Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I:1][C:2]1[CH:12]=[N:11][C:5]2[NH:6][CH2:7][C:8](=[O:10])[NH:9][C:4]=2[CH:3]=1.[Cl:13][C:14]1[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[C:15]=1[CH2:16]Br>>[Cl:13][C:14]1[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[C:15]=1[CH2:16][N:9]1[C:8](=[O:10])[CH2:7][NH:6][C:5]2[N:11]=[CH:12][C:2]([I:1])=[CH:3][C:4]1=2
Reactant: Clc1cccc(Cl)c1CBr
Reactant: O=C1CNc2ncc(I)cc2N1
Product: O=C1CNc2ncc(I)cc2N1Cc1c(Cl)cccc1Cl

Procedure:
7-Iodo-3,4-dihydro-1H-pyrido[2,3-b]pyrazin-2-one (500 mg) was treated with 2,6-dichlorobenzyl bromide as in General Procedure 1 to give the title compound as an off-white solid. M.p.>200° C., LCMS: m/z=434.37 (M+H+), 1H-NMR (DMSO-d6, 400 MHz) δ 3.30 (2H, s), 5.29 (2H, s), 7.31 (1H, d, J=8.6 Hz), 7.34 (1H, d, J=7.6 Hz), 7.45 (1H, s), 7.47 (1H, s), 7.76 (1H, d, J=1.0 Hz).
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH3:11][O:12][C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[C:18](=[O:22])[N:17]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:16]2.[CH2:30](Br)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>C1COCC1>[CH2:30]([CH:16]1[C:15]2[C:19](=[CH:20][CH:21]=[C:13]([O:12][CH3:11])[CH:14]=2)[C:18](=[O:22])[N:17]1[C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: BrCc1ccccc1
Reactant: COc1ccc2c(c1)CN(C(=O)OC(C)(C)C)C2=O
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc2c(c1)C(Cc1ccccc1)N(C(=O)OC(C)(C)C)C2=O
Temperature: -78 °C
Reaction time: 1 h
Yield: 69.9 %

Procedure:
Lithium bis(trimethysilyl)amide (4.8 mL, 4.8 mmol, 1 M in THF) was added to a solution of the tert-butyl 5-methoxy-1-oxoisoindoline-2-carboxylate (0.975 g) in THF (7 mL) at −78° C. After stirring the solution at −78° C. for 1 hr, benzyl bromide (0.88 mL, 7.41 mmol) was added, this was stirred at −78° C. for 1.5 hours. LC/MS showed complete conversion. Quenched the reaction mixture with saturated NaCl solution, then extracted with ethyl acetate, the combined organic layer was washed 1× with saturated NaCl solution. The organic phase was dried on Na2SO4 and the solvent was evaporated. The residue was purified by flash-chromatography on silica gel with 25-40% ethyl acetate in hexane, 0.92 g (2.59 mmol, 70%) of the product was obtained.
Reaction SMILES: FC(F)(F)C(O)=O.[F:8][C:9]([F:15])([F:14])[S:10]([OH:13])(=[O:12])=[O:11].COC1C=CC(C[S:23][C@@H:24]2[CH2:28][N:27]([C:29]([O:31][CH2:32][C:33]3[CH:38]=[CH:37][C:36]([N+:39]([O-:41])=[O:40])=[CH:35][CH:34]=3)=[O:30])[C@H:26]([C:42]([N:44]3[CH2:49][CH2:48][N:47]([C:50](=[N:52][C:53]([O:55][CH2:56][C:57]4[CH:62]=[CH:61][C:60]([N+:63]([O-:65])=[O:64])=[CH:59][CH:58]=4)=[O:54])[CH3:51])[CH2:46][CH2:45]3)=[O:43])[CH2:25]2)=CC=1>C1(OC)C=CC=CC=1>[F:8][C:9]([F:15])([F:14])[S:10]([OH:13])(=[O:12])=[O:11].[SH:23][C@@H:24]1[CH2:28][N:27]([C:29]([O:31][CH2:32][C:33]2[CH:34]=[CH:35][C:36]([N+:39]([O-:41])=[O:40])=[CH:37][CH:38]=2)=[O:30])[C@H:26]([C:42]([N:44]2[CH2:45][CH2:46][N:47]([C:50](=[N:52][C:53]([O:55][CH2:56][C:57]3[CH:62]=[CH:61][C:60]([N+:63]([O-:65])=[O:64])=[CH:59][CH:58]=3)=[O:54])[CH3:51])[CH2:48][CH2:49]2)=[O:43])[CH2:25]1
Reactant: COc1ccc(CS[C@H]2C[C@@H](C(=O)N3CCN(C(C)=NC(=O)OCc4ccc([N+](=O)[O-])cc4)CC3)N(C(=O)OCc3ccc([N+](=O)[O-])cc3)C2)cc1
Agent: O=S(=O)(O)C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: CC(=NC(=O)OCc1ccc([N+](=O)[O-])cc1)N1CCN(C(=O)[C@@H]2C[C@H](S)CN2C(=O)OCc2ccc([N+](=O)[O-])cc2)CC1
Reaction time: 1 h

