Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:5]1[C:13]2[C:8](=[C:9]([C:17]#[N:18])[CH:10]=[C:11]([C:14]([OH:16])=O)[CH:12]=2)[CH:7]=[CH:6]1)[CH2:2][CH2:3][CH3:4].C(N(CC)CC)C.[NH2:26][C@@H:27]([CH2:41][C:42]1[CH:47]=[C:46]([F:48])[CH:45]=[C:44]([F:49])[CH:43]=1)[C@H:28]([OH:40])[CH2:29][NH:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([CH2:38][CH3:39])[CH:33]=1>C(Cl)Cl>[CH2:1]([N:5]1[C:13]2[C:8](=[C:9]([C:17]#[N:18])[CH:10]=[C:11]([C:14]([NH:26][C@@H:27]([CH2:41][C:42]3[CH:43]=[C:44]([F:49])[CH:45]=[C:46]([F:48])[CH:47]=3)[C@H:28]([OH:40])[CH2:29][NH:30][CH2:31][C:32]3[CH:37]=[CH:36][CH:35]=[C:34]([CH2:38][CH3:39])[CH:33]=3)=[O:16])[CH:12]=2)[CH:7]=[CH:6]1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCn1ccc2c(C#N)cc(C(=O)O)cc21
Reactant: CCc1cccc(CNC[C@@H](O)[C@@H](N)Cc2cc(F)cc(F)c2)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCn1ccc2c(C#N)cc(C(=O)N[C@@H](Cc3cc(F)cc(F)c3)[C@H](O)CNCc3cccc(CC)c3)cc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 70.3 %

Procedure:
To a mixture of 1-butyl-4-cyano-1H-indole-6-carboxylic acid (0.29 g) in methylene chloride (10 mL) was added 1,1-carbonyldiimidazole (0.194 g) and triethylamine (0.267 g). The mixture was stirred at room temperature for 45 minutes at which time (2R,3S)-3-amino-4-(3,5-difluorophenyl)-1-[(3-ethylbenzyl)amino]butan-2-ol (0.5 g) dissolved in methylene chloride (10 mL) was added. The mixture was stirred at room temperature for 18 h then poured into methylene chloride (50 mL), washed with water followed by brine, dried over anhydrous magnesium sulfate and concentrated under vacuum. Column chromatography on silica gel (100 mL) using 5% methanol in methylene chloride as eluent to give 0.47 g of the title compound: MS (ESI+) for C33H36F2N4O2 m/z 559.0 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:14]([NH:15][C:16](=[O:25])[C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([CH2:23]Cl)[CH:18]=2)=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=1)=[O:4].N1C=CC=CC=1.[CH3:32][CH:33]([OH:40])[CH2:34][NH:35][CH2:36][CH:37]([OH:39])[CH3:38].ClCC1C=C(C=CC=1)C(O)=O>C(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[C:14]([NH:15][C:16](=[O:25])[C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([CH2:23][N:35]([CH2:36][CH:37]([OH:39])[CH3:38])[CH2:34][CH:33]([OH:40])[CH3:32])[CH:18]=2)=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=1)=[O:4]
Reactant: CC(O)CNCC(C)O
Reactant: COC(=O)c1cc2ccccc2cc1NC(=O)c1cccc(CCl)c1
Agent: O=C(O)c1cccc(CCl)c1
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)c1cc2ccccc2cc1NC(=O)c1cccc(CN(CC(C)O)CC(C)O)c1
Reaction time: 48 h

