Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH3:12])[C:5]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([CH2:20][C:21]([OH:23])=[O:22])=[CH:16][C:15]=2[OH:24])=[C:4]([CH3:25])[N:3]=1.[CH3:26][N:27]([CH3:33])[CH2:28][CH2:29][CH2:30][CH2:31]O>>[NH2:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH3:12])[C:5]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([CH2:20][C:21]([O:23][CH2:31][CH2:30][CH2:29][CH2:28][N:27]([CH3:33])[CH3:26])=[O:22])=[CH:16][C:15]=2[OH:24])=[C:4]([CH3:25])[N:3]=1
Reactant: CCCCNc1nc(N)nc(C)c1Cc1ccc(CC(=O)O)cc1O
Reactant: CN(C)CCCCO
Product: CCCCNc1nc(N)nc(C)c1Cc1ccc(CC(=O)OCCCCN(C)C)cc1O

Procedure:
The title compound was prepared using product of example 79 step (i) (80 mg) and 4-(dimethylamino)butan-1-ol using the general coupling method of example 74 step (iii). The product was purified by RPHPLC to give the product, 25 mg.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9](=O)[C:10]([OH:12])=[O:11])[CH:6]=[CH:7][CH:8]=1.C(=O)(O)[O-].[Na+].Cl.[CH2:20]([O:22][NH2:23])[CH3:21].Cl>O>[CH2:20]([O:22][N:23]=[C:9]([C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=1)[C:10]([OH:12])=[O:11])[CH3:21]
Reactant: CCON
Reactant: COc1cccc(C(=O)C(=O)O)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: CCON=C(C(=O)O)c1cccc(OC)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.6 %

Procedure:
A solution of 2-(3-methoxyphenyl)glyoxylic acid (1.8 g.) in an aqueous solution of sodium bicarbonate was adjusted to pH 7.0. On the other hand, a solution of O-ethylhydroxylamine hydrochloride (1.4 g.) in water (20 ml.) was adjusted to pH 7.0 with sodium bicarbonate. Two solutions were combined together, adjusted to pH 5.5 with 10% hydrochloric acid and stirred overnight at ambient temperature. The reaction mixture was adjusted to pH 7.5 with sodium bicarbonate and washed with ethyl acetate. The aqueous layer was adjusted to pH 1.0 with conc. hydrochloric acid under ice-cooling and extracted with ethyl acetate. The extract was washed with ice-water and dried over magnesium sulfate. The solvent was distilled off under reduced pressure to give oil of 2-ethoxyimino-2-(3-methoxyphenyl)acetic acid (syn isomer) (2.2 g.).
Reaction SMILES: Cl.Cl.[CH3:3][NH:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[NH2:13].C([O-])(=O)C.[K+].[C:25](=S)=[S:26].C(S)(=S)N.[Cl-].[K+]>C(O)(C)C>[CH3:3][N:4]1[C:25](=[S:26])[NH:13][CH:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[CH2:5]1
Reactant: S=C=S
Reactant: CNCc1ccccc1C(N)c1ccccc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: NC(=S)S
Solvent: CC(C)O
Product: CN1Cc2ccccc2C(c2ccccc2)NC1=S
Temperature: 25 °C
Yield: 14.9 %

