Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][CH2:11][N:12]1[N:16]=[N:15][C:14]([C:17]2[CH:18]=[N:19][CH:20]=[C:21](I)[CH:22]=2)=[N:13]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[C:24]([C:26]1[CH:27]=[C:28]([NH:32][C:33]([C:35]2[O:36][CH:37]=[CH:38][C:39]=2[CH3:40])=[O:34])[CH:29]=[CH:30][CH:31]=1)#[CH:25].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C>CN(C=O)C.C(OCC)(=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[Si:1]([O:8][CH2:9][CH2:10][CH2:11][N:12]1[N:16]=[N:15][C:14]([C:17]2[CH:22]=[C:21]([C:25]#[C:24][C:26]3[CH:27]=[C:28]([NH:32][C:33]([C:35]4[O:36][CH:37]=[CH:38][C:39]=4[CH3:40])=[O:34])[CH:29]=[CH:30][CH:31]=3)[CH:20]=[N:19][CH:18]=2)=[N:13]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OCCCn1nnc(-c2cncc(I)c2)n1
Reactant: C#Cc1cccc(NC(=O)c2occc2C)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1ccoc1C(=O)Nc1cccc(C#Cc2cncc(-c3nnn(CCCO[Si](C)(C)C(C)(C)C)n3)c2)c1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To the nitrogen bubbled solution of 3-(2-(3-((tert-butyldimethylsilyl)oxy)propyl)-2H-tetrazol-5-yl)-5-iodopyridine (89 mg, 0.2 mmol, 1 eq), N-(3-ethynylphenyl)-3-methylfuran-2-carboxamide (67.5 mg, 1.5 eq), triphenylphosphine (1.3 mg, 0.025 eq), and triethylamine (0.09 mL, 3 eq) in anhydrous DMF (2 mL) was added bis(triphenylphosphine)palladium(II) dichloride (14 mg, 0.1 eq), and copper(I) iodide (8 mg, 0.2 eq). After the reaction mixture was stirred at room temperature for 20 minutes, it was diluted with ethyl acetate, washed sequentially with saturated aqueous sodium bicarbonate, aqueous ammonium chloride, brine, and dried with anhydrous sodium sulfate. The upper liquor was decanted, concentrated under reduced pressure, and the resulting brown oily residue was loaded onto silica and columned (EtOAc-Hex 1:20 to 1:4). The fractions containing the desired product were collected, concentrated to a lesser amount, and the white fluffy solid was filtered giving N-(3-((5-(2-(3-((tert-butyldimethylsilyl)oxy)propyl)-2H-tetrazol-5-yl)pyridin-3-yl)ethynyl)phenyl)-3-methylfuran-2-carboxamide in an the amount of 78 mg.
Reaction SMILES: [C:1]([C:3]1[CH:10]=[CH:9][C:6]([CH2:7]O)=[CH:5][C:4]=1[O:11][CH3:12])#[N:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:33]>C1COCC1>[C:1]([C:3]1[CH:10]=[CH:9][C:6]([CH2:7][Br:33])=[CH:5][C:4]=1[O:11][CH3:12])#[N:2]
Reactant: BrC(Br)(Br)Br
Reactant: COc1cc(CO)ccc1C#N
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1cc(CBr)ccc1C#N
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 85.2 %