Procedure:
Subsequently, 3-(3-chloromethyl-benzoylamino)-naphthalene-2-carboxylic acid methyl ester (870 mg) was dissolved in anhydrous methylene chloride (15 ml). Pyridine (400 μl) and diisopropanolamine (compound B′) (1.0 g) were added to the solution at room temperature, and the mixture was then stirred at that temperature for 48 hr. After the completion of the reaction, distilled water was added thereto at room temperature, and the mixture was subjected to separatory extraction with chloroform. The organic layer was washed with saturated brine, was dried over sodium sulfate, and was then concentrated under the reduced pressure. The residue was purified by column chromatography eluted with a hexane-acetone system to give 3-(3-{[bis-(2-hydroxy-propyl)-amino]-methyl}-benzoylamino)-naphthalene-2-carboxylic acid methyl ester as a useful intermediate (640 mg).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:11])=[C:4]([C:7]([F:10])=[CH:8][CH:9]=1)[CH:5]=O.C([O-])([O-])=O.[Cs+].[Cs+].[CH3:18][C:19]([S@@:22]([NH2:24])=[O:23])([CH3:21])[CH3:20]>C(Cl)Cl.CCOC(C)=O>[Cl:1][C:2]1[C:3]([F:11])=[C:4]([C:7]([F:10])=[CH:8][CH:9]=1)/[CH:5]=[N:24]/[S@:22]([C:19]([CH3:21])([CH3:20])[CH3:18])=[O:23]
Reactant: O=Cc1c(F)ccc(Cl)c1F
Reactant: CC(C)(C)[S@@](N)=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(C)(C)[S@](=O)/N=C/c1c(F)ccc(Cl)c1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 100.7 %

Procedure:
To a stirred suspension of 3-chloro-2,6-difluorobenzaldehyde (0.615 g, 3.48 mmol) and Cs2CO3 (1.702 g, 5.23 mmol) in DCM (20 mL) was added a solution of (S)-2-methylpropane-2-sulfinamide (0.422 g, 3.48 mmol) in DCM (20 mL) dropwise for 10 min. The solution was then stirred at rt overnight. After overnight stirring, the reaction mixture was diluted with EtOAc and washed with brine (3×20 mL). The combined organic layers were dried over MgSO4 and concentrated in vacuo to give the desired product (0.98 g, 100%) as yellow oil. MS (ESI) m/z: 282.0 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[O:3][C:4]1[CH:12]=[CH:11][C:7]([C:8](Cl)=[O:9])=[CH:6][CH:5]=1.Cl.Cl.[NH2:17][CH2:18][CH2:19][S:20][S:21][CH2:22][CH2:23][NH2:24].[OH-:25].[Na+]>C(Cl)CCl>[CH2:19]([S:20][S:21][CH2:22][CH2:23][NH:24][C:8](=[O:9])[C:7]1[CH:11]=[CH:12][C:4]([O:25][C:2]([F:1])([F:13])[F:14])=[CH:5][CH:6]=1)[CH2:18][NH:17][C:8](=[O:9])[C:7]1[CH:11]=[CH:12][C:4]([O:3][C:2]([F:14])([F:13])[F:1])=[CH:5][CH:6]=1
Reactant: O=C(Cl)c1ccc(OC(F)(F)F)cc1
Reactant: NCCSSCCN
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: ClCCCl
Product: O=C(NCCSSCCNC(=O)c1ccc(OC(F)(F)F)cc1)c1ccc(OC(F)(F)F)cc1

Procedure:
m.p. 150°-151° C., 14.5 g., was prepared as in Example 1 using 33.6 g. of 4-trifluoromethoxybenzoyl chloride in 100 ml. of ethylene dichloride, 11.3 g. of cystamine dihydrochloride, 300 ml. of 10% sodium hydroxide solution, 400 ml. of ethylene dichloride and recrystallization from acetonitrile using decolorizing charcoal.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:10][C:11]#N)[CH:6]=[C:7]([CH3:9])[CH:8]=1.[OH-:13].[K+].[OH2:15].CC(O)C>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:10][C:11]([OH:15])=[O:13])[CH:6]=[C:7]([CH3:9])[CH:8]=1
Reactant: COc1cc(C)cc(CC#N)c1
Reactant: O
Reactant: [OH-]
Agent: [K+]
Solvent: CC(C)O
Product: COc1cc(C)cc(CC(=O)O)c1
Temperature: 120 °C
Reaction time: 8 h
Yield: 80 %

