Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][C:5]([C:7]1[N:15]=[C:14]2[C:10]([N:11]=[CH:12][N:13]2[C@H:16]2[C@H:20]([OH:21])[C@H:19]([OH:22])[C@@H:18]([CH2:23][OH:24])[O:17]2)=[C:9]([NH:25][CH2:26][CH:27]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[N:8]=1)=[O:6].[N:40]1([C:45](N)=[O:46])[CH:44]=[CH:43][N:42]=[CH:41]1>C1(C)C=CC=CC=1.C(O)(C)C>[OH:21][C@@H:20]1[C@H:19]([OH:22])[C@@H:18]([CH2:23][OH:24])[O:17][C@H:16]1[N:13]1[CH:12]=[N:11][C:10]2[C:14]1=[N:15][C:7]([C:5]([NH:4][CH2:3][CH2:2][NH:1][C:45]([NH:40][CH2:44][CH2:43][N:42]1[CH2:20][CH2:19][CH2:18][CH2:23][CH2:41]1)=[O:46])=[O:6])=[N:8][C:9]=2[NH:25][CH2:26][CH:27]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: NC(=O)n1ccnc1
Reactant: NCCNC(=O)c1nc(NCC(c2ccccc2)c2ccccc2)c2ncn([C@@H]3O[C@H](CO)[C@@H](O)[C@H]3O)c2n1
Solvent: CC(C)O
Solvent: Cc1ccccc1
Product: O=C(NCCNC(=O)c1nc(NCC(c2ccccc2)c2ccccc2)c2ncn([C@@H]3O[C@H](CO)[C@@H](O)[C@H]3O)c2n1)NCCN1CCCCC1
Yield: 145.4 %

Procedure:
N-(2-Aminoethyl)-9-[(2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydro-2-furanyl]-6-[(2,2-diphenylethyl)amino]-9H-purine-2-carboxamide (Preparation 17) (90 mg, 0.17 mmol) and N-[2-1-piperidinyl)ethyl]-1H-imidazole-1-carboxamide (Preparation 18) (40 mg, 0.18 mmol) were dissolved in a mixture of toluene (4 ml) and isopropanol (1 ml) and the solution heated under reflux for four hours. The solvent was removed under reduced pressure and the residue purified by column chromatography on silica gel eluting with dichloromethane:methanol:concentrated aqueous ammonia (85:15:1.5, by volume). Product containing fractions were evaporated and the resulting solid triturated with diethyl ether, filtered and dried to afford the title compound as a white powder (85 mg).
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[O:8][CH2:7][CH2:6][N:5]([C:9]2[S:10][C:11]3[C:17](=[O:18])[CH2:16][C:15]([CH3:20])([CH3:19])[CH2:14][C:12]=3[N:13]=2)[CH2:4]1.N1C=CC=CC=1.[C:27]1([S:33](Cl)(=[O:35])=[O:34])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>C(Cl)Cl>[CH3:19][C:15]1([CH3:20])[CH2:14][C:12]2[N:13]=[C:9]([N:5]3[CH2:6][CH2:7][O:8][CH:3]([CH2:2][NH:1][S:33]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)(=[O:35])=[O:34])[CH2:4]3)[S:10][C:11]=2[C:17](=[O:18])[CH2:16]1
Reactant: CC1(C)CC(=O)c2sc(N3CCOC(CN)C3)nc2C1
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC1(C)CC(=O)c2sc(N3CCOC(CNS(=O)(=O)c4ccccc4)C3)nc2C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 20.3 %

Procedure:
To a stirred solution of Example 154 (0.10 g, 0.34 mmol) and pyridine (0.04 g, 0.51 mmol) in DCM (10 mL) was added benzenesulphonyl chloride (0.06 g, 0.34 mmol) and the reaction mixture was stirred at room temperature for 4 h. The solvent was then removed in vacuo and purification by preparative HPLC gave the title compound (0.03 g, 20%) as a white solid. δH (CDCl3) 7.90 (2H, dd, J 6.9 and 1.5 Hz), 7.60 (3H, m), 4.87 (1H, t, J 6.0 Hz), 4.00 (2H, m), 3.75 (1H, m), 3.60 (2H, m), 3.20 (2H, m), 3.00 (2H, m), 2.70 (2H, s), 2.40 (2H, s), 1.10 (6H, s). LCMS (ES+) 436.0 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[CH:9][CH:10]=[C:6]2[N:5]=[C:4]([CH2:11][CH3:12])[CH:3]=1.NC(N)=[S:15]>C(O)C>[CH2:11]([C:4]1[CH:3]=[C:2]([SH:15])[N:7]2[N:8]=[CH:9][CH:10]=[C:6]2[N:5]=1)[CH3:12]
Reactant: NC(N)=S
Reactant: CCc1cc(Cl)n2nccc2n1
Solvent: CCO
Product: CCc1cc(S)n2nccc2n1

