Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Li])CCC.[CH2:6]1[CH2:14][O:13][C:12]2[C:8](=[CH:9][S:10][CH:11]=2)[O:7]1.[CH2:15]([Sn:19](Cl)([CH2:24][CH2:25][CH2:26][CH3:27])[CH2:20][CH2:21][CH2:22][CH3:23])[CH2:16][CH2:17][CH3:18]>C1COCC1>[CH2:24]([Sn:19]([CH2:15][CH2:16][CH2:17][CH3:18])([CH2:20][CH2:21][CH2:22][CH3:23])[C:9]1[S:10][CH:11]=[C:12]2[O:13][CH2:14][CH2:6][O:7][C:8]=12)[CH2:25][CH2:26][CH3:27]
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Reactant: c1scc2c1OCCO2
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1scc2c1OCCO2
Temperature: -40 °C
Reaction time: 1 h
Yield: 98 %

Procedure:
n-Butyllithium (77 mL, 192.5 mmol, 2.5 M solution in hexane) was added dropwise at -78° C. to a solution of 3,4-(ethylenedioxy)thiophene (25 g, 175.9 mmol) in anhydrous THF (100 mL) under nitrogen. The solution was stirred for 1 h and warmed to -40° C. Tributylstannyl chloride (85.89 g, 263.9 mmol) was added and the entire solution was finally allowed to warm to room temperature. At room temperature the mixture was filtered using Celite and the solvent was stripped. The organo-tin compound was vacuum dried to give 2-(tributylstannyl)-3,4-(ethylenedioxy)thiophene, obtained as a dark yellow liquid, yield=98%. MS(EI) m/z (rel int): 375 [(M)+ --C4H8, 100%] and 319[(M)+ --C8H16, 18%].
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][N:27]=1)[C:5]([NH:7][C:8]1[S:9][C:10]2[C:16]([CH:17]3[CH2:22][O:21][CH2:20][CH2:19][O:18]3)=[CH:15][CH:14]=[C:13]([O:23][CH3:24])[C:11]=2[N:12]=1)=[O:6].C(=O)([O-])[O-].[Cs+].[Cs+].Cl.[NH:35]1[CH2:38][CH:37]([OH:39])[CH2:36]1.CS(C)=O>CN1C(=O)CCC1>[O:18]1[CH2:19][CH2:20][O:21][CH2:22][CH:17]1[C:16]1[C:10]2[S:9][C:8]([NH:7][C:5](=[O:6])[C:4]3[CH:25]=[CH:26][N:27]=[C:2]([N:35]4[CH2:38][CH:37]([OH:39])[CH2:36]4)[CH:3]=3)=[N:12][C:11]=2[C:13]([O:23][CH3:24])=[CH:14][CH:15]=1
Reactant: OC1CNC1
Reactant: COc1ccc(C2COCCO2)c2sc(NC(=O)c3ccnc(Br)c3)nc12
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: CN1CCCC1=O
Product: COc1ccc(C2COCCO2)c2sc(NC(=O)c3ccnc(N4CC(O)C4)c3)nc12

Procedure:
From (+)-2-bromo-N-(7-[1,4]dioxan-2-yl-4-methoxy-benzothiazol-2-yl)-isonicotinamide with cesium carbonate and azetidin-3-ol hydrochloride in NMP. [α]D20=+12.2° (c=0.51, DMSO), ES-MS m/e (%): 443 (M+H+, 100).
Reaction SMILES: C(O)(C(F)(F)F)=O.[F:8][C:9]([F:41])([F:40])[C:10]1[N:14]2[N:15]=[C:16]([N:19]3[CH2:24][CH2:23][N:22]([CH2:25][C:26]4[CH:31]=[CH:30][C:29]([NH:32]C(=O)OC(C)(C)C)=[CH:28][CH:27]=4)[CH2:21][CH2:20]3)[CH:17]=[CH:18][C:13]2=[N:12][N:11]=1>C(Cl)Cl>[F:41][C:9]([F:8])([F:40])[C:10]1[N:14]2[N:15]=[C:16]([N:19]3[CH2:20][CH2:21][N:22]([CH2:25][C:26]4[CH:31]=[CH:30][C:29]([NH2:32])=[CH:28][CH:27]=4)[CH2:23][CH2:24]3)[CH:17]=[CH:18][C:13]2=[N:12][N:11]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(CN2CCN(c3ccc4nnc(C(F)(F)F)n4n3)CC2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Nc1ccc(CN2CCN(c3ccc4nnc(C(F)(F)F)n4n3)CC2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 56.5 %

