Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[C:5]2[N:10]=[C:9]([CH2:11][N:12]3[CH2:17][CH2:16][N:15]([C:18](=[O:22])[CH:19]([OH:21])[CH3:20])[CH2:14][CH2:13]3)[S:8][C:6]=2[N:7]=1.[NH2:29][C:30]1[N:35]=[CH:34][C:33](B(O)O)=[CH:32][N:31]=1>>[NH2:29][C:30]1[N:35]=[CH:34][C:33]([C:2]2[N:3]=[C:4]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)[C:5]3[N:10]=[C:9]([CH2:11][N:12]4[CH2:17][CH2:16][N:15]([C:18](=[O:22])[C@@H:19]([OH:21])[CH3:20])[CH2:14][CH2:13]4)[S:8][C:6]=3[N:7]=2)=[CH:32][N:31]=1
Reactant: CC(O)C(=O)N1CCN(Cc2nc3c(N4CCOCC4)nc(Cl)nc3s2)CC1
Reactant: Nc1ncc(B(O)O)cn1
Product: C[C@H](O)C(=O)N1CCN(Cc2nc3c(N4CCOCC4)nc(-c4cnc(N)nc4)nc3s2)CC1
Yield: 24.6 %

Procedure:
1-[4-(5-Chloro-7-morpholin-4-yl-thiazolo[5,4-d]pyrimidin-2-ylmethyl)-piperazin-1-yl]-2-hydroxy-propan-1-one (100 mg) was reacted with 62 mg of 2-aminopyrimidine-5-boronic acid, pinacol ester via General Procedure A. The product was purified by reverse phase HPLC to yield 28 mg of 108. MS (Q1) 486.2 (M)+.
Reaction SMILES: C(N)(C)C.CC1(C)[NH:11][C:10](=[O:12])[C:9]2[CH:13]=[C:14]([O:17][CH2:18][CH:19]([NH:21][CH2:22][CH:23]([OH:36])[CH2:24][O:25][C:26]3[CH:31]=[CH:30][C:29]([C:32](=[O:35])[NH:33][CH3:34])=[CH:28][CH:27]=3)[CH3:20])[CH:15]=[CH:16][C:8]=2[O:7]1>CO>[C:10]([C:9]1[CH:13]=[C:14]([CH:15]=[CH:16][C:8]=1[OH:7])[O:17][CH2:18][CH:19]([NH:21][CH2:22][CH:23]([OH:36])[CH2:24][O:25][C:26]1[CH:31]=[CH:30][C:29]([C:32](=[O:35])[NH:33][CH3:34])=[CH:28][CH:27]=1)[CH3:20])(=[O:12])[NH2:11]
Reactant: CNC(=O)c1ccc(OCC(O)CNC(C)COc2ccc3c(c2)C(=O)NC(C)(C)O3)cc1
Solvent: CO
Solvent: CC(C)N
Product: CNC(=O)c1ccc(OCC(O)CNC(C)COc2ccc(O)c(C(N)=O)c2)cc1

Procedure:
80 ml of isopropylamine are added to a solution of 18.0 g of crude 1-[2-(2,3-dihydro-2,2-dimethyl-4-oxo-4H-1,3-benzoxazin-6-yloxy)-1-methylethylamino]-3-(4-methylcarbamoylphenoxy)propan-2-ol in 300 ml of methanol and the solution is refluxed for 1 hour. The reaction mixture is concentrated by evaporation and the oil remaining is crystallised from 80 ml of isopropanol. 1-[2-(3-Carbamoyl-4-hydroxyphenoxy)-1-methylethylamino]-3-(4-methylcarbamoylphenoxy)propan-2-ol having a melting point of 172°-175° (diastereoisomeric mixture) is obtained.
Reaction SMILES: [OH-].[K+].[CH2:3]([O:6][C:7]1[C:16]([CH:17]([CH3:19])[CH3:18])=[CH:15][C:10]([C:11]([O:13]C)=[O:12])=[C:9]([OH:20])[CH:8]=1)[CH:4]=[CH2:5]>CO.O>[CH2:3]([O:6][C:7]1[C:16]([CH:17]([CH3:18])[CH3:19])=[CH:15][C:10]([C:11]([OH:13])=[O:12])=[C:9]([OH:20])[CH:8]=1)[CH:4]=[CH2:5]
Reactant: C=CCOc1cc(O)c(C(=O)OC)cc1C(C)C
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: C=CCOc1cc(O)c(C(=O)O)cc1C(C)C
Temperature: 25 °C
Yield: 96.5 %

