Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]1[CH2:13][CH2:12][C@:11]([CH2:17][CH2:18][O:19][CH3:20])([C:14]([OH:16])=O)[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.Cl.[F:23][C:24]([F:38])([F:37])[C:25]1[CH:30]=[CH:29][N:28]=[C:27]([N:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)[CH:26]=1.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1>CN(C=O)C.C(Cl)Cl>[CH3:20][O:19][CH2:18][CH2:17][C@:11]1([C:14]([N:34]2[CH2:35][CH2:36][N:31]([C:27]3[CH:26]=[C:25]([C:24]([F:38])([F:23])[F:37])[CH:30]=[CH:29][N:28]=3)[CH2:32][CH2:33]2)=[O:16])[CH2:12][CH2:13][C@@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[CH2:10]1
Reactant: COCC[C@]1(C(=O)O)CC[C@@H](NC(=O)OC(C)(C)C)C1
Reactant: FC(F)(F)c1ccnc(N2CCNCC2)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COCC[C@]1(C(=O)N2CCN(c3cc(C(F)(F)F)ccn3)CC2)CC[C@@H](NC(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 72 h
Yield: 52.4 %

Procedure:
(1S,3R)-3-[(tert-Butoxycarbonyl)amino]- 1 -(2-methoxyethyl)cyclopentanecarboxylic acid (276.6 mg, 0.96 mmol) , 1-[4-(trifluoromethyl)pyridin-2-yl]piperazine dihydrochloride (322.0 mg, 1.06 mmol) , triethylamine (0.54 mL, 3.85 mmol) and O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (547.6 mg, 1.44 mmol) (HBTU) were mixed in dry DMF (6.6 mL) and the resultanting brown solution was stirred at room temperature under N2 for three days. The reaction mixture was diluted with CH2Cl2, and washed with saturated Na2CO3. The aqueous layer was extracted with CH2Cl2 four times. The combined organic layers were dried (MgSO4), filtered, concentrated and purified by flash chromatography (EtOAc/Hexane) to provide the desired product (252 mg, 52%). MS calculated for C24H36F3N4O4(M+H) 501.3; found 401.3 (M+H-Boc).
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:11]=2)[C:6](=[C:18](OCC)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:5]1=[O:28])(=O)C.[CH2:29]([N:36]([CH2:38][C:39]1[CH:45]=[CH:44][C:42]([NH2:43])=[CH:41][CH:40]=1)[CH3:37])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>>[CH2:29]([N:36]([CH2:38][C:39]1[CH:40]=[CH:41][C:42]([NH:43]/[C:18](=[C:6]2\[C:5](=[O:28])[NH:4][C:12]3[C:7]\2=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:11]=3)/[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:44][CH:45]=1)[CH3:37])[C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: CN(Cc1ccccc1)Cc1ccc(N)cc1
Reactant: CCOC(=O)c1ccc2c(c1)N(C(C)=O)C(=O)C2=C(OCC)c1ccccc1
Product: CCOC(=O)c1ccc2c(c1)NC(=O)/C2=C(\Nc1ccc(CN(C)Cc2ccccc2)cc1)c1ccccc1

Procedure:
Prepared from 1-acetyl-3-(1-ethoxy-1-phenylmethylene)-6-ethoxycarbonyl-2-indolinone and 4-(N-benzyl-N-methyl-aminomethyl)-aniline Rf value: 0.4 (silica gel, methylene chloride/ethanol=10:1) C33H31N3O3
Reaction SMILES: [C:1]([O:4][CH:5]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15](Br)[CH:14]=1)[C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])(=[O:3])[CH3:2].C([O-])([O-])=O.[Na+].[Na+].[F:26][C:27]([F:39])([F:38])[O:28][C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1>C(#N)C.O.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>[C:1]([O:4][CH:5]([C:13]1[CH:14]=[C:15]([C:32]2[CH:31]=[CH:30][C:29]([O:28][C:27]([F:26])([F:38])[F:39])=[CH:34][CH:33]=2)[CH:16]=[CH:17][CH:18]=1)[C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])(=[O:3])[CH3:2]
Reactant: CC(=O)OC(C(=O)OC(C)(C)C)c1cccc(Br)c1
Reactant: OB(O)c1ccc(OC(F)(F)F)cc1
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: [Na+]
Solvent: CC#N
Solvent: O
Product: CC(=O)OC(C(=O)OC(C)(C)C)c1cccc(-c2ccc(OC(F)(F)F)cc2)c1
Temperature: 130 °C

