Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([CH:12]=[CH:13][C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([OH:20])[CH:15]=3)=[N:9]2)=[CH:4][CH:3]=1.[CH3:21][CH:22](Br)[C:23]([O:25][CH3:26])=[O:24].C([O-])([O-])=O.[K+].[K+]>C(C(C)=O)C>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([CH:12]=[CH:13][C:14]3[CH:15]=[C:16]([CH:17]=[CH:18][CH:19]=3)[O:20][CH:22]([CH3:21])[C:23]([O:25][CH3:26])=[O:24])=[N:9]2)=[CH:4][CH:3]=1
Reactant: COC(=O)C(C)Br
Reactant: Oc1cccc(C=Cc2ccc3ccc(Br)cc3n2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: COC(=O)C(C)Oc1cccc(C=Cc2ccc3ccc(Br)cc3n2)c1

Procedure:
To the phenol (Example 35, Step 2) (1 g) in methyl ethyl ketone (20 ml) was added methyl DL-2-bromo-propionate (2 g) and K2CO3 (1 g). The mixture was heated overnight at reflux filtered and evaporated. Flash chromatography of the residue using 10% ethyl acetate in hexane afforded the title compound. Recrystallization from ethyl acetate hexane afforded the title compound: m.p. 101°-102°.
Reaction SMILES: [C:1]([C:3]1[C:8]2[N:9]=[C:10]([CH:12]3[CH2:14][CH2:13]3)[O:11][C:7]=2[C:6]([CH:15](C(OC)=O)[C:16]([O:18][CH3:19])=[O:17])=[C:5]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:4]=1[CH3:30])#[N:2].[Cl-].[Mg+2].[Cl-]>CS(C)=O.O>[C:1]([C:3]1[C:8]2[N:9]=[C:10]([CH:12]3[CH2:14][CH2:13]3)[O:11][C:7]=2[C:6]([CH2:15][C:16]([O:18][CH3:19])=[O:17])=[C:5]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:4]=1[CH3:30])#[N:2]
Reactant: COC(=O)C(C(=O)OC)c1c(-c2ccccc2)c(C)c(C#N)c2nc(C3CC3)oc12
Agent: [Cl-]
Agent: [Mg+2]
Solvent: CS(C)=O
Solvent: O
Product: COC(=O)Cc1c(-c2ccccc2)c(C)c(C#N)c2nc(C3CC3)oc12
Temperature: 90 °C
Reaction time: 23 h
Yield: 90 %

Procedure:
Dimethyl 2-(4-cyano-2-cyclopropyl-5-methyl-6-phenyl-1,3-benzoxazol-7-yl)malonate (I-294) (2.887 g, 7.11 mmol) was dissolved in dimethyl sulfoxide (50 ml) and water (5 ml), then at room temperature, magnesium chloride (2.03 g, 21.34 mmol) was added. The solution was stirred at 90° C. for 23 hours, then cooled to room temperature. The solvent was evaporated away under reduced pressure, the residue was fractionated with ethyl acetate and saturated brine. The aqueous layer was separated, extracted twice with ethyl acetate. The organic layers were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. The insoluble matter was separated by filtration, the solvent was evaporated away, and the resulting residue was purified by middle-pressure liquid chromatography (eluent, n-hexane:ethyl acetate=3:1, v/v) to obtain the entitled compound (2.216 g, 90%) as a pale yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]([C:6]([NH:8][C:9]2[S:10][CH:11]=[C:12]([CH2:14][C:15](=[O:22])[N:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)[N:13]=2)=[O:7])=[CH:4][CH:3]=1.[O:25]=[C:26]1[CH2:30][CH2:29][CH2:28][N:27]1[CH2:31][C:32](O)=[O:33]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([NH:8][C:9]2[S:10][CH:11]=[C:12]([CH2:14][C:15](=[O:22])[N:16]3[CH2:17][CH2:18][N:19]([C:32](=[O:33])[CH2:31][N:27]4[CH2:28][CH2:29][CH2:30][C:26]4=[O:25])[CH2:20][CH2:21]3)[N:13]=2)=[O:7])=[CH:23][CH:24]=1
Reactant: O=C(O)CN1CCCC1=O
Reactant: O=C(Nc1nc(CC(=O)N2CCNCC2)cs1)c1ccc(Cl)cc1
Product: O=C(Nc1nc(CC(=O)N2CCN(C(=O)CN3CCCC3=O)CC2)cs1)c1ccc(Cl)cc1

