Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH:5]([CH2:12][CH:13]([CH3:15])[CH3:14])[CH:6]2[OH:11].C(N(CC)CC)C.[CH3:23][Si:24](Cl)([CH3:26])[CH3:25].C(=O)(O)[O-].[Na+]>C(Cl)Cl>[Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH:5]([CH2:12][CH:13]([CH3:15])[CH3:14])[CH:6]2[O:11][Si:24]([CH3:26])([CH3:25])[CH3:23]
Reactant: CC(C)CC1Cc2c(Br)cccc2C1O
Reactant: C[Si](C)(C)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)CC1Cc2c(Br)cccc2C1O[Si](C)(C)C
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 95.8 %

Procedure:
A 300-ml three-necked round flask equipped with a stirring bar, a Dimroth condenser, a dropping funnel and a thermometer was charged with 34.4 g (127.8 mmol) of 4-bromo-2-i-butyl-1-hydoxyindane, 23.1 ml (166.2 mmol) of triethylamine and 118 ml of methylene chloride. To the mixture was added dropwise 20 ml of a methylene chloride solution containing 19.45 ml (153.4 mmol) of trimethylsilyl chloride under a nitrogen atmosphere while cooling with ice bath. After the addition was completed, the temperature was elevated to room temperature, and the mixture was further stirred for 1.5 hours. The reaction mixture was poured onto a mixture of 200 ml of ice water and 20 ml of a saturated aqueous solution of sodium bicarbonate. Then, the organic phase was separated, and the aqueous phase was further extracted with 50 ml of methylene chloride two times. The combined organic phase was washed with 100 ml of a saturated NaCl aq., followed by dried over anhydrous Na2SO4. The solvent was evaporated under reduced pressure. The residue was distilled under reduced pressure to obtain 41.8 g of the desired product (mixture of two isomers) as a pale yellow liquid (yield: 96%).
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:12])=[C:4]([CH:8]=[CH:9][C:10]=1[Cl:11])[C:5]([NH2:7])=O.[H-].[H-].[H-].[H-].[Li+].[Al+3]>>[NH2:1][C:2]1[C:3]([F:12])=[C:4]([CH:8]=[CH:9][C:10]=1[Cl:11])[CH2:5][NH2:7]
Reactant: NC(=O)c1ccc(Cl)c(N)c1F
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: NCc1ccc(Cl)c(N)c1F

Procedure:
The crude sub-title compound is prepared from 3-amino-4-chloro-2-fluoro-benzamide and LiAlH4 in analogy to step Ad.
Reaction SMILES: [CH3:1][CH:2]1[CH2:6][CH2:5][CH:4]([CH3:7])[NH:3]1.C[O:9][C:10]([C:12]1[C:16]([NH:17][C:18]([C:20]2[C:25]([NH:26][C:27]3[CH:28]=[N:29][CH:30]=[N:31][CH:32]=3)=[CH:24][CH:23]=[C:22]([CH:33]3[CH2:35][CH2:34]3)[N:21]=2)=[O:19])=[CH:15][N:14]([CH3:36])[N:13]=1)=O>>[CH3:1][CH:2]1[CH2:6][CH2:5][CH:4]([CH3:7])[N:3]1[C:10]([C:12]1[C:16]([NH:17][C:18]([C:20]2[C:25]([NH:26][C:27]3[CH:28]=[N:29][CH:30]=[N:31][CH:32]=3)=[CH:24][CH:23]=[C:22]([CH:33]3[CH2:35][CH2:34]3)[N:21]=2)=[O:19])=[CH:15][N:14]([CH3:36])[N:13]=1)=[O:9]
Reactant: CC1CCC(C)N1
Reactant: COC(=O)c1nn(C)cc1NC(=O)c1nc(C2CC2)ccc1Nc1cncnc1
Product: CC1CCC(C)N1C(=O)c1nn(C)cc1NC(=O)c1nc(C2CC2)ccc1Nc1cncnc1
Yield: 10 %

