Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:13]3[CH:14]=[CH:15][C:16]([CH2:18][CH2:19][CH2:20][CH2:21][OH:22])=[CH:17][C:12]=3[S:11][N:10]=2)=[CH:5][CH:4]=1.[CH3:25][S:26](Cl)(=[O:28])=[O:27]>>[F:24][C:2]([F:1])([F:23])[C:3]1[CH:4]=[CH:5][C:6]([C:9]2[C:13]3[CH:14]=[CH:15][C:16]([CH2:18][CH2:19][CH2:20][CH2:21][O:22][S:26]([CH3:25])(=[O:28])=[O:27])=[CH:17][C:12]=3[S:11][N:10]=2)=[CH:7][CH:8]=1
Reactant: CS(=O)(=O)Cl
Reactant: OCCCCc1ccc2c(-c3ccc(C(F)(F)F)cc3)nsc2c1
Product: CS(=O)(=O)OCCCCc1ccc2c(-c3ccc(C(F)(F)F)cc3)nsc2c1

Procedure:
In analogy to example 21.1, 4-[3-(4-Trifluoromethyl-phenyl)-benzo[d]isothiazol-6-yl]-butan-1-ol and methanesulfonic acid chloride were converted to yield Methanesulfonic acid 4-[3-(4-trifluoromethyl-phenyl)-benzo[d]isothiazol-6-yl]-butyl ester, MS: 430 (MH+).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([N+:10]([O-])=O)[CH:7]=[CH:6][C:5]=1[C:13]([OH:22])([C:18]([F:21])([F:20])[F:19])[C:14](OC)=[O:15])([O-])=O>C(OCC)(=O)C.C1COCC1.[Pd]>[NH2:10][C:8]1[CH:9]=[C:4]2[C:5]([C:13]([OH:22])([C:18]([F:21])([F:20])[F:19])[C:14](=[O:15])[NH:1]2)=[CH:6][CH:7]=1
Reactant: COC(=O)C(O)(c1ccc([N+](=O)[O-])cc1[N+](=O)[O-])C(F)(F)F
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Nc1ccc2c(c1)NC(=O)C2(O)C(F)(F)F
Reaction time: 8 h
Yield: 6.2 %

Procedure:
To a solution of methyl 2-(2,4-dinitrophenyl)-3,3,3-trifluoro-2-hydroxypropanoate (1.3 g, 4.01 mmol) in ethyl acetate (18 mL) was added pH3HCl (5.2 mL) followed by 10% Pd/C (350 mg) in ethyl acetate (3 mL). The mixture was stirred overnight under an atmosphere of H2. The reaction mixture was filtered through a pad of Celite and the filtrate was concentrated in vacuo. The crude residue obtained was partitioned between, dichloromethane (25 mL) and aqueous saturated NaHCO3 (15 mL). The organic phase was separated and the aqueous phase was extracted dichloromethane (2×25 mL). The organic phases were combined, dried over Na2SO4, filtered, and concentrated. Purification by silica gel chromatography (50-100% ethyl acetate/hexanes) provided 6-amino-3-hydroxy-3-(trifluoromethyl)indolin-2-one (921 mg, 99%) To a solution of 6-amino-3-hydroxy-3-(trifluoromethyl)indolin-2-one (58 mg, 0.25 mmol) in THF (0.5 mL) at 0° C. was added BH3 THF complex (1M in THF, 1 mL, 0.95 mmol) dropwise. The mixture was stirred for 5 min at 0° C. then for 3 h at room temperature. The reaction was quenched by adding very carefully 6M HCl (3.5 mL) until no more gas release was observed. The mixture was then stirred at 80° C. for 2 h. The solvent was removed under reduce pressure and the solid residue obtained was dissolved in DMF (3 mL), filtered and purified by reverse phase HPLC (10-99% CH3CN/H2O) to provide 3-(trifluoromethyl)-1H-indol-6-amine (30 mg, 54%, TFA salt).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:10]=2[CH2:11][C:12](=[O:18])[NH:13]3)=[CH:5][CH:4]=1.[CH2:19]([N:21]([CH2:35][CH3:36])[CH2:22][CH2:23][NH:24][C:25]([C:27]1[NH:28][C:29]([CH:33]=O)=[C:30]([CH3:32])[CH:31]=1)=[O:26])[CH3:20]>C(O)C.N1CCCCC1>[CH2:35]([N:21]([CH2:19][CH3:20])[CH2:22][CH2:23][NH:24][C:25]([C:27]1[NH:28][C:29]([CH:33]=[C:11]2[C:10]3[C:14](=[CH:15][CH:16]=[CH:17][C:9]=3[C:6]3[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)[NH:13][C:12]2=[O:18])=[C:30]([CH3:32])[CH:31]=1)=[O:26])[CH3:36]
