Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][C:3]1[NH:7][C:6]2[CH:8]=[CH:9][CH:10]=[C:11]([NH:12][C:13](=[O:35])[C:14]3[CH:19]=[CH:18][C:17]([C:20]([N:22]4[C:28]5[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=5[CH2:26][CH2:25][CH2:24][CH2:23]4)=[O:21])=[CH:16][C:15]=3[O:33][CH3:34])[C:5]=2[N:4]=1.[CH3:36][S:37](Cl)(=[O:39])=[O:38].CCOCC>N1C=CC=CC=1>[CH3:34][O:33][C:15]1[CH:16]=[C:17]([C:20]([N:22]2[C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=3[CH2:26][CH2:25][CH2:24][CH2:23]2)=[O:21])[CH:18]=[CH:19][C:14]=1[C:13]([NH:12][C:11]1[C:5]2[N:4]=[C:3]([CH2:2][NH:1][S:37]([CH3:36])(=[O:39])=[O:38])[NH:7][C:6]=2[CH:8]=[CH:9][CH:10]=1)=[O:35]
Reactant: COc1cc(C(=O)N2CCCCc3ccccc32)ccc1C(=O)Nc1cccc2[nH]c(CN)nc12
Reactant: CS(=O)(=O)Cl
Solvent: CCOCC
Solvent: c1ccncc1
Product: COc1cc(C(=O)N2CCCCc3ccccc32)ccc1C(=O)Nc1cccc2[nH]c(CNS(C)(=O)=O)nc12
Temperature: 25 °C
Reaction time: 4 h
Yield: 84 %

Procedure:
To an ice-bath-cooled solution of N-(2-aminomethyl-1H-benzimidazol-4-yl)-2-methoxy-4-(2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl)carbonylbenzamide (100 mg) in pyridine (5 ml) was added methanesulfonyl chloride (24.4 mg) and the solution was stirred at room temperature for 4 hours. After removing the solvent by evaporation, the product was purified by silica gel column chromatography (chloroform) to give a syrup and the syrup was solidified with ether to give 2-methoxy-N-(2-methanesulfonylaminomethyl-1H-benzimidazol-4-yl)-4-(2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl)carbonylbenzamide (98 mg).
Reaction SMILES: [O:1]=[S:2]1(=[O:17])[CH2:7][CH2:6][N:5]([CH:8]2[CH2:13][CH2:12][N:11](C(O)=O)[CH2:10][CH2:9]2)[CH2:4][CH2:3]1.Cl>ClCCl.O1CCOCC1>[NH:11]1[CH2:10][CH2:9][CH:8]([N:5]2[CH2:4][CH2:3][S:2](=[O:1])(=[O:17])[CH2:7][CH2:6]2)[CH2:13][CH2:12]1
Reactant: O=C(O)N1CCC(N2CCS(=O)(=O)CC2)CC1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: O=S1(=O)CCN(C2CCNCC2)CC1
Reaction time: 18 h

Procedure:
0.786 g of tert-butyl ester of 4-(1,1-dioxo-1lambda6-thiomorpholin-4-yl)-piperidine-1-carboxylic acid is put in 5 ml of dichloromethane. 12.3 ml of 4M hydrochloric acid in dioxane is added at room temperature. The solution is stirred for 18 h and evaporated to dryness. The product thus obtained is returned to the basic state by means of tetraalkylammonium carbonate resin at a rate of 2 g per mmol. 0.555 g of 4-piperidin-4-yl-thiomorpholine 1,1-dioxide is obtained.
Reaction SMILES: [C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:39][CH2:38][CH:37]([CH2:40][C:41](O)=[O:42])[CH2:36][CH2:35]3)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:44][CH2:45][CH3:46])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH:47]([C:50]1[CH:51]=[C:52]([CH:54]=[CH:55][CH:56]=1)[NH2:53])([CH3:49])[CH3:48]>>[C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:39][CH2:38][CH:37]([CH2:40][C:41]([NH:53][C:52]4[CH:54]=[CH:55][CH:56]=[C:50]([CH:47]([CH3:49])[CH3:48])[CH:51]=4)=[O:42])[CH2:36][CH2:35]3)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=3)([CH3:16])[N:15]=2)=[C:7]([O:44][CH2:45][CH3:46])[CH:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)c1cccc(N)c1
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(CC(=O)O)CC1
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(CC(=O)Nc2cccc(C(C)C)c2)CC1

