Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:5]([OH:14])([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:6]#[CH:7])[CH2:4][CH2:3][CH2:2]1.C(N)(=[O:17])C.[OH-].[K+]>C(O)(=O)C.C(OC(=O)C)(=O)C.C(Cl)Cl.O>[CH:1]1([C:5]([OH:14])([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:6](=[O:17])[CH3:7])[CH2:4][CH2:3][CH2:2]1
Reactant: C#CC(O)(c1ccccc1)C1CCC1
Reactant: CC(N)=O
Agent: [K+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: CC(=O)OC(C)=O
Product: CC(=O)C(O)(c1ccccc1)C1CCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.5 %

Procedure:
To a solution of 259.9 g (1.4 mole) of 1-cyclobutyl-1-hydroxy-1-phenyl-2-propyne in 1500 mL of acetic acid and 150 mL of acetic anhydride was added 445.2 g (1.4 mole) of mercuric acetate. The mixture was stirred overnight at room temperature. The solution was diluted with 1.5 L of methylene chloride and to it was added 1.5 L of celite and 115 g of acetamide. After being stirred for 24 hours, the mixture was filtered through a pad of celite. The solid residue was washed four times with 500 mL portions of methylene chloride. The organic layers were combined, washed three times with water, three times with saturated sodium bicarbonate. The solvent was removed under reduced pressure. The residue was dissolved in 1200 mL of methanol and 102 g (1.54 mole) of potassium hydroxide was added. The mixture was brought to reflux for 2 hours and allowed to cool to room temperature. The mixture was diluted with 1500 mL of water and extracted four times with 500 mL of ether. The organic layers were combined washed three times with water, dried over anhydrous magnesium sulfate and the solvent removed under reduced pressure. The residue was distilled bulb-to-bulb to give 224.5 g of 1-cyclobutyl-1-hydroxy-1-phenyl-2-propanone, bath temperature 110° C. NMR (CDCl3) 1.7-2.2 (m, 6 H), 2.0 (s, 3 H), 3.5 (m, 1 H), 4.7 (s, 1 H), 7.2-7.5 (m, 5 H); IR (neat film) 3460, 2940, 1710, 1360, 1140, 760, 700 cm-1.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].C([O-])([O-])=O.[K+].[K+].CN(C=O)C.I[CH2:22][CH2:23][CH3:24]>C1(C)C=CC=CC=1.O>[CH2:22]([O:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6])[CH2:23][CH3:24]
Reactant: CCCI
Reactant: O=Cc1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: Cc1ccccc1
Product: CCCOc1cccc(C=O)c1
Temperature: 50 °C
Reaction time: 4 h

Procedure:
Combine 3-hydroxybenzaldehyde (790 g), K2CO3, (1627 g) and DMF (8 L). Add 1-iodopropane (1000 g) and heat to 105° C. and stir for 4 h. Cool to about 50° C. and add water (15 L), continue cooling to about room temperature and add toluene (10 L). Separate the organic layer and extract the aqueous phase with toluene (2×10 L), combine organic phases and wash with NaOH 1N (2×5.8 L), concentrate the combined organic layers in vacuo to afford the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]([C:17]([NH:19][CH3:20])=[O:18])=[C:15]3[C:10]([CH:11]=[C:12]([N:24]([CH2:29][CH2:30][N:31]4C(=O)C5C(=CC=CC=5)C4=O)[S:25]([CH3:28])(=[O:27])=[O:26])[C:13]([CH:21]4[CH2:23][CH2:22]4)=[CH:14]3)=[N:9]2)=[CH:4][CH:3]=1.O.NN>C(O)C>[NH2:31][CH2:30][CH2:29][N:24]([S:25]([CH3:28])(=[O:26])=[O:27])[C:12]1[C:13]([CH:21]2[CH2:22][CH2:23]2)=[CH:14][C:15]2[C:10]([CH:11]=1)=[N:9][N:8]([C:5]1[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][CH:6]=1)[C:16]=2[C:17]([NH:19][CH3:20])=[O:18]
Reactant: CNC(=O)c1c2cc(C3CC3)c(N(CCN3C(=O)c4ccccc4C3=O)S(C)(=O)=O)cc2nn1-c1ccc(Br)cc1
Agent: NN
Solvent: CCO
Solvent: O
Product: CNC(=O)c1c2cc(C3CC3)c(N(CCN)S(C)(=O)=O)cc2nn1-c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 95.9 %

