Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[NH:8][CH2:7][CH2:6]2.[H-].[Na+].[CH2:16](I)[CH3:17]>C1COCC1>[CH2:16]([N:8]1[CH2:7][CH2:6][C:5]2[C:10](=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[CH:4]=2)[C:9]1=[O:13])[CH3:17]
Reactant: CCI
Reactant: COc1ccc2c(c1)CCNC2=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCN1CCc2cc(OC)ccc2C1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.3 %

Procedure:
To a mixture of 6-methoxy-3,4-dihydro-2H-isoquinolin-1-one (0.30 g, 1.69 mmol) in THF (10 mL) is added sodium hydride (60% mineral oil suspension, 100 mg). The suspension is heated at reflux for 1 h, and cooled to room temperature. Ethyl iodide (1.4 mL, 17 mmol) is added, and the mixture is stirred at room temperature overnight. The mixture is partitioned between EtOAc and water. After the aqueous phase is extracted with EtOAc (2×), the combined organic phase is washed with brine and dried (MgSO4). After removal of the solvent, the residue is purified by flash chromatography (Biotage 40M SiO2, elute 45% EtOAc:hexane−50% EtOAc:hexane, linear gradient) to yield 2-ethyl-6-methoxy-3,4-dihydro-2H-isoquinolin-1-one as a colorless oil (0.275 g, 78%). The material is dissolved in CH2Cl2 (10 mL) and cooled to −78° C. To the cooled mixture is added a solution of boron tribromide (1 M, 4.7 mL, 4.7 mmol) in CH2Cl2. After 0.5 h, the temperature is warmed to 0° C. and stirred for 3 h. After the reaction is carefully quenched with ice, EtOAc and water is added, and the mixture is vigorously stirred overnight. The phases are separated, and the organic phase is extracted with EtOAc (2×). The combined organic phase is washed with brine and dried (MgSO4). The solvent is removed in vacuo, and the residue is purified by chromatography (Varian 10 g SiO2 cartridge, elute 60% EtOAc:hexane) to provide 2-ethyl-6-hydroxy-3,4-dihydro-2H-isoquinolin-1-one (0.209 g, 82%). MS (ES+) 192.0
Reaction SMILES: C([O:3][P:4]([CH2:16][C:17]([N:19]1[C@H:27]([C:28]([O:30][CH2:31][O:32][C:33](=[O:38])[C:34]([CH3:37])([CH3:36])[CH3:35])=[O:29])[CH2:26][C:21]2([S:25][CH2:24][CH2:23][S:22]2)[CH2:20]1)=[O:18])([CH2:6][CH2:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:5])C.Br[Si](C)(C)C>ClCCl>[OH:5][P:4]([CH2:16][C:17]([N:19]1[C@H:27]([C:28]([O:30][CH2:31][O:32][C:33](=[O:38])[C:34]([CH3:36])([CH3:35])[CH3:37])=[O:29])[CH2:26][C:21]2([S:22][CH2:23][CH2:24][S:25]2)[CH2:20]1)=[O:18])([CH2:6][CH2:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:3]
Reactant: CCOP(=O)(CCCCc1ccccc1)CC(=O)N1CC2(C[C@H]1C(=O)OCOC(=O)C(C)(C)C)SCCS2
Agent: C[Si](C)(C)Br
Solvent: ClCCl
Product: CC(C)(C)C(=O)OCOC(=O)[C@@H]1CC2(CN1C(=O)CP(=O)(O)CCCCc1ccccc1)SCCS2
Reaction time: 16 h

