Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[CH:10]=[N:9][CH:8]=[C:7]2[CH2:14][CH2:15][CH2:16][C:17]([O:19]CC)=O.[CH3:22][NH2:23]>O>[CH3:2][O:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[CH:10]=[N:9][CH:8]=[C:7]2[CH2:14][CH2:15][CH2:16][C:17]([NH:23][CH3:22])=[O:19]
Reactant: CN
Reactant: CCOC(=O)CCCc1cncc2ccc(OC)cc12
Agent: Cl
Solvent: O
Product: CNC(=O)CCCc1cncc2ccc(OC)cc12

Procedure:
The compound obtained in Step A (2.2 g; 7 mmol) is dissolved in 30 ml of methylamine (40% in water) and the mixture is heated at reflux for 3 hours with stirring. The reaction mixture is taken up in 50 ml of water and extracted with ether. The organic phase is washed with water, dried over magnesium sulphate, filtered and evaporated under reduced pressure. The oil obtained is purified by chromatography on silica gel (eluant: dichloromethane with the progressive addition of methanol). The oil obtained is evaporated under reduced pressure and the precipitate so formed is recrystallised from toluene to yield the title product in the form of a white solid.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7]([OH:10])(=[O:9])=[O:8])=[CH:3][CH:2]=1.[NH2:12][N:13]1[CH2:17][CH2:16][N:15]=[C:14]1SC.[NH2:20][NH2:21].C(O)(C)C>C(O)C>[C:1]1([CH3:11])[CH:2]=[CH:3][C:4]([S:7]([OH:10])(=[O:8])=[O:9])=[CH:5][CH:6]=1.[NH2:12][N:13]1[CH2:17][CH2:16][N:15]=[C:14]1[NH:20][NH2:21]
Reactant: NN
Reactant: CSC1=NCCN1N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Solvent: CC(C)O
Product: NNC1=NCCN1N
Temperature: 25 °C

Procedure:
1-Amino-2-methylthio-2-imidazoline p-toluenesulfonate (2.123 g) in ethanol (4 ml) was treated with hydrazine (0.67 ml) and stirred at 25° C. for hours. Isopropyl alcohol (6 ml) was added and after stirring for 10 min the crystalline precipitate was filtered out and washed with isopropyl alcohol to give 1.55 g of 1-amino-2-hydrazino-2-imidazoline p-toluenesulfonate, melting point 168°-169° C.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:11]=[C:10]2[C:6]([CH:7]=[CH:8][NH:9]2)=[CH:5][CH:4]=1.C([Mg]Br)C.[CH3:18][C:19]1([CH3:27])[C:21]([CH3:23])([CH3:22])[CH:20]1[C:24](Cl)=[O:25]>ClCCl.[Cl-].[Zn+2].[Cl-]>[CH3:18][C:19]1([CH3:27])[C:21]([CH3:23])([CH3:22])[CH:20]1[C:24]([C:7]1[C:6]2[C:10](=[CH:11][C:3]([C:2]([F:1])([F:12])[F:13])=[CH:4][CH:5]=2)[NH:9][CH:8]=1)=[O:25]
Reactant: FC(F)(F)c1ccc2cc[nH]c2c1
Reactant: CC1(C)C(C(=O)Cl)C1(C)C
Agent: CC[Mg]Br
Agent: [Cl-]
Agent: [Zn+2]
Solvent: ClCCl
Product: CC1(C)C(C(=O)c2c[nH]c3cc(C(F)(F)F)ccc23)C1(C)C
Yield: 9.8 %

Procedure:
A mixture of 6-(trifluoromethyl)indole (Lancaster, 1.0 g, 5.4 mmol), ethylmagnesium bromide (1.0 M solution in THF, 6.6 mL, 6.6 mmol), zinc chloride (1.0 M solution in Et2O, 6.6 mL, 6.6 mmol) and the product of Example 1A (8.1 mmol) in 40 mL of dichloromethane was processed as described in Example 1B to provide the title compound (0.17 g, 0.53 mmol, 10% yield). MS (DCI/NH3) m/z 310 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[C:5](=[O:6])[CH2:4][CH:3]1[NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11].[CH3:16][Li]>C1COCC1>[OH:6][C:5]1([CH3:16])[CH2:4][CH:3]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])[C:2]1([CH3:15])[CH3:1]
Reactant: [Li]C
Reactant: CC(C)(C)OC(=O)NC1CC(=O)C1(C)C
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC1CC(C)(O)C1(C)C
Reaction time: 1 h
Yield: 30 %

