Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O)(C(F)(F)F)=O.[CH3:8][N:9]1[CH:13]=[C:12]([C:14]2[CH:15]=[CH:16][C:17]([C:20]([O:22]C(C)(C)C)=[O:21])=[N:18][CH:19]=2)[CH:11]=[N:10]1>ClCCl>[CH3:8][N:9]1[CH:13]=[C:12]([C:14]2[CH:15]=[CH:16][C:17]([C:20]([OH:22])=[O:21])=[N:18][CH:19]=2)[CH:11]=[N:10]1
Reactant: Cn1cc(-c2ccc(C(=O)OC(C)(C)C)nc2)cn1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cn1cc(-c2ccc(C(=O)O)nc2)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 267.8 %

Procedure:
TFA (1 mL) was added to a solution of tert-butyl 5-(1-methyl-1H-pyrazol-4-yl)-pyridine-2-carboxylate (81 mg) in dichloromethane (4 mL), and the mixture was stirred at room temperature overnight. The solvent was evaporated under reduced pressure to obtain a crude product of the title compound (170 mg).
Reaction SMILES: [CH:1]1([C:7]2[C:8]3[S:20][C:19]([C:21]([O:23][CH3:24])=[O:22])=[CH:18][C:9]=3[NH:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].[CH3:27][O:28][CH2:29]Cl>CN(C=O)C>[CH:1]1([C:7]2[C:8]3[S:20][C:19]([C:21]([O:23][CH3:24])=[O:22])=[CH:18][C:9]=3[N:10]([CH2:27][O:28][CH3:29])[C:11]=2[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COC(=O)c1cc2[nH]c(-c3ccccc3)c(C3CCCCC3)c2s1
Reactant: COCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCn1c(-c2ccccc2)c(C2CCCCC2)c2sc(C(=O)OC)cc21
Temperature: 0 °C
Reaction time: 1 h
Yield: 92 %

Procedure:
A solution (0.25 M) of methyl 6-cyclohexyl-5-phenyl-4H-thieno[3,2-b]pyrrole-2-carboxylate in DMF at 0° C. was treated with NaH (1.5 eq., 60% dispersion in mineral oil), and the suspension was stirred at 0° C. for 60 min then it was treated with chloromethyl methyl ether (5 eq.). The mixture was stirred at RT for 2 h then it was quenched with ice/water and extracted with AcOEt. The combined organic phase was washed with brine and dried. Evaporation of the solvent under reduced pressure gave a residue that was purified by flash chromatography on silica gel (1:12 acetone/toluene) to afford the title compound (92%) as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]=[CH:9][C:10]1[NH:11][C:12]2[C:17]([CH:18]=1)=[CH:16][C:15]([O:19][CH3:20])=[CH:14][CH:13]=2.OC1C=CC2[NH:31][C:30]3C=C(C4C=C([N+]([O-])=O)C=CC=4O)C4C(=O)NC(=O)C=4[C:25]=3[C:24]=2C=1.C(#N)C=C>C(#N)C.N12CCCN=C1CCCCC2.O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1/[CH:8]=[CH:9]/[C:10]1[N:11]([CH2:24][CH2:25][C:30]#[N:31])[C:12]2[C:17]([CH:18]=1)=[CH:16][C:15]([O:19][CH3:20])=[CH:14][CH:13]=2
Reactant: COc1ccc2[nH]c(C=Cc3ccccc3Cl)cc2c1
Reactant: O=C1NC(=O)c2c1c(-c1cc([N+](=O)[O-])ccc1O)cc1[nH]c3ccc(O)cc3c21
Solvent: O
Solvent: CC#N
Solvent: C=CC#N
Product: COc1ccc2c(c1)cc(/C=C/c1ccccc1Cl)n2CCC#N
Temperature: 25 °C
Reaction time: 18 h
Yield: 77 %

