Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][C:3]1[N:11]=[C:10]2[C:6]([N:7]=[CH:8][N:9]2[C@H:12]2[C@H:16]([OH:17])[C@H:15]([OH:18])[C@@H:14]([CH2:19][O:20][CH3:21])[O:13]2)=[C:5]([NH:22][CH2:23][CH:24]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[N:4]=1.[CH3:37][O:38][C:39]1[CH:40]=[C:41]([CH:44]=[CH:45][C:46]=1[O:47][CH3:48])[CH:42]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>O1CCCC1>[CH3:37][O:38][C:39]1[CH:40]=[C:41]([CH:44]=[CH:45][C:46]=1[O:47][CH3:48])[CH2:42][NH:1][CH2:2][C:3]1[N:11]=[C:10]2[C:6]([N:7]=[CH:8][N:9]2[C@H:12]2[C@H:16]([OH:17])[C@H:15]([OH:18])[C@@H:14]([CH2:19][O:20][CH3:21])[O:13]2)=[C:5]([NH:22][CH2:23][CH:24]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[N:4]=1
Reactant: COC[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(CN)nc32)[C@H](O)[C@@H]1O
Reactant: COc1ccc(C=O)cc1OC
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Product: COC[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(CNCc4ccc(OC)c(OC)c4)nc32)[C@H](O)[C@@H]1O
Yield: 35.1 %

Procedure:
(2R,3R,4S,5R)-2-{2-(Aminomethyl)-6-[(2,2-diphenylethyl)amino}-9H-purin-9-yl}-5-(methoxymethyl)tetrahydro-3,4-furandiol (example 1) (200 mg, 0.4 mmol) was dissolved in stirred tetrahydrofuran (5 ml) and 3,4-dimethoxybenzaldehyde (130 mg, 0.8 mmol) added. The reagents were stirred together until everything had dissolved and then sodium triacetoxyborohydride (130 mg, 0.6 mmol) added. The reaction mixture was stirred for 24 hr and then quenched by the addition of methanol (1 ml). The solvent was removed under reduced pressure and the residue purified by column chromatography on silica gel eluting with a solvent gradient of dichloromethane:methanol:ammonia (95:5:0.5) increasing to (92:7:1). This gave the title compound (90 mg) as a foam. MS: 641 (MH+).
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1.[C:16]1(O)[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[CH:18][CH:17]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1.CO>[C:24]1([O:1][CH2:2][CH:3]2[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]2)[C:25]2[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:21]=[CH:22][CH:23]=1
Reactant: Oc1cccc2ccccc12
Reactant: CC(C)(C)OC(=O)N1CCC(CO)CC1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(COc2cccc3ccccc23)CC1
Reaction time: 8 h
Yield: 100.5 %

Procedure:
A solution of 5.0 g (23.2 mmol) of 1,1-dimethylethyl 4-(hydroxymethyl)-1-piperidine-carboxylate, 4.3 g (29.8 mmol) of 1-naphthalenol and 7.82 g (29.8 mmol) of triphenylphosphine in 120 ml of tetrahydrofuran, cooled under nitrogen by means of an ice bath, is admixed dropwise with a solution of 6.03 g (29.8 mmol) of diisopropyl azodicarboxylate. The reaction mixture is allowed to return to ambient temperature and stirring is continued overnight. 2 ml of methanol are added and then the mixture is evaporated to dryness. The residue is taken up in 200 ml of dichloromethane and washed in succession with a 10% aqueous potassium hydrogen sulfate solution, water and a 1M aqueous solution of sodium hydroxide. The system is dried over sodium sulfate and evaporated to dryness. The product is purified by chromatography on silica gel, eluting with an 80/20 then 70/30 and 50/50 mixture of cyclohexane and dichloromethane, to give 7.96 g of product in oil form, which solidifies.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][C:5]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])([C:21]([O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22])[C@H:6]([C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12])[CH2:7][CH:8]([CH3:10])[CH3:9].[C:38](OC(=O)C)(=[O:40])[CH3:39]>N1C=CC=CC=1>[C:38]([O:1][CH2:2][CH2:3][CH2:4][C:5]([C:31]([O:33][C:34]([CH3:35])([CH3:37])[CH3:36])=[O:32])([C:21]([O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22])[C@H:6]([C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12])[CH2:7][CH:8]([CH3:9])[CH3:10])(=[O:40])[CH3:39]
Reactant: CC(C)C[C@@H](C(=O)OCc1ccccc1)C(CCCO)(C(=O)OCc1ccccc1)C(=O)OC(C)(C)C
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)OCCCC(C(=O)OCc1ccccc1)(C(=O)OC(C)(C)C)[C@@H](CC(C)C)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 99.9 %

