Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[C:6]#[N:7])=O.[CH3:11][N:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].CC(O)=O>C(Cl)Cl>[CH3:11][N:12]1[CH2:17][CH2:16][N:15]([CH2:1][C:3]2[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=2)[C:6]#[N:7])[CH2:14][CH2:13]1
Reactant: CN1CCNCC1
Reactant: N#Cc1cccc(C=O)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CN1CCN(Cc2cccc(C#N)c2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 69 %

Procedure:
A mixture of 3-formyl-benzonitrile (1.5 g, 11.45 mmol), N-methyl piperazine (1.49 g, 14.9 mmol) and NaBH(OAc)3 (3.63 g, 17.18 mmol) in DCM (75 ml) and CH3COOH (0.851 ml, 14.9 mmol) was stirred overnight at room temperature, then diluted with DCM and washed with 1 M Na2CO3. The organic phase was dried over Na2SO4 and evaporated in vacuo. The crude mixture was purified by column chromatography (eluent: DCM/MeOH/NH4OH 97:3:0.5) to give 1.7 g of 3-(4-methyl-piperazin-1-ylmethyl)-benzonitrile.
Reaction SMILES: C(O[C:6]([N:8]1[CH:13]([C:14](=[O:30])[NH:15][C:16]2[CH:17]=[C:18]([Cl:29])[CH:19]=[C:20]3[C:28]=2[NH:27][C:26]2[CH:25]=[N:24][CH:23]=[CH:22][C:21]3=2)[CH2:12][O:11][C:10]([CH3:32])([CH3:31])[CH2:9]1)=O)(C)(C)C.C(OC(=O)[NH:39][CH:40](C=O)[CH:41]([CH3:43])[CH3:42])(C)(C)C>>[Cl:29][C:18]1[CH:19]=[C:20]2[C:28](=[C:16]([NH:15][C:14]([CH:13]3[CH2:12][O:11][C:10]([CH3:32])([CH3:31])[CH2:9][N:8]3[CH2:6][CH:40]([NH2:39])[CH:41]([CH3:43])[CH3:42])=[O:30])[CH:17]=1)[NH:27][C:26]1[CH:25]=[N:24][CH:23]=[CH:22][C:21]2=1
Reactant: CC(C)(C)OC(=O)N1CC(C)(C)OCC1C(=O)Nc1cc(Cl)cc2c1[nH]c1cnccc12
Reactant: CC(C)C(C=O)NC(=O)OC(C)(C)C
Product: CC(C)C(N)CN1CC(C)(C)OCC1C(=O)Nc1cc(Cl)cc2c1[nH]c1cnccc12

Procedure:
Method C was followed, using 5-(6-chloro-9H-β-carbolin-8-ylcarbamoyl)-2,2-dimethyl-morpholine-4-carboxylic acid tert-butyl ester and the appropriate aldehyde, (1-formyl-2-methyl-propyl)-carbamic acid tert-butyl ester. 1H-NMR (DMSO-d6, 300 MHz) δ 9.05 (s, 1); 8.37 (d, 1); 8.21 (d, 1); 8.16 (dd, 1); 7.90 (d, 1); 6.71 (br s, 2); 3.93-3.86 (m, 2); 3.18-3.14 (m, 1); 2.91 (d, 1); 2.70-2.65 (m, 2); 2.21 (dd, 1); 2.15 (d, 1); 1.74-1.66 (m, 1); 1.31 (s, 3); 1.19 (s, 3); 0.85 (d, 3); 0.80 (d, 3). NH4OAc standard conditions. DAD Rf=1.27 min. M+H=444.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([OH:11])=[O:10])[CH:5]=[CH:6][CH:7]=1.Br[CH:13]([CH3:15])[CH3:14].[OH-].[K+]>CCO>[CH2:14]([O:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([OH:11])=[O:10])[CH:5]=[CH:6][CH:7]=1)[C:13]1[CH:15]=[CH:6][CH:7]=[CH:2][CH:3]=1
Reactant: O=C(O)Cc1cccc(O)c1
Reactant: CC(C)Br
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)Cc1cccc(OCc2ccccc2)c1
Yield: 70.6 %

