Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:26])[CH2:9][N:10]([CH3:25])[S:11]([C:14]2[C:15]3[CH2:23][CH2:22][CH2:21][C:20](=[O:24])[C:16]=3[S:17][C:18]=2Br)(=[O:13])=[O:12])=[CH:4][CH:3]=1.[CH3:27][O-:28].[Na+].CO.O>CO>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:26])[CH2:9][N:10]([CH3:25])[S:11]([C:14]2[C:15]3[CH2:23][CH2:22][CH2:21][C:20](=[O:24])[C:16]=3[S:17][C:18]=2[O:28][CH3:27])(=[O:13])=[O:12])=[CH:4][CH:3]=1
Reactant: CN(CC(O)c1ccc(F)cc1)S(=O)(=O)c1c(Br)sc2c1CCCC2=O
Reactant: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COc1sc2c(c1S(=O)(=O)N(C)CC(O)c1ccc(F)cc1)CCCC2=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 2-bromo-7-oxo-4,5,6,7-tetrahydro-benzo[b]thiophene-3-sulfonic acid [2-(4-fluorophenyl)-2-hydroxy-ethyl]-methyl-amide (the compound of Preparation Example 58) (80 mg) in methanol (3 mL) was added a solution of 28% sodium methoxide/methanol (0.8 mL). After stirring at room temperature for 3 hours, the reaction solution was poured into water, extracted with ethyl acetate and dried with anhydrous magnesium sulfate. The residue resulting from the removal of the solvent by evaporation was purified by silica gel column chromatography (hexane/ethyl acetate), and the title compound (58 mg) was obtained as a light brown candy-like substance.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][C:7]1[CH:12]=[C:11]([NH:13]C(=O)C(F)(F)F)[CH:10]=[CH:9][C:8]=1[S:20](Cl)(=[O:22])=[O:21].[NH2:24][C:25]1[CH:26]=[CH:27][C:28]2[CH2:32][O:31][B:30]([OH:33])[C:29]=2[CH:34]=1.N1C=CC=CC=1>C(#N)C>[NH2:13][C:11]1[CH:10]=[CH:9][C:8]([S:20]([NH:24][C:25]2[CH:26]=[CH:27][C:28]3[CH2:32][O:31][B:30]([OH:33])[C:29]=3[CH:34]=2)(=[O:21])=[O:22])=[C:7]([CH2:6][C:2]2[O:1][CH:5]=[CH:4][N:3]=2)[CH:12]=1
Reactant: O=C(Nc1ccc(S(=O)(=O)Cl)c(Cc2ncco2)c1)C(F)(F)F
Reactant: Nc1ccc2c(c1)B(O)OC2
Solvent: c1ccncc1
Solvent: CC#N
Product: Nc1ccc(S(=O)(=O)Nc2ccc3c(c2)B(O)OC3)c(Cc2ncco2)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a stirred solution of 2-(oxazol-2-ylmethyl)-4-(2,2,2-trifluoroacetamido)benzene-1-sulfonyl chloride (450 mg, 1.2 mmol) and 6-aminobenzo[c][1,2]oxaborol-1(3H)-ol (212 mg, 1.42 mmol) in 10 mL of ACN was added pyridine (228 uL, 2.8 mmol) dropwise. The reaction mixture was stirred at room temperature for 3 hours. After the mixture was concentrated, the residue was extracted with ethyl acetate and washed with water, 1N HCl and brine. The organic layer was dried over Na2SO4 and concentrated to give the desired compound as a yellow residue (540 mg, yield 92%). A small portion of the crude mixture was purified by prep HPLC (SunFire Prep C18 OBD 5 uM 30×50 mm column) to give the title compound as a yellow solid.
Reaction SMILES: Br[C:2]1[C:11]2[CH2:10][CH2:9][CH2:8][CH:7]([NH:12][C:13](=[O:16])[CH2:14][CH3:15])[C:6]=2[CH:5]=[N:4][CH:3]=1.[F:17][C:18]1[CH:19]=[C:20](B(O)O)[CH:21]=[CH:22][C:23]=1[C:24]([F:27])([F:26])[F:25]>>[F:17][C:18]1[CH:19]=[C:20]([C:2]2[C:11]3[CH2:10][CH2:9][CH2:8][CH:7]([NH:12][C:13](=[O:16])[CH2:14][CH3:15])[C:6]=3[CH:5]=[N:4][CH:3]=2)[CH:21]=[CH:22][C:23]=1[C:24]([F:25])([F:26])[F:27]
Reactant: OB(O)c1ccc(C(F)(F)F)c(F)c1
Reactant: CCC(=O)NC1CCCc2c(Br)cncc21
Product: CCC(=O)NC1CCCc2c(-c3ccc(C(F)(F)F)c(F)c3)cncc21
Yield: 80 %