Procedure:
5.0 g (27.5 mmol) of the chloride from Example 1, Step B and 4.2 g (55.2 mmol) thiourea were heated in 100 ml dry ethanol for 5 h. The solvent was distilled off in vacuo and the residue crystallized from ethanol / water to give the title compound in yellow crystals, m.p. 178°-180° C.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[C:9]([CH:13]=[CH:14][N:15]=2)[C:10]([OH:12])=[O:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:16]1C=CC=CC=1.CO.C[Si](C=[N+]=[N-])(C)C>CCCCCC>[C:1]1([C:7]2[CH:8]=[C:9]([CH:13]=[CH:14][N:15]=2)[C:10]([O:12][CH3:16])=[O:11])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: c1ccccc1
Reactant: O=C(O)c1ccnc(-c2ccccc2)c1
Agent: C[Si](C)(C)C=[N+]=[N-]
Solvent: CCCCCC
Solvent: CO
Product: COC(=O)c1ccnc(-c2ccccc2)c1
Reaction time: 6 h

Procedure:
Preparation H1, Step 2: A solution of 2-phenylisonicotinic acid (459 mg, 2.30 mmol) in 9:1 benzene/methanol (20 mL) was cooled to 0° C., and treated with the dropwise addition of a 2.0 M hexane solution of (trimethylsilyl)diazomethane (1.15 mL, 2.30 mmol). The mixture was allowed to come to room temperature and stirred for 6 h. Analysis by TLC indicated incomplete reaction, so the mixture was treated with additional (trimethylsilyl)diazomethane solution (230 μL, 0.23 mmol), and the reaction was stirred for an additional 2 h. TLC of the mixture remained unchanged. The solvent was stripped, and the residue was partitioned between ethyl acetate and saturated sodium bicarbonate. The layers were separated, the organic phase was washed 2× with saturated sodium bicarbonate, the combined aqueous phases were extracted with ethyl acetate, and the combined organic phases were washed with brine, dried over sodium sulfate, and concentrated in vacuo. The residue was purified over silica gel, eluting with 20% ethyl acetate/heptane, to yield 372 mg of methyl 2-phenylisonicotinate as a colorless oil. 1H NMR (400 MHz, CDCl3) δ ppm 8.83 (d, J=5.27 Hz, 1H), 8.29 (s, 1H), 8.04 (d, J=7.03 Hz, 2H), 7.77 (d, J=3.52 Hz, 1H), 7.51-7.42 (m, 3H), 3.98 (s, 3H).
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:5].C([O-])(=O)C.[K+].[C-:17]#[N:18].[Na+]>C(O)C.O>[O:5]=[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH2:3][CH2:2][C:17]#[N:18]
Reactant: [C-]#N
Reactant: O=C(CCCl)c1ccccc1
Agent: CC(=O)[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: N#CCCC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 72.3 %

Procedure:
To a solution of 3-chloro-1-phenylpropan-1-one (5.0 g, 29.7 mmol) in hot ethanol (7 mL) was added potassium acetate (2.91 g, 29.77 mmol). After cooling to room temperature, the precipitated salt was removed via filtration. To the filtrate in a septum-sealed flask under a nitrogen bubbler was slowly added sodium cyanide (2.91 g, 59.3 mmol) as a solution in water (10 mL). After stirring at room temperature for 24 hours, ethanol (30 mL) was added, and the mixture was cooled in an ice bath. The precipitate was filtered and rinsed with ethanol to provide the product (3.42 g, 73%) as fluffy white solid.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6](=[O:17])[S:7][C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][C:11](Br)=[CH:10][CH:9]=2)=[O:4].[CH3:18][O:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1B(O)O>>[CH3:1][O:2][C:3]([C:5]1[C:6](=[O:17])[S:7][C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][C:11]([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[O:19][CH3:18])=[CH:10][CH:9]=2)=[O:4]
Reactant: COC(=O)c1c(O)c2cc(Br)ccc2sc1=O
Reactant: COc1ccccc1B(O)O
Product: COC(=O)c1c(O)c2cc(-c3ccccc3OC)ccc2sc1=O

