Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N1CCCCC1.[CH3:7][O:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][C:16]=1[O:17][CH3:18])[CH:12]=O.[Br:19][C:20]1[CH:21]=[CH:22][C:23]([NH:29][C:30](=[O:35])[CH2:31]C(O)=O)=[C:24]([CH:28]=1)[C:25]([OH:27])=[O:26].Cl>C1(C)C=CC=CC=1>[CH3:7][O:8][C:9]1[CH:10]=[C:11](/[CH:12]=[CH:31]/[C:30]([NH:29][C:23]2[CH:22]=[CH:21][C:20]([Br:19])=[CH:28][C:24]=2[C:25]([OH:27])=[O:26])=[O:35])[CH:14]=[CH:15][C:16]=1[O:17][CH3:18]
Reactant: O=C(O)CC(=O)Nc1ccc(Br)cc1C(=O)O
Reactant: COc1ccc(C=O)cc1OC
Agent: Cl
Solvent: Cc1ccccc1
Solvent: C1CCNCC1
Product: COc1ccc(/C=C/C(=O)Nc2ccc(Br)cc2C(=O)O)cc1OC
Yield: 67.1 %

Procedure:
Piperidine (0.13 mL, 1.4 mmol) was added to a suspension of 3,4-dimethoxybenzaldehyde (0.22 g, 1.4 mmol) and 5-bromo-2-[(carboxyacetyl)amino]benzoic acid (0.34 g, 1.1 mmol) in toluene (4.0 mL) and treated according to Procedure 2, acidifying with 1 M HCl. (E)-2-[[3-(3,4-Dimethoxyphenyl)-1-oxo-2-propenyl]amino]-5-bromobenzoic acid (0.30 g, 66%) was obtained as a yellow crystalline solid; mp 210-213° C.; δH (400 MHz, DMSO-d6) 3.79 (s, 3H, OCH3), 3.82 (s, 3H, OCH3), 6.78 (d, J=15.6 Hz, 1H, CH═CHCO), 6.98 (d, J5′,6′=8.4 Hz, 1H, H5′), 7.24 (d, J5′,6′=8.4 Hz, 1H, H6′), 7.36 (s, 1H, H2′), 7.56 (d, J=15.6 Hz, 1H, CH═CHCO), 7.78 (dd, J3,4=8.4, J4,6=2.0 Hz, 1H, H4), 8.06 (d, J4,6=2.0 Hz, 1H, H6), 8.62 (d, J3,4=8.4 Hz, 1H, H3), 11.30 (s, 1H, NH), 13.61 (br s, 1H, CO2H); δC (100 MHz, DMSO-d6) 28.6, 55.5, 55.6, 110.4, 111.6, 114.0, 119.5, 122.5, 122.7, 127.1, 133.1, 136.4, 140.2, 142.0, 149.0, 150.7, 164.2, 168.1; HRMS (ESI) calculated for C13H16BrNO5 [M+Na]+ 428.0104. found 428.0105; vmax 1026, 1247, 1510, 1595, 1698, 2515, 2829, 3226, 3619 cm−1.
Reaction SMILES: [H][H].[C:3]1([C:9](=[N:19]O)[CH2:10][CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>>[C:3]1([CH:9]([NH2:19])[CH2:10][CH2:11][CH2:12][C:13]2[CH:14]=[CH:15][N:16]=[CH:17][CH:18]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: ON=C(CCCc1ccncc1)c1ccccc1
Reactant: [H][H]
Product: NC(CCCc1ccncc1)c1ccccc1
Yield: 88.4 %

Procedure:
Using deprotection method A under 4.1 bar (60 psig) of hydrogen, 1-phenyl-4-(pyridin-4-yl)butan-1-one oxime (1.6 g, 6.5 mmol) afforded 1.3 g (87%) of the title compound.
Reaction SMILES: [CH3:1][NH:2][O:3][CH3:4].C(N(CC)CC)C.[C:12]([C:16]1[O:17][C:18]2[C:24]([S:25](Cl)(=[O:27])=[O:26])=[C:23]([Cl:29])[CH:22]=[CH:21][C:19]=2[N:20]=1)([CH3:15])([CH3:14])[CH3:13]>C1COCC1>[CH3:4][O:3][N:2]([CH3:1])[S:25]([C:24]1[C:18]2[O:17][C:16]([C:12]([CH3:14])([CH3:13])[CH3:15])=[N:20][C:19]=2[CH:21]=[CH:22][C:23]=1[Cl:29])(=[O:26])=[O:27]
Reactant: CNOC
Reactant: CC(C)(C)c1nc2ccc(Cl)c(S(=O)(=O)Cl)c2o1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CON(C)S(=O)(=O)c1c(Cl)ccc2nc(C(C)(C)C)oc12
Temperature: 0 °C