Procedure:
In analogy to the procedure described for the preparation of example 1, (rac)-N-(4-bromo-5,6,7,8-tetrahydroisoquinolin-8-yl)propionamide (intermediate A-1) was reacted with 3-fluoro-4-(trifluoromethyl)phenylboronic acid to give the title compound as light brown foam in 80% yield. MS: 367.1 (M+H+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:9]2[C:17]3[C:12](=[CH:13][N:14]=[C:15]([C:18]4[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=4)[CH:16]=3)[N:11](COCC[Si](C)(C)C)[N:10]=2)=[N:6][C:7]=1F.[NH:32]1[CH2:37][CH2:36][CH2:35][C@@H:34]([NH:38]C(=O)OC(C)(C)C)[CH2:33]1>>[Br:1][C:2]1[C:7]([N:32]2[CH2:37][CH2:36][CH2:35][C@@H:34]([NH2:38])[CH2:33]2)=[N:6][C:5]([C:9]2[C:17]3[C:12](=[CH:13][N:14]=[C:15]([C:18]4[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=4)[CH:16]=3)[NH:11][N:10]=2)=[CH:4][CH:3]=1
Reactant: C[Si](C)(C)CCOCn1nc(-c2ccc(Br)c(F)n2)c2cc(-c3cccnc3)ncc21
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCNC1
Product: N[C@@H]1CCCN(c2nc(-c3n[nH]c4cnc(-c5cccnc5)cc34)ccc2Br)C1
Yield: 35.9 %

Procedure:
Following the procedures as described in Example 241 and starting with 3-(5-bromo-6-fluoropyridin-2-yl)-5-(pyridin-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-c]pyridine and (R)-tert-butyl piperidin-3-ylcarbamate, 290 was obtained as an off-white solid (19.7 mg, 35.9%) over two steps. 1H NMR (400 MHz, DMSO) δ 9.31 (s, 1H), 9.22 (s, 1H), 9.03 (s, 1H), 8.59 (d, J=4.7 Hz, 1H), 8.46 (d, J=8.0 Hz, 1H), 8.05 (d, J=8.1 Hz, 1H), 7.70 (d, J=8.1 Hz, 1H), 7.62 (dd, J=11.8, 7.1 Hz, 1H), 7.54 (ddd, J=12.7, 7.2, 4.0 Hz, 2H), 3.92 (d, J=9.3 Hz, 1H), 3.84 (d, J=12.1 Hz, 1H), 2.88 (d, J=12.9 Hz, 2H), 2.81-2.69 (m, 1H), 1.95 (d, J=12.6 Hz, 1H), 1.90-1.69 (m, 2H), 1.26 (dd, J=22.3, 7.8 Hz, 1H); ESI MS m/z=450.1 (M+1)
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]([C:12]1[CH:13]=[N:14][C:15]([O:18][CH3:19])=[CH:16][CH:17]=1)=[O:11])([O-])=O>[Pd].C(O)C>[NH2:1][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]([C:12]1[CH:13]=[N:14][C:15]([O:18][CH3:19])=[CH:16][CH:17]=1)=[O:11]
Reactant: COc1ccc(C(=O)c2ccccc2[N+](=O)[O-])cn1
Agent: [Pd]
Solvent: CCO
Product: COc1ccc(C(=O)c2ccccc2N)cn1
Reaction time: 0.5 h
Yield: 87.4 %

