Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[C:6]([NH:11][CH2:12][C:13]([C:15]2[CH:16]=[N:17][N:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:19]=2[CH3:20])=O)[CH:5]=1.[C:28]([S-:30])#[N:29].[K+]>CC(O)=O>[CH3:1][O:2][C:3](=[O:27])[C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[C:6]([N:11]2[CH:12]=[C:13]([C:15]3[CH:16]=[N:17][N:18]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[C:19]=3[CH3:20])[N:29]=[C:28]2[SH:30])[CH:5]=1
Reactant: N#C[S-]
Reactant: COC(=O)c1ccc(C)c(NCC(=O)c2cnn(-c3ccccc3)c2C)c1
Agent: [K+]
Solvent: CC(=O)O
Product: COC(=O)c1ccc(C)c(-n2cc(-c3cnn(-c4ccccc4)c3C)nc2S)c1
Temperature: 100 °C
Reaction time: 4 h
Yield: 66.7 %

Procedure:
A suspension of 380 mg (1.05 mmol) of 4-methyl-3-[2-(5-methyl-1-phenyl-1H-pyrazol-4-yl)-2-oxo-ethylamino]-benzoic acid methyl ester and 203 mg (2.09 mmol) of KSCN in 4 mL of HOAc was stirred at 100° C. for 4 h, when a precipitate formed. The mixture was cooled to room temperature, filtered, and washed with cold MeOH to provide 283 mg of 3-[2-mercapto-4-(5-methyl-1-phenyl-1H-pyrazol-4-yl)-imidazol-1-yl]-4-methyl-benzoic acid methyl ester (0.70 mmol, 67%). ESI MS m/z 405 [C22H20N4O2S+H]+.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[N:5]=[C:4]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[N:3]=1.[NH2:20][C:21]1[CH:26]=[CH:25][C:24](B2OC(C)(C)C(C)(C)O2)=[CH:23][CH:22]=1>CCCCCC.C(OCC)(=O)C>[O:17]1[CH2:18][CH2:19][N:14]([C:4]2[N:5]=[C:6]([N:8]3[CH2:13][CH2:12][O:11][CH2:10][CH2:9]3)[N:7]=[C:2]([C:24]3[CH:25]=[CH:26][C:21]([NH2:20])=[CH:22][CH:23]=3)[N:3]=2)[CH2:15][CH2:16]1
Reactant: Clc1nc(N2CCOCC2)nc(N2CCOCC2)n1
Reactant: CC1(C)OB(c2ccc(N)cc2)OC1(C)C
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: Nc1ccc(-c2nc(N3CCOCC3)nc(N3CCOCC3)n2)cc1

Procedure:
Following the general procedure A, 4,4′-(6-chloro-1,3,5-triazine-2,4-diyl)dimorpholine was coupled with 4-aminophenylboronic acid pinacol ester with reaction time of 24 h. Chromatography (hexane/ethyl acetate 6:4) gave the title compound as a yellow solid.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:10]2[C:15]([F:16])=[CH:14][C:13]([C:17]([OH:20])([CH3:19])[CH3:18])=[CH:12][C:11]=2[F:21])=[CH:5][C:6]=1[C:7]([NH2:9])=[O:8].Br[C:23]1[N:28]=[C:27]([CH2:29][O:30][C@@H:31]2[CH2:35][CH2:34][CH2:33][C@H:32]2[OH:36])[CH:26]=[CH:25][CH:24]=1>>[F:16][C:15]1[CH:14]=[C:13]([C:17]([OH:20])([CH3:18])[CH3:19])[CH:12]=[C:11]([F:21])[C:10]=1[C:4]1[S:3][C:2]([NH:1][C:23]2[CH:24]=[CH:25][CH:26]=[C:27]([CH2:29][O:30][C@@H:31]3[CH2:35][CH2:34][CH2:33][C@H:32]3[OH:36])[N:28]=2)=[C:6]([C:7]([NH2:9])=[O:8])[CH:5]=1
Reactant: CC(C)(O)c1cc(F)c(-c2cc(C(N)=O)c(N)s2)c(F)c1
Reactant: O[C@@H]1CCC[C@H]1OCc1cccc(Br)n1
Product: CC(C)(O)c1cc(F)c(-c2cc(C(N)=O)c(Nc3cccc(CO[C@@H]4CCC[C@H]4O)n3)s2)c(F)c1