Procedure:
A mixture of compound 3 (811 mg, 2.46 mmol), Na2CO3 (650 mg, 6.13 mmol), Pd(PPh3)4 (207 mg, 0.18 mmol) and 4-trifluoromethoxy phenyl boronic acid (870 mg, 4.22 mmol) in acetonitrile (7.0 mL) and water (0.7 mL) was heated to 130° C. in the microwave for 30 minutes. The mixture was filtered through Celite® diatomaceous earth and washed with EtOAc. The filtrate was concentrated in vacuo and the resulting residue was purified by flash chromatography (80 g silica cartridge, 0-10% EtOAc/hexanes) to provide compound 4.
Reaction SMILES: [CH2:1]([S:3][CH:4]([CH2:20][C:21]([O-:23])=[O:22])[C:5](=O)[C:6]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][CH:11]=1)=[O:7])[CH3:2].S(Cl)([Cl:26])=O>ClCCCl>[Cl:26][C:5]1([C:6]([O:8][CH2:9][C:10]2[CH:11]=[CH:12][C:13]([N+:16]([O-:18])=[O:17])=[CH:14][CH:15]=2)=[O:7])[CH:4]([S:3][CH2:1][CH3:2])[CH2:20][C:21](=[O:22])[O:23]1
Reactant: CCSC(CC(=O)[O-])C(=O)C(=O)OCc1ccc([N+](=O)[O-])cc1
Reactant: O=S(Cl)Cl
Solvent: ClCCCl
Product: CCSC1CC(=O)OC1(Cl)C(=O)OCc1ccc([N+](=O)[O-])cc1

Procedure:
In 4 ml of 1,2-dichloroethane was dissolved 170 mg of the Compound (39) obtained in Example 39. To the solution was added 0.30 ml of thionyl chloride. The mixture was heated for 3.5 hours under reflux. The solvent was evaporated off, and the residue was subjected to a column chromatography using Florisil (Floridin Inc. U.S.A.), followed by elution with hexane and hexane-ethyl acetate (3:1) to give 79 mg of the subject Compound (40) as colorless oil.
Reaction SMILES: [NH:1]([C:3]1[N:8]([CH2:9][CH:10]([CH3:12])[CH3:11])[C:7](=[O:13])[N:6]([CH3:14])[C:5](=[O:15])[CH:4]=1)[NH2:2].[Cl:16][C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][CH:26]=1)[N:23]=[CH:22][CH:21]=[C:20]2[CH:27]=O.[CH3:29][N:30]1[CH:34]=[CH:33][CH:32]=[C:31]1[CH:35]=O>>[Cl:16][C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][CH:26]=1)[N:23]=[CH:22][CH:21]=[C:20]2[CH2:27][N:2]1[C:35]([C:31]2[N:30]([CH3:29])[CH:34]=[CH:33][CH:32]=2)=[C:4]2[C:3]([N:8]([CH2:9][CH:10]([CH3:11])[CH3:12])[C:7](=[O:13])[N:6]([CH3:14])[C:5]2=[O:15])=[N:1]1
Reactant: CC(C)Cn1c(NN)cc(=O)n(C)c1=O
Reactant: Cn1cccc1C=O
Reactant: O=Cc1ccnc2ccc(Cl)cc12
Product: CC(C)Cn1c(=O)n(C)c(=O)c2c(-c3cccn3C)n(Cc3ccnc4ccc(Cl)cc34)nc21

