Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([F:13])[CH:5]=[C:6]2[C:11]=1[N:10]=[C:9](Cl)[N:8]=[CH:7]2.[NH2:14][C:15]1[CH:20]=[CH:19][C:18]([S:21]([NH2:24])(=[O:23])=[O:22])=[CH:17][CH:16]=1.C(OCC)(=O)C>C(O)(C)C>[Br:1][C:2]1[CH:3]=[C:4]([F:13])[CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([NH:14][C:15]1[CH:20]=[CH:19][C:18]([S:21]([NH2:24])(=[O:22])=[O:23])=[CH:17][CH:16]=1)[N:8]=[CH:7]2
Reactant: Fc1cc(Br)c2nc(Cl)ncc2c1
Reactant: Nc1ccc(S(N)(=O)=O)cc1
Solvent: CC(C)O
Solvent: CCOC(C)=O
Product: NS(=O)(=O)c1ccc(Nc2ncc3cc(F)cc(Br)c3n2)cc1
Temperature: 120 °C
Reaction time: 0.5 h
Yield: 81 %

Procedure:
To a 0.4M suspension of 8-bromo-2-chloro-6-fluoroquinazoline in isopropanol was added 4-aminobenzensulfonamide (1 eq). The reaction mixture was heated to 120° C. in an oil bath for 2 days. LCMS showed that reaction was complete under the condition. Ethyl acetate was added to the reaction flask and the suspension was stirred at ambient temperature for 30 min and was filtered. Filter cake was rinsed with hexane and dried in vacuum to give product in 81% yield. ES/MS m/z 397/399 (MH+).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10](Cl)(=[O:12])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].[Cl:14][C:15]1[CH:16]=[C:17]([N:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)[CH:18]=[CH:19][CH:20]=1>C(N(CC)CC)C>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([N:24]2[CH2:23][CH2:22][N:21]([C:17]3[CH:18]=[CH:19][CH:20]=[C:15]([Cl:14])[CH:16]=3)[CH2:26][CH2:25]2)(=[O:12])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: Clc1cccc(N2CCNCC2)c1
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1ccc(S(=O)(=O)N2CCN(c3cccc(Cl)c3)CC2)cc1

Procedure:
In the manner given in Example 1A, p-nitrobenzenesulfonyl chloride, 1-(m-chlorophenyl)piperazine, and triethylamine are stirred at reflux to give 1-[(p-nitrophenyl)sulfonyl]-4-(m-chlorophenyl)piperazine.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:20][N:21]([CH3:26])[CH2:22][CH2:23][CH2:24][OH:25].CCOC(/N=N/C(OCC)=O)=O.[CH2:39]([C:41]1[CH:63]=[CH:62][CH:61]=[CH:60][C:42]=1[NH:43][C:44]1[C:53]2[C:48](=[CH:49][C:50]([O:55][CH3:56])=[C:51](O)[CH:52]=2)[N:47]=[CH:46][C:45]=1[C:57]([NH2:59])=[O:58])[CH3:40]>C(Cl)Cl.C1COCC1>[CH3:20][N:21]([CH3:26])[CH2:22][CH2:23][CH2:24][O:25][C:51]1[CH:52]=[C:53]2[C:48](=[CH:49][C:50]=1[O:55][CH3:56])[N:47]=[CH:46][C:45]([C:57]([NH2:59])=[O:58])=[C:44]2[NH:43][C:42]1[CH:60]=[CH:61][CH:62]=[CH:63][C:41]=1[CH2:39][CH3:40]
Reactant: CN(C)CCCO
Reactant: CCc1ccccc1Nc1c(C(N)=O)cnc2cc(OC)c(O)cc12
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: C1CCOC1
Product: CCc1ccccc1Nc1c(C(N)=O)cnc2cc(OC)c(OCCCN(C)C)cc12