Procedure:
54.3 Using general procedure A, 4-chloro-N-[4-(2-oxo-2-piperazin-1-yl-ethyl)-thiazol-2-yl]-benzamide was coupled with (2-oxo-pyrrolidine-1-yl)-acetic acid (CAS 53934-76-2) to give 4-chloro-N-[4-(2-oxo-2-{4-[2-(2-oxo-pyrrolidin-1-yl)-acetyl]-piperazin-1-yl}-ethyl)-thiazol-2-yl]-benzamide. White solid. MS 490.4 ([M+H]+)
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([CH:8]2[CH2:12][CH2:11][S:10](=[O:14])(=[O:13])[CH2:9]2)=[CH:4][CH:3]=1.C1C(=O)N([Br:22])C(=O)C1>C(#N)C>[NH2:1][C:2]1[N:7]=[CH:6][C:5]([CH:8]2[CH2:12][CH2:11][S:10](=[O:14])(=[O:13])[CH2:9]2)=[CH:4][C:3]=1[Br:22]
Reactant: Nc1ccc(C2CCS(=O)(=O)C2)cn1
Reactant: O=C1CCC(=O)N1Br
Solvent: CC#N
Product: Nc1ncc(C2CCS(=O)(=O)C2)cc1Br
Temperature: 0 °C
Reaction time: 0.67 h
Yield: 38 %

Procedure:
3-(6-aminopyridin-3-yl)tetrahydrothiophene 1,1-dioxide (96 mg, 0.452 mmol) was dissolved in acetonitrile (5 mL) and the solution was cooled to 0° C., to it was added NBS (80 mg, 0.452 mmol) and the mixture was stirred at 0° C. for 40 min. The reaction mixture was concentrated under reduced pressure and the residue was partitioned between EtOAc/sat. NaHCO3 (30 mL/20 mL), the EtOAc layer was washed with sat. Na2CO3 (20 mL), brine (20 mL), dried (Na2SO4), filtered off and concentrated in vacuo yielding 3-(6-amino-5-bromopyridin-3-yl)tetrahydrothiophene 1,1-dioxide as light brown oil (50 mg, 38% yield). LCMS (m/z): 293.0/291.0 (MH+), 0.29 min.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:10][C@H:11]1[CH2:16][CH2:15][C@H:14]2[C@H:17]3[C@H:27]([CH2:28][CH2:29][C@:12]12[CH3:13])[C@:25]1([CH3:26])[C@H:20]([C:21](=[O:30])[CH2:22][CH2:23][CH2:24]1)[CH2:19][CH2:18]3.[Cl-]>N1C=CC=CC=1>[C:1]([O:10][C@H:11]1[CH2:16][CH2:15][C@H:14]2[C@H:17]3[C@H:27]([CH2:28][CH2:29][C@:12]12[CH3:13])[C@:25]1([CH3:26])[C@H:20]([C:21](=[O:30])[CH2:22][CH2:23][CH2:24]1)[CH2:19][CH2:18]3)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: C[C@]12CCCC(=O)[C@@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](O)CC[C@@H]12
Agent: [Cl-]
Solvent: c1ccncc1
Product: C[C@]12CCCC(=O)[C@@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](OC(=O)c3ccccc3)CC[C@@H]12
Temperature: 0 °C

