Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[C:2]1([C@@H:14]2[CH2:18][CH2:17][C@@H:16]([NH2:19])[CH2:15]2)[N:6]2[C:7]3[CH:13]=[CH:12][NH:11][C:8]=3[N:9]=[CH:10][C:5]2=[N:4][N:3]=1.[N:20]1([C:25](Cl)=[O:26])[CH2:24][CH2:23][CH2:22][CH2:21]1>C1COCC1>[C:2]1([C@@H:14]2[CH2:18][CH2:17][C@@H:16]([NH:19][C:25]([N:20]3[CH2:24][CH2:23][CH2:22][CH2:21]3)=[O:26])[CH2:15]2)[N:6]2[C:7]3[CH:13]=[CH:12][NH:11][C:8]=3[N:9]=[CH:10][C:5]2=[N:4][N:3]=1
Reactant: N[C@@H]1CC[C@@H](c2nnc3cnc4[nH]ccc4n23)C1
Reactant: O=C(Cl)N1CCCC1
Agent: Cl
Solvent: C1CCOC1
Product: O=C(N[C@@H]1CC[C@@H](c2nnc3cnc4[nH]ccc4n23)C1)N1CCCC1
Temperature: 60 °C
Yield: 11.5 %

Procedure:
A round bottom flask was charged with (1R,3R)-3-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentanamine hydrochloride (0.150 g, 0.62 mmol, Example #D.1.4) and TEA (0.26 mL, 1.9 mmol) in THF (5.7 mL). The reaction mixture was stirred for about 5 min at ambient temperature before pyrrolidine-1-carbonyl chloride (0.052 mL, 0.46 mmol) was added. The reaction was heated at about 60° C. for about 16 h, cooled to ambient temperature, and concentrated under reduced pressure. The crude product was dissolved in DCM (40 mL) and washed with saturated aqueous NaHCO3 (20 mL), brine (20 mL), dried over anhydrous MgSO4, filtered and concentrated under reduced pressure. The material was purified by RP-HPLC (Table 2, Method i). The appropriate fractions were combined, the solvent was mostly removed under reduced pressure, and the solid was filtered and dried under lyophilization to give N-((1R,3R)-3-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyl)pyrrolidine-1-carboxamide (0.018 g, 8%): LC/MS (Table 2, Method a) Rt=1.40 min; MS m/z 340 (M+H)+.
Reaction SMILES: O[CH2:2][C:3]1[N:7]([CH2:8][CH:9]([OH:11])[CH3:10])[N:6]=[C:5]([N+:12]([O-:14])=[O:13])[CH:4]=1.P(Br)(Br)([Br:17])=O>C(Cl)(Cl)Cl>[Br:17][CH2:2][C:3]1[N:7]([CH2:8][CH:9]([OH:11])[CH3:10])[N:6]=[C:5]([N+:12]([O-:14])=[O:13])[CH:4]=1
Reactant: O=P(Br)(Br)Br
Reactant: CC(O)Cn1nc([N+](=O)[O-])cc1CO
Solvent: ClC(Cl)Cl
Product: CC(O)Cn1nc([N+](=O)[O-])cc1CBr
Temperature: 0 °C
Reaction time: 3 h
Yield: 62.5 %

Procedure:
To a mixture of 250a (4.0 g, 20.0 mmol) in chloroform (100 mL) cooled at 0° C. was added the solution of POBr3 (22.9 g, 80 mmol) in chloroform (20 mL) over 30 minutes while maintaining the internal temperature below 5° C. The reaction mixture was warmed to 50° C. and stirred at this temperature for 3 h. It was then cooled to 0° C. and quenched with water. The organic layer was separated and evaporated under reduced pressure. The residue was purified by silica-gel column chromatography eluting with 30:1 dichloromethane/methanol to afford 250b (3.3 g, 62%) as yellow solid. MS-ESI: [M+H]+ 264.1
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9](=[O:14])[CH2:8][CH2:7]2.Br[CH2:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18]>CN(C)C=O>[Br:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]([CH2:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C:9](=[O:14])[CH2:8][CH2:7]2
Reactant: CC(C)(C)OC(=O)CBr
Reactant: O=C1CCc2cc(Br)ccc2N1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)CN1C(=O)CCc2cc(Br)ccc21
Reaction time: 0.5 h
Yield: 72 %

