Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([NH:4][C:5]1[CH:22]=[CH:21][CH:20]=[CH:19][C:6]=1[CH2:7][C:8]1[S:9][CH:10]=[C:11]([C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)[N:12]=1)(=O)C.[OH-].[Na+]>Cl.C(O)C.O.C(Cl)Cl>[NH2:4][C:5]1[CH:22]=[CH:21][CH:20]=[CH:19][C:6]=1[CH2:7][C:8]1[S:9][CH:10]=[C:11]([C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)[N:12]=1
Reactant: CC(=O)Nc1ccccc1Cc1nc(-c2ccncc2)cs1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Solvent: ClCCl
Product: Nc1ccccc1Cc1nc(-c2ccncc2)cs1
Yield: 69.5 %

Procedure:
A solution of 2-(o-acetamidobenzyl)-4-(4-pyridyl)thiazole (2.30 g, 0.007 mol) in concentrated hydrochloric acid (2 mL) and ethanol (3 mL) was refluxed for 3 hours, allowed to cool, diluted with water (2 mL) and methylene chloride (5 mL), and basified with 2.5N sodium hydroxide. The layers were separated and the aqueous layer reextracted with chloroform (2×). The combined organic extracts were dried over potassium carbonate, concentrated, and chromatographed through a short column of silica gel to afford 2-(o-aminobenzyl)-4-(4-pyridyl)thiazole (1.30 g, 65%). mp. 179°-181° C. dec.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:27]3[CH:26]=[CH:25][C:24]([C:28]4[NH:32][N:31]=[N:30][N:29]=4)=[CH:23][C:22]=3[O:21][C:20]3[C:15]2=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH2:10][CH2:9]1)=O)(C)(C)C.Cl>CN(C=O)C>[NH:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:27]3[CH:26]=[CH:25][C:24]([C:28]4[NH:32][N:31]=[N:30][N:29]=4)=[CH:23][C:22]=3[O:21][C:20]3[C:15]2=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH2:10][CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCC(N2c3ccccc3Oc3cc(-c4nnn[nH]4)ccc32)CC1
Agent: Cl
Solvent: CN(C)C=O
Product: c1ccc2c(c1)Oc1cc(-c3nnn[nH]3)ccc1N2C1CCNCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 44 %

Procedure:
To a solution of 4-[3-(1H-tetrazol-5-yl)-phenoxazin-10-yl]-piperidine-1-carboxylic acid tert-butyl ester, 5a (0.265 g, 0.61 mmol) in DMF (2 mL) was added a 4N hydrochloric acid solution (4 mL). The mixture was stirred for 2 h at rt. Another 4 mL of the 4N HCl solution was added, and the mixture was stirred for 16 h at rt. The solvent was removed via evaporation, and the residue was purified via reverse phase chromatography (eluent gradient: 10 to 40% acetonitrile in water containing 0.1% TFA) to yield 0.12 g (44%) of 10-piperidin-4-yl-3-(1H-tetrazol-5-yl)-10H-phenoxazine, 6a as a TFA salt. MS m/z (MH+) 335.0.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]([CH3:10])[CH3:9])[CH:5]=[C:4]([O:11][CH3:12])[N:3]=1.[Cl:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[S:20]([N:23]=[C:24]=[O:25])(=[O:22])=[O:21]>C(#N)C>[Cl:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[S:20]([NH:23][C:24]([NH:1][C:2]1[N:7]=[C:6]([N:8]([CH3:9])[CH3:10])[CH:5]=[C:4]([O:11][CH3:12])[N:3]=1)=[O:25])(=[O:22])=[O:21]
Reactant: O=C=NS(=O)(=O)c1ccccc1Cl
Reactant: COc1cc(N(C)C)nc(N)n1
Solvent: CC#N
Product: COc1cc(N(C)C)nc(NC(=O)NS(=O)(=O)c2ccccc2Cl)n1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To 700 ml of acetonitrile containing 25 g of 2-amino-4-dimethylamino-6-methoxypyrimidine at ambient temperature was added dropwise 32.5 g of 2-chlorobenzenesulfonylisocyanate. The mixture was warmed to 40° and then allowed to stir for five hours at ambient temperature. The solid product named above was isolated by filtration and washed with a small amount of cold ethyl ether. It melted at 224°-226°.
