Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([NH:22][C:23]([N:25]([CH2:28][CH3:29])[CH2:26][CH3:27])=[O:24])[CH:17]=1)[C:10]([CH3:31])([CH3:30])[CH2:9]2)=[O:5])C.Cl>CO.O1CCCC1.[OH-].[Na+].O>[CH2:28]([N:25]([CH2:26][CH3:27])[C:23](=[O:24])[NH:22][C:18]1[CH:17]=[C:16]([CH:11]2[C:10]([CH3:30])([CH3:31])[CH2:9][C:8]3[C:13](=[CH:14][CH:15]=[C:6]([C:4]([OH:5])=[O:3])[CH:7]=3)[NH:12]2)[CH:21]=[CH:20][CH:19]=1)[CH3:29]
Reactant: CCOC(=O)c1ccc2c(c1)CC(C)(C)C(c1cccc(NC(=O)N(CC)CC)c1)N2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CCN(CC)C(=O)Nc1cccc(C2Nc3ccc(C(=O)O)cc3CC2(C)C)c1
Temperature: 60 °C
Reaction time: 16 h
Yield: 10.1 %

Procedure:
A mixture of 2-[3-(3,3-diethyl-ureido)-phenyl]-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (846 mg, 2 mmol) in methanol (10 mL) and tetrahydrofuran (15 mL), 30% sodium hydroxide in water (10 mL) was stirred at 60° C. for 16 h. The mixture was neutralized with a 3 N aqueous hydrochloric acid solution and extracted with ethyl acetate (2×100 mL), washed with water, dried over anhydrous sodium sulfate and then concentrated in vacuo. Purification by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% formic acid in water) afforded 2-[3-(3,3-diethyl-ureido)-phenyl}-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (80 mg, 10%) as a white solid: LC/MS m/e calcd for C23H29N3O3 (M+H)+: 396.51, observed: 396.2.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[NH:12][C:11](=[O:13])[N:10]([CH:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[CH2:9][CH2:8][C:7]=2[CH:20]=1.Cl[C:22]1[N:27]=[C:26]([CH3:28])[N:25]=[C:24]([O:29][C:30]2[CH:39]=[C:38]([CH3:40])[C:33]3[NH:34][C:35](=[O:37])[O:36][C:32]=3[CH:31]=2)[CH:23]=1.CCN(C(C)C)C(C)C>CN(C=O)C.O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[NH:12][C:11](=[O:13])[N:10]([CH:14]3[CH2:19][CH2:18][N:17]([C:22]4[CH:23]=[C:24]([O:29][C:30]5[CH:39]=[C:38]([CH3:40])[C:33]6[NH:34][C:35](=[O:37])[O:36][C:32]=6[CH:31]=5)[N:25]=[C:26]([CH3:28])[N:27]=4)[CH2:16][CH2:15]3)[CH2:9][CH2:8][C:7]=2[CH:20]=1
Reactant: COc1ccc2c(c1)CCN(C1CCNCC1)C(=O)N2
Reactant: Cc1nc(Cl)cc(Oc2cc(C)c3[nH]c(=O)oc3c2)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)CCN(C1CCN(c3cc(Oc4cc(C)c5[nH]c(=O)oc5c4)nc(C)n3)CC1)C(=O)N2
Temperature: 80 °C
Reaction time: 8 h