Procedure:
To a mixture of 95% dry sodium hydride (834 mg, 33.0 mmol) in anhydrous N,N-dimethylformamide (30 mL) at room temperature was added a solution of 6-bromo-3,4-dihydroquinolin-2(1H)-one (6.780 g, 30.00 mmol) in anhydrous N,N-dimethylformamide (10 mL). The reaction mixture was stirred for 30 minutes under an atmosphere of dry N2, followed by addition of a solution of tert-butyl 2-bromoacetate (7.5 mL, 49.7 mmol) in N,N-dimethylformamide (10 mL). The reaction mixture was stirred at room temperature until the majority of the starting material was converted (confirmed by LCMS). The reaction mixture was quenched with methanol (40 mL), the mixture concentrated under reduced pressure, then diluted with ethyl acetate (150 mL). The organic phase was washed with water (100 mL), 30% ammonium chloride (100 mL) and brine (100 mL), dried, and concentrated under reduced pressure. Ethyl ether (20 mL) was added, and the mixture sonicated, filtered, washed with ether (20 mL), and dried to afford tert-butyl 2-(6-bromo-2-oxo-3,4-dihydroquinolin-1(2H)-yl)acetate (7.348 g, 21.6 mmol, 72%). LCMS mz 285.9 (M-56+H), 363.9 (M+Na), anal HPLC >97% in purity. 1H NMR (400 MHz; CDCl3) δ 7.30-7.40 (m, 2H); 7.50-6.70 (m, 1H); 4.54 (s, 2H); 2.92 (m, 2H); 2.69 (m, 2H), 1.44 (s, 9H).
Reaction SMILES: C(O[C:4]([C:6]1[C:7]([OH:22])=[C:8]2[C:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[N:14][O:13][C:9]2=[C:10]([CH3:12])[N:11]=1)=[O:5])C.[NH2:23][CH2:24][C:25]([OH:27])=[O:26].C[O-].[Na+]>CO>[OH:22][C:7]1[C:6]([C:4]([NH:23][CH2:24][C:25]([OH:27])=[O:26])=[O:5])=[N:11][C:10]([CH3:12])=[C:9]2[O:13][N:14]=[C:15]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:8]=12
Reactant: NCC(=O)O
Reactant: CCOC(=O)c1nc(C)c2onc(-c3ccccc3)c2c1O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: Cc1nc(C(=O)NCC(=O)O)c(O)c2c(-c3ccccc3)noc12
Temperature: 25 °C
Yield: 87.7 %

Procedure:
A mixture of 4-hydroxy-7-methyl-3-phenyl-isoxazolo[5,4-c]pyridine-5-carboxylic acid ethyl ester (93 mg, 0.31 mmol), glycine (470 mg, 6.27 mmol), and a 0.5 M solution sodium methoxide in methanol (11.9 ml) was refluxed for 42 h before it was cooled to room temperature and concentrated in vacuo. The residue was dissolved in water (20 ml) and the solution was extracted with methyl t-butyl ether (2×25 ml). The remaining aqueous layer was acidified to pH=3 with 1N HCl. The resulting precipitate was filtered, washed with water and dried in vacuo to give the title compound as a gray solid (89 mg): 1H NMR (DMSO-d6, 200 MHz): δ=9.25 (t, 1H), 8.03 (m, 2H), 7.57 (m, 3H), 4.01 (d, J=6.2 Hz, 2H), 2.71 (s, 3H); MS: (+) m/z 327.98 (M+1), (−) m/z 325.99 (M−1).
Reaction SMILES: [C:1]([N:4]1[CH:7]([S:8][CH3:9])[CH2:6][C:5]1=[O:10])(=[O:3])[CH3:2].ClC1C=CC=C(C(OO)=[O:19])C=1>C(Cl)Cl>[C:1]([N:4]1[CH:7]([S:8]([CH3:9])=[O:19])[CH2:6][C:5]1=[O:10])(=[O:3])[CH3:2]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSC1CC(=O)N1C(C)=O
Solvent: ClCCl
Product: CC(=O)N1C(=O)CC1S(C)=O
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 39.8 %