Procedure:
To a solution of tert-butyl (2,2-dimethyl-3-oxocyclobutyl)carbamate (1.0 equiv.) in anhydrous THF (0.15 M) under nitrogen was added methyllithium (1.6 M in ether, 4.0 equiv.) drop-wise, keeping the temperature below −70° C. The mixture was stirred at this temperature for 1 h. The mixture was quenched with aqueous solution of ammonium chloride and the mixture was extracted with ethyl acetate, washed with aqueous solution of sodium bicarbonate and brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under vacuum, the residue was purified by silica gel column chromatography (5% to 25% ethyl acetate in petroleum ether) to afford the title product (30% yield). 1H NMR (400 MHz, CDCl3) δ (ppm) 4.65-4.52 (m, 1H), 3.60-3.49 (m, 1H), 2.37-2.28 (m, 1H), 1.84-1.76 (m, 1H), 1.66 (s, 1H), 1.44 (s, 9H), 1.28 (s, 3H), 1.06 (s, 3H), 1.01 (s, 3H); MS (ESI) m/z 230.2 [M+H]+.
Reaction SMILES: [ClH:1].Cl.O[CH2:4][CH:5]1[CH2:10][N:9]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:8][CH2:7][N:6]1[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>S(Cl)(Cl)=O>[Cl:1][CH2:4][CH:5]1[CH2:10][N:9]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:8][CH2:7][N:6]1[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: OCC1CN(Cc2ccccc2)CCN1Cc1ccccc1
Reactant: Cl
Solvent: O=S(Cl)Cl
Product: ClCC1CN(Cc2ccccc2)CCN1Cc1ccccc1
Yield: 99.4 %

Procedure:
A suspension of 23 g (62.3 mmol) of 2-hydroxymethyl-1,4-di-phenylmethyl piperazine, dihydrochloride in 79 ml thionyl chloride was heated 4 hours under reflux. The solution was cooled and excess thionyl chloride was evaporated under reduced pressure. The residue was crystallized in ethanol, dried with acetone to yield 19.5 g of title compound dihydrochloride M.P. 234° C. dec. A suspension of this dihydrochloride in 130 ml 1N aqueous sodium hydroxyde was stirred with 75 ml dichloromethane, the aqueous layer back washed three times with 75 ml dichloromethane. The organic layers were collected and dried over magnesium sulfate to give after evaporation 15.44 g (78%) of title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([SH:10])=[N:7][C:6]=2[CH:11]=1.Cl[CH2:13][C:14]#[N:15].C(N(CC)CC)C>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([S:10][CH2:13][C:14]#[N:15])=[N:7][C:6]=2[CH:11]=1
Reactant: Sc1nc2cc(Cl)ccc2s1
Reactant: N#CCCl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: N#CCSc1nc2cc(Cl)ccc2s1
Temperature: 25 °C