Procedure:
According to the general method described in step 5 of example 27, reaction of 2,5-dimethylpyrrolidine with 4-{[6-cyclopropyl-3-(pyrimidin-5-ylamino)-pyridine-2-carbonyl]-amino}-1-methyl-1H-pyrazole-3-carboxylic acid methyl ester provided the title compound (10%) as amorphous yellow solid.
Reaction SMILES: [OH:1][CH:2]([C:5]1[N:6]=[C:7]([C:10]([F:13])([F:12])[F:11])[S:8][CH:9]=1)[CH2:3][NH2:4].[OH:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][C:22](=O)[CH3:23])=[CH:17][CH:16]=1>>[OH:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][CH:22]([NH:4][CH2:3][CH:2]([OH:1])[C:5]2[N:6]=[C:7]([C:10]([F:13])([F:12])[F:11])[S:8][CH:9]=2)[CH3:23])=[CH:17][CH:16]=1
Reactant: NCC(O)c1csc(C(F)(F)F)n1
Reactant: CC(=O)Cc1ccc(O)cc1
Product: CC(Cc1ccc(O)cc1)NCC(O)c1csc(C(F)(F)F)n1

Procedure:
Prepared by analogy to Example 13 by reaction of 2-hydroxy-2-(2-trifluoromethyl-thiazol-4-yl)ethanamine with 4-hydroxyphenyl-propan-2-one followed by purification of the base on a silica gel column using chloroform/methanol =9:1 as eluant.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]3[C:12](=[CH:13][C:14]([S:18]([N:21]([CH2:27][C:28]4[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=4)[C:22]4[S:23][CH:24]=[CH:25][N:26]=4)(=[O:20])=[O:19])=[CH:15][CH:16]=3)[CH:11]=[CH:10][N:9]=2)=[C:4]([OH:36])[CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:44][C:45]#[N:46]>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]3[C:12](=[CH:13][C:14]([S:18]([N:21]([CH2:27][C:28]4[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=4)[C:22]4[S:23][CH:24]=[CH:25][N:26]=4)(=[O:19])=[O:20])=[CH:15][CH:16]=3)[CH:11]=[CH:10][N:9]=2)=[C:4]([O:36][CH2:44][C:45]#[N:46])[CH:3]=1
Reactant: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc3c(-c4ccc(Cl)cc4O)nccc3c2)cc1
Reactant: N#CCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc3c(-c4ccc(Cl)cc4OCC#N)nccc3c2)cc1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
To the crude material from Step 1 was added DMF (1.5 ml) followed by cesium carbonate (175 mg, 0.538 mmol) and bromoacetonitrile (24.99 μl, 0.359 mmol). The resulting mixture was stirred at 60° C. overnight affording clean conversion to desired product according to LC-MS. The mixture was filtered through Celite with the aid of DCM and the filtrate dried under reduced pressure. m/z (ESI) 577.1 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[CH2:3][N:4]=[C:5]([NH2:16])[NH:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9](S(C)=O)[N:8]=1.[H-].[Na+].[OH:21][CH2:22][CH2:23][N:24]1[CH:28]=[CH:27][N:26]=[CH:25]1>C(O)(C)(C)C>[F:1][C:2]([F:18])([F:17])[CH2:3][N:4]=[C:5]([NH2:16])[NH:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]([O:21][CH2:22][CH2:23][N:24]2[CH:28]=[CH:27][N:26]=[CH:25]2)[N:8]=1
Reactant: OCCn1ccnc1
Reactant: CS(=O)c1nccc(NC(N)=NCC(F)(F)F)n1
Agent: [H-]
Agent: [Na+]
Solvent: CC(C)(C)O
Product: NC(=NCC(F)(F)F)Nc1ccnc(OCCn2ccnc2)n1

