Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]1[CH2:14][CH2:13][N:12]([CH2:15][C@@H:16]([N:18]2[CH2:23][CH2:22][CH:21]([O:24]C(=O)C(C)(C)C)[CH2:20][CH2:19]2)[CH3:17])[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C[O-].[Na+]>>[C:1]([O:5][C:6](=[O:7])[NH:8][CH:9]1[CH2:14][CH2:13][N:12]([CH2:15][C@@H:16]([N:18]2[CH2:19][CH2:20][CH:21]([OH:24])[CH2:22][CH2:23]2)[CH3:17])[CH2:11][CH2:10]1)([CH3:2])([CH3:3])[CH3:4]
Reactant: C[C@@H](CN1CCC(NC(=O)OC(C)(C)C)CC1)N1CCC(OC(=O)C(C)(C)C)CC1
Agent: C[O-]
Agent: [Na+]
Product: C[C@@H](CN1CCC(NC(=O)OC(C)(C)C)CC1)N1CCC(O)CC1

Procedure:
Ester 54 from above (1.7 g, 3.52 mmol) is treated with NaOMe (0.5M in methanol, 21 ml, 10.5 mmol) and heated under reflux for 24 hours. The solvent is then evaporated, the residue taken up in DCM and extracted with 1N—NaOH and brine. After drying and evaporation the crued is purified by chromatography on silicagel using DCM (saturated with ammonia) and MeOH (from 1% to 3%) to give a white powder.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[CH2:4][CH2:5][C:6]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH3:16])[C:10]=1[F:17])([CH3:8])[CH3:7].C1(S(N2C(C3C=CC=CC=3)O2)(=O)=[O:26])C=CC=CC=1.[Cl-].[NH4+]>C1(C)C=CC=CC=1.O1CCCC1>[CH3:1][O:2][C:3](=[O:18])[CH:4]([OH:26])[CH2:5][C:6]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH3:16])[C:10]=1[F:17])([CH3:8])[CH3:7]
Reactant: O=S(=O)(c1ccccc1)N1OC1c1ccccc1
Reactant: COC(=O)CCC(C)(C)c1cccc(OC)c1F
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: COC(=O)C(O)CC(C)(C)c1cccc(OC)c1F
Temperature: -70 °C
Reaction time: 1 h
Yield: 58.3 %

Procedure:
19.58 g (77 mmol) of 4-(2-fluoro-3-methoxyphenyl)-4-methylpentanoic acid methyl ester is introduced into 245 ml of tetrahydrofuran, and the reaction mixture is cooled to −70° C. Within one hour, 220.7 ml of a 0.5 molar solution of potassium-bis-(trimethylsilylamide) in toluene is added in drops, and the reaction mixture is then stirred for 45 more minutes at −70° C. 28.3 g (107.79 mmol) of Davis reagent, dissolved in 245 ml of tetrahydrofuran, is now added in drops within 40 minutes. After two hours of stirring at −70° C., 250 ml of saturated ammonium chloride solution is slowly added in drops, and in this case, the batch is brought to room temperature. After extraction with methyl tert-butyl ether, the combined organic extracts are treated as usual with water and brine. After the solvent is spun off, the residue is chromatographed several times on silica gel (mobile solvent ethyl acetate/hexane). 12.14 g (58.3%) of the desired compound is ultimately isolated.
Reaction SMILES: [BH4-].[Na+].[CH:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[CH:36]=[CH:35][C:14]([CH2:15][C:16]23[C:24](=[O:25])[N:23]([C:26]4[CH:31]=[C:30]([Cl:32])[CH:29]=[C:28]([Cl:33])[CH:27]=4)[C:22](=[O:34])[N:21]2[CH2:20][CH2:19][CH2:18][CH2:17]3)=[CH:13][CH:12]=1)=[O:4]>C1COCC1.O>[OH:4][CH2:3][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[CH:12]=[CH:13][C:14]([CH2:15][C:16]23[C:24](=[O:25])[N:23]([C:26]4[CH:27]=[C:28]([Cl:33])[CH:29]=[C:30]([Cl:32])[CH:31]=4)[C:22](=[O:34])[N:21]2[CH2:20][CH2:19][CH2:18][CH2:17]3)=[CH:35][CH:36]=1
Reactant: O=Cc1ccccc1-c1ccc(CC23CCCCN2C(=O)N(c2cc(Cl)cc(Cl)c2)C3=O)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: O=C1N(c2cc(Cl)cc(Cl)c2)C(=O)C2(Cc3ccc(-c4ccccc4CO)cc3)CCCCN12
Reaction time: 0.5 h
Yield: 93438.5 %