Procedure:
(S)-7-[[Ethoxy(4-phenylbutyl)phosphinyl]acetyl]-1,4-dithia-7-azaspiro[4.4]nonane-8-carboxylic acid, (2,2-dimethyl-1-oxopropoxy)methyl ester (2.7 g) in dichloromethane (dried over alumina) is treated with bromotrimethylsilane (1.2 ml) via syringe and the reaction mixture is stirred for 16 hours under argon. The solvent and excess bromotrimethylsilane is evaporated in vacuo and the residue is taken up in ethyl acetate and water and stirred for 15 minutes. The layers are separated and the ethyl acetate is washed with 5% potassium sulfate, water, brine dried (MgSO4) and evaporated. The 2.3 g of crude product is chromatographed on silica (75 g) eluting with dichloromethane/methanol/acetic acid (19/0.5/0.5). After stripping solvent 1.9 g of product is left as a glass.
Reaction SMILES: [CH2:1]([N:3]([CH2:13][CH3:14])[C:4](=[O:12])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[Cl:11])[CH3:2].[CH3:15][Si:16](Cl)([CH3:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[CH2:13]([N:3]([CH2:1][CH3:2])[C:4](=[O:12])[C:5]1[C:10]([Si:16]([CH3:23])([CH3:15])[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:9][CH:8]=[CH:7][C:6]=1[Cl:11])[CH3:14]
Reactant: CCN(CC)C(=O)c1ccccc1Cl
Reactant: C[Si](C)(Cl)c1ccccc1
Product: CCN(CC)C(=O)c1c(Cl)cccc1[Si](C)(C)c1ccccc1

Procedure:
The title compound was prepared from the compound of Example e and 1.1 eq dimethylphenylsilyl chloride according to General Method A. Purification by HPLC with 1:9 ethyl acetate/hexanes gave 6.3 g of the desired product as a clear oil, a 91% yield.
Reaction SMILES: [OH:1][C:2]1[CH:38]=[CH:37][C:5]([C:6]([CH2:8][CH2:9][CH2:10][NH:11][C:12]2[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[CH:14][C:13]=2[CH:20]2[CH2:29][CH2:28][C:27]3[CH:26]=[C:25]([O:30]C(=O)C(C)(C)C)[CH:24]=[CH:23][C:22]=3[CH2:21]2)=O)=[CH:4][CH:3]=1.Cl[CH2:40][C:41]([N:43]1[CH2:48][CH2:47][CH2:46][CH2:45][CH2:44]1)=O>>[CH3:19][O:18][C:16]1[CH:15]=[CH:14][C:13]([CH:20]2[CH2:29][CH2:28][C:27]3[CH:26]=[C:25]([OH:30])[CH:24]=[CH:23][C:22]=3[CH2:21]2)=[C:12]([NH:11][CH2:10][CH2:9][CH2:8][CH2:6][C:5]2[CH:37]=[CH:38][C:2]([O:1][CH2:40][CH2:41][N:43]3[CH2:48][CH2:47][CH2:46][CH2:45][CH2:44]3)=[CH:3][CH:4]=2)[CH:17]=1
Reactant: O=C(CCl)N1CCCCC1
Reactant: COc1ccc(C2CCc3cc(OC(=O)C(C)(C)C)ccc3C2)c(NCCCC(=O)c2ccc(O)cc2)c1
Product: COc1ccc(C2CCc3cc(O)ccc3C2)c(NCCCCc2ccc(OCCN3CCCCC3)cc2)c1
Yield: 78 %

Procedure:
Synthesized from pivalic acid 6-{2-[(4-hydroxybenzoyl)propylamino]-4-methoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (30 mg) and 2-chloro-1-piperidin-1-ylethanone (19 mg) according to an analogous synthetic method to Example 404 and purified by LC-MS, the title compound (24 mg) was obtained.
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8]([N:10]1[CH2:14][C@H:13]([OH:15])[C@@H:12]([NH:16][C:17]([C:19]2[S:20][C:21]([Cl:24])=[CH:22][CH:23]=2)=[O:18])[CH2:11]1)=[O:9])([CH3:6])([CH3:5])[CH3:4].FC(F)(F)S(O[CH2:31][CH:32]([F:34])[F:33])(=O)=O>CN(C=O)C.CCOC(C)=O>[C:3]([O:7][C:8]([N:10]1[CH2:14][C@H:13]([O:15][CH2:31][CH:32]([F:34])[F:33])[C@@H:12]([NH:16][C:17]([C:19]2[S:20][C:21]([Cl:24])=[CH:22][CH:23]=2)=[O:18])[CH2:11]1)=[O:9])([CH3:6])([CH3:4])[CH3:5]
Reactant: O=S(=O)(OCC(F)F)C(F)(F)F
Reactant: CC(C)(C)OC(=O)N1C[C@H](NC(=O)c2ccc(Cl)s2)[C@@H](O)C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1C[C@H](NC(=O)c2ccc(Cl)s2)[C@@H](OCC(F)F)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 49.1 %

