Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[S:12][C:11](=[O:13])[NH:10][C:9]2=[O:14])=[CH:4][CH:3]=1.[C:15](O)(=O)[C:16]1[C:17](=[CH:20][CH:21]=[CH:22][CH:23]=1)[CH:18]=[O:19].[BH4-].[Na+]>C(O)C>[O:19]=[C:18]1[C:17]2[C:16](=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:15][N:1]1[C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[S:12][C:11](=[O:13])[NH:10][C:9]2=[O:14])=[CH:6][CH:7]=1
Reactant: O=Cc1ccccc1C(=O)O
Reactant: Nc1ccc(C2SC(=O)NC2=O)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: O=C1NC(=O)C(c2ccc(N3Cc4ccccc4C3=O)cc2)S1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 90.4 %

Procedure:
Into 50 ml of ethanol were dissolved 4.90 g of 5-(4-aminophenyl)-thiazolidine-2,4-dione and 3.54 g of phthalaldehydic acid, and the solution was refluxed for 2 hours. After cooling by standing, 1.78 g of sodium borohydride were added and the mixture was stirred for 20 minutes at room temperature. Thereafter, solvent was distilled off under reduced pressure and 10 ml of glacial acetic acid were added to the residue, which was stirred for 10 minutes at 100 ° C. After cooling by standing, 100 ml of water were added and the crystals deposited were collected by filtration, washed with water and dried. These were recrystallized from ethanol to obtain 6.90 g of title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:9]([CH3:11])[CH3:10])[CH:5]=[C:6]([CH3:8])[CH:7]=1.C([O-])(=O)C.[NH4+].[Br:17]N1C(=O)CCC1=O.CCOC(C)=O>C(#N)C>[Br:17][C:7]1[C:6]([CH3:8])=[CH:5][C:4]([N:9]([CH3:10])[CH3:11])=[CH:3][C:2]=1[F:1]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cc(F)cc(N(C)C)c1
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: Cc1cc(N(C)C)cc(F)c1Br
Reaction time: 1 h
Yield: 92.7 %

Procedure:
To a solution of (3-Fluoro-5-methyl-phenyl)-dimethyl-amine (2.82 g, 18.4 mmol) in acetonitrile (28 mL) were sequentially added ammonium acetate (0.142 g, 1.84 mmol) and a solution of N-bromosuccinimide (3.27 g, 18.4 mmol) in acetonitrile (23 mL) drop-wise at 0° C. After 1 h., at r.t., the solvent was switched to EtOAc, and the solution was washed with saturated NaHCO3 (aq), dried (MgSO4), filtered, and concentrated in vacuo to give an orange, oily residue. Purification of this oil by flash chromatography (SiO2, 5% EtOAc/Hexanes) gave (4-Bromo-3-fluoro-5-methyl-phenyl)-dimethyl-amine as an ivory solid (3.96 g, 93%).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([NH:9][C:10]23[CH2:19][CH:14]4[CH2:15][CH:16]([CH2:18][CH:12]([CH2:13]4)[CH2:11]2)[CH2:17]3)[N:3]=1.[NH2:20][C:21]12[CH2:30][CH:25]3[CH2:26][CH:27]([CH2:29][CH:23]([CH2:24]3)[CH2:22]1)[CH2:28]2>C(O)CCC>[C:10]12([NH:9][C:4]3[N:3]=[C:2]([NH:20][C:21]45[CH2:22][CH:23]6[CH2:29][CH:27]([CH2:26][CH:25]([CH2:24]6)[CH2:30]4)[CH2:28]5)[CH:7]=[C:6]([Cl:8])[N:5]=3)[CH2:17][CH:16]3[CH2:18][CH:12]([CH2:13][CH:14]([CH2:15]3)[CH2:19]1)[CH2:11]2
Reactant: Clc1cc(Cl)nc(NC23CC4CC(CC(C4)C2)C3)n1
Reactant: NC12CC3CC(CC(C3)C1)C2
Solvent: CCCCO
Product: Clc1cc(NC23CC4CC(CC(C4)C2)C3)nc(NC23CC4CC(CC(C4)C2)C3)n1