Procedure:
Aqueous potassium hydroxide (50% w/v, 0.2 ml) was added to a suspension of methyl 4-allyloxy-2-hydroxy-5-isopropylbenzoate (313 mg, 1.25 mmol) in methanol (6 ml) and water (2 ml) and the mixture was stirred and held at reflux for 4 hours. Upon cooling to room temperature the organic solvent was removed in vacuo and the residue acidified by the addition of 2M hydrochloric acid (10 ml). The solid material was collected by suction filtration, rinsed with water (2×10 ml) and sucked dry under reduced pressure to afford 4-allyloxy-2-hydroxy-5-isopropylbenzoic acid (285 mg, 96%) as a colourless solid. 1H NMR (DMSO-d6) 13.50 (1H, br s), 11.40 (1H, s), 7.55 (1H, s), 6.51 (1H, s), 6.06 (1H, m), 5.42 (1H, dm), 5.28 (1H, dm), 4.64 (2H, m), 3.17 (1H, m), 1.17 (6H, d). MS: [M+H]+ 237.
Reaction SMILES: [CH2:1]([N:3]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]3[NH:14][CH:15]=[CH:16][C:9]=23)[C:5]([C:17]2[CH:23]=[CH:22][C:20]([NH2:21])=[CH:19][CH:18]=2)=[N:4]1)[CH3:2].[CH:24]1[CH:28]=[C:27]([CH2:29][C:30](Cl)=[O:31])[S:26][CH:25]=1>>[CH2:1]([N:3]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]3[NH:14][CH:15]=[CH:16][C:9]=23)[C:5]([C:17]2[CH:23]=[CH:22][C:20]([NH:21][C:30](=[O:31])[CH2:29][C:27]3[S:26][CH:25]=[CH:24][CH:28]=3)=[CH:19][CH:18]=2)=[N:4]1)[CH3:2]
Reactant: O=C(Cl)Cc1cccs1
Reactant: CCn1cc(-c2ccnc3[nH]ccc23)c(-c2ccc(N)cc2)n1
Product: CCn1cc(-c2ccnc3[nH]ccc23)c(-c2ccc(NC(=O)Cc3cccs3)cc2)n1

Procedure:
Following the procedure described in Example 1 with 4-[1-ethyl-4-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-3-yl]aniline and thiophene-2-acetyl chloride provided the title compound. ESMS [M+H]+: 428.4
Reaction SMILES: B(O)O.S1C2C(=CC=CC=2)C=CC1.Br[C:15]1[CH:25]=[CH:24][CH:23]=[CH:22][C:16]=1[C:17]([O:19][CH2:20][CH3:21])=[O:18].C1(C)C=CC=CC=1>CO>[CH2:20]([O:19][C:17](=[O:18])[C:16]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:15]=1)[CH3:21]
Reactant: CCOC(=O)c1ccccc1Br
Agent: C1=Cc2ccccc2SC1
Agent: OBO
Solvent: Cc1ccccc1
Solvent: CO
Product: CCOC(=O)c1ccccc1

