Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(C(C)C)C(C)C)C.[CH3:10][C:11]1[C:12]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[C:13]([O:23][C:24]2[CH:30]=[CH:29][C:27]([NH2:28])=[CH:26][CH:25]=2)[C:14]2[C:19]([CH:20]=1)=[CH:18][C:17]([O:21][CH3:22])=[CH:16][CH:15]=2.Cl[C:38](=[O:44])[CH2:39][C:40]([O:42][CH3:43])=[O:41]>C(Cl)Cl>[CH3:10][C:11]1[C:12]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[C:13]([O:23][C:24]2[CH:30]=[CH:29][C:27]([NH:28][C:38](=[O:44])[CH2:39][C:40]([O:42][CH3:43])=[O:41])=[CH:26][CH:25]=2)[C:14]2[C:19]([CH:20]=1)=[CH:18][C:17]([O:21][CH3:22])=[CH:16][CH:15]=2
Reactant: COC(=O)CC(=O)Cl
Reactant: COc1ccc2c(Oc3ccc(N)cc3)c(-c3ccccc3)c(C)cc2c1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)CC(=O)Nc1ccc(Oc2c(-c3ccccc3)c(C)cc3cc(OC)ccc23)cc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 68.2 %

Procedure:
N-ethyldiisopropylamine (147 μL, 0.84 mmol, 3 equiv) was added to a solution of 38 (100 mg, 0.28 mmol, 1 equiv) in CH2Cl2 (5 mL) at 0° C. After 10 min, methyl 3-chloro-3-oxopropionate (60 μL, 0.56 mmol, 2 equiv) was added and the reaction was stirred at 0° C. for 3 h. The reaction mixture was diluted with CH2Cl2 (50 mL) and washed with saturated aqueous NaHCO3 (100 mL). The organic layer was dried over MgSO4, filtered, concentrated and the residue purified by silica gel flash column chromatography (30% EtOAc:hexanes) to provide 41 (87 mg, 68%) as a yellow oil. 1HNMR (400 MHz, DMSO-d6): δ 10.00 (s, 1H), 7.68 (s, 1H), 7.56 (m, 1H), 7.33-7.17 (m, 8H), 7.06-7.03 (m, 1H), 6.53 (m, 2H), 3.86 (s, 3H), 3.61 (s, 3H), 3.37 (s, 2H), 2.17 (s, 3H). MS m/z 455.87 (M+H)+.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]([O:12][CH2:13][CH3:14])=[O:11].[F:15][C:16]([F:26])([F:25])[C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=1)[CH2:20]Br.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CN(C)C=O>[F:15][C:16]([F:25])([F:26])[C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=1)[CH2:20][N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: CCOC(=O)c1cc2ccccc2[nH]1
Reactant: FC(F)(F)c1cccc(CBr)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cc2ccccc2n1Cc1cccc(C(F)(F)F)c1
Yield: 88.6 %

Procedure:
A suspension of 0.492 g (2.6 mmol) of ethyl 1H-indole-2-carboxylate, of 0.683 g (2.86 mmol) of 3-trifluoromethylbenzyl bromide and of 0.898 g (6.5 mmol) of potassium carbonate in 50 ml of dimethylformamide is stirred at 60° C. for 24 hours. The reaction mixture is cooled and is poured into a mixture of ice-cold water and of ethyl acetate. After settling, the organic phase is separated and is then washed with two times 50 ml of water and then with 50 ml of a saturated sodium chloride solution. The solution is dried over magnesium sulfate and filtered, and then the filtrate is concentrated under reduced pressure. 0.8 g of an oil is obtained, which oil is used as is in the following stage.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([OH:12])=[C:4]([C:13]([OH:15])=O)[N:3]=1.C(N(CC)CC)C.Cl.[CH3:24][O:25][C:26](=[O:30])[C@H:27]([CH3:29])[NH2:28]>C(Cl)Cl>[CH3:24][O:25][C:26](=[O:30])[C@@H:27]([NH:28][C:13]([C:4]1[N:3]=[C:2]([Cl:1])[C:11]2[C:6]([C:5]=1[OH:12])=[CH:7][CH:8]=[CH:9][CH:10]=2)=[O:15])[CH3:29]
Reactant: COC(=O)[C@H](C)N
Reactant: O=C(O)c1nc(Cl)c2ccccc2c1O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)[C@H](C)NC(=O)c1nc(Cl)c2ccccc2c1O

