Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([O:10][C:11]2[CH:12]=[CH:13][C:14]3[O:18][C:17]([C:19]([OH:21])=O)=[CH:16][C:15]=3[CH:22]=2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2].[NH:23]1[CH2:28][CH2:27][S:26](=[O:30])(=[O:29])[CH2:25][CH2:24]1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(C(C)C)C(C)C)C>C1COCC1>[O:29]=[S:26]1(=[O:30])[CH2:27][CH2:28][N:23]([C:19]([C:17]2[O:18][C:14]3[CH:13]=[CH:12][C:11]([O:10][CH:7]4[CH2:8][CH2:9][N:4]([CH:1]([CH3:2])[CH3:3])[CH2:5][CH2:6]4)=[CH:22][C:15]=3[CH:16]=2)=[O:21])[CH2:24][CH2:25]1
Reactant: O=S1(=O)CCNCC1
Reactant: CC(C)N1CCC(Oc2ccc3oc(C(=O)O)cc3c2)CC1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)N1CCC(Oc2ccc3oc(C(=O)N4CCS(=O)(=O)CC4)cc3c2)CC1
Yield: 72.3 %

Procedure:
In a flask were mixed together the above prepared 5-(1-isopropyl-piperidin-4-yloxy)-benzofuran-2-carboxylic acid (1.25 g, 3.92 mmol, calculated as 73%), thiomorpholine 1,1-dioxide (0.636 g, 1.2 eq.), (benzotriazol-1-yloxy)-tris-(dimethylamino)phosphonium hexafluorophosphate (2.081 g, 1.2 eq.) and 2.4 eq. of N-ethyldiisopropylamine (1.60 mL) in 24 mL of abs. THF and allowed to react during one night at ambient temperature. Pouring onto crashed ice/AcOEt/NH4Cl-solution, twofold extraction with AcOEt, washing with water and brine, drying over magnesium sulfate, and evaporation of the solvents, followed by flash chromatography (SiO2, NEt3/AcOEt=2/98) and trituration in hexane/AcOEt=7/3 yielded 1.192 g of the title compound as off-white crystals.
Reaction SMILES: [N+:1]([C:4]1[CH:26]=[CH:25][C:7]([O:8][CH2:9][CH2:10][N:11]([CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([O:23][CH3:24])[CH:16]=2)[CH3:12])=[C:6]([N:27]2[CH:31]=[CH:30][CH:29]=[CH:28]2)[CH:5]=1)([O-])=O.[H][H]>C(OCC)(=O)C.CO.[Pd]>[NH2:1][C:4]1[CH:26]=[CH:25][C:7]([O:8][CH2:9][CH2:10][N:11]([CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([O:23][CH3:24])[CH:16]=2)[CH3:12])=[C:6]([N:27]2[CH:31]=[CH:30][CH:29]=[CH:28]2)[CH:5]=1
Reactant: COc1ccc(CCN(C)CCOc2ccc([N+](=O)[O-])cc2-n2cccc2)cc1OC
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: COc1ccc(CCN(C)CCOc2ccc(N)cc2-n2cccc2)cc1OC
Yield: 99.1 %

