Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.[Cl:13][C:14]1[CH:23]=[CH:22][C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[N:15]=1.CN(C)[CH:26]=[O:27]>C1COCC1>[Cl:13][C:14]1[C:23]([CH:26]=[O:27])=[CH:22][C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[N:15]=1
Reactant: CN(C)C=O
Reactant: Clc1ccc2ccccc2n1
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: O=Cc1cc2ccccc2nc1Cl
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 92.2 %

Procedure:
To a solution of 0.46 mL (3.30 mmol) of diisopropylamine in 8 mL of THF at 0° C. was added 1.53 mL (3.30 mmol) of n-BuLi dropwise. After 20 min the solution was cooled to -78° C. and 2-chloroquinoline (491 mg, 3.0 mmol) was added neat. The mixture was stirred at -78° C. for 30 min, then dimethylformamide (0.39 mL, 5.04 mmol) was added dropwise and the reaction mixture was stirred an additional 30 min at this temperature. After quenching at -78° C. with glacial acetic acid (1 mL), the mixture was warmed to room temperature and diluted with ether (30 mL). The organic phase was washed with saturated NaHCO3 solution (10 mL) and brine (10 mL), and was dried over MgSO4. Concentration afforded 2-chloro-3-quinolinecarboxaldehyde (530 mg, 92%) as a light yellow solid (mp 145°-149 ° C.), which was used directly in the next step without further purification. Recrystallization from ethyl acetate afforded the pure compound as light yellow needles: mp 149°-150° C. (mp 148°-149° C. reported in Meth-Cohn, O.; Narhe, B.; Tarnowski, B. J. Chem. Soc. Perkin Trans. I 1981, 1520.). 1H NMR (300 MHz, CDCl3) δ 10.57 (s, 1H), 8.77 (s, 1H), 8.08 (d, 1H, J=9 Hz), 8.0 (d, 1H, J=9 Hz), 7.90 (t, 1H, J=9 Hz), 7.67 (t, 1H, J=9 Hz); IR (nujol) 1575, 1045, 760, 745 cm-1.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:6]=1.F[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[N+:20]([O-:22])=[O:21].C(=O)([O-])[O-].[K+].[K+]>O>[N+:20]([C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[NH:1][C:2]1[S:3][CH:4]=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:6]=1)([O-:22])=[O:21]
Reactant: O=[N+]([O-])c1ccccc1F
Reactant: Nc1nc(-c2ccccc2)cs1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: O=[N+]([O-])c1ccccc1Nc1nc(-c2ccccc2)cs1
Temperature: 150 °C
Reaction time: 24 h