Procedure:
N,O-dimethylhydroxylamine (1.98 g, 2 equiv) was suspended in dry THF (20 ml) and cooled to 0° C. in an ice bath while stirring vigourously. Triethylamine (4.51 ml, 2 equiv) was added maintaining the temperature at 0° C. followed by dropwise addition of 2-tert-butyl-6-chloro-benzooxazole-7-sulfonyl chloride (US 2007/0249672 page 9) (5 g, 16.22 mmol, 1 equiv) in THF (10 ml) over 30 minutes. The reaction mixture was stirred at 0° C. for 1 h and then allowed to warm to room temperature overnight. The resulting mixture was filtered and concentrated in vacuo and the resulting solid was dissolved in EtOAc (75 ml), washed with water (3×20 ml), sat. brine (30 ml) dried (MgSO4) and concentrated in vacuo to afford the title compound as a solid; [M+H]+ 333.
Reaction SMILES: Cl[C:2]1[C:7]([O:8][CH2:9][CH2:10][O:11]C2CCCCO2)=[CH:6][CH:5]=[CH:4][N:3]=1.[CH3:18][N:19]([CH2:23][CH2:24][OH:25])[CH:20]([CH3:22])[CH3:21].CC(C)([O-])C.[K+].C(O)(C)(C)C>C1(C)C=CC=CC=1>[CH:20]([N:19]([CH3:18])[CH2:23][CH2:24][O:25][C:2]1[C:7]([O:8][CH2:9][CH2:10][OH:11])=[CH:6][CH:5]=[CH:4][N:3]=1)([CH3:22])[CH3:21]
Reactant: CC(C)N(C)CCO
Reactant: Clc1ncccc1OCCOC1CCCCO1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CC(C)(C)O
Product: CC(C)N(C)CCOc1ncccc1OCCO
Temperature: 50 °C
Reaction time: 48 h
Yield: 76.9 %

Procedure:
A solution of 2-chloro-3-[2-(tetrahydro-2H-pyran-2-yloxy]ethoxy]pyridine (from Example 4; 100 mg, 0.39 mmol), 2-(N-methyl-N-isopropylamino)ethanol (68 μl, 0.58 mmol) and 1.0 M potassium tert-butoxide in tert-butanol (0.8 mL, 0.80 mmol) in 4 mL of toluene was heated at 100° C. for 1 day. The organic phase was washed with 3×2 mL of water and 2 mL of brine. The organic phase was shaken at 50° C. with 4 mL of 2.0 M acetic acid for 2 days. The aqueous phase was washed with 3×3 mL of ethyl acetate, made basic by addition of potassium hydroxide, saturated with sodium chloride and extracted with 3×2 mL of ethyl acetate. The organic phase was dried (MgSO4) and concentrated under reduced pressure to give 75 mg (0.30 mmol, 76%) of the title compound as a colorless oil. LC-UV purity 95%. MS m/z 255 (M+1)+, calc. 255 (M+1)+.
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].C(N(CC)CC)C.[CH3:13][C:14]1[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([O:24][CH2:25][CH3:26])([CH3:23])[CH3:22])[C:15]=1[NH2:16]>C(Cl)Cl>[CH3:13][C:14]1[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([O:24][CH2:25][CH3:26])([CH3:23])[CH3:22])[C:15]=1[NH:16][C:3](=[O:4])[CH2:2][Cl:1]
Reactant: CCOC(C)(C)c1cccc(C)c1N
Reactant: O=C(Cl)CCl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(C)(C)c1cccc(C)c1NC(=O)CCl
Reaction time: 8 h

