Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[K+].COCCOCCOCCOC.[OH:15][CH:16]1[CH2:19][N:18]([CH:20]2[CH2:44][CH2:43][C@@:42]3([CH3:45])[C@@H:22]([CH2:23][CH2:24][C@@H:25]4[C@@H:41]3[CH2:40][CH2:39][C@@:38]3([CH3:46])[C@H:26]4[CH2:27][CH2:28][C@@H:29]3[C@H:30]([CH3:37])[CH2:31][CH2:32][CH2:33][CH:34]([CH3:36])[CH3:35])[CH2:21]2)[CH2:17]1.[C:47]1([CH3:57])[CH:52]=[CH:51][C:50]([S:53](Cl)(=[O:55])=[O:54])=[CH:49][CH:48]=1>O1CCCC1>[C:47]1([CH3:57])[CH:52]=[CH:51][C:50]([S:53]([O:15][CH:16]2[CH2:17][N:18]([CH:20]3[CH2:44][CH2:43][C@@:42]4([CH3:45])[C@@H:22]([CH2:23][CH2:24][C@@H:25]5[C@@H:41]4[CH2:40][CH2:39][C@@:38]4([CH3:46])[C@H:26]5[CH2:27][CH2:28][C@@H:29]4[C@H:30]([CH3:37])[CH2:31][CH2:32][CH2:33][CH:34]([CH3:36])[CH3:35])[CH2:21]3)[CH2:19]2)(=[O:55])=[O:54])=[CH:49][CH:48]=1
Reactant: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4CC(N5CC(O)C5)CC[C@]4(C)[C@H]3CC[C@]12C
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [H-]
Agent: [K+]
Solvent: COCCOCCOCCOC
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)OC2CN(C3CC[C@@]4(C)[C@@H](CC[C@@H]5[C@@H]4CC[C@]4(C)[C@@H]([C@H](C)CCCC(C)C)CC[C@@H]54)C3)C2)cc1

Procedure:
To a nitrogen blanketed, ice-cooled, stirred suspension of 1.08 g of 35% potassium hydride in mineral oil in 58 ml dry tetrahydrofuran and 2-3 ml triglyme add 3.49 g 3-(3-hydroxy-1-azetidinyl)-5α-cholestane (a mixture of the 3α- and 3β-epimers). Continue stirring the mixture for 5 days at room temperature, adding an additional 80 ml dry tetrahydrofuran after the first 24 hours. After 5 days add a solution of 1.52 g of p-toluenesulfonyl chloride in 10 ml tetrahydrofuran and stir one hour. Destroy the excess potassium hydride by the cautious addition of approximately 70 ml of water-saturated ethyl ether; then, add 350 ml water and saturate with sodium chloride. Extract once with 300 ml ethyl ether and then twice with 150 ml portions of ethyl ether. Combine the etheral extracts, dry over anhydrous sodium sulfate, and acidify the solution with a solution of 0.93 g maleic acid in 50 ml ethyl ether. Filter the crude maleate salt and triturate with 150 ml hexane. Dissolve the triturated material in 20 ml methylene chloride and treat the solution with decolourizing carbon. Filter the carbon and dilute the filtrate with 250 ml isopropyl ether. Concentrate the solution in vacuo until a precipitate begins to form. Filter the precipitate to obtain the maleate salt of the title compound, m.p. 105°-109° C. dec. (a mixtuer of 3α- and 3β- epimers).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]([CH3:26])[C:9]2[CH:25]=[CH:24][C:12]3[N:13]([CH3:23])[C:14]([NH:16][CH:17]4[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]4)=[N:15][C:11]=3[CH:10]=2)[CH:5]=[CH:4][N:3]=1.[CH3:27][S:28]([CH2:31][C:32]1[CH:38]=[CH:37][C:35]([NH2:36])=[CH:34][CH:33]=1)(=[O:30])=[O:29]>>[CH:17]1([NH:16][C:14]2[N:13]([CH3:23])[C:12]3[CH:24]=[CH:25][C:9]([N:8]([C:6]4[CH:5]=[CH:4][N:3]=[C:2]([NH:36][C:35]5[CH:37]=[CH:38][C:32]([CH2:31][S:28]([CH3:27])(=[O:30])=[O:29])=[CH:33][CH:34]=5)[N:7]=4)[CH3:26])=[CH:10][C:11]=3[N:15]=2)[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: CS(=O)(=O)Cc1ccc(N)cc1
Reactant: CN(c1ccc2c(c1)nc(NC1CCCCC1)n2C)c1ccnc(Cl)n1
Product: CN(c1ccc2c(c1)nc(NC1CCCCC1)n2C)c1ccnc(Nc2ccc(CS(C)(=O)=O)cc2)n1