Procedure:
The title compound was prepared as described in Example 1 with 2-amino-5-[2,6-difluoro-4-(1-hydroxy-1-methylethyl)phenyl]thiophene-3-carboxamide (0.14 g, 0.43 mmol) and (1R,2R)-2-[(6-bromopyridin-2-yl)methoxy]cyclopentanol (0.12 g, 0.43 mmol) as the starting materials.
Reaction SMILES: Br[C:2]1[N:6]2[C:7]3[C:12]([N:13]=[C:14]([CH3:15])[C:5]2=[C:4]([CH3:17])[N:3]=1)=[CH:11][CH:10]=[C:9]([F:16])[CH:8]=3.[CH3:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1B(O)O.C([O-])([O-])=O.[K+].[K+]>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>[F:16][C:9]1[CH:8]=[C:7]2[C:12]([N:13]=[C:14]([CH3:15])[C:5]3[N:6]2[C:2]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[CH3:18])=[N:3][C:4]=3[CH3:17])=[CH:11][CH:10]=1
Reactant: Cc1nc(Br)n2c1c(C)nc1ccc(F)cc12
Reactant: Cc1ccccc1B(O)O
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: [K+]
Product: Cc1ccccc1-c1nc(C)c2c(C)nc3ccc(F)cc3n12
Yield: 85.1 %

Procedure:
Following the general Suzuki coupling procedure, reaction of bromide 5A (75 mg, 0.25 mmol), 2-methylphenylboronic acid (42 mg, 0.30 mmol), K2CO3 (105 mg, 0.75 mmol) and Pd(PPh3)4 (5.8 mg, 0.005 mmol) provided the coupling product as a white powder (65 mg, 86% yield). EIMS 306.1 [M+H]+.
Reaction SMILES: [O:1]=[C:2]1[C:7]([C:8]([O:10]C)=[O:9])=[CH:6][CH:5]=[CH:4][N:3]1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=1.[OH-].[Na+].C(O)(C(F)(F)F)=O>CO>[O:1]=[C:2]1[C:7]([C:8]([OH:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=1
Reactant: COC(=O)c1cccn(-c2ccccn2)c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: O=C(O)c1cccn(-c2ccccn2)c1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 55.4 %

Procedure:
A mixture of methyl 2-oxo-1-(pyridin-2-yl)-1,2-dihydropyridine-3-carboxylate (500 mg, 2.17 mmol) and 3 N NaOH (1 mL) and methanol (10 mL) was stirred at rt overnight. To the reaction was added TFA (0.5 mL) and the mixture was concentrated in vacuo. The residue was dissolved in water (3 mL) and i-PrOH (10 mL). The solid which formed was filtered, washed with a small amount of water and i-PrOH, and dried to obtain the acid (260 mg, 55%) as a white solid. 1H NMR (DMF-d7) δ 14.14 (br s, 1H), 8.72 (d, 1H, J=4.9 Hz), 8.62 (dd, 1H, J=7.7, 2.2 Hz), 8.47 (dd, 1H, J=6.6, 2.2 Hz), 8.18–7.98 (m, 2H), 7.67 (dd, 1H, J=7.2, 5.3 Hz), 6.97 (t, 1H, J=6.6 Hz); MS(ESI+) m/z 217.2 (M+H)+.
Reaction SMILES: [NH2:1]/[C:2](/[CH3:10])=[C:3](/[CH3:9])\[C:4]([O:6][CH2:7][CH3:8])=[O:5].[Cl:11][C:12]1[CH:22]=[CH:21][C:20]([N:23]=[C:24]=[O:25])=[CH:19][C:13]=1[C:14]([O:16][CH2:17][CH3:18])=[O:15]>C(OCC)C>[Cl:11][C:12]1[CH:22]=[CH:21][C:20]([NH:23][C:24]([NH:1][C:2]([CH3:10])=[C:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH3:9])=[O:25])=[CH:19][C:13]=1[C:14]([O:16][CH2:17][CH3:18])=[O:15]
Reactant: CCOC(=O)c1cc(N=C=O)ccc1Cl
Reactant: CCOC(=O)/C(C)=C(/C)N
Solvent: CCOCC
Product: CCOC(=O)C(C)=C(C)NC(=O)Nc1ccc(Cl)c(C(=O)OCC)c1
Reaction time: 2 h