Procedure:
A mixture of 130 mg (0.82 mM) N-acetyl-4-methylthioazetidinone and 200 mg (0.93 mM) 80% m-chloroperbenzoic acid in 5 ml methylene chloride was stirred at room temperature 5 minutes. After removing the solvent in vacuo. The residue was chromatographed on 2-2000μ silica gel plates in hexane/ethyl acetate to yield 57 mg (40%) of 1-acetyl-4-methylsulfinylazetidine-2-one.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:37]=[C:38]([F:40])[CH:39]=1)[CH2:5][C@H:6]([NH:20]C(C1C=C(C)N=C(N(CCC)CCC)N=1)=O)[C@H:7]([OH:19])[CH2:8][NH:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][CH3:18])[CH:12]=1.[CH2:41]([N:45]([CH3:57])[C:46]1[CH:47]=[C:48]([CH:52]=[C:53]([C:55]#[N:56])[N:54]=1)[C:49]([OH:51])=O)[CH2:42][CH2:43][CH3:44]>>[CH2:41]([N:45]([CH3:57])[C:46]1[CH:47]=[C:48]([CH:52]=[C:53]([C:55]#[N:56])[N:54]=1)[C:49]([NH:20][C@@H:6]([CH2:5][C:4]1[CH:37]=[C:38]([F:40])[CH:39]=[C:2]([F:1])[CH:3]=1)[C@H:7]([OH:19])[CH2:8][NH:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][CH3:18])[CH:12]=1)=[O:51])[CH2:42][CH2:43][CH3:44]
Reactant: CCCN(CCC)c1nc(C)cc(C(=O)N[C@@H](Cc2cc(F)cc(F)c2)[C@H](O)CNCc2cccc(CC)c2)n1
Reactant: CCCCN(C)c1cc(C(=O)O)cc(C#N)n1
Product: CCCCN(C)c1cc(C(=O)N[C@@H](Cc2cc(F)cc(F)c2)[C@H](O)CNCc2cccc(CC)c2)cc(C#N)n1

Procedure:
In the same manner as for N-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-2-(dipropylamino)-6-methylpyrimidine-4-carboxamide {EXAMPLE S-2435}, Step 3, 2-[butyl(methyl)amino]-6-cyanoisonicotinic acid (0.135 g) was converted to the title compound (0.223 g).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7](I)[C:5]([NH2:6])=[C:4]([F:10])[CH:3]=1.[Cl:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:18]#[CH:19].C(OCC)(=O)C>CCCCCCC>[Cl:1][C:2]1[CH:3]=[C:4]([F:10])[C:5]([NH2:6])=[C:7]([C:19]#[C:18][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[Cl:11])[CH:8]=1
Reactant: Nc1c(F)cc(Cl)cc1I
Reactant: C#Cc1ccccc1Cl
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: Nc1c(F)cc(Cl)cc1C#Cc1ccccc1Cl

Procedure:
The title compound was prepared in analogy to example 10 step A from 4-chloro-2-fluoro-6-iodoaniline (500 mg, 1.84 mmol) and 1-chloro-2-ethynyl-benzene (302 mg, 2.21 mmol). Brown solid (1.05 g, 68%). Rf 0.3 (1:9 Ethyl acetate:heptane) as a bright blue spot under UV light.
Reaction SMILES: Cl[C:2]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[C:9]2[C:4](=[N:5][CH:6]=[CH:7][C:8]=2[NH:16]C2C=CC=CC=2)[N:3]=1.NCCCN1CC[O:30]CC1>CC(O)C.CO>[NH2:16][C:8]1[CH:7]=[CH:6][N:5]=[C:4]2[C:9]=1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:2](=[O:30])[NH:3]2
Reactant: Clc1nc2nccc(Nc3ccccc3)c2c2ccccc12
Reactant: NCCCN1CCOCC1
Solvent: CC(C)O
Solvent: CO
Product: Nc1ccnc2[nH]c(=O)c3ccccc3c12
Temperature: 100 °C
Reaction time: 8 h
Yield: 29.6 %