Procedure:
30.1 A suspension of 37 mg NaH (55% in oil) in 2 ml DMF was treated at 0° C. under an argon atmosphere with a solution of 270 mg (3S,4S)-3-[(5-chloro-thiophene-2-carbonyl)-amino]-4-hydroxy-pyrrolidine-1-carboxylic acid tert-butyl ester (example 22.4). The reaction mixture was stirred for 1 hr at r.t. Then, 334 mg 2,2-difluoroethyl trifluoromethanesulfonate were added at 0° C. The reaction mixture was stirred for 2 days at r.t., then diluted with EtOAc and washed with water. The organic layer was dried over MgSO4, filtered and concentrated. The crude product was isolated by chromatography (silica gel; gradient: cyclohexane->cyclohexane/EtOAc 9:1) to give 157 mg (3S,4S)-3-[(5-chloro-thiophene-2-carbonyl)-amino]-4-(2,2-difluoro-ethoxy)-pyrrolidine-1-carboxylic acid tert-butyl ester. Colorless solid. MS 409.0 ([M+H]+)
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][NH:8]2)=[CH:4][C:3]=1[S:11][CH2:12][CH3:13].[N:14]1[CH:19]=[CH:18][CH:17]=[C:16]([N:20]=[C:21]=[O:22])[CH:15]=1>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][N:8]2[C:21](=[O:22])[NH:20][C:16]2[CH:15]=[N:14][CH:19]=[CH:18][CH:17]=2)=[CH:4][C:3]=1[S:11][CH2:12][CH3:13]
Reactant: CCSc1cc2c(cc1Cl)NCC2
Reactant: O=C=Nc1cccnc1
Product: CCSc1cc2c(cc1Cl)N(C(=O)Nc1cccnc1)CC2
Yield: 48 %

Procedure:
6-Chloro-5-ethylthioindoline (D64) (0.18 g, 0.85 mmol) was treated with 3-pyridylisocyanate as in the procedure described in Example 1. The crude product was recrystallised from ethanol/diethyl ether to give the title compound (0.14 g, 48%) as a white crystalline solid m.p.=225°-226° C.
Reaction SMILES: C([Li])CCC.[F:6][C:7]1[C:12]([F:13])=[CH:11][CH:10]=[CH:9][C:8]=1[CH:14]1[O:19][CH2:18][CH:17]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[CH2:16][O:15]1.I[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36]>C1COCC1>[F:6][C:7]1[C:12]([F:13])=[C:11]([CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])[CH:10]=[CH:9][C:8]=1[CH:14]1[O:15][CH2:16][CH:17]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[CH2:18][O:19]1
Reactant: CCCCCCCI
Reactant: CCCCCCCCCC1COC(c2cccc(F)c2F)OC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCCCCCCCC1COC(c2ccc(CCCCCCC)c(F)c2F)OC1
Reaction time: 8 h

Procedure:
n-Butyllithium (3.4 cm3, 10.0M in hexanes, 34mmol) was added dropwise to a stirred, cooled (-78° C.) solution of compound from Example 115 (mixture with isomers) (11.2 g, 34 mmol) in dry THF (100 cm3) under an atmosphere of dry nitrogen. The mixture was maintained under these conditions (3 h) then a solution of 1-iodoheptane (7.7 g, 34 mmol) in dry THF (20 cm3) was added dropwise at -78° C. The temperature of the reaction mixture was allowed to reach room temperature overnight. After separation, the aqueous layer was extracted with diethyl ether (2×150 cm3), the combined ethereal layers washed with water (2×150 cm3) and dried (MgSO4). The solvent was removed in vacuo to give the product as a brown oil which was purified by distillation under reduced pressure and recrystallised several times from methanol to remove the cis-isomer.
Reaction SMILES: C([N:3]([CH2:14][CH3:15])[C:4](=[O:13])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7](C)[C:6]=1[CH3:12])C.[OH:16][CH2:17][C@H:18]1[CH2:22][CH2:21][CH2:20][N:19]1[CH2:23]CC#N>>[OH:16][CH2:17][C@H:18]1[CH2:22][CH2:21][CH2:20][N:19]1[CH2:23][CH2:15][C:14]1[NH:3][C:4](=[O:13])[C:5]2[C:6]([CH:12]=1)=[CH:7][CH:8]=[CH:9][CH:10]=2
Reactant: N#CCCN1CCC[C@@H]1CO
Reactant: CCN(CC)C(=O)c1cccc(C)c1C
Product: O=c1[nH]c(CCN2CCC[C@@H]2CO)cc2ccccc12
Yield: 11.6 %