Procedure:
A mixture containing 2-(3-hydroxyphenyl)acetic acid (0.800 g, 5.26 mmol), 2-bromopropane (0.971 g, 7.89 mmol), potassium hydroxide (0.740 g, 13.2 mmol), KI (18 mg, 0.11 mmol) in 20 mL EtOH was refluxed for 18 h. The solvent was removed and the residue was dissolved in 50 mL of water and extracted with ether. The aqueous layer was acidified with aqueous 1N HCl and extracted with EtOAc. The organic layers were dried (Na2SO4) and concentrated to afford a residue which was purified by silica gel chromatography (petroleum ether/EtOAc 4:1) to get 2-(3-(benzyloxy)phenyl)acetic acid as a white solid (0.45 g, 44%).
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1([C:13]([O:15]C(C)(C)C)=[O:14])[CH2:10][CH:9]1[CH2:11][CH3:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].CC(C)([O-])C.[K+]>C(OCC)C.O>[C:1]([O:5][C:6]([C:8]1([C:13]([OH:15])=[O:14])[CH2:10][CH:9]1[CH2:11][CH3:12])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCC1CC1(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CCOCC
Product: CCC1CC1(C(=O)O)C(=O)OC(C)(C)C
Reaction time: 8 h
Yield: 69 %

Procedure:
The product of Step 1 (18.3 g, 67.8 mmol) was added to a suspension of potassium tert-butoxide (33.55 g, 299.0 mmol) in dry diethyl ether (500 mL) at 0° C., treated with H2O (1.35 mL, 75.0 mmol), and was vigorously stirred overnight at room temperature. The reaction mixture was poured in a mixture of ice and water and washed with diethyl ether (3×). The aqueous layer was adjusted to acidic pH with a 10% aqueous citric acid solution at 0° C. and extracted with ethyl acetate (3×). The combined organic layers were washed with water (2×), brine, dried (MgSO4), filtered, and concentrated in vacuo to provide the desired product as a pale yellow oil (10 g, 46.8 mmol, 69% yield).
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[C:12]2[C:7](=[CH:8][C:9]([O:13][CH3:14])=[CH:10][CH:11]=2)[O:6][CH2:5][CH2:4]1.[CH2:15](OC=O)C>C1(C)C=CC=CC=1>[CH3:15][NH:1][CH2:2][CH:3]1[C:12]2[C:7](=[CH:8][C:9]([O:13][CH3:14])=[CH:10][CH:11]=2)[O:6][CH2:5][CH2:4]1
Reactant: COc1ccc2c(c1)OCCC2CN
Reactant: CCOC=O
Solvent: Cc1ccccc1
Product: CNCC1CCOc2cc(OC)ccc21

Procedure:
The product from Example 2 (5 g) was added to ethylformate (10 ml) and toluene (100 ml) then refluxed for 21/2 hrs. The solution was evaporated to dryness and then tetrahydrofuran (THF) (100 ml) and BH3.THF 25.9 ml of a IM THF solution) was added followed by heating for 11/2 hrs. The reaction was cooled and 6N HC1 (20 ml) was carefully added followed by heating for 1 hr. The THF was evaporated and the reaction made basic with aqueous KOH. The reaction was extracted with CH2Cl2, the organic layer then separated, dried (MgSO4), filtered and evaporated. The residue was chromatographed on silica gel and eluted with (EtOAc:H2O:HCO2H) (16:2:2), giving the product (1.4 g). Mass spec: (M+H)+ 208 1H NMR(CDCl3): 2.0 (m,2H); 2.49 (s,3H); 2.8 (m,2H); 3.75 (s,3H); 4.2 (m,1H); 6.38-7.25 (m,3H).
Reaction SMILES: [F:1][C:2]([F:9])([CH2:6][CH:7]=[CH2:8])[C:3](O)=[O:4].[Cl:10]CCl.C1(C)C=CC=CC=1>CN(C)C=O>[F:1][C:2]([F:9])([CH2:6][CH:7]=[CH2:8])[C:3]([Cl:10])=[O:4]
Reactant: C=CCC(F)(F)C(=O)O
Reactant: ClCCl
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: C=CCC(F)(F)C(=O)Cl