Procedure:
10% Palladium on carbon (1 g) was added to a solution of (2-nitrophenyl)-(6-methoxypyridin-3-yl)methanone (3.6 g) in ethanol (100 ml) and the mixture was hydrogenated at 10 psi (0.7×105N.m-2) for 30 minutes. The reaction mixture was filtered then evaporated to dryness. The residue was purified by column chromatography on silica using ethyl acetate/petroleum ether (60-80) (1:4) to afford the title compound as a yellow solid (2.78 g). mp 60°-62° C. Rf =0.50 in 33% ethyl acetate/petroleum ether (60-80) on silica plates; 1H NMR (360 MHz, CDCl3) δ 4.01 (3H, s), 6.64 (1H, ddd, J=1.5 and 8 Hz), 6.74 (1H, d, J=8 Hz), 6.81 (1H, d, J=9 Hz), 7.29 (1H, ddd, J=1.5 and 8 Hz), 7.46 (1H, dd, J=1.5 and 8 Hz), 7.93 (1H, dd, J=3 and 9 Hz), 8.48 (1H, d, J=3 Hz); MS, m/z 228 for M+ ; IR (KBr) 1620 and 1600 cm-1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:14]=[C:13]([N:15]([CH3:21])[C:16](=[O:20])[CH2:17][O:18][CH3:19])[C:12]([C:22]#[N:23])=[CH:11][C:10]=1[C:24]1[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=1.CN(C)C=[C:34](C1C=CC(Cl)=CC=1)[C:35](C1C=CC(Cl)=CC=1Cl)=[O:36].COCC(Cl)=O.[H-].[Na+]>CN(C=O)C.C1COCC1>[Cl:30][C:27]1[CH:26]=[CH:25][C:24]([C:10]2[CH:11]=[C:12]3[C:13](=[N:14][C:9]=2[C:3]2[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=2[Cl:1])[N:15]([CH3:21])[C:16](=[O:20])[C:17]([O:18][CH3:19])=[C:22]3[NH:23][C:35](=[O:36])[CH3:34])=[CH:29][CH:28]=1
Reactant: CN(C)C=C(C(=O)c1ccc(Cl)cc1Cl)c1ccc(Cl)cc1
Reactant: COCC(=O)N(C)c1nc(-c2ccc(Cl)cc2Cl)c(-c2ccc(Cl)cc2)cc1C#N
Agent: COCC(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COc1c(NC(C)=O)c2cc(-c3ccc(Cl)cc3)c(-c3ccc(Cl)cc3Cl)nc2n(C)c1=O

Procedure:
N-(6-(2,4-dichlorophenyl)-5-(4-chlorophenyl)-3-cyanopyridin-2-yl)-2-methoxy-N-methylacetamide (368.5 mg, prepared by the reaction of the product of Step A Example 1 with 2-methoxyacetyl chloride using the conditions of EXAMPLE 62 Step A) was combined with THF (5 mL), DMF (0.5 mL) and NaH (48 mg, 60% dispersion in mineral oil). After 15 minutes the reaction was quenched with acetic acid (0.2 mL). The reaction was diluted with EtOAc and washed with saturated aqueous NaHCO3 solution and brine. The concentrated residue was suspended in THF (4 mL), DMF (0.5 mL) and acetyl chloride (0.5 mL). Once LC/MS indicated the acylation was complete, the reaction was diluted with EtOAc and washed with saturated aqueous NaHCO3 solution and brine. The concentrated residue was purified by flash chromatography on silica gel gradient eluted with 0-100% EtOAc in hexane affording the title compound. HPLC/MS: 502.0 (M+1), 504.00 (M+3); Rt=3.92 min.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[C:4]([CH3:9])[N:3]=1.[NH2:10][C@H:11]1[CH2:16][CH2:15][C@H:14]([OH:17])[CH2:13][CH2:12]1.C(=O)([O-])[O-].[K+].[K+].C(N(C(C)C)CC)(C)C>CC(N(C)C)=O.C(OCC)(=O)C>[NH2:1][C:2]1[N:7]=[C:6]([NH:10][C@H:11]2[CH2:16][CH2:15][C@H:14]([OH:17])[CH2:13][CH2:12]2)[CH:5]=[C:4]([CH3:9])[N:3]=1
Reactant: Cc1cc(Cl)nc(N)n1
Reactant: N[C@H]1CC[C@H](O)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: Cc1cc(N[C@H]2CC[C@H](O)CC2)nc(N)n1
Temperature: 160 °C

