Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][CH:10]=[C:9]([F:13])[C:3]=1[C:4](=[NH:8])[O:5][CH2:6][CH3:7].C(N(CC)CC)C.[CH3:21][C:22]1([C:28](Cl)=[O:29])[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1>C1(C)C=CC=CC=1>[CH3:21][C:22]1([C:28]([N:8]=[C:4]([O:5][CH2:6][CH3:7])[C:3]2[C:9]([F:13])=[CH:10][CH:11]=[CH:12][C:2]=2[Cl:1])=[O:29])[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: CC1(C(=O)Cl)CCCCC1
Reactant: CCOC(=N)c1c(F)cccc1Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCOC(=NC(=O)C1(C)CCCCC1)c1c(F)cccc1Cl

Procedure:
Ethyl 2-chloro-6-fluoro-benzimidate (1.61 g) and triethylamine (1.0 g) are dissolved in toluene (100 ml), to which is added dropwise 1-methylcyclohexylcarbonyl chloride (1.5 g) at 5°-10° C. with stirring and thereafter stirred at room temperature for 1 hour. Further, it is reacted at 80°-100° C. for 16 hours. After the completion of the reaction, the reaction solution is washed with a saline solution and further with water and then the resulting toluene layer is dried on sodium sulfate and concentrated to obtain crude product of ethyl N-(1-methylcyclohexylcarbonyl)-2-chloro-6-fluorobenzimidate.
Reaction SMILES: [C:1](=[O:27])(OC1C=CC([N+]([O-])=O)=CC=1)[O:2][CH:3]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14](=[O:16])[NH2:15])=[CH:10][N:9]=2)[CH2:4]1.[CH:28]([N:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1)([CH3:30])[CH3:29]>C(Cl)Cl>[CH:28]([N:31]1[CH2:36][CH2:35][N:34]([C:1]([O:2][CH:3]2[CH2:7][CH2:6][N:5]([C:8]3[CH:13]=[CH:12][C:11]([C:14](=[O:16])[NH2:15])=[CH:10][N:9]=3)[CH2:4]2)=[O:27])[CH2:33][CH2:32]1)([CH3:30])[CH3:29]
Reactant: NC(=O)c1ccc(N2CCC(OC(=O)Oc3ccc([N+](=O)[O-])cc3)C2)nc1
Reactant: CC(C)N1CCNCC1
Solvent: ClCCl
Product: CC(C)N1CCN(C(=O)OC2CCN(c3ccc(C(N)=O)cn3)C2)CC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 1-(5-carbamoylpyridin-2-yl)-pyrrolidin-3-yl 4-nitrophenyl carbonate (0.37 g, 1 mmol) in DCM (5 ml) was added 1-isopropylpiperazine (0.13 g, 1 mmol). The resulting solution was stirred under N2 at room temperature for 24 h. The reaction mixture was then filtered and the filter cake was washed with DCM. The combined filtrates were concentrated to afford the crude product. After further purified by preparative HPLC, the title compound was obtained as a yellow solid (36 mg, 10%). [1H NMR (500 MHz, CDCl3) δ8.60 (d, 1H), 7.94 (dd, 1H), 7.72 (s, 1H), 7.09 (s, 1H), 6.48 (d, 1H), 5.25 (s, 1H), 3.66 (m, 2H), 3.55 (m, 2H), 3.31 (m, 4H), 2.63 (m, 1H), 2.36 (m, 4H), 2.21 (m, 1H), 2.10 (m, 1H), 0.92 (d, 6H, J=6.5 Hz); LCMS RtA=1.58 min, [M+H]+=362.2].
Reaction SMILES: [Cl-].[CH3:2][O:3][CH2:4][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C([Li])CCC.[CH3:29][C:30]1[CH:37]=[CH:36][C:33]([CH:34]=O)=[CH:32][CH:31]=1.[Cl-].[Na+]>C(OCC)C>[CH3:2][O:3][CH:4]=[CH:34][C:33]1[CH:36]=[CH:37][C:30]([CH3:29])=[CH:31][CH:32]=1
Reactant: Cc1ccc(C=O)cc1
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: CCOCC
Product: COC=Cc1ccc(C)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 63.3 %

