Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:11]([CH2:12][CH:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)=[CH:10][C:9]2[C:4](=[CH:5][C:6]([F:28])=[C:7]([S:19][C:20]3[CH:21]=[C:22]([CH:25]=[CH:26][CH:27]=3)[CH:23]=O)[CH:8]=2)[N:3]=1.[CH2:29]([O:31][C:32]1[CH:39]=[CH:38][CH:37]=[CH:36][C:33]=1[CH2:34][NH2:35])[CH3:30].[BH4-].[Na+].[OH-].[Na+]>CO>[CH2:29]([O:31][C:32]1[CH:39]=[CH:38][CH:37]=[CH:36][C:33]=1[CH2:34][NH:35][CH2:23][C:22]1[CH:21]=[C:20]([S:19][C:7]2[CH:8]=[C:9]3[C:4](=[CH:5][C:6]=2[F:28])[N:3]=[C:2]([NH2:1])[C:11]([CH2:12][CH:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)=[CH:10]3)[CH:27]=[CH:26][CH:25]=1)[CH3:30]
Reactant: Nc1nc2cc(F)c(Sc3cccc(C=O)c3)cc2cc1CC1CCOCC1
Reactant: CCOc1ccccc1CN
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCOc1ccccc1CNCc1cccc(Sc2cc3cc(CC4CCOCC4)c(N)nc3cc2F)c1

Procedure:
3-[2-Amino-7-fluoro-3-(tetrahydro-pyran-4-ylmethyl)-quinolin-6-ylsulfanyl]-benzaldehyde (40 mg, 0.1 mmol) was dissolved in methanol (1 mL), and then 2-ethoxybenzyl amine (60 μL, 0.38 mmol) was added. The resulting mixture was subjected to μW @ 300W, 130° C. for 12 min. NaBH4 (50 mg, 1.3 mmol) was then added portionwise over 1.5 h. The solvent was removed to yield a residue, to which was added 0.1 N NaOH (5 mL). The resulting mixture was extracted with chloroform (3×). The organic layers were combined and dried with MgSO4 and filtered. The solvent was removed to yield a second residue which was purified on silica gel (2-10% MeOH/dichloromethane) to yield the title compound as a residue.
Reaction SMILES: [C:1]1([CH3:12])[CH:6]=[CH:5][C:4]([S:7]([C:10]#[N:11])(=[O:9])=[O:8])=[CH:3][CH:2]=1.[N:13]([CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])=[N+:14]=[N-:15]>C1C=CC=CC=1>[CH2:20]([O:19][C:17]([CH2:16][N:13]1[C:10]([S:7]([C:4]2[CH:3]=[CH:2][C:1]([CH3:12])=[CH:6][CH:5]=2)(=[O:8])=[O:9])=[N:11][N:15]=[N:14]1)=[O:18])[CH3:21]
Reactant: CCOC(=O)CN=[N+]=[N-]
Reactant: Cc1ccc(S(=O)(=O)C#N)cc1
Solvent: c1ccccc1
Product: CCOC(=O)Cn1nnnc1S(=O)(=O)c1ccc(C)cc1

Procedure:
A mixture of 7.24 g. of p-toluenesulfonyl cyanide and 5.16 g. of ethyl azidoacetate (Dictionary of Organic Compounds, Vol. 1, p. 307) in 150 ml. of benzene is heated at reflux for 12 hours. The residue after evaporation is recrystallized from benzene-hexane, m.p. 98°-100° C.
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C:3]1[CH:4]=[C:5]([C@H:13]([O:15][C@H:16]2[CH2:24][CH2:23][C@H:22]3[C@@H:18]([CH2:19][NH:20][CH2:21]3)[C@@H:17]2[C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)[CH3:14])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[C:34]1(=O)[CH2:38][CH2:37][C:36](=[O:39])[CH2:35]1.CC1C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[F:33][C:2]([F:1])([F:32])[C:3]1[CH:4]=[C:5]([C@H:13]([O:15][C@H:16]2[CH2:24][CH2:23][C@H:22]3[C@@H:18]([CH2:19][N:20]([C:34]4[CH2:38][CH2:37][C:36](=[O:39])[CH:35]=4)[CH2:21]3)[C@@H:17]2[C:25]2[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=2)[CH3:14])[CH:6]=[C:7]([C:9]([F:12])([F:10])[F:11])[CH:8]=1
Reactant: C[C@@H](O[C@H]1CC[C@@H]2CNC[C@H]2[C@@H]1c1ccc(F)cc1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: O=C1CCC(=O)C1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: C[C@@H](O[C@H]1CC[C@@H]2CN(C3=CC(=O)CC3)C[C@H]2[C@@H]1c1ccc(F)cc1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Yield: 58.8 %

