylidene)malononitrile (1, 20.7 mg, 0.12 mmol) and aldehyde 2c (25.1 mg, 0.1 mmol) were dissolved in anhydrous EtOH (0.67 ml) at 65° C. Piperidine (0.5 μl) was added and the mixture was stirred at 80° C. for 7 hours. The solvent was removed with a stream of N2, the crude mixture was dissolved in EtOAc at 5 mg/ml and purified by normal phase preparative HPLC using hexanes/ethyl acetate as eluent. Yield: 10.6 mg (26%). LCMS ESI+m/z 406 (M+H+) H-NMR (400 MHz, CD2Cl2): 8.16 (1H, d, J=8 Hz) 7.47 (1H, d, J=16 Hz) 7.29 (1H, s) 7.19 (1h, dd, J=8 Hz, 0.4 Hz) 7.1 (1H, d, J=0.4 Hz) 6.67-6.74 (2H, m) 6.56 (1H, m) 3.97 (3H, s) 2.43 (3H, s) 1.55 (9H, s). C-NMR (400 MHz, CD2Cl2) 163.02, 160.11, 157.01, 152.81, 148.32, 138.31, 131.33, 129.29, 122.99, 118.01, 116.81, 115.74, 108.45, 107.26, 106.77, 81.27, 56.35, 28.56, 20.31. This compound was treated with a 4N HCl solution in dioxane (4 N, 1.3 ml) for 3 hrs. The mixture was diluted with hexanes, the precipitate centrifuged, re-suspended and washed with hexanes, then dried under vacuum. LCMS ESI+ m/z: 306 (M+H+). H-NMR (400 MHz, CD2Cl2) 7.37 (1H, d, J=16 hz) 7.12 (1H, dd, J=16 Hz, 0.4 Hz) 7.02 (1H, d, J=0.4 Hz) 6.56-6.63 (3H, m) 6.12 (1H, m) 3.97 (3H, s) 2.42 (3H, s). C-NMR (400 MHz, CD2Cl2) 164.58, 156.12, 151.52, 140.90, 139.05, 129.73, 127.19, 121.74, 115.48, 110.73, 109.95, 102.81, 101.68, 100.79, 90.2, 55.89, 21.02.
Reaction SMILES: CS[C:3](=[NH:8])[NH:4][N+:5]([O-:7])=[O:6].[CH:9]1([NH2:12])[CH2:11][CH2:10]1>C(O)C>[CH:9]1([NH:12][C:3]([NH:4][N+:5]([O-:7])=[O:6])=[NH:8])[CH2:11][CH2:10]1
Reactant: CSC(=N)N[N+](=O)[O-]
Reactant: NC1CC1
Solvent: CCO
Product: N=C(NC1CC1)N[N+](=O)[O-]
Temperature: -5 °C

Procedure:
27 g of S-methyl-N-nitroisothiourea are heated under reflux for 3.5 hours in admixture with 12.6 g of cyclopropylamine and 15 ml of ethanol. The reaction mixture is then cooled to -5° C. and the product is filtered off and washed with a small amount of cold ethanol and diethyl ether, yielding N-cyclopropyl-N'-nitroguanidine (m.p.: 127°-130° C.).
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:4]=[C:5]([NH:9]C2C=CC=CC=2)[CH:6]=[CH:7][CH:8]=1.[C:18]([OH:22])(=[O:21])[CH:19]=[CH2:20].[OH-].[Na+]>O>[F:1][C:2]([F:16])([F:17])[C:3]1[CH:4]=[C:5]([NH:9][CH2:20][CH2:19][C:18]([OH:22])=[O:21])[CH:6]=[CH:7][CH:8]=1
Reactant: C=CC(=O)O
Reactant: FC(F)(F)c1cccc(Nc2ccccc2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)CCNc1cccc(C(F)(F)F)c1
Temperature: 100 °C
Reaction time: 1 h

