Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:15]3[N:20]=[CH:19][C:18]4=[CH:21][CH:22]=[C:23]([C:24]5[O:28][C:27]([CH:29]=O)=[CH:26][CH:25]=5)[N:17]4[N:16]=3)=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.[CH3:31][S:32]([CH2:35][CH2:36][NH2:37])(=[O:34])=[O:33].Cl.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH3:31][S:32]([CH2:35][CH2:36][NH:37][CH2:29][C:27]1[O:28][C:24]([C:23]2[N:17]3[C:18]([CH:19]=[N:20][C:15]([NH:14][C:11]4[CH:12]=[CH:13][C:8]([N:5]5[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]5)=[CH:9][CH:10]=4)=[N:16]3)=[CH:21][CH:22]=2)=[CH:25][CH:26]=1)(=[O:34])=[O:33]
Reactant: CS(=O)(=O)CCN
Reactant: CN1CCN(c2ccc(Nc3ncc4ccc(-c5ccc(C=O)o5)n4n3)cc2)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CN1CCN(c2ccc(Nc3ncc4ccc(-c5ccc(CNCCS(C)(=O)=O)o5)n4n3)cc2)CC1
Temperature: 45 °C
Reaction time: 3 h
Yield: 36 %

Procedure:
Into an 8-dram vial, 5-{2-[4-(4-Methyl-piperazin-1-yl)-phenylamino]-pyrrolo[2,1-f][1,2,4]triazin-7-yl}-furan-2-carbaldehyde (97.57 mg, 0.2424 mmol), 2-Methanesulfonyl-ethylamine; hydrochloride (0.2322 g, 1.454 mmol), 1,2-Dichloroethane (15.0 mL), and Acetic acid (100.0 uL, 1.759 mmol) were added and heated at 45° C. overnight. Sodium triacetoxyborohydride (0.1541 g, 0.7273 mmol) was added. The reaction mixture was stirred at room temperature for 3 hours. The reaction was partitioned with saturated NaHCO3 and DCM. The organic was separated, washed with Brine and dried over Na2SO4. The solid was filtered and washed with DCM. The solvent was removed under vacuum. The reaction mixture was purified via ISCO column chromatography with DCM and methanol as eluant (5 to 25% methanol). The collected fractions afforded (7-{5-[(2-Methanesulfonyl-ethylamino)-methyl]-furan-2-yl}-pyrrolo[2,1-f][1,2,4]triazin-2-yl)-[4-(4-methyl-piperazin-1-yl)-phenyl]-amine as a yellow solid (45 mg, 36%). LCMS (E/I+) 510.08 (M+H). NMR 1H (DMSO-d6)-9.23 (s, 1H), 8.91 (s, 1H), 7.63 (d, 2H, J=8.69 Hz), 7.19 (d, 1H, J=3.02 Hz), 7.00 (d, 1H, J=4.57 Hz), 6.97 (d, 2H, J=9.42 Hz), 6.90 (d, 1H, J=5.03) Hz, 6.53 (d, 1H, J=3.66 Hz), 3.81 (s, 2H Hz) 3.25 (t, 2H, J=6.40 Hz), 3.10 (t, 4H, J=5.03 Hz), 3.02 (s, 3H), 2.97 (t, 2H, J=6.40 Hz), 2.49 (t, 4H, J=5.03), 2.23 (s, 3H).
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH2:14][CH2:15][S:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)(=[O:18])=[O:17])=[CH:8][C:5]=1[CH:6]=O)([O-:3])=[O:2].[CH3:25][N:26]1[CH:30](P(OCC)(=O)OCC)[C:29](=[O:39])[NH:28][C:27]1=[O:40]>>[CH3:25][N:26]1[C:30](=[CH:6][C:5]2[CH:8]=[C:9]([O:12][CH2:13][CH2:14][CH2:15][S:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)(=[O:17])=[O:18])[CH:10]=[CH:11][C:4]=2[N+:1]([O-:3])=[O:2])[C:29](=[O:39])[NH:28][C:27]1=[O:40]
Reactant: CCOP(=O)(OCC)C1C(=O)NC(=O)N1C
Reactant: O=Cc1cc(OCCCS(=O)(=O)c2ccccc2)ccc1[N+](=O)[O-]
Product: CN1C(=O)NC(=O)C1=Cc1cc(OCCCS(=O)(=O)c2ccccc2)ccc1[N+](=O)[O-]

