Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS(Cl)(=O)=O.[C:6]1([C:12]2[CH:27]=[C:26]3[C:15]([CH2:16][C:17]4[CH:21]=[CH:20][N:19]([CH2:22][C@H:23](O)[CH3:24])[C:18]=43)=[CH:14][CH:13]=2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.C(N(CC)CC)C.[N-:35]=[N+:36]=[N-:37].[Na+]>ClCCl.CN(C)C=O.O>[N:35]([C@@H:23]([CH3:24])[CH2:22][N:19]1[CH:20]=[CH:21][C:17]2[CH2:16][C:15]3[C:26]([C:18]1=2)=[CH:27][C:12]([C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1)=[CH:13][CH:14]=3)=[N+:36]=[N-:37]
Reactant: [N-]=[N+]=[N-]
Reactant: C[C@@H](O)Cn1ccc2c1-c1cc(-c3ccccc3)ccc1C2
Agent: CS(=O)(=O)Cl
Agent: [Na+]
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@@H](Cn1ccc2c1-c1cc(-c3ccccc3)ccc1C2)N=[N+]=[N-]
Yield: 39.3 %

Procedure:
0.82 ml of methanesulfonyl chloride was added dropwise while stirring to a solution, cooled to 0°, of 1.5 g of (R)-1-(7-phenyl-1,4-dihydro-indeno[1,2-b]pyrrol-1-yl)-propan-2-ol and 3 ml of triethyl-amine in 50 ml of dichloromethane and the mixture was stirred at this temperature for an additional 1.5 hours. The reaction mixture was subsequently diluted with 150 ml of dichloromethane, washed twice with 70 ml of saturated sodium hydrogen carbonate solution each time and the combined aqueous phases were extracted once with 70 ml of dichloromethane. The combined organic phases were washed with 100 ml of saturated sodium chloride solution, dried over magnesium sulfate and evaporated in a vacuum. The green solid obtained was dissolved in 50 ml of anhydrous dimethylformamide, treated with 0.53 g of sodium azide and the reaction mixture was heated to 60° for 15 hours while stirring. After cooling, the solution was poured into 100 ml of water and extracted twice with 100 ml of ethyl acetate each time. The combined organic phases were washed once with 80 ml of water and once with 100 ml of saturated sodium chloride solution, dried over magnesium sulfate and the solution was concentrated in a vacuum. The brown oil obtained was purified by column chromatography on silica gel (toluene). 0.64 g (39%) of (S)-1-(2-azido-propyl)-7-phenyl-1,4-dihydro-indeno[1,2-b]pyrrole was obtained as a brown oil.
Reaction SMILES: [Cl:1][C:2]1[NH:7][CH:6]([CH3:8])[N:5]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[CH:10]=2)[C:3]=1[C:18]([O:20][CH2:21][CH3:22])=[O:19].C(N(CC)CC)C.C(Cl)(Cl)Cl.Cl[C:35]([O:37][CH3:38])=[O:36]>>[Cl:1][C:2]1[N:7]=[C:6]([CH3:8])[N:5]([C:35]([O:37][CH3:38])=[O:36])[CH:4]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[CH:10]=2)[C:3]=1[C:18]([O:20][CH2:21][CH3:22])=[O:19]
Reactant: CCOC(=O)C1=C(Cl)NC(C)N=C1c1cccc([N+](=O)[O-])c1
Reactant: COC(=O)Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCOC(=O)C1=C(Cl)N=C(C)N(C(=O)OC)C1c1cccc([N+](=O)[O-])c1

Procedure:
To a solution of 6-chloro-5-ethoxycarbonyl-2-methyl-4-(3'-nitrophenyl)-dihydropyrimidine (0.5 g, 1.54 millimole) and triethylamine (1.6 g, 16 millimole) in 20 ml of chloroform 1.46 g (15.4 millimole) of methyl chloroformate was added dropwise with stirring in ice and the mixture was stirred at room temperature for 3 hours. The reaction solution was washed with 2% aqueous NaOH solution and then water, dried and evaporated to obtain 0.5 g of the title product as oil.
Reaction SMILES: S(=O)(=O)(O)O.[O:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1.[OH-:11].[Na+]>O>[CH3:7][CH2:8][CH2:9][CH2:10][O:6][C@H:8]([CH2:7][OH:11])[CH2:9][CH3:10]
Reactant: C1CCOC1
Reactant: [OH-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: CCCCO[C@@H](CC)CO
Reaction time: 0.67 h