Procedure:
TFA (0.5 mL, 0.15 mmol) was added to tert-butyl N-[4-[[4-[3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperazin-1-yl]methyl]phenyl]carbamate (obtained as described in Example 146, 72 mg, 0.15 mmol) in DCM (2 mL). The resulting solution was stirred at ambient temperature for 2 hours and then evaporated to dryness. The crude product was purified by preparative HPLC using decreasingly polar mixtures of water (containing 0.1% TFA) and MeCN as eluents. Fractions containing the desired compound were evaporated and further purified by ion exchange chromatography, using an SCX column. The desired product was eluted from the column using 7M ammonia in methanol and pure fractions were evaporated to dryness to afford 4-[[4-[3-(trifluoromethyl)[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperazin-1-yl]methyl]aniline (32 mg, 56%).
Reaction SMILES: [C:1]1([N:7]2[CH2:11][C:10](=[O:12])[NH:9][C:8]2=[O:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[O:14]([C:21]1[CH:22]=[C:23]([CH:27]=[CH:28][CH:29]=1)[C:24](Cl)=[O:25])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>N1C=CC=CC=1>[O:14]([C:21]1[CH:22]=[C:23]([CH:27]=[CH:28][CH:29]=1)[C:24]([N:9]1[C:10](=[O:12])[CH2:11][N:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:8]1=[O:13])=[O:25])[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: O=C1CN(c2ccccc2)C(=O)N1
Reactant: O=C(Cl)c1cccc(Oc2ccccc2)c1
Solvent: c1ccncc1
Product: O=C1CN(c2ccccc2)C(=O)N1C(=O)c1cccc(Oc2ccccc2)c1
Yield: 74.8 %

Procedure:
In a similar manner to Example 8, 500 mg (2.80 mmol) of 1-phenyl-imidazolidin-2,4-dione were reacted with 600 mg (2.80 mmol) of 3-phenoxybenzoyl chloride. After completion of the reaction, pyridine was distilled off under reduced pressure, and the resultant residue was subjected to extraction with ethyl acetate. The organic layer was washed with dilute hydrochloric acid and with saturated saline. The thus-washed organic layer was dried over anhydrous magnesium sulfate, and the solvent was then distilled off. The resultant residue was subjected to crystallization from n-hexane/ethyl acetate to obtain 780 mg (yield: 69.9%) of the title compound.
Reaction SMILES: [CH:1]1[N:9]2[C:4]([NH:5][NH:6][C:7]3[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=32)=[N:3][N:2]=1.[C:14](Cl)(=[O:17])[CH2:15][CH3:16]>C1C=CC=CC=1>[C:14]([N:6]1[C:7]2[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=2[N:9]2[CH:1]=[N:2][N:3]=[C:4]2[NH:5]1)(=[O:17])[CH2:15][CH3:16]
Reactant: c1ccc2c(c1)NNc1nncn1-2
Reactant: CCC(=O)Cl
Solvent: c1ccccc1
Product: CCC(=O)N1Nc2nncn2-c2ccccc21
Yield: 70 %

Procedure:
A mixture of 4.0 g (0.023 mole) of 4,5-dihydro-s-triazolo[3,4-c]benzo-as-triazine, 2.2 g (0.023 mole) of propionyl chloride and 50 ml of benzene is refluxed under nitrogen atmosphere. The reaction mixture is cooled and the separated product is filtered off. The title compound, melting at 244° C., is obtained with a yield of 70%. The product does not show melting point depression in admixture with the compound prepared according to Example 4.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([S:12][C:13]1[N:17]3[N:18]=[C:19]([CH3:22])[CH:20]=[CH:21][C:16]3=[N:15][N:14]=1)=[CH:7][CH:6]=2.CC1(C)C(C)(C)OB([C:31]2[CH:32]=[N:33][N:34](COCC[Si](C)(C)C)[CH:35]=2)O1.C(=O)([O-])[O-].[Na+].[Na+].C(O)(C(F)(F)F)=O>O1CCOCC1>[CH3:22][C:19]1[CH:20]=[CH:21][C:16]2[N:17]([C:13]([S:12][C:8]3[CH:9]=[C:10]4[C:5](=[CH:6][CH:7]=3)[N:4]=[CH:3][C:2]([C:31]3[CH:32]=[N:33][NH:34][CH:35]=3)=[CH:11]4)=[N:14][N:15]=2)[N:18]=1
Reactant: Cc1ccc2nnc(Sc3ccc4ncc(Br)cc4c3)n2n1
Reactant: CC1(C)OB(c2cnn(COCC[Si](C)(C)C)c2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc2nnc(Sc3ccc4ncc(-c5cn[nH]c5)cc4c3)n2n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 44.5 %