Procedure:
4-[2-(2,2,2-Trifluoroethyl)guanidino]-2-methanesulphinylpyrimidine (140 mg.) was added to a stirred mixture at 50° of t-butanol (10 ml.), NaH (48 mg. of a 50% w/w dispersion in oil) and 1-(2-hydroxyethyl)imidazole, and the mixture stirred at 50° for 2 hours and then evaporated to dryness. The residue was partitioned between aqueous 1N HCl and ether and the aqueous phase basified with aqueous 10N NaOH and extracted with EtOAc. The EtOAc extract was dried and evaporated to dryness and the residue recrystallised from EtOAc to give 1-[2-(4-[2-(2,2,2-trifluoroethyl)guanidino]pyrimid-2-yloxy)ethyl]imidazole (135 mg.), m.p. 149°-150°.
Reaction SMILES: [ClH:1].Cl.[N:3]1([C:7]2[N:12]=[CH:11][C:10]([C:13]3([C:16]([OH:18])=O)[CH2:15][CH2:14]3)=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4]1.S(Cl)([Cl:21])=O>>[ClH:21].[ClH:1].[N:3]1([C:7]2[N:12]=[CH:11][C:10]([C:13]3([C:16]([Cl:21])=[O:18])[CH2:15][CH2:14]3)=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4]1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)C1(c2ccc(N3CCC3)nc2)CC1
Agent: Cl
Product: O=C(Cl)C1(c2ccc(N3CCC3)nc2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To 1-(6-azetidin-1-ylpyridin-3-yl)cyclopropanecarboxylic acid dihydrochloride (61.00 mg, 0.0002095 mol) were added thionyl chloride (1.00 mL, 0.0137 mol) at 0° C. and the resulting solution was stirred at rt for 1 hr. Upon completion, the reaction mixture was azeotroped with toluene (3×) and then used in the next step without further purification.
Reaction SMILES: Cl[C:2]1(Cl)[C:8](=[O:9])[CH:7]2[CH:3]1[CH2:4][CH2:5][CH:6]2[CH2:10][CH2:11][CH:12]([O:15][Si](C(C)(C)C)(C)C)[CH2:13][CH3:14].[C:24](O)(=O)C>[Zn]>[OH:15][CH:12]([CH2:13][CH3:14])[CH2:11][CH2:10][CH:6]1[CH2:5][CH2:4][CH:3]2[CH:7]1[CH2:24][C:8](=[O:9])[CH2:2]2
Reactant: CCC(CCC1CCC2C1C(=O)C2(Cl)Cl)O[Si](C)(C)C(C)(C)C
Reactant: CC(=O)O
Agent: [Zn]
Product: CCC(O)CCC1CCC2CC(=O)CC12

Procedure:
The procedure followed is the same as that described in Example 11 substituting the starting material prepared in Example 28, 6,6-dichloro-2-(3-[(1,1-dimethylethyl)dimethylsiloxy]pent-1-yl)bicyclo[3.2.0]-heptan-7-one{7,7-dichloro-4-[3,[[(1,1-dimethylethyl)dimethylsilyl]oxy]pentyl]bicyclo[3.2.0]heptan-6-one} and isomers (2.4 g, 6.1 mmoles), glacial acetic acid (17 ml), and zinc powder (5 g). The crude produce is chromatographed on silica gel and subsequently kugelrohred under vacuum leaving a clear, colorless oil (1.0 g, 4.8 mmoles).
Reaction SMILES: [CH:1](=O)[CH3:2].[NH:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]=[C:5]1[NH:13][C:14]([C:16]1[NH:20][CH:19]=[N:18][C:17]=1[C:21]([NH:23][C:24]1[CH:29]=[CH:28][C:27]([O:30][CH:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)=[CH:26][CH:25]=1)=[O:22])=[O:15].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].Cl>CN(C=O)C>[NH:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]=[C:5]1[NH:13][C:14]([C:16]1[NH:20][CH:19]=[N:18][C:17]=1[C:21]([NH:23][C:24]1[CH:29]=[CH:28][C:27]([O:30][CH:31]2[CH2:36][CH2:35][N:34]([CH2:1][CH3:2])[CH2:33][CH2:32]2)=[CH:26][CH:25]=1)=[O:22])=[O:15]
Reactant: O=C(Nc1ccc(OC2CCNCC2)cc1)c1nc[nH]c1C(=O)Nc1nc2ccccc2[nH]1
Reactant: CC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCN1CCC(Oc2ccc(NC(=O)c3nc[nH]c3C(=O)Nc3nc4ccccc4[nH]3)cc2)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Acetaldehyde (0.088 g, 2.0 mmol) was weighed out into a dry 25 ml round bottom flask. N5-(1H-benzo[d]imidazol-2-yl)-N4-(4-(piperidin-4-yloxy)phenyl)-1H-imidazole-4,5-dicarboxamide (0.0446 g, 0.1 mmol) was added, followed by DMF (3.0 ml) of sodium triacetoxyborohydride (0.106 g, 0.5 mmol). The reaction mixture was stirred at room temperature over night (16 hours). The reaction mixture was then treated with 1 mL of 1N hydrochloric acid and concentrated under reduced pressure. The resulting crude material was purified by reverse phase HPLC (ammonium acetate/acetonitrile) to give N5-1H-benzimidazol-2-yl-N4-{4-[(1-ethylpiperidin-4-yl)oxy]phenyl}-1H-imidazole-4,5-dicarboxamide as an grey-white solid. 1H-NMR (DMSO-d6) 8.05 (s, 1H), 7.68 (d, 2H), 7.43 (s, br 2H), 7.05 (dd, 2H), 6.93 (d, 2H), 4.31 (m, 1H), 2.65 (m, 2H), 2.29 (q, 2H), 2.14 (m, 2H), 1.88 (m, 2H), 1.59 (m, 2H), 0.95 (t, 3H). MS (EI): 474 (MH+).
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[OH:12])[C:5]([O:7][CH3:8])=[O:6].[C:13]1([C:19]#[CH:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.CN(C)C(=N)N(C)C.CN(C=O)C>[Cu]I.O>[CH3:8][O:7][C:5]([C:4]1[CH:9]=[CH:10][C:11]2[O:12][C:19]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[CH:20][C:2]=2[CH:3]=1)=[O:6]
Reactant: C#Cc1ccccc1
Reactant: COC(=O)c1ccc(O)c(I)c1
Agent: [Cu]I
Agent: CN(C)C(=N)N(C)C
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ccc2oc(-c3ccccc3)cc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.1 %