Procedure:
In the same reaction apparatus as in Example 15, 120 g of 25% fuming sulfuric acid was dropped from the dropping funnel into 600 g of tetrahydrofuran at -20° C. with stirring over a period of 40 minutes, and then the resulting mixture was subjected to reaction at -20° C. for 2 hours. The conversion at the end of this reaction was 32%. Then, the internal temperature was elevated to 10° C., at which the mixture was subjected to reaction for 2 hours. Thereafter, 10 g of water was added to terminate the polymerization. The final conversion was 57%. Then, the dropping funnel was replaced by the distilling column, and the contents in the apparatus were stirred vigorously and mixed with a solution prepared by dissolving 52 g of sodium hydroxide in 250 g of water (neutralization degree: 50%, corresponding to 20% by weight sulfuric acid concentration), and the mixture was heated and hydrolyzed in an oil bath at 80° C. for 2 hours while recovering unreacted tetrahydrofuran. In the same manner as in Example 15, the reaction mixture was allowed to stand to cause separation of layers. The aqueous layer was withdrawn and the PTMG layer was subjected twice to a heating and washing treatment with 300 g of a 15% by weight sodium sulfate solution at 120° C. The residual unreacted tetrahydrofuran was recovered in the first treatment. Thereafter, the same treatment as in Example 15 was conducted and finally the reaction product was filtered through a 10-μ mesh membrane filter to obtain PTMG. The results of analyses thereof were as shown in Table 2.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[C:8]([N+:11]([O-])=O)[CH:9]=[CH:10][C:5]=2[N:4]=[CH:3]1>C(O)C.[Pd]>[CH3:1][N:2]1[C:6]2[CH:7]=[C:8]([NH2:11])[CH:9]=[CH:10][C:5]=2[N:4]=[CH:3]1
Reactant: Cn1cnc2ccc([N+](=O)[O-])cc21
Agent: [Pd]
Solvent: CCO
Product: Cn1cnc2ccc(N)cc21
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Pd/C (17 mg, 10%, with 50% water) was added into the suspension of 1-methyl-6-nitro-1H-1,3-benzimidazole (85.0 mg, 0.480 mmol) in ethanol (3 mL). The mixture was degassed and filled with H2. The mixture was stirred at rt under balloon pressure for 16 h. After that time, the mixture was filtered and concentrated in vacuo to obtain the title compound as pink crystals. 1H NMR (CD3OD, 400 MHz): δ=3.67 (s, 3H), 6.69-6.73 (m, 2H), 7.33 (dd, 1H, J=0.4 & 8.8 Hz), 7.77 (s, 1H). MS (ES+): m/z 148.16 (100) [MH+]. HPLC: tR=0.43 min (ZQ2000, polar—5 min).
Reaction SMILES: C1(P([N:15]=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.C(N(CC)CC)C.[Br:25][C:26]1[C:27](C(O)=O)=[N:28][C:29]([Br:32])=[CH:30][N:31]=1>C(O)(C)(C)C>[Br:25][C:26]1[C:27]([NH2:15])=[N:28][C:29]([Br:32])=[CH:30][N:31]=1
Reactant: O=C(O)c1nc(Br)cnc1Br
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: CC(C)(C)O
Solvent: CCN(CC)CC
Product: Nc1nc(Br)cnc1Br
Reaction time: 0.5 h