Procedure:
A microwave vessel was charged with 3-bromo-6-(6-methyl-[1,2,4]triazolo[4,3-b]pyridazin-3-ylsulfanyl)-quinoline (970 mg, 2.606 mmol), 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazole (930 mg, 2.866 mmol), and dichlorobis(triphenylphosphine) palladium(0) (92 mg, 0.13 mmol). 1,4-Dioxane (10 mL) and a 2 M aqueous solution of sodium carbonate (5 mL) were added. The vessel was capped and microwaved at 130° C. for 30 min. The reaction mixture was partitioned between water and 10% methanol/dichloromethane. The aqueous layer was extracted with 10% methanol/dichloromethane, and the combined organics were adsorbed on silica gel. Purification by flash chromatography on silica gel using a gradient of 0-8% methanol/dichloromethane afforded 1.073 g of the crude coupling product as a light brown oil. The oil was treated with TFA (10 mL). The reaction mixture was stirred at room temperature for 2 h, before concentrating in vacuo. The residue was treated with 1 N aqueous NaOH, and the precipitate was filtered, washed sequentially with water and ethyl acetate. The resulting yellow solid was dissolved in 10% methanol/dichloromethane and adsorbed on silica gel. Purification by flash chromatography on silica gel using a gradient of 0-10% methanol/dichloromethane afforded 417 mg of impure 6-(6-methyl-[1,2,4]triazolo[4,3-b]pyridazin-3-ylsulfanyl)-3-(1H-pyrazol-4-yl)-quinoline. Purification of 30 mg of material by mass-triggered HPLC (5-95% CH3CN/H2O, 0.1% HCOOH modifier) provided 12 mg of pure 6-(6-methyl-[1,2,4]triazolo[4,3-b]pyridazin-3-ylsulfanyl)-3-(1H-pyrazol-4-yl)-quinoline.
Reaction SMILES: ClC1C=CC(OCC2CCNCC2C2C=CC(Cl)=CC=2)=[N:6]C=1.Cl.C([N:31]1[CH2:36][CH2:35][C@H:34]([C@@H:37]([O:39][C:40]2[CH:45]=[CH:44][C:43]([C:46](F)(F)F)=[CH:42][N:41]=2)[CH3:38])[C@@H:33]([C:50]2[CH:55]=[CH:54][C:53]([Cl:56])=[CH:52][CH:51]=2)[CH2:32]1)C1C=CC=CC=1>>[Cl:56][C:53]1[CH:52]=[CH:51][C:50]([C@@H:33]2[C@@H:34]([C@@H:37]([O:39][C:40]3[CH:45]=[CH:44][C:43]([C:46]#[N:6])=[CH:42][N:41]=3)[CH3:38])[CH2:35][CH2:36][NH:31][CH2:32]2)=[CH:55][CH:54]=1
Reactant: C[C@H](Oc1ccc(C(F)(F)F)cn1)[C@H]1CCN(Cc2ccccc2)C[C@@H]1c1ccc(Cl)cc1
Reactant: Clc1ccc(C2CNCCC2COc2ccc(Cl)cn2)cc1
Agent: Cl
Product: C[C@H](Oc1ccc(C#N)cn1)[C@H]1CCNC[C@@H]1c1ccc(Cl)cc1