Procedure:
A mixture of methyl 3-iodo-4-hydroxybenzoate 26 (1 g, 3.6 mmol), phenylacetylene (2 ml, 18 mmol), tetramethylguanidine (4.5 ml, 36 mmol), copper(I)iodide (34 mg, 1.8 mmol), bis(triphenylphosphine)palladium (II)chloride (130 mg, 1.8 mmol) and DMF (20 ml) was stirred at room temperature overnight. The reaction mixture was poured into water, extracted, washed and dried. After evaporation of the solvent, the residue was purified by chromatography to give about 0.9 g of 2-phenyl-benzofuran-5-carboxylic acid methyl ester 27.
Reaction SMILES: C([NH:4][C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[NH:15][CH2:16][C:17]([C:32]([F:35])([F:34])[F:33])([OH:31])[CH2:18][C:19]([C:22]2[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:23]=2[O:29][CH3:30])([CH3:21])[CH3:20])[N:6]=1)(=O)C.[OH-].[Na+]>CCO.C1COCC1.[Na+].[Cl-]>[NH2:4][C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[NH:15][CH2:16][C:17]([C:32]([F:35])([F:33])[F:34])([OH:31])[CH2:18][C:19]([C:22]2[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:23]=2[O:29][CH3:30])([CH3:21])[CH3:20])[N:6]=1
Reactant: COc1ccc(F)cc1C(C)(C)CC(O)(CNc1cccc2nc(NC(C)=O)ccc12)C(F)(F)F
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: COc1ccc(F)cc1C(C)(C)CC(O)(CNc1cccc2nc(N)ccc12)C(F)(F)F
Yield: 80.2 %