Procedure:
A mixture of 2-amino-4-phenylthiazole (12.5 g, 80.9 mmol), 1-fluoro-2-nitrobenzene (12.5 g, 89.0 mmol), potassium carbonate (13.4 g, 97.1 mmol) was stirred at 150° C. for 24 h. Water (100 ml) was added and the mixture was extracted twice with 1,2-dichloroethane (50 ml). The crude extract was purified by chromatography on silica gel using toluene as eluent. The product was isolated as the free base. Yield 7.95 g, 33%. M.p.114-116° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:19]3[N:20]=[C:21]([NH2:23])[N:22]=[C:18]3[CH:17]=[C:16]([C:24]3[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=3)[CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].S([N:40]=[C:41]=[O:42])(C1C=CC(C)=CC=1)(=O)=O.[CH2:43](N)[CH3:44]>CN(C=O)C.C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([C:14]2[N:19]3[N:20]=[C:21]([NH:23][C:41]([NH:40][CH2:43][CH3:44])=[O:42])[N:22]=[C:18]3[CH:17]=[C:16]([C:24]3[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=3)[CH:15]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCN
Reactant: CC(C)(C)OC(=O)N1CCN(c2cc(-c3cccnc3)cc3nc(N)nn23)CC1
Reactant: Cc1ccc(S(=O)(=O)N=C=O)cc1
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CCNC(=O)Nc1nc2cc(-c3cccnc3)cc(N3CCN(C(=O)OC(C)(C)C)CC3)n2n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The material produced in Step 1 (0.78 g, 2.0 mmol) was split into three batches. Each batch was suspended in DMF (3 mL) and then TsNCO (0.3 ml, 2 mmol) was added. The reaction mixture was stirred at rt overnight. Ethylamine (3 ml of a 2 M solution in THF, 6 mmol) was added and the resulting mixture was irradiated with microwaves at 130° C. for 40 minutes. The three batches were combined, filtered, washed with THF, and dried to afford 4-[2-(3-ethyl-ureido)-7-pyridin-3-yl-[1,2,4]triazolo[1,5-a]pyridin-5-yl]-piperazine-1-carboxylic acid tert-butyl ester as a solid. MS (APCI+) 467 (M+1).
Reaction SMILES: O1CCCC1.C([O:8][C:9](=[O:36])[CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[O:19][C:20](=[O:35])[C:21]([S:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[CH:32]([CH3:34])[CH3:33])=[C:22]([OH:24])[CH:23]=2)=[CH:14][CH:13]=1)C.[OH-].[Na+].Cl>O>[OH:24][C:22]1[CH:23]=[C:18]([C:15]2[CH:14]=[CH:13][C:12]([O:11][CH2:10][C:9]([OH:36])=[O:8])=[CH:17][CH:16]=2)[O:19][C:20](=[O:35])[C:21]=1[S:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[CH:32]([CH3:33])[CH3:34]
Reactant: CCOC(=O)COc1ccc(-c2cc(O)c(Sc3ccccc3C(C)C)c(=O)o2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)c1ccccc1Sc1c(O)cc(-c2ccc(OCC(=O)O)cc2)oc1=O
Reaction time: 1.5 h

Procedure:
To a tetrahydrofuran (10 ml) solution of 4-[4-Hydroxy-5-[(2-isopropylphenyl)thio]-6-oxo-6H-pyran-2-yl]phenoxy acetic acid ethyl ester (0.319 g. 0.75 mmol) was added 1N sodium hydroxide (1.80 mL, 1.81 mmol). The reaction was stirred for 1.5 h, and then water (10 ml) was added followed by acidification with conc. hydrochloric acid to pH 2. The aqueous layer was then extracted 2× with ethyl acetate (100 ml). the combined organic extracts were then washed with saturated sodium chloride and dried over anhydrous magnesium sulfate. After evaporation of the solvents in vacuo, the crude product was purified by column chromatography (silica gel--230 to 400 mesh) using 94/5/1 methylene chloride/methanol/acetic acid as the eluent. m.p. 217° C.; (dec.); 1H NMR (400 MHz, DMSO-d6) δ 1.25 (d, 6H), 3.42 (m, 1H), 4.79 (s, 2H), 6.75 (s, 1H), 6.90 (d, 1H), 7.06 (m, 4H), 7.26 (d, 1H), 7.79 (d, 2H).
Reaction SMILES: Cl.ClC1C2C(=CC(S(N3CCOC(=O)C43CCCC4)(=O)=O)=CC=2)C(N=C(N)N)=[N:5]C=1.Cl.[NH2:32][C:33]([NH2:35])=[NH:34].Cl[C:37]1[C:46]2[C:41](=[CH:42][CH:43]=[C:44]([S:47]([N:50]([CH2:61][CH2:62][O:63][CH:64]3[CH2:69][CH2:68][CH2:67][CH2:66][O:65]3)[C:51]3([C:56]([O:58][CH2:59][CH3:60])=[O:57])[CH2:55][CH2:54][CH2:53][CH2:52]3)(=[O:49])=[O:48])[CH:45]=2)[C:40]([Cl:70])=[CH:39][N:38]=1.O>CS(C)=O>[NH3:5].[Cl:70][C:40]1[C:41]2[C:46](=[CH:45][C:44]([S:47]([N:50]([CH2:61][CH2:62][O:63][CH:64]3[CH2:69][CH2:68][CH2:67][CH2:66][O:65]3)[C:51]3([C:56]([O:58][CH2:59][CH3:60])=[O:57])[CH2:52][CH2:53][CH2:54][CH2:55]3)(=[O:48])=[O:49])=[CH:43][CH:42]=2)[C:37]([NH:34][C:33]([NH2:35])=[NH:32])=[N:38][CH:39]=1
Reactant: CCOC(=O)C1(N(CCOC2CCCCO2)S(=O)(=O)c2ccc3c(Cl)cnc(Cl)c3c2)CCCC1
Reactant: N=C(N)N
Reactant: NC(N)=Nc1ncc(Cl)c2ccc(S(=O)(=O)N3CCOC(=O)C34CCCC4)cc12
Agent: Cl
Solvent: CS(C)=O
Solvent: O
Product: CCOC(=O)C1(N(CCOC2CCCCO2)S(=O)(=O)c2ccc3c(Cl)cnc(NC(=N)N)c3c2)CCCC1
Product: N
Temperature: 50 °C
Reaction time: 0.33 h

