Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[CH:5]2.[CH2:12]([OH:15])[CH:13]=[CH2:14].C1(N(C)C2CCCCC2)CCCCC1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCOCC1>[N:8]1[C:9]2[C:4](=[CH:3][C:2]([CH2:14][CH2:13][CH:12]=[O:15])=[CH:11][CH:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Brc1ccc2ncccc2c1
Reactant: C=CCO
Agent: [Pd]
Agent: CN(C1CCCCC1)C1CCCCC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: O=CCCc1ccc2ncccc2c1
Temperature: 30 °C
Reaction time: 24 h

Procedure:
Tris(dibenzylideneacetone)dipalladium (480 mg, 0.52 mmol) and tri-tent-butyl-phosphonium tetrafluoroborate (300 mg, 1.0 mmol) in a flask was evacuated and refilled with nitrogen (2 times). 1,4-dioxane (31 mL) was added followed by consecutive addition of 6-bromoquinoline (7.2 g, 35 mmol), 2-propen-1-ol (4.7 mL, 69 mmol) and N-cyclohexyl-N-methyl-cyclohexanamine (8.9 mL, 42 mmol). The reaction vessel was evacuated and refilled with nitrogen (2 times). The reaction mixture was stirred at 30° C. for 24 h. Diethyl ether (30 mL) was added to the reaction mixture and then filtered and washed with diethyl ether. The organic extract was concentrated under reduced pressure. The residue was purified by flash chromatography eluting with ethyl acetate in hexanes (0-50%) to afford the desired product. (˜55%) LCMS: (M+H)=186.0; (M+H2O+H)+=204.0.
Reaction SMILES: OC1C=CC([C:8]2[CH:16]=[C:15]([OH:17])[CH:14]=[CH:13][C:9]=2[C:10]([O-:12])=[O:11])=CC=1.[F:18][C:19]([F:30])([F:29])[C:20]1[CH:28]=[CH:27][C:23]([C:24](Cl)=[O:25])=[CH:22][CH:21]=1>>[F:18][C:19]([F:30])([F:29])[C:20]1[CH:28]=[CH:27][C:23]([C:24]([O:17][C:15]2[CH:16]=[CH:8][C:9]([O:12][C:10](=[O:11])[C:9]3[CH:8]=[CH:16][C:15]([O:17][C:24](=[O:25])[C:23]4[CH:27]=[CH:28][C:20]([C:19]([F:29])([F:30])[F:18])=[CH:21][CH:22]=4)=[CH:14][CH:13]=3)=[CH:13][CH:14]=2)=[O:25])=[CH:22][CH:21]=1
Reactant: O=C([O-])c1ccc(O)cc1-c1ccc(O)cc1
Reactant: O=C(Cl)c1ccc(C(F)(F)F)cc1
Product: O=C(Oc1ccc(OC(=O)c2ccc(C(F)(F)F)cc2)cc1)c1ccc(OC(=O)c2ccc(C(F)(F)F)cc2)cc1

Procedure:
4-(4-trifluoromethylbenzoyloxy)-benzoic acid-4-(4-trifluoromethylbenzoyloxy)-phenyl ester is prepared as in Example 6 from 4-hydroxyphenyl-4-hydroxybenzoate and 4-trifluoromethylbenzoyl chloride. Yield: 12.9 g (80% of the theoretical). A liquid crystalline phase was observed under a polarization microscope in the temperature range from 180° to 340° C.
Reaction SMILES: N(C(OC(C)C)=O)=NC(OC(C)C)=O.[CH3:15][C:16]1[N:21]=[C:20]([OH:22])[CH:19]=[CH:18][C:17]=1[N+:23]([O-:25])=[O:24].[C:26]([O:30][C:31]([N:33]1[CH2:38][CH2:37][CH:36](O)[CH2:35][CH2:34]1)=[O:32])([CH3:29])([CH3:28])[CH3:27].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[C:26]([O:30][C:31]([N:33]1[CH2:38][CH2:37][CH:36]([O:22][C:20]2[CH:19]=[CH:18][C:17]([N+:23]([O-:25])=[O:24])=[C:16]([CH3:15])[N:21]=2)[CH2:35][CH2:34]1)=[O:32])([CH3:29])([CH3:27])[CH3:28]
Reactant: Cc1nc(O)ccc1[N+](=O)[O-]
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1nc(OC2CCN(C(=O)OC(C)(C)C)CC2)ccc1[N+](=O)[O-]
Temperature: 22 °C
Reaction time: 8 h
Yield: 79.7 %