Procedure:
The title compound was prepared following the procedure of example 1 with N5-(2-Chloro-pyrimidin-4-yl)-N2-cyclohexyl-1,N5-dimethyl-1H-benzoimidazole-2,5-diamine (92 mg, 0.25 mmol) and 4-[(methylsulfonyl)methyl]aniline (46 mg, 0.25 mmol) as a white solid (31 mg, 24%). 1H NMR (300 MHz, D6-DMSO) δ 9.20 (s, 1H), 7.77-7.80 (M, 3H), 7.10 (s, 1H), 6.82 (d, J=7.8 Hz, 1H), 6.50 (d, J=7.5 Hz, 1H), 5.64 (d, J=6.0 Hz, 1H), 4.34 (s, 2H), 3.70 (br s, 1H), 3.51 (s, 3H), 3.44 (s, 3H), 2.85 (s, 3H), 2.01 (br s, 2H), 1.74 (br s, 2H), 1.62 (d, J=11.1 Hz, 1H), 1.16-1.32 (m, 5H) ppm. MS (ESI) m/z=520 [M+H]+.
Reaction SMILES: [Br:1]Br.[C:3]1([N:9]2[C:13]3[NH:14][C:15](=[O:18])[CH:16]=[CH:17][C:12]=3[CH:11]=[N:10]2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>C(O)(=O)C.O>[Br:1][C:16]1[C:15](=[O:18])[NH:14][C:13]2[N:9]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=3)[N:10]=[CH:11][C:12]=2[CH:17]=1
Reactant: O=c1ccc2cnn(-c3ccccc3)c2[nH]1
Reactant: BrBr
Solvent: O
Solvent: CC(=O)O
Product: O=c1[nH]c2c(cnn2-c2ccccc2)cc1Br
Reaction time: 0.5 h
Yield: 68 %

Procedure:
Bromine (76 μl, 1.47 mmol) was added to a solution of 1-phenyl-1,7-dihydropyrazolo[3,4-b]pyridin-6-one (0.31 g, 1.47 mmol) in acetic acid (7 ml) and the mixture was stirred for 30 min. The suspension was diluted with water, stirred for 10 min and then the precipitate filtered off, washing with water. The product was dried in a desiccator at 40° C. under vacuum for 17 h to give 5-bromo-1,7-dihydro-1-phenylpyrazolo[3,4-b]pyridin-6-one (0.29 g, 68%) as a brown solid. δH (400 MHz; DMSO) 7.32-7.37 (1H, m), 7.52-7.58 (2H, m), 8.12-8.24 (3H, m), 8.50 (1H, s); m/z (ES+) 290 (M+H+), 292 (M+H+).
Reaction SMILES: [CH:1]([N:4]([CH2:8][C:9]1[CH:37]=[CH:36][C:12]([C:13]([N:15]2[CH2:20][CH2:19][N:18]([S:21]([C:24]3[CH:33]=[CH:32][C:31]4[C:26](=[CH:27][CH:28]=[C:29]([O:34]C)[CH:30]=4)[CH:25]=3)(=[O:23])=[O:22])[CH2:17][CH2:16]2)=[O:14])=[CH:11][CH:10]=1)[CH:5]([CH3:7])[CH3:6])([CH3:3])[CH3:2].B(Br)(Br)Br.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[CH:1]([N:4]([CH2:8][C:9]1[CH:37]=[CH:36][C:12]([C:13]([N:15]2[CH2:20][CH2:19][N:18]([S:21]([C:24]3[CH:33]=[CH:32][C:31]4[C:26](=[CH:27][CH:28]=[C:29]([OH:34])[CH:30]=4)[CH:25]=3)(=[O:23])=[O:22])[CH2:17][CH2:16]2)=[O:14])=[CH:11][CH:10]=1)[CH:5]([CH3:7])[CH3:6])([CH3:2])[CH3:3]
Reactant: COc1ccc2cc(S(=O)(=O)N3CCN(C(=O)c4ccc(CN(C(C)C)C(C)C)cc4)CC3)ccc2c1
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)N(Cc1ccc(C(=O)N2CCN(S(=O)(=O)c3ccc4cc(O)ccc4c3)CC2)cc1)C(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 93.5 %