Procedure:
In this example 1.45 g (1.03 ml) of chloroacetyl chloride was added dropwise to a solution containing 1.44 g (2 ml) of triethylamine and 0.0129 mole of 2-methyl-6-(1-ethoxy-1-methylethyl)aniline in methylene chloride at about but below 20° C. The mixture was then refluxed and then allowed to stand overnight at room temperature. Another 0.51 ml of chloroacetyl chloride and 1 ml of triethylamine was then added dropwise. The mixture was then again refluxed and allowed to stand overnight at room temperature. The mixture was then washed with saturated aqueous sodium bicarbonate, dried and evaporated affording the title compound as a brown oil.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][C:18]=1[O:19][CH3:20])[CH2:15][NH:14][CH:13]([CH3:21])[CH2:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:22][O:23][C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][CH:31]=1)[CH2:27]Cl>CCO>[CH3:22][O:23][C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][CH:31]=1)[CH2:27][N:14]1[CH:13]([CH3:21])[CH2:12][C:11]2[C:16](=[CH:17][C:18]([O:19][CH3:20])=[C:9]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH:10]=2)[CH2:15]1
Reactant: COc1cccc(CCl)c1
Reactant: COc1cc2c(cc1OCc1ccccc1)CC(C)NC2
Solvent: CCO
Product: COc1cccc(CN2Cc3cc(OC)c(OCc4ccccc4)cc3CC2C)c1
Yield: 80.4 %

Procedure:
A solution of 213 (300 mg, 1.1 mmol), TEA (0.3 ml, 2.1 mmol) and 3-methoxybenzyl chloride (0.18 ml, 1.3 mmol) in EtOH (3 ml) was heated in the microwave at 130° C. for 1.5 h. The reaction mixture was concentrated in vacuo and the crude residue was dissolved in EtOAc (30 ml) and washed with brine (30 ml). The organic layer was dried (MgSO4) and concentrated in vacuo. Purification (flashmaster: 20 g, 100% hex to 100% EtOAc over 25 min) afforded the title compound (357 mg, 84%) as a colourless oil. 1H NMR (270 MHz; CDCl3) 1.12 (3H, d, J=6.4 Hz, CH3CH), 2.47 (1H, dd, J=16.1, 5.7 Hz, CHH), 2.86 (1H, dd, J=16.1, 4.9 Hz, CHH), 3.0-3.11 (1H, m, CH3CH), 3.55 (2H, t, J=13.4 Hz, CH2), 3.76-3.81 (2H, m, CH2), 3.80 (6H, s, 2×OCH3), 5.10 (2H, s, CH2Ph), 6.47 (1H, s, CH), 6.60 (1H, s, CH), 6.79 (1H, ddd, J=8.2, 2.5, 1.0 Hz, CH), 6.94-6.97 (2H, m, 2×CH), 7.15-7.45 (6H, m, 5×CH, phenyl and CH). 13C (67.5 MHz; CDCl3) 15.31 (CH3), 35.03 (CH2), 51.51 (CH2), 52.27 (CH), 55.32 (CH3), 56.11 (CH3), 57.24 (CH2), 71.21 (CH2), 109.95 (CH), 112.48 (CH), 114.36 (CH), 114.56 (CH), 121.32 (CH),125.83 (C), 126.95 (C), 127.37 (CH), 127.82 (CH), 128.59 (CH), 129.30 (CH), 137.47 (C), 141.35 (C), 146.73 (C), 147.91 (C), 159.77 (C). LC/MS (ES+) tr=1.52 min, m/z 404.25 (M++H).
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:29]=[CH:28][C:11]([C:12]([NH:14][CH2:15][CH2:16][C:17]3[CH:18]=[C:19]4[C:23](=[CH:24][CH:25]=3)[NH:22][CH:21]=[C:20]4[C:26]#[N:27])=[O:13])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.[C:30](OC(=O)C)(=[O:32])[CH3:31]>N1C=CC=CC=1>[C:30]([NH:1][CH:2]1[CH2:3][CH2:4][N:5]([C:8]2[CH:9]=[CH:10][C:11]([C:12]([NH:14][CH2:15][CH2:16][C:17]3[CH:18]=[C:19]4[C:23](=[CH:24][CH:25]=3)[NH:22][CH:21]=[C:20]4[C:26]#[N:27])=[O:13])=[CH:28][CH:29]=2)[CH2:6][CH2:7]1)(=[O:32])[CH3:31]
Reactant: CC(=O)OC(C)=O
Reactant: N#Cc1c[nH]c2ccc(CCNC(=O)c3ccc(N4CCC(N)CC4)cc3)cc12
Solvent: c1ccncc1
Product: CC(=O)NC1CCN(c2ccc(C(=O)NCCc3ccc4[nH]cc(C#N)c4c3)cc2)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
40 mg (0.09 mmol) of 4-(4-amino-piperidin-1-yl)-N-[2-(3-Cyano-1H-indol-5-yl)-ethyl]-benzamide. (reference Example 1aav). was dissolved in 2 ml of pyridine, 22 mg (0.22 mmol) of acetic anhydride was added and stirred at room temperature for 16 h. The reaction mixture was evaporated to dryness. MS (CI) 430 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[NH:9][S:10]([C:13]1[CH:14]=[C:15]([CH:19]=[CH:20][CH:21]=1)[C:16]([OH:18])=O)(=[O:12])=[O:11].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH2:46]1[NH:51][CH2:50][CH2:49][N:48]2[CH2:52][CH2:53][CH2:54][C@H:47]12>CN(C)C(=O)C.CC1CCCO1>[F:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[C:3]=1[NH:9][S:10]([C:13]1[CH:21]=[CH:20][CH:19]=[C:15]([C:16]([N:51]2[CH2:50][CH2:49][N:48]3[CH2:52][CH2:53][CH2:54][C@@H:47]3[CH2:46]2)=[O:18])[CH:14]=1)(=[O:12])=[O:11]
Reactant: O=C(O)c1cccc(S(=O)(=O)Nc2c(F)cccc2F)c1
Reactant: C1C[C@@H]2CNCCN2C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC1CCCO1
Solvent: CC(=O)N(C)C
Product: O=C(c1cccc(S(=O)(=O)Nc2c(F)cccc2F)c1)N1CCN2CCC[C@@H]2C1
Temperature: 25 °C
Reaction time: 5.5 h