Procedure:
To a solution of 0.73 g (1.5 mmol) of (3aR,4R,5S,7aS)-5-{(1R)-1-[3,5-bis(tri-fluoromethyl)phenyl]ethoxy}-4-(4-fluorophenyl)octahydro-1H-isoindole (Example 6) in ˜25 mL dry toluene was added 0.166 g (1.7 mmol) cyclopentane-1,3-dione and 0.03 g (0.15 mmol) of PTSA. The resulting mixture was heated at reflux for 2 hr. The solvent was removed under vacuum and the residue was purified by prep TLC eluting with CHCl3/2N NH3 in MeOH (9/1) to afford 0.49 g the title compound. The compound could be further purified by chiral HLPC on CHIRACEL AD column eluting with hexanes/EtOH (9/1). The compound could be crystallized (mp=216.5-217.5° C.) from hexanes/EtOAc or hexanes/EtOH. 1H-NMR (CDCl3): δ: 7.71 (1H, s), 7.23 (2H, s), 7.00 (2H, m), 6.93 (2H, t, J=8.2 Hz), 4.89, 4.48 (1H, s), 4.47 (1H, m), 3.71, 3.48 (1H, m), 3.35 (1H, m), 3.28-3.17 (1H, m), 2.95 (1H, m), 2.95, 2.81 (1H, m), 2.68 (2H, m), 2.45 (2H, m), 2.37 (2H, m), 2.15 (1H, m), 1.93 (2H, m), 1.60 (1H, m), 1.38 (1H, m), 1.36 (3,H, t, J=6.0 Hz). MS: (MH)+556.0.
Reaction SMILES: Cl.[NH2:2][OH:3].C(=O)(O)[O-].[Na+].O.[Cl:10][C:11]1[CH:12]=[C:13]([C:17]2[C:22]3[N:23]([CH2:36][C@H:37]4[CH2:42][CH2:41][C@H:40]([CH3:43])[CH2:39][CH2:38]4)[C:24]([N:26]4[CH2:30][C@H:29]([O:31][CH3:32])[CH2:28][C@H:27]4[CH:33]([CH3:35])[CH3:34])=[N:25][C:21]=3[CH:20]=[C:19]([C:44]#[N:45])[N:18]=2)[CH:14]=[N:15][CH:16]=1>C(O)C>[Cl:10][C:11]1[CH:12]=[C:13]([C:17]2[C:22]3[N:23]([CH2:36][C@H:37]4[CH2:38][CH2:39][C@H:40]([CH3:43])[CH2:41][CH2:42]4)[C:24]([N:26]4[CH2:30][C@H:29]([O:31][CH3:32])[CH2:28][C@H:27]4[CH:33]([CH3:35])[CH3:34])=[N:25][C:21]=3[CH:20]=[C:19]([C:44](=[N:2][OH:3])[NH2:45])[N:18]=2)[CH:14]=[N:15][CH:16]=1
Reactant: NO
Reactant: CO[C@@H]1C[C@@H](C(C)C)N(c2nc3cc(C#N)nc(-c4cncc(Cl)c4)c3n2C[C@H]2CC[C@H](C)CC2)C1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CO[C@@H]1C[C@@H](C(C)C)N(c2nc3cc(C(N)=NO)nc(-c4cncc(Cl)c4)c3n2C[C@H]2CC[C@H](C)CC2)C1
Temperature: 100 °C
Reaction time: 0.25 h

