Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(Cl)(C(Cl)=O)=O.CS(C)=O.[CH3:11][C:12]1([CH3:42])[O:16][C@H:15]([C@H:17]([OH:39])[CH2:18][O:19][C:20]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C@H:14]([CH:40]=[CH2:41])[O:13]1.C(N(CC)CC)C.[Cl-].[NH4+]>C(Cl)Cl>[CH3:11][C:12]1([CH3:42])[O:16][C@H:15]([C:17](=[O:39])[CH2:18][O:19][C:20]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C@H:14]([CH:40]=[CH2:41])[O:13]1
Reactant: C=C[C@@H]1OC(C)(C)O[C@@H]1[C@H](O)COC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C(Cl)C(=O)Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: C=C[C@@H]1OC(C)(C)O[C@@H]1C(=O)COC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 90 %

Procedure:
To a stirred solution of (COCl)2 (28.69 ml, 57.38 mmol, 2 M solution in CH2Cl2) in CH2Cl2 (200 ml) was dropwise added a solution of DMSO (8.9 ml, 125.51 mmol) in CH2Cl2 (30 ml) at −78° C., and the reaction mixture was stirred at the same temperature for 30 minutes. A solution of alcohol 3 (15.44 g, 35.86 mmol) in CH2Cl2 (30 ml) was added and the reaction mixture was stirred at −78° C. for 1 hour. Triethylamine (32.99 ml, 236.68 mmol) was added at −78° C. and then the reaction mixture was allowed to warm to room temperature and stirred for 1 hour. A saturated ammonium chloride solution was added carefully at 0° C. and the reaction mixture partitioned between CH2Cl2 and water. The organic layer was dried, filtered, and evaporated under reduced pressure. The residue was purified by silica gel column chromatography using hexane and ethyl acetate (6:1) to give ketone 4 (13.83 g, 90%) as a white solid; 1H NMR (400 MHz, CDCl3) δ 7.46-7.23 (m, 15H), 5.56 (ddd, J=17.2, 10.4, 6.8 Hz, 1H), 5.26 (td, J=16.8, 1.2 Hz, 1H), 5.13 (td, J=10.4, 1.2 Hz, 1H), 4.88-4.84 (m, 1H), 4.76 (d, J=7.6 Hz, 1H), 4.06 (d, J=18.0 Hz, 1H), 3.72 (d, J=18.4 Hz, 1H), 1.41 (s, 3H), 1.34 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1[C:3]([O:11][CH2:12][C:13]([F:16])([F:15])[F:14])=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].IC.[C:19](=O)([O-])[O-].[K+].[K+].O>CC(N(C)C)=O>[CH3:1][C:2]1[C:3]([O:11][CH2:12][C:13]([F:16])([F:14])[F:15])=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([O:9][CH3:19])=[O:8]
Reactant: Cc1cc(C(=O)O)cnc1OCC(F)(F)F
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CI
Solvent: CC(=O)N(C)C
Product: COC(=O)c1cnc(OCC(F)(F)F)c(C)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 87.9 %

Procedure:
A mixture of 5-methyl-6-(2,2,2-trifluoroethoxy)nicotinic acid (3.08 g, 13.1 mmol, Step-1 of Amine-2), iodomethane (0.983 ml, 15.72 mmol) and potassium carbonate (5.43 g, 39.3 mmol) in DMA (40 ml) is stirred at rt for 2 hours. The reaction mixture is poured into water (200 mL) and extracted with n-hexane/EtOAc (1:10, 500 mL). The organic layer is washed with 2M hydrochloric acid (300 mL×2) and dried over sodium sulfate. After filtration, the filtrate is concentrated in vacuo. The residue is purified by column chromatography on silica gel eluting with n-hexane/EtOAc (5:1) to give 2.87 g (88% yield) of the title compound as white solid.
Reaction SMILES: [CH3:1][C@@:2]12[C:18](=[O:19])[CH2:17][CH2:16][C@H:15]1[CH2:14][C@@H:13]1[C@H:4]([CH2:5][CH2:6][C@@H:7]3[C@H:12]1[CH2:11][CH2:10][C:9](=[O:20])[CH2:8]3)[CH2:3]2.C(O[AlH-](OC(C)(C)C)OC(C)(C)C)(C)(C)C.[Li+].Cl>C1COCC1>[OH:20][C@@H:9]1[CH2:8][C@H:7]2[C@H:12]([C@H:13]3[C@H:4]([CH2:5][CH2:6]2)[CH2:3][C@:2]2([CH3:1])[C:18](=[O:19])[CH2:17][CH2:16][C@H:15]2[CH2:14]3)[CH2:11][CH2:10]1
Reactant: C[C@]12C[C@H]3CC[C@H]4CC(=O)CC[C@H]4[C@@H]3C[C@@H]1CCC2=O
Agent: CC(C)(C)O[AlH-](OC(C)(C)C)OC(C)(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Product: C[C@]12C[C@H]3CC[C@H]4C[C@@H](O)CC[C@H]4[C@@H]3C[C@@H]1CCC2=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 56 %