Procedure:
1-Chloro-4-hydroxy-isoquinoline-3-carboxylic acid, 0.55 g, 1.5 ml of triethylamine, 0.55 g of DECI, and 0.56 g of (L)-Alanine methyl ester hydrochloride were stirred in 15 ml of methylene chloride at room temperature for 72 h. The reaction mixture was partitioned between ethyl acetate and water, the organic layer was separated and successively washed with 1M aqueous HCl, satd. aqueous NaHCO3, and satd. aqueous NaCl. The organic layer was dried with sodium sulfate, filtered, and concentrated under vacuum to afford 0.133 g of off-white solid product: MS-(+)-ion, M+1=308.9 Daltons.
Reaction SMILES: [OH:1][C:2]1[C:3]([Br:8])=[N:4][CH:5]=[CH:6][CH:7]=1.[C:9](OC(=O)C)(=[O:11])[CH3:10].C([O-])([O-])=O.[Na+].[Na+]>>[Br:8][C:3]1[C:2]([O:1][C:9](=[O:11])[CH3:10])=[CH:7][CH:6]=[CH:5][N:4]=1
Reactant: CC(=O)OC(C)=O
Reactant: Oc1cccnc1Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: CC(=O)Oc1cccnc1Br
Temperature: 0 °C
Yield: 98.6 %

Procedure:
A solution of 3-hydroxy-2-bromopyridine (21.4 g, 123 mmol) in acetic anhydride (25 g, 245 mmol) was refluxed for 1 hour. After cooling, the mixture was poured into ice water, neutralized with Na2CO3 and extracted with ether. The organic phase was dried and concentrated. The residue was subject to column chromatography, eluted by ether to afford Acetic acid 2-bromo-pyridin-3-yl ester (26.2 g, 99%). 1H NMR (CDCl3, 400 mHz) δ 8.28 (m, 1H), 7.46 (m, 1H), 7.30 (m, 1H), 2.38 (s, 3H).
Reaction SMILES: O=[C:2]1[NH:6][C@H:5]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:4][C@H:3]1[CH2:14][CH2:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:32])=CC=1>C1C=CC=CC=1>[C:17]1([CH2:16][CH2:15][CH2:14][CH:3]2[C:2](=[S:32])[NH:6][C@H:5]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:4]2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CC(C)(C)OC(=O)[C@@H]1C[C@@H](CCCc2ccccc2)C(=O)N1
Solvent: c1ccccc1
Product: CC(C)(C)OC(=O)[C@@H]1CC(CCCc2ccccc2)C(=S)N1
Yield: 179.8 %

Procedure:
A mixture of pyroglutamate 8c (245.4 mg, 0.809 mmol) and Lawesson's reagent (164 mg, 0.404 mmol) in 6 mL benzene was stirred at reflux for 17 h, then concentrated. The crude product was purified by flash chromatography (0.5 to 1 to 1.5 to 2% MeOH/CHCl3) to afford 232 mg (90%) of the thiolactam 8d as a 2:1 mixture of diastereomers.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]([CH:19]=[CH:20][C:21]=1[C:22]#[N:23])[C:12]([CH2:14][CH2:15][C:16]([OH:18])=[O:17])=[O:13])C1C=CC=CC=1.Br>C(O)(=O)C>[C:22]([C:21]1[CH:20]=[CH:19][C:11]([C:12]([CH2:14][CH2:15][C:16]([OH:18])=[O:17])=[O:13])=[CH:10][C:9]=1[OH:8])#[N:23]
Reactant: N#Cc1ccc(C(=O)CCC(=O)O)cc1OCc1ccccc1
Agent: Br
Solvent: CC(=O)O
Product: N#Cc1ccc(C(=O)CCC(=O)O)cc1O
Temperature: 0 °C