Procedure:
NaBH4 (13.7 mg) was added to a solution of 6-[4-(2-formyl-phenyl)benzyl]-8-(3,5-dichlorophenyl)-1,8-diazabicyclo[4.3.0]-nonane-7,9-dione (0.178 mg) in THF (5 mL) at 0° C. After stirring for 30 minutes, the reaction mixture was diluted with water and extracted with EtOAc. The extract was washed with brine, dried (Na2SO4), filtered, and concentrated. Purification by chromatography (Silica gel: EtOAc/hexane: 1/2, Chromatotron) afforded the titled compound (167 mg). MS (m/z) 477 (M+−OH).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([NH:14][NH2:15])[CH:8]=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])=[O:4].[C:16]([CH2:19][C:20](=O)[CH3:21])(=O)[CH3:17].C(N(CC)CC)C>CO>[N+:11]([C:10]1[CH:9]=[CH:8][C:7]([N:14]2[C:20]([CH3:21])=[CH:19][C:16]([CH3:17])=[N:15]2)=[CH:6][C:5]=1[C:3]([O:2][CH3:1])=[O:4])([O-:13])=[O:12]
Reactant: CC(=O)CC(C)=O
Reactant: COC(=O)c1cc(NN)ccc1[N+](=O)[O-]
Solvent: CCN(CC)CC
Solvent: CO
Product: COC(=O)c1cc(-n2nc(C)cc2C)ccc1[N+](=O)[O-]

Procedure:
A solution of 2.84 g (10 mmol) of 3-methoxycarbonyl-4-nitro-phenylhydrazine, 1.0 g (10 mmol) of acetylacetone and 3.0 ml of triethylamine in 40 ml of methanol is stirred overnight at ambient temperature. Then it is evaporated to dryness, the residue is dissolved in about 50 ml of dichloromethane, the solution is washed with 5% sodium hydrogen carbonate solution, dried and evaporated down again. The crude product thus obtained is purified by column chromatography over silica gel (eluant: dichloromethane).
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1Br.C([Li])CCC.[F:15][C:16]([F:42])([F:41])[C:17]([NH:19][C:20]1[N:21]=[C:22]2[CH:27]=[CH:26][C:25]([C:28](=[O:33])N(C)OC)=[CH:24][N:23]2[C:34]=1[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[O:18].[NH4+].[Cl-]>C1COCC1>[F:42][C:16]([F:15])([F:41])[C:17]([NH:19][C:20]1[N:21]=[C:22]2[CH:27]=[CH:26][C:25]([C:28](=[O:33])[C:3]3[CH:4]=[CH:5][CH:6]=[C:7]([F:8])[C:2]=3[F:1])=[CH:24][N:23]2[C:34]=1[C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1)=[O:18]
Reactant: CON(C)C(=O)c1ccc2nc(NC(=O)C(F)(F)F)c(-c3ccccc3)n2c1
Reactant: Fc1cccc(Br)c1F
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: O=C(c1ccc2nc(NC(=O)C(F)(F)F)c(-c3ccccc3)n2c1)c1cccc(F)c1F
Reaction time: 1.17 h
Yield: 68.4 %