Procedure:
3.2 ml of trifluoroacetic acid and 103 μl of trifluoromethanesulfonic acid were added to a solution of 430 mg of (2S,4S)-4-(4-methoxybenzylthio)-2-[4-(N-4-nitrobenzyloxycarbonylacetimidoyl)piperazin-1-ylcarbonyl]-1-(4-nitrobenzyloxycarbonyl)pyrrolidine [prepared as described in step (iii) above] in 636 μl of anisole, and the resulting mixture was stirred for 1 hour, whilst ice-cooling. An the end of this time, the reaction mixture was freed from the solvent by distillation under reduced pressure, and the residue was repeatedly washed with diethyl ether by decantation, to give 450 mg of the title compound, as a powder.
Reaction SMILES: O1CCCCC1[O:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25].CC1C=CC(S([O-])(=O)=O)=CC=1.C1C=C[NH+]=CC=1.CCO>CCOC(C)=O>[OH:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25]
Reactant: CCOC(=O)CCCCCCCCCCCCCCCCOC1CCCCO1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCOC(=O)CCCCCCCCCCCCCCCCO
Yield: 92.3 %

Procedure:
Ethyl 17-(tetrahydropyran-2-yl-oxy)-heptadecanoate 78 (365 mg, 0.916 mmol) and PPTS (12 mg, 0.046 mmol) were dissolved in abs. EtOH (6 ml) and the reaction mixture was stirred at 45° C. for 10 h. Reaction mixture was diluted with EtOAc and washed with H2O. The extract was dried over Na2SO4 and evaporated. The residue was purified by silica gel chromatography in hexane-EtOAc (95:5, 90:10) to yield the product 79 (266 mg, 92%).
Reaction SMILES: [CH2:1]([NH:10][C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[H-].[Na+].[Cl:19][CH:20]=[CH:21][CH2:22]Cl.[I-].[Na+]>CN(C)P(=O)(N(C)C)N(C)C.O>[Cl:19][CH:20]=[CH:21][CH2:22][N:10]([CH2:1][CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[C:11](=[O:16])[C:12]([F:14])([F:15])[F:13]
Reactant: ClC=CCCl
Reactant: O=C(NCC=Cc1ccccc1)C(F)(F)F
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: O=C(N(CC=CCl)CC=Cc1ccccc1)C(F)(F)F
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 250 g of N-cinnamyltrifluoroacetamide in 1 liter of hexamethylphosphoric acid triamide (HMPT) is added dropwise with ice-cooling and stirring under a nitrogen atmosphere, to a suspension of 27 g of sodium hydride in 400 ml of HMPT. After the evolution of gas has ceased, a solution of 130 g of 1,3-dichloropropene and 1 g of sodium iodide in 1 liter of HMPT is added dropwise and the mixture stirred for 16 hours at room temperature. The reaction mixture is then poured on to water and extracted with ether. The ethereal solution is dried over sodium sulphate, evaporated and the oily residue chromatographed on 3.5 kg of silica gel with toluene to yield N-(3-chloro-2-propenyl)-N-cinnamyl-trifluoroacetamide as an oil.
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[N+:11]([O-:13])=[O:12])[NH:4][N:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:21][C:22]1[N:23]=[C:24]([CH3:27])[O:25][CH:26]=1>CN(C=O)C.O>[Br:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[N+:11]([O-:13])=[O:12])[N:4]([CH2:21][C:22]2[N:23]=[C:24]([CH3:27])[O:25][CH:26]=2)[N:3]=1
Reactant: O=[N+]([O-])c1cccc2[nH]nc(Br)c12
Reactant: Cc1nc(CBr)co1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1nc(Cn2nc(Br)c3c([N+](=O)[O-])cccc32)co1
Temperature: 25 °C
Reaction time: 16 h
Yield: 43.6 %