Procedure:
By the reaction in the same manner as in Example 1a, using N,N-diethyl-2,3-dimethylbenzamide (4.975 g) and (R)-3-(2-hydroxymethylpyrrolidin-1-yl)propionitrile (2.0 g), (R)-3-[2-(2-hydroxymethylpyrrolidin-1-yl)ethyl]-2H-isoquinolin-1-one (408.4 mg) was obtained.
Reaction SMILES: [Cl:1][S:2]([OH:5])(=O)=[O:3].[CH3:6][S:7]([N:10]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[N:12]=[C:11]1[NH2:19])(=[O:9])=[O:8].C(=O)(O)[O-].[Na+]>O>[CH3:6][S:7]([N:10]1[C:14]2[CH:15]=[CH:16][C:17]([S:2]([Cl:1])(=[O:5])=[O:3])=[CH:18][C:13]=2[N:12]=[C:11]1[NH2:19])(=[O:8])=[O:9]
Reactant: CS(=O)(=O)n1c(N)nc2ccccc21
Reactant: O=S(=O)(O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: CS(=O)(=O)n1c(N)nc2cc(S(=O)(=O)Cl)ccc21
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
To 9.5 mL (20 eq., 142 mmol) of well stirred chlorosulfonic acid at ˜25° C. was added N-methanesulfonyl-2-aminobenzimidazole (1.5 g, 7.1 mmol) in small portions over 1C minutes with slight exotherming. The solution was stirred at ˜25° C. for 3.5 hours, then was added dropwise to a well stirred mixture of ice and water. The aqueous solution was slowly basified to pH ˜7.5 with solid sodium bicarbonate and extracted with EtOAc. A precipitate formed in the organic phase which was filtered off and was washed with H20 and dried on the filter to yield 1.23 g of N-methanesulfonyl-5-chlorosulfonyl-2-aminobenzimidazole. HPLC, single peak, ret. time=7.61 min. MS: Obs. M +H@ 310.0 amu.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[F:16])=[O:9])=[CH:6][CH:5]=[C:4]([NH:17][CH:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)[N:3]=1.[C:24](Cl)(=[O:26])[CH3:25]>>[NH2:1][C:2]1[N:3]=[C:4]([NH:17][CH:18]2[CH2:19][CH2:20][N:21]([C:24](=[O:26])[CH3:25])[CH2:22][CH2:23]2)[CH:5]=[CH:6][C:7]=1[C:8](=[O:9])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[F:16]
Reactant: Nc1nc(NC2CCNCC2)ccc1C(=O)c1ccccc1F
Reactant: CC(=O)Cl
Product: CC(=O)N1CCC(Nc2ccc(C(=O)c3ccccc3F)c(N)n2)CC1