Procedure:
To a solution of 2,3-difluorobromobenzene (471 ml, 4.206 mmol) in dry THF (20 mL) was added a solution of n-butyl lithium (1.6M in hexanes, 2.63 mL) at −78° C. The resulting yellow solution was stirred at the same temperature for 70 minutes, then a solution of 2-trifluoroacetamido-3-phenyl-6-(N-methyl-N-methoxycarbamoyl)imidazo[1,2-a]pyridine (0.500 g, 1.28 mmol) in dry THF (20 mL), was added dropwise via a cannula. The red-orange solution was allowed to warm over 60 minutes. Saturated NH4Cl was added and the mixture was stirred for 25 minutes before extracting with EtOAc. The organic layer was washed with brine, dried (Na2SO4), concentrated in vacuo and purified by column chromatography (CH2Cl2/CH3CN 4/1) to give 390 mg of an orange solid. (69%). MS(FAB), NMR.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([S:8]([CH3:10])=O)[C:5]([C:11]#[N:12])=[C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)[N:3]=1.SC[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=1.C1CCN2C(=NCCC2)CC1>COCCOC>[NH2:1][C:2]1[N:3]=[C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)[C:5]([C:11]#[N:12])=[C:6]([S:8][CH2:10][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=2)[N:7]=1
Reactant: SCCc1ccccn1
Reactant: CS(=O)c1nc(N)nc(-c2ccccn2)c1C#N
Solvent: COCCOC
Solvent: C1CCC2=NCCCN2CC1
Product: N#Cc1c(SCCc2ccccn2)nc(N)nc1-c1ccccn1

Procedure:
From 2-amino-4-methanesulfinyl-6-pyridin-2-yl-pyrimidine-5-carbonitrile, 2-mercaptoethylpyridine and DBU in DME. ES-MS m/e (%): 335 (M+H+, 100).
Reaction SMILES: [CH2:1]([CH:7]([CH2:39][CH2:40][CH2:41][CH2:42]CCCC)[CH2:8][O:9][C:10]1[C:18]2[S:19][CH:20]=[CH:21][C:17]=2[C:16]([O:22][CH2:23][CH:24]([CH2:33][CH2:34]CCCC)[CH2:25][CH2:26][CH2:27][CH2:28]CCCC)=[C:12]2[S:13][CH:14]=[CH:15][C:11]=12)[CH2:2]CCCC.C([Li])CCC.[CH3:52][Sn:53](Cl)([CH3:55])[CH3:54].O>C1COCC1>[CH2:1]([CH:7]([CH2:39][CH2:40][CH2:41][CH3:42])[CH2:8][O:9][C:10]1[C:18]2[S:19][C:20]([Sn:53]([CH3:55])([CH3:54])[CH3:52])=[CH:21][C:17]=2[C:16]([O:22][CH2:23][CH:24]([CH2:33][CH3:34])[CH2:25][CH2:26][CH2:27][CH3:28])=[C:12]2[S:13][C:14]([Sn:53]([CH3:55])([CH3:54])[CH3:52])=[CH:15][C:11]=12)[CH3:2]
Reactant: C[Sn](C)(C)Cl
Reactant: CCCCCCCCC(CCCCCC)COc1c2ccsc2c(OCC(CCCCCC)CCCCCCCC)c2ccsc12
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: CCCCC(CC)COc1c2cc([Sn](C)(C)C)sc2c(OCC(CC)CCCC)c2cc([Sn](C)(C)C)sc12
Temperature: -70 °C
Reaction time: 8 h
Yield: 63.1 %

