Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl-].[CH3:2][O:3][CH2:4][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1([Li])C=CC=CC=1.[CH3:31][C:32]1([CH3:41])[O:36][C@H:35]([CH2:37][CH:38]=O)[C:34](=[O:40])[O:33]1>CCOCC.CCOCC.C1COCC1>[CH3:2][O:3][CH:4]=[CH:38][CH2:37][C@H:35]1[O:36][C:32]([CH3:41])([CH3:31])[O:33][C:34]1=[O:40]
Reactant: CC1(C)OC(=O)[C@@H](CC=O)O1
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [Li]c1ccccc1
Solvent: C1CCOC1
Solvent: CCOCC
Product: COC=CC[C@H]1OC(C)(C)OC1=O
Temperature: 0 °C
Reaction time: 0.02 h
Yield: 60.1 %

Procedure:
(Conditions modified from Duttone, F. E., et. al., J. Med. Chem. 2003, 46, 2057) To a stirred solution of (methoxymethyl)triphenylphosphonium chloride (1.19 g, 3.48 mmol) in anhydrous ether (50 mL) at −10° C. under nitrogen was added phenyllithium (1.93 mL, 3.48 mmol) 1.8 M solution in diethyl ether, over 1 minute using a syringe. The mixture was stirred at 0° C. for 30 minutes and then cooled to −78° C. A solution of (R)-2-(2,2-dimethyl-5-oxo-1,3-dioxolan-4-yl)acetaldehyde (Preparation D, Step B; 0.500 g, 3.16 mmol) in ether/THF 1:1 (50 mL) was introduced via addition funnel, and the reaction mixture was stirred at −78° C. for 1 hour and then warmed to ambient temperature and stirred for 4 hours. The crude was filtered and the residue was purified over silica gel (5-50% EtOAc in hexanes) to afford (R)-5-(3-methoxyallyl)-2,2-dimethyl-1,3-dioxolan-4-one (0.355 g, 1.90 mmol, 60% yield) as a clear, colorless oil (mixture of (E)- and (Z)-isomers).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])/[C:5](/[C:12]1[CH:17]=[CH:16][C:15](SC)=[CH:14][CH:13]=1)=[CH:6]/[CH2:7][C:8]([CH3:11])([CH3:10])[CH3:9])[CH3:2].O[O:22][S:23]([O-:25])=O.[K+].[CH3:27]O>>[CH2:1]([O:3][C:4](=[O:20])/[C:5](/[C:12]1[CH:13]=[CH:14][C:15]([S:23]([CH3:27])(=[O:25])=[O:22])=[CH:16][CH:17]=1)=[CH:6]/[CH2:7][C:8]([CH3:10])([CH3:11])[CH3:9])[CH3:2]
Reactant: CO
Reactant: O=S([O-])OO
Reactant: CCOC(=O)/C(=C/CC(C)(C)C)c1ccc(SC)cc1
Agent: [K+]
Product: CCOC(=O)/C(=C/CC(C)(C)C)c1ccc(S(C)(=O)=O)cc1

Procedure:
Following the method of example 54d, oxidation of (E)-5,5-dimethyl-2-(4-methylsulfanyl-phenyl)-hex-2-enoic acid ethyl ester (680 mg, 2.34 mmol) with oxone® (1.86 g, 3.0 mmol) in methanol gives the title compound as a yellow oil (720 mg). MS (m/e): 325 (M+H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[S:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17](=[O:19])[CH3:18])=[CH:12][CH:11]=1.[CH3:20][C:21]([CH2:23]Br)=[CH2:22].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[NH2:1][C:2]1[CH:7]=[C:6]([O:8][CH2:22][C:21]([CH3:23])=[CH2:20])[CH:5]=[CH:4][C:3]=1[S:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17](=[O:19])[CH3:18])=[CH:12][CH:11]=1
Reactant: CC(=O)Nc1ccc(Sc2ccc(O)cc2N)cc1
Reactant: C=C(C)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C=C(C)COc1ccc(Sc2ccc(NC(C)=O)cc2)c(N)c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 98.5 %

