Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O-])(O)=O.[Na+].[SH:6][C:7]1[CH:8]=[C:9]([CH2:13][OH:14])[CH:10]=[CH:11][CH:12]=1.Br[C:16]1[CH:17]=[CH:18][C:19]([C:22]#[N:23])=[N:20][CH:21]=1>CN(C=O)C.C(OCC)(=O)C>[OH:14][CH2:13][C:9]1[CH:8]=[C:7]([S:6][C:16]2[CH:17]=[CH:18][C:19]([C:22]#[N:23])=[N:20][CH:21]=2)[CH:12]=[CH:11][CH:10]=1
Reactant: OCc1cccc(S)c1
Reactant: N#Cc1ccc(Br)cn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: N#Cc1ccc(Sc2cccc(CO)c2)cn1
Yield: 58.5 %

Procedure:
Add NaHCO3 (12.0 g, 143 mmol) to a solution of (3-mercaptophenyl)methanol (10.0 g, 71.3 mmol) and 5-bromopicolinonitrile (13.0 g, 71.3 mmol) in DMF. Heat the mixture overnight. Dilute with ethyl acetate. Wash the mixture with water. Dry, filter and concentrate to afford the title compound (10.1 g, 59%) (Solidifies after standing). MS (APCI-pos) m/z (rel intensity): 243 (M+H, 100%).
Reaction SMILES: C(O[C:5](=[O:7])[CH3:6])(=O)C.[Br:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH:16]([NH2:18])[CH3:17])=[CH:11][CH:10]=1>CC(O)=O>[Br:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:15][CH:16]([NH:18][C:5](=[O:7])[CH3:6])[CH3:17])=[CH:13][CH:14]=1
Reactant: CC(N)Cc1ccc(Br)cc1
Reactant: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: CC(=O)NC(C)Cc1ccc(Br)cc1
Temperature: 25 °C

Procedure:
17.0 mL (179.7 mmol) acetic anhydride are added to a mixture of 24.2 g (113 mmol) 1-(4-bromophenyl)propane-2-amine and 20 mL AcOH and the reaction mixture is stirred at r.t. over night. The solvent is evaporated in vacuo, and the residue partitonated between TBME and a saturated aq. NaHCO3 solution. The layers are separated and the organic layer is washed with water, dried with Na2SO4, filtered and the solvent is removed in vacuo. The crude product is triturated with DIPE.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=1[CH:4]=[CH:5][CH2:6]Cl.[NH2:12][C:13]1[S:14][C:15]2[CH2:16][CH2:17][NH:18][CH2:19][CH2:20][C:21]=2[N:22]=1.C(OCC)(=O)C>C(Cl)(Cl)Cl>[NH2:12][C:13]1[S:14][C:15]2[CH2:16][CH2:17][N:18]([CH2:6][CH:5]=[CH:4][C:3]3[CH:8]=[CH:9][CH:10]=[CH:11][C:2]=3[CH3:1])[CH2:19][CH2:20][C:21]=2[N:22]=1
Reactant: Cc1ccccc1C=CCCl
Reactant: Nc1nc2c(s1)CCNCC2
Solvent: ClC(Cl)Cl
Solvent: CCOC(C)=O
Product: Cc1ccccc1C=CCN1CCc2nc(N)sc2CC1
Yield: 52 %

Procedure:
Prepared from 2-methyl-cinnamyl chloride and 2 equivalents of 2-amino-4,5,7,8-tetrahydro-6H-thiazolo[5,4-d]azepine in chloroform. Yield: 52% of theory, Melting point: 112°-115° C. (ethyl acetate).
Reaction SMILES: C1(S([N:10]2[C:18]3[C:13](=[CH:14][C:15]([C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=4)=[CH:16][CH:17]=3)[CH:12]=[CH:11]2)(=O)=O)C=CC=CC=1.[CH:26]1(O)[CH2:30][CH2:29][CH2:28][CH2:27]1.CC([O-])(C)C.[K+]>C1(C)C=CC=CC=1.C1COCC1.[Cl-].[Na+].O>[Cl:25][C:21]1[CH:20]=[C:19]([C:15]2[CH:14]=[C:13]3[C:18](=[CH:17][CH:16]=2)[N:10]([CH:26]2[CH2:30][CH2:29][CH2:28][CH2:27]2)[CH:11]=[CH:12]3)[CH:24]=[CH:23][CH:22]=1
Reactant: OC1CCCC1
Reactant: O=S(=O)(c1ccccc1)n1ccc2cc(-c3cccc(Cl)c3)ccc21
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Solvent: O
Product: Clc1cccc(-c2ccc3c(ccn3C3CCCC3)c2)c1
Temperature: 150 °C