Procedure:
Polymer-bound Triphenylphosphine (0.15 g, 0.44 mmol) and 3-dimethylamino-1-propanol (26 μl, 0.22 mmol) was suspended and dissloved in CH2Cl2 and THF at −15° C. and stirred for 30 min. DEAD (70 μl, 0.44 mmol) was added dropwise at −15° C. 4-(2-Ethylanilino)-6-hydroxy-7-methoxy-3-quinolinecarboxamide (50 mg, 0.15 mmol) was suspended in THF and then added to the reaction. The reaction was stirred over night, allowing the temperature rise to ˜10° C. The polymer was filtered off and the filtrate concentrated in vacuo. The product was purified using preparative HPLC according 15 mg (24%) of white crystals.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1.[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[O:21][C:20]([CH:22]=[N:23][N:24]3[CH2:28][C:27](=[O:29])[N:26]([CH2:30][CH2:31][CH2:32]Cl)[C:25]3=[O:34])=[CH:19][CH:18]=2)=[CH:13][CH:12]=1.C(=O)(O)[O-].[Na+].[ClH:40]>CN(C)C=O>[ClH:10].[ClH:40].[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[O:21][C:20]([CH:22]=[N:23][N:24]3[CH2:28][C:27](=[O:29])[N:26]([CH2:30][CH2:31][CH2:32][N:7]4[CH2:8][CH2:9][N:4]([CH2:3][CH2:2][OH:1])[CH2:5][CH2:6]4)[C:25]3=[O:34])=[CH:19][CH:18]=2)=[CH:13][CH:12]=1
Reactant: O=C1CN(N=Cc2ccc(-c3ccc(Cl)cc3)o2)C(=O)N1CCCCl
Reactant: OCCN1CCNCC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1CN(N=Cc2ccc(-c3ccc(Cl)cc3)o2)C(=O)N1CCCN1CCN(CCO)CC1

Procedure:
A stirred solution of 4-(2-hydroxyethyl)piperazine (3.83 g, 0.03 mole) in AR grade dimethylformamide (130 ml) is treated with 1-[[[5-(4-chlorophenyl)-2-furanyl]methylene]amino]-3-(3-chloropropyl)-2,4-imidazolidinedione (6.92 g, 0.015 mole). The reaction solution is heated at near reflux for 1.5 hours and then concentrated under reduced pressure to leave an oily residue. Said residue is treated with saturated sodium bicarbonate solution to give a yellow mixture. The mixture is filtered and washed with water to give 3.92 g crude product as the free base. The solid is dissolved in alcohol and treated with a mixture of saturated ethanolic/HCl. The solution forms a crystalline solid after 5 minutes. The solid is collected by filtration to give the crude product. 1-[[[5-(4-Chlorophenyl)-2-furanyl]methylene]amino]-3-[3-[4-(2-hydroxyethyl)-1-piperazinyl]propyl]-2,4-imidazolidinedione dihydrochloride is isolated upon one recrystallization from 95% alcohol (2.57 g).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[N:5][N:6]=1.Br[CH2:8][C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=O>C(O)C>[C:11]1([C:9]2[N:1]=[C:2]3[N:6]([CH:8]=2)[N:5]=[CH:4][S:3]3)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: Nc1nncs1
Reactant: O=C(CBr)c1ccccc1
Solvent: CCO
Product: c1ccc(-c2cn3ncsc3n2)cc1

