Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]([CH3:17])([CH2:13][CH:14]([CH3:16])[CH3:15])[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:18][C:19]1[CH:20]=[CH:21][C:22]([N:34]2[CH:38]=[N:37][N:36]=[N:35]2)=[C:23]([CH:33]=1)[CH2:24][NH:25][C:26](=[O:32])[C@@H:27]1[CH2:31][CH2:30][CH2:29][NH:28]1.C(Cl)CCl.C1C=NC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>CN(C=O)C>[C:1]([O:5][C:6]([NH:8][C@:9]([CH3:17])([C:10]([N:28]1[CH2:29][CH2:30][CH2:31][C@H:27]1[C:26]([NH:25][CH2:24][C:23]1[CH:33]=[C:19]([Cl:18])[CH:20]=[CH:21][C:22]=1[N:34]1[CH:38]=[N:37][N:36]=[N:35]1)=[O:32])=[O:12])[CH2:13][CH:14]([CH3:16])[CH3:15])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: O=C(NCc1cc(Cl)ccc1-n1cnnn1)[C@@H]1CCCN1
Reactant: CC(C)CC(C)(NC(=O)OC(C)(C)C)C(=O)O
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)C[C@](C)(NC(=O)OC(C)(C)C)C(=O)N1CCC[C@H]1C(=O)NCc1cc(Cl)ccc1-n1cnnn1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of 2-tert-butyloxycarbonylamino-2,4-dimethylpentanoic acid (120 mg, 0.49 mmol), N-[5-chloro-2-(1H-tetraazol-1-yl)benzyl]-L-prolinamide (150 mg, 0.49 mmol, 1.0 equiv), EDC (141 mg, 0.73 mmol, 1.5 equiv) and HOAt (33 mg, 0.24 mmol, 0.5 equiv) in DMF (1 ml) was brought to pH 8 by dropwise addition of Hünig's Base and stirred at room temperature for 18 h. The solvent was removed in vacuo, and the resulting oil was purified by silica gel chromatography (50% EtOAc-hexanes to 70% EtOAc-hexanes to EtOAc) to afford the two separate diastereomers as white solids. Diastereomer A (less polar): 1H NMR (300 MHz, CDCl3): δ 9.32 (s, 1 H), 8.10 (t, J=5.4 Hz, 1 H), 7.72 (d, J=2.1 Hz, 1 H), 7.40 (dd, J=2.1, 8.1 Hz, 1 H), 7.27 (d, J=8.1 Hz, 1 H), 5.03 (s, 1 H), 4.55–4.50 (m, 1 H), 4.23 (dd, J=6.3, 15.3 Hz, 1 H), 4.01 (dd, J=5.1, 15.3 Hz, 1 H), 3.84–3.79 (m, 1 H), 3.55–3.52 (m, 1 H), 2.22–2.12 (m, 1 H), 1.95–1.68 (m, 5 H), 1.59 (s, 3 H), 1.51–1.45 (m, 1 H), 1.34 (s, 9 H), 0.98 (d, J=6.6 Hz, 3 H), 0.85 (d, J=6.3 Hz, 3 H). Diastereomer B (more polar): 1H NMR (300 MHz, CDCl3): δ 9.29 (s, 1 H), 8.11–8.08 (m, 1 H), 7.70 (d, J=2.1 Hz, 1 H), 7.39 (dd, J=2.1, 8.4 Hz, 1 H), 7.26 (d, J=8.4 Hz, 1 H), 5.21 (s, 1 H), 4.59–4.54 (m, 1 H), 4.25 (dd, J=6.3, 15.3 Hz, 1 H), 4.00 (dd, J=4.8, 15.3 Hz, 1 H), 3.85–3.79 (m, 1 H), 3.53–3.49 (m, 1 H), 2.24–2.22 (m, 1 H), 1.97–1.83 (m, 5 H), 1.66–1.60 (m, 1 H), 1.39 (s, 3 H), 1.36 (s, 9 H), 0.97 (d, J=6.3 Hz, 3 H), 0.91 (d, J=6.6Hz, 3 H). Diastereomeric mixture: LCMS (M+H): 534.0.
Reaction SMILES: Cl.[Br:2][C:3]1[CH:4]=[C:5]([NH:10][CH2:11][CH2:12][CH2:13][O:14][CH3:15])[C:6]([NH2:9])=[CH:7][CH:8]=1.C(=O)([O-])O.[Na+].[F:21][C:22]([F:27])([F:26])[C:23](O)=O>>[Br:2][C:3]1[CH:8]=[CH:7][C:6]2[N:9]=[C:23]([C:22]([F:27])([F:26])[F:21])[N:10]([CH2:11][CH2:12][CH2:13][O:14][CH3:15])[C:5]=2[CH:4]=1
Reactant: O=C(O)C(F)(F)F
Reactant: COCCCNc1cc(Br)ccc1N
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: COCCCn1c(C(F)(F)F)nc2ccc(Br)cc21