Procedure:
4-Hydroxy-6-(2-methoxy-phenyl)-2-oxo-2H-thiochromene-3-carboxylic acid methyl ester was prepared from 6-bromo-4-hydroxy-2-oxo-2H-thiochromene-3-carboxylic acid methyl ester under conditions analogous to Example 7(a) using 2-methoxy-phenylboronic acid. 1H NMR (200 MHz, CDCl3): 6 (ppm)=8.481 (s, 1H), 7.803 (d, 1H), 7.627-7.789 (m, 1H), 7.42-6.92 (m, 4H), 4.022 (s, 3H), 3.82 (s, 3H).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[N:9]=[C:8]([Br:11])[N:7]([CH2:12][C:13]#[C:14][CH3:15])[C:6]=2[C:5](=[O:16])[NH:4][C:3]1=[O:17].CN(C)C(=O)C.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:31][C:32]1[N:41]=[C:40]([CH3:42])[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[N:33]=1>O>[CH3:42][C:40]1[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[N:33]=[C:32]([CH2:31][N:4]2[C:5](=[O:16])[C:6]3[N:7]([CH2:12][C:13]#[C:14][CH3:15])[C:8]([Br:11])=[N:9][C:10]=3[N:2]([CH3:1])[C:3]2=[O:17])[N:41]=1
Reactant: Cc1nc(CCl)nc2ccccc12
Reactant: CC#CCn1c(Br)nc2c1c(=O)[nH]c(=O)n2C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: CC#CCn1c(Br)nc2c1c(=O)n(Cc1nc(C)c3ccccc3n1)c(=O)n2C
Temperature: 90 °C
Reaction time: 1 h
Yield: 70.8 %

Procedure:
3-Methyl-7-(2-butyn-l-yl)-8-bromo-xanthine (10 gm) and N,N-dimethylacetamide (150 mL) were charged into a 1000 mL round bottomed flask equipped with a mechanical stirrer. Potassium carbonate (9.3 gm) and 2-(chloromethyl)-4-methylquinazoline (6.8 gm) were added to the reaction mixture at room temperature. The reaction mixture was heated to 90° C. and maintained the temperature for 8 hours. The reaction mixture was cooled to 30° C. and water (450 mL) was added and the mixture was stirred for 1 hour at 30° C. The solid formed was collected by filtration and washed with water (150 mL). The wet cake was charged into 500 mL round bottomed flask and toluene (220 mL) was added and the mixture was heated to reflux temperature and maintained for 1 hour. The mixture was cooled to 10° C. and maintained for 2 hours. The solid was collected by filtration and washed with toluene (50 mL). The solid was dried in oven under vacuum at 80° C. to get 10.8 gm of the title compound. Purity by HPLC: 99.59%
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([NH:7][C:8]2[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[CH:10][CH:9]=2)=[CH:3][CH:2]=1.[NH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1>>[N:1]1[CH:2]=[CH:3][C:4]([NH:7][C:8]2[CH:9]=[CH:10][C:11]([C:12]([N:17]3[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]3)=[O:14])=[CH:15][CH:16]=2)=[CH:5][CH:6]=1
Reactant: C1CCNCC1
Reactant: O=C(O)c1ccc(Nc2ccncc2)cc1
Product: O=C(c1ccc(Nc2ccncc2)cc1)N1CCCCC1
Yield: 49.5 %