Procedure:
A solution of 535 mg (1.05 mmol) of 1-(2-acetylaminoquinolin-5-ylamino)-4-(5-fluoro-2-methoxyphenyl)-4-methyl-2-(trifluoromethyl)pentan-2-ol in 18 ml of EtOH-THF (2:1) is refluxed with 12 ml of 3N sodium hydroxide solution for 90 minutes. The batch is diluted with saturated NaCl and extracted with ethyl acetate. The extracts are dried (Na2SO4) and concentrated by evaporation in a vacuum. Column chromatography on silica gel with ethyl acetate yields 380 mg of the product as a yellow oil.
Reaction SMILES: C([O:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)=[CH:7][CH:6]=1)C=C.Cl[C:20]1[CH:25]=CC=C[C:21]=1Cl>>[CH3:18][C:15]1[CH:14]=[CH:13][C:12]([O:11][C:8]2[CH:7]=[CH:6][C:5]([OH:4])=[C:10]([CH2:25][CH:20]=[CH2:21])[CH:9]=2)=[CH:17][CH:16]=1
Reactant: Clc1ccccc1Cl
Reactant: C=CCOc1ccc(Oc2ccc(C)cc2)cc1
Product: C=CCc1cc(Oc2ccc(C)cc2)ccc1O

Procedure:
4-(4'-Methylphenoxy)phenyl allyl ether (4.00 g, 16.37 mmol) was taken up in 1,2-dichlorobenzene (50 mL) and refluxed for 20 h. After cooling, the solvent was removed in vacuo and the resulting crude oil was chromatographed on silica gel (15% ethyl acetate/hexane) to afford 4-(4'-methylphenoxy)-2-allylphenol.
Reaction SMILES: [CH3:1][N:2]1[C:6]([O:7][C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([CH2:14][NH2:15])[N:9]=2)=[CH:5][C:4]([C:16]([F:19])([F:18])[F:17])=[N:3]1.C(N(C(C)C)CC)(C)C.[C:29](Cl)(=[O:33])[CH:30]=[CH:31][CH3:32]>C(Cl)Cl>[CH3:1][N:2]1[C:6]([O:7][C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([CH:14]([C:29](=[O:33])[CH:30]=[CH:31][CH3:32])[NH2:15])[N:9]=2)=[CH:5][C:4]([C:16]([F:19])([F:17])[F:18])=[N:3]1
Reactant: CC=CC(=O)Cl
Reactant: Cn1nc(C(F)(F)F)cc1Oc1cccc(CN)n1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC=CC(=O)C(N)c1cccc(Oc2cc(C(F)(F)F)nn2C)n1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
0.100 g (0.368 mmol) of 2-(1-methyl-3-trifluoromethylpyrazol-5-yloxy)-6-(aminomethyl)-pyridine was introduced in 5 ml of methylene chloride together with 71.1 mg (0.55 mmol) of diisopropylethylamine, at room temperature 46.1 mg (0.44 mmol) of but-2-enoyl chloride were added and the mixture was stirred at room temperature for 3 h. The crude product was concentrated, subjected to extraction with 1 N HCl and ethyl acetate and then filtered over a silica gel bed. The filtrate was concentrated. The residue was crystalline.
Reaction SMILES: [CH2:1]([O:3][CH2:4][C:5]1[S:6][C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[C:9]([NH:17]C(=O)C(Cl)(Cl)Cl)[C:8]=2[N:24]=1)[CH3:2].C[O-].[Na+]>CO>[CH2:1]([O:3][CH2:4][C:5]1[S:6][C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[C:9]([NH2:17])[C:8]=2[N:24]=1)[CH3:2]
Reactant: CCOCc1nc2c(NC(=O)C(Cl)(Cl)Cl)nc3ccccc3c2s1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CCOCc1nc2c(N)nc3ccccc3c2s1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Trichloroacetyl isocyanate (0.7 mL) was added to a solution of 2-(ethoxymethyl)thiazolo[4,5-c]quinoline-5N-oxide (1.0 g) in dichloromethane (50 mL). The reaction mixture was stirred at ambient temperature for 2 hours and then concentrated under vacuum to provide N-(2-(ethoxymethyl)thiazolo[4,5-c]quinolin-4-yl)trichloroacetamide. The amide was taken up in methanol and then combined with 1 equivalent of sodium methoxide. The reaction mixture was stirred at ambient temperature for 30 minutes and then concentrated under vacuum. The reaction was run a second time using 2 g of the N-oxide. The products were combined and recrystallized from isopropanol to provide 2.25 g of 2-(ethoxymethyl)thiazolo[4,5-c]quinoline-4-amine as light yellow needles, m.p. 149–151° C. Analysis: Calculated for C13H13N3OS: % C, 60.21; % H, 5.05; % N, 16.20; Found: % C, 59.86; % H, 4.97; % N, 16.16.
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11](=[O:19])OC2C=CC=CC=2)[N:7]([C:20]2[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:27][O:28][C:29]1[CH:30]=[C:31]2[C:36](=[CH:37][C:38]=1[O:39][CH3:40])[N:35]=[CH:34][N:33]=[C:32]2[O:41][C:42]1[CH:43]=[C:44]([CH:46]=[CH:47][CH:48]=1)[NH2:45]>CN(C1C=CN=CC=1)C.C1COCC1>[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:45][C:44]2[CH:46]=[CH:47][CH:48]=[C:42]([O:41][C:32]3[C:31]4[C:36](=[CH:37][C:38]([O:39][CH3:40])=[C:29]([O:28][CH3:27])[CH:30]=4)[N:35]=[CH:34][N:33]=3)[CH:43]=2)=[O:19])[N:7]([C:20]2[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=2)[N:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)Oc2ccccc2)cc1
Reactant: COc1cc2ncnc(Oc3cccc(N)c3)c2cc1OC
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Product: COc1cc2ncnc(Oc3cccc(NC(=O)Nc4cc(C(C)(C)C)nn4-c4ccc(C)cc4)c3)c2cc1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.9 %