Procedure:
To a solution of trans-diene (27) prepared as described in example 37 (1.5 g, 5.25 mmol) in acetonitrile (30 mL) was added acrylonitrile (2.42 mL, 36.8 mmol) and 1,8-diazabicyclo[5,4,0]undec-7-ene (20 drops). The resulting solution was stirred at room temperature under nitrogen for 18 h before being diluted with water and extracted with ethyl acetate. The organic layer was dried, the drying agent was removed and the solution was concentrated to dryness. Chromatography on silica eluting with ethyl acetate/hexane (1:1), followed by trituration from methanol gave the diene (236) (1.36 g, 77%) as an off-white solid, mp 136–138° C. 1H NMR δ [(CD3)2SO] 8.05 (dd, J=7.9, 1.5 Hz, 1H), 7.50 (m, 4H), 7.41 (m, 1H), 7.33 (m, 1H), 7.04 (d, J=2.4 Hz, 1H), 6.90 (s, 1H), 6.81 (dd, J=9.0, 2.4 Hz, 1H), 4.68 (t, J=6.6 Hz, 2H), 3.77 (s, 3H), 2.93 (t, J=6.6 Hz, 2H). Found: C, 71.32; H, 5.14; N, 8.51. C20H17ClN2O requires: C, 71.31; H, 5.09; N, 8.31.
Reaction SMILES: [NH2:1][C:2]1[C:7]([O:8][CH2:9][C:10]2[C:15]([F:16])=[CH:14][CH:13]=[CH:12][C:11]=2[Cl:17])=[CH:6][CH:5]=[C:4]([CH3:18])[N:3]=1.[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([N:26]=[C:27]=[S:28])=[CH:22][CH:21]=1.C1(C)C=CC=CC=1>CCOCC>[Cl:17][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]([F:16])[C:10]=1[CH2:9][O:8][C:7]1[C:2]([NH:1][C:27]([NH:26][C:23]2[CH:24]=[CH:25][C:20]([Cl:19])=[CH:21][CH:22]=2)=[S:28])=[N:3][C:4]([CH3:18])=[CH:5][CH:6]=1
Reactant: S=C=Nc1ccc(Cl)cc1
Reactant: Cc1ccc(OCc2c(F)cccc2Cl)c(N)n1
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: Cc1ccc(OCc2c(F)cccc2Cl)c(NC(=S)Nc2ccc(Cl)cc2)n1

Procedure:
A mixture of 2-amino-3-(2-chloro-6-fluorobenzyloxy)-6-methylpyridine (2.0 g, 0.0075 mol), 4-chlorophenyl isothiocyanate (1.53 g, 0.0089 mol) and toluene (10 ml) was heated under reflux for 2 hours, then cooled and diluted with ether to induce crystallisation of the product, which was triturated with ethanol. Yield 2.6 g (82%), m.p. 204°-205 ° C.
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.[CH:11]([N:14]1[C:18]([C:19]([F:22])([F:21])[F:20])=[C:17]([C:23](OCC)=[O:24])[CH:16]=[N:15]1)([CH3:13])[CH3:12].Cl>C1(C)C=CC=CC=1>[CH:11]([N:14]1[C:18]([C:19]([F:21])([F:20])[F:22])=[C:17]([CH2:23][OH:24])[CH:16]=[N:15]1)([CH3:13])[CH3:12]
Reactant: CCOC(=O)c1cnn(C(C)C)c1C(F)(F)F
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: Cc1ccccc1
Product: CC(C)n1ncc(CO)c1C(F)(F)F
Temperature: -78 °C
Reaction time: 2 h
Yield: 105.1 %

Procedure:
Diisobutylaluminium hydride (99 mL, 120 mmol, 1.2 M solution in toluene) was added to ethyl 1-isopropyl-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate (WO 2007071900, 12 g, 48 mmol) in toluene (220 mL) at −78° C. The reaction mixture was stirred at −78° C. for 2 hours then poured into aqueous HCl (100 mL, 2M). The mixture was stirred for 4 hours at room temperature then extracted with EtOAc (400 mL). The organic phase was washed with water (200 mL), brine (200 mL) and dried over sodium sulphate. The filtrate was evaporated in vacuo to afford the title compound as a colourless oil (100%, 10.5 g).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[C@H:4]([CH2:23][CH2:24][S:25][CH3:26])[NH:5][C:6](=[O:22])[C:7]1[CH:12]=[CH:11][C:10]([CH:13]=O)=[CH:9][C:8]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[CH3:21].[NH2:28][CH2:29][CH2:30][N:31]1[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1>>[CH3:1][O:2][C:3](=[O:27])[C@H:4]([CH2:23][CH2:24][S:25][CH3:26])[NH:5][C:6](=[O:22])[C:7]1[CH:12]=[CH:11][C:10]([CH2:13][NH:28][CH2:29][CH2:30][N:31]2[CH2:36][CH2:35][O:34][CH2:33][CH2:32]2)=[CH:9][C:8]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[CH3:21]
Reactant: NCCN1CCOCC1
Reactant: COC(=O)[C@H](CCSC)NC(=O)c1ccc(C=O)cc1-c1ccccc1C
Product: COC(=O)[C@H](CCSC)NC(=O)c1ccc(CNCCN2CCOCC2)cc1-c1ccccc1C