Procedure:
To a solution of 1-(4-diisopropylaminomethylbenzoyl)-4-(6-methoxynaphthalene-2-sulfonyl)piperazine (100 mg) in CH2Cl2 (6 ml) was added dropwise at 0° C. a solution of 3.5 M BBr3 in CH2Cl2 (0.12 ml), and the solution was stirred at room temperature for 1 hour. To the reaction solution was added sodium bicarbonate solution and the organic layer was separated, dried and concentrated to give a colorless solid of the title compound (91 mg).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[NH2:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([C:15](OC)=[O:16])=[CH:10][N:9]=1.O.[OH-].[Na+]>O1CCCC1>[NH2:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([CH2:15][OH:16])=[CH:10][N:9]=1
Reactant: COC(=O)c1cnc(N)cc1C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(N)ncc1CO
Reaction time: 1 h

Procedure:
To a mixture of lithium aluminum hydride (LAH) (90 mg, 2.37 mmol) in dry tetrahydrofuran (THF) (2 mL) was added a solution of 2-amino-5-methoxycarbonyl-4-methylpyridine (100 mg, 0.602 mmol) in THF (1 mL). The reaction mixture was stirred for 1 h at reflux temperature. Excess LAH was decomposed by successive addition of water (90 uL), 15% sodium hydroxide (90 uL), and water (270 uL). Solids were removed by filtration through a pad of Celite. The title compound was obtained as a white crystalline solid after chromatography on silica gel (5-15% methanol/methylene chloride).
Reaction SMILES: [OH-].[K+:2].[OH:3][C:4]1[CH:5]=[CH:6][C:7]2[CH:8]([C:19]3[CH:27]=[CH:26][CH:25]=[CH:24][C:20]=3[C:21]([OH:23])=[O:22])[C:9]3[C:14]([O:15][C:16]=2[CH:17]=1)=[CH:13][C:12]([OH:18])=[CH:11][CH:10]=3>C(O)C>[OH:18][C:12]1[CH:11]=[CH:10][C:9]2[CH:8]([C:19]3[CH:27]=[CH:26][CH:25]=[CH:24][C:20]=3[C:21]([O-:23])=[O:22])[C:7]3[C:16]([O:15][C:14]=2[CH:13]=1)=[CH:17][C:4]([OH:3])=[CH:5][CH:6]=3.[K+:2]
Reactant: O=C(O)c1ccccc1C1c2ccc(O)cc2Oc2cc(O)ccc21
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: O=C([O-])c1ccccc1C1c2ccc(O)cc2Oc2cc(O)ccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.4 %

Procedure:
Aqueous potassium hydroxide (1 mL of 0.1 N, 0.1 mmol) was added to a solution of 2-(3,6-dihydroxy-9H-xanthen-9-yl)-benzoic acid [33 mg, 0.1 mmol, Cui, Y. et al., Yaoxue Tongbao, 1982, 17(9), 528] in 5 mL of ethanol and the mixture was stirred for additional 2 h at room temperature. The mixture was evaporated to dryness under reduced pressure to give 37 mg (100% yield) of the desired compound as a orange solid, mp>300° C. 1H NMR (D2O, 300 MHz): δ 5.76 [s, H, —CH], 6.94-6.99 [m, 1H, Ar—H], 7.09-7.13 [m, 2H, Ar—H], 7.26-7.31 [m, 6H, Ar—H], 7.49-7.54 [m, 1H, Ar—H].
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:8][NH:9][C:10]([C:12]2[C:13]([CH2:27][O:28]C)=[N:14][C:15]3[C:20]([C:21]=2[CH3:22])=[CH:19][CH:18]=[C:17]([C:23]([F:26])([F:25])[F:24])[CH:16]=3)=[O:11])[CH:5]=[CH:6][CH:7]=1.B(Br)(Br)Br.CCOC(C)=O.CCCCCC.CCOC(C)=O.C(Cl)Cl>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([CH2:8][NH:9][C:10]([C:12]2[C:13]([CH2:27][OH:28])=[N:14][C:15]3[C:20]([C:21]=2[CH3:22])=[CH:19][CH:18]=[C:17]([C:23]([F:24])([F:25])[F:26])[CH:16]=3)=[O:11])[CH:5]=[CH:6][CH:7]=1
Reactant: COCc1nc2cc(C(F)(F)F)ccc2c(C)c1C(=O)NCc1cccc(F)c1
Agent: BrB(Br)Br
Solvent: CCCCCC
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: Cc1c(C(=O)NCc2cccc(F)c2)c(CO)nc2cc(C(F)(F)F)ccc12
Temperature: 0 °C
Reaction time: 16 h
Yield: 51.9 %