Procedure:
A mixture of phenyl 3-tert-butyl-1-p-tolyl-1H-pyrazol-5-ylcarbamate (0.14 g, 0.4 mmol), 3-(6,7-dimethoxyquinazolin-4-yloxy)aniline from Example 113 (0.119 g, 0.4 mmol) and DMAP (0.025 g) in THF (6 mL) was stirred at room temperature overnight. The reaction was quenched by adding DCM and concentrated. To the residue was added Et2O to give 1-(3-tert-butyl-1-p-tolyl-1H-pyrazol-5-yl)-3-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)urea as solid (0.181 g, 82%). 1H NMR (300 MHz, DMSO-d6) δ 1.25 (s, 9H), 2.37 (s, 3H), 3.98 (s, 3H), 3.99 (s, 3H), 6.33 (s, 1H), 6.93 (d, 1H), 7.16 (d, 1H), 7.32-7.40 (m, 6H), 7.55 (d, 2H), 8.41 (s, 1H), 8.55 (s, 1H), 9.23 (s, 1H); LC-MS (ESI) m/z 553 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[C:10]([CH:11]=1)=[C:9]([N+:12]([O-])=O)[CH:8]=[CH:7][CH:6]=2.[CH3:15][NH:16][CH3:17]>>[CH3:15][N:16]([CH3:17])[C:2]1[N:3]=[CH:4][C:5]2[CH:6]=[CH:7][CH:8]=[C:9]([NH2:12])[C:10]=2[CH:11]=1
Reactant: O=[N+]([O-])c1cccc2cnc(Cl)cc12
Reactant: CNC
Product: CN(C)c1cc2c(N)cccc2cn1
Temperature: 100 °C
Yield: 59 %

Procedure:
3-Chloro-5-nitroisoquinoline (Description 108, 160 mg, 0.767 mmol) was dissolved in 33% ethanolic dimethylamine (6 ml) and the mixture then heated in a sealed tube at 100° C. for 2.5 h. After cooling to room temperature the solvent and excess dimethylamine was evaporated and the residue reduced according to the procedure of Description 45 to give the title compound (85 mg, 59%).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[N:5][N:6]=1.[C:7]([NH:10][C:11]1[CH:16]=[CH:15][C:14]([S:17](Cl)(=[O:19])=[O:18])=[CH:13][CH:12]=1)(=[O:9])[CH3:8]>N1C=CC=CC=1.Cl>[S:3]1[CH:4]=[N:5][N:6]=[C:2]1[NH:1][S:17]([C:14]1[CH:13]=[CH:12][C:11]([NH:10][C:7](=[O:9])[CH3:8])=[CH:16][CH:15]=1)(=[O:19])=[O:18]
Reactant: Nc1nncs1
Reactant: CC(=O)Nc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Solvent: c1ccncc1
Product: CC(=O)Nc1ccc(S(=O)(=O)Nc2nncs2)cc1
Temperature: 95 °C
Yield: 94.9 %