Procedure:
10.1 g. of 2-amino-1,3,4-thiadiazole are dissolved in 160 ml. of ethanol, 19.9 g. of α-bromoacetophenone is added and the solution is heated and stirred at reflux for 1 hour. After cooling, the solid is filtered off and dissolved in 750 ml. of water and 40 ml. of 48% hydrobromic acid. This solution is heated at reflux for 1 hour, neutralized by addition of solid ammonium acetate and refluxed 1/2 hour longer. After cooling, the product is collected on a filter, washed with water and dried. The yield of product is 13 g. melting at 127°-130° C. It has the formula: ##STR15##
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14](C1CCCCO1)[N:13]=[C:12]2[C:24]1[CH:29]=[CH:28][N:27]=[C:26]([NH:30][C@@H:31]2[CH2:36][CH2:35][CH2:34][N:33](C(OC(C)(C)C)=O)[CH2:32]2)[N:25]=1.C(OC(C)=O)C.Cl>CCOC(C)=O>[F:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[C:3]=1[C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][N:13]=[C:12]2[C:24]1[CH:29]=[CH:28][N:27]=[C:26]([NH:30][C@@H:31]2[CH2:36][CH2:35][CH2:34][NH:33][CH2:32]2)[N:25]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](Nc2nccc(-c3nn(C4CCCCO4)c4ccc(-c5c(F)cccc5F)cc34)n2)C1
Agent: Cl
Solvent: CCOC(C)=O
Product: Fc1cccc(F)c1-c1ccc2[nH]nc(-c3ccnc(N[C@@H]4CCCNC4)n3)c2c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of (R)-tert-butyl 3-aminopiperidine-1-carboxylate (0.28 g, 1.32 mmol) in DMF (10 mL) was treated with NaH (0.056 g, 2.34 mmol) and stirred for 15 min. The reaction mixture was cooled to 0° C. and 3-(2-chloropyrimidin-4-yl)-5-(2,6-difluorophenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (0.5 g, 1.17 mmol) was added. The resulting mixture was stirred at RT for 2 h. The reaction mixture was quenched with ice cold water and extracted with EtOAc. The organic layer was dried over Na2SO4, filtered and concentrated to yield crude compound. Purification by silica gel column chromatography, eluting with 5-15% EtOAc and hexanes to obtain (3R)-tert-butyl 3-(4-(5-(2,6-difluorophenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)pyrimidin-2-ylamino)piperidine-1-carboxylate (0.2 g, 18%). MS (ESI, pos. ion) m/z: 591.1 (M+1). To a solution of (3R)-tert-butyl 3-(4-(5-(2,6-difluorophenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)pyrimidin-2-ylamino)piperidine-1-carboxylate (0.3 g, 0.5 mmol) in EtOAc (10 mL) was added EtOAc-HCl (10 mL) and stirred at RT for 16 h. The reaction mixture was quenched with saturated NaHCO3 solution and extracted with EtOAc. The organic layer was washed with water and brine, dried over Na2SO4 and concentrated. The crude product was purified by reverse-phase preparative HPLC (using a AG/PP/C18-15/021 column, eluting with gradient, A: 5% TFE+0.01% TFA in Water; B: ACN). The title compound was obtained. MS (ESI, pos. ion) m/z: 407.2 (M+1).
Reaction SMILES: [CH:1]1([O:7][C:8]2[N:13]3[N:14]=[C:15]([NH2:17])[N:16]=[C:12]3[CH:11]=[CH:10][CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[C:19](Cl)(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[N:22][CH:21]=1>>[CH:1]1([O:7][C:8]2[N:13]3[N:14]=[C:15]([NH:17][C:19](=[O:26])[C:20]4[CH:25]=[CH:24][CH:23]=[N:22][CH:21]=4)[N:16]=[C:12]3[CH:11]=[CH:10][CH:9]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: Nc1nc2cccc(OC3CCCCC3)n2n1
Reactant: O=C(Cl)c1cccnc1
Agent: Cl
Product: O=C(Nc1nc2cccc(OC3CCCCC3)n2n1)c1cccnc1

Procedure:
The title compound was prepared following procedure and work up described for intermediate B1 but starting from 5-(cyclohexyloxy)[1,2,4]triazolo[1,5-a]pyridin-2-amine ((A11), 268 mg; 1.15 mmol; 1.0 eq.) and nicotinoyl chloride hydrochloride (247 mg; 1.38 mmol; 1.2 eq.) as an off-white foam (230 mg, 59%). HPLC, Rt: 2.36 min. (purity 94.7%). LC/MS, M−(ESI): 336.1.
Reaction SMILES: [NH2:1][CH:2]([CH:6]1[CH2:11][CH2:10][O:9][CH2:8][CH2:7]1)[C:3]([OH:5])=[O:4].[F:12][C:13]([F:31])([F:30])[C:14]([O:17][C:18](=O)[O:19]C1C=CC([N+]([O-])=O)=CC=1)([CH3:16])[CH3:15].CCN(C(C)C)C(C)C>CC#N.O>[O:9]1[CH2:8][CH2:7][CH:6]([CH:2]([NH:1][C:18]([O:17][C:14]([CH3:16])([CH3:15])[C:13]([F:31])([F:30])[F:12])=[O:19])[C:3]([OH:5])=[O:4])[CH2:11][CH2:10]1
Reactant: CC(C)(OC(=O)Oc1ccc([N+](=O)[O-])cc1)C(F)(F)F
Reactant: NC(C(=O)O)C1CCOCC1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CC(C)(OC(=O)NC(C(=O)O)C1CCOCC1)C(F)(F)F
Temperature: 25 °C
Reaction time: 16 h
Yield: 70.2 %