Reactant: COc1ccc(-c2cccc3c2CC(=O)N3)cc1
Reactant: CCN(CC)CCNC(=O)c1cc(C)c(C=O)[nH]1
Solvent: CCO
Solvent: C1CCNCC1
Product: CCN(CC)CCNC(=O)c1cc(C)c(C=C2C(=O)Nc3cccc(-c4ccc(OC)cc4)c32)[nH]1
Temperature: 25 °C
Reaction time: 72 h
Yield: 55 %

Procedure:
To a solution of 4-(4-methoxy-phenyl)-1,3-dihydro-indol-2-one (59.8 mg, 0.25 mmol) and 5-formyl-4-methyl-1H-pyrrole-2-carboxylic acid (2-diethylamino-ethyl)-amide (65.3 mg, 0.26 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. A yellow solid product was precipitated out, filtered, washed by ethanol for three times, and dried under high vacuum to provide pure product 5-[4-(4-methoxy-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-4-methyl-1H-pyrrole-2-carboxylic acid (2-diethylamino-ethyl)-amide as a yellow solid (65 mg, 55%).
Reaction SMILES: B(F)(F)F.[CH3:5]COCC.CS(Cl)(=O)=O.O.[OH:16][C:17]1[CH:22]=[C:21]([OH:23])[CH:20]=[CH:19][C:18]=1[C:24](=[O:36])[CH2:25][C:26]1[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[C:28]([O:34][CH3:35])[CH:27]=1>CN(C=O)C>[CH3:35][O:34][C:28]1[CH:27]=[C:26]([C:25]2[C:24](=[O:36])[C:18]3[C:17](=[CH:22][C:21]([OH:23])=[CH:20][CH:19]=3)[O:16][CH:5]=2)[CH:31]=[CH:30][C:29]=1[O:32][CH3:33]
Reactant: COc1ccc(CC(=O)c2ccc(O)cc2O)cc1OC
Reactant: CCOCC
Agent: CS(=O)(=O)Cl
Agent: FB(F)F
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(-c2coc3cc(O)ccc3c2=O)cc1OC

Procedure:
In a similar manner to Example 2.1 above, 1-(2,4-dihydroxyphenyl)-2-(3,4-dimethoxy-phenyl)-ethanone dissolved in DMF had added boron trifluoride diethyl etherate followed by methanesulfonyl chloride in DMF. Addition of water to the reaction mixture afforded 3-(3,4-dimethoxyphenyl)-7-hydroxychromen-4-one.
Reaction SMILES: [CH:1]1([CH:8]2[CH2:13][CH2:12][C:11](=[O:14])[CH2:10][CH2:9]2)[CH2:6][CH2:5][C:4](=[O:7])[CH2:3][CH2:2]1.O.O.O.[F-].[CH2:19]([N+](CCCC)(CCCC)CCCC)[CH2:20]CC.[F-].[K+].[CH2:38]1COC[CH2:39]1>CO>[C:19]([C:4]1([OH:7])[CH2:5][CH2:6][CH:1]([CH:8]2[CH2:9][CH2:10][C:11]([C:38]#[CH:39])([OH:14])[CH2:12][CH2:13]2)[CH2:2][CH2:3]1)#[CH:20]
Reactant: O=C1CCC(C2CCC(=O)CC2)CC1
Reactant: CCCC[N+](CCCC)(CCCC)CCCC
Reactant: C1CCOC1
Agent: [F-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: C#CC1(O)CCC(C2CCC(O)(C#C)CC2)CC1
Reaction time: 48 h

Procedure:
30.00 g of bicyclohexyl-4,4′-dione and 3.89 g of tetrabutylammonium fluoride trihydrate are dissolved in 350 ml of THF, and 30.33 g of trimethylsiylacetylene are added dropwise at RT. The reaction mixture is stirred for 2 days, a suspension of 44.86 g of potassium fluoride in 160 ml of methanol is subsequently added, and the mixture is stirred for a further 3 days. Conventional work-up gives 4,4′-diethynylbicyclohexyl-4,4′-diol.