Procedure:
A 5 mL conical glass microwave reaction vessel with stir bar, sealed with a septum and swept with nitrogen, was charged with a solution of 0.08 g (0.22 mmol) 1-(benzenesulfonyl-5-(3-chlorophenyl)-1H-indole in 1.2 mL anhydrous toluene. 32 μL (0.33 mmol) cyclopentanol was added with stirring, followed by 0.3 mL 1.0M solution of KOt-Bu in THF. The septum was removed and the vial was sealed with a cap. The reaction vessel was heated to 150° C. for 350 seconds in a microwave reactor (Personal Chemistry Inc., Milford, Mass.) and allowed to cool to room temperature. An aliquot removed for LC analysis indicated that the reaction was complete. The crude reaction mixture was taken up in 10 mL of brine and extracted with EtOAc. The organic phase was filtered through an 8 mL aqueous/organic separation column (Alltech Associates, Inc., Deerfield, Ill.) and was concentrated. The residue was purified by RP-HPLC (see Note 1 below) to give 11.2 mg 5-(3-chlorophenyl)-1-cyclopentyl-1H-indole as an oil.
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([O:10][CH:11]([F:13])[F:12])[CH:7]=[C:6]([F:14])[C:3]=1[CH2:4][OH:5].[C:15]([OH:22])(=[O:21])/[CH:16]=[CH:17]/[C:18]([OH:20])=[O:19].[CH2:23]([C@@H:25]1[CH2:30][NH:29][CH2:28][CH2:27][N:26]1[C:31](OCC1C=CC(OC(F)F)=CC=1)=[O:32])C>>[C:15]([OH:22])(=[O:21])/[CH:16]=[CH:17]/[C:18]([OH:20])=[O:19].[CH3:23][C@@H:25]1[CH2:30][NH:29][CH2:28][CH2:27][N:26]1[C:31]([O:5][CH2:4][C:3]1[C:2]([F:1])=[CH:9][C:8]([O:10][CH:11]([F:12])[F:13])=[CH:7][C:6]=1[F:14])=[O:32]
Reactant: OCc1c(F)cc(OC(F)F)cc1F
Reactant: CC[C@@H]1CNCCN1C(=O)OCc1ccc(OC(F)F)cc1
Agent: O=C(O)/C=C/C(=O)O
Product: C[C@@H]1CNCCN1C(=O)OCc1c(F)cc(OC(F)F)cc1F

