Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[CH3:9].[H-].[Na+].[CH3:12][N:13]([CH3:17])[C:14](Cl)=[S:15].O>CN(C=O)C>[CH3:12][N:13]([CH3:17])[C:14](=[S:15])[O:8][C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[C:3]([CH3:9])[CH:4]=1
Reactant: CN(C)C(=S)Cl
Reactant: Cc1cc(O)ccc1Br
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(OC(=S)N(C)C)ccc1Br
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 57.5 %

Procedure:
A solution of 4-bromo-3-methylphenol (8.15 g, 43.6 mmol) in DMF (250 mL) at RT was treated with a suspension of NaH (1.25 g, 52.3 mmol) in 10 mL of DMF. After 15 minutes the solution was cooled to 0° C. and dimethylthiocarbamoyl chloride (8.08 g, 65.4 mmol) was added. The reaction mixture was warmed up to 80° C. and stirred for 45 minutes. After cooling to RT, the mixture was poured into water (1 L). The aqueous layer was extracted with EtOAc (3×200 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated to give a yellow oil. The crude yellow oil material was purified by silica gel chromatography (5-50% EtOAc in hexanes) to afford 6.87 g of O-4-bromo-3-methylphenyl dimethylcarbamothioate as a clear, colorless oil. MS+=276.0 (M+H)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]2[CH2:14][CH2:13][CH2:12][CH2:11][CH:10]2[C:15](O)=O)[CH:6]=[CH:7][CH:8]=1.C(Cl)Cl.C(Cl)(=O)[C:22](Cl)=[O:23].Cl>Cl[Ti](Cl)(Cl)Cl.CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:6](=[CH:7][CH:8]=1)[C:22](=[O:23])[CH2:15][CH:10]1[CH:9]2[CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: O=C(Cl)C(=O)Cl
Reactant: COc1cccc(C2CCCCC2C(=O)O)c1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1ccc2c(c1)C1CCCCC1CC2=O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 92.9 %

Procedure:
Combine 2-(3-methoxy-phenyl)-cyclohexane carboxylic acid (11.50 g, 46.3 mmol), methylene chloride (200 mL), catalytic DMF (4.0 mL) and slowly add oxalyl chloride (4.8 mL, 55.6 mmol), stir at room temperature. After 1.5 hours, at 0° C. add TiCl4 (12.7 mL, 115.78 mmol) and let reaction warm to room temperature. After 3.5 hours, quench reaction with ice water and add 5N HCl. Allow reaction mixture to stir for 30 minutes then extract with ethyl acetate and wash with sodium bicarbonate solution (aq), then Brine. Dry the organic phase with anhydrous sodium sulfate then concentrate and flash chromatograph using 0% to 20% ethyl acetate/hexanes to yield the titled compound (9.91 g, 93%) as a yellow oil. TLC Rf=0.26 in 5:1 hexanes:ethyl acetate 1H NMR (CDCl3): 8.01 (d, 1H, J=8.8 Hz), 6.83 (m, 1H), 6.72 (m, 1H), 3.86 (s, 3H), 2.89 (m, 2H), 2.45 (m, 2H), 1.60 (m, 8H).
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[C:6]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:4][N+:3]=1[O-].P(Cl)(Cl)Cl.O.[OH-].[Na+]>C(Cl)Cl>[CH3:1][C:2]1[C:7]([CH3:8])=[C:6]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:4][N:3]=1
Reactant: Cc1c([N+](=O)[O-])cc[n+]([O-])c1C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Solvent: ClP(Cl)Cl
Product: Cc1nccc([N+](=O)[O-])c1C
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 94.9 %

