Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[C:17]2[C:12](=[N:13][CH:14]=[C:15]([C:18]3[CH:23]=[CH:22][C:21]([NH:24][C:25]([N:27]4[CH2:32][CH2:31][O:30][CH2:29][CH2:28]4)=[O:26])=[C:20]([C:33]([N:35]4[CH2:40][CH2:39][N:38]([CH3:41])[CH2:37][CH2:36]4)=[O:34])[CH:19]=3)[CH:16]=2)[N:11](S(C2C=CC(C)=CC=2)(=O)=O)[CH:10]=1.CN(C)C=O.[OH-].[K+]>CO>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[C:17]2[C:12](=[N:13][CH:14]=[C:15]([C:18]3[CH:23]=[CH:22][C:21]([NH:24][C:25]([N:27]4[CH2:28][CH2:29][O:30][CH2:31][CH2:32]4)=[O:26])=[C:20]([C:33]([N:35]4[CH2:36][CH2:37][N:38]([CH3:41])[CH2:39][CH2:40]4)=[O:34])[CH:19]=3)[CH:16]=2)[NH:11][CH:10]=1
Reactant: COc1ccccc1-c1cn(S(=O)(=O)c2ccc(C)cc2)c2ncc(-c3ccc(NC(=O)N4CCOCC4)c(C(=O)N4CCN(C)CC4)c3)cc12
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CO
Product: COc1ccccc1-c1c[nH]c2ncc(-c3ccc(NC(=O)N4CCOCC4)c(C(=O)N4CCN(C)CC4)c3)cc12
Reaction time: 2 h
Yield: 21.1 %

Procedure:
Crude morpholine-4-carboxylic acid [4-[3-(2-methoxy-phenyl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-2-(4-methyl-piperazine-1-carbonyl)-phenyl]-amide (0.637 mmol) was dissolved in methanol (1.0 mL) and dimethylformamide (1.0 mL) and 50% w/v aqueous potassium hydroxide (1.0 mL) was added. After 2 hours, the reaction was quenched by addition of acetic acid (1.0 mL). The mixture was carefully poured into saturated sodium bicarbonate and extracted with ethyl acetate. The organic layers were dried over sodium sulfate, filtered and dried to a residue which was purified by preparative HPLC to afford morpholine-4-carboxylic acid [4-[3-(2-methoxy-phenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-2-(4-methyl-piperazine-1-carbonyl)-phenyl]-amide (74.5 mg, 21.0%, 4 steps). 1H-NMR (500 MHz, dimethylsulfoxide-d6) δ 2.18 (s, 3H), 2.31 (br m, 4H), 3.38 (t, J=4.5 Hz, 1H), 3.61 (t, J=5.0 Hz, 1H), 3.82 (s, 3H), 7.05 (dt, J=7.5, J=1.0 Hz, 1H), 7.12 (d, J=7.5 Hz, 1H), 7.29 (dd, J=1.5, J=9.0 Hz 1H), 7.54 (d, J=2.0 Hz, 1H), 7.60 (dd, J=1.5 Hz, J=7.0 Hz, 1H), 7.60 (d, J=9.0, 1H), 7.72 (m, 2H), 8.14 (d, J=1.5 Hz, 1H), 8.53 (d, J=2.0, 1H), 8.60 (s, 1H), 11.9 (s, 1H). MS: m/z 556 (M+H+).
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[CH2:5]([O:12][C:13]([N:15]1[CH2:20][C@@H:19]([CH2:21]OS(C2C=CC(C)=CC=2)(=O)=O)[C@H:18]([C:33]2[CH:38]=[CH:37][C:36]([CH2:39][O:40][CH2:41][C@@H:42]([CH3:46])[CH2:43][O:44][CH3:45])=[CH:35][CH:34]=2)[C@@H:17]([O:47][CH2:48][C:49]2[CH:50]=[CH:51][C:52]3[O:57][CH2:56][CH2:55][N:54]([CH2:58][CH2:59][CH2:60][O:61][CH3:62])[C:53]=3[CH:63]=2)[CH2:16]1)=[O:14])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>CN1CCCN(C)C1=O.COC(C)(C)C>[CH2:5]([O:12][C:13]([N:15]1[CH2:16][C@H:17]([O:47][CH2:48][C:49]2[CH:50]=[CH:51][C:52]3[O:57][CH2:56][CH2:55][N:54]([CH2:58][CH2:59][CH2:60][O:61][CH3:62])[C:53]=3[CH:63]=2)[C@@H:18]([C:33]2[CH:38]=[CH:37][C:36]([CH2:39][O:40][CH2:41][C@@H:42]([CH3:46])[CH2:43][O:44][CH3:45])=[CH:35][CH:34]=2)[C@H:19]([CH2:21][N:1]=[N+:2]=[N-:3])[CH2:20]1)=[O:14])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: [N-]=[N+]=[N-]
Reactant: COCCCN1CCOc2ccc(CO[C@H]3CN(C(=O)OCc4ccccc4)C[C@@H](COS(=O)(=O)c4ccc(C)cc4)[C@@H]3c3ccc(COC[C@@H](C)COC)cc3)cc21
Agent: [Na+]
Solvent: CN1CCCN(C)C1=O
Solvent: COC(C)(C)C
Product: COCCCN1CCOc2ccc(CO[C@H]3CN(C(=O)OCc4ccccc4)C[C@@H](CN=[N+]=[N-])[C@@H]3c3ccc(COC[C@@H](C)COC)cc3)cc21
Temperature: 25 °C
Reaction time: 5 h