Procedure:
51.0 g (0.254 m), 5-chloro-2-mercaptobenzothiazole, 22.8 g (0.304 m) chloroacetonitrile and 30.7 g triethylamine are dissolved in 600 ml of toluene and the solution is heated to reflux for 3 hr, then allowed to cool to room temperature. The toluene solution is washed with water, dried over anhydrous magnesium sulfate and treated with Darco. After the solvent is removed, the residual solid is recrystallized from 300 ml. benzene. The recovered material is recrystallized from cyclohexane. A total yield of 52 g (86%) is obtained. The recrystallized sample has a melting point of 96°-7° C.
Reaction SMILES: [N:1]#[N:2].C([O:10][C:11]([C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][CH:22]=1)[CH:19]=[C:18]([C:23]([NH:25][C@H:26]([C:31]([NH:33][C@@H:34]([CH2:50][C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1)[C@H:35]([OH:49])[CH2:36][C@@:37]1([C:46]([NH2:48])=[O:47])[CH2:41][CH2:40][CH2:39][N:38]1[C:42]([CH3:45])([CH3:44])[CH3:43])=[O:32])[CH2:27][C:28](=[O:30])[NH2:29])=[O:24])[CH:17]=[CH:16]2)=[O:12])C1C=CC=CC=1>C(O)(C)C.[Pd]>[N:1]#[N:2].[C:11]([C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][CH:22]=1)[CH:19]=[C:18]([C:23]([NH:25][C@H:26]([C:31]([NH:33][C@@H:34]([CH2:50][C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1)[C@H:35]([OH:49])[CH2:36][C@@:37]1([C:46]([NH2:48])=[O:47])[CH2:41][CH2:40][CH2:39][N:38]1[C:42]([CH3:43])([CH3:44])[CH3:45])=[O:32])[CH2:27][C:28](=[O:30])[NH2:29])=[O:24])[CH:17]=[CH:16]2)([OH:12])=[O:10]
Reactant: CC(C)(C)N1CCC[C@@]1(C[C@@H](O)[C@H](Cc1ccccc1)NC(=O)[C@H](CC(N)=O)NC(=O)c1ccc2cc(C(=O)OCc3ccccc3)ccc2c1)C(N)=O
Agent: [Pd]
Agent: N#N
Solvent: CC(C)O
Product: CC(C)(C)N1CCC[C@@]1(C[C@@H](O)[C@H](Cc1ccccc1)NC(=O)[C@H](CC(N)=O)NC(=O)c1ccc2cc(C(=O)O)ccc2c1)C(N)=O
Yield: 55.9 %

Procedure:
294 mg of N2 -[3(S)-[[N-[6-(benzyloxycarbonyl)-2-naphthoyl]-L-asparaginyl]amino]-2(R)-hydroxy-4-phenylbutyl]-N1 -tert-butyl-L-prolinamide in 100 ml of isopropanol was hydrogenated over 10% palladium-on-carbon at 20° C. and under atmospheric pressure for 16 hours. The catalyst was removed by filtration and the filtrate was evaporated to give 145 mg of N2 -[3(S)-[[N-(6-carboxy-2-naphthoyl)-L-asparaginyl]amino]-2(R)-hydroxy-4-phenylbutyl]-N1 -tert-butyl-L-prolinamide as a white solid from methanol/ethyl acetate; MS: m/e 646 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([O:24]COC)=[C:5]([C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][C:19]=3[N+:21]([O-:23])=[O:22])[CH:14]=[N:13][CH:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)(O)[O-].[Na+]>CO>[CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[CH:7][CH:6]=[C:5]([C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][C:19]=3[N+:21]([O-:23])=[O:22])[CH:14]=[N:13][CH:12]=2)[C:4]=1[OH:24]
Reactant: COCOc1c(-c2cncc3cccc([N+](=O)[O-])c23)ccc(OC)c1OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COc1ccc(-c2cncc3cccc([N+](=O)[O-])c23)c(O)c1OC
Reaction time: 4 h