Procedure:
A mixture of the product from Example 232b (56 mg, 0.17 mmol), 2-methyl-3-bromo propene (20 mg, 0.17 mmol) and potassium carbonate (26 mg, 0.19 mmol) in DMF (1 mL) was stirred at room temperature 15 hr. The next day, the reaction mixture was poured onto ice and the solid collected by filtration providing the title compound (55 mg, 100%).
Reaction SMILES: [O:1]1[CH2:17][CH:2]1[CH2:3][O:4][C:5]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:6]=1[CH:7]=[C:8]([C:14]([NH2:16])=[O:15])[NH:9]2.[F:18][CH:19]([F:40])[O:20][C:21]1[CH:26]=[CH:25][C:24]([CH:27]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)=[CH:23][CH:22]=1>CO>[F:40][CH:19]([F:18])[O:20][C:21]1[CH:22]=[CH:23][C:24]([CH:27]([C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)[N:28]2[CH2:33][CH2:32][N:31]([CH2:17][CH:2]([OH:1])[CH2:3][O:4][C:5]3[CH:13]=[CH:12][CH:11]=[C:10]4[C:6]=3[CH:7]=[C:8]([C:14]([NH2:16])=[O:15])[NH:9]4)[CH2:30][CH2:29]2)=[CH:25][CH:26]=1
Reactant: FC(F)Oc1ccc(C(c2ccccc2)N2CCNCC2)cc1
Reactant: NC(=O)c1cc2c(OCC3CO3)cccc2[nH]1
Solvent: CO
Product: NC(=O)c1cc2c(OCC(O)CN3CCN(C(c4ccccc4)c4ccc(OC(F)F)cc4)CC3)cccc2[nH]1
Temperature: 80 °C

Procedure:
3.45 g of 4-(2,3-epoxypropoxy)-1H-indole-2-carboxamide and 4.70 g of 1-((4-difluoromethoxyphenyl)phenylmethyl)piperazine are dissolved at 40° C. in 75 ml of methanol. The mixture is then concentrated to dryness in vacuo, the syrupy residue is heated at 80° C. for 15 minutes and, after cooling, the solidified product is triturated with hexane and filtered off with suction.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:13](=[CH:14][CH:15]=1)[C:12](Cl)=[C:11]1[C:6]([CH:7]=[CH:8][C:9]([O:17][CH3:18])=[CH:10]1)=[N:5]2.[NH2:19][CH2:20][CH2:21][CH2:22][CH2:23][N:24]([CH2:29][CH3:30])[S:25]([CH3:28])(=[O:27])=[O:26]>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:13](=[CH:14][CH:15]=1)[C:12]([NH:19][CH2:20][CH2:21][CH2:22][CH2:23][N:24]([CH2:29][CH3:30])[S:25]([CH3:28])(=[O:27])=[O:26])=[C:11]1[C:6]([CH:7]=[CH:8][C:9]([O:17][CH3:18])=[CH:10]1)=[N:5]2
Reactant: CCN(CCCCN)S(C)(=O)=O
Reactant: COc1ccc2nc3cc(Cl)ccc3c(Cl)c2c1
Product: CCN(CCCCNc1c2ccc(Cl)cc2nc2ccc(OC)cc12)S(C)(=O)=O

Procedure:
Following the general procedure of Example 1 and making non-critical variations, but using 6,9-dichloro-2-methoxyacridine and N-(4-aminobutyl)-N-ethylmethanesulfonamide (Step 3), the title compound was obtained; MS (Found M+1=436).
Reaction SMILES: [C:1]1([CH2:11][CH:12]([CH2:16][C:17](=[O:25])[N:18]([CH3:24])[CH2:19][C:20]([O:22][CH3:23])=[O:21])[C:13](O)=[O:14])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.Cl.Cl.[NH2:28][C@H:29]([C:36]([NH:38][C@@H:39]([CH2:46][CH:47]([CH3:49])[CH3:48])[CH:40]([OH:45])[C:41]([O:43][CH3:44])=[O:42])=[O:37])[CH2:30][C:31]1[N:35]=[CH:34][NH:33][CH:32]=1.C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.C(N(CC)CC)C>CN(C)C=O>[C:1]1([CH2:11][CH:12]([CH2:16][C:17](=[O:25])[N:18]([CH3:24])[CH2:19][C:20]([O:22][CH3:23])=[O:21])[C:13]([NH:28][C@H:29]([C:36]([NH:38][C@@H:39]([CH2:46][CH:47]([CH3:49])[CH3:48])[CH:40]([OH:45])[C:41]([O:43][CH3:44])=[O:42])=[O:37])[CH2:30][C:31]2[N:35]=[CH:34][NH:33][CH:32]=2)=[O:14])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)CN(C)C(=O)CC(Cc1cccc2ccccc12)C(=O)O
Reactant: COC(=O)C(O)[C@H](CC(C)C)NC(=O)[C@@H](N)Cc1c[nH]cn1
Agent: Cl
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)CN(C)C(=O)CC(Cc1cccc2ccccc12)C(=O)N[C@@H](Cc1c[nH]cn1)C(=O)N[C@@H](CC(C)C)C(O)C(=O)OC
Yield: 25.1 %