Procedure:
A solution of 1.069 g of 1,2-dibenzyl 1-tert.butyl 1-(3-hydroxypropyl)-4-methyl-1,1,2(R)-pentanetricarboxylate in 10 ml of pyridine at 0° was treated with 0.643 g of acetic anhydride. The mixture was stirred at room temperature for 20 hours and evaporated. The residue was dissolved in ethyl acetate and the solution was washed with 1M hydrochloric acid and with saturated aqueous sodium hydroxide and dried over anhydrous magnesium sulfate. The solvent was removed by evaporation and there were obtained 1.155 g of 1,2-dibenzyl 1-tert.butyl 1-(3-acetoxypropyl)-4-methyl-1,1,2(R)-pentanetricarboxylate in the form of an oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:40])[C@H:4]([NH:20][C:21]([C:23]1[CH:24]=[C:25]([C:30]2[CH:35]=[CH:34][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:32][CH:31]=2)[CH:26]=[CH:27][C:28]=1[NH2:29])=[O:22])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[C:14]([Cl:19])[CH:13]=2)=[CH:8][CH:7]=1.[C:41](Cl)(=[O:45])[CH:42]([CH3:44])[CH3:43]>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:40])[C@H:4]([NH:20][C:21]([C:23]1[CH:24]=[C:25]([C:30]2[CH:31]=[CH:32][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:34][CH:35]=2)[CH:26]=[CH:27][C:28]=1[NH:29][C:41](=[O:45])[CH:42]([CH3:44])[CH3:43])=[O:22])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[C:14]([Cl:19])[CH:13]=2)=[CH:8][CH:7]=1
Reactant: CC(C)C(=O)Cl
Reactant: COC(=O)[C@@H](Cc1ccc(-c2ccc(F)c(Cl)c2)cc1)NC(=O)c1cc(-c2ccc(C(F)(F)F)cc2)ccc1N
Solvent: ClCCl
Product: COC(=O)[C@@H](Cc1ccc(-c2ccc(F)c(Cl)c2)cc1)NC(=O)c1cc(-c2ccc(C(F)(F)F)cc2)ccc1NC(=O)C(C)C
Yield: 84.7 %

Procedure:
To 20 mg (0.035 mmol) of 2(R)-[(4-amino-4′-trifluoromethyl-biphenyl-3-carbonyl)-amino]-3-(3′-chloro-4′-fluoro-biphenyl-4-yl)-propionic acid methyl ester in 1 mL of DCM was added 12 mg (0.11 mmol) of isobutyryl chloride following general procedure M to give the title compound (19 mg).
Reaction SMILES: CS(O[C@@:6]1([CH3:44])[CH2:10][C@H:9]([S:11][C:12]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:8][N:7]1[C:31]([O:33][CH2:34][C:35]1[CH:40]=[CH:39][C:38]([N+:41]([O-:43])=[O:42])=[CH:37][CH:36]=1)=[O:32])(=O)=O.[OH:45][CH2:46][C@@H:47]1[CH2:51][CH2:50][CH2:49][NH:48]1.C(N(CC)CC)C>CN(C)C=O>[OH:45][CH2:46][C@@H:47]1[CH2:51][CH2:50][CH2:49][N:48]1[CH2:44][C@@H:6]1[CH2:10][C@H:9]([S:11][C:12]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH2:8][N:7]1[C:31]([O:33][CH2:34][C:35]1[CH:40]=[CH:39][C:38]([N+:41]([O-:43])=[O:42])=[CH:37][CH:36]=1)=[O:32]
Reactant: C[C@]1(OS(C)(=O)=O)C[C@H](SC(c2ccccc2)(c2ccccc2)c2ccccc2)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1
Reactant: OC[C@@H]1CCCN1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(OCc1ccc([N+](=O)[O-])cc1)N1C[C@@H](SC(c2ccccc2)(c2ccccc2)c2ccccc2)C[C@H]1CN1CCC[C@H]1CO
Temperature: 100 °C
Reaction time: 5 h
Yield: 65.1 %

