Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][CH2:3][C@@H:4]1[CH2:6][C@@H:5]1[CH:7]1[CH2:12][CH2:11][N:10]([C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:14])[CH2:9][CH2:8]1.[Br:23][C:24]1[C:29]([F:30])=[CH:28][C:27](O)=[C:26]([F:32])[CH:25]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>C(Cl)Cl>[Br:23][C:24]1[C:29]([F:30])=[CH:28][C:27]([O:1][CH2:2][CH2:3][C@@H:4]2[CH2:6][C@@H:5]2[CH:7]2[CH2:12][CH2:11][N:10]([C:13]([O:15][CH2:16][C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)=[O:14])[CH2:9][CH2:8]2)=[C:26]([F:32])[CH:25]=1
Reactant: O=C(OCc1ccccc1)N1CCC([C@H]2C[C@H]2CCO)CC1
Reactant: Oc1cc(F)c(Br)cc1F
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: O=C(OCc1ccccc1)N1CCC([C@H]2C[C@H]2CCOc2cc(F)c(Br)cc2F)CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Benzyl 4-[(1R,2S)-2-(2-hydroxyethyl)cyclopropyl]piperidine-1-carboxylate (2.24 g, 7.38 mmol) in DCM (35 ml) was added 4-bromo-2,5-difluorophenol (1.62 g, 7.75 mmol), 3.93 g of triphenylphosphine (polymer-bound, 3.0 mmol/g) and di-tert-butyl diazene-1,2-dicarboxylate (2.21 g, 9.60 mmol). The reaction mixture was stirred at ambient temperature for 4 hours. The solid was filtered off through celite and the filtrate was concentrated. The residue was purified on Biotage column (50 g SNAP silica gel) using a gradient 0-20% then 20% EtOAc in hexanes to afford the title compound as colorless viscous oil. LC/MS (m/z): 496.2 (M+H)+.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[O:26][CH2:27][CH:28]4[CH2:30][CH2:29]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:4][CH2:3]1.[CH:31]1([C:34](Cl)=[O:35])[CH2:33][CH2:32]1>>[CH:31]1([C:34]([NH:1][C@H:2]2[CH2:7][CH2:6][C@H:5]([NH:8][C:9]([C:11]3[C:15]4[N:16]=[CH:17][N:18]=[C:19]([C:20]5[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=5[O:26][CH2:27][CH:28]5[CH2:29][CH2:30]5)[C:14]=4[NH:13][CH:12]=3)=[O:10])[CH2:4][CH2:3]2)=[O:35])[CH2:33][CH2:32]1
Reactant: O=C(Cl)C1CC1
Reactant: N[C@H]1CC[C@H](NC(=O)c2c[nH]c3c(-c4ccccc4OCC4CC4)ncnc23)CC1
Product: O=C(N[C@H]1CC[C@H](NC(=O)C2CC2)CC1)c1c[nH]c2c(-c3ccccc3OCC3CC3)ncnc12

Procedure:
Starting from trans-4-(2-Cyclopropylmethoxy-phenyl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (4-amino-cyclohexyl)-amide (example A161) and cyclopropanecarbonyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9](O)[CH:10]([C:14]3[C:19]([F:20])=[CH:18][CH:17]=[CH:16][C:15]=3[F:21])[N:11]=[CH:12][CH:13]=2)=[CH:4][CH:3]=1.O=P(Cl)(Cl)[Cl:25].[OH-].[Na+]>O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([Cl:25])[CH:10]([C:14]3[C:19]([F:20])=[CH:18][CH:17]=[CH:16][C:15]=3[F:21])[N:11]=[CH:12][CH:13]=2)=[CH:4][CH:3]=1
Reactant: ON1C(c2ccc(Br)cc2)=CC=NC1c1c(F)cccc1F
Reactant: O=P(Cl)(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Fc1cccc(F)c1C1N=CC=C(c2ccc(Br)cc2)N1Cl
Temperature: 110 °C
Reaction time: 1 h