Procedure:
A solution containing 26.0 g (87.25 mmoles) of 4,6-dichloro-2-(1-adamantylamino)pyrimidine and 39.5 g (261.6 mmoles) of 1-aminoadamantane in 200 ml of n-butanol is boiled under reflux for 75 hours, then evaporated. The evaporation residue is suspended in 400 ml of ether, the suspension is filtered off and, after drying, the product filtered off is purified by chromatography on a silica gel column. By using chloroform as eluent and recrystallizing the obtained product from ether the title compound is obtained in a yield of 23.94 g (66.44%), m.p.: 232°-236° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:4][CH:3]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].Br[CH2:32][C:33]#[N:34]>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([C:14]2[CH:15]=[CH:16][C:17]([Cl:20])=[CH:18][CH:19]=2)([CH2:32][C:33]#[N:34])[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:6][CH:7]=1
Reactant: N#CCBr
Reactant: CCOC(=O)C(c1ccc(Cl)cc1)c1ccc(Cl)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)C(CC#N)(c1ccc(Cl)cc1)c1ccc(Cl)cc1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
Ethyl 2,2-bis(4-chlorophenyl)acetate (5.50 g, 17.8 mmol) was dissolved in 100 mL of dry tetrahydrofuran and cooled to −78° C. Lithium bis(trimethylsilyl)amide (1.0 M in hexane, 18.0 mL, 18.0 mmol) was added dropwise via syringe under nitrogen. The reaction was brought to 0° C., stirred for 1 hour, and then cooled to −78° C. A solution of bromoacetonitrile (1.24 mL, 17.8 mmol) dissolved in tetrahydrofuran was added, and the reaction was stirred for 2 hours while warming to room temperature. The reaction was quenched with saturated NH4Cl solution and extracted with diethyl ether. The organic phase was washed with brine, dried over MgSO4, filtered, and concentrated. Chromatography on silica gel (Analogix Intelliflash 280; 10% ethyl acetate/hexane) yielded the title compound: 1H NMR (300 MHz, CDCl3) δ ppm 7.38-7.32 (m, 4H), 7.22-7.17 (m, 4H), 4.25 (q, J=7.2, 2H), 3.32 (s, 2H), 1.23 (t, J=7.2, 3H); MS (DCI+) m/z 365 (M+NH4)+.
Reaction SMILES: C[Si]([C:5]#[N:6])(C)C.[CH3:7][O:8][C:9]1[CH:14]=[CH:13][C:12]2[C:15]([CH2:17][CH2:18][CH2:19][C:11]=2[CH:10]=1)=O.[C-]#N.[Li+]>O1CCCC1.CN(C)C=O>[C:5]([C:15]1[C:12]2[C:11](=[CH:10][C:9]([O:8][CH3:7])=[CH:14][CH:13]=2)[CH2:19][CH2:18][CH:17]=1)#[N:6]
Reactant: COc1ccc2c(c1)CCCC2=O
Reactant: C[Si](C)(C)C#N
Agent: [C-]#N
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)CCC=C2C#N
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 60.4 %