Procedure:
The desired compound was prepared using the method described in Example 403H starting with N-[4-formyl-2-(2-methylphenyl)benzoyl]methionine methyl ester, prepared as in Example 403G, and 4-(2-aminoethyl)morpholine. m/e (ESI) 500 (MH+)
Reaction SMILES: [CH2:1]([N:8]([CH3:17])[C:9]1[C:14]([F:15])=[CH:13][NH:12][C:11](=[O:16])[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[S:18]1[CH:22]=[CH:21][CH:20]=[C:19]1[C:23](Cl)=[O:24].CCN(CC)CC>C(Cl)Cl>[CH2:1]([N:8]([CH3:17])[C:9]1[C:14]([F:15])=[CH:13][N:12]([C:23]([C:19]2[S:18][CH:22]=[CH:21][CH:20]=2)=[O:24])[C:11](=[O:16])[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1cccs1
Reactant: CN(Cc1ccccc1)c1nc(=O)[nH]cc1F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(Cc1ccccc1)c1nc(=O)n(C(=O)c2cccs2)cc1F
Temperature: 25 °C
Reaction time: 12 h
Yield: 6.3 %

Procedure:
To a round-bottomed flask charged with 4-(benzyl(methyl)amino)-5-fluoropyrimidin-2(1H)-one (250 mg, 1.06 mmol) in CH2Cl2 (11 mL) and 2-thiophene carbonyl chloride (172 mg, 1.1 mmol, 1.1 eq) was added Et3N (237 mg, 2.35 mmol) at 0° C. under N2. The reaction mixture was warmed to room temperature after complete addition and stirred at for 12 h. The reaction mixture was diluted with CH2Cl2 (25 mL), washed with satd aq NaCl solution (10 mL), dried over Na2SO4 and evaporated to dryness in vacuo at room temperature. The crude product was purified by reverse phase chromatography to yield the product as a white solid (23 mg, 6%): mp 101.3-102.4° C.; 1H NMR (methanol-d4) δ 8.10 (d, J=6.3 Hz, 1H), 8.00 (d, J=3.8 Hz, 1H), 7.91 (d, J=4.9 Hz, 1H), 7.38-7.20 (m, 6H), 4.88 (s, 2H), 3.22 (d, J=3.2 Hz, 3H); ESIMS m/z 344 ([M+H]+).
Reaction SMILES: ClC1C=C(N2C3N=CC=CC=3C(=O)C3CSCCC2=3)C=CC=1.ClC1C=C(N2C3N=CC=CC=3C(=O)C3SCCC2=3)C=CC=1.Cl[C:45]1[CH:46]=[C:47]([N:51]2[C:60]3[N:59]=[CH:58][CH:57]=[CH:56][C:55]=3[C:54](=[O:61])[C:53]3[CH2:62]S(=O)[CH2:64][CH2:65][C:52]2=3)[CH:48]=[CH:49][CH:50]=1.ClC1C=C(N2C3N=CC=CC=3C(=O)C3S(=O)CCC2=3)C=CC=1.ClC1C=C(N2C3N=CC=CC=3C(=O)C3[CH2:107][S:108](=[O:112])(=[O:111])CCC2=3)C=CC=1.ClC1C=C(N2C3N=CC=CC=3C(=O)C3S(=O)(=O)CCC2=3)C=CC=1>>[CH3:107][S:108]([C:45]1[CH:46]=[C:47]([N:51]2[C:60]3[N:59]=[CH:58][CH:57]=[CH:56][C:55]=3[C:54](=[O:61])[C:53]3[CH2:62][CH2:64][CH2:65][C:52]2=3)[CH:48]=[CH:49][CH:50]=1)(=[O:112])=[O:111]
Reactant: O=c1c2c(n(-c3cccc(Cl)c3)c3ncccc13)CCS(=O)(=O)C2
Reactant: O=c1c2c(n(-c3cccc(Cl)c3)c3ncccc13)CCS(=O)C2
Agent: O=c1c2c(n(-c3cccc(Cl)c3)c3ncccc13)CCS2
Agent: O=c1c2c(n(-c3cccc(Cl)c3)c3ncccc13)CCS2(=O)=O
Agent: O=c1c2c(n(-c3cccc(Cl)c3)c3ncccc13)CCS2=O
Product: CS(=O)(=O)c1cccc(-n2c3c(c(=O)c4cccnc42)CCC3)c1