Procedure:
To a suspension of 15 g (50 mmol) of 2-[(methylamino)methyl]-α-phenylbenzenemethanamine dihydrochloride in 100 mL of isopropyl alcohol was added 10 g (100 mmol) of potassium acetate followed by 3.3 mL (55 mmol) of carbon disulfide in 35 mL of isopropyl alcohol. The suspension was stirred at room temperature for one and one-half hours and then refluxed for 30 minutes. The reaction was chilled in ice and the internal salt of the carbamodithioic acid, contaminated with two equivalents of potassium chloride, was filtered off. The carbamodithioic acid was suspended in 125 mL of 95% ethanol, and 1.3 mL of 12N hydrochloric acid was added. The suspension was refluxed for three days, cooled, and 15.3 g (114%) of the crude benzodiazepin-3-thione was filtered off. A 6-g portion of the crude product was recrystallized from 2-ethoxy ethanol to yield 2.0 g (38%) of product, mp 208-209.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][N:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([CH:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)=[CH:8]1.C([O:24][C:25](=[O:34])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[CH2:32]Br)C>>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][N:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([CH:16]2[CH2:21][CH2:20][N:19]([CH2:32][C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=3[C:25]([OH:34])=[O:24])[CH2:18][CH2:17]2)=[CH:8]1
Reactant: CCOC(=O)c1ccccc1CBr
Reactant: c1coc(Cn2cc(C3CCNCC3)c3ccccc32)c1
Product: O=C(O)c1ccccc1CN1CCC(c2cn(Cc3ccco3)c3ccccc23)CC1

Procedure:
This compound was prepared following the procedure described in example 13 (part D) starting with 0.05 g (0.18 mmol) of 1-furan-2-ylmethyl-3-piperidin-4-yl-1H-indole (example 83, part B) and 0.056 g (0.23 mmol) of 2-bromomethyl-benzoic acid ethyl ester. After standard work-up and purification using a C18 chromatography column, 0.014 g (19% of yield) of the expected acid were obtained.
Reaction SMILES: CN(C)[CH:3]=[C:4]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:5](=O)[CH3:6].[C:15]([CH2:17][C:18]([NH2:20])=[O:19])#[N:16].C[O-].[Na+].C(OCC)(=O)C>CO.O>[C:15]([C:17]1[C:18](=[O:19])[NH:20][C:5]([CH3:6])=[C:4]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:3]=1)#[N:16]
Reactant: CC(=O)C(=CN(C)C)c1ccccc1
Reactant: N#CCC(N)=O
Agent: C[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: O
Product: Cc1[nH]c(=O)c(C#N)cc1-c1ccccc1

Procedure:
A mixture of 4-dimethylamino-3-phenyl-3-butene-2-one (14.1 grams) and cyanoacetamide (5.9 grams) in 100 ml methanol was added to sodium methoxide (7.9 grams) in 100 ml methanol. The mixture was refluxed for 18 hours and then the crude reaction was stripped and the residue dissolved in a small amount of hot water. Acidification to pH 6-7 gave a gum-like solid which was collected by filtration. Further acidification to a lower pH gave only an oil. Trituration of the gum with ethyl acetate and chilling resulted in an off-white solid which was identified by NMR as the desired product, yield 2.8 grams, m.p. 280°-290° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:30])[CH:9]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[C:18]([O:23][C:24]([F:29])([F:28])[CH:25]([F:27])[F:26])[CH:17]=2)[C:10]([O:12]CC)=[O:11])=[CH:4][CH:3]=1.[OH-].[Na+].Cl>CO>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:30])[CH:9]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[C:18]([O:23][C:24]([F:29])([F:28])[CH:25]([F:27])[F:26])[CH:17]=2)[C:10]([OH:12])=[O:11])=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(Cc1ccc(C)c(OC(F)(F)C(F)F)c1)C(O)c1ccc(F)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1ccc(CC(C(=O)O)C(O)c2ccc(F)cc2)cc1OC(F)(F)C(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.7 %