Procedure:
Diphenylphosphorylazide (2.59 mL, 12 mmol) and triethylamine (1.67 mL, 12 mmol) are added to a solution of 3,6-dibromo-pyrazin-2-carboxylic acid (3.52 g, 12 mmol) in t-butanol (90 mL). The reaction is heated at reflux for 18 hours. The reaction is quenched with water, then concentrated in vacuo and taken up in DCM. The organic solution is washed with water and 1N NaOH, dried over MgSO4 and concentrated in vacuo. The resultant solid is filtered through a pad of silica using EtOAc, then concentrated and TFA:DCM (4:1, 12 mL) is added to the solid and stirred for 30 min. The solution is concentrated in vacuo then neutralised with 1N NaOH and extracted with DCM. The organic layer is dried over anhydrous MgSO4 and concentrated in vacuo to give the product. 1H NMR (250 MHz, DMSO-d6) δ(ppm) 7.25 (br s, 2H), 7.68 (s, 1H); m/z (APCI) 254 (M+H)+; m.p 135-139° C.
Reaction SMILES: BrC1N2C=NC=C2C(=O)[N:4]([CH2:12][C:13]2C=C[C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)C=1.Br[C:22]1[CH:23]=[CH:24][C:25]2[O:29][N:28]=[C:27]([N:30]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[C:26]=2[CH:45]=1>>[CH3:20][O:19][C:16]1[C:15]([C:22]2[CH:23]=[CH:24][C:25]3[O:29][N:28]=[C:27]([N:30]([C:31]([O:33][C:34]([CH3:35])([CH3:36])[CH3:37])=[O:32])[C:38]([O:40][C:41]([CH3:42])([CH3:44])[CH3:43])=[O:39])[C:26]=3[CH:45]=2)=[CH:14][CH:13]=[CH:12][N:4]=1
Reactant: COc1ccc(Cn2cc(Br)n3cncc3c2=O)cc1
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1noc2ccc(Br)cc12
Product: COc1ncccc1-c1ccc2onc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c2c1
Yield: 71 %

Procedure:
Following the procedure as described in EXAMPLE 4 and making non-critical variations to replace 5-bromo-7-(4-methoxybenzyl)imidazo[1,5-a]pyrazin-8(7H)-one with di-tert-butyl (5-bromo-1,2-benzoxazol-3-yl)imidodicarbonate, di-tert-butyl [5-(2-methoxypyridin-3-yl)-1,2-benzoxazol-3-yl]imidodicarbonate was obtained as a yellow solid in 71% yield (0.471 g): MS (ES+) m/z 441.9 (M+1).
Reaction SMILES: [OH-].[Li+].[CH2:3]([C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[C:15]([C:19]([O:21]C)=[O:20])=[CH:14][CH:13]=[CH:12]2)[CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]>>[CH2:3]([C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[C:15]([C:19]([OH:21])=[O:20])=[CH:14][CH:13]=[CH:12]2)[CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCc1ccc2c(C(=O)OC)cccc2c1
Agent: [Li+]
Agent: [OH-]
Product: CCCCCCc1ccc2c(C(=O)O)cccc2c1
Temperature: 40 °C
Reaction time: 24 h
Yield: 97.3 %

Procedure:
Aqueous 1 N lithium hydroxide (3.6 mL, 3.6 mmol) was added to a solution of methyl 6-hexyl-1-naphthoate (198 mg, 0.73 mmol) THF (16 mL) in a scintillation vial. The vial was sealed and heated at 40° C. After 24 h, the reaction mixture was allowed to cool and the volatiles were evaporated under a stream of nitrogen. The residue was diluted with water (3 mL), acidified with 1 N aqueous HCl (5 mL) and extracted with EtOAc. (2×50 mL). The combined organic phase was dried (Na2SO4), filtered and concentrated in vacuo to afford 182 mg (97%) of 6-hexyl-1-naphthoic acid, which was used without hither purification.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[NH:18][N:17]=[N:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH2:21](Br)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([C:14]2[N:15]=[N:16][N:17]([CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[N:18]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(c2nnn[nH]2)CC1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(c2nnn(Cc3ccccc3)n2)CC1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 14.6 %