Procedure:
N"-{4-Chloro-7-[(10-oxo-9-oxa-6-azaspiro [4.5]dec-6-yl)sulphonyl]-1-isoquinolinyl}guanidine hydrochloride ##STR98## NaH (45 mg, 80% dispersion in mineral oil, 1.5 mmol) was added to a solution of guanidine hydrochloride (231 mg, 2.4 mmol) in DMSO (5 ml), and the solution stirred at 50° C. for 20 min. Ethyl 1-{[(1,4-dichloro-7-isoquinolinyl)sulphonyl][2-(tetrahydro-2H-pyran-2-yloxy)ethyl]amino}cyclopentanecarboxylate (330 mg, 0.6 mmol) was added and the reaction stirred at 70° C. for 21/2 h. The cooled reaction was poured into water, extracted with EtOAc, and the combined organic extracts washed with brine, dried (MgSO4) and evaporated in vacuo. The residual yellow gum was purified by column chromatography upon silica gel using CH2Cl2 -MeOH-0.880 NH3 (95:5:0.5) as eluant to give ethyl 1-{[(4-chloro-1-guanidino-7-isoquinolinyl)sulphonyl][2-(tetrahydro-2H-pyran-2-yloxy)ethyl]amino}cyclopentanecarboxylate as an orange oil.
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([O:10][C:11]2[CH:19]=[CH:18][C:17]3[N:16]4[CH2:20][CH2:21][NH:22][C:23](=[O:24])[C:15]4=[CH:14][C:13]=3[CH:12]=2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2].[H-].[Na+].Cl[CH2:28][C:29]([NH:31][CH3:32])=[O:30]>>[CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([O:10][C:11]2[CH:19]=[CH:18][C:17]3[N:16]4[CH2:20][CH2:21][N:22]([CH2:28][C:29]([NH:31][CH3:32])=[O:30])[C:23](=[O:24])[C:15]4=[CH:14][C:13]=3[CH:12]=2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2]
Reactant: CC(C)N1CCC(Oc2ccc3c(c2)cc2n3CCNC2=O)CC1
Reactant: CNC(=O)CCl
Agent: [H-]
Agent: [Na+]
Product: CNC(=O)CN1CCn2c(cc3cc(OC4CCN(C(C)C)CC4)ccc32)C1=O