Procedure:
0.2 ml of concentrated aqueous hydrochloric acid is added under an argon atmosphere to a solution of 12.83 g of 4-bromo-N2-(3-methoxypropyl)benzene-1,2-diamine in 5.78 ml of trifluoroacetic acid. The reaction mixture is heated to reflux for 4 hours. 2 ml of trifluoroacetic acid are once again added and the reaction mixture is heated to reflux for a further 2 hours. The reaction mixture is cooled to room temperature and neutralized with saturated aqueous sodium hydrogencarbonate solution. The mixture is extracted with ethyl acetate (3×). The combined organic phases are dried over sodium sulphate and concentrated by evaporation. The title compound is obtained as a yellow oil from the residue by means of flash chromatography (SiO2 60F). Rf=0.60 (1:2 EtOAc-heptane). Rt=4.79 (gradient I).
Reaction SMILES: [CH3:1][N:2]1[C:6](=[O:7])[CH:5]([CH3:8])[N:4]([C:9]2[CH:18]=[CH:17][C:12]([C:13]([O:15]C)=O)=[C:11]([CH3:19])[N:10]=2)[C:3]1=[O:20].[CH3:21][C:22]1[C:23]([N:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)=[N:24][CH:25]=[C:26]([CH3:28])[CH:27]=1>>[CH3:21][C:22]1[C:23]([N:29]2[CH2:30][CH2:31][N:32]([C:13]([C:12]3[CH:17]=[CH:18][C:9]([N:4]4[CH:5]([CH3:8])[C:6](=[O:7])[N:2]([CH3:1])[C:3]4=[O:20])=[N:10][C:11]=3[CH3:19])=[O:15])[CH2:33][CH2:34]2)=[N:24][CH:25]=[C:26]([CH3:28])[CH:27]=1
Reactant: Cc1cnc(N2CCNCC2)c(C)c1
Reactant: COC(=O)c1ccc(N2C(=O)N(C)C(=O)C2C)nc1C
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4C(=O)N(C)C(=O)C4C)nc3C)CC2)c(C)c1
Yield: 80.9 %

Procedure:
Using methyl 6-(3,5-dimethyl-2,4-dioxoimidazolidin-1-yl)-2-methylnicotinate (19 mg) described in Preparation Example 255 and 1-(3,5-dimethylpyridin-2-yl)piperazine (13 mg) described in Preparation Example 79 and by the reaction and treatment in the same manner as in Example 109, the title compound (24 mg) was obtained.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@@H:9]1[CH2:13][NH:12][CH2:11][C@H:10]1[C:14]([O:16][CH3:17])=[O:15].C=O.[C:20](O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@@H:9]1[CH2:13][N:12]([CH3:20])[CH2:11][C@H:10]1[C:14]([O:16][CH3:17])=[O:15]
Reactant: CC(=O)O
Reactant: COC(=O)[C@@H]1CNC[C@H]1c1ccc(F)cc1F
Agent: C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: COC(=O)[C@@H]1CN(C)C[C@H]1c1ccc(F)cc1F
Reaction time: 2 h