Procedure:
A solution of 438 mg (1.7 mmol) of 1-(t-butoxycarbonyl)-4-(1H-tetrazol-5-yl)piperidine (from Step B) in 2 mL of DMF at 0° C. was treated with 83 mg (0.50 mmol) of sodium hydride (60% in mineral oil) and 0.41 mL (3.4 mmol) of benzyl bromide. The resulting mixture was warmed to rt and stirred for 2.5 h. The mixture was partitioned between 50 mL of ether and 50 mL of water and the layers were separated. The organic layer was washed with 50 mL sat'd brine, dried over magnesium sulfate and concentrated. Flash chromatography using 2:1 v/v methylene chloride/ether, then 1:2 v/v methylene chloride/ether afforded 85 mg (15%) of 1-(t-butoxycarbonyl)-4-(2-(benzyl)-(2H)tetrazol-5-yl)piperidine. Elution with 2:1 v/v ethyl acetate/methylene chloride afforded 95 mg (17%) of 1-(t-butoxycarbonyl)-4-(1-(benzyl)-(1H)-tetrazol-5-yl)piperidine.
Reaction SMILES: [CH2:1]([N:3]1[C:15]2[CH:14]=[CH:13][C:12]([CH:16]=O)=[CH:11][C:10]=2[C:9]2[C:4]1=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH3:2].[NH:18]1[CH2:23][CH2:22][CH:21]([C:24]2[CH:25]=[C:26]([NH:30][C:31]([CH:33]3[CH2:35][CH2:34]3)=[O:32])[CH:27]=[CH:28][CH:29]=2)[CH2:20][CH2:19]1>CC(O)=O>[CH2:1]([N:3]1[C:15]2[CH:14]=[CH:13][C:12]([CH2:16][N:18]3[CH2:23][CH2:22][CH:21]([C:24]4[CH:25]=[C:26]([NH:30][C:31]([CH:33]5[CH2:34][CH2:35]5)=[O:32])[CH:27]=[CH:28][CH:29]=4)[CH2:20][CH2:19]3)=[CH:11][C:10]=2[C:9]2[C:4]1=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH3:2]
Reactant: CCn1c2ccccc2c2cc(C=O)ccc21
Reactant: O=C(Nc1cccc(C2CCNCC2)c1)C1CC1
Solvent: CC(=O)O
Product: CCn1c2ccccc2c2cc(CN3CCC(c4cccc(NC(=O)C5CC5)c4)CC3)ccc21

Procedure:
Prepared by Procedure F and Scheme R, without HOAc, using 9-ethyl-9H-carbazole-3-carbaldehyde and N-[3-(4-piperidinyl)phenyl]cyclopropanecarboxamide: ESMS m/e: 452.6 (M+H)+.
Reaction SMILES: C(O[C@@H:10]1[C@H:16]2[C@H:17]3[C@H:26]([CH2:27][CH2:28][C@:13]2([CH2:14][CH3:15])[C:12](=[O:31])[CH2:11]1)[C@@H:25]1[C:20]([CH:21]=[C:22]([O:29]C)[CH2:23][CH2:24]1)=[CH:19][CH2:18]3)(=O)C1C=CC=CC=1.[C-:32]#[C-:33].[Li+].[Li+].[Cl-].[NH4+]>C(OCC)(=O)C>[C:32]([C@:12]1([OH:31])[CH:11]=[CH:10][C@H:16]2[C@H:17]3[C@H:26]([CH2:27][CH2:28][C@:13]12[CH2:14][CH3:15])[C@@H:25]1[C:20](=[CH:21][C:22](=[O:29])[CH2:23][CH2:24]1)[CH2:19][CH2:18]3)#[CH:33]
Reactant: CC[C@]12CC[C@H]3[C@@H](CC=C4C=C(OC)CC[C@@H]43)[C@@H]1[C@@H](OC(=O)c1ccccc1)CC2=O
Reactant: [C-]#[C-]
Agent: [Cl-]
Agent: [Li+]
Agent: [NH4+]
Solvent: CCOC(C)=O
Product: C#C[C@]1(O)C=C[C@H]2[C@@H]3CCC4=CC(=O)CC[C@@H]4[C@H]3CC[C@@]21CC

