Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][C:9]([O:13][CH3:14])=[CH:10][CH:11]=2)[CH:6]([CH2:15][CH2:16][NH:17][C:18](=[O:20])[CH3:19])[CH2:5]1)(=O)C.COC1C=C2C(=CC=1)NCC2CCNC(=O)C.FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.C(OC(=O)C)(=O)C.[F:60][C:61]([F:86])([F:85])[S:62]([N:65]1[C:73]2[C:68](=[CH:69][C:70]([O:74][CH3:75])=[CH:71][CH:72]=2)[CH:67]([CH2:76][CH2:77][N:78](C(C)=O)[C:79](=[O:81])[CH3:80])[CH2:66]1)(=[O:64])=[O:63]>ClCCl.C1(C)C=CC=CC=1.C(N(CC)CC)C>[CH3:14][O:13][C:9]1[CH:8]=[C:7]2[C:12](=[CH:11][CH:10]=1)[NH:4][CH2:5][CH:6]2[CH2:15][CH2:16][NH:17][C:18](=[O:20])[CH3:19].[F:86][C:61]([F:60])([F:85])[S:62]([N:65]1[C:73]2[C:68](=[CH:69][C:70]([O:74][CH3:75])=[CH:71][CH:72]=2)[CH:67]([CH2:76][CH2:77][NH:78][C:79](=[O:81])[CH3:80])[CH2:66]1)(=[O:63])=[O:64]
Reactant: COc1ccc2c(c1)C(CCN(C(C)=O)C(C)=O)CN2S(=O)(=O)C(F)(F)F
Reactant: COc1ccc2c(c1)C(CCNC(C)=O)CN2C(C)=O
Agent: COc1ccc2c(c1)C(CCNC(C)=O)CN2
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: COc1ccc2c(c1)C(CCNC(C)=O)CN2S(=O)(=O)C(F)(F)F

Procedure:
N-[2-(5-Methoxyindolin-3-yl)ethyl]acetamide is prepared by the method described for the synthesis of N-[2-(1-acetyl-5-methoxyindolin-3-yl)ethyl]acetamide. The intermediate N-[2-(1-trifluoromethanesulphonyl-5-methoxyindolin-3-yl)ethyl]acetamide is prepared by reacting N-[2-(5-methoxyindolin-3-yl)ethyl]acetamide with trifluoromethanesulphonic anhydride in dichloromethane at -78° C. in the presence of triethylamine. The final acylation is carried out with acetic anhydride in refluxing toluene for 24 h, and allows N-[2-(1-trifluoromethanesulphonyl-5-methoxyindolin-3-yl)ethyl]diacetamide to be obtained.
Reaction SMILES: Cl.[C:2]([C:6]1[N:11]=[CH:10][C:9]([C:12]2[N:13]([C:33]([N:35]3[CH2:40][CH2:39][N:38]([CH2:41][C:42](O)=[O:43])[CH2:37][CH2:36]3)=[O:34])[C@@:14]([C:26]3[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=3)([CH3:25])[C@@:15]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)([CH3:17])[N:16]=2)=[C:8]([O:45][CH2:46][CH3:47])[CH:7]=1)([CH3:5])([CH3:4])[CH3:3].[N:48]1[CH:53]=[CH:52][CH:51]=[C:50]([NH2:54])[CH:49]=1>>[C:2]([C:6]1[N:11]=[CH:10][C:9]([C:12]2[N:13]([C:33]([N:35]3[CH2:40][CH2:39][N:38]([CH2:41][C:42]([NH:54][C:50]4[CH:49]=[N:48][CH:53]=[CH:52][CH:51]=4)=[O:43])[CH2:37][CH2:36]3)=[O:34])[C@@:14]([C:26]3[CH:27]=[CH:28][C:29]([Cl:32])=[CH:30][CH:31]=3)([CH3:25])[C@@:15]([C:18]3[CH:19]=[CH:20][C:21]([Cl:24])=[CH:22][CH:23]=3)([CH3:17])[N:16]=2)=[C:8]([O:45][CH2:46][CH3:47])[CH:7]=1)([CH3:3])([CH3:4])[CH3:5]
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCN(CC(=O)O)CC1
Reactant: Nc1cccnc1
Agent: Cl
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCN(CC(=O)Nc2cccnc2)CC1