Procedure:
In a manner analogous to the method described in example 163, {1-[(4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl]-piperidin-4-yl}-acetic acid was reacted with 3-isopropylaniline (Aldrich) to give the title product. LC-MS (ES+) 782 [(M+H)+].
Reaction SMILES: C([N:4]1[CH2:13][CH2:12][CH2:11][C:10](=[O:14])[C:9]2[C:15]([Cl:19])=[CH:16][CH:17]=[CH:18][C:8]=2[CH2:7][CH2:6][C:5]1=[O:20])(=O)C.C(=O)([O-])[O-].[K+].[K+]>CO>[Cl:19][C:15]1[C:9]2[C:10](=[O:14])[CH2:11][CH2:12][CH2:13][NH:4][C:5](=[O:20])[CH2:6][CH2:7][C:8]=2[CH:18]=[CH:17][CH:16]=1
Reactant: CC(=O)N1CCCC(=O)c2c(Cl)cccc2CCC1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: O=C1CCc2cccc(Cl)c2C(=O)CCCN1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
7.60 g of 4-acetyl-9-chloro-1,2,4,5,6,7-hexahydro-4-benzazecine-3,8-dione were dissolved in 240 ml of methanol and treated with a mixture of 36 ml of methanol and 4 ml of saturated potassium carbonate solution. The mixture was stirred at room temperature for 1 hour and thereafter the solvent was removed in vacuo. The residue was triturated in ethyl acetate. The crystallized-out 9-chloro-1,2,4,5,6,7-hexahydro-4-benzazecine-3,8-dione was filtered off and exhibited a melting point of 211°-214°. The filtrate was chromatographed on 100 g of silica gel (particle size 0.2-0.5 mm). A further portion of 9-chloro-1,2,4,5,6,7-hexahydro-4-benzazecine-3.8-dione can be isolated from the ethyl acetate eluate.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]([F:14])([F:13])[F:12])[CH:6]=1)=[O:4].[OH2:15]>C(#N)C>[F:12][C:11]([F:14])([F:13])[C:7]1[CH:6]=[C:5]([C:3](=[O:4])[CH2:2][OH:15])[CH:10]=[CH:9][CH:8]=1
Reactant: O
Reactant: O=C(CBr)c1cccc(C(F)(F)F)c1
Solvent: CC#N
Product: O=C(CO)c1cccc(C(F)(F)F)c1

Procedure:
A solution of 2-bromo-1-[3-(trifluoromethyl)phenyl]ethanone (1 g) in acetonitrile (2.5 mL) and water (10 mL) is treated under microwave irradiation (125° C., 50 min) The same experiment is repeated five times. All the vials are collected, extracted with DCM, dried over magnesium sulfate and concentrated under vacuum to give the desired compound.
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]([N:14]1[CH2:19][CH2:18][C@@H:17]([SH:20])/[C:16](=[CH:21]/[C:22]2[CH:26]=[CH:25][N:24]([CH2:27][CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])[N:23]=2)/[CH2:15]1)[C:10]([O:12][CH3:13])=[O:11].C(=O)([O-])O.[Na+]>CC(O)C.CCCCCC>[F:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C@H:9]([N:14]1[CH2:19][CH2:18][C@@H:17]([SH:20])/[C:16](=[CH:21]/[C:22]2[CH:26]=[CH:25][N:24]([CH2:27][CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])[N:23]=2)/[CH2:15]1)[C:10]([O:12][CH3:13])=[O:11]
Reactant: CCOC(=O)CCn1ccc(/C=C2\CN(C(C(=O)OC)c3ccccc3F)CC[C@H]2S)n1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Solvent: CCCCCC
Product: CCOC(=O)CCn1ccc(/C=C2\CN([C@H](C(=O)OC)c3ccccc3F)CC[C@H]2S)n1