Procedure:
To a solution of compound 13 (145 mg containing the unseparated 4aR diastereomer, 0.54 mmol) in THF (10 mL) was slowly added lithium tri-t-butyloxyaluminohydride at −40° C. After 2 h, 6 N HCl was added at −40° C. and the reaction was warmed to room temperature for 30 min. The product was extracted into EtOAc (50 mL×2). The combined extracts were dried, filtered, and removed. The residue was purified by flash column chromatography (silica gel eluted with 25% EtOAc in hexanes) and the product from the 4aR diastereomer separated to afford pure compound 14 (82 mg, 56%): mp 175-177° C.; [α]D20 +34.5 (c 0.22, CHCl3); 1H NMR (CDCl3) δ 3.58-3.49 (m, 1H), 0.76 (s, 3H); 13C NMR (CDCl3) δ 221.1, 71.4, 47.9, 45.7, 40.1, 39.2, 38.8, 38.5, 36.2, 35.6, 35.5, 31.7, 29.6, 29.3, 28.4, 25.5, 24.1, 13.5; IR νmax 3398, 1736 cm−1. Anal. Calcd for (C18H28O2): C, 78.21; H, 10.21. Found: C, 78.12; H, 10.40.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([CH3:8])[C:5]2[C:9](=[O:31])[NH:10][N:11]([C:12]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:4]=2[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[F:38][C:39]([F:50])([F:49])I1C2C=CC=CC=2CO1>CN(C=O)C>[Cl:1][C:2]1[N:7]=[C:6]([CH3:8])[C:5]2[C:9]([O:31][C:39]([F:50])([F:49])[F:38])=[N:10][N:11]([C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[C:4]=2[CH:3]=1
Reactant: FC(F)(F)I1OCc2ccccc21
Reactant: Cc1nc(Cl)cc2c1c(=O)[nH]n2C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1nc(Cl)cc2c1c(OC(F)(F)F)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 16.5 h

Procedure:
A mixture of 6-chloro-4-methyl-1-trityl-1H-pyrazolo[4,3-c]pyridin-3(2H)-one (Intermediate 4B, 207.1 mg, 0.486 mmol), potassium carbonate (217.6 mg, 1.574 mmol) and 1-trifluoromethyl-1,2-benziodoxol-3-(1H-one (227.3 mg, 0.719 mmol) in DMF (2 ml) was stirred at RT for 16.5 hr, then heated to 60° C. for 5 hr. Added water and filtered to collect precipitate, which was purified via flash chromatography (0-100% EtOAc/Hex) to provide 6-chloro-4-methyl-3-(trifluoromethoxy)-1-trityl-1H-pyrazolo[4,3-c]pyridine. MS: [M+H]+ m/z 494.
Reaction SMILES: [CH2:1]([O:8][C@H:9]1[C@@H:15]([CH2:16][C:17]#[N:18])[O:14][CH:11]([O:12][CH3:13])[C@@H:10]1OS(C(F)(F)F)(=O)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.B.CSC.CO>C1CCCCC1>[CH2:1]([O:8][C@H:9]1[C@H:15]2[CH2:16][CH2:17][NH:18][C@@H:10]1[CH:11]([O:14]2)[O:12][CH3:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC1O[C@H](CC#N)[C@H](OCc2ccccc2)[C@H]1OS(=O)(=O)C(F)(F)F
Agent: B
Solvent: CO
Solvent: C1CCCCC1
Solvent: CSC
Product: COC1O[C@@H]2CCN[C@H]1[C@H]2OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.9 %