Procedure:
After dissolving isoquinoline 4 (5.285 g, 0.014 mol) in 200 ml of methanol by gentle heating, p-toluenesulfonic acid monohydrate (8.15 g; 0.043 mol) was added in several portions. Stirring was continued for four hours at room temperature. After completion of the reaction, the solution was made basic by adding saturated sodium bicarbonate. The product was then extracted with dichlormethane (3×250 ml), dried (Na2SO4), and concentrated. The resulting yellow solid (4.65 g; 98%) was used directly in the next reaction. An analytical sample was recrystallized from methanol: mp 170-174° C.; 1H NMR: (300 MHz, CDCl3): 9.33 (s, 1H); 8.62 (s, 1H); 8.24 (dd, 1H, J=7.2, 0.9 Hz); 7.99 (dd, 1H, J=6.3, 1.2 Hz); 7.67 (t, 1H, J=7.8 Hz); 6.96 (d, 1H, J=8.7 Hz); 6.59 (d, 1H, J=8.7 Hz); 5.88 (bs, 1H); 3.94 (s, 3H); 3.92 (s, 3H). CIMS m/z: 327 (M+H+, 100%). Anal Calc'd for C17H14N2O5: C, 62.57; H, 4.32; N, 8.58; Found: C, 62.18; H, 4.38; N, 8.35.
Reaction SMILES: C([O:5][C:6](=[O:27])[CH2:7][N:8]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:10]2([CH2:15][CH2:14][N:13]([CH2:16][C:17]([F:20])([F:19])[F:18])[CH2:12][CH2:11]2)[CH2:9]1)(C)(C)C>C(Cl)Cl.C(C(O)=O)(F)(F)F>[F:19][C:17]([F:18])([F:20])[CH2:16][N:13]1[CH2:14][CH2:15][C:10]2([C:21]3[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=3)[N:8]([CH2:7][C:6]([OH:27])=[O:5])[CH2:9]2)[CH2:11][CH2:12]1
Reactant: CC(C)(C)OC(=O)CN1CC2(CCN(CC(F)(F)F)CC2)c2ccccc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)CN1CC2(CCN(CC(F)(F)F)CC2)c2ccccc21

Procedure:
A solution of tert-butyl[1′-(2,2,2-trifluoroethyl)spiro[indole-3,4′-piperidin]-1(2H)-yl]acetate (91.0 mg, 0.237 mmol) from Step B in CH2Cl2 (2 mL) and CF3CO2H (1 mL) was stirred at ambient temperature for 6 h. Added CF3CO2H (1 mL) and stirred 1 additional hour. The mixture was concentrated in vacuo. The crude product was partitioned between CH2Cl2 (20 mL) and saturated NaHCO3 (20 mL). The layers were separated and the aqueous layer was further extracted with CH2Cl2 (2×20 mL). The combined CH2Cl2 layers were dried over Na2SO4, filtered, and concentrated in vacuo to provide the title compound. MS: m/z=329 (M+1).
Reaction SMILES: [CH:1]1([C:6]2[C:7]([O:15][CH2:16][C:17]([F:20])([F:19])[F:18])=[N:8][CH:9]=[C:10]([CH:14]=2)[C:11]([OH:13])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:21]1([C:24]2[S:25][CH:26]=[C:27]([CH2:29][NH2:30])[N:28]=2)[CH2:23][CH2:22]1>>[CH:1]1([C:6]2[C:7]([O:15][CH2:16][C:17]([F:20])([F:19])[F:18])=[N:8][CH:9]=[C:10]([CH:14]=2)[C:11]([NH:30][CH2:29][C:27]2[N:28]=[C:24]([CH:21]3[CH2:23][CH2:22]3)[S:25][CH:26]=2)=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=C(O)c1cnc(OCC(F)(F)F)c(C2CCCC2)c1
Reactant: NCc1csc(C2CC2)n1
Product: O=C(NCc1csc(C2CC2)n1)c1cnc(OCC(F)(F)F)c(C2CCCC2)c1

Procedure:
This compound was prepared following the same procedure as described in Example 11 using 5-cyclopentyl-6-(2,2,2-trifluoro-ethoxy)-nicotinic acid (Example 9c) (100 mg, 0.35 mmol) and 2-cyclopropyl-4-thiazolemethanamine (CAN 1083299-53-9, 54 mg, 0.35 mmol) as starting materials; off white solid (67 mg, 45.6%). MS (ESI): 426 (M+H)+.
Reaction SMILES: [CH3:1][NH:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Cl[C:11]1[CH:16]=[N:15][CH:14]=[C:13]([Cl:17])[N:12]=1>>[CH2:3]([N:2]([CH3:1])[C:11]1[CH:16]=[N:15][CH:14]=[C:13]([Cl:17])[N:12]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CNCc1ccccc1
Reactant: Clc1cncc(Cl)n1
Product: CN(Cc1ccccc1)c1cncc(Cl)n1
Yield: 70 %