Procedure:
To a solution of 30 mg of 2-(1-naphthylmethyl)-3-(N-methyl-N-methoxycarbonylmethylcarbamoyl)propionic acid and 42 mg of methyl(2RS,3S)-3-(L-histidyl)amino-2-hydroxy-5-methylhexanoate dihydrochloride in 3 ml of N,N-dimethylformamide were added successively 0.023 ml of diphenylphosphoryl azide and 0.040 ml of triethylamine with stirring under ice-cooling, and the mixture was stirred overnight. The reaction mixture was concentrated under reduced pressure, and a 5% aqueous sodium bicarbonate solution was added to the residue. The mixture was extracted with ethyl acetate, and the ethyl acetate layer was washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by preparative silica gel thin layer chromatography (developing solvent: chloroform/methanol=5/1 by volume; Rf2 =0.31) to obtain 14 mg of methyl (2RS,3S)-3-{N-[2-(1-naphthylmethyl)-3-(N-methyl-N-methoxycarbonylmethylcarbamoyl)propionyl]-L-histidyl}amino-2-hydroxy-5-methylhexanoate as a white powder.
Reaction SMILES: [O:1]1[C:3]2([CH2:8][CH2:7][O:6][CH2:5][CH2:4]2)[CH:2]1[C:9]#[N:10].N1C=CC=CC=1.[FH:17].C(OCC)(=O)C>ClCCl>[F:17][C:3]1([CH:2]([OH:1])[C:9]#[N:10])[CH2:8][CH2:7][O:6][CH2:5][CH2:4]1
Reactant: F
Reactant: N#CC1OC12CCOCC2
Agent: *CC(*)C
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: c1ccncc1
Product: N#CC(O)C1(F)CCOCC1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
Dissolve 1,6-dioxaspiro[2,5]octane-2-carbonitrile (4.14 g, 29.8 mmol) in dry dichloromethane (10 mL) and cool to 0° C. under a nitrogen atmosphere in a polypropylene bottle. Add hydrogen fluoride-pyridine (3 mL) dropwise. Allow the mixture to slowly warm to room temperature over 3 h and then stir an additional 1.5 hours at room temperature. Pour into ethyl acetate and wash with saturated aqueous sodium bicarbonate solution until washes remain basic. Combine the aqueous washes and adjust the pH of the solution to ˜pH=8 and extract with ethyl acetate. Combine this organic extract with the ethyl acetate solution of the crude reaction mixture and wash with saturated aqueous sodium chloride solution, dry (magnesium sulfate), filter and concentrate to give the desired compound as a yellow oil which is used directly in the next reaction.
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16](=[O:65])[NH:17][C@H:18]([C:58]([O:60]C(C)(C)C)=[O:59])[CH2:19][S:20][CH2:21][C@H:22]([O:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH3:57])[CH2:23][O:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1>C(O)(C(F)(F)F)=O.C(Cl)Cl.CC(OC)(C)C>[CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16](=[O:65])[NH:17][C@H:18]([C:58]([OH:60])=[O:59])[CH2:19][S:20][CH2:21][C@H:22]([O:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH3:57])[CH2:23][O:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: CCCCCCCCCCCCCCCCOC[C@H](CSC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)OC(C)(C)C)OCCCCCCCCCCCCCCCC
Solvent: COC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCCCCCCCCCCCCCCOC[C@H](CSC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O)OCCCCCCCCCCCCCCCC