Procedure:
(R)-2,6-Difluoro-4-difluoromethoxybenzyl 2-methylpiperazine-1-carboxylate fumarate was prepared from 2,6-difluoro-4-difluoromethoxybenzyl alcohol and (R) 1-chlorocarbonyl-2-methyl-4-tert-butoxycarbonylpiperazine according to the methods described for Examples 54 to give the product as a white solid (2.9%); HPLC (XTERRA, 50/80, 220 nm) 86.0% (1.55 min); NMR δH (400 MHz, DMSO-d6) 1.154(3H, d, J 7.0 Hz), 2.639(1H, bm), 2.863(2H, bm), 3.007(2H, bm), 3.714(1H, bd), 4.122(1H, bs), 5.106(2H, q), 6.590(2H, s), 7.108(2H, d, J 8.5 Hz) and 7.360(1H, t, J 73 Hz).
Reaction SMILES: COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:10])=CC=1.[CH3:23][C@H:24]1[C@@:29]23[C:35]([O:36][C@H:27]([CH2:28]2)[CH2:26][C@@H:25]1[C:39]1[CH:40]=[CH:41][C:42]2[O:47][CH2:46][O:45][C:43]=2[CH:44]=1)=[CH:34][C:32](=O)[C:31]([O:37][CH3:38])=[CH:30]3>C1(C)C=CC=CC=1>[O:47]1[C:42]2[CH:41]=[CH:40][C:39]([CH:25]3[CH:24]([CH3:23])[C:29]45[CH2:28][CH:27]([O:36][C:35]4=[CH:34][C:32](=[S:10])[C:31]([O:37][CH3:38])=[CH:30]5)[CH2:26]3)=[CH:44][C:43]=2[O:45][CH2:46]1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: COC1=C[C@]23C[C@H](C[C@H](c4ccc5c(c4)OCO5)[C@H]2C)OC3=CC1=O
Solvent: Cc1ccccc1
Product: COC1=CC23CC(CC(c4ccc5c(c4)OCO5)C2C)OC3=CC1=S
Temperature: 60 °C

Procedure:
Lawesson's reagent (119.3 mg, 0.3 mmoles) is added to a stirred solution of futoenone (200 mg, 0.59 mmoles) in toluene (4 ml). The reaction is heated to 60° C. in an oil bath for 2-3 h. TLC of the reaction mixture shows almost complete conversion of starting material. The reaction turns from a green to violet upon heating. The reaction is concentrated in vacuo and purified by MPLC on silica gel using ethyl acetate. A purple foam (154.2 mg, 73.5%) forms upon drying in vacuo. M+(CI)=357. 1H NMR ppm: 0.59 (3H, d), 1.72 (1H, t), 2.07 (1H, m), 2.21 (1H, d), 2.30 (1H, m), 2.43 (1H, m), 2.58 (1H, m), 3.71 (3H, s), 5.08 (1H, t), 5.46 (1H, s), 5.92 (2H, s), 6.65 (4H, m).
Reaction SMILES: C(N(CC)CC)C.[Cl:8][C:9]1[C:18]([N+:19]([O-:21])=[O:20])=[C:17](Cl)[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=1.[NH2:23][CH2:24][C:25]([NH2:28])([CH3:27])[CH3:26].O>CN1CCCC1=O>[Cl:8][C:9]1[C:18]([N+:19]([O-:21])=[O:20])=[C:17]([NH:23][CH2:24][C:25]([CH3:27])([NH2:28])[CH3:26])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=1
Reactant: O=[N+]([O-])c1c(Cl)nc2ccccc2c1Cl
Reactant: CC(C)(N)CN
Solvent: O
Solvent: CN1CCCC1=O
Solvent: CCN(CC)CC
Product: CC(C)(N)CNc1c([N+](=O)[O-])c(Cl)nc2ccccc12
Temperature: 25 °C
Reaction time: 5 h

Procedure:
Triethylamine (75 mL, 0.54 mol) was slowly added to a solution of 2,4-dichloro-3-nitroquinoline (André et al, U.S. Pat. No. 4,988,815, Example 2, 114 g, 0.470 mol) in anhydrous 1-methyl-2-pyrrolidinone (NMP) (450 mL), and the resulting black solution was cooled to 0° C. A solution of 1,2-diamino-2-methylpropane (42 g, 0.54 mol) in anhydrous NMP (42 mL) was added dropwise over a period of three hours. After the addition was complete, the reaction was allowed to warm to ambient temperature, stirred for five hours, and poured slowly into warm water (4 L) with vigorous stirring. A yellow precipitate formed, and the suspension was stirred for one hour at ambient temperature. The precipitate was isolated by filtration and washed with cold water until the filtrate was colorless. The solid was dissolved in dichloromethane (4 L), and the resulting solution was washed sequentially with saturated aqueous sodium carbonate and brine, dried over magnesium sulfate and sodium sulfate, filtered through a layer of CELITE filter agent, and concentrated under reduced pressure to provide 130 g of N1-(2-chloro-3-nitroquinolin-4-yl)-2-methylpropane-1,2-diamine as a bright yellow powder.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:11]2[C:15]([CH:16]=[C:17]3[S:21][C:20](=[O:22])[NH:19][C:18]3=[O:23])=[CH:14][N:13]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[N:12]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][CH3:10].[H-].[Na+].Br[CH2:33][CH3:34].O>CN(C)C=O>[Br:1][C:2]1[CH:3]=[C:4]([C:11]2[C:15]([CH:16]=[C:17]3[S:21][C:20](=[O:22])[N:19]([CH2:33][CH3:34])[C:18]3=[O:23])=[CH:14][N:13]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[N:12]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][CH3:10]
Reactant: CCBr
Reactant: CCOc1ccc(-c2nn(-c3ccccc3)cc2C=C2SC(=O)NC2=O)cc1Br
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOc1ccc(-c2nn(-c3ccccc3)cc2C=C2SC(=O)N(CC)C2=O)cc1Br
Temperature: 25 °C
Reaction time: 2 h
Yield: 49.7 %