Procedure:
1-[4-(4-Pyridinylamino)benzoyl]piperidine was prepared from 4-(4-pyridinylamino)benzoic acid and piperidine according to a procedure analogous to that of Example 48(b), and was obtained in 49.5% yield in the form of a buff powder, m.p. 170°-172° C. when recrystallized from acetonitrile.
Reaction SMILES: [C:1]1([CH:17]=[O:18])[C:14]2[C:15]3=[C:16]4[C:11](=[CH:12][CH:13]=2)[CH:10]=[CH:9][CH:8]=[C:7]4[CH:6]=[CH:5][C:4]3=[CH:3][CH:2]=1.[BH4-].[Na+].O>C(O)C>[OH:18][CH2:17][C:1]1[C:14]2[C:15]3=[C:16]4[C:11](=[CH:12][CH:13]=2)[CH:10]=[CH:9][CH:8]=[C:7]4[CH:6]=[CH:5][C:4]3=[CH:3][CH:2]=1
Reactant: O=Cc1ccc2ccc3cccc4ccc1c2c34
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: OCc1ccc2ccc3cccc4ccc1c2c34
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a suspension of pyrene carboxaldehyde (9.6 g, 42 mmol) in ethanol (50 mL) was added NaBH4 (2 g) and the mixture was stirred at room temperature for 6 hours. Water (100 mL) was added and the mixture was extracted with ether (2×50 mL). The organic layer was dried over MgSO4, and the solvent evaporated under reduced pressure to give a light-yellow solid which was recrystallized from ethyl acetate to afford prisms, m.p. 125°-126° C., yield: 8.3 g, 86%.
Reaction SMILES: [OH:1][CH2:2][C:3]([CH2:8][OH:9])([CH2:6][OH:7])[CH2:4][OH:5].[C:10]([OH:33])(=O)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31].N#N>>[C:10]([O:1][CH2:2][C:3]([CH2:8][O:9][C:10](=[O:33])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])([CH2:6][O:7][C:10](=[O:33])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[CH2:4][O:5][C:10](=[O:33])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])(=[O:33])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31]
Reactant: CCCCCCCCCCCCCCCCCCCCCC(=O)O
Reactant: OCC(CO)(CO)CO
Agent: N#N
Product: CCCCCCCCCCCCCCCCCCCCCC(=O)OCC(COC(=O)CCCCCCCCCCCCCCCCCCCCC)(COC(=O)CCCCCCCCCCCCCCCCCCCCC)COC(=O)CCCCCCCCCCCCCCCCCCCCC
Temperature: 165 °C

Procedure:
A 1000 ml round bottomed flask was charged with 648.0 g. (0.15 mol) PEG 105 pentaerythritol and 186 g. (0.60 mol) behenic acid. The mass was heated at 100° C. with a N2 sparge, 0.75 g. methane sulfonic acid and 0.1 g. hypophosphorus acid were charged. The batch was heated to 165° C. while collecting the water of reaction, and maintained until an acid value of 11.5 was reached. The finished material was a white waxy solid having an acid value of 11.5, and a hydroxyl value of 12.
Reaction SMILES: O[CH2:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[O:8])=[CH:5][CH:4]=1.[NH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C1COCC1>[N:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[NH:11][CH2:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][OH:8])=[CH:5][CH:4]=1
Reactant: Nc1ccccn1
Reactant: O=Cc1ccc(CO)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: OCc1ccc(CNc2ccccn2)cc1
Yield: 73.6 %

Procedure:
Using general procedure B: Reaction of 4-hydroxymethyl-benzaldehyde (1.01 g, 7.42 mmol), 2-aminopyridine (697 mg, 7.42 mmol), acetic acid (0.5 mL) and sodium triacetoxyborohydride (3.2 g, 14.8 mmol) in THF (20 mL) at room temperature under N2 for 40 min., then one hour at 50° C., followed by purification of crude material using chromatography on silica gel (2:2:96 CH3OH—NH3 H2O—CH2Cl2), afforded the title compound (1.17 g, 74%) as white foam.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:32]3[CH2:36][CH2:35][NH:34][CH2:33]3)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18]([C:20]4[N:21]([CH3:29])[C:22]5[C:27]([CH:28]=4)=[CH:26][CH:25]=[CH:24][CH:23]=5)=[O:19])=[C:13]([O:30][CH3:31])[CH:12]=3)[C:3]=12.[CH3:37][O:38][CH2:39][CH2:40]Br.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:32]3[CH2:36][CH2:35][N:34]([CH2:40][CH2:39][O:38][CH3:37])[CH2:33]3)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18]([C:20]4[N:21]([CH3:29])[C:22]5[C:27]([CH:28]=4)=[CH:26][CH:25]=[CH:24][CH:23]=5)=[O:19])=[C:13]([O:30][CH3:31])[CH:12]=3)[C:3]=12
Reactant: COCCBr
Reactant: COc1cc(-c2nn(C3CCNC3)c3ncnc(N)c23)ccc1NC(=O)c1cc2ccccc2n1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COCCN1CCC(n2nc(-c3ccc(NC(=O)c4cc5ccccc5n4C)c(OC)c3)c3c(N)ncnc32)C1
Temperature: 65 °C
Reaction time: 18 h
Yield: 29.3 %

