Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][C@H:11]([NH:18][C:19]1[O:20][C:21]([CH3:35])([CH3:34])[CH:22]([C:27]2[CH:28]=[C:29]([CH3:33])[CH:30]=[CH:31][CH:32]=2)[S:23](=[O:26])(=[O:25])[N:24]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)(C(C)(C)C)(C)C.Cl>CO.C(OCC)(=O)C>[CH3:34][C:21]1([CH3:35])[O:20][C:19]([NH:18][C@H:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:10][CH2:9][OH:8])=[N:24][S:23](=[O:26])(=[O:25])[CH:22]1[C:27]1[CH:28]=[C:29]([CH3:33])[CH:30]=[CH:31][CH:32]=1
Reactant: Cc1cccc(C2C(C)(C)OC(N[C@@H](CCO[Si](C)(C)C(C)(C)C)c3ccccc3)=NS2(=O)=O)c1
Agent: Cl
Solvent: CO
Solvent: CCOC(C)=O
Product: Cc1cccc(C2C(C)(C)OC(N[C@@H](CCO)c3ccccc3)=NS2(=O)=O)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 56.9 %

Procedure:
51.7 mg of [(S)-3-(tert-butyldimethylsilanyloxy)-1-phenylpropyl]-(6,6-dimethyl-4,4-dioxo-5-m-tolyl-5,6-dihydro-4H-4lambda6-1,4,3-oxathiazin-2-yl)amine were dissolved in 2 ml of methanol, 0.1 ml of concentrated hydrochloric acid was added and the mixture was stirred at room temperature for 16 hours. The reaction solution was diluted with ethyl acetate and washed with saturated aqueous sodium chloride solution, dried over MgSO4 and concentrated by rotary evaporation. The residue was purified in a purification laboratory by means of preparative HPLC. The product-containing fractions were combined, the acetonitrile was removed under reduced pressure, and the aqueous residue was basified with saturated aqueous sodium hydrogencarbonate solution and extracted with dichloromethane. The organic phase was dried over MgSO4 and concentrated by rotary evaporation, and the residue was taken up again in a mixture of acetonitrile and water and lyophilized. This gave the product (22.9 mg) with a molecular weight of 402.5 g/mol (C21H26N2O4S); MS (ESI): m/e=403 (M+H+).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:17]([C:18]([F:21])([F:20])[F:19])=[CH:16][C:12]([C:13](O)=[O:14])=[CH:11][C:10]=1[O:22][CH3:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(C)C=CC=CC=1.S(Cl)([Cl:33])=O>CN(C)C=O>[CH2:1]([O:8][C:9]1[C:17]([C:18]([F:21])([F:20])[F:19])=[CH:16][C:12]([C:13]([Cl:33])=[O:14])=[CH:11][C:10]=1[O:22][CH3:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: COc1cc(C(=O)O)cc(C(F)(F)F)c1OCc1ccccc1
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: COc1cc(C(=O)Cl)cc(C(F)(F)F)c1OCc1ccccc1
Temperature: 60 °C
Reaction time: 16 h

Procedure:
To 4-benzyloxy-3-methoxy-5-trifluoromethylbenzoic acid (601 mg), toluene (6 mL), N,N-dimethylformamide (1 droplet) and thionyl chloride (0.16 mL) were added, and then the mixture was stirred at 60° C. for 16 hours. The solvent was distilled off under reduced pressure and then azeotroped with toluene to obtain the title compound (657 mg) as a yellow oily substance.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15](=[O:31])[C:16]([O:26][CH2:27][CH2:28][CH2:29][CH3:30])([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:17]([CH3:19])[CH3:18])[CH2:10][CH2:9]1)C1C=CC=CC=1>C(O)C.[OH-].[Pd+2].[OH-].[C]>[NH:8]1[CH2:9][CH2:10][CH:11]([NH:14][C:15](=[O:31])[C:16]([O:26][CH2:27][CH2:28][CH2:29][CH3:30])([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:17]([CH3:19])[CH3:18])[CH2:12][CH2:13]1
Reactant: CCCCOC(C(=O)NC1CCN(Cc2ccccc2)CC1)(c1ccccc1)C(C)C
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: CCCCOC(C(=O)NC1CCNCC1)(c1ccccc1)C(C)C
Reaction time: 6 h