Procedure:
In a procedure analogous to Example 21, reaction of N-methyl benzylamine and 2,6-dichloropyrazine furnished the product (70%).
Reaction SMILES: [CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH:27]([OH:31])[CH:26]([CH3:32])[CH2:25][CH:24]([O:33][CH3:34])[CH:23]2[O:35][C:19]([OH:39])([CH:20]([CH3:38])[CH2:21][CH:22]2[O:36][CH3:37])[C:18](=[O:40])[C:17](=[O:41])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:42])[O:9][CH:8]([C:43]([CH3:54])=[CH:44][CH:45]2[CH2:50][CH2:49][CH:48]([OH:51])[CH:47]([O:52][CH3:53])[CH2:46]2)[CH:7]([CH3:55])[CH:6]=[CH:5][C:4]1=[O:56])[CH3:2].[H][H]>C(OCC)(=O)C.[Rh]>[CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH:27]([OH:31])[CH:26]([CH3:32])[CH2:25][CH:24]([O:33][CH3:34])[CH:23]2[O:35][C:19]([OH:39])([CH:20]([CH3:38])[CH2:21][CH:22]2[O:36][CH3:37])[C:18](=[O:40])[C:17](=[O:41])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:42])[O:9][CH:8]([C:43]([CH3:54])=[CH:44][CH:45]2[CH2:50][CH2:49][CH:48]([OH:51])[CH:47]([O:52][CH3:53])[CH2:46]2)[CH:7]([CH3:55])[CH2:6][CH2:5][C:4]1=[O:56])[CH3:2]
Reactant: [H][H]
Reactant: CCC1C=C(C)C(O)C(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(O)C(OC)C3)C(C)C=CC1=O)C(C)CC2OC
Agent: [Rh]
Solvent: CCOC(C)=O
Product: CCC1C=C(C)C(O)C(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(O)C(OC)C3)C(C)CCC1=O)C(C)CC2OC

Procedure:
A solution of 17-ethyl-1,20-dihydroxy-12-[2'-(4"-hydroxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-14,18-diene-2,3,10,16-tetraone in ethyl acetate is hydrogenated at 40 p.s.i. in a shaker apparatus using hydrogen and 5% rhodium on carbon catalyst until one molar equivalent of hydrogen is consumed. Filtration to remove catalyst and evaporation to remove solvent affords the product reduced at the Δ14,15 -position.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[NH2:19])(C)(C)C.C(O[C:26](=[O:43])[CH2:27][C:28]([C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([C:36]2[CH:41]=[C:40]([NH2:42])[N:39]=[CH:38][N:37]=2)[CH:31]=1)=O)(C)(C)C>>[NH2:42][C:40]1[N:39]=[CH:38][N:37]=[C:36]([C:32]2[CH:31]=[C:30]([C:28]3[CH2:27][C:26](=[O:43])[NH:19][C:9]4[CH:10]=[C:11]([C:15]([F:16])([F:17])[F:18])[C:12]([CH3:14])=[CH:13][C:8]=4[N:7]=3)[CH:35]=[CH:34][CH:33]=2)[CH:41]=1
Reactant: Cc1cc(NC(=O)OC(C)(C)C)c(N)cc1C(F)(F)F
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-c2cc(N)ncn2)c1
Product: Cc1cc2c(cc1C(F)(F)F)NC(=O)CC(c1cccc(-c3cc(N)ncn3)c1)=N2

Procedure:
The title compound was prepared from (2-amino-5-methyl-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example J20) (116 mg, 0.4 mmol) and 3-[3-(6-amino-pyrimidin-4-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K53) (138 mg, 0.44 mmol) according to the general procedure M and subsequent treatment of the crude product according to the general procedure N. Obtained as a light yellow solid (90 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[C:3]=1[C:4]([NH:6][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:16]=1[N:15]=[CH:14][CH:13]=[C:12]2[NH:17][NH2:18])=[O:5].[C:24]1(=[O:30])[O:29][C:27](=[O:28])[CH2:26][CH2:25]1.O>CN(C)C=O>[Cl:1][C:2]1[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[C:3]=1[C:4]([NH:6][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:16]=1[N:15]=[CH:14][CH:13]=[C:12]2[NH:17][NH:18][C:24](=[O:30])[CH2:25][CH2:26][C:27]([OH:29])=[O:28])=[O:5]
Reactant: NNc1ccnc2c(NC(=O)c3c(Cl)cccc3Cl)cccc12
Reactant: O=C1CCC(=O)O1
Solvent: O
Solvent: CN(C)C=O
Product: O=C(O)CCC(=O)NNc1ccnc2c(NC(=O)c3c(Cl)cccc3Cl)cccc12
Temperature: 25 °C
Reaction time: 12 h
Yield: 27.4 %