Procedure:
The title compound was prepared from [2-Amino-6-(piperidin-4-ylamino)-pyridin-3-yl]-(2-fluoro-phenyl)-methanone (Example 9) and acetyl chloride (Aldrich 98.5%) using the procedure described in Example 12. HRMS, observed: 356.1655, Calcd for M+: 356.1649.
Reaction SMILES: Cl.Cl.[C:3]1([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:8]=[CH:7][CH:6]=[C:5]([N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[CH:4]=1.[F:21][C:22]([F:46])([F:45])[CH2:23][NH:24][C:25]([C:27]1([CH2:40][CH2:41][CH2:42][CH2:43]Br)[C:39]2[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=2[C:33]2[C:28]1=[CH:29][CH:30]=[CH:31][CH:32]=2)=[O:26].C(=O)([O-])[O-].[K+].[K+]>C(#N)C.O>[F:21][C:22]([F:45])([F:46])[CH2:23][NH:24][C:25]([C:27]1([CH2:40][CH2:41][CH2:42][CH2:43][N:12]2[CH2:11][CH2:10][N:9]([C:5]3[CH:4]=[C:3]([C:15]4[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=4)[CH:8]=[CH:7][CH:6]=3)[CH2:14][CH2:13]2)[C:39]2[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=2[C:33]2[C:28]1=[CH:29][CH:30]=[CH:31][CH:32]=2)=[O:26]
Reactant: c1ccc(-c2cccc(N3CCNCC3)c2)cc1
Reactant: O=C(NCC(F)(F)F)C1(CCCCBr)c2ccccc2-c2ccccc21
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: O=C(NCC(F)(F)F)C1(CCCCN2CCN(c3cccc(-c4ccccc4)c3)CC2)c2ccccc2-c2ccccc21
Temperature: 60 °C
Reaction time: 24 h

Procedure:
A suspension of 0.2 g (0.643 mmol) of 1-biphenyl-3-yl-piperazine-dihydrochloride, 0.256 g (0.6 mmol) of 9-(4-bromo-butyl)-9H-fluorene-9-carboxylic acid-(2,2,2-trifluoroethyl)-amide and 0.1 g potassium carbonate in 20 ml of acetonitrile and 0.1 ml of water is stirred for 24 hours at 60° C. The reaction mixture is poured onto water, extracted with ethyl acetate and dried over sodium sulphate. Purification is by column chromatography on silica gel (eluant: dichloromethane/ethanol=30:1).
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([F:12])=[CH:6][C:3]=1[CH:4]=O.C(O)(=O)[CH2:14][C:15]([OH:17])=[O:16]>CCO.N1C=CC=CC=1>[F:1][C:2]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([F:12])=[CH:6][C:3]=1/[CH:4]=[CH:14]/[C:15]([OH:17])=[O:16]
Reactant: O=C(O)CC(=O)O
Reactant: COc1cc(F)c(C=O)cc1F
Solvent: c1ccncc1
Solvent: CCO
Product: COc1cc(F)c(/C=C/C(=O)O)cc1F
Temperature: 70 °C
Reaction time: 8 h
Yield: 74 %

Procedure:
A 250 mL round bottom flask was charged with 2,5-difluoro-4-methyoxybenzaldehyde (commercially available from Manchester Organics Ltd., UK) (18.45 g, 107.2 mmol), malonic acid (commercially available from Sigma-Aldrich, St. Louis, Mo., USA) (12.27 g, 117.9 mmol), and 10:1 EtOH/pyridine (27 mL). The mixture was stirred overnight at 70° C. under a reflux condenser and cooled to 0° C. for 2 hours. The precipitated solid was filtered, rinsed with ether, and dried in vacuo to afford H3.1 (16.96 g, 74% yield) as a white powder.
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][CH:5]=[C:4]([Cl:8])[N:3]=1.[F:9][C:10]1[CH:11]=[C:12]([CH:16]([OH:18])[CH3:17])[CH:13]=[CH:14][CH:15]=1.[H-].[Na+].O>O1CCOCC1>[Cl:8][C:4]1[CH:5]=[N:6][CH:7]=[C:2]([O:18][CH:16]([C:12]2[CH:13]=[CH:14][CH:15]=[C:10]([F:9])[CH:11]=2)[CH3:17])[N:3]=1
Reactant: Clc1cncc(Cl)n1
Reactant: CC(O)c1cccc(F)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CC(Oc1cncc(Cl)n1)c1cccc(F)c1
Yield: 108.8 %