Procedure:
By basically the same reaction but employing two equivalents of the peracid oxidant at 25° C. for 50 hrs., the corresponding sulfone, 6,7,8,9-tetrahydro-9-(3-methylsulfonylphenyl)-5H-cyclopenta[b] [1,8]naphthyridin-5-one is prepared, m.p. 271°-273°, after crystallization from CH3CN. Similarly, starting with 10-(3-chlorophenyl)-6,8,9,10-tetrahydro-5H-thiopyrano[4,3-b] [1,8]naphthyridin-5-one or 4-(3-chlorophenyl)-2,3,4,9-tetrahydrothieno[3,2-b] [1,8]naphthyridin-9-one and one equivalent of the peracid oxidant, the sulfoxides, 10-(3-chlorophenyl)-6,8,9,10-tetrahydro-5H-thiopyrano[4,3-b] [1,8]naphthyridin-5-one-7-oxide (m.p. 211°-212° C. after crystallization from CH3CN/CH3COOC2H5) or 4-(3-chlorophenyl)-2,3,4,9-tetrahydrothieno[3,2-b] [1,8]naphthyridin-9-one-1-oxide (m.p. 266°-267° C. after crystallization form CH3CN), respectively, are prepared. By employing two equivalents of the peracid oxidant, the corresponding dioxides are prepared; i.e., 10-(3-chlorophenyl)-6,8,9,10-tetrahydro-5H-thiopyrano[4,3-b] [1,8]naphthyridin-5-one-7,7-dioxide (m.p. 249°-250° C. after crystallization from CH3CN/pet. ether) and 4-(3-chlorophenyl)-2,3,4,9-tetrahydrothieno[3,2-b] [1,8]naphthyridin-9-one-1,1-dioxide (m.p. 277°-278° C. after crystallization from CHCl3 --CH3CN).
Reaction SMILES: [C:1]([C:3]1([NH:6][C:7]([C@@H:9]2[CH2:13][C@@H:12]([S:14]([C:17]3[CH:22]=[CH:21][C:20](F)=[CH:19][C:18]=3[Cl:24])(=[O:16])=[O:15])[CH2:11][N:10]2[C:25]2[N:26]([CH:31]3[CH2:34][CH2:33][CH2:32]3)[N:27]=[C:28]([CH3:30])[CH:29]=2)=[O:8])[CH2:5][CH2:4]1)#[N:2].[CH3:35][O:36][CH2:37][CH2:38][OH:39]>>[C:1]([C:3]1([NH:6][C:7]([C@@H:9]2[CH2:13][C@@H:12]([S:14]([C:17]3[CH:22]=[CH:21][C:20]([O:39][CH2:38][CH2:37][O:36][CH3:35])=[CH:19][C:18]=3[Cl:24])(=[O:16])=[O:15])[CH2:11][N:10]2[C:25]2[N:26]([CH:31]3[CH2:34][CH2:33][CH2:32]3)[N:27]=[C:28]([CH3:30])[CH:29]=2)=[O:8])[CH2:5][CH2:4]1)#[N:2]
Reactant: COCCO
Reactant: Cc1cc(N2C[C@H](S(=O)(=O)c3ccc(F)cc3Cl)C[C@H]2C(=O)NC2(C#N)CC2)n(C2CCC2)n1
Product: COCCOc1ccc(S(=O)(=O)[C@@H]2C[C@@H](C(=O)NC3(C#N)CC3)N(c3cc(C)nn3C3CCC3)C2)c(Cl)c1