Procedure:
A solution of the alcohol from Step E (35.5 g, 218 mmol) in 500 mL of dry THF was cooled to 0° C. Triphenylphosphine was added (85.7 g, 327 mmol), followed by carbontetrabromide (108.5 g, 327 mmol). The reaction was stirred at 0° C. for 30 minutes, then at room temperature for 21 hours. Silica gel was added (ca. 300 g), and the suspension was concentrated in vacuo. The resulting solid was loaded onto a silica gel chromatography column. Purification by flash chromatography (30%-50% EtOAc/hexane) provided the titled product (42 g, 85% yield).
Reaction SMILES: Br[C:2]1[C:25]([F:26])=[CH:24][C:5]2[O:6][C:7]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:17]=3[Cl:23])([C:9]3[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=3)[O:8][C:4]=2[CH:3]=1.C([Li])CCC.[C:32](=[O:34])=[O:33]>C(OCC)C>[Cl:23][C:17]1[CH:18]=[C:19]([Cl:22])[CH:20]=[CH:21][C:16]=1[C:7]1([C:9]2[CH:10]=[CH:11][C:12]([F:15])=[CH:13][CH:14]=2)[O:6][C:5]2[CH:24]=[C:25]([F:26])[C:2]([C:32]([OH:34])=[O:33])=[CH:3][C:4]=2[O:8]1
Reactant: O=C=O
Reactant: Fc1ccc(C2(c3ccc(Cl)cc3Cl)Oc3cc(F)c(Br)cc3O2)cc1
Agent: [Li]CCCC
Solvent: CCOCC
Product: O=C(O)c1cc2c(cc1F)OC(c1ccc(F)cc1)(c1ccc(Cl)cc1Cl)O2
Temperature: 20 °C
Reaction time: 1 h
Yield: 70.4 %

Procedure:
To a cooled (−78° C.) solution of 5-bromo-2-(2,4-dichloro-phenyl)-6-fluoro-2-(4-fluoro-phenyl)-benzo[1,3]dioxole (16.5 g, 36.0 mmol) in diethyl ether (250 mL) was slowly added a solution of n-butyl lithium in hexanes (1.6M, 23 mL, 36.0 mmol, 1.0 eq.). After 1 h at −78° C., solid carbon dioxide (50 g approx.) was added to the solution and the reaction was allowed to warm up to 20° C. After 16 h at 20° C. the reaction mixture was partitioned between water (150 mL), ethyl acetate (1.5 L) and hydrochloric acid (1N, 150 mL). The aqueous layer was extracted with ethyl acetate and the combined organic layers were washed with water. The volatiles were removed in vacuo. Purification by flash chromatography afforded the title compound (10.73 g, 69%) as a light yellow solid.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)[CH:3]=1.[CH:17]([NH2:20])([CH3:19])[CH3:18].CCN(C(C)C)C(C)C.CCOC(C)=O>Cl.CCCCO>[CH:17]([NH:20][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)[N:5]=[CH:6][N:7]=1)([CH3:19])[CH3:18]
Reactant: COc1ccc(Nc2cc(Cl)ncn2)cc1
Reactant: CC(C)N
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CCCCO
Product: COc1ccc(Nc2cc(NC(C)C)ncn2)cc1
Temperature: 120 °C
Yield: 73 %

Procedure:
100 mg of 6-chloro-N-(4-methoxyphenyl)pyrimidine-4-amine in the form of a hydrochloride, 44 mg of isopropylamine and 95 mg of DIPEA were dissolved in 1 mL of n-BuOH in a screw cap vial and the vial obtained was heated to 120° C. for 1 hour. Progress of the reaction was monitored by TLC. Upon termination of the reaction n-BuOH was evaporated off and the evaporation residue obtained was subjected to flash column chromatography (PE:EtOAc 1:1). N4-Isopropyl-N6-(4-methoxyphenyl)pyrimidine-4,6-diamine was obtained in the form of a colorless solid.
Reaction SMILES: [NH2:1][C@@H:2]1[C:27](=[O:28])[N:4]2[C:5]([C:14]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=3)=[O:15])=[C:6]([CH2:9][O:10][C:11](=[O:13])[CH3:12])[CH2:7][S:8][C@:3]12[O:29][CH3:30].O.[C:32]1([CH3:42])[CH:37]=[CH:36][C:35]([S:38]([OH:41])(=[O:40])=[O:39])=[CH:34][CH:33]=1>CCOC(C)=O>[C:32]1([CH3:42])[CH:33]=[CH:34][C:35]([S:38]([OH:41])(=[O:39])=[O:40])=[CH:36][CH:37]=1.[NH2:1][CH:2]1[C:27](=[O:28])[N:4]2[C:5]([C:14]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=3)=[O:15])=[C:6]([CH2:9][O:10][C:11](=[O:13])[CH3:12])[CH2:7][S:8][C@:3]12[O:29][CH3:30]
Reactant: CO[C@]12SCC(COC(C)=O)=C(C(=O)OCc3ccc([N+](=O)[O-])cc3)N1C(=O)[C@H]2N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CCOC(C)=O
Product: CO[C@]12SCC(COC(C)=O)=C(C(=O)OCc3ccc([N+](=O)[O-])cc3)N1C(=O)C2N
Reaction time: 5 h
Yield: 31.4 %