Procedure:
To a solution of 8-(2,6-dichlorobenzoylamino)-4-hydrazinoquinoline (298 mg) in dimethylformamide (4 ml) was added succinic anhydride (94 mg), and the mixture was stirred at ambient temperature for 12 hours. To the mixture was added water (10 ml) and the precipitate was collected. The solid was treated with hot ethanol (5 ml), allowed to cool to ambient temperature, filtered and washed with water to give 8-(2,6-dichlorobenzoylamino)-4-[2-(3-carboxypropanoyl)hydrazino]quinoline as a yellow crystal (105 mg).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:9][C:10]2[C:11]([F:27])=[C:12]([CH2:17][NH:18][C:19]([C:21]3[NH:25][CH:24]=[N:23][C:22]=3[Cl:26])=[O:20])[CH:13]=[CH:14][C:15]=2[Cl:16])[CH:5]=[C:6]([Cl:8])[CH:7]=1.[CH2:28]([OH:31])[C:29]#[CH:30]>C1COCC1.CCOC(C)=O.[Cu]I>[Cl:26][C:22]1[N:23]=[CH:24][NH:25][C:21]=1[C:19]([NH:18][CH2:17][C:12]1[CH:13]=[CH:14][C:15]([Cl:16])=[C:10]([O:9][C:4]2[CH:3]=[C:2]([C:30]#[C:29][CH2:28][OH:31])[CH:7]=[C:6]([Cl:8])[CH:5]=2)[C:11]=1[F:27])=[O:20]
Reactant: O=C(NCc1ccc(Cl)c(Oc2cc(Cl)cc(Br)c2)c1F)c1[nH]cnc1Cl
Reactant: C#CCO
Agent: [Cu]I
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C(NCc1ccc(Cl)c(Oc2cc(Cl)cc(C#CCO)c2)c1F)c1[nH]cnc1Cl
Temperature: 60 °C
Reaction time: 8 h
Yield: 18.7 %