Procedure:
Prepared from 2-nitro-5-[3-(phenylsulfonyl)propoxy]benzaldehyde and diethyl 1-methyl-2,4-dioxoimidazolidine-5-phosphonate analogous to the procedure of Example (2-8), m.p. 147°-158° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][C:17]=1[O:18][CH3:19])[C:12](Cl)=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:20]1([O:25][C:26]2[CH:27]=[C:28]([C:34](=[O:44])[CH2:35][C:36]3[C:41]([Cl:42])=[CH:40][N:39]=[CH:38][C:37]=3[Cl:43])[CH:29]=[CH:30][C:31]=2[O:32][CH3:33])[CH2:24][CH2:23][CH2:22][CH2:21]1>>[CH:20]1([O:25][C:26]2[CH:27]=[C:28](/[C:34](/[O:44][C:12](=[O:13])[C:11]3[CH:15]=[CH:16][C:17]([O:18][CH3:19])=[C:9]([O:8][CH2:1][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)[CH:10]=3)=[CH:35]/[C:36]3[C:41]([Cl:42])=[CH:40][N:39]=[CH:38][C:37]=3[Cl:43])[CH:29]=[CH:30][C:31]=2[O:32][CH3:33])[CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: COc1ccc(C(=O)Cc2c(Cl)cncc2Cl)cc1OC1CCCC1
Reactant: COc1ccc(C(=O)Cl)cc1OCc1ccccc1
Product: COc1ccc(C(=O)O/C(=C\c2c(Cl)cncc2Cl)c2ccc(OC)c(OC3CCCC3)c2)cc1OCc1ccccc1

Procedure:
The compound was obtained starting from 3-benzyloxy-4-methoxy-benzoyl chloride and 1-(3-cyclopentyloxy-4-methoxy-phenyl)-2-(3,5-dichloro -pyridin-4-yl)-ethanone, following the procedure of Example 7.
Reaction SMILES: Br[C:2]1[CH:23]=[CH:22][C:5]2[C:6]3[N:7]([CH:11]=[C:12]([C:14]4[N:18]([CH:19]([CH3:21])[CH3:20])[N:17]=[CH:16][N:15]=4)[N:13]=3)[CH2:8][CH2:9][O:10][C:4]=2[CH:3]=1.[C:24]([O:29][CH3:30])(=[O:28])[C:25]([CH3:27])=[CH2:26].C(N(CC)CC)C.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>CN(C=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:30][O:29][C:24](=[O:28])/[C:25](/[CH3:27])=[CH:26]/[C:2]1[CH:23]=[CH:22][C:5]2[C:6]3[N:7]([CH2:8][CH2:9][O:10][C:4]=2[CH:3]=1)[CH:11]=[C:12]([C:14]1[N:18]([CH:19]([CH3:21])[CH3:20])[N:17]=[CH:16][N:15]=1)[N:13]=3
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(Br)cc1OCC2
Reactant: C=C(C)C(=O)OC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)/C(C)=C/c1ccc2c(c1)OCCn1cc(-c3ncnn3C(C)C)nc1-2
Temperature: 130 °C
Yield: 57.5 %