Procedure:
In a manner analogous to the method described in examples 99, {4-[(4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl]-piperazin-1-yl}-acetic acid hydrochloride (example 94) was coupled with pyridin-3-ylamine (Aldrich) to give the title compound. HR-MS (ES, m/z) calculated for C40H46Cl2N7O3 [(M+H)+] 742.3034, observed 742.3034.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([S:11]([N:14]=[CH:15][N:16]([CH3:18])[CH3:17])(=[O:13])=[O:12])[CH:5]=[C:6]([F:10])[C:7]=1[CH2:8][OH:9].CCN(CC)CC.[CH3:26][S:27](Cl)(=[O:29])=[O:28]>C(Cl)Cl>[CH3:26][S:27]([O:9][CH2:8][C:7]1[C:2]([F:1])=[CH:3][C:4]([S:11](=[O:12])(=[O:13])[N:14]=[CH:15][N:16]([CH3:18])[CH3:17])=[CH:5][C:6]=1[F:10])(=[O:29])=[O:28]
Reactant: CS(=O)(=O)Cl
Reactant: CN(C)C=NS(=O)(=O)c1cc(F)c(CO)c(F)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(C)C=NS(=O)(=O)c1cc(F)c(COS(C)(=O)=O)c(F)c1
Reaction time: 0.5 h
Yield: 88.8 %

Procedure:
To a solution of N′-(3,5-difluoro-4-(hydroxymethyl)phenylsulfonyl)-N,N-dimethyl-formimidamide (80 g, 287 mmol) in DCM (500 mL) was added Et3N (121 mL, 862 mmol, 3 eq) and methanesulfonylchloride (27 mL, 245 mmol, 1.2 eq) successively at 0° C. After 30 min, the reaction mixture was extracted with DCM (300 mL×3). The combined extracts were washed with water (1 L), dried over MgSO4, concentrated and then purified by chromatography (silica, DCM/EtOAc, 1:1) to give 4-(N-((dimethylamino)methylene)sulfamoyl)-2,6-difluorobenzyl methanesulfonate (77.5 g, 28% over 4 steps) as a ivory solid. 1H NMR (400 MHz, CDCl3) δ 8.11 (s, 1H), 7.59-7.39 (m, 2H), 5.32 (s, 2H), 3.18 (s, 3H), 3.09 (s, 3H), 3.08 (s, 3H).
Reaction SMILES: [C:1]1([CH:7]([N:11]2[C:16](=[S:17])[C:15]3[CH:18]=[N:19][NH:20][C:14]=3[N:13]=[CH:12]2)[C:8]([OH:10])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1.CN1CCOCC1.CCOC(C)=O>CN(C=O)C>[C:1]1([CH:7]([N:11]2[C:16](=[S:17])[C:15]3[CH:18]=[N:19][NH:20][C:14]=3[N:13]=[CH:12]2)[C:8]([N:30]2[CH2:31][CH2:32][N:27]([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][N:21]=3)[CH2:28][CH2:29]2)=[O:10])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: c1ccc(N2CCNCC2)nc1
Reactant: O=C(O)C(c1ccccc1)n1cnc2[nH]ncc2c1=S
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CN1CCOCC1
Product: O=C(C(c1ccccc1)n1cnc2[nH]ncc2c1=S)N1CCN(c2ccccn2)CC1
Reaction time: 8 h
Yield: 22 %