Procedure:
A suspension of 3-bromo-4-nitro-1H-indazole (Preparation B; 500 mg, 2.07 mmol) and K2CO3 (1.14 g, 8.26 mmol) in anhydrous DMF (3 mL) was treated at ambient temperature, under a nitrogen atmosphere, with a solution of 4-(bromomethyl)-2-methyloxazole (727 mg, 2.07 mmol) (Org. Biom. Chem., 2003, 1, 4173-4208) in anhydrous DMF (2 mL). The reaction mixture was stirred at ambient temperature for 16 hours. The reaction mixture was diluted with excess water and extracted multiple times with DCM and EtOAc. The combined extracts were dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford the crude product (0.5 g). The material was purified by preparative thin-layer chromatography (silica, 5% MeOH-DCM as eluent) to afford the product (304 mg) as a solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:36]=[CH:35][C:12]([C:13]([NH:15][C:16]2[C:17](Cl)=[CH:18][C:19]([O:22][CH2:23][C@@H:24]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])[CH3:25])=[N:20][CH:21]=2)=[O:14])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CN(C=O)C.[Cu]I>[CH2:1]([O:8][C:9]1[CH:36]=[CH:35][C:12]([C:13]2[O:14][C:17]3[CH:18]=[C:19]([O:22][CH2:23][C@@H:24]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])[CH3:25])[N:20]=[CH:21][C:16]=3[N:15]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[C@@H](COc1cc(Cl)c(NC(=O)c2ccc(OCc3ccccc3)cc2)cn1)NC(=O)OC(C)(C)C
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C[C@@H](COc1cc2oc(-c3ccc(OCc4ccccc4)cc3)nc2cn1)NC(=O)OC(C)(C)C
Temperature: 160 °C
Reaction time: 3.5 h
Yield: 35.7 %