Procedure:
To 3-{[(2,6-difluorophenyl)amino]sulfonyl}benzoic acid (0.96 g, 3.06 mmol) and 2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate(V) (1.28 g, 3.37 mmol) in N,N-dimethylacetamide (7.4 mL) and 2-methyltetrahydrofuran (22 mL) was added (R)-octahydropyrrolo[1,2-α]pyrazine (0.54 g, 4.28 mmol). The reaction was stirred at ambient temperature for 5.5 hours, and then it was diluted with 2-methyltetrahydrofuran (15 mL). The organic solution was washed with 6% NaHCO3/6% NaCl (35 mL), and the aqueous layer was extracted with 2-methyltetrahydrofuran (50 mL). The organic layer was washed with 6% NaHCO3/6% NaCl (50 mL) and 1:1 saturated NaCl/water (6×15 mL), and then it was concentrated. The residue was concentrated from ethanol (2×10 mL) to give the title compound.
Reaction SMILES: [C:1]([C:3](=[C:9]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:4]([O:6][CH2:7][CH3:8])=[O:5])#[N:2].[CH:22]1(O)[CH2:27]CC[CH2:24][CH2:23]1.C([O-])([O-])=O.[Na+].[Na+]>C(O)C>[C:1]([C:3](=[C:9]([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[C:4]([O:6][CH:7]1[CH2:24][CH2:23][CH2:22][CH2:27][CH2:8]1)=[O:5])#[N:2]
Reactant: OC1CCCCC1
Reactant: CCOC(=O)C(C#N)=C(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: N#CC(C(=O)OC1CCCCC1)=C(c1ccccc1)c1ccccc1
Reaction time: 6 h
Yield: 67 %

Procedure:
139 g (0.5 mol) of ethyl 2-cyano-3,3-diphenylacrylate (Uvinul 3035), 200 ml of cyclohexanol and 10 g of Na2CO3 were reacted together at 150° C. with distillative removal of the ethanol formed, assisted by a stream of nitrogen. After about 6 h, the reaction mixture was filtered hot in order to remove the Na2CO3. After the filtrate had been cooled, the precipitate which had formed was filtered off, washed with petroleum ether and dried, giving 111 g (67%) of cyclohexyl 2-cyano-3,3-diphenylacrylate as a colorless solid. [λmax 300 nm; E11, (MeOH) 381]
Reaction SMILES: [CH2:1]([NH:4][S:5]([C:8]1[C:13]([Cl:14])=[CH:12][CH:11]=[C:10]([N+:15]([O-:17])=[O:16])[C:9]=1Cl)(=[O:7])=[O:6])[CH2:2][CH3:3].[H-].[Na+].[OH2:21]>>[CH2:1]([NH:4][S:5]([C:8]1[C:13]([Cl:14])=[CH:12][CH:11]=[C:10]([N+:15]([O-:17])=[O:16])[C:9]=1[OH:21])(=[O:7])=[O:6])[CH2:2][CH3:3]
Reactant: CCCNS(=O)(=O)c1c(Cl)ccc([N+](=O)[O-])c1Cl
Reactant: O
Agent: [H-]
Agent: [Na+]
Product: CCCNS(=O)(=O)c1c(Cl)ccc([N+](=O)[O-])c1O
Yield: 69.1 %