Procedure:
Amino-(tetrahydro-pyran-4-yl)-acetic acid (80 mg, 0.5 mmol) was dissolved in CH3CN (5 mL) and H2O (1 mL), carbonic acid 4-nitro-phenyl ester 2,2,2-trifluoro-1,1-dimethyl-ethyl ester (175 mg, 0.6 mmol) and DIEA (88 μL, 0.5 mmol) were added slowly. The reaction was allowed to stir at room temperature for 16 h. After concentrated, diluted with EtOAc, washed with brine and H2O, dried over Na2SO4, the crude product was purified on silica (12 g, 25-75% EtOAc/hexanes) to give intermediate (tetrahydro-pyran-4-yl)-(2,2,2-trifluoro-1,1-dimethyl-ethoxycarbonylamino)-acetic acid as light yellow solid (110 mg, 70%).
Reaction SMILES: [S:1]1[CH2:5][CH2:4][NH:3][C:2]1=[O:6].C1(=O)[N:11](NCCCBr)[C:10](=O)[C:9]2=CC=CC=[C:8]12.C(=O)([O-])[O-].[K+].[K+].C1OCCOCCOCCOCCOCCOC1.[BH4-].[Na+]>C(#N)C.C(O)(=O)C.O.C(O)(C)C>[NH2:11][CH2:10][CH2:9][CH2:8][N:3]1[CH2:4][CH2:5][S:1][C:2]1=[O:6]
Reactant: O=C1NCCS1
Reactant: O=C1c2ccccc2C(=O)N1NCCCBr
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [BH4-]
Solvent: CC(C)O
Solvent: CC#N
Solvent: CC(=O)O
Product: NCCCN1CCSC1=O
Temperature: 60 °C
Reaction time: 22 h
Yield: 55 %

Procedure:
To a solution of 2-thiazolidinone (0.994 g, 9.64 mmol) in acetonitrile (10 ml) were added N-phthalimido-3-bromopropylamine (2.88 g, 10.7 mmol), potassium carbonate (1.64 g, 11.9 mmol), and 18-crown-6 (catalytic amount). The mixture was refluxed about 17 hours, solvent was removed in vacuo, and the resulting solid was redissolved in 1 M potassium chloride and dichloromethane (˜25 ml each). The aqueous phase was separated and extracted with 2×25 ml dichloromethane. The combined organic fraction was dried over sodium sulfate, filtered, and dried in vacuo. The crude product was recrystallized from acetone/methanol to give 1.54 g (55% yield). To a warmed solution of the phthalimido protected amine (1.53 g, 5.27 mmol) in 6:1 isopropanol:water was added sodium borohydride (1.01 g, 26.7 mmol), and the mixture was stirred at 60° C. for 22 hours. Glacial acetic acid (5.4 ml) was added, and the solution was stirred at 80° C. for 2 hours, then the solution was cooled and dried in vacuo. The product was redissolved in 6 N hydrochloric acid, washed with ether (2×30 ml), then dried in vacuo. The product was purified via recrystallization from hot water.
Reaction SMILES: [C:1]12([C:11]3[CH:20]=[C:19]4[C:14]([CH:15]=[CH:16][C:17]([C:21]5[CH:30]=[CH:29][C:24]([C:25]([O:27][CH3:28])=[O:26])=[CH:23][CH:22]=5)=[CH:18]4)=[CH:13][C:12]=3[OH:31])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.Br[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][C:38](N)=[O:39]>>[C:1]12([C:11]3[CH:20]=[C:19]4[C:14]([CH:15]=[CH:16][C:17]([C:21]5[CH:22]=[CH:23][C:24]([C:25]([O:27][CH3:28])=[O:26])=[CH:29][CH:30]=5)=[CH:18]4)=[CH:13][C:12]=3[O:31][CH2:33][CH2:34][CH2:35][CH2:36][CH:37]=[C:38]=[O:39])[CH2:8][CH:7]3[CH2:9][CH:3]([CH2:4][CH:5]([CH2:6]3)[CH2:10]1)[CH2:2]2
Reactant: COC(=O)c1ccc(-c2ccc3cc(O)c(C45CC6CC(CC(C6)C4)C5)cc3c2)cc1
Reactant: NC(=O)CCCCCBr
Product: COC(=O)c1ccc(-c2ccc3cc(OCCCCC=C=O)c(C45CC6CC(CC(C6)C4)C5)cc3c2)cc1
Yield: 66 %