Procedure:
This compound was made following the procedure described above, starting with 6-hydrazino-1-isobutyl-3-methylpyrimidine-2,4(1H,3H)-dione, and condensing first with 6-chloroquinoline-4-carbaldehyde, followed by 1-methyl-1H-pyrrole-2-carbaldehyde. 477.9 (M+H).
Reaction SMILES: O1[CH2:5][CH2:4][CH:3]([O:6][CH:7]([C:9]2[CH:17]=[CH:16][C:12]([C:13]([OH:15])=O)=[CH:11][CH:10]=2)[CH3:8])[CH2:2]1.Cl.C(N=C=N[CH2:24][CH2:25][CH2:26]N(C)C)C.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C.[NH2:47][CH2:48][C:49]1[C:50]([OH:57])=[N:51][C:52]([CH3:56])=[CH:53][C:54]=1[CH3:55]>ClCCl>[OH:57][C:50]1[C:49]([CH2:48][NH:47][C:13](=[O:15])[C:12]2[CH:11]=[CH:10][C:9]([CH:7]([O:6][C:3]3[CH:2]=[C:25]([CH3:26])[CH:24]=[CH:5][CH:4]=3)[CH3:8])=[CH:17][CH:16]=2)=[C:54]([CH3:55])[CH:53]=[C:52]([CH3:56])[N:51]=1
Reactant: Cc1cc(C)c(CN)c(O)n1
Reactant: CCN=C=NCCCN(C)C
Reactant: CC(OC1CCOC1)c1ccc(C(=O)O)cc1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cccc(OC(C)c2ccc(C(=O)NCc3c(C)cc(C)nc3O)cc2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 87.7 %

Procedure:
A mixture of 4-(1-(tetrahydrofuran-3-yloxy)ethyl)benzoic acid (311 mg, 1.32 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (380 mg, 1.98 mmol), N-hydroxybenzotriazole (267.3 mg, 1.98 mmol) and triethylamine (400 mg, 3.96 mmol) in dichloromethane (50 mL) was stirred for 30 minutes at room temperature. Then to the mixture, 3-(aminomethyl)-4,6-dimethylpyridin-2-ol (200.64 mg, 1.32 mmol) was added. The resultant mixture was stirred at room temperature for 12 hours. Then the mixture was washed with water (30 mL×3). The organic layer was concentrated to give a residue and the residue was purified by column chromatography (silica gel, dichloromethane/methanol=20:1) to give N-((2-hydroxy-4,6-dimethylpyridin-3-yl)methyl)-4-(1-(m-tolyloxy)ethyl)benzamide (Compound I-82) (452 mg, 92%). LRMS (M+H+) m/z: calcd 370. found 370. 1H NMR (300 MHz, CD3OD): a 7.78 (d, J=8.4 Hz, 2H), 7.42-7.41 (m, 2H), 6.11 (s, 1H), 4.61-4.58 (m, 1H), 4.49 (s, 2H), 4.07-4.04 (m, 1H), 3.87-3.62 (m, 4H), 2.37 (s, 3H), 2.24 (s, 3H), 1.98-1.87 (m, 2H), 1.40-1.38 (m, 3H).
Reaction SMILES: [C:1]([Li])(C)(C)[CH3:2].[CH2:6]([C:10]1[CH:11]=[C:12]([C:16]([OH:18])=[O:17])[S:13][C:14]=1[CH3:15])[CH:7]([CH3:9])[CH3:8].ICC>C1COCC1>[CH2:1]([C:11]1[C:10]([CH2:6][CH:7]([CH3:9])[CH3:8])=[C:14]([CH3:15])[S:13][C:12]=1[C:16]([OH:18])=[O:17])[CH3:2]
Reactant: Cc1sc(C(=O)O)cc1CC(C)C
Reactant: [Li]C(C)(C)C
Solvent: CCI
Solvent: C1CCOC1
Product: CCc1c(C(=O)O)sc(C)c1CC(C)C
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
At −78° C., tert.-butyllithium (20 mL, 1.5 M in pentane) is slowly added to a solution of 4-isobutyl-5-methyl-thiophene-2-carboxylic acid (2.0 g, 10.1 mmol) in THF (100 mL). The mixture turns dark. The mixture is stirred at −78° C. for 15 min, then a solution of iodoethane (6.18 g, 39.6 mmol) in THF (10 mL) is added. The mixture is stirred for 1 h at −78° C. Further iodoethane (6.18 g, 39.6 mmol) is added and the mixture allowed to warm to rt over a period of 15 h. The reaction is quenched by adding 1 M aq. NaH2PO4 (20 mL) and 1 N aq. HCl (50 mL) and the mixture is extracted with chloroform (1×100 mL, 3×30 mL). The combined organic extracts are dried over MgSO4, filtered and evaporated. The crude product is purified by MPLC on silica gel eluting with a gradient of EA in hexane to give 3-ethyl-4-isobutyl-5-methyl-thiophene-2-carboxylic acid (1.29 g) as a yellow solid; LC-MS: tR=1.00 min, [M+1+CH3CN]=268.29; 1H NMR (CDCl3): δ 2.92 (q, J=7.0 Hz, 2H), 2.40 (s, 3H), 2.37 (d, J=7.6 Hz, 2H), 1.80 (m, J=7.0 Hz, 1H), 1.15 (t, J=7.6 Hz, 3H), 0.92 (d, J=7.0 Hz, 6H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:20]([N+:21]([O-:23])=[O:22])=[CH:19][C:6]2[NH:7][C:8](=[O:18])[CH2:9][N:10](C(=O)C(F)(F)F)[CH2:11][C:5]=2[CH:4]=1.N.CO>CO>[CH3:1][O:2][C:3]1[C:20]([N+:21]([O-:23])=[O:22])=[CH:19][C:6]2[NH:7][C:8](=[O:18])[CH2:9][NH:10][CH2:11][C:5]=2[CH:4]=1
Reactant: COc1cc2c(cc1[N+](=O)[O-])NC(=O)CN(C(=O)C(F)(F)F)C2
Agent: N
Solvent: CO
Product: COc1cc2c(cc1[N+](=O)[O-])NC(=O)CNC2
Temperature: 25 °C
Yield: 95.8 %