Procedure:
To a solution of (2S,4S)-2-(methanesulfonyloxy)-methyl-1-(4-nitrobenzyloxycarbonyl)-4-(triphenylmethylthio)pyrrolidine (8.76 g) in dimethylformamide (80 ml) were added (2S)-2-(hydroxymethyl)pyrrolidine (8.72 g) and triethylamine (3.86 ml) and the mixture was stirred at 100° C. for 5 hours. The reaction mixture was poured into ice-water (300 ml) and extracted twice with ethyl acetate (200 ml). The extract was washed with saturated aqueous sodium chloride, dried over magnesium sulfate and evaporated in vacuo. The resulting residue was chromatographed on silica gel (150 g) eluting with a mixture of dichloromethane and acetone (2:1, V/V). The fractions containing the desired compound were collected and evaporated in vacuo to give (2S,4S)-2-[(2S)-2-(hydroxymethyl)pyrrolidin-1-yl]methyl-1-(4-nitrobenzyloxycarbonyl)-4-(triphenylmethylthio)pyrrolidine (5.75 g).
Reaction SMILES: Cl.[C:2]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][CH:9]=[C:8]2[CH2:14][CH2:15][CH2:16][CH2:17][N:18]1[CH2:23][CH2:22][CH:21]([C:24]2[C:32]3[C:27](=[CH:28][CH:29]=[C:30]([F:33])[CH:31]=3)[NH:26][CH:25]=2)[CH2:20][CH2:19]1)([OH:4])=[O:3].[CH3:34]O>>[CH3:34][O:3][C:2]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][CH:9]=[C:8]2[CH2:14][CH2:15][CH2:16][CH2:17][N:18]1[CH2:23][CH2:22][CH:21]([C:24]2[C:32]3[C:27](=[CH:28][CH:29]=[C:30]([F:33])[CH:31]=3)[NH:26][CH:25]=2)[CH2:20][CH2:19]1)=[O:4]
Reactant: O=C(O)c1ccc2[nH]cc(CCCCN3CCC(c4c[nH]c5ccc(F)cc45)CC3)c2c1
Reactant: CO
Agent: Cl
Product: COC(=O)c1ccc2[nH]cc(CCCCN3CCC(c4c[nH]c5ccc(F)cc45)CC3)c2c1

Procedure:
HCl gas is passed into a boiling solution of 2.5 g of 3-[1-(4-(5-carboxyindol-3-yl)butyl)-4-piperidyl]-5-fluoroindole in 50 ml of absolute methanol for hours. The mixture is then boiled for a further hour, is worked up in a conventional manner and gives 3-[1-(4-(5-methoxycarbonylindol-3-yl)butyl)-4-piperidyl]-5-fluoroindole.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][C:5]2([C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[NH:9][CH2:8]2)[CH2:4][CH2:3]1.CCN(CC)CC.Cl[C:24]([O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:25]>C(Cl)Cl>[CH2:27]([O:26][C:24]([N:9]1[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:5]2([CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH2:6]2)[CH2:8]1)=[O:25])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: CN1CCC2(CC1)CNc1ccccc12
Reactant: O=C(Cl)OCc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN1CCC2(CC1)CN(C(=O)OCc1ccccc1)c1ccccc12
Reaction time: 2 h
Yield: 71.1 %