Procedure:
48 mg (0.17 mol) 7-methoxy-3-piperidin-4-yl-1,3,4,5-tetrahydro-1,3-benzodiazepin-2-one, 50 mg (0.17 mmol) 6-(6-chloro-2-methyl-pyrimidin-4-yloxy)-4-methyl-3H-benzoxazol-2-one and 0.10 mL (0.58 mmol) DIPEA were combined in 1.8 mL DMF and stirred overnight at 80° C. The reaction mixture was diluted with water and the precipitate formed was suction filtered and dried.
Reaction SMILES: [CH3:1][N:2]([CH3:36])[C:3]([C:5]1[CH:6]=[C:7]([S:11]([C:13]2[CH:22]=[C:21]3[C:16]([C:17]([NH:26][C:27]4[CH:32]=[CH:31][CH:30]=[C:29]([O:33][CH3:34])[CH:28]=4)=[C:18]([C:23]([NH2:25])=[O:24])[CH:19]=[N:20]3)=[CH:15][C:14]=2I)=[O:12])[CH:8]=[CH:9][CH:10]=1)=[O:4].C(N(CC)CC)C>[Pd].C(O)C.CN(C)C=O>[CH3:1][N:2]([CH3:36])[C:3]([C:5]1[CH:6]=[C:7]([S:11]([C:13]2[CH:22]=[C:21]3[C:16]([C:17]([NH:26][C:27]4[CH:32]=[CH:31][CH:30]=[C:29]([O:33][CH3:34])[CH:28]=4)=[C:18]([C:23]([NH2:25])=[O:24])[CH:19]=[N:20]3)=[CH:15][CH:14]=2)=[O:12])[CH:8]=[CH:9][CH:10]=1)=[O:4]
Reactant: COc1cccc(Nc2c(C(N)=O)cnc3cc(S(=O)c4cccc(C(=O)N(C)C)c4)c(I)cc23)c1
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: CCO
Solvent: CN(C)C=O
Product: COc1cccc(Nc2c(C(N)=O)cnc3cc(S(=O)c4cccc(C(=O)N(C)C)c4)ccc23)c1
Reaction time: 4 h
Yield: 29.3 %

Procedure:
A mixture containing Intermediate 65 (0.15 g), 10% palladium on activated carbon (0.04 g) and triethylamine (5 ml) in ethanol (25 ml) and N,N-dimethylformamide (10 ml) was hydrogenated at room temperature for 4 h. The suspension was filtered through celite, the residue washed with ethanol/N,N-dimethylformamide (3:1, 50 ml), and the filtrate concentrated in vacuo. The residue was purified by mass directed preparative HPLC (Method A) to give the title compound as a yellow solid (0.035 g).
Reaction SMILES: CC1(C)COB([C:8]2[CH:9]=[C:10]([C:14]3[N:18]4[N:19]=[CH:20][C:21]([C:23]([F:26])([F:25])[F:24])=[N:22][C:17]4=[N:16][CH:15]=3)[CH:11]=[CH:12][CH:13]=2)OC1.Br[C:29]1[CH:34]=[CH:33][C:32]([F:35])=[CH:31][N:30]=1.C([O-])([O-])=O.[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.COCCOC>[F:35][C:32]1[CH:33]=[CH:34][C:29]([C:8]2[CH:9]=[C:10]([C:14]3[N:18]4[N:19]=[CH:20][C:21]([C:23]([F:24])([F:26])[F:25])=[N:22][C:17]4=[N:16][CH:15]=3)[CH:11]=[CH:12][CH:13]=2)=[N:30][CH:31]=1
Reactant: Fc1ccc(Br)nc1
Reactant: CC1(C)COB(c2cccc(-c3cnc4nc(C(F)(F)F)cnn34)c2)OC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: Fc1ccc(-c2cccc(-c3cnc4nc(C(F)(F)F)cnn34)c2)nc1
Temperature: 80 °C
Yield: 27.8 %