Procedure:
31.265 mmol of sodium azide are added to a solution of 6.253 mmol of (3R,4R,5S)-4-[4-((S)-3-methoxy-2-methyl-propoxymethyl)-phenyl]-3-[4-(3-methoxy-propyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]-5-(toluene-4-sulfonyloxymethyl) -piperidine-1-carboxylic acid benzyl ester in 50 ml of 1,3-dimethyl-tetrahydro -pyrimidin-2-one (DMPU) under argon at 45° C. After 5 hours, the reaction mixture is cooled to room temperature, diluted with tert-butyl methyl ether, washed with water and brine, dried with sodium sulfate and evaporated. The crude title compound is obtained as a yellow oil. Rf=0.58 (EtOAc-heptane 2:1); Rt=5.96 (gradient I).
Reaction SMILES: [C:1]([O:5][C:6](=[O:32])[NH:7][CH:8]([C:16]1NC(=O)C=[C:20]([C:22]2[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][CH:23]=2)[CH:21]=1)[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)([CH3:4])([CH3:3])[CH3:2].C[O:34]P(CC(=O)[C@@H](NC(OC(C)(C)C)=O)CC1C=CC=CC=1)(=O)OC.[N+](C1C=CC(C=O)=CC=1)([O-])=O.C(=O)([O-])[O-].[K+].[K+]>C(O)C.CCOC(C)=O>[C:1]([O:5][C:6](=[O:32])[NH:7][C@@H:8]([CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:16](=[O:34])/[CH:21]=[CH:20]/[C:22]1[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][CH:23]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NC(Cc1ccccc1)c1cc(-c2ccc([N+](=O)[O-])cc2)cc(=O)[nH]1
Reactant: COP(=O)(CC(=O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C)OC
Agent: O=C([O-])[O-]
Agent: O=Cc1ccc([N+](=O)[O-])cc1
Agent: [K+]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)/C=C/c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
{1-[4-(4-Nitro-phenyl)-6-oxo-1,6-dihydro-pyridin-2-yl]-2-phenyl-ethyl}-carbamic acid tert-butyl ester: A suspension of ((S)-3-tert-butoxycarbonylamino-2-oxo-4-phenyl-butyl)-phosphonic acid dimethyl ester (1.114 g, 3 mmol, Resmini, M. et al., Tetrahedron Asymmetry, 2004, 15, 1847.), 4-nitrobenzaldehyde (0.453 g, 3 mmol) and potassium carbonate (0.415 g, 3 mmol) in ethanol (60 mL) was stirred at rt for 5 h. The reaction mixture was diluted with EtOAc, washed with water, brine, and dried over Na2SO4, filtered and concentrated to give 1.276 g of [(E)-(S)-1-benzyl-4-(4-nitro-phenyl)-2-oxo-but-3-enyl]-carbamic acid tert-butyl ester as a yellow solid. This yellow solid was suspended in ethanol (30 mL), then 1-ethoxycarbonylmethyl-pyridinium chloride (0.605 g, 3 mmol) and ammonium acetate (4.63 g, 60 mmol) were added. The reaction mixture was stirred at rt for 10 min, then heated at 80° C. for 5 h to yield a white suspension. The reaction was cooled to rt and the solid was collected by filtration, washed with methanol, and dried in vacuo (50° C.) to give 0.85 g (62%) of 64A as a white solid. LCMS m/z 436.3 (M+H)+. 1HNMR (400 MHz, DMSO-D6) δ: 1.26 (s, 9H), 2.76-2.82 (m, 1H), 3.01-3.06 (m, 1H), 4.68-4.74 (m, 1H), 6.54-6.60 (m, 2H), 7.18-7.29 (m, 5H), 7.40 (d, J=9.2 Hz, 1H), 7.91 (d, J=8.8 Hz, 2H), 8.34 (d, J=8.8 Hz, 2H), 11.96 (s, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[F:12])[N:8]=[CH:7][C:6]([C:13]([CH:15]1[CH2:17][CH2:16]1)=[O:14])=[C:5]2Cl.[CH3:19][N:20]([CH3:28])[C@H:21]1[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]1>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[F:12])[N:8]=[CH:7][C:6]([C:13]([CH:15]1[CH2:17][CH2:16]1)=[O:14])=[C:5]2[NH:27][C@H:24]1[CH2:25][CH2:26][C@H:21]([N:20]([CH3:28])[CH3:19])[CH2:22][CH2:23]1
Reactant: O=C(c1cnc2cc(F)c(Br)cc2c1Cl)C1CC1
Reactant: CN(C)[C@H]1CC[C@H](N)CC1
Product: CN(C)[C@H]1CC[C@H](Nc2c(C(=O)C3CC3)cnc3cc(F)c(Br)cc23)CC1