Procedure:
To a solution of methyl (3S,4R)-4-(2,4-difluorophenyl)pyrrolidine-3-carboxylate, from preparation 31 (500 mg, 2.07 mmol) and formaldehyde (155 μL, 2.07 mmol) in dichloromethane (20 mL) was added acetic acid (188 μL, 2.07 mmol) followed by sodium triacetoxyborohydride (659 mg, 3.11 mmol) at room temperature. The reaction mixture was stirred for 2 hours, diluted with dichloromethane (10 mL) and partitioned with saturated sodium hydrogen carbonate solution (40 mL). The phases were separated and the organic phase was washed with brine (20 mL), dried over magnesium sulfate, filtered and concentrated in vacuo to give the desired product as a colourless oil, 288 mg (54%).
Reaction SMILES: C(OCC)C.Cl.[CH2:7]([O:14][NH2:15])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[OH-].[Na+].[CH2:18]([C:22]1[CH:27]=[CH:26][C:25]([N:28]=[C:29]=[O:30])=[CH:24][CH:23]=1)[CH2:19][CH2:20][CH3:21]>O>[CH2:7]([O:14][NH:15][C:29]([NH:28][C:25]1[CH:26]=[CH:27][C:22]([CH2:18][CH2:19][CH2:20][CH3:21])=[CH:23][CH:24]=1)=[O:30])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: NOCc1ccccc1
Reactant: CCCCc1ccc(N=C=O)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOCC
Product: CCCCc1ccc(NC(=O)NOCc2ccccc2)cc1
Yield: 82.1 %

Procedure:
Diethyl ether (10 mL) was added to a suspension of O-benzylhydroxylamine hydrochloride (0.82 g, 5.1 mmol) in water (1 mL). A solution of sodium hydroxide (0.23 g, 5.8 mmol) in water (1 mL) was added and the mixture was stirred for several minutes. The aqueous layer was removed by pipette and extracted with diethyl ether (3 mL). The ether extract was added to the reaction flask. 4-Butylphenyl isocyanate (0.90 g, 5.1 mole) was added to the reaction flask via pipette in a single portion. A mild reflux occurred. The reaction mixture was allowed to stir at ambient temperature for 15 minutes then purified by flash chromatography (silica gel; 1:4 ethyl acetate:hexanes) to provide 1.25 g of 1-benzyloxy-3-(4-butylphenyl)urea as a fluffy white solid, m.p. 90.6°-91.4° C.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:13]=[CH:14][C:15]=1[N:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1)[C:6]([CH2:8][CH2:9][C:10](O)=O)=[O:7])#[N:2].[CH2:22]=[O:23].[OH-:24].[Na+].Cl>C(OCC)(=O)C>[C:1]([C:3]1[CH:4]=[C:5]([CH:13]=[CH:14][C:15]=1[N:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1)[C:6]([CH:8]1[O:24][C:22](=[O:23])[CH2:10][CH2:9]1)=[O:7])#[N:2]
Reactant: C=O
Reactant: N#Cc1cc(C(=O)CCC(=O)O)ccc1N1CCOCC1
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: CCOC(C)=O
Product: N#Cc1cc(C(=O)C2CCC(=O)O2)ccc1N1CCOCC1
Temperature: 0 °C

Procedure:
10 g of 3-(3-cyano-4-morpholino-benzoyl)-propionic acid are stirred together with 2.98 g of 35% formaldehyde solution and 76.4 ml of 0.5N sodium hydroxide solution for 16 hours at room temperature. The reaction mixture, whilst being cooled with ice-water and stirred, is then rendered acid with concentrated hydrochloric acid, and is stirred for a further 16 hours at room temperature. Ethyl acetate is afterwards added until two clear phases are formed; the aqueous phase is subsequently separated, and extracted with ethyl acetate. The organic phases are washed twice with 2N sodium carbonate solution, with water and with brine; they are then dried over sodium sulfate and concentrated by evaporation. The 4-(3-cyano-4-morpholino-benzoyl)-butyrolactone obtained as an oily residue is used directly in the following stage.
Reaction SMILES: [C:1]([C:3]([C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][CH:14]=1)[C:9]([OH:11])=O)([CH3:5])[CH3:4])#[N:2].C(Cl)(=O)C(Cl)=O.O1CCCC1.[NH2:26][C:27]1[CH:28]=[C:29]([CH:44]=[CH:45][CH:46]=1)[O:30][C:31]1[CH:32]=[CH:33][C:34]2[N:35]([CH:37]=[C:38]([NH:40][C:41](=[O:43])[CH3:42])[N:39]=2)[N:36]=1>CN(C)C=O.CN1CCCC1=O>[C:41]([NH:40][C:38]1[N:39]=[C:34]2[CH:33]=[CH:32][C:31]([O:30][C:29]3[CH:28]=[C:27]([NH:26][C:9](=[O:11])[C:8]4[CH:12]=[CH:13][CH:14]=[C:6]([C:3]([C:1]#[N:2])([CH3:4])[CH3:5])[CH:7]=4)[CH:46]=[CH:45][CH:44]=3)=[N:36][N:35]2[CH:37]=1)(=[O:43])[CH3:42]
Reactant: CC(C)(C#N)c1cccc(C(=O)O)c1
Reactant: CC(=O)Nc1cn2nc(Oc3cccc(N)c3)ccc2n1
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: CN1CCCC1=O
Product: CC(=O)Nc1cn2nc(Oc3cccc(NC(=O)c4cccc(C(C)(C)C#N)c4)c3)ccc2n1
Yield: 68.2 %

