Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[CH:6]=[C:5]2[C:7]([CH2:10][C@@H:11]([NH:15][C:16]([CH2:18][CH2:19][C@@H:20]([NH2:24])[C:21](O)=[O:22])=[O:17])[C:12]([OH:14])=[O:13])=[CH:8][NH:9][C:4]2=[CH:3][CH:2]=1.[NH2:25][C@@H](C(N[C@@H](C(O)=O)CC1C2C(=CC=CC=2)NC=1)=O)CCC(=O)O>>[NH2:24][C@@H:20]([C:21](=[O:22])[NH2:25])[CH2:19][CH2:18][C:16]([NH:15][C@@H:11]([C:12]([OH:14])=[O:13])[CH2:10][C:7]1[C:5]2[C:4](=[CH:3][CH:2]=[CH:1][CH:6]=2)[NH:9][CH:8]=1)=[O:17]
Reactant: N[C@H](CCC(=O)O)C(=O)N[C@H](Cc1c[nH]c2ccccc12)C(=O)O
Reactant: N[C@H](CCC(=O)N[C@H](Cc1c[nH]c2ccccc12)C(=O)O)C(=O)O
Product: NC(=O)[C@H](N)CCC(=O)N[C@H](Cc1c[nH]c2ccccc12)C(=O)O

Procedure:
A method for the preparation of thymodepressin was disclosed in example 1 of U.S. Pat. Nos. 5,736,519, 6,103,699 and 6,410,515, However, the manufacture of thymodepressin on a large scale cannot be conducted using the experimental details of this method since a mixture of D-glutamyl-D-tryptophan and D-isoglutamyl-D-tryptophan is produced which must be separated and purified by ion exchange chromatography resulting in a very low yield (12.25%) of thymodepressin.
Reaction SMILES: [H-].[Na+].Cl[C:4]1[C:9]([Cl:10])=[N:8][CH:7]=[CH:6][N:5]=1.[CH3:11][C:12]1([CH3:19])[O:16][CH:15]([CH2:17][OH:18])[CH2:14][O:13]1>CN(C)P(=O)(N(C)C)N(C)C>[Cl:10][C:9]1[C:4]([O:18][CH2:17][CH:15]2[CH2:14][O:13][C:12]([CH3:19])([CH3:11])[O:16]2)=[N:5][CH:6]=[CH:7][N:8]=1
Reactant: CC1(C)OCC(CO)O1
Reactant: Clc1nccnc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CC1(C)OCC(COc2nccnc2Cl)O1
Temperature: 25 °C
Reaction time: 40 h