Reaction SMILES: FC(F)(F)S(O)(=O)=O.ClC(Cl)C.[F:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH:20]=[C:21]([CH3:23])[CH3:22].[N:24]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:27]=[C:26]([C:34]#[N:35])[CH:25]=1>O>[F:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:15]=1[CH2:20][C:21]([CH3:23])([CH3:22])[N:35]=[C:34]2[C:26]1[CH:25]=[N:24][C:33]2[C:28]([CH:27]=1)=[CH:29][CH:30]=[CH:31][CH:32]=2
Reactant: N#Cc1cnc2ccccc2c1
Reactant: CC(C)=Cc1ccccc1F
Agent: O=S(=O)(O)C(F)(F)F
Solvent: CC(Cl)Cl
Solvent: O
Product: CC1(C)Cc2c(F)cccc2C(c2cnc3ccccc3c2)=N1
Temperature: 25 °C
Reaction time: 18 h
Yield: 47 %

Procedure:
Trifluoromethane sulfonic acid (0.52 mL) were added while cooling with ice to a dichloroethane (0.58 mL) solution of an about 4:7 mixture of 1-fluoro-(2-methylpropen-1-yl)benzene and 1-fluoro-(2-methylpropen-2-yl)benzene (87.3 mg, 0.58 mmol) and quinoline-3-carbonitrile (89.6 mg, 0.58 mmol), and after stirring for 18 hours at room temperature, the solution was poured into water followed by extraction with ethyl acetate and applying the resulting residue to chromatography to obtain 82.2 mg of the target compound (yield: 47%).
Reaction SMILES: C[O:2][C:3](=[O:35])[CH2:4][CH2:5][CH2:6][NH:7][CH2:8][C:9](=[O:34])[CH2:10][CH2:11][N:12]1[CH2:17][CH2:16][CH:15]([O:18][C:19](=[O:33])[NH:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:14][CH2:13]1.[OH-].[Na+].Cl>C1COCC1>[C:22]1([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=1[NH:20][C:19]([O:18][CH:15]1[CH2:14][CH2:13][N:12]([CH2:11][CH2:10][C:9]([CH2:8][NH:7][CH2:6][CH2:5][CH2:4][C:3]([OH:35])=[O:2])=[O:34])[CH2:17][CH2:16]1)=[O:33]
Reactant: COC(=O)CCCNCC(=O)CCN1CCC(OC(=O)Nc2ccccc2-c2ccccc2)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)CCCNCC(=O)CCN1CCC(OC(=O)Nc2ccccc2-c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 4-({3-[4-(biphenyl-2-ylcarbamoyloxy)piperidin-1-yl]-propionyl}methylamino)butyric acid methyl ester (1.00 g, 2.08 mmol) in THF (10 mL) was added dropwise aqueous sodium hydroxide (1.0 M, 10.4 mL, 10.4 mmol) and the reaction mixture was stirred overnight at room temperature. LC-MS (Method 10-90) showed product was present (Rt 3.34 min; m/z 468.2 [M+H]+). The pH of the mixture was adjusted to pH 5 with aqueous hydrochloric acid (6 M) and the mixture was concentrated under reduced pressure. Aqueous ammonium chloride solution was added to the residue and this mixture was washed with EtOAc. The pH of the aqueous layer was adjusted to pH 4 with phosphate buffer solution and the aqueous layer was then extracted with a 1:3 mixture of isopropyl acetate/chloroform (4×). The combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure to give the title compound as a colorless oil, which was used without further purification.