Procedure:
A solution of 220 mg (0.54 mmol) N-[(3-fluorophenyl)-methyl]-2-(methoxymethyl)-4-methyl-7-(trifluoromethyl)-quinoline-3-carboxylic acid amide (Example 15) in DCM (5 ml) was cooled to −78° C. and 5.4 ml (5.4 mmol, 2M in DCM) boron tribromide was added. After heating to 0° C., the mixture was stirred for 16 h at this temperature. Quenching was then carried out with a 1M aq. NaHCO3 sol. (15 ml) and a 10%-strength aq. Na2S2O3 sol. It was then diluted with MeOH and DCM and the organic phase was separated, dried over MgSO4 and concentrated in a vacuum. After CC (EtOAc/hexane 1:1→EtOAc/DCM 1:1) of the residue, 110 mg (0.28 mmol, 52%) N-[(3-fluorophenyl)-methyl]-2-(hydroxy-methyl)-4-methyl-7-(trifluoromethyl)-quinoline-3-carboxylic acid amide (example 17) was obtained. MS: m/z 393.1 [M+H]+.
Reaction SMILES: [CH:1]1([N:4]([CH:18]2[CH2:23][CH2:22][N:21]([C:24](=[NH:27])[NH:25][OH:26])[CH2:20][CH2:19]2)[C:5](=[O:17])[C:6]2[CH:11]=[CH:10][C:9]([C:12]3[O:16][CH:15]=[N:14][CH:13]=3)=[CH:8][CH:7]=2)[CH2:3][CH2:2]1.[C:28](Cl)(=O)[CH2:29][CH2:30][CH3:31]>>[CH:1]1([N:4]([CH:18]2[CH2:23][CH2:22][N:21]([C:24]3[N:27]=[C:28]([CH2:29][CH2:30][CH3:31])[O:26][N:25]=3)[CH2:20][CH2:19]2)[C:5](=[O:17])[C:6]2[CH:11]=[CH:10][C:9]([C:12]3[O:16][CH:15]=[N:14][CH:13]=3)=[CH:8][CH:7]=2)[CH2:3][CH2:2]1
Reactant: N=C(NO)N1CCC(N(C(=O)c2ccc(-c3cnco3)cc2)C2CC2)CC1
Reactant: CCCC(=O)Cl
Product: CCCc1nc(N2CCC(N(C(=O)c3ccc(-c4cnco4)cc3)C3CC3)CC2)no1