Procedure:
(6-Chloro-benzo[c][1,8]naphthyridin-1-yl)-phenyl-amine (25 mg, 0.08 mmol) and N-(3-aminopropyl)morpholine (18 mg, 0.12 mmol) were dissolved in iPrOH (2 mL), and stirred overnight at 100° C. The reaction mixture was diluted with MeOH, filtered through a membrane, and purified via prep-LC-MS. The purified product was converted to the HCl salt via dissolving in methanolic HCl, and concentration on the Genevac to provide 141 (5 mg, 12% yield) as a dark solid. LC-MS (M+H=414, obsd.=414). 1H NMR (400 MHz, d6-DMSO): δ 10.32 (s, 1H), 9.31 (t, 1H), 8.87 (d, 1H), 8.58 (d, 1H), 8.09 (t, 1H), 7.89 (t, 1H), 7.80 (t, 1H), 7.49 (m, 2H), 7.40 (d, 2H), 7.32 (t, 1H), 6.90 (d, 1H), 3.95 (d, 2H), 3.86 (d, 2H), 3.75 (m, 2H), 3.46 (m, 2H), 3.28 (m, 2H), 3.08 (m, 2H), 2.22 (m, 2H).
Reaction SMILES: [CH:1]1[C:11]2[CH:10]=[CH:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[C:6](=[C:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[C:22]([O:26][CH2:27][CH3:28])(=[O:25])[CH:23]=[CH2:24]>C(O)C>[CH:1]1[C:11]2[CH:10]=[CH:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[C:6](=[C:16]3[CH2:17][CH2:18][N:19]([CH2:24][CH2:23][C:22]([O:26][CH2:27][CH3:28])=[O:25])[CH2:20][CH2:21]3)[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: C=CC(=O)OCC
Reactant: C1=Cc2ccccc2C(=C2CCNCC2)c2ccccc21
Solvent: CCO
Product: CCOC(=O)CCN1CCC(=C2c3ccccc3C=Cc3ccccc32)CC1

Procedure:
A mixture of 4.00 g of 4-(5H-dibenzo[a,d]cyclohepten-5-ylidene)piperidine, 2.1 ml of ethyl acrylate and 20 ml of ethanol was refluxed for 1 hr and concentrated to give 5.35 g of colorless liquid. The liquid was purified by column chromatography on silica gel (eluent: chloroform) to give 5.3 g of colorless solid, which was recrystallized from n-hexane to give colorless crystals, mp 66°-67° C.
Reaction SMILES: [Cl:1][CH2:2][C:3]([OH:5])=O.Cl.[CH2:7]([NH:9][CH2:10][CH3:11])[CH3:8].Cl.CN(C)CCCN=C=NCC.CN1CCOCC1>C(Cl)Cl>[Cl:1][CH2:2][C:3]([N:9]([CH2:10][CH3:11])[CH2:7][CH3:8])=[O:5]
Reactant: CCNCC
Reactant: O=C(O)CCl
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CCN(CC)C(=O)CCl
Temperature: 0 °C
Reaction time: 1 h
Yield: 56.5 %