Procedure:
3-(3-Benzyloxy-4-cyanobenzoyl)propionic acid was warmed with 33% hydrogen bromide in acetic acid and the solution was poured into ice-water to give 3-(4-cyano-3-hydroxybenzoyl) propionic acid.
Reaction SMILES: [CH3:1][CH:2]([CH3:5])[CH2:3][NH2:4].C(N(CC)CC)C.[I:13][C:14]1[CH:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[CH:16][CH:15]=1>C(Cl)Cl>[I:13][C:14]1[CH:19]=[CH:18][C:17]([S:20]([NH:4][CH2:3][CH:2]([CH3:5])[CH3:1])(=[O:22])=[O:21])=[CH:16][CH:15]=1
Reactant: CC(C)CN
Reactant: O=S(=O)(Cl)c1ccc(I)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)CNS(=O)(=O)c1ccc(I)cc1
Yield: 92.4 %

Procedure:
A solution of (2-methylpropyl)amine (121 mg, 1.65 mmol) and triethylamine (0.35 ml, 2.47 mmol) in DCM (10 ml) was treated with 4-iodobenzenesulfonyl chloride (500 mg, 1.65 mmol) by dropwise addition over 10 minutes with stirring under argon. The reaction mixture was stirred at room temperature for 16 hr. Then the reaction mixture was washed with water (10 ml), separated the organic layer, dried with sodium sulphate. Solvent was removed by rotary evaporation to give the title compound as a white solid (517 mg, 92%).
Reaction SMILES: [C:1]1(=O)[O:5][CH2:4][CH2:3][CH2:2]1.[NH2:7][CH2:8][CH2:9][CH2:10][OH:11]>>[OH:11][CH2:10][CH2:9][CH2:8][N:7]1[CH2:1][CH2:2][CH2:3][C:4]1=[O:5]
Reactant: O=C1CCCO1
Reactant: NCCCO
Product: O=C1CCCN1CCCO
Yield: 17.5 %

Procedure:
A solution of γ-butyrolactone (8.6g, 0.1 mol) and 3-amino-1-propanol (9 g, 0.12 mol) was heated at reflux for 18 hours. The crude product mixture was distilled under reduced pressure to give 1-(3-hydroxypropyl)-2-pyrrolidinone (2.5 g. 17%).
Reaction SMILES: [CH:1]([N:14]1[C:22]2[C:17](=[CH:18][C:19]([Cl:23])=[CH:20][CH:21]=2)[C:16]([CH2:24][CH2:25][O:26][C:27]2[CH:35]=[CH:34][C:30]([C:31]([OH:33])=[O:32])=[CH:29][CH:28]=2)=[C:15]1[CH2:36][CH2:37][NH:38][S:39]([CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)(=[O:41])=[O:40])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:49](C1C=CC(CS(Cl)(=O)=O)=CC=1)#[N:50]>>[CH:1]([N:14]1[C:22]2[C:17](=[CH:18][C:19]([Cl:23])=[CH:20][CH:21]=2)[C:16]([CH2:24][CH2:25][O:26][C:27]2[CH:28]=[CH:29][C:30]([C:31]([OH:33])=[O:32])=[CH:34][CH:35]=2)=[C:15]1[CH2:36][CH2:37][NH:38][S:39]([CH2:42][C:43]1[CH:44]=[CH:45][C:46]([C:49]#[N:50])=[CH:47][CH:48]=1)(=[O:41])=[O:40])([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: N#Cc1ccc(CS(=O)(=O)Cl)cc1
Reactant: O=C(O)c1ccc(OCCc2c(CCNS(=O)(=O)Cc3ccccc3)n(C(c3ccccc3)c3ccccc3)c3ccc(Cl)cc23)cc1
Product: N#Cc1ccc(CS(=O)(=O)NCCc2c(CCOc3ccc(C(=O)O)cc3)c3cc(Cl)ccc3n2C(c2ccccc2)c2ccccc2)cc1

