Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[CH2:4][CH2:5][NH:6][C:7](=[O:16])[C:8]1[CH:13]=[CH:12][C:11]([CH:14]=O)=[CH:10][CH:9]=1.[C:18]1([C:24]2[CH:30]=[CH:29][C:27]([NH2:28])=[CH:26][CH:25]=2)[CH2:23][CH2:22][CH2:21][CH2:20][CH:19]=1.C([BH3-])#N.[Na+]>CO>[CH3:1][O:2][C:3](=[O:17])[CH2:4][CH2:5][NH:6][C:7](=[O:16])[C:8]1[CH:13]=[CH:12][C:11]([CH2:14][NH:28][C:27]2[CH:29]=[CH:30][C:24]([C:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH:19]=3)=[CH:25][CH:26]=2)=[CH:10][CH:9]=1
Reactant: Nc1ccc(C2=CCCCC2)cc1
Reactant: COC(=O)CCNC(=O)c1ccc(C=O)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: COC(=O)CCNC(=O)c1ccc(CNc2ccc(C3=CCCCC3)cc2)cc1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 21.3 %

Procedure:
3-(4-Formylbenzoylamino)propionic acid methyl ester (10 g, 42.5 mmol) was dissolved in methanol (100 ml). With mechanical stirring a solution of 4-cyclohex-1-enylaniline (7.4 g, 42.5 mmol) in methanol (15 ml) was added and the resulting suspension was stirred at room temperature for 2.5 hours. Sodium cyano borohydride (4.01 g, 63.8 mmol) was added in portions and the resulting mixture was stirred at room temperature for 4 days. Filtration afforded 7.1 g of a solid and recrystallisation from methanol afforded 3.55 g of 3-{4-[(4-cyclohex-1-enylphenylamino)methyl]benzoylamino}propionic acid methyl ester.
Reaction SMILES: [C:1]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11]CCC(OC)=O)(=[S:3])C.Cl.[C:19]([O:22][CH2:23]C)(=[O:21])[CH3:20].C(CC(C)(C)C)(C)C.C(=O)([O-])O.[Na+]>CO.ClCCl>[SH:3][CH2:1][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:20][C:19]([O:22][CH3:23])=[O:21]
Reactant: COC(=O)CCCCCCCCCCC(C)=S
Reactant: CCOC(C)=O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Solvent: CC(C)CC(C)(C)C
Product: COC(=O)CCCCCCCCCCS
Reaction time: 48 h
Yield: 68 %

Procedure:
Compound 104 (15.6 g, 56.9 mmol) in methanol (50 ml) was added to a solution of hydrogen chloride in methanol (HCl was bubbled into 600 ml of MeOH for 10 min). The reaction was monitored by TLC (SiO2, ethyl acetate:isooctane 1:5). After 48 h, an excess of sodium hydrogen carbonate was added and the mixture was diluted with dichloromethane (150 ml), filtered and concentrated. Distillation gave pure 105 (9.0 g, 68%) with b.p. 93°-94° (7×10-2 torr). 1H-NMR (CDCl3, Me4Si) δ 3.68 (s, 3H, MeO), 2.53 (q, 2H, J~7 Hz, H--S--CH2), 2.31 (t, 2H, J=7.5 Hz, CH2CO). 13C-NMR (CDCl3, Me4Si) δ 174.2 (CO), 51.3, 34.0, 33.9, 29.3, 29.2, 29.1, 29.0, 28.9, 28.3, 24.8, 24.5.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[C:22]([CH3:28])=[N:23][NH:24][C:25](=[O:27])[CH:26]=3)=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:29]>O1CCOCC1.O>[ClH:29].[CH3:28][C:22]1[C:21]([C:18]2[CH:17]=[CH:16][C:15]([O:14][CH:11]3[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]3)=[CH:20][CH:19]=2)=[CH:26][C:25](=[O:27])[NH:24][N:23]=1
Reactant: Cc1n[nH]c(=O)cc1-c1ccc(OC2CCN(C(=O)OC(C)(C)C)CC2)cc1
Agent: Cl
Solvent: O
Solvent: C1COCCO1
Product: Cc1n[nH]c(=O)cc1-c1ccc(OC2CCNCC2)cc1
Temperature: 50 °C
Reaction time: 1 h
Yield: 92 %