Procedure:
28.5 g of methoxymethyltriphenylphosphonium chloride is introduced into 350 ml of diethyl ether under nitrogen. At 0° C., 39.95 ml of n-butyllithium solution (1.6 M in hexane) is added in drops, and it is stirred for one hour at room temperature. 10 g of 4-methylbenzaldehyde in 50 ml of diethyl ether is now added, and it is stirred for one more hour. Sodium chloride solution is added to the reaction mixture, extracted with ethyl acetate, dried on sodium sulfate and concentrated by evaporation. After chromatography on silica gel with ethyl acetate/hexane, 7.8 g of 1-methoxy-2-(4-methylphenyl)-ethene 36 (E,Z-mixture) is obtained as a colorless oil, which is dissolved in 200 ml of acetone and is stirred overnight under nitrogen with 10 ml of 2N hydrochloric acid. Sodium chloride solution is added, extracted with ethyl acetate, dried on sodium sulfate and concentrated by evaporation. Chromatographic purification on silica gel with ethyl acetate/hexane yields 4.5 g of title compound 37 as a colorless oil.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:5][CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=1)[CH2:3][OH:4].[N:15]#[C:16]Br>>[Cl:14][C:11]1[CH:10]=[CH:9][C:8]([O:7][CH2:6][CH2:5][C@H:2]2[CH2:3][O:4][C:16]([NH2:15])=[N:1]2)=[CH:13][CH:12]=1
Reactant: N[C@H](CO)CCOc1ccc(Cl)cc1
Reactant: N#CBr
Product: NC1=N[C@@H](CCOc2ccc(Cl)cc2)CO1

Procedure:
In analogy to example 1d (S)-2-amino-4-(4-chloro-phenoxy)-butan-1-ol was reacted with cyanogen bromide to give (S)-4-[2-(4-chloro-phenoxy)-ethyl]-4,5-dihydro-oxazol-2-ylamine. White solid. MS (ISP): 240.9 ([M+H]+))
Reaction SMILES: [C:1]([O:5][C:6](=[O:28])[NH:7][CH2:8][CH2:9][NH:10][CH2:11][CH2:12][CH2:13][C:14]1[C:22]2[C:17](=[CH:18][CH:19]=[C:20]([N:23]3[CH:27]=[N:26][N:25]=[CH:24]3)[CH:21]=2)[NH:16][CH:15]=1)([CH3:4])([CH3:3])[CH3:2].[CH:29](=O)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.C(O)(=O)C.C([BH3-])#N.[Na+]>CO>[C:1]([O:5][C:6](=[O:28])[NH:7][CH2:8][CH2:9][N:10]([CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH2:11][CH2:12][CH2:13][C:14]1[C:22]2[C:17](=[CH:18][CH:19]=[C:20]([N:23]3[CH:27]=[N:26][N:25]=[CH:24]3)[CH:21]=2)[NH:16][CH:15]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCCNCCCc1c[nH]c2ccc(-n3cnnc3)cc12
Reactant: O=Cc1ccccc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)NCCN(CCCc1c[nH]c2ccc(-n3cnnc3)cc12)Cc1ccccc1
Reaction time: 4 h
Yield: 77.3 %

