Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3](CC)[C:4]([C:6]1[CH:11]=[C:10]([C:12]2[CH:13]=[N:14][N:15]([CH2:17][CH2:18][CH2:19][OH:20])[CH:16]=2)[CH:9]=[CH:8][C:7]=1[NH:21][C:22]1[C:27]([C:28]([F:31])([F:30])[F:29])=[CH:26][N:25]=[C:24]([NH:32][C:33]2[CH:45]=[CH:44][C:36]([CH2:37][P:38](=[O:43])([OH:42])[O:39][CH2:40][CH3:41])=[CH:35][C:34]=2[O:46][CH3:47])[N:23]=1)=[O:5])[CH3:2].C(NC(C1C=C(C2C=NN(CCCO)C=2)C=CC=1NC1C(C(F)(F)F)=CN=C(NC2C=CC(CP(=O)(OCC)OCC)=CC=2OC)N=1)=O)C>>[CH2:1]([NH:3][C:4]([C:6]1[CH:11]=[C:10]([C:12]2[CH:13]=[N:14][N:15]([CH2:17][CH2:18][CH2:19][OH:20])[CH:16]=2)[CH:9]=[CH:8][C:7]=1[NH:21][C:22]1[C:27]([C:28]([F:31])([F:29])[F:30])=[CH:26][N:25]=[C:24]([NH:32][C:33]2[CH:45]=[CH:44][C:36]([CH2:37][P:38](=[O:42])([OH:43])[O:39][CH2:40][CH3:41])=[CH:35][C:34]=2[O:46][CH3:47])[N:23]=1)=[O:5])[CH3:2]
Reactant: CCOP(=O)(O)Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(-c4cnn(CCCO)c4)cc3C(=O)N(CC)CC)n2)c(OC)c1
Agent: CCNC(=O)c1cc(-c2cnn(CCCO)c2)ccc1Nc1nc(Nc2ccc(CP(=O)(OCC)OCC)cc2OC)ncc1C(F)(F)F
Product: CCNC(=O)c1cc(-c2cnn(CCCO)c2)ccc1Nc1nc(Nc2ccc(CP(=O)(O)OCC)cc2OC)ncc1C(F)(F)F

Procedure:
Prepared analogously to Compound 3A using diethyl (4-{[4-({2-(ethylcarbamoyl)-4-[1-(3-hydroxypropyl)-1H-pyrazol-4-yl]phenyl}amino)-5-(trifluoromethyl)pyrimidin-2-yl]amino}-3-methoxybenzyl)phosphonate (Compound 9B, 570 mg, 808 μmol) to afford the title compound as 349 mg of a white solid (65%). 1H NMR (400 MHz, CD3OD) δ 8.30 (d, J=8.6 Hz, 1H), 8.27 (s, 1H), 8.16 (s, 1H), 7.93 (s, 1H), 7.85 (d, J=8.1 Hz, 1H), 7.82 (d, J=2.0 Hz, 1H), 7.66 (dd, J=2.0, 8.6 Hz, 1H), 7.05 (s, 1H), 6.80 (d, J=8.3 Hz, 1H), 4.31 (t, J=6.8 Hz, 2H), 3.89 (s, 3H), 3.83 (quin, J=6.9 Hz, 2H), 3.58 (t, J=6.1 Hz, 2H), 3.40 (q, J=7.2 Hz, 2H), 2.91-3.01 (m, 2H), 2.10 (quin, J=6.4 Hz, 2H), 1.22 (t, J=7.2 Hz, 3H), 1.12-1.17 (m, 3H). MS (ESI): m/z 678.74 [M+H]+. UPLC: tR=1.07 min (UPLC-SQD: analytical—2 min).
Reaction SMILES: Cl[CH2:2][CH:3]([O:6][C@H:7]1[CH2:12][CH2:11][C@H:10]([C:13]2[N:22]3[C:16]([CH2:17][N:18]([CH3:28])[CH2:19][C:20]4[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:21]=43)=[N:15][N:14]=2)[CH2:9][CH2:8]1)[CH2:4][OH:5].CC(C)([O-])C.[K+]>C1(C)C=CC=CC=1>[Cl:27][C:25]1[CH:24]=[CH:23][C:21]2[N:22]3[C:16]([CH2:17][N:18]([CH3:28])[CH2:19][C:20]=2[CH:26]=1)=[N:15][N:14]=[C:13]3[C@H:10]1[CH2:9][CH2:8][C@H:7]([O:6][CH:3]2[CH2:4][O:5][CH2:2]2)[CH2:12][CH2:11]1
Reactant: CN1Cc2cc(Cl)ccc2-n2c(nnc2[C@H]2CC[C@H](OC(CO)CCl)CC2)C1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: CN1Cc2cc(Cl)ccc2-n2c(nnc2[C@H]2CC[C@H](OC3COC3)CC2)C1
Temperature: 25 °C