Procedure:
Hydroxylamine hydrochloride (20.2 mg, 0.29 mmol), sodium bicarbonate (36.6 mg, 0.44 mmol), and water (0.436 mL) were combined in a vial and stirred for 15 minutes. This solution was added to a vial containing 4-(5-chloropyridin-3-yl)-2-[(2S,4R)-4-methoxy-2-(propan-2-yl)pyrrolidin-1-yl]-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridine-6-carbonitrile (73.7 mg, 0.145 mmol) dissolved in ethanol (1 mL). The mixture was sealed and heated at 100° C. for 1 hour. The reaction was cooled to room temperature, quenched with water, and extracted with ethyl acetate (2×). The combined organic layers were dried over sodium sulfate, filtered, and concentrated to afford 4-(5-chloropyridin-3-yl)-N′-hydroxy-2-[(2S,4R)-4-methoxy-2-(propan-2-yl)pyrrolidin-1-yl]-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridine-6-carboximidamide. MS ESI calc'd. for C28H38ClN7O2 [M+H]+ 540. found 540.
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[C:15]([O:19][C:20]([N:22]1[CH2:27][CH2:26][CH:25]([NH2:28])[CH2:24][CH2:23]1)=[O:21])([CH3:18])([CH3:17])[CH3:16].[Cl:29][C:30]1[S:31][C:32]([CH:36]=O)=[C:33]([Cl:35])[N:34]=1.C(O)(=O)C.[OH-].[Na+]>ClCCCl>[C:15]([O:19][C:20]([N:22]1[CH2:27][CH2:26][CH:25]([NH:28][CH2:36][C:32]2[S:31][C:30]([Cl:29])=[N:34][C:33]=2[Cl:35])[CH2:24][CH2:23]1)=[O:21])([CH3:18])([CH3:16])[CH3:17]
Reactant: O=Cc1sc(Cl)nc1Cl
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N1CCC(NCc2sc(Cl)nc2Cl)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 62.3 %

Procedure:
Add sodium triacetoxyborohydride (1.70 g, 8.02 mmol) to a stirred solution of 4-amino-piperidine-1-carboxylic acid tert-butyl ester (1.0124 g, 5.06 mmol), 2,4-dichloro-thiazole-5-carbaldehyde (1.0113 g, 5.56 mmol), glacial acetic acid (0.31 mL, 5.42 mmol), and 1,2-dichloroethane (40 mL). Stir for 18 hours under nitrogen at room temperature. Pour the reaction into 2N NaOH (100 mL) and extract with ethyl acetate (3×100 mL). Dry the ethyl acetate over sodium sulfate and then filter off the sodium sulfate. Concentrate on a rotary evaporator and purify the crude product by flash chromatography on silica gel eluting with 35% ethyl acetate/hexanes then with 100% ethyl acetate to yield 1.1547 g (62%) of 4-{[(2,4-dichloro-thiazol-5-yl)methyl]-amino}-piperidine-1-carboxylic acid tert-butyl ester: mass spectrum (ion spray): m/z=366.1 (M+1); 1H NMR (CDCl3): δ=4.04 (br s, 2H), 3.96 (s, 2H), 2.87-2.81 (m, 2H), 2.72-2.65 (m, 1H), 1.90-1.86 (m, 2H), 1.48-1.39 (m, 10H), 1.33-1.23 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:6]2[N:7]=[C:8](N)[S:9][C:5]=2[CH:4]=1.[C:13]([Cu])#[N:14]>>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:6]2[N:7]=[C:8]([C:13]#[N:14])[S:9][C:5]=2[CH:4]=1
Reactant: N#C[Cu]
Reactant: COc1ccc2nc(N)sc2c1
Product: COc1ccc2nc(C#N)sc2c1
Yield: 22.1 %

Procedure:
6-methoxybenzo[d]thiazol-2-amine (9 g, 50 mmol) was reacted with CuCN (8.96 g, 100 mmol) according to the procedure as described in Example 61, Step A to give the title compound as a white solid (2.1 g, 22%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [OH:1]O.[CH3:3][S:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[S:11]([NH2:14])(=[O:13])=[O:12]>O.C(O)(=O)C>[CH3:3][S:4]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[S:11]([NH2:14])(=[O:13])=[O:12])=[O:1]
Reactant: OO
Reactant: CSc1ccccc1S(N)(=O)=O
Solvent: O
Solvent: CC(=O)O
Product: CS(=O)c1ccccc1S(N)(=O)=O
Reaction time: 0.75 h