Procedure:
A 1:2 mixture of the α and β anomers of methyl 3-O-benzyl-5-cyano-5-deoxy-2-O-trifluoromethanesulphonyl-D-xylofuranoside (21αβ) (2.51 g, 6.36 mmol) dissolved in cyclohexane (200 ml) at 40° C. was treated with borane-dimethyl sulphide complex (10M in THF, 955 μl, 9.55 mmol) then stirred at room temperature overnight. Methanol (1 ml) was added, and the solvents evaporated then replaced with a 1:1 mixture of methanol and pyridine (50 ml). This was stirred with potassium carbonate (5 g) at room temperature for 48 hours. The solvents were removed and the residue dissolved in dichloromethane (20 ml), filtered and concentrated by evaporation. Purification using flash chromatography produced methyl 3-O-benzyl-2,6-imino-2,5,6-trideoxy-D-lyxohexofuranoside (α:β 1:2) (1.52 g, 96%) as a partially separated mixture of colourless oils which rapidly turn brown on storage.
Reaction SMILES: [C:1]([C:20]1[CH:26]=[C:25]([OH:27])[CH:24]=[CH:23][C:21]=1[OH:22])(=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[C:28](O)(=[O:31])[CH2:29][CH3:30].S(=O)(=O)(O)O>>[CH2:1]([C:20]1[CH:26]=[C:25]([O:27][C:28](=[O:31])[CH2:29][CH3:30])[CH:24]=[CH:23][C:21]=1[OH:22])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCC(=O)O
Reactant: CCCCCCCCCCCCCCCCCC(=O)c1cc(O)ccc1O
Agent: O=S(=O)(O)O
Product: CCCCCCCCCCCCCCCCCCc1cc(OC(=O)CC)ccc1O
Temperature: 140 °C
Yield: 39.8 %

Procedure:
To 5.2 g of n-octadecanoylhydroquinone and 6.0 g of anhydrous propionic acid were added 1.5 ml of concentrated sulfuric acid and thereafter the mixture was heated on an oil bath at 140° C. for 15 minutes. After being allowed to be cooled, the mixture was added to ice and extracted with ethyl acetate. The extract was washed with water and dried. Purification through silica gel column chromatography [developing solvent: benzene/acetone (9:1)] gave 2.3 g of the end product having m.p. 75°-78° C. Elemental analysis:
Reaction SMILES: [C:1](Cl)([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)([CH3:3])[CH3:2]>O>[CH3:3][C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[CH2:2]
Reactant: CC(C)(Cl)c1ccccc1
Solvent: O
Product: C=C(C)c1ccccc1
Temperature: 110 °C
Yield: 86.9 %

Procedure:
In a flask fitted with a strirrer 500 ml of water is heated to 110° C., and 250 g of cumyl chloride is added dropwise over a period of 6 h. Continuous distillation is carried out through the column described in Example 1, yielding 166 g of alpha-methylstyrene and 190 ml of water.
Reaction SMILES: CSC(=S)N.[Na].ClCC([NH:11][C:12]1[S:13][CH:14]=[C:15]([C:17](=[N:34][O:35][CH3:36])[C:18]([NH:20][C@H:21]2[C@@H:24]([C:25]([O:27][CH3:28])=[O:26])[N:23]([S:29]([O-:32])(=[O:31])=[O:30])[C:22]2=[O:33])=[O:19])[N:16]=1)=O.[Na+:37]>>[NH2:11][C:12]1[S:13][CH:14]=[C:15]([C:17](=[N:34][O:35][CH3:36])[C:18]([NH:20][C@H:21]2[C@@H:24]([C:25]([O:27][CH3:28])=[O:26])[N:23]([S:29]([O-:32])(=[O:30])=[O:31])[C:22]2=[O:33])=[O:19])[N:16]=1.[Na+:37]
Reactant: CON=C(C(=O)N[C@@H]1C(=O)N(S(=O)(=O)[O-])[C@@H]1C(=O)OC)c1csc(NC(=O)CCl)n1
Agent: CSC(N)=S
Agent: [Na+]
Agent: [Na]
Product: CON=C(C(=O)N[C@@H]1C(=O)N(S(=O)(=O)[O-])[C@@H]1C(=O)OC)c1csc(N)n1
Reaction time: 1 h