Procedure:
To a solution of (RS)-trans-3-chloro-2-[4-(8-chloro-5-methyl-5,6-dihydro-4H-2,3,5,10b-tetraaza-benzo[e]azulen-1-yl)-cyclohexyloxy]-propan-1-ol (0.045 g, 0.11 mmol) in toluene (2 ml) was added potassium tert-butoxide (0.013 g, 0.12 mmol). The reaction mixture was heated at reflux for 2 h. After cooling to room temperature the mixture was partitioned between ethyl acetate and water. The layers were separated. The aqueous layer was extracted with two portions of ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo. Flash-chromatography with n-heptane/2-propanol as eluent gave the title compound (0.10 g, 24%) as white solid. MS m/e: 389 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[F:16])=[O:9])=[CH:6][CH:5]=[C:4]([NH:17][CH:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)[N:3]=1.[CH2:24]([N:26]=[C:27]=[O:28])[CH3:25]>>[CH2:24]([NH:26][C:27]([N:21]1[CH2:20][CH2:19][CH:18]([NH:17][C:4]2[CH:5]=[CH:6][C:7]([C:8](=[O:9])[C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[F:16])=[C:2]([NH2:1])[N:3]=2)[CH2:23][CH2:22]1)=[O:28])[CH3:25]
Reactant: CCN=C=O
Reactant: Nc1nc(NC2CCNCC2)ccc1C(=O)c1ccccc1F
Product: CCNC(=O)N1CCC(Nc2ccc(C(=O)c3ccccc3F)c(N)n2)CC1

Procedure:
The title compound was prepared from [2-Amino-6-(piperidin-4-ylamino)-pyridin-3-yl]-(2-fluoro-phenyl)-methanone (Example 9) and ethyl isocyanate (Aldrich 98%) using the procedure described in Example 12. HRMS, observed: 385.1917, calcd for M+: 385.1914.
Reaction SMILES: [N:1]1(C(OC(C)(C)C)=O)[CH2:6][CH2:5][N:4]([C:7]([O:9][C:10]2[CH:15]=[CH:14][C:13]([CH2:16][C@@H:17]3[C@@H:21]([CH2:22][C:23]4[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[C:25]([O:31][CH3:32])[CH:24]=4)[CH2:20][O:19][C:18]3=[O:33])=[CH:12][C:11]=2[O:34][CH3:35])=[O:8])[CH2:3][CH2:2]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[N:4]1([C:7]([O:9][C:10]2[CH:15]=[CH:14][C:13]([CH2:16][C@@H:17]3[C@@H:21]([CH2:22][C:23]4[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[C:25]([O:31][CH3:32])[CH:24]=4)[CH2:20][O:19][C:18]3=[O:33])=[CH:12][C:11]=2[O:34][CH3:35])=[O:8])[CH2:5][CH2:6][NH:1][CH2:2][CH2:3]1
Reactant: COc1ccc(C[C@H]2COC(=O)[C@@H]2Cc2ccc(OC(=O)N3CCN(C(=O)OC(C)(C)C)CC3)c(OC)c2)cc1OC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc(C[C@H]2COC(=O)[C@@H]2Cc2ccc(OC(=O)N3CCNCC3)c(OC)c2)cc1OC
Temperature: 25 °C
Reaction time: 3 h
Yield: 58.5 %