Procedure:
14.8 g of hydrogen peroxide (0.13 mol), 30% strength in H2O, were added dropwise at from 25° to 30° C. to a suspension of 26.5 g 6f 2-(methylthio)benzenesulfonamide (0.13 mol) and 2.1 g of Na2WO4 ·2H2O in 88 ml of glacial acetic acid. Stirring was carried out for 45 minutes at 25° C., the reaction mixture was poured onto 400 ml of water and the precipitate was filtered off with suction. It was washed with water and dried under reduced pressure from a water pump at 40° C. 24.3 g (85% of theory) of the title compound were thus obtained.
Reaction SMILES: C1C=CC(C2C=CC([C:13]3[NH:34][C:32](=O)[C:15]4=[C:16](C5C=CC(C6C=CC=CC=6)=CC=5)[NH:17][C:18](=[O:19])[C:14]=34)=CC=2)=CC=1.N(CCO)(CCO)CC[OH:38]>O>[O:38]=[C:14]1[C:13]2[C:16]([CH:15]=[CH:32][N:34]=2)=[N:17][C:18]1=[O:19]
Reactant: OCCN(CCO)CCO
Reactant: O=C1NC(c2ccc(-c3ccccc3)cc2)=C2C(=O)NC(c3ccc(-c4ccccc4)cc3)=C12
Solvent: O
Product: O=c1nc2ccnc-2c1=O
Reaction time: 7 h

Procedure:
20 g of C.I. pigment red 264 (in which the content of metal ion having a valence of at least 2 was 505 ppm), 60 g of the same aqueous dispersion of the pigment derivative (n) as obtained in Example 45 and 60 g of deionized water were mixed, 8 g of a 2% by weight triethanolamine was added so as to adjust the nuetralization ratio of the pigment derivative to 100%, and the mixture was dispersed with a paint shaker in the presence of zirconia beads as media for approximately 7 hours, to obtain a pigment dispersion.
Reaction SMILES: [CH:1]12[CH2:7][CH:4]([CH2:5][CH2:6]1)[CH2:3][CH:2]2[O:8][C:9]1[CH:10]=[C:11]([CH:19]=[CH:20][C:21]=1[O:22][CH3:23])[NH:12][C:13]1[CH2:17][CH2:16][C:15](=[O:18])[CH:14]=1.[CH2:24](Br)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[CH2:24]([N:12]([C:13]1[CH2:17][CH2:16][C:15](=[O:18])[CH:14]=1)[C:11]1[CH:19]=[CH:20][C:21]([O:22][CH3:23])=[C:9]([O:8][CH:2]2[CH2:3][CH:4]3[CH2:7][CH:1]2[CH2:6][CH2:5]3)[CH:10]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: COc1ccc(NC2=CC(=O)CC2)cc1OC1CC2CCC1C2
Reactant: BrCc1ccccc1
Product: COc1ccc(N(Cc2ccccc2)C2=CC(=O)CC2)cc1OC1CC2CCC1C2
Yield: 92.3 %