Procedure:
To a solution of ethyl(2RS,3RS)-3-(4-fluorophenyl)-3-hydroxy-2-((4-methyl-3-((1,1,2,2-tetrafluoroethyl)oxy)phenyl)methyl)propionate (4.5 g, 10.4 mmol) in methanol (20 ml) was added 2N aqueous sodium hydroxide solution (10.4 ml, 20.8 mmol), and the mixture was stirred overnight at room temperature. The reaction solution was acidified with 1N hydrochloric acid and extracted with ethyl acetate (200 ml×2). The extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was recrystallized from diethyl ether-hexane to give (2RS,3RS)-3-(4-fluorophenyl)-3-hydroxy-2-((4-methyl-3-((1,1,2,2-tetrafluoroethyl)oxy)phenyl)methyl)propionic acid (3.56 g, 85%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:24]=[CH:23][C:6]([C:7]([C:9]2[O:10][C:11]3[CH:18]=[CH:17][C:16]([O:19]CC=C)=[CH:15][C:12]=3[C:13]=2[CH3:14])=[O:8])=[CH:5][CH:4]=1.Cl[C:26]1[CH:31]=CC=C[C:27]=1Cl>>[CH3:1][O:2][C:3]1[CH:24]=[CH:23][C:6]([C:7]([C:9]2[O:10][C:11]3[CH:18]=[CH:17][C:16]([OH:19])=[C:15]([CH2:31][CH:26]=[CH2:27])[C:12]=3[C:13]=2[CH3:14])=[O:8])=[CH:5][CH:4]=1
Reactant: C=CCOc1ccc2oc(C(=O)c3ccc(OC)cc3)c(C)c2c1
Reactant: Clc1ccccc1Cl
Product: C=CCc1c(O)ccc2oc(C(=O)c3ccc(OC)cc3)c(C)c12
Yield: 87 %

Procedure:
A mixture of 2-(p-methoxybenzoyl)-3-methyl-5-allyloxybenzofuran (1 gm, 3.10 mmole) in ortho dichlorobenzene (5 mL) was refluxed under nitrogen for a period of 5 hours. On cooling, the product crystallized. It was diluted with hexane, filtered, washed with hexane, and air-dried to yield 870 mg (87%) of 2-(p-methoxybenzoyl)-3-methyl-4-allyl- 5-hydroxy-benzofuran, mp. 155°-158° C.
Reaction SMILES: [C:1]1([C:7]2[CH:16]=[C:15]([CH2:17][CH2:18][C:19](O)=[O:20])[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(OC(Cl)=O)C.Cl.[CH3:29][NH:30][CH:31]([CH2:33][CH3:34])[CH3:32].Cl>C(Cl)(Cl)Cl.CC(C)=O.C(OCC)C.C(N(CC)CC)C>[CH3:29][N:30]([CH:31]([CH3:32])[CH2:33][CH3:34])[C:19](=[O:20])[CH2:18][CH2:17][C:15]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]=[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:16]=1
Reactant: O=C(O)CCc1cc(-c2ccccc2)nc2ccccc12
Reactant: CCC(C)NC
Agent: CCOC(=O)Cl
Agent: Cl
Solvent: CC(C)=O
Solvent: ClC(Cl)Cl
Solvent: CCOCC
Product: CCC(C)N(C)C(=O)CCc1cc(-c2ccccc2)nc2ccccc12
Temperature: 20 °C
Reaction time: 20 h
Yield: 15.3 %