Procedure:
23.2 g of 4-(4-bromophenyl)-2-(2,6-difluorophenyl)-3-hydroxypyrimidine and 100 ml of POCl3 are mixed and stirred for one hour at 110° C. The reaction mixture is slowly poured into a solution of 250 g of NaOH (solid) in water, and filtered. After dissolving the precipitate in ethyl acetate, drying with magnesium sulfate, filtering and concentrating, the title compound is obtained with a melting point of 146-148° C. (compound 3.354).
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][C:5]([CH:6]=[CH:7][C:8]([OH:10])=[O:9])=[CH:4][CH:3]=1.Cl[CH2:14]CCl.S(=O)(=O)(O)O>CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:6]=[CH:7][C:8]([O:10][CH3:14])=[O:9])=[CH:11][CH:12]=1
Reactant: ClCCCl
Reactant: O=C(O)C=Cc1ccc(Cl)cc1
Agent: O=S(=O)(O)O
Solvent: CO
Product: COC(=O)C=Cc1ccc(Cl)cc1
Yield: 95 %

Procedure:
The synthesis method of Example 7-(1) was applied. 4-Chlorocinnamic acid (10.0 g), 1,2-dichloroethane (50 methanol (9.0 ml) and concentrated sulfuric acid (0.4 ml) were used as reagents to give 10.2 g of a white solid (yield 95%).
Reaction SMILES: [Mg].[C:2]([O:6][CH:7]([CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[CH2:8][CH2:9]I)([CH3:5])([CH3:4])[CH3:3].[C:16]([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27]1[C:28](=[O:32])[CH2:29][CH2:30][CH:31]=1)([O:18][CH2:19][CH3:20])=[O:17].[Cl-].[NH4+]>C(OCC)C.O>[C:2]([O:6][CH:7]([CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[CH2:8][CH2:9][C@@H:31]1[C@@H:27]([CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:28](=[O:32])[CH2:29][CH2:30]1)([CH3:5])([CH3:4])[CH3:3]
Reactant: CCOC(=O)CCCCCCC1=CCCC1=O
Reactant: CCCCCC(CCI)OC(C)(C)C
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: O
Solvent: CCOCC
Product: CCCCCC(CC[C@H]1CCC(=O)[C@@H]1CCCCCCC(=O)OCC)OC(C)(C)C
Yield: 85 %

Procedure:
To a Grignard solution, prepared from 5.05 g. of magnesium and 65.8 g. of 3-(tert-butoxy)-1-iodooctane in 150 ml. of diethyl ether under nitrogen atmosphere, is added 4.0 g. of copper iodide-tri-n-butylphosphine complex followed by dropwise addition of 49 g. of 2-(6-carbethoxyhexyl)cyclopent-2-en-1-one [Hardegger et al., Helv. Chim. Acta 50, 2501 (1967)] and the resulting mixture is stirred for 18 hours. Saturated ammonium chloride (110 ml.) is added followed by 100 ml. of water and 100 ml. of diethyl ether. Unreacted magnesium is removed by filtration. The ethereal layer is washed successively with aqueous sodium thiosulfate solution, ammonium chloride solution, and water, dried over magnesium sulfate and taken to dryness to give an oil. Distillation at 0.05 mm. (bath 100°-185° C.) gives 45.4 g. of material containing unreacted starting material and 30 g. (85% yield based on non-recovered starting material; see below) of residue which contains the desired product. This material is chromatographed on silica gel. The product is eluted with diethyl ether to give 25.2 g. (71% based on recovered starting material) of a syrup; this material has no significant ultra-violet absorption; λmaxKBr 5.74, 7.20, 7.35, 8.35 μ; nmr 2H quartetδ 4.09 (OCH2 of ester), 1H broad singlet 3.57 (carbinolic proton), 5H overlapping multiplets 2.0-2.4 (protons next to C=O), 3H triplet 1.22 (CH3 of ethyl), 9H singlet 1.17 (CH3 's to t-butyl) and 3H triplet 0.9 (terminal methyl); mass spectrum: m/e 424.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[Cl:7][C:8]1[CH:9]=[CH:10][C:11]([N:14]2[CH:22]([O:23][C:24]([O:26]C3C=CC=CC=3)=O)[C:21]3[C:16](=[N:17][CH:18]=[CH:19][N:20]=3)[C:15]2=[O:33])=[N:12][CH:13]=1>C(#N)C.C(Cl)Cl>[Cl:7][C:8]1[CH:9]=[CH:10][C:11]([N:14]2[CH:22]([O:23][C:24]([N:1]3[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]3)=[O:26])[C:21]3[C:16](=[N:17][CH:18]=[CH:19][N:20]=3)[C:15]2=[O:33])=[N:12][CH:13]=1
Reactant: O=C(Oc1ccccc1)OC1c2nccnc2C(=O)N1c1ccc(Cl)cn1
Reactant: C1CNCCN1
Solvent: ClCCl
Solvent: CC#N
Product: O=C(OC1c2nccnc2C(=O)N1c1ccc(Cl)cn1)N1CCNCC1
Temperature: 20 °C
Reaction time: 5 h
Yield: 37.8 %