Procedure:
The title compound is prepared from N-cyclopropyl-N-[1-(N-hydroxycarbamimidoyl)-piperidin-4-yl]-4-oxazol-5-yl-benzamide and butyryl chloride following a procedure analogous to that described in Example 47. LC (method 8): tR=1.33 min; Mass spectrum (ESI+): m/z=422 [M+H]+.
Reaction SMILES: [NH2:1][N:2]1[CH2:7][CH2:6][CH:5]([OH:8])[CH2:4][CH2:3]1.[Cl:9][C:10]1[CH:11]=[C:12]([C:25]2[CH:30]=[CH:29][C:28]([C:31]([N:33]3[CH2:38][CH2:37][CH:36]([C:39]([F:42])([F:41])[F:40])[CH2:35][CH2:34]3)=[O:32])=[CH:27][CH:26]=2)[CH:13]=[C:14]([Cl:24])[C:15]=1[CH2:16][C@@H:17]1[CH2:21][CH:20](O)[O:19][C:18]1=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(#N)C>[Cl:24][C:14]1[CH:13]=[C:12]([C:25]2[CH:26]=[CH:27][C:28]([C:31]([N:33]3[CH2:38][CH2:37][CH:36]([C:39]([F:42])([F:41])[F:40])[CH2:35][CH2:34]3)=[O:32])=[CH:29][CH:30]=2)[CH:11]=[C:10]([Cl:9])[C:15]=1[CH2:16][C@@H:17]1[CH2:21][CH2:20][N:1]([N:2]2[CH2:7][CH2:6][CH:5]([OH:8])[CH2:4][CH2:3]2)[C:18]1=[O:19]
Reactant: NN1CCC(O)CC1
Reactant: O=C1OC(O)C[C@H]1Cc1c(Cl)cc(-c2ccc(C(=O)N3CCC(C(F)(F)F)CC3)cc2)cc1Cl
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC#N
Product: O=C(c1ccc(-c2cc(Cl)c(C[C@@H]3CCN(N4CCC(O)CC4)C3=O)c(Cl)c2)cc1)N1CCC(C(F)(F)F)CC1
Temperature: 50 °C
Reaction time: 8 h
Yield: 20.8 %

Procedure:
Dissolve 1-Amino-piperidin-4-ol (0.204 g, 1.1 eq.) in acetonitrile (3 mL) and heat the solution to 50° C. When the temperature reaches 35° C., add (R)-3-[3,5-Dichloro-4′-(4-trifluoromethyl-piperidine-1-carbonyl)-biphenyl-4-ylmethyl]-5-hydroxy-dihydro-furan-2-one (0.829 g, 1 eq.) and continue heating to 50° C. for 1 hour. Allow the reaction to cool to room temperature and add sodium triacetoxyborohydride (0.508 g, 1.5 eq.). Allow the reaction to stir overnight at room temperature. Add water and extract with EtOAc. Remove the solvent and chromatograph the residue on silica gel to afford 200 mg of the titled compound. MS (m/z): 598 (M+1, 35Cl), 600 (M+1, 37Cl).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5](B(O)O)[CH:6]=[CH:7][CH:8]=1.[O:12]=[S:13]1(=[O:30])[CH2:18][CH2:17][N:16]2[CH2:19][CH2:20][CH2:21][C@@H:22]([C:23]3[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=3)[C:15]2=[N:14]1.N1C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CC#N.C(O[Cu]OC(=O)C)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:6]=[CH:7][CH:8]=1)[O:29][C:26]1[CH:25]=[CH:24][C:23]([C@H:22]2[C:15]3=[N:14][S:13](=[O:30])(=[O:12])[CH2:18][CH2:17][N:16]3[CH2:19][CH2:20][CH2:21]2)=[CH:28][CH:27]=1
Reactant: COc1cccc(B(O)O)c1
Reactant: O=S1(=O)CCN2CCC[C@@H](c3ccc(O)cc3)C2=N1
Agent: CC(=O)O[Cu]OC(C)=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: c1ccncc1
Solvent: CC#N
Product: COc1cccc(Oc2ccc([C@@H]3CCCN4CCS(=O)(=O)N=C34)cc2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 11.6 %

Procedure:
A mixture of (3-methoxyphenyl)boronic acid (813 mg), 4-[(9S)-2,2-dioxido-3,4,6,7,8,9-hexahydropyrido[2,1-c][1,2,4]thiadiazin-9-yl]phenol (500 mg), pyridine (3.60 mL), cesium carbonate (581 mg), diacetoxycopper (648 mg), and powdered 4A MS (5.00 g) in MeCN (18 ml) was stirred at room temperature overnight. The mixture was added with NH silica gel, concentrated in vacuo, and purified by column chromatography (NH silica gel, eluted with MeOH in EtOAc) then recrystallized from EtOAc to give the title compound (80.0 mg) as a white solid.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:7]([O:10][C:11]1[CH:23]=[CH:22][CH:21]=[CH:20][C:12]=1[CH:13]=[CH:14][C:15](OCC)=[O:16])[CH2:8][CH3:9].O.[OH-].[Na+]>C(OCC)C>[CH2:7]([O:10][C:11]1[CH:23]=[CH:22][CH:21]=[CH:20][C:12]=1[CH2:13][CH2:14][CH2:15][OH:16])[CH2:8][CH3:9]
Reactant: CCCOc1ccccc1C=CC(=O)OCC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: CCOCC
Product: CCCOc1ccccc1CCCO
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.8 %