Procedure:
Add diisopropyl azodicarboxylate (3.0 mL, 15.5 mmol) dropwise to a cold mixture of 6-methyl-5-nitro-pyridin-2-ol (1.54 g, 10.0 mmol), 4-hydroxy-piperidine-1-carboxylic acid tert-butyl ester (2.05 g, 10.0 mmol), and triphenylphosphine (4.02 g, 15.3 mmol) in THF (25 mL) at 0° C. After addition is complete, remove cooling bath and stir the reaction mixture at 22° C. overnight. Concentrate under reduced pressure. Subject residue to silica gel chromatography eluting with hexanes and ethyl acetate to provide 4-(6-Methyl-5-nitro-pyridin-2-yloxy)-piperidine-1-carboxylic acid tert-butyl ester as a colorless oil (2.69 g, 80% yield). MS(ES): m/z=338.2 [M+H].
Reaction SMILES: O1C2(CC[CH:8]([CH2:11]OC3C(Cl)=CC(C(OC(C)(C)C)=O)=C(F)C=3)[CH2:7]C2)OCC1.[O:28]1[C:32]2([CH2:37][CH2:36][CH:35]([O:38][C:39]3[C:51](Cl)=[CH:50][C:42]([C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])=[C:41]([F:53])[CH:40]=3)[CH2:34][CH2:33]2)[O:31][CH2:30][CH2:29]1>>[O:28]1[C:32]2([CH2:37][CH2:36][CH:35]([O:38][C:39]3[C:51]([CH:11]4[CH2:8][CH2:7]4)=[CH:50][C:42]([C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])=[C:41]([F:53])[CH:40]=3)[CH2:34][CH2:33]2)[O:31][CH2:30][CH2:29]1
Reactant: CC(C)(C)OC(=O)c1cc(Cl)c(OCC2CCC3(CC2)OCCO3)cc1F
Reactant: CC(C)(C)OC(=O)c1cc(Cl)c(OC2CCC3(CC2)OCCO3)cc1F
Product: CC(C)(C)OC(=O)c1cc(C2CC2)c(OC2CCC3(CC2)OCCO3)cc1F

Procedure:
Following the procedure as described in Example 305/306, Step 2 and making variations as required to replace tert-butyl 4-(1,4-dioxaspiro[4.5]decan-8-ylmethoxy)-5-chloro-2-fluorobenzoate with tert-butyl 4-(1,4-dioxaspiro[4.5]decan-8-yloxy)-5-chloro-2-fluorobenzoate, the title compound was obtained as a yellowish oil (0.557 g, 79%): 1H NMR (300 MHz, CDCl3) δ 7.36 (d, J=8.4 Hz, 1H), 6.53 (d, J=13.2 Hz, 1H), 4.54-4.39 (m, 1H), 3.97-3.93 (m, 4H), 2.07-1.58 (m, 9H), 1.55 (s, 9H), 0.92-0.82 (m, 2H), 0.63-0.57 (m, 2H).
Reaction SMILES: C[Si](C)(C)[C:3]#[C:4][C:5]1[CH2:19][C:8]2([CH2:11][N:10]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:9]2)[O:7][N:6]=1.O.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[C:4]([C:5]1[CH2:19][C:8]2([CH2:11][N:10]([C:12]([O:14][C:15]([CH3:17])([CH3:16])[CH3:18])=[O:13])[CH2:9]2)[O:7][N:6]=1)#[CH:3]
Reactant: CC(C)(C)OC(=O)N1CC2(CC(C#C[Si](C)(C)C)=NO2)C1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: C#CC1=NOC2(C1)CN(C(=O)OC(C)(C)C)C2