Procedure:
Triethlamine (3.78 cc) is added to a suspension of 2-phenyl-4-quinolinepropanoic acid (2.5 g) in chloroform (100 cc), followed, under nitrogen and after the mixture has been cooled to 10° C., by ethylchloroformate (1.24 g). The mixture is then stirred for 40 minutes at room temperature (approximately 20° C.), and N-methyl-2-butanamine hydrochloride (1.05 g) is then introduced in small portions. The mixture is stirred for 20 hours at room temperature (approximately 20° C.). After evaporation of the solvent under reduced pressure, the residue is taken up in ethyl acetate, and the organic phase is washed with saturated aqueous sodium carbonate solution and dried over magnesium sulphate. The residue obtained after evaporation of the solvent under reduced pressure is chromatographed under pressure on silica gel, initially with a cyclohexane/toluene/diethylamine (80:15:5 by volume) mixture, a second time with a cyclohexane/toluene/diethylamine (90: 7.5:2.5 by volume) mixture, and a third time with a hexane/ethyl acetate (50:50 by volume) mixture. The residue obtained is taken up in acetone and, after addition of a solution of hydrochloric acid in ethyl ether, the product is isolated in the form of the crude hydrochloride. The latter is recrystallized in an isopropanol/isopropyl ether mixture. After a return to the base using 2 N sodium hydroxide, extraction with ethyl acetate and evaporation under reduced pressure, N-methyl-N-(1-methylpropyl)-2-phenyl-4-quinolinepropanamide (0.45 g) is isolated in the form of an oil, the proton NMR spectrum of which in deuterated chloroform shows the following characteristics:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[S:10][C:11]([CH3:16])=[CH:12][C:13]=2[C:14]#[N:15])=[C:4]([N+:17]([O-])=O)[CH:3]=1.[Sn](Cl)Cl.Cl.O>C(O)C.O>[ClH:1].[Cl:1][C:2]1[CH:7]=[CH:6][C:5]2[NH:8][C:9]3[S:10][C:11]([CH3:16])=[CH:12][C:13]=3[C:14]([NH2:15])=[N:17][C:4]=2[CH:3]=1
Reactant: Cc1cc(C#N)c(Nc2ccc(Cl)cc2[N+](=O)[O-])s1
Agent: Cl
Agent: Cl[Sn]Cl
Solvent: O
Solvent: CCO
Product: Cc1cc2c(s1)Nc1ccc(Cl)cc1N=C2N
Yield: 221.2 %

Procedure:
Suspend 2-(4-chloro-2-nitro-phenylamino)-5-methyl-thiophene-3-carbonitrile (2.92 g) in ethanol (40 ml), add anhydrous tin(II)chloride(5 g,) in 1:1 concentrated hydrochloric acid/water (32 ml) and heat the mixture under reflux for 2 hours. Dilute the mixture with water and allow to cool. Collect the precipitate formed by filtration and dry under high vacuum to give 7-chloro-2-methyl-4H-3-thia-4,9-diaza-benzo[f]azulen-10-ylamine hydrochloride as a yellow solid (3.3 g, 90%): mass Spectrum (FIA) 264/266 (M+1).
Reaction SMILES: C1(C)C=CC=CC=1.Br[C:9]1[C:10]([CH3:29])=[C:11]([CH3:28])[C:12]2[O:16][C:15]([CH3:18])([CH3:17])[CH:14]([C:19]3[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=3)[C:13]=2[C:26]=1[CH3:27].[CH3:30][O:31][C:32]1[CH:33]=[C:34]([CH:37]=[CH:38][C:39]=1[O:40][CH3:41])[CH2:35][NH2:36].CC(C)([O-])C.[Na+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1C=CC(P(C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(OCC)(=O)C>[CH3:30][O:31][C:32]1[CH:33]=[C:34]([CH:37]=[CH:38][C:39]=1[O:40][CH3:41])[CH2:35][NH:36][C:9]1[C:10]([CH3:29])=[C:11]([CH3:28])[C:12]2[O:16][C:15]([CH3:18])([CH3:17])[CH:14]([C:19]3[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=3)[C:13]=2[C:26]=1[CH3:27]
Reactant: COc1ccc(CN)cc1OC
Reactant: Cc1ccc(C2c3c(C)c(Br)c(C)c(C)c3OC2(C)C)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: COc1ccc(CNc2c(C)c(C)c3c(c2C)C(c2ccc(C)cc2)C(C)(C)O3)cc1OC
Temperature: 80 °C
Reaction time: 17 h
Yield: 64.5 %