Procedure:
Anhydrous piperazine (86 g.) is added to a suspension of 6-(5-chloropyrid-2-yl)-7-oxo-5-phenoxycarbonyloxy-6,7-dihydro-5H-pyrrolo[3,4-b]pyrazine (76.4 g.) in acetonitrile (760 cc.). The reaction mixture is stirred for 5 hours at a temperature of about 20° C. and then the insoluble product is filtered off, washed with acetonitrile (3×25 cc.) and with diisopropyl ether (50 cc.). After drying, a product (30.8 g.) is obtained and is dissolved in methylene chloride (750 cc.). A small amount of insoluble matter is removed by treating the solution with decolourising charcoal (2 g.). After filtration, the solution is concentrated to dryness under reduced pressure. 6-(5-Chloropyrid-2-yl)-7-oxo-5-(piperazin-1-yl)carbonyloxy-6,7-dihydro-5H-pyrrolo[3,4-b]pyrazine (28.3 g.), which melts at 205° C., is thus obtained.
Reaction SMILES: [N:1]#[N:2].Cl.C[O:5][C:6](=[O:31])[C@H:7]([CH2:24][CH2:25][CH2:26][NH:27][C:28](=[NH:30])[NH2:29])[NH:8][S:9]([C:12]1[CH:21]=[CH:20][C:19]2[C:14](=[CH:15][CH:16]=[C:17]([O:22][CH3:23])[CH:18]=2)[CH:13]=1)(=[O:11])=[O:10].C(OCC)C.[CH2:37]([NH2:41])[CH2:38][CH2:39][CH3:40]>C(O)(=O)C>[N:1]#[N:2].[C:6]([OH:31])(=[O:5])[CH3:7].[CH3:23][O:22][C:17]1[CH:18]=[C:19]2[C:14](=[CH:15][CH:16]=1)[CH:13]=[C:12]([S:9]([NH:8][C@H:7]([C:6]([NH:41][CH2:37][CH2:38][CH2:39][CH3:40])=[O:5])[CH2:24][CH2:25][CH2:26][NH:27][C:28](=[NH:30])[NH2:29])(=[O:11])=[O:10])[CH:21]=[CH:20]2
Reactant: COC(=O)[C@H](CCCNC(=N)N)NS(=O)(=O)c1ccc2cc(OC)ccc2c1
Reactant: CCCCN
Agent: Cl
Agent: N#N
Solvent: CC(=O)O
Solvent: CCOCC
Product: CCCCNC(=O)[C@H](CCCNC(=N)N)NS(=O)(=O)c1ccc2cc(OC)ccc2c1
Reaction time: 48 h
Yield: 74 %

