Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[CH2:7][CH2:8][N:9]1[CH2:14][CH2:13][O:12][CH:11]([C:15]2[CH:20]=[CH:19][C:18]([S:21][C:22](=O)[CH3:23])=[CH:17][CH:16]=2)[CH2:10]1)([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].[Cl:28][C:29]1[CH:36]=[CH:35][CH:34]=[C:33]([Cl:37])C=1CBr>CCO.O>[C:1]([O:5][C:6](=[O:25])[CH2:7][CH2:8][N:9]1[CH2:14][CH2:13][O:12][CH:11]([C:15]2[CH:20]=[CH:19][C:18]([S:21][CH2:22][C:23]3[C:29]([Cl:28])=[CH:36][CH:35]=[CH:34][C:33]=3[Cl:37])=[CH:17][CH:16]=2)[CH2:10]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(=O)Sc1ccc(C2CN(CCC(=O)OC(C)(C)C)CCO2)cc1
Reactant: Clc1cccc(Cl)c1CBr
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(C)(C)OC(=O)CCN1CCOC(c2ccc(SCc3c(Cl)cccc3Cl)cc2)C1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 48.8 %

Procedure:
A mixture of 3-[2-(4-Acetylsulfanyl-phenyl)-morpholin-4-yl]-propionic acid tert-butyl ester (0.31 g; 0.85 mmol) and NaOH (37 mg, 0.93 mmol) in EtOH (10 mL) and water (1 mL) was stirred for 30 min at 0° C. Subsequently, 2,6-dichlorobenzyl bromide (0.22 g; 0.93 mmol), dissolved in EtOH (2.5 mL), was added, and the mixture allowed to warm to RT. After 90 min. the mixture was partitioned between EtOAc and 5% aqueous NaHCO3. The layers were separated, and the organic layer was washed with 5% aqueous NaHCO3 and brine, dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified by column chromatography (SiO2, CH2Cl2/acetone 95:5) to afford 3-{2-[4-(2,6-dichloro-benzylsulfanyl)-phenyl]-morpholin-4-yl}-propionic acid tert-butyl ester (0.20 g).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[Br:8].[C:9]([O:13][C:14](=[O:35])[NH:15][CH:16]([C:26]([N:28]1[CH2:33][CH2:32][CH:31]([CH3:34])[CH2:30][CH2:29]1)=[O:27])[CH2:17][CH2:18]C1C=CC=CC=1Cl)([CH3:12])([CH3:11])[CH3:10]>>[C:9]([O:13][C:14](=[O:35])[NH:15][CH:16]([C:26]([N:28]1[CH2:33][CH2:32][CH:31]([CH3:34])[CH2:30][CH2:29]1)=[O:27])[CH2:17][CH2:18][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[Br:8])([CH3:10])([CH3:11])[CH3:12]
Reactant: Brc1ccccc1I
Reactant: CC1CCN(C(=O)C(CCc2ccccc2Cl)NC(=O)OC(C)(C)C)CC1
Product: CC1CCN(C(=O)C(CCc2ccccc2Br)NC(=O)OC(C)(C)C)CC1

Procedure:
tert-Butyl{3-(2-bromophenyl)-1-[(4-methylpiperidin-1-yl)carbonyl]propyl}carbamate is prepared from 2-iodobromobenzene in the same manner that tert-butyl{3-(2-chlorophenyl)-1-[(4-methylpiperidin-1-yl)carbonyl]propyl}carbamate is synthesized.
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([C:12]2[CH:17]=[CH:16][C:15]([S:18]([CH:21]3[CH2:23][CH2:22]3)(=[O:20])=[O:19])=[CH:14][CH:13]=2)[C:8]([O:10]C)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.O1CCCC1.[OH-].[Na+].Cl>CO>[CH:1]1([CH2:6][CH:7]([C:12]2[CH:17]=[CH:16][C:15]([S:18]([CH:21]3[CH2:23][CH2:22]3)(=[O:19])=[O:20])=[CH:14][CH:13]=2)[C:8]([OH:10])=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COC(=O)C(CC1CCCC1)c1ccc(S(=O)(=O)C2CC2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)C(CC1CCCC1)c1ccc(S(=O)(=O)C2CC2)cc1
Temperature: 50 °C
Reaction time: 3 h
Yield: 89.4 %