Procedure:
8-Bromo-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene 194 (300 mg, 0.80 mmol), methyl methacrylate (129 μL, 1.20 mmol), triethylamine (168 μL, 1.20 mmol), tri-o-tolyl-phosphane (49 mg, 0.16 mmol) and palladium (II) acetate (9 mg, 0.04 mmol) were suspended in DMF (5 mL) and the reaction mixture degassed by bubbling argon through the suspension. The reaction mixture was heated at 130° C. for 16 h, before cooling to RT and diluting the mixture with ethyl acetate (10 mL). The reaction mixture was washed with water, extracted with ethyl acetate (2×10 mL) and the combined organic extracts washed with brine, dried (MgSO4) then concentrated in vacuo. The resultant residue was subjected to flash chromatography (SiO2, eluting with 0-5% methanol in DCM) to yield (E)-3-[2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-8-yl]-2-methyl-acrylic acid methyl ester as a white solid (181 mg, 57%) LCMS: RT=3.63 min, [M+H]+=394.
Reaction SMILES: [CH:1]1([C:8]2[S:12][C:11]([N:13]=[C:14]=[O:15])=[N:10][N:9]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:16][NH:17][CH2:18][CH2:19][CH:20]=[O:21]>C1C=CC=CC=1>[CH3:16][N:17]([CH2:18][CH2:19][CH:20]=[O:21])[C:14]([NH:13][C:11]1[S:12][C:8]([CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]2)=[N:9][N:10]=1)=[O:15]
Reactant: CNCCC=O
Reactant: O=C=Nc1nnc(C2CCCCCC2)s1
Solvent: c1ccccc1
Product: CN(CCC=O)C(=O)Nc1nnc(C2CCCCCC2)s1

Procedure:
A mixture of 5-cycloheptyl-1,3,4-thiadiazol-2-yl isocyanate dimmer (9.5 grams), the dimethyl acetal of 3-methylaminopropionaldehyde (5.8 grams) and benzene (60 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer and reflux condenser. The reaction mixture is heated at reflux for a period of about 15 minutes. After this time the mixture is stripped of benzene under reduced pressure to yield a solid product as the residue. This product is recrystallized to yield the desired product the dimethyl acetal of 3-[1-methyl-3-(5-cycloheptyl-1,3,4-thiadiazol-2-yl)ureido]propionaldehyde.
Reaction SMILES: Cl[C:2]1[CH2:6][CH2:5][N:4]([C:7]2[CH:12]=[CH:11][C:10]([O:13][C:14]([F:17])([F:16])[F:15])=[CH:9][CH:8]=2)[N:3]=1.[CH:18]([C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1)=[O:19].C([O-])([O-])=O.[Na+].[Na+].O1CCOCC1>CCOC(C)=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:15][C:14]([F:17])([F:16])[O:13][C:10]1[CH:11]=[CH:12][C:7]([N:4]2[CH2:5][CH2:6][C:2]([C:23]3[CH:24]=[CH:25][C:20]([CH:18]=[O:19])=[CH:21][CH:22]=3)=[N:3]2)=[CH:8][CH:9]=1
Reactant: FC(F)(F)Oc1ccc(N2CCC(Cl)=N2)cc1
Reactant: O=Cc1ccc(B(O)O)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: O=Cc1ccc(C2=NN(c3ccc(OC(F)(F)F)cc3)CC2)cc1
Temperature: 150 °C
Yield: 34.9 %

Procedure:
A suspension of 3-chloro-1-(4-trifluoromethoxyphenyl)-4,5-dihydro-1H-pyrazole (114 mg, 0.43 mmol, 1.00 eq), 4-formylphenylboronic acid (97 mg, 0.65 mmol, 1.50 eq), bis(triphenylphosphine)palladium(II) dichloride (10 mg, 0.01 mmol, 0.03 eq), 2 M Na2CO3 (aq) (0.43 mL, 0.86 mmol, 2.0 eq), and 1,4-dioxane (5 mL) were heated at 150° C. in a microwave reaction vessel for 45 min. The cooled solution was then diluted with EtOAc (20 mL), filtered over Celite®, concentrated to dryness, and purified via chromatography (2:2:1, hexane:EtOAc:acetone) to afford the desired intermediate (50 mg, 0.15 mmol, 31%).
Reaction SMILES: [OH-].[Na+].Cl.Cl.[CH:5]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)([CH3:7])[CH3:6].[CH:14]([C:16]1[CH:24]=[CH:23][C:19]([C:20](Cl)=[O:21])=[CH:18][CH:17]=1)=[O:15]>O.C1(C)C=CC=CC=1>[CH:5]([N:8]1[CH2:13][CH2:12][N:11]([C:14]([C:16]2[CH:24]=[CH:23][C:19]([CH:20]=[O:21])=[CH:18][CH:17]=2)=[O:15])[CH2:10][CH2:9]1)([CH3:7])[CH3:6]
Reactant: CC(C)N1CCNCC1
Reactant: O=Cc1ccc(C(=O)Cl)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)N1CCN(C(=O)c2ccc(C=O)cc2)CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 101 %