Reaction SMILES: [CH2:1]([C:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([OH:14])=[O:13])=[CH:9][CH:10]=2)[NH:5][N:4]=1)[CH3:2].N1C2C(=CC=CC=2)[CH:17]=N1.CO>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH2:1]([C:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([O:14][CH3:17])=[O:13])=[CH:9][CH:10]=2)[NH:5][N:4]=1)[CH3:2]
Reactant: c1ccc2[nH]ncc2c1
Reactant: CCc1n[nH]c2cc(C(=O)O)ccc12
Agent: CN(C)c1ccncc1
Solvent: CO
Solvent: ClCCl
Product: CCc1n[nH]c2cc(C(=O)OC)ccc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 1.35 g (7.1 mmol) of 3-ethyl-1H-indazol-6-yl-carboxylic acid, [Marfat, A., et al., “Indazole Derivatives and Their Use as Inhibitors of Phosphodiesterase Type IV and the Production of Tumor Necrosis Factor TNF, U.S. Pat. No. 6,262,040], 2.9 mL (71 mmol) of methanol, and 0.95 g (7.8 mmol) of DMAP in 60 mL of CH2Cl2 was added 1.5 g (7.8 mmol) of EDCl—nHCl. This mixture was stirred at room temperature overnight, concentrated and the residue dissolved in 50 mL of ethyl acetate. The organic layer was successively washed with 40 mL of 1N HCl, 40 mL of water and 40 mL of brine, dried (Na2SO4), and concentrated. The residue was purified by chromatography over silica gel using a gradient of 35% to 50% ethyl acetate in hexanes over 20 minutes as eluant to yield 860 mg (4.2 mmol) of methyl 3-ethyl-1H-indazol-6-yl-carboxylate. 1H-NMR (CDCl3) δ 11.7 (s, 1H), 8.18 (s, 1H), 7.73 (apparent q, 9.0 Hz, 2H), 3.94 (s, 3H), 3.03 (q, 7.5 Hz, 2H), 1.42 (t, 7.5 Hz, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:15]=[CH:14][C:13]2[O:12][C:11]3[C:6](=[N+:7]([O-])[CH:8]=[CH:9][C:10]=3[N+:16]([O-:18])=[O:17])[C:5](=[O:20])[C:4]=2[CH:3]=1.P(Cl)(Cl)([Cl:23])=O>CN(C=O)C.C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:15]=[CH:14][C:13]2[O:12][C:11]3[C:6](=[N:7][C:8]([Cl:23])=[CH:9][C:10]=3[N+:16]([O-:18])=[O:17])[C:5](=[O:20])[C:4]=2[CH:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1c2cc(Br)ccc2oc2c([N+](=O)[O-])cc[n+]([O-])c12
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: O=c1c2cc(Br)ccc2oc2c([N+](=O)[O-])cc(Cl)nc12
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A suspension of 8-bromo-4-nitro-10-oxo-10H-chromeno[3,2-b]pyridine 1-oxide (90 mg, 0.267 mmol) in 1 mL of dry DMF was added dropwise to a solution of phosphorus oxychloride (44.0 μL, 0.481 mmol) in 0.2 mL of DMF and 0.5 mL of toluene at 0° C. After stirring at 0° C. for 0.5 h, the reaction was quenched with saturated NaHCO3 and extracted with ethyl acetate (5×5 mL). The combined organics were dried over sodium sulfate, filtered and evaporated to dryness. Purification of the crude residue by column chromatography (CH2Cl2 to CH2Cl2/EA=100:3) gave 8-bromo-2-chloro-4-nitro-10H-chromeno[3,2-b]pyridin-10-one as a light yellow solid.