Procedure:
Under ice-cooling and stirring, 21 mg of sodium monomethyldithiocarbamate is added to 2 ml of an aqueous solution containing 85 mg of sodium cis-3-[2-(2-chloroacetamido-4-thiazolyl)-2-methoxyiminoacetamido]-4-methoxycarbonyl-2-oxoazetidine-1-sulfonate (anti-isomer). The mixture is stirred at room temperature for 1 hour and another 7 mg of sodium monomethyldithiocarbamate is added. The stirring is continued for an additional 1 hour, the reaction mixture is filtered and the filtrate is washed with ether. The aqueous layer is purified by column chromatography on Amberlite XAD-II and the lyophilized to give sodium cis-3-[2-(2-amino-4-thiazolyl)-2-methoxyiminoacetamido]-4-methoxycarbonyl-2-oxoazetidine-1-sulfonate (anti-isomer).
Reaction SMILES: [CH2:1]([O:3][C:4]1[N:5]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]3[C:20]([C:25]#[N:26])=[CH:21][CH:22]=[CH:23][CH:24]=3)=[CH:15][CH:14]=2)[C:6](=[O:11])[CH:7]=[C:8]([CH3:10])[N:9]=1)[CH3:2].C([O-])(=O)C.[Na+].[Br:32]Br>C(O)(=O)C.C(OCC)(=O)C>[Br:32][C:7]1[C:6](=[O:11])[N:5]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]3[C:20]([C:25]#[N:26])=[CH:21][CH:22]=[CH:23][CH:24]=3)=[CH:15][CH:14]=2)[C:4]([O:3][CH2:1][CH3:2])=[N:9][C:8]=1[CH3:10]
Reactant: CCOc1nc(C)cc(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: BrBr
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CCOc1nc(C)c(Br)c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Reaction time: 2 h
Yield: 94 %

Procedure:
To a solution of 4′-[(2-ethoxy-4-methyl-6-oxopyrimidin-1(6H)-yl)methyl]biphenyl-2-carbonitrile (6.15 g) and sodium acetate (1.46 g) in acetic acid (100 mL) was added bromine (0.91 mL), and the mixture was stirred for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with 1 M aqueous sodium thiosulfate solution, saturated aqueous sodium hydrogen carbonate and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound (7.12 g, 94%) as a colorless solid.
Reaction SMILES: [CH2:1]([Li])CCC.[Br:6][C:7]1[C:8]([CH3:27])=[C:9]([C:13]2[N:17]([CH3:18])[N:16]=[C:15]([C:19]3[C:24]([F:25])=[CH:23][CH:22]=[CH:21][C:20]=3[Cl:26])[N:14]=2)[S:10][C:11]=1Br.IC.[Cl-].[NH4+]>C1COCC1>[Cl:26][C:20]1[CH:21]=[CH:22][CH:23]=[C:24]([F:25])[C:19]=1[C:15]1[N:14]=[C:13]([C:9]2[S:10][C:11]([CH3:1])=[C:7]([Br:6])[C:8]=2[CH3:27])[N:17]([CH3:18])[N:16]=1
Reactant: Cc1c(-c2nc(-c3c(F)cccc3Cl)nn2C)sc(Br)c1Br
Reactant: [Li]CCCC
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CI
Product: Cc1sc(-c2nc(-c3c(F)cccc3Cl)nn2C)c(C)c1Br
Temperature: 25 °C
Reaction time: 1 h
Yield: 46.2 %

Procedure:
n-Butyllithium (0.7 g, 10.8 mmol) was added dropwise to a solution of 5-(4,5-dibromo-3-methylthien-2-yl)-3-(2-chloro-6-fluorophenyl)-1-methyl-1H-1,2,4-triazole (5 g, 10.8 mmol) in THF (70 mL) at −70° C. and stirred for 1 hour. Iodomethane (1.6 g, 11.29 mmol) was added to the reaction mixture and allowed to warm to 25° C. After adding saturated aq ammonium chloride (10 mL), the organic layer was separated, washed with water, followed by saturated aq sodium chloride (20 mL) and dried over sodium sulfate, filtered, and concentrated. The residue was chromatographed to give the product as a yellow oil (2.0 g, 47%): 1H NMR (CDCl3) δ 2.32 (s, 3H), 2.48 (s, 3H), 3.99 (s, 3H), 7.07-7.13 (m, 1H), 7.28-7.38 (m, 2H); EI/MS 400 m/e (M+); Calcd. for C15H12ClBrFN3S: C, 44.96; H, 3.02; N, 10.49; Found: C, 44.94; H, 3.01; N, 10.29.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][CH:15]=1)[C:5]([CH2:7][CH:8]([CH3:12])[C:9](O)=[O:10])=O.O.[NH2:17][NH2:18]>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]2[CH2:7][CH:8]([CH3:12])[C:9](=[O:10])[NH:17][N:18]=2)[CH:13]=[CH:14][CH:15]=1
Reactant: CC(CC(=O)c1cccc(Cl)c1)C(=O)O
Reactant: NN
Solvent: CCO
Solvent: O
Product: CC1CC(c2cccc(Cl)c2)=NNC1=O