Procedure:
A solution of NaOH (24.0 g, 0.600 mol) in de-ionized H2O (240 mL) and toluene (60 mL) at 0° C. was treated with isopropyl piperazine dihydrochloride salt (39.0 g, 194 mmol). The resulting biphasic solution was stirred at 0° C. for 30 min. A solution of 4-formyl-benzoyl chloride in toluene was added in a slow stream via an addition funnel over 1 h, with vigorous mechanical agitation. The mixture was allowed to warm to room temperature over 16 h, then cooled to 0° C., and the pH adjusted to 10 with 1 N NaOH. The phases were separated and the aqueous layer was extracted with toluene (2×200 mL). The organic layers were combined, washed with brine (200 mL), and concentrated to yield 4-(4-isopropyl-piperazine-1-carbonyl)-benzaldehyde (52.5 g, mass balance 101%) as a pale, yellow-brown oil. The oil was dissolved in EtOH (600 mL) and, with vigorous mechanical agitation, was treated with a solution of NaHSO3 (23.1 g, 222 mmol) in de-ionized H2O (50 mL) which was added via an addition funnel over 30 min. The resulting mixture was stirred at room temperature for 48 h, and then cooled to 0° C. Methyl-tert-butyl ether (500 mL) was added and the resulting the slurry was stirred for 30 min. The precipitate was collected by suction filtration through a medium porosity glass frit, washed with cold EtOH/EtOAc (5:1, 3×60 mL). The solids were dried under vacuum for 2 h, then at 40° C. in a vacuum oven for 16 h to yield the title compound as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][CH2:10][C:11]([C:13]2[S:14][C:15]([C:18]3[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=3)=[CH:16][CH:17]=2)=[O:12])[CH:5]=[CH:6][C:7]=1[OH:8].Br[CH2:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31]>>[F:1][C:2]1[CH:3]=[C:4]([CH2:9][CH2:10][C:11](=[O:12])[C:13]2[S:14][C:15]([C:18]3[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:25])[F:26])=[CH:20][CH:19]=3)=[CH:16][CH:17]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31]
Reactant: O=C(CCc1ccc(O)c(F)c1)c1ccc(-c2ccc(C(F)(F)F)cc2)s1
Reactant: CC(C)(C)OC(=O)CBr
Product: CC(C)(C)OC(=O)COc1ccc(CCC(=O)c2ccc(-c3ccc(C(F)(F)F)cc3)s2)cc1F