Procedure:
4.7 g of ethyl 3-amino-2-methylcrotonate, dissolved in 15 ml of absolute diethyl ether, are treated at 23° C., while stirring with a solution of 6.7 g of ethyl 2-chloro-5-isocyanatobenzoate and stirred for 2 hours. The reaction mixture is evaporated to dryness under reduced pressure and the residue is purified by chromatography on 400 g of silica gel using diethyl ether/n-hexane (1:1) as the eluent. There is obtained ethyl 2-chloro-5-{3-[2-(ethoxycarbonyl)-1-methylpropenyl]ureido}-benzoate, m.p. 88°-91° C.
Reaction SMILES: Cl.Cl[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1.[OH-].[K+].[CH3:13][C:14]1[NH:15][C:16]2[C:21]([CH:22]=1)=[CH:20][CH:19]=[CH:18][N:17]=2>CS(C)=O>[CH3:13][C:14]1[N:15]([CH2:3][CH2:4][N:5]2[CH2:10][CH2:9][O:8][CH2:7][CH2:6]2)[C:16]2=[N:17][CH:18]=[CH:19][CH:20]=[C:21]2[CH:22]=1
Reactant: ClCCN1CCOCC1
Reactant: Cc1cc2cccnc2[nH]1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: Cc1cc2cccnc2n1CCN1CCOCC1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of 2-chloroethylmorpholine HCl (169 mg, 0.91 mmol) in 0.3 mL DMSO was added pulverized KOH (128 mg, 2.27 mmol), then after 10 min, a solution of 2-methyl-7-azaindole (100 mg, 0.76 mmol) in 0.2 mL DMSO was added and the reaction stirred at room temperature overnight. The reaction mixture was partitioned between H2O and toluene, and the organic extract washed two times with H2O, dried over MgSO4, filtered, and concentrated in vacuo. The crude product was purified via silica gel chromatography using a gradient from 0 to 10% MeOH in CH2Cl2 to give a final yield of 144 mg (0.59 mmol). 1H NMR (500 MHz, CDCl3, δ): 2.46 (s, 3H), 2.47-2.58 (m, 4H), 2.67 (t, J=7.0 Hz, 2H), 3.66 (t, J=4.5 Hz, 4H), 4.33 (t, J=7.0 Hz, 2H), 6.15 (s, 1H), 6.87-7.09 (m, 1H), 7.73 (dd, J=7.7 Hz, 1.3 Hz, 1H), 8.19 (dd, J=4.6 Hz, 1.3 Hz, 1H). 13C NMR (500 MHz, CDCl3, δ): 13.51, 39.75, 54.37, 58.49, 67.18, 98.40, 116.05, 121.09, 127.47, 137.78, 141.71, 148.56. MS m/z 246.1 [M+H]+.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[B:17](OC(C)C)([O:22]C(C)C)[O:18]C(C)C.[Li]CCCC.Cl>C1COCC1.CCCCCC>[N:11]1([S:8]([C:5]2[CH:6]=[CH:7][C:2]([B:17]([OH:22])[OH:18])=[CH:3][CH:4]=2)(=[O:10])=[O:9])[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: O=S(=O)(c1ccc(I)cc1)N1CCOCC1
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: O=S(=O)(c1ccc(B(O)O)cc1)N1CCOCC1
Temperature: -60 °C
Reaction time: 0.75 h