Reaction SMILES: [SH:1][C@@H:2]1[CH2:6][N:5](C(OCC2C=CC([N+]([O-])=O)=CC=2)=O)[C@H:4]([C:20]([NH:22][C:23]2[CH:24]=[C:25]([CH:29]=[CH:30][CH:31]=2)[C:26]([OH:28])=[O:27])=[O:21])[CH2:3]1.[OH:32][C@@H:33]([C@H:35]1[C:72](=[O:73])[N:37]2[C:38]([C:59]([O:61]CC3C=CC([N+]([O-])=O)=CC=3)=[O:60])=[C:39](OP(OC3C=CC=CC=3)(OC3C=CC=CC=3)=O)[C@H:40]([CH3:41])[C@H:36]12)[CH3:34].C(N(CC)C(C)C)(C)C.O>CN(C=O)C.C(OCC)(=O)C>[CH3:41][C@H:40]1[C:39]([S:1][C@@H:2]2[CH2:6][NH:5][C@H:4]([C:20]([NH:22][C:23]3[CH:31]=[CH:30][CH:29]=[C:25]([C:26]([OH:28])=[O:27])[CH:24]=3)=[O:21])[CH2:3]2)=[C:38]([C:59]([OH:61])=[O:60])[N:37]2[C@H:36]1[C@@H:35]([C@H:33]([OH:32])[CH3:34])[C:72]2=[O:73]
Reactant: O=C(O)c1cccc(NC(=O)[C@@H]2C[C@H](S)CN2C(=O)OCc2ccc([N+](=O)[O-])cc2)c1
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(OP(=O)(Oc3ccccc3)Oc3ccccc3)[C@H](C)[C@H]12
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)O)=C(S[C@@H]3CN[C@H](C(=O)Nc4cccc(C(=O)O)c4)C3)[C@H](C)[C@H]12

Procedure:
To 3-[[[(2S,4S)-4-mercapto-1-(4-nitrobenzyloxy)carbonyl-2-pyrrolidinyl]carbonyl]amino]benzoic acid (7.68 g) in DMF (30 mL), p-nitrobenzyl (1R,5R,6S)-6-[(1R)-1-hydroxyethyl]-2-[(diphenylphosphono)oxy]-1-methylcarbapen-2em-3-carboxylate (10 g) was added. To the reaction mixture N,N-diisopropylethylamine (4.78 g) was added at −30° C. and stirred. After completion of reaction, the reaction mass was poured into water and ethyl acetate mixture at 10° C. The layers were separated and organic layer washed with brine solution. The organic layer was subjected to carbon treatment and taken for subsequent step.
Reaction SMILES: [CH2:1]([N:3]([CH2:39][CH3:40])[C:4]([C@@H:6]1[C@H:11]2[CH2:12][CH2:13][N:8]([C@@H:9]([CH:26]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C@H:10]2[NH:14][CH2:15][C:16]2[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[CH:18][C:17]=2[O:24][CH3:25])[CH2:7]1)=[O:5])[CH3:2]>CO[Na].CO>[CH2:39]([N:3]([CH2:1][CH3:2])[C:4]([C@@H:6]1[C@@H:11]2[CH2:12][CH2:13][N:8]([C@H:9]([CH:26]([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)[C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=3)[C@@H:10]2[NH:14][CH2:15][C:16]2[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[CH:18][C:17]=2[O:24][CH3:25])[CH2:7]1)=[O:5])[CH3:40]
Reactant: CCN(CC)C(=O)[C@H]1CN2CC[C@H]1[C@H](NCc1cc(OC)ccc1OC)[C@@H]2C(c1ccccc1)c1ccccc1
Agent: CO[Na]
Solvent: CO
Product: CCN(CC)C(=O)[C@H]1CN2CC[C@@H]1[C@@H](NCc1cc(OC)ccc1OC)[C@H]2C(c1ccccc1)c1ccccc1
Yield: 86 %

Procedure:
A mixture of 17 (506 mg, 0.93 mmole) and 20%-MeONa/MeOH (140 ml) was heated at reflux under a nitrogen atmosphere for 3 hours. After cooling the reaction mixture, the resulting white suspension was poured into crushed ice and extracted with CH2Cl2 (80 ml×3). The combined organic layers were washed with brine, dried over MgSO4, and concentrated down. The resulting crude solid was purified with silica-gel chromatography (CH2Cl2 :MeOH=10:1) to give 19 (0.46 g, 0.8 mmole, 92%).