Procedure:
To a solution of 1-tert-butyl 4-(4-(((3R,4R)-4-(3,4-dimethoxybenzyl)-2-oxotetrahydrofuran-3-yl)methyl)-2-methoxyphenyl) piperazine-1,4-dicarboxylate (155 mg, 0.27 mmol, 1.0 eq) in DCM (5 mL) was added TFA (1 mL). The resulting mixture was stirred at rt for 3 h, concentrated, basified by sat. NaHCO3, and extracted with DCM (30 mL×3). The combined organic layers were dried over MgSO4, filtered and concentrated to afford 4-(((3R,4R)-4-(3,4-dimethoxybenzyl)-2-oxotetrahydrofuran-3-yl)methyl)-2-methoxyphenyl piperazine-1-carboxylate (76.5 mg, 59.5%). LRMS (M+H+) m/z calculated 485.2, found 484.9. 1H NMR (CDCl3, 400 MHz) δ 6.98 (d, 1H), 6.74-6.78 (m, 2H), 6.65-6.68 (m, 1H), 6.51-6.56 (m, 2H), 4.13-4.17 (m, 1H), 3.83-3.90 (m, 1H), 3.85 (s, 3H), 3.83 (s, 3H), 3.77 (s, 3H), 3.53-3.66 (m, 4H), 2.90-2.97 (m, 6H), 2.48-2.69 (m, 4H).
Reaction SMILES: C([NH:4][C:5]1[CH:10]=[CH:9][C:8]([S:11]([CH2:14][C:15]#[CH:16])(=[O:13])=[O:12])=[CH:7][CH:6]=1)(=O)C.[ClH:17]>>[ClH:17].[NH2:4][C:5]1[CH:6]=[CH:7][C:8]([S:11]([CH2:14][C:15]#[CH:16])(=[O:13])=[O:12])=[CH:9][CH:10]=1
Reactant: C#CCS(=O)(=O)c1ccc(NC(C)=O)cc1
Agent: Cl
Product: C#CCS(=O)(=O)c1ccc(N)cc1
Temperature: 10 °C

Procedure:
205 g (0.865 mol) of 4-acetylamino-1-(prop-1-yn-3-ylsulfonyl)benzene were heated at the boil in 1000 ml of 10 % strength by weight hydrochloric acid for about 1.5 hours. After deacetylation had ended (check by TLC), the reaction mixture was clarified and cooled down to about 10° C. The precipitate formed was filtered off with suction, washed with a little 10 % strength by weight hydrochloric acid and dried, leaving 168 g of 4-amino-1-(prop-1-yn-3-ylsulfonyl)benzene hydrochloride (melting point 225°-229° C). ##STR27## 1H-NMR (D6 -DMSO): δ=3.37 (t, 1H, C≡CH), 4.33 (d, 2H, CH2), 6.90-7.65 (4H, aromatic H), 8.5 (3H, NH3 ⊕) ppm. 13C-NMR (D6 -DMSO): δ=47.6 (CH:), 73.4 (C≡C), 77.3 (C≡CH), 14.4, 125.1, 130.1, 151.4 (aromatic C) ppm.
Reaction SMILES: C[Si](C([Si](C)(C)C)C(N)=O)(C)C.C([O:21][C@:22]1([CH2:46][CH:47]=[CH2:48])[C@H:26]([O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C@@H:25]([CH2:35][O:36][CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[O:24][C@@H:23]1OC)(=O)C1C=CC=CC=1.[NH:49]1[CH:56]=[CH:55][C:53](=[O:54])[NH:52][C:50]1=[O:51].[Sn](Cl)(Cl)(Cl)Cl.C([O-])(O)=O.[Na+]>C(#N)C.C(OCC)(=O)C>[CH2:46]([C@@:22]1([OH:21])[C@H:26]([O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C@@H:25]([CH2:35][O:36][CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[O:24][C@H:23]1[N:49]1[CH:56]=[CH:55][C:53](=[O:54])[NH:52][C:50]1=[O:51])[CH:47]=[CH2:48]
Reactant: O=c1cc[nH]c(=O)[nH]1
Reactant: C=CC[C@]1(OC(=O)c2ccccc2)[C@@H](OC)O[C@H](COCc2ccccc2)[C@H]1OCc1ccccc1
Agent: C[Si](C)(C)C(C(N)=O)[Si](C)(C)C
Agent: Cl[Sn](Cl)(Cl)Cl
Agent: O=C([O-])O
Solvent: CC#N
Solvent: CCOC(C)=O
Product: C=CC[C@@]1(O)[C@H](OCc2ccccc2)[C@@H](COCc2ccccc2)O[C@H]1n1ccc(=O)[nH]c1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 87.4 %