Procedure:
Under a nitrogen atmosphere, to toluene (1 mL) were added 5-bromo-2,2,4,6,7-pentamethyl-3-(4-methylphenyl)-2,3-dihydro-1-benzofuran (100 mg) and 3,4-dimethoxybenzylamine (56 mg), then palladium acetate (0.3 mg) and (S)-(−)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (2.7 mg), and further sodium tert-butoxide (37.5 mg). The mixture was stirred at 80° C. for 17 hours. Ethyl acetate was added to the reaction mixture, insoluble materials were filtered and the filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, which was eluted with ethyl acetate-n-hexane [1:4], to obtain the title compound (80 mg, 64.5%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH:7]=[CH:8][NH:9]2)=[CH:5][CH:4]=1.Br[CH2:13][CH2:14][O:15][Si:16]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17].[H-].[Na+]>CN(C=O)C>[Si:16]([O:15][CH2:14][CH2:13][N:9]1[C:10]2[C:6](=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[CH:11]=2)[CH:7]=[CH:8]1)([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17]
Reactant: CC(C)(C)[Si](C)(C)OCCBr
Reactant: COc1ccc2cc[nH]c2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc2ccn(CCO[Si](C)(C)C(C)(C)C)c2c1
Reaction time: 1 h
Yield: 101.8 %

Procedure:
To a solution of 6-methoxy-1H-indole (7.0 g, 47.6 mmol) and (2-bromoethoxy)-tert-butyldimethylsilane (10.7 mL, 50.0 mmol) in DMF (100 mL) under nitrogen was added, portionwise, sodium hydride (65% dispersion in oil) (2.8 g, 71.4 mmol) at room temperature. The reaction mixture was stirred for 1 h, quenched with saturated aq NaHCO3 (100 mL) and diluted with EtOAc (150 mL). The organic phase was washed with water (3×150 mL), saturated aq NaHCO3 (100 mL), brine (2×100 mL), dried (MgSO4), filtered and concentrated. Flash chromatography (SiO2, 10% EtOAc/hexanes) gave the title compound (14.8 g, 98%) as a colorless oil. 1H NMR (300 MHz, CDCl3) 7.62 (d, J=7.2 Hz, 1H), 7.38 (s, 1H), 7.12 (d, J=3.1 Hz, 1H), 6.87 (d, J=7.2 Hz, 1H), 6.52 (d, J=3.1 Hz, 1H), 4.28 (m, 2H), 4.02 (m, 2H), 3.96 (s, 3H), 0.98 (s, 9H), 0.02 (s, 6H).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[CH:8][C:9]2[C:18]3[C:13](=[CH:14][C:15](=[O:19])[NH:16][N:17]=3)[CH2:12][CH2:11][C:10]=2[CH:20]=1.[CH3:21][C@@H:22]1[CH2:26][CH2:25][CH2:24][NH2+:23]1.C1(S([O-])(=O)=O)C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>C(#N)C>[CH3:21][C@@H:22]1[CH2:26][CH2:25][CH2:24][N:23]1[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[CH:8][C:9]2[C:18]3[C:13](=[CH:14][C:15](=[O:19])[NH:16][N:17]=3)[CH2:12][CH2:11][C:10]=2[CH:20]=1
Reactant: C[C@@H]1CCC[NH2+]1
Reactant: O=c1cc2c(n[nH]1)-c1ccc(OCCCCl)cc1CC2
Agent: O=C([O-])[O-]
Agent: O=S(=O)([O-])c1ccccc1
Agent: [I-]
Solvent: CC#N
Product: C[C@@H]1CCCN1CCCOc1ccc2c(c1)CCc1cc(=O)[nH]nc1-2