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][NH:6][C@H:5]([CH3:8])[CH2:4][N:3]1[C@H:9]([C:18]1[CH:30]=[CH:29][C:21]([C:22]([N:24]([CH2:27][CH3:28])[CH2:25][CH3:26])=[O:23])=[CH:20][CH:19]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH3:17])[CH:11]=1.[F:31][C:32]1[CH:39]=[CH:38][CH:37]=[CH:36][C:33]=1[CH2:34]Br.[I-].[Na+].C(N(CC)CC)C.C(=O)([O-])[O-].[Na+].[Na+].O>>[CH3:1][C@H:2]1[CH2:7][N:6]([CH2:34][C:33]2[CH:36]=[CH:37][CH:38]=[CH:39][C:32]=2[F:31])[C@H:5]([CH3:8])[CH2:4][N:3]1[C@H:9]([C:18]1[CH:19]=[CH:20][C:21]([C:22]([N:24]([CH2:25][CH3:26])[CH2:27][CH3:28])=[O:23])=[CH:29][CH:30]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH3:17])[CH:11]=1
Reactant: CCN(CC)C(=O)c1ccc([C@H](c2cccc(OC)c2)N2C[C@@H](C)NC[C@@H]2C)cc1
Reactant: Fc1ccccc1CBr
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CCN(CC)CC
Product: CCN(CC)C(=O)c1ccc([C@H](c2cccc(OC)c2)N2C[C@@H](C)N(Cc3ccccc3F)C[C@@H]2C)cc1
Yield: 96.2 %

Procedure:
By a procedure essentially identical to that of Example 3, the title compound was prepared from 1.23 g (3.00 mmol) of 4-((alpha-R)-alpha-((2S,5R)-2,5-dimethyl-1-piperazinyl)-3-methoxybenzyl)-N,N-diethylbenzamide, 2-fluorobenzyl bromide (724 μL, 6.0 mmol), sodium iodide (45 mg, 0.30 mmol), and triethylamine (1.51 mL, 10.8 mmol). The crude product was slurried with 1:1 saturated sodium carbonate/water for several hours with manual crushing of suspended solids. Crystalline product was collected by filtration, washed with water and dried to give 1.494 g of 4-((alpha-R)-alpha-((2S,5R)-2,5-dimethyl-4-(2-fluorobenzyl)-1-piperazinyl)-3-methoxybenzyl)-N,N-diethylbenzamide as a white solid. Calc. for C32H40FN3O2 0.1 H2O: C, 73.99; H, 7.80; N, 8.09; F, 3.66. Found C, 73.98; H, 7.86; N, 8.00; F, 3.77. 1H NMR (CDCl3, 300 MHz); δ 1.09 (d, J˜7 Hz, 3H); 1.11 (d, J˜7 Hz, 3H); 1.945 (apparent t, J˜9 Hz, 1H); 2.07 (apparent t, J˜9 Hz, 1H); 2.59 (m, 2H); 2.63 (d, J˜11 Hz, 1H); 2.73 (d, J˜11 Hz, 1H); 3.28 (brd m, 2H); 3.33 (half of ABq, J˜14 Hz, 1H); 3.54 (brd m, 2H); 3.78 (s, 3H); 3.88 (half of ABq, J˜14 Hz, 1H); 5.14 (s, 1H); 6.74 (s, 1H); 6.80 (m, 2H); 7.00 (t, J˜8 Hz, 1H); 7.07 (t, J˜7 Hz, 1H); 7.22 (m, 2H); 7.29 (half of ABq, J˜8 Hz, 2H); 7.37 (t, J˜7 Hz, 1H); 7.47 (half of ABq, J˜8 Hz, 2H).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[N:4][C:5]([Cl:8])=[CH:6][CH:7]=1.[F:9][C:10]([F:23])([F:22])[O:11][C:12]1[CH:13]=[C:14]([CH2:18][C:19](O)=[O:20])[CH:15]=[CH:16][CH:17]=1.CCN(C(C)C)C(C)C.CCCP(=O)=O.C(=O)(O)[O-].[Na+]>CN(C=O)C>[Cl:8][C:5]1[N:4]=[N:3][C:2]([NH:1][C:19](=[O:20])[CH2:18][C:14]2[CH:15]=[CH:16][CH:17]=[C:12]([O:11][C:10]([F:22])([F:9])[F:23])[CH:13]=2)=[CH:7][CH:6]=1
Reactant: O=C(O)Cc1cccc(OC(F)(F)F)c1
Reactant: Nc1ccc(Cl)nn1
Agent: CCCP(=O)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Cc1cccc(OC(F)(F)F)c1)Nc1ccc(Cl)nn1
Reaction time: 0.08 h

Procedure:
3-Amino-6-chloropyridazine (55.5 g, 0.428 mol) and 3-(Trifluoromethoxy)phenylacetic acid (1.1 equiv., 0.471 mol, 104 g) were dissolved in DMF (30.0 vol., 1.66 L) in a 3000 mL three neck round-bottom flask. Addition of DIEA (1.1 equiv., 0.471 mol, 82 mL) via addition funnel was done over 5 minutes. Propylphosphonic anhydride solution (300 mL of a 50% solution in DMF, 1.1 equiv., 0.471 mol,) was charged into a 500 mL addition funnel and added dropwise to reaction solution (keeping reaction temperature≦+30° C.). The reaction usually goes to completion after 3 hours (TLC: 6:4 hexanes-ethyl acetate). Reaction mixture was then poured into 7.5% sodium bicarbonate (80.0 vol., 4.4 L) which was chilled in an ice bath. Off-white crystalline powder was filtered through a Büchner funnel, rinsed with water (20.0 vol., 1.1 L). Dried in a 50° C. vacuum to a constant weight to afford N-(6-chloropyridazin-3-yl)-2-(3-(trifluoromethoxy)phenyl)acetamide 1117: yield of 119.6 g (77%). 1H NMR (300 MHz, DMSO-d6) δ 11.63 (s, 1H), 8.38 (d, J=9.4 Hz, 1H), 7.88 (d, J=9.4 Hz, 1H), 7.52-7.27 (m, 4H), 3.90 (s, 2H).
Reaction SMILES: S(Cl)(Cl)=O.[Br:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([OH:12])=[O:11])=[CH:8][C:7]=1[OH:15].[CH3:16]O>>[CH3:16][O:11][C:10](=[O:12])[C:9]1[CH:13]=[CH:14][C:6]([Br:5])=[C:7]([OH:15])[CH:8]=1
Reactant: CO
Reactant: O=C(O)c1ccc(Br)c(O)c1
Solvent: O=S(Cl)Cl
Product: COC(=O)c1ccc(Br)c(O)c1
Temperature: 50 °C
Reaction time: 0.17 h

Procedure:
1.5 ml of thionyl chloride was added to 40 ml of MeOH at 0° C. The solution was stirred for 10 min and 5 g of 4-Bromo-3-hydroxy-benzoic acid was added. The reaction was stirred for 16 h at RT then heated to 50° C. for 3 h. The solvents were removed under reduced pressure. The residue was used directly in the next step. Yield 5.92 g.
Reaction SMILES: C([Si](C1C=CC=CC=1)(C1C=CC=CC=1)[O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[NH:19][C:20](=[O:33])[CH:21]([C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=2)[O:22][CH2:23][C:24]#[CH:25])=[CH:9][C:8]=1[O:34][CH3:35])(C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>ClCCl>[Cl:32][C:29]1[CH:28]=[CH:27][C:26]([CH:21]([O:22][CH2:23][C:24]#[CH:25])[C:20]([NH:19][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[C:10]2[CH:11]=[CH:12][C:7]([OH:6])=[C:8]([O:34][CH3:35])[CH:9]=2)=[O:33])=[CH:31][CH:30]=1
Reactant: C#CCOC(C(=O)Nc1ccccc1-c1ccc(O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)c(OC)c1)c1ccc(Cl)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: ClCCl
Product: C#CCOC(C(=O)Nc1ccccc1-c1ccc(O)c(OC)c1)c1ccc(Cl)cc1

Procedure:
A solution of 10.2 g (15.5 mmol) N-[4′-(tert-butyl-diphenyl-silanyloxy)-3′-methoxy-biphenyl-2-yl]-2-(4-chlorophenyl)-2-prop-2-ynyloxy-acetamide and 24.5 g (77.5 mmol) tetrabutylammonium fluoride in 200 ml of dichloromethane is stirred for 4 hours at room temperature. After extracting with water/ethyl acetate and evaporation of the organic phase, the residue is subjected to flash-chromatography (ethyl acetate/hexane 4:6). Yield: 2-(4-chlorophenyl)-N-(4′-hydroxy-3′-methoxy-biphenyl-2-yl)-2-prop-2-ynyloxy-acetamide, m.p. 140–142° C.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[Cl:10][C:11]1[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[C:12]=1[CH2:13]Br.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Cl:10][C:11]1[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[C:12]=1[CH2:13][O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(O)cc1