Procedure:
7-[3-(5,5-Dimethyl-[1,3,2]dioxaborinan-2-yl)phenyl]-3-trifluoromethylimidazo[1,2-b][1,2,4]triazine (0.2 g, 0.53 mmol) was added to 1,2-dimethoxyethane (2 ml), 2-bromo-5-fluoropyridine (94 mg, 0.53 mmol) and 2 N Na2CO3 (0.53 ml). The mixture was degassed with a stream of nitrogen for 10 min before tetrakis(triphenylphosphine)palladium(0) (31 mg, 0.027 mmol) was added and the mixture heated at 80° C. for 6 h. The mixture was cooled to ambient temperature before partitioning between water (15 ml) and ethyl acetate (15 ml). The organic extracts were then washed with NaOH (15 ml), dried (MgSO4) and evaporated in vacuo. The residue was purified by chromatography (silica gel, 3% MeOH/CH2Cl2) then triturated with diethyl ether to give 53 mg (28%) of the title compound: 1H NMR (400 MHz, CDCl3) δ 7.51-7.56 (1H, m), 7.67 (1H, t, J 7.7 Hz), 7.83 (1H, dd, J 9.2, 4.1 Hz), 8.03 (1H, dq, J 7.7, 1.0 Hz), 8.14 (1H, dq, J 7.7, 1.0 Hz), 8.60 (1H, d, J 3.1 Hz), 8.70 (1H, s), 8.72 (1H, t, J 1.6 Hz), 8.84 (1H, s); MS (ES+) m/z 360 [M+H]+.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[C:12]([Cl:14])[CH:11]=[CH:10][C:9]=2[O:15][CH2:16][CH3:17])[N:5]=[C:4]([NH2:18])[N:3]=1.C(O)C.Cl.[O:23]1[C:27]([C:28]2[CH:33]=[CH:32][C:31]([NH2:34])=[CH:30][CH:29]=2)=[CH:26][N:25]=[CH:24]1>O1CCOCC1>[Cl:14][C:12]1[CH:11]=[CH:10][C:9]([O:15][CH2:16][CH3:17])=[C:8]([C:6]2[N:5]=[C:4]([NH2:18])[N:3]=[C:2]([NH:34][C:31]3[CH:30]=[CH:29][C:28]([C:27]4[O:23][CH:24]=[N:25][CH:26]=4)=[CH:33][CH:32]=3)[CH:7]=2)[CH:13]=1
Reactant: Nc1ccc(-c2cnco2)cc1
Reactant: CCOc1ccc(Cl)cc1-c1cc(Cl)nc(N)n1
Agent: Cl
Solvent: CCO
Solvent: C1COCCO1
Product: CCOc1ccc(Cl)cc1-c1cc(Nc2ccc(-c3cnco3)cc2)nc(N)n1
Reaction time: 0.17 h
Yield: 72.9 %

Procedure:
To a mixture of 4-chloro-6-(5-chloro-2-ethoxy-phenyl)-pyrimidin-2-ylamine (100 mg, 0.37 mmol) and ethanol (20 ml) was added a solution of hydrogen chloride in 1,4-dioxane (4 M, 0.1 ml). After stirring for 10 minutes, 4-oxazol-5-yl-phenyl-amine (60 mg, 0.37 mmol) was added and the mixture was heated under reflux for 5 hours. After concentrating under reduced pressure, the residue was stirred with ethyl acetate (10 ml) and saturated aqueous sodium bicarbonate solution (10 ml). The solid was filtered and purified by flash chromatography eluting with ethyl acetate-hexane (1:1 followed by 3:2) to yield the title compound (110 mg, 75% yield). 1H NMR (acetone-d6) δ 1.44 (t, 3H, J=7.0 Hz, CH3), 4.17 (q, 2H, J=7.0 Hz, CH2), 5.88 (br s, 2H, NH), 7.04 (s, 1H, Ar), 7.12 (d, 1H, J=8.5 Hz, Ar), 7.37 (dd, 1H, J=8.8 Hz, J=2.9 Hz, Ar), 7.46 (s, 1H, Ar), 7.68 (d, 2H, J=8.7 Hz, Ar), 7.88-7.91 (m, 2H, Ar), 8.07 (d, 1H, J=2.8 Hz, Ar), 8.16 (s, 1H, Ar), 8.64 (br s, 1H, NH).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:39])[C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:38])[CH:13]([N:20]2[C:24]3[CH:25]=[C:26]([F:30])[C:27]([F:29])=[CH:28][C:23]=3[N:22]=[C:21]2[C:31]2[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=2)[CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)=[CH:7][CH:6]=1)C.[Cl:40]C1C=CC(C2N(C(C3CCCCC3)C(O)=O)C3C=C(F)C(F)=CC=3N=2)=CC=1.NC1C=CC(C(OC)=O)=CC=1Cl>>[CH3:1][O:3][C:4](=[O:39])[C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:38])[CH:13]([N:20]2[C:24]3[CH:25]=[C:26]([F:30])[C:27]([F:29])=[CH:28][C:23]=3[N:22]=[C:21]2[C:31]2[CH:32]=[CH:33][C:34]([Cl:37])=[CH:35][CH:36]=2)[CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)=[C:7]([Cl:40])[CH:6]=1
Reactant: CCOC(=O)c1ccc(NC(=O)C(C2CCCCC2)n2c(-c3ccc(Cl)cc3)nc3cc(F)c(F)cc32)cc1
Reactant: O=C(O)C(C1CCCCC1)n1c(-c2ccc(Cl)cc2)nc2cc(F)c(F)cc21
Agent: COC(=O)c1ccc(N)c(Cl)c1
Product: COC(=O)c1ccc(NC(=O)C(C2CCCCC2)n2c(-c3ccc(Cl)cc3)nc3cc(F)c(F)cc32)c(Cl)c1