Procedure:
In a 100 mL round bottom flask, 8-(3-chloro-propoxy)-5,6-dihydro-2H-benzo[h]cinnolin-3-one (600 mg, 2.1 mmol), benzenesulfonate (R)-2-methyl-pyrrolidinium (1.02 g, 4.2 mmol), potassium carbonate (1.14 g, 8.3 mmol), and potassium iodide (10 mg, 0.06 mmol) in acetonitrile (60 mL) was heated to reflux 14 h. The reaction was cooled and the solvent concentrated under vacuum. The slurry was partitioned between methylene chloride and water, and then washed with water three times. The organics were extracted three times with 3% citric acid solution. The combined aqueous layers were basified with sat. NaHCO3 sol. and extracted with methylene chloride, then dried over MgSO4. Ethereal HCl was added and the solvents reduced under vacuum. Crystallization from MeOH/Et2O produced 85 mg (11%). Mp 289-292° C. MS m/z 340 (M+H).
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][N:7]([CH2:10][CH2:11][CH2:12][O:13][C:14]2[CH:15]=[C:16]3[C:21](=[CH:22][C:23]=2[O:24][CH3:25])[N:20]=[CH:19][N:18]=[C:17]3Cl)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[OH:27][C:28]1[CH:29]=[C:30]2[C:34](=[CH:35][CH:36]=1)[NH:33][N:32]=[CH:31]2.C(=O)([O-])[O-].[Cs+].[Cs+]>CC(C)=O>[C:1]([N:4]1[CH2:9][CH2:8][N:7]([CH2:10][CH2:11][CH2:12][O:13][C:14]2[CH:15]=[C:16]3[C:21](=[CH:22][C:23]=2[O:24][CH3:25])[N:20]=[CH:19][N:18]=[C:17]3[O:27][C:28]2[CH:29]=[C:30]3[C:34](=[CH:35][CH:36]=2)[NH:33][N:32]=[CH:31]3)[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: Oc1ccc2[nH]ncc2c1
Reactant: COc1cc2ncnc(Cl)c2cc1OCCCN1CCN(C(C)=O)CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Product: COc1cc2ncnc(Oc3ccc4[nH]ncc4c3)c2cc1OCCCN1CCN(C(C)=O)CC1
Yield: 67.7 %

Procedure:
A mixture of 6-[3-(4-acetylpiperazin-1-yl)propoxy]-4-chloro-7-methoxyquinazoline (235 mg, 0.62 mmol), 5-hydroxyindazole (100 mg, 0.75 mmol), (prepared as described for the starting material in Example 29), and cesium carbonate (303 mg, 0.93 mmol) in acetone (20 ml) was heated at reflux for 2 hours. The mixture was filtered and the filtrate concentrated under reduced pressure. The residue was purified by column chromatography eluting with methylene chloride/methanol (95/5) to give 6-[3-(4-acetylpiperazin-1-yl)propoxy]-4-(1H-indazol-5-yloxy)-7-methoxyquinazoline (200 mg, 68%) as a pale green solid.
Reaction SMILES: Br[C:2]1[C:7]([CH3:8])=[CH:6][C:5]([O:9][CH2:10][CH2:11][O:12][CH2:13][CH3:14])=[CH:4][C:3]=1[CH3:15].CCCCCC.C([Li])CCC.[B:27](OC(C)C)([O:32]C(C)C)[O:28]C(C)C.Cl>O1CCCC1>[CH2:13]([O:12][CH2:11][CH2:10][O:9][C:5]1[CH:6]=[C:7]([CH3:8])[C:2]([B:27]([OH:32])[OH:28])=[C:3]([CH3:15])[CH:4]=1)[CH3:14]
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: CCOCCOc1cc(C)c(Br)c(C)c1
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCOCCOc1cc(C)c(B(O)O)c(C)c1
Temperature: 25 °C
Yield: 67.7 %