Procedure:
To a solution of 2-[(3-[5-(1,2,4-triazol-4-yl)-1H-indol-3-yl]propyl)amino]ethyl carbamic acid tert-butyl ester (0.42 g, 1.2 mmol) in methanol (10 ml) at 0° C. was added benzaldehyde (133 μl, 1.3 mmol), acetic acid (189 μl, 3.3 mmol) and sodium cyanoborohydride (137 mg, 2.2 mmol). After addition the cooling bath was removed and the mixture stirred for 4 h. After this time more benzaldehyde (110 μl, 1.1 mmol) was added and the mixture stirred for 18 h. More benzaldehyde (110 μl, 1.1 mmol) was added and the mixture stirred for a further 10 min. The solvents were evaporated and the residue partitioned between EtOAc (2×50 ml) and water (50 ml). The combined organic layers were dried (Na2SO4) and evaporated. The residue was chromatographed on silica gel, eluting with CH2Cl2 :MeOH:NH3 (95:5:1), to give the desired product (0.44 g, 85%) as a pale yellow foam. 1H NMR (360 MHz, CDCl3) δ1.41 (9H, s), 1.84-1.96 (2H, m), 2.52-2.58 (4H, m), 2.75 (2H, t, J=7.5 Hz), 3.12-3.20 (2H, m), 3.58 (2H, s), 4.78 (1H, br s), 7.03 (1H, s), 7.14 (1H, dd, J=8.5 and 2.0 Hz), 7.21-7.36 (5H, m), 7.45 (1H, d, J=8.5 Hz), 7.51 (1H, d, J=2.0 Hz), 8.29 (1H, br s), 8.45 (2H, s). MS (ES+) (475, M+1).
Reaction SMILES: Cl.Cl.[CH2:3]([C:7]1[N:12]=[N:11][C:10]([O:13][CH2:14][CH:15]2[O:20][CH2:19][CH2:18][NH:17][CH2:16]2)=[CH:9][C:8]=1[C:21]1[CH:26]=[CH:25][C:24]([O:27][CH:28]2[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]2)=[CH:23][CH:22]=1)[CH2:4][CH2:5][CH3:6].C=O.[C:36](O[BH-](OC(=O)C)OC(=O)C)(=O)C>C(Cl)Cl>[CH2:3]([C:7]1[N:12]=[N:11][C:10]([O:13][CH2:14][CH:15]2[O:20][CH2:19][CH2:18][N:17]([CH3:36])[CH2:16]2)=[CH:9][C:8]=1[C:21]1[CH:22]=[CH:23][C:24]([O:27][CH:28]2[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]2)=[CH:25][CH:26]=1)[CH2:4][CH2:5][CH3:6]
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: CCCCc1nnc(OCC2CNCCO2)cc1-c1ccc(OC2CCCCC2)cc1
Agent: C=O
Agent: Cl
Solvent: ClCCl
Product: CCCCc1nnc(OCC2CN(C)CCO2)cc1-c1ccc(OC2CCCCC2)cc1
Reaction time: 12 h

Procedure:
To a solution of 2-[6-butyl-5-(4-cyclohexyloxy-phenyl)-pyridazin-3-yloxymethyl]-morpholine dihydrochloride (0.067 mmol, 0.031 g) and aqueous formaldehyde (37%, 0.304 mmol, 0.025 mL) in dry DCM (2 mL) was added macroporous resin-bound triacetoxyborohydride (loading 2.36 mmol/gram, 0.364 mmol, 0.154 g). The mixture was shaken for 12 hours. The reaction was filtered and the resin was washed with DCM (5 mL). The solvent was removed under reduced pressure. The crude product was purified on a 4 g SiO2 cartridge with 4-6% (2N NH3 in MeOH) in DCM to give 2-[6-butyl-5-(4-cyclohexyloxy-phenyl)-pyridazin-3-yloxymethyl]-4-methyl-morpholine. The neutral amine was treated with 2N HCl in diethyl ether (1 mL) and DCM (1 mL). The volatiles were removed under reduced pressure and the salt was triturated with diethyl ether and filtered to provide the title compound (0.022 g). LCMS: m/z 441 [M+1]. 1H NMR (400 MHz, CD3OD) δ 7.35-7.46 (3H, m), 7.09 (2H, d), 4.56-4.68 (2H, m), 4.38-4.47 (1H, m), 4.13-4.29 (2H, m), 3.91 (1H, t), 3.68 (1H, d), 3.49 (1H, d), 3.12-3.26 (2H, m), 3.00-3.09 (2H, m), 2.97 (3H, s), 1.99-2.02 (2H, m), 1.80-1.82 (2H, m), 1.19-1.66 (10H, m), 0.81 (3H, t).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[CH2:11]([O:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][NH2:20])[C:12]#[CH:13]>>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([NH:20][CH2:19][CH2:18][O:17][CH2:16][CH2:15][O:14][CH2:11][C:12]#[CH:13])=[CH:3][CH:4]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccc(Cl)cc1
Reactant: C#CCOCCOCCN
Product: C#CCOCCOCCNc1ccc([N+](=O)[O-])cc1
Temperature: 100 °C
Yield: 15.6 %