Procedure:
As is shown in the reaction scheme, the (2,2-dialkyl-4-alkyl, aryl or heteroaryl-2H-chromen-6-yl) boronic acid compounds of Formula 24 (or their corresponding thiochrom-3-ene analogs) are reacted with ethyl 2-bromobenzoate in the presence of Pd(0) catalyst in an inert solvent or solvent mixture, such as toluene and methanol, to provide 2-(2,2-dialkyl-4-alkyl, aryl or heteroaryl-2H-chromen-6-yl)benzoic acid ethyl ester compounds of Formula 60. The reagent ethyl 2-bromobenzoate is available in accordance with the chemical literature, see for example J. Org. Chem. 14 (1949) 509, 512 and Helv. Chim. Acta 39 (1956) 505-511. Other examples of reagents which can be used in this reaction instead of ethyl 2-bromobenzoate are: ethyl 2-bromopyridine-3-carboxylate, ethyl 4-bromopyridine-3-carboxylate, ethyl 3-bromothiophene-2-carboxylate, ethyl 2-bromothiophene-3-carboxylate, ethyl 3-bromofuran-2-carboxylate, ethyl 2-bromofuran-3-carboxylate, ethyl cis 2-bromo-cyclopentanecarboxylate and ethyl cis 2-bromo-cyclohexanecarboxylate. However, in the ensuing desription the primary emphasis remains on the 1,2 substituted phenylene derivative actually shown in the reaction scheme.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][C:9]([O:15][CH3:16])=[C:10]([O:13][CH3:14])[CH:11]=2)[C:6](=[C:17](OCC)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:5]1=[O:27])(=O)C.[CH3:28][N:29]([CH2:31][C:32]1[CH:38]=[CH:37][C:35]([NH2:36])=[CH:34][CH:33]=1)[CH3:30]>>[CH3:30][N:29]([CH2:31][C:32]1[CH:38]=[CH:37][C:35]([NH:36]/[C:17](=[C:6]2\[C:5](=[O:27])[NH:4][C:12]3[C:7]\2=[CH:8][C:9]([O:15][CH3:16])=[C:10]([O:13][CH3:14])[CH:11]=3)/[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:34][CH:33]=1)[CH3:28]
Reactant: CCOC(=C1C(=O)N(C(C)=O)c2cc(OC)c(OC)cc21)c1ccccc1
Reactant: CN(C)Cc1ccc(N)cc1
Product: COc1cc2c(cc1OC)/C(=C(/Nc1ccc(CN(C)C)cc1)c1ccccc1)C(=O)N2

Procedure:
Prepared from 1-acetyl-3-(1-ethoxy-1-phenyl-methylidene)-5,6-dimethoxy-2-indolinone and 4-(dimethylaminomethyl)-aniline
Reaction SMILES: [Br-:1].[Br-].[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.[OH:55][CH2:56][CH2:57][C:58]1[CH:63]=[CH:62][CH:61]=[CH:60][C:59]=1[O:64][CH3:65]>ClCCl.CO>[Br:1][C:62]1[CH:61]=[CH:60][C:59]([O:64][CH3:65])=[C:58]([CH2:57][CH2:56][OH:55])[CH:63]=1
Reactant: [Br-]
Reactant: COc1ccccc1CCO
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: ClCCl
Solvent: CO
Product: COc1ccc(Br)cc1CCO
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
35.72 g of tetrabutylammonium tribromide am added in portions to a solution of 10.7 g of 2-(2-hydroxyethyl)-anisole in 195 ml of dichloromethane and 130 ml of methanol. The reaction mixture is stirred for 150 minutes at room temperature and is then concentrated by evaporation in a rotary evaporator. The residue is partitioned between diethyl ether and water. The organic phases are combined, dried over magnesium sulfate and concentrated by evaporation, and the residue is purified by means of FC (dichloromethane), yielding the title compound: Rf (dichloromethane)=0.26; HPLC Rt =13.04 minutes.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([S:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)[CH2:10][C@H:9]1[CH:23]=[N:24][CH2:25][C:26]1[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:27]=1[F:33])=[O:7])([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+].O>CO>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([S:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)[CH2:10][C@H:9]1[CH2:23][NH:24][CH2:25][C:26]1[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:27]=1[F:33])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1ccc(CS[C@@H]2C[C@@H](C=NCc3cc(F)ccc3F)N(C(=O)OC(C)(C)C)C2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COc1ccc(CS[C@@H]2C[C@@H](CNCc3cc(F)ccc3F)N(C(=O)OC(C)(C)C)C2)cc1
Reaction time: 1.5 h
Yield: 66.6 %