Procedure:
A mixture of Compound (6) (92 mg, 0.14 mmol) and hydrazine hydrate (0.15 mL) in ethanol (7 mL) was stirred at RT for 16 h. The resulting suspension was filtered and the filtrate was concentrated to give a crude oil which then was partitioned between EtOAc (5 mL) and water (2 mL). The organic phase was separated and the aqueous phase was extracted with EtOAc (3×3 mL). The combined organic phase was dried (MgSO4) and the solvent was removed in vacuo to give 6-[(2-aminoethyl)(methylsulfonyl)amino]-2-(4-bromophenyl)-5-cyclopropyl-N-methyl-2H-indazole-3-carboxamide (7) (68 mg, 93%). ESI-MS m/z calculated for [M+H]+: 506.08/508.09; found: 505.88/507.89.
Reaction SMILES: [CH3:1][O:2][C:3]([O:13][CH3:14])([O:11][CH3:12])[C:4]1[CH:9]=[CH:8][C:7](Br)=[CH:6][CH:5]=1.C[C:16](C)(C)[CH2:17][C:18]([CH2:23]O)([CH2:21]O)[CH2:19]O>Cl>[CH3:23][C:18]([CH3:19])([CH3:21])[CH2:17][C:16]12[CH2:14][O:13][C:3]([C:4]3[CH:9]=[CH:8][C:7]([CH2:5][CH2:4][CH2:3][O:2][CH3:1])=[CH:6][CH:5]=3)([O:11][CH2:12]1)[O:2][CH2:1]2
Reactant: COC(OC)(OC)c1ccc(Br)cc1
Reactant: CC(C)(C)CC(CO)(CO)CO
Agent: Cl
Product: COCCCc1ccc(C23OCC(CC(C)(C)C)(CO2)CO3)cc1

Procedure:
Trimethyl 4-bromo-orthobenzoate (1.5 g.) (McElvain and Venerable, J. Amer.Chem.Soc., 1950,72,1661) was added to 2-(2,2-dimethylpropyl)-2-hydroxymethyl-propan-1,3-diol (1.0 g.). One drop of concentrated hydrochloric acid was added and the mixture was maintained at 140° for one hour, under a current of nitrogen. The volatile components were removed in vacuo (1.0 mm), at 140° C.
Reaction SMILES: Cl.C(O)(=O)C.C([NH:10][C:11]1[N:16]=[C:15]([N:17]2[C:26]3[C:21](=[CH:22][C:23]([F:29])=[C:24]([F:28])[C:25]=3[F:27])[C:20](=[O:30])[C:19]([C:31]([O:33]CC)=[O:32])=[CH:18]2)[C:14]([F:36])=[CH:13][C:12]=1[F:37])(C)(C)C>O>[NH2:10][C:11]1[N:16]=[C:15]([N:17]2[C:26]3[C:21](=[CH:22][C:23]([F:29])=[C:24]([F:28])[C:25]=3[F:27])[C:20](=[O:30])[C:19]([C:31]([OH:33])=[O:32])=[CH:18]2)[C:14]([F:36])=[CH:13][C:12]=1[F:37]
Reactant: CCOC(=O)c1cn(-c2nc(NC(C)(C)C)c(F)cc2F)c2c(F)c(F)c(F)cc2c1=O
Agent: Cl
Solvent: CC(=O)O
Solvent: O
Product: Nc1nc(-n2cc(C(=O)O)c(=O)c3cc(F)c(F)c(F)c32)c(F)cc1F
Reaction time: 7 h
Yield: 95 %