Reaction SMILES: C[O:2][C:3](=[O:39])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][O:11][C:12]2[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:13]=2[O:19][CH2:20][C:21]([N:23]2[CH2:28][C@H:27]([CH3:29])[N:26]([CH2:30][C:31]3[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=3)[CH2:25][C@H:24]2[CH3:38])=[O:22])=[N:6][CH:5]=1.O1CCCC1.O.[OH-].[Li+].Cl>O.CO>[Cl:18][C:16]1[CH:15]=[CH:14][C:13]([O:19][CH2:20][C:21]([N:23]2[CH2:28][C@H:27]([CH3:29])[N:26]([CH2:30][C:31]3[CH:32]=[CH:33][C:34]([F:37])=[CH:35][CH:36]=3)[CH2:25][C@H:24]2[CH3:38])=[O:22])=[C:12]([CH:17]=1)[O:11][CH2:10][C:7]1[CH:8]=[CH:9][C:4]([C:3]([OH:39])=[O:2])=[CH:5][N:6]=1
Reactant: COC(=O)c1ccc(COc2cc(Cl)ccc2OCC(=O)N2C[C@H](C)N(Cc3ccc(F)cc3)C[C@H]2C)nc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: C[C@@H]1CN(Cc2ccc(F)cc2)[C@@H](C)CN1C(=O)COc1ccc(Cl)cc1OCc1ccc(C(=O)O)cn1
Temperature: 25 °C
Reaction time: 3 h
Yield: 27.3 %

Procedure:
To a solution of 6-(5-chloro-2-{2-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl-piperazin-1-yl]-2-oxo-ethoxy}-phenoxymethyl)-nicotinic acid methyl ester (0.13 g, 0.23 mmol) in 2:2:1 tetrahydrofuran:methanol:H2O (2 mL) was added lithium hydroxide hydrate (0.020 g, 0.48 mmol). The reaction was stirred at ambient temperature for 3 hours, the pH was then adjusted to 4 with 0.2 M hydrochloric acid. The solution was extracted with ethyl acetate and the organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo. Trituration in diethyl ether provided the title compound (0.034 g, LRMS: 542.4, 544.5).
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6](I)[C:5]([OH:9])=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:17]([N:24]1[CH2:28][CH2:27][CH2:26][C@H:25]1[C:29]#[CH:30])([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18]>CN(C=O)C.CCOCC.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[C:17]([N:24]1[CH2:28][CH2:27][CH2:26][C@H:25]1[C:29]1[O:9][C:5]2[C:6](=[N:7][C:2]([Br:1])=[CH:3][CH:4]=2)[CH:30]=1)([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18]
Reactant: C#C[C@@H]1CCCN1C(=O)OC(C)(C)C
Reactant: Oc1ccc(Br)nc1I
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC[C@H]1c1cc2nc(Br)ccc2o1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A 1.84 g (6.10 mmol) sample of 6-bromo-2-iodo-3-pyridinol, from step 28d above, was dissolved in 10 mL of DMF, and (Ph3P)2PdCl2 (0.30 g, 0.4 mmol), CuI (0.3 g, 1.6 mmol) and triethylamine (1.2 mL, 8.5 mmol) were added. The mixture was stirred under N2 at room temperature for 1 hour, then 1.3 g (6.7 mmol) of 1-BOC-2-(S)-ethynylpyrrolidine, from Example 1c above, dissolved in 5 mL of DMF, was added carefully. The reaction was stirred at 80° C. for 16 hours, then cooled to room temperature. The reaction mixture was diluted with ether, then washed with 50% brine, and