Procedure:
A solution of 3-methoxy-5-methylphenylacetonitrile (9 g; 0.06 mol; from step (ii) above) and KOH (17 g; 0.3 mol) in 150 mL of water:i-PrOH (2:1) was heated while stirring in an autoclave at 120° C. overnight and then at room temperature for 2 days. The reaction mixture was concentrated and extracted with ether. The aqueous phase was acidified and extracted twice with ether. The combined organic layers were washed with water, dried (Na2SO4), and evaporated to a residue which was dissolved in EtOH, treated with activated carbon, filtered, and evaporated to yield the sub-title compound (8.1 g; 80%) as yellow crystals.
Reaction SMILES: [N:1]1([C:7]2[N:16]=[C:15]([NH2:17])[C:14]3[C:9](=[CH:10][C:11]([O:20][CH3:21])=[C:12]([O:18][CH3:19])[CH:13]=3)[N:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C(Cl)(Cl)Cl.[C:26]12([C:36](Cl)=[O:37])[CH2:35][CH:30]3[CH2:31][CH:32]([CH2:34][CH:28]([CH2:29]3)[CH2:27]1)[CH2:33]2>C(N(CC)CC)C>[C:26]12([C:36]([N:4]3[CH2:5][CH2:6][N:1]([C:7]4[N:16]=[C:15]([NH2:17])[C:14]5[C:9](=[CH:10][C:11]([O:20][CH3:21])=[C:12]([O:18][CH3:19])[CH:13]=5)[N:8]=4)[CH2:2][CH2:3]3)=[O:37])[CH2:33][CH:32]3[CH2:31][CH:30]([CH2:29][CH:28]([CH2:34]3)[CH2:27]1)[CH2:35]2
Reactant: COc1cc2nc(N3CCNCC3)nc(N)c2cc1OC
Reactant: O=C(Cl)C12CC3CC(CC(C3)C1)C2
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: COc1cc2nc(N3CCN(C(=O)C45CC6CC(CC(C6)C4)C5)CC3)nc(N)c2cc1OC

Procedure:
To a mixture of 2-piperazino-4-amino-6,7-dimethoxyquinazoline (1 g), chloroform (50 ml) and triethylamine (0.42 g), was gradually added 1-adamantanecarbonyl chloride (0.83 g). The almost dissolved mixture was heated at 45°-50° C. for 2 hours. After cooling, the mixture was washed with water, dried over anhydrous sodium sulfate and evaporated under reduced pressure to give 2-{4-(1-adamantanecarbonyl)-1-piperazinyl}-4-amino-6,7-dimethoxyquinazoline, m.p. 240°-242° C.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][OH:6].CS([C:11]1[N:16]=[C:15]([CH3:17])[C:14]([C:18]([O:20][CH2:21][CH2:22][C:23]([CH3:27])=[C:24]([F:26])[F:25])=[O:19])=[CH:13][N:12]=1)(=O)=O.C(N(CC)CC)C>O>[Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:11]1[N:16]=[C:15]([CH3:17])[C:14]([C:18]([O:20][CH2:21][CH2:22][C:23]([CH3:27])=[C:24]([F:26])[F:25])=[O:19])=[CH:13][N:12]=1
Reactant: CC(CCOC(=O)c1cnc(S(C)(=O)=O)nc1C)=C(F)F
Reactant: OCCCCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CC(CCOC(=O)c1cnc(OCCCCCl)nc1C)=C(F)F
Temperature: 25 °C
Reaction time: 14 h
Yield: 27.7 %