Procedure:
According to the same procedure as in Example 26, using 3-[3-[(1RS,2RS,4SR)-bicyclo[2.2.1]hept-2-yloxy]-4-methoxyanilino]2-cyclopenten-1-one produced in Example 8(3) instead of 3-(3-cyclopentyloxy-4-methoxyanilino)-2-cyclopenten-1-one, and using benzyl bromide instead of methyl iodide, the title compound (yield 92.3%) was obtained as a light yellow oil.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([O:10][C:11]3[C:20]4[C:15](=[CH:16][C:17]([O:23][CH2:24][CH2:25][CH2:26][N:27]5[CH2:32][CH2:31][N:30](C(OC(C)(C)C)=O)[CH2:29][CH2:28]5)=[C:18]([O:21][CH3:22])[CH:19]=4)[N:14]=[CH:13][N:12]=3)=[CH:7][N:8]=2)[CH:3]=[CH:2]1.FC(F)(F)C(O)=O>ClCCl>[NH:1]1[C:9]2[C:4](=[CH:5][C:6]([O:10][C:11]3[C:20]4[C:15](=[CH:16][C:17]([O:23][CH2:24][CH2:25][CH2:26][N:27]5[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]5)=[C:18]([O:21][CH3:22])[CH:19]=4)[N:14]=[CH:13][N:12]=3)=[CH:7][N:8]=2)[CH:3]=[CH:2]1
Reactant: COc1cc2c(Oc3cnc4[nH]ccc4c3)ncnc2cc1OCCCN1CCN(C(=O)OC(C)(C)C)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cc2c(Oc3cnc4[nH]ccc4c3)ncnc2cc1OCCCN1CCNCC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 42.8 %

Procedure:
4-(7-Azaindol-5-yloxy)-7-{3-[4-(tert-butoxycarbonyl)piperazin-1-yl]propoxy}-6-methoxyquinazoline (1.9 g, 3.55 mmol) was suspended in dichloromethane (60 ml) and trifluoroacetic acid (2 ml) added dropwise. All solid dissolved at this point giving an orange solution which was stirred for 3 hours at ambient temperature. More trifluoroacetic acid (4 ml) was added and the mixture stirred overnight. The mixture was concentrated under reduced pressure and the residue concentrated from dichloromethane (×3) and toluene to remove trifluoroacetic acid. The residue was dissolved in methanol, placed on an Isolute SCX column, washed with methanol and then eluted with 7N ammonia in methanol. The product was then purified by column chromatography eluting with methylene chloride/methanol (saturated with ammonia) (95/5 followed by 93/7) to give 4-(7-azaindol-5-yloxy)-6-methoxy-7-(3-piperazin-1-ylpropoxy)quinazoline (660 mg, 43%) as a white foam.
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[N:8][C:9]([NH2:10])=[C:4]2[CH:3]=[N:2]1.[I:11]N1C(=O)CCC1=O>CN(C)C=O.O>[I:11][C:3]1[C:4]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[NH2:10])[NH:1][N:2]=1
Reactant: Nc1ncnc2[nH]ncc12
Reactant: O=C1CCC(=O)N1I
Solvent: CN(C)C=O
Solvent: O
Product: Nc1ncnc2[nH]nc(I)c12
Temperature: 80 °C
Reaction time: 5 h
Yield: 51.8 %

Procedure:
A mixture of 1H-pyrazolo[3,4-d]pyrimidin-4-amine (150 g, 1.11 mol, 1.00 equiv) and N-iodo-succinimide (375 g, 1.67 mol, 1.58 equiv) in N,N-dimethylformamide (2.5 L) was stirred at 80° C. for 5 h. The reaction mixture was cooled to room temperature and then diluted with 10 L of water. The solid was collected by filtration, washed with 2×1 L of saturated aqueous sodium sulfite and dried under vacuum to give 150 g (52%) of 3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine as a yellow solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([OH:13])[CH2:10][C@H:9]1[CH2:14][OH:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].N1C=CN=C1.[Si:21](Cl)([C:34]([CH3:37])([CH3:36])[CH3:35])([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.O>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([OH:13])[CH2:10][C@H:9]1[CH2:14][O:15][Si:21]([C:34]([CH3:37])([CH3:36])[CH3:35])([C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)OC(=O)N1C[C@H](O)C[C@H]1CO
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1C[C@H](O)C[C@H]1CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Temperature: 25 °C
Reaction time: 18 h
Yield: 32.9 %