Procedure:
Following the general hydrolysis procedure outlined in example 15, N-propyl-2,6-dichloro-3-nitrobenzenesulfonamide (1.0 , 3.19mmol), 60% NaH (393 mg, 3.19 mmol) and water (58 μL, 3.19 mmol) were reacted to form the desired product (650 mg, 69%). LC-MS (m/z) 295.0 (M+).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:13]=1[NH:12][CH:11]=[C:10]([C:14]([OH:16])=[O:15])[C:9]2=[O:17])([O-])=O.[H][H]>CN(C)C=O.[Ni]>[NH2:1][C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:13]=1[NH:12][CH:11]=[C:10]([C:14]([OH:16])=[O:15])[C:9]2=[O:17]
Reactant: O=C(O)c1c[nH]c2c([N+](=O)[O-])cccc2c1=O
Reactant: [H][H]
Agent: [Ni]
Solvent: CN(C)C=O
Product: Nc1cccc2c(=O)c(C(=O)O)c[nH]c12
Yield: 74.2 %

Procedure:
A solution of 15.0 g (64 mmol) of 1,4-dihydro-8-nitro-4-oxo-3-quinolinecarboxylic acid [J. Amer. Chem. Soc., 68, 1264 (1946)] in 300 ml of dimethylformamide is hydrogenated using 1 g of Raney nickel catalyst at 51 psi and 23° until the required amount of hydrogen uptake is obtained. The catalyst is filtered off and the filtrate is concentrated to 50 ml and ethanol is added. The solid is collected by filtration and washed with ethanol and ether to give 9.7 g of the title compound.
Reaction SMILES: C([O:3][C:4](=[O:26])[C:5]([NH:22]C(=O)C)([CH2:11][C:12]1[C:20]2[C:15](=[N:16][CH:17]=[CH:18][C:19]=2[Cl:21])[NH:14][CH:13]=1)C(OCC)=O)C>Cl>[ClH:21].[NH2:22][CH:5]([CH2:11][C:12]1[C:20]2[C:15](=[N:16][CH:17]=[CH:18][C:19]=2[Cl:21])[NH:14][CH:13]=1)[C:4]([OH:26])=[O:3]
Reactant: CCOC(=O)C(Cc1c[nH]c2nccc(Cl)c12)(NC(C)=O)C(=O)OCC
Agent: Cl
Product: NC(Cc1c[nH]c2nccc(Cl)c12)C(=O)O
Temperature: 100 °C

Procedure:
2-Acetylamino-2-(4-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)malonic acid diethyl ester (8.5 g, 22.3 mol) was dissolved in concentrated hydrochloric acid (45 mL) and the solution heated at 100° C. for 16 hours. The mixture was allowed to cool to ambient temperature and evaporated in-vacuo. The resultant residue was azeotroped with methanol (100 mL) and toluene (2×100 mL) to afford the crude title compound as a white solid. LCMS (Method B): RT=1.88 min, M+H+=240.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:9])[CH2:5][CH2:6][CH:7]=[O:8])[CH3:2].[Br:10]Br>C(OCC)C>[CH2:1]([O:3][C:4](=[O:9])[CH2:5][CH:6]([Br:10])[CH:7]=[O:8])[CH3:2]
Reactant: CCOC(=O)CCC=O
Reactant: BrBr
Solvent: CCOCC
Product: CCOC(=O)CC(Br)C=O
Reaction time: 1.25 h
Yield: 66.5 %