Procedure:
Following the procedure of Example 12(a), but reacting 640 mg (1.55 mmol) of methyl 4-[7-(1-adamantyl)-6-hydroxy-2-naphthyl]benzoate with 450 mg (2.32 mmol) of 6-bromohexanamide, 520 mg (65%) of the expected compound were obtained, which compound had a melting point of 209°-10° C.
Reaction SMILES: I[CH2:2][CH2:3][CH3:4].[C:5]([O:16][CH3:17])(=[O:15])[C:6]1[C:7](=[CH:9][C:10](=[CH:12][C:13]=1[CH3:14])[OH:11])[OH:8].C(=O)(O)[O-].[Na+]>CN(C=O)C>[CH3:17][O:16][C:5](=[O:15])[C:6]1[C:13]([CH3:14])=[CH:12][C:10]([O:11][CH2:2][CH2:3][CH3:4])=[CH:9][C:7]=1[OH:8]
Reactant: CCCI
Reactant: COC(=O)c1c(C)cc(O)cc1O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCOc1cc(C)c(C(=O)OC)c(O)c1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
A mixture of 1-iodopropane (1.87 g, 10.98 mmol), methyl orsellinate (2.0 g, 10.98 mmol), and sodium bicarbonate (1.84 g, 21.96 mmol) in DMF is stirred at 60° C. overnight. The mixture is cooled and partitioned between EtOAc and water. The EtOAc layer is washed with brine, dried over magnesium sulfate, and concentrated to give the crude product. Purification by silica gel chromatography using 2% EtOAc in hexane as the eluent gives 2-hydroxy-6-methyl-4-propoxy-benzoic acid methyl ester.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:12][CH2:11][CH2:10][CH2:9]2)[C:5]([C:13]#[C:14][CH2:15][CH2:16][CH2:17][N:18]2[C:26](=[O:27])[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:19]2=[O:28])=[CH:4][N:3]=1.[NH2:29][C:30]1[CH:37]=[CH:36][C:33]([C:34]#[N:35])=[CH:32][CH:31]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C(OCC)(=O)C>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[O:28]=[C:19]1[C:20]2[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:26](=[O:27])[N:18]1[CH2:17][CH2:16][CH2:15][C:14]#[C:13][C:5]1[C:6]([N:8]2[CH2:12][CH2:11][CH2:10][CH2:9]2)=[N:7][C:2]([NH:29][C:30]2[CH:37]=[CH:36][C:33]([C:34]#[N:35])=[CH:32][CH:31]=2)=[N:3][CH:4]=1
Reactant: O=C1c2ccccc2C(=O)N1CCCC#Cc1cnc(Cl)nc1N1CCCC1
Reactant: N#Cc1ccc(N)cc1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: N#Cc1ccc(Nc2ncc(C#CCCCN3C(=O)c4ccccc4C3=O)c(N3CCCC3)n2)cc1
Temperature: 90 °C
Reaction time: 7 h