Procedure:
To a solution of methyl 3-cyclopentyl-2-[4-(cyclopropylsulfonyl)phenyl]propanoate (1.95 g) in a mixed solvent of tetrahydrofuran (40 mL) and methanol (20 mL) was added 2N aqueous sodium hydroxide solution (10 mL), and the mixture was stirred at 50° C. for 3 hr. The reaction mixture was acidified with 1N hydrochloric acid, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was recrystallized from hexane-diethyl ether to give the title compound (1.67 g, 89%) as colorless crystals. MS: 323 (MH+).
Reaction SMILES: [CH3:1][CH:2]([O:4][C:5](=[O:28])[NH:6][C@H:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:17]3[O:18][C:19]([CH:22]=O)=[CH:20][CH:21]=3)[CH:15]=2)[N:10]([C:24](=[O:26])[CH3:25])[C@@H:9]([CH3:27])[CH2:8]1)[CH3:3].C(O)(=O)C.[NH:33]1[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[C:24]([N:10]1[C:11]2[C:16](=[CH:15][C:14]([C:17]3[O:18][C:19]([CH2:22][N:33]4[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]4)=[CH:20][CH:21]=3)=[CH:13][CH:12]=2)[C@H:7]([NH:6][C:5](=[O:28])[O:4][CH:2]([CH3:1])[CH3:3])[CH2:8][C@@H:9]1[CH3:27])(=[O:26])[CH3:25]
Reactant: CC(=O)N1c2ccc(-c3ccc(C=O)o3)cc2[C@H](NC(=O)OC(C)C)C[C@@H]1C
Reactant: C1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CC(=O)N1c2ccc(-c3ccc(CN4CCCCC4)o3)cc2[C@H](NC(=O)OC(C)C)C[C@@H]1C
Reaction time: 0.5 h

Procedure:
1-Methylethyl[(cis)-1-acetyl-6-(5-formyl-2-furanyl)-2-methyl-1,2,3,4-tetrahydro-4-quinolinyl]carbamate (for a preparation see Intermediate 21) (18 mg, 0.047 mmol) was dissolved in dichloromethane (DCM) (1 mL), mixed with acetic acid (8.04 μL, 0.140 mmol) and piperidine (9.27 μL, 0.094 mmol) and stirred under nitrogen for 30 minutes. sodium triacetoxyborohydride (12.90 mg, 0.061 mmol) was added and the reaction was stirred again under nitrogen. After 17 hours reaction time a second quantity of sodium triacetoxyborohydride (12.90 mg, 0.061 mmol) was added. 1 hour after this another sample of sodium triacetoxyborohydride (12.90 mg, 0.061 mmol) was added. After 2 further hours the reaction was loaded onto a 2 g Flash SCX-column, eluting with MeOH (60 mL) followed by 2M MeOH/NH3 (60 mL). The product-containing fraction was evaporated to dryness to give a brown solid which was purified by MDAP. Product-containing fractions were evaporated to dryness to give a clear, colourless solid (3 mg).
Reaction SMILES: [CH3:1][N:2]1[CH2:9][CH2:8][CH:7]2[CH:3]1[CH2:4][N:5](C(OCC)=O)[CH2:6]2.C(=O)([O-])[O-].[K+].[K+]>Cl>[CH3:1][N:2]1[CH2:9][CH2:8][CH:7]2[CH:3]1[CH2:4][NH:5][CH2:6]2
Reactant: CCOC(=O)N1CC2CCN(C)C2C1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CN1CCC2CNCC21