Procedure:
In analogy to the procedure described for the synthesis of 5-chloro-2-[(3RS, 4RS)-3-(4-chloro-phenyl)-piperidin-4-ylmethoxy]-pyridine; hydrochloride (example 1, step h) the title compound was prepared from 2-{(S)-1-[(3S,4S)-1-Benzyl-3-(4-chloro-phenyl)-piperidin-4-yl]-ethoxy}-5-trifluoromethyl-pyridine as white foam as the respective HCl salt. MS (m/e): 342.1 [(M+H)+].
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:6][N:5]=[C:4]2[NH:14][N:15]=[C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:3]=12.[O:23]1[CH:27]=[C:26]([CH2:28]O)[N:25]=[CH:24]1>>[Cl:1][C:2]1[C:7]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)=[N:6][N:5]=[C:4]2[N:14]([CH2:28][C:26]3[N:25]=[CH:24][O:23][CH:27]=3)[N:15]=[C:16]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:3]=12
Reactant: OCc1cocn1
Reactant: Clc1c(-c2ccccc2)nnc2[nH]nc(-c3ccccc3)c12
Product: Clc1c(-c2ccccc2)nnc2c1c(-c1ccccc1)nn2Cc1cocn1

Procedure:
Compound IIh was synthesized from 4-chloro-3,5-diphenyl-1H-pyrazolo[3,4-c]pyridazine and oxazol-4-ylmethanol following the general procedure for the Mitsunobu reaction as described above.
Reaction SMILES: [F:1][C:2]1[CH:31]=[CH:30][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][CH2:18][N:19]4C(=O)C5=CC=CC=C5C4=O)[CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.O.NN.[ClH:35]>CO.O>[ClH:35].[ClH:35].[NH2:19][CH2:18][CH2:17][CH2:16][CH2:15][N:12]1[CH2:13][CH2:14][CH:9]([C:6]2[C:5]3[CH:30]=[CH:31][C:2]([F:1])=[CH:3][C:4]=3[O:8][N:7]=2)[CH2:10][CH2:11]1
Reactant: O=C1c2ccccc2C(=O)N1CCCCN1CCC(c2noc3cc(F)ccc23)CC1
Agent: Cl
Agent: NN
Solvent: O
Solvent: CO
Product: NCCCCN1CCC(c2noc3cc(F)ccc23)CC1

Procedure:
A mixture of N-[4-[4-(6-fluoro-1,2-benzisoxazol-3-yl) piperidinyl]-butyl]phthalimide (6.9 g, 16.4 mmol) and hydrazine monohydrate (1.64 g, 32.8 mmol) in methanol (70 ml) was heated at reflux for 3 hours. At the end of the reaction, methanol was removed to leave a crude solid. This was dissolved in water and acidified with HCl to pH 2. The insolubles were filtered. The aqueous solution was basified with 50% NaOH, and then extracted with dichloromethane. The dichloromethane solution was washed with water and brine, and then dried over MgSO4. The solvent was removed to a colorless oil: 4.48 g. This oil was treated with equivalents of HCl in ethanol. The solid was collected. Recrystallization from ethanol (65 ml) and methanol (20 ml) gave 2.0 g of 1-(4-aminobutyl)-4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidine dihydrochloride as white crystals, m.p.=234-237° C.
Reaction SMILES: Br[C:2]1[CH:11]=[N:10][C:9]2[N:8]([CH3:12])[C:7](=[O:13])[CH2:6][O:5][C:4]=2[CH:3]=1.[F:14][C:15]1[CH:16]=[C:17]([SH:29])[CH:18]=[C:19]([C:21]2([O:27][CH3:28])[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[CH:20]=1>>[F:14][C:15]1[CH:16]=[C:17]([S:29][C:2]2[CH:11]=[N:10][C:9]3[N:8]([CH3:12])[C:7](=[O:13])[CH2:6][O:5][C:4]=3[CH:3]=2)[CH:18]=[C:19]([C:21]2([O:27][CH3:28])[CH2:22][CH2:23][O:24][CH2:25][CH2:26]2)[CH:20]=1
Reactant: CN1C(=O)COc2cc(Br)cnc21
Reactant: COC1(c2cc(F)cc(S)c2)CCOCC1
Product: COC1(c2cc(F)cc(Sc3cnc4c(c3)OCC(=O)N4C)c2)CCOCC1
Yield: 4 %