Procedure:
A portion (0.53 g, 1.25 mmol) of the 1-[4-nitro-2-(1H-pyrrol-1-yl)phenoxy]-2-[N-(3,4-dimethoxyphenethyl)-N-methylamino]ethane produced in (3) above was dissolved in 50 ml of a 1:1 solvent system of ethyl acetate and methanol and 10% Pd/C (0.15 g) was slowly added to the solution, which was thereafter stirred at ordinary temperatures for 10 min as hydrogen gas was injected. Thereafter, the reaction mixture was filtered through Celite and the filtrate was evaporated, with the residue being purified by being subjected to column chromatography on silica gel using, as an eluent, ethyl acetate containing methanol (10%). The fractions containing the end product were combined and the solvent was evaporated to yield the end compound 1-[4-amino-2-(1H-pyrrol-1-yl)phenoxy]-2-[N-(3,4-dimethoxyphenethyl)-N-methylamino]ethane (0.49 g) as a yellow oil.
Reaction SMILES: [OH:1][C:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[S:4][C:3]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH3:19].C(N(CC)CC)C.[C:27](OC(=O)C)(=[O:29])[CH3:28]>C(#N)C.CN(C)C1C=CN=CC=1>[C:27]([O:1][C:2]1[CH:6]=[C:5]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[S:4][C:3]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH3:19])(=[O:29])[CH3:28]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1ccccc1-c1sc(-c2ccccc2)cc1O
Agent: CN(C)c1ccncc1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(=O)Oc1cc(-c2ccccc2)sc1-c1ccccc1C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3-Hydroxy-2-(2-methylphenyl)-5-phenylthiophene (537 mg, 2.02 mmol) was dissolved in acetonitrile (4.0 mL), and 4-dimethylaminopyridine (15 mg, 0.12 mmol) and triethylamine (0.65 mL, 470 mg, 6.9 mmol) were added followed by acetic anhydride (0.65 mL, 700 mg, 6.9 mmol). The reaction was stirred overnight at 25° C. The reaction mixture was evaporated and the residue was chromatographed on 30 g of silica gel eluting with 700 mL of 15% ethyl acetate in hexane. 3-Acetoxy-2-(2'-methylphenyl)-5-phenylthiophene was isolated as 370 mg of viscous oil. The product could be distilled bulb-to-bulb, bp (0.4 mm) 140°-150° C.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7](=[CH2:12])[C:8]2=[O:11])=[CH:4][CH:3]=1.C[Si](C)(C)[O:15][C:16]([CH:18]=[CH2:19])=[CH2:17].B(F)(F)F.CCOCC>ClCCl>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7]3([CH2:19][CH2:18][C:16](=[O:15])[CH2:17][CH2:12]3)[C:8]2=[O:11])=[CH:4][CH:3]=1
Reactant: C=CC(=C)O[Si](C)(C)C
Reactant: C=C1Cc2ccc(Br)cc2C1=O
Agent: FB(F)F
Solvent: ClCCl
Solvent: CCOCC
Product: O=C1CCC2(CC1)Cc1ccc(Br)cc1C2=O
Temperature: -78 °C
Reaction time: 0.08 h
Yield: 48.1 %

Procedure:
In a flame dried 20 mL vial was placed 6-bromo-2-methylene-2,3-dihydro-1H-inden-1-one (98 mg, 0.441 mmol) and it was dissolved in dichloromethane (4.5 mL). To this solution was added 2-trimethylsilyloxy-1,3-butadiene (98 μL, 0.565 mmol) and the solution was cooled down to −78° C. After stirring for 5 minutes, BF3.OEt2 (27 mL, 0.219 mmol) was slowly added. After 5 minutes of the BF3.OEt2 addition, TLC indicated consumption of the dienophile. The reaction was quenched with MeOH (300 μL), allowed to stir for 5 minutes at −78° C. and then warmed up to room temperature. Once at room temperature, 2M HCl (7 mL) was added. The phases were separated and the aqueous phase was back-extracted with dichloromethane twice (5 mL/each). The combined organic phases were dried over MgSO4, filtered and concentrated under reduce pressure. The crude material was purified by flash chromatography (ISCO, 12 g SiO2 cartridge, ethyl acetate/hexanes as the eluents). The corresponding fractions were combined and concentrated under reduce pressure yielding 6′-bromospiro[cyclohexane-1,2′-indene]-1′,4(3′H)-dione (62 mg, 0.212 mmol, 48% yield).
Reaction SMILES: [CH2:1]([N:3]([CH2:20][CH3:21])[CH2:4][CH2:5][N:6]1[CH2:12][CH2:11][CH2:10][C:9]2[NH:13][C:14]([CH:17]=O)=[C:15]([CH3:16])[C:8]=2[C:7]1=[O:19])[CH3:2].[Cl:22][C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][CH:31]=1)[NH:28][C:27](=[O:32])[CH2:26]2>>[Cl:22][C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][CH:31]=1)[NH:28][C:27](=[O:32])/[C:26]/2=[CH:17]\[C:14]1[NH:13][C:9]2[CH2:10][CH2:11][CH2:12][N:6]([CH2:5][CH2:4][N:3]([CH2:20][CH3:21])[CH2:1][CH3:2])[C:7](=[O:19])[C:8]=2[C:15]=1[CH3:16]
Reactant: CCN(CC)CCN1CCCc2[nH]c(C=O)c(C)c2C1=O
Reactant: O=C1Cc2cc(Cl)ccc2N1
Product: CCN(CC)CCN1CCCc2[nH]c(/C=C3\C(=O)Nc4ccc(Cl)cc43)c(C)c2C1=O
Yield: 60 %