Procedure:
To 17.31 g (36.32 mmol) (2S,4R)-2-[(2,5-difluoro-benzylimino)-methyl]-4-(4-methoxy-benzylsulfanyl)-pyrrolidine-1-carboxylic acid tert-butyl ester in 120 ml MeOH were added 1.64 g (43.58 mmol, 1.2 eq) NaBH4 slowly at 40° C. The solution was stirred at that temperature for additional 90 min, water was added carefully and the solution was concentrated. The residue was redissolved in EtOAc and washed with NaHCO3 and brine, dried over Na2SO4 and evaporated. Flash chromatography with EtOAc/hexane 1:1 yielded 11.57 g (67%) (2S,4R)-2-[(2,5-difluoro-benzylamino)-methyl]-4-(4-methoxy-benzylsulfanyl)-pyrrolidine-1-carboxylic acid tert-butyl ester as yellow oil, MS: 479 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:19])=[C:6]([C:8]2[CH:17]=[C:16]3[C:11]([CH:12]=[C:13]([NH2:18])[N:14]=[CH:15]3)=[CH:10][CH:9]=2)[CH:7]=1.CN(C)C=O.[H-].[Na+].[CH:27]1([CH2:30]Br)[CH2:29][CH2:28]1>>[CH:27]1([CH2:30][NH:18][C:13]2[N:14]=[CH:15][C:16]3[C:11]([CH:12]=2)=[CH:10][CH:9]=[C:8]([C:6]2[CH:7]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=2[CH3:19])[CH:17]=3)[CH2:29][CH2:28]1
Reactant: BrCC1CC1
Reactant: Cc1ccc(F)cc1-c1ccc2cc(N)ncc2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc(F)cc1-c1ccc2cc(NCC3CC3)ncc2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 15.8 %

Procedure:
To a solution of 7-(5-fluoro-2-methylphenyl)isoquinolin-3-amine (61.7 mg, 0.244 mmol) in N,N-dimethylformamide (2.0 mL, 26 mmol) at room temperature was added sodium hydride (20.1 mg, 0.502 mmol, 60% dispersion in mineral oil). The reaction mixture was stirred at room temperature for 30 minutes, and then cyclopropylmethyl bromide (24.0 uL, 0.247 mmol) was added and the reaction mixture was heated at 50° C. for 3 hours. The reaction mixture was cooled to room temperature and sodium hydride (66 mg, 60% dispersion in mineral oil) was added, followed by cyclopropylmethyl bromide (30.0 uL). The reaction mixture was then stirred at room temperature overnight. The mixture was then partitioned between ethyl acetate and water, and the organic layer was washed with water and brine, dried over MgSO4, filtered, and evaporated in vacuo. The crude product was purified via flash chromatography on silica gel (12 g silica, solvent gradient: 0-50% ethyl acetate in dichloromethane) to yield 11.8 mg (16%) of N-(cyclopropylmethyl)-7-(5-fluoro-2-methylphenyl)isoquinolin-3-amine. LCMS (ESI): RT (min)=4.807, M+H=307.1, method=E; 1H NMR (400 MHz, DMSO-d6) δ 8.89 (s, 1H), 7.77 (s, 1H), 7.61 (d, J=8.7 Hz, 1H), 7.47 (d, J=8.7 Hz, 1H), 7.40-7.30 (m, 1H), 7.17-7.06 (m, 2H), 6.64 (s, 1H), 6.54 (t, J=5.3 Hz, 1H), 3.16 (t, J=6.2 Hz, 2H), 2.25 (s, 3H), 1.12 (dd, J=12.4, 6.7 Hz, 1H), 0.46 (d, J=6.8 Hz, 2H), 0.26 (d, J=4.3 Hz, 2H).
Reaction SMILES: [Br:1][C:2]1[C:15](=[O:16])[N:14]([CH:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)[C:5]2[N:6]=[C:7](S(C)=O)[N:8]=[C:9]([CH3:10])[C:4]=2[CH:3]=1.[NH2:22][CH2:23][C:24]([CH3:27])([OH:26])[CH3:25].C(N(CC)CC)C>O1CCOCC1.[Cl-].[Na+].O>[Br:1][C:2]1[C:15](=[O:16])[N:14]([CH:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)[C:5]2[N:6]=[C:7]([NH:22][CH2:23][C:24]([OH:26])([CH3:27])[CH3:25])[N:8]=[C:9]([CH3:10])[C:4]=2[CH:3]=1
Reactant: Cc1nc(S(C)=O)nc2c1cc(Br)c(=O)n2C1CCCC1
Reactant: CC(C)(O)CN
Agent: [Cl-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1COCCO1
Product: Cc1nc(NCC(C)(C)O)nc2c1cc(Br)c(=O)n2C1CCCC1
Temperature: 110 °C
Yield: 88.2 %