Procedure:
As described in 1(b), 3.6 g of 15α-benzoyloxy-3-methoxy-18-methyl-3,5-estradien-17-one is reacted with lithium acetylide. After completed reaction, the reaction mixture is combined with saturated ammonium chloride solution, diluted with ethyl acetate, washed with water, and dried over sodium sulfate. The resultant 17α-ethynyl-3-methoxy-18-methyl-3,5,15-estratrien-17β-ol is stirred, in the form of the crude product, in 70 ml of methanol and 6 ml of water with 3 g of oxalic acid for 10 minutes under reflux. The reaction mixture is introduced into ice/water. The thus-precipitated product is suctioned off, dissolved in ethyl acetate, washed with water, and dried over sodium sulfate. Recrystallization from acetone/hexane yields 1.9 g of 17α-ethynyl-17β-hydroxy-18-methyl-4,15-estradien-3-one, melting point 197.8° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH2:9][NH:10][C:11]([C:13]1[C:14](=[O:38])[C:15]([O:28][CH2:29][O:30][C:31]([O:33][CH2:34][C:35](O)=[O:36])=[O:32])=[C:16]2[C:21](=[O:22])[N:20]3[C@@H:23]([CH3:26])[CH2:24][O:25][C@@H:19]3[CH2:18][N:17]2[CH:27]=1)=[O:12].[N:39]1([CH2:44][CH2:45][CH2:46][NH2:47])[CH:43]=[CH:42][N:41]=[CH:40]1.C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>>[C:31](=[O:32])([O:33][CH2:34][C:35]([NH:47][CH2:46][CH2:45][CH2:44][N:39]1[CH:43]=[CH:42][N:41]=[CH:40]1)=[O:36])[O:30][CH2:29][O:28][C:15]1[C:14](=[O:38])[C:13]([C:11]([NH:10][CH2:9][C:3]2[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=2[F:1])=[O:12])=[CH:27][N:17]2[C:16]=1[C:21](=[O:22])[N:20]1[C@@H:23]([CH3:26])[CH2:24][O:25][C@@H:19]1[CH2:18]2
Reactant: NCCCn1ccnc1
Reactant: C[C@H]1CO[C@@H]2Cn3cc(C(=O)NCc4ccc(F)cc4F)c(=O)c(OCOC(=O)OCC(=O)O)c3C(=O)N12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H]1CO[C@@H]2Cn3cc(C(=O)NCc4ccc(F)cc4F)c(=O)c(OCOC(=O)OCC(=O)NCCCn4ccnc4)c3C(=O)N12

Procedure:
The title compound was prepared from ({[({[(3S,11aR)-8-({[(2,4-difluorophenyl)methyl]amino}carbonyl)-3-methyl-5,7-dioxo-2,3,5,7,11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazin-6-yl]oxy}methyl)oxy]carbonyl}oxy)acetic acid (63 mg, 0.112 mmol), [3-(1H-imidazol-1-yl)propyl]amine (0.02 mL, 0.176 mmol), N,N-diisopropylethylamine (0.03 mL, 0.176 mmol), and HATU (67 mg, 0.176 mmol), using a process similar to that described in example 16, step (a). Purification by silica gel chromatography yielded the title compound as a white solid. 1H NMR (CDCl3) δ 10.04 (m, 1 H), 8.16 (s, 1 H), 7.54 (m, 1 H), 7.47 (s, 1 H), 7.30 (m, 1 H), 6.94 (s, 1 H), 6.87 (s, 1 H), 6.77 (m, 2 H), 6.00 (d, J=6.8 Hz, 1 H), 5.65 (d, J=6.8 Hz, 1 H), 5.31-5.25 (m, 2 H), 4.62-4.41 (m, 4 H), 4.31 (m, 1 H), 4.19 (m, 1 H), 4.01-3.29 (m, 3 H), 3.02 (m, 1 H), 3.36 (m, 1 H), 3.03 (m, 1 H), 1.97 (m, 2 H), 1.28 (d, J=6.4 Hz, 3 H). ES+ MS: 645 (M+1).
Reaction SMILES: [C:1]1([S:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:14](Cl)([CH3:17])([CH3:16])[CH3:15].[Al+3].[Cl-].[Cl-].[Cl-]>C(=S)=S>[C:14]([C:11]1[CH:10]=[CH:9][C:8]([S:7][C:1]2[CH:2]=[CH:3][C:4]([C:14]([CH3:17])([CH3:16])[CH3:15])=[CH:5][CH:6]=2)=[CH:13][CH:12]=1)([CH3:17])([CH3:16])[CH3:15]
Reactant: CC(C)(C)Cl
Reactant: c1ccc(Sc2ccccc2)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Product: CC(C)(C)c1ccc(Sc2ccc(C(C)(C)C)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.3 %