Procedure:
This compound was prepared in analogy to example 22, intermediate d, from [2-(4-chloro-phenyl)-5,6-difluoro-benzoimidazol-1-yl]-cyclohexyl-acetic acid and methyl 4-amino-3-chlorobenzoate.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:22]=[CH:21][C:6]([C:7]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)([OH:12])[C:8]([O:10][CH3:11])=[O:9])=[CH:5][CH:4]=1.[C@@:23]12(O)[N:30](C)[C@@H:27]([CH2:28][CH2:29]1)[CH2:26][CH:25]=[CH:24]2>>[CH3:20][O:19][C:16]1[CH:17]=[CH:18][C:13]([C:7]([C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:22][CH:21]=2)([OH:12])[C:8]([O:10][C@@:11]23[N:30]([CH3:23])[C@@H:27]([CH2:28][CH2:29]2)[CH2:26][CH:25]=[CH:24]3)=[O:9])=[CH:14][CH:15]=1
Reactant: CN1[C@@H]2CC=C[C@@]1(O)CC2
Reactant: COC(=O)C(O)(c1ccc(OC)cc1)c1ccc(OC)cc1
Product: COc1ccc(C(O)(C(=O)O[C@]23C=CC[C@H](CC2)N3C)c2ccc(OC)cc2)cc1

Procedure:
4.14 is prepared analogously to the method according to II.1. Yield: 3.3 g (78% of theory) starting from 3.0 g (0.01 mol) of 3g and 1.39 g (0.01 mol) of tropenol; melting point: 146° C.-147° C.
Reaction SMILES: [OH:1][C:2]1[CH:14]=[CH:13][C:5]2[N:6]=[C:7]([S:9]([NH2:12])(=[O:11])=[O:10])[S:8][C:4]=2[CH:3]=1.C(N(CC)CC)C.[C:22](Cl)(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.Cl>CN(C)C1C=CN=CC=1.CN(C)C=O>[C:22]([O:1][C:2]1[CH:14]=[CH:13][C:5]2[N:6]=[C:7]([S:9](=[O:11])(=[O:10])[NH2:12])[S:8][C:4]=2[CH:3]=1)(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: NS(=O)(=O)c1nc2ccc(O)cc2s1
Reactant: O=C(Cl)c1ccccc1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: NS(=O)(=O)c1nc2ccc(OC(=O)c3ccccc3)cc2s1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of 6-hydroxy-2-benzothiazolesulfonamide (7.0 g., 0.03 mole), triethylamine (4.2 ml., 0.03 mole) and 4-dimethylaminopyridine (200 mg., catalyst) in dimethylformamide (25 ml.) is added benzoyl chloride (1.4 g., 0.01 mole). The reaction mixture is stirred at 25° C. for 11/2 hours and then poured into ice water (150 ml.) containing excess hydrochloric acid to give 3.3 g. of 2-sulfamoyl-6-benzothiazolyl benzoate which melts at 208°-210° C. after recrystallization from toluene.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[C@H:4]([CH3:23])[NH:5][C:6](=[O:22])[C@H:7]([CH3:21])[NH:8][C:9](=[O:20])[C@H:10]([CH2:12][CH2:13][CH2:14][CH2:15][NH:16][C:17](=[S:19])[CH3:18])[NH2:11].[N:25]([C:28]1[CH:36]=[CH:35][C:31]([C:32](O)=[O:33])=[CH:30][CH:29]=1)=[N+:26]=[N-:27].C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C1COCC1>[CH3:1][O:2][C:3](=[O:24])[C@H:4]([CH3:23])[NH:5][C:6](=[O:22])[C@H:7]([CH3:21])[NH:8][C:9](=[O:20])[C@H:10]([CH2:12][CH2:13][CH2:14][CH2:15][NH:16][C:17](=[S:19])[CH3:18])[NH:11][C:32](=[O:33])[C:31]1[CH:30]=[CH:29][C:28]([N:25]=[N+:26]=[N-:27])=[CH:36][CH:35]=1
Reactant: [N-]=[N+]=Nc1ccc(C(=O)O)cc1
Reactant: COC(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)[C@@H](N)CCCCNC(C)=S
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)[C@H](CCCCNC(C)=S)NC(=O)c1ccc(N=[N+]=[N-])cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 82.1 %