Procedure:
To a solution of chloroacetic acid (10 g, 0.11 mol) in methylene chloride (530 ml) at 0° C. was added diethylamine HCl (15.3 g, 0.14 mol), 1-(3-dimethylaminopropyl)-3-ethyl carbodiimide hydrochloride (26.4 g, 0.14 mol) and 4-methyl morpholine (29 ml, 0.27 mol). After the reaction stirred 1 hour at 0° C., the reaction was stirred at room temperature for 4 hours. The reaction mixture was then washed with water, 1N hydrochloric acid (until the aqueous phase was colorless) and saturated sodium chloride, dried over anhydrous magnesium sulfate, filtered and concentrated to give the title A compound as a yellow oil (9.3 g).
Reaction SMILES: [CH2:1]([CH:7]([O:30][C:31](=[O:41])[C:32]1[CH:37]=[CH:36][C:35]([N+:38]([O-])=O)=[CH:34][CH:33]=1)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]([O:20][C:21]1[CH:26]=[CH:25][C:24]([N+:27]([O-])=O)=[CH:23][CH:22]=1)=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]>C(OCC)(=O)C.CN(C=O)C.[Ni]>[NH2:27][C:24]1[CH:23]=[CH:22][C:21]([O:20][C:18]([CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH:7]([O:30][C:31](=[O:41])[C:32]2[CH:33]=[CH:34][C:35]([NH2:38])=[CH:36][CH:37]=2)[CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])=[O:19])=[CH:26][CH:25]=1
Reactant: CCCCCCC(CCCCCCCCCCC(=O)Oc1ccc([N+](=O)[O-])cc1)OC(=O)c1ccc([N+](=O)[O-])cc1
Agent: [Ni]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCCCCC(CCCCCCCCCCC(=O)Oc1ccc(N)cc1)OC(=O)c1ccc(N)cc1
Temperature: 62.5 °C
Reaction time: 4 h

Procedure:
To a solution of 4-Nitro-benzoic acid 1-hexyl-11-(4-nitro-phenoxy carbonyl)-undecyl ester (290 g) in a mixture of Ethyl acetate (1.5 L) and DMF (300 mL) taken in a pressure vessel was added Raney Nickel (80 g). The reaction mixture was stirred under an atmosphere of Hydrogen (8-10 Kg) for 4 hours at a temperature of 60-65° C. The catalyst was removed by filtration. 75% of the solvent was distilled off and poured into cold water (2 L). The resulting solid was filtered off and washed with chilled water (100 mL) and do the slurry with 1 lit diisopropylether and filtered off, then dried the material properly in vacuum oven at 60-80° C. to yield pure 4-amino-benzoic acid 11-(4-amino-phenoxycarbonyl)-1-hexyl-undecyl ester product as off white powder (190 g) with a melting point of 156-159° C. The resulting compound was characterized by 1H NMR (CDCl3) δ 0.83 (t, 3H, CH3), 1.2-1.65 (m, 26H, 13×CH2), 1.81 (m, 2H, CH2), 2.12 (t, 2H, COCH2), 3.50 (m, 1H, CH), 5.5-6.1 (m, 4H, 2×NH2) 6.8-7.2 (m, 4H, Ar), 7.2-7.8 (m, 4H, Ar). The hydrolytic degradation of the compound was carried out in pH 9.0 buffer solution. The study showed that 1% solution is 100% hydrolyzed in 15 hours at 50° C.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([O:11][C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)=[C:7]([CH:10]=1)[C:8]#[N:9].Cl[C:19]1[CH:29]=[C:23]2[N:24]([CH3:28])[CH2:25][CH2:26][CH2:27][N:22]2[C:21](=[O:30])[N:20]=1>>[CH3:28][N:24]1[CH2:25][CH2:26][CH2:27][N:22]2[C:21](=[O:30])[N:20]=[C:19]([O:1][CH2:2][C:3]3[CH:4]=[CH:5][C:6]([O:11][C:12]4[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=4)=[C:7]([CH:10]=3)[C:8]#[N:9])[CH:29]=[C:23]12
Reactant: CN1CCCn2c1cc(Cl)nc2=O
Reactant: N#Cc1cc(CO)ccc1Oc1cccnc1
Product: CN1CCCn2c1cc(OCc1ccc(Oc3cccnc3)c(C#N)c1)nc2=O

Procedure:
The title compound or its salt was prepared by a procedure similar to that described for E2 starting from 5-(hydroxymethyl)-2-(pyridin-3-yloxy)benzonitrile and 8-chloro-1-methyl-3,4-dihydro-1H-pyrimido[1,6-a]pyrimidin-6(2H)-one.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[O:19][N:18]=[C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[N:16]=2)=[CH:11][CH:10]=1)C1C=CC=CC=1>CO.C1COCC1.[Pd]>[C:20]1([C:17]2[N:16]=[C:15]([C:12]3[CH:11]=[CH:10][C:9]([OH:8])=[CH:14][CH:13]=3)[O:19][N:18]=2)[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: c1ccc(COc2ccc(-c3nc(-c4ccccc4)no3)cc2)cc1
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: Oc1ccc(-c2nc(-c3ccccc3)no2)cc1
Yield: 10.9 %