Procedure:
To a solution of 25 g of the compound obtained in Step A (70.8 mmol) and 26 ml of triisopropyl borate in 400 ml of THF cooled to −60° C. there are added, dropwise, over 45 minutes and under a gentle current of nitrogen, 53 ml of a 1.6M solution of BuLi (84.9 mmol) in hexane. The reaction solution is then stirred for 1 hour 30 minutes at −60° C. and is subsequently returned to ambient temperature over 2 hours. The reaction mixture is treated with about 100 ml of 1N HCl and is extracted 3 times with ethyl acetate. The organic phases are collected, washed with brine, dried (MgSO4) and evaporated under reduced pressure. The residue obtained is chromatographed on an SiO2 column, eluting with CH2Cl2 and then with a mixture of CH2Cl2/MeOH 98/2 and then 95/5. After evaporation of the fractions, the residue is triturated in ethyl ether to yield the title product after filtration.
Reaction SMILES: C[Si](C)(C)N[Si](C)(C)C.[Li].[C:11]([O:14][CH2:15][CH3:16])(=[O:13])[CH3:12].[C:17]1([C:23]([CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([O:32][CH3:33])[CH:27]=2)=[O:24])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C1COCC1>[CH3:33][O:32][C:28]1[CH:27]=[C:26]([CH2:25][C:23]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)([OH:24])[CH2:12][C:11]([O:14][CH2:15][CH3:16])=[O:13])[CH:31]=[CH:30][CH:29]=1
Reactant: COc1cccc(CC(=O)c2ccccc2)c1
Reactant: CCOC(C)=O
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: [Li]
Solvent: C1CCOC1
Product: CCOC(=O)CC(O)(Cc1cccc(OC)c1)c1ccccc1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 86 %

Procedure:
Lithium hexamethyldisilazane (88.5 mL, 88.5 mmol) was added to THF (150 mL) at −78° C. After 15 minutes, ethyl acetate (7.79 g, 88.5 mmol) was added over 10 minutes and stirred at −78° C. for 30 minutes. The m-methoxybenzyl phenyl ketone in (10.0 g, 44.25 mmol) THF (100 mL) was added over 15 minutes and kept at that temperature for 3 hours. The reaction mixture was quenched at that temperature with saturated ammonium chloride (15 mL). The reaction mixture was diluted with ether (200 mL) and the organic layer was washed with brine, (100 mL), dried and concentrated to afford the desired product (12 g, 86% yield). NMR was consistent with the desired structure.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:14][CH2:13][C:12]3([CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[C:11]2=[O:20])=[CH:6][CH:5]=1.[Cl:23][C:24]1[C:29]([S:30](Cl)(=[O:32])=[O:31])=[CH:28][CH:27]=[CH:26][N:25]=1>>[Cl:23][C:24]1[C:29]([S:30]([N:17]2[CH2:16][CH2:15][C:12]3([C:11](=[O:20])[N:10]([C:7]4[CH:8]=[CH:9][C:4]([O:3][C:2]([F:1])([F:21])[F:22])=[CH:5][CH:6]=4)[CH2:14][CH2:13]3)[CH2:19][CH2:18]2)(=[O:32])=[O:31])=[CH:28][CH:27]=[CH:26][N:25]=1
Reactant: O=C1N(c2ccc(OC(F)(F)F)cc2)CCC12CCNCC2
Reactant: O=S(=O)(Cl)c1cccnc1Cl
Product: O=C1N(c2ccc(OC(F)(F)F)cc2)CCC12CCN(S(=O)(=O)c1cccnc1Cl)CC2

Procedure:
The title compound was prepared in analogy to example 180 step D from 2-(4-trifluoromethoxy-phenyl)-2,8-diaza-spiro[4.5]decan-1-one (described in example 180 step C) and 2-chloro-pyridine-3-sulfonyl chloride. White solid. MS (ESI): 490.2 (MH+)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13](=[O:14])[O:12][N:11]=[C:10]2[C:15]2[N:16]=[N:17][S:18][C:19]=2[CH2:20][OH:21])[CH:5]=[CH:6][C:7]=1[F:8].[CH3:22][S:23](Cl)(=[O:25])=[O:24]>C(Cl)Cl>[CH3:22][S:23]([O:21][CH2:20][C:19]1[S:18][N:17]=[N:16][C:15]=1[C:10]1[N:9]([C:4]2[CH:5]=[CH:6][C:7]([F:8])=[C:2]([Cl:1])[CH:3]=2)[C:13](=[O:14])[O:12][N:11]=1)(=[O:25])=[O:24]
Reactant: O=c1onc(-c2nnsc2CO)n1-c1ccc(F)c(Cl)c1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Product: CS(=O)(=O)OCc1snnc1-c1noc(=O)n1-c1ccc(F)c(Cl)c1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 65 %