Procedure:
To 12 ml of dry pyridine and 6 ml of benzoyl chloride is added 2.0 g of the product of Step F to form a solution which is heated on a steam bath for 30 min. and then poured into 175 ml of ice water and stirred to decompose the excess chloride. The reaction mixture is filtered, washed with water, and pumped dry under high vacuum at 50° C. to yield 1.7 g of final product.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]1([F:36])[CH2:12][N:11]([C:13](=[O:35])/[CH:14]=[CH:15]\[N:16]2[CH:20]=[N:19][C:18]([C:21]3[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[C:23]([C:31]([F:34])([F:33])[F:32])[CH:22]=3)=[N:17]2)[CH2:10]1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:7][CH2:8][C:9]1([F:36])[CH2:12][N:11]([C:13](=[O:35])/[CH:14]=[CH:15]\[N:16]2[CH:20]=[N:19][C:18]([C:21]3[CH:22]=[C:23]([C:31]([F:32])([F:33])[F:34])[CH:24]=[C:25]([C:27]([F:30])([F:28])[F:29])[CH:26]=3)=[N:17]2)[CH2:10]1
Reactant: CC(C)(C)OC(=O)NCC1(F)CN(C(=O)/C=C\n2cnc(-c3cc(C(F)(F)F)cc(C(F)(F)F)c3)n2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NCC1(F)CN(C(=O)/C=C\n2cnc(-c3cc(C(F)(F)F)cc(C(F)(F)F)c3)n2)C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 12.3 %

Procedure:
(Z)-tert-Butyl(1-(3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)acryloyl)-3-fluoroazetidin-3-yl)methylcarbamate (0.15 g, 0.279 mmol) was dissolved in DCM (10 mL) and TFA (0.1 mL) was added at 0° C. The reaction mixture was stirred at rt for 4 h and concentrated under reduced pressure to afford 0.5 g of crude product, which was purified by chromatography (0-5% methanol in DCM) to afford 15 mg of (Z)-1-(3-(aminomethyl)-3-fluoroazetidin-1-yl)-3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)prop-2-en-1-one (Yield 15%). 1H NMR (400 MHz, CDCl3, ppm) δ=9.4 (s, 1H); 8.54 (s, 2H); 8.32 (s, 1H); 8.13 (s, 3H); 7.49-7.46 (d, J=10 Hz, 1H); 6.0-5.97 (d, J=10 Hz, 1H); 4.41-4.06 (m, 4H); 3.49-3.36 (m, 3H). LCMS calcd for C17H15F7N5O [M+H]+ 438.3. found: 438.19 (retention time 2.298 min).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[CH:18]=[CH:17][CH:16]=[C:12]([C:13]([OH:15])=O)[C:11]=2[C:19]([OH:21])=O)=[C:5]([O:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:4]=1.Cl.[NH2:30][CH:31]1[CH2:37][CH2:36][C:35](=[O:38])[NH:34][C:32]1=[O:33]>N1C=CC=CC=1>[O:33]=[C:32]1[CH:31]([N:30]2[C:19](=[O:21])[C:11]3[C:12](=[CH:16][CH:17]=[CH:18][C:10]=3[NH:9][C:6]3[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][C:5]=3[O:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:13]2=[O:15])[CH2:37][CH2:36][C:35](=[O:38])[NH:34]1
Reactant: NC1CCC(=O)NC1=O
Reactant: COc1ccc(Nc2cccc(C(=O)O)c2C(=O)O)c(Oc2ccccc2)c1
Agent: Cl
Solvent: c1ccncc1
Product: COc1ccc(Nc2cccc3c2C(=O)N(C2CCC(=O)NC2=O)C3=O)c(Oc2ccccc2)c1
Yield: 89 %