Procedure:
A solution of Compound 28b (557 mg, 1.81 mmol) and tetrabutylammonium fluoride hydrate (759 mg, 2.72 mmol) in 10 mL of THF was stirred at r.t. for 4 h. After the usual work-up with EtOAc-water the crude residue was used in the next step without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:26]=[CH:25][C:6]([C:7]([NH:9][C:10]2[C:11]([NH:16][C:17]([CH:19]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)=[O:18])=[CH:12][CH:13]=[CH:14][CH:15]=2)=[O:8])=[CH:5][CH:4]=1.[CH:27]1[C:32]([CH:33]=O)=[CH:31][C:30]2[O:35][CH2:36][O:37][C:29]=2[CH:28]=1>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:7]([NH:9][C:10]2[C:11]([NH:16][C:17]([CH:19]3[CH2:20][CH2:21][N:22]([CH2:33][C:32]4[CH:27]=[CH:28][C:29]5[O:37][CH2:36][O:35][C:30]=5[CH:31]=4)[CH2:23][CH2:24]3)=[O:18])=[CH:12][CH:13]=[CH:14][CH:15]=2)=[O:8])=[CH:25][CH:26]=1
Reactant: COc1ccc(C(=O)Nc2ccccc2NC(=O)C2CCNCC2)cc1
Reactant: O=Cc1ccc2c(c1)OCO2
Product: COc1ccc(C(=O)Nc2ccccc2NC(=O)C2CCN(Cc3ccc4c(c3)OCO4)CC2)cc1

Procedure:
Using the general procedure described in Example 3, N1-(4-methoxybenzoyl)-N2-(piperidin-4-ylcarbonyl)-1,2-benzenediamine (0.045 mmol) was reacted with piperonal to provide 21 mg of the title product as the free base. Treatment with hydrochloric acid and concentration in vacuo yielded the salt of the title compound.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[C:5]([O:10][C:11]3[CH:20]=[C:19]([N:21]4[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]4)[CH:18]=[CH:17][C:12]=3[C:13]([O:15][CH3:16])=[O:14])[CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[Br:27]N1C(=O)CCC1=O>ClCCl.CN(C)C=O>[Br:27][C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][C:5]=2[O:10][C:11]2[CH:20]=[C:19]([N:21]3[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]3)[CH:18]=[CH:17][C:12]=2[C:13]([O:15][CH3:16])=[O:14])[NH:1][CH:2]=1
Reactant: COC(=O)c1ccc(N2CCNCC2)cc1Oc1cccc2[nH]ccc12
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COC(=O)c1ccc(N2CCNCC2)cc1Oc1cccc2[nH]cc(Br)c12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of EXAMPLE 339B (1 g) in dichloromethane (50 mL) and N,N-dimethylformamide (5 mL) was cooled in an ice bath. N-bromosuccinimide (0.582 g) was added and the mixture was stirred overnight while warming to ambient temperature. The reaction was concentrated and the crude product was chromatographed on silica gel with a methanol/methylene chloride gradient.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][CH:3]=1.[OH-].[Na+].[F:12][C:13]1[CH:21]=[CH:20][C:16]([C:17](Cl)=[O:18])=[CH:15][CH:14]=1>C(Cl)Cl>[F:12][C:13]1[CH:21]=[CH:20][C:16]([C:17]([NH:7][CH2:6][C:5]2[CH:8]=[CH:9][C:2]([F:1])=[CH:3][CH:4]=2)=[O:18])=[CH:15][CH:14]=1
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: NCc1ccc(F)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: O=C(NCc1ccc(F)cc1)c1ccc(F)cc1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 90.5 %