Procedure:
To a solution of N-(1-benzyl-4-piperidinyl)-2-butoxy-3-methyl-2-phenylbutanamide (invention compound, Compound No. 4) (4.5 g, 10.6 mmole) in ethanol (60 ml) was added palladium hydroxide-carbon (1.2 g), followed by hydrogenation for 6 hours at room temperature. The catalyst was filtered off and the filtrate was removed under reduced pressure to obtain the invention compound (Compound No. 27, quantitative yield) as a colorless oil.
Reaction SMILES: [CH2:1]([S:3]([CH2:6][CH2:7][C:8]12[CH2:15][CH2:14][C:11]([C:16]([NH:18][CH3:19])=O)([CH2:12][CH2:13]1)[CH2:10][CH2:9]2)(=[O:5])=[O:4])[CH3:2].C(Cl)(=O)C(Cl)=O.[F:26][C:27]([F:40])([F:39])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[C:34]1NN=[N:36][N:35]=1>C(Cl)Cl.CN(C=O)C>[CH2:1]([S:3]([CH2:6][CH2:7][C:8]12[CH2:15][CH2:14][C:11]([C:16]3[N:18]([CH3:19])[C:34]([C:29]4[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=4[C:27]([F:26])([F:40])[F:39])=[N:35][N:36]=3)([CH2:12][CH2:13]1)[CH2:10][CH2:9]2)(=[O:5])=[O:4])[CH3:2]
Reactant: FC(F)(F)c1ccccc1-c1nnn[nH]1
Reactant: CCS(=O)(=O)CCC12CCC(C(=O)NC)(CC1)CC2
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCS(=O)(=O)CCC12CCC(c3nnc(-c4ccccc4C(F)(F)F)n3C)(CC1)CC2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Methyl amide 10-5 (220 mg, 0.77 mmol) was dissolved in anhydrous methylene chloride (2 mL) and treated with oxalyl chloride (2M in methylene chloride, 0.77 mL, 1.54 mmol) and DMF (2 drops). The solution was stirred at room temperature for 1 h, then solvent removed by evaporation under diminished pressure. The residue was redissolved in anhydrous toluene (2 mL) and treated with 5[2-(trifluoromethyl)phenyl]1H-tetrazole (214 mg, 1 mmol). The mixture was refluxed for 18 h. The reaction was cooled to room temperature and the cream-colored precipitate was filtered and washed to give 300 mg of crude product as the HCl salt. The salt was taken up in methylene chloride/1N HCl and the aqueous layer was washed with two additional portions of methylene chloride. The organic layers were combined and evaporated and the residue was chromatographed by flash silica gel chromatography. Elution was carried out with a gradient ranging from 0 to 5% methanol/methylene chloride. The appropriate fractions were combined and evaporated to give 3-{4-[2-(ethylsulfonyl)ethyl]bicyclo[2.2.2]oct-1-yl}-4-methyl-5-[2-(trifluoromethyl)phenyl]4H-1,2,4-triazole (10-6) as a white powder. MS (ESI+)=456.2 (M+1); 1H NMR (500 MHz, CDCl3): δ 1.46 (3H, t, J=7.3 Hz), 1.63 (6H, m), 1.78 (2H, m), 2.19 (6H, m), 2.96 (2H,m), 3.05 (2H, q, J=7.2 Hz), 3.50 (3H, s), 7.56 (1H, m), 7.72 (2H, m), 7.87 (1H, m) ppm.
Reaction SMILES: C(O[C:6]([NH:8][C@@H:9]([CH2:19][CH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1)[C@@H:10]([OH:18])[CH2:11][C@@H:12]([CH3:17])[C:13]([NH:15][CH3:16])=[O:14])=[O:7])(C)(C)C.Cl.[C:27]([O:31][C:32]([NH:34][C@H:35](C(O)=O)[CH2:36][C:37]1[N:38]=[CH:39][S:40][CH:41]=1)=[O:33])([CH3:30])([CH3:29])[CH3:28].C(P(=O)(OCC)OCC)#N.C(N(CC)CC)C>O1CCOCC1>[C:27]([O:31][C:32]([NH:34][C@H:35]([C:6]([NH:8][C@@H:9]([CH2:19][CH:20]1[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]1)[C@@H:10]([OH:18])[CH2:11][C@@H:12]([CH3:17])[C:13]([NH:15][CH3:16])=[O:14])=[O:7])[CH2:36][C:37]1[N:38]=[CH:39][S:40][CH:41]=1)=[O:33])([CH3:30])([CH3:28])[CH3:29]
Reactant: CNC(=O)[C@H](C)C[C@H](O)[C@H](CC1CCCCC1)NC(=O)OC(C)(C)C
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1cscn1)C(=O)O
Agent: CCOP(=O)(C#N)OCC
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: CNC(=O)[C@H](C)C[C@H](O)[C@H](CC1CCCCC1)NC(=O)[C@H](Cc1cscn1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 90.9 %