the extract was dried over MgSO4. The solvent was removed, and the residue was chromatographed on silica gel, eluting with 100:0 to 60:40 hexane:EtOAc to give 1.4 g of title compound: 1H NMR (CDCl3, 300 MHz) δ 1.31(s, 9H), 1.89-2.06 (m, 3H), 2.27-2.34 (m, 1H), 3.43-3.5 (m, 2H), 4.96-5.0 (m, 1H), 6.72 (s, 1H), 7.38-7.41 (d, 1H, J=8.6 Hz), 7.83-7.86 (d, 1H, J=8.6 Hz); MS m/z: 367 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[C:6]2[C:7](=[O:19])[N:8]([CH2:11][CH2:12][N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[CH2:9][CH2:10][C:5]=2[NH:4][C:3]=1[CH:20]=O.[Br:22][C:23]1[CH:24]=[C:25]2[CH2:31][C:30](=[O:32])[NH:29][C:26]2=[N:27][CH:28]=1>>[Br:22][C:23]1[CH:24]=[C:25]2[C:31](=[CH:20][C:3]3[NH:4][C:5]4[CH2:10][CH2:9][N:8]([CH2:11][CH2:12][N:13]5[CH2:14][CH2:15][O:16][CH2:17][CH2:18]5)[C:7](=[O:19])[C:6]=4[C:2]=3[CH3:1])[C:30](=[O:32])[NH:29][C:26]2=[N:27][CH:28]=1
Reactant: Cc1c(C=O)[nH]c2c1C(=O)N(CCN1CCOCC1)CC2
Reactant: O=C1Cc2cc(Br)cnc2N1
Product: Cc1c(C=C2C(=O)Nc3ncc(Br)cc32)[nH]c2c1C(=O)N(CCN1CCOCC1)CC2
Yield: 33 %

Procedure:
The title compound was prepared under the same conditions as described in Example 13 with 3-methyl-5-(2-morpholin-4-yl-ethyl)-4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine-2-carbaldehyde and 5-bromo-1,3-dihydro-pyrrolo[2,3-b]pyridin-2-one (prepared according to Heterocycles, 60 (4), 865-877, 2003) as starting materials to give 2-(5-bromo-2-oxo-1,2-dihydro-pyrrolo[2,3-b]pyridin-3-ylidenemethyl)-3-methyl-5-(2-morpholin-4-yl-ethyl)-1,5,6,7-tetrahydro-pyrrolo[3,2-c]pyridin-4-one (30 mg, 33%) as a yellow solid.
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[CH:5][N:6]=1.[Li]CCCC.CCCCCC.[Sn:18](Cl)([CH2:27][CH2:28][CH2:29][CH3:30])([CH2:23][CH2:24][CH2:25][CH3:26])[CH2:19][CH2:20][CH2:21][CH3:22].O>CCOCC>[CH2:27]([Sn:18]([CH2:19][CH2:20][CH2:21][CH3:22])([CH2:23][CH2:24][CH2:25][CH3:26])[C:2]1[S:3][CH:4]=[CH:5][N:6]=1)[CH2:28][CH2:29][CH3:30]
Reactant: Brc1nccs1
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CCCCCC
Solvent: O
Product: CCCC[Sn](CCCC)(CCCC)c1nccs1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 90 %

Procedure:
To a mixture of 2-bromothiazole (4.6 mL, 50 mmol) and anhydrous ether (50 mL), there was added an n-BuLi hexane solution (22 mL, 55 mmol) dropwise at −70° C. under nitrogen atmosphere, and the mixture was stirred for 30 minutes. A solution of n-Bu3SnCl (14 mL, 50 mmol) in ether (20 mL) was then added at −70° C., and after stirring for 4 hours, the mixture was raised to room temperature and stirred for another hour. After adding water (50 mL), the organic layer was extracted three times with ether (50 mL), and the solvent was distilled away. It was then purified by silica gel chromatography (hexane:ethyl acetate=20:1) to yield the title compound (17g, 90%).