Procedure:
The title compound was prepared from 4-{2-[2-(2-amino-ethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]-ethoxy}-benzoic acid methyl ester (Step 6, Example 1) and (4-cyano-phenyl)-methanesulfonyl chloride according to Example 1 Step 7.
Reaction SMILES: Br[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[F:8][C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=1)[CH2:12][CH2:13][NH2:14]>CO>[F:8][C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=1)[CH2:12][CH2:13][NH:14][CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4]
Reactant: NCCc1cccc(F)c1
Reactant: CCOC(=O)CBr
Solvent: CO
Product: CCOC(=O)CNCCc1cccc(F)c1

Procedure:
Ethyl bromoacetate (0.166 g, 0.11 mL, 0.001 mol) and 3-fluorophenethylamine (0.139 g, 0.13 mL, 0.001 mol) were stirred in MeOH (10 mL) for 48 h. The solvent was removed in vacuo, and the residue was purified by column chromatography (silica gel, hexanes:EtOAc=2:3) to generate VIII-3 (0.083 g, 37%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N:11]2[C:15]([C:16]([F:19])([F:18])[F:17])=[N:14][N:13]=[N:12]2)[CH:5]=[C:6]2[C:10]=1[NH:9][CH:8]=[CH:7]2.[H-].[Na+].I[CH3:23]>CN(C=O)C.C(OCC)C>[Br:1][C:2]1[CH:3]=[C:4]([N:11]2[C:15]([C:16]([F:19])([F:17])[F:18])=[N:14][N:13]=[N:12]2)[CH:5]=[C:6]2[C:10]=1[N:9]([CH3:23])[CH:8]=[CH:7]2
Reactant: FC(F)(F)c1nnnn1-c1cc(Br)c2[nH]ccc2c1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: Cn1ccc2cc(-n3nnnc3C(F)(F)F)cc(Br)c21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 7-bromo-5-(5-trifluoromethyl-tetrazol-1-yl)-1H-indole (115 mg, 0.346 mmol) in DMF (2 mL) was added sodium hydride (80% dispersion in mineral oil) (12 mg, 0.417 mmol). After gas evolution ceased, iodomethane (33 μL, 0.530 mmol) was added, and the mixture was stirred for 2 hours at room temperature. The mixture was diluted with diethyl ether, washed with water, 2N hydrochloric acid, saturated sodium hydrogencarbonate solution, saturated brine solution, dried (MgSO4), and evaporated. Silica gel chromatography eluting with 10% diethyl ether/hexane afforded pure title compound; yield 83 mg of a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]([O:13][CH3:14])[CH:10]=[C:9]2[C:4]=1[C:5](O)=[CH:6][CH:7]=[N:8]2.CCN(C(C)C)C(C)C.O=P(Cl)(Cl)[Cl:27]>C1(C)C=CC=CC=1>[Cl:27][C:5]1[C:4]2[C:9](=[CH:10][C:11]([O:13][CH3:14])=[CH:12][C:3]=2[O:2][CH3:1])[N:8]=[CH:7][CH:6]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1cc(OC)c2c(O)ccnc2c1
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1
Product: COc1cc(OC)c2c(Cl)ccnc2c1