Procedure:
Using 3-(1-cyano-1-methylethyl)benzoic acid (160 mg, 0.85 mmol), oxalyl chloride (90 μL, 1.1 mmol), N,N-dimethylformamide (1 drop), tetrahydrofuran (4.0 mL), N-[6-(3-aminophenoxy)imidazo[1,2-b]pyridazin-2-yl]acetamide (200 mg, 0.71 mmol) and N-methylpyrrolidone (5.0 mL) as starting materials and in the same manner as in Example 335, the title compound (220 mg, 69%) was obtained as a white powder.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([S:12]([CH2:15][CH2:16][CH2:17][OH:18])(=[O:14])=[O:13])[CH:5]=[C:6]([CH3:11])[C:7]=1[N+:8]([O-:10])=[O:9].[C:19](=O)([O-])[O-].[Cs+].[Cs+].IC.O>C(#N)C>[CH3:19][O:18][CH2:17][CH2:16][CH2:15][S:12]([C:4]1[CH:5]=[C:6]([CH3:11])[C:7]([N+:8]([O-:10])=[O:9])=[C:2]([CH3:1])[CH:3]=1)(=[O:14])=[O:13]
Reactant: Cc1cc(S(=O)(=O)CCCO)cc(C)c1[N+](=O)[O-]
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Solvent: CI
Solvent: O
Product: COCCCS(=O)(=O)c1cc(C)c([N+](=O)[O-])c(C)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3-(3,5-Dimethyl-4-nitro-benzenesulfonyl)-propan-1-ol (1.4 g) is dissolved in 20 mL of acetonitrile, cesium carbonate (3.34 g) and iodometane (638 mL) are added and the reaction mixture is stirred at room temperature overnight. Water is added and the reaction mixture is extracted with ethyl ether. The organic phase is separated, dried over sodium sulfate and concentrated under vacuum. The residue is chromatographed on silica gel (hexane/ethyl acetate 100:0→50.50) to give the title compound. Yield: 1 g.
Reaction SMILES: [CH2:1]([O:4][N:5]=[C:6]([C:10]1[N:11]=[C:12]([NH:15][CH:16]=[O:17])[S:13][CH:14]=1)[C:7]([OH:9])=O)[CH2:2][CH3:3].[NH2:18][CH:19]1[C:40](=[O:41])[N:21]2[C:22]([C:37]([OH:39])=[O:38])=[C:23]([CH2:26][S:27][C:28]3[N:32]([CH2:33][C:34]([OH:36])=[O:35])[N:31]=[N:30][N:29]=3)[CH2:24][S:25][C@H:20]12>>[CH2:1]([O:4][N:5]=[C:6]([C:10]1[N:11]=[C:12]([NH:15][CH:16]=[O:17])[S:13][CH:14]=1)[C:7]([NH:18][CH:19]1[C:40](=[O:41])[N:21]2[C:22]([C:37]([OH:39])=[O:38])=[C:23]([CH2:26][S:27][C:28]3[N:32]([CH2:33][C:34]([OH:36])=[O:35])[N:31]=[N:30][N:29]=3)[CH2:24][S:25][C@H:20]12)=[O:9])[CH2:2][CH3:3]
Reactant: CCCON=C(C(=O)O)c1csc(NC=O)n1
Reactant: NC1C(=O)N2C(C(=O)O)=C(CSc3nnnn3CC(=O)O)CS[C@H]12
Product: CCCON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(CSc3nnnn3CC(=O)O)CS[C@H]12)c1csc(NC=O)n1
Yield: 70.6 %