Procedure:
To 1-chloro-4-nitrobenzene (152 mg, 0.97 mmol, 1.0 equiv.) was added neat 2-(2-(prop-2-ynyloxy)ethoxy)ethanamine (s-5) (900 mg, 6.31 mmol, 6.5 equiv.), and the resulting slurry was heated to 100° C. for 19 hours. At the end of this period, the heating bath was removed, and the reaction content was mixed with water (50 mL) and then extracted with CH2Cl2 (3×50 mL). The organic layers were combined, dried with Na2SO4, concentrated under reduced pressure, and chromatographed (silica gel, 1×25 cm, 0% EtOAc in CH2Cl2, then 30% EtOAc in CH2Cl2 to yield 4-nitro-N-(2-(2-(prop-2-ynyloxy)ethoxy)ethyl)aniline (s-7) as a dark yellow oil (40 mg, 16%). IR (thin film) 3351 (m), 3239 (m), 2858 (w), 2112 (w), 1599 (s), 1535 (w), 1500 (w), 1467 (s), 1284 (s), 1086 (s), 1034 (w); 1H NMR (400 MHz, CDCl3) δ 8.06 (d, J=9.2 Hz, 2H), 6.53 (d, J=9.2 Hz, 2H), 5.05 (bs, 1H), 4.19 (d, J=2.4 Hz, 2H), 3.76-3.70 (m, 2H), 3.70-3.64 (m, 4H), 3.38 (q, J=5.3 Hz, 2H), 2.45 (t, J=2.4 Hz, 1H). 13C NMR (125 MHz, CDCl3) □153.4, 138.0, 126.4, 111.2, 79.5, 74.9, 70.3, 69.1, 69.0, 58.5, 42.9. HRMS (ES+) calc'd for C13H16N2O4 (M+H) m/z 265.1144 Found 265.1177.
Reaction SMILES: C(N(C(C)C)CC)(C)C.Cl.[CH2:11]([O:18][C:19]1[C:20]([C:42]2[CH:47]=[CH:46][C:45]([F:48])=[CH:44][CH:43]=2)=[CH:21][C:22]([CH2:40][CH3:41])=[C:23]([CH:39]=1)[O:24][CH2:25][CH2:26][CH2:27][O:28][C:29]1[C:30]([CH2:36][CH2:37][CH3:38])=[C:31]([CH:33]=[CH:34][CH:35]=1)[NH2:32])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[CH3:49][C:50]1([CH3:57])[CH2:54][C:53](=[O:55])[O:52][C:51]1=[O:56]>C1COCC1>[CH2:11]([O:18][C:19]1[C:20]([C:42]2[CH:43]=[CH:44][C:45]([F:48])=[CH:46][CH:47]=2)=[CH:21][C:22]([CH2:40][CH3:41])=[C:23]([CH:39]=1)[O:24][CH2:25][CH2:26][CH2:27][O:28][C:29]1[C:30]([CH2:36][CH2:37][CH3:38])=[C:31]([NH:32][C:53](=[O:55])[CH2:54][C:50]([CH3:57])([CH3:49])[C:51]([OH:56])=[O:52])[CH:33]=[CH:34][CH:35]=1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: CC1(C)CC(=O)OC1=O
Reactant: CCCc1c(N)cccc1OCCCOc1cc(OCc2ccccc2)c(-c2ccc(F)cc2)cc1CC
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCCc1c(NC(=O)CC(C)(C)C(=O)O)cccc1OCCCOc1cc(OCc2ccccc2)c(-c2ccc(F)cc2)cc1CC
Temperature: 35 °C
Yield: 82.4 %