Procedure:
To lithium aluminum hydride (6.87 g) suspended in diethyl ether (300 ml) was added dropwise at 0° C. a solution of ethyl 2-propoxycinnamate (21.2 g) in diethyl ether (100 ml) over a period of 40 minutes. After the dropwise addition, the resulting mixture was stirred at room temperature for one hour. Water (7 ml), a 15% aqueous solution of sodium hydroxide (7 ml) and water (21 ml) were added to the reaction mixture, and the resulting mixture was further stirred at room temperature for one hour. The reaction mixture was diluted with diethyl ether and was dried by addition of anhydrous magnesium sulfate. After the resulting mixture was filtered, the filtrate was concentrated under reduced pressure to obtain 3-(2-propoxyphenyl)-1-propanol (17.01 g) as a colorless oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C@H:10]([CH2:14][C:15]1[CH:24]=[CH:23][C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=1)[C:11](O)=[O:12])[CH3:9])=[O:7])([CH3:4])([CH3:3])[CH3:2].ON1C2N=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.[CH3:47][N:48]([CH3:61])[C:49](=[O:60])[C@H:50]([NH:58][CH3:59])[CH2:51][C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1.C(N(C(C)C)CC)(C)C>ClCCl>[C:1]([O:5][C:6](=[O:7])[N:8]([C@@H:10]([C:11](=[O:12])[N:58]([C@@H:50]([C:49](=[O:60])[N:48]([CH3:47])[CH3:61])[CH2:51][C:52]1[CH:53]=[CH:54][CH:55]=[CH:56][CH:57]=1)[CH3:59])[CH2:14][C:15]1[CH:24]=[CH:23][C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=1)[CH3:9])([CH3:2])([CH3:4])[CH3:3]
Reactant: CN(C(=O)OC(C)(C)C)[C@H](Cc1ccc2ccccc2c1)C(=O)O
Reactant: CN[C@H](Cc1ccccc1)C(=O)N(C)C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CN(C)C(=O)[C@@H](Cc1ccccc1)N(C)C(=O)[C@@H](Cc1ccc2ccccc2c1)N(C)C(=O)OC(C)(C)C
Reaction time: 0.5 h
Yield: 57.8 %

Procedure:
To a solution of (2R)-(N-tert-butoxycarbonyl-N-methylamino)-3-(2-naphthyl)propionic acid (8.78 g, 26.6 mmol) in dichloromethane (30 ml) were added 1-hydroxy-7-azabenzotriazole (3.62 g, 26.6 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (5.54 mg, 28.9 mmol) and the mixture was stirred for 30 min. Then (2R)-N,N-dimethyl-2-methylamino-3-phenylpropionamide (4.58 g, 22.2 mmol) in dichloromethane (15 ml) and diisopropylethylamine (4.94 ml, 28.9 mmol) were added and the mixture was stirred overnight at room temperature. The mixture was washed with water (20 ml), aqueous sodium bicarbonate (20 ml), water (2×20 ml), brine (20 ml), dried over magnesium sulfate and concentrated in vacuo. The crude product was chromatographed on silica (400 g) with ethyl acetate/heptane 1:4 to give 6.64 g of N-((1R)-1-(N-((1R)-1-(dimethylcarbamoyl)-2-phenylethyl)-N-methylcarbamoyl)-2-(2-naphthyl)ethyl)-N-methylcarbamic acid tert-butylester.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][CH:4]=1.[CH3:11][N:12]1[C:16](=[O:17])[CH2:15][NH:14][C:13]1=[O:18]>>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[C:15]2[NH:14][C:13](=[O:18])[N:12]([CH3:11])[C:16]2=[O:17])=[CH:5][CH:4]=1
Reactant: COc1ccc(C=O)cc1
Reactant: CN1C(=O)CNC1=O
Product: COc1ccc(C=C2NC(=O)N(C)C2=O)cc1
Yield: 41 %