Procedure:
To a mixture of 93 g of phenyl sulfide, 92.5 g of t-butyl chloride and 200 mL of CS2 cooled in an ice bath, 133 g of AlCl3 was added over a period of 1 hour. Following complete addition, the mixture was allowed to warm slowly to room temperature and stirred overnight. The mixture was subjected to decomposition with ice, extraction with ether and washing of the ether solution successively with water, 5% NaHCO3, water and saturated NaCl solution and gave after evaporation of dried (MgSO4) extracts, a solid which upon crystallization from methanol gave 145 g (97%) of the sulfide as white crystals, m.p. 83-84; 'H NMR (CDCl3) δ 1.32 (s, 18H, CH3), 7.35 (s, 8H, aryl).
Reaction SMILES: [F:1][C:2]([F:51])([F:50])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[CH:22][C:21]=3[C:30]3[CH:31]=[C:32]([C:38]4[CH:43]=[CH:42][C:41]([C:44]([O:46]C)=[O:45])=[CH:40][C:39]=4[CH3:48])[C:33]([F:37])=[CH:34][C:35]=3[F:36])[C@H:14]2[CH3:49])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.O.[OH-].[Li+].O>O1CCOCC1>[F:51][C:2]([F:1])([F:50])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[CH:25]=[C:24]([C:26]([F:27])([F:28])[F:29])[CH:23]=[CH:22][C:21]=3[C:30]3[CH:31]=[C:32]([C:38]4[CH:43]=[CH:42][C:41]([C:44]([OH:46])=[O:45])=[CH:40][C:39]=4[CH3:48])[C:33]([F:37])=[CH:34][C:35]=3[F:36])[C@H:14]2[CH3:49])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: COC(=O)c1ccc(-c2cc(-c3ccc(C(F)(F)F)cc3CN3C(=O)O[C@H](c4cc(C(F)(F)F)cc(C(F)(F)F)c4)[C@@H]3C)c(F)cc2F)c(C)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: Cc1cc(C(=O)O)ccc1-c1cc(-c2ccc(C(F)(F)F)cc2CN2C(=O)O[C@H](c3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@@H]2C)c(F)cc1F

Procedure:
methyl 2″-({(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-2-oxo-1,3-oxazolidin-3-yl}methyl)-4′,6′-difluoro-2-methyl-4″-(trifluoromethyl)-1,1′:3′,1″-terphenyl-4-carboxylate (73.5 mg, 0.10 mmol), lithium hydroxide monohydrate (42 mg, 1 mmol), water (1 mL) and 1,4-dioxane (2 mL) were stirred at room temperature for 2 hrs. Volatiles were removed under reduced pressure. Pot residue was dissolved in a MeCN/1N HCl (aq) mixture and purified by reverse-phase prep-HPLC (Kromasil 100-5C18, 100×21.1 mm) eluting w/a MeCN (0.1% TFA, v/v)/H2O (0.1% TFA, v/v) gradient mixture. Corresponding fractions were pooled & evaporated in vacuo to afford the title compound. LCMS (ESI) calc.=717.14; found=718.17 (M+1)+. 1H NMR (CDCl3, 500 MHz): δ 8.04 (s, 1H), 7.97 (d, J=8 Hz, 1H), 7.88 (s, 1H), 7.74-7.67 (m, 4H), 7.51-7.45 (m, 1H), 7.34 (d, J=8 Hz, 1H), 7.19 (br s, 1H), 7.09 (t, J=9 Hz, 1H), 5.59 (d, J=8 Hz, 1H), 5.08-4.80 (m, 1H), 4.20-3.78 (m, 2H), 2.32 (s, 3H), 0.62 (s, 3H).
Reaction SMILES: Br[C:2]1[C:3]2[C:4]3[CH:17]=[CH:16][S:15][C:5]=3[C:6](=[O:14])[NH:7][C:8]=2[CH:9]=[CH:10][C:11]=1[O:12][CH3:13].[N:18]1([CH:24]([C:26]2[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][CH:27]=2)[CH3:25])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1>>[CH3:13][O:12][C:11]1[CH:10]=[CH:9][C:8]2[NH:7][C:6](=[O:14])[C:5]3[S:15][CH:16]=[CH:17][C:4]=3[C:3]=2[C:2]=1[C:29]1[CH:28]=[CH:27][C:26]([CH:24]([N:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)[CH3:25])=[CH:31][CH:30]=1
Reactant: COc1ccc2[nH]c(=O)c3sccc3c2c1Br
Reactant: CC(c1ccc(B(O)O)cc1)N1CCCCC1
Product: COc1ccc2[nH]c(=O)c3sccc3c2c1-c1ccc(C(C)N2CCCCC2)cc1
Yield: 5 %