Procedure:
4-Flourobenzyl amine (27 grams, 0.22 mole) was dissolved in 200 mL of CH2Cl2. To this was added 400 mL of 1N NaOH and the resulting mixture cooled to 0° C. 4-Fluorobenzoyl chloride (33 grams, 0.21 mole) was added dropwise with stirring. The reaction was allowed to proceed for 20 min after which the organic layer was separated, dried over Na2SO4, filtered and the solvent removed under vacuum to yield 47 grams (92% yield) of 4-fluoro-N-(4-fluoro-benzyl)-benzamide as a solid. MS (M−H) calcd for C14H10F2NO: 246.1. found: 246.0. Anal. Calcd for C14H11F2NO; C, 68.01; H, 4.48; N, 5.66; found: C, 67.76; H, 4.54; N, 5.45. 1H NMR (500 MHz, DMSO) δ: 4.45 (d, 2, J=6), 7.15 (m, 2), 7.34 (overlapping m, 4), 7.97 (m, 2), 9.09 (t, 1, J=6). 13C NMR (125 MHz, DMSO) δ: 41.88, 114.81, 114.98, 115.06, 115.23, 129.08, 129.15, 129.76, 129.83, 130.60, 130.62, 135.66, 135.68, 160.10, 162.03, 162.83, 164.81, 165.04.
Reaction SMILES: [OH:1][C:2]1([CH:16]([CH3:20])[C:17](O)=O)[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=1.C(OC(=O)C(C1(O)CCCCC1C1C=CC(OC)=CC=1)C)C.OC1(C(C)CO)CCCCC1C1C=CC(OC)=CC=1.S(C1C=CC(C)=CC=1)([O-])(=O)=O.[CH3:73][NH:74][CH3:75].[ClH:76]>>[ClH:76].[CH3:73][N:74]([CH3:75])[CH2:17][CH:16]([C:2]1([OH:1])[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=1)[CH3:20]
Reactant: COc1ccc(C2CCCCC2(O)C(C)C(=O)O)cc1
Reactant: CNC
Agent: CCOC(=O)C(C)C1(O)CCCCC1c1ccc(OC)cc1
Agent: COc1ccc(C2CCCCC2(O)C(C)CO)cc1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Product: COc1ccc(C2CCCCC2(O)C(C)CN(C)C)cc1

Procedure:
The procedure of Example II is followed except that 2-phenylcyclohexanone is replaced by 2-(p-Methoxyphenyl)cyclohexanone and piperidine is replaced by dimethylene. By this method is obtained 196 g crude Ethyl-2-(1-hydroxy-2-[p-methoxyphenyl]cyclohexyl) propionate from 128.7 g 2-(p-Methoxyphenyl)cyclohexanone (which is prepared by known methods) and 121.8 g Ethyl-2-bromopropionate; 50 g crude 2-(1-Hydroxy-2-[p-methoxyphenyl]cyclohexyl) propionic acid from 196 g Ethyl-2-(1-hydroxy-2-[p-methoxyphenyl]cyclohexyl)propionate; 54.6 g crude 2-(1-Hydroxy-2-[p-methoxyphenyl]cyclohexyl)propanol from 50 g 2-(1-Hydroxy-2-[p-methoxyphenyl]cyclohexyl)propionic acid. The crude 2-(1-Hydroxy-2-[p-methoxyphenyl]cyclohexyl)propanol is converted to the tosylate and treated with 125 ml dimethylamine (according to the procedure of Example II) to give 44 g crude base which is converted to the hydrochloride and recrystallized from isopropanol to give 33.5 g product, m. 245-6.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:12]([OH:14])=O)[C:10]=1[F:11])[NH:7][CH:6]=[CH:5]2.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)C(C)C)(C)C.[C:46]([C:50]1[CH:67]=[CH:66][C:53]([CH2:54][NH:55][CH2:56][CH:57]([C:59]2[CH:64]=[CH:63][C:62]([F:65])=[CH:61][CH:60]=2)[OH:58])=[CH:52][CH:51]=1)([CH3:49])([CH3:48])[CH3:47]>CN(C=O)C.O>[C:46]([C:50]1[CH:67]=[CH:66][C:53]([CH2:54][N:55]([CH2:56][CH:57]([C:59]2[CH:60]=[CH:61][C:62]([F:65])=[CH:63][CH:64]=2)[OH:58])[C:12]([C:9]2[C:10]([F:11])=[C:2]([F:1])[CH:3]=[C:4]3[C:8]=2[NH:7][CH:6]=[CH:5]3)=[O:14])=[CH:52][CH:51]=1)([CH3:49])([CH3:47])[CH3:48]
Reactant: O=C(O)c1c(F)c(F)cc2cc[nH]c12
Reactant: CC(C)(C)c1ccc(CNCC(O)c2ccc(F)cc2)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)c1ccc(CN(CC(O)c2ccc(F)cc2)C(=O)c2c(F)c(F)cc3cc[nH]c23)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 47 %