Procedure:
(4R)-(E)-1-[(1RS)-1-(2-Fluorophenyl)-2-methoxy-2-oxoethyl]-3-({1-[2-(ethoxycarbonyl)ethyl]-1H-pyrazol-3-yl}methylidene)-4-sulfanylpiperidine hydrochloride was treated with an aqueous sodium hydrogen carbonate solution. The liberated base was extracted with dichloromethane. The free base thus obtained (ca. 200 mg) was divided into five portions and subjected to preparative HPLC (Chiralcel OD-H, 20φ×250 mm, Daicel Chemical Industries Co., Ltd., eluent: 2-propanol/hexane=1/2, 4 ml/minute) to afford the more mobile isomer, (4R)-(E)-1-[(1S)-1-(2-fluorophenyl)-2-methoxy-2-oxoethyl]-3-({1-[2-(ethoxycarbonyl)ethyl]-1H-pyrazol-3-yl}methylidene)-4-sulfanylpiperidine (103.9 mg), and the less mobile isomer, (4R)-(E)-1-[(1R)-1-(2-fluorophenyl)-2-methoxy-2-oxoethyl]-3-({1-[2-(ethoxycarbonyl)ethyl]-1H-pyrazol-3-yl}methylidene)-4-sulfanylpiperidine (100.3 mg), both as colourless oils.
Reaction SMILES: [CH3:1][NH:2][S:3]([C:6]1[CH:11]=[CH:10][C:9]([Br:12])=[CH:8][CH:7]=1)(=[O:5])=[O:4].[H-].[Na+].[CH3:15][O:16][C:17]1[CH:24]=[CH:23][C:20]([CH2:21]Cl)=[CH:19][CH:18]=1>CN(C=O)C>[CH3:1][N:2]([CH2:21][C:20]1[CH:23]=[CH:24][C:17]([O:16][CH3:15])=[CH:18][CH:19]=1)[S:3]([C:6]1[CH:11]=[CH:10][C:9]([Br:12])=[CH:8][CH:7]=1)(=[O:5])=[O:4]
Reactant: COc1ccc(CCl)cc1
Reactant: CNS(=O)(=O)c1ccc(Br)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(CN(C)S(=O)(=O)c2ccc(Br)cc2)cc1
Reaction time: 0.75 h
Yield: 97.2 %

Procedure:
To a solution of N-methyl-4-bromophenylsulfonamide (2.5 g, 10 mmol) in DMF (20 mL) at room temperature was added in portions NaH (264 rag, 11 mmol). The mixture was stirred for 45 minutes and then p-methoxybenzylchloride (1.49 mL, 11 mmol) was added dropwise. The mixture was stirred for 1 hour, quenched with water and the precipitate which formed was collected by filtration and dried in vacuo at 60° C. to afford 3.6 g (97%) of N-methyl-N-(4-methoxybenzyl)-4-bromophenylsulfonamide.
Reaction SMILES: [CH2:1]([NH:3][C:4]([N:6]1[C:14]2[C:9](=[CH:10][C:11]([O:15][C:16]3[CH:21]=[CH:20][N:19]=[C:18]([NH:22][C:23](=[O:31])OC4C=CC=CC=4)[N:17]=3)=[CH:12][CH:13]=2)[CH:8]=[CH:7]1)=[O:5])[CH3:2].C(N(CC)CC)C.Cl.[O:40]([NH2:42])[CH3:41]>O1CCCC1>[CH2:1]([NH:3][C:4]([N:6]1[C:14]2[C:9](=[CH:10][C:11]([O:15][C:16]3[CH:21]=[CH:20][N:19]=[C:18]([NH:22][C:23]([NH:42][O:40][CH3:41])=[O:31])[N:17]=3)=[CH:12][CH:13]=2)[CH:8]=[CH:7]1)=[O:5])[CH3:2]
Reactant: CON
Reactant: CCNC(=O)n1ccc2cc(Oc3ccnc(NC(=O)Oc4ccccc4)n3)ccc21
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCNC(=O)n1ccc2cc(Oc3ccnc(NC(=O)NOC)n3)ccc21
Temperature: 25 °C
Yield: 21.5 %