Procedure:
9.6 g of sodium hydride are added in portions, whilst stirring, to a solution of 59.6 g of 2,3-dichloropyrazine and 52.8 g of 2,2-dimethyl-4-hydroxymethyl-1,3-dioxolane in 500 ml of hexamethylphosphoric acid triamide at 0°-5° C. (duration of the addition: 40 minutes). The reaction mixture is then stirred for 40 hours at room temperature after which it is poured onto an ice-water mixture. The aqueous phase is extracted with diethyl ether. The combined organic extracts are washed with water, dried over sodium sulphate and evaporated under a waterpump vacuum. 4-(2-Chloro-3-pyrazinyloxymethyl)-2,2-dimethyl-1,3-dioxolane is obtained as an oily residue.
Reaction SMILES: [Mg].Br[CH2:3][CH2:4][CH2:5][CH2:6]Br.[CH3:8][C:9]1[CH2:14][CH2:13][CH:12]([C:15]([OH:17])=O)[CH2:11][CH:10]=1.S(=O)(=O)(O)O>O1CCCC1>[CH3:8][C:9]1[CH2:14][CH2:13][CH:12]([C:15]2([OH:17])[CH2:6][CH2:5][CH2:4][CH2:3]2)[CH2:11][CH:10]=1
Reactant: BrCCCCBr
Reactant: CC1=CCC(C(=O)O)CC1
Agent: O=S(=O)(O)O
Agent: [Mg]
Solvent: C1CCOC1
Product: CC1=CCC(C2(O)CCCC2)CC1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a stirred suspension of 46.8 g of magnesium in 250 ml of tetrahydrofuran was added 182 g of 1,4-dibromobutane in 700 ml of dry tetrahydrofuran over 1 hour. The gently refluxing reaction mixture was maintained at reflux for 2 more hours and then cooled to room temperature. A solution of 100 g of the methyl ester of 4-methyl-3-cyclohexene-1-carboxylic acid in 20 ml of dry tetrahydrofuran was added at 20°-30° C. with cooling by an ice bath. The reaction mixture was stirred at room temperature for 2 days, and the excess Grignard reagent was decomposed by careful addition of dilute sulfuric acid. Most of the tetrahydrofuran was evaporated, and the reaction product was extracted with ether. The ether phase was washed successively with water and saturated NaCl solution, dried with MgSO4, and stripped to give 120 g of crude product as an oil. Multiple redistillation of the oil gave 32 g of product b.p. 90°-92° C. (0.5 mm).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=O)[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=O.[NH:18]([C:22]1[NH:23][C:24]2[CH:30]=[CH:29][CH:28]=[CH:27][C:25]=2[N:26]=1)[C:19]([NH2:21])=[NH:20].[OH-].[Na+]>CO.O>[N:26]1[C:25]2[CH:27]=[CH:28][CH:29]=[CH:30][C:24]=2[NH:23][C:22]=1[N:18]=[C:19]1[NH:21][C:9]2([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[NH:21][C:19](=[N:18][C:22]3[NH:26][C:25]4[CH:27]=[CH:28][CH:29]=[CH:30][C:24]=4[N:23]=3)[NH:20][C:8]2([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])[NH:20]1
Reactant: O=C(C(=O)c1ccccc1Cl)c1ccccc1
Reactant: N=C(N)Nc1nc2ccccc2[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Clc1ccccc1C12NC(=Nc3nc4ccccc4[nH]3)NC1(c1ccccc1)NC(=Nc1nc3ccccc3[nH]1)N2

Procedure:
Following the procedure of Example 1, 1-(2-chlorophenyl)-2-phenylethanedione (0.25 g, 1.0 mmol) and 2-guanidinobenzimidazole (0.215 g, 1.2 mmol) in methanol (12 mL) was treated with a solution of sodium hydroxide (48 mg, 1.2 mmol) in 1.2 mL of water. The title compound was isolated as pale yellow crystals (130 mg, 39% yield). MS (ESI) m/z 559 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:15]=[C:6]2[C:7]([CH:13]=[O:14])=[CH:8][CH:9]=[C:10]([O:11][CH3:12])[N:5]2[N:4]=1.[CH2:18]([Mg]Br)[CH2:19][CH3:20].O1CCCC1.[Cl-].[NH4+]>O1CCCC1>[OH:14][CH:13]([C:7]1[C:6]2[N:5]([N:4]=[C:3]([C:2]([F:1])([F:16])[F:17])[CH:15]=2)[C:10]([O:11][CH3:12])=[CH:9][CH:8]=1)[CH2:18][CH2:19][CH3:20]
Reactant: COc1ccc(C=O)c2cc(C(F)(F)F)nn12
Reactant: CCC[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCCC(O)c1ccc(OC)n2nc(C(F)(F)F)cc12
Temperature: -40 °C
Reaction time: 3 h

Procedure:
The compound of Example 115 (300 mg) was dissolved in tetrahydrofuran (12.0 mL) in an argon atmosphere. While this solution was kept at −78° C., 1.04 mol/L n-propyl magnesium bromide/tetrahydrofuran solution (1.40 mL) was added dropwise and the mixture was stirred for 3 hours as it was allowed to gradually warm to −40° C. Subsequently, a saturated aqueous solution of ammonium chloride was added and the mixture was extracted with ethyl acetate. The organic layer was washed sequentially with water and saturated brine and dried over anhydrous sodium sulfate. Evaporation of the solvent and subsequent purification of the residue by silica gel column chromatography (hexane:ethyl acetate=1:1) afforded the title compound as a yellow oil (265 mg).
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:12]=[CH:11][C:8]([CH:9]=[O:10])=[CH:7][CH:6]=1.[C:13]1(=[O:23])[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[N:15][NH:14]1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[O:23]=[C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[N:15][N:14]1[CH2:2][CH2:3][O:4][C:5]1[CH:12]=[CH:11][C:8]([CH:9]=[O:10])=[CH:7][CH:6]=1
Reactant: O=Cc1ccc(OCCBr)cc1
Reactant: O=c1[nH]ncc2ccccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=Cc1ccc(OCCn2ncc3ccccc3c2=O)cc1
Temperature: 80 °C
Reaction time: 5 h
Yield: 83.9 %

Procedure:
A mixture of 4-(2-bromoethoxy)benzaldehyde (4.97 g), 1(2H)-phthalazinone (3.27 g), potassium carbonate (6.20 g) and N,N-dimethylformamide (50 ml) was stirred at 80° C. for 5 hours. After cooling, the reaction mixture was poured into water, which was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4) and concentrated to obtain 4-[2-[1-oxo-2(1H)-phthalazinyl]ethoxy]benzaldehyde (5.36 g, yield 84%) as colorless crystals. This was recrystallized from ethyl acetate-hexane. Melting point: 126–127° C.
Reaction SMILES: C([O:8][C:9]1[C:13]([CH:14]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)O)=[C:12]([C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=2)[N:11]([CH:32]([CH3:34])[CH3:33])[N:10]=1)C1C=CC=CC=1.ClCCl>C(O)C.[C].[Pd]>[CH:32]([N:11]1[C:12]([C:24]2[CH:25]=[CH:26][C:27]([O:30][CH3:31])=[CH:28][CH:29]=2)=[C:13]([CH2:14][C:16]2[CH:17]=[CH:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=2)[C:9](=[O:8])[NH:10]1)([CH3:33])[CH3:34]
Reactant: COc1ccc(-c2c(C(O)c3ccc(OC)cc3)c(OCc3ccccc3)nn2C(C)C)cc1
Agent: [Pd]
Solvent: CCO
Solvent: ClCCl
Product: COc1ccc(Cc2c(-c3ccc(OC)cc3)n(C(C)C)[nH]c2=O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.9 %

Procedure:
To a solution of [3-benzyloxy-1-isopropyl-5-(4-methoxyphenyl)-1H-pyrazol-4-yl]4-methoxy-phenyl methanol (0.11 g) in ethanol (4 mL) was added a catalytic amount of 10% palladium-carbon powder and the mixture was stirred at room temperature under a hydrogen atmosphere overnight. Dichloromethane was added to the mixture and the insoluble material was removed by filtration. The solvent of filtrate was removed under reduced pressure to give the title compound (0.076 g).
Reaction SMILES: [NH2:1][C:2]1[C:12]2[CH2:11][CH2:10][N:9]([C:13](=[O:18])[C:14]([F:17])([F:16])[F:15])[CH2:8][CH2:7][C:6]=2[CH:5]=[CH:4][C:3]=1[Cl:19].Br[CH2:21][C:22]1[CH:36]=[CH:35][C:25]2[N:26]=[C:27]([CH:29]3[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]3)[S:28][C:24]=2[CH:23]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1>[Cl:19][C:3]1[CH:4]=[CH:5][C:6]2[CH2:7][CH2:8][N:9]([C:13](=[O:18])[C:14]([F:17])([F:15])[F:16])[CH2:10][CH2:11][C:12]=2[C:2]=1[NH:1][CH2:21][C:22]1[CH:36]=[CH:35][C:25]2[N:26]=[C:27]([CH:29]3[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]3)[S:28][C:24]=2[CH:23]=1
Reactant: Nc1c(Cl)ccc2c1CCN(C(=O)C(F)(F)F)CC2
Reactant: BrCc1ccc2nc(C3CCCCC3)sc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: O=C(N1CCc2ccc(Cl)c(NCc3ccc4nc(C5CCCCC5)sc4c3)c2CC1)C(F)(F)F
Temperature: 100 °C

Procedure:
Using a method similar to the General Procedure 5-4, combine 6-amino-7-chloro-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (60 mg, 0.21 mmol), 6-bromomethyl-2-cyclohexyl-benzothiazole (0.1 g, 0.31 mmol), potassium carbonate (58 mg, 0.42 mmol) and anhydrous toluene (2 mL) in a sealed tube and heat at 100° C. for 72 h to obtain 7-chloro-6-[(2-cyclohexyl-benzothiazol-6-yl-methyl)-amino]-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine as a colorless oil.
Reaction SMILES: [CH2:1]([N:8]([C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([N+:39]([O-:41])=[O:40])[C:34]=1[CH3:42])[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH2:24][CH2:25][O:26]C3CCCCO3)[CH:18]=2)=[CH:12][CH:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>CCO.C(OCC)(=O)C>[CH2:1]([N:8]([CH2:9][C:10]1[CH:11]=[CH:12][C:13]([O:16][C:17]2[CH:18]=[C:19]([CH:20]=[CH:21][CH:22]=2)[O:23][CH2:24][CH2:25][OH:26])=[CH:14][CH:15]=1)[C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([N+:39]([O-:41])=[O:40])[C:34]=1[CH3:42])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1c(N(Cc2ccccc2)Cc2ccc(Oc3cccc(OCCOC4CCCCO4)c3)cc2)cccc1[N+](=O)[O-]
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CCO
Solvent: CCOC(C)=O
Product: Cc1c(N(Cc2ccccc2)Cc2ccc(Oc3cccc(OCCO)c3)cc2)cccc1[N+](=O)[O-]
Temperature: 55 °C

Procedure:
The product from Example 92A (0.480 g, 0.845 mmoles) in EtOH (2.0 mL) was treated with pyridinium p-toluenesulfonate (0.0106 g, 0.0422 mmoles) and heated at 55° C. for four hours. The reaction was diluted with ethyl acetate, washed with H2O, brine, dried (Na2SO4), filtered, and the filtrate concentrated under reduced pressure. The residue was purified by chromatography on a pre-packed Biotage silica gel column (hexanes to 50% ethyl acetate:hexanes) to provide the title compound.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]([CH:15]([O:19][CH3:20])[C:16]([OH:18])=[O:17])[CH:12]=[CH:13][CH:14]=1)C1C=CC=CC=1>[Pd].CCO>[OH:8][C:9]1[CH:10]=[C:11]([CH:15]([O:19][CH3:20])[C:16]([OH:18])=[O:17])[CH:12]=[CH:13][CH:14]=1
Reactant: COC(C(=O)O)c1cccc(OCc2ccccc2)c1
Agent: [Pd]
Solvent: CCO
Product: COC(C(=O)O)c1cccc(O)c1

Procedure:
(RS)-(3-Benzyloxy-phenyl)-methoxy-acetic acid (example 8.1) was hydrogenated at rt and normal pressure using 10% Pd/C as a catalyst and EtOH as a solvent to give (RS)-(3-hydroxy-phenyl)-methoxy-acetic acid as a colorless foam.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11](Br)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:16]1[CH2:21][CH2:20][C:19](=[O:22])[CH2:18][CH2:17]1>>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:19]2([OH:22])[CH2:20][CH2:21][O:16][CH2:17][CH2:18]2)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CCOCC1
Reactant: Brc1cccc(OCc2ccccc2)c1
Product: OC1(c2cccc(OCc3ccccc3)c2)CCOCC1
Yield: 77 %

Procedure:
Using the Grignard reaction procedure described in the portion of Example 1 which is concerned with the preparation of starting materials, 3-benzyloxybromobenzene was reacted with tetrahydropyran-4-one to give 4-(3-benzyloxyphenyl)-4-hydroxytetrahydropyran in 77% yield, m.p. 84°-86° C.
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[C:9]([S:11]([CH3:14])(=[O:13])=[O:12])[CH:8]=[C:7]([F:15])[CH:6]=1.[CH:16]1([NH2:20])[CH2:19][CH2:18][CH2:17]1>C(O)C>[F:15][C:7]1[CH:6]=[C:5]([CH:10]=[C:9]([S:11]([CH3:14])(=[O:13])=[O:12])[CH:8]=1)[O:4][CH2:3][CH2:2][NH:20][CH:16]1[CH2:19][CH2:18][CH2:17]1
Reactant: NC1CCC1
Reactant: CS(=O)(=O)c1cc(F)cc(OCCBr)c1
Solvent: CCO
Product: CS(=O)(=O)c1cc(F)cc(OCCNC2CCC2)c1
Yield: 82.9 %

Procedure:
Preparation according to Example 1 but performed in one portion: 1-(2-bromoethoxy)-3-fluoro-5-methylsulfonyl-benzene (0.5 g, 1.68 mmol) and cyclobutylamine (1.17 ml, 13.46 mmol) in ethanol (4 ml). Purification by flash column chromatography (ethyl acetate/methanol, 100:0 to 85:15) gave the title compound (400 mg, 82.7%). The amine was converted to the hydrochloric acid salt and re-crystallized from methanol/diethyl ether: M.p. 202° C. MS m/z (relative intensity, 70 eV) 287 (M+, 0), 260 (33), 259 (91), 216 (bp), 215 (23), 56 (73).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[CH2:5][N:6]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH:7]1[CH2:9][CH2:8]1)[CH3:2].[C:18](Cl)(=[O:20])[CH3:19]>C1COCC1>[CH2:1]([O:3][C:4](=[O:17])[CH:5]([N:6]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH:7]1[CH2:8][CH2:9]1)[C:18](=[O:20])[CH3:19])[CH3:2]
Reactant: CC(=O)Cl
Reactant: CCOC(=O)CN(C(=O)OC(C)(C)C)C1CC1
Solvent: C1CCOC1
Product: CCOC(=O)C(C(C)=O)N(C(=O)OC(C)(C)C)C1CC1
Reaction time: 1 h
Yield: 67.8 %

Procedure:
To solution of 63 ml (1 M in THF, 63 mmol) of lithium hexamethyldisilylazide cooled to −78° C. under Ar was added, drop wise, a solution of 7.3 g (30 mmol) of (tert-butoxycarbonyl-cyclopropyl-amino)-acetic acid ethyl ester in 10 ml of THF. The mixture was brought to −40° C. and stirred for 1 h. 2.3 ml (30 mmol) of acetyl chloride was then added and the mixture allowed to reach room temperature over 1 h after which time the reaction was quenched by addition to 10% citric acid solution. The mixture was then extracted with EtOAc, dried with sodium sulfate and concentrated. Purification by flash column chromatography [n-heptane/EtOAc 1:9 to 2:8] afforded 5.8 g (67%) of the title compound as colorless oil, partially contaminated with the starting material. MS: 286.1 (MH+).
Reaction SMILES: C(O[C:4]([C:6]1[C:11](=[O:12])[N:10]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:9]2[CH:20]=[CH:21][CH:22]=[C:8]2[C:7]=1[OH:23])=[O:5])C.[NH2:24][CH2:25][C:26]([O-:28])=[O:27].[Na+]>COCCO>[CH2:13]([N:10]1[C:11](=[O:12])[C:6]([C:4]([NH:24][CH2:25][C:26]([OH:28])=[O:27])=[O:5])=[C:7]([OH:23])[C:8]2=[CH:22][CH:21]=[CH:20][N:9]12)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: NCC(=O)[O-]
Reactant: CCOC(=O)c1c(O)c2cccn2n(Cc2ccccc2)c1=O
Agent: [Na+]
Solvent: COCCO
Product: O=C(O)CNC(=O)c1c(O)c2cccn2n(Cc2ccccc2)c1=O
Yield: 75.3 %

Procedure:
A mixture of 1-benzyl-4-hydroxy-2-oxo-1,2-dihydro-pyrrolo[1,2-b]pyridazine-3-carboxylic acid ethyl ester (78 mg, 0.249 mmol) and sodium glycinate (122 mg, 1.25 mmol) in 2-methoxyethanol (5 mL) was refluxed for 20 h; subsequently, the reaction was cooled and solvent was removed by rotovaping; the residue was dissolved in water and then acidified with 2 M HCl solution; the precipitates were collected via filtration, washed with water and vacuum dried at 50° C. to give the desired product (64 mg) as yellow solid. ESI (m/z): 342 (M+H)+.
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3[N:17]=[CH:18][N:19]=[C:20]([C:21]4[CH:26]=[C:25]([F:27])[C:24]([O:28][CH3:29])=[CH:23][C:22]=4[O:30][CH2:31][CH:32]4[CH2:34][CH2:33]4)[C:15]=3[NH:14][C:13]=2[CH3:35])=[O:11])[CH2:5][CH2:4]1.C([O:39][C@@H:40]([CH3:44])[C:41](Cl)=[O:42])(=O)C>>[CH:32]1([CH2:31][O:30][C:22]2[CH:23]=[C:24]([O:28][CH3:29])[C:25]([F:27])=[CH:26][C:21]=2[C:20]2[C:15]3[NH:14][C:13]([CH3:35])=[C:12]([C:10]([NH:9][C@H:6]4[CH2:7][CH2:8][C@H:3]([NH:2][C:41](=[O:42])[C@@H:40]([OH:39])[CH3:44])[CH2:4][CH2:5]4)=[O:11])[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:34][CH2:33]1
Reactant: CC(=O)O[C@@H](C)C(=O)Cl
Reactant: COc1cc(OCC2CC2)c(-c2ncnc3c(C(=O)N[C@H]4CC[C@H](N)CC4)c(C)[nH]c23)cc1F
Agent: Cl
Product: COc1cc(OCC2CC2)c(-c2ncnc3c(C(=O)N[C@H]4CC[C@H](NC(=O)[C@H](C)O)CC4)c(C)[nH]c23)cc1F

Procedure:
Starting from N-(trans-4-aminocyclohexyl)-4-[2-(cyclopropylmethoxy)-5-fluoro-4-methoxyphenyl]-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f45) and commercially available (2S)-1-chloro-1-oxopropan-2-yl acetate the title compound is obtained as colorless solid.
Reaction SMILES: C([O:4][C:5]1[CH:12]=[C:11]([Br:13])[C:10]([O:14][CH3:15])=[CH:9][C:6]=1[CH:7]=[O:8])(=O)C.C([O-])([O-])=O.[K+].[K+]>CO>[OH:4][C:5]1[CH:12]=[C:11]([Br:13])[C:10]([O:14][CH3:15])=[CH:9][C:6]=1[CH:7]=[O:8]
Reactant: COc1cc(C=O)c(OC(C)=O)cc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: COc1cc(C=O)c(O)cc1Br
Temperature: 25 °C
Reaction time: 1 h
Yield: 85 %

Procedure:
To a 200 mL round-bottomed flask containing 6.90 g (25.3 mmol) 2 acetoxy-4-bromo-5-methoxybenzaldehyde (2) in 100 mL of 1% aqueous methanol at room temperature was added 5 g K2CO3, and the mixture was allowed to stir at room temperature for 1 h, at which time TLC analysis indicated complete consumption of starting material and the presence of a slightly more polar compound as the only detectable product. The reaction mixture was then neutralized to pH 5 with the addition of 1N HCl, and the solvent was subsequently removed under diminished pressure. The residue was then dissolved in ethyl acetate (200 mL), washed successively with 1N HCl (1×50 mL), saturated aqueous NaHCO3 (1×50 mL), and brine (1×50 mL), dried over Na2SO4, and concentrated under diminished pressure to give 4.97 g (85%) of the bromophenol as a brownish-red oily solid. A portion of this crude material was recrystallized from 2:1 hexanes/ethyl acetate to give white needles. 1H NMR (400 MHz, CDCl3) δ 3.89 (s, 3H, OCH3), 6.97 and 7.27 (2s, 2×1H, Ar--H), 9.83 (s, 1H, OH), 10.71 ppm (s, 1H, CHO). The remainder of the material was carried on to the next step without further purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[CH2:9][C:10]([OH:12])=O.Cl.[C:14]1([C:20]2([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH:28]3[CH:24]([CH2:25][NH:26][CH2:27]3)[C:23](=[O:29])[CH2:22][CH2:21]2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(N(CC)CC)C>ClCCl>[F:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[C:3]=1[CH2:9][C:10]([N:26]1[CH2:25][CH:24]2[CH:28]([C:20]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH2:21][CH2:22][C:23]2=[O:29])[CH2:27]1)=[O:12]
Reactant: O=C(O)Cc1c(F)cccc1F
Reactant: O=C1CCC(c2ccccc2)(c2ccccc2)C2CNCC12
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C1CCC(c2ccccc2)(c2ccccc2)C2CN(C(=O)Cc3c(F)cccc3F)CC12
Reaction time: 0.75 h
Yield: 67.6 %

Procedure:
N,N'-Carbonyldiimidazole (1.13 g) is added to a solution of 2-(2,6-difluorophenyl)acetic acid (1.2 g) in dry dichloromethane (30 cc), cooled to +5° C. The mixture is stirred for 45 minutes at +5° C. and a solution of (3aRS,7aRS)-7,7-diphenyl-4-perhydroisoindolone hydrochloride (2.3 g) and triethylamine (0.98 cc) in dichloromethane (40 cc) is then added. The reaction mixture is stirred at 20° C. for 16 hours, then washed with distilled water (2×50 cc), dried over magnesium sulphate and filtered and the filtrate is concentrated to dryness under reduced pressure (2.7 kPa). The residue is crystallized from ethyl acetate (10 cc). The crystals obtained are drained, washed with isopropyl ether (10 cc) and dried. (3aRS,7aRS)-2-[(2,6-difluorophenyl)acetyl]-7,7-diphenyl-4-perhydroisoindolone (2.1 g) melting at 218° C. is obtained.
Reaction SMILES: Br[CH2:2][C:3]([O:5][CH3:6])=[O:4].C([O-])([O-])=O.[K+].[K+].[CH:13]1([N:16]2[C:24]3[C:19](=[C:20]([OH:49])[CH:21]=[C:22]([C:25]([N:27]4[CH2:32][CH2:31][C:30]5([CH2:41][C:40](=[O:42])[C:39]6[C:34](=[CH:35][CH:36]=[C:37]([C:43]7[CH:44]=[N:45][N:46]([CH3:48])[CH:47]=7)[CH:38]=6)[O:33]5)[CH2:29][CH2:28]4)=[O:26])[CH:23]=3)[CH:18]=[CH:17]2)[CH2:15][CH2:14]1>CN(C=O)C.CCOC(C)=O>[CH:13]1([N:16]2[C:24]3[C:19](=[C:20]([O:49][CH2:2][C:3]([O:5][CH3:6])=[O:4])[CH:21]=[C:22]([C:25]([N:27]4[CH2:28][CH2:29][C:30]5([CH2:41][C:40](=[O:42])[C:39]6[C:34](=[CH:35][CH:36]=[C:37]([C:43]7[CH:44]=[N:45][N:46]([CH3:48])[CH:47]=7)[CH:38]=6)[O:33]5)[CH2:31][CH2:32]4)=[O:26])[CH:23]=3)[CH:18]=[CH:17]2)[CH2:14][CH2:15]1
Reactant: Cn1cc(-c2ccc3c(c2)C(=O)CC2(CCN(C(=O)c4cc(O)c5ccn(C6CC6)c5c4)CC2)O3)cn1
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)COc1cc(C(=O)N2CCC3(CC2)CC(=O)c2cc(-c4cnn(C)c4)ccc2O3)cc2c1ccn2C1CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Methyl bromoacetate (0.059 ml, 0.604 mmol) was added to a stirred mixture of K2CO3 (111 mg, 0.806 mmol), 1′-[(1-cyclopropyl-4-hydroxy-1H-indol-6-yl)carbonyl]-6-(1-methyl-1H-pyrazol-4-yl)spiro[chroman-2,4′-piperidin]-4-one (200 mg, 0.403 mmol) in DMF (2 ml) and the mixture was stirred at room temperature overnight. The mixture was diluted with EtOAc, washed with water, brine, and dried over MgSO4. After filteration and evaporation, the residue was purified by silicagel column chromatography (CHCl3/MeOH) to give intended compound as yellow oil.
Reaction SMILES: O[CH2:2][C:3]1[CH:4]=[N:5][C:6]([S:9][CH3:10])=[N:7][CH:8]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:31]>C1C=CC=CC=1>[Br:31][CH2:2][C:3]1[CH:4]=[N:5][C:6]([S:9][CH3:10])=[N:7][CH:8]=1
Reactant: CSc1ncc(CO)cn1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccccc1
Product: CSc1ncc(CBr)cn1
Yield: 59.9 %

Procedure:
5-hydroxymethyl-2-methylthiopyrimidine (0.1 g, 0.61 mmol), triphenylphosphine (0.45 g, 1.7 mmol) and carbon tetrabromide (0.28 g, 0.85 mmol) are stirred in benzene (5 mL) for 24 h. The mixture is evaporated and the residue is purified by flash chromatography (silica gel, 4:1 hexanes/ethyl acetate) to provide the intermediate title compound as a white solid (0.08 g, 61%). MS (ES), 219/221 [M+H]+ (Br).
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[N:5][C:6]([C@@H:9]([NH2:11])[CH3:10])=[N:7][CH:8]=1.Cl[C:13]1[N:18]=[C:17]([NH:19][C:20]2[CH:24]=[C:23]([CH:25]3[CH2:27][CH2:26]3)[NH:22][N:21]=2)[C:16]([F:28])=[CH:15][N:14]=1.CCN(C(C)C)C(C)C>CCCCO>[CH:25]1([C:23]2[NH:22][N:21]=[C:20]([NH:19][C:17]3[C:16]([F:28])=[CH:15][N:14]=[C:13]([NH:11][C@H:9]([C:6]4[N:7]=[CH:8][C:3]([F:2])=[CH:4][N:5]=4)[CH3:10])[N:18]=3)[CH:24]=2)[CH2:27][CH2:26]1
Reactant: Fc1cnc(Cl)nc1Nc1cc(C2CC2)[nH]n1
Reactant: C[C@H](N)c1ncc(F)cn1
Agent: Cl
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](Nc1ncc(F)c(Nc2cc(C3CC3)[nH]n2)n1)c1ncc(F)cn1
Temperature: 180 °C
Yield: 242.5 %

Procedure:
A mixture of (S)-1-(5-fluoropyrimidin-2-yl)ethanamine hydrochloride (Method 7, 93 mg), 2-chloro-N-(5-cyclopropyl-1H-pyrazol-3-yl)-5-fluoropyrimidin-4-amine (Method 16, 127 mg) and DIPEA (0.22 ml) in n-BuOH (2.5 ml) was charged into a microwave reaction vessel. The vessel was sealed and heated in microwave reactor at 180° C. for 6 hours. The solvent was removed under reduced pressure and the residue was purified by Gilson (10-50% MeCN/H2O, 15 minutes) to give the titled compound as solid (435 mg). NMR 11.28 (s, 1H), 8.92 (s, 3H), 8.24 (s, 1H), 6.04 (s, 1H), 4.92-5.54 (m, 1H), 1.82-1.98 (m, 1H), 1.56 (d, 3H), 0.94-1.06 (m, 2H), 0.64-0.80 (m, 2H). m/z 395.