Procedure:
A mixture of 2-amino-4-chloro-6-methylpyrimidine (1.18 g, 8.24 mmol), trans-4-aminocyclohexanol (1.00 g, 6.60 mmol), potassium carbonate (1.82 g, 13.2 mmol), and diisopropylethyl amine (1.44 mL, 8.24 mmol) in dimethylacetamide (20.0 mL) was heated at 160° C. in a sealed tube overnight. The reaction mixture was diluted with ethyl acetate, filtered, and the filtrate was concentrated. The residue was purified by flash chromatography eluting with chloroform/7 N ammonia in methanol (0.5-5%) to afford the title compound as a foamy solid (1.47 g, 99%).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([NH:12][C:13]3[CH:18]=[CH:17][C:16]([S:19]([OH:22])(=[O:21])=O)=[CH:15][CH:14]=3)=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.Cl.S(Cl)(Cl)(=O)=O.[NH2:29][CH:30]1[CH2:35][CH2:34][CH2:33][N:32]([CH2:36][CH3:37])[CH2:31]1>>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([NH:12][C:13]3[CH:14]=[CH:15][C:16]([S:19]([NH:29][CH:30]4[CH2:35][CH2:34][CH2:33][N:32]([CH2:36][CH3:37])[CH2:31]4)(=[O:22])=[O:21])=[CH:17][CH:18]=3)=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1
Reactant: O=S(=O)(O)c1ccc(Nc2ccnc3cc(Br)ccc23)cc1
Reactant: CCN1CCCC(N)C1
Agent: Cl
Solvent: O=S(=O)(Cl)Cl
Product: CCN1CCCC(NS(=O)(=O)c2ccc(Nc3ccnc4cc(Br)ccc34)cc2)C1

Procedure:
4-(7-Bromo-4-quinolylamino)benzenesulphonic acid is converted to the corresponding sulphonyl chloride hydrochloride and reacted with 3-amino--ethylpiperidine in a similar manner to that described in Example 1(b) to give the title compound.
Reaction SMILES: COC1C=CC([C@H]([N:11]2[C:15](=[O:16])[CH2:14][C@@H:13]([C@H:17]([O:19][C:20]3[C:21]4[N:22]([N:41]=[CH:42][CH:43]=4)[CH:23]=[C:24]([C:26]4[N:31]=[CH:30][C:29]([N:32]5[CH2:37][CH2:36][N:35](C([O-])=O)[CH2:34][CH2:33]5)=[CH:28][CH:27]=4)[CH:25]=3)[CH3:18])[CH2:12]2)C)=CC=1>C(O)(C(F)(F)F)=O>[N:32]1([C:29]2[CH:28]=[CH:27][C:26]([C:24]3[CH:25]=[C:20]([O:19][C@@H:17]([C@H:13]4[CH2:12][NH:11][C:15](=[O:16])[CH2:14]4)[CH3:18])[C:21]4[N:22]([N:41]=[CH:42][CH:43]=4)[CH:23]=3)=[N:31][CH:30]=2)[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1
Reactant: COc1ccc([C@@H](C)N2C[C@H]([C@@H](C)Oc3cc(-c4ccc(N5CCN(C(=O)[O-])CC5)cn4)cn4nccc34)CC2=O)cc1
Solvent: O=C(O)C(F)(F)F
Product: C[C@@H](Oc1cc(-c2ccc(N3CCNCC3)cn2)cn2nccc12)[C@H]1CNC(=O)C1
Temperature: 60 °C

Procedure:
4-(6-(4-((R)-1-((R)-1-((R)-1-(4-methoxyphenyl)ethyl)-5-oxopyrrolidin-3-yl)ethoxy)pyrazolo[1,5-a]pyridin-6-yl)pyridin-3-yl)piperazine-1-carboxylate 6.20 (30 mg, 0.036 mmol) was dissolved in TFA (2.0 mL) and heated to 60° C. overnight. The reaction was concentrated to dryness (solvent exchange was performed with acetonitrile and toluene). The residue was passed through a polymer-supported bicarbonate column to provide (R)-4-((R)-1-((6-(5-(piperazin-1-yl)pyridin-2-yl)pyrazolo[1,5-a]pyridin-4-yl)oxy)ethyl)pyrrolidin-2-one 6.21, as the free base, and was used without further purification.
Reaction SMILES: [CH:1]1([C:6]([OH:18])([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)[C:7]([OH:9])=[O:8])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:19]12[CH2:24][CH:23]1[CH2:22][N:21]([CH2:25][C:26]#[C:27][CH2:28]O)[CH2:20]2>>[C@@H:19]12[CH2:24][C@@H:23]1[CH2:22][N:21]([CH2:25][C:26]#[C:27][CH2:28][O:8][C:7](=[O:9])[C:6]([C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=1)([CH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1)[OH:18])[CH2:20]2
Reactant: COc1ccc(C(O)(C(=O)O)C2CCCC2)cc1
Reactant: OCC#CCN1CC2CC2C1
Product: COc1ccc(C(O)(C(=O)OCC#CCN2C[C@H]3C[C@H]3C2)C2CCCC2)cc1