Procedure:
1-[3-(dimethylamino)propyl]-3-ethycabodiimide HCl (1.5 eq. mmol) and following 1-hydrobenzatriazole hydrate (HOBT) (0.5 eq. mmol) was added to a solution of 2-phenyl-(4-thioxo-1,4-dihydro-pyrazolo[3,4-d]pyrimidin-5-yl) acetic acid (XIVa) (1.0 eq. mmol) and a corresponding amine such as 1-(2-pyridyl)piperazine(1.5 eq. mmol) with 4-methylmorpholine (3.0 eq. mmol) in DMF at 0° C. The resulting mixture was stirred overnight at 0° C. to room temperature. The yellow reaction mixture was filtered off and washed well with EtOAc. The filtrate was extracted with brine, saturated NaHCO3, brine. The organic layer was dried over anhydrous Na2SO4, and then was concentrated under vacuum. The crude product was chromatographed using silica gel and eluted with CH2Cl2:EtOAc/1:1 to afford (XVIi) (0.029 g, 0.07 mmol, 22% yield) as a white solid.
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([CH2:14][CH2:15][CH2:16][C:17]([C:20]2[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=2)([CH3:19])[CH3:18])[CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[CH:33](Br)([CH3:35])[CH3:34].CN(C)C=O>O>[O:1]([C:8]1[CH:9]=[C:10]([CH2:14][CH2:15][CH2:16][C:17]([C:20]2[CH:21]=[CH:22][C:23]([O:26][CH:33]([CH3:35])[CH3:34])=[CH:24][CH:25]=2)([CH3:19])[CH3:18])[CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(CCCc1cccc(Oc2ccccc2)c1)c1ccc(O)cc1
Reactant: CC(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)Oc1ccc(C(C)(C)CCCc2cccc(Oc3ccccc3)c2)cc1
Temperature: 130 °C
Reaction time: 2 h

Procedure:
A mixture of 0.5 g of 1-(3-phenoxyphenyl)-4-(4-hydroxyphenyl)-4-methylpentane, 1.5 g of K2CO3, 3 ml of isopropyl bromide and 20 ml of dimethylformamide was stirred at 130° C. for two hours. The reaction mixture was poured into water and extracted with benzene. The benzene extract was washed with water and dried, and the solvent was evaporated under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: benzene) to give 0.3 g of 1-(3-phenoxyphenyl)-4-(4-isopropoxyphenyl)-4-methylpentane.
Reaction SMILES: [N:1]1[C:10]2[CH:9]([N:11]([CH2:30][C:31]3[CH:47]=[CH:46][C:34]([CH2:35][NH:36][S:37]([C:40]4[CH:45]=[CH:44][CH:43]=[CH:42][N:41]=4)(=[O:39])=[O:38])=[CH:33][CH:32]=3)[CH2:12][C:13]3[N:17](COCC[Si](C)(C)C)[C:16]4[CH:26]=[CH:27][CH:28]=[CH:29][C:15]=4[N:14]=3)[CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.Cl>>[NH:14]1[C:15]2[CH:29]=[CH:28][CH:27]=[CH:26][C:16]=2[N:17]=[C:13]1[CH2:12][N:11]([CH2:30][C:31]1[CH:32]=[CH:33][C:34]([CH2:35][NH:36][S:37]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][N:41]=2)(=[O:38])=[O:39])=[CH:46][CH:47]=1)[CH:9]1[C:10]2[N:1]=[CH:2][CH:3]=[CH:4][C:5]=2[CH2:6][CH2:7][CH2:8]1
Reactant: C[Si](C)(C)CCOCn1c(CN(Cc2ccc(CNS(=O)(=O)c3ccccn3)cc2)C2CCCc3cccnc32)nc2ccccc21
Agent: Cl
Product: O=S(=O)(NCc1ccc(CN(Cc2nc3ccccc3[nH]2)C2CCCc3cccnc32)cc1)c1ccccn1
Yield: 84.2 %

Procedure:
Using General Procedure E: Reaction of pyridine-2-sulfonic acid 4-({(5,6,7,8-tetrahydro-quinolin-8-yl)-[1-(2-trimethylsilanyl-ethoxymethyl)-1 H-benzoimidazol-2-ylmethyl]-amino}-methyl)-benzylamide (100 mg, 0.15 mmol), and 6N HCl (3.9 mL) for 3 h at 50° C. followed by column chromatography on silica gel (CH2Cl2/MeOH/NH4OH: 94:3:3) gave the title compound (68 mg, 85%) as a white foam.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH2:11])=[S:10])=[CH:4][CH:3]=1.Cl[CH2:13][CH:14]=O.C(OCC)(=O)C>C(O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]2[S:10][CH:13]=[CH:14][N:11]=2)=[CH:6][CH:7]=1
Reactant: O=CCCl
Reactant: NC(=S)Nc1ccc(F)cc1
Solvent: CCO
Solvent: CCOC(C)=O
Product: Fc1ccc(Nc2nccs2)cc1
Temperature: 80 °C