Procedure:
The title compound was synthesized in analogy to example 17, from 8-(1-isopropyl-piperidin-4-yloxy)-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one (example 1), sodium hydride and 2-chloro-N-methylacetamide, to give the desired product in a yield of 68%.
Reaction SMILES: Cl[C:2]1C=C(C=CC=1Cl)CN(C)C(=O)C=C1C(=O)OC(C)(C)O1.C=O.Cl.[NH2:26][CH2:27][C:28]1[CH:36]=[CH:35][C:31]([C:32]([OH:34])=[O:33])=[CH:30][CH:29]=1.C(N(CC)CC)C.[Cl:44][C:45]1[CH:46]=[C:47]([CH:70]=[CH:71][C:72]=1[Cl:73])[CH2:48][N:49]([CH3:69])[C:50]([C:52]1[CH2:56]N(CCC(NCCC(O)=O)=O)[C:54](=[O:67])[C:53]=1[OH:68])=[O:51]>>[CH3:2][O:33][C:32](=[O:34])[C:31]1[CH:30]=[CH:29][C:28]([CH2:27][N:26]2[CH2:56][C:52]([C:50](=[O:51])[N:49]([CH2:48][C:47]3[CH:70]=[CH:71][C:72]([Cl:73])=[C:45]([Cl:44])[CH:46]=3)[CH3:69])=[C:53]([OH:68])[C:54]2=[O:67])=[CH:36][CH:35]=1
Reactant: CN(Cc1ccc(Cl)c(Cl)c1)C(=O)C=C1OC(C)(C)OC1=O
Reactant: NCc1ccc(C(=O)O)cc1
Reactant: CN(Cc1ccc(Cl)c(Cl)c1)C(=O)C1=C(O)C(=O)N(CCC(=O)NCCC(=O)O)C1
Agent: C=O
Agent: Cl
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(CN2CC(C(=O)N(C)Cc3ccc(Cl)c(Cl)c3)=C(O)C2=O)cc1
Yield: 26 %

Procedure:
N-(3,4-Dichloro-benzyl)-2-(2,2-dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-N-methyl-acetamide (Compound 37-A) was treated with paraformaldehyde and 4-(aminomethyl)-benzoate hydrochloride salt with 1 equivalent of triethyl amine as described in the preparation of Compound 37. The title compound was purified by chromatography (YMC Combiprep ODS-A, 30 mm×50 mm, MeOH/H2O/0.1% TFA) to yield the title compound as a yellow foam (0.060 g, 26% yield). 1H NMR (300 MHz, CDCl3) δ: 2.98 (s, 3H), 3.91 (s, 3H), 4.05 (s, 2H), 4.56 (s, 2H), 7.07 (dd, J=1.8 Hz, J=8.1 Hz, 1H), 7.30 (m, 3H), 7.40 (m, 1H), 8.00 (d, J=8.1 Hz, 1H). HRMS (M−H) calcd for C22H20N2Cl2O5: 461.0671. found: 461.0690.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:10]2([C:32]([F:35])([F:34])[F:33])[O:14][N:13]=[C:12]([C:15]3[C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[C:18]([C:25]([NH:27][CH2:28][CH2:29][S:30][CH3:31])=[O:26])=[CH:17][CH:16]=3)[CH2:11]2)[CH:5]=[C:6]([Cl:9])[C:7]=1[Cl:8].ClC1C=C(C2(C(F)(F)F)ON=C(C3C4C(=CC=CC=4)C(C(NCCSC)=O)=CC=3)C2)C=C(Cl)C=1.[F:70][C:71]([F:76])([F:75])[C:72]([NH2:74])=[O:73].C(OI(C1C=CC=CC=1)OC(=O)C)(=O)C>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([C:10]2([C:32]([F:33])([F:34])[F:35])[O:14][N:13]=[C:12]([C:15]3[C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[C:18]([C:25]([NH:27][CH2:28][CH2:29][S:30]([CH3:31])=[N:74][C:72](=[O:73])[C:71]([F:76])([F:75])[F:70])=[O:26])=[CH:17][CH:16]=3)[CH2:11]2)[CH:5]=[C:6]([Cl:9])[C:7]=1[Cl:8]
Reactant: NC(=O)C(F)(F)F
Reactant: CSCCNC(=O)c1ccc(C2=NOC(c3cc(Cl)c(Cl)c(Cl)c3)(C(F)(F)F)C2)c2ccccc12
Agent: CC(=O)OI(OC(C)=O)c1ccccc1
Agent: CSCCNC(=O)c1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)c2ccccc12
Solvent: ClCCl
Product: CS(CCNC(=O)c1ccc(C2=NOC(c3cc(Cl)c(Cl)c(Cl)c3)(C(F)(F)F)C2)c2ccccc12)=NC(=O)C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 30 %