Procedure:
5-[3-(3-Bromo-4-ethoxy-phenyl)-1-phenyl-1H-pyrazol-4-yl-methylene]-thiazolidine-2,4-dione (Compound No. 77, 0.10 mg, 0.21 mmol) was dissolved in 1.00 mL of anhydrous dimethylformamide. Sodium hydride (12.74 mg, 0.32 mmol) was added under nitrogen atmosphere and bromoethane (23.72 μL, 0.32 mmol) was added 5 minutes later. The mixture was stirred at room temperature for 2 hours. When the reaction was completed, 10 mL of water was added and the solution was extracted with dichloromethane (10 mL×2 times). The organic layer was washed with brine and dried with anhydrous magnesium sulfate. The solvent was removed under reduced pressure. The product was purified with silica gel chromatography (n-hexane/ethyl acetate=4:1) to obtain 52 mg (49.2%) of the target product in yellow solid form.
Reaction SMILES: [CH:1]1([S:4]([NH:7][C:8]([C:10]2([NH:15][C:16]([CH:18]3[CH2:22][CH:21]([O:23][C:24]4[CH:29]=[CH:28][N:27]=[C:26](Cl)[N:25]=4)[CH2:20][CH:19]3[C:31]([N:33]([CH2:35][CH2:36][CH2:37][CH2:38][CH:39]=[CH2:40])[CH3:34])=[O:32])=[O:17])[CH2:12][CH:11]2[CH:13]=[CH2:14])=[O:9])(=[O:6])=[O:5])[CH2:3][CH2:2]1.[C:41]1(B(O)O)[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH:1]1([S:4]([NH:7][C:8]([C:10]2([NH:15][C:16]([CH:18]3[CH2:22][CH:21]([O:23][C:24]4[CH:29]=[CH:28][N:27]=[C:26]([C:41]5[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=5)[N:25]=4)[CH2:20][CH:19]3[C:31]([N:33]([CH2:35][CH2:36][CH2:37][CH2:38][CH:39]=[CH2:40])[CH3:34])=[O:32])=[O:17])[CH2:12][CH:11]2[CH:13]=[CH2:14])=[O:9])(=[O:6])=[O:5])[CH2:3][CH2:2]1
Reactant: C=CCCCCN(C)C(=O)C1CC(Oc2ccnc(Cl)n2)CC1C(=O)NC1(C(=O)NS(=O)(=O)C2CC2)CC1C=C
Reactant: OB(O)c1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Product: C=CCCCCN(C)C(=O)C1CC(Oc2ccnc(-c3ccccc3)n2)CC1C(=O)NC1(C(=O)NS(=O)(=O)C2CC2)CC1C=C
Temperature: 120 °C
Yield: 8.5 %