Procedure:
A mixture of 200 mg (0.56 mmole) of (2R, 4S, 5S)-5-(t-butoxycarbonyl)amino-6-cyclohexyl-4-hydroxy-2,N-dimethylhexanamide (prepared as described in Preparation 5) and 4 ml of a 4N solution of hydrogen chloride in dioxane was stirred at room temperature for 30 minutes. At the end of this time, the solvent was removed by distillation under reduced pressure, and the resulting residue was mixed with benzene; the solvent was then removed by distillation under reduced pressure. This operation was repeated three times in total. After drying the final residue in vacuo for 8 hours, the dried material was suspended in 10 ml of anhydrous tetrahydrofuran. 150 mg (1.68 mmole) of N-(t-butoxycarbonyl)-3-(4-thiazolyl)-L-alanine were then added to the suspension. After this, 0.1 ml (0.67 mmole) of 95% diethyl cyanophosphonate and 0.23 ml (1.68 mmole) of triethylamine were added to the mixture, whilst ice-cooling and under an atmosphere of nitrogen. The mixture was then stirred for 15 hours. At the end of this time, the reaction solvent was stripped from the mixture by distillation under reduced pressure and the residue was mixed with water. The precipitate which deposited was collected by filtration and washed with water. It was then dissolved in methylene chloride and the resulting solution was dried over anhydrous magnesium sulfate. The solvent was then removed by distillation under reduced pressure, to afford 260 mg of the title compound as a pale yellow powder, melting at 158°-160° C.
Reaction SMILES: [P:1]([O:50]CC[Si](C)(C)C)([O:43]CC[Si](C)(C)C)([O:3][C:4]([CH3:42])([CH2:6][CH2:7][S:8]([N:11]1[CH2:16][CH2:15][C:14]([C:17]2[CH:41]=[CH:40][C:20]3[N:21]=[C:22]([O:24][CH:25]4[CH2:30][CH2:29][N:28]([C:31]5[N:36]=[CH:35][C:34]([CH2:37][CH2:38][CH3:39])=[CH:33][N:32]=5)[CH2:27][CH2:26]4)[S:23][C:19]=3[CH:18]=2)=[CH:13][CH2:12]1)(=[O:10])=[O:9])[CH3:5])=[O:2].C(O)(C(F)(F)F)=O.C([O-])(O)=O.[Na+]>C(Cl)Cl>[P:1]([OH:43])([OH:50])([O:3][C:4]([CH3:42])([CH2:6][CH2:7][S:8]([N:11]1[CH2:16][CH2:15][C:14]([C:17]2[CH:41]=[CH:40][C:20]3[N:21]=[C:22]([O:24][CH:25]4[CH2:30][CH2:29][N:28]([C:31]5[N:32]=[CH:33][C:34]([CH2:37][CH2:38][CH3:39])=[CH:35][N:36]=5)[CH2:27][CH2:26]4)[S:23][C:19]=3[CH:18]=2)=[CH:13][CH2:12]1)(=[O:9])=[O:10])[CH3:5])=[O:2]
Reactant: CCCc1cnc(N2CCC(Oc3nc4ccc(C5=CCN(S(=O)(=O)CCC(C)(C)OP(=O)(OCC[Si](C)(C)C)OCC[Si](C)(C)C)CC5)cc4s3)CC2)nc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCc1cnc(N2CCC(Oc3nc4ccc(C5=CCN(S(=O)(=O)CCC(C)(C)OP(=O)(O)O)CC5)cc4s3)CC2)nc1
Temperature: 25 °C
Yield: 80.6 %