Procedure:
The title compound was prepared under the same conditions as described in step 10 of Example 1 with 5-(2-diethylamino-ethyl)-3-methyl-4-oxo-1,4,5,6,7,8-hexahydro-pyrrolo[3,2-c]azepine-2-carbaldehyde 1j obtained from step 9 of Example 1 and 5-chloro-1,3-dihydro-indol-2-one as starting materials to obtain (Z)-2-(5-chloro-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-5-(2-diethylamino-ethyl)-3-methyl-5,6,7,8-tetrahydro-1H-pyrrolo[3,2-c]azepin-4-one 2 (27 mg, yield 60.0%) as a nacarat solid.
Reaction SMILES: [C:1]([N:8]1[CH:12]=[CH:11][N:10]=[CH:9]1)([N:3]1[CH:7]=[CH:6][N:5]=[CH:4]1)=[S:2].NC1[S:15][C:16]2C=C[CH:20]=[CH:19][C:17]=2N=1>C(#N)C>[S:15]1[C:16]2[CH:17]=[CH:19][CH:20]=[CH:12][C:11]=2[N:10]=[C:9]1[NH:8][C:1]([N:3]1[CH:7]=[CH:6][N:5]=[CH:4]1)=[S:2]
Reactant: S=C(n1ccnc1)n1ccnc1
Reactant: Nc1nc2ccccc2s1
Solvent: CC#N
Product: S=C(Nc1nc2ccccc2s1)n1ccnc1
Yield: 44.2 %

Procedure:
A solution of 1,1'-thiocarbonyldiimidazole (8.9 g, 50 mmol) and 2-aminobenzothiazole (7.5 g, 50 mmol) in acetonitrile (125 mL) was stirred at room temperature for 20 h. The resulting precipitate was collected by filtration to provide 5.75 g (44%) of the title product:
Reaction SMILES: [C:1](Cl)(=[O:9])[O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(=O)([O-])O.[Na+].O.[NH2:17][C:18]1[S:19][C:20]2[CH:26]=[C:25]([S:27][C:28]#[N:29])[CH:24]=[CH:23][C:21]=2[N:22]=1>O1CCCC1>[S:27]([C:25]1[CH:24]=[CH:23][C:21]2[N:22]=[C:18]([NH:17][C:1](=[O:9])[O:2][C:3]3[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=3)[S:19][C:20]=2[CH:26]=1)[C:28]#[N:29]
Reactant: O=C(Cl)Oc1ccccc1
Reactant: N#CSc1ccc2nc(N)sc2c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: N#CSc1ccc2nc(NC(=O)Oc3ccccc3)sc2c1
Temperature: 20 °C
Reaction time: 20 h
Yield: 87.4 %

Procedure:
7.5 g of phenyl chlorocarbonate and then 4.05 g of sodium hydrogen carbonate and 9.4 cm3 of water are added, at 20° C., to a solution of 2.5 g of commercial 2-amino-1,3-benzothiazol-6-yl thiocyanate in 94 cm3 of tetrahydrofuran. The resulting mixture is subsequently stirred at 20° C. for 20 h and then extracted with 2×150 cm3 of ethyl acetate. The organic phases are combined and then washed with 3×50 cm3 of a saturated aqueous solution of sodium hydrogen carbonate. The organic phase obtained is dried over magnesium sulphate and then concentrated to dryness under reduced pressure. The residue is taken up in 50 cm3 of water and the product is spin-filter-dried and dried under vacuum at 20° C. 3.45 g of phenyl (6-thiocyanato-1,3-benzothiazol-2-yl)carbamate are thus obtained in the form of a pale yellow solid, the characteristics of which are as follows:
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]2[N:9]=[CH:10][N:11]([C:12]3[S:16][C:15]([C:17]([O:19]C)=O)=[C:14]([O:21][CH2:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[C:29]([F:32])([F:31])[F:30])[CH:13]=3)[C:6]2=[CH:5][CH:4]=1.[NH3:33]>CO>[CH3:1][O:2][C:3]1[N:8]=[C:7]2[N:9]=[CH:10][N:11]([C:12]3[S:16][C:15]([C:17]([NH2:33])=[O:19])=[C:14]([O:21][CH2:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[C:29]([F:32])([F:31])[F:30])[CH:13]=3)[C:6]2=[CH:5][CH:4]=1
Reactant: COC(=O)c1sc(-n2cnc3nc(OC)ccc32)cc1OCc1ccccc1C(F)(F)F
Reactant: N
Solvent: CO
Product: COc1ccc2c(ncn2-c2cc(OCc3ccccc3C(F)(F)F)c(C(N)=O)s2)n1