Procedure:
Compound 10f (43 mg, 72.4 mmol), phenylboronic acid (13 mg, 109 μmol) and (PPh3)2PdCl2 (5 mg, 7.2 umol) were mixed in a microwave reaction vial and heated in the microwave at 120° C. for 20 min. The reaction mixture was then quenched by addition of citric acid (20 ml) and extracted 2 times with DCM (10 ml). The combined organic phases were washed with water (2×10 ml) and brine (10 ml), dried over MgSO4 and filtered. The solvent was removed in vacuo and the crude product was purified by preparative LC-MS which gave the title compound (5.9 mg, 13%), (ESI+)=636 (MH+).
Reaction SMILES: Cl.[Br:2][C:3]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][C:4]=1[CH2:5][CH:6]1[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1.[OH-].[Na+].[CH2:20](Br)[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>C(#N)C>[CH2:20]([N:9]1[CH2:8][CH2:7][CH:6]([CH2:5][C:4]2[CH:12]=[C:13]([O:16][CH3:17])[CH:14]=[CH:15][C:3]=2[Br:2])[CH2:11][CH2:10]1)[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: BrCCc1ccccc1
Reactant: COc1ccc(Br)c(CC2CCNCC2)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CC#N
Product: COc1ccc(Br)c(CC2CCN(CCc3ccccc3)CC2)c1
Yield: 58.1 %

Procedure:
4-(2-Bromo-5-methoxybenzyl)piperidine hydrochloride (192 mg, 0.60 mmol) was neutralized with a 1N-aqueous sodium hydroxide solution, followed by extraction with diethyl ether, whereby a corresponding free compound was obtained. A mixture of the free compound, phenethyl bromide (110 mg, 0.594 mmol), potassium carbonate (250 mg, 1.81 mmol), potassium iodide (10.3 mg, 0.062 mmol) and acetonitrile (3.6 mL) was heated under reflux under nitrogen for 8 hours. After the inorganic matters were filtered off, the filtrate was concentrated under reduced pressure and the concentration residue was purified by a flash silica gel column chromatography (hexane/ethyl acetate/triethylamine=5/15/0 to 5/15/1) to obtain N-phenethyl-4-(2-bromo-5-methoxy-benzyl)piperidine (134 mg, 58%) as an oil.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][C:11]([NH2:13])=[O:12])=[CH:2]1.C[O:15][C:16]([C:18]([C:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[NH:22][CH:21]=1)=O)=O.CC(C)([O-])C.[K+].CCOC(C)=O>C1COCC1.[Cl-].[Na+].O.O>[CH:6]1[CH:5]=[C:4]2[C:3]([C:10]3[C:11](=[O:12])[NH:13][C:16](=[O:15])[C:18]=3[C:20]3[C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[NH:22][CH:21]=3)=[CH:2][NH:1][C:9]2=[CH:8][CH:7]=1
Reactant: NC(=O)Cc1c[nH]c2ccccc12
Reactant: COC(=O)C(=O)c1c[nH]c2ccccc12
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C1NC(=O)C(c2c[nH]c3ccccc23)=C1c1c[nH]c2ccccc12
Reaction time: 3 h
Yield: 108.6 %