Procedure:
Prepared according to the procedure described in Example 93 using 4-methoxybenzaldehyde (3.4 g, 25 mmoles) and 3-methyl hydantoin (3.0 g, 21 mmoles). Recrystallization from acetonitrile gave the pure product (2.0 g), mp 221°-222° C.
Reaction SMILES: [I:1][C:2]1[CH:11]=[N:10][C:5]2[NH:6][CH2:7][CH2:8][NH:9][C:4]=2[CH:3]=1.[F:12][C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=1[S:20](Cl)(=[O:22])=[O:21]>N1C=CC=CC=1>[F:12][C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=1[S:20]([N:9]1[CH2:8][CH2:7][NH:6][C:5]2[N:10]=[CH:11][C:2]([I:1])=[CH:3][C:4]1=2)(=[O:22])=[O:21]
Reactant: O=S(=O)(Cl)c1cc(F)ccc1F
Reactant: Ic1cnc2c(c1)NCCN2
Solvent: c1ccncc1
Product: O=S(=O)(c1cc(F)ccc1F)N1CCNc2ncc(I)cc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 13 %

Procedure:
7-Iodo-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine (100 mg) was dissolved in anhydrous pyridine. 2,5-difluorobenzene sulfonyl chloride (1.0 eq) was added and the mixture stirred at room temperature for 16 hours. The reaction mixture was concentrated and purified by column chromatography to give the title compound as a pale yellow solid (13% yield). M.p. 187-188° C., LCMS: m/z=437.73 (M+H+), 1H-NMR (CDCl3, 400 MHz) δ 3.29-3.33 (m, 2H), 3.83 (t, J=4.8 Hz, 2H), 5.08 (bs, 1H), 7.11-7.19 (m, 1H), 7.26-7.33 (m, 1H), 7.58-7.63 (m, 1H), 7.96 (d, J=1.5 Hz, 1H), 8.03 (d, J=1.8 Hz, 1H).
Reaction SMILES: C(O)=O.[I:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9](=[O:15])[NH:10][CH:11]=[N:12]2)=[CH:7][C:6]=1[S:16][CH3:17].Br[CH2:19][C:20](=[O:36])[CH2:21][C@H:22]1[C@H:27]([O:28][CH3:29])[CH2:26][CH2:25][CH2:24][N:23]1[C:30]([O:32][CH2:33][CH:34]=[CH2:35])=[O:31]>>[I:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9](=[O:15])[N:10]([CH2:19][C:20](=[O:36])[CH2:21][C@H:22]3[C@H:27]([O:28][CH3:29])[CH2:26][CH2:25][CH2:24][N:23]3[C:30]([O:32][CH2:33][CH:34]=[CH2:35])=[O:31])[CH:11]=[N:12]2)=[CH:7][C:6]=1[S:16][CH3:17]
Reactant: C=CCOC(=O)N1CCC[C@@H](OC)[C@@H]1CC(=O)CBr
Reactant: CSc1cc2c(=O)[nH]cnc2cc1I
Solvent: O=CO
Product: C=CCOC(=O)N1CCC[C@@H](OC)[C@@H]1CC(=O)Cn1cnc2cc(I)c(SC)cc2c1=O

Procedure:
In the manner of Example 4, 1.09 g (0.003 mol) of 7-iodo-6-methylthioquinazolin-4(3H)-one formic acid salt and 1.0 g (0.003 mol) of allyl trans-2-(3-bromo-2-oxopropyl)-3-methoxy-1-piperidinecarboxylate were converted into the title compound: yield 0.53 g (31%); mass spectrum m/e 571 (molecular ion), 539 (-32, --CH3OH), 221 (parent peak). 1H--NMR(CDCl3) 1.4-2.1 ppm (multiplet, 4H, OCHCH2CH2CH2N), 2.6 (singlet, 3H, SCH3), 2.8-3.4 (multiplet, 4H, NCH2, COCH2CH), 3.4 (singlet, 3H, OCH3), 4.0 (broad singlet, 1H, CHNCO), 4.6 (doublet, 2H, CH2CH=CH2), 5.0 (singlet, 2H, NCH2CO), 5.0-5.5 (multiplet, 2H, CH=CH2), 5.6-6.1 (octet, 1H, CH2 = CH), 7.7 (singlet, 1H, aromatic H), 7.8 (singlet, 1H, N=CH--N), 8.2 (singlet, 1H, aromatic H).
Reaction SMILES: [CH3:1][C:2]([CH3:21])([CH3:20])[C:3]([NH:5][C:6]1[C:15]([C:16]([O:18][CH3:19])=[O:17])=[C:14]2[C:9]([CH:10]=[CH:11][CH2:12][O:13]2)=[CH:8][CH:7]=1)=[O:4].[OH-].[Na+].[CH:24](Br)([Br:26])[Br:25]>[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1>[Br:25][C:24]1([Br:26])[CH:10]2[CH:11]1[CH2:12][O:13][C:14]1[C:9]2=[CH:8][CH:7]=[C:6]([NH:5][C:3](=[O:4])[C:2]([CH3:21])([CH3:20])[CH3:1])[C:15]=1[C:16]([O:18][CH3:19])=[O:17]
Reactant: BrC(Br)Br
Reactant: COC(=O)c1c(NC(=O)C(C)(C)C)ccc2c1OCC=C2
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Product: COC(=O)c1c(NC(=O)C(C)(C)C)ccc2c1OCC1C2C1(Br)Br
Temperature: 60 °C