Procedure:
A suspension of N2-[4-(4-amino-1-tetrahydro-1H-3-pyrrolyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-2-methoxyphenyl]-1-methyl-1H-2-indolecarboxamide (0.250 g, 0.518 mmol) in dimethylformamide (5 mL) was treated with 2-bromoethyl methyl ether (0.079 g, 0.569 mmol) and potassium carbonate (0.143 g, 1.04 mmol). The reaction mixture was stirred at 65° C. for 18 h under a nitrogen atmosphere. Water (25 mL) was added to the reaction mixture. The precipitate formed was filtered and dried on the lyophilizer. The crude material was purified by flash chromatography on silica gel using 10% methanol in dichloromethane (15 min), 15% methanol in dichloromethane (15 min), 20% methanol in dichloromethane (20 min) and 50% methanol in dichloromethane (5 min) as the eluent. The column afforded 0.082 g (29%) of pure N2-(4-{4-amino-1-[1-(2-methoxyethyl)tetrahydro-1H-3-pyrrolyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}-2-methoxyphenyl)-1-methyl-1H-2-indolecarboxamide. 1H NMR (DMSO-d6, 400 MHz) δ 9.447 (s, 1H), 8.265 (s, 1H), 8.1278-8.1075 (d, 1H, J=8.12 Hz), 7.7192-7.6993 (d, 1H, J=7.96 Hz), 7.5996-7.5799 (d, 1H, J=7.88 Hz), 7.349-7.295 (m, 4H), 7.172-7.133 (m, 1H), 5.42 (m, 1H), 4.042 (s, 3H), 3.96 (s, 3H), 3.479 (m, 2H), 3.266-3.258 (m, 3H), 2.95-2.60 (m, 4H), 2.332 (m, 2H); LCMS (Thermoquest AQA single-quad MS, Genesis C18 column, 3 μm particle size, 33×4.6 mm; 70% 50 mM ammonium acetate in water to 95% acetonitrile over 6 min, 0.8 to 0.5 mL/min) Rt 2.34 min (100%), MH+ 541.3.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH:12]2[CH2:20][C:19]3[C:14](=[CH:15][CH:16]=[C:17]([NH:21][CH2:22][C:23]([O:25]C)=[O:24])[CH:18]=3)[CH2:13]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[OH-].[Na+:28]>CO.O1CCCC1>[Na+:28].[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([NH:11][CH:12]2[CH2:20][C:19]3[C:14](=[CH:15][CH:16]=[C:17]([NH:21][CH2:22][C:23]([O-:25])=[O:24])[CH:18]=3)[CH2:13]2)(=[O:10])=[O:9])=[CH:6][CH:7]=1
Reactant: COC(=O)CNc1ccc2c(c1)CC(NS(=O)(=O)c1ccc(Cl)cc1)C2
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C([O-])CNc1ccc2c(c1)CC(NS(=O)(=O)c1ccc(Cl)cc1)C2
Temperature: 25 °C
Reaction time: 8 h
Yield: 77 %

Procedure:
Into a solution of 0.46 g of methyl N-[2-(4-chlorophenyl)sulfonylaminoindan-5-yl]glycinate dissolved in 20 ml of a mixture of methanol-tetrahydrofuran (1:1) is added 1.22 ml of an aqueous 1 N sodium hydroxide solution, and the mixture is stirred at room temperature overnight, and further at 60° C. for 3 hours. After the reaction, the solvent is evaporated, and the residue is recrystallized from an isopropyl alcohol-water mixture to give 0.37 g of N-[2-(4-chlorophenyl)sulfonylaminoindan-5-yl]glycine sodium salt as colorless crystals.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10]([O:12][CH3:13])=[O:11])=[CH:4][CH:3]=1.[H-].[Na+].Br[C:17]1[C:18]2[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][C:19]=2[S:20](=[O:30])[C:21]=1[C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=1>CN(C=O)C>[CH3:36][O:35][C:32]1[CH:33]=[CH:34][C:18]2[C:17]([O:1][C:2]3[CH:3]=[CH:4][C:5](/[CH:8]=[CH:9]/[C:10]([O:12][CH3:13])=[O:11])=[CH:6][CH:7]=3)=[C:21]([C:22]3[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=3)[S:20](=[O:30])[C:19]=2[CH:31]=1
Reactant: COC(=O)/C=C/c1ccc(O)cc1
Reactant: COc1ccc(C2=C(Br)c3ccc(OC)cc3S2=O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)/C=C/c1ccc(OC2=C(c3ccc(OC)cc3)S(=O)c3cc(OC)ccc32)cc1
Temperature: 80 °C
Yield: 97.6 %