Procedure:
In a separate experiment, the crude amine mixture (226 mg.) in EtOAc (1 ml.) is treated with a solution of p-toluenesulfonic acid monohydrate (98 mg., 0.52 mMol) in EtOAc (4 ml.). The resulting solution is stored at 0° C. for ca. 5 hrs., during which time a fine, white precipitate forms. The precipitate is collected, washed with cold EtOAc and hexane, and dried in vacuo to yield the p-toluenesulfonic acid salt of p-nitrobenzyl 7-amino-6-methoxy-3-acetoxymethyl-ceph-3-em-4-carboxylate (71 mg.): mp 170°-175° C. (dec.). The salt (71 mg., 0.12 mMol) is shaken with aqueous K2CO3 (18 mg., 0.13 mMol in 5 ml.) and EtOAc (5 ml.). The layers are separated and the aqueous portion is extracted with more EtOAc (3 × 3 ml.). The combined EtOAc solution is washed with brine, dried with MgSO4, filtered and evaporated in vacuo to provide the major isomer of p-nitrobenzyl 7-amino-6-methoxy-3-acetoxymethyl-ceph-3-em-4-carboxylate (53 mg.) as a pale yellow oil: ir (neat) 3.97, 5.60, 5.74, 6.55, and 7.40μ; nmr (CDCl 3) δ 1.93 (s, 2, NH2), 2.08 (s, 3, COCH3), 3.25, 3.58 (ABq, 2, J=18Hz, SCH2), 3.52 (s, 3, OCH3), 4.28 (s, 1, H7), 4.80, 5.15 (ABq, 2, J=14Hz, CH2OAc), 5.38 (s, 2, CH2Ar), and 7.60, 8.23 (ABq, 4, J=9Hz, ArH); mass spectrum m/e 437 (M+), 380, 321, 257, 186, 169, and 136.
Reaction SMILES: [Cl:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([NH:11][CH2:12][C:13]([CH3:16])([NH2:15])[CH3:14])[C:5]([CH3:17])=[C:4]([CH3:18])[N:3]=1.C(N(CC)CC)C.[C:26](OC(=O)C)(=[O:28])[CH3:27]>C(Cl)Cl>[Cl:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([NH:11][CH2:12][C:13]([NH:15][C:26](=[O:28])[CH3:27])([CH3:14])[CH3:16])[C:5]([CH3:17])=[C:4]([CH3:18])[N:3]=1
Reactant: Cc1nc(Cl)c([N+](=O)[O-])c(NCC(C)(C)N)c1C
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)NC(C)(C)CNc1c(C)c(C)nc(Cl)c1[N+](=O)[O-]
Reaction time: 2 h
Yield: 83.1 %