Procedure:
For example, 2,2-difluoro-4-pentenoic acid 12c is contacted with about 1.0 to 1.5 molar equivalents of an appropriate chlorinating agent. The reaction is carried out in a suitable solvent, such as dichloromethane, toluene or dimethylformamide. The reaction is carried out at a temperature of from about 20° C. to about 35° C. and generally requires about 4 to 24 hours. The product, 2,2-difluoro-4-pentenoyl chloride 12a, can be isolated by fractional distillation and purified by techniques well known in the art, such as chromatography.
Reaction SMILES: Br[C:2]1[C:3]([C:16]([F:19])([F:18])[F:17])=[CH:4][C:5]([N+:13]([O-:15])=[O:14])=[C:6]([N:8]2[CH:12]=[CH:11][N:10]=[CH:9]2)[CH:7]=1.[CH2:20]([NH2:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(N(C(C)C)CC)(C)C>C(#N)C>[CH2:20]([NH:27][C:2]1[CH:7]=[C:6]([N:8]2[CH:12]=[CH:11][N:10]=[CH:9]2)[C:5]([N+:13]([O-:15])=[O:14])=[CH:4][C:3]=1[C:16]([F:19])([F:18])[F:17])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)c(Br)cc1-n1ccnc1
Reactant: NCc1ccccc1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: O=[N+]([O-])c1cc(C(F)(F)F)c(NCc2ccccc2)cc1-n1ccnc1
Temperature: 60 °C
Reaction time: 16 h
Yield: 31.9 %

Procedure:
A solution of 1-[5-bromo-2-nitro-4-(trifluoromethyl)phenyl]-1H-imidazole (580 mg; 1.73 mmol; 1 eq) prepared as in example 52 step 2, benzylamine (210 μl; 1.9 mmol; 1.1 eq) and diisopropylethylamine (331 μl; 1.9 mmol; 1.1 eq) in anhydrous acetonitrile is stirred at 60° C. for 16 h. Concentration, partition (ethyl acetate/aqueous ammonium chloride), extraction of the aqueous phase (ethyl acetate), reunion of the organic phases, drying (magnesium sulfate), concentration and purification by prep CCM on silicagel (dichloromethane/ethyl acetate 50:50) affords the title product (200 mg; 0.552 mmol; 32%) as a yellow solid.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[N:6]([CH:9]1[CH:13]([OH:14])[CH2:12][N:11]([C:15]2[CH:20]=[CH:19][C:18]([N:21]3[CH2:25][C@H:24]([CH2:26][NH:27][C:28](=[O:30])[CH3:29])[O:23][C:22]3=[O:31])=[CH:17][C:16]=2[F:32])[CH2:10]1)=[N+:7]=[N-:8].C(N(CC)CC)C>ClCCl>[N:6]([CH:9]1[CH:13]([O:14][S:2]([CH3:1])(=[O:4])=[O:3])[CH2:12][N:11]([C:15]2[CH:20]=[CH:19][C:18]([N:21]3[CH2:25][C@H:24]([CH2:26][NH:27][C:28](=[O:30])[CH3:29])[O:23][C:22]3=[O:31])=[CH:17][C:16]=2[F:32])[CH2:10]1)=[N+:7]=[N-:8]
Reactant: CC(=O)NC[C@H]1CN(c2ccc(N3CC(O)C(N=[N+]=[N-])C3)c(F)c2)C(=O)O1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)NC[C@H]1CN(c2ccc(N3CC(N=[N+]=[N-])C(OS(C)(=O)=O)C3)c(F)c2)C(=O)O1
Reaction time: 1 h