Procedure:
A solution of the product from step 2 (4-[4-(3-methyl-6-oxo-1,6-dihydro-pyridazin-4-yl)-phenoxy]-piperidine-1-carboxylic acid tert-butyl ester) (7.6 g, 20 mmol) in 30 mL of dioxane and 3.0 mL of water was cooled to 0° C. as 24 mL of 4M HCl in dioxane was added dropwise. After stirring at 50° C. for 1 h, the solvent was evaporated. The white solid was triturated with ether to give 6-methyl-5-[4-(piperidin-4-yloxy)-phenyl]-2H-pyridazin-3-one HCl (6.2 g, 92%): Mp 225-7° C.; MS m/z 286 (M+H).
Reaction SMILES: [CH2:1]([S:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17]([C:19]2[CH2:20][CH2:21][O:22][C:23]3[CH:29]=[CH:28][C:27]([C:30]4[CH:35]=[CH:34][C:33]([CH3:36])=[CH:32][CH:31]=4)=[CH:26][C:24]=3[CH:25]=2)=[O:18])=[CH:12][CH:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClC1C=CC=C(C(OO)=[O:45])C=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>ClCCl>[CH2:1]([S:8]([CH2:9][C:10]1[CH:11]=[CH:12][C:13]([NH:16][C:17]([C:19]2[CH2:20][CH2:21][O:22][C:23]3[CH:29]=[CH:28][C:27]([C:30]4[CH:31]=[CH:32][C:33]([CH3:36])=[CH:34][CH:35]=4)=[CH:26][C:24]=3[CH:25]=2)=[O:18])=[CH:14][CH:15]=1)=[O:45])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CSCc4ccccc4)cc2)CCO3)cc1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: Cc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CS(=O)Cc4ccccc4)cc2)CCO3)cc1
Reaction time: 0.17 h
Yield: 64.6 %

Procedure:
To a solution of N-(4—(benzylthiomethyl)phenyl)-7—(4-methylphenyl)-2,3-dihydro-1-benzoxepine-4-carboxamide (0.12 g) in dichloromethane (25 ml) was added 70% m-chloroperbenzoic acid (0.06 g) at the temperature ranging from −20 to −10° C., and the mixture was stirred for 10 minutes. To the mixture was added sodium thiosulfate solution, and the mixture was concentrated and extracted with ethyl acetate. The organic layer was washed with sodium hydrogen carbonate solution, water and saturated sodium chloride solution, and dried with anhydrous magnesium sulfate. Under reduced pressure, the solvent was evaporated to give crude crystals, which were recrystallized from ethyl acetate-hexane to give N-(4—(benzylsulfinylmethyl)phenyl)-7—(4-methylphenyl)-2,3-dihydro-1-benzoxepine-4-carboxamide (Compound 109) (0.08 g) as colorless crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:31])([F:30])[F:29])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=3)[C:21](O)=[O:22])=[CH:17][C:9]1=2.[CH3:32][S:33]([C:36]1[CH:43]=[CH:42][C:39]([CH2:40][NH2:41])=[CH:38][CH:37]=1)(=[O:35])=[O:34]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:31])([F:29])[F:30])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=3)[C:21]([NH:41][CH2:40][C:39]3[CH:38]=[CH:37][C:36]([S:33]([CH3:32])(=[O:35])=[O:34])=[CH:43][CH:42]=3)=[O:22])=[CH:17][C:9]1=2
Reactant: O=C(O)c1cccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)c1
Reactant: CS(=O)(=O)c1ccc(CN)cc1
Product: CS(=O)(=O)c1ccc(CNC(=O)c2cccc(-c3cnc4c(c3)N(Cc3cc(Cl)ccc3C(F)(F)F)CCN4)c2)cc1

Procedure:
3-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoic acid was reacted with 4-methanesulfonylbenzylamine as in General Procedure 10 to give the title compound. LCMS: m/z=614.91 (M+H+); retention time=0.81 minutes.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[C:6]1(C#N)[CH:11]=[CH:10][CH:9]=[CH:8][NH:7]1.C[Mg]Br.[Cl-].[NH4+].[O:19]1CC[CH2:21][CH2:20]1>C(OCC)C>[O:3]1[CH2:4][CH2:5][O:1][CH:2]1[C:6]1[N:7]=[C:8]([C:20](=[O:19])[CH3:21])[CH:9]=[CH:10][CH:11]=1
Reactant: C1CCOC1
Reactant: N#CC1(C2OCCO2)C=CC=CN1
Agent: C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Product: CC(=O)c1cccc(C2OCCO2)n1
Temperature: -10 °C
Reaction time: 3 h
Yield: 83 %