Procedure:
A suspension of tert-butyl ((2S)-1-((5-((4-(benzyloxy)benzoyl)amino)-4-chloropyridin-2-yl)oxy)propan-2-yl)carbamate (2.50 g), potassium carbonate (1.35 g) and copper(I) iodide (93.9 mg) in DMF (20 mL) was stirred at 160° C. for 3.5 hr. The reaction mixture was subjected to silica gel chromatography (NH, ethyl acetate), washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated, and the obtained solid was washed with ethyl acetate/hexane to give the title compound (830 mg).
Reaction SMILES: C([O:3][C:4](=[O:21])[C:5](=[CH:17]OCC)[C:6](=[O:16])[C:7]1[CH:12]=[C:11]([F:13])[C:10]([Cl:14])=[CH:9][C:8]=1Cl)C.[CH:22]1([NH2:25])[CH2:24][CH2:23]1>C(Cl)Cl>[Cl:14][C:10]1[CH:9]=[C:8]2[C:7]([C:6](=[O:16])[C:5]([C:4]([OH:3])=[O:21])=[CH:17][N:25]2[CH:22]2[CH2:24][CH2:23]2)=[CH:12][C:11]=1[F:13]
Reactant: CCOC=C(C(=O)OCC)C(=O)c1cc(F)c(Cl)cc1Cl
Reactant: NC1CC1
Solvent: ClCCl
Product: O=C(O)c1cn(C2CC2)c2cc(Cl)c(F)cc2c1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 4 (80 g) in methylene chloride (800 mL), cyclopropylamine (44.0 g) was added with cooling below 10° C. The mixture was stirred at room temperature for 1 h and evaporated to a dry mixture. To the dry mixture in dimethoxyethane (800 mL), a 60% sodium hydride-in-oil suspension (12.0 g) was added slowly with cooling and stirring. The mixture was heated at 80-85° C. for 3 h under nitrogen atmosphere. It was cooled and water (5 L) was added and the precipitate was filtered and washed with water and dried. The ester was suspended in tetrahydrofuran (800 mL). A solution of sodium hydroxide (20.0 g) in water (500 mL) was added and the mixture was refluxed for 2 h. It was cooled and acidified with acetic acid and the precipitate was filtered. The solid was washed with water and acetone. wt=19.0 g of (7). m.p.=235-240° C.
Reaction SMILES: ClC[C:3]1[N:4]=[C:5]2[CH2:14][C:13]3[N:12]=[CH:11][C:10]([C:15]#[N:16])=[C:9]([NH:17][C:18]4[CH:23]=[C:22]([O:24][CH3:25])[C:21]([O:26][CH3:27])=[C:20]([O:28][CH3:29])[CH:19]=4)[C:8]=3[CH:7]=[C:6]2[N:30]=1.N1CCOCC1.C(=O)([O-])[O-].[K+].[K+]>C(O)C>[CH3:25][O:24][C:22]1[CH:23]=[C:18]([CH:19]=[C:20]([O:28][CH3:29])[C:21]=1[O:26][CH3:27])[NH:17][C:9]1[C:8]2[CH:7]=[C:6]3[N:30]=[CH:3][NH:4][C:5]3=[CH:14][C:13]=2[N:12]=[CH:11][C:10]=1[C:15]#[N:16]
Reactant: COc1cc(Nc2c(C#N)cnc3c2C=C2N=C(CCl)N=C2C3)cc(OC)c1OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCN1
Solvent: CCO
Product: COc1cc(Nc2c(C#N)cnc3cc4[nH]cnc4cc23)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 0.09 g (0.2 mmol) of 2-(chloromethyl)-8-(3,4,5-trimethoxyanilino)imidazo[4,5-g]quinoline-7-carbonitrile, 0.2 mL (2.3 mmol) of morpholine and 0.3 g (2.2 mmol) of anhydrous potassium carbonate in 5 mL of ethanol is stirred at room temperature overnight. The product mixture is filtered to remove the inorganic salts and the filtrate is evaporated to dryness to yield an oil. The oil is purified by silica gel chromatography utilizing a gradient of methylene chloride/methanol(97:3 to 90:10) to yield 0.087 g of 2-(4-morpholinylmethyl)-8-(3,4,5-trimethoxyanilino)-3H-imidazo[4,5-g]quinoline-ylmethyl)-8-(3,4,5-trimethoxyanilino)-3H-imidazo[4,5-g]quinoline-7-carbonitrile as a yellow solid, mp 258-260° C. (dec).
Reaction SMILES: [Cl:1][C:2]12[C:14]([Cl:16])([Cl:15])[C:5]([Cl:17])([C:6]3[C:7]([OH:13])=[CH:8][CH:9]=[C:10]([OH:12])[C:11]=31)[C:4]([Cl:18])=[C:3]2[Cl:19].[C:20](O)(=[O:22])[CH3:21]>>[CH3:21][C:20]([C:8]1[C:7]([OH:13])=[C:6]2[C:11](=[C:10]([OH:12])[CH:9]=1)[C:2]1([Cl:1])[C:14]([Cl:15])([Cl:16])[C:5]2([Cl:17])[C:4]([Cl:18])=[C:3]1[Cl:19])=[O:22]
Reactant: CC(=O)O
Reactant: Oc1ccc(O)c2c1C1(Cl)C(Cl)=C(Cl)C2(Cl)C1(Cl)Cl
Product: CC(=O)c1cc(O)c2c(c1O)C1(Cl)C(Cl)=C(Cl)C2(Cl)C1(Cl)Cl
Temperature: 40 °C