Procedure:
Methanesulfonyl chloride (8 μL, 0.10 mmol) was added to a solution of N-({(5S)-3-[4-(3-azido-4-hydroxypyrrolidin-1-yl)-3-fluorophenyl]-2-oxo-1,3-oxazolidin-5-yl}methyl)acetamide (30 mg, 0.08 mmol) and triethylamine (16 μL, 0.12 mmol) in dichloromethane (0.5 mL) at 0° C. After 1 h, the solution was diluted with more dichloromethane, washed with dilute NaHCO3, brine and dried (MgSO4), filtered and concentrated to give the title compound as an oil. This material was used directly in the next reaction.
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[N:15]2[N:16]=[CH:17][C:18]([C:19](O)=[O:20])=[C:14]2[N:13]=[CH:12][C:11]=1[C:22]([N:24]1[CH2:29][CH2:28][CH:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH2:26][CH2:25]1)=[O:23].[CH2:36]([S:38]([NH2:41])(=[O:40])=[O:39])[CH3:37]>>[Cl:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[N:15]2[N:16]=[CH:17][C:18]([C:19]([NH:41][S:38]([CH2:36][CH3:37])(=[O:40])=[O:39])=[O:20])=[C:14]2[N:13]=[CH:12][C:11]=1[C:22]([N:24]1[CH2:25][CH2:26][CH:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH2:28][CH2:29]1)=[O:23]
Reactant: CCS(N)(=O)=O
Reactant: O=C(O)c1cnn2c(Nc3cccc(F)c3Cl)c(C(=O)N3CCC(c4ccccc4)CC3)cnc12
Product: CCS(=O)(=O)NC(=O)c1cnn2c(Nc3cccc(F)c3Cl)c(C(=O)N3CCC(c4ccccc4)CC3)cnc12
Yield: 29.9 %

Procedure:
In the same manner as in Example 1, step 6 and using 7-(2-chloro-3-fluorophenylamino)-6-(4-phenylpiperidine-1-carbonyl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (77 mg, 0.16 mmol) obtained in step 2 and ethanesulfonamide (84 mg, 0.80 mmol), the title compound (28 mg, 28%) was obtained.
Reaction SMILES: [Cl:1][CH2:2][C:3]([CH2:5]Cl)=O.[Cl:7][C:8]1[N:13]=[C:12]([S:14][CH3:15])[N:11]=[C:10]([NH2:16])[CH:9]=1.O>CC(O)=O>[Cl:7][C:8]1[N:13]=[C:12]([S:14][CH3:15])[N:11]2[CH:5]=[C:3]([CH2:2][Cl:1])[N:16]=[C:10]2[CH:9]=1
Reactant: CSc1nc(N)cc(Cl)n1
Reactant: O=C(CCl)CCl
Solvent: O
Solvent: CC(=O)O
Product: CSc1nc(Cl)cc2nc(CCl)cn12
Temperature: 110 °C
Reaction time: 16 h
Yield: 44.2 %

Procedure:
1,3-Dichloroacetone (2.89 g, 22.77 mmol) was added to a solution 6-chloro-2-methylsulfanyl-pyrimidin-4-ylamine (4 g, 22.77 mmol) in AcOH (15 mL) and the mixture was stirred at 110° C. for 16 hours. Then H2O was added and the solid formed was filtered off and dried in vacuo to yield 7-chloro-2-chloromethyl-5-methylsulfanyl-imidazo[1,2-c]pyrimidine (2.5 g, 44% yield) as a pale brown solid that was used in the next step without further purification.
Reaction SMILES: [CH:1]#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]#[CH:9].I[C:11]#[C:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]>[Cu]I.N1CCCC1>[CH:1]#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]#[C:9][C:11]#[C:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: C#CCCCCCC#C
Reactant: CCCCCCCCC#CI
Agent: [Cu]I
Solvent: C1CCNC1
Product: C#CCCCCCC#CC#CCCCCCCCC
Reaction time: 24 h