Procedure:
Tert-butyl 2-(2-fluoro-4-(3-oxo-3-(5-(4-(trifluoromethyl)phenyl)thien-2-yl)propyl)phenoxy)-acetate is prepared from 3-(3-fluoro-4-hydroxyphenyl)-1-(5-(4-(trifluoromethyl)phenyl)thien-2-yl)propan-1-one and tert-butyl bromoacetate according to general procedure D.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2[C:13]([CH3:25])([CH3:24])[C:14](=[O:23])[N:15]([CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11].[Cl:26][C:27]1[CH:32]=[CH:31][C:30]([S:33](Cl)(=[O:35])=[O:34])=[CH:29][CH:28]=1>>[Cl:26][C:27]1[CH:32]=[CH:31][C:30]([S:33]([N:20]2[CH2:21][CH2:22][CH:17]([N:15]3[C:14](=[O:23])[C:13]([CH3:25])([CH3:24])[C:12]([C:6]4[CH:7]=[CH:8][C:9]([O:10][CH3:11])=[C:4]([O:3][CH3:2])[CH:5]=4)=[N:16]3)[CH2:18][CH2:19]2)(=[O:35])=[O:34])=[CH:29][CH:28]=1
Reactant: COc1ccc(C2=NN(C3CCNCC3)C(=O)C2(C)C)cc1OC
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Agent: Cl
Product: COc1ccc(C2=NN(C3CCN(S(=O)(=O)c4ccc(Cl)cc4)CC3)C(=O)C2(C)C)cc1OC

Procedure:
The title compound is prepared analogously as described for GP1 using 5-(3,4-dimethoxyphenyl)-4,4-dimethyl-2-(piperidin-4-yl)-2,4-dihydro-3H-pyrazol-3-one hydrochloride (compound B1*HCl) and 4-chlorobenzenesulfonyl chloride as starting compounds. The crude product is purified by crystallization from methanol to yield the title compound.
Reaction SMILES: [CH3:1][N:2]([CH3:33])[CH2:3][C:4]([N:6]1[CH2:10][CH2:9][CH:8]([O:11][C:12]2[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=2[NH:19][C:20]2[C:21]3[C:28]([CH3:29])=[C:27]([C:30]([OH:32])=O)[S:26][C:22]=3[N:23]=[CH:24][N:25]=2)[CH2:7]1)=[O:5].[NH3:34]>CO>[CH3:33][N:2]([CH3:1])[CH2:3][C:4]([N:6]1[CH2:10][CH2:9][CH:8]([O:11][C:12]2[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=2[NH:19][C:20]2[C:21]3[C:28]([CH3:29])=[C:27]([C:30]([NH2:34])=[O:32])[S:26][C:22]=3[N:23]=[CH:24][N:25]=2)[CH2:7]1)=[O:5]
Reactant: N
Reactant: Cc1c(C(=O)O)sc2ncnc(Nc3ccc(F)cc3OC3CCN(C(=O)CN(C)C)C3)c12
Solvent: CO
Product: Cc1c(C(N)=O)sc2ncnc(Nc3ccc(F)cc3OC3CCN(C(=O)CN(C)C)C3)c12

Procedure:
Prepared analogously to example 1.4 from 4-{2-[1-(2-Dimethylamino-acetyl)-pyrrolidin-3-yloxy]-4-fluoro-phenylamino}-5-methyl-thieno[2,3-d]pyrimidine-6-carboxylic acid and ammonia in methanol.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:29])[C:7]([CH2:18][NH:19][C:20]([NH:22][CH:23]3[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]3)=[O:21])=[CH:8][N:9]2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:4][CH:3]=1.[C:30](Cl)(=[O:37])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>>[C:30]([N:26]1[CH2:27][CH2:28][CH:23]([NH:22][C:20]([NH:19][CH2:18][C:7]2[C:6](=[O:29])[C:5]3[C:10](=[CH:11][C:2]([Cl:1])=[CH:3][CH:4]=3)[N:9]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:8]=2)=[O:21])[CH2:24][CH2:25]1)(=[O:37])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: O=C(NCc1cn(-c2ccccc2)c2cc(Cl)ccc2c1=O)NC1CCNCC1
Reactant: O=C(Cl)c1ccccc1
Product: O=C(NCc1cn(-c2ccccc2)c2cc(Cl)ccc2c1=O)NC1CCN(C(=O)c2ccccc2)CC1