Procedure:
Trimethylsilylcyanide (50.0 g, 510 mmol) was added to a suspension of 75.0 g (430 mmol) of 6-methoxy-α-tetralone (commercially available from Aldrich Chemical Company) in 75 mL of anhydrous tetrahydrofuran (THF) at ambient temperature. Lithium cyanide (100 mL of a 0.5M solution in N,N-dimethylformamide (DMF)) was added to the resultant mixture in one portion. The reaction mixture was stirred at ambient temperature for 1.5 h and then the THF was removed under reduced pressure. The concentrate was partitioned between diethyl ether and water (5:1 v/v). The aqueous layer was extracted with diethyl ether and the combined organic extract was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was dissolved in 400 mL of anhydrous toluene, containing 15 g of p-toluenesulfonic acid, previously refluxed in order to remove residual water by azeotropic distillation. The mixture was heated at reflux (with a Dean Stark trap) for 1 h. The resultant solution was cooled to ambient temperature and washed with cold 1N aqueous sodium hydroxide solution. The organic layer was separated, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was purified on silica gel eluted with 10% ethyl acetate in hexane to afford 48.09 g (60% yield) of the title compound. The physical properties of the product were identical to the properties reported for this compound by F. Z. Basha, et al. in J. Organic Chemistry, 50: 4160-2 (1985).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N+:27]([O-])=O)[CH:5]=[C:6]([Cl:26])[C:7]=1[O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][Si:16]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17])=[C:11]([CH:23]([CH3:25])[CH3:24])[CH:10]=1>[Pt].C(O)C>[Cl:26][C:6]1[CH:5]=[C:4]([CH:3]=[C:2]([Cl:1])[C:7]=1[O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][Si:16]([C:19]([CH3:20])([CH3:21])[CH3:22])([CH3:17])[CH3:18])=[C:11]([CH:23]([CH3:24])[CH3:25])[CH:10]=1)[NH2:27]
Reactant: CC(C)c1cc(Oc2c(Cl)cc([N+](=O)[O-])cc2Cl)ccc1O[Si](C)(C)C(C)(C)C
Agent: [Pt]
Solvent: CCO
Product: CC(C)c1cc(Oc2c(Cl)cc(N)cc2Cl)ccc1O[Si](C)(C)C(C)(C)C

Procedure:
3,5-Dichloro-4-(3'-isopropyl-4'-t-butyldimethylsiloxyphenoxy)-nitrobenzene and 1.15 g of 10% platinum on carbon in 200 ml of ethanol is hydrogenated on a Parr shaker. Catalyst is removed by filtration through Celite and the filtrate stripped to afford 3,5-dichloro-4-(3'-isopropyl-4'-t-butyldimethylsiloxyphenoxy)-aniline. This is dissolved with 3.08 ml of ethyl bromoacetate and 3.43 g of diisopropylethylamine in 50 ml dimethylformamide and heated at 140° for 18 hours. Solvent is removed with high vacuum and the residue taken up in ethyl acetate and extracted twice with water. The ethyl acetate is dried, filtered and stripped to give crude product. Chromatography on silica gel with 85:15 to 80:20 hexane:ethyl acetate as eluent affords ethyl N-[3,5-dichloro-4-(3'-isopropyl-4'-t-butyldimethylsiloxyphenoxy)phenyl]aminoacetate. NMR (CDCl3): δ0.2 (6H,s), 1.0 (9H,s), 1.2 (6H,d), 1.3 (3H,t), 3.3 (1H,m), 3.9 (2H,d), 4.3 (2H,q), 4.4 (1H,t), 6.4 (1H,d of d), 6.6 (2H,s), 6.6 (1H,d), 6.9 (1H,d).
Reaction SMILES: C[O:2][C:3](=[O:58])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][CH2:12][O:13][C:14]2[C:19]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[CH:21]=3)=[CH:18][C:17]([C:30](=[O:46])[NH:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)=[CH:16][C:15]=2[C:47]2[CH:52]=[CH:51][CH:50]=[C:49]([C:53]([F:56])([F:55])[F:54])[CH:48]=2)=[CH:6][C:5]=1[OH:57].[OH-].[Na+].Cl>CCO.O>[OH:57][C:5]1[CH:6]=[C:7]([O:10][CH2:11][CH2:12][O:13][C:14]2[C:15]([C:47]3[CH:52]=[CH:51][CH:50]=[C:49]([C:53]([F:54])([F:55])[F:56])[CH:48]=3)=[CH:16][C:17]([C:30](=[O:46])[NH:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)=[CH:18][C:19]=2[C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:27])([F:28])[F:29])[CH:21]=2)[CH:8]=[CH:9][C:4]=1[C:3]([OH:58])=[O:2]
Reactant: COC(=O)c1ccc(OCCOc2c(-c3cccc(C(F)(F)F)c3)cc(C(=O)NCCCCCCCCc3ccccc3)cc2-c2cccc(C(F)(F)F)c2)cc1O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(NCCCCCCCCc1ccccc1)c1cc(-c2cccc(C(F)(F)F)c2)c(OCCOc2ccc(C(=O)O)c(O)c2)c(-c2cccc(C(F)(F)F)c2)c1
Temperature: 25 °C
Yield: 95.8 %