Procedure:
In a similar manner as described for example 22, 1.5 g of methyl 5-(5-methoxy-1H-imidazo[4,5-b]pyridin-1-yl)-3-{[2-(trifluoromethyl)benzyl]oxy}thio-phene-2-carboxylate (compound B7a) and 200 ml of a saturated solution of ammonia in methanol yield the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:35]=[CH:34][C:5]([O:6][C:7]2[C:16]3[C:11](=[CH:12][C:13]([O:19][CH2:20][CH:21]4[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23][CH2:22]4)=[C:14]([C:17]#[N:18])[CH:15]=3)[N:10]=[CH:9][CH:8]=2)=[CH:4][C:3]=1[F:36].N1C=CC=CC=1.Cl[C:44]([O:46][C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)=[O:45]>O1CCCC1>[C:17]([C:14]1[CH:15]=[C:16]2[C:11](=[CH:12][C:13]=1[O:19][CH2:20][CH:21]1[CH2:22][CH2:23][N:24]([C:27]([O:29][C:30]([CH3:32])([CH3:31])[CH3:33])=[O:28])[CH2:25][CH2:26]1)[N:10]=[CH:9][CH:8]=[C:7]2[O:6][C:5]1[CH:34]=[CH:35][C:2]([NH:1][C:44]([O:46][C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)=[O:45])=[C:3]([F:36])[CH:4]=1)#[N:18]
Reactant: CC(C)(C)OC(=O)N1CCC(COc2cc3nccc(Oc4ccc(N)c(F)c4)c3cc2C#N)CC1
Reactant: O=C(Cl)Oc1ccccc1
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)N1CCC(COc2cc3nccc(Oc4ccc(NC(=O)Oc5ccccc5)c(F)c4)c3cc2C#N)CC1
Reaction time: 0.25 h

Procedure:
tert-Butyl 4-(((4-(4-amino-3-fluorophenoxy)-6-cyano-7-quinolyl)oxy)methyl)-1-piperidinecarboxylate (523 mg), pyridine (0.17 ml) and tetrahydrofuran (10 ml) were stirred while cooling on ice, and then phenyl chloroformate was added dropwise. Immediately after completion of the dropwise addition, the cooling bath was removed and the mixture was returned to room temperature. After 15 minutes of stirring, water and ethyl acetate were added for extraction. Silica gel was added to the extract and the solvent was distilled off under reduced pressure for adsorption. The reaction solution-adsorbed silica gel was purified by column chromatography (hexane:ethyl acetate=1:1, followed by 1:2, ethyl acetate) in a dry column packed with silica gel, to obtain 490 mg of a yellow powder.
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12](O)=[O:13])=[C:7]2[N:6]=[C:5]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)[CH:4]=1.[NH2:27][C:28]1[CH:29]=[C:30]([S:34]([NH:37][CH2:38][CH2:39][OH:40])(=[O:36])=[O:35])[CH:31]=[CH:32][CH:33]=1>>[OH:40][CH2:39][CH2:38][NH:37][S:34]([C:30]1[CH:29]=[C:28]([NH:27][C:12]([C:11]2[CH:10]=[N:9][N:8]3[C:3]([C:2]([F:26])([F:25])[F:1])=[CH:4][C:5]([C:15]4[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:22])[F:23])=[CH:17][CH:16]=4)=[N:6][C:7]=23)=[O:13])[CH:33]=[CH:32][CH:31]=1)(=[O:36])=[O:35]
Reactant: O=C(O)c1cnn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Reactant: Nc1cccc(S(=O)(=O)NCCO)c1
Product: O=C(Nc1cccc(S(=O)(=O)NCCO)c1)c1cnn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12