Procedure:
A solution of 99 g (489 mmol) of 1'-methylspiro(indoline-3,4'-piperidine) (prepared according to Ong, H. H. et al, J. Med. Chem., 1983, 26, 981-986) in 1 L of CH2Cl2 and 82 mL (539 mmol) of Et3N was cooled to 0-5° C. with an ice bath and 77 mL (539 mmol) of benzyl chloroformate was added over 30 min keeping the reaction temperature below 10° C. After stirring for 2 h 19 mL (136 mmol) of Et3N and 15 mL (105 mmol) of benzyl chloroformate were added since the reaction was incomplete and stirred for 2 h. At this time, additional 19 mL (136 mmol) of Et3N and 15 mL (105 mmol) of benzyl chloroformate were added. After 1 h, when a TLC indicated a complete reaction, the solution was concentrated in vacuo and the residue was partitioned between ether and saturated NaHCO3. The layers were separated, the organic layer was washed with saturated NaHCO3 and brine, and dried over MgSO4. The filtrate was concentrated and the residue was chromatographed on 2 kg of silica gel using 1-5% MeOH/CH2Cl2 to obtain 117 g (71%) of 1-benzyloxycarbonyl-1'-methylspiro(indoline-3,4'-piperidine) as a yellow oil.
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[NH:7][C:8]1[C:12]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[C:15]=2[Cl:21])=[C:11]([OH:22])[NH:10][N:9]=1)([CH3:4])([CH3:3])[CH3:2].[C:24]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CO.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[C:1]([O:5][C:6](=[O:23])[NH:7][C:8]1[C:12]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[C:15]=2[Cl:21])=[C:11]([OH:22])[N:10]([CH3:24])[N:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1n[nH]c(O)c1Cc1cccc(Cl)c1Cl
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Solvent: CO
Solvent: C1CCOC1
Product: Cn1nc(NC(=O)OC(C)(C)C)c(Cc2cccc(Cl)c2Cl)c1O
Yield: 30 %

Procedure:
To a solution of tert-butyl(4-(2,3-dichlorobenzyl)-5-hydroxy-1H-pyrazol-3-yl)carbamate (160 mg, 0.447 mmol), triphenylphosphine (128 mg, 0.491 mol) and methanol (16 mg, 0.491 mol) in anhydrous THF (25 mL), a solution of DIAD (99 mg, 0.491 mmol) in anhydrous THF (2 mL) was added dropwise at 0° C. with stirring. The reaction mixture was stirred at room temperature for 1 h. The reaction mixture was concentrated. The resulting residue was purified by silica gel chromatography eluted with PE:EA=2:1 to provide the titled compound (50 mg, 30%), as a white solid; LC/MS: MS (ES+) m/e 372 (MH+); 1H NMR (300 MHz, DMSO-d6) δ ppm 1.56 (s, 9H), 3.05 (s, 3H), 3.52 (s, 2H), 7.00 (d, J=7.8 Hz, 1H), 7.11 (s, 2H), 7.25 (t, J=7.8 Hz, 1H), 7.46 (d, J=7.8 Hz, 1H).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[C:9]([N:10]=1)=[CH:8][CH:7]=[C:6]([O:11][C:12]1[CH:13]=[C:14]([NH:19][C:20](=[O:32])[C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[C:22]=3[Cl:31])[CH:15]=[CH:16][C:17]=1[CH3:18])[N:5]=2.[CH:33]1([C:36](Cl)=[O:37])[CH2:35][CH2:34]1>N1C=CC=CC=1.C(OCC)(=O)C>[Cl:31][C:22]1[C:23]([C:27]([F:29])([F:28])[F:30])=[CH:24][CH:25]=[CH:26][C:21]=1[C:20]([NH:19][C:14]1[CH:15]=[CH:16][C:17]([CH3:18])=[C:12]([O:11][C:6]2[N:5]=[C:4]3[S:3][C:2]([NH:1][C:36]([CH:33]4[CH2:35][CH2:34]4)=[O:37])=[N:10][C:9]3=[CH:8][CH:7]=2)[CH:13]=1)=[O:32]
Reactant: Cc1ccc(NC(=O)c2cccc(C(F)(F)F)c2Cl)cc1Oc1ccc2nc(N)sc2n1
Reactant: O=C(Cl)C1CC1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: Cc1ccc(NC(=O)c2cccc(C(F)(F)F)c2Cl)cc1Oc1ccc2nc(NC(=O)C3CC3)sc2n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 50.4 %