Procedure:
0.88 g of 2-[1,3]dioxolan-2-yl-pyridine-2-carbonitrile (4.99 mmol) is dissolved in 10 ml of tetrahydrofuran. 3.50 ml of a 3M solution of methylmagnesium bromide in diethyl ether are introduced dropwise into the solution cooled to -10° C. The reaction mixture is stirred for 3 hours at room temperature under a nitrogen atmosphere. The mixture is poured into a saturated aqueous solution of ammonium chloride, the mixture is extracted with ethyl acetate, the organic phase is washed with a saturated aqueous solution of ammonium chloride and then dried over magnesium sulfate, filtered and concentrated under vacuum. The title product is isolated by chromatography on a silica column (eluent: chloroform). 0.80 g of a yellow oil is recovered.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8](I)=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=3)[N:10]=2)[N:7]=1.O1CCCC1.C(=O)([O-])[O-].[Cs+].[Cs+].CC1(C)C(C)(C)OB([C:38]2[CH:43]=[CH:42][N:41]=[C:40]([NH:44][C:45](=[O:51])[O:46][C:47]([CH3:50])([CH3:49])[CH3:48])[CH:39]=2)O1>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:38]3[CH:43]=[CH:42][N:41]=[C:40]([NH:44][C:45](=[O:51])[O:46][C:47]([CH3:49])([CH3:48])[CH3:50])[CH:39]=3)=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=3)[N:10]=2)[N:7]=1
Reactant: Clc1ccc(-c2nc3ccc(Cl)nn3c2I)cc1
Reactant: CC(C)(C)OC(=O)Nc1cc(B2OC(C)(C)C(C)(C)O2)ccn1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1cc(-c2c(-c3ccc(Cl)cc3)nc3ccc(Cl)nn23)ccn1
Yield: 209.8 %

Procedure:
To a suspension of 3 g (7.31 mmol) of 6-chloro-2-(4-chlorophenyl)-3-iodoimidazo[1,2-b]pyridazine in 183 mL of a mixture of tetrahydrofuran and water (9:1) are added 7.1 g (22 mmol) of cesium carbonate and 2.90 g (8.8 mmol) of tert-butyl [4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrid-2-yl]carbamate. After sparging with a stream of argon for a few moments, 0.54 g (0.66 mmol) of [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) is added and the reaction mixture is refluxed under argon for 18 hours. After filtering through a Whatman filter and through Celite, the filtrate is then concentrated under reduced pressure to give 7.0 g of a brown residue. The residue is taken up in water, the product is extracted with dichloromethane, the organic phase is dried over sodium sulfate and filtered, and the solvent is evaporated off to give 3.5 g of a dark powder.
Reaction SMILES: O.Cl.[Cl:3][C:4]1[C:5]([CH3:26])=[C:6]([S:10]([NH:13][C:14]2[S:15][CH:16]=[C:17]([CH2:19][CH2:20][CH2:21][NH:22][CH2:23][CH2:24][OH:25])[N:18]=2)(=[O:12])=[O:11])[CH:7]=[CH:8][CH:9]=1.Cl[CH2:28][C:29](Cl)=[O:30].[OH-].[K+]>O.C1COCC1>[Cl:3][C:4]1[C:5]([CH3:26])=[C:6]([S:10]([NH:13][C:14]2[S:15][CH:16]=[C:17]([CH2:19][CH2:20][CH2:21][N:22]3[CH2:23][CH2:24][O:25][CH2:28][C:29]3=[O:30])[N:18]=2)(=[O:11])=[O:12])[CH:7]=[CH:8][CH:9]=1
Reactant: O=C(Cl)CCl
Reactant: Cc1c(Cl)cccc1S(=O)(=O)Nc1nc(CCCNCCO)cs1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1c(Cl)cccc1S(=O)(=O)Nc1nc(CCCN2CCOCC2=O)cs1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 51.8 %