Procedure:
The title compound was prepared from 7-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.2) and 3-amino-N-(2-hydroxy-ethyl)-benzenesulfonamide [CAS 436095-41-9] according to general procedure II. Yellow solid. MS (ISP) 572.0 [(M−H)−]; mp 227° C.
Reaction SMILES: [CH:1]1[C:11]2[C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[CH2:8][N:7]([C:16](=[NH:20])[O:17][CH2:18][CH3:19])[CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[C:21](Cl)(=[O:30])[C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=1>>[C:21]([N:20]=[C:16]([N:7]1[CH2:6][C:5]2[CH:4]=[CH:3][CH:2]=[CH:1][C:11]=2[C:10]2[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=2[CH2:8]1)[O:17][CH2:18][CH3:19])(=[O:30])[C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=1
Reactant: CCOC(=N)N1Cc2ccccc2-c2ccccc2C1
Reactant: COc1ccc(C(=O)Cl)cc1
Product: CCOC(=NC(=O)c1ccc(OC)cc1)N1Cc2ccccc2-c2ccccc2C1

Procedure:
starting from ethyl 5,7-dihydro-6H-dibenz[c,e]azepine-6-carboximidate and p-anisoyl chloride, there is obtained ethyl N-(p-anisoyl)-5,7-dihydro-6H-dibenz[c,e]azepine-6-carboximidate, m.p. 71°-78° C.;
Reaction SMILES: O1CCCC1.[OH-].[Na+].[NH2:8][C:9]1[C:14]([C:15]2[O:19][N:18]=[C:17]([CH2:20][C:21]3[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=3)[CH:16]=2)=[CH:13][CH:12]=[CH:11][N:10]=1.Cl[CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([F:36])[N:31]=1>CN(C)C=O>[F:36][C:32]1[N:31]=[C:30]([CH2:29][O:27][C:24]2[CH:25]=[CH:26][C:21]([CH2:20][C:17]3[CH:16]=[C:15]([C:14]4[C:9]([NH2:8])=[N:10][CH:11]=[CH:12][CH:13]=4)[O:19][N:18]=3)=[CH:22][CH:23]=2)[CH:35]=[CH:34][CH:33]=1
Reactant: Fc1cccc(CCl)n1
Reactant: Nc1ncccc1-c1cc(Cc2ccc(O)cc2)no1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: Nc1ncccc1-c1cc(Cc2ccc(OCc3cccc(F)n3)cc2)no1
Temperature: 25 °C
Reaction time: 3 h
Yield: 70.7 %

Procedure:
Tetrahydrofuran (3 mL) and a 5 N aqueous sodium hydroxide solution (36.0 μL, 0.18 mmol) were added to 4-(5-(2-amino-pyridin-3-yl)-isoxazol-3-ylmethyl)-phenol (48.2 mg, 0.18 mmol) described in Manufacturing Example 5-1-1, which was dissolved by irradiating ultrasonic wave for 1 minute. The reaction mixture was then concentrated under a reduced pressure to obtain a white solid. This solid and 2-chloromethyl-6-fluoro-pyridine (63.2 mg, 0.43 mmol) described in Manufacturing Example 45-1-1 were added to N,N-dimethylformamide (3 mL), which was stirred for 3 hours at room temperature. This mixture was partitioned into water and ethyl acetate. This organic layer was separated, washed with water and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure, and the residue was purified by NH silica gel column chromatography (heptane:ethyl acetate=1:1) to obtain the title compound (47.9 mg, 59%).
Reaction SMILES: [OH-].[K+].[C:3]([O:9][CH2:10][CH3:11])(=[O:8])CC(C)=O.CCCCCCCCC[C:21]1[CH:22]=[CH:23][C:24]([OH:27])=[CH:25][CH:26]=1>C(Cl)Cl>[C:3]([C:25]1([CH3:26])[C:24](=[O:27])[CH:23]1[CH:22]=[CH2:21])([O:9][CH2:10][CH3:11])=[O:8]
Reactant: CCOC(=O)CC(C)=O
Reactant: CCCCCCCCCc1ccc(O)cc1
Agent: [K+]
Agent: [OH-]
Solvent: ClCCl
Product: C=CC1C(=O)C1(C)C(=O)OCC
Yield: 74 %