Procedure:
To 1.02 g (9.4 mmol) of 4-chlorobutanol was dissolved 1.00 g (3.1 mmol) of 4,4-difluoro-3-methyl-3-butenyl 2-methanesulfonyl-4-methylpyrimidine-5-carboxylate, followed by the addition of 0.38 g (3.8 mmol) of triethylamine under ice-cooling and stirring at room temperature for 14 hours. The reaction liquid was then poured in water and extracted with diethyl ether. The organic layer was washed with water and a saturated saline solution in this order, followed by drying over anhydrous magnesium sulfate and concentration under reduced pressure. The residue was purified with silica gel column chromatography (ethyl acetate:hexane=1:9) to obtain 0.30 g (yield: 27%) of 4,4-difluoro-3-methyl-3-butenyl 2-(4-chlorobutoxy)-4-methylpyrimidine-5-carboxylate.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:21]2[C:26]([Cl:27])=[CH:25][CH:24]=[CH:23][C:22]=2[Cl:28])=[CH:4][C:5]2[CH:10]=[N:9][C:8]([NH:11][CH2:12][CH2:13][CH2:14][N:15]([CH2:18][CH3:19])[CH2:16][CH3:17])=[N:7][C:6]=2[N:20]=1.[CH3:29][N:30]([CH:32](OC)OC)[CH3:31]>CN(C=O)C>[Cl:28][C:22]1[CH:23]=[CH:24][CH:25]=[C:26]([Cl:27])[C:21]=1[C:3]1[C:2]([N:1]=[CH:29][N:30]([CH3:32])[CH3:31])=[N:20][C:6]2[N:7]=[C:8]([NH:11][CH2:12][CH2:13][CH2:14][N:15]([CH2:18][CH3:19])[CH2:16][CH3:17])[N:9]=[CH:10][C:5]=2[CH:4]=1
Reactant: CCN(CC)CCCNc1ncc2cc(-c3c(Cl)cccc3Cl)c(N)nc2n1
Reactant: COC(OC)N(C)C
Solvent: CN(C)C=O
Product: CCN(CC)CCCNc1ncc2cc(-c3c(Cl)cccc3Cl)c(N=CN(C)C)nc2n1
Temperature: 25 °C
Reaction time: 5.5 h
Yield: 68 %

Procedure:
To a suspension of 210 mg (1 mmol) of 7-amino-6-(2,6-dichlorophenyl)-2-[3-(diethylamino)propylamino]-pyrido[2,3-d]pyrimidine from Example 20 in 0.8 mL of DMF was added 0.8 mL of DMF dimethyl acetal. The mixture was stirred at room temperature for 5.5 hours, then concentrated in vacuo. The residual oil was distributed between dichloromethane and water. The organic phase was dried over magnesium sulfate, then concentrated to a glass that was crystallized from acetonitrile to give 160 mg (68%) of N'-[6-(2,6-dichlorophenyl)-2-{3-(diethylamino)propylamino}-pyrido[2,3-d]pyrimidin-7-yl]-N,N-dimethylformamidine, mp 100-104° C. CIMS (1% ammonia in methane): m/z (relative intensity) 476 (MH+ +2, 60), 474 (MH+, 94), 361 (100).
Reaction SMILES: Br[CH:2]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[C:3]([OH:5])=[O:4].[Cl-:16].[Ca+2].[Cl-]>C(#N)C.[Cl-].C([N+](CC)(CC)CC)C>[Cl:16][CH:2]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[C:3]([OH:5])=[O:4]
Reactant: CCCCCCCCCCC(Br)C(=O)O
Reactant: [Cl-]
Agent: CC[N+](CC)(CC)CC
Agent: [Ca+2]
Solvent: CC#N
Product: CCCCCCCCCCC(Cl)C(=O)O

Procedure:
To 2-bromododecanoic acid (1 g), after having been dissolved in acetonitrile (50 ml ), were added calcium chloride (2 g) and tetraethylammonium chloride (1 g), and the mixture was heated under reflux for 4 hours. The reaction mixture was filtered, concentrated and distributed into ethyl acetate and water, and the ethyl acetate layer was dried over anhydrous sodium sulfate and concentrated to give 2-chlorododecanoic acid.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]=O.[Br-].[C:9]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([OH:11])=[O:10]>C1COCC1>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]=[CH:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][C:9]([OH:11])=[O:10]
Reactant: O=Cc1ccco1
Reactant: O=C(O)CCCCCCCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: C1CCOC1
Product: O=C(O)CCCCCCCCC=Cc1ccco1
Yield: 58.9 %