Procedure:
4-(3-Chloro-4-fluorophenyl)-3-[5-(hydroxymethyl)-1,2,3-thiadiazol-4-yl]-1,2,4-oxadiazol-5(4H)-one was dissolved in anhydrous DCM (2 mL) followed by addition of TEA (26 μL, 0.19 mmol). The reaction was stirred at 0° C. for 15 minutes. Methanesulfonyl chloride (13 μL, 0.17 mmol) was added drop-wise and stirred for 15 minutes at 0° C. The reaction was concentrated in vacuo and the crude purified by flash chromatography to give the desired product (42 mg, 65%). 1H NMR (400 MHz, CDCl3): δ 7.50 (m, 1H), 7.25 (m, 2H), 5.83 (s, 2H), 3.20 (s, 3H). MF C12H8ClFN4O5S2; LCMS calculated for C12H9ClFN4O5S2(M+H)+: m/z=406.9.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:16]([CH2:17][C:18]([OH:20])=O)[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:4][CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH:33]([NH2:36])([CH3:35])[CH3:34]>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:16]([CH2:17][C:18]([NH:36][CH:33]([CH3:35])[CH3:34])=[O:20])[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:6][CH:7]=1
Reactant: CC(C)N
Reactant: O=C(O)Cn1c(-c2ccc(Cl)cc2)nc2cccnc21
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CC(C)NC(=O)Cn1c(-c2ccc(Cl)cc2)nc2cccnc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 2-(4-chlorophenyl)-3H-imidazo[4,5-b]pyridine-3-acetic acid (5.0 g, 0.017 mole) and 1,1'-carbonyldiimidazole (2.82 g, 0.017 mole) in 150 ml of tetrahydrofuran was stirred at room temperature for 2 hours with a stream of nitrogen bubbling through it. A solution of isopropylamine (2.06 g, 0.035 mole) in tetrahydrofuran was added dropwise and the reaction mixture was allowed to stir at room temperature overnight. The tetrahydrofuran was evaporated and the solid residue was triturated with water. The solid was collected and dried under high vacuum overnight. The solid was recrystallized from isopropyl alcohol with cooling in the freezer, collected by filtration, washed with water, and dried under high vacuum at 50° C. overnight to give 4.0 g (70%), mp 248°-9° C.
Reaction SMILES: [Al].[CH2:2](Br)[C:3]#[CH:4].[F:6][C:7]([F:27])([F:26])[C:8](=[O:25])[CH2:9][C:10]1([CH3:24])[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([S:20]([CH3:23])(=[O:22])=[O:21])[CH:18]=2)[O:13][CH2:12][CH2:11]1>C1COCC1.C1(C)C=CC=CC=1>[F:27][C:7]([F:6])([F:26])[C:8]([CH2:9][C:10]1([CH3:24])[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([S:20]([CH3:23])(=[O:21])=[O:22])[CH:18]=2)[O:13][CH2:12][CH2:11]1)([OH:25])[CH2:4][C:3]#[CH:2]
Reactant: C#CCBr
Reactant: CC1(CC(=O)C(F)(F)F)CCOc2ccc(S(C)(=O)=O)cc21
Agent: [Al]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: C#CCC(O)(CC1(C)CCOc2ccc(S(C)(=O)=O)cc21)C(F)(F)F
Temperature: 40 °C
Reaction time: 0.33 h