Procedure:
1-(4-fluorophenyl)thiourea (2.00 g, 11.7 mmol) and 2-chloroacetaldehyde (3.72 mL, 58.6 mmol) in anhydrous ethanol (5 mL) were added to a microwave vial. The reaction mixture was heated to 80° C. in a microwave reactor for 20 min. On cooling, ethyl acetate (2 mL) was added to the crude product reaction mixture and pure product crystallized out. This filtered off, washed with hexane and air-dried to afford the title compound as a crystalline brown solid, 1.568 g. MS (M+H)+ 195.
Reaction SMILES: Br[C:2]1[C:3]2[N:4]([CH:9]=[CH:10][N:11]=2)[N:5]=[C:6]([Cl:8])[CH:7]=1.[CH3:12][N:13]1[CH2:18][CH2:17][N:16]([CH2:19][C:20]2[CH:21]=[CH:22][C:23]([NH2:26])=[N:24][CH:25]=2)[CH2:15][CH2:14]1.[H-].[Na+]>CN(C=O)C>[Cl:8][C:6]1[CH:7]=[C:2]([NH:26][C:23]2[CH:22]=[CH:21][C:20]([CH2:19][N:16]3[CH2:15][CH2:14][N:13]([CH3:12])[CH2:18][CH2:17]3)=[CH:25][N:24]=2)[C:3]2[N:4]([CH:9]=[CH:10][N:11]=2)[N:5]=1
Reactant: Clc1cc(Br)c2nccn2n1
Reactant: CN1CCN(Cc2ccc(N)nc2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1CCN(Cc2ccc(Nc3cc(Cl)nn4ccnc34)nc2)CC1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 51.6 %

Procedure:
A mixture of 8-bromo-6-chloroimidazo[1,2-b]pyridazine (214 mg, 921 μmol, Eq: 0.95) and 5-((4-methylpiperazin-1-yl)methyl)pyridin-2-amine (200 mg, 970 μmol, Eq: 1.00) in DMF (10.0 ml) was cooled to 0° C. To this was added sodium hydride (60% in mineral oil, 124 mg, 3.1 mmol, Eq: 3.2). The reaction was allowed to stir at 0° C. for 10 min and then allowed to warm to room temperature and stirred for 72 h. The reaction was quenched with saturated NaHCO3 (aq) and then diluted with water and EtOAc. The organic layer was separated and the aqueous phase was washed with EtOAc. The organic layers were combined, dried over MgSO4 and concentrated in vacuo. The residue was dissolved in Et2O. The organic layer was washed with water and dried over MgSO4. The drying agent was removed by filtration. The resulting solution was concentrated in vacuo to give (6-chloro-imidazo[1,2-b]pyridazin-8-yl)-[5-(4-methyl-piperazin-1-ylmethyl)-pyridin-2-yl]-amine (170 mg, 49%) as a solid. LC/MS-ESI observed [M+H]+ 358.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH2:8][N:9]2[CH2:14][CH2:13][O:12][CH:11]([CH2:15][CH2:16][OH:17])[CH2:10]2)[N:3]=1.[NH2:18][C:19]1[S:20][C:21]([C:27]2[CH:32]=[CH:31][C:30]([C:33]([OH:36])([CH3:35])[CH3:34])=[CH:29][C:28]=2[F:37])=[CH:22][C:23]=1[C:24]([NH2:26])=[O:25]>>[F:37][C:28]1[CH:29]=[C:30]([C:33]([OH:36])([CH3:34])[CH3:35])[CH:31]=[CH:32][C:27]=1[C:21]1[S:20][C:19]([NH:18][C:2]2[CH:7]=[CH:6][N:5]=[C:4]([CH2:8][N:9]3[CH2:14][CH2:13][O:12][CH:11]([CH2:15][CH2:16][OH:17])[CH2:10]3)[N:3]=2)=[C:23]([C:24]([NH2:26])=[O:25])[CH:22]=1
Reactant: OCCC1CN(Cc2nccc(Cl)n2)CCO1
Reactant: CC(C)(O)c1ccc(-c2cc(C(N)=O)c(N)s2)c(F)c1
Product: CC(C)(O)c1ccc(-c2cc(C(N)=O)c(Nc3ccnc(CN4CCOC(CCO)C4)n3)s2)c(F)c1