Procedure:
To a solution of 43 mg (0.22 mmol) of 5,6-difluoro-1H-indole-7-carboxylic acid and 68 mg of TBTU (0.22 mmol) in 2 ml DMF, were added 0.19 ml (1.09 mmol) of N,N-diisopropylethyl amine. After stirring for 5 min at rt, 66 mg (0.22 mmol) of [rac]-(4-tert-butyl-benzyl)-[2-(4-fluoro-phenyl)-2-hydroxy-ethyl]-amine were added. After stirring for 17 h at rt, the reaction mixture was diluted with 20 ml water and extracted with EtOAc (2×). The combined organic phases were washed with water and brine, dried with magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (8 g silica gel; EtOAc/heptane 1:2) to give 56 mg light yellow foam (47%). MS(ISP): 481.4 (M+H)+.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][C@@H:2]1[C:6]#[C:7][CH2:8][N:9]1[CH2:13][CH2:12][CH2:11][CH2:10]1.[CH3:14][N:15]([CH3:19])[C:16](Cl)=[O:17].C(OC(=O)C)(=O)C>CO>[CH3:14][N:15]([CH3:19])[C:16]([N:1]1[CH2:5][CH2:4][CH2:3][C@H:2]1[C:6]#[C:7][CH2:8][N:9]1[CH2:13][CH2:12][CH2:11][CH2:10]1)=[O:17]
Reactant: C(#C[C@H]1CCCN1)CN1CCCC1
Reactant: CN(C)C(=O)Cl
Solvent: CC(=O)OC(C)=O
Solvent: CO
Product: CN(C)C(=O)N1CCC[C@H]1C#CCN1CCCC1

Procedure:
This compound was obtained following Example 51, Part A but substituting (S)-1-[3-(2-pyrrolidinyl)-2-propynyl]pyrrolidine for (R)-1-[3-(2-pyrrolidinyl)-2-propynyl]pyrrolidine and dimethyl carbamoyl chloride for acetic anhydride. [α]D -78° (c 1.13, MeOH).
Reaction SMILES: [NH2:1][CH2:2][CH:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[CH:6]=1)[OH:4].O=[C:13]([CH3:28])[CH2:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][C:24](OC)=[O:25])=[CH:18][CH:17]=1.C1C=CC=CC=1.[BH4-].[Na+]>CO>[OH:25][CH2:24][CH2:23][CH2:22][C:19]1[CH:20]=[CH:21][C:16]([O:15][CH2:14][CH:13]([NH:1][CH2:2][CH:3]([C:5]2[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[CH:6]=2)[OH:4])[CH3:28])=[CH:17][CH:18]=1
Reactant: COC(=O)CCc1ccc(OCC(C)=O)cc1
Reactant: NCC(O)c1cccc(Cl)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: CO
Product: CC(COc1ccc(CCCO)cc1)NCC(O)c1cccc(Cl)c1
Yield: 53.8 %

Procedure:
A procedure similar to that described in Example 2 was repeated, except that 4.3 g of 2-amino-1-(3-chlorophenyl)ethanol (prepared as described in Preparation 8), 3.5 g of methyl 3-[4-(2-oxopropoxy)phenyl]propionate (prepared as described in Preparation 5), 150 ml of benzene, 150 ml of absolute methanol and 6.12 g of sodium borohydride were used. A crude product was obtained, and this was purified by column chromatography through silica gel, using a 10:1 by volume mixture of ethyl acetate and ethanol as the eluent, to give 2.9 g of the title compound having an Rf=0.40 (thin layer chromatography over silica gel, using a 10:1 by volume mixture of ethyl acetate and ethanol as the developing solvent).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([O:16][CH3:17])=[O:15])=[CH:10][C:9]=2[OH:18])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:25][O:26][CH2:27][CH2:28]Br>CN(C=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([O:16][CH3:17])=[O:15])=[CH:10][C:9]=2[O:18][CH2:28][CH2:27][O:26][CH3:25])=[CH:6][CH:7]=1
Reactant: COCCBr
Reactant: COC(=O)c1ccc(-c2ccc(F)cc2)c(O)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COCCOc1cc(C(=O)OC)ccc1-c1ccc(F)cc1
Temperature: 80 °C
Yield: 101.5 %