Procedure:
To a stirred suspension of 4-[4,5-dihydro-5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-3-isoxazolyl]-N-[2-(methylthio)ethyl]-1-naphthalenecarboxamide (prepared analogously as described for the compound of Example 3, Step A) (200 mg), 2,2,2-trifluoroacetamide (80 mg), MgO (57 mg), and Rh2(OAc)4 (4 mg) in dichloromethane (4 mL) was added PhI(OAc)2 (172 mg) at room temperature. The resulting mixture was stirred overnight at room temperature, then filtered through a short pad of Celite® diatomaceous filter aid, and rinsed with ethyl acetate. The filtrate was concentrated, and the residue was purified by column chromatography on silica gel using hexanes/ethyl acetates (1:1 to 1:4) as eluent to afford the title compound as a semisolid (70 mg, 30% yield).
Reaction SMILES: [Br:1][C:2]1[C:10]2[CH:9]=[N:8][C:7]([Cl:11])=[N:6][C:5]=2[NH:4][CH:3]=1.Br[CH2:13][CH2:14][CH2:15][N:16]1[C:24](=[O:25])[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:17]1=[O:26].C([O-])([O-])=O.[K+].[K+]>CS(C)=O.C1COCC1.C(OCC)(=O)C>[Br:1][C:2]1[C:10]2[CH:9]=[N:8][C:7]([Cl:11])=[N:6][C:5]=2[N:4]([CH2:13][CH2:14][CH2:15][N:16]2[C:24](=[O:25])[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17]2=[O:26])[CH:3]=1
Reactant: O=C1c2ccccc2C(=O)N1CCCBr
Reactant: Clc1ncc2c(Br)c[nH]c2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CS(C)=O
Product: O=C1c2ccccc2C(=O)N1CCCn1cc(Br)c2cnc(Cl)nc21
Temperature: 100 °C

Procedure:
A suspension of 5-bromo-2-chloro-7H-pyrrolo[2,3-d]pyrimidine (100 mg, 0.43 mmol), 2-(3-bromopropyl)isoindoline-1,3-dione (173 mg, 0.65 mmol) and K2CO3 (119 mg, 0.86 mmol) in a mixture of DMSO and THF (8.0 mL, 1:3, v/v) was heated at 100° C. under microwave irradiation for 30 min. The mixture was diluted with ethyl acetate (35 mL), washed with water (3×) and concentrated to provide the crude 2-(3-(5-bromo-2-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)propyl)isoindoline-1,3-dione (MS m/z 420.05 [M+H]+) which was used in next step without further purification.
Reaction SMILES: [CH2:1]([O:6][C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=O)=[CH:9][N:8]=1)[CH:2]=[C:3]([CH3:5])[CH3:4].[NH2:16][CH2:17][CH:18]1[CH2:22][CH2:21][CH2:20][N:19]1[CH2:23][CH3:24]>>[CH2:23]([N:19]1[CH2:20][CH2:21][CH2:22][CH:18]1[CH2:17][NH:16][C:11](=[O:13])[C:10]1[CH:14]=[CH:15][C:7]([O:6][CH2:1][CH:2]=[C:3]([CH3:4])[CH3:5])=[N:8][CH:9]=1)[CH3:24]
Reactant: CCN1CCCC1CN
Reactant: CC(C)=CCOc1ccc(C(=O)O)cn1
Product: CCN1CCCC1CNC(=O)c1ccc(OCC=C(C)C)nc1
Yield: 68.1 %