Procedure:
To a solution of N-({3-[(3-bromo-5-chlorophenyl)oxy]-4-chloro-2-fluorophenyl}methyl)-4-chloro-1H-imidazole-5-carboxamide (100 mg, 0.203 mmol), dichlorobisthiphenylphosphinepalladium(II) (14.22 mg, 0.020 mmol), copper(I) iodide (1.929 mg, 10.13 μmol) and TEA (0.141 ml, 1.013 mmol) in THF (5 ml) was added propargyl alcohol (22.72 mg, 0.405 mmol) and the reaction mixture was stirred at 60° C. overnight. The reaction mixture was diluted with EtOAc and washed with water. The solvent was removed and the crude material was purified via silica gel chromatography to give 4-chloro-N-[(4-chloro-3-{[3-chloro-5-(3-hydroxy-1-propyn-1-yl)phenyl]oxy}-2-fluorophenyl)methyl]-1H-imidazole-5-carboxamide (18 mg, 0.038 mmol, 19% yield).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15](=[O:24])[CH2:16][C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[Cl:23][C:20]1[CH:21]=[CH:22][C:17]([CH2:16][C:15]([NH:14][CH:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)=[O:24])=[CH:18][CH:19]=1
Reactant: CC(C)(C)OC(=O)N1CCC(NC(=O)Cc2ccc(Cl)cc2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(Cc1ccc(Cl)cc1)NC1CCNCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 4-[2-(4-chloro-phenyl)-acetylamino]-piperidine-1-carboxylic acid tert-butyl ester (0.55 g, 1.54 mmol) in dichloromethane (8.0 mL) cooled at 0° C. was treated with trifluoroacetic acid (20%) and warmed to room temperature and stirred for 2 h. The reaction mixture was concentrated in vacuo, diluted with ethyl acetate and free based with 10% aqueous sodium bicarbonate. The combined organic layers were dried over sodium sulfate and concentrated in vacuo. The crude product was purified on silica using gradient elution from ethyl acetate/methanol (2%) to ethyl acetate/methanol (20%). 1H-NMR (CDCL3) δ: 1.15–1.25 (2H, m), 1.80–1.90 (2H, m), 2.60–2.75 (2H, m), 2.90–3.10 (2H, m), 3.5 (2H, s), 3.85 (1H, m), 5.20 (1H, d), 7.15–7.35 (4H, m). ESI-MS m/z: 253 (M+1), UV retention time: 0.87 min.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:19][CH3:20])[C@@:4]1([CH3:18])[C@@H:9]2[O:10][C@@H:8]2[C:7]2[CH:11]=[C:12]([N+:15]([O-:17])=[O:16])[CH:13]=[CH:14][C:6]=2[O:5]1.[CH3:21][O:22][C:23]1[CH:28]=[CH:27][C:26]([NH:29][CH2:30][C:31]2[NH:32][CH:33]=[CH:34][N:35]=2)=[CH:25][CH:24]=1>>[CH3:1][O:2][CH:3]([O:19][CH3:20])[C@@:4]1([CH3:18])[C@H:9]([OH:10])[C@@H:8]([N:29]([C:26]2[CH:27]=[CH:28][C:23]([O:22][CH3:21])=[CH:24][CH:25]=2)[CH2:30][C:31]2[NH:35][CH:34]=[CH:33][N:32]=2)[C:7]2[CH:11]=[C:12]([N+:15]([O-:17])=[O:16])[CH:13]=[CH:14][C:6]=2[O:5]1
Reactant: COC(OC)[C@]1(C)Oc2ccc([N+](=O)[O-])cc2[C@H]2O[C@H]21
Reactant: COc1ccc(NCc2ncc[nH]2)cc1
Product: COc1ccc(N(Cc2ncc[nH]2)[C@H]2c3cc([N+](=O)[O-])ccc3O[C@@](C)(C(OC)OC)[C@@H]2O)cc1
Yield: 86.8 %

Procedure:
The title compound (446 mg, 86%) was prepared using (2R,3R,4R)-3,4-dihydro-2-dimethoxymethyl-3,4-epoxy-2-methyl-6-nitro-2H-1-benzopyran (300 mg, 1.06 mmol) and 4-methoxyphenyl-1H-imidazol-2-ylmethylamine (216 mg, 1.06 mmol), according to the same procedure used for the preparation of example 1 above.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([O:8][CH3:9])[CH:5]=[CH:6][CH:7]=1.[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([SH:17])=[CH:13][CH:12]=1.C([O-])([O-])=O.[K+].[K+].C(O)CO>[Cu]I.CC(O)C>[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([S:17][C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH3:9])[CH:3]=2)=[CH:13][CH:12]=1
Reactant: Sc1ccc(Cl)cc1
Reactant: COc1cccc(I)c1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: OCCO
Solvent: CC(C)O
Product: COc1cccc(Sc2ccc(Cl)cc2)c1
Yield: 81 %