Procedure:
A mixture of 3-(4-methoxy-2-phenoxy-phenylamino)-phthalic acid (0.60 g, 1.6 mmol) and rac-α-aminoglutarimide hydrochloride (0.26 g, 1.6 mmol) in pyridine (10 mL) were heated to reflux for 20 hours. The mixture was cooled and evaporated under vacuum. The residue was dissolved in ethyl acetate (100 mL) and washed with dilute aqueous HCl (3×100 mL) and water (100 mL), and then evaporated under vacuum. The residue was purified by ISCO silica gel flash chromatography using a methylene chloride-methanol gradient, eluting 0.66 g of the product, an orange solid, at 95:5 methylene chloride-methanol, in 89% yield: mp 142-144° C.; HPLC, Waters Symmetry C-18, 3.9×150 mm, 5 μm, 1 mL/min, 240 nm, 60/40 CH3CN/0.1% H3PO4, 4.71 min (96.79%); 1H NMR (DMSO-d6) δ 1.98-2.04 (m, 1H), 2.49-2.61 (m, 2H), 2.81-2.90 (m, 1H), 3.73 (s, 3H), 5.06 (dd, J=12.8 Hz, J=5.3 Hz, 1H), 6.58 (d, J=2.8 Hz, 1H), 6.84 (dd, J=8.8, J=2.8 Hz, 1H), 6.90-6.94 (m, 2H), 7.04-7.10 (m, 2H), 7.16 (d, J=7.0 Hz, 1H), 7.27-7.34 (m, 2H), 7.45 (d, J=8.7 Hz, 1H), 7.57 (dd, J=8.3 Hz, J=7.4 Hz, 1H), 7.95 (s, 1H), 11.10 (s, 1H); 13C NMR (DMSO-d6) δ 22.1, 30.9, 48.6, 55.5, 105.9, 109.6, 110.7, 112.6, 117.9, 118.7, 122.8, 123.5, 127.2, 129.9, 132.0, 136.0, 144.0, 151.1, 156.2, 157.8, 167.1, 168.5, 169.9, 172.8; Anal. calcd For C26H21N3O6.0.3H2O: C, 65.49; H, 4.55; N, 8.84. Found: C, 65.43; H, 4.29; N, 8.73.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[CH2:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:14]=2[CH2:23]O)[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1.P(Br)(Br)[Br:27]>COCCOC>[CH3:1][O:2][C:3](=[O:25])[CH2:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:14]=2[CH2:23][Br:27])[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1
Reactant: COC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2CO)c1
Reactant: BrP(Br)Br
Solvent: COCCOC
Product: COC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2CBr)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To (2′-hydroxymethyl-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl)-acetic acid methyl ester (1.66 g, 4.68 mmol) in DME (17 mL) was added phosphorus tribromide (0.66 mL, 7.03 mmol), and the reaction was stirred at room temperature for 3 hours. The mixture was cooled to 0° C. and quenched with aqueous NaHCO3 and CH2Cl2. The aqueous layer was separated and extracted with CH2Cl2, and the combined organic layers were dried over MgSO4, filtered, and concentrated. The crude material was purified by silica gel chromatography to give the title compound.
Reaction SMILES: [OH:1][C@@H:2]([C@H:4]1[C:39](=[O:40])[N:6]2[C:7]([C:26]([O:28][CH2:29][C:30]3[CH:35]=[CH:34][C:33]([N+:36]([O-:38])=[O:37])=[CH:32][CH:31]=3)=[O:27])=[C:8](OP(C3C=CC=CC=3)(C3C=CC=CC=3)=O)[C@H:9]([CH3:10])[C@H:5]12)[CH3:3].[OH:41][CH:42]([C@@H:66]1[CH2:70][C@H:69]([SH:71])[CH2:68][N:67]1[C:72]([O:74][CH2:75][C:76]1[CH:81]=[CH:80][C:79]([N+:82]([O-:84])=[O:83])=[CH:78][CH:77]=1)=[O:73])[CH2:43][C:44]([N:46]1[CH2:50][CH2:49][C@@H:48]([N:51]([CH3:65])[C:52]([O:54][CH2:55][C:56]2[CH:61]=[CH:60][C:59]([N+:62]([O-:64])=[O:63])=[CH:58][CH:57]=2)=[O:53])[CH2:47]1)=[O:45]>>[OH:1][C@@H:2]([C@H:4]1[C:39](=[O:40])[N:6]2[C:7]([C:26]([O:28][CH2:29][C:30]3[CH:31]=[CH:32][C:33]([N+:36]([O-:38])=[O:37])=[CH:34][CH:35]=3)=[O:27])=[C:8]([S:71][C@@H:69]3[CH2:68][N:67]([C:72]([O:74][CH2:75][C:76]4[CH:77]=[CH:78][C:79]([N+:82]([O-:84])=[O:83])=[CH:80][CH:81]=4)=[O:73])[C@H:66]([CH:42]([OH:41])[CH2:43][C:44]([N:46]4[CH2:50][CH2:49][C@H:48]([N:51]([CH3:65])[C:52]([O:54][CH2:55][C:56]5[CH:57]=[CH:58][C:59]([N+:62]([O-:64])=[O:63])=[CH:60][CH:61]=5)=[O:53])[CH2:47]4)=[O:45])[CH2:70]3)[C@H:9]([CH3:10])[C@H:5]12)[CH3:3]
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(OP(=O)(c3ccccc3)c3ccccc3)[C@H](C)[C@H]12
Reactant: CN(C(=O)OCc1ccc([N+](=O)[O-])cc1)[C@@H]1CCN(C(=O)CC(O)[C@@H]2C[C@H](S)CN2C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(S[C@H]3C[C@@H](C(O)CC(=O)N4CC[C@H](N(C)C(=O)OCc5ccc([N+](=O)[O-])cc5)C4)N(C(=O)OCc4ccc([N+](=O)[O-])cc4)C3)[C@H](C)[C@H]12
Yield: 71.7 %