Procedure:
A 1.0 gram amount of N2 -(6-methoxy-2-naphthalene-sulfonyl)-L-arginine methyl ester hydrochloride was dissolved in 2 ml of butylamine with vigorous agitation. After the resulting solution was allowed to stand at room temperature for 2 days, the butylamine was removed in vacuo and the residual syrup was washed well with 5 ml of water to obtain a powdery product. And then this powder was dissolved in minimum volume of acetic acid. To this solution ethyl ether was added to precipitate the viscous oily product. Reprecipitation from ethanol-ethyl ether gave N2 -(6-methoxy-2-naphthalenesulfonyl)-N-butyl-L-argininamide acetate in a powder form in 74% yield.
Reaction SMILES: [C:1]([C:3]1[CH:31]=[CH:30][C:6]([CH2:7][NH:8][C:9](=[O:29])[CH:10]([C:13]2[CH:18]=[CH:17][C:16](B3OC(C)(C)C(C)(C)O3)=[CH:15][C:14]=2[F:28])[O:11][CH3:12])=[CH:5][CH:4]=1)#[N:2].Cl.Br[C:34]1[CH:39]=[CH:38][N:37]=[CH:36][CH:35]=1>>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([CH2:7][NH:8][C:9](=[O:29])[CH:10]([C:13]2[CH:18]=[CH:17][C:16]([C:34]3[CH:39]=[CH:38][N:37]=[CH:36][CH:35]=3)=[CH:15][C:14]=2[F:28])[O:11][CH3:12])=[CH:30][CH:31]=1)#[N:2]
Reactant: Brc1ccncc1
Reactant: COC(C(=O)NCc1ccc(C#N)cc1)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1F
Agent: Cl
Product: COC(C(=O)NCc1ccc(C#N)cc1)c1ccc(-c2ccncc2)cc1F

Procedure:
In analogy to example 57.1 (RS)-N-(4-cyano-benzyl)-2-[2-fluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-2-methoxy-acetamide (example 73.1) was reacted with 4-bromopyridine, hydrochloride to give (RS)-N-(4-cyano-benzyl)-2-(2-fluoro-4-pyridin-4-yl-phenyl)-2-methoxy-acetamide. Light brown amorphous solid. MS 376.3 ([M+H]+)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH:32][C:33]2[CH:34]=[C:35]([CH3:43])[C:36]3[O:40][N:39]=[C:38]([CH3:41])[C:37]=3[CH:42]=2)[C:9]2[C:10]([C:27]([O:29]CC)=[O:28])=[N:11][N:12]([C:17]3[C:18]([O:25][CH3:26])=[N:19][C:20]([O:23][CH3:24])=[N:21][CH:22]=3)[C:13]=2[CH:14]([CH3:16])[CH3:15])=[CH:4][CH:3]=1.[OH-].[Na+].Cl>CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([NH:32][C:33]2[CH:34]=[C:35]([CH3:43])[C:36]3[O:40][N:39]=[C:38]([CH3:41])[C:37]=3[CH:42]=2)[C:9]2[C:10]([C:27]([OH:29])=[O:28])=[N:11][N:12]([C:17]3[C:18]([O:25][CH3:26])=[N:19][C:20]([O:23][CH3:24])=[N:21][CH:22]=3)[C:13]=2[CH:14]([CH3:15])[CH3:16])=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1nn(-c2cnc(OC)nc2OC)c(C(C)C)c1C(Nc1cc(C)c2onc(C)c2c1)c1ccc(Cl)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1ncc(-n2nc(C(=O)O)c(C(Nc3cc(C)c4onc(C)c4c3)c3ccc(Cl)cc3)c2C(C)C)c(OC)n1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 97.9 %