Procedure:
A mixture of 70 mg (2.75 mmol) of aluminum foil and 0.8 mg (0.003 mmol) of mercuric chloride in 3 mL of anhydrous THF was vigorously stirred. After 20 minutes, 0.31 mL (2.75 mmol) of a 80% solution of propargyl bromide in toluene was added and the reaction was warmed at 40° C. for one hour. The dark grey solution was then added to a chilled (0° C.) solution of 300 mg (0.88 mmol) of 1,1,1-trifluoro-3-(6-methanesulfonyl-4-methylchroman-4-yl)propan-2-one in 10 mL of dry tetrahydrofuran. The reaction was warmed to room temperature overnight, concentrated in vacuo, quenched with ice and extracted with diethyl ether. The combined organic fractions were dried over magnesium sulfate, filtered and concentrated in vacuo to afford 330 mg of crude 1,1,1-trifluoro-2-(6-methanesulfonyl-4-methylchroman-4-ylmethyl)pent-4-yn-2-ol as an oil.
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][O:20][C:21]([C:23]1[NH:24][CH:25]=[CH:26][N:27]=1)=[O:22])([O:6][CH2:7][CH3:8])=[O:5])[CH3:2].C(Cl)(=O)C(Cl)=O.[N+:34]([C:37]1[CH:42]=CC(O)=[CH:39][CH:38]=1)([O-:36])=[O:35].CCN(CC)CC>C(Cl)Cl>[CH2:1]([O:3][P:4]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][O:20][C:21]([C:23]1[NH:27][CH:26]=[CH:25][N:24]=1)=[O:22])([O:6][C:7]1[CH:39]=[CH:38][C:37]([N+:34]([O-:36])=[O:35])=[CH:42][CH:8]=1)=[O:5])[CH3:2]
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: CCOP(=O)(CCCCCCCCCCCOC(=O)c1ncc[nH]1)OCC
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOP(=O)(CCCCCCCCCCCOC(=O)c1ncc[nH]1)Oc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 16 (1.2 g, 3.0 mmol) dissolved in 25 mL of CH2Cl2 was added oxalyl chloride (0.65 n-flL, 7.5 mmol) dropwise at 0° C. The reaction mixture was allowed to slowly warm to room temperature. After stirring for 8 h, the mixture was concentrated to remove excess oxalyl chloride. The crude residue was redissolved in 20 mL of CH2Cl2, followed by the addition of 4-nitrophenol (414 mg, 3.0 mmol) and Et3N (0.80 mL, 6.0 mmol). After stirring at room temperature for 10 h, the reaction mixture was concentrated. The residue was purified by flash chromatography (hexane/EA=1:1) to give 601 mg (41%) of pure 17. 1H NMR (CDCl3, 500 MHz) δ 8.16 (d, J=9.0 Hz, 2H), 8.10 (s, 1H), 7.37 (s, 1H), 7.32 (d, J=9.0 Hz, 2H), 7.01 (s, 1H), 4.35 (t, J=6.5 Hz, 2H), 4.11 (m, 2H), 1.87 (m, 2H), 1.72 (m, 2H), 1.62 (m, 2H), 1.38-1.17 (br m, 20H). 31P NMR (CDCl3, 500 MHz) δ 30.49.
Reaction SMILES: [H-].[Na+].[SH:3][C:4]1[N:9]2[CH:10]=[CH:11][N:12]=[C:8]2[CH:7]=[CH:6][CH:5]=1.[CH2:13]([C:20]1[C:21](=[O:38])[N:22]([CH2:33][CH2:34][CH2:35][CH2:36]Cl)[C:23](=[O:32])[N:24]2[CH2:29][CH2:28][CH2:27][S:26](=[O:31])(=[O:30])[C:25]=12)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[I-].[Na+]>CN(C)C=O.O>[N:12]1[CH:11]=[CH:10][N:9]2[C:4]([S:3][CH2:36][CH2:35][CH2:34][CH2:33][N:22]3[C:21](=[O:38])[C:20]([CH2:13][C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)=[C:25]4[S:26](=[O:31])(=[O:30])[CH2:27][CH2:28][CH2:29][N:24]4[C:23]3=[O:32])=[CH:5][CH:6]=[CH:7][C:8]=12
Reactant: Sc1cccc2nccn12
Reactant: O=c1c(Cc2ccccc2)c2n(c(=O)n1CCCCCl)CCCS2(=O)=O
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=c1c(Cc2ccccc2)c2n(c(=O)n1CCCCSc1cccc3nccn13)CCCS2(=O)=O
Reaction time: 0.5 h