Procedure:
To a solution of 2-hydroxy-4-{2-[5′-(8-phenyl-octylcarbamoyl)-3,3″-bis-trifluoromethyl[1,1′:3′,1″]terphenyl-2′-yloxy]-ethoxy}-benzoic acid methyl ester (0.980 g, 1.21 mmol, 1 eq) in EtOH (20 mL) was added 50% NaOH (10 mL) and the reaction was heated at reflux overnight. It was cooled to rt, diluted with H2O, and acidified with 2M HCl to pH 1. It was extracted with EtOAc, dried over MgSO4 and concentrated in vacuo. The residue was purified by flash chromatography (30% EtOAc:hexane) to afford the title compound (0.92 g, 96%) as a white foam. 1H NMR (DMSO-d6) δ 13.60 (bs, 1H); 11.40 (bs, 1H); 8.59 (bt, 1H); 8.00–7.92 (m, 6H); 7.74–7.65 (m, 4H); 7.56 (d, 1H); 7.25–7.10 (m, 5H); 6.08–6.00 (m, 2H); 3.66 (bd, 2H); 3.52 (bd, 2H); 3.25 (dd, 2H); 2.52 (t, 2H); 1.53 (m, 4H); 1.27 (m, 8H); IR (KBr) 3350, 2950, 2850, 1670, 1620, 1550, 1500, 1460, 1320, 1230, 1220, 1160, 1120, 1095, cm−1; mass spectrum [(−)APCI], m/z 792 (M−H)−; Anal. Calcd. for C44H41F6NO6: C, 66.58; H, 5.21; N, 1.76. Found: C, 64.86; H, 5.22; N, 1.68.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]2[C:10]([C:11]([C:13]3[CH:14]=[N:15][CH:16]=[C:17]([NH2:19])[CH:18]=3)=[O:12])=[CH:9][N:8]([C:20]([CH3:23])([CH3:22])[CH3:21])[C:6]=2[N:7]=1.[C:24]([C:26]1[CH:31]=[CH:30][C:29]([CH2:32][C:33](O)=[O:34])=[CH:28][CH:27]=1)#[N:25]>>[NH2:1][C:2]1[N:3]=[CH:4][C:5]2[C:10]([C:11]([C:13]3[CH:18]=[C:17]([NH:19][C:33](=[O:34])[CH2:32][C:29]4[CH:30]=[CH:31][C:26]([C:24]#[N:25])=[CH:27][CH:28]=4)[CH:16]=[N:15][CH:14]=3)=[O:12])=[CH:9][N:8]([C:20]([CH3:23])([CH3:22])[CH3:21])[C:6]=2[N:7]=1
Reactant: N#Cc1ccc(CC(=O)O)cc1
Reactant: CC(C)(C)n1cc(C(=O)c2cncc(N)c2)c2cnc(N)nc21
Product: CC(C)(C)n1cc(C(=O)c2cncc(NC(=O)Cc3ccc(C#N)cc3)c2)c2cnc(N)nc21