Procedure:
Pyrollidine (20 mL) and CuI (0.65 g, 3.42 mmol) were added to a nitrogen flushed reaction vessel. Nona-1,8-diyne (1.58 g, 13.17 mmol) was added via syringe. 1-Iodo-1decyne (2.26 g, 8.53 mmol) was added via syringe dropwise to the solution over ten minutes. The reaction was stirred under nitrogen for 24 h. The reaction mix was then quenched with ammonium chloride (10 mL), separated with diethyl ether, and dried with anhydrous magnesium sulfate. Nonadeca-1,8,10-triyne was then isolated using silica column chromatography with a 1% ether/hexane eluting solution obtaining 1.06 g of an oil. 50% yield; 1H NMR (CDCl3) δ 2.29 (m, 4H, CH2—C≡C), 2.22 (dt, 2H, CH2—C≡C, J=7, 2.7 Hz), 1.97 (t, 1H, H—C≡C, J=2.7 Hz), 1.54 (m, 6H, CH2—C—C≡C), 1.33-1.40 (sextuplet, 2H, CH2—CH2—CH3), 1.27 (m, 10H, C—CH2—C), 0.88 (t, 3H, CH3); 13C NMR (CDCl3) δ: 84.62, 77.99, 77.36, 68.63, 65.76, 65.45, 32.21, 29.54, 29.46, 29.25, 28.72, 28.34, 28.31, 28.23, 23.06, 19.61, 19.52, 14.53; MS (ESI) [M+Na]+ calc. 279.2083 found 279.1723 (very unstable to any MS technique). Elemental analysis calc. for C19H28: C, 88.99; H, 11.01. Found: C, 88.80; H, 10.96.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11](F)[C:12]=3[F:14])[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2)[CH2:3][CH2:2]1.Cl.[N:22]1([CH:27]2[CH2:31][CH2:30][NH:29][CH2:28]2)[CH:26]=[N:25][CH:24]=[N:23]1.C1CCN2C(=NCCC2)CC1>N1C=CC=CC=1>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11]([N:29]4[CH2:30][CH2:31][CH:27]([N:22]5[CH:26]=[N:25][CH:24]=[N:23]5)[CH2:28]4)[C:12]=3[F:14])[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2)[CH2:2][CH2:3]1
Reactant: c1ncn(C2CCNC2)n1
Reactant: O=C(O)c1cn(C2CC2)c2c(F)c(F)c(F)cc2c1=O
Agent: Cl
Solvent: c1ccncc1
Solvent: C1CCC2=NCCCN2CC1
Product: O=C(O)c1cn(C2CC2)c2c(F)c(N3CCC(n4cncn4)C3)c(F)cc2c1=O
Temperature: 95 °C
Yield: 49.8 %

Procedure:
To a solution of 1-cyclopropyl-6,7,8-trifluoro -1,4-dihydro-4-oxoquinoline-3-carboxylic acid (70.75 mg, 0.25 mmol) and 3-(1,2,4-triazol-1-yl)pyrrolidine hydrochloride (100 mg) 3 ml of dry pyridine under nitrogen was added 152 mg (1 mmol) of DBU and the solution was heated at 95° C. overnight. The orange solution was then concentrated under reduced pressure and water was added to the residue and the solid was collected and dried to yield 50 mg (50%) of a gray solid, m.p. 219.7°-220.7° C. 1H NMR (TFA) δ: 9.8 (s, 1H), 9.29 (s, 1H), 8.78 (s, 1H), 8.11 (d, J=12.5, 1H), 5.85-5.58 (m, 1H), 4.9-4.2 (m, 5H), 3.00-2.7 (m, 2H), 1.75-1.3 (m, 4H). Anal. calcd. for C19H17F2N5O3 : C, 56.86; H, 4.27; N, 17.45. Found: C, 56.80; H, 4.41; N, 17.48.
Reaction SMILES: [Li]C(CC)C.[Cl:6][C:7]1[CH:8]=[C:9]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[CH:10]=[C:11]([Cl:13])[CH:12]=1.CN([CH:23]=[O:24])C.O>C1COCC1>[Cl:6][C:7]1[CH:8]=[C:9]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[CH:10]=[C:11]([Cl:13])[C:12]=1[CH:23]=[O:24]
Reactant: CN(C)C=O
Reactant: Clc1cc(Cl)cc(N2CCOCC2)c1
Agent: [Li]C(C)CC
Solvent: O
Solvent: C1CCOC1
Product: O=Cc1c(Cl)cc(N2CCOCC2)cc1Cl
Reaction time: 0.5 h