Procedure:
A solution of (5R,9R)-tert-butyl 1-(9H-fluoren-9-yl)-9-(hexadecyloxy)-3-oxo-2,11-dioxa-7-thia-4-azaheptacosane-5-carboxylate in 40% TFA in DCM (0.3 M) was stirred at room temperature until complete deprotection of tert-butyl group (2 hours). The reaction mixture was diluted in MTBE, washed three times with 1 M citric acid (pH 3), and once with 1:2 HCl (3 M)/brine. The organic layer was dried over anhydrous Na2SO4 and concentrated en vaccuo. The resulting waxy solid was used in the next step without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([O:21][C:22]2[CH:23]=[N:24][C:25]([S:28]([CH3:31])(=[O:30])=[O:29])=[CH:26][CH:27]=2)[CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12]1[S:13][CH:14]([CH2:17][C:18]([OH:20])=O)[CH2:15][N:16]=1)=[CH:8]2.Cl.[CH2:33]([N:35]=[C:36]=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.CNC>O.CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([O:21][C:22]2[CH:23]=[N:24][C:25]([S:28]([CH3:31])(=[O:30])=[O:29])=[CH:26][CH:27]=2)[CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12]1[S:13][CH:14]([CH2:17][C:18]([N:35]([CH3:36])[CH3:33])=[O:20])[CH2:15][N:16]=1)=[CH:8]2
Reactant: CCN=C=NCCCN(C)C
Reactant: COc1cc(Oc2ccc(S(C)(=O)=O)nc2)cc2cc(C3=NCC(CC(=O)O)S3)[nH]c12
Agent: CNC
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(Oc2ccc(S(C)(=O)=O)nc2)cc2cc(C3=NCC(CC(=O)N(C)C)S3)[nH]c12
Temperature: 25 °C
Reaction time: 15 h
Yield: 69.9 %

Procedure:
A mixture of [2-(7-methoxy-5-{[6-(methylsulfonyl)pyridin-3-yl]oxy}-1H-indol-2-yl)-4,5-dihydro-1,3-thiazol-5-yl]acetic acid (500 mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (330 mg), 1-hydroxybenzotriazole (230 mg), dimethylamine (2M solution in tetrahydrofuran, 1.1 mL) and N,N-dimethylformamide (10 mL) was stirred at room temperature for 15 h. Water was added to the mixture and the resultant was extracted with ethyl acetate. The organic layer was washed successively with saturated aqueous sodium hydrogen carbonate solution and brine, dried (MgSO4), filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (ethyl acetate:methanol=100:0 to 95:5, volume ratio) to give pale yellow crystals. The crystals were recrystallized from acetone-methanol to give the title compound (370 mg, 69%) as pale yellow prisms. MS 489 (MH+). mp 206-207° C.
Reaction SMILES: [C:1]12([CH2:11]OC3C=CC(C#N)=CC=3Br)CC3CC(CC(C3)[CH2:2]1)C2.[CH:22]12[CH2:31][CH:26]3[CH2:27][CH:28]([CH2:30][CH:24]([CH2:25]3)[CH:23]1[CH2:32][O:33][C:34]1[CH:41]=[CH:40][C:37]([C:38]#[N:39])=[CH:36][C:35]=1Br)[CH2:29]2>>[CH:22]12[CH2:31][CH:26]3[CH2:27][CH:28]([CH2:30][CH:24]([CH2:25]3)[CH:23]1[CH2:32][O:33][C:34]1[CH:41]=[CH:40][C:37]([C:38]#[N:39])=[CH:36][C:35]=1[CH:11]1[CH2:1][CH2:2]1)[CH2:29]2
Reactant: N#Cc1ccc(OCC23CC4CC(CC(C4)C2)C3)c(Br)c1
Reactant: N#Cc1ccc(OCC2C3CC4CC(C3)CC2C4)c(Br)c1
Product: N#Cc1ccc(OCC2C3CC4CC(C3)CC2C4)c(C2CC2)c1