Reactant: Clc1cccc(Cl)c1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=Cc1ccc(OCc2c(Cl)cccc2Cl)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A suspension of 4-hydroxybenzaldehyde (19.2 g, 157.5 mmol), 2,6-dichlorobenzylbromide (36 g, 150 mmol) and potassium carbonate (22.77 g, 165 mmol) in DMF (150 ml) was stirred at room temperature overnight. The mixture was filtered and the filtrate evaporated under reduced pressure. The residue was dissolved in ether (500 ml), and washed with aqueous NaOH (5%, 100 ml), water (100 ml) and brine (100 ml), dried (Na2SO4) and evaporated under reduced pressure. The orange crystalline solid obtained was recrystallised from diisopropylether to give the title compound as slightly orange needles (35.8 g, 85%), m.p. 70-71°. δH (CDCl3) 9.91 (1H, s, CHO), 7.87 (2H, d, J 8.9 Hz, ArH), 7.40-7.24 (3H, m, ArCl2H), 7.12 (2H, d, J 8.7 Hz, ArH) and 5.36 (2H, s, ArCH2OAr); m/z (ESI, 60V) 281 (M++1); Found: C, 59.76; H, 3.57. C14H10O2Cl2 requires C, 59.81; H, 3.59%.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][C@@H:2]1[C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7].C(=O)([O-])[O-].[K+].[K+].[I-].[K+].[CH3:21][C:22]1[CH:27]=[C:26]([CH3:28])[CH:25]=[C:24]([CH3:29])[C:23]=1[S:30]([O:33][C:34]1[C:39]([CH2:40][C:41]2[CH:46]=[CH:45][C:44]([O:47][CH2:48][CH2:49][CH2:50]OS(C)(=O)=O)=[CH:43][C:42]=2[O:56][CH3:57])=[C:38]([CH3:58])[N:37]=[C:36]([NH2:59])[N:35]=1)(=[O:32])=[O:31]>CC#N.O>[NH2:59][C:36]1[N:35]=[C:34]([O:33][S:30]([C:23]2[C:24]([CH3:29])=[CH:25][C:26]([CH3:28])=[CH:27][C:22]=2[CH3:21])(=[O:32])=[O:31])[C:39]([CH2:40][C:41]2[CH:46]=[CH:45][C:44]([O:47][CH2:48][CH2:49][CH2:50][N:1]3[CH2:5][CH2:4][CH2:3][C@@H:2]3[C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])=[CH:43][C:42]=2[O:56][CH3:57])=[C:38]([CH3:58])[N:37]=1
Reactant: COc1cc(OCCCOS(C)(=O)=O)ccc1Cc1c(C)nc(N)nc1OS(=O)(=O)c1c(C)cc(C)cc1C
Reactant: CC(C)(C)OC(=O)[C@H]1CCCN1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: COc1cc(OCCCN2CCC[C@@H]2C(=O)OC(C)(C)C)ccc1Cc1c(C)nc(N)nc1OS(=O)(=O)c1c(C)cc(C)cc1C
Temperature: 70 °C
Reaction time: 16 h

Procedure:
(R)-tert-butyl pyrrolidine-2-carboxylate (485 mg) was added to the mixture of potassium carbonate (393 mg), potassium iodide (31 mg) and the crude product from step (viii) in CH3CN (20 mL). After the mixture was stirred at 70° C. for 16 h, the reaction mixture was cooled to RT, diluted with water and extracted with EtOAc. The combined organic layer was washed with water and brine, dried and concentrated under reduced pressure. The residue was purified by flash column chromatography on amino silica gel to afford the sub-title compound (975 mg) as a white amorphous solid; 1H NMR (300 MHz, CDCl3); 6.92 (2H, s), 6.67 (1H, d), 6.39 (1H, d), 6.30 (1H, dd), 4.64 (2H, br s), 4.03-3.90 (2H, m), 3.76 (3H, s), 3.73 (2H, s), 3.20-3.00 (2H, m), 2.96-2.80 (1H, m), 2.66-2.50 (1H, m), 2.57 (6H, s), 2.46-2.30 (1H, m), 2.28 (3H, s), 2.22 (3H, s), 2.21-1.74 (6H, m), 1.43 (9H, s); LC-MS: m/z 655.