Procedure:
To a solution of 7-methoxy-8-nitro-4-(2,2,2-trifluoro-acetyl)-1,3,4,5-tetrahydro-benzo[e][1,4]diazepin-2-one (1.10 g, 3.3 mmol) in methanol (10 mL) cooled in an ice-water bath was added 7M NH3/MeOH (10 mL, 70 mmol). The mixture was stirred while being allowed to warm slowly to room temperature over 1.5 hours, concentrated on a rotary evaporator, and purified by flash chromatography over silica gel (0-20% MeOH/DCM) to afford 7-methoxy-8-nitro-1,3,4,5-tetrahydro-benzo[e][1,4]diazepin-2-one (0.75 g, 96%) as a yellow solid; NMR (400 MHz, DMSO-d6) δ 9.90 (s, 1H), 7.68 (s, 1H), 7.20 (s, 1H), 3.97 (s, 2H), 3.88 (3H), 3.51 (s, 2H); MS (m/e) 238 (M+1); mp 203° C. (dec.).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([O:11][CH2:12][CH3:13])[C:9]=1[OH:10])[CH:5]=O.[CH3:14]/[C:15](/[NH2:19])=[CH:16]\[C:17]#[N:18].[CH2:20]([CH:23]1[CH2:28][C:27](=[O:29])[CH2:26][C:25](=O)[CH2:24]1)[CH2:21][CH3:22]>C(O)C>[Br:1][C:2]1[CH:3]=[C:4]([CH:5]2[C:26]3[C:27](=[O:29])[CH2:28][CH:23]([CH2:20][CH2:21][CH3:22])[CH2:24][C:25]=3[NH:19][C:15]([CH3:14])=[C:16]2[C:17]#[N:18])[CH:7]=[C:8]([O:11][CH2:12][CH3:13])[C:9]=1[OH:10]
Reactant: CCCC1CC(=O)CC(=O)C1
Reactant: C/C(N)=C\C#N
Reactant: CCOc1cc(C=O)cc(Br)c1O
Solvent: CCO
Product: CCCC1CC(=O)C2=C(C1)NC(C)=C(C#N)C2c1cc(Br)c(O)c(OCC)c1
Temperature: 80 °C
Reaction time: 4 h