Procedure:
2-n-Propoxyimino-2-(2-formamido-1,3-thiazol-4-yl)acetic acid (syn isomer) (1.73 g.) and 7-amino-3-(1-carboxymethyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (2.0 g.) were reacted according to similar manners to those of Examples 1(b), 2(b), 3(b) and 6(b) to give white powder of 7-[2-n-propoxyimino-2-(2-formamido-1,3-thiazol-4-yl)acetamido]-3-(1-carboxymethyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer) (2.32 g.).
Reaction SMILES: C(O)(C(F)(F)F)=O.[NH2:8][C:9](=[O:50])[CH2:10][C:11]1[CH:48]=[CH:47][C:46]([CH3:49])=[CH:45][C:12]=1[CH2:13][CH2:14][C:15]1[C:20]([C:21]([F:24])([F:23])[F:22])=[CH:19][N:18]=[C:17]([NH:25][C:26]2[CH:31]=[CH:30][C:29]([CH:32]3[CH2:37][CH2:36][N:35](C(OC(C)(C)C)=O)[CH2:34][CH2:33]3)=[CH:28][CH:27]=2)[N:16]=1>C(Cl)Cl.C1CCCCC1>[CH3:49][C:46]1[CH:47]=[CH:48][C:11]([CH2:10][C:9]([NH2:8])=[O:50])=[C:12]([CH2:13][CH2:14][C:15]2[C:20]([C:21]([F:24])([F:22])[F:23])=[CH:19][N:18]=[C:17]([NH:25][C:26]3[CH:27]=[CH:28][C:29]([CH:32]4[CH2:33][CH2:34][NH:35][CH2:36][CH2:37]4)=[CH:30][CH:31]=3)[N:16]=2)[CH:45]=1
Reactant: Cc1ccc(CC(N)=O)c(CCc2nc(Nc3ccc(C4CCN(C(=O)OC(C)(C)C)CC4)cc3)ncc2C(F)(F)F)c1
Solvent: C1CCCCC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1ccc(CC(N)=O)c(CCc2nc(Nc3ccc(C4CCNCC4)cc3)ncc2C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 17 h
Yield: 96.5 %

Procedure:
TFA (0.5 mL) was added to a solution of tert-butyl 4-(4-((4-(2-(2-amino-2-oxoethyl)-5-methylphenethyl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)piperidine-1-carboxylate (A90) (0.106 g, 0.177 mmol) in DCM (5 mL) and the resulting mixture stirred at room temperature for 17 hours. The solvent was removed in vacuo and the residue partitioned between EtOAc (20 mL) and 2 M aqueous NaOH (20 mL). The aqueous layer was extracted with EtOAc (2×10 mL) and the combined organic layers washed with water (20 mL), brine (20 mL) and dried over MgSO4. The volatiles were removed in vacuo to give a solid which was suspended in DCM and cyclohexane. The resulting suspension was filtered to give the title compound 21 as a white solid (0.085 g, 96%); 1H NMR (400 MHz, d4-MeOH) δ 8.54 (s, 1H), 7.62 (d, J=8.6 Hz, 2H), 7.22 (d, J=8.5 Hz, 2H), 7.14 (d, J=7.7 Hz, 1H), 7.06-6.98 (m, 2H), 3.62 (s, 2H), 3.28-3.21 (m, 2H), 3.15-3.08 (m, 2H), 3.08-3.01 (m, 2H), 2.86 (td, J=12.6, 2.6 Hz, 2H), 2.78-2.67 (m, 1H), 2.26 (s, 3H), 1.91 (d, J=12.0 Hz, 2H), 1.74 (qd, J=12.9, 4.0 Hz, 2H). LCMS-A: rt 4.94 min; m/z 498.3 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][C:3]=1[S:11]([Cl:14])(=[O:13])=[O:12].[OH:15][CH2:16][CH2:17][N:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1.S(Cl)(Cl)(=O)=O.CCOCC>C(Cl)Cl>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:15][CH2:16][CH2:17][N:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)=[O:7])=[CH:4][C:3]=1[S:11]([Cl:14])(=[O:13])=[O:12]
Reactant: O=C(Cl)c1ccc(Cl)c(S(=O)(=O)Cl)c1
Reactant: OCCN1CCOCC1
Solvent: CCOCC
Solvent: ClCCl
Solvent: O=S(=O)(Cl)Cl
Product: O=C(OCCN1CCOCC1)c1ccc(Cl)c(S(=O)(=O)Cl)c1