Procedure:
In a manner identical to Example 15, 6-prenyloxynicotinic acid (0.70 g) was subjected to a condensation reaction with 2-aminomethyl-1-ethylpyrrolidine (0.90 g), thereby yielding 0.73 g(68%) of the aimed compound.
Reaction SMILES: Cl[S:2]([N:5]=[C:6]=[O:7])(=[O:4])=[O:3].[C:8]([OH:12])([CH3:11])([CH3:10])[CH3:9].[N:13]1C=CC=CC=1.[OH-].[NH4+]>C1(C)C=CC=CC=1.O>[C:8]([O:12][C:6]([NH:5][S:2]([NH2:13])(=[O:4])=[O:3])=[O:7])([CH3:11])([CH3:10])[CH3:9]
Reactant: c1ccncc1
Reactant: CC(C)(C)O
Reactant: O=C=NS(=O)(=O)Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)NS(N)(=O)=O
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
To chlorosulfonyl isocyanate (2.45 mL, 28 mmol) in toluene (38 mL) at −10° C. (ice/methanol bath) was added t-butyl alcohol (2.66 mL, 28 mmol) dropwise. The resulting solution was stirred at 0° C. (ice bath) for 20 min. Pyridine (5.0 mL, 62 mmol) was added dropwise with the ice/methanol bath at −15° C. to −10° C. The resulting mixture was stirred with ice bath at 0° C. for 40 min. Ammonium hydroxide (28%, 10 mL, 163 mmol) was then added dropwise with the ice/methanol bath at −10° C., followed by H2O (3 mL). The resulting mixture resulting was stirred with ice bath at 0° C. for 2.5 h. The resulting two layers were separated. The aqueous layer was washed with toluene (15 mL). The combined toluene layers were extracted with H2O (13 mL). The combined aqueous layers were acidified with 24% H2SO4 to pH 2. The resulting precipitate was filtered, washed with H2O (2×13 mL) and dried to yield the title compound as a white solid.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]=[CH:7][C:8]#[N:9].[ClH:10].CC[OH:13]>>[ClH:10].[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]=[CH:7][C:8](=[NH:9])[OH:13]
Reactant: N#CC=Cc1ccco1
Reactant: CCO
Agent: Cl
Product: N=C(O)C=Cc1ccco1
Reaction time: 18 h
Yield: 63 %

Procedure:
A solution of 2-furanacrylonitrile (10.9 g; 91 mmol) in EtOH (75 mL) was cooled in an ice bath. The cold mixture was then saturated with hydrogen chloride. The reaction solution was refrigerated for 18 hours. The reaction mixture was concentrated to 20 mL and diethyl ether was added. The brown solid gave 10.5 g (63% yield) of 2-Furanacryloimidate hydrochloride which was used in the next reaction.
Reaction SMILES: [C:1]1([S:7]([CH2:9][Cl:10])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:11]1([CH:17]([CH3:19])[CH3:18])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[F:20][C:21]([F:34])([F:33])[S:22]([O:25]S(C(F)(F)F)(=O)=O)(=[O:24])=[O:23]>C(OCC)C>[O-:25][S:22]([C:21]([F:34])([F:33])[F:20])(=[O:24])=[O:23].[Cl:10][CH2:9][S+:7]([C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[CH:17]([CH3:19])[CH3:18])[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: O=S(CCl)c1ccccc1
Reactant: CC(C)c1ccccc1
Solvent: CCOCC
Product: CC(C)c1ccccc1[S+](CCl)c1ccccc1
Product: O=S(=O)([O-])C(F)(F)F
Temperature: 25 °C

Procedure:
Chloromethyl phenyl sulfoxide (170 mg, 1.1 mmol) of example 21 was dissolved in dry diethyl ether (5 mL) under an argon atmosphere. Cumene (145 mg, 1.1 eq) was added to the previous solution and the mixture was cooled to a temperature below −60° C. After stabilizing the temperature, trifluoromethanesulfonic anhydride (0.184 mL, 1 eq) was added slowly maintaining the same temperature. The mixture was stirred until the reaction was complete. The orange precipitated triflate salt was quickly filtered at −60° C. affording 0.399 g as orange viscous oil after heating at room temperature, which was a mixture by proton NMR.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[CH2:9]1[O:13][C:10]1([CH3:12])[CH3:11]>>[F:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][CH2:9][C:10]([OH:13])([CH3:12])[CH3:11])=[CH:4][CH:3]=1
Reactant: Nc1ccc(F)cc1
Reactant: CC1(C)CO1
Product: CC(C)(O)CNc1ccc(F)cc1
Temperature: 120 °C
Yield: 65.5 %