Procedure:
Following the procedure as described in Example 39 step 1 and making variation as required to replace 4-(adamantan-1-ylmethoxy)-3-bromobenzonitrile with 4-(adamantan-2-ylmethoxy)-3-bromobenzonitrile the title compound was obtained as a colorless solid (0.68 g, 84%): MS (ES+) m/z 308.3 (M+1).
Reaction SMILES: [S:1](=[O:33])(=[O:32])([O:3][CH2:4][C@@H:5]1[C@@H:12]2[C@@H:8]([O:9]C(C)(C)[O:11]2)[C@H:7]([NH:15][C:16]2[CH:21]=[C:20]([NH:22][C@@H:23]3[C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[CH2:25][CH2:24]3)[N:19]=[CH:18][N:17]=2)[CH2:6]1)[NH2:2].FC(F)(F)C(O)=O.O>>[S:1](=[O:33])(=[O:32])([O:3][CH2:4][C@H:5]1[CH2:6][C@@H:7]([NH:15][C:16]2[CH:21]=[C:20]([NH:22][C@@H:23]3[C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[CH2:25][CH2:24]3)[N:19]=[CH:18][N:17]=2)[C@H:8]([OH:9])[C@@H:12]1[OH:11])[NH2:2]
Reactant: CC1(C)O[C@@H]2[C@@H](COS(N)(=O)=O)C[C@@H](Nc3cc(N[C@H]4CCc5ccccc54)ncn3)[C@@H]2O1
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: NS(=O)(=O)OC[C@H]1C[C@@H](Nc2cc(N[C@H]3CCc4ccccc43)ncn2)[C@H](O)[C@@H]1O
Reaction time: 0.17 h
Yield: 49.2 %

Procedure:
A solution of [(3aR,4R,6R,6aS)-6-({6-[(1S)-2,3-dihydro-1H-inden-1-ylamino]pyrimidin-4-yl}amino)-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl]-methyl sulfamate (60.0 mg, 0.126 mmol) was treated with a 9:1 mixture of trifluoroacetic acid in H2O (5.00 mL, 58.4 mmol) and the mixture was stirred for 10 min before being concentrated in vacuo. The crude material was purified via reverse phase C18 preparative HPLC eluting with a gradient of 5 to 70% of 0.1% FA/95% ACN/5% H2O in 0.1% FA/99% H2O/1% ACN over 16 min to afford the title compound (27.0 mg, 49%). 1H NMR (400 MHz, DMSO-d6, δ): 8.13 (s, 1H), 7.98 (s, 1H), 7.44 (s, 2H), 7.28-7.02 (m, 5H), 6.72 (bs, 1H), 5.53 (s, 1H), 5.41 (s, 1H), 4.63 (d, J=5.3 Hz, 1H), 4.09 (dd, J=5.1, 9.5 Hz, 1H), 3.97 (dd, J=7.0, 9.5 Hz, 1H), 3.81 (bs, 1H), 3.71-3.60 (m, 2H), 3.01-2.87 (m, 1H), 2.87-2.70 (m, 1H), 2.47-2.37 (m, 1H), 2.30-2.09 (m, 2H), 1.89-1.72 (m, 1H), 1.19-1.05 (m, 1H) ppm. LC/MS: Rt=1.13 min, ES+ 436 (AA standard).
Reaction SMILES: F[C:2](F)(F)[C:3]([OH:5])=O.[CH3:8][O:9][CH2:10][N:11]1[C:15]([CH2:16][N:17]2[C:22]3[CH:23]=[C:24]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[S:25]C=3C(=O)[N:19]([CH:33]3[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]3)[C:18]2=[O:39])=[N:14][N:13]=[N:12]1.[CH2:40]([O:42][C:43]1[C:52]([O:53][CH3:54])=[CH:51][C:50]2[C:49]([C:55]3[CH:63]=[CH:62][C:58]([C:59]([OH:61])=O)=[CH:57][CH:56]=3)=[N:48][C@@H:47]3[CH2:64][CH2:65][S:66][CH2:67][C@@H:46]3[C:45]=2[CH:44]=1)[CH3:41].[B-](F)(F)(F)F.CCOC(C(C#N)=NOC(N(C)C)=[N+](C)C)=O.C1C=NC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH2:40]([O:42][C:43]1[C:52]([O:53][CH3:54])=[CH:51][C:50]2[C:49]([C:55]3[CH:56]=[CH:57][C:58]([C:59]([N:36]4[CH2:35][CH2:34][CH:33]([N:19]5[C:3](=[O:5])[C:2]6[S:25][C:24]([C:26]7[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=7)=[CH:23][C:22]=6[N:17]([CH2:16][C:15]6[N:11]([CH2:10][O:9][CH3:8])[N:12]=[N:13][N:14]=6)[C:18]5=[O:39])[CH2:38][CH2:37]4)=[O:61])=[CH:62][CH:63]=3)=[N:48][C@@H:47]3[CH2:46][CH2:67][S:66][CH2:65][C@@H:64]3[C:45]=2[CH:44]=1)[CH3:41]
Reactant: COCn1nnnc1Cn1c(=O)n(C2CCNCC2)c(=O)c2sc(-c3ccccc3)cc21
Reactant: O=C(O)C(F)(F)F
Reactant: CCOc1cc2c(cc1OC)C(c1ccc(C(=O)O)cc1)=N[C@@H]1CCSC[C@H]21
Agent: CCOC(=O)C(C#N)=NOC(N(C)C)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: On1nnc2cccnc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOc1cc2c(cc1OC)C(c1ccc(C(=O)N3CCC(n4c(=O)c5sc(-c6ccccc6)cc5n(Cc5nnnn5COC)c4=O)CC3)cc1)=N[C@@H]1CCSC[C@H]21