Procedure:
To a solution of tris(dibenzylideneacetone)dipalladium(0) (835 mg) and 4,5′-bis(diphenylphosphino)-9,9′-dimethylxanthene (1.06 g) in 1,4-dioxane (125 mL), 2-(5-(2-chloro-4-(pyrrolidin-1-yl)pyrimidin-5-yl)-4-pentyn-1-yl)isoindoline-1,3-dione (H2, 3.60 g), 4-aminobenzonitrile (2.69 g) and cesium carbonate (8.90 g) were added at room temperature under a nitrogen atmosphere, and the mixture was stirred at 90° C. for 7 hours. The reaction mixture was cooled to room temperature, and then ethyl acetate was added to the reaction mixture. The insoluble matter was removed by filtration through Cerite, and then the solvent was evaporated under reduced pressure. To the obtained residue, water was added. The solid matter was taken by filtration, and washed with water to obtain 4-((5-(5-(1,3-dioxoisoindolin-2-yl)-1-pentyn-1-yl)-4-(pyrrolidin-1-yl)pyrimidin-2-yl)amino)benzonitrile (H3).
Reaction SMILES: [CH2:1]([N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[C:5]([C:14]#[N:15])=[C:4]1[C:16]1[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH2:24]O)=[CH:18][CH:17]=1)[CH3:2].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Br:45]N1C(=O)CCC1=O>C(Cl)Cl>[Br:45][CH2:24][CH2:23][O:22][C:19]1[CH:20]=[CH:21][C:16]([C:4]2[N:3]([CH2:1][CH3:2])[C:11]3[C:6]([C:5]=2[C:14]#[N:15])=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=3)=[CH:17][CH:18]=1
Reactant: CCn1c(-c2ccc(OCCO)cc2)c(C#N)c2ccc(OC)cc21
Reactant: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCn1c(-c2ccc(OCCBr)cc2)c(C#N)c2ccc(OC)cc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 94.6 %

Procedure:
1-Ethyl-6-methoxy-2-[4-(2-hydroxyethoxy)-phenyl]-1H-indole-3-carbonitrile (450 mg, 1.34 mmol), prepared as in example 1AZ, was combined with PPh3 (878 mg, 3.35 mmol) in CH2Cl2 (32 mL) at 0° C. N-bromosuccinimide (600 mg, 3.37 mmol) was added in one portion. The reaction mixture was stirred at room temperature for 30 minutes. The reaction mixture was washed with aqueous NaHCO3. The organic layer was dried and concentrated, and purified by silica gel chromatography (CH2Cl2) to yield 2-[4-(2-bromoethoxy)-phenyl]-1-ethyl-6-methoxy-1H-indole-3-carbonitrile (506 mg, 95%), compound 253 as a white solid.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH2:8]Br)=[N:4][CH:5]=[CH:6][CH:7]=1.[C-:10]#[N:11].[Na+]>O1CCOCC1.O>[Br:1][C:2]1[C:3]([CH2:8][C:10]#[N:11])=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: BrCc1ncccc1Br
Reactant: [C-]#N
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: N#CCc1ncccc1Br
Temperature: 25 °C
Reaction time: 16 h
Yield: 39.9 %

Procedure:
To a stirred solution of the above crude 3-bromo-2-bromomethylpyridine (70 g, 0.28 mol) in dioxane (500 mL) and water (250 mL), was added NaCN (28 g, 0.74 mol) at 0° C. and then stirred at RT for 16 h. The reaction mixture was quenched with 3 Lit of water and extracted with ethylacetate (4×500 mL). The organic layer was washed with water (400 L), brine (250 mL), dried over Na2SO4 and concentrated to give crude product. The crude was purified by column chromatography over silica gel (pet. ether/ethylacetate, 8:2) to give 3-bromopyridine-2-yl-acetonitrile (22 g, 40%). [TLC: Pet. ether/ethylacetate, 7:3, Rf=0.35]
Reaction SMILES: Br[C:2]1[C:11]2[N:10]=[CH:9][C:8](=[O:12])[NH:7][C:6]=2[N:5]=[C:4]([S:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[C:16]=2[F:22])[N:3]=1.[NH2:23][CH:24]([CH2:27][OH:28])[CH2:25][OH:26]>>[Cl:21][C:17]1[C:16]([F:22])=[C:15]([CH2:14][S:13][C:4]2[N:3]=[C:2]([NH:23][CH:24]([CH2:27][OH:28])[CH2:25][OH:26])[C:11]3[N:10]=[CH:9][C:8](=[O:12])[NH:7][C:6]=3[N:5]=2)[CH:20]=[CH:19][CH:18]=1
Reactant: NC(CO)CO
Reactant: O=c1cnc2c(Br)nc(SCc3cccc(Cl)c3F)nc2[nH]1
Product: O=c1cnc2c(NC(CO)CO)nc(SCc3cccc(Cl)c3F)nc2[nH]1
Yield: 66.3 %