Procedure:
Using the procedure described in Example 11, 7-bromo-4-methyl-2,3-dihydro-4H-pyrido[3,2-b][1,4]oxazin-3-one was reacted with 4-(5-fluoro-3-mercaptophenyl)-4-methoxytetrahydropyran to give 4-[5-fluoro-3-(4-methyl-3-oxo-2,3-dihydro-4H-pyrido[3,2-b]-[1,4]oxazin-7-ylthio)phenyl]-4-methoxytetrahydropyran in 4% yield, m.p. 127°-128° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([N:8]2[CH2:12][CH:11]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([O:21][CH:22]4[CH2:26][CH2:25][CH2:24][CH2:23]4)[CH:14]=3)[CH2:10][C:9]2=[O:27])[CH:5]=[CH:6][CH:7]=1.[CH3:28][O:29][C:30]1[CH:31]=[C:32]([S:36](Cl)(=[O:38])=[O:37])[CH:33]=[CH:34][CH:35]=1>N1C=CC=CC=1.C(Cl)Cl>[CH:22]1([O:21][C:15]2[CH:14]=[C:13]([CH:11]3[CH2:12][N:8]([C:4]4[CH:3]=[C:2]([NH:1][S:36]([C:32]5[CH:33]=[CH:34][CH:35]=[C:30]([O:29][CH3:28])[CH:31]=5)(=[O:38])=[O:37])[CH:7]=[CH:6][CH:5]=4)[C:9](=[O:27])[CH2:10]3)[CH:18]=[CH:17][C:16]=2[O:19][CH3:20])[CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: COc1ccc(C2CC(=O)N(c3cccc(N)c3)C2)cc1OC1CCCC1
Reactant: COc1cccc(S(=O)(=O)Cl)c1
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1cccc(S(=O)(=O)Nc2cccc(N3CC(c4ccc(OC)c(OC5CCCC5)c4)CC3=O)c2)c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 65.2 %

Procedure:
A mixture of 1-(3-aminophenyl)-4-(3-cyclopentyloxy-4-methoxyphenyl)-pyrrolidin-2-one (15 mg, 0.04 mmol) and 3-methoxybenzenesulfonyl chloride (10 mg, 0.042 mol) in pyridine (30 μL) and CH2Cl2 (0.5 mL) was created in a dry round bottom flask. The mixture was stirred at r.t. for 15 h. After removal of solvent, the residue was purified by preparative LC-MS to give 14 mg of N-{3-[4-(3-cyclopentyloxy-4-methoxyphenyl)-2-oxo-pyrrolidin-1-yl]phenyl}-3-methoxybenzenesulfonamide. Yield: 65%.
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[NH2:19])([CH3:4])([CH3:3])[CH3:2].C([O:23][C:24](=O)[CH2:25][C:26](=[O:38])[C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([N:33]2[CH:37]=[CH:36][N:35]=[N:34]2)[CH:28]=1)C>>[C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[NH:19][C:24](=[O:23])[CH2:25][C:26](=[O:38])[C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([N:33]2[CH:37]=[CH:36][N:35]=[N:34]2)[CH:28]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)CC(=O)c1cccc(-n2ccnn2)c1
Reactant: Cc1cc(NC(=O)OC(C)(C)C)c(N)cc1C(F)(F)F
Product: Cc1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-n3ccnn3)c2)cc1C(F)(F)F

Procedure:
The title compound was prepared from (2-amino-5-methyl-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example J15) (290 mg, 1.0 mmol) and 3-oxo-3-(3-[1,2,3]triazol-1-yl-phenyl)-propionic acid ethyl ester (Example K1) (259 mg, 1.0 mmol) according to the general procedure M. Obtained as a light yellow oil (300 mg, 60%).
Reaction SMILES: [Cl-].[Li+].[CH:3]([O:6][C:7]([N:9]1[CH:14]([CH2:15][CH3:16])[CH:13](C(OCC)=O)[C:12](=[O:22])[C:11]2[S:23][CH:24]=[CH:25][C:10]1=2)=[O:8])([CH3:5])[CH3:4]>CS(C)=O.O>[CH:3]([O:6][C:7]([N:9]1[CH:14]([CH2:15][CH3:16])[CH2:13][C:12](=[O:22])[C:11]2[S:23][CH:24]=[CH:25][C:10]1=2)=[O:8])([CH3:4])[CH3:5]
Reactant: CCOC(=O)C1C(=O)c2sccc2N(C(=O)OC(C)C)C1CC
Agent: [Cl-]
Agent: [Li+]
Solvent: CS(C)=O
Solvent: O
Product: CCC1CC(=O)c2sccc2N1C(=O)OC(C)C
Temperature: 160 °C
Yield: 57.7 %