Procedure:
To a stirred solution of ethyl 4-((4-chlorophenyl)((3,7-dimethylbenzo[d]isoxazol-5-yl)amino)-methyl)-1-(2,4-dimethoxypyrimidin-5-yl)-5-isopropyl-1H-pyrazole-3-carboxylate (Step 46.12) (455 mg, 0.677 mmol) in MeOH (10 mL) cooled down to 0° C. was added dropwise 4M NaOH (2.54 mL, 10.15 mmol). The reaction mixture was allowed to warm up and stir at RT for 45 min, acidified with 4N HCl and MeOH was removed under reduced pressure. The aq. layer was extracted with EtOAc, combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated under reduced pressure to afford the title product (450 mg, 0.663 mmol, 98% yield) as a beige amorphous solid. tR: 1.20 min (LC-MS 2); ESI-MS: 577 [M+H]+, ESI-MS: 575 [M−H]− (LC-MS 2).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH:8][C@@H:9]([CH2:12][CH2:13][CH3:14])[CH2:10][OH:11])[C:5]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([CH2:22][C:23]([OH:25])=[O:24])=[CH:18][C:17]=2[OH:26])=[C:4]([CH3:27])[N:3]=1.[Si](Cl)(C)(C)[CH3:29]>CO>[NH2:1][C:2]1[N:7]=[C:6]([NH:8][C@@H:9]([CH2:12][CH2:13][CH3:14])[CH2:10][OH:11])[C:5]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([CH2:22][C:23]([O:25][CH3:29])=[O:24])=[CH:18][C:17]=2[OH:26])=[C:4]([CH3:27])[N:3]=1
Reactant: C[Si](C)(C)Cl
Reactant: CCC[C@@H](CO)Nc1nc(N)nc(C)c1Cc1ccc(CC(=O)O)cc1O
Solvent: CO
Product: CCC[C@@H](CO)Nc1nc(N)nc(C)c1Cc1ccc(CC(=O)OC)cc1O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The product from step (i) (120 mg) was dissolved in MeOH (10 mL) and TMS-Cl (0.205 ml) was added and stirred at rt overnight. The crude product was purified by RPHPLC to give the title compound as a white solid, 35 mg.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH:8]2[C:13]3=[N:14][S:15](=[O:19])(=[O:18])[CH2:16][CH2:17][N:12]3[CH2:11][CH2:10][N:9]2[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH:5]=[CH:4][C:3]=1[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.I[CH3:34].[H-].[Na+].O>CN(C=O)C>[F:1][C:2]1[CH:7]=[C:6]([C:8]2([CH3:34])[C:13]3=[N:14][S:15](=[O:18])(=[O:19])[CH2:16][CH2:17][N:12]3[CH2:11][CH2:10][N:9]2[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH:5]=[CH:4][C:3]=1[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: CI
Reactant: CC(C)(C)OC(=O)N1CCN2CCS(=O)(=O)N=C2C1c1ccc(-c2ccccc2)c(F)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN2CCS(=O)(=O)N=C2C1(C)c1ccc(-c2ccccc2)c(F)c1
Reaction time: 8 h

Procedure:
A suspension of tert-butyl 9-(2-fluorobiphenyl-4-yl)-3,4,6,7-tetrahydropyrazino[2,1-c][1,2,4]thiadiazine-8(9H)-carboxylate 2,2-dioxide (0.71 g), iodomethane (0.115 mL) and NaH (60%, 93 mg) in DMF (16 mL) was stirred at 0° C. to room temperature overnight. The reaction mixture was added with water and extracted with EtOAc. The organic layer was washed with brine and water, dried over anhydrous magnesium sulfate and concentrated. The residue was purified by column chromatography (silica gel, eluted with EtOAc in hexane). The obtained material was purified by column chromatography (silica gel, eluted with EtOAc in hexane) to give the title compound (150 mg) as a white solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11](OB(O)O)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:19]1(=[O:24])[CH2:23][CH2:22][CH:21]=[CH:20]1>>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([C@@H:21]2[CH2:22][CH2:23][C:19](=[O:24])[CH2:20]2)=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1C=CCC1
Reactant: OB(O)Oc1cccc(OCc2ccccc2)c1
Product: O=C1CC[C@@H](c2ccc(OCc3ccccc3)cc2)C1
Yield: 104.5 %