Procedure:
The titled compound (51 mg) was prepared by the method of Example 6, step (f) using the product from Example 6, step (e) (75 mg) and 2-amino-1,3-propanediol (37 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[CH:10][NH:11][CH:12]=2)=[CH:4][CH:3]=1.[CH:13](O)=[O:14]>>[NH:11]1[CH:12]=[C:8]([C:5]2[CH:4]=[CH:3][C:2]([NH:1][CH:13]=[O:14])=[CH:7][CH:6]=2)[N:9]=[CH:10]1
Reactant: O=CO
Reactant: Nc1ccc(-c2c[nH]cn2)cc1
Product: O=CNc1ccc(-c2c[nH]cn2)cc1

Procedure:
A solution of 4-(4-aminophenyl)-1-H-imidazole (10 g) in formic acid (100 ml) was refluxed for 4 hours and evaporated to dryness. The residue was dissolved in water, and the solution was filtered through charcoal and made basic to give 10 g of N-[4-(imidazol-4-yl)-phenyl]-formamide, M.p. 108°-109° C.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]1[N:10]([CH2:32][CH:33]([CH3:35])[CH3:34])[C:11](=[O:31])[C:12]2[C:17]([C:18]=1[O:19][CH2:20][CH2:21][CH2:22][CH3:23])=[CH:16][C:15](/[CH:24]=[CH:25]/[C:26]1[N:27]=[CH:28][S:29][CH:30]=1)=[CH:14][CH:13]=2)(C)(C)C.[ClH:37]>C(OCC)(=O)C>[ClH:37].[NH2:7][CH2:8][C:9]1[N:10]([CH2:32][CH:33]([CH3:34])[CH3:35])[C:11](=[O:31])[C:12]2[C:17]([C:18]=1[O:19][CH2:20][CH2:21][CH2:22][CH3:23])=[CH:16][C:15](/[CH:24]=[CH:25]/[C:26]1[N:27]=[CH:28][S:29][CH:30]=1)=[CH:14][CH:13]=2
Reactant: CCCCOc1c(CNC(=O)OC(C)(C)C)n(CC(C)C)c(=O)c2ccc(/C=C/c3cscn3)cc12
Agent: Cl
Solvent: CCOC(C)=O
Product: CCCCOc1c(CN)n(CC(C)C)c(=O)c2ccc(/C=C/c3cscn3)cc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 84.6 %

Procedure:
Tert-butyl{4-butoxy-2-isobutyl-1-oxo-6-[(E)-2-(1,3-thiazol-4-yl)ethenyl]-1,2-dihydro-3-isoquinolinyl}methylcarbamate (0.16 g, 0.3 mmol) was dissolved in a solution of 4N hydrogen chloride in ethyl acetate solution (5 ml). The solution was stirred at room temperature for 1 h. The reaction was concentrated under reduced pressure, and the residue was recrystallized from methanol-diisopropyl ether to give 3-(aminomethyl)-4-butoxy-2-isobutyl-6-[(E)-2-(1,3-thiazol-4-yl-)ethenyl]-1(2H)-isoquinolinone hydrochloride (0.11 g, 84.6%) as crystals.
Reaction SMILES: C(OC([O:9][C:10]([NH:12][CH2:13][CH:14]([CH2:19][CH:20]([CH3:22])[CH3:21])[CH2:15][C:16]([OH:18])=[O:17])=[O:11])C)(=O)C(C)C.C(=O)([O-])O[C:25]1C=CC([N+]([O-])=O)=[CH:27][C:26]=1[CH:34]([O:36][C:37](=[O:41])[CH:38]([CH3:40])[CH3:39])C>>[C:37]([O:36][CH:34]([O:11][C:10]([NH:12][CH2:13][CH:14]([CH2:19][CH:20]([CH3:22])[CH3:21])[CH2:15][C:16]([OH:18])=[O:17])=[O:9])[CH:26]([CH3:25])[CH3:27])(=[O:41])[CH:38]([CH3:39])[CH3:40]
Reactant: CC(C)C(=O)OC(C)c1cc([N+](=O)[O-])ccc1OC(=O)[O-]
Reactant: CC(C)CC(CNC(=O)OC(C)OC(=O)C(C)C)CC(=O)O
Product: CC(C)CC(CNC(=O)OC(OC(=O)C(C)C)C(C)C)CC(=O)O
Yield: 51 %