Reaction SMILES: [Cl:1][C:2]1[C:8]([N:9]2[CH2:14][CH2:13][CH:12]([C:15]([F:18])([F:17])[F:16])[CH2:11][CH2:10]2)=[CH:7][C:5]([NH2:6])=[C:4]([N+:19]([O-])=O)[CH:3]=1.C1COCC1>CO>[Cl:1][C:2]1[C:8]([N:9]2[CH2:14][CH2:13][CH:12]([C:15]([F:16])([F:17])[F:18])[CH2:11][CH2:10]2)=[CH:7][C:5]([NH2:6])=[C:4]([NH2:19])[CH:3]=1
Reactant: Nc1cc(N2CCC(C(F)(F)F)CC2)c(Cl)cc1[N+](=O)[O-]
Solvent: C1CCOC1
Solvent: CO
Product: Nc1cc(Cl)c(N2CCC(C(F)(F)F)CC2)cc1N
Temperature: 25 °C
Reaction time: 22 h

Procedure:
A mixture of 4-chloro-2-nitro-5-(4-trifluoromethyl-piperidin-1-yl)aniline (0.63 g, 1.9 mmol), THF (10 mL), MeOH (20 mL) and 50%-Pt-on-carbon (60 mg) was stirred for 22 h at rt under a hydrogen atmosphere (3 bar). The catalyst was removed by filtration and the mixture was concentrated to give the sub-title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:25][CH:26]2[CH2:30][CH2:29][CH2:28][CH2:27]2)[C:13]([NH:15][C:16]2[CH:20]=[CH:19][N:18]([CH2:21][C:22]([OH:24])=O)[N:17]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].[C:31](Cl)(=O)[C:32](Cl)=O.N1C(C)=CC=CC=1C.NC1C=CN(CC2(O)CC2)N=1>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:25][CH:26]2[CH2:30][CH2:29][CH2:28][CH2:27]2)[C:13]([NH:15][C:16]2[CH:20]=[CH:19][N:18]([CH2:21][C:22]3([OH:24])[CH2:32][CH2:31]3)[N:17]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9]
Reactant: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2)C(=O)Nc2ccn(CC(=O)O)n2)cc1Cl
Reactant: O=C(Cl)C(=O)Cl
Agent: Nc1ccn(CC2(O)CC2)n1
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Product: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2)C(=O)Nc2ccn(CC3(O)CC3)n2)cc1Cl
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 45 %

Procedure:
2-(R)-(3-Chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid (prepared as in PCT WO 2004/052869 A1, Example 1, 248 mg, 0.75 mmol) was dissolved in methylene chloride (4 mL) and a 2.0 M solution of oxalyl chloride in methylene chloride (0.376 mL, 0.75 mmol) was added and the reaction stirred at 25° C. for 15 min. The solution was chilled to 0° C. and 2,6-lutidine (175 μL, 1.50 mmol) was added dropwise. The reaction continued to stir at 0° C. for 15 min. The 1-(3-amino-pyrazol-1-ylmethyl)-cyclopropanol (115 mg, 0.75 mmol) was added as a pre-dissolved reaction in methylene chloride (4 mL), the ice bath was removed and the reaction continued to stir at 25° C. for 25 min. The reaction was diluted with methylene chloride (50 mL), washed with water (2×25 mL), saturated aqueous brine solution (1×20 mL), dried over magnesium sulfate and concentrated in vacuo to a beige foam. Purification by flash column chromatography (Merck silica gel 60, 40-63 μm; 0% ethyl acetate/methylene chloride to 80% ethyl acetate/methylene chloride) afforded 2-(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-[1-(1-hydroxy-cyclopropylmethyl)-1H-pyrazol-3-yl]-propionamide (158 mg, 45%) as a white brittle foam: ESI-LRMS m/e calcd for C22H28ClN3O4S [M+] 465.15, found 466.20 [M+H+], 488.11 [M+Na+]; 1H NMR (400 MHz, CDCl3) δ ppm 0.65-0.72 (m, 2H, CH2), 0.87-0.92 (m, 2H, CH2), 1.08-1.25 (m, 2H, CH2), 1.44-1.98 (m, 8H, 4×CH2), 2.15-2.38 (m, 1H, CH), 3.24 (brs, 1H, OH), 3.28 (s, 3H, SO2CH3), 3.60 (t, J=7.5 Hz, 1H, CH), 4.06 (s, 2H, NCH2), 6.71 (d, Jo=2.3 Hz, 1H, Ar), 7.32 (d, Jo=2.3 Hz, 1H, Ar), 7.49 (dd, Jo=8.2, Jm=1.7 Hz. 1H, Ar), 7.62 (d, Jm=1.7 Hz, 1H, Ar), 8.09 (d, Jo=8.2 Hz, 1H, Ar), 8.12 (s, 1H, NH).