Procedure:
2,3-Dimethyl-4-nitropyridin-N-oxide (75.6 g, 0.45 mol) prepared in Step 1 was dissolved in 300 ml of methylene chloride. A solution of phosphorus trichloride (44 ml) in methylene chloride (60 ml) was slowly added to the solution for 30 minutes at −15° C.˜−20° C. The reaction mixture was stirred for 15 minutes at the same temperature and further stirred for 15 minutes at room temperature. The reaction mixture was cooled to −78° C. 50 ml of water was added to the reaction mixture, which was neutralized with a sodium hydroxide solution and then extracted with methylene chloride. The separated organic layer was dried on anhydrous magnesium sulfate and then concentrated under reduced pressure to give the titled compound as a pale yellow solid (65 g, 95%).
Reaction SMILES: [C:1]1([CH3:18])[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[C:8](=[O:17])[N:9]([CH3:16])[C:10](=[O:15])[N:11]([CH3:14])[C:12]=2[CH3:13])[CH:2]=1.[Br:19]Br>C(Cl)Cl.CC(C)=O>[Br:19][CH2:13][C:12]1[N:11]([CH3:14])[C:10](=[O:15])[N:9]([CH3:16])[C:8](=[O:17])[C:7]=1[C:3]1[CH:2]=[C:1]([CH3:18])[CH:6]=[CH:5][CH:4]=1
Reactant: BrBr
Reactant: Cc1cccc(-c2c(C)n(C)c(=O)n(C)c2=O)c1
Solvent: CC(C)=O
Solvent: ClCCl
Product: Cc1cccc(-c2c(CBr)n(C)c(=O)n(C)c2=O)c1
Reaction time: 0.17 h
Yield: 101.2 %

Procedure:
In a 25 mL 2-neck round bottom flask equipped with a condenser, addition funnel and air lock, compound 3d (1.00 g, 3.67 mmol) was dissolved in CH2Cl2 (6 mL) and held at reflux. Bromine (200 μL, 0.624 g, 3.9 mmol) was mixed with CH2Cl2 (9 mL) in the addition funnel and added dropwise to the solution of 3d at such a rate that the color was discharged between drops. The last few drops caused the reaction to stay brown. The reaction continued for 10 min before the color was discharged by the addition of a few drops of acetone. TLC showed the reaction was quantitative. The reaction was dried in vacuo and the remaining solid crystallized from 2-propanol to yield 4d (1.20 g, 93%); m.p. 136.1-137° C. 1H NMR (600 MHz, CD2Cl2) δ 7.67 (s, 1H), 7.63 (d, J=7.8, 1H), 7.45 (d, J=7.5, 1H), 7.37 (t, J=7.6, 1H), 4.22 (s, 2H), 3.60 (d, J=6.6, 3H), 3.30 (d, J=7.7, 3H), 2.41 (s, 3H). 13C NMR (151 MHz, CD2Cl2) δ 193.00, 160.95, 152.09, 149.09, 139.30, 137.77, 135.37, 130.22, 129.04, 127.11, 115.04, 31.98, 28.62, 23.75, 21.55. MS (ES+) (m/z): [M+1]+ calculated for C15H16BrN2O3, 351.03. found 350.99.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH2:8][C:9]([OH:11])=O)[CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.CCN(C(C)C)C(C)C.[CH2:33]([O:35][C:36](=[O:48])[CH2:37][CH2:38][NH:39][CH2:40][CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)[CH3:34]>C1COCC1>[CH2:33]([O:35][C:36](=[O:48])[CH2:37][CH2:38][N:39]([C:9](=[O:11])[CH2:8][C:4]1[CH:3]=[C:2]([CH3:1])[CH:7]=[CH:6][N:5]=1)[CH2:40][CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)[CH3:34]
Reactant: CCOC(=O)CCNCCc1ccccc1
Reactant: Cc1ccnc(CC(=O)O)c1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCOC(=O)CCN(CCc1ccccc1)C(=O)Cc1cc(C)ccn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 32.1 %