Procedure:
To a reactor containing 5.6 g potassium hydroxide and 60 mls. methylene dichloride were added 6.5 g ethyl acetoacetate and 1.33 g ethoxylated (9 E.O.) nonylphenol. The mixture was agitated and 10.7 g 1,4-dibromobutene-2 slowly added while maintaining the temperature at 30°-35° C. The reaction was continued with stirring at 30° C. for one hour after which time 74% yield 1-carboethoxy-1-methylketo-2-vinylcyclopropane was obtained. Similar results are obtained when the reaction is repeated using 1,4-dichlorobutene-2 and 1,4-diacetoxybutene-2.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][C:7]=1[C@H:13]1[CH2:17][CH2:16][CH2:15][N:14]1[C:18]1[CH:23]=[CH:22][N:21]2[N:24]=[CH:25][C:26]([C:27]([O:29]CC)=O)=[C:20]2[N:19]=1.CCN(C(C)C)C(C)C>CCO>[F:12][C:9]1[CH:8]=[C:7]2[C:6](=[CH:11][CH:10]=1)[O:5][CH2:4][CH2:3][CH2:2][NH:1][C:27](=[O:29])[C:26]1=[C:20]3[N:19]=[C:18]([CH:23]=[CH:22][N:21]3[N:24]=[CH:25]1)[N:14]1[C@@H:13]2[CH2:17][CH2:16][CH2:15]1
Reactant: CCOC(=O)c1cnn2ccc(N3CCC[C@@H]3c3cc(F)ccc3OCCCN)nc12
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: O=C1NCCCOc2ccc(F)cc2[C@H]2CCCN2c2ccn3ncc1c3n2
Temperature: 200 °C
Yield: 51.3 %

Procedure:
(R)-ethyl 5-(2-(2-(3-aminoprop oxy)-5-fluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylate (10 mg, 0.023 mmol) and DIEA (8.1 μL, 0.047 mmol) were combined in dry EtOH (0.1 mL) in a sealed vessel and heated at 200° C. overnight. The reaction was concentrated and purified by reverse-phase column chromatography (0-70% acetonitrile/H2O) to afford the title compound (4.5 mg, 50% yield). MS (apci) m/z=382.2 (M+H).
Reaction SMILES: [C:1]([Cl:4])(Cl)=[O:2].[Cl-].[Cl-].[O:7]=[C:8]1[NH:16][C:11]2=[NH+:12][CH:13]=[CH:14][CH:15]=[C:10]2[N:9]1[CH:17]1[CH2:22][CH2:21][NH2+:20][CH2:19][CH2:18]1.N1C(C)=CC=CC=1C.C(=O)(O)[O-].[Na+]>ClCCl>[O:7]=[C:8]1[NH:16][C:11]2=[N:12][CH:13]=[CH:14][CH:15]=[C:10]2[N:9]1[CH:17]1[CH2:22][CH2:21][N:20]([C:1]([Cl:4])=[O:2])[CH2:19][CH2:18]1
Reactant: O=C(Cl)Cl
Reactant: O=c1[nH]c2[nH+]cccc2n1C1CC[NH2+]CC1
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Product: O=C(Cl)N1CCC(n2c(=O)[nH]c3ncccc32)CC1
Reaction time: 2 h
Yield: 49.9 %