Procedure:
The title compound was prepared according to the method described for Example 1 using (2-amino-7-tert-butyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-(5-amino-pyridin-3-yl)-methanone (see Preparation 65) and 4-cyano phenyl acetic acid to afford the title compound as off white solid in 58%, 23 mg.
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[NH:7][C@H:8]([C@@H:18]1[CH2:20][O:19]1)[CH2:9][C:10]1[CH:15]=[C:14]([F:16])[CH:13]=[C:12]([F:17])[CH:11]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:22][C:23]1([CH3:40])[N:27]([C:28](=[O:32])[CH2:29][CH2:30][CH3:31])[C@H:26]2[C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][C:38]=3[CH2:39][C@H:25]2[O:24]1.[Li]CCCC>C1COCC1>[C:1]([O:5][C:6](=[O:21])[NH:7][C@@H:8]([CH2:9][C:10]1[CH:15]=[C:14]([F:16])[CH:13]=[C:12]([F:17])[CH:11]=1)[C@@H:18]([OH:19])[CH2:20][C@H:29]([C:28]([N:27]1[C@H:26]2[C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][C:38]=3[CH2:39][C@H:25]2[O:24][C:23]1([CH3:22])[CH3:40])=[O:32])[CH2:30][CH3:31])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1cc(F)cc(F)c1)[C@@H]1CO1
Reactant: CCCC(=O)N1[C@H]2c3ccccc3C[C@H]2OC1(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC[C@H](C[C@H](O)[C@H](Cc1cc(F)cc(F)c1)NC(=O)OC(C)(C)C)C(=O)N1[C@H]2c3ccccc3C[C@H]2OC1(C)C
Temperature: -78 °C

Procedure:
(1S,2S)-[2-(3,5-Difluorophenyl)-1-oxiranylethyl]-carbamic acid tert-butyl ester (VI, 113 mg) and 1-((3aS,8aR)-2,2-Dimethyl-8,8a-dihydro-3aH-indeno[1,2-d]oxazol-3-yl)-butan-1-one (VII, 94 mg) were combined in dry THF (3 mL), and cooled to −78° C. To this solution was added BuLi (2.5 M in hexanes, 0.32 mL) over 5 min., whereupon the solution was allowed to warm to 0° C. for 1.5 h. The reaction mixture was partitioned between 0.5 N HCl (4 mL) and 1:1 EtOAc/hexanes (2×4 mL). The combined organic layers were dried (MgSO4), filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (20–30% EtOAc/hexanes) to give an oil: MH+559.1.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([NH:10][C:11]2[N:16]=[C:15]([C:17]3[S:21][C:20]([S:22][CH3:23])=[C:19]([C:24]#[N:25])[C:18]=3[CH:26]3[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]3)[C:14]([CH3:32])=[CH:13][N:12]=2)[CH:7]=[CH:8][CH:9]=1)([O-])=O.CCOC(C)=O>[Pd].CO>[NH2:1][C:4]1[CH:5]=[C:6]([NH:10][C:11]2[N:16]=[C:15]([C:17]3[S:21][C:20]([S:22][CH3:23])=[C:19]([C:24]#[N:25])[C:18]=3[CH:26]3[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]3)[C:14]([CH3:32])=[CH:13][N:12]=2)[CH:7]=[CH:8][CH:9]=1
Reactant: CSc1sc(-c2nc(Nc3cccc([N+](=O)[O-])c3)ncc2C)c(C2CCCCC2)c1C#N
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: CSc1sc(-c2nc(Nc3cccc(N)c3)ncc2C)c(C2CCCCC2)c1C#N
Reaction time: 8 h