Procedure:
Bis(trimethylsilyl)acetamide (BSA; 29.2 mL, 118 mmol) was added to a mixture of 6 (14.0 g, 23.1 mmol) and uracil (5.99 g, 53.4 mmol) in anhydrous acetonitrile (300 mL). The reaction mixture was refluxed for 1 hour and the clear solution was allowed to cool down to room temperature. Tinchloride (11.55 mL, 99 mmol) was added dropwise at room temperature and the mixture was further stirred for 1 hour. The mixture was then stirred at reflux for 1.5 hour and again cooled to room temperature. Ethyl acetate (250 mL) was added, followed by saturated aqueous NaHCO3 (250 mL) and the mixture was stirred for 15 minutes. After filtration through Celite, the organic layer was separated and washed with saturated aqueous NaHCO3 (250 mL). The combined aqueous layer was extracted with ethyl acetate (250 mL) and the combined organic layer was dried (MgSO4), filtered and evaporated to dryness under reduced pressure. The resulting yellow oil was dissolved in methanol and 25% sodium methanolate (25 mL) was added. Stirring continued overnight. More 25% sodium methanolate (15 mL) was added and stirring was continued overnight. Acetic acid (30 mL) was added and the solvent was removed. The residue was purified by column chromatography with heptane/ethyl acetate 50:50 to 100% ethyl acetate. Intermediate 7 (9.38 g, 76%) was obtained as a colorless oil. HPLC Condition A, Rt: 2.49 min, m/z=465 (M+H)+. 1H NMR (400 MHz, CDCl3) δ ppm 8.39 (1H, NH), 7.75 (d, 1H, J=8.0 Hz), 7.22-7.43 (m, 10H), 6.05 (s, 1H), 5.71-5.84 (m, 1H), 5.35 (d, 1H, J=8.0 Hz), 5.00-5.11 (m, 2H), 4.70 (d, 1H, J=11.5 Hz), 4.53 (d, 1H, J=11.5 Hz), 4.47 (d, 1H, J=11.1 Hz), 4.47 (d, 1H, J=11.1 Hz), 4.11-4.16 (m, 1H), 4.04 (d, 1H, J=8.0 Hz), 3.81-3.87 (m, 1H), 3.45-3.52 (m, 1H), 3.17 (bs, OH), 2.15-2.33 (m, 2H).
Reaction SMILES: [CH3:1][C:2]([CH2:4][C@@H:5]([C@@H:7]([CH2:9]OS(C1C=CC(C)=CC=1)(=O)=O)[OH:8])[OH:6])=[O:3].[N-:21]=[N+:22]=[N-:23].[Na+]>CN(C=O)C>[CH3:1][C:2]([CH2:4][C@@H:5]([C@@H:7]([CH2:9][N:21]=[N+:22]=[N-:23])[OH:8])[OH:6])=[O:3]
Reactant: CC(=O)C[C@H](O)[C@H](O)COS(=O)(=O)c1ccc(C)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)C[C@H](O)[C@H](O)CN=[N+]=[N-]
Temperature: 25 °C
Yield: 79.6 %

Procedure:
To a solution of methyl-2-deoxy-5-O-tosyl-D-ribose (13.6 g, 45 mmol) in DMF (250 mL) was added sodium azide (4.4 g, 67 mmol). The mixture was refluxed for 4 hours, cooled to room temperature, quenched with ice water (1.5 mL), and extracted with ethyl-acetate. The extract was washed with water, dried, and concentrated to give an oil (6.2 g, 86% yield). NMR
Reaction SMILES: [CH3:1][N:2]([CH3:32])[C:3]1[C:27]([C:28]([F:31])([F:30])[F:29])=[CH:26][C:6]2[NH:7][C:8](=[O:25])[CH2:9][C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([C:18]4[O:22][N:21]=[C:20]([CH2:23]O)[CH:19]=4)[CH:13]=3)=[N:11][C:5]=2[CH:4]=1.O=S(Cl)Cl.[NH:37]([CH3:39])[CH3:38]>>[CH3:1][N:2]([CH3:32])[C:3]1[C:27]([C:28]([F:31])([F:29])[F:30])=[CH:26][C:6]2[NH:7][C:8](=[O:25])[CH2:9][C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([C:18]4[O:22][N:21]=[C:20]([CH2:23][N:37]([CH3:39])[CH3:38])[CH:19]=4)[CH:13]=3)=[N:11][C:5]=2[CH:4]=1
Reactant: CN(C)c1cc2c(cc1C(F)(F)F)NC(=O)CC(c1cccc(-c3cc(CO)no3)c1)=N2
Reactant: CNC
Solvent: O=S(Cl)Cl
Product: CN(C)Cc1cc(-c2cccc(C3=Nc4cc(N(C)C)c(C(F)(F)F)cc4NC(=O)C3)c2)on1