Procedure:
9 g (45.4 mmol) of ethyl 2-methyl-2,7-diazabicyclo[3.3.0]octane-7-carboxylate together with 50 ml of concentrated hydrochloric acid are refluxed overnight. The batch is rendered alkaline using potassium carbonate and extracted ten times using 50 ml portions of chloroform, and the extracts are dried over potassium carbonate, concentrated and distilled.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9](=O)[CH2:10][C:11](=O)[C:12]([F:15])([F:14])[F:13].[NH2:18][C:19]1[N:20]=[CH:21][NH:22][C:23]=1[C:24]#[N:25]>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:10]=[C:11]([C:12]([F:15])([F:14])[F:13])[N:20]2[CH:21]=[N:22][C:23]([C:24]#[N:25])=[C:19]2[N:18]=1
Reactant: O=C(CC(=O)C(F)(F)F)c1ccc(Cl)cc1Cl
Reactant: N#Cc1[nH]cnc1N
Product: N#Cc1ncn2c(C(F)(F)F)cc(-c3ccc(Cl)cc3Cl)nc12
Yield: 12 %

Procedure:
Reaction of 1-(2,4-dichloro-phenyl)-4,4,4-trifluoro-butane-1,3-dione (285 mg, 1.0 mmol), prepared from commercially available 2,4-dichloro-acetophenone according to general procedure A, and 4-amino-5-cyano-1H-imidazole (108 mg, 1.0 mmol) according to general procedure B yielded the title compound as a yellow solid (43 mg, 12%). MS (ISP) 357.0 [(M+H)+]; mp 139° C.
Reaction SMILES: COC1C=C[C:6]2N=CC=[C:9]([C@@H](O)[C@H]3N4C[C@H](C=C)[C@@H](CC4)C3)[C:7]=2[CH:8]=1.C1(C(N)CC2C=CC=CC=2)C=CC=CC=1.CC(N(C)C)C(O)C1C=CC=CC=1.[CH3:53][C:54]1([CH3:60])[CH2:56][CH:55]1[C:57](O)=[O:58]>>[CH:7]1([CH3:9])[CH2:8][CH2:56][CH:55]([CH:54]([CH3:60])[CH3:53])[CH:57]([OH:58])[CH2:6]1
Reactant: C=C[C@H]1CN2CC[C@H]1C[C@H]2[C@H](O)c1ccnc2ccc(OC)cc12
Reactant: CC1(C)CC1C(=O)O
Agent: CC(C(O)c1ccccc1)N(C)C
Agent: NC(Cc1ccccc1)c1ccccc1
Product: CC1CCC(C(C)C)C(O)C1

Procedure:
With 1-phenylethylamine neither a satisfactory yield nor an adequate optical purity could be achieved. Quinine yielded enantiomer in good optical purity but poor yield, no yield was indicated for N-methylephedfine With 1,2-diphenylethylamine the yield is satisfactory and the optical purity very good but the reagent, as is also N-methylephedrine is very expensive. Further, it is known that 2,2-dimethylcyclopropanecarboxylic acid can be separated into the enantiomers by the diastereomeric menthyl esters, which can be obtained from the acid chloride with (+) or (-) menthol (U.S. Pat. No. 4,487,956). This process does provide usable yields and optical purities, but is relatively complicated in working up and requires the relatively expensive menthol.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]3[CH:19]=[C:18]([CH3:20])[C:17](=[O:21])[C:8]4[CH:9]=[C:10]([O:15]C)[CH:11]=[C:12]([C:13]=2[CH:14]=1)[C:7]3=4.B(Br)(Br)Br>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]3[CH:19]=[C:18]([CH3:20])[C:17](=[O:21])[C:8]4[CH:9]=[C:10]([OH:15])[CH:11]=[C:12]([C:13]=2[CH:14]=1)[C:7]3=4
Reactant: COc1cc2c(=O)c(C)cn3c4ccc(Br)cc4c(c1)c23
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Cc1cn2c3ccc(Br)cc3c3cc(O)cc(c1=O)c32
Temperature: 25 °C
Reaction time: 12 h
Yield: 99.9 %