Procedure:
By using 4-nitrobenzyl (1R,5R,6S)-6-[(1R)-1-hydroxyethyl]-1-methyl-2-(diphenylphosphoryloxy)-1-carbapen-2-em-3-carboxylate (819 mg) and (2S,4S)-2-[1-hydroxy-2-[(3R)-3-(N-methyl-N-4-nitrobenzyloxycarbonylamino)pyrrolidin-1-ylcarbonyl]ethyl]-4-mercapto-1-(4-nitrobenzyloxycarbonyl)pyrrolidine (830 mg), reaction and purification were carried out in a similar manner to that described in Example 40-(1), whereby 4-nitrobenzyl (1R,5S,6S)-6-[(1R)-1-hydroxyethyl]-2-[(2S,4S)-2-[1-hydroxy-2-[(3S)-3-(N-methyl-N-4-nitrobenzyloxycarbonylamino)pyrrolidin-1-ylcarbonyl]ethyl]-1-(4-nitrobenzyloxycarbonyl)pyrrolidin-4-ylthio]-1-methyl-1-carbapen-2-em-3-carboxylate (919 mg) was obtained.
Reaction SMILES: [C:1]([NH:4][CH2:5][C:6]1[NH:7][C:8](=[O:13])[NH:9][C:10](=O)[CH:11]=1)(=O)[CH3:2].P(Cl)(Cl)([Cl:16])=O>>[Cl:16][C:10]1[CH:11]=[C:6]2[CH:5]=[N:4][CH:1]([CH3:2])[N:7]2[C:8](=[O:13])[N:9]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CC(=O)NCc1cc(=O)[nH]c(=O)[nH]1
Product: CC1N=Cc2cc(Cl)nc(=O)n21

Procedure:
A suspension of 6.63 g (36.2 mmole) of 4-acetylaminomethylpyrimidine-2,6-dione in 250 ml of phosphorous oxychloride was heated at reflux for 20 hours, and was cooled and evaporated. The residue was added to about 700 ml of cold saturated sodium bicarbonate solution. To the resulting mixture was added 200 ml of chloroform and enough solid sodium bicarbonate to neutralize the mixture. The solid was separated by filtration, washed with water and ethanol, and recrystallized from ethanol to provide yellow solid 7-chloro-3-methylimidazo[1,5-c]pyrimidin-5-one, m.p. 239° C. (dec.). Analysis: Calculated for C7H6ClN3O; %C, 45.8; %H, 3.3; %N, 22.9; Found; %C, 45.8; %H, 3.1; %N, 22.8.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]([CH2:25][C:26](O)=[O:27])[C:15]2[CH:16]=[C:17]3[C:22](=[CH:23][CH:24]=2)[N:21]=[CH:20][CH:19]=[CH:18]3)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:29]([NH:36][CH2:37][CH2:38][OH:39])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>>[CH2:29]([N:36]([CH2:37][CH2:38][OH:39])[C:26](=[O:27])[CH2:25][N:14]([S:11]([C:8]1[CH:7]=[CH:6][C:5]([C:1]([CH3:2])([CH3:3])[CH3:4])=[CH:10][CH:9]=1)(=[O:12])=[O:13])[C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][CH:24]=1)[N:21]=[CH:20][CH:19]=[CH:18]2)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: CC(C)(C)c1ccc(S(=O)(=O)N(CC(=O)O)c2ccc3ncccc3c2)cc1
Reactant: OCCNCc1ccccc1
Product: CC(C)(C)c1ccc(S(=O)(=O)N(CC(=O)N(CCO)Cc2ccccc2)c2ccc3ncccc3c2)cc1