Procedure:
The title compound was prepared from 7-dimethylamino-4-[3-(3-hydroxymethyl-isoxazol-5-yl)-phenyl]-8-trifluoromethyl-1,3-dihydro-benzo[b][1,4]diazepin-2-one (Example 46) (53 mg, 0.12 mmol) by treatment with SOCl2 (3 eq.) and 40% aqueous Me2NH-sol. (10 eq.) as described in Example 45. Obtained as a light yellow solid (21 mg).
Reaction SMILES: [Br:1]Br.[CH3:3][CH:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][C:6](=[O:14])[CH2:5]1>C(O)(=O)C>[Br:1][C:11]1[CH:12]=[C:13]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:14])[CH2:5][CH:4]2[CH3:3]
Reactant: BrBr
Reactant: CC1CC(=O)Nc2ccccc21
Solvent: CC(=O)O
Product: CC1CC(=O)Nc2ccc(Br)cc21
Reaction time: 2 h

Procedure:
A solution of bromine (0.08 cm3) in acetic acid (1 cm3) was added at room temperature to a stirred solution of 4-methyl-3,4-dihydro-2-(1H)-quinolone (0.5 g) in acetic acid (4.0 cm3). After 2 hours, volatile material was removed in vacuo, the residue was partitioned between chloroform (50 cm3) and water (20 cm3), and the organic phase was further extracted with chloroform (2×20 cm3). The combined and dried (MgSO4) organic extracts were evaporated in vacuo and the solid residue was recrystallised from ethyl acetate to afford 6-bromo-4-methyl-3,4-dihydro-2-(1H)-quinolone, m.p. 190°, (0.35 g).
Reaction SMILES: Cl.[NH2:2][C@@H:3]([CH2:15][O:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23]#[N:24])[CH:18]=1)[CH2:4][C:5]([O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:6].ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.C(N(CC)CC)C.[N:54]1([C:59]([C:61]2[CH:69]=[CH:68][C:64]([C:65](O)=[O:66])=[CH:63][CH:62]=2)=[O:60])[CH2:58][CH2:57][CH2:56][CH2:55]1>ClCCl>[C:23]([C:19]1[CH:18]=[C:17]([CH:22]=[CH:21][CH:20]=1)[O:16][CH2:15][C@H:3]([NH:2][C:65](=[O:66])[C:64]1[CH:63]=[CH:62][C:61]([C:59]([N:54]2[CH2:58][CH2:57][CH2:56][CH2:55]2)=[O:60])=[CH:69][CH:68]=1)[CH2:4][C:5]([O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:6])#[N:24]
Reactant: O=C(O)c1ccc(C(=O)N2CCCC2)cc1
Reactant: N#Cc1cccc(OC[C@H](N)CC(=O)OCc2ccccc2)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: N#Cc1cccc(OC[C@@H](CC(=O)OCc2ccccc2)NC(=O)c2ccc(C(=O)N3CCCC3)cc2)c1

Procedure:
1.8 g (5.2 mmol) of benzyl (3R)-3-amino-4-(3-cyanophenoxy)butyrate hydrochloride (the compound in step 2 in Example 52), 703 mg (5.2 mmol) of 1-hydroxybenzotriazole (hydrate), 997 mg (5.2 mmol) of 1-(3-dimethylaminopropyl)-3-ethyl carbodiimide hydrochloride, 526 mg (5.2 mmol) of triethylamine, and 1.14 g (5.2 mmol) of 4-(1-pyrrolidyl carbonyl)benzoic acid were stirred in dichloromethane overnight. The reaction solution was washed with 1 N hydrochloric acid, 1 N aqueous sodium hydroxide and saturated saline and dried over sulfate magnesium anhydride, and the solvent was distilled off. The resulting residue was purified by silica gel chromatography (ethyl acetate) to obtain the title compound.
Reaction SMILES: [CH:1]1([CH2:6][CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([S:15]([O-:18])(=O)=[O:16])=[CH:11][CH:10]=2)[CH2:5]CC[CH2:2]1.[Na+].S(Cl)([Cl:22])=O>CN(C)C=O>[CH3:2][CH:1]([CH3:5])[CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([S:15]([Cl:22])(=[O:18])=[O:16])=[CH:11][CH:10]=1
Reactant: O=S(=O)([O-])c1ccc(OCCC2CCCC2)cc1
Reactant: O=S(Cl)Cl
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)CCOc1ccc(S(=O)(=O)Cl)cc1