Procedure:
4,8-Bis[(2-hexyldecyl)oxy]-benzo[1,2-b:4,5-b′]dithiophene (0.80 g, 1.19 mmol) was dissolved in dry THF (10 mL) under nitrogen. The solution was cooled to −70° C. and butyllithium (1.0 mL, 2.M solution in hexanes, 2.5 mmol) was added dropwise. The reaction was allowed to warm to room temperature over 2 hours and cooled back to −78° C. Trimethyltin chloride (0.61 g, 3.0 mmol) was added. The reaction was allowed to warm to room temperature and stirred under nitrogen overnight. Water (50 mL) was added and the reaction was extracted with ether. Organic layer was separated and dried over Na2SO4. Solvent was removed under vacuum. To the residue was added ethanol (10 mL) and the suspension was stirred overnight. The resulting white solids were collected by filtration and dried under vacuum to afford the product 4,8-bis[(2-ethylhexyl)oxy]-2,6-bis(1,1,1-trimethyl-stannanyl)benzo[1,2-b:4,5-b′]dithiophene (0.58 g, 49%). 1H NMR (CDCl3, 500 MHz) δ=7.52 (m, 2H), 4.17 (d, J=5.0 Hz, 4H), 1.86 (m, 2H), 1.67 (m, 4H), 1.28-1.55 (m, 44H), 0.86 (m, 12H), 0.55 (m, 18H).
Reaction SMILES: [CH2:1]([N:3]1[C:15]2[CH:14]=[CH:13][C:12]([CH:16]=O)=[CH:11][C:10]=2[C:9]2[C:4]1=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH3:2].[NH:18]1[CH2:23][CH2:22][CH:21]([C:24]2[CH:29]=[CH:28][C:27]([NH:30][C:31](=[O:35])[CH2:32][CH2:33][CH3:34])=[CH:26][CH:25]=2)[CH2:20][CH2:19]1>CC(O)=O>[CH2:1]([N:3]1[C:15]2[CH:14]=[CH:13][C:12]([CH2:16][N:18]3[CH2:23][CH2:22][CH:21]([C:24]4[CH:29]=[CH:28][C:27]([NH:30][C:31](=[O:35])[CH2:32][CH2:33][CH3:34])=[CH:26][CH:25]=4)[CH2:20][CH2:19]3)=[CH:11][C:10]=2[C:9]2[C:4]1=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH3:2]
Reactant: CCn1c2ccccc2c2cc(C=O)ccc21
Reactant: CCCC(=O)Nc1ccc(C2CCNCC2)cc1
Solvent: CC(=O)O
Product: CCCC(=O)Nc1ccc(C2CCN(Cc3ccc4c(c3)c3ccccc3n4CC)CC2)cc1

Procedure:
Prepared by Procedure F and Scheme R, without HOAc, using 9-ethyl-9H-carbazole-3-carbaldehyde and N-[4-(4-piperidinyl)phenyl]butanamide: ESMS m/e: 454.2 (M+H)+.
Reaction SMILES: CC#N.[Cl:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][NH:12][C@@H:13]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[CH:16]=2)[CH3:14])=[CH:7][C:6]=1[OH:22].[CH2:23]1[O:26][CH:24]1[CH3:25].C(=O)([O-])[O-].[Cs+].[Cs+]>CCOC(C)=O>[Cl:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][NH:12][C@@H:13]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[CH:16]=2)[CH3:14])=[CH:7][C:6]=1[O:22][CH2:23][CH:24]([OH:26])[CH3:25]
Reactant: C[C@@H](NCc1ccc(Cl)c(O)c1)c1cccc(Cl)c1
Reactant: CC1CO1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CC(O)COc1cc(CN[C@H](C)c2cccc(Cl)c2)ccc1Cl
Yield: 61.8 %