Procedure:
A suspension of 5-(4-(benzyloxy)phenyl)-3-phenyl-1,2,4-oxadiazole (90 mg, 0.27 mmol) and 10% Pd/C (2 mg, 7 μmol) in methanol (3.0 mL) and THF (3.0 mL) was stirred in a single necked round bottom flask fitted with a condenser under an atmosphere of hydrogen at 55° C. for 72 hours. The solution was filtered through Celite and the solvent was removed under reduced pressure and then purified by column chromatography (EtOAc/Hex 1:2) to give the product (7 mg, 11%) as a white solid. 1H NMR (500 MHz, CDCL3) δ(ppm): 6.86 (2H, d, J=8.8 Hz), 6.99 (2H, d, J=9.2 Hz), 8.01 (2H, d, J=8.8 Hz), 8.05 (2H, d, J=9.2 Hz).
Reaction SMILES: C(N(C(C)C)CC)(C)C.[CH3:10][NH:11][CH3:12].[Br:13][C:14]1[CH:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[CH:16][C:15]=1[CH3:24]>O1CCCC1>[Br:13][C:14]1[CH:19]=[CH:18][C:17]([S:20]([N:11]([CH3:12])[CH3:10])(=[O:22])=[O:21])=[CH:16][C:15]=1[CH3:24]
Reactant: CNC
Reactant: Cc1cc(S(=O)(=O)Cl)ccc1Br
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: Cc1cc(S(=O)(=O)N(C)C)ccc1Br
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 94.8 %

Procedure:
Diisopropylethylamine (4.95 mL, 27.8 mmol) was added at 0° C. to a stirred solution of dimethylamine (3.70 mL, 55.6 mmol) in tetrahydrofuran (25 mL) and the reaction mixture was stirred at room temperature for 15 minutes. A 0.1 M solution of 4-bromo-3-methyl-benzenesulfonyl chloride (3.0 g, 11 mmol) in tetrahydrofuran was added at room temperature and the reaction mixture was stirred at room temperature for 2 hours. The solvent was evaporated off under reduced pressure. The residue was diluted with ethyl acetate, and the inorganic salts were filtered through a celite bed. The filtrate was washed with 2 N aqueous HCl, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to afford 2.90 g (94%) of 4-bromo-3-methyl-N,N-dimethyl-benzenesulfonamide, which was used in subsequent reactions without further purification. MS cald. for C9H12BrNO2S [M+] 278.2, obsd. 280.0.
Reaction SMILES: [CH:1]([C:3]1[N:4]=[C:5]([CH:8]2[CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10][CH2:9]2)[S:6][CH:7]=1)=[O:2].[ClH:21].C(OCC)C>ClCCl>[ClH:21].[NH:11]1[CH2:10][CH2:9][CH:8]([C:5]2[S:6][CH:7]=[C:3]([CH:1]=[O:2])[N:4]=2)[CH2:13][CH2:12]1
Reactant: CC(C)(C)OC(=O)N1CCC(c2nc(C=O)cs2)CC1
Agent: Cl
Solvent: CCOCC
Solvent: ClCCl
Product: O=Cc1csc(C2CCNCC2)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 1,1-dimethylethyl 4-(4-formyl-2-thiazolyl)-1-piperidinecarboxylate (1.0 g, 3.4 mmol) in dichloromethane (20 mL) was added a solution of hydrogen chloride in diethyl ether (2.0 mL, 15 ml, 30 mmol). The reaction mixture was stirred under nitrogen at room temperature for 2 h and then evaporated under reduced pressure to give 1.2 g of the title compound as a white solid.
Reaction SMILES: [C:1]([NH:8][CH2:9][C:10]([OH:12])=O)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[CH2:13]([O:15][C:16]([C@:18]1([NH2:30])[CH2:23][C@H:22]([OH:24])[C@@H:21]2[C@H:19]1[C@H:20]2[C:25]([O:27][CH2:28][CH3:29])=[O:26])=[O:17])[CH3:14]>>[CH2:13]([O:15][C:16]([C@:18]1([NH:30][C:10](=[O:12])[CH2:9][NH:8][C:1]([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2])[CH2:23][C@H:22]([OH:24])[C@@H:21]2[C@H:19]1[C@H:20]2[C:25]([O:27][CH2:28][CH3:29])=[O:26])=[O:17])[CH3:14]
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Reactant: CCOC(=O)[C@H]1[C@H]2[C@@H]1[C@](N)(C(=O)OCC)C[C@@H]2O
Product: CCOC(=O)[C@H]1[C@H]2[C@@H]1[C@](NC(=O)CNC(=O)OC(C)(C)C)(C(=O)OCC)C[C@@H]2O