Procedure:
In analogy to the procedure described in example 392, (2S,4R)-4-(2-chloro-4-fluoro-benzenesulfonyl)-1-(2-cyclobutyl-5-methyl-2H-pyrazol-3-yl)-pyrrolidine-2-carboxylic acid (1-cyano-cyclopropyl)-amide (example 385b) was reacted with 2-methoxyethanol (CAS Reg. No. 109-86-4) to give the title compound as colorless oil. MS (ESI): m/z=562.2 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH2:11])=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([NH2:9])=[O:8].Cl[CH2:13][C:14](=O)[CH3:15].C(=O)(O)[O-].[Na+].[CH3:22][S:23]([OH:26])(=[O:25])=[O:24]>CN(C)C=O>[S:23]([OH:26])(=[O:25])(=[O:24])[CH3:22].[NH2:1][C:2]1[C:3]2[N:4]([CH:13]=[C:14]([CH3:15])[N:11]=2)[CH:5]=[C:6]([C:7]([NH2:9])=[O:8])[CH:10]=1
Reactant: NC(=O)c1cnc(N)c(N)c1
Reactant: CC(=O)CCl
Agent: CS(=O)(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cn2cc(C(N)=O)cc(N)c2n1
Temperature: 25 °C
Reaction time: 72 h
Yield: 33.3 %

Procedure:
5,6-diaminonicotinamide (10 g, 66 mmol), chloroacetone (6.1 g, 66 mmol) and sodium bicarbonate (11.2 g, 132 mmol) were added to dimethylformamide (200 ml) and the mixture was stirred for 72 h. at room temperature. Most of the solvent was evaporated under reduced pressure and methanesulfonic acid (6 g, 63 mmol) was added. More solvent was evaporated under reduced pressure and ethanol was added to the residue. Upon warming the mixture to 60° C. the product crysstallized as salt and was filtred off to give 6 g (32%) of the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]1.[CH3:18][O:19][CH2:20][C:21](Cl)=[O:22]>>[CH3:18][O:19][CH2:20][C:21]([NH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]1)=[O:22]
Reactant: COCC(=O)Cl
Reactant: CN1CCC(c2c[nH]c3ccc(N)cc23)CC1
Product: COCC(=O)Nc1ccc2[nH]cc(C3CCN(C)CC3)c2c1
Yield: 84.1 %

Procedure:
Beginning with 13 mg (0.056 mMol) 5-amino-3-(1-methylpiperidin-4-yl)-1H-indole and 6.5 mg (0.059 mMol) methoxyacetyl chloride, 14.2 mg (84%) of the title compound were recovered.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[CH:10][C:9]2[N:8]([CH2:12][C:13]([CH3:22])([O:15][CH:16]3[CH2:21][CH2:20][CH2:19][CH2:18][O:17]3)[CH3:14])[C:7](=[O:23])[CH:6]3[CH2:24][O:25][CH2:26][CH2:27][N:5]3[C:4]=2[N:3]=1.IC.[CH3:30]C([O-])(C)C.[Na+]>CS(C)=O>[Cl:1][C:2]1[N:11]=[CH:10][C:9]2[N:8]([CH2:12][C:13]([CH3:14])([O:15][CH:16]3[CH2:21][CH2:20][CH2:19][CH2:18][O:17]3)[CH3:22])[C:7](=[O:23])[C:6]3([CH3:30])[CH2:24][O:25][CH2:26][CH2:27][N:5]3[C:4]=2[N:3]=1
Reactant: CC(C)(C)[O-]
Reactant: CC(C)(CN1C(=O)C2COCCN2c2nc(Cl)ncc21)OC1CCCCO1
Agent: [Na+]
Solvent: CI
Solvent: CS(C)=O
Product: CC(C)(CN1C(=O)C2(C)COCCN2c2nc(Cl)ncc21)OC1CCCCO1
Temperature: 25 °C
Reaction time: 16 h
Yield: 133.1 %