Procedure:
To a solution of 2,6-dichloropyrazine (298 mg, 2.00 mmol) and 1-(3-fluorophenyl)ethanol (308 mg, 2.2 mmol) in dioxane (5 mL) was added NaH (55% in oil, 96 mg, 2.2 mmol) at room temperature. The reaction mixture was stirred over night. Water (0.5 mL) was added and the mixture was stirred for 15 min. Drying (K2CO3), filtration, and concentration in vacuo gave the title compound as an oil (0.55 g) that was used directly in the next step. MS m/z 254 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]#[C:9][CH:10]=[C:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)[N:3]=1.F[C:18]1[CH:19]=[C:20]([CH3:27])[CH:21]=[CH:22][C:23]=1[N+:24]([O-:26])=[O:25]>>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]#[C:9][CH:10]=[C:11]2[CH2:12][CH2:13][N:14]([C:18]3[CH:19]=[C:20]([CH3:27])[CH:21]=[CH:22][C:23]=3[N+:24]([O-:26])=[O:25])[CH2:15][CH2:16]2)[N:3]=1
Reactant: Cc1ccc([N+](=O)[O-])c(F)c1
Reactant: Cc1cccc(C#CC=C2CCNCC2)n1
Product: Cc1ccc([N+](=O)[O-])c(N2CCC(=CC#Cc3cccc(C)n3)CC2)c1
Yield: 39.9 %

Procedure:
A well homogenised mixture of the Compound of Example 3 (19 mg, 0.89 mmol) and 3-fluoro-4-nitrotoluene (20.2 mg, 0.13 mmol) was stirred at 120° C. for 0.5 h. The reaction crude was purified by flash chromatography (EtOAc—Petroleum Ether gradient from 2:8 to 3:7) affording the title product (18 mg).
Reaction SMILES: [Br:1][C:2]1[CH:23]=[CH:22][C:5]([O:6][C:7]2[N:16]=[C:15]([F:17])[C:14]([Si:18]([CH3:21])([CH3:20])[CH3:19])=[CH:13][C:8]=2[C:9]([O:11]C)=O)=[C:4](I)[CH:3]=1.C([Mg]Cl)(C)C>C1COCC1.C(OCC)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:22][CH:23]=1)[O:6][C:7]1=[N:16][C:15]([F:17])=[C:14]([Si:18]([CH3:19])([CH3:21])[CH3:20])[CH:13]=[C:8]1[C:9]2=[O:11]
Reactant: COC(=O)c1cc([Si](C)(C)C)c(F)nc1Oc1ccc(Br)cc1I
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Solvent: CCOCC
Product: C[Si](C)(C)c1cc2c(=O)c3cc(Br)ccc3oc2nc1F
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
Methyl 2-(4-bromo-2-iodophenoxy)-6-fluoro-5-(trimethylsilyl)nicotinate (2.04 g, 3.89 mmol) was dissolved in dry THF (80 mL) and cooled in a dry ice bath to −78° C. Isopropylmagnesium chloride (2.0 M solution in diethyl ether, 3.89 mL (7.78 mmol) was added and the solution stirred for 15 minutes. The mixture was removed from the cold bath and allowed to slowly warm to RT. Water (100 mL), saturated ammonium chloride (10 mL), and EtOAc (200 mL) were added and the phases mixed and separated. The organics were dried with magnesium sulfate and evaporated to dryness under reduced pressure. The crude was purified using silica chromatography (hexane to ethyl acetate gradient) to give 7-bromo-2-fluoro-3-(trimethylsilyl)-5H-chromeno[2,3-b]pyridin-5-one.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Cl[C:16]1[C:25]2[C:20](=[CH:21][C:22]([O:28][CH2:29][CH2:30][N:31]3[CH2:36][CH2:35][O:34][CH2:33][CH2:32]3)=[C:23]([O:26][CH3:27])[CH:24]=2)[N:19]=[CH:18][N:17]=1>C(O)(C)C>[CH3:27][O:26][C:23]1[CH:24]=[C:25]2[C:20](=[CH:21][C:22]=1[O:28][CH2:29][CH2:30][N:31]1[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1)[N:19]=[CH:18][N:17]=[C:16]2[O:8][C:4]1[CH:3]=[C:2]([CH:7]=[CH:6][CH:5]=1)[NH2:1]
Reactant: Nc1cccc(O)c1
Reactant: COc1cc2c(Cl)ncnc2cc1OCCN1CCOCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)O
Product: COc1cc2c(Oc3cccc(N)c3)ncnc2cc1OCCN1CCOCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 22 %