Procedure:
Following general procedure C, (6-bromo-4-chloro-7-fluoroquinolin-3-yl)(cyclopropyl)methanone (297 mg, 0.900 mmol) was reacted with trans-N1,N1-dimethylcyclohexane-1,4-diamine (290 mg, 1.35 mmol) to afford the desired product (212 mg, 54%) as an off-white solid: ESI MS m/z 435 [C21H25BrFN3O+H]+.
Reaction SMILES: S(O)(O)(=O)=O.[CH3:6][NH:7][C:8]([NH2:10])=[NH:9].[OH-].[Na+].S([O-])([O-])(=O)=O.[Na+].[Na+].[CH2:20]([C:22]1[CH:27]=[C:26]([N+:28]([O-:30])=[O:29])[CH:25]=[C:24]([CH2:31][CH3:32])[C:23]=1[N:33]=[C:34]=[O:35])[CH3:21].[ClH:36].CO>O1CCCC1.O.CO>[ClH:36].[CH2:20]([C:22]1[CH:27]=[C:26]([N+:28]([O-:30])=[O:29])[CH:25]=[C:24]([CH2:31][CH3:32])[C:23]=1[NH:33][C:34]([NH:10][C:8](=[NH:9])[NH:7][CH3:6])=[O:35])[CH3:21]
Reactant: CNC(=N)N
Reactant: CCc1cc([N+](=O)[O-])cc(CC)c1N=C=O
Agent: Cl
Agent: O=S(=O)(O)O
Agent: O=S(=O)([O-])[O-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CCc1cc([N+](=O)[O-])cc(CC)c1NC(=O)NC(=N)NC
Reaction time: 1 h