Procedure:
1-(1-Benzoyl-piperidin-4-yl)-3-(7-chloro-4-oxo-1-phenyl-1,4-dihydro-quinolin-3-yl methyl)-urea was prepared starting from intermediate N and benzoyl chloride. MS calcd. for C29H28ClN4O3 [(M+H)+] 515.2, obsd. 515.2.
Reaction SMILES: Cl[C:2]([O:4][CH3:5])=[O:3].[NH:6]1[CH2:11][CH2:10][CH:9]([N:12]2[CH2:16][CH2:15][C:14]3([CH2:21][CH2:20][CH2:19][N:18]([C:22]4[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][N:23]=4)[CH2:17]3)[C:13]2=[O:32])[CH2:8][CH2:7]1.C(N(CC)C(C)C)(C)C.C(Cl)Cl>>[O:32]=[C:13]1[C:14]2([CH2:21][CH2:20][CH2:19][N:18]([C:22]3[CH:27]=[CH:26][C:25]([C:28]([F:30])([F:31])[F:29])=[CH:24][N:23]=3)[CH2:17]2)[CH2:15][CH2:16][N:12]1[CH:9]1[CH2:10][CH2:11][N:6]([C:2]([O:4][CH3:5])=[O:3])[CH2:7][CH2:8]1
Reactant: COC(=O)Cl
Reactant: O=C1N(C2CCNCC2)CCC12CCCN(c1ccc(C(F)(F)F)cn1)C2
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)N1CCC(N2CCC3(CCCN(c4ccc(C(F)(F)F)cn4)C3)C2=O)CC1
Reaction time: 0.5 h

Procedure:
Methyl chloroformate (4.4 μL, 0.000057 mol) was added to a solution of 2-piperidin-4-yl-7-[5-(trifluoromethyl)pyridin-2-yl]-2,7-diazaspiro[4.5]decan-1-one (18.3 mg, 0.0000478 mol) and N,N-diisopropylethylamine (27 μL, 0.00016 mol) in methylene chloride (1.0 mL, 0.016 mol); and the mixture was stirred for 0.5 h. The volatiles were removed in-vacuo and the product was purified by prep-HPLC. LC-MS: 441.2 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([CH3:8])[NH:5][C:4]2=[CH:9][C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[N:11][C:3]=12.[NH:18]1[CH:22]=[N:21][CH:20]=[N:19]1.C([O-])([O-])=O.[Na+].[Na+].Cl>CCOC(C)=O>[ClH:1].[CH3:8][C:6]1[NH:5][C:4]2=[CH:9][C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[N:11][C:3]2=[C:2]([C:22]2[N:21]=[CH:20][NH:19][N:18]=2)[N:7]=1
Reactant: c1nc[nH]n1
Reactant: Cc1nc(Cl)c2nc(-c3ccccc3)cc-2[nH]1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Product: Cc1nc(-c2nc[nH]n2)c2nc(-c3ccccc3)cc-2[nH]1
Temperature: 195 °C
Reaction time: 1 h
Yield: 45 %