Procedure:
(4-Methyl-pyridin-2-yl)-acetic acid (1.0 g), carbonyldiimidazole (CDI, 1.07 g) and DIPEA (0.856 g) were added to THF (15 ml) and the light brown suspension was allowed to stir at RT for 1 hour. To the mixture was added 3-phenethylamino-propionic acid ethyl ester (0.898 g) dropwise and the resulting mixture was stirred at 55° over night. The mixture was poured into ice/water and the pH was adjusted to 5.0. The mixture was extracted with ethyl acetate and the organic layer was separated, washed with brine, dried over Na2SO4, filtered and evaporated. The residue was purified by flash chromatography (ethyl acetate/hexanes 2:1) to give the desired product as a light brown liquid (0.462 g). MS (ESI): 355.0 (MH+).
Reaction SMILES: ClC[C:3]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:20])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[CH3:19])=[CH:7][C:6]=1[CH3:21])=[O:4].ClCC(C1C=CC(C)=CC=1NC(=O)C1C=CC=CC=1C)=[O:25].Cl>C1(C)C=CC=CC=1>[CH3:21][C:6]1[CH:7]=[C:8]([NH:11][C:12](=[O:20])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[CH3:19])[CH:9]=[CH:10][C:5]=1[C:3]([OH:4])=[O:25]
Reactant: Cc1ccc(C(=O)CCl)c(NC(=O)c2ccccc2C)c1
Reactant: Cc1cc(NC(=O)c2ccccc2C)ccc1C(=O)CCl
Agent: Cl
Solvent: Cc1ccccc1
Product: Cc1cc(NC(=O)c2ccccc2C)ccc1C(=O)O
Yield: 86 %

Procedure:
A toluene solution of a mixture of 2-chloro-2′-methyl-4′-(2-methylbenzoylamino)acetophenone and 2-chloro-4′-methyl-2′-(2-methylbenzoylamino)acetophenone obtained in the above Reference Example 5 is concentrated and to the residue is added isopropyl alcohol (twice volume). To the mixture is added dropwise an aqueous sodium hypochlorite solution (twice molar amount) at 10-20° C. After completion of the reaction (30 minutes to one hour), the reaction mixture is acidified with hydrochloric acid, and the precipitated crystals are separated by filtration to give a crude product of 2-methyl-4-(2-methylbenzoylamino)benzoic acid in a yield of 86-100%. This crude product is recrystallized from methanol to give the desired product (yield 57%, purity by HPLC 99.3%).
Reaction SMILES: [F:1][C:2]1[N:7]=[C:6]([C:8]2[CH:30]=[CH:29][C:11]([CH2:12][N:13]3[CH:21]=[C:20]4[C:15]([N:16]([CH2:25][CH:26]([CH3:28])[CH3:27])[C:17](=[O:24])[N:18]([CH3:23])[C:19]4=[O:22])=[N:14]3)=[CH:10][CH:9]=2)[CH:5]=[CH:4][CH:3]=1.[Cl:31]C(Cl)(Cl)C(Cl)(Cl)Cl.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.O>C(Cl)Cl.C1COCC1>[Cl:31][C:21]1[N:13]([CH2:12][C:11]2[CH:29]=[CH:30][C:8]([C:6]3[CH:5]=[CH:4][CH:3]=[C:2]([F:1])[N:7]=3)=[CH:9][CH:10]=2)[N:14]=[C:15]2[C:20]=1[C:19](=[O:22])[N:18]([CH3:23])[C:17](=[O:24])[N:16]2[CH2:25][CH:26]([CH3:28])[CH3:27]
Reactant: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Reactant: CC(C)Cn1c(=O)n(C)c(=O)c2cn(Cc3ccc(-c4cccc(F)n4)cc3)nc21
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: O
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC(C)Cn1c(=O)n(C)c(=O)c2c(Cl)n(Cc3ccc(-c4cccc(F)n4)cc3)nc21
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 107 %

Procedure:
2-(4-(6-fluoropyridin-2-yl)benzyl)-7-isobutyl-5-methyl-2H-pyrazolo[3,4-d]pyrimidine-4,6(5H,7H)-dione (450 mg, 1.1 mmol) and hexachloroethane (523 mg, 2.2 mmol) are dissolved in 5 mL of methylene chloride, and then 1.0 M LiHMDS (2.2 mL, 2.2 mmol) in THF is added dropwise. After the reaction mixture is stirred at room temperature for 10 min, water is added, and then extracted with methylene chloride three times. The combined organic phase is evaporated to dryness to give 520 mg of crude product as off-white solids, which is used in the next step without further purification. MS (ESI) m/z 442.2 [M+H]+.
Reaction SMILES: OC[C@]12CC[C@H]3[C@@H](CCC4[C@]3(C)CCC(=O)C=4)[C@@H]1CCC2=O.[OH:23][C@@H:24]1[C:41]2[C@:36]([CH3:43])([CH2:37][CH2:38][C:39](=[O:42])[CH:40]=2)[C@@H:35]2[C@H:26]([C@H:27]3[C@@:31]([CH2:33][CH2:34]2)([CH3:32])[C:30](=[O:44])[CH2:29][CH2:28]3)[CH2:25]1>CCCCCC.C(OCC)(=O)C>[OH:23][C@H:24]1[C:41]2[C@:36]([CH3:43])([CH2:37][CH2:38][C:39](=[O:42])[CH:40]=2)[C@@H:35]2[C@H:26]([C@H:27]3[C@@:31]([CH2:33][CH2:34]2)([CH3:32])[C:30](=[O:44])[CH2:29][CH2:28]3)[CH2:25]1
Reactant: C[C@]12CCC(=O)C=C1[C@@H](O)C[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Agent: C[C@]12CCC(=O)C=C1CC[C@H]1[C@@H]3CCC(=O)[C@@]3(CO)CC[C@@H]12
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: C[C@]12CCC(=O)C=C1[C@H](O)C[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12