Procedure:
Following General Procedure B, 9-bromo-8-methoxythieno[2,3-c]quinolin-4(5H)-one (150 mg, 0.48 mmol) was reacted with 4-[1-(piperidin-1-yl)ethyl]phenylboronic acid (170 mg, 0.73 mmol) to afford the desired product (10 mg, 5%) as a yellow solid: 1H NMR (500 MHz, CD3OD) δ 7.74-7.66 (m, 2H), 7.62-7.53 (m, 2H), 7.49-7.34 (m, 3H), 5.94 (d, J=5.4 Hz, 1H), 4.61 (q, J=6.9 Hz, 1H), 3.86-3.78 (m, 1H), 3.76 (s, 1H), 3.47 (d, J=12.6 Hz, 1H), 3.10-2.98 (m, 1H), 2.96-2.82 (m, 1H), 2.11-1.91 (m, 2H), 1.89 (d, J=7.0 Hz, 2H), 1.85-1.70 (m, 1H).
Reaction SMILES: [C:1]([CH2:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=1)=[O:5])#[N:2].N12CCN(CC1)CC2.CO/[CH:24]=[CH:25]/[C:26](=O)[CH2:27][CH3:28]>COCCO.Cl.C(OCC)(=O)C>[CH2:27]([C:26]1[N:6]([C:7]2[CH:8]=[CH:9][C:10]([F:13])=[CH:11][CH:12]=2)[C:4](=[O:5])[C:3]([C:1]#[N:2])=[CH:24][CH:25]=1)[CH3:28]
Reactant: N#CCC(=O)Nc1ccc(F)cc1
Reactant: CCC(=O)/C=C/OC
Agent: C1CN2CCN1CC2
Agent: Cl
Solvent: COCCO
Solvent: CCOC(C)=O
Product: CCc1ccc(C#N)c(=O)n1-c1ccc(F)cc1
Temperature: 120 °C
Reaction time: 12 h
Yield: 16 %

Procedure:
To a solution of 2-cyano-N-(4-fluorophenyl)acetamide (1.7 g, 10.6 mmol) in dimethyleneglycol monomethylether (20 mL) were added 1,4-diazabicyclo[2.2.2]octane (1.2 g, 10.6 mmol) and (1E)-1-methoxypent-1-en-3-one (1.82 g, 15.9 mmol), and the mixture was stirred at 120° C. for 12 hr. The reaction mixture was diluted with 1N hydrochloric acid and ethyl acetate, and extracted 3 times with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and filtered. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (NH silica gel, ethyl acetate/hexane=50/50→100/0) to give a white solid. The white solid was washed with ethyl acetate to give the title compound (410 mg, 16%) as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].OS(O)(=O)=O.[N+:17]([O-])([OH:19])=[O:18]>>[Br:1][C:2]1[CH:3]=[C:4]([N+:17]([O-:19])=[O:18])[C:5]([CH3:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8]
Reactant: Cc1ccc(Br)cc1C(=O)O
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: Cc1c(C(=O)O)cc(Br)cc1[N+](=O)[O-]
Temperature: -2.5 °C
Reaction time: 2 h
Yield: 92 %