Procedure:
Phosgene (20% wt. in toluene; 1.8 mL, 3.43 mmol) was added to a suspension of 2-oxo-1-piperidinium-4-yl-2,3-dihydro-1H-imidazo[4,5-b]pyridin-4-ium dichloride (100 mg, 0.343 mmol) and 2,6-lutidine (0.50 mL, 4.293 mmol) in dichloromethane (5 mL) at 0° C. After 2 h, the solution was added to saturated aqueous sodium bicarbonate and extracted with ethyl acetate. The organic layer was washed with water (2×), saturated brine, dried over magnesium sulfate, filtered and concentrated. Dichloromethane (10 mL) was added, and the mixture was filtered to give the title compound as a solid (48 mg). MS 281 (M+1). 1H NMR (500 MHz, (CD3)2SO) δ 11.58 (s, 1H), 7.90 (d, J=5.1 Hz, 1H), 7.67 (d, J=7.6 Hz, 1H), 7.01-6.99 (m, 1H), 4.52-4.46 (m, 1H), 4.31-4.23 (m, 2H), 3.38-3.33 (m, 1H), 3.19-3.14 (m, 1H), 2.32-2.24 (m, 2H), 1.84-1.81 (m, 2H).
Reaction SMILES: [CH3:1][C:2]1([CH3:23])[CH2:11][CH:10]([C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=[CH:14][CH:13]=2)[C:9]2[C:4](=[CH:5][C:6]([OH:22])=[CH:7][CH:8]=2)[O:3]1.[H-].[Na+].[CH3:26][N:27]([CH3:31])[CH2:28][CH2:29]Cl>C1(C)C=CC=CC=1.O>[CH3:1][C:2]1([CH3:23])[CH2:11][CH:10]([C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=[CH:14][CH:13]=2)[C:9]2[C:4](=[CH:5][C:6]([O:22][CH2:29][CH2:28][N:27]([CH3:31])[CH3:26])=[CH:7][CH:8]=2)[O:3]1
Reactant: CC1(C)CC(c2cccc3ccccc23)c2ccc(O)cc2O1
Reactant: CN(C)CCCl
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: CN(C)CCOc1ccc2c(c1)OC(C)(C)CC2c1cccc2ccccc12
Reaction time: 8 h
Yield: 67.2 %