Procedure:
A mixture of 3-bromo-5-ethoxy-4-hydroxy-benzaldehyde (6 g), 3-aminocrotonitrile (2.01 g) and 5-propylcyclohexane-1,3-dione (3.8 g) in ethanol (20 ml) was stirred at 80° C. for 4 h. The reaction mixture was concentrated in vacuo and the residue was chromatographed on silica gel in heptane/EtOAc=1/1 (v/v) as eluent. Yield: 6.3 g. MS-ESI: [M+H]+=445/447
Reaction SMILES: [C:1]1([S:7]([C:10]2[CH:20]=[CH:19][C:13]3[NH:14][C:15](=O)[CH2:16][O:17][C:12]=3[CH:11]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.O.C(=O)([O-])[O-].[K+].[K+]>C1COCC1>[C:1]1([S:7]([C:10]2[CH:20]=[CH:19][C:13]3[NH:14][CH2:15][CH2:16][O:17][C:12]=3[CH:11]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C1COc2cc(S(=O)(=O)c3ccccc3)ccc2N1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: O=S(=O)(c1ccccc1)c1ccc2c(c1)OCCN2
Temperature: 25 °C
Yield: 79.5 %

Procedure:
A suspension of 7-benzenesulfonyl-4H-benzo[1,4]oxazin-3-one (2.314 g., 8.00 mmol) in 30 ml anhydrous THF was brought to reflux, and borane-dimethyl sulfide complex (2.4 mL, 10 M solution) was added dropwise via syringe. The solution was refluxed for two hours, at which time the solution was cooled to room temperature and ethanolic HCl (10 mL., 2 N solution) was added dropwise. The resulting solution was refluxed for 3 hours and allowed to cool to room temperature. The reaction mixture was poured into 100 mL water, the resulting solution made basic with potassium carbonate and extracted three times with 50 mL Et2O. The organic fractions were washed with 100 mL brine, dried over Na2SO4 and concentrated in vacuo. The resulting residue was purified by flash chromatography (20 to 50% EtOAc in hexanes) to give 1.75 g of 7-benzenesulfonyl-3,4-dihydro-2H-benzo[1,4]oxazine (79.5%) as a yellow solid. MS: 276 (M+H)+.
Reaction SMILES: [C:1]([C:5]([O:7][CH2:8][C:9]([NH2:11])=[S:10])=[O:6])([CH3:4])([CH3:3])[CH3:2].Br[CH2:13][C:14]([C:16]1[CH:29]=[CH:28][C:27]2[S:26][C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[N:19](C(=O)CCl)[C:18]=2[CH:17]=1)=O.BrCC(C1C=C(C(C)(C)C)C(O)=C(C(C)(C)C)C=1)=O>>[C:5]([O:7][CH2:8][C:9]1[S:10][CH:13]=[C:14]([C:16]2[CH:29]=[CH:28][C:27]3[S:26][C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[NH:19][C:18]=3[CH:17]=2)[N:11]=1)(=[O:6])[C:1]([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)C(=O)OCC(N)=S
Reactant: O=C(CBr)c1ccc2c(c1)N(C(=O)CCl)c1ccccc1S2
Agent: CC(C)(C)c1cc(C(=O)CBr)cc(C(C)(C)C)c1O
Product: CC(C)(C)C(=O)OCc1nc(-c2ccc3c(c2)Nc2ccccc2S3)cs1
Yield: 63.2 %

Procedure:
This compound is prepared according to a protocol identical to that described for Stage 350.3 of Example 350, respectively using 2-(tert-butylcarbonyloxy)thioacetamide and 2-bromo-1-[10-(chloroacetyl)-10H-phenothiazin-2-yl]ethanone instead of intermediate 1.2 and bromo-1-(3,5-ditert-butyl-4-hydroxyphenyl)ethanone. The expected compound is obtained in the form of a greenish solid with a yield of 63.2%. Melting point: 120.0-122.0° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:24]1[CH:29]=[CH:28][C:27]([CH2:30][OH:31])=[CH:26][C:25]=1[N+:32]([O-:34])=[O:33])[C:9]1[N:14]=[CH:13][N:12]=[C:11]([N:15]([CH3:23])[C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:35](=O)([O-])[O-].[K+].[K+].S(OC)(OC)(=O)=O>CC(C)=O>[C:1]([O:5][C:6]([N:8]([C:24]1[CH:29]=[CH:28][C:27]([CH2:30][O:31][CH3:35])=[CH:26][C:25]=1[N+:32]([O-:34])=[O:33])[C:9]1[N:14]=[CH:13][N:12]=[C:11]([N:15]([CH3:23])[C:16](=[O:22])[O:17][C:18]([CH3:20])([CH3:21])[CH3:19])[CH:10]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CN(C(=O)OC(C)(C)C)c1cc(N(C(=O)OC(C)(C)C)c2ccc(CO)cc2[N+](=O)[O-])ncn1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: COS(=O)(=O)OC
Solvent: CC(C)=O
Product: COCc1ccc(N(C(=O)OC(C)(C)C)c2cc(N(C)C(=O)OC(C)(C)C)ncn2)c([N+](=O)[O-])c1
Temperature: 25 °C
Yield: 17.6 %