Procedure:
The title compound is prepared analogously as described for example 28 using 1-{[1-(methoxymethyl)-1H-tetrazol-5-yl]methyl}-6-phenyl-3-(piperidin-4-yl)thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione trifluoroacetate (compound B48) (235 mg), 4-[(4aR,10bR)-9-ethoxy-8-methoxy-3,4,4a,10b-tetrahydro-1H-thiopyrano[4,3-c]isoquinolin-6-yl]benzoic acid (165 mg; compound C10), TOTU (177 mg), HOAT (85 mg) and DIPEA (214 mg) in DCM (8 ml). After stirring for 4.5 h at RT additional 4-[(4aR,10bR)-9-ethoxy-8-methoxy-3,4,4a,10b-tetrahydro-1H-thiopyrano[4,3-c]isoquinolin-6-yl]benzoic acid (82.5 mg; compound C10), TOTU (177 mg) and HOAT (85 mg) are added. Purification by flash column chromatography [amino phase silica gel, eluation gradient: cyclohexane/EtOAc, 100/0 to 0/100 (v/v)] gives the title compound as a solid.
Reaction SMILES: [C:1]([CH2:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH2:15][CH2:14][CH:13]([CH:16]([CH3:25])[CH2:17][CH2:18][CH:19]([S:21]([NH2:24])(=[O:23])=[O:22])[CH3:20])[CH2:12][CH:11]=2)=[CH:6][CH:5]=1)#N.[OH-:26].[Na+].S(=O)(=O)(O)[O-:29].[Na+]>O1CCOCC1>[C:1]([CH2:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH2:15][CH2:14][CH:13]([CH:16]([CH3:25])[CH2:17][CH2:18][CH:19]([S:21]([NH2:24])(=[O:23])=[O:22])[CH3:20])[CH2:12][CH:11]=2)=[CH:6][CH:5]=1)([OH:29])=[O:26]
Reactant: [OH-]
Reactant: CC(CCC(C)S(N)(=O)=O)C1CC=C(c2ccc(CC#N)cc2)CC1
Reactant: O=S(=O)([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: CC(CCC(C)S(N)(=O)=O)C1CC=C(c2ccc(CC(=O)O)cc2)CC1
Temperature: 100 °C