Procedure:
A solution of gave N1-(2-chloro-5,6-dimethyl-3-nitropyridin-4-yl)-2-methylpropane-1,2-diamine (3.14 g, 10.9 mmol) in 50 mL of CH2Cl2 was cooled to 0° C. under N2 and treated with triethylamine (2.84 mL, 20.4 mmol) and acetic anhydride (1.01 mL, 10.7 mmol). After stirring for 2 h, the reaction was quenched by the addition of saturated aqueous NaHCO3. CH2Cl2 (100 mL) was added and the organic layer was separated. The organic layer was then washed with cold H2O (2×) and brine. The organic portion was dried with Na2SO4 and concentrated to give N-{2-[(2-chloro-5,6-dimethyl-3-nitropyridin-4-yl)amino]-1,1-dimethylethyl}acetamide (2.80 g) as a yellow foam.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][O:16][C:17]2[CH:22]=[CH:21][C:20]([N:23]3[C:27]([NH:28][C:29]([NH:31][C:32]4[CH:37]=[CH:36][C:35]([O:38][C:39]5[CH:40]=[N:41][CH:42]=[CH:43][CH:44]=5)=[CH:34][CH:33]=4)=[O:30])=[CH:26][C:25]([C:45]([CH3:48])([CH3:47])[CH3:46])=[N:24]3)=[CH:19][CH:18]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[C:45]([C:25]1[CH:26]=[C:27]([NH:28][C:29]([NH:31][C:32]2[CH:33]=[CH:34][C:35]([O:38][C:39]3[CH:40]=[N:41][CH:42]=[CH:43][CH:44]=3)=[CH:36][CH:37]=2)=[O:30])[N:23]([C:20]2[CH:21]=[CH:22][C:17]([O:16][CH2:15][CH2:14][CH:11]3[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]3)=[CH:18][CH:19]=2)[N:24]=1)([CH3:48])([CH3:46])[CH3:47]
Reactant: CC(C)(C)OC(=O)N1CCC(CCOc2ccc(-n3nc(C(C)(C)C)cc3NC(=O)Nc3ccc(Oc4cccnc4)cc3)cc2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)c1cc(NC(=O)Nc2ccc(Oc3cccnc3)cc2)n(-c2ccc(OCCC3CCNCC3)cc2)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 26.3 %

Procedure:
To a solution of 4-{2-[4-(3-tert-butyl-5-{3-[4-(pyridin-3-yloxy)-phenyl]-ureido}-pyrazol-1-yl)-phenoxy]-ethyl}-piperidine-1-carboxylic acid tert-butyl ester (210 mg, 0.32 mmol) in DCM (1 mL) was added trifluoroacetic acid (0.3 mL). The reaction mixture was stirred at room temperature for 16 h, concentrated at reduced pressure, re-dissolved in methanol and purified by preparative HPLC. The HPLC fraction containing the desired product was basified by addition of saturated aq Na2CO3 and then extracted with EtOAc. Evaporation of the solvent at reduced pressure gave the desired product 1-{5-tert-butyl-2-[4-(2-piperidin-4-yl-ethoxy)-phenyl]-2H-pyrazol-3-yl}-3-[4-(pyridin-3-yloxy)-phenyl]-urea (46.6 mg, 26%). 1H-NMR (DMSO-d6) δ 9.20 (s, 1H), 8.30 (m, 3H), 7.45-7.35 (m, 5H), 7.00 (m, 3H), 6.30 (s, 1H), 4.0 (m, 4H), 2.40 (m, 2H), 1.70-1.60 (m, 6H), 1.40 (s, 9H), 1.05 (m, 1H); MS LC-MS [M+H]+=555.3, RT=2.73 min.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH:12]([CH2:23][CH:24]([CH3:26])[CH3:25])[C:13]([O:15]N1C(=O)CCC1=O)=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:28][CH2:29][C:30]#[N:31].C(N(CC)CC)C.CN(C=O)C>C(#N)C>[C:29]([CH2:30][NH:31][C:13]([C@@H:12]([NH:11][C:9](=[O:10])[O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[CH2:23][CH:24]([CH3:25])[CH3:26])=[O:15])#[N:28]
Reactant: CC(C)CC(NC(=O)OCc1ccccc1)C(=O)ON1C(=O)CCC1=O
Reactant: N#CCN
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Solvent: CN(C)C=O
Product: CC(C)C[C@H](NC(=O)OCc1ccccc1)C(=O)NCC#N
Temperature: 25 °C
Reaction time: 27 h
Yield: 61.5 %