Procedure:
3-Benzyloxyphenylboric acid (15.0 g, 66 mmol) and cyclopentenone (2.5 mL, 30 mmol) were used and treated in a similar manner to (Step 1) of (Example 3) to give the title compound (8.35 g).
Reaction SMILES: [Br-].[CH3:2][C:3]1([CH3:35])[C:11]2[C:6](=[CH:7][C:8]([CH:12]([P+](C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[CH3:13])=[CH:9][CH:10]=2)[C:5]([CH3:34])([CH3:33])[CH2:4]1.[CH2:36]([O:38][C:39]([C:41]1[CH:48]=[CH:47][C:44]([CH:45]=O)=[CH:43][CH:42]=1)=[O:40])[CH3:37]>C1OCCC1>[CH2:36]([O:38][C:39](=[O:40])[C:41]1[CH:48]=[CH:47][C:44](/[CH:45]=[C:12](/[C:8]2[CH:7]=[C:6]3[C:11](=[CH:10][CH:9]=2)[C:3]([CH3:35])([CH3:2])[CH2:4][C:5]3([CH3:33])[CH3:34])\[CH3:13])=[CH:43][CH:42]=1)[CH3:37]
Reactant: CC(c1ccc2c(c1)C(C)(C)CC2(C)C)[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCOC(=O)c1ccc(C=O)cc1
Agent: [Br-]
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc(/C=C(\C)c2ccc3c(c2)C(C)(C)CC3(C)C)cc1
Temperature: 65 °C
Reaction time: 12 h

Procedure:
300 ml of butylene oxide are added to 30.5 g of [1-(1,1,3,3-tetramethyl-5-indanyl)ethyl]-triphenylphosphonium bromide and 8 g of 4-ethoxycarbonylbenzaldehyde and the mixture is then stirred at 65° C. for 12 hours in an inert gas atmosphere. The resulting clear solution is cooled, introduced into ca 500 ml of ice/water and extracted twice with hexane. The organic extract is extracted three times with methanol/water, dried over sodium sulphate and concentreated under reduced pressure. The residue is purified by adsorption on silica gel using hexane/ether (19:1) for the elution. The p-[(E)-2-(1,1,3,3-tetramethyl-5-indanyl)propenyl]-benzoic acid ethyl ester obtained from the eluate melts at 70°-71° C. after recrystallization from ether/hexane.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([S:8][CH3:9])[N:5]=[C:4]([NH2:10])[CH:3]=1.[O:11](C(OC(C)(C)C)=O)[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=O>CN(C1C=CN=CC=1)C>[Cl:1][C:2]1[N:7]=[C:6]([S:8][CH3:9])[N:5]=[C:4]([N:10]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:11])[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:11])[CH:3]=1
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Reactant: CSc1nc(N)cc(Cl)n1
Agent: CN(C)c1ccncc1
Product: CSc1nc(Cl)cc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)n1

Procedure:
Method 24 was followed using 6-chloro-2-(methylthio)pyrimidin-4-amine (1.0 equiv.), BOC2O (2.0 equiv.), and DMAP (cat.) to afford 6-chloro-N,N-di-BOC-2-(methylthio)pyrimidin-4-amine in >95%. LCMS (m/z): 376.1 (MH+); LC Rt=4.9 min.
Reaction SMILES: [C:1]1([CH:7]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[O:8][C:9]2[CH:16]=[CH:15][C:12]([CH2:13]O)=[CH:11][CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:43]>C1COCC1>[C:1]1([CH:7]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[O:8][C:9]2[CH:16]=[CH:15][C:12]([CH2:13][Br:43])=[CH:11][CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: BrC(Br)(Br)Br
Reactant: OCc1ccc(OC(c2ccccc2)c2ccccc2)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: BrCc1ccc(OC(c2ccccc2)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 1-4 (3.6 g, 12 mmol), triphenyl phosphine (3.1 g, 11.8 mmol) in THF (100 ml) was treated with carbon tetrabromide (3.9 g, 11.8 mmol). After 12 h additional triphenylphosphine (3.1 g, 11.8 mmol) was added and the mixture allowed to stir at room temperature overnight. Some triphenyl phosphine oxide was then filtered off and the filtrate concentrated to dryness. The residue was chromatographed on a Still column (70 mm) and the product eluted with 5% EtOAc-hexane to yield 1-5.
Reaction SMILES: [F:1][C:2]1[CH:21]=[CH:20][C:5]([C:6]([NH:8][C:9]2[C:17]([O:18][CH3:19])=[CH:16][CH:15]=[CH:14][C:10]=2[C:11]([NH2:13])=[O:12])=O)=[CH:4][CH:3]=1>[OH-].[Na+]>[F:1][C:2]1[CH:21]=[CH:20][C:5]([C:6]2[NH:13][C:11](=[O:12])[C:10]3[C:9](=[C:17]([O:18][CH3:19])[CH:16]=[CH:15][CH:14]=3)[N:8]=2)=[CH:4][CH:3]=1
Reactant: COc1cccc(C(N)=O)c1NC(=O)c1ccc(F)cc1
Agent: [Na+]
Agent: [OH-]
Product: COc1cccc2c(=O)[nH]c(-c3ccc(F)cc3)nc12
Temperature: 60 °C
Reaction time: 5 h
Yield: 98.8 %