Procedure:
Similarly to Production example 27-2, a crude product of phenyl N-(4-(1-(ethylamino)carbonyl-1H-5-indolyl)oxy-2-pyrimidyl)carbamate (546 mg, 1.31 mmol, 56.3%) was obtained as pale brown powder from N1-ethyl-5-(2-amino-4-pyrimidyl)oxy-1H-1-indolecarboxamide (691 mg, 2.32 mmol) and phenyl chlorocarbonate. The crude carbamate product (273 mg, 0.65 mmol) was dissolved in tetrahydrofuran (7.0 ml); and triethylamine (0.91 ml, 6.53 mmol) and methoxylamine hydrochloride (273 mg, 3.27 mmol) was added thereto while stirred at room temperature. After the reaction mixture was stirred overnight, the reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with water and brine, and was dried over anhydrous sodium sulfate. The solvent was distilled off, and the residue was purified by silica gel column chromatography (eluent; ethyl acetate:hexane=1:1). The crystals were precipitated from ethyl acetate-hexane (1:10), filtered off, and dried under aeration to yield the title compound (52.5 mg, 0.14 mmol, 21.7%) as white crystals.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:13]#[N:14])=[CH:7][N:8]2[CH2:11][CH3:12])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].I[CH2:22][CH3:23]>C(C(C)=O)C.O>[CH2:22]([O:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:13]#[N:14])=[CH:7][N:8]2[CH2:11][CH3:12])=[CH:4][CH:3]=1)[CH3:23]
Reactant: CCI
Reactant: CCn1cc(C#N)c2ccc(O)cc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Solvent: O
Product: CCOc1ccc2c(C#N)cn(CC)c2c1
Reaction time: 8 h
Yield: 102 %

Procedure:
To a solution 6-hydoxy-1-ethyl-1H-indole-3-carbonitrile (80 mg, 0.43 mmol) in 5 mL of methyl ethyl ketone is added anhydrous K2CO3 (71 mg, 0.52 mmol) and iodoethane (0.05 mL, 0.60 mmol). After stirring overnight at reflux, the reaction mixture is cooled, diluted with H2O and extracted with EtOAc (3×). The combined organic phases are dried and concentrated. Flash chromatography (CH2Cl2) gives 94 mg (100%) of 6-ethoxy-1-ethyl-1H-indole-3-carbonitrile as a white wax.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11]P(=O)(OCC)OCC.[Li]CCCC.[CH:25]([C:27]1[N:28]=[C:29]2[C:34]([N:35]3[CH2:40][CH2:39][O:38][CH2:37][CH2:36]3)=[CH:33][CH:32]=[N:31][N:30]2[C:41]=1[C:42]1[CH:54]=[CH:53][C:45]([C:46]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:47])=[CH:44][CH:43]=1)=O.[NH4+].[Cl-]>C1COCC1.O>[O:38]1[CH2:37][CH2:36][N:35]([C:34]2[C:29]3[N:30]([C:41]([C:42]4[CH:54]=[CH:53][C:45]([C:46]([O:48][C:49]([CH3:50])([CH3:51])[CH3:52])=[O:47])=[CH:44][CH:43]=4)=[C:27](/[CH:25]=[CH:11]/[C:2]4[CH:3]=[CH:4][C:5]5[CH2:6][CH2:7][CH2:8][CH2:9][C:10]=5[N:1]=4)[N:28]=3)[N:31]=[CH:32][CH:33]=2)[CH2:40][CH2:39]1
Reactant: CC(C)(C)OC(=O)c1ccc(-c2c(C=O)nc3c(N4CCOCC4)ccnn23)cc1
Reactant: CCOP(=O)(Cc1ccc2ccccc2n1)OCC
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)c1ccc(-c2c(/C=C/c3ccc4c(n3)CCCC4)nc3c(N4CCOCC4)ccnn23)cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of compound 58a (125 mg, 0.441 mmol) in 2.5 mL of THF at RT was added n-BuLi (275 μL, 0.441 mmol, 1.6M in hexane) dropwise. After stirring at rt for 15 min, the mixture was added slowly to a suspension of compound 5f (150 mg, 0.367 mmol) in 2.5 mL of THF. The resulting mixture was stirred at rt for 30 min, then 2 mL of saturated NH4Cl was added. The mixture was diluted with 10 mL of water, then extracted with EtOAc (2×20 mL). The combined organic layers were washed with brine (15 mL) and dried with Na2SO4, filtered and concentrated. The solvent was removed in vacuo and the residue was purified by flash column chromatography on silica gel (0:1-1:4 EtOAc/DCM) to afford compound 60a as a pale yellow solid. 1H-NMR (CDCl3; 400 MHz) δ 8.16 (d, J=8.1 Hz, 2H), 7.98 (d, J=5.6 Hz, 1H), 7.79 (d, J=8.6 Hz, 2H), 7.73 (d, J=15.7 Hz, 1H), 7.50-7.58 (m, 1H), 7.29-7.35 (m, 1H), 7.21-7.26 (m, 1H), 6.11 (d, J=5.6 Hz, 1H), 4.02-4.09 (m, 4H), 3.93-4.02 (m, 4H), 2.93 (t, J=6.3 Hz, 2H), 2.77 (t, J=6.1 Hz, 2H), 1.86-1.95 (m, 2H), 1.77-1.86 (m, 2H), 1.63 (s, 9H). Mass spectrum (ESI, m/z): Calcd. for C32H35N5O3, 538.1 (M+H). found 538.0.
Reaction SMILES: [NH2:1][CH:2]([C:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=[CH:12][C:11]=1[O:20][CH3:21])[CH2:3][CH2:4][CH2:5][C:6]([O:8]C)=O.[N:22]1[CH:27]=[CH:26][CH:25]=[N:24][C:23]=1[C:28]1[CH:29]=[C:30]([CH:33]=[CH:34][CH:35]=1)[CH:31]=O>>[CH3:21][O:20][C:11]1[CH:12]=[CH:13][C:14]2[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:10]=1[CH:2]1[N:1]([CH2:31][C:30]2[CH:33]=[CH:34][CH:35]=[C:28]([C:23]3[N:22]=[CH:27][CH:26]=[CH:25][N:24]=3)[CH:29]=2)[C:6](=[O:8])[CH2:5][CH2:4][CH2:3]1
Reactant: COC(=O)CCCC(N)c1c(OC)ccc2ccccc12
Reactant: O=Cc1cccc(-c2ncccn2)c1
Product: COc1ccc2ccccc2c1C1CCCC(=O)N1Cc1cccc(-c2ncccn2)c1