Procedure:
The title compound was prepared as described in Example 106, Step 2 with 2-{4-[(4-chloropyrimidin-2-yl)methyl]morpholin-2-yl}ethanol (50 mg, 0.19 mmol) and 2-amino-5-[2-fluoro-4-(1-hydroxy-1-methylethyl)phenyl]thiophene-3-carboxamide (57 mg, 0.19 mmol) as starting materials.
Reaction SMILES: CCC(C)[BH-](C(C)CC)C(C)CC.[Li+].[C:15]1([CH2:21][O:22][C:23]([C@:25]2([NH:42][C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[CH2:30][C:29](=[O:31])[C@@H:28]3[C@H:26]2[C@H:27]3[C:32]([O:34][CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=[O:33])=[O:24])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>O1CCCC1>[CH2:21]([O:22][C:23]([C@:25]1([NH:42][C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[CH2:30][C@H:29]([OH:31])[C@@H:28]2[C@H:26]1[C@H:27]2[C:32]([O:34][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)=[O:33])=[O:24])[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: CC(C)(C)OC(=O)N[C@@]1(C(=O)OCc2ccccc2)CC(=O)[C@H]2[C@H](C(=O)OCc3ccccc3)[C@H]21
Agent: CCC(C)[BH-](C(C)CC)C(C)CC
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@@]1(C(=O)OCc2ccccc2)C[C@H](O)[C@H]2[C@H](C(=O)OCc3ccccc3)[C@H]21
Reaction time: 0.75 h

Procedure:
Add 1M L-selectride solution in THF (30 mL, 30 mmol) dropwise to a stirred solution of bis[(phenyl)methyl](1S,2S,5R,6R)-2-(tert-butoxycarbonylamino)-4-oxo-bicyclo[3.1.0]hexane-2,6-dicarboxylate (9.15 g, 19.08 mmol) in tetrahydrofuran (20 mL) at −78° C. Stir the resulting orange mixture under nitrogen for 1 hour 45 minutes. Quench with a saturated solution of sodium hydrogen carbonate at −78° C. Dilute with water and ethyl acetate. Separate the layers and wash the organic phase with brine and water. Dry over sodium sulfate, filter and concentrate to dryness to give the crude material as pale yellow oil. Purify the combined material by flash chromatography eluting with ethyl acetate:hexanes (20:80 to 50:50) to give the title product as a single isomer (9.19 g, 100%). MS (m/z): 504 (M+23)
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[CH:11][CH:10]=[N:9]2)=[CH:4][CH:3]=1.[CH2:13]([OH:16])[C:14]#[CH:15]>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>[N:8]1([C:5]2[CH:6]=[CH:7][C:2]([C:15]#[C:14][CH2:13][OH:16])=[CH:3][CH:4]=2)[CH:12]=[CH:11][CH:10]=[N:9]1
Reactant: C#CCO
Reactant: Brc1ccc(-n2cccn2)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Product: OCC#Cc1ccc(-n2cccn2)cc1
Temperature: 80 °C
Reaction time: 0.08 h
Yield: 36.7 %

Procedure:
A mixture of 1-(4-bromophenyl)-1H-pyrazole (prepared as described in Bull. Soc. Chim. Fr. 1966, 2832) (2.24 g, 10.04 mmol), Pd(Ph3P)2Cl2 (180 mg, 0.26 mmol), and copper(I) iodide (95 mg, 0.50 mmol) in TEA (20 mL) was stirred for 5 min, propargyl alcohol (0.70 mL, 12.02 mmol) was added, and the mixture was heated to 80° C. for 48 h. The volatiles were evaporated, ethyl acetate (50 mL) and water (50 mL) were added to the residue, and the mixture was filtered through a pad of Celite. The organic layer from the filtrate was washed with brine (50 mL), dried (Na2SO4), and concentrated. Purification by chromatography (SiO2, 3:2 hexane/ethyl acetate) yielded 0.73 g (37%) of the title compound as a brown solid. MS 199 (M+H)+.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([S:10]([NH2:13])(=[O:12])=[O:11])[CH:6]=[CH:7][C:8]=1F)#[N:2].[O:14]1[CH2:19][CH2:18][CH:17]([CH2:20][NH2:21])[CH2:16][CH2:15]1.C(N(CC)C(C)C)(C)C>O1CCCC1.C(OCC)(=O)C>[C:1]([C:3]1[CH:4]=[C:5]([S:10]([NH2:13])(=[O:12])=[O:11])[CH:6]=[CH:7][C:8]=1[NH:21][CH2:20][CH:17]1[CH2:18][CH2:19][O:14][CH2:15][CH2:16]1)#[N:2]
Reactant: NCC1CCOCC1
Reactant: N#Cc1cc(S(N)(=O)=O)ccc1F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: N#Cc1cc(S(N)(=O)=O)ccc1NCC1CCOCC1