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]2)=[CH:7][C:6]=1[CH2:18][C:19]([NH2:21])=[O:20])(=[O:3])[CH3:2].C[O:23][C:24](=O)[C:25]([C:27]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[NH:29][CH:28]=1)=O.CC([O-])(C)C.[K+]>C1COCC1>[NH:29]1[C:30]2[C:35](=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:27]([C:25]2[C:24](=[O:23])[NH:21][C:19](=[O:20])[C:18]=2[C:6]2[CH:7]=[C:8]([N:11]3[CH2:12][CH2:13][N:14]([CH3:17])[CH2:15][CH2:16]3)[CH:9]=[CH:10][C:5]=2[NH:4][C:1](=[O:3])[CH3:2])=[CH:28]1
Reactant: CC(=O)Nc1ccc(N2CCN(C)CC2)cc1CC(N)=O
Reactant: COC(=O)C(=O)c1c[nH]c2ccccc12
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(=O)Nc1ccc(N2CCN(C)CC2)cc1C1=C(c2c[nH]c3ccccc23)C(=O)NC1=O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a suspension of 2-[2-Acetylamino-5-(4-methyl-piperazin-1-yl)-phenyl]-acetamide (145 mg, 0.50 mmol) and (1H-indol-3-yl)-oxo-acetic acid methyl ester (183 mg, 0.90 mmol) in dry THF (6.0 mL) is added a solution of 1.0 M t-BuOK in THF (2.0 mL, 2.0 mmol) at 0° C. under argon. The resulting yellow suspension is stirred for 18 h at RT. The now dark red reaction mixture is partitioned between EtOAc (25 mL) and brine (25 mL), and the layers are separated. The pH of the aqueous layer is adjusted to 6 with a sat., aqueous NH4Cl solution. The aqueous layer is extracted with EtOAc (2×25 mL) and the combined organic layers are washed with brine (25 mL), dried over Na2SO4, and concentrated at reduced pressure. The crude product is purified by FCC (EtOAc/AcOH/H2O 5.5:1:1) to afford the title compound as its water soluble acetate salt. Orange solid. 1H NMR (DMSO-de, 400 MHz): δ 1.75 (s, 12H, CH3COO), 2.16 (s, 3H), 2.31-2.38 (m, 4H), 2.92-2.99 (m, 4H), 6.61 (d, J=7.8 Hz, 1H), 6.66 (t, J=7.4 Hz, 1H), 6.75 (d, J=2.5 Hz, 1H), 6.92 (dd, J=9.0 Hz, J=2.7 Hz, 1H), 6.99 (t, J=7.5 Hz, 1H), 7.32 (d, J=8.1 Hz, 1H), 7.47 (d, J=8.9 Hz, 1H), 7.75 (s, 1H), 8.69 (s, 1H), 11.86 (bs, 1H). ES+-MS: 444 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:14]=[C:13](O)[N:12]3[N:16]=[CH:17][N:18]=[C:11]3[CH:10]=2)=[CH:5][CH:4]=1.P(Cl)(Cl)([Cl:23])=O>[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1.C(=O)(O)[O-].[Na+]>[Cl:23][C:13]1[N:12]2[N:16]=[CH:17][N:18]=[C:11]2[CH:10]=[C:9]([C:6]2[CH:7]=[CH:8][C:3]([C:2]([F:20])([F:19])[F:1])=[CH:4][CH:5]=2)[N:14]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Oc1nc(-c2ccc(C(F)(F)F)cc2)cc2ncnn12
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: O=C([O-])O
Agent: [Cl-]
Product: FC(F)(F)c1ccc(-c2cc3ncnn3c(Cl)n2)cc1
Temperature: 120 °C
Reaction time: 4 h

Procedure:
1320 mg (4.7 mmol) of 7-[4-(trifluoromethyl)phenyl][1,2,4]triazolo[1,5-c]pyrimidin-5-ol (Example 138A) are introduced into phosphoryl chloride (20 ml), 3.20 g (14 mmol) of benzyltriethylammonium chloride are added, and the reaction mixture is stirred at 120° C. for 4 h. The reaction mixture is slowly poured, while stirring vigorously, into saturated sodium bicarbonate solution (150 ml) and ice, and solid sodium bicarbonate (approx. 10 g) is added until a pH of 8 is reached. The solid is filtered off with suction. 1300 mg (92% of theory) of the crude product are obtained.