Procedure:
To a solution of 6-bromo-8-cyclopentyl-4-methyl-2-(methylsulfinyl)pyrido[2,3-d]pyrimidin-7(8H)-one (600 mg, 1.62 mmol) and 1-amino-2-methylpropan-2-ol (294 mg, 2.34 mmol) in dioxane (6 mL) was added triethylamine (1.2 mL, 8.6 mmol). The mixture was then heated at 110° C. in a sealed tube for 1 h. The solution was poured into brine and extracted with ethyl acetate. The organic was dried (anhydrous sodium sulfate), filtered and concentrated to dryness. The crude product was purified by silica gel flash chromatography to give the title compound as a solid (565 mg, 88%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=2)[CH2:9][CH2:10][N:11]([CH3:16])[CH2:12][CH2:13][CH2:14][NH2:15])=[CH:4][CH:3]=1.[C:23]([NH:25][C:26](=[N:34][CH2:35][CH2:36][CH2:37][O:38][C:39]1[CH:44]=[CH:43][CH:42]=[C:41]([CH2:45][N:46]2[CH2:51][CH2:50][CH2:49][CH2:48][CH2:47]2)[CH:40]=1)OC1C=CC=CC=1)#[N:24]>>[C:23]([NH:25][C:26]([NH:15][CH2:14][CH2:13][CH2:12][N:11]([CH2:10][CH2:9][CH:8]([C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=1)[CH3:16])=[N:34][CH2:35][CH2:36][CH2:37][O:38][C:39]1[CH:44]=[CH:43][CH:42]=[C:41]([CH2:45][N:46]2[CH2:47][CH2:48][CH2:49][CH2:50][CH2:51]2)[CH:40]=1)#[N:24]
Reactant: N#CNC(=NCCCOc1cccc(CN2CCCCC2)c1)Oc1ccccc1
Reactant: CN(CCCN)CCC(c1ccc(F)cc1)c1ccccn1
Product: CN(CCCNC(=NCCCOc1cccc(CN2CCCCC2)c1)NC#N)CCC(c1ccc(F)cc1)c1ccccn1

Procedure:
Preparation is effected analogously to Example 1, using 0.8 g (2.7 mmol) of N-[3-(4-fluorophenyl)-3-(2-pyridyl)propyl]-N-methyl-1,3-propanediamine and 1.04 g (2.6 mmol) of N-cyano-O-phenyl-N'-[3-[3-(piperidinomethyl)phenoxy]propyl]isourea as starting materials. Working up by chromatography analogously to Example 1 yields the purified title compound in the form of a viscous oil; MS (+FAB method): m/z (rel. int.[%])=600 ([M+H]+ 22.4), 214 (100); IR (KBr): 2164 cm-1 (C≡N).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4]2[N:13]([Si](C(C)C)(C(C)C)C(C)C)[CH:14]=[CH:15][C:3]=12.[CH:26]1([NH2:32])[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1>>[CH2:11]([O:10][C:8]([C:7]1[C:2]([NH:32][CH:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)=[C:3]2[CH:15]=[CH:14][NH:13][C:4]2=[N:5][CH:6]=1)=[O:9])[CH3:12]
Reactant: CCOC(=O)c1cnc2c(ccn2[Si](C(C)C)(C(C)C)C(C)C)c1Cl
Reactant: NC1CCCCC1
Product: CCOC(=O)c1cnc2[nH]ccc2c1NC1CCCCC1
Temperature: 80 °C
Reaction time: 24 h
Yield: 48.2 %