Procedure:
10-bromo-2-methoxy-5-methyl-4H-pyrido[3,2,1-jk]carbazole-4-one (4.8 g) obtained in Example 48 was suspended in anhydrous methylene chloride (400 ml), and boron tribromide (25 g) was added dropwise to the suspension at room temperature. The mixture was stirred at room temperature for 12 hours and the reaction mixture was poured into ice water (1500 ml) and the crystals precipitated were recovered by filtration. The resulting crude crystals were washed with ether, and recovered by filtration to obtain the title compound (4.6 g, constant amount).
Reaction SMILES: [CH2:1]([C:3]1[N:7]([C:8]2[N:16]=[C:15]3[C:11]([N:12]=[C:13]([C:18]4([OH:24])[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]4)[N:14]3[CH3:17])=[C:10]([N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)[N:9]=2)[C:6]2[CH:31]=[CH:32][CH:33]=[CH:34][C:5]=2[N:4]=1)[CH3:2].[OH:35][C:36]([CH3:41])([CH3:40])[C:37](O)=[O:38].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[CH2:1]([C:3]1[N:7]([C:8]2[N:16]=[C:15]3[C:11]([N:12]=[C:13]([C:18]4([OH:24])[CH2:19][CH2:20][N:21]([C:37](=[O:38])[C:36]([OH:35])([CH3:41])[CH3:40])[CH2:22][CH2:23]4)[N:14]3[CH3:17])=[C:10]([N:25]3[CH2:26][CH2:27][O:28][CH2:29][CH2:30]3)[N:9]=2)[C:6]2[CH:31]=[CH:32][CH:33]=[CH:34][C:5]=2[N:4]=1)[CH3:2]
Reactant: CC(C)(O)C(=O)O
Reactant: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C3(O)CCNCC3)n(C)c2n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C3(O)CCN(C(=O)C(C)(C)O)CC3)n(C)c2n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 34.2 %

Procedure:
To a mixture of 4-[2-(2-ethylbenzoimidazol-1-yl)-9-methyl-6-morpholin-4-yl-9H-purin-8-yl]piperidin-4-ol (150 mg, 0.32 mmol), 2-hydroxyisobutyric acid (41 mg, 0.39 mmol) and DIPEA (68 μL, 0.39 mmol) in DCM (2 mL) was added HATU (149 mg, 0.39 mmol). The resulting mixture was allowed to stir at r.t. for 18 h then diluted with DCM and washed with sat. aq. NaHCO3. The organic phase was dried (Na2SO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, MeOH:EtOAc, 0-20%) affording 790 (60 mg, 34%). LCMS (method I): RT 3.09 min, [M+H]+ 549.3. 1H NMR (DMSO, 400 MHz): δ 8.02-8.01 (1 H, m), 7.64-7.63 (1 H, m), 7.27-7.23 (2 H, m), 5.84 (1 H, s), 5.42 (1 H, s), 4.25 (6 H, brd s), 3.98 (3 H, s), 3.77 (4 H, t, J=4.55 Hz), 3.60 (1 H, brd s), 3.2-3.24 (3 H, m), 2.11-2.10 (2 H, m), 2.06-1.94 (2 H, m), 1.38-1.30 (9 H, m)
Reaction SMILES: N[CH2:2][CH2:3][CH2:4][CH2:5][C:6]([OH:8])=[O:7].C(N(CC)CC)C.[CH3:16][C:17]([O:20][C:21](ON=C(C1C=CC=CC=1)C#N)=[O:22])([CH3:19])[CH3:18]>O1CCOCC1>[C:17]([O:20][C:21]([CH2:2][CH2:3][CH2:4][CH2:5][C:6]([OH:8])=[O:7])=[O:22])([CH3:19])([CH3:18])[CH3:16]
Reactant: NCCCCC(=O)O
Reactant: CC(C)(C)OC(=O)ON=C(C#N)c1ccccc1
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)CCCCC(=O)O
Yield: 52.7 %