Procedure:
A suspension of 5-[2-(3-Nitrophenylamino)-5-methyl-pyrimidin-4-yl]-4-cyclohexyl-2-methylsulfanyl-thiophene-3-carbonitrile (0.187 g, 402 umol) and 10% palladium on carbon in methanol was stirred under a hydrogen atmosphere overnight resulting in complete conversion to product as determined by TLC (40% EtOAc:hexanes). The reaction was filtered through celite and concentrated in vacuo to afford the desired amine V-8 (0.186 g, 426 umol) in quantitative yield. 1NMR (CDCl3) δ1.0-1.1(m, 10H), 2.1 (s, 3H), 2.6 (s, 3H), 6.2 (d, 1H), 6.8 (d, 1H), 6.9-7.0 (m, 3H) , 8.2 (s, 1H).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][C:6]([NH:8][C:9]1[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=1[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[O:7].[N:20]1([C:26]2[CH:35]=[CH:34][C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[N:27]=2)[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1.C(N(CC)CC)C>C1(C)C=CC=CC=1>[N:27]1[C:28]2[C:33](=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:34]=[CH:35][C:26]=1[N:20]1[CH2:25][CH2:24][N:23]([CH2:2][CH2:3][CH2:4][CH2:5][C:6]([NH:8][C:9]2[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=2[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[O:7])[CH2:22][CH2:21]1
Reactant: CCOC(=O)C1=C(NC(=O)CCCCBr)CCCC1
Reactant: c1ccc2nc(N3CCNCC3)ccc2c1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCOC(=O)C1=C(NC(=O)CCCCN2CCN(c3ccc4ccccc4n3)CC2)CCCC1
Yield: 85.8 %

Procedure:
In 350 ml of toluene, 66.5 g of ethyl 2-(5-bromopentanoylamino)cyclohex-1-enecarboxylate as synthesized in above Step 4-1-B, 46.9 g of 2-piperazin-1-ylquinoline and 22.3 g of triethylamine were dissolved and heated under reflux for an overnight. The solvent was distilled off under reduced pressure, and ethyl acetate was added to the residue, followed by washing with saturated aqueous sodium hydrogencarbonate solution. The organic layer was dried over anhydrous magnesium sulfate, and from which the solvent was distilled off under reduced pressure. Purifying the residue on silica gel column chromatography (n-hexane:ethyl acetate:methanol=1:6:0.2) to provide 79.8 g (86%) of ethyl 2-[5-(4-quinolin-2-ylpiperazin-1-yl)pentanoylamino]cyclohex-1-enecarboxylate.
Reaction SMILES: [NH2:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[C:9]([NH2:19])[CH:10]=[C:11]([Br:18])[C:12]=3[OH:17])[C:7](=[O:20])[C:6]=2[C:5]([OH:21])=[C:4](Br)[CH:3]=1.C1[C:36]2[C:35](=[O:37])[C:34]3[C:29](=CC=CC=3)[C:28](=O)[C:27]=2C=CC=1>>[NH2:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[C:9]([NH2:19])[CH:10]=[C:11]([Br:18])[C:12]=3[OH:17])[C:7](=[O:20])[C:6]=2[C:5]([OH:21])=[C:4]([O:37][C:35]2[CH:36]=[CH:27][CH:28]=[CH:29][CH:34]=2)[CH:3]=1
Reactant: O=C1c2ccccc2C(=O)c2ccccc21
Reactant: Nc1cc(Br)c(O)c2c1C(=O)c1c(O)c(Br)cc(N)c1C2=O
Product: Nc1cc(Br)c(O)c2c1C(=O)c1c(O)c(Oc3ccccc3)cc(N)c1C2=O

Procedure:
When 11.7 g of 1,5-diamino-4,8-dihydroxy-3,7-dibromoanthraquinone, compared Example 349a, are used as the anthraquinone component in Example 415a, then 3.9 g, corresponding to 32% of theory, of 1,5-diamino-4,8-dihydroxy-3-phenoxy-7-bromoanthraquinone are obtained quite analogously, the colour shade of which, adsorbed on silica gel, is a blue of Indicator Number 14 (Colour Index Hue Indication Chart).
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[C:22]3[C:17](=[N:18][CH:19]=[N:20][C:21]=3[NH2:23])[N:16]([C:24]3[CH:29]=[CH:28][C:27](Br)=[CH:26][N:25]=3)[N:15]=2)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C)C=O.[H][H]>C(O)C.[Pd]>[O:1]([C:8]1[CH:9]=[CH:10][C:11]([C:14]2[C:22]3[C:17](=[N:18][CH:19]=[N:20][C:21]=3[NH2:23])[N:16]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=3)[N:15]=2)=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [H][H]
Reactant: Nc1ncnc2c1c(-c1ccc(Oc3ccccc3)cc1)nn2-c1ccc(Br)cn1
Agent: [Pd]
Solvent: CN(C)C=O
Solvent: CCO
Product: Nc1ncnc2c1c(-c1ccc(Oc3ccccc3)cc1)nn2-c1ccccn1