Procedure:
To a stirred suspension of 7.3 g (30.0 mmol) of methylguanidine sulfate in tetrahydrofuran (80 ml) is added 4.3 g (60.0 mmol) of 50% w/w sodium hydroxide in water with continued stirring for one hour. Anhydrous sodium sulfate (10.0 g) is added and the mixture stirred an additional hour after which 6.6 g (30.0 mmol) of 2,6-diethyl-4-nitrophenylisocyanate is added and the resulting mixture stirred at room temperature over-night. The tetrahydrofuran is removed under vacuum and the residue partitioned between water and chloroform. The layers are separated and the aqueous layer extracted with chloroform (1×100 ml). The combined extracts are dried (MgSO4) and concentrated to give a yellow foam which is dissolved in methanol and acidified with HCl/MeOH. The methanol is removed under vacuum to give a yellow viscous oil which solidifies on scratching. Crystallization from methanol-ethyl acetate gives 1-(2,6-diethyl-4-nitrophenyl)-3-methylamidinourea hydrochloride as a pale yellow solid, m.p. 173°-175° C.
Reaction SMILES: [CH:1]1[C:11]2=[C:12]3[C:7](=[CH:8][CH:9]=[CH:10]2)[C:6]([N:13]2[CH2:18][CH2:17][NH:16][C@H:15]([CH3:19])[CH2:14]2)=[CH:5][CH:4]=[C:3]3[CH:2]=1.CS(O[CH2:25][CH2:26][C@H:27]1[C:32]2[CH:33]=[CH:34][C:35]([C:37]([NH2:39])=[O:38])=[CH:36][C:31]=2[CH2:30][CH2:29][O:28]1)(=O)=O>>[CH:1]1[C:11]2=[C:12]3[C:7](=[CH:8][CH:9]=[CH:10]2)[C:6]([N:13]2[CH2:18][CH2:17][N:16]([CH2:25][CH2:26][C@H:27]4[C:32]5[CH:33]=[CH:34][C:35]([C:37]([NH2:39])=[O:38])=[CH:36][C:31]=5[CH2:30][CH2:29][O:28]4)[C@H:15]([CH3:19])[CH2:14]2)=[CH:5][CH:4]=[C:3]3[CH:2]=1
Reactant: CS(=O)(=O)OCC[C@@H]1OCCc2cc(C(N)=O)ccc21
Reactant: C[C@@H]1CN(c2ccc3c4c(cccc24)C=C3)CCN1
Product: C[C@@H]1CN(c2ccc3c4c(cccc24)C=C3)CCN1CC[C@@H]1OCCc2cc(C(N)=O)ccc21

Procedure:
(3R)-1-(5-Acenaphthylenyl)-3-methylpiperazine was condensed with 2-[(1S)-6-(aminocarbonyl)-3,4-dihydro-1H-2-benzopyran-1-yl]ethyl methanesulfonate, as described for Example 1b), to yield the title compound. M+H=454.
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[CH2:7][CH:8]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[C:12](=[O:19])[N:11]([CH2:20][C:21]([OH:23])=O)[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[NH2:25][CH2:26][C@H:27]1[CH2:32][CH2:31][C@H:30]([NH:33][C:34]2[NH:38][C:37]3[CH:39]=[CH:40][CH:41]=[CH:42][C:36]=3[N:35]=2)[CH2:29][CH2:28]1>>[NH:35]1[C:36]2[CH:42]=[CH:41][CH:40]=[CH:39][C:37]=2[N:38]=[C:34]1[NH:33][CH:30]1[CH2:29][CH2:28][CH:27]([CH2:26][NH:25][C:21](=[O:23])[CH2:20][N:11]2[CH2:10][CH2:9][CH:8]([CH2:7][C:6]([O:5][C:1]([CH3:3])([CH3:4])[CH3:2])=[O:24])[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[C:12]2=[O:19])[CH2:32][CH2:31]1
Reactant: NC[C@H]1CC[C@H](Nc2nc3ccccc3[nH]2)CC1
Reactant: CC(C)(C)OC(=O)CC1CCN(CC(=O)O)C(=O)c2ccccc21
Product: CC(C)(C)OC(=O)CC1CCN(CC(=O)NCC2CCC(Nc3nc4ccccc4[nH]3)CC2)C(=O)c2ccccc21