Procedure:
A suspension of indole-3-acetamide (1.00 g, 5.74 mmol) and methyl indolyl-3-glyoxylate (1.28 g, 6.30 mmole) in THF (10 mL) was treated with a 1 molar solution of potassium tert-butoxide in THF (17.2 mL, 17.2 mmol) at room temperature under N2. The resultant dark reaction mixture was stirred 3 hrs. at room temperature and was then treated with concentrated (37%) HCl (8 mL) allowing the reaction to exotherm. The reaction was worked up extractively using EtOAc (125 mL), water (2× 100 mL), brine (25 ml) and the organic layer dried (MgSO4) and solvent removed in vacuo to give a solid that was purified by flash chromatography using a gradient of 2:1 to 1:1 hexanes:EtOAc to give 2.04 g (100%) of arcyriarubin A [1.28 g (68%) when using glyoxylyl chloride]. 3,4-(3-indolyl-1H-pyrrole-2,5-dione could also be recrystallized from EtOH to give a stiochiometric ethanol monosolvate in high purity (>99%) and yield (88%). NMR. MS (FD) m/z=327 (M+, 100%). Analytical calculated for C22H19N3O3C, 70.76; H, 5.13; N, 11.25. Found C, 70.97; H, 5.22; N, 11.12.
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:8][CH2:7][N:6]([C:9]2[C:14](F)=[CH:13][N:12]=[C:11]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([N:23]4[CH2:28][CH2:27][N:26]([C:29](=[O:31])[CH3:30])[CH2:25][CH2:24]4)=[CH:19][CH:18]=3)[N:10]=2)[CH2:5][CH2:4]1.[Cl:32]C1N=C(Cl)C(Cl)=CN=1>>[NH2:1][CH2:2][CH:3]1[CH2:8][CH2:7][N:6]([C:9]2[C:14]([Cl:32])=[CH:13][N:12]=[C:11]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([N:23]4[CH2:28][CH2:27][N:26]([C:29](=[O:31])[CH3:30])[CH2:25][CH2:24]4)=[CH:19][CH:18]=3)[N:10]=2)[CH2:5][CH2:4]1
Reactant: CC(=O)N1CCN(c2ccc(Nc3ncc(F)c(N4CCC(CN)CC4)n3)cc2)CC1
Reactant: Clc1ncc(Cl)c(Cl)n1
Product: CC(=O)N1CCN(c2ccc(Nc3ncc(Cl)c(N4CCC(CN)CC4)n3)cc2)CC1

Procedure:
The titled compound was synthesized analogously as compound 1-(4-(4-(4-(4-(aminomethyl)piperidin-1-yl)-5-fluoropyrimidin-2-ylamino)phenyl)piperazin-1-yl)ethanone, by using 2,4,5-trichloropyrimidine. MS 444.3 and 446.3 (M+H, Cl pattern); UV 210.7, 265.7 nm.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[NH:8]1[C:16]2[C:11](=[CH:12][C:13]([NH:17][C:18]3[C:19]4[S:26][C:25]([C:27]5[CH:34]=[CH:33][C:30]([CH:31]=O)=[CH:29][CH:28]=5)=[CH:24][C:20]=4[N:21]=[CH:22][N:23]=3)=[CH:14][CH:15]=2)[CH:10]=[CH:9]1>>[NH:8]1[C:16]2[C:11](=[CH:12][C:13]([NH:17][C:18]3[C:19]4[S:26][C:25]([C:27]5[CH:34]=[CH:33][C:30]([CH2:31][N:5]6[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]6)=[CH:29][CH:28]=5)=[CH:24][C:20]=4[N:21]=[CH:22][N:23]=3)=[CH:14][CH:15]=2)[CH:10]=[CH:9]1
Reactant: CN1CCNCC1
Reactant: O=Cc1ccc(-c2cc3ncnc(Nc4ccc5[nH]ccc5c4)c3s2)cc1
Product: CN1CCN(Cc2ccc(-c3cc4ncnc(Nc5ccc6[nH]ccc6c5)c4s3)cc2)CC1

Procedure:
The title compound was prepared from N-methylpiperazine and 4-[4-(1H-indol-5-ylamino)-thieno[3,2-d]pyrimidin-6-yl]-benzaldehyde by the procedure analogous to example 17.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[CH3:12].CC1(C)C(C)(C)OB([C:21]2[CH:31]=[CH:30][CH:29]=[CH:28][C:22]=2[C:23]([O:25][CH2:26][CH3:27])=[O:24])O1.C1(C)C=CC=CC=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[CH3:12][C:3]1[CH:4]=[C:5]([C:6]([O:8][CH3:9])=[O:7])[CH:10]=[CH:11][C:2]=1[C:21]1[C:22]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: COC(=O)c1ccc(Br)c(C)c1
Reactant: CCOC(=O)c1ccccc1B1OC(C)(C)C(C)(C)O1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: CCOC(=O)c1ccccc1-c1ccc(C(=O)OC)cc1C
Temperature: 25 °C
Yield: 80.6 %