Procedure:
Prepared according to general procedure 1 (GP1) using methyl 5-amino-5-(2-methoxynaphthalen-1-yl)pentanoate and commercially available 3-(pyrimidin-2-yl)benzaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.84 min.; [M+H]+: 424.10 g/mol.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][N:6]2[C@@H:11]1[O:28][C@H:27]([CH2:29][O:30][C:31](=[O:33])[CH3:32])[C@@H:22]([O:23][C:24](=[O:26])[CH3:25])[C@H:17]([O:18][C:19](=[O:21])[CH3:20])[C@H:12]1[O:13][C:14](=[O:16])[CH3:15].[CH2:34]([O:36][C:37]1[CH:45]=[CH:44][C:40]([C:41](Cl)=[O:42])=[CH:39][CH:38]=1)[CH3:35]>>[CH2:34]([O:36][C:37]1[CH:45]=[CH:44][C:40]([C:41]([C:4]2[C:3]3[C:7](=[CH:8][CH:9]=[CH:10][C:2]=3[Cl:1])[N:6]([C@@H:11]3[O:28][C@H:27]([CH2:29][O:30][C:31](=[O:33])[CH3:32])[C@@H:22]([O:23][C:24](=[O:26])[CH3:25])[C@H:17]([O:18][C:19](=[O:21])[CH3:20])[C@H:12]3[O:13][C:14](=[O:16])[CH3:15])[CH:5]=2)=[O:42])=[CH:39][CH:38]=1)[CH3:35]
Reactant: CC(=O)OC[C@H]1O[C@@H](n2ccc3c(Cl)cccc32)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: CCOc1ccc(C(=O)Cl)cc1
Product: CCOc1ccc(C(=O)c2cn([C@@H]3O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]3OC(C)=O)c3cccc(Cl)c23)cc1