Procedure:
Analogously to Example V, compound 3 was reacted with 0.57 g (1.8 mmol) of compound 7 and the mixture was purified; 0.5 g of white amorphous powder; ESI-MS [M+H+]: 560.
Reaction SMILES: [CH:1]([C:4]1[C:5]([O:33]CC=C)=[CH:6][C:7]([O:29]CC=C)=[C:8]([C:10]2[N:11]([C:16]3[CH:21]=[CH:20][C:19]([CH2:22][N:23]4[CH2:28][CH2:27][O:26][CH2:25][CH2:24]4)=[CH:18][CH:17]=3)[C:12]([OH:15])=[N:13][N:14]=2)[CH:9]=1)([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+]>[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CO>[OH:15][C:12]1[N:11]([C:16]2[CH:17]=[CH:18][C:19]([CH2:22][N:23]3[CH2:24][CH2:25][O:26][CH2:27][CH2:28]3)=[CH:20][CH:21]=2)[C:10]([C:8]2[CH:9]=[C:4]([CH:1]([CH3:3])[CH3:2])[C:5]([OH:33])=[CH:6][C:7]=2[OH:29])=[N:14][N:13]=1
Reactant: C=CCOc1cc(OCC=C)c(C(C)C)cc1-c1nnc(O)n1-c1ccc(CN2CCOCC2)cc1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: CC(C)c1cc(-c2nnc(O)n2-c2ccc(CN3CCOCC3)cc2)c(O)cc1O
Yield: 14.2 %

Procedure:
A methanol solution of 5-(5-isopropyl-2,4-bis-allyloxy-phenyl)-4-[4-(morpholin-4-ylmethyl)-phenyl]-4H-[1,2,4]triazol-3-ol (37.9 mg, 0.077 mmol) was mixed with tetrakis(triphenylphosphine) palladium (7 mg, 0.007 mmol) and potassium carbonate (64 mg, 0.46 mmol) and reacted at 80° C. for 12 hours. The residue obtained after the concentration was purified by silica gel column chromatography (dichloromethane:methanol 15:1-10:1) to obtain the title compound (OH-a02: white solid, 4.5 mg, 14%).
Reaction SMILES: [C:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([S:11](Cl)(=[O:13])=[O:12])=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[CH3:15][O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH2:23][NH2:24].C(N(CC)CC)C>ClCCl>[C:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([S:11](=[O:13])(=[O:12])[NH:24][CH2:23][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[O:16][CH3:15])=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1ccc(S(=O)(=O)Cl)cc1
Reactant: COc1ccccc1CN
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccccc1CNS(=O)(=O)c1ccc(OC(C)=O)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 97.8 %

Procedure:
A solution of 4-(chlorosulfonyl)phenyl acetate (example 5-42b) (531 mg, 2.265 mmol) in 5.0 mL of dichloromethane, was cooled to 0° C. in an ice bath. (2-methoxyphenyl)methanamine (325 μL, 2.492 mmol) and triethylamine (347 μL, 2.492 mmol) were added. The ice bath was then removed and the mixture warmed to ambient temperature and stirred for 2 hours. The reaction mixture was concentrated and the crude product was purified by column chromatography (hexanes/ethyl acetate=90/10 to 30/70) to afford pure 4-(N-(2-methoxybenzyl)sulfamoyl)phenyl acetate (743 mg, 89%) as a white solid. MS (M+H, 336.1) 1H NMR (400 MHz, CDCl3): δ, ppm: 2.32 (s, 3H), 3.71 (s, 3H), 4.18 (d, 2H, J=5.8 Hz), 5.15 (t, 1H, J=5.8 Hz), 6.71 (d, 1H, J=8.2 Hz), 6.82 (br t, 1H, J=7.4 Hz), 7.07 (br d, 1H, J=7.4 Hz), 7.10 (d, 2H, J=8.7 Hz), 7.19 (br t, 1H, J=7.8 Hz), 7.74 (d, 2H, J=8.7 Hz).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].O[N:14]1C2C=CC=CC=2N=N1.CCN=C=NCCCN(C)C.N>C(Cl)Cl.CN(C)C1C=CN=CC=1>[C:1]([O:5][C:6](=[O:7])[NH:8][CH2:9][C:10](=[O:12])[NH2:14])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: N
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCC(N)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 24 %