Procedure:
To a stirred solution of trans-1-tert-butoxycarbonyl-(2S)-hydroxymethyl-4-hydroxypyrrolidine (2.17 g, 10.0 mmol) and imidazole (2.04 g, 30.0 mmol) in DMF (50 ml) was added TBDPS-Cl (3.03 g, 11.0 mmol) at 0° C. The reaction mixture was stirred at room temperature for 18 hr. Water was added thereto, and extracted with EtOAc. The extract was washed with water, then dried over Na2SO4, and concentrated in vacuo. The residue was purified by column chromatography on silica gel with n-hexane-EtOAc(3:2, v/v) as eluent to give trans-1-tert-butoxycarbonyl-(2S)-(tert-butyldiphenylsilyloxy)methyl-4-hydroxypyrrolidine (1.5 g, 33%) as a white crystalline solid. 1H-NMR (CDCl3) δ 1.03 (s9H), 1.25 and 1.32 (each s, 9H), 1.90–2.10 (m, 1H), 2.30–2.40 (m, 1H), 3.40–3.80 (m, 3H), 3.95–4.15 (m, 2H), 4.45–4.55 (m, 1H), 7.37–7.39 (m, 6H), 7.63–7.64 (m, 4H).
Reaction SMILES: [C:1]([CH2:4][CH2:5][CH:6]1[C:14]2[C:9](=[C:10]([NH:17][C:18](=[O:23])[C:19]([CH3:22])([CH3:21])[CH3:20])[C:11]([CH3:16])=[CH:12][C:13]=2[CH3:15])[NH:8][CH2:7]1)([OH:3])=[O:2].[CH3:24]COC(C)=O>CCOCC>[CH3:24][O:2][C:1]([CH2:4][CH2:5][CH:6]1[C:14]2[C:9](=[C:10]([NH:17][C:18](=[O:23])[C:19]([CH3:20])([CH3:22])[CH3:21])[C:11]([CH3:16])=[CH:12][C:13]=2[CH3:15])[NH:8][CH2:7]1)=[O:3]
Reactant: Cc1cc(C)c2c(c1NC(=O)C(C)(C)C)NCC2CCC(=O)O
Reactant: CCOC(C)=O
Solvent: CCOCC
Product: COC(=O)CCC1CNc2c(NC(=O)C(C)(C)C)c(C)cc(C)c21

Procedure:
N-[3-(2-Carboxyethyl)-4,6-dimethylindolin-7-yl]-2,2-dimethylpropanamide (1.5 g) was dissolved in AcOEt (10 ml) and a solution of CH2N2 in ether was added. AcOEt (100 ml) was added, and after washing with water, the mixture was dried over anhydrous sodium sulfate. AcOEt was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: CHCl3 /MeOH=50/1-10/1) to give 1.0 g of N-[3-(2-methoxycarbonylethyl)-4,6-dimethylindolin-7-yl]-2,2-dimethylpropanamide.
Reaction SMILES: Br.C[O:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH:8]=[C:7]2[C:18]([C:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[CH:22][CH:21]=1)=[O:19]>O>[OH:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH:8]=[C:7]2[C:18]([C:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[CH:22][CH:21]=1)=[O:19]
Reactant: CCCCCn1cc(C(=O)c2cccc3ccccc23)c2cc(OC)ccc21
Agent: Br
Solvent: O
Product: CCCCCn1cc(C(=O)c2cccc3ccccc23)c2cc(O)ccc21
Temperature: 25 °C
Yield: 71.9 %

Procedure:
To a solution of hydrobromic acid (48 w/w %) in water (150 ml) was added 5 (6.5 g, 17.5 mmol) and the mixture was heated at reflux for 3 h. The solution was cooled to room temperature and concentrated to dryness. Water was then added (200 ml), the solution neutralized to pH 7-8 and then extracted with ethyl acetate (3×150 ml). The combined organic layers were washed by water (150 ml), brine (150 ml), dried over Na2SO4, filtered and concentrated to dryness. The crude product was then recrystallized from ethyl acetate/hexane to give a white solid of 5-hydroxy-3-(1-naphthoyl)-N-pentyl-1H-indole 6 (4.5 g, 72%)
Reaction SMILES: C([N:8]([S:16]([CH2:19][CH2:20][CH2:21][N:22]([CH3:27])[CH2:23][CH2:24][NH:25][CH3:26])(=[O:18])=[O:17])[C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])C1C=CC=CC=1>[OH-].[OH-].[Pd+2].CCO>[C:11]([O:10][C:9](=[O:15])[NH:8][S:16]([CH2:19][CH2:20][CH2:21][N:22]([CH3:27])[CH2:23][CH2:24][NH:25][CH3:26])(=[O:17])=[O:18])([CH3:14])([CH3:13])[CH3:12]
Reactant: CNCCN(C)CCCS(=O)(=O)N(Cc1ccccc1)C(=O)OC(C)(C)C
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: CNCCN(C)CCCS(=O)(=O)NC(=O)OC(C)(C)C
Reaction time: 4 h
Yield: 98 %