Procedure:
This compound was synthesized from 2-furaldehyde (1.92 g, 20 mmol) and 9-carboxynonyltriphenylphosphonium bromide (10.27 g, 20 mmol) in THF (100 mL) by a Wittig reaction. Crystallization (petroleum ether) afforded the product (2.95 g, 59%) as white crystals (mp 45°-46° C.); IR: 3450-2500 cm-1 ; 1H-NMR: 1.33 (m, 8H), 1.46 (m, 2H), 1.65 (m, 2H), 2.34 (t, 2H), 2.45 (m, 2H), 5.55 (m, 1H), 6.18 (d, 1H), 6.25 (d, 1H), 6.38 (d, 1H), 7.38 (s, 1H), 9.80 (bs, 1H). Anal. Calcd. for C15 H22O3 :C, 71.97, H, 8.86%; Found: C, 71.93, H, 8.87%. Z:E=43:57.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4][C:3]=1[CH2:11][CH2:12][NH:13][CH:14]([C:16]1[N:17]=[CH:18][N:19]([C:22]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:20]=1[CH3:21])[CH3:15].C1CCN2C(=NCCC2)CC1.[O:52]1CCC[CH2:53]1>C(OCC)(=O)C>[CH3:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]2[C:53](=[O:52])[N:13]([CH:14]([C:16]3[N:17]=[CH:18][N:19]([C:22]([C:29]4[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=4)([C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=4)[C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)[C:20]=3[CH3:21])[CH3:15])[CH2:12][CH2:11][C:3]=12
Reactant: Cc1c(CCNC(C)c2ncn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c2C)[nH]c2ccccc12
Reactant: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CCOC(C)=O
Product: Cc1c2n(c3ccccc13)C(=O)N(C(C)c1ncn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c1C)CC2

Procedure:
A mixture of 3-methyl-2-[2-[[1-(5-methyl-1-trityl-1H-imidazol-4-yl)ethyl]amino]ethyl]indole (262 mg), N,N'-carbonxyldiimidazole (210 mg), 1.8-diazabicyclo[5.4.0]-7-undecene (84 mg) and molecular sieves (100 mg) in dry tetrahydrofuran (3 ml) was stirred at reflux for 2 hours. The reaction mixture was diluted with ethyl acetate, washed with water and brine, dried over anhydrous magnesium sulfate and evaporated in vacuo. The residue was chromatographed over silica gel (eluted with 5% methanol in chloroform) to give 3,4-dihydro-5-methyl-2-[1-(5-methyl-1-trityl-1H-imidazol-4-yl)ethyl]-pyrimido[1,6-a]indol-1(2H)-one (208 mg) as glassy solid.
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].[F:22][C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][C:31]=1[NH:32][C:33](=[O:37])[CH:34]([OH:36])[CH3:35])[NH:28][C:27](=[O:38])[CH2:26]2>>[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]=[C:26]3\[C:27](=[O:38])[NH:28][C:29]4[C:25]\3=[CH:24][C:23]([F:22])=[C:31]([NH:32][C:33](=[O:37])[C@@H:34]([OH:36])[CH3:35])[CH:30]=4)=[C:15]([CH3:16])[C:8]=2[C:7]1=[O:19])[CH3:2]
Reactant: CC(O)C(=O)Nc1cc2c(cc1F)CC(=O)N2
Reactant: CCN(CC)CCN1CCCc2[nH]c(C=O)c(C)c2C1=O
Product: CCN(CC)CCN1CCCc2[nH]c(/C=C3\C(=O)Nc4cc(NC(=O)[C@H](C)O)c(F)cc43)c(C)c2C1=O
Yield: 40.8 %

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 N-(5-fluoro-2-oxo-2,3-dihydro-1H-indol-6-yl)-2-hydroxy-propionamide 8b as starting materials to obtain (S,Z)—N-{3-[5-(2-diethylamino-ethyl)-3-methyl-4-oxo-1,4,5,6,7,8-hexahydro-pyrrolo[3,2-c]azepin-2-ylmethylene]-5-fluoro-2-oxo-2,3-dihydro-1H-indol-6-yl}-2-hydroxy-propionamide 8 (28 mg, yield 40.8%) as a yellow solid.
Reaction SMILES: [N:1]1[CH:2]=[CH:3][N:4]2[C:9]=1[CH:8]=[CH:7][C:6]([NH2:10])=[N:5]2.Cl[C:12]([O:14][CH2:15][C:16]([Cl:19])([Cl:18])[Cl:17])=[O:13].[OH2:20]>CN(C)C1C=CN=CC=1.O1CCCC1>[N:1]1[CH:2]=[CH:3][N:4]2[C:9]=1[CH:8]=[CH:7][C:6]([N:10]([C:12]([O:14][CH2:15][C:16]([Cl:19])([Cl:18])[Cl:17])=[O:20])[C:12]([O:14][CH2:15][C:16]([Cl:19])([Cl:18])[Cl:17])=[O:13])=[N:5]2
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Reactant: O
Reactant: Nc1ccc2nccn2n1
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Product: O=C(OCC(Cl)(Cl)Cl)N(C(=O)OCC(Cl)(Cl)Cl)c1ccc2nccn2n1
Temperature: 60 °C
Reaction time: 15 h
Yield: 53.1 %