Procedure:
To a solution of 2-bromo-5-(2-ethoxyethoxy)-1,3-dimethylbenzene (10.0 g, 36.6 mmol) in tetrahydrofuran (100 mL) was added n-butyllithium hexane solution (1.6 M, 25.1 mL, 40.2 mmol) at −78° C. with stirring. The reaction mixture was stirred at the same temperature for 30 min. and triisopropyl borate (10.5 mL, 45.5 mmol) was added. The reaction mixture was warmed to room temperature and stirred for 3 hrs. 5 N Hydrochloric acid (20 mL) was added to the reaction mixture and the mixture was partitioned between ethyl acetate and water. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was washed with hexane/diethyl ether and dried to give the title compound (5.9 g, yield 68%) as pale-yellow crystals.
Reaction SMILES: CC1(C)[O:6][C@@H:5]([CH2:7][O:8][NH:9][C:10]([C:12]2[C:13]([Cl:30])=[C:14]3[CH:19]=[CH:18][N:17]=[CH:16][N:15]3[C:20]=2[NH:21][C:22]2[CH:27]=[CH:26][C:25]([I:28])=[CH:24][C:23]=2[F:29])=[O:11])[CH2:4][O:3]1.Cl.O1CCOCC1>CO.C(OCC)(=O)C>[OH:6][C@H:5]([CH2:4][OH:3])[CH2:7][O:8][NH:9][C:10]([C:12]1[C:13]([Cl:30])=[C:14]2[CH:19]=[CH:18][N:17]=[CH:16][N:15]2[C:20]=1[NH:21][C:22]1[CH:27]=[CH:26][C:25]([I:28])=[CH:24][C:23]=1[F:29])=[O:11]
Reactant: CC1(C)OC[C@H](CONC(=O)c2c(Cl)c3ccncn3c2Nc2ccc(I)cc2F)O1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CO
Solvent: C1COCCO1
Product: O=C(NOC[C@H](O)CO)c1c(Cl)c2ccncn2c1Nc1ccc(I)cc1F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 5-chloro-7-(2-fluoro-4-iodo-phenylamino)-pyrrolo[1,2-c]pyrimidine-6-carboxylic acid ((R)-2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-amide (57 mg, 0.1 mmol) in methanol (1 mL) was added a solution of hydrochloric acid in dioxane (1 mL, 4M, 4 mmol). The reaction was stirred at room temperature for 1 hour then diluted with ethyl acetate (5 mL), washed with saturated aqueous sodium bicarbonate solution (10 mL) and the aqueous fraction extracted twice with ethyl acetate (2×10 mL). The combined organic fractions were washed with brine, dried (MgSO4) and concentrated in vacuo. The resultant residue was subjected to flash chromatography (SiO2, gradient 0-10% methanol in DCM) to yield a light brown solid. The solid was triturated with acetonitrile (3 mL) to yield the title compound as an off white solid (13 mg, 45%). 1H NMR (CH3 OH-d4): 8.74 (1H, d, J=1.57 Hz), 7.49 (1H, d, J=6.61 Hz), 7.42 (1H, dd, J=10.78, 1.91 Hz), 7.38 (1H, dd, J=6.61, 1.58 Hz), 7.21 (1H, ddd, J=8.48, 1.90, 1.11 Hz), 6.14 (1H, t, J=8.76 Hz), 3.89-3.80 (1H, m), 3.79-3.71 (2H, m), 3.56-3.42 (2H, m). LCMS (Method A): RT=7.70 min, M+H+=521.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:9][CH2:10][NH:11][C:12]([CH:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)=[O:13])=[CH:4][CH:3]=1.C1C(=O)N(Cl)C(=O)C1.C(O)(C(F)(F)F)=O>ClC1C=CC=CC=1.C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[O:13][C:12]([CH:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)=[N:11][CH:10]=2)=[CH:4][CH:3]=1
Reactant: O=C(NCCSc1ccc(Cl)cc1)C1CCOCC1
Agent: O=C1CCC(=O)N1Cl
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: Clc1ccccc1
Product: Clc1ccc(Sc2cnc(C3CCOCC3)o2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 79.7 %