Procedure:
To a solution of Nε-thioacetyl-lysinyl-alaninyl-alanine methyl ester (50 mg, 0.14 mmol) in 0.8 mL of THF was added a solution of 4-azidobenzoic acid (35 mg, 0.21 mmol) in 0.8 mL of THF. PyBOP (109 mg, 0.21 mmol) and DIPEA (59 mg, 0.42 mmol) were introduced into the reaction mixture. The reaction was stirred at room temperature for 6 h, and then solvent was removed under reduced pressure. Silica gel column chromatography (ethyl acetate: hexanes 10:1) afforded Nα-4-azidobenzoyl-Nε-thioacetyl-lysinyl-alaninyl-alanine methyl ester (58 mg, 0.115 mmol, 82%) as a pale yellow solid. 1H NMR (CD2Cl2, 500 MHz) δ (ppm): 1.39 (s, 3H), 1.40 (s, 3H), 1.47 (m, 2H), 1.67 (m, 2H), 1.88 (m, 2H), 2.87 (s, 3H), 3.57 (m, 2H), 3.68 (s, 3H), 4.41 (m, 1H), 4.46 (m, 1H), 4.64 (m, 1H), 7.05 (d, J=8.6 Hz, 2H), 7.20 (d, J=7.2 Hz, 1H), 7.36 (d, J=6.8 Hz, 1H), 7.44 (d, J=7.0 Hz, 1H), 7.86 (d, J=8.6 Hz, 2H), 8.32 (m, 1H).
Reaction SMILES: [CH3:1][C:2]1[C:7]2[C:8](=O)[CH2:9][CH2:10][S:11](=[O:13])(=[O:12])[C:6]=2[C:5]([CH3:15])=[CH:4][C:3]=1[C:16]([OH:18])=[O:17].[CH2:19]([SH:22])[CH2:20][SH:21].B(F)(F)F.CCOCC>C(Cl)Cl>[CH3:1][C:2]1[C:7]2[C:8]3([CH2:9][CH2:10][S:11](=[O:13])(=[O:12])[C:6]=2[C:5]([CH3:15])=[CH:4][C:3]=1[C:16]([OH:18])=[O:17])[S:22][CH2:19][CH2:20][S:21]3
Reactant: Cc1cc(C(=O)O)c(C)c2c1S(=O)(=O)CCC2=O
Reactant: SCCS
Agent: FB(F)F
Solvent: ClCCl
Solvent: CCOCC
Product: Cc1cc(C(=O)O)c(C)c2c1S(=O)(=O)CCC21SCCS1