Procedure:
To a solution of tert-butyl (6-((tert-butoxycarbonyl)(4-(hydroxymethyl)-2-nitrophenyl)amino)pyrimidin-4-yl)(methyl)carbamate (1.5 g, 3.488 mmol) in acetone (20 mL) under an argon atmosphere at 0° C., was added potassium carbonate (0.48 g, 6.97 mmol) followed by dimethyl sulfate (0.87 g, 6.97 mmol). The resulting reaction mixture was then refluxed for 24 h and then allowed to cool to rt. The reaction mixture was concentrated under vacuum to obtain a crude residue. The residue was purified by silica gel column chromatography to afford the title compound (0.3 g, yield: 19%) as a solid. MS (ESI): 490.55 [M+H]+.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[C:9]([CH:17]=[CH2:18])[C:10]([F:16])=[C:11](F)[C:12]=3[F:14])[C:7](=[O:19])[C:6]([C:20]([OH:22])=[O:21])=[CH:5]2)[CH2:3][CH2:2]1.[CH2:23]1[CH:27]2[CH2:28][CH:29]3[N:33]([CH:26]2[CH2:25][NH:24]1)[CH2:32][CH2:31][CH2:30]3.C1N2CCN(CC2)C1.O>C(#N)C.CN(C)C=O>[CH:1]1([N:4]2[C:13]3[C:8](=[C:9]([CH:17]=[CH2:18])[C:10]([F:16])=[C:11]([N:24]4[CH2:25][CH:26]5[CH:27]([CH2:28][CH:29]6[N:33]5[CH2:32][CH2:31][CH2:30]6)[CH2:23]4)[C:12]=3[F:14])[C:7](=[O:19])[C:6]([C:20]([OH:22])=[O:21])=[CH:5]2)[CH2:3][CH2:2]1
Reactant: C1CC2CC3CNCC3N2C1
Reactant: C=Cc1c(F)c(F)c(F)c2c1c(=O)c(C(=O)O)cn2C1CC1
Agent: C1CN2CCN1CC2
Solvent: CC#N
Solvent: CN(C)C=O
Solvent: O
Product: C=Cc1c(F)c(N2CC3CC4CCCN4C3C2)c(F)c2c1c(=O)c(C(=O)O)cn2C1CC1

Procedure:
0.93 g of 1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-5-vinyl-3-quinolinecarboxylic acid, 0.69 g of decahydropyrrolo[3,4-b]pyrrolizine and 0.36 g of DABCO are refluxed for 2 hours in a mixture of 6 ml of acetonitrile and 3 ml of dimethylformamide. At room temperature, the reaction mixture is treated with 20 ml of water, and the solid is filtered off with suction, washed with water and dried. 0.7 g. of 1-cyclopropyl-6,8-difluoro-1,4-dihydro-7-(octahydro-pyrrolo[3,4-b]pyrrolizin-2-yl)-4-oxo-5-vinyl-3-quinolinecarboxylic acid is obtained.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:5]=[CH:6][C:7]([O:11][CH2:12][CH2:13][CH3:14])=[C:8]([OH:10])[CH:9]=1.C(N(CC)CC)C.CO[CH:24]=[C:25]1[C:34]2[C:29](=[CH:30][CH:31]=[C:32]([N:35]3[CH:39]=[CH:38][CH:37]=[CH:36]3)[CH:33]=2)[C:28](=[O:40])[NH:27][C:26]1=[O:41]>CN(C)C=O>[OH:10][C:8]1[CH:9]=[C:4]([CH:5]=[CH:6][C:7]=1[O:11][CH2:12][CH2:13][CH3:14])[CH2:3][NH:2][CH:24]=[C:25]1[C:34]2[C:29](=[CH:30][CH:31]=[C:32]([N:35]3[CH:39]=[CH:38][CH:37]=[CH:36]3)[CH:33]=2)[C:28](=[O:40])[NH:27][C:26]1=[O:41]
Reactant: CCCOc1ccc(CN)cc1O
Reactant: COC=C1C(=O)NC(=O)c2ccc(-n3cccc3)cc21
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCCOc1ccc(CNC=C2C(=O)NC(=O)c3ccc(-n4cccc4)cc32)cc1O
Reaction time: 0.25 h