Procedure:
prepared by reaction of [(4-tert-butyl-benzenesulfonyl)-quinolin-6-yl-amino]-acetic acid with 2-benzylamino-ethanol
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:10]([I:11])=[CH:9][N:8]([S:12]([C:15]3[CH:21]=[CH:20][C:18]([CH3:19])=[CH:17][CH:16]=3)(=[O:14])=[O:13])[C:5]2=[N:6][CH:7]=1.IC1C2C(=NC=C([C:32]3[CH:33]=[C:34]([NH:38][S:39]([CH3:42])(=[O:41])=[O:40])[CH:35]=[CH:36][CH:37]=3)C=2)NC=1.C1(C)C=CC(S(Cl)(=O)=O)=CC=1.[H-].[Na+]>CN(C=O)C>[I:11][C:10]1[C:4]2[C:5](=[N:6][CH:7]=[C:2]([C:32]3[CH:33]=[C:34]([NH:38][S:39]([CH3:42])(=[O:40])=[O:41])[CH:35]=[CH:36][CH:37]=3)[CH:3]=2)[N:8]([S:12]([C:15]2[CH:21]=[CH:20][C:18]([CH3:19])=[CH:17][CH:16]=2)(=[O:14])=[O:13])[CH:9]=1
Reactant: CS(=O)(=O)Nc1cccc(-c2cnc3[nH]cc(I)c3c2)c1
Reactant: Cc1ccc(S(=O)(=O)n2cc(I)c3cc(Br)cnc32)cc1
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)n2cc(I)c3cc(-c4cccc(NS(C)(=O)=O)c4)cnc32)cc1

Procedure:
Using similar reaction conditions as described in, step ii of Intermediate 1, N-(3-(3-iodo-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)methanesulfonamide (800 mg, 1.93 mmol) was tosylated with p-toluene sulfonylchloride (100 mg, 2.09 mmol) and 60% suspension of sodium hydride in paraffin (193 mg, 4.82 mmol) in DMF (10 mL) to afford 800 mg of the titled compound.
Reaction SMILES: Br[C:2]1[CH:17]=[CH:16][C:5]([C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:7])=[C:4]([F:18])[CH:3]=1.[OH:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:18][C:4]1[CH:3]=[C:2]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[OH:19])[CH:17]=[CH:16][C:5]=1[C:6]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7]
Reactant: O=C(OCc1ccccc1)c1ccc(Br)cc1F
Reactant: OB(O)c1ccccc1O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: O=C(OCc1ccccc1)c1ccc(-c2ccccc2O)cc1F
Temperature: 0 °C
Yield: 89.5 %

Procedure:
To a mixed solvent solution of benzyl 4-bromo-2-fluorobenzoate (67.0 g) and 2-hydroxyphenylboronic acid (31.3 g) in 1,2-dimethoxyethane (750 ml) and water (250 ml) were added sodium carbonate (68.7 g) and tetrakis(triphenylphosphine)palladium (12.5 g), followed by stirring under heating at reflux for 5 hours. The reaction solution was brought back to room temperature, and then poured into ice water, followed by extraction with ethyl acetate. The organic layer was washed sequentially with water and saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography, and further washed with hexane to afford benzyl 3-fluoro-2′-hydroxybiphenyl-4-carboxylate (62.5 g).
Reaction SMILES: [CH2:1]([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.NN.C(C1OC(C2C=CC=CC=2)C(C2C=CC=CC=2)[N:23]=1)=O>C(O)C.C(O)(=O)C.[Zn]>[CH2:1]([N:8]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[NH2:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: c1ccc(CNc2ccccc2)cc1
Reactant: O=CC1=NC(c2ccccc2)C(c2ccccc2)O1
Agent: NN
Agent: [Zn]
Solvent: CCO
Solvent: CC(=O)O
Product: NN(Cc1ccccc1)c1ccccc1
Temperature: 10 °C
Yield: 17.8 %