Procedure:
2-Amino-1,3,4-thiadiazole (500 mg, 4.95 mmol) was suspended in pyridine (1.26 mL). p-Acetamidobenzenesulfonyl chloride (1.2 g, 5.15 mmol) was added and the mixture was heated to 95° C. for 1 h. The mixture was dissolved in 10% aqueous HCl and extracted with ethyl acetate. The organic extracts were washed with water and dried over anhydrous Na2SO4. Evaporation of the solvent yielded the crude product (1.4 g, 4.7 mmol, 95%). Recrystallization from CH2Cl2/MeOH gave pure product, mp 216-217° C. (lit1 mp 214-215° C.); 1H NMR (250 MHz, CDCl3) δ 2.07 (3, s), 7.73 (4, s), 8.74 (1, s), 10.35 (1, s), 14.35 (1, br s); 13C NMR (62.5 MHz, DMSO) δ 24.2, 118.7, 127.0, 135.6, 143.0, 144.9, 167.2, 169.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:9]2[N:13]([CH2:14][CH:15]3[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]3)[C:12]3[CH:21]=[CH:22][CH:23]=[CH:24][C:11]=3[N:10]=2)=[C:6]([OH:8])[CH:7]=1.Br[CH2:26][C:27]1[CH:34]=[CH:33][C:30]([C:31]#[N:32])=[CH:29][C:28]=1[F:35]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:9]2[N:13]([CH2:14][CH:15]3[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]3)[C:12]3[CH:21]=[CH:22][CH:23]=[CH:24][C:11]=3[N:10]=2)=[C:6]([CH:7]=1)[O:8][CH2:26][C:27]1[CH:34]=[CH:33][C:30]([C:31]#[N:32])=[CH:29][C:28]=1[F:35]
Reactant: N#Cc1ccc(CBr)c(F)c1
Reactant: Oc1cc(Cl)ccc1-c1nc2ccccc2n1CC1CCCCC1
Product: N#Cc1ccc(COc2cc(Cl)ccc2-c2nc3ccccc3n2CC2CCCCC2)c(F)c1

Procedure:
The title compound was prepared in analogy to Example 19, from 5-chloro-2-(1-cyclohexylmethyl-1H-benzoimidazol-2-yl)-phenol and 4-bromomethyl-3-fluoro-benzonitrile (105942-09-4). Brown solid (69%). MS (Turbo Spray): m/z=474.4 (M+H).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:3]=1[CH:4]=O.[NH2:11][C:12](N)=[O:13]>>[Cl:10][C:8]1[CH:9]=[C:2]2[C:3]([CH:4]=[N:11][C:12]([OH:13])=[N:1]2)=[CH:6][CH:7]=1
Reactant: Nc1cc(Cl)ccc1C=O
Reactant: NC(N)=O
Product: Oc1ncc2ccc(Cl)cc2n1
Temperature: 170 °C
Reaction time: 2 h

Procedure:
In a 500 mL round bottom flask, the uniform mixture of 2-amino-4-chlorobenzaldehyde (16 g, 103.2 2 mmol) and urea (123.8 g, 2063 mmol) was heated at 170° C. with vigorous stirring for 2 h. On completion of reaction, the reaction mixture was cooled to rt and diluted with ice-cold water. The solid that formed was collected by filtration and washed with ice-cold water. The solid was dried under reduced pressure to give crude 7-chloroquinazolin-2-ol as a yellow solid. Yield: 19 g. LCMS (ESI, m/z): 181 (M+1)+
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[O:6][C@@H:5]([C:7]2[CH:12]=[CH:11][C:10]([N+:13]([O-])=O)=[CH:9][CH:8]=2)[CH2:4][O:3]1.[H][H]>[Pd].CO>[CH3:1][C:2]1([CH3:16])[O:6][C@@H:5]([C:7]2[CH:12]=[CH:11][C:10]([NH2:13])=[CH:9][CH:8]=2)[CH2:4][O:3]1
Reactant: CC1(C)OC[C@H](c2ccc([N+](=O)[O-])cc2)O1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CC1(C)OC[C@H](c2ccc(N)cc2)O1
Yield: 99.6 %