Procedure:
To a solution of (E)-methyl 3-(4-hydroxyphenyl)acrylate (190 mg, 1.07 mmol) in DMF (5 mL) was added sodium hydride (60% suspension in oil, 42.7 mg, 1.07 mmol). The resulting mixture was allowed to stir for 10 min at room temperature after which 3-bromo-6-methoxy-2-(4-methoxyphenyl)benzo[b]thiophene 1-oxide (300 mg, 0.82 mmol) was added, as a solid. The reaction was heated to 80° C. for 18 h and upon completion was cooled to room temperature, quenched with water and diluted with DCM. The organic phase was collected (phase separator) and concentrated in vacuo to afford the crude product which was purified by column chromatography (SiO2, 0-80% EtOAc/Heptane) to afford (E)-methyl 3-(4-((6-methoxy-2-(4-methoxyphenyl)-1-oxidobenzo[b]thiophen-3-yl)oxy)phenyl)acrylate (370 mg, 0.80 mmol, 97% yield) as a yellow solid. 1H NMR (400 MHz, CDCl3) δ ppm=7.75 (d, J=9.09 Hz, 2H), 7.65 (d, J=15.66 Hz, 1H), 7.54 (d, J=2.02 Hz, 1H), 7.43-7.52 (m, J=9.09 Hz, 2H), 7.07-7.16 (m, J=8.59 Hz, 2H), 6.98-7.07 (m, 1H), 6.93 (d, J=9.09 Hz, 3H), 6.35 (d, J=16.17 Hz, 1H), 3.91 (s, 3H), 3.82 (d, J=1.52 Hz, 6H). LC/MS (m/z, MH+): 463.4.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.Cl[C:12]1[N:20]=[C:19]2[C:15]([N:16]=[C:17]([CH2:22][N:23]3[CH2:28][CH2:27][N:26]([CH:29]([CH:32]([CH3:34])[CH3:33])[CH2:30][OH:31])[CH2:25][CH2:24]3)[N:18]2[CH3:21])=[C:14]([N:35]2[CH2:40][CH2:39][O:38][CH2:37][CH2:36]2)[N:13]=1>>[CH3:33][CH:32]([CH3:34])[C@H:29]([N:26]1[CH2:25][CH2:24][N:23]([CH2:22][C:17]2[N:18]([CH3:21])[C:19]3[C:15]([N:16]=2)=[C:14]([N:35]2[CH2:36][CH2:37][O:38][CH2:39][CH2:40]2)[N:13]=[C:12]([N:3]2[C:4]4[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=4[N:6]=[C:2]2[CH3:1])[N:20]=3)[CH2:28][CH2:27]1)[CH2:30][OH:31]
Reactant: CC(C)C(CO)N1CCN(Cc2nc3c(N4CCOCC4)nc(Cl)nc3n2C)CC1
Reactant: Cc1nc2ccccc2[nH]1
Product: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3CCN([C@H](CO)C(C)C)CC3)n(C)c2n1

Procedure:
Following General Procedure I for Buchwald coupling, 2-methylbenzimidazole and racemic 2-(4-((2-chloro-9-methyl-6-morpholino-9H-purin-8-yl)methyl)piperazin-1-yl)-3-methylbutan-1-ol were reacted. The enantiomers were separated by SFC to give 361. LCMS m/z: 534.3 (MH+)
Reaction SMILES: [OH:1][C@H:2]1[C@H:7]([OH:8])[C@@H:6]([C:9]#[C:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[O:5][C:3]1=[O:4].[H][H]>C(O)C>[OH:1][C@H:2]1[C@H:7]([OH:8])[C@H:6](/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[O:5][C:3]1=[O:4]
Reactant: CCCCCCC#C[C@H]1OC(=O)[C@@H](O)[C@@H]1O
Reactant: [H][H]
Solvent: CCO
Product: CCCCCC/C=C\[C@@H]1OC(=O)[C@@H](O)[C@@H]1O
Yield: 94 %