Procedure:
3-Aminophenol (338 mg, 3.09 mmol) was treated with cesium carbonate (2 g, 6.2 mmol) in anhydrous isopropanol (10 mL) and the mixture stirred at room temperature for 30 minutes. 4-(2-(4-chloro-6-methoxyquinazolin-7-yloxy)ethyl)morpholine from the previous step (1 g, 3.09 mmol) was added and the mixture stirred at 80° C. for 2 h. Cesium carbonate was filtered off, washed with isopropanol and the filtrate concentrated under reduced pressure. The residue was purified by silica gel chromatography (dichloromethane/methanol 9:1) to afford 3-(6-methoxy-7-(2-morpholinoethoxy)quinazolin-4-yloxy)aniline (236 mg, 22%) as a brownish solid. 1H NMR (300 MHz, DMSO-d6) δ 8.54 (s, 1H), 7.51 (s, 1H), 7.41 (s, 1H), 7.09 (t, 1H), 6.50-6.37 (m, 3H), 5.30 (bs, 2H), 4.34-4.30 (m, 2H), 3.91 (s, 3H), 3.60 (s, 4H), 2.82-2.70 (m, 2H) 2.59-2.42 (m, 4H); LC-MS (ESI) m/z 397 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]=[CH:10][C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][C:12]=2[N+:18]([O-])=O)=[CH:5][CH:4]=1.[H][H]>[Pd].C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][C:12]=2[NH2:18])=[CH:7][CH:8]=1
Reactant: [H][H]
Reactant: COc1ccc(C=Cc2ccc(C)cc2[N+](=O)[O-])cc1
Agent: [Pd]
Solvent: CCO
Product: COc1ccc(CCc2ccc(C)cc2N)cc1
Yield: 96.7 %

Procedure:
To a solution of the product from Example 75A (164 mg, 0.6 mmol) and 10% palladium on charcoal (50 mg) in ethanol (20 ml) was hydrogenated with a hydrogen balloon for three days. The solvent was filtered through celite, washed with ethanol and evaporated under vacuum to provide the title compound (140 mg, 97%).
Reaction SMILES: [C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7](O)=O)=[CH:5][CH:4]=1)#[N:2].[CH3:12][N:13]([C:15]([NH2:17])=[S:16])[NH2:14].O=P(Cl)(Cl)Cl.C([O-])(O)=O.[Na+]>O1CCOCC1>[CH:3]1([N:17]=[C:15]2[S:16][C:7]([C:6]3[CH:10]=[CH:11][C:3]([C:1]#[N:2])=[CH:4][CH:5]=3)=[N:14][N:13]2[CH3:12])[CH2:11][CH2:10][CH2:6][CH2:5][CH2:4]1
Reactant: N#Cc1ccc(C(=O)O)cc1
Reactant: CN(N)C(N)=S
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O=P(Cl)(Cl)Cl
Product: Cn1nc(-c2ccc(C#N)cc2)sc1=NC1CCCCC1
Temperature: 95 °C
Yield: 76.2 %