Procedure:
Pearlman's catalyst (0.10 eq.) was suspended in a 0.35 M EtOH solution of tert-butyl benzyl[(3-{methyl[2(methylamino)ethyl]amino}propyl)sulfonyl]carbamate and the mixture was stirred under an hydrogen atmosphere for 4h. The crude was filtered on a CELITE pad and washed with EtOH; after evaporation of the solvent the product was obtained as white solid which was used without further characterisation (98% yield, two steps). (ES+) m/z 310 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([S:8][CH3:9])[N:5]2[C:10]([C:13]3[O:14][CH:15]=[CH:16][CH:17]=3)=[N:11][N:12]=[C:4]2[CH:3]=1.C1CCN2C(=NCCC2)CC1>C1COCC1>[Cl:1][C:2]1[N:7]=[C:6]([S:8][CH3:9])[N:12]2[N:11]=[C:10]([C:13]3[O:14][CH:15]=[CH:16][CH:17]=3)[N:5]=[C:4]2[CH:3]=1
Reactant: CSc1nc(Cl)cc2nnc(-c3ccco3)n12
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: CSc1nc(Cl)cc2nc(-c3ccco3)nn12
Temperature: 25 °C
Reaction time: 1 h
Yield: 78.7 %

Procedure:
Into 8.5 mL of THF, 2.7 g (10 mmol) of Compound B was dissolved, and 1.5 mL (10 mmol) of DBU was added thereto under ice cooling, followed by stirring at room temperature for about 1 hour. During the period, crystals were precipitated from the reaction solution. After completion of the reaction, the precipitated solid was washed with THF to obtain 2.1 g of Compound C as a white solid (yield: 81%).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[Si:6]([O:23][CH2:24][C@@H:25]1[C@@H:29]([CH2:30][O:31][Si:32]([C:45]([CH3:48])([CH3:47])[CH3:46])([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH2:28][CH2:27][C@@H:26]1[OH:49])([C:19]([CH3:22])([CH3:21])[CH3:20])([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(N(CC)CC)C.P([O-])([O-])([O-])=O>C(Cl)Cl>[CH3:1][S:2]([O:49][C@H:26]1[CH2:27][CH2:28][C@H:29]([CH2:30][O:31][Si:32]([C:45]([CH3:48])([CH3:47])[CH3:46])([C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[C@H:25]1[CH2:24][O:23][Si:6]([C:19]([CH3:20])([CH3:21])[CH3:22])([C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)(=[O:4])=[O:3]
Reactant: CC(C)(C)[Si](OC[C@H]1CC[C@H](O)[C@@H]1CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)(c1ccccc1)c1ccccc1
Reactant: CS(=O)(=O)Cl
Agent: O=P([O-])([O-])[O-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)[Si](OC[C@H]1CC[C@H](OS(C)(=O)=O)[C@@H]1CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)(c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 96.4 %