Procedure:
Meta-chloroperbenzoic acid (11-25 g) was added to the crude 3-acetoxyandrosta-3,5-dien-17-one (i.e., from 15 g of androst-4-ene-3,17-dione) in dioxan (500 ml) and water (5 ml) and cooled to 5° C. in an ice bath. The reaction mixture was then kept at this temperature for 24 h and then diluted with water (500 ml) and extracted with ethyl acetate (3×500 ml). The organic phase was washed with sodium bisulphite (200 ml, 10%), after which a negative starch iodide test was obtained. The organic phase was then washed with a saturated solution of sodium bicarbonate (3×100 ml), a saturated solution of sodium chloride (1×100 ml) dried with sodium sulphate and evaporated to yield a solid (21.7 g). TLC (hexane-ethyl acetate, 1:3) showed no starting material and largely 6β and 6α forms of hydroxyandrost-4-ene-3,17-dione. NMR showed 6β and 6α-hydroxyandrost-4-ene-3,17-dione in a ratio of approximately 4:1. Crystallization of 16.4 g of the crude product from ethyl acetate-hexane (1:3) gave 7.75 g of 6α+6β-hydroxyandrost-4-ene-3,17-dione (with a similar 6α:6β ratio as for crude). The 6α and 6β isomers can be optionally separated if desired although both isomers alone or in admixture can be used. Recrystallization from ethyl acetate gave pure 6β-hydroxyandrost-4-ene-3,17-dione (2.4 g). And, a second crop of crystals contained the 6β and 6α isomers.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:20]=[CH:21][CH:22]=1)[CH2:6][N:7]1[CH2:12][CH2:11][N:10]([C:13]2[CH:18]=[CH:17][C:16]([NH2:19])=[CH:15][CH:14]=2)[CH2:9][CH2:8]1)#[N:2].[CH:23]([C:26]1[CH:31]=[CH:30][C:29]([C:32]2[C:33]([C:40](O)=[O:41])=[CH:34][CH:35]=[CH:36][C:37]=2[O:38][CH3:39])=[CH:28][CH:27]=1)([CH3:25])[CH3:24].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>C(Cl)Cl.CCN(CC)CC>[C:1]([C:3]1[CH:4]=[C:5]([CH:20]=[CH:21][CH:22]=1)[CH2:6][N:7]1[CH2:12][CH2:11][N:10]([C:13]2[CH:18]=[CH:17][C:16]([NH:19][C:40]([C:33]3[C:32]([C:29]4[CH:28]=[CH:27][C:26]([CH:23]([CH3:25])[CH3:24])=[CH:31][CH:30]=4)=[C:37]([O:38][CH3:39])[CH:36]=[CH:35][CH:34]=3)=[O:41])=[CH:15][CH:14]=2)[CH2:9][CH2:8]1)#[N:2]
Reactant: N#Cc1cccc(CN2CCN(c3ccc(N)cc3)CC2)c1
Reactant: COc1cccc(C(=O)O)c1-c1ccc(C(C)C)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cccc(C(=O)Nc2ccc(N3CCN(Cc4cccc(C#N)c4)CC3)cc2)c1-c1ccc(C(C)C)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 37.4 %