Procedure:
To a solution of N-{3-[(2-amino[1,3]thiazolo[5,4-b]pyridin-5-yl)oxy]-4-methylphenyl}-2-chloro-3-(trifluoromethyl)benzamide (200 mg, 0.417 mmol) in pyridine (5 mL) was added cyclopropanecarbonyl chloride (57.4 μL, 0.835 mmol), and the mixture was stirred at room temperature for 18 hr. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous magnesium sulfate. The residue was filtered through a pad filled with silica gel, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate/hexane=10/90→70/30), and recrystallized from tetrahydrofuran to give the title compound (115 mg, 50%) as white crystals.
Reaction SMILES: [NH2:1][C@@:2]([C:6]1[S:7][C:8]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])=[C:13]([C:26]([F:29])([F:28])[F:27])[CH:12]=2)=[CH:9][N:10]=1)([CH3:5])[CH2:3][OH:4].[P:30](Cl)([O:35]CC)([O:32]CC)=[O:31].C(N(CC)CC)C.Br[Si](C)(C)C>C(Cl)Cl>[P:30]([OH:35])([OH:32])([O:4][CH2:3][C@:2]([NH2:1])([C:6]1[S:7][C:8]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])=[C:13]([C:26]([F:28])([F:29])[F:27])[CH:12]=2)=[CH:9][N:10]=1)[CH3:5])=[O:31]
Reactant: CCCCCCCCOc1ccc(-c2cnc([C@@](C)(N)CO)s2)cc1C(F)(F)F
Reactant: CCOP(=O)(Cl)OCC
Agent: C[Si](C)(C)Br
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCCCCOc1ccc(-c2cnc([C@@](C)(N)COP(=O)(O)O)s2)cc1C(F)(F)F

Procedure:
E1 (25 mg, 1.0 equiv), DCM (5 mL), diethyl chlorophosphate (85 μL, 10.0 equiv) and triethylamine (165 μL, 20.0 equiv) were stirred overnight. The obtained phospho-diester intermediate was reacted with excess bromotrimethylsilane in DCM for 5 hrs. The resulting phosphate was purified by preparative HPLC as the trifluoroacetate salt (10 mg). MS (ESI, M+H+)=511.1.
Reaction SMILES: COC[C@H](C)O[C:6]1[CH:7]=[C:8]([CH:12]=[C:13](O[C@@H](C)CC2C=CC=CC=2)[CH:14]=1)[C:9]([OH:11])=O.[N:26]1[CH:31]=[CH:30][C:29]([CH2:32][N:33]2[CH:37]=[CH:36][C:35]([NH2:38])=[N:34]2)=[CH:28][CH:27]=1>S(Cl)(Cl)=O>[N:26]1[CH:31]=[CH:30][C:29]([CH2:32][N:33]2[CH:37]=[CH:36][C:35]([NH:38][C:9](=[O:11])[C:8]3[CH:7]=[CH:6][CH:14]=[CH:13][CH:12]=3)=[N:34]2)=[CH:28][CH:27]=1
Reactant: Nc1ccn(Cc2ccncc2)n1
Reactant: COC[C@H](C)Oc1cc(O[C@@H](C)Cc2ccccc2)cc(C(=O)O)c1
Solvent: O=S(Cl)Cl
Product: O=C(Nc1ccn(Cc2ccncc2)n1)c1ccccc1
Temperature: 70 °C
Reaction time: 96 h
Yield: 17 %