Procedure:
At 0° C., methanesulfonyl chloride (0.20 ml, 2.6 mmoles) was added to a solution of (1S, 2S, 3S)-2,3-bis-(t-butyldiphenylsilyloxymethyl)-1-cyclopentanol (1.08 g, 1.73 mmoles) and triethylamine (0.44 ml, 3.2 mmoles) in methylene chloride (9 ml). After stirring the mixture at 0° C. for 15 minutes, 0.2M phosphate buffer (pH 7.0) was added to the reaction mixture and the mixture was subjected to extraction with ethyl ether. The ether extract solution was dried on anhydrous sodium sulfate and then the solvent was distilled off. The residue was purified by silica gel column chromatography (ethyl acetate:n-hexane=1:9, v/v) to obtain (1S,2S,3S)-2,3-bis-(t-butyldiphenylsilyloxymethyl)-1-cyclopentyl methanesulfonate (1.169 g, Yield 96%).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6](=[NH:29])[NH:7][C:8]1[CH:9]=[CH:10][C:11]2[N:16]([CH2:17][CH2:18][N:19](C)[C:20](=O)OC(C)(C)C)[CH2:15][CH2:14][S:13][C:12]=2[CH:28]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[CH3:20][NH:19][CH2:18][CH2:17][N:16]1[CH2:15][CH2:14][S:13][C:12]2[CH:28]=[C:8]([NH:7][C:6]([C:2]3[O:1][CH:5]=[CH:4][CH:3]=3)=[NH:29])[CH:9]=[CH:10][C:11]1=2
Reactant: CN(CCN1CCSc2cc(NC(=N)c3ccco3)ccc21)C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CNCCN1CCSc2cc(NC(=N)c3ccco3)ccc21
Temperature: 0 °C
Reaction time: 2 h
Yield: 75.1 %

Procedure:
A solution of tert-butyl 2-(7-(furan-2-carboximidamido)-2H-benzo[b][1,4]thiazin-4(3H)-yl)ethyl(methyl)carbamate (0.823 g, 1.978 mmol) in CH2Cl2 (20 mL) was cooled to 0° C. and was treated with trifluoroacetic acid (5 mL). The mixture was stirred at 0° C. under argon atmosphere for 2 hours. The mixture was quenched with 1N NaOH solution (70 mL) and transferred to a separatory funnel. The solution was diluted with water (50 mL) and extracted with CH2Cl2 (2×50 mL). The organic phase was washed with brine (50 mL) and dried (Na2SO4). The crude material was concentrated and subjected to flash chromatography on silica gel (5-15% (2M NH3MeOH):CH2Cl2). The collected fractions were concentrated to give compound 20 as a yellow viscous oil (0.47 g, 76%). 1H NMR (CDCl3) δ 7.85 (s, 1H), 7.44-7.43 (m, 1H), 6.77-6.74 (m, 2H), 6.70 (d, J=2.4 Hz, 1H), 6.62 (dd, J=2.4, 8.7 Hz, 1H), 3.59-3.56 (m, 2H), 3.47 (s, 1H), 3.40 (t, J=6.6 Hz, 2H), 3.05-3.01 (m, 2H), 2.81 (t, J=6.3, 2H), 2.48 (s, 3H); ESI-MS (m/z, %): 319, 317 (MH+, 96), 260 (100).
Reaction SMILES: CN([CH:4]=[C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:8][CH2:7][C:6]1=O)C.[C:16]([CH2:18][C:19]([NH2:21])=[O:20])#[N:17].C[O-].[Na+]>CN(C)C=O.C(#N)C>[C:16]([C:18]1[C:19](=[O:20])[NH:21][C:6]2[CH2:7][CH2:8][C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=3[C:5]=2[CH:4]=1)#[N:17]
Reactant: CN(C)C=C1C(=O)CCc2ccccc21
Reactant: N#CCC(N)=O
Agent: C[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC#N
Product: N#Cc1cc2c([nH]c1=O)CCc1ccccc1-2

Procedure:
Heat 11.4 g of 1-dimethylaminomethylene-2-tetralone, 4.46 gm of cyanoacetamide and 6.6 gm of sodium methoxide in 100 ml of dimethylformamide for 8 hours at 80°. Cool and dilute the reaction mixture with 150 ml of acetonitrile. Remove the tan solid by filtration. Dissolve the solid in hot water and filter the mixture. Acidify this aqueous solution with concentrated hydrochloric acid to give a tan precipitate. Filter and wash the tan solid with chloroform to give the title compound, m.p. 301°-3°. Concentrate the remaining dimethylformamide:acetonitrile solution in vacuo to give a green-black residue and chromatograph on 800 ml of silica gel using cloroform:methanol 98:2 as eluant to give an additional amount the title compound.