Procedure:
3-Methoxy-2-nitrobenzoic acid (2000 mg, 10.15 mmol) was dissolved under argon in abs. tetrahydrofuran (10 ml), and oxalyl chloride (1288 mg, 10.15 mmol) and a catalytic amount of DMF were added. The resulting reaction mixture was stirred at 60° C. for 2 h and then concentrated under reduced pressure. The crude product was dissolved directly in abs. dioxane (8 ml) under argon and the solution was cooled to 0° C. Thereafter, ammonia gas was introduced for 10 min. After the introduction of gas had ended, the reaction solution was poured onto ice-water and extracted repeatedly with ethyl acetate. The combined organic phases were dried over magnesium sulfate, filtered and concentrated under reduced pressure. The 3-methoxy-2-nitrobenzamide (1950 mg, 9.94 mmol) thus prepared was then dissolved in abs. methanol (60 ml). After the addition of catalytic amounts of palladium on activated carbon (content of 10% in water-moist form; 543 mg, 0.51 mmol), hydrogen was introduced at room temperature until conversion was complete. The catalyst was then filtered off and the solvent was concentrated under reduced pressure. The crude product was used without further purification in the next reaction step, and the 2-amino-3-methoxybenzamide (350 mg, 2.11 mmol) thus obtained was dissolved in abs. tetrahydrofuran (5 ml). After addition of triethylamine (0.32 ml, 2.32 mmol) and stirring at room temperature for a further 10 minutes, 4-fluorobenzoyl chloride (0.28 ml, 2.32 mmol) was added. The resulting reaction mixture was stirred at room temperature for 3 h, then the solvent was removed under reduced pressure, and water and ethyl acetate were added to the residue. The aqueous phase was extracted repeatedly with ethyl acetate, and the combined organic phases were then dried over magnesium sulfate, filtered and concentrated under reduced pressure. Column chromatography purification (ethyl acetate/n-heptane gradient) of the crude product gave 2-[(4-fluorobenzoyl)amino]-3-methoxybenzamide (550 mg, 91% of theory) as a colorless solid. 2-[(4-Fluorobenzoyl)amino]-3-methoxybenzamide (500 mg, 1.73 mmol) was dissolved in aqueous sodium hydroxide solution (2M, 5 ml) and stirred at 60° C. for 5 h. After cooling to room temperature, filtration with suction and thorough drying gave 2-(4-fluorophenyl)-8-methoxyquinazolin-4(3H)-one (462 mg, 98% of theory) as a colorless solid. 1H NMR (400 MHz, d6-DMSO δ, ppm) 12.60 (br. s, 1H, NH), 8.24 (m, 2H), 7.70 (dd, 1H), 7.46 (d, 1H), 7.42 (d, 1H), 7.38 (m, 2H), 3.96 (s, 3H).
Reaction SMILES: C(OC([NH:11][C@H:12]1[CH2:16][CH2:15][N:14]([C@@H:17]([CH3:25])[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C:13]1=[O:26])=O)C1C=CC=CC=1>[Pd].C(O)C>[NH2:11][C@H:12]1[CH2:16][CH2:15][N:14]([C@@H:17]([CH3:25])[C:18]([O:20][C:21]([CH3:23])([CH3:22])[CH3:24])=[O:19])[C:13]1=[O:26]
Reactant: C[C@@H](C(=O)OC(C)(C)C)N1CC[C@H](NC(=O)OCc2ccccc2)C1=O
Agent: [Pd]
Solvent: CCO
Product: C[C@@H](C(=O)OC(C)(C)C)N1CC[C@H](N)C1=O
Reaction time: 18 h
Yield: 101.3 %