Procedure:
The more polar compound, 3-(4-phenoxyphenyl)-1-(5-bromo-2-pyridyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine, was suspended in absolute ethanol (10 mL) and N,N-dimethylformamide (5 mL) and 10% palladium on carbon (0.007 g) was added. The mixture was stirred under a balloon atmosphere of hydrogen for 18 hours. The mixture was filtered through pad of Celite® 521, washing with absolute ethanol. The solvent was removed in vacuo to give 3-(4-phenoxyphenyl)-1-(2-pyridyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.030 g, 0.00007 mol) as a white solid.
Reaction SMILES: CO[C:3](=[O:20])[C:4]1[C:9]([NH2:10])=[CH:8][N:7]=[C:6]([O:11][C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:13]=2[F:19])[CH:5]=1.[NH2:21][C:22](N)=[O:23]>O>[F:19][C:13]1[CH:14]=[C:15]([F:18])[CH:16]=[CH:17][C:12]=1[O:11][C:6]1[N:7]=[CH:8][C:9]2[NH:10][C:22](=[O:23])[NH:21][C:3](=[O:20])[C:4]=2[CH:5]=1
Reactant: COC(=O)c1cc(Oc2ccc(F)cc2F)ncc1N
Reactant: NC(N)=O
Solvent: O
Product: O=c1[nH]c(=O)c2cc(Oc3ccc(F)cc3F)ncc2[nH]1
Temperature: 25 °C
Reaction time: 2 h
Yield: 98.6 %

Procedure:
Compound (1C) (4.2 g, 15.0 mmol) and urea (9.0 g, 10 eq) were heated to a melt at 160° C. with stirring. After 2 hours, the melt solidified and by TLC the reaction was complete. The reaction mixture was cooled to room temperature, water (250 mL) was added, and the resulting mixture was left to stand for 1 hour. Then the solids were broken up with a spatula and the mixture was stirred vigorously for 1 hour. After suction filtration, a tan powder was collected which was air-dried in the frit for two days. Drying under high vacuum at 56° C. gave the title compound (1D) as a tan powder (4.307 g, (M−H)−=290, M.P.>300° C.).
Reaction SMILES: [NH:1]([C:8]1[S:9][C:10]2[N:18]=[CH:17][CH:16]=[CH:15][C:11]=2[C:12](=[O:14])[N:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Li+].[CH2:21](Br)[CH:22]=[CH2:23]>>[CH2:23]([N:13]1[C:12](=[O:14])[C:11]2[CH:15]=[CH:16][CH:17]=[N:18][C:10]=2[S:9][C:8]1=[N:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[CH:22]=[CH2:21]
Reactant: O=c1nc(Nc2ccccc2)sc2ncccc12
Reactant: C=CCBr
Agent: [H-]
Agent: [Li+]
Product: C=CCn1c(=Nc2ccccc2)sc2ncccc2c1=O

Procedure:
The reaction procedure of Example 11 was followed except that 383 mg of 2-anilino-4H-pyrido[3,2-e]-1,3-thiazin-4-one, 14 mg of lithium hydride and 0.13 ml of allyl bromide were used. As a result, 297 mg of 3-allyl-2-phenylimino-2,3-dihydro-4H-pyrido[3,2-e]-1,3-thiazin-4-one was obtained.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:13][N:12]=[CH:11][C:10]=2[CH2:14]O)=[CH:5][CH:4]=1.O1CCCC1.S(Cl)([Cl:23])=O>C1(C)C=CC=CC=1>[Cl:23][CH2:14][C:10]1[CH:11]=[N:12][O:13][C:9]=1[C:6]1[CH:7]=[CH:8][C:3]([S:2][CH3:1])=[CH:4][CH:5]=1
Reactant: O=S(Cl)Cl
Reactant: CSc1ccc(-c2oncc2CO)cc1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CSc1ccc(-c2oncc2CCl)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 96.7 %