Procedure:
To a solution of 4-chloro-3-(chlorosulfonyl)benzoyl chloride (1.0 g, 3.6 mmol) in DCM (10 ml) was added a solution of hydroxy ethyl morpholine (443 μl, 3.6 mmol) in DCM (1 ml). The reaction mixture was stirred for 12 h after which time no sulfonyl chloride was observed by LC-MS. Upon concentration of the crude reaction mixture a solid was isolated, which was trituated with ether to afford the desired compound as a brown solid. (1.54 g, 100%) IR (neat) vmax/cm−1 1724, 1174, 1450; 6H (500 MHz, DMSO-d6) 8.49 (1H, d, 1.8 Hz), 7.97 (1H, dd, 8.2, 1.9 Hz), 7.56 (1H, d, 8.2 Hz), 4.38-5.00 (2H, m), 3.88-4.07 (2H, m), 3.76-3.83 (2H, m), 3.56-3.62 (2H, m), 3.36-3.54 (2H, m), 3.14-3.28 (2H, m).
Reaction SMILES: C(O[C:6]([N:8]1[CH2:15][C:14](=[CH2:16])[CH2:13][C@H:9]1[C:10]([OH:12])=O)=[O:7])(C)(C)C.[O:17]=[C:18]1[C:23](C(Cl)=O)=[CH:22][CH:21]=[C:20]([CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[O:19]1.[C:32]([NH2:36])([CH3:35])([CH3:34])[CH3:33]>>[C:32]([NH:36][C:10]([C@@H:9]1[CH2:13][C:14](=[CH2:16])[CH2:15][N:8]1[C:6]([C:23]1[C:18](=[O:17])[O:19][C:20]([CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])=[CH:21][CH:22]=1)=[O:7])=[O:12])([CH3:35])([CH3:34])[CH3:33]
Reactant: CC(C)(C)N
Reactant: CCCCCc1ccc(C(=O)Cl)c(=O)o1
Reactant: C=C1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Product: C=C1C[C@@H](C(=O)NC(C)(C)C)N(C(=O)c2ccc(CCCCC)oc2=O)C1

Procedure:
Following the general method as outlined in Example 22, starting from 1-(tert-butoxycarbonyl)-4-methyleneproline, 2-oxo-6-pentyl-2H-pyran-3-carbonyl chloride, and tert-butylamine the title compound was obtained in 100% purity by LC/MS. MS(ESI+): m/z=375.4.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9]/[C:10](=[C:17]2\[C:18](=[O:26])[NH:19][C:20]3[C:25]\2=[CH:24][CH:23]=[CH:22][CH:21]=3)/[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:5][CH:4]=1)#[N:2].[H][H]>N.[Ni]>[NH2:2][CH2:1][C:3]1[CH:4]=[CH:5][C:6]([NH:9]/[C:10](=[C:17]2\[C:18](=[O:26])[NH:19][C:20]3[C:25]\2=[CH:24][CH:23]=[CH:22][CH:21]=3)/[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:7][CH:8]=1
Reactant: [H][H]
Reactant: N#Cc1ccc(N/C(=C2\C(=O)Nc3ccccc32)c2ccccc2)cc1
Agent: [Ni]
Agent: N
Product: NCc1ccc(N/C(=C2\C(=O)Nc3ccccc32)c2ccccc2)cc1

Procedure:
900 mg (2.7 mmol) of (Z)-3-[1-(4-cyanophenylamino)-1-phenyl-methylidene]-2-indolinone are hydrogenated in 200 ml of methanolic ammonia for 7 hours over 1.4 g of Raney nickel at a hydrogen pressure of 3 bar. The catalyst is filtered off, the solution is concentrated by evaporation and the residue is divided between water/dichloromethane. The organic phase is dried, concentrated by evaporation, triturated with ether, suction filtered and dried.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:23][CH2:24][O:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([N+:32]([O-:34])=[O:33])[CH:27]=1>CN(C)C=O.O>[N+:32]([C:28]1[CH:27]=[C:26]([CH:31]=[CH:30][CH:29]=1)[O:25][CH2:24][CH2:23][NH:1][C:2]1[CH:3]=[C:4]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:12])([CH3:14])[CH3:13])[CH:5]=[CH:6][CH:7]=1)([O-:34])=[O:33]
Reactant: O=[N+]([O-])c1cccc(OCCBr)c1
Reactant: CC(C)(C)OC(=O)Nc1cccc(N)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)Nc1cccc(NCCOc2cccc([N+](=O)[O-])c2)c1
Temperature: 80 °C
Reaction time: 16 h