Procedure:
To an aqueous solution of 3-trifluoromethylphenyl aniline (5.0 g) in water (15.0 ml) was added acrylic acid (3.2 ml) and the resulting mixture was stirred at 100° C. for one hour. The reaction mixture was basified with 5N aqueous sodium hydroxide solution and extracted with ethyl acetate (100 ml×2). The resulting organic layer was washed with saturated saline (50 ml), dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: chloroform/methanol) to afford 3-(3-trifluoromethylphenylamino)propionic acid (8.4 g).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[N:14]=[C:13]([C:15]2[S:16][CH:17]=[CH:18][N:19]=2)[NH:12][C:11]([CH2:20][N:21]2[CH2:26][CH2:25][O:24][CH:23]([CH2:27][CH2:28][C:29](O)=[O:30])[CH2:22]2)=[C:10]1[C:32]([O:34][CH2:35][CH3:36])=[O:33].Cl.[CH3:38][NH2:39]>>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[C:10]([C:32]([O:34][CH2:35][CH3:36])=[O:33])=[C:11]([CH2:20][N:21]2[CH2:26][CH2:25][O:24][CH:23]([CH2:27][CH2:28][C:29]([NH:39][CH3:38])=[O:30])[CH2:22]2)[NH:12][C:13]([C:15]2[S:16][CH:17]=[CH:18][N:19]=2)=[N:14]1
Reactant: CN
Reactant: CCOC(=O)C1=C(CN2CCOC(CCC(=O)O)C2)NC(c2nccs2)=NC1c1ccc(F)cc1Br
Agent: Cl
Product: CCOC(=O)C1=C(CN2CCOC(CCC(=O)NC)C2)NC(c2nccs2)=NC1c1ccc(F)cc1Br
Yield: 38.2 %

Procedure:
3-(4-((6-(2-bromo-4-fluorophenyl)-5-(ethoxycarbonyl)-2-(thiazol-2-yl)-3,6-dihydropyrimidin-4-yl)methyl)morpholin-2-yl)propanoic acid (0.69 g, 1.19 mmol) was reacted with methanamine hydrochloride (0.12 g, 1.8 mmol) according to the procedure as described in Example 62, Step B to give the title compound as a yellow solid (0.27 g, 38%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: C(N(CC)CC)C.[C:8]1([CH3:18])[CH:13]=[CH:12][C:11]([S:14](Cl)(=[O:16])=[O:15])=[CH:10][CH:9]=1.[C:19]1([C:25]2[CH:29]=[C:28]([CH2:30][N:31]3[CH2:36][CH2:35][CH:34]([CH2:37][OH:38])[CH2:33][CH2:32]3)[O:27][N:26]=2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>ClCCl>[CH3:18][C:8]1[CH:13]=[CH:12][C:11]([S:14]([O:38][CH2:37][CH:34]2[CH2:33][CH2:32][N:31]([CH2:30][C:28]3[O:27][N:26]=[C:25]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH:29]=3)[CH2:36][CH2:35]2)(=[O:16])=[O:15])=[CH:10][CH:9]=1
Reactant: OCC1CCN(Cc2cc(-c3ccccc3)no2)CC1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCC2CCN(Cc3cc(-c4ccccc4)no3)CC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 12.3 %

Procedure:
Triethylamine (12.1 mL) and p-toluene sulfonylchloride (6.61 g) were added sequentially to a room temperature mixture of the compound prepared in Example 64 (7.86 g) in dichloromethane (100 mL). The reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with dichloromethane and washed sequentially with a saturated aqueous sodium bicarbonate solution and brine. The combined organics were dried over anhydrous magnesium sulfate and concentrated. The residue was purified by column chromatography on silica gel to obtain the title compound (1.52 g) having the following physical data.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2/[CH:18]=[C:19](/[C:21]([OH:23])=[O:22])\[CH3:20])[C:10]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[C:9]([CH3:29])[NH:8][C:7]=1[CH3:30])=[O:5])[CH3:2].[CH:31]1(Br)[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1>>[CH2:1]([O:3][C:4]([C:6]1[CH:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2/[CH:18]=[C:19](\[CH3:20])/[C:21]([O:23][CH:31]2[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]2)=[O:22])[C:10]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[C:9]([CH3:29])[NH:8][C:7]=1[CH3:30])=[O:5])[CH3:2]
Reactant: BrC1CCCCC1
Reactant: CCOC(=O)C1=C(C)NC(C)=C(C(=O)OCC)C1c1ccccc1/C=C(\C)C(=O)O
Product: CCOC(=O)C1=C(C)NC(C)=C(C(=O)OCC)C1c1ccccc1/C=C(\C)C(=O)OC1CCCCC1