Procedure:
4-Chloro-1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-indole obtained in Example 1-(3) and 4-ethoxybenzoyl chloride were treated in a manner similar to Example 2-(4) to give 4-chloro-1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-indol-3-yl 4-ethoxyphenyl ketone as a colorless powder. APCI-Mass m/Z 630/632 (M+H). 1H-NMR (DMSO-d6) δ 1.37 (t, J=7.0 Hz, 3H), 1.69 (s, 3H), 1.98 (s, 6H), 2.04 (s, 3H), 4.11-4.12 (m, 2H), 4.14 (q, J=7.3 Hz, 2H), 4.28-4.32 (m, 1H), 5.29 (t, J=9.7 HZ, 1H), 5.54 (t, J=9.5 Hz, 1H), 5.71 (t, J=9.2 Hz, 1H), 6.32 (d, J=9.0 Hz, 1H), 7.04 (d, J=8.8 Hz, 2H), 7.25 (d, J=7.5 Hz, 1H), 7.35 (t, J=8.0 Hz, 1H), 7.79 (d, 1H), 7.99 (d, J=8.8 Hz, 2H), 8.07 (s, 1H).
Reaction SMILES: [Na].[C:2]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])(=[O:7])[CH2:3][C:4]([CH3:6])=[O:5].Br[CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C(O)C>[C:16]1([CH2:15][CH2:14][CH:3]([C:4](=[O:5])[CH3:6])[C:2]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: BrCCc1ccccc1
Reactant: CC(=O)CC(=O)OC(C)(C)C
Agent: [Na]
Solvent: CCO
Product: CC(=O)C(CCc1ccccc1)C(=O)OC(C)(C)C
Reaction time: 0.17 h

Procedure:
Sodium (2.3 g; 0.10 mol) was allowed to react with dry ethanol (50 ml) under nitrogen. The resulting clear solution was cooled (ice bath) and t-butyl acetoacetate (15.8 g; 0.10 mol) was added during 10 minutes with stirring. After 10 minutes, 2-(bromoethyl)benzene (18.5 g; 0.10 mol) was added during 30 minutes. The resulting solution was heated at reflux for 4 hours, then cooled and filtered. After concentration, the residue was partitioned between water and ether, and the ether layer was dried (MgSO4) and concentrated. Distillation of the residue gave 21.0 g (0.080 mol; 80%) of the title product; bp 110°-120° (0.3 mm). NMR (CDCL3); 1.45 (9H,s), 2.17 (3H,s), 1.8-2.4 (2H,m), 2.5-2.7 (2H,m); 3.28 (1H,J=7); 7.2-7.4 (5H, broad s). MS (m/e); 262 (M+).
Reaction SMILES: [CH2:1]([Mg]Br)[CH3:2].[CH3:5][C:6]1([CH3:26])[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:16]#[C:17][C:18]3[CH:23]=[CH:22][C:21]([CH:24]=[O:25])=[CH:20][N:19]=3)[CH:14]=2)[O:9][CH2:8][CH2:7]1>CCOCC>[CH3:5][C:6]1([CH3:26])[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:16]#[C:17][C:18]3[CH:23]=[CH:22][C:21]([CH:24]([OH:25])[CH2:1][CH3:2])=[CH:20][N:19]=3)[CH:14]=2)[O:9][CH2:8][CH2:7]1
Reactant: CC[Mg]Br
Reactant: CC1(C)CCOc2ccc(C#Cc3ccc(C=O)cn3)cc21
Solvent: CCOCC
Product: CCC(O)c1ccc(C#Cc2ccc3c(c2)C(C)(C)CCO3)nc1
Reaction time: 1 h