Procedure:
To a mixture of 0.60 g of 3,4-dihydro-5,8-dimethyl4-oxo-2H-1-benzothiopyran-6-carboxylic acid 1,1-dioxide in 30 mL of methylene chloride was added 0.24 mL of 1,2-ethanedithiol (purchased from Aldrich Chemical Co.) and 0.35 mL of boron trifluoride diethyl etherate (purchased from Janssen Chimica). The mixture was refluxed overnight and then concentrated under reduced pressure to dryness. To the resulting residue was added 10 mL of dilute hydrochloric acid of pH 1. The mixture was extracted with ethyl acetate, and the combined organic extracts were dried over MgSO4, filtered, and concentrated under reduced pressure to afford 0.62 g of the title compound of Step A as an orange solid which had a melting point >250° C. 1H NMR ((CD3)2SO): δ 2.65 (s, 3H), 2.77 (s, 3H), 2.94 (m, 2H), 3.55-3.80 (m, 6H), 7.50 (s, 1H).
Reaction SMILES: [I-].[CH3:2][S+](C)(C)=O.[H-].[Na+].[C:9]([N:16]1[CH2:21][CH2:20][C:19](=[O:22])[CH2:18][CH2:17]1)([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10]>CN(C=O)C>[O:22]1[C:19]2([CH2:20][CH2:21][N:16]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:17][CH2:18]2)[CH2:2]1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: C[S+](C)(C)=O
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC2(CC1)CO2
Reaction time: 2 h
Yield: 71 %

Procedure:
Trimethylsulfoxonium iodide (580 mg, 2.64 mmol) was added to a suspension of NaH (106 mg, 2.64 mmol) at 0° C. under nitrogen atmosphere. After 15 min. under stirring at the same temperature, N-Boc-4-piperidone (500 mg, 2.51 mmol) dissolved in DMF (5 mL) was added. Stirring was continued and, after 2 h at r.t., the reaction mixture was quenched with water and EtOAc. The combined extracts were washed, dried over Na2SO4 and evaporated to dryness. The crude residue was purified by flash chromatography (EtOAc—Petroleum Ether 9:1) affording the title product (380 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[S:9](Cl)(=[O:11])=[O:10].[NH3:13].Cl>N1C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[S:9]([NH2:13])(=[O:11])=[O:10]
Reactant: O=S(=O)(Cl)c1c(Cl)cccc1Cl
Reactant: N
Agent: Cl
Solvent: c1ccncc1
Product: NS(=O)(=O)c1c(Cl)cccc1Cl
Reaction time: 4 h
Yield: 90 %

Procedure:
A solution of 2,6-dichlorobenzenesulfonyl chloride (10.50 g, 42.77 mmol) in 100 mL of pyridine was added into 100 mL of pyridine dropwise while anhydrous ammonia gas was passing through the solution simultaneously for 4 hours at 0° C. The mixture was acidified to pH>1 with 6N aq. HCl, then extracted with ethyl acetate. The combined organic layer was then dried (Na2SO4) and concentrated to give the desired product (8.69 g, 90%). EI-MS (m/z) 225.0, 227.1 (M−).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:26]=[CH:25][C:19]([O:20][CH2:21][C:22]([OH:24])=O)=[CH:18][CH:17]=1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.[CH2:49]([CH:56]1[CH2:61][CH2:60][NH:59][CH2:58][CH2:57]1)[C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1.C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl.O>[CH2:49]([CH:56]1[CH2:61][CH2:60][N:59]([C:22](=[O:24])[CH2:21][O:20][C:19]2[CH:18]=[CH:17][C:16]([O:15][C:6]3[C:5]4[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=4)[N:9]=[CH:8][N:7]=3)=[CH:26][CH:25]=2)[CH2:58][CH2:57]1)[C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1
Reactant: c1ccc(CC2CCNCC2)cc1
Reactant: COc1cc2ncnc(Oc3ccc(OCC(=O)O)cc3)c2cc1OC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: O
Solvent: ClC(Cl)Cl
Product: COc1cc2ncnc(Oc3ccc(OCC(=O)N4CCC(Cc5ccccc5)CC4)cc3)c2cc1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 25 %