Procedure:
1.02 g (4.51 mmol) of the compound (25) obtained in step e' were dissolved in 20 ml of ethanol, 40 mg of 5 wt % Pd--CaCO3 /Pb (Lindlar catalyst) were added thereto, and the resultant solution was strongly stirred in a hydrogen atmosphere. The solid product in the reaction solution was filtered with Celite, and the solvent was distilled at a reduced pressure, thereby obtaining a white crystal. This crystal was recrystallized from a dichloromethane/hexane solution mixture to obtain 967 mg (4.24 mmol) of a white fibrous compound (26) (yield:94%). The physical data of the resultant compound (26) were as follows:
Reaction SMILES: Cl[C:2]([O:4][CH3:5])=[O:3].[NH2:6][C@H:7]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9].Cl.C(N(C(C)C)CC)(C)C>C1COCC1>[CH3:5][O:4][C:2]([NH:6][C@H:7]([C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])=[O:3]
Reactant: COC(=O)Cl
Reactant: CC(C)(C)OC(=O)[C@H](N)c1ccccc1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)N[C@@H](C(=O)OC(C)(C)C)c1ccccc1
Reaction time: 5.5 h
Yield: 71.6 %

Procedure:
ClCO2Me (3.2 mL, 41.4 mmol) was added dropwise to a cooled (ice/water) THF (410 mL) semi-solution of (R)-tert-butyl 2-amino-2-phenylacetate/HCl (9.877 g, 40.52 mmol) and diisopropylethylamine (14.2 mL, 81.52 mmol) over 6 min, and stirred at similar temperature for 5.5 hours. The volatile component was removed in vacuo, and the residue was partitioned between water (100 mL) and ethyl acetate (200 mL). The organic layer was washed with 1N HCl (25 mL) and saturated NaHCO3 solution (30 mL), dried (MgSO4), filtered, and concentrated in vacuo. The resultant colorless oil was triturated from hexanes, filtered and washed with hexanes (100 mL) to provide (R)-tert-butyl 2-(methoxycarbonylamino)-2-phenylacetate as a white solid (7.7 g). 1H NMR (DMSO-d6, δ=2.5 ppm, 400 MHz): 7.98 (d, J=8.0, 1H), 7.37-7.29 (m, 5H), 5.09 (d, J=8, 1H), 3.56 (s, 3H), 1.33 (s, 9H). LC (Cond. 1): RT=1.53 min; ˜90% homogeneity index; LC/MS: Anal. Calcd. for [M+Na]+ C14H19NNaO4: 288.12; found 288.15.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([O:9][CH3:10])=[C:4]([CH3:11])[CH:3]=1.C([Li])CCC.[Br:17][C:18]1[CH:23]=[CH:22][C:21]([CH:24]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=2[CH3:38])[CH2:25][C:26](N(OC)C)=[O:27])=[CH:20][CH:19]=1>>[Br:17][C:18]1[CH:19]=[CH:20][C:21]([CH:24]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=2[CH3:38])[CH2:25][C:26]([C:2]2[CH:7]=[C:6]([CH3:8])[C:5]([O:9][CH3:10])=[C:4]([CH3:11])[CH:3]=2)=[O:27])=[CH:22][CH:23]=1
Reactant: COc1c(C)cc(Br)cc1C
Reactant: CON(C)C(=O)CC(c1ccc(Br)cc1)c1ccccc1C
Agent: [Li]CCCC
Product: COc1c(C)cc(C(=O)CC(c2ccc(Br)cc2)c2ccccc2C)cc1C

Procedure:
In analogy to example 151, step 1, 4-bromo-2,6-dimethylanisole was reacted first with n-butyllithium and later with 3-(4-bromo-phenyl)-N-methoxy-N-methyl-3-o-tolyl-propionamide (example 74, step 4) to give the title compound as a light yellow solid, MS (ESI+): m/z=437.4 [M+H]+.