Procedure:
To a solution of imidazo[1,2-b]pyridazine-6-amine (1.00 g, 7.45 mmol) and 4-dimethylaminopyridine (2.73 g, 22.4 mmol) in tetrahydrofuran (75 ml) was added 2,2,2-trichloroethyl chloroformate (3.09 ml, 22.4 mmol) with ice-cooling, and the mixture was stirred at 60° C. for 15 hours. Water was poured into the reaction solution, and the mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. Hexane was added to the residue, and a solid was collected by filtration to give 1.92 g (53.1%) of the desired product.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][CH:6]=[CH:7][C:8]=1[CH3:9])#[N:2].CO[CH:12](OC)[N:13]([CH3:15])[CH3:14]>CN(C=O)C>[CH3:12][N:13]([CH3:15])[CH:14]=[CH:9][C:8]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[C:1]#[N:2]
Reactant: Cc1ccncc1C#N
Reactant: COC(OC)N(C)C
Solvent: CN(C)C=O
Product: CN(C)C=Cc1ccncc1C#N

Procedure:
A solution of 3-cyano-4-methylpyridine (25 g, 0.21 mol), and N,N-dimethylformamide dimethyl acetal (29.2 mL, 0.22 mol) in dry DMF was heated at reflux overnight. Most of the DMF was removed under reduced pressure. The crude red oil was partitioned between EtOAc (300 mL) and H2O (300 mL) and the organic phase was washed with H2O, brine and dried (Na2SO4). Removal of the solvent afforded the product (34.3 g, 94%, as a light red solid of suitable purity for use directly in the next step, mp 80°-83° C.). An analytical sample was prepared by recrystallizing a sample of the crude product from benzene/petroleum ether, (mp 88°-89° C., light red solid).
Reaction SMILES: Br.[N+:2]([C:5]1[CH:6]=[C:7]([C:11]2[N:12]=[C:13]([NH2:16])[S:14][CH:15]=2)[CH:8]=[CH:9][CH:10]=1)([O-:4])=[O:3].[C:17]1([CH2:23][O:24][C:25]2[CH:30]=[CH:29][C:28]([S:31](Cl)(=[O:33])=[O:32])=[CH:27][CH:26]=2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.Cl>N1C=CC=CC=1>[CH2:23]([O:24][C:25]1[CH:30]=[CH:29][C:28]([S:31]([NH:16][C:13]2[S:14][CH:15]=[C:11]([C:7]3[CH:8]=[CH:9][CH:10]=[C:5]([N+:2]([O-:4])=[O:3])[CH:6]=3)[N:12]=2)(=[O:33])=[O:32])=[CH:27][CH:26]=1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: O=S(=O)(Cl)c1ccc(OCc2ccccc2)cc1
Reactant: Nc1nc(-c2cccc([N+](=O)[O-])c2)cs1
Agent: Br
Agent: Cl
Solvent: c1ccncc1
Product: O=[N+]([O-])c1cccc(-c2csc(NS(=O)(=O)c3ccc(OCc4ccccc4)cc3)n2)c1