Procedure:
To a suspension of methyl 4′-fluoro-2-hydroxy-1,1′-biphenyl-4-carboxylate (D75) (400 mg, 1.6 mmol) in DMF (10 ml) was added cesium carbonate (1.27 g, 3.9 mmol) and 2-methoxyethylbromide (400 mg, 1.6 mmol) and the reaction was heated at 80° C. overnight. The solvent was evaporated and the residue was dissolved in EtOAc, washed with water and brine, then dried over MgSO4 to give the title compound (494 mg) which was used without further purification in the next step. MS(ES): (M-MeOH)H+ 273.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7](O)=[O:8])=[CH:5][C:4]=1/[CH:12]=[CH:13]/[C:14]1[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=1.[NH2:24][CH2:25][CH:26]([OH:29])[CH2:27][OH:28]>>[OH:29][CH:26]([CH2:27][OH:28])[CH2:25][NH:24][C:7](=[O:8])[C:6]1[CH:10]=[CH:11][C:3]([O:2][CH3:1])=[C:4](/[CH:12]=[CH:13]/[C:14]2[CH:15]=[CH:16][C:17]([C:20]([F:21])([F:22])[F:23])=[CH:18][CH:19]=2)[CH:5]=1
Reactant: NCC(O)CO
Reactant: COc1ccc(C(=O)O)cc1/C=C/c1ccc(C(F)(F)F)cc1
Product: COc1ccc(C(=O)NCC(O)CO)cc1/C=C/c1ccc(C(F)(F)F)cc1

Procedure:
The captioned compound was synthesized from 4-methoxy-3-[(E)-2-(4-trifluoromethylphenyl)vinyl]benzoic acid obtained in step A of Example 2-2-38 and 3-amino-1,2-propanediol in accordance with the same procedure as in the methods described in step C of Example 1-2-3.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH2:11][CH2:12][CH2:13][N:14]1[CH2:20][CH2:19][CH2:18][N:17]([CH3:21])[CH2:16][CH2:15]1)[CH:5]=O.[Cl:22][C:23]1[CH:24]=[C:25]([NH2:31])[C:26]([NH2:30])=[CH:27][C:28]=1[CH3:29]>>[Cl:22][C:23]1[C:28]([CH3:29])=[CH:27][C:26]2[NH:30][C:5]([C:4]3[CH:7]=[CH:8][C:9]([O:10][CH2:11][CH2:12][CH2:13][N:14]4[CH2:20][CH2:19][CH2:18][N:17]([CH3:21])[CH2:16][CH2:15]4)=[C:2]([Cl:1])[CH:3]=3)=[N:31][C:25]=2[CH:24]=1
Reactant: CN1CCCN(CCCOc2ccc(C=O)cc2Cl)CC1
Reactant: Cc1cc(N)c(N)cc1Cl
Product: Cc1cc2[nH]c(-c3ccc(OCCCN4CCCN(C)CC4)c(Cl)c3)nc2cc1Cl
Yield: 7.9 %