Procedure:
A microwave compatible vial was charged with 2 mL of CH3CN, (R)-2-chloro-5-((1-(3-chlorophenyl)ethylamino)methyl)phenol 96 (115 mg, 388 μmol), propylene oxide (33 μL, 466 μmol), and cesium carbonate (139 mg, 427 μmol). The vial was sealed and was subjected to microwave irradiation at 140° C. for 30 min. The reaction was checked for completion by TLC. The reaction solution was diluted with EtOAc and it was washed with water (2×) and then brine. The organic layer was dried over MgSO4, filtered, and concentrated in vacuo. The crude material was purified by silica gel chromatography using a 10% to 70% gradient of EtOAc in hexanes as the eluant. The desired fractions were combined and concentrated to give 1-(2-chloro-5-(((R)-1-(3-chlorophenyl)ethylamino)methyl)phenoxy)propan-2-ol 97 (85 mg, 62% yield), as a colorless oil and as a mixture of diastereomers. 1H NMR (400 MHz, d4-methanol) δ ppm 1.32 (d, J=6.46 Hz, 3H) 1.73 (d, J=6.85 Hz, 3H) 3.92-4.02 (m, 3H) 4.13-4.21 (m, 2H) 4.49 (q, J=6.78 Hz, 1H) 6.98 (dd, J=8.12, 1.66 Hz, 1H) 7.43-7.49 (m, 2H) 7.49-7.53 (m, 2H) 7.58 (s, 1H). Mass spectrum: calculated for C18H21Cl2NO2 354.3. found 355.4 (M++1).
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[OH:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([Li])CCC.[Cl:19][Ti:20](Cl)([Cl:31])[C:21]1([CH3:30])[C:25]([CH3:26])=[C:24]([CH3:27])[C:23]([CH3:28])=[C:22]1[CH3:29]>C1(C)C=CC=CC=1>[Cl:19][Ti:20]([Cl:31])([C:21]1([CH3:30])[C:22]([CH3:29])=[C:23]([CH3:28])[C:24]([CH3:27])=[C:25]1[CH3:26])[O:13][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=1[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC1=C(C)C(C)([Ti](Cl)(Cl)Cl)C(C)=C1C
Reactant: Oc1ccccc1-c1ccccc1
Agent: [Li]CCCC
Solvent: Cc1ccccc1
Product: CC1=C(C)C(C)([Ti](Cl)(Cl)Oc2ccccc2-c2ccccc2)C(C)=C1C
Reaction time: 12 h
Yield: 85 %

Procedure:
After 0.86 g of 2-phenylphenol (5.07 mmol) (Aldrich, 99%) were dissolved in 40 mL of toluene, 2.4 mL of butyl lithium (2.5 M hexane solution) were slowly dropped thereonto at 0° C. After the reaction was conducted at normal temperature for 12 hours, a solution in which (trichloro)(pentamethylcyclopentadienyl)titanium(IV) (1.32 g, 4.56 mmol) was dissolved in 10 mL of toluene was slowly dropped thereonto at 0° C. After agitation was conducted at normal temperature for 12 hours, filtration was conducted, volatile materials were removed, and recrystallization was conducted using a mixed solution of toluene/hexane at −35° C. to produce 1.64 g of an orange-colored solid component.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([OH:8])[CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:15](Cl)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CN(C)C=O>[CH2:15]([O:8][C:6]1[CH:5]=[CH:4][CH:3]=[C:2]([Cl:1])[N:7]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: Oc1cccc(Cl)n1
Reactant: ClCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Clc1cccc(OCc2ccccc2)n1
Yield: 93.2 %

Procedure:
To a flask were added 5.0 g 6-chloro-2-hydroxypyridine, 5.3 g potassium carbonate and 75 ml N,N-dimethylformamide. After cooling to 5 C under nitrogen, 5.9 g of benzyl chloride were added drop wise and the reaction mixture was warmed to 60 C for 3 hours. After cooling to 10 C, the reaction mixture was quenched with 75 ml of water and the product was extracted with ethyl acetate and washed with water. Following solvent removal, the product was purified by silica gel chromatography using 5% ethyl acetate in hexane to give a clear colorless oil 7.9 g.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[N:6][C:5]([CH2:10]Cl)=[CH:4][N:3]=1.[CH3:12][OH:13]>>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[N:6][C:5]([CH2:10][O:13][CH3:12])=[CH:4][N:3]=1
Reactant: CO
Reactant: N#Cc1nc(CCl)cnc1N
Product: COCc1cnc(N)c(C#N)n1