Procedure:
To a mixture of crude 5,7-dimethoxyquinolin-4-ol (5.36 g, 26 mmol) and Hunig's Base (9.1 ml, 52 mmol) in toluene, was added POCl3 (29 ml, 313 mmol). The mixture was refluxed for 5 h. Excess POCl3 was removed under reduced pressure and azeotroped with toluene. The resultant gum was treated with sat. NaHCO3 until no gas generated. The mixture was extracted with EtOAc, the organic extracts were combined and washed with sodium bicarbonate and solvent removed under reduced pressure. The crude product was purified via column chromatography on silica gel (RediSep 120 g column, gradient elution with 0-50% EtOAc/DCM) to afford 4-chloro-5,7-dimethoxyquinoline as a yellow solid. MS Found m/z=[M+H]+. 224.2 Calc'd for C11H10ClN: 223.7.
Reaction SMILES: N#N.[N+:3]([C:6]1[CH:10]=[N:9][N:8]([CH2:11][C:12]2[O:16][C:15]([CH2:17][OH:18])=[CH:14][CH:13]=2)[N:7]=1)([O-:5])=[O:4].[CH3:19]I>C(Cl)Cl>[CH3:19][O:18][CH2:17][C:15]1[O:16][C:12]([CH2:11][N:8]2[N:7]=[C:6]([N+:3]([O-:5])=[O:4])[CH:10]=[N:9]2)=[CH:13][CH:14]=1
Reactant: CI
Reactant: O=[N+]([O-])c1cnn(Cc2ccc(CO)o2)n1
Agent: N#N
Solvent: ClCCl
Product: COCc1ccc(Cn2ncc([N+](=O)[O-])n2)o1
Temperature: 40 °C
Reaction time: 8 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of (5-((4-nitro-2H-1,2,3-triazol-2-yl)methyl)furan-2-yl)methanol (WO 2009077990A1) (186 mg, 0.83 mmol) in CH2Cl2 (3.0 mL) was added to a suspension of Ag2O (288 mg, 1.24 mmol) and MeI (0.06 mL, 0.99 mmol). The resulting mixture (protected form light) was stirred overnight at 40° C. The reaction mixture was filtered and the solvent was removed under reduced pressure. Purification of the residue by FC (7:3 hept-EA) gave the title compound as a yellow oil: TLC: rf (7:3 hept-EA)=0.27. LC-MS-conditions 07: tR=0.74 min.
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[CH2:10][C:9]2[C:4](=[C:5]([OH:13])[CH:6]=[CH:7][C:8]=2[O:11][CH3:12])[C:3]1=O.CS(O)(=O)=O.C([SiH](CC)CC)C>ClCCl>[CH3:1][C:2]1([CH3:15])[CH2:10][C:9]2[C:4](=[C:5]([OH:13])[CH:6]=[CH:7][C:8]=2[O:11][CH3:12])[CH2:3]1
Reactant: COc1ccc(O)c2c1CC(C)(C)C2=O
Agent: CC[SiH](CC)CC
Agent: CS(=O)(=O)O
Solvent: ClCCl
Product: COc1ccc(O)c2c1CC(C)(C)C2
Yield: 49.3 %

Procedure:
To a stirred solution of 2,2-dimethyl-7-hydroxy-4-methoxyindan-1-one (500 mg) and methanesulfonic acid (466 mg) in dichloromethane (12 mL) was added triethylsilane (564 mg). Every 0.5 h, over a 3 h period, additional portions of methanesulfonic acid and triethylsilane were added. The reaction was partitioned between water and dichloromethane, the organic layer dried over sodium sulfate, concentrated in vacuo and the resulting oil flash chromatographed (1:1, chloroform:hexanes) to afford 2,2-dimethyl-7-hydroxy-4-methoxyindane (230 mg) as a colorless waxy solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[O:10][C:11]3[CH:17]=[C:16]([O:18][CH2:19][C@@H:20]([NH:22][C:23](=[O:25])[CH3:24])[CH3:21])[CH:15]=[CH:14][C:12]=3[N:13]=2)[CH:5]=[CH:6][C:7]=1[OH:8].C(=O)([O-])[O-].[K+].[K+].[CH2:32](I)[CH3:33]>CN(C=O)C.C(OCC)(=O)C>[CH2:32]([O:8][C:7]1[CH:6]=[CH:5][C:4]([C:9]2[O:10][C:11]3[CH:17]=[C:16]([O:18][CH2:19][C@@H:20]([NH:22][C:23](=[O:25])[CH3:24])[CH3:21])[CH:15]=[CH:14][C:12]=3[N:13]=2)=[CH:3][C:2]=1[F:1])[CH3:33]
Reactant: CC(=O)N[C@@H](C)COc1ccc2nc(-c3ccc(O)c(F)c3)oc2c1
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOc1ccc(-c2nc3ccc(OC[C@H](C)NC(C)=O)cc3o2)cc1F
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 77.2 %