Procedure:
To a solution of EXAMPLE 208B (187 mg, 0.44 mmol) in H2O (2 mL)/THF (1 mL) was chloroacetyl chloride (110 mg, 0.97 mmol) in THF (3 mL) dropwise added under a period of 40 min. The temperature was kept at 8° C. and 2 M KOH was added continuously to adjust the pH to around 6-8. Aqueous potassium hydroxide (6 M, 0.38 mL, 1.41 mmol) was added and the mixture was stirred at room temperature for 20 min. The pH was adjusted to 8 and the mixture was extracted with ethyl acetate. The organic phase was separated and the solvent was evaporated. The residue was flash chromatographed on silica gel eluting with 30% acetone in DCM, yielding 98 mg (52 %) of the title compound: MS (Ionspray, [M+H]+) m/z 429. Anal. Calcd. (found) for C17H20ClN3O4S2: C, 47.5 (47.4)%; H, 4.7 (4.9)%; N, 9.8 (9.5)%.
Reaction SMILES: [CH2:1]([NH:3][C:4]([NH:6][C:7]1[S:8][C:9]2[C:15]([CH:16]=O)=[CH:14][C:13]([C:18]3[CH:19]=[N:20][C:21]([N:24]4[CH2:29][CH2:28][C:27]([CH3:35])([C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH2:26][CH2:25]4)=[N:22][CH:23]=3)=[CH:12][C:10]=2[N:11]=1)=[O:5])[CH3:2].[CH3:36][NH2:37].[BH4-].[Na+]>C1COCC1.O>[CH2:1]([NH:3][C:4]([NH:6][C:7]1[S:8][C:9]2[C:15]([CH2:16][NH:37][CH3:36])=[CH:14][C:13]([C:18]3[CH:19]=[N:20][C:21]([N:24]4[CH2:29][CH2:28][C:27]([CH3:35])([C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH2:26][CH2:25]4)=[N:22][CH:23]=3)=[CH:12][C:10]=2[N:11]=1)=[O:5])[CH3:2]
Reactant: CN
Reactant: CCNC(=O)Nc1nc2cc(-c3cnc(N4CCC(C)(C(=O)OCC)CC4)nc3)cc(C=O)c2s1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCNC(=O)Nc1nc2cc(-c3cnc(N4CCC(C)(C(=O)OCC)CC4)nc3)cc(CNC)c2s1
Yield: 91 %

Procedure:
Ethyl 1-[5-[2-(ethylcarbamoylamino)-7-formyl-1,3-benzothiazol-5-yl]pyrimidin-2-yl]-4-methyl-piperidine-4-carboxylate (140 mg, 0.28 mmol) was stirred in a 7M solution of methylamine in THF (8 mL) in a microwave tube equipped with a stirrer. The reaction was irradiated to 80° C. for 1 h in a CEM explorer microwave with stirring. After cooling, the solvents were removed under reduced pressure, the resulting residue dissolved in anhydrous MeOH (8 mL) and the reaction transferred to a round bottomed flask equipped with a calcium chloride drying tube. Sodium borohydride (43 mg, 1.12 mmol) was added and the reaction stirred at rt for 18 h. After this time LCMS indicated 70% conversion to the desired material. The reaction was diluted with water (20 mL), extracted with EtOAc (3×20 mL) and the combined organic extracts washed with brine, dried (MgSO4) and concentrated under reduced pressure to afford the crude product as a glassy brown/grey solid 130 mg (91% yield).
Reaction SMILES: [C:1]([C:5]1[CH:14]=[C:13]2[C:8]([C:9](C)=[C:10]([CH2:15][N:16]3[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]3)[CH2:11][CH2:12]2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl.N1CCCCC1.C(C1C=C2C(=CC=1)C(=[O:44])CCC2)(C)(C)C.C=O>C(O)C.Cl>[C:1]([C:5]1[CH:14]=[C:13]2[C:8](=[CH:7][CH:6]=1)[C:9](=[O:44])[CH:10]([CH2:15][N:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1)[CH2:11][CH2:12]2)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC1=C(CN2CCCCC2)CCc2cc(C(C)(C)C)ccc21
Reactant: CC(C)(C)c1ccc2c(c1)CCCC2=O
Agent: C=O
Agent: Cl
Solvent: CCO
Solvent: C1CCNCC1
Product: CC(C)(C)c1ccc2c(c1)CCC(CN1CCCCC1)C2=O
Yield: 83 %