Procedure:
2-Amino-3-cyano-5-chloromethyl pyrazine (0.95 g) was reacted with a large excess of dry methanol, under nitrogen, at reflux, for about 18 hours. The resulting reaction mixture was filtered and the filtrate was taken to dryness by evaporation. A yellow residue was collected and extracted twice with boiling methylene chloride. These extracts were filtered and the solvent evaporated to give 2-amino-3-cyano-5-methoxymethylpyrazine which was then treated with an excess of guanidine in methanol according to the method of Taylor (J. Org. Chem., 2817, 38, (1973)). Most of the product of this reaction precipitated and was collected by filtration. The filtrate was mixed with silica gel, stripped of solvent by evaporation, and the residue was placed on a silica gel column. This column was eluted with methanol (5%) in ethylacetate to yield a second crop of product which was added to that previously collected. The combined crops were recrystallized from methanol to yield 2,4-diamino-6-methoxymethyl pteridine (mp 248°-251°).
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[C:8]([O:13][CH2:14][CH:15]3[O:17][CH2:16]3)[CH:9]=[CH:10][CH:11]=2)[CH:6]=[N:5]1)(=O)C.N.C(=O)=O.O>C(Cl)Cl>[O:17]1[CH2:16][CH:15]1[CH2:14][O:13][C:8]1[CH:9]=[CH:10][CH:11]=[C:12]2[C:7]=1[CH:6]=[N:5][NH:4]2
Reactant: CC(=O)n1ncc2c(OCC3CO3)cccc21
Agent: N
Agent: O=C=O
Solvent: ClCCl
Solvent: O
Product: c1cc(OCC2CO2)c2cn[nH]c2c1

Procedure:
1-Acetyl-4-(2,3-epoxypropoxy)-indazole is stirred for 4 hours in a mixture of methylene chloride and liquid ammonia, using a solid carbon dioxide cooler. The reaction mixture is then evaporated in a vacuum to give a brownish oil which is pure enough for further reactions. By stirring with water, there is obtained a beige product which melts at about 60° C. (after melting, it again solidifies and then melts again at <260° C.).
Reaction SMILES: [CH:1]1[C:11]2[CH2:10][CH2:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[CH:6]([CH:16](C(O)=O)[C:17]([OH:19])=[O:18])[C:5]=2[CH:4]=[CH:3][CH:2]=1.C1C=CC=CC=1>CCCCCC>[CH:12]1[C:8]2[CH2:9][CH2:10][C:11]3[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=3[CH:6]([CH2:16][C:17]([OH:19])=[O:18])[C:7]=2[CH:15]=[CH:14][CH:13]=1
Reactant: O=C(O)C(C(=O)O)C1c2ccccc2CCc2ccccc21
Solvent: c1ccccc1
Solvent: CCCCCC
Product: O=C(O)CC1c2ccccc2CCc2ccccc21
Reaction time: 0.5 h

Procedure:
200 g of 10,11-dihydro-5H-dibenzo[a,d]cycloheptene-5-malonic acid are heated to 180° while stirring for 30 minutes. After cooling to 120°, the residue is treated with about 1 l of benzene and heated to boiling while stirring and under reflux until all crystallized-out material has again dissolved. Subsequently, the mixture is treated with 500 ml of hexane, cooled to about 10° while stirring and while cooling with ice, left to stand in the cold overnight and subsequently the crystal slurry obtained is removed by filtration under suction. After washing with petroleum ether and drying at 50° in a vacuum drying oven, there is obtained 10,11-dihydro-5H-dibenzo[a,d]cycloheptene-5-acetic acid as beige crystals of melting point 163°-165°.
Reaction SMILES: [C:1]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([C:17]3[C:25]4[C:20](=[CH:21][CH:22]=[C:23]([O:26][CH:27]([F:29])[F:28])[CH:24]=4)[NH:19][N:18]=3)[N:15]=2)[N:10]([CH2:30][O:31][CH2:32][CH2:33][Si:34]([CH3:37])([CH3:36])[CH3:35])[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[CH2:39][CH2:40][CH2:41][C:42]([O:44][CH3:45])=[O:43].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[CH3:45][O:44][C:42](=[O:43])[CH2:41][CH2:40][CH2:39][N:19]1[C:20]2[C:25](=[CH:24][C:23]([O:26][CH:27]([F:28])[F:29])=[CH:22][CH:21]=2)[C:17]([C:14]2[N:15]=[C:16]3[C:8]([C:6](=[O:7])[NH:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[CH:9][N:10]([CH2:30][O:31][CH2:32][CH2:33][Si:34]([CH3:37])([CH3:36])[CH3:35])[C:11]3=[N:12][CH:13]=2)=[N:18]1
Reactant: COC(=O)CCCBr
Reactant: CC(C)(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3n[nH]c4ccc(OC(F)F)cc34)nc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(=O)CCCn1nc(-c2cnc3c(n2)c(C(=O)NC(C)(C)C)cn3COCC[Si](C)(C)C)c2cc(OC(F)F)ccc21
Temperature: 100 °C
Yield: 82.6 %