Procedure:
To a stirred solution of 4-[4-(3-cyano-benzyl)-piperazin-1-yl]-phenylamine (400 mg), 4′-isopropyl-6-methoxy-biphenyl-2-carboxylic acid (444 mg), HOBt (222 mg), and Et3N (166 mg) in CH2Cl2 (20 mL) was added at room temperature EDCl (315 mg) and the mixture was stirred at room temperature for 16 hours. The organic solution was then washed with water, with a saturated solution of NaHCO3 and dried over Na2SO4. After filtration and evaporation of the filtrate, the residue was purified by flash chromatography eluting with CH2Cl2/MeOH (95/5) to give the title compound (279 mg) as white crystals.
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([O:8]C(OC(C)(C)C)=O)=O)(C)C.[CH3:16][O:17][C:18]1[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=1[NH2:20].[Br:25]CCO>C(Cl)Cl.CN(C1C=CN=CC=1)C>[Br:25][CH2:1][CH2:2][O:5][C:6](=[O:8])[NH:20][C:19]1[CH:21]=[CH:22][CH:23]=[CH:24][C:18]=1[O:17][CH3:16]
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Reactant: OCCBr
Reactant: COc1ccccc1N
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: COc1ccccc1NC(=O)OCCBr
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 97 %

Procedure:
In a 50 ml two-necked flask placed under an argon atmosphere, 1.5 g (7 mmol, 1.4 eq) of (Boc)2O is dissolved in 5 ml of anhydrous CH2Cl2. 61 mg (0.5 mol, 10% eq) of DMAP dissolved in 5 ml of anhydrous CH2Cl2 is added, then 0.56 ml (5 mmol) of 2-methoxyaniline is added dropwise. The mixture is stirred at room temperature for 20 min before adding 0.5 ml (7 mmol, 1.4 eq) of 2-bromoethanol diluted in 5 ml of anhydrous CH2Cl2. The reaction is allowed to progress for 30 min at room temperature then for approximately 20 hours under reflux of dichlormethane. Then, the medium is cooled and concentrated under vacuum. The resulting dark pink solid is purified by chromatography on a silica gel column (eluent CH2Cl2) to give 1.33 g of a colorless oil (yield: 95%).
Reaction SMILES: [N:1]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[N:4]([C:10]1[CH:15]=[CH:14][C:13]([NH2:16])=[CH:12][CH:11]=1)[CH2:3][CH2:2]2.[C:17]([Cl:25])(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>ClCCl>[ClH:25].[N:1]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[N:4]([C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17](=[O:24])[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:12][CH:11]=1)[CH2:3][CH2:2]2
Reactant: Nc1ccc(N2CCN3CCC2CC3)cc1
Reactant: O=C(Cl)c1ccccc1
Solvent: ClCCl
Product: Cl
Product: O=C(Nc1ccc(N2CCN3CCC2CC3)cc1)c1ccccc1