Procedure:
A mixture of 4-fluoroaniline (1.12 g, 10 mmol) and isobutene oxide (0.70 g, 10 mmol) was heated in a sealed tube at 120° C. overnight. The resultant oil was purified by flash chromatography to give the title compound as an oil (1.20 g, 65%).
Reaction SMILES: C[O:2][C:3]([C:5]1[N:6]=[CH:7][N:8]([CH2:10][CH2:11][N:12]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C@@:14]3([CH2:22][C@@H:21]3[C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=3)[C:13]2=[O:30])[CH:9]=1)=[O:4].COC(C1N=CN(CCN2C3C(=CC=CC=3)[C@]3(C[C@H]3C3C=CC(Cl)=CC=3)C2=O)C=1)=O.O[Li].O>CO.O>[Cl:29][C:26]1[CH:27]=[CH:28][C:23]([C@H:21]2[C@@:14]3([C:15]4[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=4)[N:12]([CH2:11][CH2:10][N:8]4[CH:9]=[C:5]([C:3]([OH:4])=[O:2])[N:6]=[CH:7]4)[C:13]3=[O:30])[CH2:22]2)=[CH:24][CH:25]=1
Reactant: COC(=O)c1cn(CCN2C(=O)[C@]3(C[C@@H]3c3ccc(Cl)cc3)c3ccccc32)cn1
Agent: COC(=O)c1cn(CCN2C(=O)[C@@]3(C[C@H]3c3ccc(Cl)cc3)c3ccccc32)cn1
Agent: [Li]O
Solvent: O
Solvent: CO
Product: O=C(O)c1cn(CCN2C(=O)[C@@]3(C[C@H]3c3ccc(Cl)cc3)c3ccccc32)cn1
Temperature: 25 °C
Reaction time: 3 h
Yield: 88 %

Procedure:
To a solution of methyl-1-(2-((1S,2R)-2-(4-chlorophenyl)-2′-oxospiro[cyclopropane-1,3′-indoline]-1′-yl)ethyl)-1H-imidazole-4-carboxylate and methyl-1-(2-((1R,2S)-2-(4-chlorophenyl)-2′-oxospiro[cyclopropane-1,3′-indoline]-1′-yl)ethyl)-1H-imidazole-4-carboxylate (0.07 mmol) in methanol (2 mL) and water (1 mL) was added LiOH.H2O (18 mg, 0.4 mmol) in one portion. The mixture was stirred at room temperature for 3 hours until the starting material was consumed. The mixture was concentrated under reduced pressure and acidified to pH˜3. The residue was dissolved in 2 mL of DMF. Purification by preparative HPLC gave the title compound as a white powder (26 mg, 88%). LC/MS m/e calcd. for C22H18ClN3O3: 407, observed (M+H)+: 408.8 1H NMR (400 MHz, MeOD) δppm 2.10 (dd, J=28.17, 8.46 Hz, 2 H) 3.10 (s, 1 H) 4.31 (s, 2 H) 4.86 (s, 2 H) 6.05 (d, J=7.33 Hz, 1 H) 6.75 (s, 1 H) 6.90-7.45 (m, 6 H) 7.86 (s, 1 H) 8.27 (s, 1 H).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][CH:5]=[CH:4][N:3]=1.Br.Br.Br.[NH2:11][CH2:12][CH2:13][N:14]1[CH2:19][CH2:18][CH:17]([NH:20][C:21]2[N:25](CC3C=CC(F)=CC=3)[C:24]3[CH:34]=[CH:35][C:36]([OH:38])=[CH:37][C:23]=3[N:22]=2)[CH2:16][CH2:15]1.C(=O)([O-])O.[Na+]>C(O)C>[N:3]1[CH:4]=[CH:5][CH:6]=[N:7][C:2]=1[NH:11][CH2:12][CH2:13][N:14]1[CH2:19][CH2:18][CH:17]([NH:20][C:21]2[NH:25][C:24]3[CH:34]=[CH:35][C:36]([OH:38])=[CH:37][C:23]=3[N:22]=2)[CH2:16][CH2:15]1
Reactant: NCCN1CCC(Nc2nc3cc(O)ccc3n2Cc2ccc(F)cc2)CC1
Reactant: Clc1ncccn1
Agent: Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: Oc1ccc2[nH]c(NC3CCN(CCNc4ncccn4)CC3)nc2c1