Procedure:
To a solution of 2-methyl-4-(4-(2-(1-(5-propylpyrimidin-2-yl)piperidin-4-yloxy)benzo[d]thiazol-6-yl)-5,6-dihydropyridin-1(2H)-ylsulfonyl)butan-2-yl bis(2-(trimethylsilyl)ethyl) phosphate (85 mg, 0.098 mmol) in CH2Cl2 (511 μl) at 0° C. was added TFA (51.1 μl, 0.663 mmol). The mixture was stirred and gradually warmed to rt for 4 h. It was cooled to 0° C. and an aqueous solution of NaHCO3 (saturated, 0.5 mL) was added. The solvent was removed and the solid was collected via filtering. The solid was rinsed with cold H2O and ether. It was dried under vacuum to yield 2-methyl-4-(4-(2-(1-(5-propylpyrimidin-2-yl)piperidin-4-yloxy)benzo[d]thiazol-6-yl)-5,6-dihydropyridin-1(2H)-ylsulfonyl)butan-2-yl dihydrogen phosphate (53 mg, 0.079 mmol, 80% yield) as a white solid. 1H NMR (500 MHz, DMSO) δ 8.17 (s, 2H), 7.90 (s, 1H), 7.56 (d, J=8.5 Hz, 1H), 7.43 (d, J=8.6 Hz, 1H), 6.14 (s, 1H), 5.33 (s, 1H), 4.12 (d, J=13.6 Hz, 2H), 3.90 (s, 2H), 3.47 (dd, J=24.6, 14.8 Hz, 4H), 2.53 (s, 4H), 2.35-2.24 (m, 3H), 2.06 (m, 2H), 1.90 (m, 2H), 1.69 (m, 2H), 1.46 (dd, J=14.7, 7.4 Hz, 2H), 1.20 (s, 6H), 0.81 (t, J=7.3 Hz, 3H). LCMS (m/z)=665 (M+H)+.
Reaction SMILES: [C:1]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:6]=[CH:5][C:4]([S:7]([NH:10][CH:11]([CH2:16][CH:17]2[O:19][CH2:18]2)[C:12]([O:14]C)=[O:13])(=[O:9])=[O:8])=[CH:3][CH:2]=1.[C:26]1(C2C=CC=CC=2)[CH:31]=[CH:30][C:29]([S:32](NC(CC=C)C(OC)=O)(=O)=O)=[CH:28][CH:27]=1.O.ClC1C=CC=C(C(OO)=O)C=1>C(Cl)Cl.C([O-])(O)=O.[Na+]>[C:1]1([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:6]=[CH:5][C:4]([S:7]([NH:10][CH:11]([CH2:16][CH:17]([OH:19])[CH2:18][S:32][C:29]2[CH:30]=[CH:31][CH:26]=[CH:27][CH:28]=2)[C:12]([OH:14])=[O:13])(=[O:8])=[O:9])=[CH:3][CH:2]=1
Reactant: COC(=O)C(CC1CO1)NS(=O)(=O)c1ccc(-c2ccccc2)cc1
Reactant: C=CCC(NS(=O)(=O)c1ccc(-c2ccccc2)cc1)C(=O)OC
Agent: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: O=C(O)C(CC(O)CSc1ccccc1)NS(=O)(=O)c1ccc(-c2ccccc2)cc1
Reaction time: 8 h

Procedure:
Methyl 2-[[(1,1′-biphenyl)-4-yl]sulfonyl]amino-4,5-epoxypentanoate: To a solution of methyl 2-[[(1,1′-biphenyl)-4-yl]sulfonyl]amino-4-pentenoate 16a (2.0 g, 5.8 mmol) in CH2Cl2 (15 mL), NaHCO3 (0.58 g, 7 mmol) and water (10 mL) at 0° C., is added slowly m-chloroperbenzoic acid (3.3 g, 11.6 mmol, 57-86%). The reaction mixture is stirred overnight. The resulting mixture is diluted with aqueous NaHCO3, and the mixture is extracted three times with CH2Cl2. The combined CH2Cl2 layers are washed with NaHCO3, brine, dried over MgSO4 and concentrated to an oil which is purified by column chromatography eluting with EtOAc/hexane (4:6) to give the desired product as a mixture of two isomers (ratio 2:3).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[CH2:13][CH2:12][CH2:11][C:10]=2[C:14]#[N:15])=[CH:4][CH:3]=1>[Ti](Cl)(Cl)(Cl)Cl.[OH-].[Na+]>[NH2:15][C:14]1[C:4]2[CH:3]=[C:2]([Cl:1])[CH:7]=[CH:6][C:5]=2[N:8]=[C:9]2[CH2:13][CH2:12][CH2:11][C:10]=12
Reactant: N#CC1=C(Nc2ccc(Cl)cc2)CCC1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Product: Nc1c2c(nc3ccc(Cl)cc13)CCC2
Temperature: 140 °C