Procedure:
3-((S)-2-Methoxy-1-methyl-ethoxy)-5-((S)-1-methyl-2-phenyl-ethoxy)-benzoic acid (0.58 mmol) is dissolved in thionylchloride (1.1 ml) and heated to 70° C. for 1 hour. After cooling to RT, the solvent is removed in vacuo. The residue is dissolved in dichloromethane (1.2 ml) and ethyldiisopropylamine (150 μl) is added and 1-pyridine-4-ylmethyl-1H-pyrazole-3-ylamine (1.2 eq.) is added. The suspension is stirred 4 days at room temperature. The reaction solution is extracted with water. The organic layer is washed with water and brine and dried over MgSO4 and the solvent is removed in vacuo. 3-(S)-2-Methoxy-1-methyl-ethoxy)-5-(S)-1-methyl-2-phenyl-ethoxy)-N-(1-pyridine-4-ylmethyl-1H-pyrazole-3-yl)-benzamide (“A8”) is isolated after column chromatography as colorless oil in a yield of 17%; HPLC (method B): 3.17 min; LC-MS (method B): 1.98 min, 501.3 (M+H+);
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:10]([O:11]C(=O)C)[C@H:9]([O:15]C(=O)C)[C@@H:8]([CH2:19][O:20]C(=O)C)[O:7][C@H:6]1[C:24]1[CH:29]=[CH:28][C:27]([CH3:30])=[C:26]([CH2:31][C:32]2[S:33][C:34](Br)=[CH:35][CH:36]=2)[CH:25]=1)(=O)C.C([Sn](CCCC)(CCCC)[C:43]1[S:44][CH:45]=[CH:46][N:47]=1)CCC>>[C@@H:6]1([C:24]2[CH:29]=[CH:28][C:27]([CH3:30])=[C:26]([CH2:31][C:32]3[S:33][C:34]([C:43]4[S:44][CH:45]=[CH:46][N:47]=4)=[CH:35][CH:36]=3)[CH:25]=2)[O:7][C@H:8]([CH2:19][OH:20])[C@@H:9]([OH:15])[C@H:10]([OH:11])[C@H:5]1[OH:4]
Reactant: CC(=O)OC[C@H]1O[C@@H](c2ccc(C)c(Cc3ccc(Br)s3)c2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: CCCC[Sn](CCCC)(CCCC)c1nccs1
Product: Cc1ccc([C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)cc1Cc1ccc(-c2nccs2)s1

Procedure:
1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-3-(5-bromo-2-thienylmethyl)-4-methylbenzene obtained in Example 159-(1) and tri-n-butyl(2-thiazolyl)tin were treated in a manner similar to Example 128-(5) and (6) to give the target compound. APCI-Mass m/Z 434 (M+H).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:27]=[C:28]([CH3:30])[N:29]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][CH2:19][CH2:20][N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)=[CH:10][CH:9]=1)=[O:6].[CH3:31][CH:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1>>[N:21]1([CH2:20][CH2:19][O:18][C:11]2[C:12]3[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:8]([NH:7][C:5]([C:4]3[CH:27]=[C:28]([CH3:30])[N:29]=[C:2]([N:35]4[CH2:36][CH2:37][CH:32]([CH3:31])[CH2:33][CH2:34]4)[CH:3]=3)=[O:6])=[CH:9][CH:10]=2)[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1
Reactant: CC1CCNCC1
Reactant: Cc1cc(C(=O)Nc2ccc(OCCN3CCOCC3)c3ccccc23)cc(Cl)n1
Product: Cc1cc(C(=O)Nc2ccc(OCCN3CCOCC3)c3ccccc23)cc(N2CCC(C)CC2)n1

Procedure:
Compound is formed by reacting 2-chloro-6-methyl-N-[4-(2-morpholin-4-yl-ethoxy)-naphthalen-1-yl]-isonicotinamide with 4-methylpiperidine under conditions described in general procedure A. 1H NMR (300 MHz, DMSO-d6) δ 10.28 (s, 1H), 8.22 (m, 1H), 7.85 (m, 1H), 7.57 (m, 2H), 7.34 (d, 1H), 7.18 (s, 1H), 7.04 (m, 2H), 4.41 (d, 2H), 4.31 (t, 2H), 3.60 (t, 4H), 2.90-2.78 (m, 7H), 2.56 (t, 4H), 1.67 (m, 4H), 1.13 (m, 1H), 0.95-0.86 (m, 3H). MS: 489.2 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([N+:23]([O-])=O)=[CH:5][C:6]([CH3:22])=[C:7]([N:9]2[CH2:14][CH2:13][CH:12]([N:15]3[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]3)[CH2:11][CH2:10]2)[CH:8]=1>[Pd].CO>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([N:9]2[CH2:14][CH2:13][CH:12]([N:15]3[CH2:16][CH2:17][N:18]([CH3:21])[CH2:19][CH2:20]3)[CH2:11][CH2:10]2)[C:6]([CH3:22])=[CH:5][C:4]=1[NH2:23]
Reactant: COc1cc(N2CCC(N3CCN(C)CC3)CC2)c(C)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Product: COc1cc(N2CCC(N3CCN(C)CC3)CC2)c(C)cc1N
Temperature: 25 °C
Reaction time: 15 h