Procedure:
To a solution of N-[2-[4-(4-cyanomethylphenyl)-3-cyclohexen-1-yl]propyl 2-propanesulfonamide (see Example 15) in dioxane is added 5 N sodium hydroxide. The mixture is heated to 100° C. for 24 hr. The mixture is then cooled, and acidified with 10% aqueous sodium bisulfate. The mixture is extracted three times with ethyl acetate and the combined organic extracts are dried, filtered and concentrated in vacuo to afford the title compound.
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([C:11]3[CH:12]=[CH:13][C:14]([O:22][CH3:23])=[C:15]([S:17]([NH:20][CH3:21])(=[O:19])=[O:18])[CH:16]=3)[CH:9]=2)[N:4]([S:24]([C:27]2[CH:33]=[CH:32][C:30]([CH3:31])=[CH:29][CH:28]=2)(=[O:26])=[O:25])[CH:3]=1.[F:34][C:35]1[CH:36]=[C:37]([CH:55]=[CH:56][CH:57]=1)[CH2:38][N:39]1[C:43]([CH3:44])=[C:42](B2OC(C)(C)C(C)(C)O2)[C:41]([CH3:54])=[N:40]1.C(=O)([O-])[O-].[Na+].[Na+]>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.C1(C)C=CC=CC=1.C(O)C>[F:34][C:35]1[CH:36]=[C:37]([CH:55]=[CH:56][CH:57]=1)[CH2:38][N:39]1[C:43]([CH3:44])=[C:42]([C:2]2[C:10]3[C:5](=[N:6][CH:7]=[C:8]([C:11]4[CH:12]=[CH:13][C:14]([O:22][CH3:23])=[C:15]([S:17]([NH:20][CH3:21])(=[O:19])=[O:18])[CH:16]=4)[CH:9]=3)[N:4]([S:24]([C:27]3[CH:33]=[CH:32][C:30]([CH3:31])=[CH:29][CH:28]=3)(=[O:26])=[O:25])[CH:3]=2)[C:41]([CH3:54])=[N:40]1
Reactant: Cc1nn(Cc2cccc(F)c2)c(C)c1B1OC(C)(C)C(C)(C)O1
Reactant: CNS(=O)(=O)c1cc(-c2cnc3c(c2)c(I)cn3S(=O)(=O)c2ccc(C)cc2)ccc1OC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: CNS(=O)(=O)c1cc(-c2cnc3c(c2)c(-c2c(C)nn(Cc4cccc(F)c4)c2C)cn3S(=O)(=O)c2ccc(C)cc2)ccc1OC
Yield: 50.7 %

Procedure:
Using similar reaction conditions as described in step-i of example-1, 5-(3-iodo-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-methoxy-N-methylbenzenesulfonamide (intermediate 22) (140 mg, 0.234 mmol) was coupled with 1-(3-fluorobenzyl)-3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (intermediate 16) (154 mg, 0.469 mmol), Pd(PPh3)2Cl2 (3.22 mg, 0.011 mmol), sodium carbonate (75 mg, 0.702 mmol), Toluene/ethanol (3/5 ml) to afford 80 mg (51% yield) of the titled compound. 1H NMR (CDCl3, 300 MHz): δ 8.63 (s, 1H), 8.14-8.12 (d, 2H), 8.04 (s, 1H), 7.73-7.64 (m, 3H), 7.49-7.46 (m, 1H), 7.33-7.30 (m, 3H), 7.15-7.12 (d, 1H), 7.01-6.95 (m, 2H), 6.86-6.83 (d, 1H), 5.31 (s, 2H), 4.84-4.83 (m, 1H), 4.03 (s, 3H), 2.63-2.61 (d, 3H), 2.39 (s, 3H), 2.20 (s, 3H), 2.13 (s, 3H). MS: m/z=674.2 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[Br:8][C:9]1[CH:18]=[CH:17][C:12]([C:13](=O)[CH2:14]Br)=[CH:11][CH:10]=1.C(=O)([O-])O.[Na+].C(O)C>O>[Br:8][C:9]1[CH:18]=[CH:17][C:12]([C:13]2[N:1]=[C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][N:3]3[CH:14]=2)=[CH:11][CH:10]=1
Reactant: O=C(CBr)c1ccc(Br)cc1
Reactant: Nc1ccccn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Brc1ccc(-c2cn3ccccc3n2)cc1
Temperature: 80 °C
Reaction time: 6 h
Yield: 76.6 %