Procedure:
A solution of 5-bromo-2-methylbenzoic acid (5.0 g, 23 mmol) in concentrated H2SO4 (27 ml, 512 mmol) was cooled to 5° C. in an acetone/ice bath. A mixture of concentrated nitric acid (1.9 ml, 30 mmol) and concentrated H2SO4 (2.8 ml, 52 mmol) was added dropwise to the reaction mixture at −5 to 0° C. over 15 minutes. The yellow reaction mixture was stirred at −5 to 0° C. for 2 hours during which time a yellow precipitate formed. The reaction mixture was poured onto ice (150 g) and the precipitate was then collected by filtration. The precipitate was air dried to give the title compound (5.5 g, 52%) as a pale yellow solid. LC-MS 57%, 1.82 min (3.5 minute LC-MS method), no ionization; 1H NMR (500 MHz, DMSO-d6) δ ppm 8.29 (s, 1H) 8.13 (d, J=1.58 Hz, 1H) 2.43 (s, 3H).
Reaction SMILES: [C:1]([C:3]1[C:4]([O:17][CH3:18])=[C:5]([C:13]([O:15]C)=[O:14])[C:6]2[CH2:7][CH2:8][CH2:9][CH2:10][C:11]=2[CH:12]=1)#[N:2].[OH-].[Na+].C(=O)(O)[O-].[Na+].Cl>C1COCC1.O.CCOCC.CO>[C:1]([C:3]1[C:4]([O:17][CH3:18])=[C:5]([C:13]([OH:15])=[O:14])[C:6]2[CH2:7][CH2:8][CH2:9][CH2:10][C:11]=2[CH:12]=1)#[N:2]
Reactant: COC(=O)c1c2c(cc(C#N)c1OC)CCCC2
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Solvent: C1CCOC1
Product: COc1c(C#N)cc2c(c1C(=O)O)CCCC2
Temperature: 25 °C
Reaction time: 96 h
Yield: 18.8 %

Procedure:
To a stirred solution of methyl 3-cyano-2-methoxy-5,6,7,8-tetrahydro-1-naphthalenecarboxylate (0.65 g, 2.64 mmol) in THF (12 mL) and H2O (4 mL) was added 1N NaOH (3 mL). Methanol was added dropwise until the cloudy solution became clear. After stirring for 96 h at room temperature, the reaction was treated with sat. aqueous sodium bicarbonate and Et2O. The collected aqueous layer was acidified to pH 2 with 1N HCl, the resulting precipitate extracted with DCM (3×25 mL), dried (Na2SO4), filtered and concentrated to afford a white solid (0.115 g, 19%). 1H NMR (CDCl3) δ 7.39 (s, 1H), 4.09 (s, 3H), 2.82 (m, 4H), 1.80 (m, 4H).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[N:16][N:15]([CH3:18])[C:14](=[O:19])[CH:13]=2)=[CH:8][CH:7]=1.[NH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1>>[CH3:18][N:15]1[C:14](=[O:19])[CH:13]=[C:12]([C:9]2[CH:10]=[CH:11][C:6]([O:5][CH2:4][CH2:3][CH2:2][N:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)=[CH:7][CH:8]=2)[CH:17]=[N:16]1
Reactant: Cn1ncc(-c2ccc(OCCCCl)cc2)cc1=O
Reactant: C1CCNCC1
Product: Cn1ncc(-c2ccc(OCCCN3CCCCC3)cc2)cc1=O

Procedure:
This compound was prepared as the hydrochloride salt using 5-[4-(3-chloropropoxy)-phenyl]-2-methyl-2H-pyridazin-3-one and piperidine using the procedure described in Example 91 Step 5; Mp 253-4° C.; MS m/z 328 (M+H).