Procedure:
A mixture of sodium 4-(2-cyclopentylethoxy)-benzenesulfonate (2.5 grams, 8.6 mmole), thionyl chloride (15 mL), and a few drops of N,N-dimethylformamide was heated at reflux for 5 hours. After cooling, the excess thionyl chloride was evaporated and the residue was taken up in ethyl acetate. The solution was cooled in an ice bath and water was added. The organic phase was separated and washed with water and brine. After drying over sodium sulfate, the solvent was evaporated to afford the title compound as an oil, 2.24 grams (90%).
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([CH:24]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:26]=1)[C:5]([N:7]([C:9]1[CH:10]=[N:11][CH:12]=[CH:13][C:14]=1[C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=1[O:22][CH3:23])[CH3:8])=[O:6].[CH2:31]1[C:34]2([CH2:37][N:36]([S:38](C3C=C(C=C(C(F)(F)F)C=3)C(O)=O)(=[O:40])=[O:39])[CH2:35]2)[CH2:33][O:32]1>>[F:21][C:18]1[CH:19]=[CH:20][C:15]([C:14]2[CH:13]=[CH:12][N:11]=[CH:10][C:9]=2[N:7]([CH3:8])[C:5](=[O:6])[C:4]2[CH:24]=[C:25]([C:27]([F:30])([F:28])[F:29])[CH:26]=[C:2]([S:38]([N:36]3[CH2:37][C:34]4([CH2:31][O:32][CH2:33]4)[CH2:35]3)(=[O:40])=[O:39])[CH:3]=2)=[C:16]([O:22][CH3:23])[CH:17]=1
Reactant: O=C(O)c1cc(C(F)(F)F)cc(S(=O)(=O)N2CC3(COC3)C2)c1
Reactant: COc1cc(F)ccc1-c1ccncc1N(C)C(=O)c1cc(F)cc(C(F)(F)F)c1
Product: COc1cc(F)ccc1-c1ccncc1N(C)C(=O)c1cc(C(F)(F)F)cc(S(=O)(=O)N2CC3(COC3)C2)c1

Procedure:
The title compound was prepared in analogy to example 90, from [4-(4-fluoro-2-methoxy-phenyl)-pyridin-3-yl]-methyl-amine (example 129, intermediate) and 3-(2-oxa-6-azaspiro[3.3]heptan-6-ylsulfonyl)-5-(trifluoromethyl)benzoic acid after a reaction time of 90 hours at room temperature. The compound was purified by silica gel chromatography on a 20 g column using an MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of n-heptane:EtOAc (100:0 to 0:100). Colorless solid (61%). MS (ESI): m/z=566.136 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][C:10](=[O:30])[N:11]([CH2:13][C:14]([NH:16][C:17]([CH3:29])([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=3)[CH3:18])=[O:15])[CH:12]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[F:37][C:38]([F:43])([F:42])[CH:39]1[O:41][CH2:40]1>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C=O)C.C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH2:40][CH:39]([OH:41])[C:38]([F:43])([F:42])[F:37])[C:10](=[O:30])[N:11]([CH2:13][C:14]([NH:16][C:17]([CH3:18])([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:27])([F:26])[F:28])[CH:20]=3)[CH3:29])=[O:15])[CH:12]=2)=[CH:4][CH:3]=1
Reactant: FC(F)(F)C1CO1
Reactant: CC(C)(NC(=O)Cn1cc(-c2ccc(Cl)cc2)[nH]c1=O)c1cccc(C(F)(F)F)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [Br-]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(NC(=O)Cn1cc(-c2ccc(Cl)cc2)n(CC(O)C(F)(F)F)c1=O)c1cccc(C(F)(F)F)c1
Temperature: 130 °C
Reaction time: 1 h