Reaction SMILES: [F:1][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[C:4]([F:9])[C:3]=1[NH:10][C:11]1[C:16]([C:17]2[N:25]=[CH:24][N:23]=[C:22]3[C:18]=2[N:19]=[CH:20][N:21]3[CH:26]2[CH2:31][CH2:30][CH2:29][CH2:28][O:27]2)=[CH:15][CH:14]=[CH:13][N:12]=1.[CH3:32][N:33]1[C:41]2[C:36](=[CH:37][CH:38]=[CH:39][C:40]=2[S:42](Cl)(=[O:44])=[O:43])[CH:35]=[CH:34]1.N1C=CC=CC=1>ClCCl>[F:1][C:2]1[C:3]([NH:10][C:11]2[C:16]([C:17]3[N:25]=[CH:24][N:23]=[C:22]4[C:18]=3[N:19]=[CH:20][N:21]4[CH:26]3[CH2:31][CH2:30][CH2:29][CH2:28][O:27]3)=[CH:15][CH:14]=[CH:13][N:12]=2)=[C:4]([F:9])[CH:5]=[CH:6][C:7]=1[NH:8][S:42]([C:40]1[CH:39]=[CH:38][CH:37]=[C:36]2[C:41]=1[N:33]([CH3:32])[CH:34]=[CH:35]2)(=[O:43])=[O:44]
Reactant: Cn1ccc2cccc(S(=O)(=O)Cl)c21
Reactant: Nc1ccc(F)c(Nc2ncccc2-c2ncnc3c2ncn3C2CCCCO2)c1F
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cn1ccc2cccc(S(=O)(=O)Nc3ccc(F)c(Nc4ncccc4-c4ncnc5c4ncn5C4CCCCO4)c3F)c21
Temperature: 50 °C
Reaction time: 2 h

Procedure:
The 2,6-difluoro-N1-(3-(9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)pyridin-2-yl)benzene-1,3-diamine (20 mg, 0.047 mmol) prepared at Step 9 was added and dissolved into dichloromethane solvent. 1-methyl-1H-indole-7-sulfonyl chloride (16 mg, 0.07 mmol) and pyridine (8 uL, 0.094 mmol) were added into the reaction solution and stirred at 50° C. for 2 hours. After the reaction, the reactant was washed with 1N aqueous hydrochloric acid solution and salt water. After extraction with dichloromethane, the organic layer was dried with sulfuric anhydride magnesium and vacuum concentrated, and then refined by means of column chromatography, so that the target compound was obtained.
Reaction SMILES: Cl.[NH2:2][N:3]=[CH:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:18])[CH2:13][CH2:14][C:15]([OH:17])=O)=[CH:7][CH:6]=1.CN1CCOCC1.ClC(OCC(C)C)=O.[CH2:34]([O:36][C:37](=[O:48])[CH2:38][CH:39]([NH2:47])[CH2:40][CH2:41][C:42]([O:44][CH2:45][CH3:46])=[O:43])[CH3:35].CN(C1C=CC=CN=1)C>CN(C=O)C>[CH2:34]([O:36][C:37](=[O:48])[CH2:38][CH:39]([NH:47][C:15](=[O:17])[CH2:14][CH2:13][C:12]([NH:11][C:8]1[CH:7]=[CH:6][C:5]([CH:4]=[N:3][NH2:2])=[CH:10][CH:9]=1)=[O:18])[CH2:40][CH2:41][C:42]([O:44][CH2:45][CH3:46])=[O:43])[CH3:35]
Reactant: CCOC(=O)CCC(N)CC(=O)OCC
Reactant: NN=Cc1ccc(NC(=O)CCC(=O)O)cc1
Agent: CC(C)COC(=O)Cl
Agent: CN(C)c1ccccn1
Agent: Cl
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CCOC(=O)CCC(CC(=O)OCC)NC(=O)CCC(=O)Nc1ccc(C=NN)cc1
Reaction time: 0.08 h
Yield: 37.5 %

Procedure:
4-[[4-(Aminoiminomethyl)phenyl]-amino]-4-oxobutanoic acid hydrochloride prepared in Example 1, Step 1 (5.0 g, 18.5 mmol) was added to dry DMF (250 ml) followed by N-methylmorpholine (1.8 g, 18.5 mmol) and isobutyl chloroformate (2.7 g, 17 mmol) at 25° C. The mixture was stirred for 5 min. Diethyl-3-aminoadipate (4.0 g, 18.5 retool) was added followed by dimethylaminopyridine. After 1 hour, the solvent was removed under reduced pressure and the product purified by reverse phase chromatography (0.05% TFA water/acetonitrile) to result in 3.0 g of a white solid: 1HNMR (d6 -DMSO) δ1.14 (t, 6H, J=7 Hz), 1.55 (m, 1H), 1.7 (m, 1H), 2.3 (m, 2H), 2.57 (m, 2H), 2.67 (m, 2H), 4.02 (q, 4H, J=7 Hz), 4.03 (m, 1H), 7.79 (s, 4H), 7.99 (d, 1, J=8.1 Hz), 9.06 (bs, 2H), 9.15 (bs, 2H), 10.22 (s, 1H); MS (FAB) m/z 435.2 (MH+).