Procedure:
This compound was prepared by the method described in Example 1, using 3-chloro-4-[3-(4-methyl-[1,4]diazepan-1-yl)-propoxy]-benzaldehyde (61 mg, 0.20 mmol, 1.0 equiv), 4-chloro-5-methyl-benzene-1,2-diamine (31 mg, 0.20 mmol, 1.0 equiv), and Na2S2O5 (48 mg, 0.25 mmol, 1.3 equiv) in General Procedure 3. Purification by Method 2 afforded 7.1 mg (8%) of the title compound. MS (electrospray): mass calculated for C23H28Cl2N4O, 446.16; m/z found, 447.3 [M+H]+. 1H NMR (400 MHz, CD3OD): 7.96 (d, J=2.2 Hz, 1H), 7.83 (dd, J=8.6, 2.2 Hz, 1H), 7.45 (s, 1H), 7.34 (s, 1H), 7.10 (d, J=8.7 Hz, 1H), 4.08 (t, J=6.0 Hz, 2H), 2.76-2.64 (m, 10H), 2.36 (s, 3H), 2.30 (s, 3H), 1.96-1.88 (m, 2H), 1.80-1.73 (m, 2H).
Reaction SMILES: [O-]S([O-])(=O)=O.[Ca+2].O=P(Cl)(Cl)Cl.[C:12]([OH:24])(=[O:23])[CH2:13][C:14]1[C:15](=[CH:19][CH:20]=[CH:21][CH:22]=1)[C:16]([OH:18])=O.[CH3:25][N:26]([CH:28]=O)[CH3:27]>>[CH3:25][N:26]([CH:28]=[C:13]1[C:14]2[CH:22]=[CH:21][CH:20]=[CH:19][C:15]=2[C:16](=[O:18])[O:24][C:12]1=[O:23])[CH3:27]
Reactant: CN(C)C=O
Reactant: O=C(O)Cc1ccccc1C(=O)O
Agent: O=S(=O)([O-])[O-]
Agent: [Ca+2]
Solvent: O=P(Cl)(Cl)Cl
Product: CN(C)C=C1C(=O)OC(=O)c2ccccc21
Temperature: 25 °C

Procedure:
100 ml of anhydrous DMF in a 1 liter round-bottomed, three necked flask (fitted with a drying tube containing drierite, and a 125 ml dropping funnel) is cooled in an ice-salt bath, and 31 ml of POCl3 is subsequently added over a period of half an hour while stirring the DMF. The 125 ml dropping funnel is replaced with a 150 ml dropping funnel, and a solution of 54 g of homopthalic acid in 100 ml of DMF is added to the flask over a period of one hour at <10° C. The reaction mixture is then stirred at room temperature until a yellow paste was formed, and then poured into ice water. The solid is collected by filtration, washed with water and dried to give 54 g of the title compound as a yellow solid, m.p. 137-40° C.
Reaction SMILES: [C:1]([CH2:3][CH2:4][NH:5][CH2:6][CH2:7][CH2:8][OH:9])#[N:2].[CH:10](O)=[O:11]>>[C:1]([CH2:3][CH2:4][N:5]([CH2:6][CH2:7][CH2:8][OH:9])[CH:10]=[O:11])#[N:2]
Reactant: N#CCCNCCCO
Reactant: O=CO
Product: N#CCCN(C=O)CCCO

Procedure:
A solution of 127.7 g. of 3-(2-cyanoethyl)aminopropanol in 1 liter of 99% formic acid is heated at 85° for 15 hours. The reaction mixture is concentrated under reduced pressure at 80° and the residue is taken up in 60 ml. of methylene chloride-ethyl acetate (1:1). A 1500 g. silica gel G column packed in methylene chloride-ethyl acetate is prepared, and the product is purified by adsorption on silica gel G followed by elution using the 1:1 methylene chloride-ethyl acetate system. Concentration of the combined eluates yields the formate ester of 3-[N-(2-cyanoethyl)-N-formylamino]propanol.
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:13])=[C:4]([CH:10]=[CH:11][CH:12]=1)[C:5]([O:7]CC)=[O:6].C(N(CC)CC)C.[C:21](Cl)(=[O:37])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36]>C(Cl)(Cl)Cl>[C:21]([NH:1][C:2]1[C:3]([CH3:13])=[C:4]([CH:10]=[CH:11][CH:12]=1)[C:5]([OH:7])=[O:6])(=[O:37])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36]
Reactant: CCOC(=O)c1cccc(N)c1C
Reactant: CCCCCCCCCCCCCCCC(=O)Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCCCCC(=O)Nc1cccc(C(=O)O)c1C
Yield: 72 %