Procedure:
A suspension of N-((2S)-1-((2-(3-fluoro-4-hydroxyphenyl)-1,3-benzoxazol-6-yl)oxy)propan-2-yl)acetamide (200 mg), potassium carbonate (161 mg) and ethyl iodide (181 mg) in DMF (5 mL) was stirred at 60° C. for 30 min. The reaction mixture was diluted with ethyl acetate, and washed with saturated brine, and the organic layer was subjected to silica gel column chromatography (NH, ethyl acetate), and the solvent was evaporated. The obtained solid was recrystallized from hexane/ethyl acetate to give the title compound (167 mg).
Reaction SMILES: [F:1][CH:2]([F:23])[O:3][C:4]1[C:5]([OH:22])=[C:6]([C:12]2[CH:20]=[CH:19][CH:18]=[C:17]3[C:13]=2[CH2:14][CH2:15][C:16]3=[O:21])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11].C(=O)([O-])[O-].[K+].[K+].[CH2:30](Br)[CH2:31][CH3:32]>C(#N)C>[F:1][CH:2]([F:23])[O:3][C:4]1[C:5]([O:22][CH2:30][CH2:31][CH3:32])=[C:6]([C:12]2[CH:20]=[CH:19][CH:18]=[C:17]3[C:13]=2[CH2:14][CH2:15][C:16]3=[O:21])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11]
Reactant: COc1ccc(-c2cccc3c2CCC3=O)c(O)c1OC(F)F
Reactant: CCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCCOc1c(-c2cccc3c2CCC3=O)ccc(OC)c1OC(F)F
Temperature: 70 °C
Yield: 22.1 %

Procedure:
To a stirring solution of 4-(3-(difluoromethoxy)-2-hydroxy-4-methoxyphenyl)-2,3-dihydro-1H-inden-1-one (80 mg, 0.25 mmol) in acetonitrile (10 mL) was added potassium carbonate (102 mg, 0.75 mmol) and propyl bromide (92 mg, 0.75 mmol) and the resultant reaction mixture was heated to 70° C. for 16 h. The reaction mixture was cooled to RT, filtered through celite and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 0-20% ethyl acetate in pet ether) to afford the title compound as a solid (20 mg, 22%).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[Br:5][C:6]1[CH:14]=[CH:13][C:9]([C:10](Cl)=[O:11])=[C:8]([Cl:15])[CH:7]=1.[C:16]1([O:22][CH3:23])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>[N+](C1C=CC=CC=1)([O-])=O>[Br:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([C:19]2[CH:20]=[CH:21][C:16]([O:22][CH3:23])=[CH:17][CH:18]=2)=[O:11])=[C:8]([Cl:15])[CH:7]=1
Reactant: O=C(Cl)c1ccc(Br)cc1Cl
Reactant: COc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: O=[N+]([O-])c1ccccc1
Product: COc1ccc(C(=O)c2ccc(Br)cc2Cl)cc1
Temperature: 25 °C