Procedure:
Following the procedure of preparation for (110), and substituting (114) for (111), provided the title compound as a mixture of two diastereomers in 51% yield. 1H-NMR (CDCl3, 400 MHz): δ 0.89 (m, 12H), 1.17 (m, 8H), 1.65 (m, 1H), 2.02 (m, 1H), 2.16 (m, 1H), 2.33 (m, 2H), 2.56 (m, 1H), 3.13 (m, 1H), 3.30 (m, 1H), 5.00 (m, 1H), 6.57-6.56 (m, 1H).
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][CH2:9][C:10]1[N:15]=[C:14]([C:16]2[S:17][C:18]3[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=3[C:20](=[O:22])[N:21]=2)[CH:13]=[CH:12][CH:11]=1.[C:27](Cl)(=[O:31])[CH:28]([CH3:30])[CH3:29].C(OCC)(=O)C.O>CN(C)C(=O)C>[CH3:29][CH:28]([CH3:30])[C:27]([NH:8][CH2:9][C:10]1[CH:11]=[CH:12][CH:13]=[C:14]([C:16]2[S:17][C:18]3[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=3[C:20](=[O:22])[N:21]=2)[N:15]=1)=[O:31]
Reactant: CC(C)C(=O)Cl
Reactant: NCc1cccc(-c2nc(=O)c3ccccc3s2)n1
Solvent: CC(=O)N(C)C
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: CC(C)C(=O)NCc1cccc(-c2nc(=O)c3ccccc3s2)n1
Temperature: 60 °C
Reaction time: 16 h
Yield: 61.9 %

Procedure:
2-[6-(Aminomethyl)-2-pyridyl]-4H-1,3-benzothiazine-4-one trifluoroacetic acid salt (450 mg, 1.1 mmol) was dissolved in N,N-dimethylacetamide (10 ml), and isobutyryl chloride (365 mg, 3.9 mmol) was added thereto. The reaction mixture was stirred at 60° C. for 16 hrs and combined with ethyl acetate and water. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated, and the residue was subjected to a silica gel column chromatography. The fractions eluted with methanol-ethyl acetate (1:30, v/v) were collected, concentrated and recrystallized from hexane-ethanol to give the titled compound (231 mg, 58%) as white crystals.
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[NH:7][CH2:8][C:9]1[C:10]([O:18][CH3:19])=[N:11][CH:12]=[C:13]([N+:15]([O-])=O)[CH:14]=1)([CH3:4])([CH3:3])[CH3:2]>CO.C(Cl)Cl.[Pd]>[C:1]([O:5][C:6](=[O:20])[NH:7][CH2:8][C:9]1[C:10]([O:18][CH3:19])=[N:11][CH:12]=[C:13]([NH2:15])[CH:14]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1ncc([N+](=O)[O-])cc1CNC(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CO
Solvent: ClCCl
Product: COc1ncc(N)cc1CNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 7 h
Yield: 84.4 %

Procedure:
10% Pd/C (1 g) was added to a solution of tert-butyl(2-methoxy-5-nitropyridin-3-yl)methylcarbamate (9.8 g, 34.6 mmol) in MeOH (150 mL) and DCM (75 mL) and the mixture stirred at rt for 7 h under an atmosphere of H2. The reaction mixture was then filtered through celite and washed with MeOH and the filtrate concentrated in vacuo. Purification by flash column chromatography eluting with 2:1 to 1:1 heptane-EtOAc yielded the title compound (7.4 g, 29.2 mmol) as a tan solid.