Procedure:
1-benzyl-1-phenylhydrazine was prepared in the same manner as Synthesis Example 1 except for using 208.6 g (1.14 mol) of N-benzylaniline in place of diphenylamine. Said hydrazine was dissolved in a mixture of 1 l of ethanol and 50 ml of acetic acid, and 286 g (1.14 mol) of 2-formyl-4,5-diphenyloxazoline, represented by the formula ##STR9## was added. The resulting mixture was cooled to 10° C., and 250 g (3.82 mol) of zinc metal was added with caution not to raise the temperature over 20° C. After completion of the reaction, the reaction mixture was filtered and the filtrate was poured into water, thus giving a yellow precipitate. Recrystallization of the precipitate from a methyl ethyl ketone-ethanol (1:1) mixture gave 87.5 g of yellow crystals (yield 17.8% based on the amine).
Reaction SMILES: Cl.Cl.[O:3]1[C:8]2=[CH:9][CH:10]=[CH:11][C:7]2=[C:6]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][N:13]2[CH2:18][CH2:19][C@H:20]2[CH2:25][CH2:24][C@H:23]([NH2:26])[CH2:22][CH2:21]2)[CH:5]=[CH:4]1.[O:27]1[CH2:32][CH2:31][O:30][CH2:29][CH:28]1[CH2:33][C:34](O)=[O:35]>>[O:3]1[C:8]2=[CH:9][CH:10]=[CH:11][C:7]2=[C:6]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][N:13]2[CH2:18][CH2:19][C@H:20]2[CH2:21][CH2:22][C@H:23]([NH:26][C:34](=[O:35])[CH2:33][CH:28]3[CH2:29][O:30][CH2:31][CH2:32][O:27]3)[CH2:24][CH2:25]2)[CH:5]=[CH:4]1
Reactant: O=C(O)CC1COCCO1
Reactant: N[C@H]1CC[C@H](CCN2CCCCC2c2ccoc3cccc2-3)CC1
Agent: Cl
Product: O=C(CC1COCCO1)N[C@H]1CC[C@H](CCN2CCCCC2c2ccoc3cccc2-3)CC1

Procedure:
The title compound, off-white solid (81 mg, 62%), MS (ISP) m/z=455.4 [(M+H)+], mp 165° C., was prepared in accordance with the general method of example 1 from trans-4-[2-(4-benzofuran-4-yl-piperidin-1-yl)-ethyl]-cyclohexyl-amine dihydrochloride (intermediate A) (115 mg, 0.29 mmol) and rac-(1,4-dioxan-2-yl)-acetic acid.
Reaction SMILES: [I-:1].[NH2:2][C:3]1[N:8]=[C:7](Cl)[CH:6]=[C:5]([CH3:10])[N+:4]=1[CH3:11].[C:12]1([CH:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C(O)C>[I-:1].[NH2:2][C:3]1[N:8]=[C:7]([N:21]2[CH2:22][CH2:23][CH:18]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH2:19][CH2:20]2)[CH:6]=[C:5]([CH3:10])[N+:4]=1[CH3:11]
Reactant: c1ccc(C2CCNCC2)cc1
Reactant: Cc1cc(Cl)nc(N)[n+]1C
Agent: [I-]
Solvent: CCO
Product: Cc1cc(N2CCC(c3ccccc3)CC2)nc(N)[n+]1C
Yield: 50 %