Procedure:
Add lithium chloride (0.162 g, 3.83 mmol) in one portion to a mixture of 5-ethyl-7-oxo-6,7-dihydro-5H-thieno[3,2-b]pyridine-4,6-dicarboxylic acid 6-ethyl ester 4-isopropyl ester (0.520 g, 1.53 mmol) in dimethylsulfoxide (15 ml) and water (2 drops). Heat the mixture at 160° C. for 4 h. Cool the reaction to room temperature and partition between ethyl acetate (50 ml) and brine (50 ml). Separate the organic layer and wash with brine (3×50 ml). Dry the organic portion over sodium sulfate, filter and concentrate. Purify using silica gel column chromatography (gradient eluent, 0-15% ethyl acetate in hexane) to give 5-ethyl-7-oxo-6,7-dihydro-5H-thieno[3,2-b]pyridine-4-carboxylic acid isopropyl ester (0.236 g, 58% for two steps) as an oil. MS (ES+): 268 (M+H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.[CH3:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][C:19]([S:22]([NH:25][CH:26]([CH2:31][CH:32]3[O:34][CH2:33]3)[C:27]([O:29]C)=[O:28])(=[O:24])=[O:23])=[CH:18][CH:17]=2)=[CH:12][CH:11]=1>>[CH3:8][O:9][C:10]1[CH:11]=[CH:12][C:13]([C:16]2[CH:17]=[CH:18][C:19]([S:22]([NH:25][CH:26]([CH2:31][CH:32]([OH:34])[CH2:33][O:1][C:2]3[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=3)[C:27]([OH:29])=[O:28])(=[O:23])=[O:24])=[CH:20][CH:21]=2)=[CH:14][CH:15]=1
Reactant: COC(=O)C(CC1CO1)NS(=O)(=O)c1ccc(-c2ccc(OC)cc2)cc1
Reactant: Oc1cccnc1
Product: COc1ccc(-c2ccc(S(=O)(=O)NC(CC(O)COc3cccnc3)C(=O)O)cc2)cc1

Procedure:
Example 55 is prepared from 3-hydroxypyridine and 1d using the procedure described for compound 20.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[C:5]1[CH:10]=[CH:9][C:8]([O:11][C:12]2[C:17]([N+:18]([O-])=O)=[CH:16][N:15]=[C:14]([Cl:21])[N:13]=2)=[CH:7][CH:6]=1)[CH3:2]>CC(O)=O.CO.[Zn]>[CH2:1]([O:3][C:4](=[O:22])[C:5]1[CH:10]=[CH:9][C:8]([O:11][C:12]2[C:17]([NH2:18])=[CH:16][N:15]=[C:14]([Cl:21])[N:13]=2)=[CH:7][CH:6]=1)[CH3:2]
Reactant: CCOC(=O)c1ccc(Oc2nc(Cl)ncc2[N+](=O)[O-])cc1
Agent: [Zn]
Solvent: CC(=O)O
Solvent: CO
Product: CCOC(=O)c1ccc(Oc2nc(Cl)ncc2N)cc1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a solution of Compound 16a (2.12 g; 6.55 mmol) in AcOH (15 mL) and CH3OH (20 mL) was added Zn (2.57 g; 39.31 mmol) in portions at room temperature. The reaction mixture was stirred at room temperature for 6 h. The solid was collected by filtration and washed with CH3OH. The filtrate was concentrated. The residue was quenched with aqueous NaOH (<1 N) and adjusted to pH ˜7, and extracted with EtOAc (2×20 mL). The organic layer was dried over MgSO4 and concentrated. The crude product was purified by normal phase chromatography (SiO2) to give Compound 16b. 1H NMR (300 MHz, CDCl3): δ 8.15 (d, 2H), 7.95 (s, 1H), 7.25 (d, 2H), 4.45 (q, 2H), 1.4 (t, 3H); MS: m/z 294.1 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[C:19]2[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=2)[C:13]([C:24](O)=[O:25])=[CH:12][N:11]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:27]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH2:30][CH2:29][NH:28]1.C(P(=O)(OCC)OCC)#N>C1COCC1>[C:1]([O:5][C:6](=[O:7])[NH:8][CH2:9][C:10]1[C:19]2[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=2)[C:13]([C:24]([N:28]2[CH2:29][CH2:30][C:31]3[C:36](=[CH:35][CH:34]=[CH:33][CH:32]=3)[CH2:27]2)=[O:25])=[CH:12][N:11]=1)([CH3:3])([CH3:2])[CH3:4]
Reactant: c1ccc2c(c1)CCNC2
Reactant: COc1cc2c(C(=O)O)cnc(CNC(=O)OC(C)(C)C)c2cc1OC
Agent: CCOP(=O)(C#N)OCC
Solvent: C1CCOC1
Product: COc1cc2c(C(=O)N3CCc4ccccc4C3)cnc(CNC(=O)OC(C)(C)C)c2cc1OC
Yield: 61.4 %