Procedure:
A mixture of ethyl 4-chloro-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate (1.5 g, 3.9 mmol) and cyclohexylamine (2.34 g, 23.6 mmol) was stirred at about 80° C. for about 24 h. The solvent was removed under reduced pressure. The residue was suspended in Et2O and the precipitate was collected by filtration and dried under vacuum. The solid was washed with water and dried under vacuum again to give ethyl-4-(cyclohexylamino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate (0.54 g, 48%): LC/MS (Table 2, Method b) Rt=2.56 min.; MS m/z: 288 (M+H)+.
Reaction SMILES: [CH:1]1([C:7]2[S:17][C:10]3[N:11]=[C:12]([CH3:16])[NH:13][C:14](=O)[C:9]=3[CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C1(C)C=CC=CC=1.P(Cl)(Cl)([Cl:27])=O>CN(C=O)C>[Cl:27][C:14]1[C:9]2[CH:8]=[C:7]([CH:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)[S:17][C:10]=2[N:11]=[C:12]([CH3:16])[N:13]=1
Reactant: Cc1nc2sc(C3CCCCC3)cc2c(=O)[nH]1
Reactant: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: Cc1nc(Cl)c2cc(C3CCCCC3)sc2n1
Temperature: 150 °C

Procedure:
To a mixture of 6-cyclohexyl-2-methylthieno[2,3-d]pyrimidin-4(3H)-one (25.0 g) and toluene (300 mL) were added phosphorous oxychloride (14 mL) and DMF (200 μL), followed by heating to reflux at 150° C. for 14 hours. The reaction mixture was left to be cooled to room temperature and concentrated under reduced pressure. To the residue were added chloroform, water, and saturated aqueous sodium bicarbonate, followed by stirring. The reaction mixture was extracted with chloroform. The organic layer was washed sequentially with water and brine. To the organic layer were added MgSO4, activated carbon (2 g), and silica gel (100 mL), followed by stirring. The mixture was filtered through Celite and then concentrated under reduced pressure to obtain 4-chloro-6-cyclohexyl-2-methylthieno[2,3-d]pyrimidine (27.4 g).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[NH:12][CH2:13][CH3:14])[N:8]=[CH:7][N:6]=[C:5]2[N:15]1[CH2:20][CH2:19][N:18]([C:21](=[S:30])[NH:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:17][CH2:16]1.[CH2:31](N(CC)CC)[CH3:32].C(OC(=O)C)(=O)C.[Cl-].[Na+]>CN(C)C=O.O>[CH2:23]([NH:22][C:21]([N:18]1[CH2:19][CH2:20][N:15]([C:5]2[C:4]3[CH:3]=[C:2]4[N:1]=[C:13]([CH3:14])[N:12]([CH2:31][CH3:32])[C:11]4=[CH:10][C:9]=3[N:8]=[CH:7][N:6]=2)[CH2:16][CH2:17]1)=[S:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: CCNc1cc2ncnc(N3CCN(C(=S)NCc4ccccc4)CC3)c2cc1N
Reactant: CCN(CC)CC
Agent: [Cl-]
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: CCn1c(C)nc2cc3c(N4CCN(C(=S)NCc5ccccc5)CC4)ncnc3cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 5 %

Procedure:
To a solution of 528 mg (1.25 mmol) of 4-(6-amino-7-ethylamino-4-quinazolinyl)-N-benzyl-1-piperazinethiocarboxamide obtained in Example 461 in 15 ml of dimethylformamide were added 0.57 ml (4.09 mmol) of triethylamine and 0.31 ml (3.29 mmol) of acetic anhydride, followed by overnight stirring at room temperature in an atmosphere of argon. The reaction mixture was poured into water, and sodium chloride was addeed thereto. The precipitated crystals were collected by filtration, washed with water, and dried, followed by purification by silica gel chromatography to give the desired compound as colorless crystals.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13](=[O:14])[O:12][N:11]=[C:10]2[C:15]2[C:16]([NH:20][CH2:21][CH2:22][N:23](CC3C=CC(OC)=CC=3)[S:24]([N:27](CC3C=CC(OC)=CC=3)C(=O)OC(C)(C)C)(=[O:26])=[O:25])=[N:17][O:18][N:19]=2)[CH:5]=[CH:6][C:7]=1[F:8].FC(F)(F)C(O)=O>>[Br:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13](=[O:14])[O:12][N:11]=[C:10]2[C:15]2[C:16]([NH:20][CH2:21][CH2:22][NH:23][S:24]([NH2:27])(=[O:25])=[O:26])=[N:17][O:18][N:19]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: COc1ccc(CN(CCNc2nonc2-c2noc(=O)n2-c2ccc(F)c(Br)c2)S(=O)(=O)N(Cc2ccc(OC)cc2)C(=O)OC(C)(C)C)cc1
Solvent: O=C(O)C(F)(F)F
Product: NS(=O)(=O)NCCNc1nonc1-c1noc(=O)n1-c1ccc(F)c(Br)c1
Temperature: 70 °C
Reaction time: 1 h
Yield: 86.2 %