Procedure:
Prepare according to General Procedure A using Boc-Glycine (458 mg, 2.62 mmol, Aldrich) and (1S,2S,4S,5R,6R)-2-amino-4-hydroxy-bicyclo[3.1.0]hexane-2,6-dicarboxylic acid diethyl ester (450 mg, 1.75 mmol, Preparation 22). Purify on 35 g of silica eluting with a gradient from 50/50 to 20/80 hexanes/ethyl acetate. Yield: 560 mg (77%).
Reaction SMILES: C(O[C:4](=[C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([N+:20]([O-:22])=[O:21])[CH:18]=2)[NH:13][C:12]1=[O:23])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)C.[OH:24][CH:25]1[CH2:30][CH2:29][N:28]([CH2:31][C:32]2[CH:38]=[CH:37][C:35]([NH2:36])=[CH:34][CH:33]=2)[CH2:27][CH2:26]1>CN(C=O)C>[OH:24][CH:25]1[CH2:26][CH2:27][N:28]([CH2:31][C:32]2[CH:38]=[CH:37][C:35]([NH:36]/[C:4](=[C:11]3\[C:12](=[O:23])[NH:13][C:14]4[C:19]\3=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=4)/[C:5]3[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=3)=[CH:34][CH:33]=2)[CH2:29][CH2:30]1
Reactant: CCOC(=C1C(=O)Nc2ccc([N+](=O)[O-])cc21)c1ccccc1
Reactant: Nc1ccc(CN2CCC(O)CC2)cc1
Solvent: CN(C)C=O
Product: O=C1Nc2ccc([N+](=O)[O-])cc2/C1=C(/Nc1ccc(CN2CCC(O)CC2)cc1)c1ccccc1

Procedure:
Prepared analogously to Example 89 from 3-(1-ethoxy-1-phenyl-methylidene)-5-nitro-2-indolinone and 4-(4-hydroxypiperidinomethyl)-aniline in DMF.
Reaction SMILES: Cl.[CH2:2]([N:4]1[CH2:13][CH2:12][C@@:11]2([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[CH:15]=3)[C@@H:6]([CH2:7][CH2:8][C:9](=O)[CH2:10]2)[CH2:5]1)[CH3:3].[C:23]1([NH:29][C:30](=[O:43])[C:31](=[N:35]NC2C=CC=CC=2)[C:32](=O)[CH3:33])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>[Zn].C(O)(=O)C>[CH2:2]([N:4]1[CH2:13][CH2:12][C@:11]2([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[CH:15]=3)[C@H:6]([CH2:7][C:8]3[C:32]([CH3:33])=[C:31]([C:30]([NH:29][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)=[O:43])[NH:35][C:9]=3[CH2:10]2)[CH2:5]1)[CH3:3]
Reactant: CCN1CC[C@]2(c3cccc(OC)c3)CC(=O)CC[C@H]2C1
Reactant: CC(=O)C(=NNc1ccccc1)C(=O)Nc1ccccc1
Agent: Cl
Agent: [Zn]
Solvent: CC(=O)O
Product: CCN1CC[C@@]2(c3cccc(OC)c3)Cc3[nH]c(C(=O)Nc4ccccc4)c(C)c3C[C@@H]2C1
Yield: 25.6 %