Procedure:
To a 0-5° C. mechanically-stirred solution in diethyl ether (100 mL) of succinaldehydic acid ethyl ester (10.0 g, 77 mmol) was added bromine (3.9 g, 151 mmol) over 2.5 hours. The reaction mixture was stirred for an additional 1.25 hours and the ether was distilled at atmospheric pressure. The remaining yellow oil was distilled (6.0-6.5 mm Hg, bp 95-101° C.) to give 3-bromosuccinaldehydic acid ethyl ester (10.7 g, 66%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:8]2[C@@:12]3([CH2:17][CH2:16][NH:15][C@@H:14]([CH3:18])[CH2:13]3)[C:11]([NH:19][CH3:20])=[N:10][C:9]2=[O:21])[CH:5]=[CH:6][CH:7]=1.C([O-])([O-])=O.[K+].[K+].[I:28][C:29]1[CH:30]=[C:31]([CH:34]=[CH:35][CH:36]=1)[CH2:32]Br>CS(C)=O.O>[F:1][C:2]1[CH:3]=[C:4]([N:8]2[C@@:12]3([CH2:17][CH2:16][N:15]([CH2:32][C:31]4[CH:34]=[CH:35][CH:36]=[C:29]([I:28])[CH:30]=4)[C@@H:14]([CH3:18])[CH2:13]3)[C:11]([NH:19][CH3:20])=[N:10][C:9]2=[O:21])[CH:5]=[CH:6][CH:7]=1
Reactant: BrCc1cccc(I)c1
Reactant: CNC1=NC(=O)N(c2cccc(F)c2)[C@@]12CCN[C@@H](C)C2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CNC1=NC(=O)N(c2cccc(F)c2)[C@@]12CCN(Cc1cccc(I)c1)[C@@H](C)C2
Reaction time: 8 h

Procedure:
(5R,7S)-1-(3-fluorophenyl)-7-methyl-4-(methylamino)-1,3,8-triazaspiro[4.5]dec-3-en-2-one (250 mg, 0.86 mmol) from step 2 above was dissolved in DMSO (8.0 mL). The flask was charged with K2CO3 (594 mg, 4.30 mmol) and 3-iodo-benzylbromide (255 mg, 0.86 mmol). The mixture was then sealed with a septum and placed in 50° C. oil bath and allowed to stir overnight. The mixture was diluted with water and extracted with EtOAc (three times). The combined organic layers were washed with aqueous LiCl (three times), followed by brine and then dried over Na2SO4. Solvent removal under reduced pressure gave crude product. Purification over silica via automated flash chromatography (0 to 20% MeOH/CH2Cl2 over 20 min.) gave after solvent removal the product as a white solid: LCMS [M+H]=507.3
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:8][N:9]=[C:10](Cl)[C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:5]=[CH:6][CH:7]=1.N1([C:23]2[C:24](=[O:38])[N:25]([C:29]3[CH:34]=[CH:33][C:32]([N+:35]([O-:37])=[O:36])=[CH:31][CH:30]=3)[CH2:26][CH2:27][CH:28]=2)CCOCC1.C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH2:14]([O:13][C:11]([C:10]1[C:28]2[CH2:27][CH2:26][N:25]([C:29]3[CH:34]=[CH:33][C:32]([N+:35]([O-:37])=[O:36])=[CH:31][CH:30]=3)[C:24](=[O:38])[C:23]=2[N:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)[N:9]=1)=[O:12])[CH3:15]
Reactant: CCOC(=O)C(Cl)=NNc1cccc(Cl)c1
Reactant: O=C1C(N2CCOCC2)=CCCN1c1ccc([N+](=O)[O-])cc1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCOC(=O)c1nn(-c2cccc(Cl)c2)c2c1CCN(c1ccc([N+](=O)[O-])cc1)C2=O
Temperature: 80 °C
Yield: 47.6 %