Procedure:
Under a nitrogen atmosphere, to a mixture of methyl 4-bromo-3-methylbenzoate (2.291 g), ethyl 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (3.313 g), toluene (20 ml), water (10 ml) and tripotassium phosphate (4.246 g) was added tetrakis(triphenylphosphine)palladium(0) (0.578 g) at room temperature, and the mixture was stirred with heating under reflux overnight. The reaction mixture was cooled to room temperature, and partitioned in a separatory funnel. The organic layer was successively washed with water and saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure and the obtained residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=95/5) to give the title compound (2.404 g, 81%)
Reaction SMILES: [Br-].[C:2]([NH:5][C:6]1[S:7][CH:8]=[C:9]([CH2:11][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[N:10]=1)(=[O:4])[CH3:3].[OH:31][C:32]1[CH:39]=[CH:38][C:35]([CH:36]=O)=[CH:34][CH:33]=1.CC(C)([O-])C.[K+].O>CN(C)C=O.C(OCC)(=O)C>[OH:31][C:32]1[CH:39]=[CH:38][C:35]([CH:36]=[CH:11][C:9]2[N:10]=[C:6]([NH:5][C:2](=[O:4])[CH3:3])[S:7][CH:8]=2)=[CH:34][CH:33]=1
Reactant: CC(=O)Nc1nc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cs1
Reactant: O=Cc1ccc(O)cc1
Agent: CC(C)(C)[O-]
Agent: [Br-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)Nc1nc(C=Cc2ccc(O)cc2)cs1
Temperature: 90 °C
Reaction time: 12 h
Yield: 64.4 %

Procedure:
{[2-(Acetylamino)-1,3-thiazol-4-yl]methyl}(triphenyl)phosphoniumbromide (261.1 mg, 0.525 mmol) and 4-hydroxybenzaldehyde (183.2 mg, 1.50 mmol) were dissolved in anhydrous N,N-dimethylformamide (2 ml), and potassium tert-butoxide (56.1 mg, 0.50 mmol) was added at 0° C. After stirring at 90° C. for 12 hr, the mixture was cooled to room temperature. Water and ethyl acetate were added, and the mixture was stirred, stood still and then partitioned. The aqueous layer was extracted with ethyl acetate, and the combined organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The concentrated residue was purified by silica gel column chromatography (FUJI SILYSIA CHEMICAL LTD. BW-300SP 25 g, ethyl acetate:hexane=4:6→5:5) to give N-{4-[2-(4-hydroxyphenyl)vinyl]-1,3-thiazol-2-yl}acetamide (87.9 mg, 0.338 mmol, yield 67.5%) as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([Br:8])[C:5]([O:9]C)=[CH:4][C:3]=1[N:11]1[C:15](=[O:16])[N:14]([CH:17]([F:19])[F:18])[C:13]([CH3:20])=[N:12]1.B(Br)(Br)Br>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[C:6]([Br:8])[C:5]([OH:9])=[CH:4][C:3]=1[N:11]1[C:15](=[O:16])[N:14]([CH:17]([F:18])[F:19])[C:13]([CH3:20])=[N:12]1
Reactant: COc1cc(-n2nc(C)n(C(F)F)c2=O)c(Br)cc1Br
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Cc1nn(-c2cc(O)c(Br)cc2Br)c(=O)n1C(F)F
Temperature: 25 °C
Reaction time: 18 h
Yield: 96.1 %

Procedure:
A mixture of 17.2 g (0.042 mole) of 1-(2,4-dibromo-5-methoxyphenyl)-4-difluoromethyl-4,5-dihydro-3-methyl-1,2,4-triazol-5-(1H)-one and 50.6 g (0.020 mole) of boron tribromide in 100 mL of methylene chloride was stirred at room temperature for 18 hours. The mixture was washed with 50 mL of water, and the organic phase was dried over anhydrous magnesium sulfate. This mixture was filtered, and the filtrate was evaporated under reduced pressure to yield 16.1 g of 1-(2,4-dibromo-5-hydroxyphenyl)4-difluoromethyl-4,5-dihydro-3-methyl-1,2,4-triazol-5-(1H)-one as a solid.
Reaction SMILES: [Cl:1][C:2]1[N:7]([CH3:8])[C:6](=[O:9])[C:5]([O:10]C)=[CH:4][N:3]=1.B(Br)(Br)Br>C(Cl)Cl>[Cl:1][C:2]1[N:7]([CH3:8])[C:6](=[O:9])[C:5]([OH:10])=[CH:4][N:3]=1
Reactant: COc1cnc(Cl)n(C)c1=O
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Cn1c(Cl)ncc(O)c1=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 100.4 %