Procedure:
7.2 g of aluminium chloride are added to 80 ml of nitrobenzene at 5° C. and a solution of 8 g of 4-bromo-2-chloro-benzoyl chloride in 20 ml of nitrobenzene is added dropwise in such a manner that the temperature does not exceed 10° C. After stirring and adding 3.26 ml of anisole the reaction mixture is warmed to room temperature, stirred and subsequently poured on to ice-water and extracted with methylene chloride. The extracts are washed with saturated sodium chloride solution, dried and evaporated. There are obtained 10.0 g of (4-bromo-2-chloro-phenyl)-(4-methoxy-phenyl)-methanone, MS: m/e 324 (M+H+, 1 Br).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([O:11][CH2:12][CH2:13][CH2:14][CH3:15])[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH2:16][C:17]1[CH:18]=[C:19]([CH2:23][P:24]([CH3:29])(=[O:28])[O:25][CH2:26][CH3:27])[CH:20]=[CH:21][CH:22]=1.[Br:30]Br>C(Cl)(Cl)Cl>[NH2:1][C:2]1[N:10]=[C:9]([O:11][CH2:12][CH2:13][CH2:14][CH3:15])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([Br:30])[N:6]2[CH2:16][C:17]1[CH:18]=[C:19]([CH2:23][P:24]([CH3:29])(=[O:28])[O:25][CH2:26][CH3:27])[CH:20]=[CH:21][CH:22]=1
Reactant: CCCCOc1nc(N)c2ncn(Cc3cccc(CP(C)(=O)OCC)c3)c2n1
Reactant: BrBr
Solvent: ClC(Cl)Cl
Product: CCCCOc1nc(N)c2nc(Br)n(Cc3cccc(CP(C)(=O)OCC)c3)c2n1
Yield: 54 %

Procedure:
To a solution of 68 (204.0 mg, 0.488 mmol) in CHCl3 (5 mL) was added a 10% (v) solution of Br2 in chloroform. The reaction was stopped when starting material was consumed, monitored by HPLC. Bromine was quenched with a saturated Na2SO3 solution and product extracted with DCM (2×10 mL). Organics were washed with water (2×10 mL) and brine (1×10 mL) and dried over Na2SO4. Purified by flash column eluting 10% methanol in ethyl acetate. Evaporation of solvent gave 130.4 mg (54%) of 69 as a yellow solid. LCMS: m/z for C20H27BrN5O3P++H observed 496.2 and 498.1 at 2.18 minutes of a 3.5 minute run, eluting 5-95% CH3CN in H2O.
Reaction SMILES: O=[CH:2][CH2:3][CH:4]1[CH2:12][C:11]2[C:6](=[CH:7][C:8]([Cl:14])=[C:9]([Cl:13])[CH:10]=2)[C:5]1=O.C1(C)C=CC(S(O)(=O)=O)=CC=1.O.[NH2:28][CH2:29][CH:30]([OH:32])[CH3:31]>C1(C)C=CC=CC=1>[Cl:13][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[Cl:14])[C:5]1[N:28]([CH2:29][CH:30]([OH:32])[CH3:31])[CH:2]=[CH:3][C:4]=1[CH2:12]2
Reactant: O=CCC1Cc2cc(Cl)c(Cl)cc2C1=O
Reactant: CC(O)CN
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CC(O)Cn1ccc2c1-c1cc(Cl)c(Cl)cc1C2
Reaction time: 0.75 h
Yield: 26.7 %

Procedure:
A solution of 2.0 g of (RS)-2-(2-oxoethyl)-5,6-dichloro-1-indanone and 70 mg of p-toluenesulfonic acid in 70 ml of anhydrous toluene was heated on a water separator. A solution of 2.47 g of (RS)-1-amino-2-propanol in 20 ml of anhydrous toluene was added dropwise to the boiling solution over a period of 5 minutes. Subsequently, the mixture was boiled for an additional 45 minutes, during which time the solvent was reduced to a volume of 20 ml. The cooled reaction mixture was purified by column chromatography on silica gel (diethyl ether/hexane 4:1). 0.62 g (27%) of (RS)-1-(6,7-dichloro-1,4-dihydro-indeno[1,2-b]pyrrol-1-yl)-propan-2-ol was obtained as a brown oil.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[N:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[O:12][CH3:13].Br[CH2:15][CH2:16][CH2:17][Cl:18].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[Cl:18][CH2:17][CH2:16][CH2:15][O:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[N:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[O:12][CH3:13]
Reactant: ClCCCBr
Reactant: COc1cc2cncnc2cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc2cncnc2cc1OCCCCl
Temperature: 40 °C
Yield: 85.7 %