Procedure:
To a 25-mL flask was added tert-butyl {[[2-({4-[4-(3-bromo-4-fluorophenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl]-1,2,5-oxadiazol-3-yl}amino)ethyl](4-methoxybenzyl)amino]sulfonyl}(4-methoxybenzyl)carbamate (40.2 mg, 0.050 mmol) in trifluoroacetic acid (TFA, 0.50 mL, 6.5 mmol) at ambient temperature. This reaction mixture was heated to 70° C. under N2 and stirred for 1 h. HPLC indicated reaction completed. The reaction mixture was cooled to room temperature and the TFA was evaporated. The residual TFA was removed by treatment with dichloromethane (3×10 mL) followed by evaporation in vacuum. The residue was then triturated with dichloromethane and methanol to give the desired product (20 mg, 87%) as a crude off-white solid. 1H NMR (400 MHz, DMSO-d6) δ 8.08 (dd, J=6.2, 2.5 Hz, 1 H), 7.72 (m, 1 H), 7.59 (t, J=8.7 Hz, 1 H), 6.67 (t, J=5.9 Hz, 1H), 6.55 (s, 2H) 6.52 (t, J=6.0 Hz, 1 H), 3.38 (dd, J=12.7, 6.3 Hz, 2 H), 3.11 (dd, J=12.3, 6.3 Hz, 2H); C12H11BrFN7O5S (MW 464.23), LCMS (EI) m/e 487.8/489.8 (M++Na).
Reaction SMILES: [CH3:1][C:2]1([C:7]2[O:11][C:10]([CH2:12][N:13]3[CH:17]=[C:16]([NH2:18])[CH:15]=[N:14]3)=[CH:9][CH:8]=2)[O:6]CCO1.[F:19][C:20]1[CH:21]=[C:22]([C:26]2[O:30][C:29]([CH3:31])=[N:28][C:27]=2[C:32](O)=[O:33])[CH:23]=[CH:24][CH:25]=1>>[C:2]([C:7]1[O:11][C:10]([CH2:12][N:13]2[CH:17]=[C:16]([NH:18][C:32]([C:27]3[N:28]=[C:29]([CH3:31])[O:30][C:26]=3[C:22]3[CH:23]=[CH:24][CH:25]=[C:20]([F:19])[CH:21]=3)=[O:33])[CH:15]=[N:14]2)=[CH:9][CH:8]=1)(=[O:6])[CH3:1]
Reactant: CC1(c2ccc(Cn3cc(N)cn3)o2)OCCO1
Reactant: Cc1nc(C(=O)O)c(-c2cccc(F)c2)o1
Product: CC(=O)c1ccc(Cn2cc(NC(=O)c3nc(C)oc3-c3cccc(F)c3)cn2)o1

Procedure:
Following general procedure B followed by T, starting from 1-[5-(2-methyl-[1,3]dioxolan-2-yl)-furan-2-ylmethyl]-1H-pyrazol-4-ylamine and 5-(3-fluoro-phenyl)-2-methyl-oxazole-4-carboxylic acid. LC-MS-conditions 05b: tR=1.06 min; [M+H]+=409.11.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10](=[O:20])[C:11]1[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:27](Br)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>CN(C)C=O>[CH2:27]([O:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10](=[O:20])[C:11]1[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: BrCc1ccccc1
Reactant: Cc1ccc(NC(=O)c2ccc([N+](=O)[O-])cc2)c(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1ccc(NC(=O)c2ccc([N+](=O)[O-])cc2)c(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 94.9 %