Procedure:
To a mixture of 2-chloro-5-(2-methyl-2-(tetrahydro-2H-pyran-2-yloxy)propyl)-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-6(5H)-one (96.2 mg, 0.242 mmol) and iodomethane (0.076 ml, 1.21 mmol) in DMSO (4 ml) at 0° C. was added sodium 2-methylpropan-2-olate (46.6 mg, 0.485 mmol). The ice-bath was removed and the reaction mixture was stirred at room temperature for 16 h, followed by being poured into water. Extraction with EtOAc, washing with water, drying and concentration in vacuo gave crude 2-chloro-6a-methyl-5-(2-methyl-2-(tetrahydro-2H-pyran-2-yloxy)propyl)-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-6(5H)-one (133 mg, 0.322 mmol) as a red oil which was used without further purification. MS [M+H] found 411.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[O:7][C:6](=[O:8])[N:5]([C:9]2[CH:14]=[CH:13][C:12]([CH:15]3[CH2:20][CH2:19][S:18](=[O:22])(=[O:21])[CH2:17][CH2:16]3)=[C:11]([F:23])[CH:10]=2)[CH2:4]1.C(N(C(C)C)CC)(C)C.[C:33](Cl)(=[O:40])[O:34][CH2:35][O:36][C:37](=[O:39])[CH3:38]>C(Cl)Cl>[C:37]([O:36][CH2:35][O:34][C:33]([NH:1][CH2:2][C@@H:3]1[O:7][C:6](=[O:8])[N:5]([C:9]2[CH:14]=[CH:13][C:12]([CH:15]3[CH2:20][CH2:19][S:18](=[O:21])(=[O:22])[CH2:17][CH2:16]3)=[C:11]([F:23])[CH:10]=2)[CH2:4]1)=[O:40])(=[O:39])[CH3:38]
Reactant: NC[C@H]1CN(c2ccc(C3CCS(=O)(=O)CC3)c(F)c2)C(=O)O1
Reactant: CC(=O)OCOC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(=O)OCOC(=O)NC[C@H]1CN(c2ccc(C3CCS(=O)(=O)CC3)c(F)c2)C(=O)O1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 165.7 %

Procedure:
To a stirred suspension of the 4-{4-[(5S)-5-(aminomethyl)-2-oxo-1,3-oxazolidin-3-yl]-2-fluorophenyl}tetrahydro-1λ6-thiopyran-1,1(2H)-dione (4.68 g, 13.74 mmol) prepared according to the PCT international publication WO 97/09328 in CH2Cl2 (100 mL) cooled to 0° C. is added diisopropylethylamine (4.8 ml, 27.48 mmol) followed by a solution of 2.4 g (1.5 7 mmol) of the acid chloride (from Step 4) in CH2Cl2 (10 mL) with a 2 mL rinse. The reaction mixture is stirred at 0° C. fro 30 min then at RT for 3 h. The reaction mixture is partitioned between CH2Cl2 (300 mL) and H2O (200 mL). The phases are separated. The organics are washed with 1N HCl (100 mL), brine (100 mL), dried (MgSO4), filtered and concentrated. The residue is dissolved in CH2Cl2, absorbed onto silca gel and purified on a Biotage 40M with a SIM using 2% CH3OH in CH2Cl2 as the eluent to afford 5.32 g (11.6 mmol, 85%) of the desired carbamate as a white foam. 1H NMR (DMSO) δ 7.96 (t, J=6 Hz, 1H), 7.48 (dd, J=14, 2 Hz, 1H), 7.38 (t, J=9 Hz, 1H), 7.24 (dd, J=9, 2 Hz, 1H), 5.61(s, 2H), 4.74 (m, 1H), 4.12 (t, J=9 Hz, 1H), 3.76 (dd, J=9, 7 Hz, 1H), 3.38 (m, 4 H), 3.16 (m, 1H), 3.11 (m, 2H), 2.13 (m, 2H), 2.06 (m, 1H), 2.01 (s, 3H); 13C NMR (DMSO-d6) δ 169.3, 160.6, 158 (d, J=246 Hz), 154.8, 153.8, 138.3 (d, J=8 Hz), 128.1, 125.2 (d, J=11 Hz), 113.7, 105.2 (d, J=26 Hz), 79.3, 71.7, 54.8, 50.3, 46.8, 43.1, 33.3, 29.8, 20.4; IR (diffuse reflectance) 2415, 2351, 2328, 1921, 1916, 1753, 1744, 1515, 1411, 1292, 1247, 1223, 1121, 1010, 983 cm−1. % Water (KF titration): 1.08. [a]25D=−36° (c 0.91, DMSO). Anal. Calcd for C19H23FN2O8S plus 1.08% H2O: C, 49.24; H, 5.12; N, 6.04; S, 6.85. Found: C, 49.05; H, 5.21; N, 5.81; S, 6.85.
Reaction SMILES: [N+:1]([C:4]1[CH:22]=[CH:21][C:7]([CH2:8][O:9][C:10]([N:12]2[CH2:17][CH2:16][C:15](=[CH:18][CH2:19]O)[CH2:14][CH2:13]2)=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:42]N1C(=O)CCC1=O>O1CCCC1>[N+:1]([C:4]1[CH:22]=[CH:21][C:7]([CH2:8][O:9][C:10]([N:12]2[CH2:17][CH2:16][C:15](=[CH:18][CH2:19][Br:42])[CH2:14][CH2:13]2)=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=C(OCc1ccc([N+](=O)[O-])cc1)N1CCC(=CCO)CC1
Reactant: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C(OCc1ccc([N+](=O)[O-])cc1)N1CCC(=CCBr)CC1
Reaction time: 2 h