Procedure:
2-{4-[(6,7-Dimethoxy-4-quinazolinyl)oxy]phenoxy}acetic acid (100 mg), WSC.HCl (81 mg), and HOBT.H2O (57 mg) were dissolved in chloroform (3 ml) to prepare a solution. 4-Benzylpiperidine (59 mg) was then added to the solution, and the mixture was stirred at room temperature overnight. A saturated aqueous sodium hydrogencarbonate solution was added to the reaction solution, and the mixture was extracted with chloroform. The extract was washed with saturated brine and was then dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure. The residue was purified by thin-layer chromatography using chloroform/methanol for development. Diethyl ether was added to the purification product, and the precipitated crystal was collected by filtration and was washed to give the title compound (36 mg, yield 25%).
Reaction SMILES: [C:1]1([OH:21])[C:2]([C:11]2[CH:20]=[CH:19][C:18]3[CH2:17][CH2:16][CH2:15][CH2:14][C:13]=3[CH:12]=2)=[CH:3][CH:4]=[C:5]2[C:10]=1[CH2:9][CH2:8][CH2:7][CH2:6]2.[CH:22]1[CH2:26][CH2:25][CH2:24][CH:23]=1>O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.P.[W].[W].[W].[W].[W].[W].[W].[W].[W].[W].[W].[W]>[CH:22]1([C:3]2[CH:4]=[C:5]3[C:10]([CH2:9][CH2:8][CH2:7][CH2:6]3)=[C:1]([OH:21])[C:2]=2[C:11]2[C:20]([CH:22]3[CH2:26][CH2:25][CH2:24][CH2:23]3)=[CH:19][C:18]3[CH2:17][CH2:16][CH2:15][CH2:14][C:13]=3[CH:12]=2)[CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: C1=CCCC1
Reactant: Oc1c(-c2ccc3c(c2)CCCC3)ccc2c1CCCC2
Agent: [W]
Agent: P
Solvent: O
Product: Oc1c2c(cc(C3CCCC3)c1-c1cc3c(cc1C1CCCC1)CCCC3)CCCC2
Yield: 41.3 %

Procedure:
A mixture of 5,5′,6,6′,7,7′,8,8′-octahydro-2,2′-binapthol (48 g), phosphotungstic acid (2.4 g) and cyclopentene (58 g) was charged into a Hastelloy reactor. The reactor was heated to 180 C for 40 hours. The mixture was purified by column chromatography (silica gel, eluting with 2% ethyl acetate/hexane) to yield 29.5 g (42%) of 3,3′-dicyclopentyl-5,5′,6,6′,7,7′,8,8′-octahydro-2,2′-binapthol, mp 143–152° C. 13C NMR (CDCl3): 22.96, 25.31, 26.68, 29.19, 32.72, 32.75, 39.20, 118.58, 128.14, 129.20, 129.74, 133.91, 149.14 ppm. 1H NMR (CDCl3): 1.60 (m, 10H), 2.0 (d, 4H), 2.65 (t, J=4 Hz, 2H), 3.27 (quintet, J=7 Hz, 1H), 4.55 (s, 1H), 6.92 (s, 1H) ppm.
Reaction SMILES: P(Cl)(Cl)(Cl)(Cl)[Cl:2].[CH2:7]([P:9]([CH2:15][O:16][S:17]([C:20]1[C:25]([CH3:26])=[CH:24][CH:23]=[CH:22][C:21]=1[Cl:27])(=[O:19])=[O:18])(=O)[O:10]C(C)C)[CH3:8]>ClCCCl>[CH2:7]([P:9]([Cl:2])([CH2:15][O:16][S:17]([C:20]1[C:25]([CH3:26])=[CH:24][CH:23]=[CH:22][C:21]=1[Cl:27])(=[O:19])=[O:18])=[O:10])[CH3:8]
Reactant: CCP(=O)(COS(=O)(=O)c1c(C)cccc1Cl)OC(C)C
Reactant: ClP(Cl)(Cl)(Cl)Cl
Solvent: ClCCCl
Product: CCP(=O)(Cl)COS(=O)(=O)c1c(C)cccc1Cl
Temperature: 25 °C
Reaction time: 72 h