Procedure:
Prepared as described for L3 from stirring 5-aminopentanoic acid (3.40 g, 29.1 mmol) in 50% aqueous dioxane with triethylamine (6.0 mL, 43.1 mmol) and BOC-ON (7.91 g, 32.1 mmol) to yield a cream solid (3.10 g, 48.8%).
Reaction SMILES: C[O:2][C:3]([CH:5]1[CH:10]([N:11]([CH3:34])[S:12]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]3[C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[N:26]=[C:25]([CH3:33])[CH:24]=3)=[CH:17][CH:16]=2)(=[O:14])=[O:13])[CH2:9][CH2:8][O:7][CH2:6]1)=[O:4].[OH-].[Li+].Cl>C1COCC1.CO.O.C(OCC)(=O)C>[CH3:34][N:11]([S:12]([C:15]1[CH:16]=[CH:17][C:18]([O:21][CH2:22][C:23]2[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[N:26]=[C:25]([CH3:33])[CH:24]=2)=[CH:19][CH:20]=1)(=[O:13])=[O:14])[CH:10]1[CH2:9][CH2:8][O:7][CH2:6][CH:5]1[C:3]([OH:4])=[O:2]
Reactant: COC(=O)C1COCCC1N(C)S(=O)(=O)c1ccc(OCc2cc(C)nc3ccccc23)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(COc2ccc(S(=O)(=O)N(C)C3CCOCC3C(=O)O)cc2)c2ccccc2n1

Procedure:
A solution of 4-{methyl-[4-(2-methyl-quinolin-4-ylmethoxy)-benzenesulfonyl]-amino}-tetrahydro-pyran-3-carboxylic acid methyl ester (0.2 g, 0.41 mmol) and lithium hydroxide (0.148 g, 4.1 mmol) in THF:methanol:H2O (2.5: 1.5:1.5 mL) was stirred at 25° C. for 19 h. The solution was then diluted with ethyl acetate (2×30 mL) and the aqueous layer was acidified with 2N HCl to pH ˜2. The aqueous layer was washed with ethyl acetate (3×40 mL). The combined organic layers were dried over MgSO4, filtered and concentrated to produce 4-{methyl-[4-(2-methyl-quinolin-4-ylmethoxy)-benzenesulfonyl]-amino}-tetrahydro-pyran-3-carboxylic acid as a crude solid (0.120 g, 63%). MS: 457 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([C:13]2[CH:18]=[CH:17][C:16]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([S:25]([CH3:28])(=[O:27])=[O:26])[CH:20]=3)=[C:15]([C:29]([N:31]3[CH2:36][CH2:35][O:34][CH2:33][CH2:32]3)=O)[CH:14]=2)=[CH:11][C:10]([C:37]([F:40])([F:39])[F:38])=[N:9]1.CO>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([C:13]2[CH:18]=[CH:17][C:16]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([S:25]([CH3:28])(=[O:26])=[O:27])[CH:20]=3)=[C:15]([CH2:29][N:31]3[CH2:36][CH2:35][O:34][CH2:33][CH2:32]3)[CH:14]=2)=[CH:11][C:10]([C:37]([F:38])([F:39])[F:40])=[N:9]1
Reactant: CS(=O)(=O)c1cccc(-c2ccc(-c3cc(C(F)(F)F)nn3-c3ccccc3Cl)cc2C(=O)N2CCOCC2)c1
Solvent: CO
Solvent: C1CCOC1
Product: CS(=O)(=O)c1cccc(-c2ccc(-c3cc(C(F)(F)F)nn3-c3ccccc3Cl)cc2CN2CCOCC2)c1
Temperature: 20 °C
Reaction time: 8 h
Yield: 44.5 %

Procedure:
To a solution of BH3 (1 M, 4 mL) in THF was added (4-(1-(2-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)-3′-(methylsulfonyl)biphenyl-2-yl)(morpholino)-methanone (4.60 mg, 0.78 mmol) and the solution was stirred overnight at 20° C. MeOH was added to quench borane and solvent was evaporated to afford a crude, which was purified by column chromatography on silica gel eluting with MeOH-DCM (1:19) to afford 4-((4-(1-(2-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)-3′-(methylsulfonyl)biphenyl-2-yl)methyl)morpholine (0.2 g). 1H-NMR (CDCl3): δ 8.25 (m, 1H), 7.93 (m, 1H), 7.72 (m, 1H), 7.60 (m, 1H), 7.55 (m, 1H), 7.49-7.39 (m, 3H), 7.33-7.26 (m, 2H), 7.18 (m, 1H), 6.85 (s, 1H), 3.58 (m, 4H), 3.16 (s, 3H), 3.07 (s, 3H), 2.14 (m, 4H). MS(ES): 576 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6](I)[C:5]([O:11][CH3:12])=[C:4]([O:13][CH3:14])[CH:3]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.B([O-])O[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][N:37]=1.C([O-])([O-])=O.[K+].[K+]>CC([O-])=O.CC([O-])=O.[Pd+2].O.C1COCC1>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][N:37]=2)[C:5]([O:11][CH3:12])=[C:4]([O:13][CH3:14])[CH:3]=1
Reactant: COc1cc(N)c(C#N)c(I)c1OC
Reactant: [O-]BOc1ccccn1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1CCOC1
Product: COc1cc(N)c(C#N)c(-c2ccccn2)c1OC
Temperature: 25 °C
Yield: 89.8 %