Procedure:
A solution of tert-butyl (3-aminophenyl)carbamate (1.0 g, 4.8 mmol) and potassium carbonate (1.3 g, 9.6 mmol) in N,N-dimethylformamide (10 mL) was treated with a solution of 1-(2-bromoethoxy)-3-nitrobenzene (1.2 g, 5.0 mmol) in N,N-dimethylformamide (5 mL) was stirred at 20° C. for 2 h and at 80° C. for 16 h. The reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (3×80 mL). The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate, filtered, and evaporated to give the desired product as a crude residue. This material was purified by flash column chromatography to give the desired product (1.0 g, 56%) as a yellow gum. LCMS for C19H24N3O5 (M+H)+: m/z=374.2.
Reaction SMILES: [Cl:1][C:2]1[C:23]2[O:22][C:9]3[C:10](=[O:21])[N:11]([C@@H:13]([CH2:17][CH:18]([CH3:20])[CH3:19])[C:14](O)=[O:15])[CH2:12][C:8]=3[CH2:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[NH2:24][C:25]1[S:26][CH:27]=[CH:28][N:29]=1.ON1C2C=CC=CC=2N=N1>C(Cl)Cl.O>[S:26]1[CH:27]=[CH:28][N:29]=[C:25]1[NH:24][C:14](=[O:15])[C@@H:13]([N:11]1[CH2:12][C:8]2[CH2:7][C:6]3[CH:5]=[CH:4][CH:3]=[C:2]([Cl:1])[C:23]=3[O:22][C:9]=2[C:10]1=[O:21])[CH2:17][CH:18]([CH3:19])[CH3:20]
Reactant: CC(C)C[C@@H](C(=O)O)N1CC2=C(Oc3c(Cl)cccc3C2)C1=O
Reactant: Nc1nccs1
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClCCl
Product: CC(C)C[C@@H](C(=O)Nc1nccs1)N1CC2=C(Oc3c(Cl)cccc3C2)C1=O
Yield: 99.1 %

Procedure:
A solution of (S)-2-(5-chloro-3-oxo-3,9-dihydro-1H-chromeno[2,3-c]pyrrol-2-yl)-4-methyl-pentanoic acid (130 mg, 0.35 mmol) (Example 22, Step 1c), commercially available 2-aminothiazole (47 mg, 0.36 mmol), N-ethyl-N-dimethyaminopropyl carbodiimide hydrochloride (EDCI. HCl) (82 mg, 0.43 mmol), and N-hydroxybenzotriazole (HOBt) (57 mg, 0.43 mmol) in methylene chloride (15 mL) was stirred for 16 hours at 25° C. The reaction mixture was diluted with water and extracted with ethyl acetate (3×). The combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo. The resulting residue, upon silica gel flash chromatography using hexane-ethyl acetate gradient elution, afforded (S)-2-(5-chloro-3-oxo-3,9-dihydro-1H-chromeno[2,3-c]pyrrol-2-yl)-4-methyl-pentanoic acid thiazol-2-ylamide (145 mg, 58.2%), as a white solid. 1H NMR (DMSO-d6) δ: 12.57 (s, 1H), 7.50 (d, J=3.4 Hz, 1H), 7.40 (d, J=7.8 Hz, 1H), 7.20-7.29 (m, 2H), 7.08-7.16 (m, 1H), 5.05 (dd, J=10.8, 4.4 Hz, 1H), 4.39 (d, J=19.1 Hz, 1H), 4.09 (d, J=19.1 Hz, 1H), 3.75-3.91 (m, 2H), 1.80-1.93 (m, 1H), 1.62-1.75 (m, 1H), 1.46 (br. s., 1H), 0.94 (t, J=6.6 Hz, 6H).
Reaction SMILES: [CH3:1][N:2](C)/[CH:3]=[CH:4]/[C:5](=[O:11])[CH:6]([O:9][CH3:10])[O:7][CH3:8].C(N)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C1(C)C=CC=CC=1>[CH2:1]([NH:2]/[CH:3]=[CH:4]/[C:5](=[O:11])[CH:6]([O:9][CH3:10])[O:7][CH3:8])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: COC(OC)C(=O)/C=C/N(C)C
Reactant: NCc1ccccc1
Solvent: Cc1ccccc1
Product: COC(OC)C(=O)/C=C/NCc1ccccc1
Yield: 42.8 %

