Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: B(Br)(Br)Br.C[O:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[CH:12]([C:16]1[CH:29]=[CH:28][C:19]([O:20][CH2:21][CH2:22][N:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)=[CH:18][CH:17]=1)[CH:11]([C:30]1[CH:35]=[CH:34][C:33]([O:36]C)=[CH:32][CH:31]=1)[CH2:10]2>ClCCl>[OH:36][C:33]1[CH:32]=[CH:31][C:30]([CH:11]2[CH2:10][C:9]3[C:13](=[CH:14][CH:15]=[C:7]([OH:6])[CH:8]=3)[CH:12]2[C:16]2[CH:29]=[CH:28][C:19]([O:20][CH2:21][CH2:22][N:23]3[CH2:24][CH2:25][CH2:26][CH2:27]3)=[CH:18][CH:17]=2)=[CH:35][CH:34]=1
Reactant: COc1ccc(C2Cc3cc(OC)ccc3C2c2ccc(OCCN3CCCC3)cc2)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Oc1ccc(C2Cc3cc(O)ccc3C2c2ccc(OCCN3CCCC3)cc2)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 60.2 %

Procedure:
Boron tribromide (0.16 mL, 1M in CH2Cl2, 0.16 mmol) was added dropwise to a solution of 1-(2-(4-(5-methoxy-2-(4-methoxyphenyl)-2,3-dihydro-1H-inden-1-yl)phenoxy)ethyl)pyrrolidine (18 mg, 0.04 mmol) and dichloromethane (2.5 mL) at 0° C. under N2. After 20 min, the reaction was allowed to warm to rt. After an additional hour, the reaction was quenched with methanol (0.4 mL), poured into saturated aqueous NaHCO3 (40 mL), and extracted with 5% methanol in dichloromethane (50 mL×2). The organic extracts were dried (MgSO4), filtered, concentrated, and purified by reverse-phase HPLC (CH3CN, H2O, TFA) to give 10 mg of 2-(4-hydroxyphenyl)-1-(4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)-2,3-dihydro-1H-inden-5-ol as the trifluoroacetate salt. 1H NMR (400 MHz, DMSO-d6): δ 9.61 (br, 1H), 9.22 (br, 1H), 8.99 (br, 1H), 6.81-6.75 (m, 2H), 6.72-6.62 (m, 4H), 6.60-6.52 (m, 3H), 6.44 (d, 2H), 4.45 (d, 1H), 4.15 (t, 2H), 3.91-3.79 (m, 1H), 3.62-3.48 (m, 4H), 3.23-2.98 (m, 4H), 2.08-1.80 (m, 4H); LCMS: 416.6 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]([N+:12]([O-:14])=[O:13])=[CH:9][C:10]=1[F:11])[C:5](O)=[O:6].CO>C1COCC1>[F:11][C:10]1[C:2]([F:1])=[CH:3][C:4]([CH2:5][OH:6])=[C:8]([N+:12]([O-:14])=[O:13])[CH:9]=1
Reactant: O=C(O)c1cc(F)c(F)cc1[N+](=O)[O-]
Solvent: CO
Solvent: C1CCOC1
Product: O=[N+]([O-])c1cc(F)c(F)cc1CO
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 3,4-difluoro-6-nitrobenzoic acid (3.05 g, 15 mmol) in THF (20 mL) was added BH3 THF (30 mL). The resulting mixture was stirred at room temperature for 2 h and then at 50° C. for 5 h. The resulting mixture was then cooled to room temperature, and methanol (20 mL) was added slowly. The resulting mixture was concentrated, and the residue was treated with methanol twice more, to yield a yellow solid.
Reaction SMILES: [C:1]1([CH2:11][C:12]#[N:13])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[H-].[Na+].Br[CH2:17][CH2:18][CH2:19][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22]>CN(C=O)C.O>[C:12]([CH:11]([C:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1)[CH2:17][CH2:18][CH2:19][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])#[N:13]
Reactant: N#CCc1cccc2ccccc12
Reactant: CCOC(=O)CCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CCCCC(C#N)c1cccc2ccccc12
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 77.5 %

Procedure:
In 125 ml of DMF was dissolved 12.54 g (75 mmol) of 1-naphthaleneacetonitrile. Then, 3.30 g (82.5 mmol) of 60% sodium hydride was added at room temperature and the mixture was heated to 60° C. and stirred for 30 minutes. After cooling to room temperature, 13.17 ml (82.5 mmol) of ethyl 5-bromovalerate was added. The reaction was further conducted at 60° C. for 30 minutes, after which the reaction mixture was cooled to <10° C. and diluted with 500 ml of pure water. The diluted mixture was extracted with 200 ml of ethyl acetate twice and the organic layer was washed with saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate. The solvent was then distilled off and the residue was purified by silica gel column chromatography (hexane-CH2Cl2 -ethyl acetate=4:2:1) to provide 17.16 g (yield 77.5%) of the title compound as light-yellow oil.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][C:5](Cl)=O.[Cl:8][C:9]1[C:10]([CH3:31])=[C:11]([CH2:15][NH:16][C:17]2[N:18]=[C:19]([N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)[S:20][C:21]=2[C:22]([NH2:24])=[O:23])[CH:12]=[CH:13][CH:14]=1.[OH-].[Na+].Cl>COCCOC>[Cl:8][C:9]1[C:10]([CH3:31])=[C:11]([CH2:15][N:16]2[C:17]3[N:18]=[C:19]([N:25]4[CH2:26][CH2:27][O:28][CH2:29][CH2:30]4)[S:20][C:21]=3[C:22](=[O:23])[N:24]=[C:5]2[CH2:4][CH2:3][O:2][CH3:1])[CH:12]=[CH:13][CH:14]=1
Reactant: Cc1c(Cl)cccc1CNc1nc(N2CCOCC2)sc1C(N)=O
Reactant: COCCC(=O)Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: COCCOC
Product: COCCc1nc(=O)c2sc(N3CCOCC3)nc2n1Cc1cccc(Cl)c1C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3-methoxypropionyl chloride (66.8 mg, 0.545 mmol) in 1,2-Dimethoxyethane (DME) (400 μl) was added to a solution of 4-{[(3-chloro-2-methylphenyl)methyl]amino}-2-(4-morpholinyl)-1,3-thiazole-5-carboxamide (100 mg, 0.273 mmol) in 1,2-Dimethoxyethane (DME) (1000 μl). The mixture was stirred at room temperature overnight, then quenched with methanol and concentrated. To the residue was added methanol (1 mL) followed by 6N NaOH (1 equiv.). The mixture was stirred at room temperature for 3 h, neutralized (pH ˜8) with 6N HCl, and concentrated. The residue was partitioned between dichloromethane and water. The organic layer was dried (sodium sulfate), filtered, and concentrated. The crude product was purified by reversed-phase HPLC and the fractions were neutralized with sat. aq. sodium bicarbonate. The combined fractions were concentrated to remove acetonitrile and the remaining water was extracted with dichloromethane. The organic layer was dried (sodium sulfate), filtered, and concentrated to provide 4-[(3-chloro-2-methylphenyl)methyl]-5-[2-(methyloxy)ethyl]-2-(4-morpholinyl)[1,3]thiazolo[4,5-d]pyrimidin-7(4H)-one. (14 mg, 12%); LC/MS: MS (ES+) m/e 435 (MH+); 1H NMR (400 MHz, DMSO-d6) δ ppm 2.44 (s, 3H), 2.80 (t, J=6.7 Hz, 2H), 3.19 (s, 3H), 3.52 (m, 4H), 3.62-3.72 (m, 6H), 5.57 (s, 2H), 6.51 (d, J=7.6 Hz, 1H), 7.16 (m, 1H), 7.39 (d, J=7.8 Hz, 1H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[CH2:17][CH:18]([OH:27])[CH2:19][CH2:20][C:21]1[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=1.[OH-].[Na+]>C(O)C.O>[C:2]1([CH2:1][O:8][C:9]2[CH:10]=[CH:11][C:12]([O:15][CH2:17][CH:18]([OH:27])[CH2:19][CH2:20][C:21]3[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=3)=[CH:13][CH:14]=2)[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Oc1ccc(OCc2ccccc2)cc1
Reactant: OC(CCl)CCc1cccnc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: OC(CCc1cccnc1)COc1ccc(OCc2ccccc2)cc1
Yield: 61.6 %

Procedure:
Prepared according to the method described in Example 24b) from 4-(benzyloxy)phenol (1.00 g), (±)-α-(chloromethyl)-3-pyridinepropanol (0.50 g) and sodium hydroxide (0.23 g) in ethanol (20 ml) and water (5 ml) with heating at reflux for 45 minutes. After work up the residue was purified by column chromatography over silica eluting with dichloromethane:ethanol (19:1) and then using a fresh column of silica eluting with ethyl acetate to give the title compound as a solid (0.58 g). Recrystallisation from ethyl acetate:hexane gave colourless crystals.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[O:9][C:8]([CH3:12])([CH3:11])[C:7](=[S:13])[C:6]=2[CH:5]=[CH:4][CH:3]=1.[Cl:14]N1C(=O)CCC1=O>CN(C)C=O>[NH2:1][C:2]1[C:10]2[O:9][C:8]([CH3:11])([CH3:12])[C:7](=[S:13])[C:6]=2[C:5]([Cl:14])=[CH:4][CH:3]=1
Reactant: CC1(C)Oc2c(N)cccc2C1=S
Reactant: O=C1CCC(=O)N1Cl
Solvent: CN(C)C=O
Product: CC1(C)Oc2c(N)ccc(Cl)c2C1=S

Procedure:
By the method of Example 3, Step C, 2.51 g (0.013 mole) of 7-amino-2,3-dihydro-2,2-dimethylbenzofuran-3-thione is reacted with 1.74 g (0.013 mole) of N-chlorosuccinimide in 35 mL of N,N-dimethylformamide, yielding 7-amino-4-chloro-2,3-dihydro-2,2-dimethylbenzofuran-3-thione.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7][C:8](Cl)=[N:9]2)([O-])=O.[CH2:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH2:17][CH:16]1[NH2:24]>>[CH2:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH2:17][CH:16]1[NH:24][C:8]1[CH:7]=[CH:6][C:5]2[C:4]([NH2:1])=[CH:13][CH:12]=[CH:11][C:10]=2[N:9]=1
Reactant: O=[N+]([O-])c1cccc2nc(Cl)ccc12
Reactant: NC1Cc2ccccc2C1
Product: Nc1cccc2nc(NC3Cc4ccccc4C3)ccc12

Procedure:
The title compound, MS: m/e=276.0 (M+H+), was prepared in accordance with the general method of example 16 from 5-nitro-2-chloroquinoline and indane-2-ylamine.
Reaction SMILES: [C:1]1([S:7]([NH:10][C:11]2[CH:12]=[C:13]([C:17]3[CH:18]=[CH:19][C:20]4[N:21]=[CH:22][N:23]=[C:24]([O:27][CH:28]5[CH2:33][CH2:32][N:31](C(OC(C)(C)C)=O)[CH2:30][CH2:29]5)[C:25]=4[N:26]=3)[CH:14]=[N:15][CH:16]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH:31]1[CH2:32][CH2:33][CH:28]([O:27][C:24]2[C:25]3[N:26]=[C:17]([C:13]4[CH:12]=[C:11]([NH:10][S:7]([C:1]5[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=5)(=[O:8])=[O:9])[CH:16]=[N:15][CH:14]=4)[CH:18]=[CH:19][C:20]=3[N:21]=[CH:22][N:23]=2)[CH2:29][CH2:30]1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ncnc3ccc(-c4cncc(NS(=O)(=O)c5ccccc5)c4)nc23)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=S(=O)(Nc1cncc(-c2ccc3ncnc(OC4CCNCC4)c3n2)c1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 99.6 %

Procedure:
To a solution of tert-butyl 4-(6-(5-(phenylsulfonamido)-pyridine-3-yl)pyrido[3,2-d]pyrimidin-4-yloxy)piperidine-1-carboxylate (0.15 g, 0.267 mmol) in DCM (1.333 ml) was added TFA (0.205 ml, 2.67 mmol) at room temperature. After stirring for 30 min at room temperature, the reaction mixture was evaporated in vacuo, to give N-(5-(4-(piperidin-4-yloxy)pyrido[3,2-d]pyrimidin-6-yl)pyridin-3-yl)benzenesulfonamide (0.123 g, 100%) as a yellow oil, which was used in the next step without further purification. 1H-NMR (CDCl3, Varian 400 MHz) δ 1.87-1.92 (2H, m), 2.15-2.22 (2H, m), 2.79-2.85 (2H, m), 3.20-3.24 (2H, m), 5.58-5.62 (1H, m), 7.39-7.42 (3H, m), 7.92-7.94 (2H, m), 8.18-8.20 (2H, m), 8.28 (1H, s), 8.59 (1H, d, J=1.6 Hz), 8.74 (1H, s).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[CH:5](Cl)[C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([F:14])[CH:9]=1)=O)[CH3:2].[C:17]([NH2:20])(=[S:19])[CH3:18]>>[CH2:1]([O:3][C:4]([C:5]1[S:19][C:17]([CH3:18])=[N:20][C:6]=1[C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([F:14])[CH:9]=1)=[O:16])[CH3:2]
Reactant: CC(N)=S
Reactant: CCOC(=O)C(Cl)C(=O)c1cccc(F)c1
Product: CCOC(=O)c1sc(C)nc1-c1cccc(F)c1

Procedure:
prepared by reaction of 2-chloro-3-(3-fluoro-phenyl)-3-oxo-propionic acid ethyl ester with thioacetamide. LC-MS: tR=0.95 min; [M+H]+=266.1.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.[OH-].[Na+].C([O:16][CH2:17][CH2:18][CH2:19][CH2:20]Br)(=O)C.Cl>O>[OH:16][CH2:17][CH2:18][CH2:19][CH2:20][O:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccc(O)cc1
Reactant: CC(=O)OCCCCBr
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)c1ccc(OCCCCO)cc1
Temperature: 10 °C
Reaction time: 1 h

Procedure:
In a 22 liter stirred reactor, 1.16 kilograms of p-hydroxy-benzoic acid (M.W. 138) in 4 liters of water are neutralized by the addition of 0.5 liter of 40% aqueous sodium hydroxide. The temperature is adjusted to 50° C. and over a period of one hour, 1200 milliliters of 4-bromobutyl acetate are slowly added. The temperature is then raised to 90° C.+10° C. and the hot reaction mixture kept at pH 10 by continuous titration with a 40% sodium hydroxide solution. When no change in pH is noted for a period of 45 minutes the reaction is considered complete, an additional liter of water is then added, and sufficient 40% sodium hydroxide solution to raise the pH to 11. While still hot, concentrated hydrochloric acid is added in large enough quantities to lower the pH to 1.2. The mixture is allowed to cool overnight while stirring and the precipitate collected on a filter. The precipitate is then thoroughly washed with water to remove excess acid until the wash has attained a pH of at least 5. The precipitate is then dried and dissolved in hot methanol (15% solution), and the solution filtered to remove any insolubles (usually about 6-7%). While the clear methanol solution is still hot, hot water is added to adjust the solvent ratio to 10:1 methanol/water, and set aside to let the product crystallize out overnight yielding p-(4-hydroxy-n-butoxy)benzoic acid having a melting point of 146°-148° C.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:18](O)=[O:19])[C:5]2[O:9][C:8]([C:10]3[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=3)=[CH:7][C:6]=2[CH:17]=1>C1COCC1>[OH:19][CH2:18][C:4]1[C:5]2[O:9][C:8]([C:10]3[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=3)=[CH:7][C:6]=2[CH:17]=[C:2]([OH:1])[CH:3]=1
Reactant: O=C(O)c1cc(O)cc2cc(-c3ccc(O)cc3)oc12
Solvent: C1CCOC1
Product: OCc1cc(O)cc2cc(-c3ccc(O)cc3)oc12
Temperature: 65 °C
Reaction time: 6 h
Yield: 38.3 %

Procedure:
Acid 24 (0.030 g, 0.112 mmole) in 5 mL THF was added a solution of Borane-THF complex (2.0 mL, 2.0 mmole) in THF. After stirring at 65° C. for 6 hours, the THF was evaporated and the residue was poured into 2N HCl and extracted with ethyl acetate. The combined organic phases were washed with saturated sodium bicarbonate, water, brine, and dried with magnesium sulfate. The organic phases were concentrated and the residue was separated by HPLC (70:30, H2O/AcCN) to afford 0.011 g (36%) of benzyl alcohol 25 as a white solid: Mp=258-260° C.; 1H NMR (DMSO-d6) δ 9.81 (s, 1 H), 9.45 (s, 1 H), 7.70 (d, 2 H, J=8.9 Hz), 7.00 (s, 1 H), 6.86 (d, 2 H, J=8.7 Hz), 6.76 (s, 2H), 5.27 (m, 1 H), 4.75 (d, 2 H, J=5.6 Hz); MS 255 (M−H)−
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:13]=[C:12]2[C:8]([CH:9]=[CH:10][NH:11]2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].CC(C)([O-])C.[K+].[NH2:20]Cl>CN(C=O)C.CCOCC>[CH3:1][S:2]([C:5]1[CH:13]=[C:12]2[C:8]([CH:9]=[CH:10][N:11]2[NH2:20])=[CH:7][CH:6]=1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)c1ccc2cc[nH]c2c1
Reactant: NCl
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1ccc2ccn(N)c2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 51 %

Procedure:
A solution of 6-methanesulfonyl-1H-indole (2.66 mmol) and potassium tert-butoxide (5.32 mmol) in DMF (15 mL) is stirred at rt under N2 for 2 h. 0.15 M NH2Cl in ether (26.6 mL) is added drop-wise for 15 minutes at rt and the reaction mixture is stirred at rt for 2 h. The reaction mixture is quenched with 10% Na2S2O3 aqueous solution, and extracted with ether (3×20 mL). The combined organic layer is washed with brine (20 mL), dried (Na2SO4), filtered and concentrated in vacuo. The residue is triturated with EtOAc to give 6-methanesulfonyl-indole-1-ylamine (270 mg, 51%) as a solid. MS: 211 (M+H); 1H NMR (300 MHz, CDCl3): δ 3.09 (s, 3H), 6.49 (d, H), 7.41 (m, H), 7.61 (d, H), 7.71 (d, H), 8.12 (s, H).
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:9]([C:10]#[N:11])=[C:8](F)[C:7]([CH2:13][OH:14])=[CH:6][CH:5]=1)[CH3:2].[SH:15][CH2:16][C:17]([NH2:19])=[O:18].[O-]CC.[Na+]>CN(C=O)C.[OH-].[Na+]>[NH2:11][C:10]1[C:9]2[C:4]([O:3][CH2:1][CH3:2])=[CH:5][CH:6]=[C:7]([CH2:13][OH:14])[C:8]=2[S:15][C:16]=1[C:17]([NH2:19])=[O:18]
Reactant: NC(=O)CS
Reactant: CCOc1ccc(CO)c(F)c1C#N
Agent: CC[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: CCOc1ccc(CO)c2sc(C(N)=O)c(N)c12
Temperature: 80 °C
Reaction time: 8 h
Yield: 66.8 %

Procedure:
To a stirred solution of the above benzonitrile intermediate (500 mg, 2.56 mmol) in dry DMF (3 mL) was added 2-mercaptoacetamide (1.1 M in MeOH, 3.50 mL, 3.85 mmol) and sodium ethoxide (2.68 M in EtOH, 1.05 mL, 2.81 mmol). The reaction was stirred at 80° C. overnight, and then it was cooled to room temperature and diluted with 2 M sodium hydroxide solution (30 mL). The precipitate formed was collected by filtration, and dried in vacuo to give the title compound (0.455 g, 1.71 mmol, 88.9%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:12]3([CH2:17][CH2:16][CH2:15][N:14]([C:18](=[O:45])[C@H:19]([NH:30][C:31](=[O:44])[C:32]([N:35](C)[C:36](=O)OC(C)(C)C)([CH3:34])[CH3:33])[CH2:20][O:21][CH2:22][C:23]4[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=4)[CH2:13]3)[C:11](=[O:46])[N:10]([CH3:47])[CH2:9]2)=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:12]3([CH2:17][CH2:16][CH2:15][N:14]([C:18](=[O:45])[C@H:19]([NH:30][C:31](=[O:44])[C:32]([CH3:33])([NH:35][CH3:36])[CH3:34])[CH2:20][O:21][CH2:22][C:23]4[CH:24]=[CH:25][C:26]([CH3:29])=[CH:27][CH:28]=4)[CH2:13]3)[C:11](=[O:46])[N:10]([CH3:47])[CH2:9]2)=[CH:4][CH:3]=1
Reactant: Cc1ccc(COC[C@@H](NC(=O)C(C)(C)N(C)C(=O)OC(C)(C)C)C(=O)N2CCCC3(C2)C(=O)N(C)CC3c2ccc(F)cc2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CNC(C)(C)C(=O)N[C@H](COCc1ccc(C)cc1)C(=O)N1CCCC2(C1)C(=O)N(C)CC2c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To tert-butyl 1-((2R)-1-(4-(4-fluorophenyl)-2-methyl-1-oxo-2,7-diazaspiro[4.5]decan-7-yl)-3-(4-methylbenzyloxy)-1-oxopropan-2-ylamino)-2-methyl-1-oxopropan-2-yl(methyl)carbamate (128 mg, 0.196 mmol) in DCM (2 ml) was added TFA (0.6 ml, 7.79 mmol). The mixture was stirred at RT for 30 mins then concentrated in vacuo. The residue was suspended in sat. sodium bicarbonate soln. (10 ml) and extracted with EtOAc (2×50 ml). The extracts were dried and concentrated. The residue was applied to a 20 g silica cartridge in DCM and this was eluted with 5% MeOH/DCM [diluted from 10% MeOH/DCM containing 1% aqueous 880 ammonia]. The relevant fractions were combined and concentrated to give a foam. This was dried at 40° C. overnight under vacuum to give the title compound as a glass.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=1)[C:6]([C:19](O)=[O:20])=[CH:5]2.[CH3:22][O:23][C:24]1[C:29]([NH2:30])=[CH:28][N:27]=[C:26]([N:31]2[CH2:35][CH2:34][CH2:33][CH2:32]2)[CH:25]=1>>[CH3:22][O:23][C:24]1[CH:25]=[C:26]([N:31]2[CH2:32][CH2:33][CH2:34][CH2:35]2)[N:27]=[CH:28][C:29]=1[NH:30][C:19]([C:6]1[N:7]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=2)[C:8]2[C:4]([CH:5]=1)=[CH:3][C:2]([F:1])=[CH:10][CH:9]=2)=[O:20]
Reactant: COc1cc(N2CCCC2)ncc1N
Reactant: O=C(O)c1cc2cc(F)ccc2n1Cc1cccc(F)c1
Product: COc1cc(N2CCCC2)ncc1NC(=O)c1cc2cc(F)ccc2n1Cc1cccc(F)c1
Yield: 73.3 %

Procedure:
The process is carried out according to the method described in example 2, using 0.5 g (1.74 mmol) of 5-fluoro-1-(3-fluorobenzyl)-1H-indole-2-carboxylic acid (example 1.1) and 0.424 g (2.09 mmol) of 4-methoxy-2-(pyrrolidin-1-yl)-5-aminopyridine, obtained in step 6.1 (Compound Vb). 0.59 g of the expected product is thus isolated.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([O:9][CH2:10][CH2:11][CH2:12][O:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][C:21]([F:24])([F:23])[F:22])=[CH:16][CH:15]=2)=[C:4]([CH2:25][CH3:26])[CH:3]=1.C([Li])CCC.COB([O:37][CH3:38])OC.Cl>O1CCCC1>[CH2:7]([C:6]1[CH:8]=[C:38]([OH:37])[CH:3]=[C:4]([CH2:25][CH3:26])[C:5]=1[O:9][CH2:10][CH2:11][CH2:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][C:21]([F:22])([F:23])[F:24])=[CH:16][CH:15]=1)[CH3:2]
Reactant: COB(OC)OC
Reactant: CCc1cc(Br)cc(C)c1OCCCOc1ccc(OC(F)(F)F)cc1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCc1cc(O)cc(CC)c1OCCCOc1ccc(OC(F)(F)F)cc1
Temperature: -70 °C
Reaction time: 2 h
Yield: 69.2 %

Procedure:
Then, 7.0 g of 4-bromo-2-ethyl-6-methyl-1-[3-(4-trifluoromethoxyphenoxy)propyloxy]benzene was dissolved in 200 ml of tetrahydrofuran, followed by stirring at -70° C., to which 10.0 ml of n-butyl lithium solution (in hexane, 1.58 mol/liter) was added dropwise, followed by further stirring at -70° C. for 2 hours. To this reaction mixture was added dropwise a solution of 2.4 g of trimethoxy borane dissolved in 60 ml of tetrahydrofuran. The reaction mixture was stirred for 1 hour, while warming to room temperature, and 13 ml of 10% aqueous hydrochloric acid solution was added in small portions, followed by stirring at room temperature for 20 minutes. The tetrahydrofuran layer was washed with water, dried with anhydrous magnesium sulfate, and concentrated, to which 50 ml of toluene was added, and the mixture was heated at 70° C. under stirring, to which 6 ml of 30% aqueous hydrogen peroxide solution was added dropwise. The mixture was heated under reflux for 1 hours, and washed once with water, and twice with 10% aqueous ammonium ferrous sulfate solution and once with water. The toluene layer was dried with anhydrous magnesium sulfate, and concentrated to obtain a crude product. The crude product was subjected to silica gel chromatography, which afforded 4.3 g of 3,5-diethyl-4-[3-(4-trifluoromethoxyphenoxy)propyloxy]phenol (50% yield), nD25.4 1.5060.
Reaction SMILES: ClC(Cl)(Cl)[C:3]([C:5]1[N:14]2[C:8]([CH2:9][N:10]([C:19]([C:21]3[CH:26]=[CH:25][C:24]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[CH3:33])=[C:23]([O:34][CH3:35])[CH:22]=3)=[O:20])[C:11]3[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=3[CH2:13]2)=[CH:7][CH:6]=1)=[O:4].Cl.[CH2:39]1[C:47]2[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=2)[CH2:41][CH:40]1[NH2:48].C(N(CC)CC)C>>[CH2:39]1[C:47]2[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=2)[CH2:41][CH:40]1[NH:48][C:3]([C:5]1[N:14]2[C:8]([CH2:9][N:10]([C:19]([C:21]3[CH:26]=[CH:25][C:24]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[CH3:33])=[C:23]([O:34][CH3:35])[CH:22]=3)=[O:20])[C:11]3[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=3[CH2:13]2)=[CH:7][CH:6]=1)=[O:4]
Reactant: COc1cc(C(=O)N2Cc3ccc(C(=O)C(Cl)(Cl)Cl)n3Cc3ccccc32)ccc1-c1ccccc1C
Reactant: NC1Cc2ccccc2C1
Agent: Cl
Solvent: CCN(CC)CC
Product: COc1cc(C(=O)N2Cc3ccc(C(=O)NC4Cc5ccccc5C4)n3Cc3ccccc32)ccc1-c1ccccc1C

Procedure:
The title compound was prepared in the manner of Example 36 from 2,2,2-trichloro-1-{10-[(2-methoxy-2′-methyl-1,1′-biphenyl-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}ethanone of Example 35 and indan-2-ylamine hydrochloride in the presence of one equivalent of triethylamine. Purification was performed using HPLC with a normal phase column. Elution with a two phase solvent system (A=hexane, B=dichloromethane/methanol, 4:1) gave the title compound in 45% yield, m.p. 230-231° C. MS [(+)ESI, m/z]: 568 [M+H]+
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:13][O:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=2)[C:8]([O:10]CC)=[O:9])[N:6]=1.[OH-].[Na+].CN1C=CN=C1.CO>O1CCCC1>[NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:13][O:14][CH2:15][C:16]2[CH:17]=[CH:18][C:19]([CH3:22])=[CH:20][CH:21]=2)[C:8]([OH:10])=[O:9])[N:6]=1
Reactant: CCOC(=O)C(=NOCc1ccc(C)cc1)c1csc(N)n1
Agent: Cn1ccnc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1ccc(CON=C(C(=O)O)c2csc(N)n2)cc1
Yield: 93.7 %

Procedure:
Ethyl 2-(2-aminothiazol-4-yl)-2-(4-methylbenzyloxyimino)acetate (syn isomer, 4.00 g.), 1 N sodium hydroxide solution (19.5 ml.), 1-methylimidazole (214 mg.), methanol (40 ml.) and tetrahydrofuran (25 ml.) were treated in a similar manner that of Example P-(4) to give 2-(2-aminothiazol-4-yl)-2-(4-methylbenzyloxyimino)acetic acid (syn isomer, 3.42 g.).
Reaction SMILES: [C:1]([N:4]1[CH2:10][CH2:9][CH2:8][C:7]2[CH:11]=[CH:12][S:13][C:6]=2[CH2:5]1)(=[O:3])[CH3:2].[Cl:14][CH2:15][CH2:16][CH2:17][C:18](Cl)=[O:19].[Cl-].[Al+3].[Cl-].[Cl-].O>ClCCl>[C:1]([N:4]1[CH2:10][CH2:9][CH2:8][C:7]2[CH:11]=[C:12]([C:18](=[O:19])[CH2:17][CH2:16][CH2:15][Cl:14])[S:13][C:6]=2[CH2:5]1)(=[O:3])[CH3:2]
Reactant: O=C(Cl)CCCCl
Reactant: CC(=O)N1CCCc2ccsc2C1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: O
Product: CC(=O)N1CCCc2cc(C(=O)CCCCl)sc2C1
Reaction time: 0.5 h
Yield: 75.6 %

Procedure:
To a solution of 2.5 g of 7-acetyl-5,6,7,8-tetrahydro-4H-thieno-[2,3-c]azepine and 2.7 g of 4-chlorobutyryl chloride in 25 ml of dichloromethane was added 6.0 g of aluminum chloride under ice-cooling. The mixture was stirred for 30 minutes, poured into water and extracted with chloroform. The extract was washed with water, dried over magnesium sulfate and concentrated. The residue was purified by column chromatography on a silica gel to give 2.9 g of 7-acetyl-2-(4-chlorobutyryl)-5,6,7,8-tetrahydro-4H-thieno[2,3-c]azepine as an oil.