Procedure:
Under nitrogen, to anhydrous THF (1000 ml) was added 6-amino-2-iodo-3,4-dimethoxybenzonitrile (see Example 1, 50.0 g, 164 mmol), Pd(OAc)2 (1.85 g, 8.22 mmol), PPh3 (triphenylphosphine, 4.31 g, 16.4 mmol), THF wet boronate [from step (a), 286 g, 493 mmol], Cul (12.5 g, 65 mmol) and K2CO3 (45.5 g, 328 mmol). The reaction mixture was then stirred at reflux for 16 hours. After this time, the reaction mixture was cooled to room temperature and water (1000 ml) added. The mixture was then filtered through an Arbocel™ filter aid pad and the pad washed with THF (500 ml). The filtrate was then extracted with CH2Cl2 (1000 ml). The aqueous phase was back extracted with CH2Cl2 (500 ml) and the combined CH2Cl2 extracts were evaporated in vacuo to yield the crude product as a dark brown solid. Recrystallisation from EtOAc (250 ml) afforded 37.6 g (87%) of the title compound as a beige solid.
Reaction SMILES: [C:1]([OH:6])(=O)[CH:2]([CH3:4])[CH3:3].[CH3:7][C:8]1[O:9][CH:10]=[CH:11][CH:12]=1.ClC(Cl)C(OC(=O)C(Cl)Cl)=O>C1(C)C=CC=CC=1>[C:1]([C:10]1[O:9][C:8]([CH3:7])=[CH:12][CH:11]=1)(=[O:6])[CH:2]([CH3:4])[CH3:3]
Reactant: Cc1ccco1
Reactant: CC(C)C(=O)O
Agent: O=C(OC(=O)C(Cl)Cl)C(Cl)Cl
Solvent: Cc1ccccc1
Product: Cc1ccc(C(=O)C(C)C)o1
Temperature: 50 °C
Reaction time: 3 h
Yield: 88.6 %

Procedure:
In 50 ml of toluene were dissolved 4.41 g (0.05 mole) of isobutyric acid, 5.34 g (0.065 mole) of 2-methylfuran and 14.39 g (0.06 mole) of dichloroacetic anhydride. To the resulting solution was added 0.71 g of boron trifluoride-diethyl ether complex and the resulting mixture was then stirred at 50° C. for 3 hours. After completion of the reaction, the reaction solution was cooled and washed successively with 5% aqueous sodium carbonate solution and water. The organic layer was concentrated under reduced pressure and the resulting concentrated residue was then purified by silica gel-filled column chromatography to obtain 6.74 g of 2-isobutyryl-5-methylfuran.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][CH:5]([C:8](=[O:10])[CH3:9])[CH2:4][CH2:3]1.[CH3:11][C:12]([CH2:16]O)([CH2:14][OH:15])[CH3:13]>CC1C=CC(S(O)(=O)=O)=CC=1.C1(C)C=CC=CC=1>[CH3:9][C:8]1([CH:5]2[CH2:6][CH2:7][CH:2]([OH:1])[CH2:3][CH2:4]2)[O:15][CH2:14][C:12]([CH3:16])([CH3:13])[CH2:11][O:10]1
Reactant: CC(C)(CO)CO
Reactant: CC(=O)C1CCC(O)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CC1(C)COC(C)(C2CCC(O)CC2)OC1
Temperature: 25 °C
Yield: 62 %