Procedure:
A microwave vial was charged with 2-(5-difluoromethoxy-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid tert-butylamide (100 mg, 0.19 mmol), methyl 4-bromobutanoate (69 mg, 0.38 mmol), cesium carbonate (184 mg, 0.57 mmol) and DMF (0.85 ml). The vial was flushed with argon, sealed and heated in a microwave reactor at 100° C. for 2 h. The reaction was quenched with water and extracted with diethyl ether (2×). The combined organic layers were washed twice with water and once with brine then dried over sodium sulfate, filtered and concentrated. The residue was chromatographed over 12 g silica gel with EtOAc/hexanes (gradient: 0-30% EtOAc) to afford 99 mg (83%) of 4-{3-[7-tert-butylcarbamoyl-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]-5-difluoromethoxy-indazol-1-yl}-butyric acid methyl ester as a light yellow solid.
Reaction SMILES: [CH2:1]([C@:4]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:9][CH2:8][N:7]([C@H:10]([C:12]2[CH:17]=[CH:16][C:15]([Br:18])=[CH:14][CH:13]=2)[CH3:11])[C:6](=[O:19])[CH2:5]1)[CH:2]=[CH2:3].CN(C=[O:30])C>Cl[Pd]Cl.Cl[Cu]>[Br:18][C:15]1[CH:14]=[CH:13][C:12]([C@@H:10]([N:7]2[CH2:8][CH2:9][C@:4]([CH2:1][C:2](=[O:30])[CH3:3])([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:5][C:6]2=[O:19])[CH3:11])=[CH:17][CH:16]=1
Reactant: C=CC[C@]1(c2ccccc2)CCN([C@@H](C)c2ccc(Br)cc2)C(=O)C1
Reactant: CN(C)C=O
Agent: Cl[Cu]
Agent: Cl[Pd]Cl
Product: CC(=O)C[C@]1(c2ccccc2)CCN([C@@H](C)c2ccc(Br)cc2)C(=O)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 29.6 %

Procedure:
In a three-necked flask, a mixture of PdCl2 (180 mg, 1 mmol) and CuCl (500 mg, 5 mmol) in aqueous DMF (15 mL of DMF and 5 mL of water) was stirred under an oxygen atmosphere for 1 h at rt, and (S)-4-allyl-1-((S)-1-(4-bromophenyl)ethyl)-4-phenylpiperidin-2-one (2 g, purity=65%, 3.3 mmol) was added. The mixture was stirred vigorously under an oxygen atmosphere for 24 h at rt. The reaction mixture was quenched with aq NaHCO3 solution. The organic phase was washed with brine, and dried over NaSO4. After evaporation of the solvent, the residue was purified by prep TLC to give (R)-1-((S)-1-(4-bromophenyl)ethyl)-4-(2-oxopropyl)-4-phenylpiperidin-2-one (400 mg, 29.6%))
Reaction SMILES: [F:1][C:2]1[CH:14]=[CH:13][C:12]([Br:15])=[CH:11][C:3]=1[CH2:4][O:5][CH2:6][CH2:7][CH2:8][CH2:9][OH:10].[CH3:16]C(C)([O-])C.[K+].CI>O1CCCC1>[CH3:16][O:10][CH2:9][CH2:8][CH2:7][CH2:6][O:5][CH2:4][C:3]1[CH:11]=[C:12]([Br:15])[CH:13]=[CH:14][C:2]=1[F:1]
Reactant: OCCCCOCc1cc(Br)ccc1F
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CI
Product: COCCCCOCc1cc(Br)ccc1F
Temperature: -78 °C