Procedure:
From Compound A and cyclohexyl bromide stirring for 20 h at 40°.
Reaction SMILES: [CH3:1][C:2]1([CH3:26])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([CH2:14][C:15]#[C:16][C:17]3[CH:25]=[CH:24][C:20]([C:21]([OH:23])=[O:22])=[CH:19][CH:18]=3)[CH:5]=[CH:4][C:3]1=2.CN(C=O)C.C(=O)(O)[O-].[Na+].I[CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH3:43]>C1OCCOCCOCCOCCOC1.O>[CH3:1][C:2]1([CH3:26])[CH2:11][CH2:10][C:9]([CH3:12])([CH3:13])[C:8]2[CH:7]=[C:6]([CH2:14][C:15]#[C:16][C:17]3[CH:25]=[CH:24][C:20]([C:21]([O:23][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH3:43])=[O:22])=[CH:19][CH:18]=3)[CH:5]=[CH:4][C:3]1=2
Reactant: CCCCCCI
Reactant: CC1(C)CCC(C)(C)c2cc(CC#Cc3ccc(C(=O)O)cc3)ccc21
Agent: C1COCCOCCOCCOCCO1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCCCOC(=O)c1ccc(C#CCc2ccc3c(c2)C(C)(C)CCC3(C)C)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
2 g (5.8 mmol) of 4-[3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-1-propynyl]benzoic acid, 30 ml of DMF, 2 drops of 15-crown-5 and 2 g (23.8 mmol) of sodium bicarbonate are introduced into a round-bottomed flask. 3.1 ml (20.8 mmol) of 1-iodohexane are added and the mixture is stirred at room temperature for 24 hours. The reaction medium is poured into water and extracted with ethyl acetate and the organic phase is separated out after settling has taken place, washed with water, dried over magnesium sulphate and evaporated. 2 g (80%) of the expected hexyl ester are collected in the form of a pale red oil.
Reaction SMILES: [OH:1][C:2]1[C:7]2[C:8]([CH3:16])=[C:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[O:10][C:6]=2[CH:5]=[CH:4][CH:3]=1.[Cl-].[Al+3].[Cl-].[Cl-].[C:21](Cl)(=[O:23])[CH3:22].O>ClC(Cl)C>[C:21]([C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:8]([CH3:16])[C:7]=2[C:2]=1[OH:1])(=[O:23])[CH3:22]
Reactant: CCOC(=O)c1oc2cccc(O)c2c1C
Reactant: CC(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CC(Cl)Cl
Solvent: O
Product: CCOC(=O)c1oc2ccc(C(C)=O)c(O)c2c1C
Temperature: 25 °C
Reaction time: 5 h
Yield: 49.6 %

Procedure:
To a solution of ethyl 4-hydroxy-3-methylbenzofuran-2-carboxylate (220 mg, 1 mmol) in dichloroethane (10 ml) was added aluminum chloride (665 mg, 5 mmol). To the resulting brown solution was added acetyl chloride (0.178 ml, 2.5 mmol). The mixture was stirred for 5 hours at room temperature. Ice and water (20 ml) was added. The mixture was extracted with ethyl acetate. The extracts were dried and concentrated to a white solid which was then treated with 1 ml of 10% K2CO3 aqueous solution in 10 ml methanol for 2 hours. The resulting mixture was poured into 0.1N HCl (25 ml) and filtered. The solid obtained was recrystallized from ethyl acetate/toluene to give the title compound (130 mg, 50%).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[C:4]([F:10])[CH:3]=1.[C:11]([NH2:15])([CH3:14])([CH3:13])[CH3:12]>C(Cl)Cl>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[N:15][C:11]([CH3:14])([CH3:13])[CH3:12])=[C:4]([F:10])[CH:3]=1
Reactant: CC(C)(C)N
Reactant: O=Cc1ccc(Br)cc1F
Solvent: ClCCl
Product: CC(C)(C)N=Cc1ccc(Br)cc1F
Temperature: 25 °C
Reaction time: 18 h
Yield: 81.6 %

Procedure:
A mixture of 4-bromo-2-fluorobenzaldehyde (10 g, 47 mmol), tert-butyl amine (6.1 mL, 57 mmol) and 4 Å powder molecular sieves (8.0 g) in 160 mL CH2Cl2 (160 mL) was stirred at rt for 18 h. The reaction mixture was filtered through a pad of celite and concentrated to give the title compound (9.9 g, 78%). MS (ESI): mass calcd. for C11H13BrFNO, 258.1; m/z found, 260.0 [M+H]+. 1H NMR (CDCl3): 10.32 (s, 1H), 8.48 (s, 1H), 7.89 (t, J=8.1 Hz, 1H), 7.50-7.20 (m, 1H), 1.49-1.08 (m, 9H).