Procedure:
The general procedure in example 39 was followed. 3-Iodoanisole (234 mg, 1.0 mmol), 4-chlorothiophenol (145 mg, 1.0 mmol), CuI (10 mg, 0.05 mmol), K2CO3 (276 mg, 2.0 mmol), ethylene glycol (111 μL, 2.0 mmol) and 2-propanol (1.0 mL) were used to obtain the 3-methoxyphenyl 4-chlorophenyl sulfide (203 mg, 81% yield) as colorless liquid. Column chromatographic solvent (hexane/ethyl acetate=50/1). Rf=0.4 (hexane/ethyl acetate=40/1). 1H NMR (CDCl3, 300 MHz) δ 7.13-7.26 (m, 2 H), 6.88 (ddd, 2 H, J=1.2 Hz, 1.8 Hz, 7.8 Hz), 6.83 (t, 2 H, J=1.5 Hz), 6.78 (ddd, 2 H, J=0.9 Hz, 2.7 Hz, 8.1 Hz), 3.75 (s, 3 H). 13C NMR (CDCl3, 75 MHz) δ 160.2, 136.6, 134.3, 133.4, 132.5, 130.3, 129.5, 123.4, 116.4, 113.3, 55.7. IR (neat, cm−1) 3065, 3002, 2962, 2949, 2820. MS (E) m/z (relative intensity) 252 (30), 250 (100). Anal Cald for C13H11ClOS, Cald. C, 62.27; H, 4.42. Found C, 62.58; H, 4.46.
Reaction SMILES: F[C:2]1[C:7]([F:8])=[C:6]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[C:5]([F:15])=[C:4]([O:16][CH2:17][CH2:18][N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[N:3]=1.[NH2:25][NH2:26]>O1CCOCC1>[F:8][C:7]1[C:2]([NH:25][NH2:26])=[N:3][C:4]([O:16][CH2:17][CH2:18][N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)=[C:5]([F:15])[C:6]=1[N:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1
Reactant: Fc1nc(OCCN2CCOCC2)c(F)c(N2CCOCC2)c1F
Reactant: NN
Solvent: C1COCCO1
Product: NNc1nc(OCCN2CCOCC2)c(F)c(N2CCOCC2)c1F
Temperature: 100 °C

Procedure:
4-[2,3,5-Trifluoro-6-(2-morpholin-4-yl-ethoxy)-pyridin-4-yl]-morpholine (1.2 g; 3.5 mmol) and hydrazine (2 g) were added to dioxane (10 mL) and heated to 100° C. for six hours. The solvent was evaporated, and the residue was dissolved in dichloromethane (20 mL) and washed with a 10% sodium carbonate solution (2 mL). It was dried over magnesium sulfate, and evaporated, to give crude [3,5-Difluoro-4-morpholin-4-yl-6-(2-morpholin-4-yl-ethoxy)-pyridin-2-yl]-hydrazine. The crude product was then dissolved in ethanol. To the solution was added one drop of acetic acid, and m-tolylaldehyde (600 mL; 5 mmol) and it was heated at 60° C. overnight. The solvent was then evaporated, and the residue was purified by column chromatography to give Compound 12 (850 mg). Theoretical Mass Ion: 461.1; observed MH+peak: 462.1.
Reaction SMILES: [CH2:1]([CH:3]([C:6]1[CH:11]=[C:10]([CH3:12])[N:9]=[N:8][C:7]=1[NH:13]C(=O)C(C)(C)C)[CH2:4][CH3:5])[CH3:2]>Cl>[CH2:1]([CH:3]([C:6]1[CH:11]=[C:10]([CH3:12])[N:9]=[N:8][C:7]=1[NH2:13])[CH2:4][CH3:5])[CH3:2]
Reactant: CCC(CC)c1cc(C)nnc1NC(=O)C(C)(C)C
Agent: Cl
Product: CCC(CC)c1cc(C)nnc1N
Temperature: 95 °C
Yield: 82.2 %

Procedure:
N-[4-(1-Ethyl-propyl)-6-methyl-pyridazin-3-yl]-2,2-dimethyl-propionamide (12.0 g, 45 mmol) is dissolved in 60 mL of concentrated hydrochloric acid. The reaction mixture is heated to 95° C. in a sealed flask for 2 hours. The reaction is worked up by pouring over ice and extracting with ethyl acetate three times. The organic layer is discarded, and the pH of the aqueous layer is adjusted using 2 N sodium hydroxide. The basic solution is extracted with ethyl acetate five times. The organic extracts are combined, dried over magnesium sulfate, filtered, and evaporated to obtain 6.68 g (37 mmol, 81%) of the title compound as a brownish oil. 1H-NMR (DMSO-d6), δ 6.95 (s, 1H); 5.89 (s, br, 2H); 2.52-2.56 (m, 1H); 2.34 (s, 3H); 1.44-1.58 (m, 4H); 0.72 (t, J=7.04 Hz, 6H) ppm. MS/ES+=180 (100%, M+1).