Procedure:
A mixture of 5-aminomethyl-2-propoxy-phenol hydrochloride (109 mg, 0.50 mmole), 4 mL of N,N-dimethylformamide and triethylamine (75 μL, 0.54 mmole) is stirred for 15 minutes. Then (4-methoxymethylene-6-pyrrol-1-yl-4H-isoquinoline-1,3-dione (134 mg, 0.50 mmole) is added and the reaction mixture stirred for one hour. The reaction mixture is evaporated to dryness, taken up in 5% methanol in chloroform and passed through a short pad of Florisil eluting with 5% methanol in chloroform. The eluate is evaporated in vacuo and treated with acetonitrile, filtered and dried to give a beige solid, 94 mg, (45%), mp 215-216° C. dec; MS (ES+): m/z 418.2 (M+H).
Reaction SMILES: FC(F)(F)C(O)=O.[N:8]1([C:14]2[CH:37]=[CH:36][C:17]3[C:18]([CH2:21][CH2:22][CH:23]4[CH2:28][CH2:27][N:26]([C:29](OC(C)(C)C)=O)[CH2:25][CH2:24]4)=[N:19][O:20][C:16]=3[CH:15]=2)[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1.[C:38]1(SC)[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1.C(N(CC)CC)C.C(Br)C1C=CC=CC=1>C(Cl)Cl>[N:8]1([C:14]2[CH:37]=[CH:36][C:17]3[C:18]([CH2:21][CH2:22][CH:23]4[CH2:28][CH2:27][N:26]([CH2:29][C:38]5[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=5)[CH2:25][CH2:24]4)=[N:19][O:20][C:16]=3[CH:15]=2)[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCC(CCc2noc3cc(N4CCOCC4)ccc23)CC1
Reactant: CSc1ccccc1
Agent: BrCc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: c1ccc(CN2CCC(CCc3noc4cc(N5CCOCC5)ccc34)CC2)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 73.2 %

Procedure:
Trifluoroacetic acid (TFA) (5 mL) was added to a cold (0° C.) solution of the piperidine formed in step b (0.40 g, 0.96 mmol) and thioanisole (1.13 mL, 9.60 mmol) in CH2Cl2 (10 mL). The resulting mixture was stirred at 0° C. for 30 min. Volatiles were removed under reduced pressure and 1N sodium hydroxide (NaOH) was added to the residue. The aqueous layer was extracted with EtOAc (2 times) and the combined organic layer was washed with water and brine and dried (MgSO4), filtered, and concentrated. The yellow oil obtained was redissolved in CH2Cl2 (10 mL), and triethylamine (0.267 mL, 1.92 mmol) and benzyl bromide (0.148 mL, 1.25 mmol) were added. The resulting mixture was stirred overnight at room temperature. The mixture was washed with water and brine and dried (MgSO4), filtered, and concentrated. Purification by silica gel flash chromatography (CH2Cl2 →10% MeOH/CH2Cl2) gave the title compound (0.285 g, 73%) as a white solid. A small sample was further purified by recrystallization (EtOH) to give a white solid.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]([NH2:13])=[O:12])=[CH:6][CH:5]=1)([O-:3])=[O:2].Br[CH2:15][C:16](=O)[CH2:17][CH3:18].CN(C)C=O.C(=O)([O-])[O-].[K+].[K+]>C(OCC)(=O)C.O>[CH2:17]([C:16]1[N:13]=[C:11]([CH2:10][C:7]2[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=2)[O:12][CH:15]=1)[CH3:18]
Reactant: CCC(=O)CBr
Reactant: NC(=O)Cc1ccc([N+](=O)[O-])cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: CCc1coc(Cc2ccc([N+](=O)[O-])cc2)n1
Temperature: 140 °C
Reaction time: 2 h
Yield: 14.1 %