Procedure:
Add diisopropylethylamine (57 mL, 327 mmol) to a suspension of 3-[3-[5-benzyloxy-2-ethyl-4-(4-fluorophenyl)phenoxy]propoxy]-2-propyl-aniline hydrochloride (90 g, 175 mmol) in THF (450 mL). To this mixture, add dihydro-3,3-dimethyl-2,5-furandione (32.1 g, 251 mmol) and stir at 35° C. until LCMS indicates 5% starting material remaining. Concentrate the mixture in vacuo and add methyl tert-butyl ether (100 mL) and water (75 mL). Adjust to pH=2-3 with phosphoric acid and separate the layers. Wash the aqueous layer with additional methyl tert-butyl ether (2×50 mL). Wash the combined organic extracts with brine and concentrate in vacuo. Dissolve the crude residue in methyl tert-butyl ether (180 mL) and add hexane (450 mL) to obtain a suspension and stir for 30 min. Collect the suspension by filtration and dry to yield the title compound (92.5 g, 88%) as a white solid. ES/MS m/z 642 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:13]=[CH:12][C:6]2[N:7]([CH3:11])[CH2:8][CH2:9][O:10][C:5]=2[CH:4]=1.[Cl-].[Cl-].[Cl-].[Al+3].[C:18](Cl)(=[O:20])[CH3:19].Cl>ClCCCl>[CH3:1][O:2][C:3]1[C:13]([C:18](=[O:20])[CH3:19])=[CH:12][C:6]2[N:7]([CH3:11])[CH2:8][CH2:9][O:10][C:5]=2[CH:4]=1
Reactant: CC(=O)Cl
Reactant: COc1ccc2c(c1)OCCN2C
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: COc1cc2c(cc1C(C)=O)N(C)CCO2
Temperature: 0 °C
Reaction time: 2.5 h
Yield: 7.6 %

Procedure:
7-Methoxy-4-methyl-3,4-dihydro-2H-benzo[1,4]oxazine (11.17 g, 0.625 mol) in 400 mL of 1,2-dichloroethane was stirred at 0° C. under nitrogen. Aluminum trichloride (8.3 g, 0.625 mol) was added in portions, followed by dropwise addition of acetyl chloride (4.9 mL, 0.678 mol). The reaction mixture was stirred at 0° C. for 2.5 hours. Aluminum trichloride (3 g) was added, and the reaction mixture was stirred at room temperature for 24 hours. The reaction mixture was pourd into ice and 550 mL 3N HCl was added. The aqueous mixture was extracted with methylene chloride, and the combined organic layers were dried (MgSO4), filtered, and evaporated under reduced pressure to yield 10.48 g of 1-(7-Methoxy-4-methyl-3,4-dihydro-2H-benzo[1,4]oxazin-6-yl)-ethanone. (M+H)=222.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[N:10]1[CH2:15][CH2:14][CH2:13][CH2:12][C@H:11]1[C:16]([OH:18])=O.[NH2:19][C@H:20]1[CH2:24][N:23]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[C@H:22]([CH2:32][O:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH2:21]1>>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[N:10]1[CH2:15][CH2:14][CH2:13][CH2:12][C@H:11]1[C:16]([NH:19][C@H:20]1[CH2:24][N:23]([C:25]([O:27][C:28]([CH3:30])([CH3:31])[CH3:29])=[O:26])[C@H:22]([CH2:32][O:33][CH2:34][C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)[CH2:21]1)=[O:18]
Reactant: O=C(O)[C@@H]1CCCCN1c1nc2ccccc2o1
Reactant: CC(C)(C)OC(=O)N1C[C@H](N)C[C@H]1COCc1ccccc1
Product: CC(C)(C)OC(=O)N1C[C@H](NC(=O)[C@@H]2CCCCN2c2nc3ccccc3o2)C[C@H]1COCc1ccccc1

Procedure:
The title compound was prepared by a similar method to Example 1 from (2S)-1-(1,3-benzoxazol-2-yl)-2-piperidinecarboxylic acid [see Preparation 3] and tert-butyl (2S,4R)-4-amino-2-[(benzyloxy)methyl]pyrrolidine-1-carboxylate [see Preparation 34]. The crude product was purified by column chromatography on silica gel eluting with a solvent gradient of 70:30 changing to 50:50, by volume, hexane: ethyl acetate to afford tert-butyl (2S,4R)-4-([(2S)-1-(1,3-benzoxazol-2-yl)-2-piperidinyl]carbonylamino)-2-[(benzyloxy)methyl]pyrrolidine-1-carboxylate as a foam.
Reaction SMILES: [C:1]1([CH:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[O:8][NH2:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:16]([C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH:25]([CH3:27])[CH3:26])[C:20]=1[N:28]=[C:29]=[O:30])([CH3:18])[CH3:17]>C(OCC)(=O)C>[CH3:18][CH:16]([C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH:25]([CH3:26])[CH3:27])[C:20]=1[NH:28][C:29]([NH:9][O:8][CH:7]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)=[O:30])[CH3:17]
Reactant: CC(C)c1cccc(C(C)C)c1N=C=O
Reactant: NOC(c1ccccc1)c1ccccc1
Solvent: CCOC(C)=O
Product: CC(C)c1cccc(C(C)C)c1NC(=O)NOC(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 80 %