Procedure:
A solution of 4-(2-fluoro-5-bromobenzyloxy)butanol (897 mg, 3.24 mmol) in tetrahydrofuran (22 ml) was cooled to −40° C. and then treated with potassium t-butoxide (3.56 ml of a 1 M solution in tetrahydrofuran, 3.56 mmol). The resulting orange solution was stirred for thirty minutes, cooled to −78° C. and treated with methyl iodide (0.40 ml, 6.48 mmol). The reaction was warmed to 0° C. and stirred for 1.5 hours. The reaction mixture was then partitioned between methylene chloride and saturated sodium bicarbonate. The organic fraction was dried over sodium sulfate, and the solvents were removed in vacuo. The desired title intermediate was further purified by high performance liquid chromatography to yield 687 mg (73%) as a clear oil.
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C@@H:10]([CH2:14][C:15]([O:17][CH3:18])=[O:16])[C:9]1=[O:19])([CH3:4])([CH3:3])[CH3:2].[CH2:21]([O:28][C:29]([NH:31][C@H:32]([C:41](O)=[O:42])[CH2:33][C:34]1[CH:39]=[CH:38][C:37]([OH:40])=[CH:36][CH:35]=1)=[O:30])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.Cl.C(N=C=NCCCN(C)C)C>ClCCl.C(OCC)(=O)C>[C:1]([O:5][C:6](=[O:20])[CH2:7][N:8]1[CH2:13][CH2:12][N:11]([C:41](=[O:42])[C@H:32]([CH2:33][C:34]2[CH:39]=[CH:38][C:37]([OH:40])=[CH:36][CH:35]=2)[NH:31][C:29]([O:28][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:30])[C@@H:10]([CH2:14][C:15]([O:17][CH3:18])=[O:16])[C:9]1=[O:19])([CH3:3])([CH3:2])[CH3:4]
Reactant: COC(=O)C[C@@H]1NCCN(CC(=O)OC(C)(C)C)C1=O
Reactant: O=C(N[C@@H](Cc1ccc(O)cc1)C(=O)O)OCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COC(=O)C[C@H]1C(=O)N(CC(=O)OC(C)(C)C)CCN1C(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OCc1ccccc1
Reaction time: 1 h
Yield: 59.5 %

Procedure:
In 15 ml of dichloromethane were dissolved 1.65 g of (S)-3-methoxycarbonylmethyl-2-oxopiperazine-1-acetic acid tert-butyl ester and 1.9 g of N-benzyloxycarbonyl-L-tyrosine. To the solution was added, while stirring for one hour, 1.44 g of 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride, and the mixture was stirred for one hour. The reaction mixture was concentrated under reduced pressure to leave an oily substance, which was dissolved in ethyl acetate. The organic layer was washed with a 5% aqueous solution of potassium hydrogen carbonate and dried over anhydrous magnesium sulfate, followed by distilling off the solvent under reduced pressure. The residue was subjected to a silica gel column chromatography (eluent: ethyl acetate: hexane=7:3) to afford 2.0 g of (S)-4-(N-benzyloxycarbonyl-L-tyrosyl)-3-methoxycarbonylmethyl-2-oxopiperazine-1-acetic acid tert-butyl ester as a colorless oily product. IR γmax cm-1 : 3332, 2952, 1740, 1646, 1613, 1514, 1444, 1367, 1227, 1153. NMR(CDCl3) δ: 1.46(9H,s), 2.30-2.53(1H,m), 2.72-3.13(5H,m), 3.50-3.72(2H,m), 3.63(3H,s), 3.85(1H,d,J=12 Hz), 4.07(1H,d,J=12 Hz), 4.70-4.90(1H,m), 4.90-5.05(1H,m), 5.11(2H,s), 5.50-5.67(2H,m), 6.76(2H,d,J=8.2 Hz), 7.03(2H,d,J=8.2 Hz), 7.36(5H,s).