Procedure:
To a solution of N-{2-[(4-chlorophenyl)sulfanyl]ethyl}tetrahydro-2H-pyran-4-carboxamide (9.48 g, 31.6 mmol) in chlorobenzene (316 ml) was added NCS (8.44 g, 63.2 mmol) by portions and the reaction mixture was stirred at RT for 1 h. TFA (1.218 ml, 15.81 mmol) was added and the reaction mixture was stirred at RT for 16 h. The reaction mixture was diluted with DCM, washed with aq NaHCO3, dried over sodium sulfate, concentrated in vacuo and purified by flash chromatography (silica 2×330 g, 0 to 50% EtOAc in hexane), to give 5-[(4-chlorophenyl)sulfanyl]-2-(tetrahydro-2H-pyran-4-yl)-1,3-oxazole (7.45 g) as a white solid. MS: M+H=296. H1NMR (400 MHz, CDCl3) δ: 7.27 (d, 0.1=10.3 Hz, 2H), 7.26 (s, 1H), 7.17 (d, J=10.3 Hz, 2H), 4.01 (dt, J=12.2 Hz, 3.7 Hz, 2H), 3.51 (td, J=12.2 Hz, 3.7 Hz, 2H), 3.10-3.00 (m, 1H), 2.04-1.85 (m, 4H).
Reaction SMILES: [CH:1]([C:4]1[CH:23]=[C:22]([C:24](=[O:30])[CH:25]=[CH:26][C:27](O)=[O:28])[CH:21]=[CH:20][C:5]=1[O:6][CH2:7][C:8]([NH:10][C:11]1[S:12][C:13]2[CH:19]=[CH:18][CH:17]=[CH:16][C:14]=2[N:15]=1)=[O:9])([CH3:3])[CH3:2].[CH3:31][N:32]1[CH2:37][CH2:36][N:35]([CH:38]2[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]2)[CH2:34][CH2:33]1.P(C#N)(OCC)(OCC)=O.[ClH:54]>CN(C)C=O.O.C(N(CC)CC)C>[ClH:54].[ClH:54].[CH:1]([C:4]1[CH:23]=[C:22]([C:24](=[O:30])[CH:25]=[CH:26][C:27]([N:41]2[CH2:40][CH2:39][CH:38]([N:35]3[CH2:34][CH2:33][N:32]([CH3:31])[CH2:37][CH2:36]3)[CH2:43][CH2:42]2)=[O:28])[CH:21]=[CH:20][C:5]=1[O:6][CH2:7][C:8]([NH:10][C:11]1[S:12][C:13]2[CH:19]=[CH:18][CH:17]=[CH:16][C:14]=2[N:15]=1)=[O:9])([CH3:3])[CH3:2]
Reactant: CN1CCN(C2CCNCC2)CC1
Reactant: CC(C)c1cc(C(=O)C=CC(=O)O)ccc1OCC(=O)Nc1nc2ccccc2s1
Agent: CCOP(=O)(C#N)OCC
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)c1cc(C(=O)C=CC(=O)N2CCC(N3CCN(C)CC3)CC2)ccc1OCC(=O)Nc1nc2ccccc2s1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of 2-[2-isopropyl-4-(3-carboxyacryloyl)phenoxymethylcarbonylamino]benzothiazole (0.97 g) in dimethylformamide (10 ml) are added dropwise 4-(4-methyl-1-piperazinyl)piperidine (0.65 g) and diethyl cyanophosphate (0.6 ml) at room temperature. To the mixture is added triethylamine (0.5 ml), and the mixture is stirred at room temperature for 10 minutes. To the mixture is added water, and the mixture is extracted with ethyl acetate. The extract is washed with water, dried, and concentrated under reduced pressure. The residue is purified by silica gel column chromatography (solvent; dichloromethane:methanol=100:1→10:1). The compound thus obtained is converted into a hydrochloride thereof in ethanol by a conventional method, and recrystallized from ethanol-diethyl ether to give 2-{2-isopropyl-4-[3-[4-(4-methyl-1-piperazinyl)-1-piperidinylcarbonyl]acryloyl]phenoxymethylcarbonylamino}benzothiazole dihydrochloride (0.45 g).