Procedure:
To a mixture of 2-(1-p-nitrobenzyloxycarbonyl-4-piperidinylidene)ethyl alcohol (1.13 g) and triphenyl phosphine (1.94 g) in tetrahydrofuran (65 ml) was added N-bromosuccinimide (1.31 g) at room temperature and stirred for 2 hours. The reaction mixture was filtered to remove any insoluble materials and the filtrate was concentrated in vacuo to give an oily residue which was purified by silica gel chromatography to give 2-(1-p-nitrobenzyloxycarbonyl-4-piperidinylidene)ethylbromide.
Reaction SMILES: [OH:1][C:2]1([CH3:21])[CH:9]2[C:10](=O)[C:5]([CH2:18][C:19]#[N:20])([C:6]3[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:7]=3[CH2:8]2)[CH2:4][CH2:3]1.N1CCCC1.C1C=CC=CC=1.C([O-])(=O)C.[Na+]>O.C(O)(=O)C>[CH3:17][O:16][C:14]1[CH:15]=[C:6]2[C:7](=[CH:12][CH:13]=1)[CH2:8][CH2:9][C:10]1[C:5]2([CH2:18][C:19]#[N:20])[CH2:4][CH2:3][C:2](=[O:1])[CH:21]=1
Reactant: COc1ccc2c(c1)C1(CC#N)CCC(C)(O)C(C2)C1=O
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: CC(=O)O
Solvent: O
Product: COc1ccc2c(c1)C1(CC#N)CCC(=O)C=C1CC2
Reaction time: 24 h

Procedure:
A mixture of the ketol II (285 g., 1.00 mole), pyrrolidine (213 g., 3.0 mole), acetic acid (180 g., 3.0 mole) and benzene (2l) was refluxed with water separation (Dean-Stark trap) under nitrogen for 30 hours. A buffer solution of sodium acetate (285 g) in water (670 ml) and acetic acid (560 ml) was added and refluxing was continued for 24 hours. The mixture was cooled, washed with 3N sulphuric acid (2 × 500 ml) and work up to give the crude enone III (orange gum). A sample crystallized from methanol as pale yellow prisms; m.p. 133°-134° C.
Reaction SMILES: C([O:3][C:4](=[O:32])[CH2:5][O:6][C:7]1[CH:12]=[C:11]([CH:13]([CH3:15])[CH3:14])[CH:10]=[CH:9][C:8]=1[CH2:16][CH2:17][NH:18][S:19]([C:22]1[CH:27]=[C:26]([C:28]#[N:29])[CH:25]=[CH:24][C:23]=1[O:30][CH3:31])(=[O:21])=[O:20])C.[OH-].[Na+]>C(O)C>[C:28]([C:26]1[CH:25]=[CH:24][C:23]([O:30][CH3:31])=[C:22]([S:19]([NH:18][CH2:17][CH2:16][C:8]2[CH:9]=[CH:10][C:11]([CH:13]([CH3:15])[CH3:14])=[CH:12][C:7]=2[O:6][CH2:5][C:4]([OH:32])=[O:3])(=[O:20])=[O:21])[CH:27]=1)#[N:29]
Reactant: CCOC(=O)COc1cc(C(C)C)ccc1CCNS(=O)(=O)c1cc(C#N)ccc1OC
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1ccc(C#N)cc1S(=O)(=O)NCCc1ccc(C(C)C)cc1OCC(=O)O
Temperature: 25 °C
Reaction time: 3 h
Yield: 98 %