Procedure:
1.0 g (11 mmol) of 2-aminopyridine, 3.0 g (11 mmol) of 4-bromophenacyl bromide, and 1.9 g (14 mmol) of sodium hydrogen carbonate were put in a 50 mL three-neck flask, and the air in the flask was replaced with nitrogen. This mixture was added with 10 mL of ethanol, and then heated and stirred at 80° C. for six hours. After the stirring, the mixture was added with water and subjected to suction filtration to give a solid. The obtained solid was washed with water and methanol in this order, whereby 2.3 g of the target white solid was obtained in a yield of 76%.
Reaction SMILES: [CH3:1][O:2][CH:3]([C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=1)[CH2:4][CH2:5]Cl.[CH3:14][CH:15]([CH3:31])[C:16]([NH:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[CH:20]=1)=[O:17].C(N(C(C)C)CC)(C)C>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.O1CCOCC1>[Cl:13][C:10]1[CH:11]=[CH:12][C:7]([CH:3]([O:2][CH3:1])[CH2:4][CH2:5][N:28]2[CH2:29][CH2:30][CH:25]([C:21]3[CH:20]=[C:19]([NH:18][C:16](=[O:17])[CH:15]([CH3:14])[CH3:31])[CH:24]=[CH:23][CH:22]=3)[CH2:26][CH2:27]2)=[CH:8][CH:9]=1
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Reactant: COC(CCCl)c1ccc(Cl)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: COC(CCN1CCC(c2cccc(NC(=O)C(C)C)c2)CC1)c1ccc(Cl)cc1
Temperature: 90 °C
Reaction time: 72 h
Yield: 73.7 %

Procedure:
A mixture of 3-methoxy-3-(p-chlorophenyl)-1-chloropropane (27.4 mg, 0.125 mmol), 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide (28.3 mg, 0.125 mmol), diisopropylethylamine (0.50 mL) and catalytic amount of tetrabutylammonium iodide in dioxane (2.0 mL) was stirred at 90° C. for 72 hrs. The reaction mixture was concentrated to a small volume and chromatographed using preparative TLC plates [2.5% of NH3 (2.0 M in methanol) in CHCl3] gave N-(3-{1-[3-(4-chlorophenyl)-3-methoxypropyl]-4-piperidinyl}phenyl)-2-methylpropanamide (39.5 mg, 73.8% yield) as a thick oil: 1H NMR δ 7.48 (s, 1H), 7.34-7.3 (m, 2H), 7.25 (m, 4H), 6.96 (d, 1H, J=7.4 Hz), 4.20 (apparent dd, 1H, J=5.9, 7.6 Hz), 3.2 (s, 3H), 3.04 (d, 1H, J=10.1 Hz), 2.99 (d, 1H, J=10.1 Hz), 2.49 (h, 4H, J=6.6 Hz), 2.20-2.10 (m, 4H), 1.82 (m, 4H), 1.25 (d, 6H, J=7.1 Hz); ESMS m/e: 429.4 (M+H)+.
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:7][O:6][CH2:5][CH2:4][NH:3]1.C(N=C=NCCCN(C)C)C.OC1C2N=NNC=2C=CC=1.[NH2:29][C:30]1[CH:38]=[CH:37][C:33]([C:34](O)=[O:35])=[CH:32][N:31]=1>C(O)C>[NH2:29][C:30]1[N:31]=[CH:32][C:33]([C:34]([N:3]2[CH2:4][CH2:5][O:6][CH2:7][C@H:2]2[CH3:1])=[O:35])=[CH:37][CH:38]=1
Reactant: C[C@@H]1COCCN1
Reactant: Nc1ccc(C(=O)O)cn1
Agent: CCN=C=NCCCN(C)C
Agent: Oc1cccc2[nH]nnc12
Solvent: CCO
Product: C[C@@H]1COCCN1C(=O)c1ccc(N)nc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 49.9 %

Procedure:
To a solution of (R)-3-methylmorpholine (2.02 g, 20 mmol) in ethanol (25 mL) was added 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide (EDCI) (3.33 g, 17.4 mmol), hydroxybenzotriazole (HOBt) (2.35 g, 17.4 mmol), and 6-aminonicotinic acid (2.0 g, 14.5 mmol). After stirring for 18 h at room temperature, the reaction suspension was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica-gel column chromatography eluting with 3:1 ethyl acetate/petroleum ether to afford 132a as a white solid (1.6 g, 36%). MS-ESI: [M+H]+ 222.3.