Procedure:
A mixture of 1-(4-hydroxy-cyclohexyl)-ethanone (2.24 g, 1 eq.), toluene (160 mL), neopentylglycol (1.96 g, 1.2 eq.) and pTsOH (150 mg, 0.05 eq.) in a flask equipped with Dean-Stark apparatus was heated to reflux overnight. The mixture was cooled down to room temperature and contentrated. The crude product was purified by silic gel column chromatography (25% to 50% EtOAc/hexanes) to give 4-(2,5,5-trimethyl-[1,3]dioxan-2-yl)-cyclohexanol (2.23 g, 62%).
Reaction SMILES: [CH2:1]([O:3][C@@H:4]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[N:17]([CH3:24])[N:18]=[C:19]([N+:21]([O-])=O)[N:20]=2)=[CH:12][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6])[CH3:2]>C(O)C.CO.[Pd]>[NH2:21][C:19]1[N:20]=[C:16]([C:13]2[CH:12]=[CH:11][C:10]([CH2:9][C@H:4]([O:3][CH2:1][CH3:2])[C:5]([O:7][CH3:8])=[O:6])=[CH:15][CH:14]=2)[N:17]([CH3:24])[N:18]=1
Reactant: CCO[C@@H](Cc1ccc(-c2nc([N+](=O)[O-])nn2C)cc1)C(=O)OC
Agent: [Pd]
Solvent: CCO
Solvent: CO
Product: CCO[C@@H](Cc1ccc(-c2nc(N)nn2C)cc1)C(=O)OC
Reaction time: 3 h
Yield: 99.8 %

Procedure:
0.4 g (0.4 mass equivalent) of 10% palladium-on-charcoal is added to a solution of 0.9 g (2.7 mmol) of methyl 2(S)-ethoxy-3-[4-(2-methyl-5-nitro-2H-[1,2,4]triazol-3-yl)phenyl]propanoate in 40 ml of ethanol and 10 ml of methanol, degassed beforehand, and the reaction medium is placed under an atmospheric pressure of hydrogen for 3 hours. After filtration through Celite and washing with ethyl acetate, the filtrate is evaporated under vacuum. 0.82 g (100%) of methyl 3-[4-(5-amino-2-methyl-2H-[1,2,4]triazol-3-yl)phenyl]-2(S)-ethoxypropanoate is obtained.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:23]=[CH:24][CH:25]=1)[CH2:5][C:6]1[CH:7]=[C:8]([CH:20]=[CH:21][CH:22]=1)[C:9]([NH:11][CH2:12][CH2:13][C:14]#[C:15][Si:16]([CH3:19])([CH3:18])[CH3:17])=[O:10].[Cl:26][C:27]1[CH:33]=[C:32]([Cl:34])[CH:31]=[C:30](I)[C:28]=1[NH2:29].C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Cl:34][C:32]1[CH:31]=[C:30]2[C:28](=[C:27]([Cl:26])[CH:33]=1)[NH:29][C:15]([Si:16]([CH3:17])([CH3:18])[CH3:19])=[C:14]2[CH2:13][CH2:12][NH:11][C:9](=[O:10])[C:8]1[CH:20]=[CH:21][CH:22]=[C:6]([CH2:5][C:4]2[CH:23]=[CH:24][CH:25]=[C:2]([F:1])[CH:3]=2)[CH:7]=1
Reactant: Nc1c(Cl)cc(Cl)cc1I
Reactant: C[Si](C)(C)C#CCCNC(=O)c1cccc(Cc2cccc(F)c2)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: C[Si](C)(C)c1[nH]c2c(Cl)cc(Cl)cc2c1CCNC(=O)c1cccc(Cc2cccc(F)c2)c1
Temperature: 100 °C
Yield: 24 %