Procedure:
To a solution of N-(t-butoxycarbonyl)glycine (3.01 g, 17.2 mmol) in anhydrous methylene chloride (150 ml) were added 1-hydroxybenzotriazole (4.63 g, 34.3 mmol), WSC (6.60 g, 34.4 mmol) and 4-dimethylaminopyridine (210 mg, 1.72 mmol) in an ice bath. The mixture was stirred at room temperature under an atmosphere of nitrogen overnight. After checking the completion of the reaction, 28% aqueous ammonia solution was added thereto and resulting mixture was stirred for 15 minutes. After checking the completion of the reaction, the reaction mixture was partitioned between methylene chloride and saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using ethyl acetate:methanol (10:1) as the eluant to afford (carbamoylmethyl)carbamic acid t-butyl ester (717.7 mg, yield 24%) as a colorless and transparent syrup.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([OH:14])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CS(C)=O.O.C(N(CC)CC)C>C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C:10](=[O:14])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCCC(O)C1
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCCC(=O)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 57.4 %

Procedure:
To a solution of give N-t-butoxycarbonyl-3-hydroxypiperidine (1.07 g, 5.23 mmol) in 1:1 dimethyl sulfoxide:water (50 ml) is added triethyl amine (3.7 ml) and sulfur trioxide pyridine complex (4.24 g, 26.6 mmol). The reaction mixture is stirred at 25° C. for 3 hrs. The reaction mixture is diluted with ethyl acetate, washed with 1 N KHSO4, water and brine, dried over sodium sulfate and concentrated in vacuo. The crude product is purified by flash chromatography (silica gel, 50% ethyl acetate in hexane) to give N-t-butoxycarbonyl-3-ketopiperidine (598 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([CH:15]=[CH2:16])=[CH:11][CH:10]=2)=[CH:4][C:3]=1[C:17]([F:20])([F:19])[F:18].B1C2CCCC1CCC2.[OH-:30].[Na+].OO>O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:10]=[CH:11][C:12]([CH2:15][CH2:16][OH:30])=[CH:13][CH:14]=2)=[CH:4][C:3]=1[C:17]([F:18])([F:19])[F:20]
Reactant: C=Cc1ccc(Oc2ccc(Cl)c(C(F)(F)F)c2)cc1
Reactant: [OH-]
Agent: B1C2CCCC1CCC2
Agent: OO
Agent: [Na+]
Solvent: C1CCOC1
Product: OCCc1ccc(Oc2ccc(Cl)c(C(F)(F)F)c2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 49.6 %

Procedure:
To a mixture of 1-chloro-4-[(4-ethenylphenyl)oxy]-2-(trifluoromethyl)benzene (3.8 g, 12.72 mmol) in anhydrous tetrahydrofuran (50 mL) was added 9-BBN (50.9 mL, 25.4 mmol) dropwise at 0° C. The reaction mixture was stirred at rt overnight, then sodium hydroxide (42.4 mL, 127 mmol) and H2O2 (2.60 mL, 25.4 mmol) were added at 0° C. The reaction mixture was stirred for 2 h at 50° C., and quenched with aq. Na2SO3 and then concentrated. Purification via mass-directed auto-preparation afforded the title compound (2.0 g).
Reaction SMILES: [NH:1]([C:5]1[S:6][CH:7]=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([CH2:16][NH2:17])[CH:11]=2)[N:9]=1)[C:2]([NH2:4])=[NH:3]>C(O)C>[NH:1]([C:5]1[S:6][CH:7]=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([CH2:16][NH:17][C:5](=[N:1][C:2]#[N:3])[S:6][CH3:7])[CH:11]=2)[N:9]=1)[C:2]([NH2:4])=[NH:3]
Reactant: N=C(N)Nc1nc(-c2cccc(CN)c2)cs1
Solvent: CCO
Product: CSC(=NC#N)NCc1cccc(-c2csc(NC(=N)N)n2)c1
Reaction time: 1 h

Procedure:
To a solution of 2-guanidino-4-(3-aminomethylphenyl)thiazole (0.5 g.) in warm ethanol (10 ml.) was added dimethyl (cyanoimido)dithiocarbonate (0.3 g.). The mixture was stirred for 1 hour during which time a precipitate gradually formed. This precipitate was filtered off to give 2-guanidino-4-[3-(3-cyano-2-methylisothioureidomethyl)phenyl]thiazole.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[CH:9][C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:6]2[N:5]=[CH:4][C:3]=1[C:16]([N:18]1[CH2:23][CH2:22][C:21]([CH3:30])([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:20][CH2:19]1)=[O:17].[NH2:31][C:32]1[C:33]([CH3:38])=[CH:34][CH:35]=[CH:36][CH:37]=1>>[CH2:14]([O:13][C:11]([C:10]1[CH:9]=[N:8][N:7]2[C:2]([NH:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=3[CH3:38])=[C:3]([C:16]([N:18]3[CH2:23][CH2:22][C:21]([CH3:30])([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[CH2:20][CH2:19]3)=[O:17])[CH:4]=[N:5][C:6]=12)=[O:12])[CH3:15]
Reactant: CCOC(=O)c1cnn2c(Cl)c(C(=O)N3CCC(C)(c4ccccc4)CC3)cnc12
Reactant: Cc1ccccc1N
Product: CCOC(=O)c1cnn2c(Nc3ccccc3C)c(C(=O)N3CCC(C)(c4ccccc4)CC3)cnc12
Yield: 62.8 %