Procedure:
To an oven-dried, 50-mL, round-bottomed flask was added 4-chloro-2-methyl-6-phenylpyrrolo[3,2-d]pyrimidine (Example 1(e)) (350 mg, 1.44 mmol) followed by 1,2,4-triazole (Aldrich Chemical Company) (200 mg, 2.88 mmol) and solid Na2CO3 (610 mg, 5.76 mmol). The flask was purged with N2 and heated to 190-200° C. for 4 h. The reaction was allowed to cool to room temperature and the residue was dissolved in MeOH (25 mL). The remaining salts were filter off and the organic layer evaporated under reduced pressure. The residue was purified by silica gel chromatography with 50% EtOAc/hexanes as eluant to give 180 mg (45% yield) of an off white solid. The free base (168 mg, 0.608 mmol) was dissolved in hot EtOAc (15 mL) and anhydrous ethereal HCl (0.61 mL, 1.0 M soln, 0.61 mmol) was added dropwise. A precipitate formed and the reaction was allowed to cool to room temperature and stirred for 1 h. The solid was filtered off and dried under vacuum at 60° C. overnight to give 182 mg (96% yield) of an off white solid. Mp: 264-265° C. 1H NMR (DMSO-d6; 400 MHz): d 2.77 (s, 3), 7.22 (s, 1), 7.57 (m, 3), 8.10 (d, 2, J=5.5), 8.6 (d, 1, J=3.4), 9.64 (d, 1, J=4.2), 11.87 (br m, 1). MS m/z: 277.0 (M+1); 275 (M−1).
Reaction SMILES: [H-].[Na+].C([O:10][C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[CH:17]=[C:16](O)[CH:15]=[CH:14]2)C1C=CC=CC=1.FC(F)(F)S([O:27][CH2:28][C:29]([F:41])([F:40])[C:30]([F:39])([F:38])[C:31]([F:37])([F:36])[CH2:32][O:33][CH2:34][CH3:35])(=O)=O>COCCOC>[CH2:34]([O:33][CH2:32][C:31]([F:36])([F:37])[C:30]([F:38])([F:39])[C:29]([F:40])([F:41])[CH2:28][O:27][C:16]1[CH:17]=[C:18]2[C:13](=[CH:14][CH:15]=1)[CH:12]=[C:11]([OH:10])[CH:20]=[CH:19]2)[CH3:35]
Reactant: Oc1ccc2cc(OCc3ccccc3)ccc2c1
Reactant: CCOCC(F)(F)C(F)(F)C(F)(F)COS(=O)(=O)C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: CCOCC(F)(F)C(F)(F)C(F)(F)COc1ccc2cc(O)ccc2c1
Reaction time: 18 h
Yield: 42.9 %

Procedure:
0.7 g of 60% sodium hydride in mineral oil was added to 25 ml of dry 1,2-dimethoxyethane. The contents were stirred, and 2.5 g (0.010 moles) of 6-benzyloxy-2napthol was slowly added. After stirring the resulting solution for 20 minutes at room temperature, it was cooled with an ice bath. 4.1 g (0.011 moles) of 5-ethoxy-2,2,3,3,4,4-hexafluoropentyl trifluoromethanesulfonate (prepared essentially as in Example 3) was then added slowly. When this addition was complete, the ice bath was removed, and the product-containing mixture was stirred overnight at room temperature. The solvent was then removed under reduced pressure, and 30 ml of water, followed by 30 ml of diethyl ether, were added sequentially. Once all of the solids had dissolved, two homogeneous liquid layers formed. The layers were separated, and the aqueous layer was extracted twice with 25 ml aliquots of diethyl ether. The resulting ether layers were combined, washed three times with 20 ml aliquots of deionized water, dried with anhydrous magnesium sulfate, and stripped to dryness using a rotary evaporator. The resulting solid was dissolved in tetrahydrofuran and was hydrogenated at 60 psi in the presence of catalytic 10% palladium on carbon for 18 hours. When the hydrogenation was complete, the catalyst was removed by filtration, and the solvent was removed on a rotary evaporator. The resulting brown semisolid material was then purified by using chromatography on silica gel (2.5% methanol in chloroform) to yield 1.64 g of 6-(5-ethoxy-2,2,3,3,4,4-hexafluoropentoxy)-2-hydroxynapthalene product.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([S:19]([NH2:22])(=[O:21])=[O:20])=[CH:15][CH:14]=3)[N:11]=[C:10]([CH2:23]Cl)[CH:9]=2)=[CH:4][CH:3]=1.[C-:25]#[N:26].[Na+]>CS(C)=O.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:12]([C:13]3[CH:14]=[CH:15][C:16]([S:19]([NH2:22])(=[O:20])=[O:21])=[CH:17][CH:18]=3)[N:11]=[C:10]([CH2:23][C:25]#[N:26])[CH:9]=2)=[CH:6][CH:7]=1
Reactant: NS(=O)(=O)c1ccc(-n2nc(CCl)cc2-c2ccc(Cl)cc2)cc1
Reactant: [C-]#N
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: N#CCc1cc(-c2ccc(Cl)cc2)n(-c2ccc(S(N)(=O)=O)cc2)n1
Temperature: 100 °C
Yield: 74.8 %