Procedure:
A mixture of 0.5 g of 4-(3-nitro-phenyl)-thiazol-2-ylamine hydrobromide with 0.51 g of 4-phenylmethoxy-benzenesulfonyl chloride was stirred overnight with 2 ml of pyridine. The resulting, red colored suspension was poured into 30 ml of 1N hydrochloric acid. The mixture was extracted three times with ethyl acetate. The organic phases were combined, dried with magnesium sulphate and freed from solvent. The residue was boiled with 30 ml of ethyl acetate, insoluble constituents were filtered off and the solution was treated at boiling with 20 ml of hexane. 0.5 g of 4-benzyloxy-N-[4-(3-nitro-phenyl)-thiazol-2-yl]-benzenesulfonamide separated as beige crystals upon cooling.
Reaction SMILES: [CH2:1](Cl)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:9][C:10]1[C:19]([O:20][CH3:21])=[CH:18][C:13]([C:14]([O:16][CH3:17])=[O:15])=[CH:12][C:11]=1[O:22][CH3:23].C([O-])([O-])=O.[K+].[K+]>CO>[CH2:1]([O:9][C:10]1[C:11]([O:22][CH3:23])=[CH:12][C:13]([C:14]([O:16][CH3:17])=[O:15])=[CH:18][C:19]=1[O:20][CH3:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1cc(OC)c(O)c(OC)c1
Reactant: ClCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: COC(=O)c1cc(OC)c(OCc2ccccc2)c(OC)c1
Yield: 73.2 %

Procedure:
Benzyl chloride (11.04 g, 86.9 mmol) was added to a stirred solution of 121 (19.22 g, 90.8 mmol) over K2CO3 (6.59 g, 47.7 mmol) in anhydrous MeOH (175 mL) and the mixture was heated at reflux for 12 h. Excess solvent was removed under reduced pressure and the residue was extracted with benzene (3×100 mL). The organic layer was washed with H2O (3×100 mL), brine (3×100 mL) and dried over anhydrous MgSO4. Evaporation of the solvent afforded an orange oil which crystallised on standing. The solid was redissolved in EtOAc, and briefly washed with 1N NaOH (100 mL), H2O (100 mL), brine (100 mL) and dried over MgSO4. Evaporation of excess solvent yielded the product as a yellow solid 122 (19.20 g, 63.6 mmol); 1H NMR (270 MHz, CDCl3) δ 3.8 (s, 3H), 3.85 (s, 3H), 3.9 (s, 3H), 5.1 (s, 2H), 7.3-7.5 (m, 7H); 13C NMR (67.8 MHz, CDCl3) δ 166.7, 153.2, 140.8, 137.3, 128.7, 128.6, 128.4, 128.4, 128.2, 128.0, 127.7, 125.3, 106.7, 74.9, 56.1, 52.2.
Reaction SMILES: C(OCC)(OCC)O[CH2:3][CH3:4].[C:11]([O:14][C@@H:15]1[C@H:21]2[C@H:22]3[C@H:31]([CH2:32][CH2:33][C@:18]2([CH2:19][CH3:20])[C:17](=[O:35])[CH2:16]1)[C@@H:30]1[C:25](=[CH:26][C:27](=[O:34])[CH2:28][CH2:29]1)[CH2:24][CH2:23]3)(=[O:13])[CH3:12]>CCO.C1(C)C=CC(S(O)(=O)=O)=CC=1>[C:11]([O:14][C@@H:15]1[C@H:21]2[C@H:22]3[C@H:31]([CH2:32][CH2:33][C@:18]2([CH2:19][CH3:20])[C:17](=[O:35])[CH2:16]1)[C@@H:30]1[C:25]([CH:26]=[C:27]([O:34][CH2:3][CH3:4])[CH2:28][CH2:29]1)=[CH:24][CH2:23]3)(=[O:13])[CH3:12]
Reactant: CC[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@H]43)[C@@H]1[C@@H](OC(C)=O)CC2=O
Reactant: CCOC(OCC)OCC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Product: CCOC1=CC2=CC[C@@H]3[C@H](CC[C@]4(CC)C(=O)C[C@H](OC(C)=O)[C@@H]34)[C@H]2CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.2 %