Procedure:
Under nitrogen, titanium tetrachloride (1.2 ml, 11 mmol) was added to the above enamine (Example 14) (2.2 g, 10 mmol) and the stirred mixture was heated at 140° C. for 1 hour. After cooling, 10M-sodium hydroxide solution (20 ml) was added and the mixture heated under reflux for 1 hour. After being allowed to cool, this mixture was filtered and the solids washed with dichloromethane. Any organics in the filtrate were also extracted into dichloromethane. All extracts were combined, dried (Na2SO4), filtered and the solvent evaporated, Kugelrohr distillation (200° C., 2 mm Hg) gave the product as a pale yellow powder.
Reaction SMILES: C([O:3][C:4](=[O:40])[C:5]([CH3:39])([O:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][C:17]2[N:18]=[C:19]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]4[C:38]5[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=5)[CH:32]=[CH:31][CH:30]=4)[CH:24]=3)[O:20][C:21]=2[CH3:22])=[CH:10][CH:9]=1)[CH3:6])C.[OH-].[Na+].Cl.C(OCC)(=O)C>C(O)C>[CH3:39][C:5]([O:7][C:8]1[CH:9]=[CH:10][C:11]([O:14][CH2:15][CH2:16][C:17]2[N:18]=[C:19]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]4[C:38]5[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=5)[CH:32]=[CH:31][CH:30]=4)[CH:24]=3)[O:20][C:21]=2[CH3:22])=[CH:12][CH:13]=1)([CH3:6])[C:4]([OH:40])=[O:3]
Reactant: CCOC(=O)C(C)(C)Oc1ccc(OCCc2nc(-c3cccc(-c4cccc5ccccc45)c3)oc2C)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CCO
Product: Cc1oc(-c2cccc(-c3cccc4ccccc34)c2)nc1CCOc1ccc(OC(C)(C)C(=O)O)cc1
Temperature: 25 °C

Procedure:
A stirred solution of 2-methyl-2-(4-{2-[5-methyl-2-(3-naphthalen-1-ylphenyl)oxazol-4-yl]ethoxy}phenoxy)propionic acid ethyl ester (0.711 mmol) in ethanol (8.9 mL) was treated with NaOH(aq) (0.854 mL of a 5M solution), and heated at reflux for 1 h. The hot solution was acidified to pH 1 with 1M HCl (6 mL). The mixture was cooled to ambient temperature, then further cooled to 0° C. before filtering the product. Following washing with H2O, the product was dried under vacuum at 50° C. to yield a white, crystalline solid: Rf=0.22 in 6:4 ethyl acetate:hexanes; 1H NMR (400 MHz, CDCl3) δ8.08 (s, 1H), 8.03 (d, J=8.8 Hz, 1H), 7.90-7.82 (m, 3H), 7.53-7.39 (m, 6H), 6.86-6.75 (m, 4H), 4.16 (t, J=6.4 Hz, 2H), 2.95 (t, J=6.4 Hz, 2H), 2.35 (s, 3H), 1.47 (s, 6H); MS (EI) 508.1 (M+H)+.
Reaction SMILES: C(O[C:6]([NH:8][CH2:9][CH2:10][C:11]1[C:19]2[C:14](=[CH:15][C:16]([Cl:20])=[CH:17][CH:18]=2)[NH:13][CH:12]=1)=O)(C)(C)C.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[CH3:6][NH:8][CH2:9][CH2:10][C:11]1[C:19]2[C:14](=[CH:15][C:16]([Cl:20])=[CH:17][CH:18]=2)[NH:13][CH:12]=1
Reactant: CC(C)(C)OC(=O)NCCc1c[nH]c2cc(Cl)ccc12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CNCCc1c[nH]c2cc(Cl)ccc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Combine N-t-butoxycarbonyl-2-(6-chloro-1H-indol-3-yl)ethylamine (1.3 g, 4.41 mmol) and dry THF (20 ml) and add dropwise to an ice bath cooled suspension of LiAlH4 (1.0 g, 26.5 mmol) in dry THF (30 ml). Heat to reflux. After 2 hours, cool to, ambient temperature and stir. After 15 hours, quench with saturated NaSO4 (100 ml/mol), stir for 1 hour at ambient temperature, then filter under vacuum. Wash precipitate with THF and evaporated filtrate and washes to residue. Chromatograph the residue on silica gel eluting with dichloromethane/2N NH3(methanol) (84/16) to give the title compound: MS (ACPI): m/e 209.0 (M+1).
Reaction SMILES: Cl[CH2:2][C:3]([N:5]([O:7][CH3:8])[CH3:6])=[O:4].[Br:9][C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[C:12]([O:17][CH3:18])[CH:11]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(Cl)Cl>[Br:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:2][C:3]([N:5]([O:7][CH3:8])[CH3:6])=[O:4])=[C:12]([O:17][CH3:18])[CH:11]=1
Reactant: CON(C)C(=O)CCl
Reactant: COc1cc(Br)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1cc(Br)ccc1OCC(=O)N(C)OC
Temperature: 60 °C
Reaction time: 16 h
Yield: 81.4 %