Procedure:
To a solution of 4.52 g of ethyl[2-[2-(5-cyano-2-methoxybenzenesulfonylamino)ethyl]-5-isopropylphenoxy]acetate in ethanol was added 12.3 mL of 2 mol/L sodium hydroxide solution to neutralize. After being stirred at room temperature for 3 hours, the reaction mixture was concentrated, and 1 mol/L hydrochloric acid was added to the residue. After the mixture was extracted with ethyl acetate, the organic layer was washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure to give 4.16 g of [2-[2-(5-cyano-2-methoxybenzenesulfonylamino)ethyl]-5-isopropylphenoxy]acetic acid.
Reaction SMILES: [Mg].Br[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[O:9][CH2:10][CH3:11].II.[I:14][C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[NH:20][C:19](=[O:24])[C:18]2=[O:25].[NH4+].[Cl-]>CCOCC.O1CCCC1>[CH2:10]([O:9][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[C:18]1([OH:25])[C:17]2[C:21](=[CH:22][CH:23]=[C:15]([I:14])[CH:16]=2)[NH:20][C:19]1=[O:24])[CH3:11]
Reactant: CCOc1ccccc1Br
Reactant: O=C1Nc2ccc(I)cc2C1=O
Agent: II
Agent: [Cl-]
Agent: [Mg]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCOc1ccccc1C1(O)C(=O)Nc2ccc(I)cc21
Temperature: 20 °C
Reaction time: 2 h

Procedure:
4 g (164 mMol) of magnesium turnings and 5% of the total amount of 2-bromo-1-ethoxybenzene were put into 20 ml of ether and, after addition of a little iodine, were heated until the reaction started. 33.1 g (165 mMol) of 2-bromo-1-ethoxybenzene dissolved in 100 ml of ether were slowly added dropwise to the boiling solution in such a way that the reaction continued with gentle boiling. Then, while cooling slightly to 20° C., 15 g (54.9 mMol) of 5-iodoisatin in 400 ml of anhydrous tetrahydrofuran were added dropwise. The mixture was then stirred at room temperature for 2 h. The reaction solution was poured into an aqueous NH4Cl solution with stirring. This aqueous phase was extracted several times with ethyl acetate, and the combined aqueous phase was washed four times with water, dried and concentrated in vacuo, resulting in the product as a crystalline precipitate. 19.2 g of the product were obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:9])=[C:6]([CH:8]=1)[NH2:7].Br.Br[CH:12]([C:14]1[CH:15]=[C:16]([C:31]([N:33]([CH3:35])[CH3:34])=[O:32])[CH:17]=[C:18]2[C:23]=1[O:22][C:21]([N:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1)=[CH:20][C:19]2=[O:30])[CH3:13]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:9])=[C:6]([NH:7][CH:12]([C:14]2[CH:15]=[C:16]([C:31]([N:33]([CH3:35])[CH3:34])=[O:32])[CH:17]=[C:18]3[C:23]=2[O:22][C:21]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)=[CH:20][C:19]3=[O:30])[CH3:13])[CH:8]=1
Reactant: Cc1ccc(Cl)cc1N
Reactant: CC(Br)c1cc(C(=O)N(C)C)cc2c(=O)cc(N3CCOCC3)oc12
Agent: Br
Product: Cc1ccc(Cl)cc1NC(C)c1cc(C(=O)N(C)C)cc2c(=O)cc(N3CCOCC3)oc12
Yield: 59.6 %

Procedure:
5-chloro-2-methylaniline (0.098 mL, 0.82 mmol) was reacted with 8-(1-bromoethyl)-N,N-dimethyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide hydrobromide (100 mg, 0.20 mmol) using an analogous procedure to the one described in Example 3.03 to give 8-(1-(5-chloro-2-methylphenylamino)ethyl)-N,N-dimethyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide (56 mg, 58%) as a white solid. Mass Spectrum: M+H+ 470. NMR Spectrum (DMSOd6): 1.61 (d, 3H), 2.21 (s, 3H), 2.71 (bs, 3H), 2.93 (bs, 3H), 3.52-3.65 (m, 4H), 3.70-3.80 (m, 4H), 5.03-5.11 (m, 1H), 5.55 (d, 1H), 5.62 (s, 1H), 6.19 (d, 1H), 6.49 (dd, 1H), 6.97 (d, 1H), 7.62 (d, 1H), 7.79 (d, 1H).