Procedure:
Part A: A 500 mL flask was charged with N-(3-chlorophenyl)-1-(ethoxycarbonyl)-methanehydrazonoyl chloride (3.67 g, 14.1 mmol), 3-morpholin-4-yl-1-(4-nitro-phenyl)-5,6-dihydro-1H-pyridin-2-one (2.14 g, 7.05 mmol), 50 mL of toluene, and triethylamine (3.57 g, 35.3 mmol). The mixture was heated at 80° C. overnight. After cooling to room temperature, the reaction mixture was treated with trifuloroacetic acid (10.1 g) at rt for 5 h. The mixture was concentrated to dryness under reduced pressure. The residue was dissolved in methylene chloride, washed water and brine, and dried with sodium sulfate. The crude product, after evaporation of the solvent, was purified by silica gel chromatography, eluting with 1:2 ethyl acetate/hexane to yield 1-(3-chloro-phenyl)-6-(4-nitro-phenyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid ethyl ester (1.48 g). 1H NMR (300 MHz, CDCl3) δ 8.24 (2H, d, J=9.1 Hz), 7.60 (1H, t, J=1.8 Hz), 7.52 (2H, d, J=9.1 Hz), 7.47˜7.36(2H, m), 4.48 (2H, q, J=7.0 Hz), 4.22 (2H, t, J=6.6 Hz), 3.39 (2H, t, J=6.6 Hz), 1.45 (3H, t, J=7.0 Hz) ppm.
Reaction SMILES: C(OC([N:8]1[CH2:12][C@H:11]([NH:13][S:14]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)(=[O:16])=[O:15])[CH2:10][C@H:9]1/[CH:24]=[CH:25]\[CH2:26][CH2:27][CH2:28][C:29]([OH:31])=[O:30])=O)(C)(C)C.Cl.[CH3:33]O>>[Cl:23][C:20]1[CH:19]=[CH:18][C:17]([S:14]([NH:13][C@H:11]2[CH2:12][NH:8][C@H:9](/[CH:24]=[CH:25]\[CH2:26][CH2:27][CH2:28][C:29]([O:31][CH3:33])=[O:30])[CH2:10]2)(=[O:15])=[O:16])=[CH:22][CH:21]=1
Reactant: CC(C)(C)OC(=O)N1C[C@H](NS(=O)(=O)c2ccc(Cl)cc2)C[C@H]1/C=C\CCCC(=O)O
Reactant: CO
Agent: Cl
Product: COC(=O)CCC/C=C\[C@@H]1C[C@@H](NS(=O)(=O)c2ccc(Cl)cc2)CN1

Procedure:
A solution of (2S,4R)-1-t-butoxycarbonyl-2-[{Z)-5-carboxy-1-pentenyl]-4-(4-chlorophenylsulfonylamino)pyrrolidine (2.90 g) in methanol (50 ml) saturated with hydrogen chloride was stirred at room temperature overnight and the solvent was evaporated in vacuo. The residue was dissolved in chloroform (50 ml) and the solution was washed successively with saturated aqueous sodium bicarbonate and brine. The organic layer was dried over magnesium sulfate and the solvent was evaporated in vacuo to give (2S,4R)-4-(4-chlorophenylsulfonylamino)-2-[(Z)-5-methoxycarbonyl-1-pentenyl]pyrrolidine (2.28 g) as a pale brown oil.
Reaction SMILES: [F:1][C:2]([F:14])([CH3:13])[CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[CH:11]=[CH:10][C:9]([NH2:12])=[N:8]1.[C:15]1([CH3:26])[CH:20]=[CH:19][CH:18]=[C:17](/[CH:21]=[CH:22]/[C:23](O)=[O:24])[CH:16]=1>>[F:14][C:2]([F:1])([CH3:13])[CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[CH:11]=[CH:10][C:9]([NH:12][C:23](=[O:24])/[CH:22]=[CH:21]/[C:17]2[CH:16]=[C:15]([CH3:26])[CH:20]=[CH:19][CH:18]=2)=[N:8]1
Reactant: Cc1cccc(/C=C/C(=O)O)c1
Reactant: CC(F)(F)CCCCn1ccc(N)n1
Product: Cc1cccc(/C=C/C(=O)Nc2ccn(CCCCC(C)(F)F)n2)c1

Procedure:
Following general procedure B, starting from 1-(5,5-difluoro-hexyl)-1H-pyrazol-3-ylamine and (E)-3-m-tolyl-acrylic acid. LC-MS-conditions 05b: tR=1.13 min; [M+H]+=348.31.
Reaction SMILES: [CH:1]([O:4][CH2:5][CH2:6][N:7]([C:12]1[CH:20]=[CH:19][C:15]([C:16](Cl)=[O:17])=[CH:14][CH:13]=1)[C:8](=[O:11])[CH2:9][Cl:10])([CH3:3])[CH3:2].[Br:21][C:22]1[CH:27]=[CH:26][C:25]([CH2:28][CH2:29][N:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)=[CH:24][CH:23]=1>>[CH:1]([O:4][CH2:5][CH2:6][N:7]([C:12]1[CH:20]=[CH:19][C:15]([C:16]([N:33]2[CH2:32][CH2:31][N:30]([CH2:29][CH2:28][C:25]3[CH:26]=[CH:27][C:22]([Br:21])=[CH:23][CH:24]=3)[CH2:35][CH2:34]2)=[O:17])=[CH:14][CH:13]=1)[C:8](=[O:11])[CH2:9][Cl:10])([CH3:3])[CH3:2]
Reactant: CC(C)OCCN(C(=O)CCl)c1ccc(C(=O)Cl)cc1
Reactant: Brc1ccc(CCN2CCNCC2)cc1
Product: CC(C)OCCN(C(=O)CCl)c1ccc(C(=O)N2CCN(CCc3ccc(Br)cc3)CC2)cc1