Procedure:
A mixture of (S)-2,2-dimethyl-4-(4-nitrophenyl)-1,3-dioxolane (3.6 g, 16.1 mmol) and 5% palladium on carbon (50% wet, 700 mg) in methanol (30 mL) was stirred under 1 atm hydrogen atmosphere (H2 balloon) at RT for 16 h. After the reaction mixture was filtered through a pad of Celite, the filtrate was concentrated to afford the title compound (3.1 g, 100%) as a yellow solid. MS (ES+) C11H15NO2 requires: 193, found: 194 [M+H]+.
Reaction SMILES: [C:1]([C:4]1[CH:18]=[CH:17][CH:16]=[CH:15][C:5]=1[C:6](=[C:8]1[S:12]C(=S)N[C:9]1=[O:14])[CH3:7])([OH:3])=O.C([OH:21])C.O>>[CH3:7][C:6]1[C:5]2[C:4](=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:1](=[O:3])[S:12][C:8]=1[C:9]([OH:21])=[O:14]
Reactant: CC(=C1SC(=S)NC1=O)c1ccccc1C(=O)O
Reactant: CCO
Solvent: O
Product: Cc1c(C(=O)O)sc(=O)c2ccccc12

Procedure:
4-Methyl-2-thiaisocoumarin-3-carboxylic acid mp. (EtOH-H2O) 250.5°-251.5° (lit mp. 243°-5°), (Found: C, 60.40; H, 3.98; S, 14.80 C11H8SO3 requires C, 59.99; H, 3.66; S, 14.56) was prepared from 5-(o-carboxy-α-methylbenzylidene) rhodanine by an analogous procedure to that described in Example 12.
Reaction SMILES: C1CO[CH:3]([CH2:4][CH2:5][CH2:6][C:7]2[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[CH:9][CH:8]=2)[O:2]1.O1CCCC1.Cl>O>[C:11]([C:10]1[CH:13]=[CH:14][C:7]([CH2:6][CH2:5][CH2:4][CH:3]=[O:2])=[CH:8][CH:9]=1)#[N:12]
Reactant: N#Cc1ccc(CCCC2OCCO2)cc1
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: N#Cc1ccc(CCCC=O)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 116.5 %

Procedure:
A mixture of 2.8 g of p-(4,4-ethylenedioxybutyl)benzonitrile, 56 ml of tetrahydrofuran and 56 ml of 10% hydrochloric acid was stirred for 3 hours at room temperature and then left to stand overnight. Thereafter, the reaction mixture was diluted with water and extracted three times with diethyl ether. The organic phases were washed twice with water, dried over magnesium sulphate, filtered and concentrated. There were obtained 2.6 g of 4-(p-cyanophenyl)butyraldehyde which was processed without additional purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-:10])=[O:9])[C:3]=1[CH3:11].[CH2:12]=[O:13]>CO.CS(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-:10])=[O:9])[C:3]=1[CH2:11][CH2:12][OH:13]
Reactant: C=O
Reactant: Cc1c(Cl)cccc1[N+](=O)[O-]
Solvent: CS(C)=O
Solvent: CO
Product: O=[N+]([O-])c1cccc(Cl)c1CCO
Temperature: 90 °C
Reaction time: 2 h
Yield: 66.2 %

Procedure:
Triton B (2 ml, 35% in MeOH) was added to a mixture composed of 2-chloro-6-nitrotoluene (25 g, 146 mmol) and paraformaldehyde (1.9 g, 60 mmol) in DMSO (20 ml, synthesis quality, additionally dried for 2 d over molecular sieve 4 Å) and was stirred at 90° C. After 2 h, the reaction mixture was neutralized with a few drops of conc. HCl, diluted with H2O (50 ml) and extracted with EtOAc (4×150 ml). The combined organic phases were dried over MgSO4, filtered and concentrated under reduced pressure. The crude product was purified by sublimation in a high vacuum (p=0.06 torr, oil bath temperature 95° C.). 2-(2-chloro-6-nitrophenyl)ethanol (8.01 g, 66%) was obtained in the form of bright yellow crystals.