Procedure:
To a mixture of 5-(4-methylthiophenyl)-4-isoxazolylmethanol (7.35 g), tetrahydrofuran (20 ml) and toluene (80 ml) was added dropwise thionyl chloride (5.93 g) at 0° C. and the mixture was stirred at room temperature for 2 hr. The reaction mixture was concentrated, saturated aqueous sodium hydrogencarbonate was added to the residue, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and 4-chloromethyl-5-(4-methylthiophenyl)isoxazole (7.70 g, yield 97%) was obtained as crystals from a fraction eluted with ethyl acetate-hexane (1:3, volume ratio) and recrystallized from diethyl ether-hexane to give a colorless prism. melting point: 73–74° C.
Reaction SMILES: [OH-:1].[Na+].Br[CH:4]([CH3:23])[C:5]([C:7]1[CH:12]=[CH:11][C:10]([C@H:13]2[CH2:18][CH2:17][C@H:16]([C:19]([O:21][CH3:22])=[O:20])[CH2:15][CH2:14]2)=[CH:9][CH:8]=1)=[O:6]>O.CN(C=O)C>[C:5]([C:7]1[CH:12]=[CH:11][C:10]([C@H:13]2[CH2:18][CH2:17][C@H:16]([C:19]([O:21][CH3:22])=[O:20])[CH2:15][CH2:14]2)=[CH:9][CH:8]=1)(=[O:6])[CH:4]([CH3:23])[OH:1]
Reactant: [OH-]
Reactant: COC(=O)[C@H]1CC[C@H](c2ccc(C(=O)C(C)Br)cc2)CC1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)[C@H]1CC[C@H](c2ccc(C(=O)C(C)O)cc2)CC1
Reaction time: 0.67 h

Procedure:
Sodium hydroxide (370 mg, 9.25 mmol) in water (2 mL) was added to a stirred solution of methyl trans-4-[4-(2-bromopropanoyl)phenyl]cyclohexanecarboxylate (prepared as described in Patent Application WO2004/047755) (3.264 g, 9.25 mmol) in DMF (10 mL). The mixture was stirred for 40 minutes then extracted with ether (5×20 mL). The extracts were combined, dried and concentrated. The crude product was purified by flash column chromatography eluting with 20-40% EtOAc/hexanes to give the title compound (1.76 g, 66%) as a solid; 1H NMR δ 7.94 (2H, d), 7.39 (2H, d), 5.29 (1H, d), 5.08-4.98 (1H, m), 3.62 (3H, s), 2.68-2.54 (1H, m), 2.48-2.35 (1H, m), 2.08-1.94 (2H, m), 1.90-1.79 (2H, m), 1.60-1.40 (4H, m), 1.28 (3H, s); MS 313 (M+Na)+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][C:11]([OH:13])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:14]([O:21][C:22](=[O:32])[CH2:23][CH:24]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[NH2:25])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[CH2:14]([O:21][C:22](=[O:32])[CH2:23][CH:24]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[NH:25][C:11](=[O:13])[CH2:10][CH2:9][NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: CC(C)(C)OC(=O)NCCC(=O)O
Reactant: NC(CC(=O)OCc1ccccc1)c1ccccc1
Product: CC(C)(C)OC(=O)NCCC(=O)NC(CC(=O)OCc1ccccc1)c1ccccc1

Procedure:
N-(t-butoxycarbonyl)-β-alanine was reacted with DL-3-phenyl-β-alanine benzyl ester to give DL-N-[N-(t-butoxycarbonyl)-β-alanyl]-3-phenyl-β-alanine benzyl ester, m.p. 124.5°-126° C.