Procedure:
A mixture of 2-chloro-N-methoxy-N-methylacetamide (2.7 g, 19.63 mmol), 4-bromo-2-methoxyphenol (3.98 g, 19.63 mmol), and potassium carbonate (5.43 g, 39.3 mmol) in DMF (20 mL) was heated at 60° C. for 1 hour and stirred at RT overnight (16 hours). The reaction mixture was diluted with CH2Cl2, washed with sat NaHCO3, brine and dried (Na2SO4). After concentration, the crude product was purified by ISCO flash chromatography (silica gel/hexanes-ethyl acetate 100:0 to 0:100 gradient) to afford 2-(4-bromo-2-methoxyphenoxy)-N-methoxy-N-methylacetamide 16A (4.86 g, 15.98 mmol, 81% yield) as a yellow solid. 1H NMR (400 MHz, chloroform-d) δ 6.97-7.04 (2H, m), 6.76 (1H, d, J=8.03 Hz), 4.86 (2H, s), 3.87 (3H, s), 3.75 (3H, s), 3.23 (3H, s).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:27]=[CH:26][C:9]([C:10]([N:12]([C@H:14]3[CH2:23][CH2:22][C:21]4[C:16](=[CH:17][CH:18]=[C:19]([CH:24]=O)[CH:20]=4)[CH2:15]3)[CH3:13])=[O:11])=[CH:8][CH:7]=2)[CH2:3][CH2:2]1.C1COCC1.[O:33]1[CH2:38][CH2:37][CH:36]([CH2:39][NH2:40])[CH2:35][CH2:34]1.C([BH3-])#N.[Na+]>C(O)(=O)C>[CH:1]1([CH2:4][O:5][C:6]2[CH:27]=[CH:26][C:9]([C:10]([N:12]([CH3:13])[C@H:14]3[CH2:23][CH2:22][C:21]4[C:16](=[CH:17][CH:18]=[C:19]([CH2:24][NH:40][CH2:39][CH:36]5[CH2:37][CH2:38][O:33][CH2:34][CH2:35]5)[CH:20]=4)[CH2:15]3)=[O:11])=[CH:8][CH:7]=2)[CH2:3][CH2:2]1
Reactant: CN(C(=O)c1ccc(OCC2CC2)cc1)[C@H]1CCc2cc(C=O)ccc2C1
Reactant: NCC1CCOCC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CN(C(=O)c1ccc(OCC2CC2)cc1)[C@H]1CCc2cc(CNCC3CCOCC3)ccc2C1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a mixture of 4-cyclopropylmethoxy-N—((S)-6-formyl-1,2,3,4-tetrahydronaphthalen-2-yl)-N-methylbenzamide (0.20 g), THF (5 ml), C-(tetrahydropyran-4-yl)methylamine (63 mg) and acetic acid (33 mg) was added polymer-bound sodium cyanoborohydride (0.55 mmol), and the suspension was shaken at room temperature for 12 hours. The polymer was filtered off with suction and the filtrate was concentrated. The residue was purified by preparative HPLC. The product was thus obtained with the monoisotopic molecular weight of 462.29 (C28H38N2O3); MS (ESI): 463.3 (M+H+).
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[CH2:10][CH2:9][N:8]([C:11]2[CH:16]=[C:15]([O:17][CH3:18])[C:14]([Cl:19])=[CH:13][C:12]=2[F:20])[CH2:7][C@@H:6]1[CH3:21])=[O:4].[I:22][C:23]1[C:31]2[C:26](=[N:27][CH:28]=[CH:29][CH:30]=2)[NH:25][N:24]=1.C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>C(OCC)(=O)C>[Cl:19][C:14]1[C:15]([O:17][CH3:18])=[CH:16][C:11]([N:8]2[CH2:9][CH2:10][N:5]([C:3](=[O:4])[CH2:2][N:25]3[C:26]4=[N:27][CH:28]=[CH:29][CH:30]=[C:31]4[C:23]([I:22])=[N:24]3)[C@@H:6]([CH3:21])[CH2:7]2)=[C:12]([F:20])[CH:13]=1
Reactant: Ic1n[nH]c2ncccc12
Reactant: COc1cc(N2CCN(C(=O)CCl)[C@@H](C)C2)c(F)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1cc(N2CCN(C(=O)Cn3nc(I)c4cccnc43)[C@@H](C)C2)c(F)cc1Cl
Temperature: 90 °C
Reaction time: 8 h
Yield: 99.2 %