Procedure:
The title compound was prepared by following the procedure described in Step-b of Example-3, using 2-cyclopentyl-2-hydroxy-2-(4-methoxyphenyl)acetic acid instead of 2-cyclopentyl-2-hydroxy-2-phenyl acetic acid and 4-(3-azabicyclo[3.1.0]hex-3-yl)-2-butynol instead of 4-(1,5-dimethyl-3-azabicyclo[3.1.0]hex-3-yl)-2-butynol.
Reaction SMILES: [CH2:1]([O:5][C:6]1[C:15]([OH:16])=[C:14]2[C:9]([C:10](=[O:19])[CH2:11][C:12]([CH3:18])([CH3:17])[O:13]2)=[CH:8][CH:7]=1)[CH:2]([CH3:4])[CH3:3].S(OC)(O[CH3:24])(=O)=O>[OH-].[Na+].O>[CH2:1]([O:5][C:6]1[C:15]([O:16][CH3:24])=[C:14]2[C:9]([C:10](=[O:19])[CH2:11][C:12]([CH3:17])([CH3:18])[O:13]2)=[CH:8][CH:7]=1)[CH:2]([CH3:4])[CH3:3]
Reactant: COS(=O)(=O)OC
Reactant: CC(C)COc1ccc2c(c1O)OC(C)(C)CC2=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COc1c(OCC(C)C)ccc2c1OC(C)(C)CC2=O
Temperature: 50 °C
Reaction time: 3 h
Yield: 93 %

Procedure:
In 50 ml of a 10% sodium hydroxide solution under nitrogen 5.2 g (20 millimoles) of 7-isobutoxy-8-hydroxy-2,2-dimethyl-4-chromanone are dissolved, whereupon 2.6 g (2 ml, 21 millimoles) of dimethyl sulfate are added and the reaction mixture is intensively stirred for 3 hours at 50° C. The mixture is diluted with 100 ml of icecold water, extracted three times with 50 ml of chloroform each, the organic phase is washed twice with 40 ml of water dried over sodium sulfate and the solvent is evaporated. Thus 5.2 g of the desired compound are obtained in the form of yellow oil, yield 93%.
Reaction SMILES: [Cl:1][CH2:2][C:3](=[N:17][OH:18])[CH2:4][O:5][C:6]1[C:10]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)=[N:9][S:8][N:7]=1.Cl>CCOCC>[ClH:1].[CH:3]([NH:17][CH2:2][C:3](=[N:17][OH:18])[CH2:4][O:5][C:6]1[C:10]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)=[N:9][S:8][N:7]=1)([CH3:4])[CH3:2]
Reactant: ON=C(CCl)COc1nsnc1N1CCOCC1
Agent: Cl
Solvent: CCOCC
Product: CC(C)NCC(COc1nsnc1N1CCOCC1)=NO
Reaction time: 0.17 h
Yield: 89 %

Procedure:
The oxime 4b (0.25 g) was dissolved in ether and ether saturated with HCl was introduced dropwise into the solution. The mixture was stirred for 10 minutes, filtered and dried in vacuo overnight. Yield: 89%. Anal. (C12H22N5O3SCl) C,H,N.
Reaction SMILES: C1([C@H]([NH:9][C@@H:10]2[C:19]3[CH2:18][O:17][CH:16]=[CH:15][C:14]4=[CH:20][NH:21][CH:22]=[C:12]([C:13]=34)[CH2:11]2)C)C=CC=CC=1.[H][H]>O1CCCC1.[OH-].[Pd+2].[OH-]>[CH:22]1[NH:21][CH:20]=[C:14]2[CH:15]=[CH:16][O:17][CH2:18][C:19]3[C@@H:10]([NH2:9])[CH2:11][C:12]=1[C:13]2=3
Reactant: [H][H]
Reactant: C[C@@H](N[C@H]1CC2=CNC=C3C=COCC1=C32)c1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: C1CCOC1
Product: N[C@H]1CC2=CNC=C3C=COCC1=C32
Yield: 86 %