Procedure:
174 mg (0.397 mmol) of 2-[4-(4-chlorophenyl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl]-N-{1-methyl-1-[3-(trifluoromethyl)phenyl]ethyl}-acetamide from Example 234A, 12.8 mg (0.04 mmol) of tetra-n-butylammonium bromide and 37.5 mg (0.199 mmol) of potassium carbonate are placed in 0.45 ml of DMF and treated with 49.0 mg (0.437 mmol) of 1,1,1-trifluoro-2,3-epoxypropane. This is stirred for 1 hr at 130° C. The suspension is diluted with 5 ml of ethyl acetate and washed twice with 5 ml of water each time. The organic phase is dried over sodium sulphate and filtered. After evaporation the crude product is purified by preparative HPLC [Method 10]. 48 mg (22% of theory) of the target compound are obtained.
Reaction SMILES: CO[C:3](=[O:23])[C:4]1[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][C:5]=1[NH:11][C:12](=[O:22])[CH2:13][C:14]1[CH:19]=[C:18]([CH3:20])[CH:17]=[C:16]([CH3:21])[CH:15]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+]>O1CCCC1>[Cl:10][C:7]1[CH:6]=[C:5]2[C:4]([C:3]([OH:23])=[C:13]([C:14]3[CH:15]=[C:16]([CH3:21])[CH:17]=[C:18]([CH3:20])[CH:19]=3)[C:12](=[O:22])[NH:11]2)=[CH:9][CH:8]=1
Reactant: COC(=O)c1ccc(Cl)cc1NC(=O)Cc1cc(C)cc(C)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1cc(C)cc(-c2c(O)c3ccc(Cl)cc3[nH]c2=O)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 83.5 %

Procedure:
To a solution of 4-chloro-2-[2-(3,5-dimethylphenyl)-acetylamino]-benzoic acid methyl ester (3.05 g in 20 mL dry tetrahydrofuran) at 0° C. was added dropwise a solution of sodium bis(trimethylsilyl)amide (20 mL of a 1.0M solution in tetrahydrofuran) and the mixture warmed to room temperature. After 2 hours, the reaction was cooled to 0° C. and quenched by the addition of 100 mL iced 6N hydrochloric acid. The slurry was stirred for 15 minutes then filtered and washed (2×) with ice cold acetonitrile. The residue was dried in vacuo overnight to give the title compound (2.3 g).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([OH:11])=[CH:8][CH:9]=2)[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[C:3]1[CH3:18].[Na].[H-].[Na+].[CH2:22]([O:24][C:25](=[O:30])[C:26](Br)([CH3:28])[CH3:27])[CH3:23]>CN(C)C=O>[CH2:22]([O:24][C:25](=[O:30])[C:26]([CH3:28])([O:11][C:7]1[CH:6]=[C:5]2[C:10](=[CH:9][CH:8]=1)[N:2]([CH3:1])[C:3]([CH3:18])=[C:4]2[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)[CH3:27])[CH3:23]
Reactant: CCOC(=O)C(C)(C)Br
Reactant: Cc1c(-c2ccccc2)c2cc(O)ccc2n1C
Agent: [H-]
Agent: [Na+]
Agent: [Na]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)(C)Oc1ccc2c(c1)c(-c1ccccc1)c(C)n2C

Procedure:
One gram (42 m mole) of 1,2-dimethyl-3-phenyl-1H-indole-5-ol was converted to the sodium salt in 10 of absolute dimethylformamide in the presence of 223 mg (5 m mole) of 55% sodium hydride immersion in oil, and the sodium salt was mixed at room temperature with 990 mg (5 m mole) of 2-bromo-2-methyl-propanoic acid ethylester. After a reaction time of six hours, the solvent was distilled off in vacuo and the reaction product was purified by chromatography on a silicagel column (eluant: toluene/ethyl acetate (9:1)). The evaporation residue of the combined fractions, which contained the purified ester, was treated with petroleum ether.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH2:10][N:11]([CH3:13])[CH3:12])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[Cl:14][C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[NH:20][C:19](=[O:24])[C:18]2=[O:25]>>[Cl:14][C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[NH:20][C:19](=[O:24])[C:18]2([C:2]1[CH:3]=[C:4]([CH2:10][N:11]([CH3:13])[CH3:12])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9])[OH:25]
Reactant: O=C1Nc2ccc(Cl)cc2C1=O
Reactant: COc1ccc(CN(C)C)cc1Br
Product: COc1ccc(CN(C)C)cc1C1(O)C(=O)Nc2ccc(Cl)cc21
Yield: 26.9 %