Procedure:
To a stirred solution of 2,2-dimethyl-4-(1-naphthyl)-7-chromanol (7.48 g) in dry toluene (50 ml) was added sodium hydride (1.5 g, ~1.5 eq., 60% dispersion in oil) and the mixture was brought to reflux. To the resulting solution was added dropwise over 10 minutes a solution of 2-dimethylaminoethyl chloride (2.70 g, ~1.1 eq.) in dry toluene (10 ml) and the mixture was stirred under reflux for 2 hours, cooled, diluted with water and left to stand overnight. Next day the toluene layer was separated and evaporated in vacuo. The aqueous layer was extracted with ether and the extract used to dissolve the residue from the toluene evaporation. The organic layer was extracted with 5N hydrochloric acid (45, 35 and 20 ml respectively), the combined acid extract was basified and extracted into ether. After being dried the ether was removed in vacuo to give a yellow oil (6.2 g) which was chromatographed on alumina in 8% ether -- 92% petroleum ether (b.p. 60-80) to give the title compound (4.71 g, 51%) as a colourless oil. The hydrochloric salt had m.p. 178.5°-181.5° C.
Reaction SMILES: C(N(CC(O)=O)CCN(CC(O)=O)CC(O)=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=[O:9].ON1C(=O)CCC1=O.[CH:43]1([N:49]=[C:50]=[N:51][CH:52]2[CH2:57][CH2:56][CH2:55][CH2:54][CH2:53]2)[CH2:48][CH2:47][CH2:46][CH2:45][CH2:44]1>CS(C)=O>[CH:52]1([NH:51][C:50](=[O:9])[NH:49][CH:43]2[CH2:44][CH2:45][CH2:46][CH2:47][CH2:48]2)[CH2:57][CH2:56][CH2:55][CH2:54][CH2:53]1
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Reactant: O=C(O)CN(CCN(CCN(CC(=O)O)CC(=O)O)CC(=O)O)CCN(CC(=O)O)CC(=O)O
Agent: O=C1CCC(=O)N1O
Solvent: CS(C)=O
Product: O=C(NC1CCCCC1)NC1CCCCC1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution consisting of 0.7 g (1.3 mmol) N,N'-(2-aminoethyl) trans-1,2-diaminocyclohexane-N,N',N",N'",N'"hexaacetic acid in 50 ml dimethylsulfoxide was added 0.9 g (7.8 mmol) N-hydroxysuccinimide and 0.8 g (3.9 mmol) dicyclohexylcarbodiimide. This was stirred at room temperature for 48 hr., during which the white fluffy solid of dicyclohexyl urea formed. This solid was removed by filtration and the filtrate was concentrated to a thick oil under reduced pressure. A solid precipitated from the oil upon the addition of acetonitrile. This solid was collected, washed with cold acetonitrile and dried under vacuum to give 0.54 g of a light brown solid. NMR showed an average of 2 NHS esters so the yield is 56%. No further purification of the solid was attempted; mp 125°-140° C.
Reaction SMILES: [CH:1]12[CH:6]([N:7]3[C:11](=[O:12])[C:10]([CH2:19][C:20]4[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=4)([CH2:13][C:14]4[CH:18]=[CH:17][S:16][CH:15]=4)[NH:9][C:8]3=[CH:26][C:27]([C:29]3[CH:36]=[CH:35][C:32]([C:33]#[N:34])=[CH:31][CH:30]=3)=[O:28])[CH:5]1[CH2:4][NH:3][CH2:2]2.[C:37]1([S:43](Cl)(=[O:45])=[O:44])[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>>[C:37]1([S:43]([N:3]2[CH2:4][CH:5]3[CH:1]([CH:6]3[N:7]3[C:11](=[O:12])[C:10]([CH2:19][C:20]4[CH:21]=[CH:22][N:23]=[CH:24][CH:25]=4)([CH2:13][C:14]4[CH:18]=[CH:17][S:16][CH:15]=4)[NH:9][C:8]3=[CH:26][C:27]([C:29]3[CH:30]=[CH:31][C:32]([C:33]#[N:34])=[CH:35][CH:36]=3)=[O:28])[CH2:2]2)(=[O:45])=[O:44])[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: N#Cc1ccc(C(=O)C=C2NC(Cc3ccncc3)(Cc3ccsc3)C(=O)N2C2C3CNCC32)cc1
Reactant: O=S(=O)(Cl)c1ccccc1
Product: N#Cc1ccc(C(=O)C=C2NC(Cc3ccncc3)(Cc3ccsc3)C(=O)N2C2C3CN(S(=O)(=O)c4ccccc4)CC32)cc1

Procedure:
According to the procedure of Example 13, the title compound of 37A (60 mg, 0.12 mmol) and benzenesulfonyl chloride (0.023 ml, 0.18 mmol) were reacted to generate the title compound as a white solid (58 mg, 0.091 mmol, 76% yield).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[C:15]([C:16]2[C:25]3[C:20](=[CH:21][C:22]([OH:26])=[CH:23][CH:24]=3)[N:19]=[CH:18][CH:17]=2)=[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][N:9]2[N:8]=1.CN(C=O)C.Br[CH2:33][CH2:34][Cl:35].C(=O)([O-])[O-].[Cs+].[Cs+]>CO>[Cl:35][CH2:34][CH2:33][O:26][C:22]1[CH:21]=[C:20]2[C:25]([C:16]([C:15]3[C:7]([C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=4)=[N:8][N:9]4[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=34)=[CH:17][CH:18]=[N:19]2)=[CH:24][CH:23]=1
Reactant: Oc1ccc2c(-c3c(-c4ccccn4)nn4ccccc34)ccnc2c1
Reactant: ClCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CO
Product: ClCCOc1ccc2c(-c3c(-c4ccccn4)nn4ccccc34)ccnc2c1
Temperature: 60 °C
Reaction time: 8 h
Yield: 30 %

Procedure:
4-(2-Pyridin-2-yl-pyrazolo[1,5-a]pyridin-3-yl)-quinolin-7-ol in a solution of DMF and MeOH was treated with 1-bromo-2-chloroethane (3 equiv) and cesium carbonate (2 equiv). The reaction was heated to 60° C. and stirred overnight. As described above, the desired product was then obtained upon chromatographic purification (EtOAc, followed by MeOH, then 2 M NH3 in MeOH). Yield; 30% overall from Prep. 90. MS ES+ m/e 401.0 (M+1).