Procedure:
To a solution of 1.18 g (6.76 mmol) 2-chloro-5-methoxy-3-methylpyrimidin-4(3H)-one in 35 ml CH2Cl2 was added 47.3 ml (47.3 mmol) of a 1 M solution of BBr3 in CH2Cl2. The reaction mixture was stirred for 1 h, cooled to 0° C., quenched with 100 ml MeOH, and concentrated in vacuo. The solid was suspended in ether, and collected by filtration to give 1.09 g (100% yield) of 2-chloro-5-hydroxy-3-methylpyrimidin-4(3H)-one. LCMS [M+H]+=161.0.
Reaction SMILES: C(N)(=S)C1C=CC=CC=1.[Cl:10][C:11]1[CH:12]=[C:13]([C:23]2[N:24]=[C:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[S:26][CH:27]=2)[CH:14]=[C:15]([Cl:22])[C:16]=1[O:17][CH2:18][CH2:19][CH2:20]Cl.[CH2:34]([NH:38][CH2:39][CH2:40][CH2:41][CH3:42])[CH2:35][CH2:36][CH3:37]>>[Cl:22][C:15]1[CH:14]=[C:13]([C:23]2[N:24]=[C:25]([C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)[S:26][CH:27]=2)[CH:12]=[C:11]([Cl:10])[C:16]=1[O:17][CH2:18][CH2:19][CH2:20][N:38]([CH2:39][CH2:40][CH2:41][CH3:42])[CH2:34][CH2:35][CH2:36][CH3:37]
Reactant: CCCCNCCCC
Reactant: ClCCCOc1c(Cl)cc(-c2csc(-c3ccccc3)n2)cc1Cl
Agent: NC(=S)c1ccccc1
Product: CCCCN(CCCC)CCCOc1c(Cl)cc(-c2csc(-c3ccccc3)n2)cc1Cl

Procedure:
Following the procedure of Example 1, 3,5-dichloro-4-hydroxyacetophenone (10 g, 49 mmol) was used in place of p-hydroxyacetophenone with 1-bromo-3-chloropropane (21 ml, 0.20 mol) to give 10.5 g (76% yield) of 3,5-dichloro-4-chloropropoxyacetophenone. 1H NMR (CDCl3): δ7.88 (s, 2H), 4.24 (t, J=5.7 Hz, 2H), 3.86 (t, J=6.4 Hz, 2H), 2.57 (s, 3H), 2.24 (m, 2H). Bromination (6.0 g, 37 mmol) followed by condensation with thiobenzamide (2.6 g, 19 mmol) of this product in accordance with Example 1 afforded 4-[3,5-dichloro-4-(chloropropoxy)phenyl]-2-phenylthiazole in 98% yield (7.4 g). 1H NMR (CD3OD): δ8.08-7.48 (m, 8H), 4.22 (t, J=5.7 Hz, 2H), 3.89 (t, J=6.4 Hz, 2H), 2.32 (m, 2H). Treatment of this product (3.9 g, 9.8 mmol) with dibutylamine in accordance with Example 1 gave 2.5 g (48% yield) of the free base of the title compound which was converted to the HCl salt, mp 167°-169° C. IR(KBr): 2440 cm-1, MS: 491(MH+). 1H NMR (CD3OD): 8.05-7.46 (m, 8H), 4.20 (t, J=5.0 Hz, 2H), 3.64-3.16 (m, 6H), 2.28 (m, 2H), 1.85-1.34 (m, 8H), 1.01 (m, 6H).