Procedure:
Four ml of a 3M (12 mmol) solution of ethylmagnesium bromide in ether is placed in a 3-necked flask fitted with a mechanical stirrer, a reflux condenser protected by a drying tube and a pressure-equalizing dropping funnel protected by a drying tube. The flask is cooled in an ice bath and a solution of 2.8 g (10 mmol) of 2-(2-(4,4-Dimethylchroman-6-yl)ethynyl)pyridine-5-carboxaldehyde in 10 ml of dry ether is added slowly with vigorous stirring. The cooling bath is then removed and the mixture heated at reflux for 3 hours. The mixture is then cooled in an ice-salt bath and 5 ml of saturated ammonium chloride solution added. The mixture is stirred for a further 1 hour and then filtered and the residue washed with two 10 ml portions of ether. The ether solution is then separated, dried (MgSO4) and the ether removed in vacuo. The residue is then purified by chromatography followed by recrystallization to give the title compound.
Reaction SMILES: [F:1][C:2]1[C:3](F)=[C:4]2[O:9][CH2:8][CH:7]([CH3:10])[N:6]3[CH:11]=[C:12]([C:17]([OH:19])=[O:18])[C:13](=[O:16])[C:14]([CH:15]=1)=[C:5]23.[OH:21][C:22]([P:34]([O:39][O:40][CH3:41])([O:36][O:37][CH3:38])=[O:35])([P:26]([O:31][O:32][CH3:33])([O:28][O:29][CH3:30])=[O:27])[CH2:23][CH2:24][NH2:25]>>[F:1][C:2]1[C:3]([NH:25][CH2:24][CH2:23][C:22]([OH:21])([P:26]([O:28][O:29][CH3:30])([O:31][O:32][CH3:33])=[O:27])[P:34]([O:36][O:37][CH3:38])([O:39][O:40][CH3:41])=[O:35])=[C:4]2[O:9][CH2:8][CH:7]([CH3:10])[N:6]3[CH:11]=[C:12]([C:17]([OH:19])=[O:18])[C:13](=[O:16])[C:14]([CH:15]=1)=[C:5]23
Reactant: CC1COc2c(F)c(F)cc3c(=O)c(C(=O)O)cn1c23
Reactant: COOP(=O)(OOC)C(O)(CCN)P(=O)(OOC)OOC
Product: COOP(=O)(OOC)C(O)(CCNc1c(F)cc2c(=O)c(C(=O)O)cn3c2c1OCC3C)P(=O)(OOC)OOC

Procedure:
9,10-Difluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido[1,2,3-de][1,4]benzoxazine-6-carboxylic acid, prepared according to the procedure of example 1 of U.S. Pat. No. 4,382,892, is reacted with 3-hydroxy-3,3-bis(dimethoxyphosphono)-1-propylamine and a quantity of base sufficient to neutralize the acid groups of both reactants and the acid formed in the reaction, thus yielding 9-fluoro-3-methyl-10-[3-hydroxy-3,3-bis(dimethoxyphosphono)-1-propylamino]-7-oxo-2,3-dihydro-7H-pyrido[1,2,3-de](1,4]benzoxazine-6-carboxylic acid.
Reaction SMILES: [CH3:1][N:2]([CH3:25])[S:3]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([NH2:18])=[C:14]([C:19]3[CH2:24][CH2:23][CH2:22][CH2:21][CH:20]=3)[CH:13]=2)=[CH:8][CH:7]=1)(=[O:5])=[O:4].[K+].[C:27]([C:29]1[N:30]=[C:31]([C:42]([O-])=[O:43])[N:32]([CH2:34][O:35][CH2:36][CH2:37][Si:38]([CH3:41])([CH3:40])[CH3:39])[CH:33]=1)#[N:28].C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>>[C:19]1([C:14]2[CH:13]=[C:12]([C:9]3[CH:8]=[CH:7][C:6]([S:3](=[O:4])(=[O:5])[N:2]([CH3:25])[CH3:1])=[CH:11][CH:10]=3)[CH:17]=[CH:16][C:15]=2[NH:18][C:42]([C:31]2[N:32]([CH2:34][O:35][CH2:36][CH2:37][Si:38]([CH3:41])([CH3:40])[CH3:39])[CH:33]=[C:29]([C:27]#[N:28])[N:30]=2)=[O:43])[CH2:24][CH2:23][CH2:22][CH2:21][CH:20]=1
Reactant: CN(C)S(=O)(=O)c1ccc(-c2ccc(N)c(C3=CCCCC3)c2)cc1
Reactant: C[Si](C)(C)CCOCn1cc(C#N)nc1C(=O)[O-]
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Agent: [K+]
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)S(=O)(=O)c1ccc(-c2ccc(NC(=O)c3nc(C#N)cn3COCC[Si](C)(C)C)c(C3=CCCCC3)c2)cc1