Procedure:
A solution of 1-(tert-butoxycarbonylamino-methyl)-6,7-dimethoxy-isoquinoline-4-carboxylic acid (100 mg, 0.3 mmol) in 20 mL of THF was treated with 1,2,3,4-tetrahydroisoquinoline (44 mg, 0.33 mmol), TEA (56 mg, 0.552 mmol) and diethyl cyanophosphonate (55 mg, 0.33 mmol) according to the procedure described in example 1E to give [4-(3,4-Dihydro-1H-isoquinoline-2-carbonyl)-6,7-dimethoxy-isoquinolin-1-ylmethyl]-carbamic acid tert-butyl ester (88 mg, 66.9%). H1-NMR (CDCl3): δ, 8.31 (br s, 1H), 7.38 (br s, 1H), 7.15 (m, 5H), 6.82 (m, 1H), 6.18 (br s, 1H), 4.93 (s, 2H), 4.43 (m, 2H), 4.02 (br s, 3H), 3.92 (s, 2H), 3.58 (br s, 3H), 3.10 (br s, 1H), 2.80 (br s, 1H), 1.51 (s, 9H) [Note: broadening of peaks observed due to Boc group, rotamers also observed.]; MS: APCI (M+H) calc'd for C27H31N3O5+H 478.6; found 478.0.
Reaction SMILES: [CH:1]1([N:5]2[CH2:11][CH2:10][C:9]3[CH:12]=[CH:13][C:14]([O:16][C:17]4[CH:24]=[CH:23]C(C#N)=[CH:19][C:18]=4[F:25])=[CH:15][C:8]=3[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1.[OH-].[Na+].[C:28]([OH:31])(=[O:30])[CH3:29]>C(O)C.O>[CH:1]1([N:5]2[CH2:11][CH2:10][C:9]3[CH:12]=[CH:13][C:14]([O:16][C:17]4[CH:24]=[CH:23][C:29]([C:28]([OH:31])=[O:30])=[CH:19][C:18]=4[F:25])=[CH:15][C:8]=3[CH2:7][CH2:6]2)[CH2:2][CH2:3][CH2:4]1
Reactant: N#Cc1ccc(Oc2ccc3c(c2)CCN(C2CCC2)CC3)c(F)c1
Reactant: CC(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)c1ccc(Oc2ccc3c(c2)CCN(C2CCC2)CC3)c(F)c1