Procedure:
A solution of 4-[5-(4-chlorophenyl)-3-chloromethyl-1H-pyrazol-1-yl]benzenesulfonamide from step 1 (350 mg, 0.9 mmol) and sodium cyanide (200 mg), dissolved in 15 mL of dimethylsulfoxide, was warmed to 100° C. for 4 hours. The solution was cooled to room temperature, diluted with water and extracted with ethyl acetate. The ethyl acetate extracts were combined and washed with water, dried over anhydrous MgSO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography over silica gel eluting with 1:1 (v:v) hexane/ethyl acetate. The appropriate fractions were combined and concentrated, and the residue crystallized from ethanol/water to give 4-[5-(4-chlorophenyl)-3-cyanomethyl-1-H-pyrazol-1-yl]benzenesulfonamide as a white solid (251 mg, 75%): mp 212-214° C. Anal. Calc'd. for C17H13ClN4O2S1: C, 54.77; H, 3.51; N, 15.03. Found: C, 54.94; H, 3.61; N, 14.88.
Reaction SMILES: [C:1]([N+:5]1[CH2:9][CH2:8][CH2:7][C:6]=1OC)([CH3:4])([CH3:3])[CH3:2].COS([O-])(=O)=O.[Cl:18][C:19]1[CH:27]=[CH:26][C:22]([CH2:23][C:24]#[N:25])=[CH:21][CH:20]=1.[Na]>C(O)C>[C:1]([N:5]1[CH2:9][CH2:8][CH2:7][C:6]1=[C:23]([C:24]#[N:25])[C:22]1[CH:26]=[CH:27][C:19]([Cl:18])=[CH:20][CH:21]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: COC1=[N+](C(C)(C)C)CCC1
Reactant: N#CCc1ccc(Cl)cc1
Agent: COS(=O)(=O)[O-]
Agent: [Na]
Solvent: CCO
Product: CC(C)(C)N1CCCC1=C(C#N)c1ccc(Cl)cc1
Reaction time: 2 h
Yield: 20 %

Procedure:
Heat 56.8 g of 1-tert.-butyl-2-methoxy-1-pyrrolinium-methylsulfate and 30.3 g of 4-chlorobenzylcyanide to 80°. Add thereto (dropwise, within 2 hours, with stirring) a solution of 8.1 g of sodium in 160 ml of ethanol. After completion of the addition, boil the prepared admixture for a further 2 hours. Concentrate the boiled admixture and distil off (at 10-3 mm of Hg) the excess 4-chlorobenzylcyanide. Recrystallize the resulting residue from 170 ml of ethanol to obtain 11 g of the title compound. Concentrate the mother liquor to obtain a further 2.5 g (24% of theory) of the title compound in the form of light-brown crystals of m.p. 150° to 153°.
Reaction SMILES: [NH:1]([C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4])[NH2:2].C1(C)C=CC=CC=1.[C:17]1(=O)[O:22][C:20](=[O:21])[C:19]2=[CH:23][CH:24]=[CH:25][CH:26]=[C:18]12>O>[O:21]=[C:20]1[C:19]2[C:18](=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:17](=[O:22])[N:2]1[NH:1][C:3](=[O:4])[O:5][C:6]([CH3:9])([CH3:8])[CH3:7]
Reactant: CC(C)(C)OC(=O)NN
Reactant: O=C1OC(=O)c2ccccc21
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)NN1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Yield: 104.1 %

Procedure:
Tert-butyl hydrazinecarboxylate (250 g) was added to a toluene (3 L) solution of phthalic anhydride (280 g). In a Dean Stark water separator, the reaction mixture was heated under reflux for 3 hours. After cooled to room temperature, the formed solid was collected through filtration to give crude tert-butyl (1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)carbamate (516 g).