Procedure:
Analogously to Example 55, 1.5 g of 4-[N-(2-isopropyloxyethyl)-N-chloroacetylamino]benzoyl chloride are reacted with 1.07 g of [2-(4-bromophenyl)ethyl]-piperazine, yielding 1-{4-[N-(2-isopropyloxyethyl)-N-chloroacetylamino]benzoyl}-4-[2-(4-bromophenyl)ethyl]piperazine having a melting point of 92°-93°.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][C@@H:10]2[CH2:13][N:14]([C:16]([O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[O:17])[CH2:15][C@H:9]12)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[CH2:19]([O:18][C:16]([N:14]1[CH2:13][C@@H:10]2[C@@H:9]([NH:8][CH2:12][CH2:11]2)[CH2:15]1)=[O:17])[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H]2CN(C(=O)OCc3ccccc3)C[C@@H]21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(OCc1ccccc1)N1C[C@H]2CCN[C@H]2C1

Procedure:
The product of Example 1A ((3aR,6aR)-hexahydro-pyrrolo[3,4-b]pyrrole-1,5-dicarboxylic acid 5-benzyl ester 1-tert-butyl ester) (4.5 g, 12.5 mmole), was stirred with a mixture of dichloromethane and trifluoroacetic acid (15 ml/15 ml) for 2 hours. The solvent was removed under reduced pressure, and the residue was basified with saturated sodium bicarbonate, then extracted with dichloromethane (3×). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (0.6% ammonium hydroxide and 6% methanol in dichloromethane) to provide the title compound. 1H NMR (CDCl3) δ ppm 7.28-7.40 (m, 5H) 5.12 (s, 2H) 3.74-3.87 (m, 1H) 3.53-3.71 (m, 2H) 3.36-3.48 (m, 1H) 3.18-3.32 (m, 1H) 3.01-3.13 (m, 1H) 2.88-3.01 (m, 1H) 2.70-2.83 (m, 1H) 1.87-2.03 (m, 1H) 1.58-1.76 (m, 1H). MS: (M+H)+=247.
Reaction SMILES: [BH4-].[Na+].B(F)(F)F.CCOCC.[C:12]1([CH3:30])[CH:17]=[CH:16][C:15]([S:18]([N:21]2[CH2:28][CH:27]([OH:29])[CH2:26][C@@H:22]2[C:23](O)=[O:24])(=[O:20])=[O:19])=[CH:14][CH:13]=1>C1COCC1>[OH:24][CH2:23][C@@H:22]1[CH2:26][C@H:27]([OH:29])[CH2:28][N:21]1[S:18]([C:15]1[CH:16]=[CH:17][C:12]([CH3:30])=[CH:13][CH:14]=1)(=[O:20])=[O:19]
Reactant: Cc1ccc(S(=O)(=O)N2CC(O)C[C@@H]2C(=O)O)cc1
Agent: FB(F)F
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: Cc1ccc(S(=O)(=O)N2C[C@@H](O)C[C@H]2CO)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 68.7 %

Procedure:
4.14 g (109.5 mmol) of sodium borohydride was suspended in 150 ml of THF at 0° C. and 17.6 ml (142.2 mmol) of borontrifluoride etherate was added dropwise over a period of 10 minutes. 15.6 g (54.7 mmol) of 1-(4-toluenesulfonyl)-4-hydroxy-D-proline was added in portions and the mixture was allowed to stir at room temperature for 16 hours. The reaction was then cooled to 0° C. and quenched with methanol: 10% aqueous HC1 solution was then added and the mixture was gently heated to 60° C. for 1 hour. The pH of the reaction was adjusted to neutral with 50% aqueous sodium hydroxide solution and the volatiles were evaporated under reduced pressure. The product was then isolated via filtration and the filter cake was washed with water. Drying under vacuum at 60° C. for 12 hours yielded 10.2 g of the product as a white solid in 69% yield. M.P.=103°-105° C.