Procedure:
To a mixed solution of 0.5 ml of 4N hydrochloric acid and 0.5 ml of acetic acid was added 235 mg of ethyl 1-[6-(t-butylamino)-3,5-difluoropyridine-2-yl]-6,7,8-trifluoro-4-oxo-1,4-dihydroquinoline-3-carboxylate, and the mixture was heated under reflux with stirring for 7 hours. After adding 1 ml of distilled water, the mixture was allowed to cool, and the precipitate was collected by filtration and washed with ethanol and diisopropylether successively to obtain 182 mg of the title compound as a colorless powder.
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)[CH:2]=[CH2:3].[CH3:11][O:12][C:13]1[CH:20]=[CH:19][C:16]([CH2:17]Cl)=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CC(C)=O.O>[CH2:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:17][C:16]2[CH:19]=[CH:20][C:13]([O:12][CH3:11])=[CH:14][CH:15]=2)=[CH:6][CH:5]=1)[CH:2]=[CH2:3]
Reactant: COc1ccc(CCl)cc1
Reactant: C=CCc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: C=CCc1ccc(OCc2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4-Allylphenol, (6.14 g, 0.046 moles), 4-methoxybenzyl chloride, (6.3 ml, 0.046 moles), potassium carbonate (8.3 g, 0.06 moles) and a catalytic amount of potassium iodide were mixed together in about 200 ml acetone, and heated to reflux, with stirring. The reaction was allowed to proceed overnight, then cooled to room temperature and diluted with about 100 ml water. The product was extracted into ethyl acetate (3 times, 300 ml each time), and then dried over magnesium sulfate/potassium carbonate, filtered and concentrated in vacuo to yield the title compound as a light yellow solid, m.p. 59-61° C.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([N:15]3[CH:19]=[CH:18][N:17]=[CH:16]3)=[C:11]([F:20])[CH:10]=2)[C:5]([C:21]([O:23]CC)=[O:22])=[CH:4][N:3]=1.[Li+].[OH-]>C1COCC1>[Cl:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([N:15]3[CH:19]=[CH:18][N:17]=[CH:16]3)=[C:11]([F:20])[CH:10]=2)[C:5]([C:21]([OH:23])=[O:22])=[CH:4][N:3]=1
Reactant: CCOC(=O)c1cnc(Cl)nc1Nc1ccc(-n2ccnc2)c(F)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)c1cnc(Cl)nc1Nc1ccc(-n2ccnc2)c(F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 19.2 %

Procedure:
To a solution of ethyl 2-chloro-4-(3-fluoro-4-(1H-imidazol-1-yl)phenylamino)pyrimidine-5-carboxylate (383 mg, 1.06 mmol) in THF (5 mL), aq. 1N LiOH (2.00 mL, 2.00 mmol) was added. The mixture was stirred at room temperature overnight. THF was removed in vacuo. Upon acidification with 1N HCl, the mixture was purified by HPLC to give 2-chloro-4-(3-fluoro-4-(1H-imidazol-1-yl)phenylamino)pyrimidine-5-carboxylic acid (68 mg). MS 334.1 and 336.1 (M+H, Cl pattern)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH2:9][N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[CH:6]=[CH:5][C:4]=1[NH:16][C:17]1[N:22]=[CH:21][C:20]2=[CH:23][CH:24]=[C:25]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[N:32]([CH3:37])[S:33]([CH3:36])(=[O:35])=[O:34])[N:19]2[N:18]=1.[O:38]1[CH2:40][C@H:39]1[CH2:41][OH:42].CO>>[OH:38][C@@H:39]([CH2:41][OH:42])[CH2:40][N:13]1[CH2:14][CH2:15][N:10]([CH2:9][C:7]2[CH:6]=[CH:5][C:4]([NH:16][C:17]3[N:22]=[CH:21][C:20]4=[CH:23][CH:24]=[C:25]([C:26]5[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=5[N:32]([CH3:37])[S:33]([CH3:36])(=[O:35])=[O:34])[N:19]4[N:18]=3)=[C:3]([O:2][CH3:1])[CH:8]=2)[CH2:11][CH2:12]1
Reactant: COc1cc(CN2CCNCC2)ccc1Nc1ncc2ccc(-c3ccccc3N(C)S(C)(=O)=O)n2n1
Reactant: OC[C@@H]1CO1
Solvent: CO
Product: COc1cc(CN2CCN(C[C@@H](O)CO)CC2)ccc1Nc1ncc2ccc(-c3ccccc3N(C)S(C)(=O)=O)n2n1
Temperature: 25 °C
Yield: 16.8 %