Procedure:
3-Cyano-4-fluorobenzenesulfonamide (500 mg), (tetrahydropyran-4-yl)methylamine (288 mg), and N,N-diisopropylethylamine (1.3 mL) were heated at 80° C. in tetrahydrofuran (15 mL) overnight. The mixture was diluted with ethyl acetate, washed with NaHCO3 solution and brine, and dried (Na2SO4), filtered and concentrated. The product was triturated from ethyl acetate.
Reaction SMILES: C([O:4][CH2:5][C:6]1[CH:11]=[C:10]([O:12][CH2:13][CH2:14][CH2:15][S:16]([CH3:19])(=[O:18])=[O:17])[CH:9]=[C:8]([CH3:20])[C:7]=1[C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([CH2:27][O:28][C:29]2[CH:42]=[CH:41][C:32]3[C@H:33]([CH2:36][C:37]([O:39]C)=[O:38])[CH2:34][O:35][C:31]=3[CH:30]=2)[CH:22]=1)(=O)C.CO.[OH-].[Na+].Cl>O.O1CCCC1>[OH:4][CH2:5][C:6]1[CH:11]=[C:10]([O:12][CH2:13][CH2:14][CH2:15][S:16]([CH3:19])(=[O:18])=[O:17])[CH:9]=[C:8]([CH3:20])[C:7]=1[C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([CH2:27][O:28][C:29]2[CH:42]=[CH:41][C:32]3[C@H:33]([CH2:36][C:37]([OH:39])=[O:38])[CH2:34][O:35][C:31]=3[CH:30]=2)[CH:22]=1
Reactant: COC(=O)C[C@@H]1COc2cc(OCc3cccc(-c4c(C)cc(OCCCS(C)(=O)=O)cc4COC(C)=O)c3)ccc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(OCCCS(C)(=O)=O)cc(CO)c1-c1cccc(COc2ccc3c(c2)OC[C@H]3CC(=O)O)c1
Temperature: 50 °C
Reaction time: 2 h
Yield: 50.5 %

Procedure:
To a solution of methyl [(3S)-6-({2′-(acetoxymethyl)-6′-methyl-4′-[3-(methylsulfonyl)propoxy]biphenyl-3-yl}methoxy)-2,3-dihydro-1-benzofuran-3-yl]acetate (1.11 g, 1.86 mmol) in a mixed solvent of methanol (4 mL) and tetrahydrofuran (8 mL) was added 2 M aqueous sodium hydroxide solution (2 mL), and the mixture was stirred at 50° C. for 2 hr. The reaction mixture was diluted with water, acidified with 1 M hydrochloric acid, and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=50:50-100:0) and preparative HPLC, and the obtained crystals were recrystallized from heptane-ethyl acetate to give the title compound (0.508 g, yield 51%) as colorless crystals.
Reaction SMILES: [CH:1]1([C:4]2[CH:20]=[CH:19][C:18]([CH:21]3[C@H:26]([O:27]CC4C=CC=CC=4)[C@@H:25]([O:35]CC4C=CC=CC=4)[C@H:24]([O:43]CC4C=CC=CC=4)[C@@H:23]([CH2:51][O:52]CC4C=CC=CC=4)[O:22]3)=[CH:17][C:5]=2[CH2:6][C:7]2[CH:8]=[C:9]3[C:14](=[CH:15][CH:16]=2)[O:13][CH2:12][CH2:11][CH2:10]3)[CH2:3][CH2:2]1>C1COCC1.[Pd]>[O:13]1[C:14]2[C:9](=[CH:8][C:7]([CH2:6][C:5]3[CH:17]=[C:18]([C@H:21]4[C@H:26]([OH:27])[C@@H:25]([OH:35])[C@H:24]([OH:43])[C@@H:23]([CH2:51][OH:52])[O:22]4)[CH:19]=[CH:20][C:4]=3[CH:1]3[CH2:2][CH2:3]3)=[CH:16][CH:15]=2)[CH2:10][CH2:11][CH2:12]1
Reactant: c1ccc(COC[C@H]2OC(c3ccc(C4CC4)c(Cc4ccc5c(c4)CCCO5)c3)[C@H](OCc3ccccc3)[C@@H](OCc3ccccc3)[C@@H]2OCc2ccccc2)cc1
Agent: [Pd]
Solvent: C1CCOC1
Product: OC[C@H]1O[C@@H](c2ccc(C3CC3)c(Cc3ccc4c(c3)CCCO4)c2)[C@H](O)[C@@H](O)[C@@H]1O
Reaction time: 8 h
Yield: 17.9 %