Procedure:
A mixture of 2-Chloro-1-[(S)-4-(4-chloro-2-fluoro-5-methoxy-phenyl)-2-methyl-piperazin-1-yl]-ethanone (1.37 g, 4.08 mmol, 1 eq), 3-Iodo-1H-pyrazolo[3,4-b]pyridine (1.0 g, 4.08 mmol, 1 eq), potassium carbonate (2.26 g, 16.4 mmol, 4 eq), and DMF (15 ml) was stirred overnight at 90° C. The reaction solution was diluted with ethyl acetate, washed with saturated aqueous NaHCO3, and concentrated in vacuo. The crude product was purified by flash chromatography to provide 1-[(S)-4-(4-Chloro-2-fluoro-5-methoxy-phenyl)-2-methyl-piperazin-1-yl]-2-(3-iodo-pyrazolo[3,4-b]pyridin-1-yl)-ethanone (2.2 g).
Reaction SMILES: C([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH2:12][CH:13]=[CH2:14])[CH:6]=1)(=O)C.[OH-].[Na+].CO>C1COCC1>[CH2:12]([O:11][C:7]1[CH:6]=[C:5]([OH:4])[CH:10]=[CH:9][CH:8]=1)[CH:13]=[CH2:14]
Reactant: C=CCOc1cccc(OC(C)=O)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: C=CCOc1cccc(O)c1
Reaction time: 1 h

Procedure:
The product from Example 61A (7.19 g, 37.4 mmoles) in THF (30 mL) was treated with 4N NaOH (19 mL, 75 mmoles) and MeOH (5 mL). After one hour, the reaction mixture was concentrated under reduced pressure. The residue was dissolved in ethyl acetate, washed with aqueous NH4Cl, brine, dried (Na2SO4), filtered, and the filtrate concentrated under reduced pressure to provide the title compound without further purification.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:11](CCC)[C:10]2[CH:15]=[CH:16][C:17](=[O:24])[C:18]([O:20][CH2:21][CH2:22][CH3:23])=[CH:19][C:9]=2[C:8](=[O:25])[CH:7]=1)=[O:5])C.Cl.C>>[O:25]=[C:8]1[CH:7]=[C:6]([C:4]([OH:5])=[O:3])[NH:11][C:10]2[CH:15]=[CH:16][C:17](=[O:24])[C:18]([O:20][CH2:21][CH2:22][CH3:23])=[CH:19][C:9]1=2
Reactant: CCCOc1cc2c(=O)cc(C(=O)OCC)n(CCC)c2ccc1=O
Agent: Cl
Product: CCCOc1cc2c(=O)cc(C(=O)O)[nH]c2ccc1=O
Temperature: 25 °C