Procedure:
A stirred solution of ethyl 3-amino-2-methylbenzoate (17.9 g) in chloroform (150 ml), containing triethylamine (15 ml), was treated with a solution of n-hexadecanoyl chloride (28 g) in chloroform (50 ml), during 30 minutes. The temperature of the reaction mixture was maintained at 0°-10° C. during the addition by ice cooling. The mixture was then refluxed for 90 minutes, washed with water (2×150 ml) and was dried over magnesium sulphate. The solvent was removed in vacuo to give a white solid, which was recrystallised from ethanol. The solid was dissolved in warm ethanol (500 ml) and the solution was treated with sodium hydroxide (10 g) in water (50 ml). The mixture was then refluxed for one hour and was poured onto a mixture of crushed ice and dilute hydrochloric acid (150 ml of strength 2N). The solid was collected and was recrystallised from ethanol (1000 ml) to give 3-(n-hexadecanamido)-2-methylbenzoic acid (28 g), in the form of a white solid, m.p. 163°-165° C.
Reaction SMILES: [Br:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([NH2:9])=[CH:4][C:3]=1[CH3:10].[F:11][CH2:12][CH2:13]OS(C1C=CC(C)=CC=1)(=O)=O.N1C(C)=CC=CC=1C>CC(N(C)C)=O>[Br:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([NH:9][CH2:13][CH2:12][F:11])=[CH:4][C:3]=1[CH3:10]
Reactant: Cc1cc(N)cc(C)c1Br
Reactant: Cc1ccc(S(=O)(=O)OCCF)cc1
Solvent: CC(=O)N(C)C
Solvent: Cc1cccc(C)n1
Product: Cc1cc(NCCF)cc(C)c1Br
Temperature: 120 °C
Reaction time: 4 h
Yield: 53.2 %

Procedure:
A solution of 4-bromo-3,5-dimethyl-phenylamine (400 mg, 2 mmol), toluene-4-sulfonic acid 2-fluoro-ethyl ester (567 mg, 2.6 mmol) and 2,6-lutidine (429 mg, 4.0 mmol) in DMA (5 ml) was heated with stirring at 120° C. for four hours. The mixture was quenched with water and then extracted with ethyl acetate. The organic layer was sequentially washed with water and saturated brine and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate-hexane) to give (4-bromo-3,5-dimethyl-phenyl)-(2-fluoro-ethyl)-amine (262 mg, 53%).
Reaction SMILES: [ClH:1].Cl.[CH:3]1([NH:6][C:7]([C:9]2[C:17]3[CH:16]=[C:15]([C:18]4[C:23](F)=[CH:22][N:21]=[C:20]([NH:25][CH2:26][CH2:27][CH2:28][CH:29]5[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][CH2:30]5)[N:19]=4)[S:14][C:13]=3[CH:12]=[CH:11][CH:10]=2)=[O:8])CC1.CNC(C1C2C=C(C3C([Br:55])=CN=C(NCCCC4CCNCC4)N=3)SC=2C=CC=1)=O>>[ClH:1].[ClH:1].[CH3:3][NH:6][C:7]([C:9]1[C:17]2[CH:16]=[C:15]([C:18]3[C:23]([Br:55])=[CH:22][N:21]=[C:20]([NH:25][CH2:26][CH2:27][CH2:28][CH:29]4[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][CH2:30]4)[N:19]=3)[S:14][C:13]=2[CH:12]=[CH:11][CH:10]=1)=[O:8]
Reactant: CN1CCC(CCCNc2ncc(F)c(-c3cc4c(C(=O)NC5CC5)cccc4s3)n2)CC1
Reactant: CNC(=O)c1cccc2sc(-c3nc(NCCCC4CCNCC4)ncc3Br)cc12
Agent: Cl
Product: CNC(=O)c1cccc2sc(-c3nc(NCCCC4CCN(C)CC4)ncc3Br)cc12

Procedure:
Using the method of 2-{5-fluoro-2-[3-(1-methylpiperidin-4-yl)-propylamino]-pyrimidin-4-yl}-benzo[b]thiophene-4-carboxylic acid cyclopropylamide di-hydrochloride, the title compound is synthesized from 2-[5-bromo-2-(3-piperidin-4-yl-propylamino)-pyrimidin-4-yl]-benzo[b]thiophene-4-carboxylic acid methylamide and isolated as a yellow solid. ES+(m/z) 502 (79Br) and 504 (81Br) [M(free base)+H].