Procedure:
Phosphorus pentachloride, 8.32 g, was added in approximately three equal portions over 15 minutes to a mixture at 20° C. of 11.4 g of O-isopropyl P-ethyl[[(2-chloro-6-methylphenyl)-sulfonyloxy]methyl]phosphinate (Compound 119) and 30 ml of 1,2-dichloroethane. Each addition of the phosphorus pentachloride caused a mild exotherm, but the reaction temperature did not exceed 32° C. The reaction slowly cooled to room temperature and was allowed to stir for 72 hours. A 3 ml aliquot of the reaction mixture was concentrated and analyzed by 31P NMR. The 31P NMR indicated that the reaction was complete. The remainder of the reaction mixture was concentrated, 100 ml of toluene was added, the mixture reconcentrated and then high vacuum was pulled on the sample at 55° C. for one hour to yield 10.5 g of the crude desired product.
Reaction SMILES: [CH:1]1([CH2:6][C:7]2[CH:8]=[C:9]([CH:15]3[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]3)[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:5][CH2:4][CH2:3][CH2:2]1.[O-:21][C:22]#[N:23].[Na+]>C(O)(=O)C.O>[CH:1]1([CH2:6][C:7]2[CH:8]=[C:9]([CH:15]3[CH2:16][CH2:17][N:18]([C:22]([NH2:23])=[O:21])[CH2:19][CH2:20]3)[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: N#C[O-]
Reactant: COc1ccc(C2CCNCC2)cc1CC1CCCC1
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: COc1ccc(C2CCN(C(N)=O)CC2)cc1CC1CCCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 4-(3-cyclopentylmethyl-4-methoxyphenyl)piperidine (1.8 mmol, 0.500 g) in acetic acid (5 mL) was added a solution of sodium cyanate (10.8 mmol, 0.702 g) in water (15 mL) dropwise over 20 minutes at room temperature. The resulting solution was stirred at room temperature overnight, after which the acetic acid was removed in vacuo. The residue was partitioned between EtOAc (200 mL) and H2O (200 mL). The aqueous phase was extracted with EtOAc (1×200 mL), the combined organics dried (Na2SO4), concentrated in vacuo and purified by flash chromatography (SiO2 ; EtOAc) to give the title compound as a white solid, mp=168°-169° C. (0.5 mmol, 1.054 g, 27%).
Reaction SMILES: C1O[CH:4]([C:5]2[CH:10]=[CH:9][C:8]([F:11])=[C:7]([O:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH:6]=2)[O:3]C1>C(O)C.O.Cl>[F:11][C:8]1[CH:9]=[CH:10][C:5]([CH:4]=[O:3])=[CH:6][C:7]=1[O:12][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: Fc1ccc(C2OCCO2)cc1Oc1ccccc1
Agent: Cl
Solvent: CCO
Solvent: O
Product: O=Cc1ccc(F)c(Oc2ccccc2)c1
Yield: 90.7 %

Procedure:
A solution of 26 g (0.1 mol) of 4-fluoro-3-phenoxy-benzaldehyde ethyleneacetal in 60 ml of ethanol, 20 ml of water and 1 ml of concentrated hydrochloric acid was stored at room temperature for 3 hours. The ethanol was then distilled off in vacuo, and 100 ml of toluene were added to the residue. The water was separated off and the organic phase was washed twice with 50 ml of water each time, dried over sodium sulphate and evaporated in vacuo. The residue was distilled in vacuo. 19.6 g (91% of theory) of 4-fluoro-3-phenoxy-benzaldehyde were obtained in this manner in the form of a colorless oil with a boiling point of 102°-104° C./0.1 mm Hg.