Procedure:
Add sec-BuLi (1.4M in cyclohexane, 5.44 mL) in a dropwise manner to a solution of 4-(3,5-Dichloro-phenyl)-morpholine (Tetrahedron (2001), 57(36), 7657-7664, 1.60 g, 6.93 mmol) in dry THF (20 mL) under N2 at −78° C. Allow to stir for 30 min. Slowly add DMF (2.68 mL, 34.7 mmol) to the cold solution. Upon disappearance of the starting material by TLC, warm the reaction to 0° C. Quench the reaction by addition of H2O (15 mL) and extract the mixture with EtOAc (150 mL). Dry the organic phase over Na2SO4 and evaporate the solvent. Triturate the resulting solid with Et2O to yield the title compound. Evaporate the filtrate to yield another crop of the title compound as a yellow solid: 1H NMR (400 MHz, ACETONITRILE-d3) δ ppm 3.46-3.54 (m, 4H) 3.85-3.93 (m, 4H) 7.06 (s, 2H) 10.44 (s, 1H); MS (m/z) 260.0 (M+1).
Reaction SMILES: C([O:8][C:9]1[N:14]=[CH:13][C:12]([O:15][C:16]2[CH:44]=[C:43]([N:45]3[CH2:50][CH2:49][N:48]([CH2:51][C:52]4[CH2:57][CH2:56][C:55]([CH3:59])([CH3:58])[CH2:54][C:53]=4[C:60]4[CH:65]=[CH:64][C:63]([Cl:66])=[CH:62][CH:61]=4)[CH2:47][CH2:46]3)[CH:42]=[CH:41][C:17]=2[C:18]([NH:20][S:21]([C:24]2[CH:29]=[CH:28][C:27]([NH:30][CH2:31][CH:32]3[CH2:37][CH2:36][O:35][CH2:34][CH2:33]3)=[C:26]([N+:38]([O-:40])=[O:39])[CH:25]=2)(=[O:23])=[O:22])=[O:19])=[CH:11][CH:10]=1)C1C=CC=CC=1.FC(F)(F)C(O)=O>ClCCl>[Cl:66][C:63]1[CH:62]=[CH:61][C:60]([C:53]2[CH2:54][C:55]([CH3:58])([CH3:59])[CH2:56][CH2:57][C:52]=2[CH2:51][N:48]2[CH2:47][CH2:46][N:45]([C:43]3[CH:42]=[CH:41][C:17]([C:18]([NH:20][S:21]([C:24]4[CH:29]=[CH:28][C:27]([NH:30][CH2:31][CH:32]5[CH2:37][CH2:36][O:35][CH2:34][CH2:33]5)=[C:26]([N+:38]([O-:40])=[O:39])[CH:25]=4)(=[O:23])=[O:22])=[O:19])=[C:16]([O:15][C:12]4[CH:13]=[N:14][C:9]([OH:8])=[CH:10][CH:11]=4)[CH:44]=3)[CH2:50][CH2:49]2)=[CH:65][CH:64]=1
Reactant: CC1(C)CCC(CN2CCN(c3ccc(C(=O)NS(=O)(=O)c4ccc(NCC5CCOCC5)c([N+](=O)[O-])c4)c(Oc4ccc(OCc5ccccc5)nc4)c3)CC2)=C(c2ccc(Cl)cc2)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC1(C)CCC(CN2CCN(c3ccc(C(=O)NS(=O)(=O)c4ccc(NCC5CCOCC5)c([N+](=O)[O-])c4)c(Oc4ccc(O)nc4)c3)CC2)=C(c2ccc(Cl)cc2)C1
Temperature: 40 °C
Reaction time: 16 h

Procedure:
To 2-(6-(benzyloxy)pyridin-3-yloxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)-N-(3-nitro-4-((tetrahydro-2H-pyran-4-yl)methylamino)phenylsulfonyl)benzamide (0.132 g) in dichloromethane (1 mL) was added trifluoroacetic acid (0.33 mL) and the reaction was sealed in a vial under nitrogen and heated to 40° C. After stirring for 16 hours, the reaction was cooled, diluted with dichloromethane (50 mL) and washed with sodium carbonate (2×25 mL). The organic layer was dried over magnesium sulfate, filtered, and concentrated. Silica gel chromatography (GraceResolv 12 g) eluting with a gradient of 0.3% to 3% methanol/dichloromethane (Flow=36 mL/minute) over 30 minutes gave the title compound. 1H NMR (300 MHz, CDCl3) δ 12.51-11.38 (m, 1H), 9.78 (s, 1H), 8.89 (d, 1H), 8.52 (t, 1H), 8.19 (dd, 1H), 7.92 (d, 1H), 7.43-7.33 (m, 2H), 7.24 (d, 2H), 7.00-6.89 (m, 3H), 6.74-6.67 (m, 1H), 6.55 (dd, 1H), 6.00 (d, 1H), 4.00 (d, 2H), 3.42 (dd, 2H), 3.34-3.23 (m, 2H), 3.16 (s, 4H), 2.79 (s, 2H), 2.24 (d, 6H), 1.99 (s, 3H), 1.72 (s, 2H), 1.55-1.33 (m, 4H), 0.96 (s, 6H).
Reaction SMILES: [CH2:1]([NH:5][CH2:6][C:7]1[S:8][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([S:18]([CH3:21])(=[O:20])=[O:19])[CH:13]=2)=[CH:10][CH:11]=1)[CH:2]([CH3:4])[CH3:3].[CH3:22][O:23][C:24](=[O:35])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[S:31](Cl)(=[O:33])=[O:32].C(N(CC)C(C)C)(C)C>ClCCl>[CH3:22][O:23][C:24](=[O:35])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[S:31](=[O:32])(=[O:33])[N:5]([CH2:1][CH:2]([CH3:4])[CH3:3])[CH2:6][C:7]1[S:8][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([S:18]([CH3:21])(=[O:20])=[O:19])[CH:13]=2)=[CH:10][CH:11]=1
Reactant: COC(=O)c1ccccc1S(=O)(=O)Cl
Reactant: CC(C)CNCc1ccc(-c2cccc(S(C)(=O)=O)c2)s1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccccc1S(=O)(=O)N(Cc1ccc(-c2cccc(S(C)(=O)=O)c2)s1)CC(C)C