Procedure:
76 g. of 1,2,3,4,9,9-hexachloro-1,4-dihydro-1,4-methanonaphthalene-5,8-diol, prepared according to Example 2, were suspended in 100 ml. of acetic acid and then 20 ml. of boron trifluoride-diethyl ether complex were added. This mixture was heated at 100°-105° C. for 5 hours. After being cooled to 40° C., the mixture was poured into ice water. After repeated recrystallization from benzene white crystals were obtained, m.p. 135°-140° C.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]([CH3:23])[C:13](=[O:22])[N:14]([C:15]4[C:16]([CH3:21])=[N:17][N:18]([CH3:20])[CH:19]=4)[C:5]=3[C:4]=2[CH:3]=1.[NH2:24][C:25]1[N:34]=[CH:33][C:32](B2OC(C)(C)C(C)(C)O2)=[CH:31][C:26]=1[C:27]([NH:29][CH3:30])=[O:28]>>[NH2:24][C:25]1[N:34]=[CH:33][C:32]([C:2]2[CH:11]=[CH:10][C:9]3[N:8]=[CH:7][C:6]4[N:12]([CH3:23])[C:13](=[O:22])[N:14]([C:15]5[C:16]([CH3:21])=[N:17][N:18]([CH3:20])[CH:19]=5)[C:5]=4[C:4]=3[CH:3]=2)=[CH:31][C:26]=1[C:27]([NH:29][CH3:30])=[O:28]
Reactant: Cc1nn(C)cc1-n1c(=O)n(C)c2cnc3ccc(Br)cc3c21
Reactant: CNC(=O)c1cc(B2OC(C)(C)C(C)(C)O2)cnc1N
Product: CNC(=O)c1cc(-c2ccc3ncc4c(c3c2)n(-c2cn(C)nc2C)c(=O)n4C)cnc1N

Procedure:
The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate A) and 2-amino-N-methyl-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-nicotinamide (Stage 224.1.1) to give the title compound as an off-white solid. (HPLC: tR 2.01 min (Method A); M+H=443 MS-ES; 1H-NMR (d6-DMSO, 400 MHz) 8.92 (s, 1H), 8.54 (q, 1H), 8.14-8.11 (m, 2H), 8.10-8.06 (m, 2H), 7.96-7.92 (m, 1H), 7.47-7.44 (m, 1H), 7.27 (s, br, 2H), 3.89 (s, 3H), 3.57 (s, 3H), 2.78 (d, 3H), 1.95 (s, 3H))
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][C:5]2[C:6](=[O:18])[C:7]3[C:14]([C:15]([OH:17])=[O:16])=[N:13][NH:12][C:8]=3[C:9](=[O:11])[NH:10][C:4]=2[CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[C:33]1(O)[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.O>CN(C)C=O>[Cl:1][C:2]1[CH:20]=[CH:19][C:5]2[C:6](=[O:18])[C:7]3[C:14]([C:15]([O:17][C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)=[O:16])=[N:13][NH:12][C:8]=3[C:9](=[O:11])[NH:10][C:4]=2[CH:3]=1
Reactant: Oc1ccccc1
Reactant: O=C(O)c1n[nH]c2c(=O)[nH]c3cc(Cl)ccc3c(=O)c12
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: O
Solvent: CN(C)C=O
Product: O=C(Oc1ccccc1)c1n[nH]c2c(=O)[nH]c3cc(Cl)ccc3c(=O)c12
Temperature: 70 °C
Reaction time: 24 h
Yield: 52.2 %

Procedure:
A solution of 7-chloro-3-(carboxy)pyrazolo[3,4-c][1]benzazepine-4,10(1H,9H)-dione (500 mg, 1.72 mmol) (compound of Example 9) and 1,1′-carbonyldiimidazole (418 mg, 2.58 mmol) in N,N-dimethylformamide (7 mL) was stirred for 16.75 hours. In one portion, phenol (486 mg, 5.16 mmol) was added and the solution was stirred for 24 hours at 70° C. To the resulting solution was added water (30 mL), giving a precipitate which was separated by filtration. This crude product was purified by chromatography eluting with chloroform: 2-propanol (98:2-90:10) to give the title compound (330 mg, 53% yield, m.p. 265° C.).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]([CH:22]2[CH2:24][CH2:23]2)[C:11](N2[C@@H](C(C)C)COC2=O)=[O:12])=[CH:6][CH:5]=1.[F:25][C:26]1[CH:31]=[CH:30][C:29]([CH2:32]Cl)=[CH:28][C:27]=1[O:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.Cl>CN(C)C=O.O>[CH:22]1([CH:10]([C:7]2[CH:6]=[CH:5][C:4]([Cl:3])=[CH:9][CH:8]=2)[CH2:11][O:12][CH2:32][C:29]2[CH:30]=[CH:31][C:26]([F:25])=[C:27]([O:34][C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=3)[CH:28]=2)[CH2:23][CH2:24]1
Reactant: CC(C)[C@H]1COC(=O)N1C(=O)C(c1ccc(Cl)cc1)C1CC1
Reactant: Fc1ccc(CCl)cc1Oc1ccccc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Fc1ccc(COCC(c2ccc(Cl)cc2)C2CC2)cc1Oc1ccccc1