Procedure:
A mixture of 3-(3-fluorobenzyl)-N-(4-(trimethylsilyl)but-3-ynyl)benzamide (0.130 g; 0.365 mmol), 2,4-dichloro-6-iodoaniline (0.127 g; 0.441 mmol), palladium (II) acetate (0.016 g; 0.073 mmol) and sodium carbonate (0.195 g; 1.84 mmol) in DMF (8 mL) was heated at 100° C. for 18 hours in a sealed tube and concentrated under reduced pressure. The residue was suspended in brine and extracted with dichloromethane (2×100 mL). The organic layer was dried and concentrated under reduced pressure. The crude material was purified by flash chromatography on silica gel (eluent 2 to 10% ethyl acetate in dichloromethane) to furnish 0.045 g (23%) of N-(2-(5,7-dichloro-2-(trimethylsilyl)-1H-indol-3-yl)ethyl)-3-(3-fluorobenzyl)benzamide.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:11]2[C:7]([CH2:8][CH2:9][NH:10]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH3:13][N:14]1[CH2:19][CH2:18][C:17](=O)[CH2:16][CH2:15]1.C([O-])(O)=O.[Na+]>ClC(Cl)C>[CH3:13][N:14]1[CH2:19][CH2:18][CH:17]([N:10]2[C:11]3[C:7](=[CH:6][CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:12]=3)[CH2:8][CH2:9]2)[CH2:16][CH2:15]1
Reactant: CN1CCC(=O)CC1
Reactant: O=[N+]([O-])c1ccc2c(c1)NCC2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(Cl)Cl
Product: CN1CCC(N2CCc3ccc([N+](=O)[O-])cc32)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
6-Nitroindoline (5 g) was dissolved in 200 mL of dichloroethane. N-Methyl-4-piperidone (5 g) was added to the mixture, followed by NaHB(OAc)3 (12 g) and 1 mL of glacial ACOH. The mixture was stirred at RT overnight. A saturated NaHCO3 (200 mL) solution was added to the reaction mixture and stirred for 1 h. The resulting mixture was separated by separation funnel. The organic layer was extracted once with saturated NaHCO3 solution and once with brine. The resulting organic layer was dried over MgSO4, filtered and concentrated in vacuo. The crude material was purified by flash chromatography on silica gel with 2:1 EtOAc:MeOH to afford orange oil. MS: 262 (M+1). Calc'd. for C14H19N3O2−261.3.
Reaction SMILES: [Li]CCCC.Br[C:7]1[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=1.[O:13]1[C:17]2([CH2:22][CH2:21][C:20](=[O:23])[CH2:19][CH2:18]2)[O:16][CH2:15][CH2:14]1.O>C1COCC1>[N:10]1[CH:11]=[CH:12][C:7]([C:20]2([OH:23])[CH2:21][CH2:22][C:17]3([O:16][CH2:15][CH2:14][O:13]3)[CH2:18][CH2:19]2)=[CH:8][CH:9]=1
Reactant: O=C1CCC2(CC1)OCCO2
Reactant: Brc1ccncc1
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: OC1(c2ccncc2)CCC2(CC1)OCCO2
Temperature: -78 °C
Reaction time: 1.5 h
Yield: 64 %

Procedure:
n-BuLi (32 ml, 64.0 mmol, 2 eq, 2 M solution in hexane) was placed in THF (60 ml) and cooled to −78° C. A solution of 4-bromopyridine (6.3 g, 40.0 mmol, 1.25 eq) in THF (50 ml) was slowly added dropwise at that temperature, and stirring was carried out for 1.5 h. A solution of 1,4-dioxaspiro[4.5]decan-8-one (5.0 g, 32.0 mmol, 1 eq) in THF (50 ml) was added likewise at −78° C., and stirring was carried out for 2 h. After monitoring by thin-layer chromatography, the reaction solution was hydrolyzed with water (100 ml), while cooling, and extracted with ethyl acetate (2×200 ml). The combined organic phases were washed with water (100 ml) and sat. NaCl solution (100 ml), dried over sodium sulfate and concentrated under reduced pressure. After purification by column chromatography (silica gel, 2% MeOH in dichloromethane), the desired product was obtained in the form of a light-brown solid. Yield: 64% (6.0 g, 25.53 mmol).