Procedure:
In analogy to example 13, step 2, isobutyl-[5-(3-methanesulfonyl-phenyl)-thiophen-2-ylmethyl]-amine (example 15, step 2) was reacted with methyl-2-(chlorosulfonyl)-benzoate and N,N-diisopropyl ethyl amine in dichloromethane to give 2-{isobutyl-[5-(3-methanesulfonyl-phenyl)-thiophen-2-ylmethyl]-sulfamoyl}-benzoic acid methyl ester as a colorless oil. MS: 522.3 ([M+H]+)
Reaction SMILES: [CH:1](=O)[CH2:2][CH2:3][CH:4]=C.[C:7]([OH:13])(=[O:12])[CH2:8][C:9](O)=O.N1CCCCC1.Cl>N1C=CC=CC=1>[C:7]([OH:13])(=[O:12])/[CH:8]=[CH:9]/[CH2:4][CH2:3][CH:2]=[CH2:1]
Reactant: C=CCCC=O
Reactant: O=C(O)CC(=O)O
Agent: Cl
Solvent: C1CCNCC1
Solvent: c1ccncc1
Product: C=CCC/C=C/C(=O)O
Temperature: 90 °C
Reaction time: 5 h

Procedure:
4-Pentenal (4.45 g, 51.4 mmol) and malonic acid (6.41 g, 61.6 mmol) were dissolved in pyridine (9.9 mL). To the solution, piperidine (1.9 mL) was added, and the mixture was then stirred at 90° C. for 5 hours. The mixture was allowed to cool and then made acidic by the addition of 2 N hydrochloric acid, followed by extraction with diethyl ether. The organic layer was washed with saturated saline and dried over anhydrous magnesium sulfate, and the filtrate was then concentrated under reduced pressure. The residue was distilled under reduced pressure to obtain the compound of interest as a colorless oil substance (3 mmHg, 110-116° C., 3.27 g, 50%).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C[O:8][C:9]([C:11]1[N:12]([CH2:24][C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)[C:13]2[C:18]([CH:19]=1)=[CH:17][C:16]([S:20]([CH3:23])(=[O:22])=[O:21])=[CH:15][CH:14]=2)=O.O>O1CCCC1>[F:31][C:28]1[CH:29]=[CH:30][C:25]([CH2:24][N:12]2[C:13]3[C:18](=[CH:17][C:16]([S:20]([CH3:23])(=[O:21])=[O:22])=[CH:15][CH:14]=3)[CH:19]=[C:11]2[CH2:9][OH:8])=[CH:26][CH:27]=1
Reactant: COC(=O)c1cc2cc(S(C)(=O)=O)ccc2n1Cc1ccc(F)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CS(=O)(=O)c1ccc2c(c1)cc(CO)n2Cc1ccc(F)cc1
Reaction time: 0.5 h
Yield: 104.9 %