Procedure:
0.8 g (2.47 mmol) of (±)-trans-2-ethyl-4a-(3-methoxyphenyl)-6-oxo-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline hydrochloride, 0.7 g (2.47 mmol) of N-phenyl-2-phenylhydrazono-3-oxobutyramide, 0.24 g (3 mmol) of CH3 COONa, 0.74 g (11.3 mmol) of zinc dust and 2.5 ml of glacial acetic acid were treated as described in example 1. The residue was purified by flash chromatography (EtOAc/MeOH/conc. NH4OH 90:10:1) yielding 0.28 g of the title compound. M.p.=178-180° C.
Reaction SMILES: Cl.[OH:2][CH2:3][CH2:4][O:5][NH2:6].[CH:7]([C:9]1[CH:14]=[CH:13][N:12]2[C:15]([C:18]3[CH:19]=[C:20]([C:24]4[CH:28]=[CH:27][S:26][C:25]=4[C:29]#[N:30])[CH:21]=[CH:22][CH:23]=3)=[CH:16][N:17]=[C:11]2[CH:10]=1)=O>>[OH:2][CH2:3][CH2:4][O:5][N:6]=[CH:7][C:9]1[CH:14]=[CH:13][N:12]2[C:15]([C:18]3[CH:19]=[C:20]([C:24]4[CH:28]=[CH:27][S:26][C:25]=4[C:29]#[N:30])[CH:21]=[CH:22][CH:23]=3)=[CH:16][N:17]=[C:11]2[CH:10]=1
Reactant: N#Cc1sccc1-c1cccc(-c2cnc3cc(C=O)ccn23)c1
Reactant: NOCCO
Agent: Cl
Product: N#Cc1sccc1-c1cccc(-c2cnc3cc(C=NOCCO)ccn23)c1

Procedure:
The title compound was prepared in a similar manner to that described in Example 14 using O-(2-hydroxyethyl)hydroxylamine hydrochloride (93 mg, 0.82 mmol) and 3-[3-(7-formylimidazo[1,2-α]pyridin -3-yl)phenyl]thiophene-2-carbonitrile (67 mg, 0.20 mmol) to afford a white crystalline solid (43 mg, 55%), essentially as a single geometric isomer, m.p. 224-225° C. 1H NMR (360 MHz, CDCl3) δH 3.94-3.97 (2H, m), 4.32-4.36 (2H, m), 7.31-7.38 (2H, m), 7.64-7.72 (5H, m), 7.80 (1H, s), 7.88 (1H, s), 8.17 (1H, s), 8.47 (1H, d, J 7); m/z (ES+) 389 (M++H).
Reaction SMILES: N[C:2]1[S:3][C:4]2[C:9]([NH:10][CH:11]([CH2:14][O:15][CH3:16])[CH2:12][OH:13])=[N:8][C:7]([S:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[C:20]=3[F:26])=[N:6][C:5]=2[N:27]=1.[ClH:28].N([O-])=O.[Na+]>O>[Cl:28][C:2]1[S:3][C:4]2[C:9]([NH:10][CH:11]([CH2:14][O:15][CH3:16])[CH2:12][OH:13])=[N:8][C:7]([S:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[C:20]=3[F:26])=[N:6][C:5]=2[N:27]=1
Reactant: Cl
Reactant: COCC(CO)Nc1nc(SCc2cccc(F)c2F)nc2nc(N)sc12
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: COCC(CO)Nc1nc(SCc2cccc(F)c2F)nc2nc(Cl)sc12
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of the product from example 40 step b) (1.0 g) in a mixture of concentrated hydrochloric acid (40 ml) and water (32 ml) cooled in ice water was added a solution of sodium nitrite (0.4 g) in water (5 mL), stirred at this temp for 2 hours. The mixture was then extracted into ethyl acetate, dried and evaporated to give the subtitle compound, (0.6 g).