Procedure:
The title compound was prepared from 4′-amino-3′-cyclohex-1-enyl-biphenyl-4-sulfonic acid dimethylamide (as prepared in the previous step, 64 mg, 0.17 mmol), potassium 4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylate (as prepared in Example 11, step (d), 60 mg, 0.19 mmol), PyBroP (117 mg, 0.350 mmol) and DIEA (69 μL, 0.39 mmol) according to the procedure in Example 11, step (f) (84 mg, 70%). Mass spectrum (ESI, m/z): Calcd. for C31H39N5O4SSi, 606.2 (M+H), found 605.9.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Br[C:8]1[S:9][CH:10]=[CH:11][N:12]=1.[C:13]([O:17][C:18](=[O:26])[NH:19][CH:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1)([CH3:16])([CH3:15])[CH3:14]>CN(C=O)C>[C:13]([O:17][C:18](=[O:26])[NH:19][CH:20]1[CH2:25][CH2:24][N:23]([C:8]2[S:9][CH:10]=[CH:11][N:12]=2)[CH2:22][CH2:21]1)([CH3:16])([CH3:14])[CH3:15]
Reactant: Brc1nccs1
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NC1CCN(c2nccs2)CC1
Temperature: 120 °C
Yield: 26.7 %

Procedure:
6.91 g (75.0 mmol) potassium carbonate was added to a solution of 1.35 ml (15.0 mmol) 2-bromothiazole and 3.00 g (15.0 mmol) piperidin-4-yl-carbamic acid-tert-butyl ester in DMF (50 ml) and heated to 120° C. for 8 h. Subsequently, the solvent was removed in vacuo and the residue taken up by chloroform. This solution was washed with water and brine in turn, dried over MgSO4, filtered and concentrated in vacuo. Column chromatography (SiO2, chloroform) was carried out on the residue, yielding 1.14 g (4.0 mmol, 27%) (1-thiazol-2-yl-piperidin-4-yl)-carbamic acid-tert-butyl ester.
Reaction SMILES: CON(C)[C:4]([C:6]1[C:7]([NH2:15])=[N:8][C:9]([S:12][CH2:13][CH3:14])=[N:10][CH:11]=1)=[O:5].[F:17][C:18]1[CH:23]=[CH:22][C:21]([Mg]Br)=[CH:20][CH:19]=1>>[NH2:15][C:7]1[C:6]([C:4]([C:21]2[CH:22]=[CH:23][C:18]([F:17])=[CH:19][CH:20]=2)=[O:5])=[CH:11][N:10]=[C:9]([S:12][CH2:13][CH3:14])[N:8]=1
Reactant: CCSc1ncc(C(=O)N(C)OC)c(N)n1
Reactant: Fc1ccc([Mg]Br)cc1
Product: CCSc1ncc(C(=O)c2ccc(F)cc2)c(N)n1

Procedure:
The same procedure as described in Example 353 was used, starting from 4-amino-2-ethylsulfanyl-pyrimidine-5-carboxylic acid methoxy-methyl-amide (Example 1) and 4-fluorophenyl magnesium bromide (Aldrich) to give (4-amino-2-ethylsulfanyl-pyrimidin-5-yl)-(4-fluoro-phenyl)-methanone. MS (M+H)+, 278.
Reaction SMILES: S(Cl)([Cl:3])=O.O[CH2:6][C:7]#[C:8][CH2:9][NH:10][C:11](=[O:26])[C:12]([OH:25])([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>CN(C)C=O.C(Cl)(Cl)Cl>[Cl:3][CH2:6][C:7]#[C:8][CH2:9][NH:10][C:11](=[O:26])[C:12]([OH:25])([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C(NCC#CCO)C(O)(c1ccccc1)c1ccccc1
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: O=C(NCC#CCCl)C(O)(c1ccccc1)c1ccccc1
Temperature: 40 °C
Reaction time: 1 h

Procedure:
Thionyl chloride (0.81 ml) was added to a solution of N-(4-hydroxy-2-butynyl)-2-hydroxy-2,2-diphenylacetamide (3.32 g) and N,N-dimethylformamide (6 drops) in chloroform (20 ml) at room temperature. The mixture was stirred at 40° C. for 1 hour, washed with water, dried over magnesium sulfate, and evaporated in vacuo. The residue was purified by column chromatography on silica gel with a mixture of chloroform and ethyl acetate (5:1) as an eluent to give N-(4-chloro-2-butynyl) -2-hydroxy-2,2-diphenylacetamide (4.12 g) as oil.