Procedure:
A mixture of (E)-4-(dimethylamino)-1,1-dimethoxybut-3-en-2-one (11 g, 63.5 mmol) and benzylamine (6.94 ml, 63.5 mmol) in toluene (130 ml) was stirred under reflux for 4 hours. Evaporated to dryness under vacuum, the residue was applied on a column, eluted with petroleum ether-ethyl acetate mixture 3:1, fractions collected to give (E)-4-(benzylamino)-1,1-dimethoxybut-3-en-2-one (6.4 g, 27.2 mmol, 42.8% yield) as dark yellow oil.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([CH:6]=[O:7])[CH:3]=[N:2]1.[H-].[Na+].[F:10][C:11]([F:25])([F:24])[CH2:12]OS(C1C=CC(C)=CC=1)(=O)=O>CN(C=O)C>[F:10][C:11]([F:25])([F:24])[CH2:12][N:1]1[CH:5]=[C:4]([CH:6]=[O:7])[CH:3]=[N:2]1
Reactant: Cc1ccc(S(=O)(=O)OCC(F)(F)F)cc1
Reactant: O=Cc1cn[nH]c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=Cc1cnn(CC(F)(F)F)c1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
Add 1H-pyrazole-4-carbaldehyde (0.400 g, 4.16 mmol) as a solution in DMF (2 mL) dropwise to a suspension of sodium hydride (0.333 g, 8.32 mmol) in DMF (5 mL) at 0° C. Stir for 15 min. at 0° C. Add 2,2,2-trifluoroethyl-p-toluenesulfonate (1.27 g, 5.00 mmol) and DMF (3 mL) to the reaction mixture. Heat to 60° C. for 18 hr. Quench with aqueous saturated sodium bicarbonate solution and add ethyl acetate. Separate organic layer. Extract aqueous layer twice with ethyl acetate, wash combined organics with brine, dry (magnesium sulfate), filter, concentrate and purify (silica gel chromatography, eluting with 0:100 to 100:0 ethyl acetate:hexanes) to give the title preparation (309 mg, 42%). GC-MS: m/z=178 [M+].
Reaction SMILES: S(Cl)(Cl)(=O)=O.C(S[S:9][CH2:10][CH3:11])C.[CH3:12][NH:13][C:14]([NH:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[C:19]([Cl:25])[CH:18]=1)=[O:15].Cl>C(Cl)Cl.N1C=CC=CC=1>[CH3:12][N:13]([S:9][CH2:10][CH3:11])[C:14]([NH:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[C:19]([Cl:25])[CH:18]=1)=[O:15]
Reactant: CCSSCC
Reactant: CNC(=O)Nc1ccc(OC)c(Cl)c1
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: O=S(=O)(Cl)Cl
Product: CCSN(C)C(=O)Nc1ccc(OC)c(Cl)c1
Temperature: -5 °C
Reaction time: 0.08 h

Procedure:
A mixture of 67 g of sulfuryl chloride and 100 ml of methylene chloride was slowly added at -40° C. to 68 g of diethyl disulfide in 600 ml of methylene chloride and after the temperature was slowly raised to -5° C., the mixture was stirred at -5° C. for 5 minutes. The mixture was then cooled to -40° C. and a solution of 56 g of N-methyl-N'-(3-chloro-4-methoxyphenyl)-urea in 800 ml of pyridine was added thereto. The mixture was stirred at -20° C. for 2 hours and was then added to a water-ice mixture. The pH of the mixture was adjusted to 5 by addition of an aqueous concentrated solution of hydrochloric acid and was extracted with methylene chloride. The combined organic extracts were washed with water until the wash water was neutral, then dried and distilled to dryness under reduced pressure. The residue was chromatographed over silica gel and eluted with a 7-3 benzene-ethyl acetate mixture. The product was crystallized from isopropyl ether to obtain 23.5 g of N-methyl-N-ethylthio-N'-(3-chloro-4-methoxyphenyl)-urea melting at 60° C.