Procedure:
A mixture of 7.11 g. of 3-(m-chlorobenzoyl)-2-methylpropionic acid, 50 ml. of ethanol and 3.0 ml. of hydrazine hydrate is refluxed for 2 hrs. Cooling and filtering gives crystals, (m.p. 150°-151° C.) which are recrystallized from ethanol to give 5.72 g. of crystals, m.p. 152°-153°.
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:12]2[CH:11]=[CH:10][N:9]=[C:8]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[CH2:6][CH2:5]1.[CH3:28][O:29][CH2:30][C:31](O)=[O:32]>>[O:4]1[C:12]2[CH:11]=[CH:10][N:9]=[C:8]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][C:31](=[O:32])[CH2:30][O:29][CH3:28])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[CH2:6][CH2:5]1
Reactant: COCC(=O)O
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3CCO4)CC2)CC1
Agent: Cl
Product: COCC(=O)N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3CCO4)CC2)CC1

Procedure:
The title compound, white solid (86 mg, 71%), MS (ISP) m/z=403.4 [(M+H)+], mp 169.5° C., was prepared in accordance with the general method of example 32 from trans-4-{2-[4-(2,3-dihydrofuro[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexanamine trihydrochloride (intermediate C) (132 mg, 0.3 mmol) and methoxyacetic acid.
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:15]2[C:24]3[C:19](=[CH:20][C:21](I)=[CH:22][CH:23]=3)[N:18]=[CH:17][CH:16]=2)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Sn](CCCC)(CCCC)[C:31]1[O:32][C:33]([CH:36]2[O:40][CH2:39][CH2:38][O:37]2)=[CH:34][CH:35]=1)CCC>CC(N(C)C)=O.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[O:1]([C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:15]2[C:24]3[C:19](=[CH:20][C:21]([C:31]4[O:32][C:33]([CH:36]5[O:40][CH2:39][CH2:38][O:37]5)=[CH:34][CH:35]=4)=[CH:22][CH:23]=3)[N:18]=[CH:17][CH:16]=2)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccc(C2OCCO2)o1
Reactant: Ic1ccc2c(Nc3ccc(Oc4ccccc4)cc3)ccnc2c1
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC(=O)N(C)C
Product: c1ccc(Oc2ccc(Nc3ccnc4cc(-c5ccc(C6OCCO6)o5)ccc34)cc2)cc1
Yield: 68.1 %

Procedure:
(4-Phenoxyphenyl)-(7-iodo-quinolin-4-yl)amine (2 g) was treated with 2-(tributylstannyl)-5-(1,3-dioxolan-2-yl)-furan (2.16 g) and tetrakis (triphenylphosphine) palladium (0) (0.26 g) in dimethylacetamide (20 ml) in accordance with Procedure B. Purification via column chromatography, eluting with ethyl acetate, followed by trituration with diethylether afforded a yellow solid (1.4 g); δ H [2H6] DMSO 9.10 (1H, s), 8.45 (2H, m), 8.13 (1H, s), 7.96 (1H, d), 7.41 (4H, m), 7.22 (1H, d), 7.20-7.03 (5H, m), 6.83 (1H, d), 6.75 (1H, d), 6.02 (1H, s), 4.13 (2H, m), 4.01 (2H, m); m/z 451 (M+1)+.
Reaction SMILES: [CH:1]1([O:5][C:6]2[C:14]([CH3:15])=[CH:13][CH:12]=[CH:11][C:7]=2[C:8]([OH:10])=O)[CH2:4][CH2:3][CH2:2]1.[CH2:16]([O:18][C:19](=[O:31])[CH2:20][C:21]1([NH2:30])[CH2:29][C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:22]1)[CH3:17].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>CN(C=O)C>[CH2:16]([O:18][C:19](=[O:31])[CH2:20][C:21]1([NH:30][C:8](=[O:10])[C:7]2[CH:11]=[CH:12][CH:13]=[C:14]([CH3:15])[C:6]=2[O:5][CH:1]2[CH2:2][CH2:3][CH2:4]2)[CH2:29][C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:22]1)[CH3:17]
Reactant: CCOC(=O)CC1(N)Cc2ccccc2C1
Reactant: Cc1cccc(C(=O)O)c1OC1CCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)CC1(NC(=O)c2cccc(C)c2OC2CCC2)Cc2ccccc2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 96 %