Procedure:
To a stirred solution of 6-[2-cyclopropyl-5-((3S,4R,5R,6R)-3,4,5-tris-benzyloxy-6-benzyloxymethyl-tetrahydro-pyran-2-yl)-benzyl]-chroman (650 mg) in THF (5 mL) was added 10% palladium charcoal activated (dry) (100 mg), methanol (5 mL), and conc. HCl (0.2 mL). The reaction mixture was stirred under hydrogen atmosphere (bladder pressure) overnight then filtered through a celite bed. The filtrate was concentrated and purified by preparative HPLC to furnish (2S,3R,4R,5S,6R)-2-(3-chroman-6-ylmethyl-4-cyclopropyl-phenyl)-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol (63 mg).
Reaction SMILES: [CH:1]1[C:14]2[CH:13]([C:15]([OH:17])=O)[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[S:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[NH2:18][C@H:19]1[CH2:23][CH2:22][N:21]([CH2:24][CH2:25][C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=2)[CH2:20]1>>[F:32][C:29]1[CH:30]=[CH:31][C:26]([CH2:25][CH2:24][N:21]2[CH2:22][CH2:23][C@H:19]([NH:18][C:15]([CH:13]3[C:14]4[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=4[S:6][C:7]4[C:12]3=[CH:11][CH:10]=[CH:9][CH:8]=4)=[O:17])[CH2:20]2)=[CH:27][CH:28]=1
Reactant: N[C@H]1CCN(CCc2ccc(F)cc2)C1
Reactant: O=C(O)C1c2ccccc2Sc2ccccc21
Product: O=C(N[C@H]1CCN(CCc2ccc(F)cc2)C1)C1c2ccccc2Sc2ccccc21

Procedure:
9-Thioxanthenylcarboxylic acid and (S)-3-amino-1-(2-(4-fluorophenyl)ethyl)pyrrolidine were reacted under the same conditions as in Example 23 to give (S)-N-(1-(2-(4-fluorophenyl)ethyl)pyrrolidin-3-yl)-9-thioxanthenylcarboxamide.
Reaction SMILES: [OH:1][N:2]1[C:7]([CH3:9])([CH3:8])[CH2:6][CH:5]([O:10][C:11](=[O:18])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:4][C:3]1([CH3:20])[CH3:19].[C:21](O)(=O)[CH3:22].OO.S([O-])([O-])=O.[Na+].[Na+].S(=O)(=O)(O)O>[Zn].N1C=CC=CC=1.O.C1CCCCC1>[CH:22]1([O:1][N:2]2[C:7]([CH3:9])([CH3:8])[CH2:6][CH:5]([O:10][C:11](=[O:18])[C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH2:4][C:3]2([CH3:20])[CH3:19])[CH2:21][CH2:5][CH2:4][CH2:3][CH2:19]1
Reactant: CC1(C)CC(OC(=O)c2ccccc2)CC(C)(C)N1O
Reactant: CC(=O)O
Agent: O=S(=O)(O)O
Agent: O=S([O-])[O-]
Agent: OO
Solvent: c1ccncc1
Solvent: O
Solvent: C1CCCCC1
Product: CC1(C)CC(OC(=O)c2ccccc2)CC(C)(C)N1OC1CCCCC1
Temperature: 45 °C
Reaction time: 8 h
Yield: 105.7 %