Procedure:
Into an 8-dram vial, N-{2-[2-(2-Methoxy-4-piperazin-1-ylmethyl-phenylamino)-pyrrolo[2,1-f][1,2,4]triazin-7-yl]-phenyl}-N-methyl-methanesulfonamide (80 mg, 0.2 mmol), (R)-Oxiranemethanol (0.0350 g, 0.472 mmol), and Methanol (5.87 mL, 145 mmol) were added. The reaction was stirred at room temperature over the weekend. The solvent was removed under vacuum. The reaction mixture was purified via HPLC reverse phase chromatography with 0.1% TFA in Water and 0.1% TFA in ACN. The selected fractions were concentrated. The residue was partitioned with DCM and sat. NaHCO3. The organic was separated, washed with Brine and dried over Na2SO4. The solid was filtered wand washed with DCM. The solvent was removed under vacuum to give N-[2-(2-{4-[4-((R)-2,3-Dihydroxy-propyl)-piperazin-1-ylmethyl]-2-methoxy-phenylamino}-pyrrolo[2,1-f][1,2,4]triazin-7-yl)-phenyl]-N-methyl-methanesulfonamide as a yellow solid (20 mg, 21%). LCMS (E/I+) 596.11 (M+H). NMR 1H (DMSO-d6)-8.97 (s, 1H), 7.90-7.98 (m, 1H), 7.88 (d, 1H, J=8.21 Hz), 7.72 (s, 1H), 7.62-7.66 (m, 1H), 7.51-7.56 (m, 1H), 7.00 (d, 1H, J=4.67 Hz), 6.96 (d, 1H, J=4.67 Hz), 6.92 (bs, 1H), 6.72 (d, 1H, J=8.01 Hz), 4.51 (t, 1H, J=5.55), 4.34 (d, 1H, J=4.34 Hz), 3.82 (s, 3H), 2.18-3.70 (bm, 21H).
Reaction SMILES: [C:1]1([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:6]=[CH:5][C:4]([CH2:7][C@H:8]2[NH:12][C:11](=[O:13])[CH2:10][CH2:9]2)=[CH:3][CH:2]=1.C([Li])CCC.[C:25](Cl)(=[O:27])[CH3:26]>C1COCC1>[C:25]([N:12]1[C@H:8]([CH2:7][C:4]2[CH:3]=[CH:2][C:1]([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)=[CH:6][CH:5]=2)[CH2:9][CH2:10][C:11]1=[O:13])(=[O:27])[CH3:26]
Reactant: O=C1CC[C@@H](Cc2ccc(-c3ccccc3)cc2)N1
Reactant: CC(=O)Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(=O)N1C(=O)CC[C@H]1Cc1ccc(-c2ccccc2)cc1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
(S)-5-biphenyl-4-ylmethylpyrrolidin-2-one (1-a, R1=H) (5 g, 19.9 mmol) is dissolved in THF (50 ml). The mixture is cooled to −78° C. and n-butyllithium (14 ml, 1.6 M) added. After 0.5 h, acetyl chloride (1.7 ml, 24 mmol) is added and the mixture is allowed to warm to room temperature. After 1 h, the mixture is quenched with saturated ammonium chloride (40 ml) and water (10 ml) and ethyl acetate (20 ml) are added. The organic phase is washed with brine, dried (MgSO4) and concentrated in vacuo to give (S)-1-Acetyl-5-biphenyl-4-ylmethyl-pyrrolidin-2-one (1-a, R1=Ac). 1H NMR (CDCl3): 1.84 (1H), 1.93 (1H), 2.30 (1H), 2.32 (1H), 2.50 (3H), 2.72 (1H), 3.09 (1H), 4.56 (1H), 7.20 (2H), 7.28 (1H), 7.37 (2H), 7.49 (4H).
Reaction SMILES: S(=O)(=O)(O)[OH:2].[CH3:6][O:7][C:8](=[O:17])[CH:9]([O:11][C:12]([CH3:16])([CH3:15])[C:13]#[CH:14])[CH3:10]>C([O-])(=O)C.[Hg+2].C([O-])(=O)C.O>[CH3:6][O:7][C:8](=[O:17])[CH:9]([O:11][C:12]([CH3:16])([CH3:15])[C:13](=[O:2])[CH3:14])[CH3:10]
Reactant: C#CC(C)(C)OC(C)C(=O)OC
Reactant: O=S(=O)(O)O
Agent: CC(=O)[O-]
Agent: [Hg+2]
Solvent: O
Product: COC(=O)C(C)OC(C)(C)C(C)=O
Temperature: 60 °C
Yield: 141.7 %