Procedure:
To a solution of 2-cyclobutyloxy-3-methylbenzoic acid (210 mg-1.02 mmol), 2-aminoindan-2-acetic acid ethyl ester (A6) (260 mg-1.02 mmol) and HATU (470 mg-1.224 mmol-1.2 eq) in dry DMF (10 mL) is added diisopropylethylamine (0.36 mL-2.24 mmol-2.2 eq) and the resulting solution is stirred at RT overnight. After the removal of the DMF in vacuo, the residue is dissolved in EtOAc (60 mL) and washed with water (2×20 mL) and brine (2×20 mL). The organic layer is dried over MgSO4 and concentrated in vacuo. The residue is purified by flash chromatography (120 g silica gel, 15% EtOAc in heptane) to give the pure product as colorless oil (400 mg, 96%).
Reaction SMILES: Cl.[C:2]1([C:7]2([CH2:13][CH2:14][N:15]([CH3:17])[CH3:16])[CH2:11][CH2:10][CH2:9][C:8]2=[O:12])[CH2:6][CH2:5][CH2:4][CH:3]=1.[Cl:18][C:19]1[CH:26]=[CH:25][C:22]([CH:23]=O)=[CH:21][CH:20]=1.O>C(O)C.[OH-].[Na+]>[ClH:18].[C:2]1([C:7]2([CH2:13][CH2:14][N:15]([CH3:16])[CH3:17])[CH2:11][CH2:10]/[C:9](=[CH:23]\[C:22]3[CH:25]=[CH:26][C:19]([Cl:18])=[CH:20][CH:21]=3)/[C:8]2=[O:12])[CH2:6][CH2:5][CH2:4][CH:3]=1
Reactant: CN(C)CCC1(C2=CCCC2)CCCC1=O
Reactant: O=Cc1ccc(Cl)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CN(C)CCC1(C2=CCCC2)CC/C(=C\c2ccc(Cl)cc2)C1=O
Reaction time: 12 h

Procedure:
To a solution of 1.0 g (3.9 mmole) of 2-(1-cyclopenten-1-yl)-2-dimethylaminoethyl cyclopentanone hydrochloride and 8.1 mmole of 4-chloro-benzaldehyde in 40 ml of ethanol, 3.2 ml of 5N NaOH was added dropwise. The resulting mixture was stirred at about room temperature for about 12 hours and then mixed with 60 ml of water and extracted with ether. The ether extract was extracted with 6N HCl. The HCl extract was basified and extracted with ether, and then dried over anhydrous MgSO4. The ether solution was treated with ethanolic hydrogen chloride to give a precipitate, which was recrystallized from ethanol to give the 2-(1-Cyclopenten-1-yl)-2-dimethylaminoethyl-5-(E)-[(4-chloro) benzylidene] cyclopentanone hydrochloride. The melting point of the product was determined to be 234°-236° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:28])[CH2:5][CH2:6][CH2:7][N:8]1[C:12]2[CH:13]=[CH:14][C:15]([C:17](=[O:26])[N:18]([CH:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)[CH3:19])=[CH:16][C:11]=2[N:10]=[C:9]1[NH2:27])[CH3:2].[S:29]1[CH:33]=[CH:32][CH:31]=[C:30]1[C:34](Cl)=[O:35]>N1C=CC=CC=1>[CH2:1]([O:3][C:4](=[O:28])[CH2:5][CH2:6][CH2:7][N:8]1[C:12]2[CH:13]=[CH:14][C:15]([C:17](=[O:26])[N:18]([CH:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)[CH3:19])=[CH:16][C:11]=2[N:10]=[C:9]1[NH:27][C:34]([C:30]1[S:29][CH:33]=[CH:32][CH:31]=1)=[O:35])[CH3:2]
Reactant: O=C(Cl)c1cccs1
Reactant: CCOC(=O)CCCn1c(N)nc2cc(C(=O)N(C)C3CCCCC3)ccc21
Solvent: c1ccncc1
Product: CCOC(=O)CCCn1c(NC(=O)c2cccs2)nc2cc(C(=O)N(C)C3CCCCC3)ccc21
Reaction time: 6 h
Yield: 68.2 %