Procedure:
With 2.00 g of the compound obtained in Step 195-1 and 1.24 g of 5-chloroisatin as starting material, 637 mg of the title compound (pale red solid) was obtained by a similar method to Step 21-1.
Reaction SMILES: C([N-:3][CH:4]=O)=O.[Na+].C(#N)C.ClC/[C:12](=[CH:22]/[F:23])/[CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=1.[Cl-].[Na+]>C1(C)C=CC=CC=1.O.CN(C)C=O>[NH2:3][CH2:4]/[C:12](=[CH:22]/[F:23])/[CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=1
Reactant: F/C=C(/CCl)CCc1ccc(F)cc1
Reactant: O=C[N-]C=O
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CC#N
Product: NC/C(=C/F)CCc1ccc(F)cc1
Temperature: 80 °C
Reaction time: 6 h

Procedure:
Combine sodium diformylamide (70 lb) and acetonitrile (903 lb). With agitation, add N,N-dimethylformamide (119 lb). Add a solution of (E)-1-chloro-2-(fluoromethylene)-4-(p-fluorophenyl)butane (126 lb) in toluene. Warm to 80° C. After 6 hours, add a 10% by weight solution of sodium chloride in water (1168 lb). Agitate for 15 minutes, separate the layers. Remove the organic layer to give the title compound as a solution in acetonitrile/N,N-dimethylformamide.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([Cl:12])[CH:9]=[CH:8][C:3]=1[O:4][CH2:5][CH2:6][NH2:7].[CH3:13][O:14][C:15](=[O:38])[CH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[O:27][N:26]=[C:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:24]=2[C:34](Cl)=[O:35])=[C:19]([Cl:37])[CH:18]=1.O>C1(C)C=CC=CC=1>[CH3:13][O:14][C:15](=[O:38])[CH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[O:27][N:26]=[C:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:24]=2[C:34](=[O:35])[NH:7][CH2:6][CH2:5][O:4][C:3]2[CH:8]=[CH:9][C:10]([Cl:12])=[CH:11][C:2]=2[Cl:1])=[C:19]([Cl:37])[CH:18]=1
Reactant: COC(=O)Cc1ccc(-c2onc(-c3ccccc3)c2C(=O)Cl)c(Cl)c1
Reactant: NCCOc1ccc(Cl)cc1Cl
Solvent: Cc1ccccc1
Solvent: O
Product: COC(=O)Cc1ccc(-c2onc(-c3ccccc3)c2C(=O)NCCOc2ccc(Cl)cc2Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 2-(2,4-Dichloro-phenoxy)-ethylamine 29 (19 mg, 0.09 mmol) in toluene (0.2 mL) is cooled to 0° C. The above solution of intermediate 61 (0.06 mmol) is added and the solution is warmed to room temperature. After stirring at room temperature for 1 hour the mixture is poured into H2O and extracted three times with DCM. The organic layers are combined, dried (MgSO4), filtered, and concentrated to afford crude (3-Chloro-4-{4-[2-(2,4-dichloro-phenoxy)-ethyl-carbamoyl]-3-phenyl-isoxazol-5-yl}-phenyl)-acetic acid methyl ester 62.
Reaction SMILES: [C:1](Cl)(=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].[NH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19](=[O:26])[CH2:20][CH2:21][C:22]([O:24]C)=[O:23])=[CH:15][CH:14]=1>>[C:1]([NH:12][C:13]1[CH:14]=[CH:15][C:16]([C:19](=[O:26])[CH2:20][CH2:21][C:22]([OH:24])=[O:23])=[CH:17][CH:18]=1)(=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: COC(=O)CCC(=O)c1ccc(N)cc1
Reactant: CCCCCCCCC(=O)Cl
Product: CCCCCCCCC(=O)Nc1ccc(C(=O)CCC(=O)O)cc1
Yield: 66 %

Procedure:
In a manner similar to that described in Example 3, nonanoyl chloride (0.055 g, 0.00031 mol) was allowed to react with 4-(4-amino-phenyl)-4-oxo-butyric acid, methyl ester (0.052 g, 0.00025 mol), and the resulting intermediate was hydrolyzed to give 0.055 g of 4-[4-(nonanoylamino)-phenyl]-4-oxo-butyric acid as an off-white solid; MS-(AP+) MH+334.