Procedure:
This Example illustrates the preparation of 7-tert-butyl-4-methyl-3-piperidinomethyl,1,2-dihydronaphthalene (Compound number 3 of Table I). Piperidine hydrochloride (12.6 g 0.103 mol), 6-tert-butyl-1,2,3,4-tetrahydronaphthalen-1-one (80.0 g, 0.04 mol) and paraformaldehyde (2.64 g, 0.088 mol) were refluxed in ethanol (200 ml) with concentrated hydrochloric acid (1 ml) as a catalyst for 48 hours. The reaction mixture was concentrated under reduced pressure and the residue dissolved in water then extracted with diethyl ether. The resulting aqueous solution was neutralized with sodium bicarbonate and extracted with diethyl ether (2×200 ml); the ethereal extracts were dried over magnesium sulphate and concentrated under reduced pressure to give 6-tert-butyl-2-piperidinomethyl-1,2,3,4-tetrahydronaphthalen-1-one (10.0 g 83% yield) melting at 47°-9°.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[N:8]([CH2:11][C:12]3[CH:20]=[CH:19][CH:18]=[C:17]4[C:13]=3[CH:14]=[CH:15][N:16]4C(OC(C)(C)C)=O)[N:9]=[CH:10][C:5]2=[C:4]([C:28]2[O:29][CH:30]=[CH:31][CH:32]=2)[N:3]=1.C[O-].[Na+]>CO.O>[O:29]1[CH:30]=[CH:31][CH:32]=[C:28]1[C:4]1[N:3]=[C:2]([NH2:1])[N:7]=[C:6]2[N:8]([CH2:11][C:12]3[CH:20]=[CH:19][CH:18]=[C:17]4[C:13]=3[CH:14]=[CH:15][NH:16]4)[N:9]=[CH:10][C:5]=12
Reactant: CC(C)(C)OC(=O)n1ccc2c(Cn3ncc4c(-c5ccco5)nc(N)nc43)cccc21
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: Nc1nc(-c2ccco2)c2cnn(Cc3cccc4[nH]ccc34)c2n1
Yield: 80.1 %

Procedure:
A solution of tert-butyl 4-(6-amino-4-(2-furyl)-1H-pyrazolo[3,4-d]pyrimidine-1-ylmethyl)indole-1-carboxylate (92 mg, 0.17 mmol) in MeOH (3 mL) was treated with NaOMe (45 mg, 0.84 mmol), refluxed for 2 h, cooled, diluted with water (15 mL) and filtered to give the title compound (45 mg, 82%) as an off white powder.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([NH:11][CH3:12])(=[O:10])=[O:9])=[N:6][CH:7]=1.[H-].[Na+].[CH3:15][O:16][C:17]1[CH:24]=[CH:23][C:20]([CH2:21]Cl)=[CH:19][CH:18]=1.O>CN(C)C=O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([N:11]([CH2:21][C:20]2[CH:23]=[CH:24][C:17]([O:16][CH3:15])=[CH:18][CH:19]=2)[CH3:12])(=[O:10])=[O:9])=[N:6][CH:7]=1
Reactant: CNS(=O)(=O)c1ccc(Cl)cn1
Reactant: COc1ccc(CCl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(CN(C)S(=O)(=O)c2ccc(Cl)cn2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 58.1 %

Procedure:
5-Chloro-N-methylpyridine-2-sulfonamide (889 mg, 4.30 mmol) synthesized in Example (121a) was dissolved in N,N-dimethylformamide (15 mL), and sodium hydride (172 mg, 4.30 mmol) was added. After ice cooling, p-methoxybenzyl chloride (0.70 mL, 5.16 mmol) was added, and the temperature was raised to room temperature, followed by stirring for 3 hours. Water (20 mL) was added to the reaction solution, and extraction was carried out twice with ethyl acetate (20 mL). The organic layer was washed with saturated brine, and subsequently dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: ethyl acetate/hexane=0%-20%) to afford the desired compound (817 mg, yield 58%) as a colorless oil.
Reaction SMILES: Cl.C(O)C.C(OC([NH:15][CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][CH2:27][N:28]([CH2:33][CH2:34][CH2:35][CH3:36])[CH2:29][CH2:30][CH2:31][CH3:32])=[CH:20][CH:19]=1)=O)C1C=CC=CC=1>O.[C].[Pd]>[CH2:33]([N:28]([CH2:29][CH2:30][CH2:31][CH3:32])[CH2:27][CH2:26][CH2:25][O:24][C:21]1[CH:22]=[CH:23][C:18]([CH2:17][CH2:16][NH2:15])=[CH:19][CH:20]=1)[CH2:34][CH2:35][CH3:36]
Reactant: CCCCN(CCCC)CCCOc1ccc(CCNC(=O)OCc2ccccc2)cc1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Solvent: O
Product: CCCCN(CCCC)CCCOc1ccc(CCN)cc1
Reaction time: 1.5 h
Yield: 85.2 %