Procedure:
A mixture of 1.7 parts of 2-chloropyrimidine, 9.66 parts of 2-[[1-(2-aminoethyl)-4-piperidinyl]amino]-1-[(4-fluorophenyl)-methyl]-1H-benzimidazol-5-ol trihydrobromide, 5 parts of sodium hydrogen carbonate and 80 parts of ethanol was stirred and refluxed overnight. The reaction mixture was evaporated and the residue was taken up in trichloromethane. The organic phase was washed with water, dried, filtered and evaporated. The residue was crystallized from a mixture of acetonitrile and methanol, yielding 5.2 parts (83%) of 1-[(4-fluorophenyl)methyl[-2-[[1-[2-(2-pyrimidinylamino)-ethyl]-4-piperidinyl]amino]-1H-benzimidazol-5-ol; mp. 194.4° C. (compound 64).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[Br:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]Br.O>CN(C)C=O>[Br:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][O:14][CH:11]1[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:9][CH2:10]1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: BrCCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(OCCCCCBr)CC1

Procedure:
To a solution of 1-N-t-butyloxycarbonyl-4-hydroxypiperidine (5.0 g) in dimethylformamide (DMF) (25 ml) was portionwise added sodium hydride (60% in oil) (1.29 g) with stirring under ice-cooling. The mixture was successively stirred at ambient temperature for 30 minutes, stirred at 60° C. for 1 hour and cooled with an ice bath. To the reaction mixture was added 1,5-dibromopentane (6.72 ml), and the mixture was stirred at ambient temperature for 3 hours. The reaction solution was poured into water (100 ml) and extracted twice with a mixture of ethyl acetate (80 ml) and n-hexane (30 ml). The extract was washed with saturated aqueous sodium chloride, dried over magnesium sulfate and evaporated in vacuo. The resulting residue was chromatographed on silica gel (200 ml) eluting with a mixture of n-hexane and ethyl acetate (5:1 v/v). The fractions containing the desired compound were collected and evaporated under reduced pressure to give 4-(5-bromopentyloxy)-1-N-t-butyloxycarbonylpiperidine (2.44 g).
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]([CH2:14][CH2:15][NH2:16])[CH:7]=[CH:8][C:9]=1[O:10][CH2:11][C:12]#[CH:13].C(N(CC)C(C)C)(C)C.[OH:26][CH:27]([CH2:31][C:32]1[CH:37]=[CH:36][C:35]([CH3:38])=[CH:34][CH:33]=1)[C:28](O)=[O:29].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C)C=O>[OH:26][CH:27]([CH2:31][C:32]1[CH:33]=[CH:34][C:35]([CH3:38])=[CH:36][CH:37]=1)[C:28]([NH:16][CH2:15][CH2:14][C:6]1[CH:7]=[CH:8][C:9]([O:10][CH2:11][C:12]#[CH:13])=[C:4]([O:3][CH3:2])[CH:5]=1)=[O:29]
Reactant: Cc1ccc(CC(O)C(=O)O)cc1
Reactant: C#CCOc1ccc(CCN)cc1OC
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C#CCOc1ccc(CCNC(=O)C(O)Cc2ccc(C)cc2)cc1OC
Temperature: 25 °C
Reaction time: 16 h

Procedure:
2-(3-Methoxy-4-prop-2-ynyloxy-phenyl)-ethylamine hydrochloride (11.5 g, 47 mmol) and N,N-diisopropylethylamine (23 g, 0.18 mol) are dissolved in 100 ml of N,N-dimethylformamide. To this solution 2-hydroxy-3-p-tolyl-propionic acid (8.1 g, 45 mmol) and (benzotriazol-1-yloxy)-tris-(dimethylamino)-phosphonium hexafluorophosphate (22 g, 49 mmol) are added successively. The reaction mixture is stirred for 16 hours at room temperature, subsequently poured on ice-water and extracted several times with ethyl acetate. The combined organic layer is washed with brine, dried over sodium sulfate and evaporated in vacuum. The remaining oil is purified by chromatography on silicagel (ethyl acetate/hexane 1:1) to afford 2-hydroxy-N-[2-(3-methoxy-4-prop-2-ynyloxy-phenyl)-ethyl]-3-p-tolyl-propionamide (E1.16).