Reaction SMILES: Br[C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([NH:6][CH3:7])=[O:5].[CH:15]1([NH2:18])[CH2:17][CH2:16]1>C1COCC1.CCOC(C)=O>[CH:15]1([NH:18][C:2]2[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][CH:9]=[CH:8][C:3]=2[C:4]([NH:6][CH3:7])=[O:5])[CH2:17][CH2:16]1
Reactant: CNC(=O)c1cccc([N+](=O)[O-])c1Br
Reactant: NC1CC1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CNC(=O)c1cccc([N+](=O)[O-])c1NC1CC1
Temperature: 60 °C

Procedure:
A mixture of 2-bromo-N-methyl-3-nitrobenzamide (830 mg, 3.20 mmol), cyclopropanamine (666 μL, 9.61 mmol) in THF (10 mL) under N2 was heated at 60° C. for 18 h. The reaction mixture was diluted with EtOAc, washed with water and brine, dried over MgSO4, and concentrated under reduced pressure. The residue was purified by column chromatography on a silica gel column using DCM-EtOAc (1:1) as eluent to give 2-(cyclopropylamino)-N-methyl-3-nitrobenzamide: 1H NMR (400 MHz, DMSO-d6) δ 8.54-8.47 (m, 2H), 7.95 (dd, J=8, 4 Hz, 1H), 7.64 (dd, J=8, 4 Hz, 1H), 6.77 (dd, J=8, 4 Hz, 1H), 2.76 (d, J=8 Hz, 3H), 2.68-2.62 (m, 1H), 0.67-0.60 (m, 2H), 0.44-0.40 (m, 2H); LC-MS (ESI) m/z 236.1 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:9]([F:12])([F:11])[F:10])[CH:5]=[CH:6][C:7]=1[F:8].[NH2:13][C:14]1[CH:15]=[C:16]2[C:21]3=[C:22]([CH2:24][CH2:25][N:20]3[CH2:19][C@@H:18]3[CH2:26][N:27](C(OC(C)(C)C)=O)[CH2:28][C@H:17]23)[CH:23]=1>>[F:8][C:7]1[CH:6]=[CH:5][C:4]([C:9]([F:12])([F:11])[F:10])=[CH:3][C:2]=1[NH:13][C:14]1[CH:15]=[C:16]2[C:21]3=[C:22]([CH2:24][CH2:25][N:20]3[CH2:19][C@@H:18]3[CH2:26][NH:27][CH2:28][C@H:17]23)[CH:23]=1
Reactant: Fc1ccc(C(F)(F)F)cc1Br
Reactant: CC(C)(C)OC(=O)N1C[C@H]2CN3CCc4cc(N)cc(c43)[C@H]2C1
Product: Fc1ccc(C(F)(F)F)cc1Nc1cc2c3c(c1)[C@H]1CNC[C@H]1CN3CC2

Procedure:
Using 3-bromo-4-fluorobenzotrifluoride and following the procedures described in EXAMPLE 17, Parts B and C, (±)-cis tert-butyl 2-amino-4,5,7a,8,10,10a-hexahydrodipyrrolo[3,4-c:3′,2′,1′-ij]quinoline-9(7H)-carboxylate was converted into (±) -cis-N-[2-fluoro-5-(trifluoromethyl)phenyl]-4,5,7,7a,8,9,10,10a-octahydrodipyrrolo[3,4-c:3′,2′,1′-ij]quinolin-2-amine, bis-trifluoroacetic acid salt, after HPLC purification (C18 reverse phase column, elution with a H2O/CH3CN gradient with 0.5% TFA). This material was free-based with aq ammonium hydroxide, extracted with chloroform, washed with brine, dried (K2CO3) and concentrated to the title compound of EXAMPLE 115 as the free base. LRMS (ES)+: 378.3 (M+H)+.