Procedure:
Conc. hydrochloric acid (2.1 ml) and g of 10% palladium-carbon (Pd-C) were added to 100 ml of an ethanol solution containing 5.4 g of N-benzyloxycarbonyl-2-[4-(3-dibutylaminopropyloxy)phenyl]ethylamine. The mixture was subjected to catalytic reduction at normal temperature under normal pressure for 1.5 hours. After removing the catalyst by filtration, the filtrate was condensed and the residue was dissolved in water. The aqueous solution was washed with diethyl ether and made alkaline with potassium carbonate, and the mixture was extracted with ethyl acetate. The extract was washed and dried, and the solvent was removed under reduced pressure to give 3.2 g of 2-[4-(3-dibutylaminopropyloxy)phenyl]ethylamine (yield: 85%, oily product).
Reaction SMILES: [C:1]([O:5][C:6]([C@@H:8]1[S:12][C@@H:11]([CH2:13]Cl)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C-:15]#[N:16].[Na+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CN(C)C=O>[C:1]([O:5][C:6]([C@@H:8]1[S:12][C@@H:11]([CH2:13][C:15]#[N:16])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)[C@H]1CC[C@H](CCl)S1
Reactant: [C-]#N
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)[C@H]1CC[C@H](CC#N)S1
Reaction time: 5 h

Procedure:
To a stirred solution of trans-5-tert-butoxycarbonyl-2-chloromethyltetrahydrothiophene (3.5 g) in dimethylformamide (15 ml), sodium cyanide (1.5 g) is added and the mixture was stirred for 5 hours at 60°-70° C. 5% aqueous citric acid solution is added to the mixture and extracted with ethyl acetate - benzene (1:1). The organic layer is washed with water and saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate and concentrated in vacuo. The oily residue is purified by a silica gel column chromatography to give trans-5-tert-butoxycarbonyl-2-cyanomethyltetrahydrothiophene.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:20])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([OH:16])=O)=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18].[CH2:21]([N:23]1[CH:27]=[N:26][C:25]([NH2:28])=[N:24]1)[CH3:22]>>[Cl:20][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([Cl:1])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([NH:28][C:25]2[N:26]=[CH:27][N:23]([CH2:21][CH3:22])[N:24]=2)=[O:16])=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18]
Reactant: O=C(O)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1
Reactant: CCn1cnc(N)n1
Product: CCn1cnc(NC(=O)c2cc([N+](=O)[O-])c(Sc3c(Cl)cncc3Cl)s2)n1

Procedure:
Prepared according to the procedure described for example 44 from 5-[(3,5-dichloro-4-pyridyl)sulfanyl]-4-nitro-thiophene-2-carboxylic acid (35 mg, 0.1 mmol) and 1-ethyl-1H-1,2,4-triazol-3-amine (11.2 mg, 0.12 mmol). The title compound was obtained as a solid (8.9 mg, 20% yield). MS m/z: 466.95, 468.95 [M+H]+.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1B(O)O.[Cl:9][C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[NH:15][CH:14]=[C:13]2[CH2:19][CH2:20][NH:21][C:22](=[O:31])[C:23]1[CH:28]=[CH:27][C:26]([CH2:29]Cl)=[CH:25][CH:24]=1.ClCCl.[I-].[Na+].C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Cl:9][C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[NH:15][CH:14]=[C:13]2[CH2:19][CH2:20][NH:21][C:22](=[O:31])[C:23]1[CH:28]=[CH:27][C:26]([CH2:29][C:2]2[O:1][CH:5]=[CH:4][CH:3]=2)=[CH:25][CH:24]=1
Reactant: OB(O)c1ccco1
Reactant: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1ccc(CCl)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: COCCOC
Solvent: O
Solvent: ClCCl
Product: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1ccc(Cc2ccco2)cc1
Yield: 18.3 %

Procedure:
N-(2-(5-Chloro-1H-indol-3-yl)ethyl)-4-(furan-2-ylmethyl)benzamide was prepared according to method B with furan-2-yl boronic acid (0.027 g; 0.242 mmol), N-(2-(5-chloro-1H-indol-3-yl)ethyl)-4-(chloromethyl)benzamide (0.080 g; 0.231 mmol), [1,1′-bis(diphenylphosphino)ferrocene]palladium(II) chloride, complex with dichloromethane (0.018; 0.023 mmol), sodium iodide (0.070 g; 0.461 mmol) and sodium carbonate (0.049 g; 0.461 mmol) in dimethoxyethane (3 mL) and water (1 mL) was irradiated in the microwave at 130° C. for 15 minutes. Flash chromatography on silica gel (eluent 20 to 80% ethyl acetate in heptane) furnished 0.016 g (19%) of the title compound as a white solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1/[CH:15]=[CH:16]/[C:17]1[CH:25]=[CH:24][C:20]([C:21]([OH:23])=[O:22])=[C:19]([OH:26])[CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:27](OC1C=CC=CC=1CCC1C=CC(C(OC)=O)=CC=1N)C1C=CC=CC=1>>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:15][CH2:16][C:17]1[CH:25]=[CH:24][C:20]([C:21]([O:23][CH3:27])=[O:22])=[C:19]([OH:26])[CH:18]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1ccc(CCc2ccccc2OCc2ccccc2)c(N)c1
Reactant: O=C(O)c1ccc(/C=C/c2ccccc2OCc2ccccc2)cc1O
Product: COC(=O)c1ccc(CCc2ccccc2OCc2ccccc2)cc1O

Procedure:
Methyl 4-[2-(2-benzyloxyphenyl)ethyl]-2-hydroxybenzoate was prepared from a Z/E mixture of methyl 4-[2-(2-benzyloxyphenyl)-ethenyl]-2-hydroxybenzoate (prepared as described in Example 10) using the hydrogenation method described in Example 10 for the synthesis of methyl 4-[2-(2-benzyloxyphenyl)ethyl]-3-aminobenzoate.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[C:16]([C:30]([OH:32])=[O:31])=[N:17][N:18]([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([Cl:29])[CH:23]=3)[C:19](=[O:21])[CH:20]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.Cl.O1CCOCC1.CCOCC>C(Cl)Cl>[ClH:28].[Cl:29][C:24]1[CH:23]=[C:22]([N:18]2[C:19](=[O:21])[CH:20]=[C:15]([O:14][CH:11]3[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]3)[C:16]([C:30]([OH:32])=[O:31])=[N:17]2)[CH:27]=[CH:26][C:25]=1[Cl:28]
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2cc(=O)n(-c3ccc(Cl)c(Cl)c3)nc2C(=O)O)CC1
Agent: Cl
Solvent: CCOCC
Solvent: C1COCCO1
Solvent: ClCCl
Product: O=C(O)c1nn(-c2ccc(Cl)c(Cl)c2)c(=O)cc1OC1CCNCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 181.8 %

Procedure:
To a stirring solution of 4-(1-(tert-butoxycarbonyl)piperidin-4-yloxy)-1-(3,4-dichlorophenyl)-6-oxo-1,6-dihydropyridazine-3-carboxylic acid (from example 15 step A) (105 mg, 0.217 mmol) in DCM (2 mL) at room temperature under argon was added 4 M HCl in dioxane (0.271 mL, 1.1 mmol). The reaction mixture was stirred at room temperature overnight. Et2O (10 mL) was added to the reaction mixture. The solid product was collected by filtration and further washed with ether (5 mL×2). After drying under reduce pressure over night, 83 mg (100%) of 1(3,4-dichlorophenyl)-6-oxo-4-(piperidin-4-yloxy)-1,6-dihydropyridazine-3-carboxylic acid HCl salt was obtained as an off-white solid. MS (ESI) 384 (M+H).