Procedure:
A mixture comprised of 2,5dioxopyrrolidin-1-yl 2-benzyloxycarbonylamino-4-methylvalerate (39.6 g, 0.109 mol), aminoacetonitrile hydrochloride (10.1 g, 0.109 mol), triethylamine (61 mL, 0.436 mol), DMF (40 mL) and acetonitrile (360 mL) was stirred at room temperature for 27 hours. The mixture was filtered, concentrated to a volume of 100 mL and poured into ice water (1000 mL). The mixture was stirred until a precipitate had formed. The precipitate was collected, washed with water and dried. The dry product was recrystallized from 55% ethanol/water (80 mL). The crystals were collected and recrystallized from 65% ethanol/water (70 mL). The crystals were collected and dried to provide benzyl (S)-1-cyanomethylcarbamoyl-3-methylbutylcarbamate (21.1 g, 0.067 mol) as white needles, m.p. 120-121° C. Proton NMR (300 MHz, DMSO-d6): δ8.68 (t, J=6 Hz, 1H), δ7.54 (d, J=8 Hz, 1H), δ7.33 (m, 5H), δ5.00 (Abq, 2H), δ4.09 (d, J=6 Hz, 2H), 4.03 (m, 1H), δ1.24-1.64 (m, 3H), δ0.84 (apparent t, J=7 Hz, 6H). MS (electrospray): mH+303.9 (100%). Calcd. for C16H21N3O3: C, 63.35; H, 6.98; N, 13.85. Found: C, 63.55; H, 7.01; N, 13.74.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([NH:9][C:10](=[O:23])[C:11]2[CH:16]=[CH:15][C:14]([N:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)=[N:13][CH:12]=2)[CH:5]=[CH:6][C:7]=1[CH3:8].[CH2:24](N=C=O)C.C(OC(=O)CCNC(N1CCN(C2C=CC([C:50](=[O:60])[NH:51][C:52]3[CH:57]=CC(C)=C(I)[CH:53]=3)=CN=2)CC1)=O)C>>[C:52]([NH:51][C:50]([N:20]1[CH2:19][CH2:18][N:17]([C:14]2[CH:15]=[CH:16][C:11]([C:10](=[O:23])[NH:9][C:4]3[CH:5]=[CH:6][C:7]([CH3:8])=[C:2]([I:1])[CH:3]=3)=[CH:12][N:13]=2)[CH2:22][CH2:21]1)=[O:60])([CH3:24])([CH3:57])[CH3:53]
Reactant: CCN=C=O
Reactant: CCOC(=O)CCNC(=O)N1CCN(c2ccc(C(=O)Nc3ccc(C)c(I)c3)cn2)CC1
Reactant: Cc1ccc(NC(=O)c2ccc(N3CCNCC3)nc2)cc1I
Product: Cc1ccc(NC(=O)c2ccc(N3CCN(C(=O)NC(C)(C)C)CC3)nc2)cc1I

Procedure:
4-[5-(3-Iodo-4-methyl-phenylcarbamoyl)-pyridin-2-yl]-piperazine-1-carboxylic acid tert-butylamide was synthesized from N-(3-iodo-4-methyl-phenyl)-6-piperazin-1-yl-nicotinamide and ethyl isocyanate in a manner similar to the one described in the synthesis of 3-({4-[5-(3-iodo-4-methyl-phenylcarbamoyl)-pyridin-2-yl]-piperazine-1-carbonyl}-amino)-propionic acid ethylester above. LCMS calcd for C20H24IN5O2 (m/e) 493, obsd 494 (M+H).
Reaction SMILES: [CH3:1][N:2]([CH2:4][CH2:5]CO)[CH3:3].[F:8][CH:9]([F:34])[N:10]1[C:19]2[C:14](=[CH:15][C:16]3[O:22][CH2:21][O:20][C:17]=3[CH:18]=2)[C:13](=[O:23])[C:12]([C:24]([O:26][CH2:27]CN(CC)CC)=[O:25])=[CH:11]1>>[F:8][CH:9]([F:34])[N:10]1[C:19]2[C:14](=[CH:15][C:16]3[O:22][CH2:21][O:20][C:17]=3[CH:18]=2)[C:13](=[O:23])[C:12]([C:24]([O:26][CH2:27][CH2:5][CH2:4][N:2]([CH3:3])[CH3:1])=[O:25])=[CH:11]1
Reactant: CCN(CC)CCOC(=O)c1cn(C(F)F)c2cc3c(cc2c1=O)OCO3
Reactant: CN(C)CCCO
Product: CN(C)CCCOC(=O)c1cn(C(F)F)c2cc3c(cc2c1=O)OCO3

Procedure:
The product can be obtained by substituting 3-(N,N-dimethylamino)-n-propanol for the 2-(N,N-dimethylamino)ethanol of Example 3.
Reaction SMILES: [H-].[Na+].[NH:3]1[CH:7]=[CH:6][N:5]=[CH:4]1.[CH2:8]([O:10][C:11]([C:13]1[CH:24]=[CH:23][C:16]2[S:17][C:18]([CH2:21]Cl)=[C:19]([CH3:20])[C:15]=2[CH:14]=1)=[O:12])[CH3:9]>CN(C)C=O>[CH2:8]([O:10][C:11]([C:13]1[CH:24]=[CH:23][C:16]2[S:17][C:18]([CH2:21][C:4]3[NH:3][CH:7]=[CH:6][N:5]=3)=[C:19]([CH3:20])[C:15]=2[CH:14]=1)=[O:12])[CH3:9]
Reactant: c1c[nH]cn1
Reactant: CCOC(=O)c1ccc2sc(CCl)c(C)c2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc2sc(Cc3ncc[nH]3)c(C)c2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 46.7 %

Procedure:
Sodium hydride (0.5 g of 50% dispersion in mineral oil) was added portionwise to a stirred solution of imidazole (0.68 g) in dry N,N-dimethylformamide (DMF) (30 ml) and the mixture was stirred at room temperature for 30 minutes. A solution of 2-chloromethyl-3-methylbenzo[b]thiophene-5-carboxylic acid ethyl ester (2.70 g) in dry N,N-dimethylformamide (5 ml) was added, the mixture was stirred for 2 hours and then evaporated. The residue was dissolved in ethyl acetate and the solution was washed well with water and dried (Na2SO4). Evaporation of the solvent gave an oil which was chromatographed on silica gel. Elution with chloroform/petrol (b.p. 40°-60° C.) (3:1) first gave some impurity followed by pure product. Evaporation of the product containing fractions gave a solid which was crystallized from ethyl acetate/petrol (b.p. 60°-80° C.) to give 2-(1-imidazolylmethyl)-3-methylbenzo[b]thiophene-5-carboxylic acid ethyl ester (1.40 g), m.p. 126°-127° C.
Reaction SMILES: [C:1]1([C:7]2[CH:11]=[CH:10]N[C:8]=2[C:12]([O:14][CH3:15])=[O:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].NCl.[CH3:20][N:21](C=O)C>>[NH2:21][CH:20]1[C:8]([C:12]([O:14][CH3:15])=[O:13])=[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:11]=[CH:10]1
Reactant: CN(C)C=O
Reactant: COC(=O)c1[nH]ccc1-c1ccccc1
Agent: NCl
Agent: [H-]
Agent: [Na+]
Product: COC(=O)C1=C(c2ccccc2)C=CC1N
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 82 %

Procedure:
To a solution of methyl 3-phenyl-1H-pyrrole-2-carboxylate (2.50 g, 12.4 mmol) in DMF (25 mL) was added NaH (0.358 g, 14.9 mmol) and the reaction mixture was stirred for 45 min at room temperature. Monochloramine (0.15 M, 150 mL, 0.225 g, 4.40 mmol) was added via syringe. The reaction was stirred for 2 h and was quenched by the addition of saturated aqueous sodium thiosulfite. The reaction mixture was diluted with water and the aqueous portion extracted with ethyl acetate. The organic layer dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography using CombiFlash (REDISEP®, neutral alumina, 40 g, 25% EtOAc/hexanes) to afford methyl 5-amino-2-phenylcyclopenta-1,3-dienecarboxylate (2.20 g, 82.0%). LCMS Condition B-38: retention time 1.79 min, [M+1]=217.0. 1H NMR (400 MHz, DMSO-d6) δ ppm 3.63 (s, 3H), 6.07 (d, J=2.8 Hz, 1H), 6.28 (s, 2H), 7.05 (d, J=2.8 Hz, 1H), 7.33-7.35 (m, 5H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:16][CH2:15][S:14][C:13]3[CH:17]=[CH:18][C:19]([C:21](Cl)=[O:22])=[CH:20][C:12]2=3)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[NH:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1.N1C=CC=CC=1>ClCCCl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:16][CH2:15][S:14][C:13]3[CH:17]=[CH:18][C:19]([C:21]([N:24]4[CH2:29][CH2:28][O:27][CH2:26][CH2:25]4)=[O:22])=[CH:20][C:12]2=3)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: C1COCCN1
Reactant: O=C(Cl)c1ccc2c(c1)N(S(=O)(=O)c1ccc(F)cc1)CCS2
Solvent: c1ccncc1
Solvent: ClCCCl
Product: O=C(c1ccc2c(c1)N(S(=O)(=O)c1ccc(F)cc1)CCS2)N1CCOCC1
Temperature: 70 °C
Reaction time: 16 h
Yield: 67.9 %

Procedure:
To a suspension of 4-(4-fluorophenylsulfonyl)-3,4-dihydro-2H-benzo[b][1,4]thiazine-6-carbonyl chloride (0.027 g, 72.6 μmol) in DCE (1 mL) was added morpholine (15.97 μL, 182 μmol) and pyridine (350 μL). The reaction was heated to 70° C. and stirred at that temperature for 16 hours. LCMS analysis of the reaction mixture indicated complete consumption of starting material. The resulting solid was purified by flash column chromatography using a gradient elution of hexanes with 0-60% EtOAc to provide (4-(4-fluorophenylsulfonyl)-3,4-dihydro-2H-benzo[b][1,4]thiazin-6-yl)(morpholino)methanone (21.8 mg, 49.3 μmol, 88% yield for 2 steps) as off-white solid. LCMS (+ESI) m/z=423.5 [M+H]−.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[C:5](=O)/[CH:6]=[C:7](\O)/[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=1)[CH3:2].[CH3:17][NH:18][NH2:19].C(Cl)Cl.CO>CCO>[CH2:1]([O:3][C:4]([C:5]1[CH:6]=[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[N:18]([CH3:17])[N:19]=1)=[O:16])[CH3:2]
Reactant: CNN
Reactant: CCOC(=O)C(=O)/C=C(\O)c1ccccn1
Solvent: CCO
Solvent: ClCCl
Solvent: CO
Product: CCOC(=O)c1cc(-c2ccccn2)n(C)n1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 61.8 %

Procedure:
To a stirred solution of (Z)-4-hydroxy-2-oxo-4-pyridin-2-yl-but-3-enoic acid ethyl ester (2.32 g, 10 mmol) at r.t. in EtOH (15 ml) under an argon atmosphere was added methylhydrazine (0.55 ml, 10 mmol). The mixture was heated to reflux and stirring was continued for 90 min. The mixture was cooled to r.t. and concentrated to leave a brown paste. After silica gel chromatography using a CH2Cl2/MeOH gradient, the product (1.43 g, 59%) was obtained as yellow waxy solid. MS: M=232.1 (M+H)+
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[S:12](=[O:15])(=[O:14])[NH2:13])[CH2:8][CH2:7][CH2:6]2.CO[CH:18](OC)[N:19]([CH3:21])[CH3:20]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[S:12]([N:13]=[CH:18][N:19]([CH3:21])[CH3:20])(=[O:15])=[O:14])[CH2:8][CH2:7][CH2:6]2
Reactant: COc1cc2c(cc1S(N)(=O)=O)CCC2
Reactant: COC(OC)N(C)C
Product: COc1cc2c(cc1S(=O)(=O)N=CN(C)C)CCC2

Procedure:
This compound is prepared analogously to Example 1c from 5-methoxy-6-sulfamoylindane and dimethylformamide dimethylacetal.
Reaction SMILES: [O-]CC.[Na+].[Cl:5][C:6]1[CH:25]=[CH:24][C:9]([C:10]([NH:12][CH:13]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:14]([O:16][CH2:17][CH3:18])=[O:15])=[O:11])=[CH:8][CH:7]=1.Br[CH2:27][C:28]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[NH:31][C:30](=[O:38])[CH:29]=1>C(O)C>[Cl:5][C:6]1[CH:7]=[CH:8][C:9]([C:10]([NH:12][C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])([CH2:27][C:28]2[C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[NH:31][C:30](=[O:38])[CH:29]=2)[C:19]([O:21][CH2:22][CH3:23])=[O:20])=[O:11])=[CH:24][CH:25]=1
Reactant: CCOC(=O)C(NC(=O)c1ccc(Cl)cc1)C(=O)OCC
Reactant: O=c1cc(CBr)c2ccccc2[nH]1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)C(Cc1cc(=O)[nH]c2ccccc12)(NC(=O)c1ccc(Cl)cc1)C(=O)OCC
Reaction time: 1 h

Procedure:
100 ml of anhydrous ethyl alcohol and 2.23 g of sodium ethoxide (96%) were added to a 500 ml flask, and the mixture was cooled down to below 5° C. After adding 7.91 g of diethyl 4-chlorobenzamidomalonate, the resulting solution was stirred at below 5° C. for one hour. 5.00 g of 4-bromomethylquinolinon was added to the mixture and the resulting solution was stirred at the room temperature for 16 hours to produce an intermediate, ethyl 2-(4-chlorobenzoylamino)-2-ethoxycarbonyl-3-[2(1H)-quinolinon-4-yl]propionate. After the completion of the reaction, 2.71 g of sodium hydroxide (93%) was dissolved in 30 ml of purified water and this aqueous solution was added to the above solution, which was then stirred at the room temperature for about 2 hours. Subsequently, the resulting solution was warmed to about 60° C. and stirred for 2 hours to complete the reaction. The ethyl alcohol was removed through vacuum concentration, and purified water and 1N HCl were added to the residue for crystallization. The crystal thus obtained was filtered and then subjected to recrystallization with methanol and potassium hydroxide to yield 6.7 g (86.0%) of 2-(4-chlorobenzoylamino)-3-[2(1H)-quinolinon-4-yl]propionic acid.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][C:8]([OH:10])=[O:9])[CH2:3][CH2:2]1.[C:11](OC(=O)C)(=[O:13])[CH3:12]>>[C:11]([N:1]1[CH2:6][CH2:5][CH:4]([CH2:7][C:8]([OH:10])=[O:9])[CH2:3][CH2:2]1)(=[O:13])[CH3:12]
Reactant: CC(=O)OC(C)=O
Reactant: O=C(O)CC1CCNCC1
Product: CC(=O)N1CCC(CC(=O)O)CC1
Yield: 98.7 %

Procedure:
4-Piperidinylacetic acid (5 grams) (35.0 mmoles) was reacted with acetic anhydride (10.7 grams) (105.0 mmoles) as described in Preparative Example 13A to give the title compound (Yield: 6.4 grams, 99%, MH+ 185).
Reaction SMILES: [F:1][C:2]1[CH:13]=[CH:12][C:5]2[C:6](=[O:11])[O:7][C:8](=[O:10])[NH:9][C:4]=2[CH:3]=1.[H-].[Na+].[CH3:16]I>CC(N(C)C)=O>[F:1][C:2]1[CH:13]=[CH:12][C:5]2[C:6](=[O:11])[O:7][C:8](=[O:10])[N:9]([CH3:16])[C:4]=2[CH:3]=1
Reactant: O=c1[nH]c2cc(F)ccc2c(=O)o1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: Cn1c(=O)oc(=O)c2ccc(F)cc21
Reaction time: 1.25 h

Procedure:
A stirred solution of 7-fluoro-1H-3,1-benzoxazine-2,4-dione (9.0 g) in dimethylacetamide (100 ml) at 18.5° was treated portionwise with sodium hydride (80% dispersion in mineral oil, 1.65 ) during 10 minutes. The mixture was stirred for a further 75 minutes. Methyl iodide (7.81 g) was then added dropwise to the stirred mixture during 5 minutes and the mixture was stirred for a further 18.5 hours at ambient temperature. Solvent (60 ml) was removed by distillation in vacuo. The residue was cooled to 3° and poured into ice-water. The resulting precipitate was collected, dried in vacuo and recrystallised from dichloromethane to give 7-fluoro-1-methyl-1H-3,1-benzoxazine-2,4-dione m.p. 158°-159.5°.