Procedure:
4-[(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-3-fluorobenzonitrile (E271(150 mg, 0.45 mmol) was dissolved in a mixture of ethanol (1 ml) and water (1.5 ml), treated with sodium hydroxide (150 mg, 4.5 mmol) and heated at reflux for 2 hours. The reaction was then treated with acetic acid (0.39 ml, 6.75 mmol) and concentrated in vacuo. The resulting residue was purified by column chromatography eluting with a mixture of 0.880 ammonia:methanol:dichloromethane (2:18:80) to afford the title compound. MS (ES+) m/e 356 [M+H]+.
Reaction SMILES: [CH:1]1([N:5]2[CH2:10][CH2:9][N:8]([C:11]([C:13]3[CH:14]=[C:15]4[C:19](=[CH:20][CH:21]=3)[NH:18][C:17]([C:22]([N:24]3[CH2:29][CH2:28][S:27](=[O:31])(=[O:30])[CH2:26][CH2:25]3)=[O:23])=[CH:16]4)=[O:12])[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1.[H-].[Na+].CS(O[CH2:39][C:40]([F:43])([F:42])[F:41])(=O)=O>CN(C)C=O>[CH:1]1([N:5]2[CH2:6][CH2:7][N:8]([C:11]([C:13]3[CH:14]=[C:15]4[C:19](=[CH:20][CH:21]=3)[N:18]([CH2:39][C:40]([F:43])([F:42])[F:41])[C:17]([C:22]([N:24]3[CH2:29][CH2:28][S:27](=[O:30])(=[O:31])[CH2:26][CH2:25]3)=[O:23])=[CH:16]4)=[O:12])[CH2:9][CH2:10]2)[CH2:2][CH2:3][CH2:4]1
Reactant: O=C(c1ccc2[nH]c(C(=O)N3CCS(=O)(=O)CC3)cc2c1)N1CCN(C2CCC2)CC1
Reactant: CS(=O)(=O)OCC(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(c1ccc2c(c1)cc(C(=O)N1CCS(=O)(=O)CC1)n2CC(F)(F)F)N1CCN(C2CCC2)CC1
Yield: 73 %

Procedure:
The title compound was synthesized in analogy to example 51, from [5-(4-cyclobutyl-piperazine-1-carbonyl)-1H-indol-2-yl]-(1,1-dioxothiomorpholin-4-yl)-methanone (example 202), sodium hydride and 2,2,2-trifluoroethyl methanesulfonate in N,N-dimethylformamide, to give the desired product as a yellow solid (73%).
Reaction SMILES: Cl.[N+:2]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][NH2:12])=[CH:7][CH:6]=1)([O-:4])=[O:3].[C:13](OCC)(=[O:18])[CH2:14][C:15]([CH3:17])=O>C(O)C>[CH3:17][C:15]1[CH2:14][C:13](=[O:18])[N:11]([C:8]2[CH:7]=[CH:6][C:5]([N+:2]([O-:4])=[O:3])=[CH:10][CH:9]=2)[N:12]=1
Reactant: CCOC(=O)CC(C)=O
Reactant: NNc1ccc([N+](=O)[O-])cc1
Agent: Cl
Solvent: CCO
Product: CC1=NN(c2ccc([N+](=O)[O-])cc2)C(=O)C1

Procedure:
1.63 g of p-nitrophenylhydrazine hydrochloride and 1.26 g of ethyl acetoacetate are heated under reflux in 30 ml of ethanol for 45 min. The mixture is concentrated somewhat in vacuo. The crystals which have separated out are then filtered off with suction.
Reaction SMILES: [Mg].Br[CH2:3][C:4]([CH3:7])([CH3:6])[CH3:5].[F:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][C:10]=1[C:17]1[C:18]([CH:33]=[O:34])=[CH:19][C:20]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=2)=[CH:21][CH:22]=1.[Cl-].[NH4+]>C(OCC)C>[F:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][C:10]=1[C:17]1[CH:22]=[CH:21][C:20]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=2)=[CH:19][C:18]=1[CH:33]([OH:34])[CH2:3][C:4]([CH3:7])([CH3:6])[CH3:5]
Reactant: CC(C)(C)CBr
Reactant: COc1ccc(COc2ccc(-c3cc(OC)ccc3F)c(C=O)c2)cc1
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: CCOCC
Product: COc1ccc(COc2ccc(-c3cc(OC)ccc3F)c(C(O)CC(C)(C)C)c2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a mixture of magnesium (133 mg) and diethyl ether (10 mL) was added 1-bromo-2,2-dimethylpropane (0.68 mL), and the mixture was stirred at room temperature for 30 min. To the reaction mixture was added a solution of 2′-fluoro-5′-methoxy-4-((4-methoxybenzyl)oxy)biphenyl-2-carbaldehyde (1.02 g) in diethyl ether (5 mL), and the mixture was stirred at room temperature for 2 hr. To the reaction mixture was added saturated aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (674 mg) as a pale-yellow oil.