Procedure:
To a solution of 1,1-diphenylmethoxyamine (0.9 g, 0.0045 mol) (E. L. Schumann, et al, Journal of Medicinal Chemistry, Volume 7, pages 329-334 (1964)) in 20 ml of ethyl acetate is added 2,6-diisopropylphenyl isocyanate (0.91 g, 0.0045 mol) and the reaction mixture is stirred for 20 hours at room temperature. The volatiles are removed under reduced pressure and the residue treated with 30 ml hexane-ethyl acetate (4:1). The precipitated solid is filtered and dried affording 1.45 g of N-[2,6-bis(1-methylethyl)phenyl]-N'-(diphenylmethoxy)-urea; mp 152°-154° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([N+:14]([O-:16])=[O:15])[CH:13]=1)[C:8](Cl)=[O:9])=[O:4].CC(C)=O.[NH2:21][CH2:22][C:23]([OH:25])=[O:24].C(=O)(O)[O-].[Na+]>O>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([N+:14]([O-:16])=[O:15])[CH:13]=1)[C:8]([NH:21][CH2:22][C:23]([OH:25])=[O:24])=[O:9])=[O:4]
Reactant: COC(=O)c1cc(C(=O)Cl)cc([N+](=O)[O-])c1
Reactant: NCC(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: COC(=O)c1cc(C(=O)NCC(=O)O)cc([N+](=O)[O-])c1

Procedure:
Under agitation and during the course of 21/2 hours, 183.0 g. (0.75 mole) of 3-methoxycarbonyl-5-nitrobenzoyl chloride in 750 ml. of acetone is added dropwise to a solution of 62.0 g. (0.825 mole) of glycine and 189.0 G. of sodium bicarbonate in 3 l. of water. The first-obtained precipitate is gradually dissolved again after an additional three hours of agitation. Thereafter, the reaction mixture is extracted twice with ether, the acqueous phase is acidified with concentrated hydrochloric acid, the thus-precipitated oil is extracted repeatedly with ethyl acetate, and the combined ethyl acetate extracts, after washing with water and drying with sodium sulfate, are mixed with a stoichiometric amount of dicyclohexylamine. After allowing the reaction mixture to stand for some time, it is filtered off from the precipitated dicyclohexylammonium salt (m.p. 204°-205° C. from chloroform/ether), washed several times with ether, and the acid is liberated again by distributing the reaction mixture between ethyl acetate and 2N sulfuric acid. After washing the ethyl phases with water, drying with sodium sulfate, and concentrating under vacuum, 181.0 g. of the above-identified compound is obtained. M.P. 142°-143°C.
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([C:8]([OH:11])([CH3:10])[CH3:9])=[CH:4][CH:3]=1.[NH2:12][C:13]1[S:14][C:15]([C:21]2[CH:26]=[CH:25][C:24]([C:27]([OH:30])([CH3:29])[CH3:28])=[CH:23][C:22]=2[F:31])=[CH:16][C:17]=1[C:18]([NH2:20])=[O:19]>>[F:31][C:22]1[CH:23]=[C:24]([C:27]([OH:30])([CH3:28])[CH3:29])[CH:25]=[CH:26][C:21]=1[C:15]1[S:14][C:13]([NH:12][C:2]2[N:7]=[N:6][C:5]([C:8]([OH:11])([CH3:10])[CH3:9])=[CH:4][CH:3]=2)=[C:17]([C:18]([NH2:20])=[O:19])[CH:16]=1
Reactant: CC(C)(O)c1ccc(Cl)nn1
Reactant: CC(C)(O)c1ccc(-c2cc(C(N)=O)c(N)s2)c(F)c1
Product: CC(C)(O)c1ccc(-c2cc(C(N)=O)c(Nc3ccc(C(C)(C)O)nn3)s2)c(F)c1