Procedure:
4-(1,4-Diaza-bicyclo[3.2.2]non-4-yl)-phenylamine (0.76 g, 3.5 mmol), benzoyl chloride (0.41 g, 3.5 mmol) and dichloromethane (33 ml) was stirred at room temperature for 17 hours. The mixture was evaporated and triturated with diethyl ether (50 ml). The crystals were recrystallised from methanol (40 ml). The hydrochloric acid salt was isolated. Yield 0.54 g (44%). Mp. 260° C. (decomp.).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:20]([NH:22][NH2:23])=[O:21])=[N:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([S:14]([CH:17]([CH3:19])[CH3:18])(=[O:16])=[O:15])=[CH:10][CH:9]=2)=[CH:6][N:7]=1.[C:24]([O:28][C:29]([NH:31][CH2:32][C:33]1[CH:41]=[CH:40][C:36]([C:37](O)=[O:38])=[CH:35][CH:34]=1)=[O:30])([CH3:27])([CH3:26])[CH3:25].C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>O>[NH2:1][C:2]1[C:3]([C:20]([NH:22][NH:23][C:37]([C:36]2[CH:35]=[CH:34][C:33]([CH2:32][NH:31][C:29](=[O:30])[O:28][C:24]([CH3:25])([CH3:26])[CH3:27])=[CH:41][CH:40]=2)=[O:38])=[O:21])=[N:4][C:5]([C:8]2[CH:9]=[CH:10][C:11]([S:14]([CH:17]([CH3:19])[CH3:18])(=[O:15])=[O:16])=[CH:12][CH:13]=2)=[CH:6][N:7]=1
Reactant: CC(C)S(=O)(=O)c1ccc(-c2cnc(N)c(C(=O)NN)n2)cc1
Reactant: CC(C)(C)OC(=O)NCc1ccc(C(=O)O)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: O
Solvent: CCN(CC)CC
Product: CC(C)S(=O)(=O)c1ccc(-c2cnc(N)c(C(=O)NNC(=O)c3ccc(CNC(=O)OC(C)(C)C)cc3)n2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3-amino-6-(4-isopropylsulfonylphenyl)pyrazine-2-carbohydrazide (100 mg, 0.2833 mmol) and 4-[(tert-butoxycarbonylamino)methyl]benzoic acid (71.19 mg, 0.2833 mmol) in dmf (1.000 mL) was treated with triethylamine (28.67 mg, 39.49 μL, 0.2833 mmol) followed by TBTU (109.2 mg, 0.3400 mmol) and the resulting solution stirred at room temperature overnight. The solution was poured dropwise onto rapidly stirred water (15 ml), stirred at room temperature for 1 h and then filtered to give the product as a pale yellow solid which was dried under high vacuum at 83° C. and then used directly in the next step without further purification (136 mg, 84%)
Reaction SMILES: [C:1]([O:5][OH:6])([CH3:4])([CH3:3])[CH3:2].[OH-:7].[Na+].[C:9](Cl)(=[O:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>O>[C:9]([O:16][O:6][O:5][C:1]([CH3:4])([CH3:3])[CH3:2])(=[O:7])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: [OH-]
Reactant: CC(C)(C)OO
Agent: [Na+]
Solvent: O
Product: CC(C)(C)OOOC(=O)c1ccccc1
Reaction time: 0.5 h

Procedure:
129 parts (1 mol) of t-butyl hydroperoxide diluted with water to about 70% (TBHP-70) and 100 parts of water were fed into a 1-1 glass beaker, followed by the addition of 182 parts of LUP. 160 parts (1 mol) of caustic soda diluted with water to 25% was added dropwise thereto, while keeping the contents at 20° C. on an ice-water bath. After the completion of the dropwise addition, 140 parts (1 mol) of benzoyl chloride was added dropwise thereto over a period of 30 minutes. The contents were stirred for 60 minutes, while keeping them at 20° C. 250 parts of 5% aqueous caustic soda was added to the formed organic layer. The obtained mixture was stirred for 30 minutes to transfer unreacted materials to the aqueous layer from the organic layer. The resulting organic layer was thrice washed with water and dehydrated with a dehydrating agent to obtain 364 parts of t-butylperoxy benzoate diluted with LUP to 50% (hereinafter abbreviated to "TBPB-LUP 50") as a final product.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:12]2[CH2:17][CH2:16][CH:15]([N:18]3[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]3)[CH2:14][CH2:13]2)[CH:6]=[CH:7][C:8]=1[N+:9]([O-])=O>CO.ClCCl.[Ni]>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:12]2[CH2:17][CH2:16][CH:15]([N:18]3[CH2:19][CH2:20][N:21]([CH3:24])[CH2:22][CH2:23]3)[CH2:14][CH2:13]2)[CH:6]=[CH:7][C:8]=1[NH2:9]
Reactant: COc1cc(N2CCC(N3CCN(C)CC3)CC2)ccc1[N+](=O)[O-]
Agent: [Ni]
Solvent: ClCCl
Solvent: CO
Product: COc1cc(N2CCC(N3CCN(C)CC3)CC2)ccc1N
Temperature: 50 °C
Reaction time: 6 h
Yield: 100 %