Procedure:
Compound (29) 609 mg was dissolved in tetrahydrofuran 20 ml. 20% Palladium(II)hydroxide 200 mg was added. A mixture was stirred in a hydrogen atomosphere for 22 h. The catalyst was filtered off and the filtrate was concentrated under reduced pressure. The residue obtained was chromatographed on aluminum oxide in chloroform to give the titled compound (31) as pale brown crystals, 337 mg. Yield 86%. Furthermore, this was recrystallized from methanol-isopropanol to give the titled compound (31) as pale brown crystals, m.p. 202-203° C.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:10]2[C:15]([F:16])=[CH:14][C:13]([C:17]([OH:20])([CH3:19])[CH3:18])=[CH:12][C:11]=2F)=[CH:5][C:6]=1[C:7]([NH2:9])=[O:8].Br[C:23]1[N:28]=[C:27]([CH2:29][N:30]2[CH2:34][C@H:33]([OH:35])[CH2:32][C:31]2=[O:36])[CH:26]=[CH:25][CH:24]=1>>[F:16][C:15]1[CH:14]=[C:13]([C:17]([OH:20])([CH3:19])[CH3:18])[CH:12]=[CH:11][C:10]=1[C:4]1[S:3][C:2]([NH:1][C:23]2[CH:24]=[CH:25][CH:26]=[C:27]([CH2:29][N:30]3[CH2:34][C@H:33]([OH:35])[CH2:32][C:31]3=[O:36])[N:28]=2)=[C:6]([C:7]([NH2:9])=[O:8])[CH:5]=1
Reactant: O=C1C[C@@H](O)CN1Cc1cccc(Br)n1
Reactant: CC(C)(O)c1cc(F)c(-c2cc(C(N)=O)c(N)s2)c(F)c1
Product: CC(C)(O)c1ccc(-c2cc(C(N)=O)c(Nc3cccc(CN4C[C@H](O)CC4=O)n3)s2)c(F)c1

Procedure:
The title compound was prepared as described in Example 1 using 2-amino-5-[2,6-difluoro-4-(1-hydroxy-1-methylethyl)phenyl]thiophene-3-carboxamide (0.16 g, 0.54 mmol) and (4R)-1-[(6-bromopyridin-2-yl)methyl]-4-hydroxypyrrolidin-2-one (0.14 g, 0.53 mmol) as the starting materials.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([CH3:30])=[C:7]([C:13]3[CH:29]=[CH:28][C:16]([C:17]([NH:19][CH2:20][CH2:21][N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)=[O:18])=[CH:15][CH:14]=3)[C:8](=[O:12])[O:9]2)=[CH:4][CH:3]=1.C1N2CN3CN(C2)CN1C3.[C:41](O)(C(F)(F)F)=[O:42]>>[CH:41]([C:11]1[C:2]([OH:1])=[CH:3][CH:4]=[C:5]2[C:10]=1[O:9][C:8](=[O:12])[C:7]([C:13]1[CH:14]=[CH:15][C:16]([C:17]([NH:19][CH2:20][CH2:21][N:22]3[CH2:23][CH2:24][O:25][CH2:26][CH2:27]3)=[O:18])=[CH:28][CH:29]=1)=[C:6]2[CH3:30])=[O:42]
Reactant: O=C(O)C(F)(F)F
Reactant: Cc1c(-c2ccc(C(=O)NCCN3CCOCC3)cc2)c(=O)oc2cc(O)ccc12
Agent: C1N2CN3CN1CN(C2)C3
Product: Cc1c(-c2ccc(C(=O)NCCN3CCOCC3)cc2)c(=O)oc2c(C=O)c(O)ccc12
Temperature: 115 °C
Yield: 31 %

Procedure:
A mixture of 4-(7-hydroxy-4-methyl-2-oxo-2H-chromen-3-yl)-N-(2-morpholinoethyl)benzamide (3) (8.17 g, 20.0 mmol) and hexamethylenetetramine (11.22 g, 80.0 mmol) in TFA (200 mL) was heated in a pressure flask in a 115° C. oil bath for 40 minutes. This process was repeated once. Upon cooling, the unified solutions were evaporated to 158 g weight and, after addition of CH2Cl2 (500 mL) and water (100 mL) it was cooled to 0° C. The mixture was neutralized with NaOH (2N, 350 mL) and then close to the end point with NaHCO3 (10%) with cooling and stirring. The product was extracted with CH2Cl2 (5×100 mL), washed with water (backextracted), dried on MgSO4 and evaporated to afford 17.2 g crude product. The crude product was loaded on 40 g silica and purified by medium pressure chromatography (4×100 g columns) using 1-3% MeOH in CH2Cl2 by collecting the front fractions to afford 6.2 g (31%) of the title compound. This product can be turned into its HCl salt by dissolving it in EtOH (100 mL) and adding 6N HCl (10 mL). The salt was filtered and washed with 70% EtOH (2×20 mL), dried on air then at 50° C. under 5 Hgmm vacuum to afford 6.0 g HCl salt of the title compound.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][C:13](=O)[CH2:12][CH2:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[F:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH:25]=2)=[CH:20][CH:19]=1>>[F:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[CH2:29][CH2:28][N:27]([CH:13]3[CH2:14][CH2:15][N:10]([C:7]4[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=4)[CH2:11][CH2:12]3)[CH2:26][CH:25]=2)=[CH:20][CH:19]=1
Reactant: O=C1CCN(c2ccc([N+](=O)[O-])cc2)CC1
Reactant: Fc1ccc(C2=CCNCC2)cc1
Product: O=[N+]([O-])c1ccc(N2CCC(N3CC=C(c4ccc(F)cc4)CC3)CC2)cc1

Procedure:
5.5 g of 1-(4-nitrophenyl)-4-piperidone and 4.4 g of 4-(4-fluorophenyl)-1,2,5,6-tetrahydropyridine were reacted as in Example 1. The product crystallized as fumarate.
Reaction SMILES: [OH:1][C@@:2]1([CH3:20])[C:7](=[N:8][CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][C@H:5]2[CH2:17][C@@H:3]1[C:4]2([CH3:19])[CH3:18].C[Mg]Br.C(OCC)C.N12CCCN=C1CCCCC2.[C:40]([O:45][CH2:46][CH3:47])(=[O:44])/[CH:41]=[CH:42]/[CH3:43]>O1CCCC1>[OH:1][C@@:2]1([CH3:20])[C:7](=[N:8][C@H:9]([C:10]([O:12][C:13]([CH3:14])([CH3:16])[CH3:15])=[O:11])[CH:42]([CH3:43])[CH2:41][C:40]([O:45][CH2:46][CH3:47])=[O:44])[CH2:6][C@H:5]2[CH2:17][C@@H:3]1[C:4]2([CH3:19])[CH3:18]
Reactant: CC(C)(C)OC(=O)CN=C1C[C@H]2C[C@H](C2(C)C)[C@@]1(C)O
Reactant: C/C=C/C(=O)OCC
Agent: C[Mg]Br
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: C1CCC2=NCCCN2CC1
Product: CCOC(=O)CC(C)[C@H](N=C1C[C@H]2C[C@H](C2(C)C)[C@@]1(C)O)C(=O)OC(C)(C)C
Temperature: -30 °C
Reaction time: 0.33 h

Procedure:
A solution of 1,1-dimethylethyl N-[(1R,2R,5R)-2-hydroxy-2,6,6-trimethylbicyclo[3.1.1]hept-3-ylidene]glycinate (11.05 g, 39.3 mmol) in anhydrous tetrahydrofuran (100 ml) was cooled to −30° C. and treated with a 3M solution of methylmagnesium bromide in diethyl ether (17.1 ml, 51.1 mmol). 1,8-Diazabicyclo[5.4.0]undec-7-ene (7.78 g, 51.1 mmol) was then added and the mixture was stirred for an additional 20 minutes at −30° C. The mixture was then treated with ethyl crotonate and stirring continued for 1 hr. The mixture was quenched by addition of saturated aqueous ammonium chloride solution (35 ml) and then extracted with ethyl acetate (3×100 ml). The combined organic extracts were dried over sodium sulphate, filtered and evaporated to give a yellow oil. This material was purified by automated flash silica-gel column chromatography (using a Biotage SP4), eluting with a gradient of 0-20% (over 5 column volumes) then 20-35% (over 14 column volumes) ethyl acetate in hexane, to give 1-(1,1-dimethylethyl) 5-ethyl N-[(1R,2R,5R)-2-hydroxy-2,6,6-trimethylbicyclo[3.1.1]hept-3-ylidene]-3-methylglutamate (4.2 g) which was used in the next step.
Reaction SMILES: C1(C)C=CC(S([O:10][S:11]([C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=2)(=[O:13])=[O:12])(=O)=O)=CC=1.[C:22]([N:30]1[CH2:35][CH2:34][CH:33]([CH2:36][CH2:37]O)[CH2:32][CH2:31]1)(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(N(CC)CC)C>ClCCl.C(OCC)(=O)C>[C:22]([N:30]1[CH2:35][CH2:34][CH:33]([CH2:36][CH2:37][O:10][S:11]([C:14]2[CH:15]=[CH:16][C:17]([CH3:20])=[CH:18][CH:19]=2)(=[O:12])=[O:13])[CH2:32][CH2:31]1)(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: Cc1ccc(S(=O)(=O)OS(=O)(=O)c2ccc(C)cc2)cc1
Reactant: O=C(c1ccccc1)N1CCC(CCO)CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: Cc1ccc(S(=O)(=O)OCCC2CCN(C(=O)c3ccccc3)CC2)cc1
Reaction time: 2 h
Yield: 88.9 %

Procedure:
A solution of p-toluene sulfonic anhydride (6.0 g, 18 mmol) in dichloromethane (50 mL) was added dropwise over 1 hour to a room temperature solution of 1-benzoyl-4-hydroxyethylpiperidine (4.3 g, 18 mmol) and dry triethylamine (2.8 mL, 2 mmol) in dichloromethane. After 2 hours, the mixture was diluted with ethyl acetate (500 mL) and extracted successively with H2O (2 ×100 mL), cold 0.1 M aqueous HCl (100 mL), saturated aqueous NaHCO3 (100 mL), and brine (50 mL), dried (MgSO4), filtered, and concentrated in vacuo. The crude product was purified by chromatography on silica gel, eluting with ethyl acetate, and concentrated to yield a crystalline solid (6.2 g, 89%) which melted at 81°-83° C. Analysis: Calculated for C21H25NO4S: C,65.09; H,6.50; N,3.61; S,8.27; found: C.,65.31; H,6.74; N,3.41; S,8.30.
Reaction SMILES: O.Cl.[Cl:3][C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[C:6]([C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])[CH:5]=1.C1CCCCC1.[OH-].[Na+].[C:25](O)([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>CC1C=CC(S(O)(=O)=O)=CC=1.O.CC(OC)(C)C>[C:26]1([C:25]([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)([C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=2)[NH:8][C:7]2[CH:9]=[CH:10][C:4]([Cl:3])=[CH:5][C:6]=2[C:11](=[O:16])[C:12]([F:14])([F:15])[F:13])[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: OC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: Nc1ccc(Cl)cc1C(=O)C(F)(F)F
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Agent: [Na+]
Solvent: COC(C)(C)C
Solvent: O
Solvent: C1CCCCC1
Product: O=C(c1cc(Cl)ccc1NC(c1ccccc1)(c1ccccc1)c1ccccc1)C(F)(F)F
Yield: 89.3 %

Procedure:
4-Chloro-2-trifluoroacetylaniline, hydrochloride hydrate (84.4 g, 304 mmol), cyclohexane (350 mL), MTBE (95 mL), and water (100 mL) were stirred at room temperature. The resulting slurry was neutralized with 30 mL 10 N NaOH. To the organic phase was added trityl alcohol (91.0 g, 350 mmol) and TsOH (0.36 g, 1.9 mmol). The mixture was heated to reflux and 300 mL of solvent was distilled. Acetonitrile (350 mL) and diisopropylethyl amine (0.5 mL) were added and the distillation continued to remove 220 mL additional solvent. The solution was cooled in an ice bath and the product filtered to give 126.5 g (89%) of product with the same spectral and physical properties as the sample prepared in Method A.