Procedure:
The title compound was prepared by using the procedure listed in Example 1 with starting materials 2-(6-chloropyridazin-3-yl)propan-2-ol (Intermediate 45) (117 mg, 0.68 mmol) and 2-amino-5-[2-fluoro-4-(1-hydroxy-1-methylethyl)phenyl]thiophene-3-carboxamide (200 mg, 0.68 mmol).
Reaction SMILES: C([O:5][C:6](=[O:30])[CH2:7][CH2:8][N:9]1[CH2:14][CH2:13][O:12][CH:11]([C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:22]3[C:27]([Cl:28])=[CH:26][CH:25]=[CH:24][C:23]=3[Cl:29])=[CH:17][CH:16]=2)[CH2:10]1)(C)(C)C.Cl.O1CCOCC1>>[ClH:28].[Cl:28][C:27]1[CH:26]=[CH:25][CH:24]=[C:23]([Cl:29])[C:22]=1[NH:21][C:18]1[CH:17]=[CH:16][C:15]([CH:11]2[O:12][CH2:13][CH2:14][N:9]([CH2:8][CH2:7][C:6]([OH:30])=[O:5])[CH2:10]2)=[CH:20][CH:19]=1
Reactant: CC(C)(C)OC(=O)CCN1CCOC(c2ccc(Nc3c(Cl)cccc3Cl)cc2)C1
Agent: Cl
Solvent: C1COCCO1
Product: O=C(O)CCN1CCOC(c2ccc(Nc3c(Cl)cccc3Cl)cc2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 173.7 %

Procedure:
3-{2-[4-(2,6-Dichloro-phenylamino)-phenyl]-morpholin-4-yl}-propionic acid tert-butyl ester (0.36 g; 0.80 mmol) was treated with HCl in 1,4-dioxane (3.99 mL; 4.00 mol/L; 15.95 mmol) and stirred overnight at room temperature. The solvent was removed in vacuo and the residue treated with iPr2O. The formed precipitate was collected by filtration and dried in vacuo, overnight to afford 3-{2-[4-(2,6-Dichloro-phenylamino)-phenyl]-morpholin-4-yl}-propionic acid hydrochloride (0.30 g). 1H NMR (400 MHz, DMSO-d6) δ ppm 2.83-2.98 (1H, m) 2.98-3.20 (1H, m) 3.21-3.36 (1H, m) 3.38-3.48 (1H, m) 3.49-3.55 (1H, m) 3.97 (1H, t, J=12.6 Hz) 4.04-4.18 (1H, m) 4.72 (1H, d) 6.53 (1H, d) 7.14 (1H, d) 7.29 (1H, t, J=8.1 Hz) 7.57 (1H, d) 8.03 (1H, s).
Reaction SMILES: [CH2:1]([O:3][C:4]([CH2:6][N:7]1[C:12]2[S:13][CH:14]=[C:15]([CH3:16])[C:11]=2[C:10](=[O:17])[N:9]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([Cl:26])[CH:20]=2)[C:8]1=[O:27])=[O:5])[CH3:2].[Br:28]N1C(=O)CCC1=O>ClC(Cl)(Cl)Cl>[CH2:1]([O:3][C:4]([CH2:6][N:7]1[C:12]2[S:13][C:14]([Br:28])=[C:15]([CH3:16])[C:11]=2[C:10](=[O:17])[N:9]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([Cl:26])[CH:20]=2)[C:8]1=[O:27])=[O:5])[CH3:2]
Reactant: CCOC(=O)Cn1c(=O)n(Cc2ccc(Cl)c(Cl)c2)c(=O)c2c(C)csc21
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)Cn1c(=O)n(Cc2ccc(Cl)c(Cl)c2)c(=O)c2c(C)c(Br)sc21
Yield: 85 %