Procedure:
Under a nitrogen atmosphere a suspension of 0.06 gram (0.0024 mole) of 97% sodium hydride in 2.2 mL of dimethylformamide was stirred, and a solution of 0.40 gram (0.002 mole) of stereoisomer (A) of 2-cyclopropyl-2-(4-chlorophenyl)ethyl ethanol in 1.0 mL of dimethylformamide was slowly added. Upon completion of addition, the reaction mixture was stirred for 1.5 hours, and then a solution of 0.46 gram (0.0019 mole) of (4-fluoro-3-phenoxyphenyl)methyl chloride in 1.0 mL of dimethylformamide was added. Upon completion of addition, the reaction mixture was stirred for one hour, and then 2-3 mL of water was added. The mixture was poured into 75 mL of aqueous, 10% hydrochloric acid and then was extracted with two 50 mL portions of hexane. The combined hexane layers were washed with 25 mL of a saturated, aqueous solution of sodium chloride. The organic layer was dried with sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to a residual oil. The oil was subjected to rotating disk thin layer chromatography on silica gel using diethyl ether: hexane (19:1) as eluant. The appropriate fractions were combined and concentrated under reduced pressure, yielding 0.55 gram of stereoisomer (A) of (4-fluoro-3-phenoxyphenyl)methyl 2-cyclopropyl-2-(4-chlorophenyl)ethyl ether as an oil. The nmr spectrum was consistent with the proposed structure. [α]D25 =(+)22.19°.
Reaction SMILES: Cl.[OH:2][CH:3]([CH3:11])[CH2:4][CH:5]1[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1.[NH:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[C:13]1[C:21](O)=[O:22].Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.Cl>CN(C=O)C.C(N(CC)CC)C>[NH:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[C:13]1[C:21]([N:8]1[CH2:9][CH2:10][CH:5]([CH2:4][CH:3]([OH:2])[CH3:11])[CH2:6][CH2:7]1)=[O:22]
Reactant: O=C(O)c1cc2ccccc2[nH]1
Reactant: CC(O)CC1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(O)CC1CCN(C(=O)c2cc3ccccc3[nH]2)CC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 233 mg of tert-butyl 4-(2-hydroxy propyl)piperidine-1-carboxylate in 4 mL of ethyl acetate was added 3 mL of 4M HCl/EtOAc, followed by stirring at room temperature for 2 hours. The reaction liquid was concentrated under reduced pressure to obtain 4-(2-hydroxypropyl)piperidine hydrochloride. To a solution of the 4-(2-hydroxypropyl)piperidine hydrochloride and 155 mg of indole-2-carboxylic acid in 5 mL of DMF were added 0.15 mL of triethylamine, 190 mg of 1-ethyl-3-(dimethylaminopropyl)carbodiimide hydrochloride and 130 mg of 1-hydroxybenzotriazole, followed by stirring at room temperature for 1 day. 0.5M aqueous hydrochloric acid was added to the reaction liquid, followed by extraction with ethyl acetate. The organic layer was washed with 0.5M aqueous sodium hydroxide solution and saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography [chloroform:methanol=1:0-10:1], and then solidified using diisopropyl ether to obtain 49 mg of 1-[1-(1H-indol-2-ylcarbonyl)piperidin-4-yl]propan-2-ol as a white solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[CH:17][C:12]([C:13]([O:15]C)=[O:14])=[CH:11][C:10]=1/[C:19](/[CH3:22])=[CH:20]\[CH3:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[K+]>CO.O>[CH2:1]([O:8][C:9]1[CH:18]=[CH:17][C:12]([C:13]([OH:15])=[O:14])=[CH:11][C:10]=1/[C:19](/[CH3:22])=[CH:20]\[CH3:21])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C/C=C(/C)c1cc(C(=O)OC)ccc1OCc1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: C/C=C(/C)c1cc(C(=O)O)ccc1OCc1ccccc1
Yield: 81.5 %