Procedure:
A mixture of 2-(4-nitrophenyl)acetamide (14.6 g), 1-bromo-2-butanone (20.46 g) and N,N-dimethylformamide (2 mL) was stirred at 140° C. for 2 hrs. Water, potassium carbonate and ethyl acetate were added to basify the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to give 4-ethyl-2-(4-nitrobenzyl)-1,3-oxazole as brown crystals (2.65 g, yield 14%) from a fraction eluted with hexane-ethyl acetate (2:1, v/v). Recrystallization thereof from ethyl acetate-hexane gave brown prism crystals. melting point: 58-59° C.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[Cl:13][C:14]1[CH:15]=[C:16]([C@@H:24]([CH2:38][CH:39]2[CH2:43][CH2:42][CH2:41]C2)[C:25](NC2C=CN(CCC(O)=O)N=2)=[O:26])[CH:17]=[CH:18][C:19]=1[S:20]([CH3:23])(=O)=O.IC[C@H]1CC[CH2:48][O:47]1.[O:51]1CCCC1>CN1CCCN(C)C1=O>[CH3:48][O:47][C:25](=[O:26])[CH:24]([C:16]1[CH:17]=[CH:18][C:19]([S:20][CH3:23])=[C:14]([Cl:13])[CH:15]=1)[CH2:38][C@H:39]1[CH2:43][CH2:42][CH2:41][O:51]1
Reactant: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2)C(=O)Nc2ccn(CCC(=O)O)n2)cc1Cl
Reactant: C1CCOC1
Reactant: IC[C@H]1CCCO1
Agent: [Li]CCCC
Solvent: CN1CCCN(C)C1=O
Solvent: CC(C)NC(C)C
Product: COC(=O)C(C[C@H]1CCCO1)c1ccc(SC)c(Cl)c1
Temperature: -78 °C
Reaction time: 1 h
Yield: 34 %

Procedure:
In a round bottom flask under argon was placed tetrahydrofuran (15 mL) and diisopropyl amine (357 μL, 2.55 mmol) and it was cooled to −78° C. in a dry ice/acetone bath. To this cooled solution was then added n-butyl lithium (2.5 M solution in hexanes, 970 μL, 2.43 mmol) and it was stirred for 15 min at −78° C. To this cooled solution was then added a solution of (3-chloro-4-methylsulfanyl-phenyl)-acetic acid methyl ester (prepared as in PCT WO 2003/095438 A1, Example 4, 511 mg, 2.21 mmol) in tetrahydrofuran (5 mL) and 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (2 mL) dropwise. This was then stirred for one hour at −78° C. After such time, 2(R)-iodomethyl-tetrahydro-furan (657 mg, 3.1 mmol) in 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (1 mL) was added dropwise at −78° C. The reaction was then allowed to slowly warm to 25° C. and it was stirred for 16 h. After such time, the reaction was quenched with a saturated aqueous ammonium chloride solution (20 mL) and then extracted with ethyl acetate (3×20 mL). The organics were dried over magnesium sulfate, filtered and then concentrated in vacuo. Purification on an AnaLogix Intelliflash system (40 g column, 5% ethyl acetate/hexanes to 20% ethyl acetate/hexanes) afforded 2-(3-chloro-4-methylsulfanyl-phenyl)-3-(tetrahydro-furan-2(R)-yl)-propionic acid methyl ester (237 mg, 34%) as a reaction of two diastereomers which was a light yellow oil: ES-HRMS m/e calcd for C15H19O3SCl (M+Na)+ 337.0635, observed 337.0635.