Procedure:
To a solution of lithium aluminum hydride (366 mg) in tetrahydrofuran (20 ml), a solution of 1-(4-fluorobenzyl)-5-methanesulfonylindole-2-carboxylic acid methyl ester obtained in Example 27 (3) (1.86 g) in tetrahydrofuran (20 ml) was added dropwise at 0° C. under nitrogen atmosphere and the mixture was stirred at the same temperature for 30 minutes. The reaction solution was poured into water, filtered through Celite and extracted with chloroform. The organic layer was washed with water and dried. The solvent was distilled off under reduced pressure to obtain (1-(4-fluorobenzyl)-5-methanesulfonylindol-2-yl)-methanol (1.8 g). To a solution of the resulting alcohol (1.8 g) in dichloromethane (100 ml) was added manganese dioxide (15.3 g) at 15 to 30° C. and the mixture was stirred at the same temperature for 30 minutes. The reaction solution was filtered through Celite. The solvent was distilled off under reduced pressure to obtain 1.5 g (88.4%) of the desired product as a yellow powder.
Reaction SMILES: [CH3:1][N:2]([CH3:8])[C@H:3]1[CH2:7][CH2:6][NH:5][CH2:4]1.C(N(CC)CC)C.F[C:17]1[C:18]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)=[C:19]([CH3:34])[C:20]([C:32]#[N:33])=[C:21]2[C:25]=1[O:24][C:23]([C:26]1[CH:31]=[N:30][CH:29]=[CH:28][N:27]=1)=[N:22]2>CS(C)=O>[CH3:1][N:2]([CH3:8])[C@H:3]1[CH2:7][CH2:6][N:5]([C:17]2[C:18]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)=[C:19]([CH3:34])[C:20]([C:32]#[N:33])=[C:21]3[C:25]=2[O:24][C:23]([C:26]2[CH:31]=[N:30][CH:29]=[CH:28][N:27]=2)=[N:22]3)[CH2:4]1
Reactant: Cc1c(-c2ccccc2)c(F)c2oc(-c3cnccn3)nc2c1C#N
Reactant: CN(C)[C@H]1CCNC1
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: Cc1c(-c2ccccc2)c(N2CC[C@H](N(C)C)C2)c2oc(-c3cnccn3)nc2c1C#N
Temperature: 95 °C
Reaction time: 0.2 h
Yield: 38.6 %

Procedure:
(3S)-3-(Dimethylamino)pyrrolidine (93.4 μl, 0.736 mmol) and triethylamine (121 μl, 0.866 mmol) were added to a dimethyl sulfoxide (4 ml) solution of 7-fluoro-5-methyl-6-phenyl-2-(pyrazin-2-yl)-1,3-benzoxazole-4-carbonitrile (I-187) (143 mg, 0.433 mmol), followed by stirring in an oil bath at 95° C. for 0.2 hours. The reaction liquid was concentrated under reduced pressure, the residue was dissolved in chloroform (100 ml), washed with saturated brine (50 ml). After drying over anhydrous sodium sulfate, the solvent was evaporated away, and the resulting residue was purified by silica gel column chromatography (eluent, chloroform:methanol=9:1), the eluate was recrystallized from isopropanol to obtain the entitled compound (71.0 mg, 38.6%) as a pale yellow acicular crystal.
Reaction SMILES: C[O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH2:7][NH:8][C:9]2=[O:12])=[CH:5][CH:4]=1.B(Br)(Br)Br.CO>C(Cl)Cl>[OH:2][C:3]1[CH:11]=[C:10]2[C:6]([CH2:7][NH:8][C:9]2=[O:12])=[CH:5][CH:4]=1
Reactant: COc1ccc2c(c1)C(=O)NC2
Agent: BrB(Br)Br
Solvent: CO
Solvent: ClCCl
Product: O=C1NCc2ccc(O)cc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 98.6 %

Procedure:
A mixture of 6-methoxy-2,3-dihydro-isoindol-1-one (167 mg, 1.0 mmol) and boron tribromide (1 M in CH2Cl2, 3.6 mL, 3.6 mmol) in CH2Cl2 (8 mL) at −78° C. was stirred for 18 h at RT. The mixture was then cooled to −78° C. and MeOH (20 mL) was added. After 2 h at −78° C. the mixture was evaporated and the residue purified by chromatography (SiO2, CH2Cl2:2N NH3-MeOH 9:1) to afford the title product (147 mg, 100%) as a white solid. MS m/e=148.0 (M−H+).