Procedure:
Palladium on carbon (10% Degussa Type) (100 mg, 0.94 mmol) was added to a stirring solution of 1-(1-(5-methoxy-2-methyl-4-nitrophenyl)piperidin-4-yl)-4-methylpiperazine (INTERMEDIATE 12, 697 mg, 2.00 mmol) in methanol (10 mL). The reaction mixture was then stirred under hydrogen (1 atm) at RT for 15 h. The reaction mixture was filtered through Celite® and the filtrate was concentrated in vacuo to give the title product which was used in the next step without further purification (566 mg, 66.1%). m/z 319.
Reaction SMILES: Cl.[F:2][C:3]([F:24])([F:23])[C:4]1[CH:22]=[CH:21][CH:20]=[CH:19][C:5]=1[CH:6]([O:14][CH:15]1[CH2:18][NH:17][CH2:16]1)[C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=1.[N-:25]=[C:26]=[O:27]>>[F:24][C:3]([F:2])([F:23])[C:4]1[CH:22]=[CH:21][CH:20]=[CH:19][C:5]=1[CH:6]([O:14][CH:15]1[CH2:18][N:17]([C:26]([NH:25][C@@H:6]([CH3:7])[C:5]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:4]=2)=[O:27])[CH2:16]1)[C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=1
Reactant: FC(F)(F)c1ccccc1C(OC1CNC1)c1ccc(Cl)cc1
Reactant: [N-]=C=O
Agent: Cl
Product: C[C@H](NC(=O)N1CC(OC(c2ccc(Cl)cc2)c2ccccc2C(F)(F)F)C1)c1ccccc1

Procedure:
This material was prepared from 3-[2-(trifluoromethyl)-4′-chlorobenzhydryloxy]azetidine hydrochloride (98) and the corresponding isocyanate using the procedure described for compound (10).
Reaction SMILES: [C:1]1([S:7]([C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:17]3[C:18]4[CH:26]=[C:25](Cl)[N:24]=[CH:23][C:19]=4[N:20]=[CH:21][N:22]=3)=[CH:12][CH:11]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[O:28]1[CH2:32][CH2:31][O:30][CH:29]1[C:33]1[O:37][C:36]([Sn](CCCC)(CCCC)CCCC)=[CH:35][CH:34]=1>O1CCOCC1>[C:1]1([S:7]([C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:17]3[C:18]4[CH:26]=[C:25]([C:36]5[O:37][C:33]([CH:29]6[O:30][CH2:31][CH2:32][O:28]6)=[CH:34][CH:35]=5)[N:24]=[CH:23][C:19]=4[N:20]=[CH:21][N:22]=3)=[CH:12][CH:11]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccc(C2OCCO2)o1
Reactant: O=S(=O)(c1ccccc1)c1ccc(Nc2ncnc3cnc(Cl)cc23)cc1
Solvent: C1COCCO1
Product: O=S(=O)(c1ccccc1)c1ccc(Nc2ncnc3cnc(-c4ccc(C5OCCO5)o4)cc23)cc1
Yield: 56 %