Procedure:
To a suspension of 0.22 g (5.5 mmol) of 60% oily sodium hydride in 30 ml of N,N-dimethylformamide, 0.83 g (5.5 mmol) of 5-mercaptoimidazo[1,2-a]pyridine was added at room temperature, followed by stirring for 30 minutes. To this mixture, 1.98 g (5 mmol) of 9-benzyl-7-(4-chlorobutyl)-1,1-dioxo-3,4-dihydro-2H,6H-pyrimido[6,1-b][1,3]thiazine-6,8(7H)-dione and 0.82 g (5.5 mmol) of sodium iodide were added, followed by stirring at 100° C. for 2 hours. After cooling, the reaction mixture was poured into water and extracted with ethyl acetate 3 times. The organic layer was washed with water and dried, after which the solvent was distilled off. The residue was purified by column chromatography (eluent, ethyl acetate→ethyl acetate/ethanol=10/1) to yield 1.95 g (78.2%, white powder) of the desired product.
Reaction SMILES: [CH3:1][CH:2]1[S:6][CH2:5][NH:4][C:3]1=[O:7].CN(C=O)C.[OH-].[K+].[Br:15][CH2:16][CH2:17][CH2:18][CH2:19]Br>O>[Br:15][CH2:16][CH2:17][CH2:18][CH2:19][N:4]1[C:3](=[O:7])[CH:2]([CH3:1])[S:6][CH2:5]1
Reactant: BrCCCCBr
Reactant: CC1SCNC1=O
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: CC1SCN(CCCCBr)C1=O
Reaction time: 3.5 h

Procedure:
To 12.35 g of 5-methyl-4-thiazolidinone placed in a 500 ml round bottom flask was added 210 ml of DMF and the mixture stirred for 3.5 h. An additional 30 ml of DMF was added and the mixture stirred for 10 minutes and thereafter 11.8 g of KOH was added all at once. The resultant solution was stirred for 0.5 h at room temperature and thereafter 38 ml of 1,4-dibromobutane was added rapidly. The mixture was stirred at room temperature overnight. After 24 hours of stirring at room temperature, the reaction mixture was poured into 600 ml of water and the resultant mixture extracted with EtOAc (2×175 ml). The combined EtOAc layers were washed successively with water (200 ml) and brine (150 ml), dried over MgSO4 and concentrated in vacuo to 49.68 g of oil. After removal of DMF by vacuum distillation, the residual oil was purified by flash chromatography (silica gel column) to obtain the desired product.
Reaction SMILES: [CH:1](=O)[CH3:2].[C:4]([NH:7][C:8]([CH2:29][CH2:30][CH:31]1[CH2:40][C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH2:33][NH:32]1)([CH2:16][CH2:17][CH2:18][CH2:19][B:20]1[O:24][C:23]([CH3:26])([CH3:25])[C:22]([CH3:28])([CH3:27])[O:21]1)[C:9]([NH:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])(=[O:6])[CH3:5].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[C:4]([NH:7][C:8]([CH2:29][CH2:30][CH:31]1[CH2:40][C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH2:33][N:32]1[CH2:1][CH3:2])([CH2:16][CH2:17][CH2:18][CH2:19][B:20]1[O:21][C:22]([CH3:27])([CH3:28])[C:23]([CH3:25])([CH3:26])[O:24]1)[C:9]([NH:11][C:12]([CH3:13])([CH3:14])[CH3:15])=[O:10])(=[O:6])[CH3:5]
Reactant: CC=O
Reactant: CC(=O)NC(CCCCB1OC(C)(C)C(C)(C)O1)(CCC1Cc2ccccc2CN1)C(=O)NC(C)(C)C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CCN1Cc2ccccc2CC1CCC(CCCCB1OC(C)(C)C(C)(C)O1)(NC(C)=O)C(=O)NC(C)(C)C
Reaction time: 8 h
Yield: 83.1 %