Procedure:
Methyl (Z)-4-benzyloxy-3-(1-methyl-propenyl)-benzoate (592 mg, 2.0 mmol) was dissolved in methanol (20 ml), a solution of potassium hydroxide (336 mg, 6.0 mmol) in water (7 ml) was added and the mixture was stirred and held at reflux for 3 hours. Upon cooling the solvent was removed in vacuo and the mixture acidified to pH 2 or below by the addition of 2M hydrochloric acid. The mixture was extracted with dichloromethane, the organic layer was separated and the solvent removed in vacuo to afford (Z)-4-benzyloxy-3-(1-methyl-propenyl)-benzoic acid (460 mg, 82%) as a colourless solid. 1H NMR (DMSO-d6) 7.85 (1H, dd), 7.57 (1H, d), 7.40 (4H, m), 7.34 (1H, m), 7.18 (1H, d), 5.57 (1H, q), 5.21 (2H, s), 1.96 (3H, s), 1.40 (3H, d). MS: [M+H]+ 283.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[N:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.[Cl:15][C:16]1[C:17]([C:26]([F:29])([F:28])[F:27])=[N:18][N:19]([CH2:22][C:23](O)=[O:24])[C:20]=1[CH3:21].C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C)C=O>[Cl:15][C:16]1[C:17]([C:26]([F:28])([F:27])[F:29])=[N:18][N:19]([CH2:22][C:23]([N:12]2[CH2:11][CH2:10][N:9]([C:3]3[CH:4]=[C:5]([CH3:8])[CH:6]=[CH:7][C:2]=3[CH3:1])[CH2:14][CH2:13]2)=[O:24])[C:20]=1[CH3:21]
Reactant: Cc1ccc(C)c(N2CCNCC2)c1
Reactant: Cc1c(Cl)c(C(F)(F)F)nn1CC(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1ccc(C)c(N2CCN(C(=O)Cn3nc(C(F)(F)F)c(Cl)c3C)CC2)c1
Reaction time: 6 h

Procedure:
To 38 mg (0.20 mmol) of 1-(2,5-Dimethylphenyl)piperazine and 53 mg (0.22 mmol) of (4-Chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-acetic acid in 1.6 mL of anhydrous dimethylformamide was added 62 mg (0.6 mmol) of triethylamine, followed by 84 mg (0.22 mmol) of O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU). After 6 hours, the reaction was partitioned between ethyl acetate and water, and the phases were separated. The aqueous phase was back-extracted once with ethyl acetate, and the combined ethyl acetate phases were washed once each with 0.5M pH=7 phosphate buffer, water, 1M NaOH, water, brine. The ethyl acetate phase was then dried over Na2SO4, filtered, and concentrated to a residue in vacuo. The residue was dissolved in a minimum volume of 5M HCl in isopropanol, and was precipitated by diluting the solution with ethyl acetate. The product was isolated by filtration to give a white solid: 1H NMR (DMSO-d6, 400 MHz) 7.07 (d 1H), 6.90 (s, 1H), 6.82 (d, 1H), 5.39 (s, 2H), 3.66 (m, 4H), 2.98 (m, 2H), 2.89 (m, 2H), 2.26 (s, 3H), 2.24 (s, 3H), 2.20 (s, 3H) ppm; MS (ES) M+H expected=415.1, found 415.1.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2.[H-].[Na+].[Si:13](Cl)([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14].C(OCC)(=O)C>CN(C)C=O>[Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][N:6]2[Si:13]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14]
Reactant: Brc1cccc2[nH]ccc12
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)n1ccc2c(Br)cccc21
Temperature: -10 °C
Reaction time: 0.5 h
Yield: 66.7 %

Procedure:
A solution of 4-bromo-1H-indole (36 g) in dimethylformamide (80 mL) was treated with a suspension of NaH (60% in mineraloil, 6.9 g) in dimethylformamide (200 mL) at 20° C. After stirring for 30 min the mixture was cooled to −10° C. an treated portionwise with t-butyldimethylsilyl chloride (38 g) followed by stirring for 1 h at room temperature. Standard work-up with ethyl acetate gave and oil which was purified by flash chromatography giving 4-bromo-1-(t-butyldimethylsilyl)-1H-indole (38 g) as a crystalline material.