Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]2[C:14]([C:15]3[CH:20]=[CH:19][C:18]([Br:21])=[CH:17][CH:16]=3)=[CH:13][S:12][C:11]=2[CH:22]=1.[CH3:23][O:24][CH2:25][CH2:26][NH:27][CH2:28][CH2:29][O:30][CH3:31]>>[Br:21][C:18]1[CH:19]=[CH:20][C:15]([C:14]2[C:10]3[CH:9]=[CH:8][C:7]([O:6][CH2:5][CH2:4][CH2:3][CH2:2][N:27]([CH2:28][CH2:29][O:30][CH3:31])[CH2:26][CH2:25][O:24][CH3:23])=[CH:22][C:11]=3[S:12][CH:13]=2)=[CH:16][CH:17]=1
Reactant: BrCCCCOc1ccc2c(-c3ccc(Br)cc3)csc2c1
Reactant: COCCNCCOC
Product: COCCN(CCCCOc1ccc2c(-c3ccc(Br)cc3)csc2c1)CCOC

Procedure:
According to the method in example 29, 6-(4-Bromo-butoxy)-3-(4-bromo-phenyl)-benzo[b]thiophene and bis(2-methoxyethyl)amine were converted to yield {4-[3-(4-Bromo-phenyl)-benzo[b]thiophen-6-yloxy]-butyl}-bis-(2-methoxy-ethyl)-amine as light brown oil, MS: 492 (MH+, 1Br).
Reaction SMILES: [N:1]1([C:23]([O:25][CH:26]2[CH:33]3[CH2:34][CH:29]4[CH2:30][CH:31]([CH2:35][CH:27]2[CH2:28]4)[CH2:32]3)=[O:24])[CH2:6][CH2:5][C:4]2([C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH2:9][N:8](C(OC(C)(C)C)=O)[CH2:7]2)[CH2:3][CH2:2]1>C(O)(C(F)(F)F)=O.C(Cl)Cl>[N:1]1([C:23]([O:25][CH:26]2[CH:27]3[CH2:35][CH:31]4[CH2:30][CH:29]([CH2:34][CH:33]2[CH2:32]4)[CH2:28]3)=[O:24])[CH2:6][CH2:5][C:4]2([C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH2:9][NH:8][CH2:7]2)[CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)N1Cc2ccccc2C2(CCN(C(=O)OC3C4CC5CC(C4)CC3C5)CC2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(OC1C2CC3CC(C2)CC1C3)N1CCC2(CC1)CNCc1ccccc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 104.4 %

Procedure:
2-Tert-butyl 1′-(2-adamantyl) 1H-spiro[isoquinoline-4,4′-piperidine]-1′,2(3H)-dicarboxylate (35 mg, 0.073 mmol) was dissolved in 1:2 TFA/CH2Cl2 (6 mL) and stirred for 30 min at rt. The mixture was concentrated to afford crude 2-adamantyl 2,3-dihydro-1H-spiro[isoquinoline-4,4′-piperidine]-1′-carboxylate (29 mg, quant). LC-MS Method 1 tR=1.48 min, m/z=381; 1H NMR (CD3OD) δ=7.52 (d, 1H), 7.38 (t, 1H), 7.28 (t, 1H), 7.21 (d, 1H), 4.85 (s, 1H), 4.38 (s, 2H), 4.19 (m, 2H), 3.68 (s, 2H), 3.28-3.01 (m, 2H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:13])[NH:7][N:8]1[CH:12]=[CH:11][CH:10]=[CH:9]1)([CH3:4])([CH3:3])[CH3:2].[F:14][C:15]1[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[C:16]=1[CH2:17]Cl.[H-].[Na+]>>[C:1]([O:5][C:6](=[O:13])[N:7]([CH2:17][C:16]1[C:15]([F:14])=[CH:22][CH:21]=[CH:20][C:19]=1[F:23])[N:8]1[CH:12]=[CH:11][CH:10]=[CH:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Fc1cccc(F)c1CCl
Reactant: CC(C)(C)OC(=O)Nn1cccc1
Agent: [H-]
Agent: [Na+]
Product: CC(C)(C)OC(=O)N(Cc1c(F)cccc1F)n1cccc1

Procedure:
Prepared according to the benzylation condition used in Example 1 step b) from pyrrol-1-yl-carbamic acid tert-butyl ester (1.0 eq.), 2,6-difluorobenzyl chloride (1.0 eq.) and sodium hydride (1.3 eq.). ESI (m/z): 309 (M+H)+.
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH:2]1[CH2:11][OH:12].[CH3:13]OS(C)(=O)=O.C(=O)([O-])[O-].[Ca+2].O>CCOCC>[CH3:13][N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH:2]1[CH2:11][OH:12]
Reactant: OCC1CCc2ccccc2N1
Reactant: COS(C)(=O)=O
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: CCOCC
Solvent: O
Product: CN1c2ccccc2CCC1CO
Temperature: 25 °C
Reaction time: 6 h

Procedure:
In 120 ml of ethanol, 6 g of methyl quinaldinate was reduced by hydrogen in the presence of 400 mg of platinum oxide to give 6.8 g of methyl 1,2,3,4-tetrahydroquinaldinate as an oil. 3.0 g of the resulting methylester was further reduced in a dry ether by 1 g of lithium aluminum hydride to give 2.6 g of 1,2,3,4-tetrahydro-2-quinolinemethanol. A mixture of 1.6 g of the resulting alcohol, 0.93 ml of dimethylsulfonic acid, 2.16 g of calcium carbonate and 8 ml of water was stirred at room temperature for 6 hours. To the reaction mixture was added ether and insolubles were removed by filtration. The organic portion was separated, washed with water and dried over anhydrous sodium sulfate. After removal of the solvent under reduced pressure, the organic portion was purified by silica gel column chromatography (eluent: chloroform) to give 1.4 g of 1-methyl-1,2,3,4-tetrahydro-2-quinolinemethanol as a pale yellow oil.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([CH:14]=[CH:15][CH:16]=1)[C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:7])[CH3:2].[Br:17]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:17][CH:1]([C:3]1[CH:4]=[C:5]([CH:14]=[CH:15][CH:16]=1)[C:6]([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)=[O:7])[CH3:2]
Reactant: CCc1cccc(C(=O)c2ccccc2)c1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CC(Br)c1cccc(C(=O)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Into a 200 ml reactor equipped with a reflux condenser and a stirrer, 60 ml of carbon tetrachloride and 10 g of 3-ethylbenzophenone were introduced. While stirring the resultant mixture at room temperature, 8.6 g of N-bromosuccinimide and 0.14 g of benzoyl peroxide were added thereto, and reflux was performed for 8 hours while stirring the reaction solution. After the reaction solution had been cooled to room temperature, the succinimide was filtered out, and carbon tetrachloride was distilled off from a filtrate under a reduced pressure. The spectrum data of the obtained product were in accord with those of 3-(1-bromoethylbenzophenone.
Reaction SMILES: [CH3:1][C:2]1[CH2:6][CH2:5][CH:4]([C:7]([CH3:9])=[CH2:8])[C:3]=1[CH2:10][C:11]([CH3:15])([CH3:14])[CH2:12][OH:13].[C:16](Cl)(=[O:18])[CH3:17].N1C=CC=CC=1>>[CH3:1][C:2]1[CH2:6][CH2:5][CH:4]([C:7]([CH3:9])=[CH2:8])[C:3]=1[CH2:10][C:11]([CH3:15])([CH3:14])[CH2:12][O:13][C:16](=[O:18])[CH3:17]
Reactant: CC(=O)Cl
Reactant: C=C(C)C1CCC(C)=C1CC(C)(C)CO
Solvent: c1ccncc1
Product: C=C(C)C1CCC(C)=C1CC(C)(C)COC(C)=O
Yield: 95 %

Procedure:
This compound was prepared by esterifying 32 g (0.25 mole) of the product from Example 3 with 24 g (0.3 mole) of acetyl chloride and 24 g (0.3 mole) of pyridine at from 15° to 20° C. On working up in the conventional manner, the ester was obtained in 95% yield; boiling point: 88°-90° C/25 mm Hg; nD25 : 1.4743; the structure was confirmed by the nuclear resonance spectrum. Fragrance: musk-like, floral; good tenacity.
Reaction SMILES: FC1C=C(C=CC=1F)[C:5](O)=[O:6].[NH2:12][C:13]1[CH:14]=[CH:15][C:16]([O:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[C:26](=O)[CH3:27])=[N:17][CH:18]=1>>[NH2:12][C:13]1[CH:14]=[CH:15][C:16]([O:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]3[C:21]=2[CH2:26][CH2:27][C:5]3=[O:6])=[N:17][CH:18]=1
Reactant: CC(=O)c1ccccc1Oc1ccc(N)cn1
Reactant: O=C(O)c1ccc(F)c(F)c1
Product: Nc1ccc(Oc2cccc3c2CCC3=O)nc1

Procedure:
According to the same manner as that described in Example 1 except for using an equimolar amount of 3,4-difluorobenzoic acid in place of 3,4-dichlorobenzoic acid and using an equimolar amount of 1-{2-[(5-amino-2-pyridinyl)oxy]phenyl}-1-ethanone obtained in Reference Example 23 in place of 4-[(5-amino-2-pyridinyl)oxy]-1-indanone, the reaction was carried out to obtain the titled compound.
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([Cl:12])[C:3]=1[C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][CH:22]=1)[N:19]=[C:18]([NH:23][C@H:24]1[C@@H:29]([NH2:30])[CH2:28][C@H:27]3[C@@H:25]1[CH2:26]3)[N:17]=[CH:16]2.CCN(C(C)C)C(C)C.[C:40](Cl)(=[O:43])[CH:41]=[CH2:42]>ClCCl>[Cl:12][C:4]1[C:5]([O:10][CH3:11])=[CH:6][C:7]([O:8][CH3:9])=[C:2]([Cl:1])[C:3]=1[C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][CH:22]=1)[N:19]=[C:18]([NH:23][C@H:24]1[C@@H:29]([NH:30][C:40](=[O:43])[CH:41]=[CH2:42])[CH2:28][C@H:27]3[C@@H:25]1[CH2:26]3)[N:17]=[CH:16]2
Reactant: C=CC(=O)Cl
Reactant: COc1cc(OC)c(Cl)c(-c2ccc3nc(N[C@@H]4[C@H]5C[C@H]5C[C@@H]4N)ncc3c2)c1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C=CC(=O)N[C@H]1C[C@@H]2C[C@@H]2[C@H]1Nc1ncc2cc(-c3c(Cl)c(OC)cc(OC)c3Cl)ccc2n1
Reaction time: 1 h
Yield: 76.7 %

Procedure:
To a solution of (1S,2R,3S,5S)—N2-(6-(2,6-dichloro-3,5-dimethoxyphenyl)quinazolin-2-yl)bicyclo[3.1.0]hexane-2,3-diamine (42 mg, 0.094 mmol) in dichloromethane (1.9 mL) at 0° C. was added DIEA (0.025 mL, 0.14 mmol) and acryloyl chloride (0.009 mL, 0.11 mmol) and the reaction was stirred for 1 h. LC-MS indicated complete consumption of SM. The reaction mixture was purified by silica gel chromatography to yield N-((1S,2R,3S,5S)-2-((6-(2,6-dichloro-3,5-dimethoxyphenyl)quinazolin-2-yl)amino)bicyclo[3.1.0]hexan-3-yl)acrylamide (36 mg, 76%) as a pale yellow solid. MS (ES+) C25H24Cl2N4O3 requires: 498, found: 499
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:18][CH2:19][CH2:20][Cl:21]>C(C(C)=O)C>[Cl:21][CH2:20][CH2:19][CH2:18][O:10][C:7]1[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1
Reactant: ClCCCBr
Reactant: O=[N+]([O-])c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: O=[N+]([O-])c1ccc(OCCCCl)cc1

Procedure:
4-Nitrophenol (69.56 g, 0.5 mol), potassium carbonate (138.21 g, 1 mol) and 1-bromo-3-chloro propane (236.16 g, 1.5 mol) are refluxed in methyl ethyl ketone (800 ml) for 24 h. After filtration solvents are removed, the residue dissolved in ethyl acetate (1000 ml) and washed with NaOH (1M, 150 ml) and water (2×200 ml). Drying over sodium sulfate and concentration in vacuo yields 1-(3-Chloro-propoxy)-4-nitro-benzene as a yellow liquid.
Reaction SMILES: Cl.[NH2:2][C@H:3]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.CN1CCOCC1.[C:23]1(=[O:42])[N:27]([C@@H:28]([CH2:32][CH2:33][CH2:34][CH2:35][OH:36])[C:29](O)=[O:30])[C:26](=[O:37])[C:25]2=[CH:38][CH:39]=[CH:40][CH:41]=[C:24]12.OC1C2N=NNC=2C=CC=1>CN(C)C=O>[C:26]1(=[O:37])[N:27]([CH:28]([CH2:32][CH2:33][CH2:34][CH2:35][OH:36])[C:29]([NH:2][C@@H:3]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:4][C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)=[O:30])[C:23](=[O:42])[C:24]2=[CH:41][CH:40]=[CH:39][CH:38]=[C:25]12
Reactant: O=C(O)[C@H](CCCCO)N1C(=O)c2ccccc2C1=O
Reactant: CCOC(=O)[C@@H](N)Cc1ccccc1
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CCOC(=O)[C@@H](Cc1ccccc1)NC(=O)C(CCCCO)N1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of L-phenylalanine, ethyl ester, hydrochloride salt (998 mg., 4.3 mmol.) in dimethylformamide (10 ml.) was added 4-methylmorpholine (575 μl., 529 mg, 5.2 mmol). After stirring at room temperature for 5 minutes, the solution was cooled to 0° C. and treated successively with (S)-2-phthalimido-6-hydroxyhexanoic acid (1.002 g., 3.6 mmol.), hydroxybenzotriazole (582 mg., 4.3 mmol.), and ethyl-3-(3-dimethylamino)propyl carbodiimide, hydrochloride salt (770 mg., 4.0 mmol.). The resulting mixture was stirred at 0° C. for 0.5 hour and at room temperature for 1.5 hours. The solution was partitioned between ethyl acetate and water and the organic extract was washed successively with 0.5N hydrochloric acid, water, 50% saturated sodium bicarbonate, and brine, then dried (sodium sulfate), filtered and stripped to give 1.63 g. of essentially pure title product as an oil/foam. TLC (acetone:hexanes, 1:1) Rf =0.30.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([O:29][CH2:30][CH:31]2[CH2:33][CH2:32]2)=[C:6]([C:8]2[C:9]3[CH:18]=[CH:17][N:16](S(C4C=CC(C)=CC=4)(=O)=O)[C:10]=3[C:11](=[O:15])[N:12]([CH3:14])[CH:13]=2)[CH:7]=1.CC1(C)C(C)(C)OB([C:42]2[CH:43]=[N:44]OC=2)O1.ClCCl.[F-].[K+].[OH-].[Na+]>CS(C)=O.O.Cl[Pd]Cl.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[CH:31]1([CH2:30][O:29][C:5]2[CH:4]=[CH:3][C:2]([CH2:42][C:43]#[N:44])=[CH:7][C:6]=2[C:8]2[C:9]3[CH:18]=[CH:17][NH:16][C:10]=3[C:11](=[O:15])[N:12]([CH3:14])[CH:13]=2)[CH2:33][CH2:32]1
Reactant: CC1(C)OB(c2cnoc2)OC1(C)C
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(-c4cc(Br)ccc4OCC4CC4)cn(C)c(=O)c32)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: [F-]
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: O
Product: Cn1cc(-c2cc(CC#N)ccc2OCC2CC2)c2cc[nH]c2c1=O
Temperature: 130 °C
Reaction time: 2 h
Yield: 47.4 %

Procedure:
A mixture of Example 314b (100 mg, 0.190 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoxazole (44.4 mg, 0.228 mmol), [1,1′-bis(diphenylphosphino)ferrocene]-dichloropalladium (II), complex with dichloromethane (1:1) (15.5 mg, 0.019 mmol), and potassium fluoride (44.1 mg, 0.758 mmol) in dimethylsulfoxide (1.9 mL) and water (0.75 mL) was purged with nitrogen gas and heated under microwave conditions at 130° C. at for 1.5 hours. The mixture was then treated with 1 mL 4N NaOH and stirred at ambient temperature for 2 hours. The reaction mixture was partitioned between water and ethyl acetate, and the aqueous layers was extracted with ethyl acetate. The combined organic phases were washed with water (2×), saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated and the residue was purified by flash chromatography (silica gel, 0-8% methanol/dichloromethane gradient) to give the title compound (30 mg, 48% yield). 1H NMR (300 MHz, DMSO-d6) δ ppm 12.00 (s, 1H), 12.00 (s, 1H), 7.32 (d, J=2.4 Hz, 1H), 7.34-7.25 (m, 4H), 7.30-7.25 (m, 3H), 7.10 (d, J=8.4 Hz, 1H), 7.10 (d, J=8.4 Hz, 1H), 6.14 (dd, J=2.6, 2.2 Hz, 1H), 6.14 (dd, J=2.6, 2.2 Hz, 1H), 3.99 (s, 2H), 3.99 (s, 2H), 3.84 (d, J=6.7 Hz, 2H), 3.84 (d, J=6.7 Hz, 2H), 3.56 (s, 3H), 3.56 (s, 3H), 1.11-1.02 (m, 1H), 1.12-1.02 (m, 1H), 0.48-0.39 (m, 2H), 0.49-0.35 (m, 2H), 0.31-0.18 (m, 2H), 0.26-0.19 (m, 2H). MS (ESI+) m/z 334.1 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N:8]1[CH2:12][CH2:11][NH:10][C:9]1=[O:13].Br[C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=1[CH3:22].N[C@@H]1CCCC[C@H]1N.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>[Cu](I)I.O1CCOCC1>[Cl:21][C:18]1[CH:19]=[CH:20][C:15]([N:10]2[CH2:11][CH2:12][N:8]([C:3]3[CH:4]=[N:5][CH:6]=[CH:7][C:2]=3[CH3:1])[C:9]2=[O:13])=[C:16]([CH3:22])[CH:17]=1
Reactant: Cc1cc(Cl)ccc1Br
Reactant: Cc1ccncc1N1CCNC1=O
Agent: I[Cu]I
Agent: N[C@@H]1CCCC[C@H]1N
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Product: Cc1cc(Cl)ccc1N1CCN(c2cnccc2C)C1=O
Yield: 78.2 %

Procedure:
Using the same reaction conditions as in Example 14, 1-(4-methyl-pyridin-3-yl)-imidazolidin-2-one (I-14b: 150 mg, 0.8474 mmol) was reacted with 1-bromo-4-chloro-2-methyl-benzene (174 mg, 0.8474 mmol), 1,4-dioxane (5 mL), copper iodide (16.19 mg, 0.08474 mmol), trans-1,2-diamino cyclohexane (29.1 mg, 0.2542 mmol) and potassium phosphate (539.63 g, 2.542 mmol) to afford 200 mg of the product (78.43% yield).
Reaction SMILES: C([O-])([O-])=O.[Cs+].[Cs+].[F:7][C:8]1[N:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1.Br[CH2:16][CH2:17][O:18][CH3:19]>CN(C=O)C>[F:7][C:8]1[CH:9]=[CH:10][C:11]([O:14][CH2:16][CH2:17][O:18][CH3:19])=[CH:12][N:13]=1
Reactant: COCCBr
Reactant: Oc1ccc(F)nc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COCCOc1ccc(F)nc1
Temperature: 110 °C
Reaction time: 0.25 h
Yield: 92.5 %

Procedure:
To a 0° C. suspension of Cs2CO3 (18.73 g, 57.48 mmol) in 150 mL DMF was added 6-fluoropyridin-3-ol (5.0 g, 44.21 mmol). The cloudy brown mixture was stirred for 15 minutes, then 1-bromo-2-methoxyethane (6.232 mL, 66.32 mmol) was added. The reaction mixture was heated in a 110° C. sand bath and stirred for 17 hours, after which it was cooled to ambient temperature and the DMF was removed in vacuo. The resulting residue was combined with saturated NH4Cl and the mixture was extracted with DCM. The combined extracts were dried (Na2SO4), filtered, and concentrated. The crude material was purified on silica gel (5-50% ethyl acetate in hexanes gradient) to give the desired product (7.00 g, 92.50% yield) as a clear, colorless oil.
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([C:10]1[N:14]([C:15]2[CH:16]=[N:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=2)[C:13]2[CH:23]=[C:24]([F:27])[CH:25]=[CH:26][C:12]=2[N:11]=1)[CH3:9])(C)(C)C>C(Cl)Cl.C(O)(C(F)(F)F)=O>[F:27][C:24]1[CH:25]=[CH:26][C:12]2[N:11]=[C:10]([C@@H:8]([NH2:7])[CH3:9])[N:14]([C:15]3[CH:16]=[N:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=3)[C:13]=2[CH:23]=1
Reactant: COc1ccc(-n2c([C@H](C)NC(=O)OC(C)(C)C)nc3ccc(F)cc32)cn1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(-n2c([C@H](C)N)nc3ccc(F)cc32)cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 92.3 %

Procedure:
A mixture of {(S)-1-[6-fluoro-1-(6-methoxypyridin-3-yl)-1H-benzoimidazol-2-yl]ethyl}carbamic acid tert-butyl ester (52 mg, 0.14 mmol) in DCM (3 mL) and TFA (1 mL) was stirred at RT for 2 h. The crude reaction mixture was loaded onto an Isolute® SCX-2 cartridge and washed with MeOH followed by 2M NH3/MeOH. The basic fractions were combined and concentrated in vacuo to afford (S)-1-[6-fluoro-1-(6-methoxypyridin-3-yl)-1H-benzoimidazol-2-yl]ethylamine as a pink oil (37 mg, 96%). LCMS (Method C): RT 1.98 min [M+H]+ 287.2.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:10]([CH2:13][CH3:14])=[C:9]2[C:5]=1[CH2:6][CH2:7][NH:8]2)([O-])=O.[N+](C1C(CC)=C2C(CCN2)=CC=1)([O-])=O>>[NH2:1][C:4]1[CH:12]=[CH:11][C:10]([CH2:13][CH3:14])=[C:9]2[C:5]=1[CH:6]=[CH:7][NH:8]2
Reactant: CCc1ccc([N+](=O)[O-])c2c1NCC2
Agent: CCc1c([N+](=O)[O-])ccc2c1NCC2
Product: CCc1ccc(N)c2cc[nH]c12

Procedure:
4-nitro 7-ethylindoline was reduced in the same manner than 6-nitro 7-ethylindoline. 6 g of indole recrystallized from a ethylacetate/isopropylic ether (1/3) mixture were obtained.
Reaction SMILES: Cl.O1CCOCC1.[N:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH2:14][N:15]1[C:23]2[C:18](=[CH:19][C:20]([NH2:24])=[CH:21][CH:22]=2)[CH:17]=[N:16]1.Cl[C:26]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][C:34]=2[F:36])[N:29]=[CH:28][N:27]=1>C(#N)C>[F:36][C:34]1[CH:33]=[CH:32][CH:31]=[C:30]2[C:35]=1[C:26]([NH:24][C:20]1[CH:19]=[C:18]3[C:23](=[CH:22][CH:21]=1)[N:15]([CH2:14][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][N:8]=1)[N:16]=[CH:17]3)=[N:27][CH:28]=[N:29]2
Reactant: Fc1cccc2ncnc(Cl)c12
Reactant: Nc1ccc2c(cnn2Cc2ccccn2)c1
Agent: Cl
Solvent: CC#N
Solvent: C1COCCO1
Product: Fc1cccc2ncnc(Nc3ccc4c(cnn4Cc4ccccn4)c3)c12
Temperature: 75 °C
Reaction time: 1.5 h
Yield: 71.7 %

Procedure:
4N Hydrogen chloride in dioxane (9.6 ml, 38.4 mmol) was added to a mixture of 1-(pyridin-2-ylmethyl)-1H-indazol-5-amine (8.78 g, 39.2 mmol) and 4-chloro-5-fluoroquinazoline (7 g, 38.4 mmol; prepared as described in WO 2001/094341) in acetonitrile (100 ml). The mixture was stirred at 75° C. for 1.5 hours. After cooling, the mixture was evaporated to dryness. The residue was diluted in 6N methanolic ammonia. The mixture was evaporated to dryness and was diluted in DCM. After filtration of the solids, the filtrate was evaporated to dryness. The residue was purified by chromatography on silica gel (eluant: methanol in DCM) to give 5-fluoro-N-[1-(pyridin-2-ylmethyl)-1H-indazol-5-yl]quinazolin-4-amine as a beige solid (10.2 g, 72%); NMR spectrum (CDCl3) 5.76 (s, 2H), 6.89 (d, 1H), 7.22-7.18 (m, 2H), 7.58-7.45 (m, 3H), 7.72 (m, 2H), 8.11 (s, 1H), 8.21 (s, 1H), 8.47 (m, 1H), 8.60 (d, 1H), 8.68 (s, 1H); Mass spectrum MH+ 371.
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]2[CH:7]=[C:8]([CH2:11][CH2:12][CH2:13][CH2:14][OH:15])[CH:9]=[CH:10][C:4]=2[C:3]=1[C:16]1[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=1.[CH3:26][S:27](Cl)(=[O:29])=[O:28]>>[CH3:1][C:2]1[S:6][C:5]2[CH:7]=[C:8]([CH2:11][CH2:12][CH2:13][CH2:14][O:15][S:27]([CH3:26])(=[O:29])=[O:28])[CH:9]=[CH:10][C:4]=2[C:3]=1[C:16]1[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:23])[F:24])=[CH:18][CH:17]=1
Reactant: CS(=O)(=O)Cl
Reactant: Cc1sc2cc(CCCCO)ccc2c1-c1ccc(C(F)(F)F)cc1
Product: Cc1sc2cc(CCCCOS(C)(=O)=O)ccc2c1-c1ccc(C(F)(F)F)cc1

Procedure:
In analogy to example 21.1, the 4-[2-Methyl-3-(4-trifluoromethyl-phenyl)-benzo[b]thiophen-6-yl]-butan-1-ol was treated with methanesulfonic acid chloride to yield the Methanesulfonic acid 4-[2-methyl-3-(4-trifluoromethyl-phenyl)-benzo[b]thiophen-6-yl]-butyl ester as yellowish oil, MS: 442 (M+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[CH:5][CH:4]=1.C(N(CC)CC)C.[N+:17]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[S:26](Cl)(=[O:28])=[O:27])([O-:19])=[O:18].S(Cl)(Cl)(=O)=O>ClCCl>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][S:26]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[N+:17]([O-:19])=[O:18])(=[O:27])=[O:28])=[CH:5][CH:4]=1
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Reactant: COc1ccc(N)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O=S(=O)(Cl)Cl
Product: COc1ccc(NS(=O)(=O)c2ccccc2[N+](=O)[O-])cc1

Procedure:
A 250 mL round bottom flask was equipped with a magnetic stirrer, charged with p-anisidine (13.0 mmol), followed by dichloromethane (75 mL). The flask was then placed in an ice bath to chill the contents. Triethylamine was added and an addition funnel was installed. The addition funnel was charged with 2-nitrobenzenesulfonyl chloride (32.4 mmol) in dichloromethane (75 mL). The sulfonyl chloride was added dropwise very slowly and the reaction monitored by TLC (dichloromethane/silica) several times during the addition. The reaction was complete after addition of 50 mL (21.6 mmol) of the sulfonyl chloride solution. The reaction solvent was removed at 0° C. and immediately loaded onto a 600 mL sintered glass funnel charged with silica gel (400 g), eluted with dichloromethane collecting 100 mL fractions. Fractions containing the desired product were combined and evaporated under diminished pressure to yield the title compound as a yellow powder in excellent yield. 3.67 g, (92%). 1H-NMR (CDCl3): δ 3.20 (s, 3H); 6.78-6.79 (d, 2H, J=8.9 Hz); 7.07-7.10 (d, 3H, J=8.9 Hz); 7.53-7.58 (t, 1H, J=7.7 Hz); 7.66-7.71 (t, 1H, J=7.8 Hz); 7.73-7.76 (d, 1H, J=7.8 Hz); 7.84-7.87 (d, 1H, J=7.9 Hz).
Reaction SMILES: NC1N(C(OC(C)(C)C)=O)N=C(C2C=CC(O)=CC=2)C=1C#N.C([O:30][C:31]1[CH:45]=[CH:44][C:34]([O:35][CH2:36][CH2:37][N:38]2[CH2:43][CH2:42][O:41][CH2:40][CH2:39]2)=[CH:33][CH:32]=1)C1C=CC=CC=1>>[O:41]1[CH2:40][CH2:39][N:38]([CH2:37][CH2:36][O:35][C:34]2[CH:44]=[CH:45][C:31]([OH:30])=[CH:32][CH:33]=2)[CH2:43][CH2:42]1
Reactant: c1ccc(COc2ccc(OCCN3CCOCC3)cc2)cc1
Agent: CC(C)(C)OC(=O)n1nc(-c2ccc(O)cc2)c(C#N)c1N
Product: Oc1ccc(OCCN2CCOCC2)cc1

Procedure:
Compound 88B was prepared in a similar manner to the synthesis of compound 31F by substituting compound 31E with compound 88A: 1H NMR (DMSO-d6): δ 8.84 (s, 1H), 6.72-6.75 (m, 2H), 6.64-6.67 (m, 2H), 3.96 (d, J=5.83 Hz, 2H), 3.55-3.58 (m 4H), 2.63 (d, J=5.83 Hz, 2H), 2.42-2.46 (m, 4H). ESI (+)/MS: 224 (M+H)+.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[O:11][CH:10]2C([O-])=O)=[CH:5][C:4]=1[CH3:15])#[N:2].CC[O-].[Na+].O>C(O)C>[CH3:15][C:4]1[CH:5]=[C:6]([CH2:9][CH:10]=[O:11])[CH:7]=[CH:8][C:3]=1[C:1]#[N:2]
Reactant: Cc1cc(C2OC2C(=O)[O-])ccc1C#N
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Cc1cc(CC=O)ccc1C#N
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
A solution of 3-(4-cyano-3-methylphenyl)oxirane-2-carboxylate (927 mg, 4.0 mmol) in 5 mL of dry ethanol was cooled to 0° C. Freshly prepared EtONa (5 mmol) in 4 mL of ethanol was added and stirred at 0° C. for 10 min. Then dropwise addition of 0.1 g of water, stirred at 0° C. for 2 hours, and the sodium salt of the epoxy compound was filtered. The sodium salt of the epoxy compound was then dissolved in 5 mL of water and added 5 mL of 1 N of HCl and 20 mL of toluene. The mixture was heated to reflux for 2 hours. The organic phase was separated, washed by saturated sodium chloride, dried over Na2SO4 and distilled off solvent to afford crude 2-methyl-4-(2-oxoethyl)benzonitrile. MS m/z: 160 (M+1)+.