Procedure:
A mixture of mercury (II) acetate (7.76 g, 0.024 mol), sulfuric acid (9 ml, 0.09 mol) and water (450 ml) is heated at 60° C. 2-(1,1-dimethylprop-2-ynyloxy)propionic acid methyl ester (90 g, 0.529 mol) is added carefully at 60° C. The reaction mixture is maintained at 60° C. for 8 hours and cooled to ambient temperature. The aqueous phase is extracted with diethyl ether (3×250 ml), the organic phases are combined, washed with water, and dried over anhydrous sodium sulfate. The mixture is filtered, and the filtrate is evaporated under reduced pressure. The residue is purified by column chromatography on silica gel to give 2-(1,1-dimethyl-2-oxopropoxy)propionic acid methyl ester (24 g) as a colorless oil.
Reaction SMILES: [CH2:1]([CH:3]1[O:5][CH2:4]1)[Cl:2].[SH2:6]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C1(C)C=CC=CC=1>[Cl:2][CH2:1][CH:3]([OH:5])[CH2:4][S:6][CH2:4][CH:3]([OH:5])[CH2:1][Cl:2]
Reactant: S
Reactant: ClCC1CO1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Solvent: Cc1ccccc1
Product: OC(CCl)CSCC(O)CCl
Temperature: 22.5 °C
Yield: 96 %

Procedure:
185 g (2.0 mol) of epichlorohydrin, 10 ml of toluene and 0.97 g of tetra-n-butylammonium bromide were mixed together, and 35 g (1.0 mol) of hydrogen sulfide was blown into the mixture with stirring with the temperature of the solution being maintained at 20 to 25° C. After that, extraction was carried out using toluene to distil away the solvent, thereby obtaining 210 g (0.96 mol, yield: 96%) of bis(3-chloro-2-hydroxypropyl)sulfide (the compound represented by formula (1) above).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([C:13](O)=[O:14])=[C:11]([CH2:16][O:17][CH3:18])[O:10][N:9]=2)=[CH:4][CH:3]=1.S(Cl)([Cl:21])=O>CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([C:13]([Cl:21])=[O:14])=[C:11]([CH2:16][O:17][CH3:18])[O:10][N:9]=2)=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: COCc1onc(-c2ccc(F)cc2)c1C(=O)O
Solvent: CN(C)C=O
Product: COCc1onc(-c2ccc(F)cc2)c1C(=O)Cl
Temperature: 60 °C
Yield: 100 %

Procedure:
To a suspension of 3-(4-fluoro-phenyl)-5-methoxymethyl-isoxazole-4-carboxylic acid (2.51 g, 10.0 mmol) in thionyl chloride (4.0 mL) was added two drops of DMF, and the resulting reaction mixture was heated at 60° C. for 3 h. After cooling to room temperature, the mixture was concentrated under reduced pressure to afford the crude title compound (2.7 g, 100%) which was obtained as a light yellow liquid and used directly in the next step without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5]([OH:7])=[O:6].CC(N=NC(C#N)(C)C)(C#N)C.C1C(=O)N([Br:31])C(=O)C1>FC(F)(F)C1C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH2:11][Br:31])[C:5]([OH:7])=[O:6]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(C(=O)O)cc1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: FC(F)(F)c1ccccc1
Product: O=C(O)c1ccc(CBr)c(Br)c1
Temperature: 90 °C
Yield: 60 %

Procedure:
To a solution of 3-bromo-4-methylbenzoic acid (1.0 equiv.) and AIBN (0.05 equiv.) in trifluorotoluene (0.28 M) was added NBS (1.1 equiv.). The mixture was heated at 90° C. overnight. The reaction mixture was partitioned between EtOAc and H2O. The organic layer was washed with NaCl(sat.), dried over MgSO4, filtered, concentrated to yield 3-bromo-4-(bromomethyl)benzoic acid in 60% yield. LC/MS (m/z)=294.8 (MH+), Rt=0.80 min.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][N:6]=[CH:7]2.C(P(C(C)(C)C)C1C=CC=CC=1C1C=CC=CC=1)(C)(C)C.[C:33]([O:37][C:38](=[O:45])[N:39]([CH2:41][CH2:42][CH2:43][NH2:44])[CH3:40])([CH3:36])([CH3:35])[CH3:34].CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1>[C:33]([O:37][C:38]([N:39]([CH3:40])[CH2:41][CH2:42][CH2:43][NH:44][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][N:6]=[CH:7]2)=[O:45])([CH3:36])([CH3:35])[CH3:34]
Reactant: Brc1cccc2cnccc12
Reactant: CN(CCCN)C(=O)OC(C)(C)C
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CN(CCCNc1cccc2cnccc12)C(=O)OC(C)(C)C
Temperature: 70 °C
Yield: 85.1 %