Procedure:
To a stirred solution of the above amino benzimidazole (0.7 g, 1.8 mmol) in pyridine (10 mL) was added 2-thiophenecarbonyl chloride (0.41 mL, 3.8 mmol). The reaction was complete in 6 h. The pyridine was evaporated and the resulting orange solid was purified by flash chromatography with 1% MeOH/dichloromethane to give the title compound (0.61 g, 67%), m.p. 82-84° C.
Reaction SMILES: [CH3:1][C@H:2]1[O:7][C@@H:6]([CH3:8])[CH2:5][N:4]([CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:14]=[CH:15][C:16]3[C:17]4[N:18]([CH2:26][CH2:27][N:28]=4)[C:19]([NH2:25])=[N:20][C:21]=3[C:22]=2[O:23][CH3:24])[CH2:3]1.[C:29](O)(=[O:36])[C:30]1[CH:35]=[CH:34][CH:33]=[N:32][CH:31]=1.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>CN(C=O)C.CCOC(C)=O>[CH3:1][C@H:2]1[O:7][C@@H:6]([CH3:8])[CH2:5][N:4]([CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:14]=[CH:15][C:16]3[C:17]4[N:18]([CH2:26][CH2:27][N:28]=4)[C:19]([NH:25][C:29](=[O:36])[C:30]4[CH:35]=[CH:34][CH:33]=[N:32][CH:31]=4)=[N:20][C:21]=3[C:22]=2[O:23][CH3:24])[CH2:3]1
Reactant: O=C(O)c1cccnc1
Reactant: COc1c(OCCCN2C[C@@H](C)O[C@@H](C)C2)ccc2c1N=C(N)N1CCN=C21
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1c(OCCCN2C[C@@H](C)O[C@@H](C)C2)ccc2c1N=C(NC(=O)c1cccnc1)N1CCN=C21
Temperature: 25 °C
Reaction time: 8 h
Yield: 60.9 %

Procedure:
8-{3-[(2R,6S)-2,6-Dimethylmorpholin-4-yl]propoxy}-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-amine (200 mg, 0.52 mmol) was dissolved in DMF (2.0 mL), and nicotinic acid (76 mg, 0.62 mmol) was added. PYBOP (322 mg, 0.62 mmol) and diisopropylethylamine (0.33 mL, 1.55 mmol) were subsequently added, and the mixture was stirred at room temperature overnight. EtOAc was added, and the precipitate was isolated by vacuum filtration to give the title compound (156 mg, 61%): HPLC MS RT=1.34 min, MH+=493.3; 1H NMR (DMSO-d6+2 drops TFA-d) δ: 9.53 (1H, s), 9.03 (1H, d), 9.00 (1H, d), 8.07 (1H, d), 8.01 (1H, dd), 7.49 (1H, d), 4.58 (2H, m), 4.34 (2H, t), 4.27 (2H, m), 4.03 (3H, s), 3.81 (2H, m), 3.53 (2H, d), 3.29 (2H, m), 2.69 (2H, m), 2.27 (2H, m), 1.15 (6H, d).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:15]3[C:14]([CH3:16])=[N:13][N:12]([CH:17]4[CH2:19][CH2:18]4)[C:11]=3[C:10](=[O:20])[N:9]2CC2C=CC(OC)=CC=2)=[CH:4][CH:3]=1>CCCCCC.CCOC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:15]3[C:14]([CH3:16])=[N:13][N:12]([CH:17]4[CH2:19][CH2:18]4)[C:11]=3[C:10](=[O:20])[NH:9]2)=[CH:4][CH:3]=1
Reactant: COc1ccc(CN2C(=O)c3c(c(C)nn3C3CC3)C2c2ccc(Cl)cc2)cc1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: Cc1nn(C2CC2)c2c1C(c1ccc(Cl)cc1)NC2=O

Procedure:
The title compound was prepared in analogy to the procedure described in Step 23.9 using 4-(4-chlorophenyl)-1-cyclopropyl-5-(4-methoxybenzyl)-3-methyl-4,5-dihydropyrrolo[3,4-c]pyrazol-6(1H)-one (Step 85.5) under MW irradiation 140° C. for 2 hr. tR: 4.22 min (HPLC 1); tR: 0.94 min (LC-MS 2); ESI-MS: 288 [M+H]+ (LC-MS 2); Rf=0.31 (Hexane/EtOAc 1:1).