Procedure:
A mixture of 4,7-dihydro-4,7-dioxo-6-propoxy-1-propyl-1H-cyclohepta[b]pyridine-2-carboxlic acid ethyl ester (3.8 g, described in Example 22) and 19% hydrochloric acid (113 ml) is refluxed for 30 minutes. Charcoal is added and the hot mixture is filtered. The filtrate is cooled to room temperature and the crystalline precipitate is collected and dried to obtain the title compound, mp > 250° C.
Reaction SMILES: CO[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][CH2:10][C:11](C)([OH:19])CC1CCCCN1.Br>C(O)(=O)C>[O:19]1[C:3]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:9][CH2:10][CH2:11]1
Reactant: COc1ccccc1CCC(C)(O)CC1CCCCN1
Agent: Br
Solvent: CC(=O)O
Product: c1ccc2c(c1)CCCO2

Procedure:
Mother liquors made as in part (a), (24 g) are taken up in 200 ml of glacial acetic acid and treated with 100 ml of 48% HBr. After refluxing for 3 hours under nitrogen the mixture is evaporated to an oil, basified (sodium hydroxide), extracted with chloroform, dried (potassium carbonate) and evaporated to 20 g of oil. This is chromatographed on 200 g of alumina (basic, activity I) in chloroform. Intermediate fractions (500 ml) give 12 g (57%) of single spot oily chroman.
Reaction SMILES: [O:1]=[C:2]1[N:7]2[N:8]=[CH:9][C:10]3[CH:14]=[CH:13][S:12][C:11]=3[C:6]2=[C:5]([C:15]([O:17][CH3:18])=[O:16])[CH:4]=[C:3]1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[C:25]([BH3-])#N.[Na+]>C(O)=O.O1CCCC1>[CH3:25][N:8]1[CH2:9][C:10]2[CH:14]=[CH:13][S:12][C:11]=2[C:6]2=[C:5]([C:15]([O:17][CH3:18])=[O:16])[CH:4]=[C:3]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:2](=[O:1])[N:7]12
Reactant: COC(=O)c1cc(-c2ccccc2)c(=O)n2ncc3ccsc3c12
Reactant: [BH3-]C#N
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O=CO
Product: COC(=O)c1cc(-c2ccccc2)c(=O)n2c1-c1sccc1CN2C
Temperature: 25 °C
Reaction time: 24 h

Procedure:
0.34 g of methyl 7-oxo-8-phenyl-7H-pyrido[1,2-b]thieno[2,3-d]pyridazine-10-carboxylate in 10 ml of formic acid are treated dropwise under argon at 25°-30° with 0.31 g of sodium cyanoborohydride in 2 ml of tetrahydro-furan. The mixture is left to stir at room temperature for 24 hours. The solution is poured into 50 ml of ice-water. The yellowish crystals are removed by filtration and washed with water. After drying in vacuo, recrystallization is carried out from ethyl acetate. There is obtained methyl 4,5-dihydro-5-methyl-7-oxo-8-phenyl-7H-pyrido[1,2-b]thieno-[2,3-d]pyridazine-10-carboxylate of m.p. 180°-181°.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][N:7]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH:8]=1)([O-])=O>[Pd].C(O)C>[NH2:1][C:4]1[CH:5]=[N:6][N:7]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH:8]=1
Reactant: CC(C)(C)OC(=O)n1cc([N+](=O)[O-])cn1
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)n1cc(N)cn1

Procedure:
tert-butyl 4-nitro-1H-pyrazole-1-carboxylate was stirred with palladium on carbon (10%, 170 mg) in ethanol (20 mL) under an atmosphere of hydrogen at 20° C. for 18 h. The palladium was removed by filtration and the solvent was removed in vacuo to give tert-butyl 4-amino-1H-pyrazole-1-carboxylate (1.48 g). 1H NMR (d6-DMSO) δ 7.35 (d, 1H), 7.33 (d, 1H), 4.40 (s, 2H), 1.54 (s, 9H).