Procedure:
A solution of acetaldehyde (0.06 mL, 1.1 mmol) and 2-acetamido-N-tert-butyl-2-(2-(1,2,3,4-tetrahydroisoquinolin-3-yl)ethyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)hexanamide (0.51 g, 1.0 mmol) in dichloromethane was stirred at room temperature for 1 h, then treated with sodium triacetoxyborohydride (0.63 g, 3 mmol). After stirring overnight, the reaction was quenched with 5% aq NaHCO3 (W/V) and extracted with dichloromethane. The organic layer was washed successively with 1 M HCl, sat'd aq sodium chloride, dried over MgSO4, filtered and concentrated. Purification by flash chromatography (1% methanol in chloroform) gave 2-acetamido-N-tert-butyl-2-(2-(2-ethyl-1,2,3,4-tetrahydroisoquinolin-3-yl)ethyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)hexanamide as an oil (0.45 g, 83%). ESI MS found for C31H52BN3O4 m/z [b.e.542.7 (M+1)].
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[S:9]([CH:12]1[CH2:16][CH2:15][CH:14]([C:17]([OH:19])=O)[CH2:13]1)(=[O:11])=[O:10].[NH2:20][C:21]1([C:24]#[N:25])[CH2:23][CH2:22]1>>[C:24]([C:21]1([NH:20][C:17]([C@@H:14]2[CH2:15][CH2:16][C@@H:12]([S:9]([C:3]3[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=3[Cl:1])(=[O:10])=[O:11])[CH2:13]2)=[O:19])[CH2:23][CH2:22]1)#[N:25]
Reactant: N#CC1(N)CC1
Reactant: O=C(O)C1CCC(S(=O)(=O)c2ccc(F)cc2Cl)C1
Product: N#CC1(NC(=O)[C@@H]2CC[C@@H](S(=O)(=O)c3ccc(F)cc3Cl)C2)CC1

Procedure:
The title compound was synthesized in analogy to Example 68/69, Step 11, from rac-(1S,3S)-3-(2-chloro-4-fluoro-benzenesulfonyl)-cyclopentanecarboxylic acid and 1-amino-cyclopropanecarbonitrile to afford the desired product as a light yellow oil. MS (EI): 371.0 (M+H)+.
Reaction SMILES: CS(OCC1O[N:10]=[C:9]([C@@H:12]2[CH2:16][CH2:15][CH2:14][N:13]2[C:17](=[O:32])[C:18]([F:31])([F:30])[C:19]2([OH:29])[CH2:24][C:23]([CH3:26])([CH3:25])[CH2:22][C:21]([CH3:28])([CH3:27])[CH2:20]2)C=1)(=O)=O.CS(OCC1[O:40][C:41]([C@@H:44]2CC[CH2:46][N:45]2[C:49](=O)C(F)(F)C2(O)CC(C)(C)CC(C)(C)C2)=[N:42]N=1)(=O)=O>>[CH3:46][N:45]([CH2:44][C:41]1[O:40][C:9]([C@@H:12]2[CH2:16][CH2:15][CH2:14][N:13]2[C:17](=[O:32])[C:18]([F:31])([F:30])[C:19]2([OH:29])[CH2:20][C:21]([CH3:28])([CH3:27])[CH2:22][C:23]([CH3:26])([CH3:25])[CH2:24]2)=[N:10][N:42]=1)[CH3:49]
Reactant: CC1(C)CC(C)(C)CC(O)(C(F)(F)C(=O)N2CCC[C@H]2c2cc(COS(C)(=O)=O)on2)C1
Reactant: CC1(C)CC(C)(C)CC(O)(C(F)(F)C(=O)N2CCC[C@H]2c2nnc(COS(C)(=O)=O)o2)C1
Product: CN(C)Cc1nnc([C@@H]2CCCN2C(=O)C(F)(F)C2(O)CC(C)(C)CC(C)(C)C2)o1

Procedure:
The procedure of Example 6 was repeated, except that the compound obtained in Example 3-(5) was replaced by the compound obtained in Example 9-(6); this gave the titled compound.