Procedure:
A mixture of tert-butyl(2S)-2-((3S)-3-{[(benzyloxy)carbonyl]amino}-2-oxopyrrolidin-1-yl)propanoate (2.82 g), 10% palladium on carbon (0.3 g) and ethanol (150 ml) was stirred under an atmosphere of hydrogen for 18 h. The reaction mixture was filtered through Harbolite™ and the filtrate was concentrated under reduced pressure to give the title compound (1.8 g) as a pale yellow oil.
Reaction SMILES: [C:1]([C:5]1[N:10]=[C:9]([N:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)[CH:8]=[C:7]([CH:17]2[CH2:20][CH2:19][CH2:18]2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl[CH2:22][CH2:23][CH2:24][O:25][C:26](=[O:28])[CH3:27].C(N(CC)CC)C>CN(C)C=O>[C:1]([C:5]1[N:10]=[C:9]([N:11]2[CH2:12][CH2:13][N:14]([CH2:22][CH2:23][CH2:24][O:25][C:26](=[O:28])[CH3:27])[CH2:15][CH2:16]2)[CH:8]=[C:7]([CH:17]2[CH2:20][CH2:19][CH2:18]2)[N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1nc(C2CCC2)cc(N2CCNCC2)n1
Reactant: CC(=O)OCCCCl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(=O)OCCCN1CCN(c2cc(C3CCC3)nc(C(C)(C)C)n2)CC1
Temperature: 80 °C
Reaction time: 12 h

Procedure:
5.5 g of 2-tert-butyl-4-piperazin-1-yl-6-cyclobutyl-pyrimidine (20.0 mmol), 3.15 g of acetic acid 3-chloro-propyl ester (23.1 mmol) and 2.76 g of triethylamine (27.3 mmol) were dissolved in 70 ml of dimethylformamide and stirred for 12 h at 80° C. After cooling, the dimethylformamide was evaporated, and the reaction mixture was partitioned between water and ethyl acetate. The organic layer was dried over magnesium sulfate, filtered, and the solvent was evaporated. The crude product (7 g) was directly used in the subsequent reaction step.
Reaction SMILES: Br[CH2:2][CH3:3].[F:4][C:5]1[CH:6]=[C:7]([CH:15]=[CH:16][CH:17]=1)[CH2:8][CH:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH2:2]([N:12]1[CH2:13][CH2:14][CH:9]([CH2:8][C:7]2[CH:15]=[CH:16][CH:17]=[C:5]([F:4])[CH:6]=2)[CH2:10][CH2:11]1)[CH3:3]
Reactant: CCBr
Reactant: Fc1cccc(CC2CCNCC2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCN1CCC(Cc2cccc(F)c2)CC1
Reaction time: 20 h

Procedure:
Bromoethane (0.1 mL) was added to a mixture of 4-(3-fluorobenzyl)piperidine (Intermediate 180, 0.259 g) and potassium carbonate (0.204 g) in acetonitrile (10 mL). The mixture was stirred for 20 hours then filtered. The filtrate acidified by addition of few drops of 2M HCl and the solution was passed through a SCX-2 column (10 g). The product was eluted with 2M ammonia in methanol and the residue after evaporation was triturated with diethyl ether. The solid was filtered off and the filtrated was concentrated in vacuo to give 1-ethyl-4-(3-fluorobenzyl)piperidine (0.210 g)