Procedure:
A mixture of 44-chloro-2-fluoroanilino)-7-hydroxy-6-methoxyquinazoline (957 mg, 3 mmol), (prepared as described for the starting material in Example 2), 1-bromo-3-chloropropane (2.36 g, 15 mmol) and potassium carbonate (2.1 g, 15 mmol) in DMF (20 ml) was heated at 40° C. for 1.5 hours. The mixture was allowed to cool, was diluted with water and extracted with ethyl acetate (3×50 ml). The organic extracts were combined, washed with water and brine, dried (MgSO4) and the volatiles were removed by evaporation. The residue was triturated with hexane/ethyl acetate, collected by filtration and dried under vacuum to give 4-chloro-2-fluoroanilino)-7-(3-chloropropoxy)6-methoxyquinazoline (650 mg, 55%).
Reaction SMILES: [C:1]1([CH:7]2[CH2:16][CH2:15][C:14]3[C:9](=[CH:10][CH:11]=[C:12]([O:17][CH:18]4[CH2:23][CH2:22][C:21](=[O:24])[CH2:20][CH2:19]4)[CH:13]=3)[O:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:25]([Mg]Cl)[CH2:26][CH3:27].C(OCC)C.[Cl-].[NH4+]>O1CCCC1>[C:1]1([CH:7]2[CH2:16][CH2:15][C:14]3[C:9](=[CH:10][CH:11]=[C:12]([O:17][CH:18]4[CH2:23][CH2:22][C:21]([CH2:25][CH2:26][CH3:27])([OH:24])[CH2:20][CH2:19]4)[CH:13]=3)[O:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C1CCC(Oc2ccc3c(c2)CCC(c2ccccc2)O3)CC1
Reactant: CCC[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCCC1(O)CCC(Oc2ccc3c(c2)CCC(c2ccccc2)O3)CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
100 mg of 4-(2-phenyl-chroman-6-yloxy)-cyclohexanone were dissolved at room temperature in 5 ml of tetrahydrofuran. A 2M solution of propylmagnesium chloride in diethyl ether (0.31 ml, 2 eq) was added, and stirring at room temperature was continued for 4 h. The reaction was stopped by careful addition of saturated aqueous ammonium chloride solution. The aqueous layer was extracted with methyl tert-butyl ether. The organic layer was dried over sodium sulfate and filtered, and the solvent removed by evaporation. The resulting oil was chromatographed over silica gel using heptane/ethyl acetate 20:1 as the eluent. 54 mg of the title compound were isolated as a pale yellow oil (48%).
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][NH:13][C:14](=[O:19])[C:15]([CH3:18])([CH3:17])[CH3:16])[CH:6]=[CH:7][C:8]=1[O:9]C.[Cl-].[Al+3].[Cl-].[Cl-].Cl>C1C=CC=CC=1>[OH:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][NH:13][C:14](=[O:19])[C:15]([CH3:17])([CH3:16])[CH3:18])[CH:6]=[CH:7][C:8]=1[OH:9]
Reactant: COc1ccc(CCNC(=O)C(C)(C)C)cc1OC
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: c1ccccc1
Product: CC(C)(C)C(=O)NCCc1ccc(O)c(O)c1
Temperature: 25 °C

Procedure:
Dissolve 0.53 g. of N-[β-(3,4-dimethoxyphenyl)-ethyl]-2,2-dimethylpropionamide in 10 ml. of benzene and 15 g. of aluminum chloride. Reflux the mixture overnight (17 hours) with vigorous stirring. Cool the mixture to room temperature and, cautiously, pour the reaction mixture into dilute hydrochloric acid and ice with vigorous stirring. Separate the liquid phases and discard the benzene layer. Extract the aqueous layer with ethyl-acetate, then wash the extract with saturated sodium bicarbonate and water. Dry the extract over anhydrous sodium sulfate, filter and evaporate to a residue. Crystallize the residue from a 9:1 mixture of toluene:ethanol to obtain the title product.