Procedure:
(4-Benzenesulphonyl-phenyl)-(6-chloro-pyrido[3,4-d]pyrimidin-4-yl)-amine (3.67 g) and 5-(1,3-dioxolan-2-yl)-2-(tributylstannyl)-furan (6.9 g) were reacted together in dioxan (100 ml) as in Procedure B. Purification by column chromatography gave a cream solid (2.59 g); [2H6]DMSO 10.6 (1H, s) 9.26 (1H, s) 8.82 (1H, s) 8.78 (1H, s) 8.25 (2H, d) 8.0-8.3 (4H, d+m) 7.65-7.8 (3H, m) 7.21 (1H, d) 6.82 (1H, d) 6.09 (1H, s) 4.0-4.2 (4H, m); m/z 501 (M+1)+.
Reaction SMILES: [CH3:1][N:2]([CH3:14])[C:3]1[CH:13]=[CH:12][CH:11]=[C:5]2[C:6]([O:8][C:9](=[O:10])[C:4]=12)=O.Cl.[NH2:16][CH:17]1[CH2:22][CH2:21][C:20](=[O:23])[NH:19][C:18]1=[O:24].C([O-])(=O)C.[Na+]>C(O)(=O)C>[CH3:14][N:2]([CH3:1])[C:3]1[CH:13]=[CH:12][CH:11]=[C:5]2[C:4]=1[C:9](=[O:10])[N:16]([CH:17]1[CH2:22][CH2:21][C:20](=[O:23])[NH:19][C:18]1=[O:24])[C:6]2=[O:8]
Reactant: NC1CCC(=O)NC1=O
Reactant: CN(C)c1cccc2c1C(=O)OC2=O
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Product: CN(C)c1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O

Procedure:
4-Dimethylamino-2-(2,6-dioxo(3-piperidyl))isoindoline-1,3-dione was prepared by the procedure of Example 1 from 3-dimethylaminophthalic anhydride (1.34 g, 7.0 mmol), 3-aminopiperidine-2,6-dione hydrogen chloride (1.15 g, 7.0 mmol) and sodium acetate (0.60 g, 7.3 mmol) in acetic acid (20 mL). The product was a yellow solid (1.59 g, 75% yield); mp, 214.5-216.5° C.; 1H NMR (DMSO-d6) δ1.98-2.09 (m, 1H, CHH), 2.49-2.62 (m, 2H, CH2), 2.81-2.95 (m, 1H, CHH), 3.04 (s, 6H, CH3), 5.08 (dd, J=5.5, 12.7 Hz, 1H, NCH), 7.23 (d, J=6.6 Hz, 1H, Ar), 7.26 (d, J=8.1 Hz, 1H, Ar), 7.63 (dd, J=6.9, 8.6 Hz, 1H, Ar), 11.09 (br s, 1H, NH); 13C NMR (DMSO-d6) δ22.10, 30.96, 42.95, 48.77, 112.99, 113.41, 122.59, 133.90, 135.22, 149.88, 166.29, 167.13, 170.06, 172.83; Anal Calcd for C15H15N3O4: C, 59.80; H, 5.02; N, 13.95. Found: C, 59.60; H, 4.94; N, 13.80.
Reaction SMILES: C(N(CC)CC)C.[CH2:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9]1.[N+:17]([C:20]1[CH:25]=[CH:24][C:23](I)=[CH:22][CH:21]=1)([O-:19])=[O:18]>CC([O-])=O.CC([O-])=O.[Pd+2].C(O)C>[N+:17]([C:20]1[CH:25]=[CH:24][C:23]([C:9]2[CH2:10][C:11]3[C:16]([CH:8]=2)=[CH:15][CH:14]=[CH:13][CH:12]=3)=[CH:22][CH:21]=1)([O-:19])=[O:18]
Reactant: O=[N+]([O-])c1ccc(I)cc1
Reactant: C1=Cc2ccccc2C1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CCO
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1ccc(C2=Cc3ccccc3C2)cc1
Temperature: 25 °C
Yield: 40.9 %

Procedure:
20 ml of triethylamine, 2.2 g (20 mmole) of indene, 4.98 g (20 mmole) of para-nitro iodo-benzene and 0.134 g (0.6 mmole) of Pd(OAc)2 were stirred under reflux for 10 h. After that the mixture was cooled to room temperature and treated with 100 ml of ethanol. The crystalline yellow precipitate was isolated, recrystallized from ethanol, washed with cold ethanol and dried under vacuum to obtain 1.94 g (41%) of 2-(4-nitro-phenyl)-indene.