Procedure:
A mixture of 2-amino-4-chloro-1,6-dimethylpyrimidinium iodide (0.571 g; 2 mM; described in Indian Research, 1976, 21 p. 96) and 4-phenylpiperidine (0.644 g; 4 mM) in ethanol (30 ml) was heated under reflux for 15 hours. The solvent was removed in vacuo and the residue was triturated with ether. The solid was removed by filtration and recrystallised from a mixture of methanol and ether to give 2-amino-1,6-dimethyl-4-(4-phenylpiperidino)pyrimidinium iodide as a solid (0.41 g, 50% yield), m.p. 248°-250° C. (decomp.); microanalysis, found: C,50.0; H,5.6; N,13.7%; C17H23N4I requires C,49.8; H,5.6; N,13.7%; NMR (220 MHz; d5): 1.4-1.75 (2H, b, piperidine 3-H axial and 5-H axial), 1.85-2.0 (2H, d, piperidine 3-H equatorial and 5-H equatorial), 2.4 (3H, s, CH3), 2.8-3.3 (3H, b, piperidine 4-H and piperidine 2-H axial and 6-H axial), 3.45 (3H, s, N--CH3), 4.2-4.4 (1H, broad d, piperidine 2-H equatorial or 6-H equatorial), 4.85-5.05 (1H, broad d, piperidine 6-H equatorial or 2-H equatorial), 6.7 (1H, s pyrimdine 5H), 7.1-7.4 (5H, complex, aromatic H), 7.85-8.0 (2H, br, NH2).
Reaction SMILES: [CH3:1][O:2][C:3]1[NH:4][C:5]([CH3:10])=[CH:6][C:7]=1[C:8]#[N:9].[F:11][C:12]([S:15]Cl)([Cl:14])[Cl:13]>C(Cl)Cl>[CH3:1][O:2][C:3]1[NH:4][C:5]([CH3:10])=[C:6]([S:15][C:12]([Cl:14])([Cl:13])[F:11])[C:7]=1[C:8]#[N:9]
Reactant: COc1[nH]c(C)cc1C#N
Reactant: FC(Cl)(Cl)SCl
Solvent: ClCCl
Product: COc1[nH]c(C)c(SC(F)(Cl)Cl)c1C#N
Temperature: 25 °C
Reaction time: 14 h

Procedure:
A suspension of 2-methoxy-3-cyano-5-methylpyrrole (0.5 g) in 5 ml of CH2Cl2 was treated with Cl2FCSCl (0.45 ml) and stirred at room temperature for 14 h. The resulting precipitate was filtered, washed with CH2Cl2, and dried under high vacuum to afford an off-white solid (0.59 g), m.p. 175° C.
Reaction SMILES: Cl.[C:2]1([C:8]2[CH:9]=[C:10]3[C:14](=[C:15]([C:17]([NH2:19])=[O:18])[CH:16]=2)[NH:13][N:12]=[C:11]3[CH:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.[CH3:35][N:36]1[CH:40]=[C:39]([S:41](Cl)(=[O:43])=[O:42])[N:38]=[C:37]1[CH3:45]>CN(C=O)C.CN(C1C=CN=CC=1)C>[CH3:35][N:36]1[CH:40]=[C:39]([S:41]([N:23]2[CH2:24][CH2:25][CH:20]([C:11]3[C:10]4[C:14](=[C:15]([C:17]([NH2:19])=[O:18])[CH:16]=[C:8]([C:2]5[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=5)[CH:9]=4)[NH:13][N:12]=3)[CH2:21][CH2:22]2)(=[O:43])=[O:42])[N:38]=[C:37]1[CH3:45]
Reactant: Cc1nc(S(=O)(=O)Cl)cn1C
Reactant: NC(=O)c1cc(-c2ccccc2)cc2c(C3CCNCC3)n[nH]c12
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc(S(=O)(=O)N2CCC(c3n[nH]c4c(C(N)=O)cc(-c5ccccc5)cc34)CC2)cn1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 37.3 %

Procedure:
To a solution of 5-phenyl-3-(4-piperidinyl)-1H-indazole-7-carboxamide hydrochloride (Example 2) (50 mg, 0.14 mmol) in DMF (3 mL) was added diisopropylethylamine (100 uL, 0.56 mmol), DMAP (20 mg, 0.014 mmol) and 1,2-dimethyl-1H-imidazole-4-sulfonyl chloride (33 mg, 0.168 mmol). The reaction mixture was stirred at room temperature overnight. The solution was filtered. The filtrate was concentrated and the residue was purified by using a Gilson semi-preparative HPLC system, eluting with 10% B to 80% B, where A=H2O (0.1% trifluoroacetic acid) and B=CH3CN (0.1% trifluoroacetic acid) pumped at 25 mL/min to afford the title compound (25 mg, 37%)