Procedure:
A 0.3 g quantity of 1-ethoxycarbonylmethyl-3-(3,4-dichlorobenzyl)-5-methylthieno[2,3-d]pyrimidin-2,4(1H,3H)-dione (compound IV-5) synthesized in Reference Example 6 and 0.137 g of N-bromosuccinimide were dissolved in 30 ml of anhydrous tetrachloromethane, and the mixture was refluxed for 2 hours. The solvent was distilled off under reduced pressure and the residual solid obtained was purified by silica gel column chromatography (eluent:chloroform:n-hexane=2:1) to afford 0.30 g of 1-ethoxycarbonylmethyl-3-(3,4-dichlorobenzyl)-6-bromo-5-methylthieno[2,3-d]pyrimidin-2,4(1H,3H)-dione having m.p. of 165.5° to 167° C. in a yield of 85%.
Reaction SMILES: [O:1]=[C:2]1[C@@H:8]([NH:9]C(=O)OC(C)(C)C)[CH2:7][CH2:6][S:5][C@H:4]2[CH2:17][CH2:18][CH2:19][C@@H:20]([CH:21]=[CH2:22])[N:3]12.[C:23]([OH:29])([C:25]([F:28])([F:27])[F:26])=[O:24]>C(Cl)Cl>[F:26][C:25]([F:28])([F:27])[C:23]([OH:29])=[O:24].[NH2:9][C@H:8]1[CH2:7][CH2:6][S:5][C@H:4]2[CH2:17][CH2:18][CH2:19][C@@H:20]([CH:21]=[CH2:22])[N:3]2[C:2]1=[O:1]
Reactant: C=C[C@@H]1CCC[C@@H]2SCC[C@H](NC(=O)OC(C)(C)C)C(=O)N12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C=C[C@@H]1CCC[C@@H]2SCC[C@H](N)C(=O)N12
Temperature: 25 °C
Reaction time: 1 h
Yield: 103.1 %

Procedure:
To a solution of tert-butyl (4S,7S,10aS)-5-oxo-7-vinyloctahydro-2H-pyrido[2,1-b][1,3]thiazepin-4-ylcarbamate (44 mg, 0.13 mmol) in DCM (1 mL) was added TFA (1.0 mL, 13 mmol). The reaction was stirred at rt for 1 hr. The reaction mixture was concentrated and dried under high vacuum to afford (4S,7S,10aS)-4-amino-7-vinylhexahydro-2H-pyrido[2,1-b][1,3]thiazepin-5(7H)-one trifluoroacetate (46 mg, 0.134 mmol, 100% yield) as an oil. Anal. Calcd. for C11H18N2OS m/z 226.3. found: 227.1 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][NH2:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:10](Br)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C([O-])([O-])=O.[K+].[K+]>C(O)C>[CH2:10]([NH:9][O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: NOCc1ccccc1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: c1ccc(CNOCc2ccccc2)cc1
Temperature: 50 °C
Reaction time: 8 h
Yield: 33.7 %

Procedure:
A mixture of 4 g of O-benzylhydroxylamine, 4.28 g of benzyl bromide, and 12 g of K2CO3 in 50 ml of ethanol was stirred at 50° C. overnight. After removal of organic solvent, water was added to the residue and the mixture was then extracted with ethyl acetate. The combined extracts were dried and evaporated to give 4 g of crude product. Purification by dry column chromatography gave 1.8 g of oily product.
Reaction SMILES: C(O[C@H:5]1[C@H:9]([CH2:10][CH2:11][CH3:12])[CH2:8][C:7](=[O:13])[CH2:6]1)(=O)C.C1CCN2C(=NCCC2)CC1>CCOCC>[CH2:10]([C@@H:9]1[CH2:8][C:7](=[O:13])[CH:6]=[CH:5]1)[CH2:11][CH3:12]
Reactant: CCC[C@@H]1CC(=O)C[C@H]1OC(C)=O
Solvent: C1CCC2=NCCCN2CC1
Solvent: CCOCC
Product: CCC[C@H]1C=CC(=O)C1
Temperature: -30 °C
Reaction time: 0.5 h
Yield: 67.8 %

Procedure:
The acetoxy cyclopentanone 1 (approx. 28.5 mmol) in ether (40 ml) was added dropwise over 1 hr to a stirred solution of DBU (4.27 ml, 28.5 mmol) in ether (50 ml) at −40° C. under argon. The mixture was allowed to warm to −30° C. and stirred for 30 minutes before being quenched with dilute hydrochloric acid (20 ml). The reaction mixture was partitioned between ether (100 ml) and 1N HCl (150 ml). The organic layer was separated and the aqueous layer was further extracted with ether (2×100 ml). The combined ether layers were washed with brine, dried (MgSO4) and the solvent was evaporated under reduced pressure. The residue was chromatographed (SiO2, pentane-ether, 1:0 to 8:2) to give the propylcyclopentenone 2 (2.4 g, 68% from (R)-4-acetoxycyclopent-2-enone). νmax(film)/cm−1 1708 (C═O).