Procedure:
To a mixture of 4-cyanobenzoic acid (74.8 mmol, 11 g), 2-methylthiosemicarbazide (5a) (74.8 mmol, 13.42 g) in anhydrous dioxane (110 mL) at 70° C., POCl3 (89.65 mmol, 76.76 mL) was added, and the mixture was warmed at 95° C. for 4 hours. The solvent was removed by distillation under reduced pressure to give a crude material which was basified at pH 8-7 with a saturated solution of NaHCO3. The aqueous phase was extracted with dichloromethane. The organic layer was washed with water and saturated solution of NaCl, dried over magnesium sulfate, filtered, and distilled to give a residue which was purified by silica gel chromatography (eluted with a gradient of cyclohexane/ethyl acetate finishing with the ratio 90:10) to afford 8.5 g of the title compound. Yield: 42%.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]([CH3:23])[C:13](=[O:22])[N:14]([C:15]4[C:16]([CH3:21])=[N:17][N:18]([CH3:20])[CH:19]=4)[C:5]=3[C:4]=2[CH:3]=1.[F:24][C:25]1[CH:26]=[C:27](B(O)O)[CH:28]=[C:29]([OH:31])[CH:30]=1>>[CH3:20][N:18]1[CH:19]=[C:15]([N:14]2[C:5]3[C:4]4[CH:3]=[C:2]([C:27]5[CH:28]=[C:29]([OH:31])[CH:30]=[C:25]([F:24])[CH:26]=5)[CH:11]=[CH:10][C:9]=4[N:8]=[CH:7][C:6]=3[N:12]([CH3:23])[C:13]2=[O:22])[C:16]([CH3:21])=[N:17]1
Reactant: OB(O)c1cc(O)cc(F)c1
Reactant: Cc1nn(C)cc1-n1c(=O)n(C)c2cnc3ccc(Br)cc3c21
Product: Cc1nn(C)cc1-n1c(=O)n(C)c2cnc3ccc(-c4cc(O)cc(F)c4)cc3c21

Procedure:
The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate A, 40 mg, 0.107 mmol) and 3-fluoro-5-hydroxyphenylboronic acid (Combi-Blocks, San Diego, USA, 21 mg, 0.132 mmol) to give the title compound as a white solid. (HPLC: tR 2.58 min (Method A); M+H=404 MS-ES; 1H-NMR (d6-DMSO, 400 MHz) 10.09 (s, 1H), 8.96 (s, 1H), 8.17 (s, 1H), 8.10-8.03 (m, 1H), 7.87-7.80 (m, 1H), 7.52-7.46 (m, 1H), 6.75-6.64 (m, 2H), 6.63-6.52 (m, 1H), 3.92 (s, 3H), 3.57 (s, 3H), 1.94 (s, 3H))
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:9]([CH2:15][CH:16]([CH3:18])[CH3:17])[C:10]([O:12]CC)=[O:11])[CH:5]=[CH:6][C:7]=1[OH:8].[N+:19]([O-])([OH:21])=[O:20]>C(O)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]([CH:9]([CH2:15][CH:16]([CH3:18])[CH3:17])[C:10]([OH:12])=[O:11])[CH:5]=[C:6]([N+:19]([O-:21])=[O:20])[C:7]=1[OH:8]
Reactant: CCOC(=O)C(CC(C)C)c1ccc(O)c(Br)c1
Reactant: O=[N+]([O-])O
Solvent: CC(=O)O
Product: CC(C)CC(C(=O)O)c1cc(Br)c(O)c([N+](=O)[O-])c1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Ethyl 2-(3-bromo-4-hydroxyphenyl)-4-methylpentanoate (16 g) was taken in acetic acid (100 ml) and to it added drop wise 70% nitric acid (10 ml) below 15° C. The reaction mixture was stirred for 2 h. After completion of the reaction; it was poured into 300 ml of ice water and extracted with ethyl acetate (300 ml×3). The ethyl acetate layer was washed with bicarbonate solution, water and finally brine solution. The organic layer was then distilled off and the crude residue was purified by column chromatography using Ethyl acetate:hexane (2:3) as eluent provided 12 g of 2-(3-bromo-4-hydroxy-5-nitrophenyl)-4-methylpentanoic acid. The acid was taken in 50 ml of absolute ethanol and 2 ml of concentrated sulfuric acid and refluxed for 1 h. The ethanol layer was distilled off, washed it with water and dried gave 13 g of ethyl 2-(3-bromo-4-hydroxy-5-nitrophenyl)-4-methylpentanoate intermediate. 1H NMR (CDCl3): δ 8.20 (s 1H), 7.20 (s, 1H), 4.90 (bs,1H),4.15 (q, 2H), 3.60 (t, 1H),1.95-2.00(m,1H), 1.75-1.80(m,1H), 1.45-1.50(m,1H), 1.20(t,3H), 1.00 (m,6H). Mass: (360, M+1, 100%).