Procedure:
In the same manner as in Example 19, step 5 and using 7-chloro-3-ethoxycarbonyl-6-(4-methyl-4-phenylpiperidine-1-carbonyl)pyrazolo[1,5-a]pyrimidine (210 mg, 0.49 mmol) obtained in step 2 and o-toluidine (0.08 mL, 0.74 mmol), the title compound (153 mg, 63%) was obtained.
Reaction SMILES: [Cl-].[Cl-].[Cl-].[Al+3].[C:5]([O:8][CH2:9][C@H:10]1[CH2:15][CH2:14][CH2:13][C@H:12](S(C2C=CC=CC=2)(=O)=O)[O:11]1)(=[O:7])[CH3:6].[CH2:25]([Si](C)(C)C)[CH:26]=[CH2:27]>ClCCl>[C:5]([O:8][CH2:9][C@H:10]1[CH2:15][CH2:14][CH2:13][C@H:12]([CH2:27][CH:26]=[CH2:25])[O:11]1)(=[O:7])[CH3:6]
Reactant: CC(=O)OC[C@H]1CCC[C@H](S(=O)(=O)c2ccccc2)O1
Reactant: C=CC[Si](C)(C)C
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: C=CC[C@H]1CCC[C@H](COC(C)=O)O1
Temperature: -78 °C
Reaction time: 2 h

Procedure:
Aluminium trichloride (1 g) was cooled to -78° C. under a nitrogen atmosphere and dichloromethane (15 ml) was added. A solution of trans-6-(benzenesulfonyl)tetrahydro-2H-pyran-2-methanol acetate (S. V. Ley et al., Tetrahedron (1989), 45 (13), 4293) (1 g) and allyl trimethylsilane (835 mg) in dichloromethane (10 ml) was then added dropwise. The reaction was stirred at -78° C. for 2 h, then -35° C. for 1 h. After quenching with 1N HCl and extracting with dichloromethane the crude product was purified by flash chromatography (40% EtOAc/hexane) to give the title compound of (414 mg).
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[C:6]([O:11][CH3:12])[CH:5]=1.C(N(CC)CC)C.[CH3:20][C:21]1([C:26](ON2C(=O)CCC2=O)=[O:27])[CH2:25][S:24][S:23][CH2:22]1>CC1OCCC1>[OH:10][C:7]1[CH:8]=[CH:9][C:4]([CH2:3][NH:2][C:26]([C:21]2([CH3:20])[CH2:25][S:24][S:23][CH2:22]2)=[O:27])=[CH:5][C:6]=1[O:11][CH3:12]
Reactant: COc1cc(CN)ccc1O
Reactant: CC1(C(=O)ON2C(=O)CCC2=O)CSSC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC1CCCO1
Product: COc1cc(CNC(=O)C2(C)CSSC2)ccc1O
Reaction time: 8 h