Procedure:
Under nitrogen atmosphere, a suspension of 5-bromoisoquinoline (252 mg), tris(dibenzylideneacetone)palladium(0) (59 mg), 2-(di-tert-butylphosphino)biphenyl (74 mg), (3-aminopropyl)methylcarbamic acid tert-butyl ester (274 mg, Asta Tech), and sodium tert-butoxide (163 mg) in toluene was stirred with heating at 70° C. for 3 hours. The reaction mixture was returned to room temperature and purified by silica gel column chromatography (n-hexane:ethyl acetate=1:1) to obtain the title compound (325 mg).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([OH:9])=[C:4]([Cl:10])[CH:3]=1.[C:11]([O-])([O-])=O.[K+].[K+].S(OC)(OC)(=O)=O>CC(C)=O>[Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([O:9][CH3:11])=[C:4]([Cl:10])[CH:3]=1
Reactant: Cc1cc(Br)cc(Cl)c1O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: COS(=O)(=O)OC
Product: COc1c(C)cc(Br)cc1Cl
Temperature: 25 °C
Reaction time: 22 h

Procedure:
4-Bromo-2-chloro-6-methylphenol (50 g, 0.225 mole) and K2CO3 (31.8 g, 0.23 mole) were combined in acetone (300 ml). Dimethyl sulfate (32 ml, 0.34 mole) was added dropwise and the mixture stirred 22 hours at room temperature, filtered and concentrated to an oil in vacuo. The oil was taken up in 250 ml ether, washed 2×2N NaOH, 1×saturated NaHCO3, 2×brine, dried over MgSO4, reconcentrated to an oil and distilled to yield purified title product, 42.9 g, b.p. 122°-124°/0.9 mm, pnmr/CDCl3 /delta/TMS: 2.3 (s, 3H), 3.8 (s, 3H), 7.3 (q, 2H).
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[NH:6]1[C:14]2[C:9](=[CH:10][C:11]([CH2:15][NH:16][C:17](=[O:19])[CH3:18])=[CH:12][CH:13]=2)[CH:8]=[CH:7]1.[C:20](OCC)(=[O:22])C>CN(C)C=O>[CH:20]([C:8]1[C:9]2[C:14](=[CH:13][CH:12]=[C:11]([CH2:15][NH:16][C:17](=[O:19])[CH3:18])[CH:10]=2)[NH:6][CH:7]=1)=[O:22]
Reactant: CC(=O)NCc1ccc2[nH]ccc2c1
Reactant: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: CC(=O)NCc1ccc2[nH]cc(C=O)c2c1
Reaction time: 0.25 h
Yield: 17 %

Procedure:
The synthesis was performed with reference to the known literature (International Patent Publication WO2000/75139). N,N-Dimethylformamide (2.0 mL) cooled to 0° C. was added dropwise with phosphorus oxychloride (0.54 g, 3.5 mmol), and then the mixture was stirred for 15 minutes. Then, the mixture was added with a solution of N-[(1H-indol-5-yl)methyl]acetamide (0.60 g, 3.2 mmol) in N,N-dimethylformamide (4.0 mL), and then the mixture was stirred overnight at room temperature. The reaction mixture was added with ethyl acetate, and then the organic layer was washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and then the residue was subjected to silica gel column chromatography (eluted with chloroform/methanol (90:10)) to obtain a solid containing the objective substance. This solid was washed with ethyl acetate to obtain N-[(3-formyl-1H-indol-5-yl)methyl]acetamide (0.12 g, 17%).
Reaction SMILES: [Cl:1][C:2]1[C:3](I)=[CH:4][C:5]([NH:8][C@H:9]2[CH2:14][CH2:13][C@H:12]([CH2:15][NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH2:11][CH2:10]2)=[N:6][CH:7]=1.[F:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28](B2OC(C)(C)C(C)(C)O2)[N:27]=1.C(Cl)Cl.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(OCC)(=O)C.COCCOC>[Cl:1][C:2]1[C:3]([C:28]2[CH:29]=[CH:30][CH:31]=[C:26]([F:25])[N:27]=2)=[CH:4][C:5]([NH:8][C@H:9]2[CH2:14][CH2:13][C@H:12]([CH2:15][NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH2:11][CH2:10]2)=[N:6][CH:7]=1
Reactant: CC1(C)OB(c2cccc(F)n2)OC1(C)C
Reactant: CC(C)(C)OC(=O)NC[C@H]1CC[C@H](Nc2cc(I)c(Cl)cn2)CC1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NC[C@H]1CC[C@H](Nc2cc(-c3cccc(F)n3)c(Cl)cn2)CC1
Temperature: 100 °C
Reaction time: 2 h