Procedure:
Triethyl orthoformate (30 ml, 180 mmol) and p-Toluenesulfonic acid (300 mg, 1.57 mmol) were added to a suspension of 15α-acetoxy-18-methyl-estr-4-en-3,17-dione (30 g, 87 mmol) in EtOH (180 ml). The mixture was stirred at room temperature for 1 h, and then cooled to 0° C. The precipitate was filtered, washed with cooled ethanol and dried under vacuum to afford 15α-acetoxy-3-ethoxy-18-methyl-estra-3,5-dien-17-one (31.5 g, yield: 97%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([C:19]([CH3:23])([CH3:22])[CH2:20][NH2:21])[O:11][C:12]=2[C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[CH:4][C:3]=1[OH:24].[C:25]([N:32]1[CH2:40][CH2:39][CH:35]([C:36](O)=[O:37])[CH2:34][CH2:33]1)([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26]>>[C:28]([O:27][C:25]([N:32]1[CH2:40][CH2:39][CH:35]([C:36](=[O:37])[NH:21][CH2:20][C:19]([C:10]2[O:11][C:12]([C:13]3[CH:14]=[CH:15][N:16]=[CH:17][CH:18]=3)=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([OH:24])[CH:4]=3)[CH:9]=2)([CH3:22])[CH3:23])[CH2:34][CH2:33]1)=[O:26])([CH3:31])([CH3:30])[CH3:29]
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Reactant: CC(C)(CN)c1cc(-c2ccc(Cl)c(O)c2)c(-c2ccncc2)o1
Product: CC(C)(C)OC(=O)N1CCC(C(=O)NCC(C)(C)c2cc(-c3ccc(Cl)c(O)c3)c(-c3ccncc3)o2)CC1

Procedure:
The title compound was prepared from the product of Example 7 Step 2 and N—BOC-isonipecotic acid as described in Example 4 Step 3; MS (ES+) m/e 554, 556 [M+H]+.
Reaction SMILES: CC[C@H]1[C@H]2C[C@H]([C@H](OC3C4C(=CC=CC=4)C(O[C@H](C4C=CN=C5C=4C=C(OC)C=C5)[C@@H]4N5C[C@H](CC)[C@@H](CC5)C4)=NN=3)C3C=CN=C4C=3C=C([O:22]C)C=C4)N(CC2)C1.[C:59]([OH:63])(C)([CH3:61])[CH3:60].O.[Cl:65][C:66]1[CH:75]=[C:74]2[C:69]([CH:70]=[CH:71][C:72]([CH3:76])=[N:73]2)=[C:68]([C:77]2[CH:82]=[CH:81][C:80]([Cl:83])=[CH:79][CH:78]=2)C=1C=C>C(OCC)(=O)C>[Cl:65][C:66]1[CH:75]=[C:74]2[C:69]([CH:70]=[CH:71][C:72]([CH3:76])=[N:73]2)=[C:68]([C:77]2[CH:82]=[CH:81][C:80]([Cl:83])=[CH:79][CH:78]=2)[C:60]=1[C@H:59]([OH:63])[CH2:61][OH:22]
Reactant: CC[C@@H]1CN2CC[C@@H]1C[C@@H]2[C@H](Oc1nnc(O[C@H](c2ccnc3ccc(OC)cc23)[C@H]2C[C@@H]3CCN2C[C@@H]3CC)c2ccccc12)c1ccnc2ccc(OC)cc12
Reactant: CC(C)(C)O
Reactant: C=Cc1c(Cl)cc2nc(C)ccc2c1-c1ccc(Cl)cc1
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1ccc2c(-c3ccc(Cl)cc3)c([C@H](O)CO)c(Cl)cc2n1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 84 %

Procedure:
AD-mix-α (1 g, excess) was added to a mixed solvent of t-butanol and water (4 mL/4 mL) and stirred at room temperature for 5 min and cooled to 0° C. The mixture was transferred to another flask containing 7-chloro-5-(4-chlorophenyl)-2-methyl-6-vinylquinoline (1G) (30 mg, 0.096 mmol) and stirred at 0° C. for 16 hours. The mixture was diluted with ethyl acetate, washed with NaHCO3 solution, water and brine, dried over Na2SO4, filtered and concentrated in vacuo. The obtained residue was purified by flash chromatography to provide the desired product 1H (28 mg, 84%). LCMS-ESI+ (m/z): 348.2, 350.2 (M+H)+.