Procedure:
To a solution of N-(2-hydroxy-4-methylphenyl)-4-nitrobenzamide (3.8 g) in N,N-dimethylformamide (25 ml) was added potassium carbonate (3.85 g) and benzyl bromide (2.63 g). The reaction mixture was stirred at ambient temperature for 3 hours. The mixture was extracted with ethyl acetate and washed with water and brine. The organic solution was dried over magnesium sulfate. The solvent was removed by evaporation to give N-(2-benzyloxy-4-methylphenyl)-4-nitrobenzamide (4.8 g).
Reaction SMILES: C(N(CC)CC)C.[C:8](OC(=O)C)(=[O:10])[CH3:9].[NH2:15][C:16]1[N:21]=[C:20]([C:22]([OH:46])([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][N:41]=2)[C:23]2[C:31]3[NH:30][C:29](=[O:32])[NH:28][C:27]=3[CH:26]=[C:25]([C:33]3[C:34]([CH3:39])=[N:35][O:36][C:37]=3[CH3:38])[CH:24]=2)[CH:19]=[CH:18][CH:17]=1>CN(C)C1C=CN=CC=1.CN(C)C=O>[C:8]([N:28]1[C:27]2[CH:26]=[C:25]([C:33]3[C:34]([CH3:39])=[N:35][O:36][C:37]=3[CH3:38])[CH:24]=[C:23]([C:22]([C:20]3[CH:19]=[CH:18][CH:17]=[C:16]([NH2:15])[N:21]=3)([OH:46])[C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][N:41]=3)[C:31]=2[NH:30][C:29]1=[O:32])(=[O:10])[CH3:9]
Reactant: Cc1noc(C)c1-c1cc(C(O)(c2ccccn2)c2cccc(N)n2)c2[nH]c(=O)[nH]c2c1
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(=O)n1c(=O)[nH]c2c(C(O)(c3ccccn3)c3cccc(N)n3)cc(-c3c(C)noc3C)cc21
Temperature: 0 °C

Procedure:
To a microwave vial capped with a septum, 4-(dimethylamino)pyridine (5.8 mg, 0.047 mmol) and triethylamine (9 μL, 0.07 mmol) in N,N-dimethylformamide (0.5 mL) were cooled to 0° C. in a nitrogen atmosphere. Acetic anhydride (4.4 μL, 0.047 mmol) was added and the reaction mixture was stirred for 15 minutes at 0° C. before a solution of 4-((6-aminopyridin-2-yl)(hydroxy)(pyridin-2-yl)methyl)-6-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-2(3H)-one (10 mg, 0.023 mmol) in N,N-dimethylformamide (0.25 mL) was added dropwise to the reaction mixture. The reaction was allowed to warm to room temperature and stirred for thirty minutes (or until completion). The reaction was quenched with water and diluted with ethyl acetate. The organic layer was separated and saved and the organic layer was extracted with ethyl acetate (three times, 20 mL each). The organic fractions were collected, dried over MgSO4, filtered and concentrated. The product was isolated by preparatory HPLC to yield a clear oil.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([CH3:7])=[CH:5][N:6]=1.[Cl:8][CH2:9][C:10](=O)[CH2:11][C:12](OCC)=[O:13]>>[Cl:8][CH2:9][C:10]1[N:1]=[C:2]2[S:3][C:4]([CH3:7])=[CH:5][N:6]2[C:12](=[O:13])[CH:11]=1
Reactant: CCOC(=O)CC(=O)CCl
Reactant: Cc1cnc(N)s1
Product: Cc1cn2c(=O)cc(CCl)nc2s1
Yield: 63.9 %

Procedure:
This compound was synthesized from 2-amino-5-methyl thiazole (5.0 g, 43.710 mmol) and ethyl chloroacetoacetate (9.893 g, 59.561 mmol) in polyphosphoric acid (40.0 g) according to the procedure described in Step 1, Intermediate 2 to afford 6.0 g of the desired compound as a black solid; 1H NMR (300 MHz, DMSO-d6) δ 2.43 (s, 3H), 4.58 (s, 2H), 6.39 (s, 1H), 7.87 (s, 1H); ESI-MS (m/z) 215.37 (M+H)+.