Procedure:
Methyl 7-(2,2-dimethylpropionylamino)-2H-chromene-8-carboxylate (Intermediate 45, 2.372 g) and benzyl triethyl ammonium chloride (0.373 g) were suspended in bromoform (6.45 mL) and aqueous sodium hydroxide solution (50%, 3.64 mL) was added dropwise. The resultant black suspension was heated to 60° C. for 2 hours. After cooling, the mixture was partitioned between water and ethyl acetate. The emulsion formed was filtered through a pad of Celite and the organic layer was decanted off. The aqueous was re-extracted with ethyl acetate and the combined organic layers were dried (MgSO4) and filtered. The filtrate was concentrated in vacuo and the residue was purified by chromatography on silica, eluting with a mixture of ethyl acetate and cyclohexane, with a gradient of 2.5-15% to give methyl 1,1-dibromo-5-(2,2-dimethylpropionylamino)-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylate (1.557 g) as an off-white solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[C:5](=O)[CH2:6][C:7]([C:9]1[CH:14]=[C:13]([S:15][CH3:16])[CH:12]=[CH:11][N:10]=1)=O)[CH3:2].[NH:19]([C:21]1[CH:22]=[CH:23][C:24]([O:27][CH3:28])=[N:25][CH:26]=1)[NH2:20]>>[CH2:1]([O:3][C:4]([C:5]1[CH:6]=[C:7]([C:9]2[CH:14]=[C:13]([S:15][CH3:16])[CH:12]=[CH:11][N:10]=2)[N:19]([C:21]2[CH:26]=[N:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=2)[N:20]=1)=[O:18])[CH3:2]
Reactant: CCOC(=O)C(=O)CC(=O)c1cc(SC)ccn1
Reactant: COc1ccc(NN)cn1
Product: CCOC(=O)c1cc(-c2cc(SC)ccn2)n(-c2ccc(OC)nc2)n1
Yield: 16.3 %

Procedure:
The general procedure of Referential Example 3-2) was repeated through use of 4-(4-methylthio-2-pyridyl)-2,4-dioxobutanoic acid ethyl ester (1.62 g) and the 5-hydrazino-2-methoxypyridine (0.843 g) prepared in Referential Example 2, to thereby give the title compound as a solid (0.366 g, 16%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[C:5](=[CH2:17])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH:12]1[CH2:16][CH2:15][CH2:14][CH2:13]1)[CH3:2].ClC1C=CC=C(C(OO)=[O:27])C=1>C(Cl)Cl>[CH2:1]([O:3][C:4]([C:5]1([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH:12]2[CH2:13][CH2:14][CH2:15][CH2:16]2)[CH2:17][O:27]1)=[O:18])[CH3:2]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C=C(CCCCCCC1CCCC1)C(=O)OCC
Solvent: ClCCl
Product: CCOC(=O)C1(CCCCCCC2CCCC2)CO1

Procedure:
5.33 g of the title compound, in the form of a nearly colourless oil, which is purified by chromatography on silica gel (migrating agent: 90:10 petroleum ether/ethyl acetate), are obtained by the procedure described in Example (1a) from 11.4 g of 8-cyclopentyl-2-methyleneoctanoic acid ethyl ester and 15.6 g of m-chloroperbenzoic acid in 120 ml of methylene chloride