Reaction SMILES: [C:1](Cl)(=[O:4])[CH2:2][CH3:3].[C:6]1([CH2:12][N:13]2[CH2:18][CH2:17][C@H:16]([NH:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C@H:15]([O:26][CH3:27])[CH2:14]2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>ClCCl.[OH-].[Na+]>[C:20]1([N:19]([C@H:16]2[CH2:17][CH2:18][N:13]([CH2:12][C:6]3[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=3)[CH2:14][C@H:15]2[O:26][CH3:27])[C:1](=[O:4])[CH2:2][CH3:3])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CO[C@@H]1CN(Cc2ccccc2)CC[C@@H]1Nc1ccccc1
Reactant: CCC(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CCC(=O)N(c1ccccc1)[C@H]1CCN(Cc2ccccc2)C[C@H]1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.5 %

Procedure:
Propionyl chloride (0.77g, 8.3 mmol) was added to cis-1-phenylmethyl-3-methoxy-4-phenylaminopiperidine (7b, 1.6g, 5.3 mmol) from Example 4 in 30ml of dichloromethane. The reaction solution was stirred at room temperature overnight and subsequently diluted with 20ml of 10% sodium hydroxide solution. The organic layer was separated and the aqueous layer was extracted with 2×50ml of dichloromethane. The combined organic layers were dried and concentrated under vacuum to yield 1.84g (99%) of crude cis-N-phenyl-N-(1-phenylmethyl-3-methoxy-4-piperidinyl) propanamide (I).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([NH:8][CH2:9][C:10]([OH:12])=[O:11])=O.[CH3:13][N:14]([CH3:23])[C:15]1[C:20]([CH:21]=O)=[CH:19][CH:18]=[CH:17][N:16]=1.C([O-])(=O)C.[Na+].C(OC(=O)C)(=O)C>O>[CH3:13][N:14]([CH3:23])[C:15]1[C:20]([CH:21]=[C:9]2[C:10](=[O:11])[O:12][C:6]([C:2]3[S:1][CH:5]=[CH:4][CH:3]=3)=[N:8]2)=[CH:19][CH:18]=[CH:17][N:16]=1
Reactant: CN(C)c1ncccc1C=O
Reactant: O=C(O)CNC(=O)c1cccs1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Solvent: O
Product: CN(C)c1ncccc1C=C1N=C(c2cccs2)OC1=O
Temperature: 90 °C
Yield: 32.3 %

Procedure:
To a screw-capped test tube, N-(2-thienylcarbonyl)glycine (56 mg, 0.3 mmol), 2-(dimethylamino)-3-pyridinecarboxaldehyde (50 mg, 0.3 mmol), sodium acetate (25 mg, 0.3 mmol) and acetic anhydride (0.3 mL) were added. The test tube was sealed, and it was then stirred at an external temperature of 90° C. Three hours later, the temperature of the reaction solution was returned to room temperature, and water (1.5 mL) was then added thereto. The obtained mixture was stirred at the same temperature as described above for 1.5 hours. Thereafter, the precipitated crystal was collected by filtration, and it was washed with water (5 mL) and was then dried under reduced pressure, so as to obtain 29 mg of the above-captioned compound.