Procedure:
A mixture of tert-butyl (trans-4-(5-chloro-4-iodopyridin-2-yl-amino)cyclohexyl)methylcarbamate (510 mg, 1.095 mmol), 2-fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (440 mg, 1.971 mmol), PdCl2(dppf).CH2Cl2 adduct (89 mg, 0.109 mmol), DME (7.5 ml), and 2M sodium carbonate (2.464 ml, 4.93 mmol) reaction mixture was stirred at about 100° C. for about 2 hours. The reaction mixture was cooled to room temperature, mixed with 20 ml ethyl acetate, filtered and concentrated to yield a crude solid. The crude solid was purified by silica gel chromatography using 40 g column, eluting from 0%-45% ethyl acetate with hexane. The desired fractions were concentrated to constant mass, yielding 396 mg of titled compound as a free base. LCMS (m/z): 435.2 (MH+), retention time=0.85 min.
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[NH:11][C:12]([C:14]1[N:19]=[C:18]([N:20]3[CH2:25][CH2:24][N:23](C(OC(C)(C)C)=O)[CH2:22][CH2:21]3)[CH:17]=[CH:16][CH:15]=1)=[O:13])[CH2:8]2.CO>FC(F)(F)C(O)=O>[CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[NH:11][C:12](=[O:13])[C:14]1[CH:15]=[CH:16][CH:17]=[C:18]([N:20]3[CH2:21][CH2:22][NH:23][CH2:24][CH2:25]3)[N:19]=1)[CH2:8]2
Reactant: CC(C)(C)OC(=O)N1CCN(c2cccc(C(=O)NC3C4CC5CC(C4)CC3C5)n2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: O=C(NC1C2CC3CC(C2)CC1C3)c1cccc(N2CCNCC2)n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 97.9 %

Procedure:
After tert-butyl 4-(6-(adamantan-2-ylcarbamoyl)pyridin-2-yl)piperazine-1-carboxylate (86 mg, 0.195 mmol) was dissolved in MC (2 ml), trifluoroacetic acid (2 ml) was added thereto, and then the resulting mixture was stirred at room temperature under nitrogen stream for 4 hours. The resulting reaction liquid was concentrated under reduced pressure, followed by addition of a saturated aqueous NaHCO3 solution (10 ml), and then extracted with MC (15 ml×2). The organic layer was dried over anhydrous magnesium sulfate, followed by filtration and concentration, and then the residue thus obtained was subjected to MPLC (10% MeOH/MC), to obtain 65 mg of colorless oil (98%). MS (ESI): 341 [M+H]+
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([F:9])[CH:3]=1.CC(C)([O-])C.[K+].[F:16][C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][C:24]=1F)[C:20]#[N:21].O>CS(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:24]2[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[CH:18][C:17]=2[F:16])=[C:4]([F:9])[CH:3]=1
Reactant: N#Cc1ccc(F)c(F)c1
Reactant: Oc1ccc(Cl)cc1F
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: N#Cc1ccc(Oc2ccc(Cl)cc2F)c(F)c1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
A solution of 1.6 mL (15 mmol) of 4-chloro-2-fluorophenol and 1.68 g (15 mmol) of potassium tert. butoxide in 10 mL DMSO was stirred for one hour at ambient temperature. Then 2.1 g (15 mmol) of 3,4-difluoro-benzonitrile were added and the mixture was stirred overnight at 60° C. The mixture was then combined with approx. 50 mL water, then extracted three times with 30 ml of ethyl acetate. The organic extracts were washed with sodium chloride solution, dried on sodium sulphate and evaporated down. The product thus obtained was reacted further without any further purification.