Procedure:
24.3 mmol of N-hydroxysuccinimide are added to 24.3 mmol of dithiolane acid dissolved in 60 ml of dichloromethane cooled to 0° C. (on an ice bath). The reaction medium is stirred for 30 minutes at 0° C. A solution of 24.3 mmol of DCC in 50 ml of dichloromethane is added and the mixture is then stirred at 20° C. for 4 hours. The reaction medium is filtered and washed, and the filtrate is then evaporated to dryness on a rotavapor at 40° C. under vacuum to give 1-{[(4-methyl-1,2-dithiolan-4-yl)carbonyl]oxy}pyrrolidine-2,5-dione (m=7 g, quantitative yield). 10 ml of MeTHF, 3.16 mmol of 4-(aminomethyl)-2-methoxyphenol hydrochloride and 3.16 mmol of triethylamine are added to 1.58 mmol of 1-{[(4-methyl-1,2-dithiolan-4-yl)carbonyl]oxy}pyrrolidine-2,5-dione. After stirring overnight, the mixture is filtered, rinsed with MeTHF and then evaporated. Flash chromatography, eluting with 98/2 dichloromethane/methanol, gives Compound 16 in the form of a yellow oil (84% yield).
Reaction SMILES: [CH3:1][C:2]1([CH3:25])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]([OH:24])=[O:23])=[CH:18][CH:17]=3)[CH:5]=[CH:4][C:3]1=2.C(=O)([O-])[O-].[K+].[K+].I[CH2:33][CH3:34].O>CC(=O)CC>[CH3:1][C:2]1([CH3:25])[CH2:11][CH2:10][C:9]([CH3:12])([CH3:13])[C:8]2[CH:7]=[C:6]([O:14][CH2:15][C:16]3[CH:17]=[CH:18][C:19]([C:22]([O:24][CH2:33][CH3:34])=[O:23])=[CH:20][CH:21]=3)[CH:5]=[CH:4][C:3]1=2
Reactant: CC1(C)CCC(C)(C)c2cc(OCc3ccc(C(=O)O)cc3)ccc21
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCC(C)=O
Product: CCOC(=O)c1ccc(COc2ccc3c(c2)C(C)(C)CCC3(C)C)cc1
Yield: 40.9 %

Procedure:
2 g (6 mmol) of 4-carboxybenzyl 5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl ether, 2.7 g (19.6 mmol) of anhydrous potassium carbonate and 19 g (12.4 mmol) of iodoethane in 18 ml of butanone were refluxed for 7 h. The mixture was then poured into water and extracted with ether, and the organic phase was washed with water, dried over Na2SO4 and concentrated. Recrystallization from methanol resulted in 0.9 g of the title compound of melting point 76°-77° C.
Reaction SMILES: [CH3:1][O:2][CH2:3]/[CH:4]=[CH:5]/[CH2:6][O:7][C:8]1[CH:15]=[CH:14][CH:13]=[C:12]([N+:16]([O-])=O)[C:9]=1[C:10]#[N:11].CCO.O>CC(O)=O.[Fe]>[NH2:16][C:12]1[CH:13]=[CH:14][CH:15]=[C:8]([O:7][CH2:6]/[CH:5]=[CH:4]/[CH2:3][O:2][CH3:1])[C:9]=1[C:10]#[N:11]
Reactant: COC/C=C/COc1cccc([N+](=O)[O-])c1C#N
Agent: [Fe]
Solvent: CC(=O)O
Solvent: CCO
Solvent: O
Product: COC/C=C/COc1cccc(N)c1C#N
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 87.1 %

Procedure:
To a solution of (E)-2-(4-methoxybut-2-enyloxy)-6-nitrobenzonitrile (Example 184c) (0.25 g, 1.00 mmol) in a mixture of AcOH, EtOH and water (33 mL, 1:1:1) was added iron powder (0.56 g, 10.00 mmol) at rt. The obtained mixture was stirred at rt for 20 min, then was heated to 50° C. for a further 15 min, and allowed to cool. The suspension was concentrated under reduced pressure; the residue was treated with water (50 mL) and extracted with EtOAc (4×50 mL). The combined extract was washed with saturated aqueous NaHCO3 and brine, and was dried over anhydrous MgSO4. The filtrate was evaporated and the residue was purified by silica gel flash chromatography using gradient hexanes→hexanes/EtOAc (1:1), to give 0.19 g (86%) of the title compound as a white solid. 1H-NMR (400 MHz, DMSO-d6) δ 7.17 (t, J=8.4 Hz, 1H), 6.34 (d, J=8.8 Hz, 1H), 6.22 (d, J=8.4 Hz, 1H), 6.00 (broad s, 2H), 5.82-5.96 (m, 2H), 4.56-4.62 (m, 2H), 3.88-3.93 (m, 2H), 3.23 (s, 3H).