Procedure:
To a mixture of 3.00 g (10.9 mmol) of 1-oxyl-4-benzoyloxy-2,2,6,6-tetramethylpiperidine, 20 ml of pyridine, and 12 ml of cyclohexane are added 2.2 ml (38.4 mmol, 3.5 equivalents) of glacial acetic acid, 1 ml of water, 0.124 g (0.446 mmol) of ferrous sulfate heptahydrate, and finally, 0.57 g (8.7 mmol, 0.80 equivalents) of zinc powder. A slight exothermic reaction occurs upon the addition of zinc. The reaction mixture is heated to 45° C. A solution of 3.0 g (44 mmol) of 50% aqueous hydrogen peroxide is added dropwise over 1.5 hours to the reaction mixture while the temperature is brought to and maintained at 60-64° C. After the peroxide is added, the mixture is heated at 62° C. for 15 minutes, then allowed to cool slowly. After the reaction mixture is stirred overnight at room temperature, residual peroxide is decomposed by the addition of aqueous sodium sulfite solution. A mixture of 15 ml of concentrated sulfuric acid and 76 g of ice is carefully added to the reaction mixture to form a salt from the pyridine. Work-up and purification according to the procedure of Example 40A afford 2.07 g (53% yield) of the title compound, a white solid, GC assay 100%.
Reaction SMILES: [CH:1]1([C:7]2[C:15]3[C:10](=[CH:11][C:12]([C:16]([O:18][CH3:19])=[O:17])=[CH:13][CH:14]=3)[NH:9][C:8]=2[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[CH:26]=[CH2:27])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].[CH2:30](Br)[C:31]#[CH:32].C1(C)C=CC=CC=1>CN(C=O)C>[CH:1]1([C:7]2[C:15]3[C:10](=[CH:11][C:12]([C:16]([O:18][CH3:19])=[O:17])=[CH:13][CH:14]=3)[N:9]([CH2:32][C:31]#[CH:30])[C:8]=2[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[CH:26]=[CH2:27])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C=Cc1ccccc1-c1[nH]c2cc(C(=O)OC)ccc2c1C1CCCCC1
Reactant: C#CCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: C#CCn1c(-c2ccccc2C=C)c(C2CCCCC2)c2ccc(C(=O)OC)cc21
Yield: 84 %

Procedure:
Methyl 3-cyclohexyl-2-(2-vinylphenyl)-1H-indole-6-carboxylate was dissolved in DMF (0.277 M) and sodium hydride (1.2 eq.) was added. After the evolution of gas had ceased, a solution of propargylbromide in toluene (80% solution, 1.6 eq.) was added. After 3 h all volatiles were evaporated in vacuo. The residual material was purified by flash chromatography (PE:EtOAc, 20:1). After evaporation of the solvents, the product was obtained as a colourless foam (84%). MS (ES+): 398.4 (M+H+).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][NH:5][C:6](=[O:22])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21].[CH3:23][C:24]1([CH3:40])[O:29][CH:28]([C:30]([NH:32][CH2:33][CH2:34][C:35](O)=[O:36])=[O:31])[C:27]([CH3:39])([CH3:38])[CH2:26][O:25]1>>[CH3:23][C:24]1([CH3:40])[O:29][CH:28]([C:30]([NH:32][CH2:33][CH2:34][C:35]([O:1][CH2:2][CH2:3][CH2:4][NH:5][C:6](=[O:22])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[O:36])=[O:31])[C:27]([CH3:39])([CH3:38])[CH2:26][O:25]1
Reactant: CC1(C)OCC(C)(C)C(C(=O)NCCC(=O)O)O1
Reactant: CCCCCCCCCCCCCCCC(=O)NCCCO
Product: CCCCCCCCCCCCCCCC(=O)NCCCOC(=O)CCNC(=O)C1OC(C)(C)OCC1(C)C
Yield: 98.9 %

Procedure:
N-(3-Hydroxypropyl)hexadecanamide (3.13 g) and 2.59 g of 3-[N-(2,2,5,5-tetramethyl-1,3-dioxane-4-carbonyl)amino]propionic acid were reacted in the same manner as in Example 15 to obtain 5.48 g of the title compound (yield: 99%)