Procedure:
To a solution of Example 206a (6.88 g, 20.57 mmol) in a mixture of methanol (180 mL) and dichloromethane (20 mL) was added Raney nickel (50% in water, 3 g). This suspension was purged with hydrogen and stirred under hydrogen of 40 psi at 50° C. for 6 hours. Solid material was removed, and the filtrate was concentrated to provide the title product. Yield: 100%. MS (DCI) m/z 305 (M+H)+; 1H NMR (300 MHz, DMSO-d6): δ 1.47-1.59 (m, 2H), 1.84 (d, J=11.87 Hz, 2H), 2.33 (s, 3H), 2.44-2.71 (m, 12H), 3.28-3.48 (m, J=12.21 Hz, 4H), 3.73 (s, 2H), 6.29 (dd, J=8.31, 2.54 Hz, 1H), 6.46-6.54 (m, 2H).
Reaction SMILES: [NH2:1][C@@H:2]([CH2:29][C:30]1[CH:39]=[CH:38][C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH:31]=1)[C:3]([NH:5][CH2:6][CH2:7][CH2:8][CH2:9][C@H:10]([N:13]([S:18]([C:21]1[CH:26]=[CH:25][C:24]([F:27])=[C:23]([NH2:28])[CH:22]=1)(=[O:20])=[O:19])[CH2:14][CH:15]([CH3:17])[CH3:16])[CH2:11][OH:12])=[O:4].[CH:40]1([C:46](Cl)=[O:47])[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41]1>>[NH2:28][C:23]1[CH:22]=[C:21]([S:18]([N:13]([CH2:14][CH:15]([CH3:16])[CH3:17])[C@H:10]([CH2:11][OH:12])[CH2:9][CH2:8][CH2:7][CH2:6][NH:5][C:3]([C@@H:2]([NH:1][C:46]([CH:40]2[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41]2)=[O:47])[CH2:29][C:30]2[CH:39]=[CH:38][C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[CH:31]=2)=[O:4])(=[O:19])=[O:20])[CH:26]=[CH:25][C:24]=1[F:27]
Reactant: CC(C)CN([C@H](CO)CCCCNC(=O)[C@@H](N)Cc1ccc2ccccc2c1)S(=O)(=O)c1ccc(F)c(N)c1
Reactant: O=C(Cl)C1CCCCC1
Product: CC(C)CN([C@H](CO)CCCCNC(=O)[C@H](Cc1ccc2ccccc2c1)NC(=O)C1CCCCC1)S(=O)(=O)c1ccc(F)c(N)c1

Procedure:
The title compound was prepared from (2S,5S)-2-amino-N-{5-[(3-amino-4-fluoro-benzenesulfonyl)-isobutyl-amino]-6-hydroxy-hexyl}-3-naphthalen-2-yl-propionamide (example 81) as described in general procedure D using cyclohexanecarbonyl chloride. The final product was obtained in 48% yield.
Reaction SMILES: [CH2:1]1[CH:5]2[CH2:6][NH:7][CH2:8][CH:4]2[CH2:3][N:2]1[C:9]1[CH:10]=[CH:11][C:12]2[N:13]([C:15]([C:18]([F:21])([F:20])[F:19])=[N:16][N:17]=2)[N:14]=1.[N:22]1[CH:27]=[CH:26][C:25]([CH:28]=O)=[CH:24][CH:23]=1>>[N:22]1[CH:27]=[CH:26][C:25]([CH2:28][N:7]2[CH2:8][CH:4]3[CH:5]([CH2:1][N:2]([C:9]4[CH:10]=[CH:11][C:12]5[N:13]([C:15]([C:18]([F:20])([F:21])[F:19])=[N:16][N:17]=5)[N:14]=4)[CH2:3]3)[CH2:6]2)=[CH:24][CH:23]=1
Reactant: FC(F)(F)c1nnc2ccc(N3CC4CNCC4C3)nn12
Reactant: O=Cc1ccncc1
Product: FC(F)(F)c1nnc2ccc(N3CC4CN(Cc5ccncc5)CC4C3)nn12

Procedure:
Reductive amination of 6-(hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine with pyridine-4-carbaldehyde was carried out according to General Synthetic Method 10. The crude product was purified by hplc using a Waters XBridge Prep C18 OBD column, 5μ silica, 30 mm diameter, 100 mm length eluted with decreasingly polar mixtures of water (containing 0.1% aqueous ammonia) and acetonitrile as eluents to give 6-[2-(pyridin-4-ylmethyl)-1,3,3a,4,6,6a-hexahydropyrrolo[3,4-c]pyrrol-5-yl]-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine.